Economic Analysis for the 

Renovation, Repair, and 

Painting Program Proposed 

Rule 

Economic and Policy Analysis Branch 

Economics, Exposure and Technology Division 

Office of Pollution Prevention and Toxics 

U.S. Environmental Protection Agency 

February 2006 
Acknowledgment

EPA acknowledges the analytical and draft preparation support of Abt Associates Inc. of 

Cambridge, Massachusetts, and Bethesda, Maryland, provided under Contract No. 68-

W2-077, in the preparation of this report. 

Notice 

This is not an official guidance document and should not be relied upon to determine 

applicable regulatory requirements. This document was prepared to provide economic 

information for the rulemaking process, and to meet various administrative and 

legislative requirements. Due to the nature of the information available to EPA, the 

document contains various assumptions that may not reflect the regulatory 

determinations that an individual firm would make were it to apply the rule's 

requirements to its specific circumstances. Persons seeking information on regulatory 

requirements as they apply to specific facilities should consult 40 CFR Part 745, the 

preamble for the regulatory action, EPA guidance documents, and EPA’s National 

Lead Information Center. 
§402(c) Economic Analysis Table of Contents i

Table of Contents

Executive Summary .................................................................................................................................... 1 

Cost of the Various Options................................................................................................................ 2 

Benefits of the Rule............................................................................................................................. 6 

Net Benefits......................................................................................................................................... 9 

Impact on Small Entities and Other Analyses................................................................................... 11 

Table of Contents......................................................................................................................................... i 

1. Introduction....................................................................................................................................... 1 

1.1 Purpose of the Proposed Rule ................................................................................................... 1 

1.2 Goal of the Economic Analysis................................................................................................. 2 

1.3 Organization of this Report ....................................................................................................... 4 

2. Renovation, Repair and Painting Industry Profile ........................................................................ 1 

 2.1 The Supply of Renovation Services .......................................................................................... 1 

2.1.1 Industry Definition and Characteristics........................................................................ 2 

2.1.2 Renovation Establishment Characteristics ................................................................... 3 

2.1.3 Financial Profile ......................................................................................................... 11 

2.1.4 Establishment Size by Revenue Bracket .................................................................... 13 

 2.2 The Demand for Renovation Services..................................................................................... 16 

2.2.1 Number of Renovation Activities Performed............................................................. 17 

2.2.2 Determinants of Demand............................................................................................ 19 

 2.3 Market Organization................................................................................................................ 21 

 2.4 Property Owners & Managers................................................................................................. 23 

2.4.1 Industry Definitions and Characteristics .................................................................... 23 

2.4.2 Establishment Size and Industry Environment........................................................... 24 

2.4.3 Industry Outlook ........................................................................................................ 25 

 2.5 Training Providers................................................................................................................... 25 

2.5.1 Definitions and Industry Characteristics .................................................................... 25 

2.5.2 Number and Type of Training Establishments........................................................... 26 

References......................................................................................................................................... 29 

3. Problem Definition and Regulatory Options.................................................................................. 1 

3.1 Lead Contamination Problem.................................................................................................... 1 

3.1.1 Exposure Sources ......................................................................................................... 1 

3.1.2 Health Effects of Lead Exposure.................................................................................. 2 

3.2 Justification for Federal Regulations of Lead Exposure during Renovation............................. 4 

3.2.1 Market Failure .............................................................................................................. 4 

3.2.2 Justification for Regulation at the Federal Level ......................................................... 7 

3.2.3 Regulatory Background.............................................................................................. 10 

3.3 Regulatory Options for Reducing Lead Exposure Resulting from Renovation ...................... 28 

3.3.1 Information Provision................................................................................................. 28 

3.3.2 Containment and Clean-up Work Standards .............................................................. 29 

3.3.3 Alternative Regulatory Options.................................................................................. 35 

Appendix 3A: The Role of Elasticities in Determining the Impacts of a Rule.......................... 36 

3A.1 Elasticities of Supply and Demand ............................................................................ 36 
§402(c) Economic Analysis Table of Contents ii

3A.2 How Price Elasticity of Demand Affects the RRP Rule................................................ 40 

3A.2.1 Effect of RRP Rule on the Cost of Production (Supply Shift) .................... 40 

3A.2.2 Justification for Regulation at the Federal Level......................................... 41 

3A.2.3 Application to Renovation........................................................................... 41 

Appendix 3B: Elasticities of Demand and Supply for Housing / Renovation Services............ 42 

References......................................................................................................................................... 44 

4. Compliance Costs of the Renovation, Repair, and Painting Rule ................................................ 1 

4.1 Definitions of Options............................................................................................................... 1 

4.1.1 Affected Universe, by Option ...................................................................................... 2 

4.1.2 Proposed Containment, Cleaning, and Verification Standards, by Option .................. 4 

4.2 Estimating the Number of Regulated Renovation, Repair, and Painting Events ...................... 6 

4.2.1 Data Sources................................................................................................................. 6 

4.2.2 Number of Regulated Events in Owner-Occupied Housing Units............................... 8 

4.2.3 Number of Regulated Events in Renter-Occupied Housing Units............................. 11 

4.2.4 Number of Regulated Events in Compliance During First Year of Regulation......... 14 

4.2.5 Number of Events Employing Lead-Safe Work Practices ......................................... 15 

4.2.6 Number of Regulated Events over 50-Year Period.................................................... 19 

4.3 Estimating the Number of Establishments and Personnel Seeking Certification and 

 Training ................................................................................................................................... 20 

4.3.1 Estimating the Number of Construction Establishments with Employees Seeking 

Certification................................................................................................................ 20

4.3.2 Estimating the Number of People who will Seek Renovator and Worker Training .. 23 

4.3.3 Estimating the Number of Self-Employed Contractors that will Seek Certified 

Renovator Training .................................................................................................... 26 

4.3.4 Estimating the Number of Residential Property Management Establishments and 

Employees that will Seek Certification and Training................................................. 28 

4.3.5 Total Numbers of Establishments and Individuals that will Seek Certification and 

Training During the First Three Years ....................................................................... 30 

4.3.6 Sampling Technicians ................................................................................................ 32 

4.4 Training Costs ......................................................................................................................... 33 

4.4.1 Estimates of Wages .................................................................................................... 33 

4.4.2 Tuition Rate Estimates ............................................................................................... 33 

4.4.3 Aggregated Incremental Cost of Training.................................................................. 35 

4.5 Work Practice Compliance Costs............................................................................................ 36 

4.5.1 LBP Test Kit Compliance Costs ................................................................................ 37 

4.5.2 Containment, Cleaning, and Verification................................................................... 38 

4.5.3 Cost of Each Containment and Cleaning Practice...................................................... 40 

4.5.4 Baseline Work Practices............................................................................................. 42 

4.5.5 Estimating the Size of Events..................................................................................... 43 

4.5.6 Estimating Total Per Event Containment and Cleaning Costs................................... 46 

4.5.7 Cleaning Verification Costs ....................................................................................... 46 

4.5.8 Summary of Containment, Cleaning, and Verification Costs .................................... 46 

4.6 Certification Costs: Firm Paperwork Burden and EPA Administrative and 

 Enforcement Costs .................................................................................................................. 49 

4.6.1 Costs for Accrediting Renovator Training Providers and Processing Training 

Notifications............................................................................................................... 50 

4.6.2 Costs of Certifying Renovation Firms........................................................................ 52 
§402(c) Economic Analysis Table of Contents iii

4.6.3 Costs of Enforcement ................................................................................................. 53 

4.6.4 Administrative and Enforcement Costs: Contribution to Total Costs........................ 54 

4.6.5 Firm Paperwork Burden ............................................................................................. 54 

4.6.6 Total Certification Costs: Firm Paperwork Burden and EPA Administrative and 

Enforcement Costs ..................................................................................................... 55 

4.7 Total Costs............................................................................................................................... 56 

4.7.1 Total Costs in the First Year of Regulation................................................................ 56 

4.7.2 Total Costs in the Second and Third Years of Regulation ......................................... 57 

4.7.3 Total 50-Year and 50-Year Annualized Costs ........................................................... 58 

Appendix 4A. Lead Abatement..................................................................................................... 61 

4A.1 Abatements in EPA Administered States................................................................... 61 

4A.2 Abatements in States Administering their Own Lead Programs................................ 62 

4A.3 Percent of Housing Abated......................................................................................... 63 

References......................................................................................................................................... 65 

5. Benefits............................................................................................................................................... 1 

5.1 Overview of Approach .............................................................................................................. 3 

5.2 Estimating Lead Dust Contamination Levels from RRP Activities .......................................... 8 

5.2.1 Initial Dust Loadings from Interior RRP Activities ..................................................... 8 

5.2.2 Effect of Cleaning on Interior Dust Loadings .............................................................. 9 

5.2.3 Soil Loadings from Exterior RRP events ................................................................... 13 

5.3 Benefits Assessment -- Children ............................................................................................. 15 

5.3.1 Estimation of the change in blood-lead levels resulting from lead contamination..... 16 

5.3.2 Estimation of the adverse health effects (e.g., loss in IQ points) due to increased 

blood-lead................................................................................................................... 17

5.3.3 Populations at risk ...................................................................................................... 21 

5.3.4 Assignment of a medical cost, reduced income or other proxy for willingness to pay 

to avoid the adverse health effects ............................................................................. 22 

5.4 Benefits Assessment - Adults.................................................................................................. 22 

5.4.1 Estimation of lead contamination levels and estimation of the change in blood-lead 

levels resulting from lead contamination ................................................................... 22 

5.4.2 Estimation of adverse health effects from changes in blood-lead levels.................... 24 

5.4.3 Blood pressure data .................................................................................................... 28

5.4.4 Assignment of medical cost or other proxy for willingness to pay to avoid the adverse 

health effects .............................................................................................................. 28 

5.5 Results ..................................................................................................................................... 29 

5.5.1 The Monte Carlo Model............................................................................................. 31 

5.5.2 Alternative Blood-lead Modeling Assumptions......................................................... 31 

5.5.3 Size of Population that Avoids Exposure After the Rule ........................................... 32 

5.5.4 Summary of Inputs to the Monte Carlo Model .......................................................... 37 

5.5.5 Uncertainties in Adult Benefit Estimates ................................................................... 42 

5.5.6 Summary of Results ................................................................................................... 42 

Appendix 5A Lead-Related Health Effects and Ecological Effects............................................ 62 

5A.1 Health Effects to Children and Adults, Excerpted from Chapters 5 and 6 of the First 

External Review Draft of EPA’s Air Quality Criteria Document for Lead ............... 62 

5A.2 Ecological Effects .................................................................................................... 810 

Appendix 5B Adult Health Benefits Calculations...................................................................... 812 

5B.1 Health Benefits to Men............................................................................................. 812 
§402(c) Economic Analysis Table of Contents iv

5B.1.1 Changes in Hypertension.............................................................................. 812 

5B.1.2 Changes In Coronary Heart Disease.......................................................... 813 

5B.1.3 Changes in Initial Cerebrovascular Accidents and Initial 

 Atherothrombotic Brain Infarctions .......................................................... 814 

5B.1.4 Changes in Premature Mortality................................................................... 815 

5B.2 Health Benefits to Women ....................................................................................... 816 

5B.2.1 Blood Lead-Blood Pressure Relationship.................................................. 816 

5B.2.2 Changes in Coronary Heart Disease .......................................................... 817 

5B.2.3 Changes in Atherothrombotic Brain Infarctions and Initial 

 Cerebrovascular Accidents........................................................................ 817 

5B.2.4 Changes in Premature Mortality................................................................ 818 

Appendix 5C Identifying and Characterizing Lead Loadings for Interior Renovation, Repair 

 and Painting Tasks................................................................................................ 819 

5C.1 Renovation, Repair, and Painting Tasks, Work Components, and Estimated Time 

Requirements............................................................................................................ 819 

5C.2 Work Component Lead Loading Levels .................................................................. 822 

5C.3 Estimated Contamination Levels Throughout the House......................................... 823 

5C.4 Renovation, Repair, and Painting Tasks and Lead Loading Estimates .................... 826 

5C.5 Interior Painting........................................................................................................ 829 

5C.5.1 Number of Homes Painted......................................................................... 829 

5C.6 Background Lead Loadings in Homes ..................................................................... 829 

Appendix 5D Distributions of Inputs and Results...................................................................... 831 

5D.1 Custom Distributions for Input Parameters .................................................................. 831 

6. Comparison of Benefits to Cost........................................................................................................ 1 

7. Sensitivity Analysis............................................................................................................................ 1 

7.1 Alternative Estimate 1: Adjusted for State and Local RRP Regulations................................... 1 

7.1.1 Overlap between State and Local Regulations and the Renovation, Repair and 

Painting Rule................................................................................................................ 2 

7.1.2 Adjustment of the Work Practice Compliance Costs ................................................... 3 

7.1.3 Comparison of the Costs .............................................................................................. 4 

7.1.4 Comparison of the Benefits.......................................................................................... 4 

7.2 Alternative Estimate 2: 100% Compliance Assumption .......................................................... 5 

7.2.1 Comparison of the Costs .............................................................................................. 5 

7.2.2 Comparison of the Benefits.......................................................................................... 5 

7.3 Alternative Estimate 3: 60% Compliance Assumption ............................................................ 7 

7.3.1 Comparison of the Costs .............................................................................................. 7 

7.3.2 Comparison of the Benefits.......................................................................................... 7 

7.4 Alternative Estimate 4: 30% Compliance Assumption ............................................................ 8 

7.4.1 Comparison of the Costs .............................................................................................. 9 

7.4.2 Comparison of the Benefits.......................................................................................... 9 

7.5 Alternative Estimate 5: Test Kits with 47% Rate of False Positives....................................... 10 

7.5.1 Comparison of the Costs ............................................................................................ 10 

7.5.2 Comparison of the Benefits........................................................................................ 11 

7.6 Alternative Estimate 6: Test Kits with 78% Rate of False Positives....................................... 11 

7.6.1 Comparison of the Costs ............................................................................................ 11 

7.6.2 Comparison of the Benefits........................................................................................ 11 
§402(c) Economic Analysis Table of Contents v

7.7 Alternative Estimate 7: Test Kits with 5% Rate of False Negatives ....................................... 11 

7.7.1 Comparison of the Costs ............................................................................................ 12 

7.7.2 Comparison of the Benefits........................................................................................ 12 

7.8 Alternative Estimate 8: Test Kits Cost $20 per Event............................................................. 12 

7.8.1 Comparison of the Costs ............................................................................................ 12 

7.8.2 Comparison of the Benefits........................................................................................ 13 

7.9 Alternative Estimate 9: One Year Delay in Development of Improved Test Kits .................. 13 

7.9.1 Comparison of the Costs ............................................................................................ 13 

7.9.2 Comparison of the Benefits........................................................................................ 13 

7.10 Alternative Estimate 10: Improved Test Kit Delayed Four Years .......................................... 14 

7.10.1 Comparison of the Costs ............................................................................................ 14 

7.10.2 Comparison of the Benefits........................................................................................ 14 

7.11 Alternative Estimate 11: Improved Test Kit and Regulatory Universe Expansion Delayed 

Four Years ............................................................................................................................... 14 

7.11.1 Comparison of the Costs ............................................................................................ 14 

7.11.2 Comparison of the Benefits........................................................................................ 15 

7.12 Alternative Estimate 12: Improved Test Kits Have 15% Rate of False Positives................... 15 

7.12.1 Comparison of the Costs ............................................................................................ 15 

7.12.2 Comparison of the Benefits........................................................................................ 16 

7.13 Alternative Estimate 13: More Firms and Individuals Seek Certification ............................. 16 

7.13.1 Comparison of the Costs ............................................................................................ 17 

7.13.2 Comparison of the Benefits........................................................................................ 17 

7.14 Alternative Estimate 14: No Cleaning Verification Required................................................. 17 

7.14.1 Comparison of the Costs ............................................................................................ 18 

7.14.2 Comparison of the Benefits........................................................................................ 18 

7.15 Summary of Alternatives......................................................................................................... 19 

References......................................................................................................................................... 26 

8. Estimated Impacts of §402(c)........................................................................................................... 1 

8.1 Paperwork Reduction Act ......................................................................................................... 1 

8.1.1 RRP Firm Paperwork Burden....................................................................................... 1 

8.1.2 Training Provider Paperwork Burden .......................................................................... 2 

8.2 Unfunded Mandates Reform Act (UMRA)............................................................................... 4 

8.2.1 Affected Government Entities...................................................................................... 5 

8.2.2 Expenditures by State, Local, and Tribal Governments............................................... 6 

8.3 Regulatory Flexibility Act......................................................................................................... 6 

8.3.1 Definitions of Small Entity........................................................................................... 7 

8.3.2 Impacts on Small Businesses - General Methodology Overview ................................ 8 

8.3.3 Number of Small Establishments and Individuals Affected Under Each Option ...... 10 

8.3.4 Average Small Establishment Revenues, Employment Size and Number of 

Renovation Events Performed.................................................................................... 13 

8.3.5 Estimating the Costs of the RRP Rule Incurred by Small Establishments................. 17 

8.3.6 Impacts on Small Governments ................................................................................. 25 

8.3.7 Impacts on Small Non-profit Organizations............................................................... 25 

8.3.8 Conclusions ................................................................................................................ 25 

8.4 Executive Order 13132 - Federalism....................................................................................... 26

8.5 Executive Order 13175 - Tribal Implications.......................................................................... 26 

8.6 Protection of Children from Environmental Health Risk and Safety Risks ............................ 26 
§402(c) Economic Analysis Table of Contents vi

8.7 Executive Order 13211 - Energy Effects................................................................................. 27 

8.8 National Technology Transfer and Advancement Act............................................................ 27 

8.9 Executive Order 12898 – Environmental Justice .................................................................... 28 

References......................................................................................................................................... 31 
§402(c) Economic Analysis Executive Summary 1 

Executive Summary 

This report presents an economic analysis of alternative regulatory options to establish work practice 

standards, plus training and certification requirements, for persons engaged in renovation activities for 

compensation in housing units containing lead-based paint. These requirements apply to contractors who 

renovate, remodel and/or paint housing units where there is lead-based paint, as well as to residential 

building owners and managers who may perform these activities themselves or have their staff do so. The 

regulation is being proposed under authority of §402(c) of the Toxic Substances Control Act (TSCA). 

Title IV of TSCA was established by the Residential Lead-Based Paint Hazard Reduction Act of 1992, 

also known as Title X of the Housing and Community Development Act of 1992 (Public Law 102-550). 

Past use of lead-based paint has resulted in contamination that continues to pose human health hazards. 

Disturbing the lead-based paint, such as happens during renovation activities, is likely to create lead 

hazards. Since many residences built before 1978 have lead-based paint, it is likely that renovation 

activities occurring in these units will contribute to lead hazards unless appropriate containment and 

clean-up practices are employed. The Renovation, Repair and Painting (RRP) Rule is designed to prevent 

lead hazards from renovation activities. 

The training and work practice standards required and fostered by the proposed RRP rule will yield health 

benefits to individuals living in renovated units and to their neighbors. The proposed rule will reduce lead 

exposure by containing the lead contamination generated by renovation activities and reducing the 

amount of such contamination remaining after completion of the activities. EPA anticipates that the rule 

will further develop a market for lead-safe renovation services that has been established by past lead 

awareness rules, such as the §406(b) rule which requires compensated renovators to distribute lead 

awareness pamphlets to owners and occupants of most pre-1978 residential housing before beginning 

renovations. 

The proposed rule requires certification of firms (including self-employed contractors and property 

manager/lessors) that perform renovation, remodeling and/or painting in housing units subject to the 

regulations. A certified firm must assign to each renovation performed by the firm at least one renovator 

who has received formal training in EPA-approved work practices from an EPA-accredited course. In 

addition, certified firms must provide on-the-job training in these approved work practices for the rest of 

their staff who will be performing RRP activities in regulated housing. The proposed rule also requires 

containment of the work area to prevent the spread of dust and debris, specialized cleaning practices, and 

cleaning verification procedures to ensure that proper cleanup has occurred. 

EPA considered two regulatory approaches: prescriptive and flexible regulations for the proposed work 

practice standards. Under the prescriptive approach, EPA would require the use of specific work 

practices for all RRP jobs covered under the rule and that are at risk of causing lead contamination. The 

flexible approach relies on the required training, and the renovator’s own experience, to determine the 

extent of containment needed in any particular situation. The flexible approach increases the cost 

effectiveness of the regulation by reducing work practice costs. 

This economic analysis considers four regulatory options with two phases. In Phase 1, Option A 

addresses pre-1978 housing, Option B and D both address pre-1960 housing, and Option C addresses pre1950 housing. In Phase 2, all the options address pre-1978 housing. In both phases coverage of the rule 

is limited to rental housing and owner-occupied housing where a child under the age of six resides. Table 

ES-1 describes the housing stock subject to the regulations under each of the four options. Options A, B 
§402(c) Economic Analysis Executive Summary 2 

and C are flexible in terms of the application of specific work practices while Option D is prescriptive. 

EPA is proposing Option B. 

Table ES-1: Definitions of the Regulatory Options 

First Year – Phase 1 Second Year – Phase 2 

Option A 

All renter-occupied target housing units built 

before 1978, and owner-occupied target 

housing units built before 1978 where a 

child under the age of six resides. Flexible 

application of work practices 

All renter-occupied target housing built 

before 1978, and owner-occupied target 

housing units built before 1978 where a 

child under the age of six resides. 

Flexible application of work practices 

Option B 

All renter-occupied target housing units built 

before 1960, and owner-occupied target 

housing units built before 1960 where a 

child under the age of six resides, plus all 

target housing units built before 1978 where 

a child with an increased blood-lead level 

resides.a

 Flexible application of work 

practices 

Same as Option A. 

Option C 

All renter-occupied target housing units built 

before 1950, and owner-occupied target 

housing units built before 1950 where a 

child under the age of six resides, plus all 

target housing units built before 1978 where 

a child with an increased blood-lead level 

resides.a

 Flexible application of work 

practices 

Same as Option A. 

Option D 

The prescriptive option. Covers the same 

housing units as Option B – but requires 

specific work practices. 

The prescriptive option. Covers the 

same housing units as Option B – but 

requires specific work practices. a

 Where increased is defined as greater than or equal to 10 μg/dL or a State or local government level 

of concern, if lower. 

The proposed rule is Option B. 

Cost of the Various Options 

For purposes of this analysis, the costs associated with the regulatory impact of the Renovation, Repair, 

and Painting (RRP) Rule are divided into three categories: (1) training costs, (2) work practice costs, and 

(3) certification costs (which include the firm’s paperwork burden and government administrative and 

enforcement costs). The general approach of the analysis is to first estimate the number of affected 

activities or entities, then estimate the incremental regulatory cost per-activity or entity affected. Finally, 

the incremental costs and the number of affected activities and entities are combined to estimate the total 

costs. 

The number of RRP events covered by the rule varies across regulatory options in Phase 1 because the 

coverage of the regulation in Phase 1 varies across options, but under any of the options the number of 

events covered is substantial, as are the number of events that are performed in compliance with the rule. 

As shown in Table ES-2, approximately 10.7 million events per year would be conducted in compliance 

with the rule under Option A. Slightly more than one-half this amount, about 5.8 million events, would 

be conducted in compliance with the rule in the first year under Options B and D. In the first year, about 

4.3 million events would be conducted in compliance with the rule under Option C. (Based on existing 
§402(c) Economic Analysis Executive Summary 3 

literature about regulatory compliance rates in the construction industry, the analysis assumes that 75 

percent of events in regulated housing are conducted in compliance with the rule.) In Phase 2 of the rule, 

the number of RRP events conducted in compliance with the rule is the same for all four options, about 

4.4 million events per year. 

Because not all housing units built before 1978 have lead-based paint, the number of RRP events that 

need to use lead safe work practices (LSWP) is a subset of the total number of units covered by the rule. 

In Phase 1, between 8.1 million (Option A) and 3.7 million (Option C) events will use LSWP. In Phase 2, 

an estimated 4.4 million RRP events will be using LSWP. Despite the increased coverage of the rule in 

Phase 2, the number of events with LSWP in Phase 2 is smaller than in Phase 1 because the accuracy of 

lead paint test kits in terms of detecting the presence or absence of lead is expected to have improved by 

then. The current tests have a high false positive rate (estimated to average 63 percent), resulting in the 

frequent use of LSWP when they are not necessary, i.e., when lead is not present. The improved tests are 

expected to have a false positive rate of 10 percent. 

Table ES-2: Number of RRP Events 

Description of Options Number of Events per Year (millions) 

Phase 1 

Scope 

Phase 2 

Scope 

Work 

Practices 

Flexible? 

Phase 1 

Events 

Phase 1 

Events with 

LSWP 

Phase 2 

Events 

Phase 2 

Events with 

LSWP 

Option Aa Pre-78 R/C Pre-78 R/C Yes 10.7 8.1 10.7 4.4 

Option Ba Pre-60 R/C Pre-78 R/C Yes 5.8 4.8 10.7 4.4 

Option Ca Pre-50 R/C Pre-78 R/C Yes 4.3 3.7 10.7 4.4 

Option Da Pre-60 R/C Pre-78 R/C No 5.8 4.8 10.7 4.4 

Notes: 

R/C = All rental units plus owner-occupied units with children under the age of 6 years 

LSWP = Lead Safe Work Practices 

Number of events assumes 75% post-rule compliance 

In Phase I, paint spot tests assumed to have a false positive rate of 63%, in Phase 2 they are assumed to have a 

10% false positive rate. 

a About 65 percent of U.S. households reside in buildings constructed before 1980, 34 percent reside in buildings 

constructed before 1960 and 22 percent reside in building constructed before 1950. Approximately 58 percent 

of all RRP events in pre-1978 and pre-1960 housing take place in renter-occupied or child-occupied housing. 

This percentage is slightly higher (about 63 percent) for RRP events in pre-1950 housing. 

Work practice costs are estimated for each of several types of RRP events and for different sizes of 

housing units. These unit costs are multiplied by the number of events of each RRP type and housing 

type to estimate the total work practice-related costs for each regulatory option. The RRP events and the 

range of unit costs associated with each type are shown in Table ES-3. 
§402(c) Economic Analysis Executive Summary 4 

Table ES-3: Summary of Housing Unit Containment, Cleaning, and Verification 

Compliance Costs (2005$) 

Event Type Range of Costs per Event 

 Low High 

Kitchen Remodel $28 $132 

Bathroom Remodel $23 $63 

Additions $26 $117 

Non-Room-Specific Interior Walla $57 $528 

Non-Room-Specific Window/Doorb $58 $528 

Interior Paint $42 $285 

Whole Exterior Remodel $161 $281 

Exterior Remodel in Contained Areac $77 $77 

Exterior Paint $161 $281 

a Events that involve changes to a wall or walls, where the location is not specified. For 

example: re-wiring or repair/replace heating or cooling systems. b Repair/replacement of windows and/or doors, where the room is not specified. 

c Outside repair/remodeling work that involves a specified part of the home, e.g. 

installation of a deck. 

Source: See Section 4.5.8. 

In addition to the number of covered RRP events in compliance with the rule and their unit costs, the 

other major factors in determining the costs of the rule are the number of firms certified, the number of 

personnel trained, and the costs of training and certification. All of the regulatory options require that 

each certified firm (including property managers and lessors who perform their own RRP work in 

regulated housing, as well as construction firms conducting RRP in regulated housing) employ at least 

one renovator who has taken an EPA-accredited training course and provide on-the-job training for all 

other staff who will be performing RRP activities in regulated housing. As shown in Table ES-4, the 

number of firms certified and the number of persons trained expands as the coverage of the rule expands. 

Thus Options B/D and C have larger numbers in the first year of Phase 2 than does Option A. By the 

second year of Phase 2, the number of firms certified and persons trained each year has leveled out to 

approximately 54 thousand firms certified or recertified, approximately 62 thousand renovators taking 

training or refresher courses, and nearly 277 thousand other workers getting on-the-job training each year. 
§402(c) Economic Analysis Executive Summary 5 

The costs of the various regulatory options follow the number of events, with Option A having the largest 

costs under Phase 1 (see Table ES-5). Option D costs exceed the costs of Option B, even though they 

cover the same units, because Option D provides less flexibility in defining the extent of the area to be 

contained and cleaned. Option A costs decline substantially in Phase 2 for two reasons. First, most of the 

initial training and certification costs for Option A have been borne in Phase 1, while under Options B, C 

and D, a substantial amount of initial training and certification is occurring in Phase 2. Second, with the 

improved lead paint test kits available in Phase 2, the number of RRP events that use LSWP declines for 

all the options. The 50-year annualized costs provide a measure of the steady-state costs for each option. 

As shown, once the initial start-up costs have been absorbed, Options A through C have relatively similar 

annual costs of between $488 million and $505 million, using a 3 percent discount rate, or between $518 

million and $551 million using a 7 percent discount rate. Option D continues to have substantially higher 

costs due to its prescriptive nature. 

The cost estimates account for the RRP events in the baseline that already use some of the work practices 

to be required under this rule. In situations where contractors are already using these practices they will 

experience a smaller increase in operating costs, which is accounted for in the cost estimates. All 

Table ES-4: Estimated Number of Establishments Seeking Certification and Workers and 

Renovators Seeking Training 

Option Aa

 Options B & Da Option Ca

Year 1 

Total Number of Establishments (with Employees and 

without) Seeking Certification c 163,979 86,539 59,571 

Total Number of Renovators Trained b,c 186,811 98,588 67,866 

Total Number of Workers Trained b,c 279,221 147,357 101,437 

Year 2

Total Number of Establishments (with Employees and 

without) Seeking Certification c 54,436 105,851 123,756 

Total Number of Renovators Trained b,c 62,015 120,589 140,987 

Total Number of Workers Trained b,c 278,076 278,076 278,076 

Year 3

Total Number of Establishments (with Employees and 

without) Seeking Certification c 54,212 54,212 54,212 

Total Number of Renovators Trained b,c 61,761 61,761 61,761 

Total Number of Workers Trained b,c 276,935 276,935 276,935 a About 65 percent of U.S. households reside in buildings constructed before 1980, 34 percent reside in 

buildings constructed before 1960 and 22 percent reside in building constructed before 1950. 

Approximately 58 percent of all RRP events in pre-1978 and pre-1960 housing take place in renteroccupied target housing units and owner-occupied target housing units where a child under the age of six 

resides. This percentage is slightly higher (about 63 percent) for RRP events in pre-1950 housing. Of 

the regulated housing, 75 percent are assumed to comply with the regulations. b Components may not add up to totals due to rounding. c The number of firms and individuals certified and trained, respectively, is reduced by 0.04 percent per 

year to account for housing that is removed from the regulated housing stock due to demolition or 

conversion to non-housing uses. Thus the demand for lead-safe renovation services is reduced over time. 

See Table ES-1 for option descriptions.

Source: EPA calculations – see Section 4.3. 
§402(c) Economic Analysis Executive Summary 6 

contractors that perform RRP in regulated housing, however, will incur the training and certification costs 

due to the rule. 

Table ES-5: Estimated Total Costs 

Description of Options Costs (millions 2005$) 

50-Year Annualized

Phase 1 

Scope 

Phase 2 

Scope 

Work 

Practices 

Flexible? 

Phase 1 Phase 2 3% 

Discount 

Rate 

7% 

Discount 

Rate 

Option A Pre-78 R/C Pre-78 R/C Yes $ 924 $ 495 $ 505 $ 551 

Option B Pre-60 R/C Pre-78 R/C Yes $ 531 $ 552 $ 492 $ 526 

Option C Pre-50 R/C Pre-78 R/C Yes $ 393 $ 572 $ 488 $ 518 

Option D Pre-60 R/C Pre-78 R/C No $ 645 $ 649 $ 588 $ 629 

Notes: 

R/C = All rental units plus owner-occupied units with children under the age of 6 years 

Assumes 75% post-rule compliance 

In Phase I, lead paint test kits are assumed to have a false positive rate of 63%, in Phase 2 they are 

assumed to have a 10% false positive rate 

Benefits of the Rule 

The number of people protected by this rule varies with the variation in the universe of housing units 

covered by the rule. In Phase 1, Option A covers the largest number of individuals, including the largest 

number of children under the age of six years (see Table ES-6). By Phase 2, all options cover nearly 5.3 

million individuals per year, including over 780 thousand children under the age of six years old. Similar 

to the cost estimates, the number of individuals and children protected assumes that 75 percent of RRP 

work will be in compliance after the rule takes effect, and that there is some baseline use of LSWP. 

Based on the limited amount of information currently available about the baseline use of LSWP, the 

analysis assumes that approximately 20 percent of individuals and children living in regulated units with 

RRP already receive the benefits that the rule would provide. 

As discussed earlier, based on other compliance studies, this analysis assumes a compliance rate of 75 

percent. However, the Agency’s goal continues to be 100 percent compliance. If that goal were 

achieved, then over 1 million children under the age of six years old would be protected by the rule. At 

that rate, however, both the costs and the benefits would be higher than shown in the other tables. 
§402(c) Economic Analysis Executive Summary 7 

Table ES-6: Number of Individuals Protected by the Regulatory Options 

Description of Options Number of Individuals Occupying Units with LBP, where 

LSWP are Used Due to the Rulea

 (thousands per year) 

Children under 6 Years of Age All Individuals 

75% Compliance 

Rate 

100% 

Compliance 

Rateb 

75% Compliance 

Rate 

Phase 1 

Scope 

Phase 2 

Scope 

Work 

Practices 

Flexible? 

Phase 1 Phase 2 Phase 2 Phase 1 Phase 2 

Option A Pre-78 R/C Pre-78 R/C Yes 787 783 1,138 5,309 5,287 

Option B Pre-60 R/C Pre-78 R/C Yes 668 783 1,138 4,529 5,287 

Option C Pre-50 R/C Pre-78 R/C Yes 520 783 1,138 3,659 5,287 

Option D Pre-60 R/C Pre-78 R/C No 668 783 1,138 4,529 5,287 

Notes: 

R/C = All rental units plus owner-occupied units with children under the age of 6 years 

LSWP = Lead Safe Work Practices 

In Phase 1, lead paint test kits are assumed to have false positive rate of 63%, in Phase 2 they are assumed to have 

a 10% false positive rate 

a

Number of individuals is incremental above those occupying units where LSWP are currently practiced in the 

baseline. 

b

 If 100 percent compliance were achieved, both the costs and the benefits would be higher than shown in the 

tables based on 75 percent compliance. 

Lead causes a number of adverse health effects in people of all ages. Of particular concern are children 

under the age of six years, but older children and adults also suffer effects from lead exposure In this 

analysis, only a few of these health effects have been quantified. One of the factors restricting the scope 

of the benefits estimation is the limited amount of available data, including well-specified dose response 

relationships, on which to quantify and monetize many of the health and developmental effects. Therefore 

this benefits assessment focuses on two major categories of health effects: effects on cognitive function 

in young children (under the age of six) and cardiovascular disease (hypertension, coronary heart disease 

and stroke) and premature mortality in adults. There are additional uncertainties in the quantification of 

adult effects, which are addressed in Section 5.5.5. 

Even where the dose-response relationships are known, many cases are not included in the estimates 

because exposure levels cannot be estimated for all potentially affected individuals. For example, the 

benefit estimates presented in this report are based on reductions in lead ingestion; they do not include 

reductions in lead inhalation, although that is also likely to occur. Likewise, benefits are estimated only 

for people living in the housing units; they do not include potential benefits to visitors or neighbors. In 

addition, ecological benefits, as well as benefits to family pets, are not included in the estimates. 

It is important to note that the monetary values assigned to the avoided adverse health effects are based on 

medical costs avoided, not willingness-to-pay to avoid these ailments and/or premature death. Likewise, 

the value of the IQ points that will be gained due to this rule are valued in terms of increased earnings, not 

willingness-to-pay.1

 

1 Note that dose-response functions only allow for estimating IQ impacts among children less than six years of age, 

and the health effects only for adults over the age of 40. Other groups who are among the total individuals 

occupying units with lead-based paint in Table ES-6 are not included in the benefit estimates. 
§402(c) Economic Analysis Executive Summary 8 

This analysis estimates the benefits of the proposed regulation in terms of IQ deficits in children and 

increased blood pressure and related health effects in adults. Quantitative estimates of benefits are 

provided in two scenarios. Scenario 1 quantifies benefits for both children and adults. Scenario 2 

assumes additional cleaning in the baseline compared to Scenario 1, and only quantifies benefits for 

children. This approach is in recognition of the relatively larger uncertainties associated with adult health 

effects (pending completion of other EPA documents), as well as the particular concern about children 

expressed in Title X of the Residential Lead-Based Paint Hazard Reduction Act of 1992. The Agency is 

more confident in the estimates for children’s IQ effects then it is for the estimates of adult benefits. 

While recognizing that adults may also benefit from the training and practices required under the rule, 

Scenario 2 does not try to quantify these benefits due to the uncertainties that currently exist. 

Net Benefits 

Based on the subset of benefits that have been monetized in this analysis, Table ES-7 and Table ES-8 

display the annualized net benefits estimated for the four regulatory options under Scenarios 1 and 2, 

respectively. Each table presents annualized net benefits calculated at both a 3 percent and a 7 percent 

discount rate. Net benefits under Scenario 1 are substantially greater than those under Scenario 2. 

Scenario 1 assumes less baseline cleaning than Scenario 2 and it quantifies adult health benefits as well as 

children’s IQ benefits. Under either Scenario, annualized net benefits calculated using a 7 percent 

discount rate are slightly larger than those calculated using a 3 percent discount rate. Under both 

scenarios and all options net benefits are positive, i.e., the benefits are larger than the costs. 

When comparing options on the basis of annualized net benefits, there is relatively little difference among 

the three flexible options (Options A, B and C). This is not surprising, since the primary differences in 

these options occur in the first year the rule takes effect. After that year, all options address the same 

universe of pre-1978 housing. And after the second year, the population of firms and renovators being 

trained and re-trained levels off to approximately the same number each year. The only substantial 

difference is between the flexible options and the prescriptive Option D. The lack of flexibility appears as 

a roughly $100 - $150 million reduction in annualized net benefits as compared to the other options. 
§402(c) Economic Analysis Executive Summary 9 

Table ES-7: Comparison of Options – Scenario 1 -- Annualized Costs and Net Benefits 

Annualized 

Cost 

(millions 

2005$)a 

Children’s IQ 

Benefits – 

Annualized 

(millions 

2005$)b 

Adult Health 

Benefits – 

Annualized 

(millions 

2005$) b

Sum of Children’s 

IQ and Adult 

Benefits -- 

Annualized 

(millions 2005$)

Net Benefits – 

Children’s IQ 

and Adult Health 

-- Annualized c

(millions 2005$)

Annualized using 3 Percent Discount Rate 

Option A $ 505 $947 - $5,336 $2,262 $3,209 - $7,599 $2,704 - $7,093 

Option B $ 492 $941 - $5,311 $2,250 $3,191 - $7,562 $2,699 - $7,069 

Option C $ 488 $934 - $5,267 $2,235 $3,170 - $7,503 $2,682 - $7,015 

Option D $ 588 $941 - $5,311 $2,250 $3,191 - $7,562 $2,603 - $6,973 

Annualized using 7 Percent Discount Rate

Option A $551 $1,008 - $5,680 $2,408 $3,415 - $8,087 $2,865 - $7,537 

Option B $526 $997 - $5,633 $2,385 $3,383 - $8,019 $2,857 - $7,493 

Option C $518 $984 - $5,551 $2,358 $3,342 - $7,909 $2,824 - $7,391 

Option D $629 $997 - $5,633 $2,385 $3,383 - $8,019 $2,754 - $7,390 a Developed in Chapter 4 

b Developed in Chapter 5 – range for children’s IQ benefits reflects alternative models for blood lead, 

exposure estimates and population of children c Difference between sum of benefits and costs 

Table ES-8: Comparison of Options – Scenario 2a – Annualized Costs and Net 

Benefits 

Annualized 

Costb 

(millions 2005$)

Children’s IQ Benefits 

– Annualizedc 

(millions 2005$) 

Net Benefitsd

 – 

Children’s IQ Only 

(millions 2005$)

Annualized using 3 Percent Discount Rate 

Option A $ 505 $774 - $4,354 $269 - $3,849 

Option B $ 492 $770 - $4,329 $277 - $3,837 

Option C $ 488 $764 - $4,298 $276 - $3,810 

Option D $ 588 $770 - $4,329 $181 - $3,741 

Annualized using 7 Percent Discount Rate 

Option A $551 $824 - $4,635 $273 - $4,084 

Option B $526 $816 - $4,587 $290 - $4,061 

Option C $518 $805 - $4,530 $287 - $4,012 

Option D $629 $816 - $4,587 $187 - $3,958 

a While recognizing that adults will benefit from the rule, Scenario 2 does not try to 

quantify adult benefits. There are additional uncertainties in the quantification of 

adult effects, which are addressed in Section 5.5.5. 

b Developed in Chapter 4 

c Developed in Chapter 5 – range reflects alternative models for blood lead, 

exposure estimates and population of children d Difference between sum of benefits and costs 
§402(c) Economic Analysis Executive Summary 10 

Impact on Small Entities and Other Analyses 

The vast majority of firms in the industries affected by this rule are small firms: approximately 145,000 

small contractors and real estate establishments will be affected per year under the proposed Option B. 

Using studies from the economic literature, the analysis estimates that nearly 90 percent of the cost of the 

rule will be passed on to the purchasers of RRP services in the form of higher prices. The rest of the costs 

will be borne directly by the firms involved. This annual direct cost to small firms is estimated to range 

from about $1,600 to $6,100 per year per firm, depending on the number of RRP events typically 

undertaken by a small firm in the industry sector involved (see Table ES-9). These costs range from sixtenths of one percent for small Lessors of Residential Real Estate up to about 2.0 percent of revenues for 

small Painting and Wall Covering Contractors. They represent less than 1 percent of revenues for all 

types of small firms. The number of small governments and small non-profits affected was not 

calculated, but the cost per event is expected to be similar to that for businesses. 

Table ES-9: Impact on Small Businesses 

NAICS Industry Description 

Direct Cost 

of Rule 

Incurred by

Contractor 

CostImpact 

Ratio 

236118 Residential remodelers $1,659 0.9% 

238170 Siding contractors $2,212 1.1% 

238350 Finish carpentry contractors $1,558 1.5% 

238290 Other building equipment contractors $4,825 0.8% 

238390 Other building finishing contractors $2,463 1.1% 

238340 Tile and terrazzo contractors $1,810 1.4% 

238220 Plumbing and HVAC contractors $3,619 0.8% 

238150 Glass and glazing contractors $2,614 0.8% 

238320 Painting and wall covering contractors $1,759 2.0% 

238210 Electrical contractors $3,619 1.0% 

238310 Drywall and insulation contractors $2,563 1.1% 

Average, Small Construction Establishments $2,111 1.0% 

531311 Residential Property Managers $6,082 1.8% 

531110 Lessors of Residential Real Estate $4,725 0.6% 

Average, All Industries $2,563 0.9% 

In terms of potential unfunded mandates, the rule is not expected to result in the expenditure by State, 

local, and Tribal governments, in the aggregate, of $100 million or more. The impacts on Children’s 

Health and Environmental Justice are both likely to be positive. By focusing on owner-occupied housing 

with children under six years of age and all rental housing the regulatory options are structured to 

maximize protection of children and low income/minority households. The rule is not anticipated to have 

any negative impacts in terms of technology transfer, energy availability or federalism. 
§402(c) Economic Analysis Chapter 1 1 

1. Introduction 

This report presents an economic analysis of alternative regulatory options to establish work practice 

standards, plus training and certification requirements for renovators, remodelers and painters who work 

in housing units containing lead-based paint. These regulations will ensure that persons engaged in 

renovation activities for compensation, in housing units with lead-based paint, are trained and certified by 

EPA approved programs. The regulation is being proposed under authority of §402(c) of the Toxic 

Substances Control Act (TSCA). Section IV of TSCA was established by the Residential Lead-Based 

Paint Hazard Reduction Act of 1992, also known as Title X of the Housing and Community Development 

Act of 1992, Public Law 102-550. While some of the regulatory options considered in this analysis 

would allow for a phasing in of the requirements, eventually these rules will apply to all renovation 

activities performed in renter-occupied target housing units constructed before 1978 and owner-occupied 

target housing units constructed before 1978 where children under the age of six reside. 

Past use of lead-based paint has resulted in contamination that continues to pose human health hazards. 

While intact lead-based paint is not likely to contribute to such hazards, the deterioration of a structure 

over time or acute environmental stresses, such as are commonly present during renovation activities, 

have been found to create lead hazards. Since many residences built before 1978 have lead-based paint, it 

is likely that renovation activities occurring in these units will contribute to lead hazards unless 

appropriate containment and clean-up practices are employed. 

1.1 Purpose of the Proposed Rule 

The training and work practice standards required and fostered by the proposed RRP rule will yield health 

benefits to renovation households and their neighboring communities (not including the RRP workers). 

The proposed rule will reduce lead exposure by reducing the amount of lead contamination generated by 

renovation activities, and thus reduce the health and ecological risks in their vicinity. EPA anticipates 

that the rule will further develop a market1

 for lead safe renovation services that has been established by 

past lead awareness rules, such as the §406(b) rule, which requires compensated renovators to distribute 

lead awareness pamphlets to owners and occupants of most pre-1978 residential housing before beginning 

renovations. 

The proposed rule requires certification of firms (including sole practitioners) that perform renovation, 

remodeling and/or painting in housing units subject to the regulations. To be certified, the firm must 

employ at least one renovator who has received formal training in EPA-approved work practices from an 

EPA-accredited course. In addition, certified firms must provide on-the-job training in these approved 

work practices for workers who will be performing RRP activities in regulated housing. In addition, the 

proposed rule requires cleaning verification procedures to ensure that proper cleanup has occurred. 

Supporting these work practices, training and certification requirements, EPA will be undertaking an 

enhanced outreach program to educate the general public about the dangers of lead exposure and ways to 

limit exposure resulting from RRP activities. 

EPA has considered two regulatory approaches: prescriptive and flexible regulations for the proposed 

work practice standards. Under the prescriptive approach, EPA prescribes the size of the work area that 

must be contained, cleaned, and verified. The flexible approach relies on the required training, and the 

 

1

 These markets are expected to consist of suppliers who offer lead safe renovation services (LSRS) and consumers 

who are willing to pay the incremental costs associated with using LSRS over non-LSRS.
§402(c) Economic Analysis Chapter 1 2 

renovator’s own experience, to determine the size of the work area in any particular situation. The 

flexible approach increases the cost effectiveness of the regulation by reducing work practice costs. 

1.2 Goal of the Economic Analysis 

The purpose of this report is to present policy options that are under consideration and to analyze their 

respective costs and benefits. The report also meets the requirements for economic analysis of Executive 

Order 12866 – Regulatory Planning and Review; the Regulatory Flexibility Act (RFA) and Small 

Business Regulatory Enforcement Fairness Act (SBRFA); Executive Order 12898 – Federal Actions to 

Address Environmental Justice in Minority Populations and Low-Income Populations; Executive Order 

13045 – Protection of Children from Environmental Health Risks and Safety Risks; the Unfunded 

Mandates Act and Executive Order 12875 – Enhancing the Intergovermental Partnership; and the 

Paperwork Reduction Act (PRA). 

This economic analysis considers four regulatory options. Options A, B, and C allow certified renovators 

who are performing the RRP activity to decide the work practices necessary, while under Option D, the 

required work practices are specified by the rule. The options also differ in terms of the age of housing 

subject to the regulation in the first year – by the second year they all cover the same housing stock. 

Options A, B, C and D cover the following housing units (Note that Options B and D are the same in 

terms of the housing subject to the regulations). The proposed rule is Option B. 
§402(c) Economic Analysis Chapter 1 3 

First Year Second Year 

Option A 

All renter-occupied target housing units 

built before 1978, and owner-occupied 

target housing units built before 1978 

where a child under the age of six 

resides. 

All renter-occupied target housing 

built before 1978, and owneroccupied target housing units built 

before 1978 where a child under the 

age of six resides. 

Option B 

All renter-occupied target housing units 

built before 1960, and owner-occupied 

target housing units built before 1960 

where a child under the age of six 

resides, plus all target housing units built 

before 1978 where a child with an 

increased blood-lead level resides.a

 

Same as Option A. 

Option C 

All renter-occupied target housing units 

built before 1950, and owner-occupied 

target housing units built before 1950 

where a child under the age of six 

resides, plus all target housing units built 

before 1978 where a child with an 

increased blood-lead level resides.a

 

Same as Option A. 

Option D 

The prescriptive option. Covers the 

same housing units as Option B – but 

requires specific work practices. 

The prescriptive option. Covers the 

same housing units as Option B – 

but requires specific work practices. a

 Where increased is defined as greater than or equal to 10 μg/dL or a State or local government level 

of concern, if lower. 

The proposed rule is Option B.
§402(c) Economic Analysis Chapter 1 4 

1.3 Organization of this Report 

Chapter 2 examines the supply of and demand for renovation, remodeling and painting services. Using 

data from the U.S. Economic Census, the chapter discusses the size of the RRP industry and 

characteristics of its firms, as well as the organizational structure and competitiveness of the industry. 

Using a variety of secondary source material the demand for RRP services is characterized and the factors 

that affect demand are discussed. Other affected industries (e.g. training providers, property owners and 

managers) are also profiled in this chapter. 

Chapter 3 characterizes the lead contamination problem to be addressed under the proposed rule. It 

discusses how incomplete information and external costs have resulted in inefficient levels of lead 

contamination resulting from renovation activity, and introduces regulation as a reasonable solution for 

these market failures. The chapter also reviews state and local regulations that affect RRP activities and 

demonstrates that these are not sufficient to address the problem. 

Chapter 4 describes in detail the methods used to calculate costs of the various regulatory options 

considered. It describes the data sources used and is organized around the four general categories of costs 

for complying with the proposed rule: training costs, work practice compliance costs, cleaning 

verification costs, and administrative costs. The last section of the chapter estimates the costs of each 

option over a 50-year period. 

Chapter 5 describes in detail the benefit estimation, covering IQ benefits in children and a variety of 

health effects in adults. Four appendixes are presented that include a technical discussion of how the 

benefits were estimated and provide a brief discussion of the lead-related adverse health effects, both 

included and not included in the benefit analysis, as well as ecological effects. 

Chapter 6 provides a summary of the costs and benefits, and the corresponding net benefits. This chapter 

also provides a summary of the number of individuals living in these units who would otherwise be at 

risk. 

Chapter 7 presents the results of several sensitivity analyses conducted to measure the effect of particular 

components of the model. These analyses address uncertainties in both the cost and the benefit analyses. 

Finally, Chapter 8 presents findings of distributional analyses relevant to specific rule-making 

requirements, including small business impacts, environmental justice, protection of children and 

unfunded mandates.
§402(c) Economic Analysis Chapter 2 1 

2. Renovation, Repair and Painting Industry Profile 

Under the Renovation, Repair and Painting (RRP) Rule, firms that renovate, repair or paint housing 

subject to the regulations will need to obtain EPA certification, train their employees as either renovators 

or workers and ensure that lead-safe work practices are used whenever a project disturbs more than the 

exempt amount of lead-based paint. Eleven construction industry sectors and two residential real estate 

sectors include, in all likelihood, the vast majority of firms affected by the RRP Rule. These industries 

are the primary focus of this profile. Because the proposed rule will also affect the training provider 

market by requiring training for certified renovators, this profile examines the technical trade school 

industry as well. 

The industry profile is organized into six sections. Section 2.1 examines the supply-side of renovation by 

defining the relevant industry sectors and identifying the number of potentially affected firms. Section 

2.1 also contains financial profiles of the renovation industry sectors, highlighting each sector’s firm size 

and value of construction work. Section 2.2 focuses on the demand-side of renovation by identifying the 

quantity of renovation activities performed. This section also discusses trends in the demand for 

renovation services. Section 2.3 focuses on the overall market organization for the renovation industry 

and assesses the competitiveness of the industry. Section 2.4 discusses property owners and managers 

likely to be affected by the rule. Section 2.5 discusses training providers. 

2.1 The Supply of Renovation Services 

Renovation encompasses a wide variety of construction activities. Renovation is defined as

the modification of any existing structure, or portion thereof, that results in the disturbance of 

painted surfaces, unless that activity is performed as part of an abatement as defined by this part 

(40 CFR 745.223). The term renovation includes (but is not limited to): the removal or 

modification of painted surfaces or painted components (e.g., modification of painted doors, 

surface preparation activity (such as sanding, scraping, or other such activities that may generate 

paint dust)); the removal of large structures (e.g., walls, ceiling, large surface replastering, major 

replumbing); and window replacement (40 CFR 745.83). 

Thus, renovation includes repair and painting work. Renovation activities are conducted without the 

intent of removing lead, but may disturb it in the process. Lead abatement activities, on the other hand, 

are conducted with the intent to remove lead-based paint or otherwise permanently eliminate a lead-based 

paint hazard. Depending on the reason they are undertaken, many activities, such as replacing windows, 

can be either renovation or abatement. Because the proposed RRP regulations will address renovation, 

rather than abatement activity, this profile focuses on the residential renovation industry as opposed to the 

abatement services industry. Providers of abatement services (i.e. abatement supervisors and workers) 

will not require additional training to perform renovation work and will be grandfathered in under the 

RRP regulations. 
§402(c) Economic Analysis Chapter 2 2 

2.1.1 Industry Definition and Characteristics 

Data from the U.S. Economic Census were used to identify North American Industry Classification 

System (NAICS) industry groups that may be involved in renovation, repair and painting work (U.S. 

Census Bureau 2001). An establishment is assigned to a NAICS group based on the activities from which 

it derives the greatest share of its revenues. These activities may or may not make up the majority of 

work (i.e. labor hours) performed by the establishment, which may also be involved in a variety of other 

related (or unrelated) lines of work. EPA identified eleven NAICS codes that are likely to include the 

vast majority of establishments that will be affected by the RRP regulations. Affected industry groups 

include one building construction sector (NAICS 236118 – Residential Remodelers) and ten specialty 

trade contractor sectors. These sectors, as well as examples of the work they perform, are presented in 

Table 2-1. 
§402(c) Economic Analysis Chapter 2 3 

Table 2-1: Sectors likely to be affected by the RRP regulation 

2002 NAICS Examples of Work Performed 

236118 - Residential Remodelers • Addition, alteration and renovation of single-family homes 

• Addition, alteration and renovation of multifamily building 

• Home improvement (e.g., adding on, remodeling, 

renovating) 

238220 - Plumbing, Heating & Air 

Conditioning Contractors 

• Heating equipment installation 

• Plumbing fixture installation 

• Plumbing and heating contractors 

238320 - Painting and Wall Covering 

Contractors 

• House painting 

• Paint and Wallpaper Stripping 

• Paperhanging and removal contractors 

238210 - Electrical contractors • Electrical wiring contractors 

• Lighting system installation 

• Electric power control panel and outlet installation 

238350 – Finish Carpentry contractors • Door and window, prefabricated, installation 

• Millwork installation 

• Paneling installation 

238310 - Drywall and Insulation Contractors • Panel or rigid board insulation installation 

• Mineral wool insulation installation 

• Plastering (i.e., ornamental, plain) contractors 

238170 - Siding Contractors • Vinyl Siding, soffit and fascia, installation 

• Wood Siding, installation 

238340 - Tile and Terrazzo Contractors • Ceramic tile installation 

• Mantel, marble or stone, installation 

• Mosaic work 

238150 - Glass and Glazing Contractors • Mirror installation 

• Window pane or sheet installation 

238390 - Other Building Finishing Contractors • Window shade and blind installation 

• Building fixture and fitting (except mechanical equipment) 

installation 

• Drapery fixture (e.g., hardware, rods, tracks) installation 

238290 - Other Building Equipment 

Contractors 

• Pipe, duct and boiler insulation 

• Water pipe insulating 

• Deodorization (i.e., air filtration) system installation

Source: U.S. Census Bureau 2001 

2.1.2 Renovation Establishment Characteristics 

Establishments that provide renovation services fall into two general categories: those with employees 

(employer establishments) and self-employed contractors, also referred to as non-employer 

establishments.
§402(c) Economic Analysis Chapter 2 4 

Number of Establishments with Employees

Although some establishments1

 in the identified NAICS industries may specialize in residential 

renovation, the majority (with the exception of Residential Remodelers), in all likelihood, do not. 

Establishments in these sectors work on commercial, educational and industrial structures in addition to 

residential buildings. An establishment that does specialize in residential structures may perform work on 

new construction as well as on existing structures; the former is, of course, not considered a renovation. 

The U.S. Economic Census does not provide data on the number of establishments that specialize in 

residential renovation, but does present the number of establishments that specialize in single-family and 

apartment building construction, a category that includes both new construction and renovation work. 

Because the RRP rule applies only to residential renovations, however, these numbers provide an idea of 

the extent to which the regulations will affect each of the industry sectors. 

The U.S. Economic Census tracks businesses with paid employees (employer establishments) and nonemployer establishments (self-employed contractors) separately. This discussion deals with employer 

establishments only; non-employers are addressed later in this section. 

Table 2-2 presents the total number of establishments as well as the number of establishments specializing 

in residential construction in each of the identified NAICS industries. The number of establishments 

“includes all establishments that were in business at any time during the year. It covers all full-year and 

part-year operations” (U.S. Census Bureau 2005j). According to the U.S. Census Bureau, an 

establishment is considered to specialize in a certain type of construction if it derives at least 51 percent of 

its revenues from this construction type. Note that for NAICS 236118 and NAICS 238320, the number of 

establishments specializing in residential construction includes establishments that specialize in singlefamily and apartment building work. For the remaining NAICS codes, the number of establishments 

specializing in apartment building work is not provided (number specializing in single-family 

construction is available) and the number specializing in Other Building Construction was used as a 

proxy. Because the Other Building Construction category includes both apartment buildings and various 

types of non-residential structures, this approach is likely to lead to an overestimate of the number of 

establishments specializing in residential construction. 

As demonstrated in Table 2-2, about 54 percent of Residential Remodeler (NAICS 236118) 

establishments specialize in residential work. The portion of specialty contractor establishments that 

specialize in residential work varies from 86 percent of Finish and Carpentry contractors to only 31 

percent of Other Building Equipment contractors. Notably, none of the Other Building Equipment 

contractor establishments specialize in single-family residential construction; all potentially affected 

establishments specialize in Other Building construction, which may include apartment buildings. Based 

on the data presented in Table 2-2, up to 215,513 of the 357,154 establishments in the identified NAICS 

sectors (60 percent) may specialize in residential construction (including both new construction and 

renovation). 

 

1

 The U.S. Census Bureau defines an “establishment” as “a single physical location at which business is conducted. 

It is not necessarily identical with a company or enterprise, which may consist of more than one establishment” 

(U.S. Census Bureau 2005j). Most economic census data represent a summary of reports for individual 

establishments rather than companies. For cases where a census report was received, separate information was 

obtained for each location where business was conducted.” (U.S. Census Bureau 2005j) 
§402(c) Economic Analysis Chapter 2 5 

Table 2-2: Number of Employer Establishments in Construction Sectors Affected by the RRP Rule 

NAICS 

code Industry 

Total 

Number of 

Establishments 

Number of 

Establishments 

Specializing in 

Residential Work 

Residential 

Establishments 

as Percent of 

Total 

238350 Finish carpentry contractors 35,087 30,232b 86 

238340 Tile and terrazzo contractors 8,950 7,583 b 85 

238170 Siding contractors 6,632 5,596 b 84 

238320 Painting and wall covering contractors 38,943 27,021 a 69 

238310 Drywall and insulation contractors 19,598 13,271 b 68 

238220 Plumbing and HVAC contractors 87,501 52,443 b 60 

236118 Residential remodelers 82,747 44,492 a 54 

238390 Other building finishing contractors 3,729 1,947 b 52 

238210 Electrical contractors 62,586 28,758 b 46 

238150 Glass and glazing contractors 5,294 2,281 b 43 

238290 Other building equipment contractors 6,087 1,889 b 31 

Total 357,154 215,513 60 

a. Sum of establishments specializing 51 percent or more in single family attached and detached units 

construction and establishments specializing 51 percent or more in apartment building construction. 

b. Sum of establishments specializing 51 percent or more in single family attached and detached units 

construction and establishments specializing 51 percent or more in other building construction. Data 

on establishments specializing in apartment building construction not available. 

Sources: U.S. Census Bureau 2005e,f 

Number of Employees 

Table 2-3 presents the number of employees in each NAICS group of interest, as well as the total for 

establishments specializing in residential construction for each industry. The 215,513 establishments that 

specialize in residential construction employ about 1.4 million people. 

Table 2-3 also presents the average per-establishment employment numbers by NAICS code, for all 

establishments and for establishments specializing in residential construction. Average employment 

numbers are also presented in the form of a bar graph in Figure 2.1. The average employment numbers 

are small for all affected sectors. Overall, Other Building Equipment contractors have the largest number 

of employees per establishment (20.8 people), while Residential Remodelers have the smallest (3.9 

people). While establishments that specialize in residential construction make up 60 percent of all 

establishments in the identified sectors, they employ only 47 percent of the people who work in these 

industries. 
§402(c) Economic Analysis Chapter 2 6 

Table 2-3: Number of Employer Establishments and Employees by NAICS Code 

NAICS 

code Industry 

Number of 

Establishments

Number of 

Employees Average Size

236118 Residential Remodelers 82,747 320,201 3.9 

Establishments specializing in residential work 44,492 208,867 4.7 

238170 Siding contractors 6,632 43,042 6.5 

Establishments specializing in residential work 5,596 33,493 b 6.0 

238210 Electrical contractors 62,586 771,184 12.3 

Establishments specializing in residential work 28,758 236,815 b 8.2 

238220 Plumbing and HVAC contractors 87,501 974,368 11.1 

Establishments specializing in residential work 52,443 393,599 b 7.5 

238310 Drywall and Insulation contractors 19,598 311,077 15.9 

Establishments specializing in residential work 13,271 165,202 b 12.4 

238320 Painting and Wall Covering contractors 38,943 234,562 6.0 

Establishments specializing in residential work 27,021 115,645 a 4.3 

238350 Finish Carpentry contractors 35,087 179,476 5.1 

Establishments specializing in residential work 30,232 148,171 b 4.9 

238340 Tile and Terrazzo contractors 8,950 60,001 6.7 

Establishments specializing in residential work 7,583 42,658 b 5.6 

238150 Glass and Glazing contractors 5,294 50,800 9.6 

Establishments specializing in residential work 2,281 14,725 b 6.5 

238290 Other Building Equipment contractors 6,087 126,559 20.8 

Establishments specializing in residential work 1,889 31,923 b 16.9 

238390 Other Building Finishing contractors 3,729 50,617 13.6 

Establishments specializing in residential work 1,947 22,237 b 11.4 

Total, All sectors 357,154 3,121,887 8.7 

Total, All establishments specializing in residential work 215,513 1,413,335 6.6 

a. Sum of establishments specializing 51percent or more in single family attached and detached units 

construction and establishments specializing 51percent or more in apartment building construction. 

b. Sum of establishments specializing 51percent or more in single family attached and detached units 

construction and establishments specializing 51percent or more in other building construction. Data on 

establishments specializing in apartment building construction not available. 

Sources: U.S. Census Bureau 2005e,f
§402(c) Economic Analysis Chapter 2 7 

Table 2-4 presents the total number of employees and the number of construction workers in each 

identified industry. These data are only available at the industry level and can not be obtained for 

establishments that specialize in residential construction. The number of employees “includes all fulltime and part-time individuals on the payrolls of construction establishments during any part of the pay 

period which included the 12th of March, May, August and November” (U.S. Census Bureau 2005f). The 

number of construction workers “includes all payroll workers (up through working supervisory level) 

directly engaged in construction operations” including, but not limited to “painters, carpenters, plumbers 

and electricians... journeymen, mechanics... truck drivers and helpers.” Non-construction employees 

include “executives, purchasing, accounting, personnel... and routine office functions” (U.S. Census 

Bureau 2005f). Because construction workers form the vast majority of the people who require training 

under the RRP rule, their role in the composition of each sector’s labor force provides an indication of the 

extent to which each sector will be affected by the regulations. 

In total, over 3 million people work for the 357,154 establishments in the potentially affected industries. 

About 75 percent of these employees are construction workers. The affected sectors differ in terms of the 

composition of their labor force. For example, construction workers make up 84 percent of employees in 

the Drywall and Insulation contractor sector. In the Finish Carpentry contractor and the Residential 

Remodeler sectors, however, construction workers make up only 72 percent and 65 percent of the labor 

force, respectively (U.S. Census Bureau 2005b,f). 

0.0

5.0

10 .0

15.0

20.0

2 5.0

Establishment Size (number of employees)

Other building

equipment

co ntracto rs

Drywall and

ins ulatio n

co ntracto rs

Other building

finis hing

co ntracto rs

Electrical

co ntracto rs

P lumbing and

HVAC

co ntracto rs

Glas s and

glazing

co ntracto rs

Tile and

terrazzo

co ntracto rs

Siding

co ntracto rs

P ainting and

wall co vering

co ntracto rs

Finis h

carpentry

co ntracto rs

Res idential

remo delers

Industry

Figure 2.1: Industry Average Establishment Size as Compared to Average Size of Establishments Specializing in 

Residential Construction

All Es tablis hments

Es tablis hments Specializing in

Res idential Co ns tructio n

0.0

5.0

10 .0

15.0

20.0

2 5.0

Establishment Size (number of employees)

Other building

equipment

co ntracto rs

Drywall and

ins ulatio n

co ntracto rs

Other building

finis hing

co ntracto rs

Electrical

co ntracto rs

P lumbing and

HVAC

co ntracto rs

Glas s and

glazing

co ntracto rs

Tile and

terrazzo

co ntracto rs

Siding

co ntracto rs

P ainting and

wall co vering

co ntracto rs

Finis h

carpentry

co ntracto rs

Res idential

remo delers

Industry

Figure 2.1: Industry Average Establishment Size as Compared to Average Size of Establishments Specializing in 

Residential Construction

All Es tablis hments

Es tablis hments Specializing in

Res idential Co ns tructio n
§402(c) Economic Analysis Chapter 2 8 

Table 2-4: Number of Employer Establishments, Total Employees and Employees involved in 

Construction 

NAICS 

Code Industry 

Total Number 

of Employees

Number of 

Construction 

Workers 

Construction 

Workers as Percent 

of Total Employees

238310 Drywall and Insulation contractors 311,077 261,239 84 

238210 Electrical contractors 771,184 606,403 79 

238320 Painting and Wall Covering contractors 234,562 184,328 79 

238340 Tile and Terrazzo contractors 60,001 44,729 75 

238390 Other Building Finishing contractors 50,617 37,353 74 

238220 Plumbing and HVAC contractors 974,368 712,452 73 

238350 Finish Carpentry contractors 179,476 129,888 72 

238290 Other Building Equipment contractors 126,559 90,504 72 

238170 Siding contractors 43,042 30,284 70 

238150 Glass and Glazing contractors 50,800 34,086 67 

236118 Residential Remodelers 320,201 207,633 65 

Total 3,121,887 2,338,899 75 

Sources: U.S. Census Bureau 2005b,e,f 

Number of Non-Employer Establishments 

As mentioned at the beginning of this section, the U.S. Economic Census tracks non-employer 

establishments separately from establishments with employees. Data on the number of non-employer 

establishments was available from the U.S. Small Business Administration. A non-employer firm “is 

defined as one that has no paid employees, has annual business receipts of $1,000 or more ($1 or more in 

the construction industries), and is subject to federal income taxes” (U.S. Small Business Administration 

2005). Essentially, non-employers are self-employed contractors. Because little financial and operational 

data is available for non-employers, the vast majority of this profile focuses on establishments with 

employees. This subsection discusses the number of non-employers in the affected industry sectors and 

the receipts of these establishments. Non-employers are addressed further in Chapter 4 of this Economic 

Analysis. 

The U.S. Small Business Administration does not currently provide data on the number or revenues of 

non-employer establishments in each of the 6-digit level NAICS industries addressed in this profile. Data 

on the number of such establishments is available for Plumbing and HVAC contractors (NAICS 238220) 

and Electrical contractors (NAICS 238210) only; for the remaining industries, data is provided at the 

more general 4-digit NAICS level. 

To estimate the number of non-employer establishments in each of the 6-digit sectors, EPA assumed that 

the distribution of non-employer establishments in each 4-digit NAICS code is the same as the 

distribution of establishments with payroll in the same 4-digit group. Similarly, to estimate the revenues 

of these establishments, EPA assumed that the distribution of receipts in each 4-digit NAICS code is the 

same as the distribution of revenues of payroll establishments in the same 4-digit industry. In other 

words, EPA assumed that if Residential Remodeler establishments with employees (NAICS 236118) 

make up 48 percent of the Residential Construction sector (NAICS 2361) and earn 30 percent of the 

revenues in that sector, then 48 percent of non-employers in the Residential Construction sector would be 

involved in the Residential Remodeling industry, and would earn 30 percent of the NAICS 2361 nonemployer receipts. 
§402(c) Economic Analysis Chapter 2 9 

Table 2-5 presents the estimated number and revenues of non-employer establishments in each of the 

eleven sectors affected by the RRP regulations. 

Table 2-5: Number and Annual Revenues of Non-Employer Establishments in Affected Sectors 

NAICS Description 

Number of Non-Employer 

Establishments 

Revenues of NonEmployer Establishments 

(000) 

236118 Residential Remodelers 194,182 $6,187,917 

238170 Siding contractors 15,939 $485,112 

238350 Finish Carpentry contractors 185,118 $5,254,955 

238290 Other Building Equipment contractors 9,710 $356,461 

238390 Other Building Finishing contractors 19,674 $1,396,611 

238340 Tile and Terrazzo contractors 47,220 $1,684,174 

238220 Plumbing and HVAC contractors 110,183 $5,920,986 

238150 Glass and Glazing contractors 12,723 $720,934 

238320 Painting and Wall Covering contractors 205,462 $4,823,217 

238210 Electrical contractors 102,219 $3,834,347 

238310 Drywall and Insulation contractors 103,398 $8,798,899 

Total Non-Employer Establishments 1,005,829 39,463,613 

Source: U.S. Small Business Administration 2005, U.S. Census Bureau 2005i 

Contribution of Residential Renovation Work to Total Value of Construction

Another way to assess the relative importance of renovation work to each of the NAICS industries is to 

compare each sector’s value of renovation work to that sector’s total value of construction work. The 

Value of Construction is defined as “receipts, billings and sales for construction work... [including] new 

construction, additions, alterations or reconstruction, and maintenance and repair construction work.” The 

Value of Construction includes the value of the installation and receipts covering the price of the items 

installed,” but excludes “the cost of industrial and other special machinery and equipment that are not an 

integral part of a structure” (U.S. Census Bureau 2005f). Although the 2002 Economic Census does not 

provide data on the number of establishments involved in residential renovation, it does provide the total 

value of construction work derived from these activities. These data are only available for each industry 

sector as a whole and are not available for establishments that specialize in residential construction. 

Table 2-6 presents the total value of construction, as well as the value of construction from residential 

renovation activities, for each of the eleven identified industries in order (highest to lowest) of the 

percentage of revenues contributed by residential renovation to total value of construction. Residential 

renovation activity includes additions, alterations, reconstruction, maintenance and repair work performed 

in single-family buildings (attached or detached) and apartment buildings. When data on the value of 

construction work performed in apartment buildings was not available, the value of construction work 

performed in Other Buildings was used instead.2

As demonstrated in Table 2-6, residential RRP plays a different role for establishments in each 

construction sector. Residential Remodelers rely more on residential RRP than the other industries, 

deriving about 56 percent of their construction revenues from these activities. Specialty contractors, on 

 

2

 This may lead to an overestimate of the percent contribution of residential RRP activity to total value of 

construction as Other Buildings include non-residential structures as well as apartment buildings. 
§402(c) Economic Analysis Chapter 2 10 

the other hand, derive between 21 and 50 percent of their construction revenues from residential 

renovation (U.S. Census Bureau 2005d,f). Note that the percentage of total value of construction derived 

from residential RRP is a better indicator of the importance of RRP to that industry sector than the value 

of RRP construction. For example, although Plumbing and HVAC contractors have the highest 

residential RRP revenues of the eleven sectors, these contribute just over a quarter of the total value of 

construction for that industry. The interpretation of data is further complicated by the inclusion of 

materials used and installed, which is likely to be greater for sectors such as Plumbing/HVAC than for 

sectors such as Painting/Wall Covering. 

Table 2-6: Annual Value of Construction Work: Renovation Activities Compared to Totals 

NAICS 

Code Industry 

Total Value of 

Construction 

Work (000) 

Value of 

Residential RRPa 

(000) 

Value of Residential 

RRP as percent of 

Total Value of 

Construction 

236118 Residential Remodelers $45,031,231 $25,439,187 56 

238170 Siding contractors $4,253,327 $2,145,705 c 50 

238350 Finish Carpentry contractors $18,153,924 $9,107,821 c 50 

238290 Other Building Equipment contractors $14,503,280 $4,788,697 c 33 

238390 Other Building Finishing contractors $4,861,928 $1,467,134 c 30 

238340 Tile and Terrazzo contractors $5,858,390 $1,643,848 c 28 

238220 Plumbing and HVAC contractors $117,785,785 $31,416,931 c 27 

238150 Glass and Glazing contractors $6,284,748 $1,643,915 c 26 

238320 Painting and Wall Covering contractors $16,852,809 $4,208,354 b 25 

238210 Electrical contractors $82,141,261 $19,118,532 c 23 

238310 Drywall and Insulation contractors $30,821,528 $6,386,249 c 21 

Total $346,548,211 $107,366,373 31 

a. Value of includes additions, alterations, reconstruction, maintenance and repair. 

b. Sum of value of RRP work in single-family homes (attached and detached) and in apartment buildings. 

c. Sum of value of RRP work in single-family homes (attached and detached) and in Other Buildings. 

Source: U.S. Census Bureau 2005d,f 
§402(c) Economic Analysis Chapter 2 11 

2.1.3 Financial Profile 

In this section, Census data is used to examine key financial indicators for the renovation industry. The 

indicators include net value of construction (value of construction less value of construction 

subcontracted out to others) and labor costs. Net value of construction work is used instead of the total 

value of construction work because it is a measure of the work actually performed by the establishment. 

Table 2-7 presents the average per establishment net value of construction work (NVCW) for each 

industry sector and for establishments that specialize in residential construction. The table also presents 

labor costs as a percent of the net value of construction for each of the affected NAICS codes and for 

those establishments in each industry that specialize in residential construction.3

Data on the value of construction and payroll was not available for Residential Remodeler establishments 

that specialize in apartment building construction. As such, the NVCW reported in Table 2-7, which 

includes single-family buildings only, understates the total value of residential work performed by these 

establishments. 

 

3 Residential construction includes both new construction and renovation work. Data on the number or financial characteristics 

of establishments that specialize in residential renovation work is not available from the 2002 U.S. Economic Census. 
§402(c) Economic Analysis Chapter 2 12 

Table 2-7: Financial Summary for Industry Sectors Affected by the RRP Rule 

NAICS 

code Industry 

Annual Net Value of 

Construction Work 

(000) 

Net Value of 

Construction Work 

per Establishment 

(000) 

Payroll as % of 

Net Value of 

Construction 

Work 

236118 Residential Remodelers $30,626,002 $370 28 

Estab. specializing in residential work $18,054,608 $406a

 31 a

238150 Glass and Glazing contractors $6,016,766 $1,137 29 

Estab. specializing in residential work $1,702,264 $746 27 

238170 Siding contractors $3,810,070 $574 31 

Estab. specializing in residential work $2,954,747 $528 30 

238210 Electrical contractors $77,671,846 $1,241 38 

Estab. specializing in residential work $20,553,832 $715 37 

238220 Plumbing and HVAC contractors $105,323,163 $1,204 34 

Estab. specializing in residential work $39,115,100 $746 31 

238290 Other Building Equipment contractors $13,680,062 $2,247 36 

Estab. specializing in residential work $3,134,176 $1,659 36 

238310 Drywall and Insulation contractors $27,046,301 $1,380 36 

Estab. specializing in residential work $14,217,161 $1,071 32 

238320 Painting and Wall Covering contractors $15,316,726 $393 39 

Estab. specializing in residential work $6,759,709 $250 36 

238340 Tile and Terrazzo contractors $5,639,641 $630 33 

Estab. specializing in residential work $3,916,447 $516 31 

238350 Finish Carpentry contractors $15,640,544 $446 30 

Estab. specializing in residential work $12,525,747 $414 30 

238390 Other Building Finishing contractors $4,560,138 $1,223 38 

Estab. specializing in residential work $1,992,734 $1,023 34 

Total, All Establishments in All Industries $305,331,259 $855 32 

Total, Estab. Specializing in residential work only $124,926,525 $580 32 

a. Includes establishments specializing in single-family building construction only. Note that the revenue 

figures presented in this table include both new construction and renovation revenues. 

Source: US Census Bureau 2002a,e,f 

The data in Table 2-7 indicate that the average net value of construction work of Residential Remodeler 

establishments that specialize in residential construction is significantly higher than the industry sector 

average. The opposite is true for all 10 specialty contractor sectors. The difference is most pronounced 

in the electric industry sector, where the NVCW of specialized establishments is 42 percent lower than 

the industry sector average. The difference is smallest (7 percent) for Finishing Carpentry contractors 

(U.S. Census Bureau 2005e,f). 

As demonstrated in Table 2-7, while labor constitutes about 32 percent of net value of construction for all 

the industry sectors and for those establishments that specialize in residential work, the within-industry 

differences vary across industry sectors. Glass and Glazing, Plumbing, Drywall/Insulation, Painting/Wall 

Covering and Other Building Finishing contractors that specialize in residential construction spend a 

slightly smaller portion of their net value of construction work on payroll expenditures than their industry 
§402(c) Economic Analysis Chapter 2 13 

average. For example, labor costs of Drywall and Insulation contractors specializing in residential work 

amount to 32 percent of net value of construction, as compared to 36 percent for all establishments in that 

industry sector. On the other hand, Residential Remodeler establishments that specialize in residential 

work spend a slightly larger portion of the net value of construction work on labor than that industry’s 

average (U.S. Census Bureau 2005a,e,f). 

The Painting and Wall Covering contractor (NAICS 238320) industry is most dependent on labor, with an 

overall labor cost to net value of construction ratio of 39 percent. Glass and Glazing contractors, with an 

overall labor cost to net value of construction work ratio of 29 percent, are least labor dependent of the 

eleven sectors (U.S. Census Bureau 2005a,e,f). 

2.1.4 Establishment Size by Revenue Bracket 

The Small Business Administration (SBA) defines a small business in the Residential Remodeler industry 

as one that has revenues of $28.5 million a year or less. The small business definition for the ten affected 

specialty contractor industries is $12 million per year (U.S. Small Business Administration 2004). The 

SBA size standards apply to firms rather than establishments; revenue data in the 2002 Economic Census, 

however, is only available at the establishment level. By using establishment rather than firm data, this 

analysis overestimates the number of small businesses in the affected industries. 

The remainder of this section examines the number of establishments, number of employees, net value of 

construction work and value of business done4

 distributed by establishment revenue bracket. These data 

were available from the 2002 Economic Census at the NAICS code level only. Establishments were 

classified into two revenue categories based on the total value of business done – those with revenues less 

than $10 million and those with revenues greater than $10 million. Because the Census groups all 

establishments with revenues of $10 million or more into one revenue bracket, it is not possible to 

determine what percentage of Residential Remodeler establishments have revenues of $28.5 million or 

less. Note, however, that nearly 100 percent of Residential Remodeler establishments have revenues of 

less than $10 million per year. The percent of establishments, employees and net value of construction 

contributed by establishments in each revenue bracket is presented in Table 2-8. 

 

4

 Total value of business done is defined by the U.S. Census Bureau as “the sum of value of construction work and 

other business receipts. Value of business done is the sum of receipts, billings, or sales from establishments of 

construction business activities plus receipts from other business activities” (U.S. Census Bureau 2005f). As such, 

total value of business done represents the total revenues of a typical construction establishment. 
§402(c) Economic Analysis Chapter 2 14 

Table 2-8: Small and Large Establishments as Percent of Industry 

NAICS Industry Description 

Percent of 

Establishments

Percent of 

Employees

Percent of Net 

Value of 

Construction 

Percent of Value 

of Business Done

238220 Plumbing and HVAC contractors 

 Revenues < $10 million 98 70 63 61 

 Revenues $10 million or more 2 30 37 39 

236118 Residential remodelers

 Revenues < $10 million 100a 95 92 91 

 Revenues $10 million or more 0 5 8 9 

238210 Electrical contractors

 Revenues < $10 million 98 68 61 60 

 Revenues $10 million or more 2 32 39 40 

238350 Finish carpentry contractors

 Revenues < $10 million 100 a 86 84 83 

 Revenues $10 million or more 0 14 16 17 

238310 Drywall and insulation contractors

 Revenues < $10 million 97 64 60 60 

 Revenues $10 million or more 3 36 40 40 

238290 Other building equipment contractors

 Revenues < $10 million 95 60 55 55 

 Revenues $10 million or more 5 40 45 45 

238320 Painting and wall covering contractors

 Revenues < $10 million 100 a 92 88 88 

 Revenues $10 million or more 0 8 12 12 

238170 Siding contractors

 Revenues < $10 million 100 a 90 88 87 

 Revenues $10 million or more 0 10 12 13 

238340 Tile and terrazzo contractors

 Revenues < $10 million 100 a 91 86 86 

 Revenues $10 million or more 0 9 14 14 

238390 Other building finishing contractors

 Revenues < $10 million 98 81 74 74 

 Revenues $10 million or more 2 19 26 26 

238150 Glass and glazing contractors 

 Revenues < $10 million 98 82 77 77 

 Revenues $10 million or more 2 18 23 23 

Total

 Revenues < $10 million 99 75 68 68 

 Revenues $10 million or more 1 25 32 32 

a. 100 percent = establishments in this revenue category make up over 99.5, but less than 100 percent of 

establishments in the industry. 

Source: U.S. Census Bureau 2005c,f 
§402(c) Economic Analysis Chapter 2 15 

The distribution of the number of establishments for all eleven NAICS codes is greatly skewed toward 

smaller establishments. In five out of eleven industry sectors, over 99.5 percent of establishments have 

revenues below $10 million. Establishments with revenues greater than $10 million make up less than 

five percent of establishments in any sectors and about 1 percent of the total establishments in the affected 

industries (U.S. Census Bureau 2005c,f). As such, over 95 percent of establishments in each of the 

sectors have revenues below $12 million, which is the SBA small business definition for ten of the eleven 

industry sectors. 

Establishments with revenues of less than $10 million account for between 60 and 95 percent of total 

employment for each sector, and about 75 percent of employment overall. The distribution of the net 

value of construction work and the total value of business done for all six-digit NAICS codes is skewed 

toward smaller establishments in a manner similar to the distribution of employees. Establishments with 

revenues of less than $10 million account for between 55 and 92 percent of the net value of construction 

work and between 55 and 91 percent of the total value of business done for each sector. Overall (across 

all industry sectors) they contribute about 68 percent of both the net value of construction work and the 

total value of business (U.S. Census Bureau 2005c,f). 

Labor and Material Costs as a Percentage of Total Value of Business Done 

In order to better understand the potential impacts of the RRP rule on the affected industries, and 

particularly on small businesses, it is important to observe whether establishment costs as a percentage of 

the establishments’ total revenues differ for small and large establishments. Figure 2.2 examines labor 

and material costs as a percentage of the total value of business done for the eleven affected sectors. Each 

of the sectors was broken down into two size categories by revenue bracket: less than $10 million and $10 

million and more. Labor and material costs as a percentage of the total value of business were calculated 

for each individual sector. An overall ratio of labor and material costs to the total value of business were 

also calculated for all sectors (the sum of labor (materials) costs for the eleven industries divided by the 

sum of the total value of business done for these sectors). 

As demonstrated in Figure 2.2, based on data for all eleven affected sectors, the ratio of labor costs to the 

total value of business done is approximately 30 percent for both small and large establishments (U.S. 

Census Bureau 2005c,f). While material costs make up a slightly higher percent of revenues for small 

establishments (32 percent vs. 30 percent for large establishments), the ratios are not significantly 

different. As such, based on Census data for the eleven affected industries, it appears that the costs 

structure for small establishments is similar to the cost structure for larger establishments. 
§402(c) Economic Analysis Chapter 2 16 

Source: U.S. Census Bureau 2005c,f 

2.2 The Demand for Renovation Services 

The demand for renovation is responsive to changes in the overall economic conditions. The same factors 

that stimulate economic growth, such as low unemployment, high consumer confidence and low interest 

rates, also stimulate the demand for renovation services. Using U.S. Department of Commerce data, 

Figure 2.3 illustrates the relationships between the value of new construction, residential improvements 

and maintenance spending and real GDP.5

 Both new construction and real GDP experienced a substantial 

increase over the past 10 years. In the 1995 – 2002 period, GDP increased at a faster rate than new 

construction. In the 2002 – 2004 period, new construction has greatly outpaced GDP. Expenditures on 

residential improvements have also increased during this ten-year period, but at a slower rate than new 

construction. Like new construction, improvement expenditures are highly volatile. Spending on 

maintenance and repairs has remained fairly constant over this period and is not nearly as volatile as 

either new construction or improvements. This is expected because much of the maintenance (e.g., 

replacing heating systems or roofs) is not voluntary and the choices usually involve the amount to be 

spent, not whether the spending should be done. 

 

5

 U.S. Department of Commerce 2004a,b; U.S. Department of Commerce 2005. 

Labo r Co s t as % o f To tal Value o f

Bus ines s Do ne Material Co s ts as % o f To tal Value o f

Bus ines s Do ne

0%

5%

10%

15%

20%

25%

30%

35%

40%

Type of Cost

Figure 2.2: Labor and Material Costs as % of Total Value of Business Done

< $ 10 millio n

$ 10 millio n+

Labo r Co s t as % o f To tal Value o f

Bus ines s Do ne Material Co s ts as % o f To tal Value o f

Bus ines s Do ne

0%

5%

10%

15%

20%

25%

30%

35%

40%

Type of Cost

Figure 2.2: Labor and Material Costs as % of Total Value of Business Done

< $ 10 millio n

$ 10 millio n+
§402(c) Economic Analysis Chapter 2 17 

2.2.1 Number of Renovation Activities Performed 

The American Housing Survey (AHS) collects data on the number of owner-occupied households 

performing a renovation activity.6

 The AHS is a bi-annual survey of approximately 55,000 households in 

the United States conducted by the U.S. Census Bureau for the U.S. Department of Housing and Urban 

Development (HUD). The AHS includes data on single-family and multi-family units as well as data on 

publicly-owned and privately-owned housing units. The survey is stratified and weighted to represent the 

nation’s housing stock and can be used to determine the state of the housing stock in a given year or to 

document changes in the housing stock over time.7

 The AHS traces the same set of households, adding 

observations each year to represent new construction. 

Renovation tasks can be classified as “professional” projects and “do-it-yourself” projects. A project was 

classified as a “do-it-yourself” job if the AHS respondent reported that they or someone in their 

household completed the work. Professional jobs encompass all other work performed, and classification 

of a project as professional does not necessarily indicate that the contractor was licensed, certified or 

trained. The distinction between professional and do-it-yourself work is important because the regulatory 

requirements apply only to professional contractors. 

 

6

 The AHS collects renovation data only from owner-occupied units; the number of events in rented units was 

calculated from another data source. 

7

 As described in more detail in Chapter 4, the weights used throughout this analysis were developed by the Harvard 

Figure 2.3: New Construction Compared to Improvement and GDP

0

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Value of Private Residential Construction Put in Place (Minus Improvements) in millions of 2004 dollars - left scale

Residential Improvements in millions of 2004 dollars - left scale

Maintenance and Repairs in millions of 2004 dollars - left scale

Real GDP, Seasonally Adjusted in billions of constant 2000 dollars - right scale

Source: U.S. Department of Commerce 2004a,b; U.S. Department of Commerce 2005

Figure 2.3: New Construction Compared to Improvement and GDP

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Value of Private Residential Construction Put in Place (Minus Improvements) in millions of 2004 dollars - left scale

Residential Improvements in millions of 2004 dollars - left scale

Maintenance and Repairs in millions of 2004 dollars - left scale

Real GDP, Seasonally Adjusted in billions of constant 2000 dollars - right scale

Source: U.S. Department of Commerce 2004a,b; U.S. Department of Commerce 2005
§402(c) Economic Analysis Chapter 2 18 

Renovation activities are not done with the intent to remove lead from the housing unit, although leadbased paint may be disturbed. Abatement activities, on the other hand, are performed with the sole intent 

to remove the lead-based paint from the housing unit. The AHS does not provide the data necessary to 

determine the intent of an activity. Hence, it is not possible to differentiate between the demand for 

renovation services or abatement activities. 

Since the AHS is a bi-annual survey, the weights have been adjusted to calculate annual counts. As 

shown in Table 2-9, over 13.5 million pre-1980 owner-occupied housing units performed at least one 

renovation event in 2003.8

 Of these, over 70 percent had at least one professionally conducted RRP event 

and over 52 percent undertook at least one do-it-yourself RRP event. Note that a household’s renovation 

activities can include a combination of both professionally done and do-it-yourself events. Thus the sum 

of households in these two categories exceeds the total number of households performing any renovation 

project. “In-scope” activities refers to households that had professionals undertake one or more 

renovation events that are likely to disturb more than two-square-feet of paint and thus might be subject to 

these regulations.9

 Approximately 5.9 million households undertook in-scope renovation projects in 2003. 

They comprise about 43 percent of all households undertaking RRP that year. In other words, about 12 

percent of all households in owner-occupied target housing undertook at least one RRP event in 2003 that 

would fall under this regulation. 

 

University’s Joint Center for Housing. 

8

 The housing unit age groupings in the AHS require that homes built in the 1975 to 1979 period be treated as a 

group. Thus the number of target housing units (defined as pre-1978 units except housing for the elderly or persons 

with disabilities where no children under age 6 reside or are expected to reside, or any 0-bedroom dwelling) 

undertaking RRP is slightly overestimated. 

9

 This estimate does not adjust for the likelihood of lead in the paint. Unless an inspection or risk assessment has 

been conducted and no lead found (or an abatement performed) the regulatory requirements would apply. 
§402(c) Economic Analysis Chapter 2 19 

Table 2- 9: Owner-Occupied Households Performing Renovations in 2003 (Pre-1980 Housing Only) 

Type of Renovation 

Activity 

Number of 

Households 

(thousands) a

Percent of All 

Housing Units 

Total Annual 

RRP Spending 

(billions, 2005$)

Median RRP Spending b

 (per-household, 2005$)

All Activities 14,000 28% $88 $2,100 

Professional Activities 10,000 20% $63 $2,140 

Do-It-Yourself Activities 7,000 15% $25 $790 

In-Scope-Activities c,d 6,000 12% $53 $2,500 

a. Rounded to the nearest million households. 

b. Median spending per-household reporting some positive amount. Rounded to nearest $10. 

c. In-scope activities are renovation projects that may disturb over 2 sq. ft. of paint. Out-of-scope 

activities are projects that are not likely to disturb more than 2 sq. ft. of paint. 

d. Total and Median household RRP spending includes out-of scope RRP spending. 

Note: It is assumed that all RRP reported by a household occurred in the same year. That is, the number of 

households estimated to have RRP performed annually is half the number of households that reported RRP in 

the bi-annual 2003 AHS. 

Source: EPA Calculations Using the American Housing Survey (2003) and revised weights provided by the 

Joint Center for Housing Studies

The AHS also provides data on the amount that households typically spend for renovation. Because some 

households spend very large amounts on renovation, the median expenditure is a better indicator of 

typical behavior than is average expenditures. As shown in Table 2-10, in 2003 the median amount spent 

by households that undertook renovation was $2,100. The median amount spent on professional 

renovation work (at $2,140) was only slightly higher, while the median amount spent on do-it-yourself 

renovation was substantially less (at $790). The do-it-yourself expenditure does not include the value of 

the respondents’ labor, just materials and other direct costs. 

2.2.2 Determinants of Demand 

Renovation spending tends to be volatile and is affected by a complex set of factors including, but not 

limited to, the income and age of the homeowner, the length of time that the homeowner has resided on 

the property and the location of the home. Although it is often hard to predict future spending on 

renovation in any particular year, impacts of these and other factors on the renovation and remodeling 

market have been studied extensively by Harvard University’s Joint Center for Housing Studies. The 

work of the Joint Center serves as the basis for this discussion. 10

As discussed earlier in this chapter, there are two main types of renovation projects – discretionary 

renovations and maintenance/repair projects. Unlike discretionary renovations, maintenance and repair 

projects are usually performed out of necessity and, as demonstrated in Figure 2.2, are less volatile than 

discretionary renovation and improvement projects. Note that a significant portion of the projects 

affected by the RRP Rule are likely to be repair/maintenance projects, rather than home improvement 

activities and thus may be less affected by the factors discussed in this section. 

Income of the Homeowner 

Traditionally, higher income households have spent more on improvement projects than other income 

groups, but recently the high-end market has grown expansively. Households with annual incomes over 

 

10 See reference list at the end of this chapter for the Joint Center studies used. 
§402(c) Economic Analysis Chapter 2 20 

$120,000 have more than doubled their improvement spending from 1995-2001. In particular, spending 

on projects that cost over $35,000 has increased substantially in the past decade. The projects in this 

high-end market are more likely to be discretionary projects (e.g., room additions) as opposed to required 

system replacement (e.g., heating and roofing). It is important to note that despite the rapid growth in the 

high-end market, the vast majority of renovation projects are still comparably low-budget, with the 

median spending per household equal to about $2,100 per year. 

Contrary to some impressions, improvement work in the high-end market is not done entirely by 

professionals. High-income households have greatly increased their share of do-it-yourself spending. 

From 1995-2001; owners with annual incomes over $120,000 were responsible for 54 percent of the 

growth in do-it-yourself expenditures. Once again, note that despite the fact that these households are 

spending a lot on do-it-yourself projects, the spending does not necessarily mean that the high-income 

households are taking on the greatest number of do-it-yourself projects. According to Harvard 

University’s Joint Center for Housing (JCFH), most do-it-yourself projects cost less than $2,500 and are 

done by those with $40-80,000 annual incomes. While do-it-yourself projects have long played an 

important role in renovation, their share of RRP expenditures has decreased over time. The do-it-yourself 

share declined for all but 2 of the 15 years before 1999. 

Age of the Homeowner 

In addition to income, certain age ranges undertake more home improvement work. Households with 

heads between the ages of 35 and 44 take on many more home improvement projects than other age 

ranges. This age range includes families who are more likely to have children living at home and are 

more likely to be active in the housing market. On the other hand, the oldest segments of the population 

spend significantly less on improvements, especially discretionary improvements. Between 1994 and 

2001, 35-44 year olds spent an annual average of $2,270 compared to $1,050 for those 65 and older. 

When considering older homeowners it is important to remember that the baby boomer generation is 

reaching retirement age. This has important implications for the home improvement industry. As the 

population ages, and especially among those over 65, there is a noticeable decline in improvement 

spending. Those over 65 do, however, spend a larger share (over 80 percent) of their improvement 

budget on professional contractors as opposed to do-it-yourself projects. This may cause a future shift in 

the type of service demanded by homeowners. 

Amount of Time Owner Has Resided in the Home 

The amount of time that a family has resided in a home is another strong determinant of demand for home 

improvement. Households spend the most immediately after they move into a home, usually in the first 

two years. In all income brackets, trade-up buyers (those who sold a previous home and bought a new 

one) spent substantially more than first time buyers. First time buyers in turn spent substantially more 

than families that stayed in their homes without moving. Regardless of whether a home is the owner’s 

first or not, improvement spending tends to taper off steadily as the time spent in a home increases. The 

improvement spending cycle for rental properties is slightly different. Rental properties are frequently 

improved during the turnover period after previous renters move out. 
§402(c) Economic Analysis Chapter 2 21 

Changes in Family Composition 

When a change occurs in family composition, such as the birth of a child, households are significantly 

more likely to do home improvement work. Although the demographics of households that have children 

already match those that are doing the majority of home improvement projects, the addition of a family 

member, with all other factors held constant, is a significant determinant of demand for home 

improvement. Households often want to optimize the space within their home and changes frequently 

include the renovation or the addition of bedrooms and bathrooms. Households adding a family member 

are also more likely to take on do-it-yourself projects rather than hiring a professional, typically because 

they are younger and have lower incomes than other households. 

Location of Home 

Geographically, the demand for home improvement has been strong in urban areas. For example, almost 

half of all home improvement spending occurs in the 35 largest metropolitan areas. Recently, as 

metropolitan housing prices have increased quickly, home improvement has become an attractive 

alternative to buying a new home. On the other hand, improvement spending is also shifting to high 

growth suburban areas in the South and West. A sizeable share of the housing stock in these areas is 

nearing the 25-30 year old range when improvement spending is common. 

Minority Spending 

Another factor in the changes in demand for home improvement is the recent growth in minority 

spending. From 1995-2001, minorities accounted for around 60 percent of the total increase in 

households. The largest growth was in the Hispanic community, in which home improvement spending 

increased almost 80 percent in inflation-adjusted terms over the same 1995-2001 period. This was more 

than 3 times the growth of spending for white households. In the future, minority spending is expected to 

continue as one of the largest areas of home improvement growth. 

Interest Rates and Other Financial Factors 

Recent low interest rates and escalating housing prices have sparked a large increase in home equity 

borrowing. The current pace of new construction is slow when compared to the demand for new housing 

and sellers have benefited from resulting price escalation. Thus the housing market has become one of 

the main supporters of consumer spending and the overall economy. The relative rate of construction and 

the increase in borrowing have provided a strong boost to the demand for home improvement. 

The costs and ease of investment in home improvement are sometimes preferred over restructuring of 

debt. In a recent analysis, the Federal Reserve of New York found that households buffer fluctuations in 

year-to-year income with spending on home improvements (Fed of NY 2003). Discretionary projects like 

additions and remodeling are used more frequently than system replacements to buffer against income 

fluctuations. Thus fluctuations in economic growth, as well as the long-term trend, influence the 

decisions of homeowners to spend on discretionary improvements. 

2.3 Market Organization 

The previous sections focused on the supply and demand for renovation services. This section discusses 

the overall market structure of the renovation industry. 

Firms and consumers interact in markets for goods and services. The results of these interactions differ 

depending on the competitive characteristics of the market. Competitive markets are characterized as 

markets with a large number of buyers (e.g., consumers) and sellers (e.g., firms) and relatively 
§402(c) Economic Analysis Chapter 2 22 

homogenous goods. In competitive markets, neither firms nor consumers can influence the price of the 

good by altering their supply or demand decisions. Oligopolistic, monopolistic and monopsonistic 

markets are markets where either firms or consumers have market power and exhibit strategic behavior 

designed to change the price of the good sold. The competitive nature of an industry can be estimated by 

examining the following market characteristics: 

• Number of establishments; 

• Specialization of establishments; 

• Number of consumers; 

• Barriers to entry; 

• Availability of substitutes; and 

• Homogeneity of the good/service. 

The data in Section 2.1 indicate that there is a large number of firms in the renovation industry. Using 

data for the eleven NAICS codes, there are approximately 357,154 establishments with employees in 

construction sectors affected by the RRP rule. Of these establishments, approximately 68 percent have 

annual revenues under $500,000, and only 1.4 percent have revenues of $10 million or more. In addition, 

there are about 1.1 million self-employed contractors in these industries, all of which are, in all 

likelihood, considered small by SBA standards. Given the large number of small establishments, it is 

unlikely that any one firm exhibits substantial market share in the overall market for residential 

renovation services. It is possible in some geographic areas for a small number of firms or a single firm 

to establish a market niche, but overall the market for renovation services appears to be quite competitive 

on the supply side. 

Competition within the renovation industry is enhanced by the relatively low barriers to entry in this 

industry. Much of the work covered by this rule does not require particularly unusual or high levels of 

skills. Renovation work has traditionally attracted recent immigrants because lack of English is not 

important (Farzad 2005). While any training required as part of this rule will increase the skill level, the 

cost of the training is expected to be relatively low. 

There are also a large number of consumers in the industry. As such, no single consumer of renovation 

services is expected to exhibit influence over the price of these services. 

There are three sources of substitutes for renovation services. First, consumers can substitute from one 

contractor to another. Second, consumers can substitute away from professional renovation and into doit-yourself work. Third, consumers can reduce the extent of the project or forgo renovation all together. 

This may occur if they decide to purchase new housing rather than renovate old housing, or if they choose 

to defer maintenance or renovation on their home. Together these sources of substitutes usually result in 

consumers being price sensitive (i.e. a relatively elastic demand with respect to prices). 

Offsetting this are other characteristics of the RRP market. First, some differentiation in RRP services 

does exist. Contractors can provide services at a higher price if they can convince consumers that their 

services are better or distinctly different from their competitors. This is an important factor in 

anticipating the impact of the RRP requirements on contractors. The costs of safely renovating or 

repairing a home are expected to be higher than traditional methods. If the consumer is indifferent 

between safe- or unsafe-lead work practices, then those companies that choose not to safely renovate and 

repair homes may have a competitive advantage in the market due to lower costs. However, if the 

consumer recognizes that higher quality renovation jobs are those jobs completed with lead-safe work 
§402(c) Economic Analysis Chapter 2 23 

practices, then firms may be able to comply with the regulation and charge a higher price. Under such a 

scenario, the consumer’s marginal benefit for an additional unit of safe renovation may be higher than for 

an additional unit of unsafe renovation. The consumer who has a preference for lead-safe work practices 

would choose to do lead-safe renovation as long as the incremental cost of the lead-safe renovation is less 

than the incremental benefit of such a renovation. Because the lead-safe practices, training and 

certification will be required of all firms, it will be easier for firms to increase their prices than it is under 

the current voluntary situation. In addition, the market for RRP services is fragmented and there are 

substantial costs involved in getting prices. Getting bids from various contractors takes time and 

consumers need to compare prices across services that differ along many dimensions. These difficulties 

make it easier for firms to increase their prices to cover the costs for the new requirements. 

The combination of a large number of firms, a large number of consumers, low barriers to entry, and 

available substitutes indicates that the renovation industry is likely to have a relatively high price 

elasticity of supply. The price elasticity of demand, however, maybe small in absolute value. 

2.4 Property Owners & Managers 

Property owners and managers also will be affected by the RRP rule if they choose to perform their own 

RRP projects rather than hire an outside contractor or if their renovation and maintenance costs rise as a 

result of the regulations. 

Property owners and managers may have in-house crews that perform RRP activities. If this is the case, 

then the property owners and managers will directly bear the costs of training and certifying their workers 

as well as the cost of safe work practices. Furthermore, because all firms that perform regulated RRP 

projects will experience an increase in costs due to training of supervisors and workers and the use of safe 

work practices, it is assumed that costs to property owners and managers who hire outside contractors will 

increase. 

2.4.1 Industry Definitions and Characteristics 

Establishments involved in the leasing of apartments and other residential units are classified under 

NAICS 531110 - Lessors of Residential Buildings and Dwellings. This industry, in turn, is divided into 

two sub-sectors, NAICS 5311101—Lessors of Apartment Buildings and NAICS 5311109—Lessors of 

Dwellings Other than Apartment Buildings. According to the 2002 U.S. Economic Census data, together 

these industries include a total of 61,787 establishments that employ 292,405 people (U.S. Census Bureau 

2004b). 

Establishments involved in the management of residential properties are classified under NAICS 

531311—Residential Property Managers. In 2002, this industry included 26,233 establishments that 

employed 289,870 people (U.S. Census Bureau 2004b). Table 2-10 presents summary statistics for the 

businesses in NAICS 531311 as well as NAICS 531110 and its sub-sectors. 
§402(c) Economic Analysis Chapter 2 24 

Table 2-10: Summary Statistics for NAICS 531110, NAICS 5311101 and NAICS 5311109 

NAICS Code and Description Establishments Annual Revenues 

(000) 

Annual Payroll 

(000) Paid Employees 

5311101 - Lessors of Apartment 

Buildings 51,502 $51,708,553 $5,831,398 257,624 

5311109 - Lessors of Dwellings 

other than Apartment Buildings 10,285 $5,263,795 $748,821 34,781 

531311 - Residential property 

managers 26,223 $19,988,344 $8,193,831 289,870 

Total 88,010 $76,960,692 $14,774,050 582,275 

Source: U.S. Census Bureau 2004b

2.4.2 Establishment Size and Industry Environment 

The U.S. Small Business Administration indicates that to qualify for small business status, a firm in 

NAICS 531110 must have annual revenues of less than $6 million, while establishments in NAICS 

531311 must have revenues of less than $1.5 million (U.S. Small Business Administration, 2004). 

Although data on the number of firms by revenue bracket is not yet available from the 2002 U.S. 

Economic Census, average revenues of establishments in these NAICS codes are significantly below the 

small business designation threshold (Table 2-11). 

Table 2-11: Summary Statistics for NAICS 531110, NAICS 5311101 and NAICS 5311109 (Per 

Establishment) 

NAICS Code and Description Average Annual 

Revenues ($) 

Average Annual 

Payroll ($) 

Paid Employees per 

Establishment 

5311101 - Lessors of Apartment 

Buildings $1,004,011 $113,227 5.0 

5311109 - Lessors of dwellings 

other than apartment buildings $511,793 $72,807 3.4 

531311 - Residential property 

managers $762,245 $312,467 11.1 

Source: U.S. Census Bureau 2004b 

In 1997, 98.7 percent of the then 51,572 establishments in the Lessors of Residential Buildings and 

Dwellings sector had annual revenues below $5 million and about 85 percent of the 19,000 

establishments in NAICS 531311 had revenues less than $1 million (U.S. Census Bureau 2000a)11. 

Because 2002 data on the number of establishments by revenue bracket is not yet available, 1997 data 

was used to estimate the percent of establishments in each industry that qualify for small business status. 

Table 2-12 presents the percent of NAICS 531311 and NAICS 531110 establishments that have revenues 

below $1 million and $5 million, respectively. The table also presents the percent of industry revenues 

and employment that can be attributed to these establishments. 

 

11 Includes establishments open year-round only. 
§402(c) Economic Analysis Chapter 2 25 

Table 2-12: Small and Large Establishments as Percent of Industry

NAICS 

Code Description 

Percent of 

Establishments by

Revenue Bracket

Percent of Industry

Revenues by 

Revenue Bracket 

Percent of Industry

Employees by 

Revenue Bracket 

531311 Residential Property Managers 

 Establishments with Revenues < $1 million 85 35 40 

 Establishments with Revenues of $1 million+ 15 65 60 

531110 Lessors of Residential Buildings and Dwellings 

 Establishments with Revenues < $5 million 99 82 86 

 Establishments with Revenues of $5 million+ 1 18 14 

Source: U.S. Economic Census 2000a 

Based on 1997 data over 85 percent of NAICS 531311 establishments, and about 99 percent of NAICS 

53110 establishments have revenues below the small business threshold defined by SBA. In the 

Residential Property Manager industry, these establishments contribute only 35 percent of the revenues, 

and employ only 40 percent of the workforce. The revenue and employment distribution is less skewed 

in the Lessor of Residential Buildings and Dwellings sector. Small establishments in this industry 

contribute about 82 percent of the revenues and employ 86 percent of the workforce (U.S. Census Bureau 

2000a). 

2.4.3 Industry Outlook 

The market for lead-safe renovation activities will depend in part on the state of the rental housing 

market—an increase in rents would provide resources to construct new housing and/or renovate existing 

housing. According to Harvard University’s Joint Center for Housing Studies (JCHS), “rents fell in 9 of 

the 27 metropolitan areas tracked by the federal government [in 2003]. Nationally, real contract and gross 

rents barely increased last year.” The JCHS indicates that both the weak labor market and increased 

home ownership contributed to the softening of the rental market (JCHS 2004). 

At the same time as rents fell, the nation-wide rental vacancy rate increased from 8.9 percent in 2002 to 

9.8 percent in 2003. The vacancy rate was slightly above 10 percent during the first three quarters of 

2004 (U.S. Census Bureau 2004e). None-the-less, the JCHS predicts a strengthening of the rental market 

over the next ten years due to the influx of immigrants and the aging of the “echo baby-boom generation.” 

The strengthening of the market may also come from overall economic growth and a stemming of home 

ownership growth due to rising interest rates and/or house prices (JCHS 2004). 

2.5 Training Providers 

Impacts of the RRP regulations will be felt beyond the construction industry. Certified renovators will 

need accredited training. Both initial and refresher training courses will be required for certified 

renovators. 

2.5.1 Definitions and Industry Characteristics 

It is likely that lead-based paint training courses will be provided by establishments categorized as 

NAICS: Other Technical and Trade Schools. Census defines NAICS 611519 as “establishments 

primarily engaged in offering job or career vocational or technical courses (except cosmetology and 

barber training, aviation and flight training, and apprenticeship training). The curriculums offered by 
§402(c) Economic Analysis Chapter 2 26 

these schools are highly structured and specialized and lead to job-specific certification” and these 

establishments are believed to currently provide training for lead abatement professionals (U.S. Census 

Bureau 2004a). 

According to the 2002 Economic Census, there are a total of 3,323 establishments in the U.S. classified as 

Other Technical and Trade Schools (see Table 2-13). On average, each establishment employs 15.3 

people. A striking characteristic is that about 19 percent of these establishments are exempt from the 

Federal Income Tax (FIT). Exempt establishments include non-profit organizations and educational 

institutions such as colleges or universities (U.S. Census 2004a). 

Table 2-13: Number of Establishments in NAICS 611519 

Industry 

Number of 

Establishments

Total Number of 

Employees 

Average Number of 

Employees 

NAICS 611519 – Other Technical and Trade Schools 3,323 50,709 15.3 

Source: U.S. Census Bureau 2004a

Table 2-14 summarizes available financial information for establishments categorized under NAICS 

611519. These include total revenues for the sector, average annual revenues per establishment, annual 

payroll for the sector, and payroll as percent of revenue. As Table 2-14 indicates, for Other Technical and 

Trade schools, annual payroll is equal to about 35 percent of establishment revenues. 

Table 2-14: Summary Statistics for NAICS 611519 (By Tax Status) 

Industry Number of 

Establishments 

Annual Sector 

Revenue 

(000) 

Average Revenue 

per Establishment

(000) 

Average Payroll 

per Establishment 

(000) 

Labor Cost as 

percent of 

Revenue 

NAICS 611519 – Other 

Technical and Trade 

Schools 

3,323 $ 4,118,995 $1,240 $429 35 

Source: U.S. Census Bureau 2004a 

According to the U.S. Small Business Administration, in order to qualify as a small business, a firm 

categorized under NAICS 611519 must have annual revenues of $6 million or less (U.S. Small Business 

Administration 2004).12 At the time of this report, the 2002 Economic Census did not provide data on the 

number of firms by revenue bracket. In 1997, however, 97 percent of the then 2,459 establishments 

classified as Other Technical and Trade Schools had revenues under $5 million (U.S. Census Bureau 

2000b). This figure indicates that a large percentage of firms had revenues under the $6 million threshold 

and thus qualified for small business status. Per-establishment average revenues for 2002 indicate that a 

large percentage of firms have revenues of less than $6 million per year and would thus qualify for small 

business status. 

2.5.2 Number and Type of Training Establishments 

As mentioned in Section 2.5.1, there are over 3,000 establishments in the Other Technical and Trade 

school industry. It is likely that only a small portion of these establishments are involved in lead 

abatement training. To help characterize the lead training segment of the training provider industry, a 

random sample of firms that offer one or more of the courses required for EPA lead abatement 

 

12 Effective January 28th, 2004. 
§402(c) Economic Analysis Chapter 2 27 

certification were identified. Since it is likely that these firms will also provide certified renovator 

training required by the RRP rule, the findings are briefly discussed in this section. The goal was both to 

collect tuition data for currently offered lead abatement training courses (used to estimate tuition rates for 

certified renovator training; see Chapter 4) and to learn what types of institutions (private establishments, 

non-profits, unions, etc.) offer these classes. 

The sample consisted of 83 establishments selected from the Lead Listing13 directory of 194 training 

providers.14 Data were collected from company web sites (when available) and/or over the phone. 

Information was obtained from 68 training providers; a total of 15 providers could not be reached. Seven 

of the 68 contacted providers no longer offered lead abatement training. 

There were five types of training providers in the sample: private for-profit establishments, non-profit 

establishments, educational institutions, trade unions and public/government training institutions. Trade 

unions provide tuition-free training to their members. Public/government providers train state employees 

and workers who qualify for financial assistance through government programs. They do not offer 

training to the general public. 

Table 2-15 summarizes the number of private establishments, educational institutions, non-profits, unions 

and public/government providers that appeared in the sample. The table also presents the estimated 

national number of providers that fall into each of these categories. More than a third of lead hazard 

reduction training providers are private, for-profit establishments. The next largest group of providers are 

labor unions, followed by educational institutions (colleges and universities). None of the unions, 

however, are certified to offer the Project Designer course. About 13 percent of certified providers either 

do not offer training at this time, or have permanently stopped offering lead courses. 

More than half of the privately owned, for-profit establishments in the sample (19 out of 35) offer 

environmental consulting services in addition to training. Thirteen of the 35 privately-owned providers 

specialize in training and do not offer other services. All of these 13 firms offer both lead and asbestos 

training courses, as well as, in most cases, OSHA safety, HAZ-MAT and/or mold classes. Although there 

was not enough information to determine the services provided by the remaining three companies, these 

findings indicate that lead-based paint training providers generally participate in several lines of business. 

 

13 The Lead Listing (www.leadlisting.org) website was run for the U.S. Department of Housing and Urban 

Development’s Office of Healthy Homes and Lead Hazard Control that contained a directory of lead service 

providers. It is no longer in operation (as of late 2004). 

14 The sample included all the establishments on the list that are certified to offer a Project Designer course (42 

total), as well as a random sample of 41 establishments that are not certified to offer this class. The data were 

weighted by the inversed probability of selection into the sample (P=1 for providers that offer a Project Designer 

course and P=.270 for providers that do not offer this class). It was assumed that there was no non-response bias. 
§402(c) Economic Analysis Chapter 2 28 

Table 2-15: Estimated Number of Training Providers 

National Estimatesa

Type of Provider Number in 

Sample Total Percent 

Private Providers 35 74 38 

Educational Institutions 11 27 14 

Non-Profit 4 19 10 

Union 9 42 22 

Pub/Gov Providers 2 6 3 

No Longer Offer Training 7 26 13 

Total Companies 68 194 

a. Adjusted for non-response assuming no non-response bias and weighted based on the probability 

of selection into the sample. 

Source: EPA Calculations, see Section 4.4 of Chapter 4 
§402(c) Economic Analysis Chapter 2 29 

REFERENCES 

Farzad, Roben. "A Housing Boom Brings Jobs and, Sometimes, Abuse." The New York Times 07 Jul. 

2005. 

Federal Reserve Bank of New York Staff Reports. Gyourko, Joseph and Joseph Tracy. “Using Home 

Maintenance and Repairs to Smooth Variable Earnings” May, 2003. 

Joint Center for Housing Studies of Harvard University. 1999. Improving America’s Housing.

Joint Center for Housing Studies of Harvard University. 2000. “Impact of Changes in Household 

Composition on Home Improvement Decisions.” Working Paper W00-6. 

Joint Center for Housing Studies of Harvard University. 2001. Remodeling Homes for Changing 

Households.

Joint Center for Housing Studies of Harvard University. 2003. Measuring the Benefits of Home 

Remodeling.

Joint Center for Housing Studies (JCHS) at Harvard University. 2004. The State of the Nation’s 

Housing. Available at: http://www.jchs.harvard.edu/publications/markets/son2004.pdf. (January 

21, 2004). 

Joint Center for Housing Studies of Harvard University. 2005. The State of the Nations Housing: 2005. 

U.S. Census Bureau. 2001. North American Industry Classification System - Revisions for 2002. 

Available at: http://www.census.gov/epcd/naics02/ (Accessed 6/30/2005). 

U.S. Census Bureau. 2000a. Establishment and Firm Size (Including Legal Form and Organization). 

1997 Economic Census: Subject Series for Real Estate and Rental and Leasing. Subject Series. 

EC97F53S-SZ. Available at: http://www.census.gov/prod/ec97/97f53-sz.pdf. 

U.S. Census Bureau. 2000b. Establishment and Firm Size (Including Legal Form and Organization). 

1997 Economic Census: Subject Series for Educational Services. Subject Series. EC97S61S-SZ. 

Available at: http://www.census.gov/prod/ec97/97s61-sz.pdf.

U.S. Census Bureau. 2004a. 2002 Economic Census: Industry Series (For NAICS 61). Available at: 

http://www.census.gov/econ/census02/guide/INDSUMM.HTM. (January 12, 2004). 

U.S. Census Bureau. 2004b. “Sector 53: Industry Series: Summary Statistics for the US: 2002.” 

American Fact Finder. Available at: 

http://factfinder.census.gov/servlet/EconSectorServlet?caller=dataset&sv_name=*&_SectorId=53

&ds_name=EC0200A1&_lang=en&_ts=141736463723 (Downloaded 8/3/2005) 

U.S. Census Bureau. 2004e. Housing Vacancy Survey. Available at: 

http://www.census.gov/hhes/www/housing/hvs/annual03/ann03t1.html. (January 21, 2004). 

U.S. Census Bureau. 2005a. “Sector 23: Industry Series: Employment Statistics for Establishments by 

State: 2002.” American Fact Finder. Available at: 

http://factfinder.census.gov/servlet/EconSectorServlet?caller=dataset&sv_name=*&_SectorId=23

&ds_name=EC0200A1&_lang=en&_ts=141735361508 (Downloaded 6/30/2005) 
§402(c) Economic Analysis Chapter 2 30 

U.S. Census Bureau. 2005b. “Sector 23: Industry Series: Detailed Statistics for Establishments: 2002.” 

American Fact Finder. Available at: 

http://factfinder.census.gov/servlet/EconSectorServlet?caller=dataset&sv_name=*&_SectorId=23

&ds_name=EC0200A1&_lang=en&_ts=141735361508 (Downloaded 6/30/2005) 

U.S. Census Bureau. 2005c. “Sector 23: Industry Series: Selected Statistics for Establishments by Value 

of Business Done: 2002.” American Fact Finder. Available at: 

http://factfinder.census.gov/servlet/EconSectorServlet?caller=dataset&sv_name=*&_SectorId=23

&ds_name=EC0200A1&_lang=en&_ts=141735361508 (Downloaded 6/30/2005) 

U.S. Census Bureau. 2005d. “Sector 23: Industry Series: Value of Construction for Establishments by 

Type of Construction: 2002.” American Fact Finder. Available at: 

http://factfinder.census.gov/servlet/EconSectorServlet?caller=dataset&sv_name=*&_SectorId=23

&ds_name=EC0200A1&_lang=en&_ts=141735361508 (Downloaded 6/30/2005) 

U.S. Census Bureau. 2005e. “Sector 23: Construction: Industry Series: Selected Statistics for 

Establishments by Specialization in Types of Construction: 2002.” American Fact Finder. 

Available at: 

http://factfinder.census.gov/servlet/EconSectorServlet?caller=dataset&sv_name=*&_SectorId=23

&ds_name=EC0200A1&_lang=en&_ts=141735361508 (Downloaded 6/30/2005) 

U.S. Census Bureau. 2005f. 2002 Economic Census: Industry Series: Residential Remodelers EC02-

23I-236118 (RV). Available at: http://www.census.gov/prod/ec02/ec0223i236118.pdf (Accessed 

8/3/2005). 

U.S. Census Bureau. 2005i. 2002 Economic Census: Construction: By Industry. Available at: 

http://www.census.gov/econ/census02/data/us/US000_23.HTM (Accessed 8/3/2005). 

U.S. Census Bureau. 2005j. “Number of Establishments: General Definition.” Census Data Information. 

American Fact Finder. Available at: 

http://factfinder.census.gov/servlet/MetadataBrowserServlet?type=dataItem&id=ESTAB&dataset

=EC0223I02&dsspName=ECN_2002&_lang=en (Accessed 8/3/2005). 

U.S. Department of Commerce. 2004a. Current Construction Reports: Expenditures for Residential 

Improvements and Repairs, 2nd Quarter. 

U.S. Department of Commerce. 2004b. Current Construction Reports: Value of Construction Put in 

Place. 

U.S. Department of Commerce. 2005. Real Gross Domestic Product, 3 Decimal. GDP C96. Last 

updated: June 29, 2005.

U.S. Small Business Administration. 2004. “Small Business Size Standards matched to North American 

Industry Classification System.” Available at: http://www.sba.gov/size/sizetable2002.html. 

(January 21, 2004). 

U.S. Small Business Administration. 2005. “Non-Employer Statistics.” Firm Size Data. Available at: 

http://www.sba.gov/advo/research/data.html. (Downloaded 8/3/2005). 
§402(c) Economic Analysis Chapter 3 1 

3. Problem Definition and Regulatory Options 

This chapter begins by characterizing the lead contamination problem to be addressed under the RRP 

regulations. The various sources of exposure, along with related adverse health effects, are presented in 

Section 3.1. This is followed by a discussion of how the market failures of incomplete information and 

external costs have resulted in inefficient levels of lead containment and control in renovation activities. 

Section 3.2 summarizes existing federal, state and local regulations and argues that additional federal 

regulation is a reasonable solution for these market failures. Alternative regulatory options are presented 

in Section 3.3. 

3.1 Lead Contamination Problem 

Despite recent reductions in air, water, and food contamination, important sources of lead exposure 

remain, due largely to the widespread presence of lead-based paint in home environments. Exposure to 

lead results in increased blood lead levels associated with various adverse health effects, including 

reductions in IQ and other negative cognitive effects, particularly in children. In addition, exposure to 

lead can result in a variety of adverse health effects in adults. 

3.1.1 Exposure Sources 

As described in Appendix 5A, lead may cause adverse health effects in any individual, exposed at any 

stage of life (in utero through adulthood) (U.S. EPA 2005c). However, young children are particularly 

susceptible to lead hazards because their central nervous systems are rapidly developing, and because 

their behavior is likely to result in greater exposure than older groups experience. The benefit analysis 

presented in Chapter 5 includes benefits of protecting both adult and child occupants of renovated 

housing units from the resulting lead hazards. 

Currently the most significant high-dose source of lead exposure in children under school age is leadbased paint. Through the 1940's, paint manufacturers used lead as a primary ingredient in many oil-based 

interior and exterior house paints. During the 1950's and 1960's, the usage gradually decreased as new 

paints were developed, and in 1978 the Consumer Product Safety Commission (CPSC) ruled that paint 

used for residences, toys, furniture, and public areas must not contain more than 0.06% lead by weight. 

Nevertheless, about 50 percent of housing units built before 1980 still contain lead-based paint (U.S. 

HUD 2000). Children’s exposure to lead from lead-based paint is likely to be high when the paint is in a 

deteriorated state or is found on accessible, chewable, impact, or friction surfaces, making the lead paint 

available to children who ingest paint chips. This “pica” behavior appears to be rare, but is the likely 

cause of a many of the highest blood lead levels observed in children. Renovation activities can create 

lead-based paint hazards for children by making paint chips more accessible for ingestion. These hazards 

can occur both within and outside the housing unit being renovated. 

In addition to being a source of direct exposure, lead-based paint can be the source of lead contamination 

in soil and dust. Children are exposed to lead from soil or dust in their homes as a result of typical handto-mouth activities. Lead-contaminated dust and soil are thought to be the major pathway through which 

most young children are exposed to lead from lead-based paint hazards. Renovation activities increase 

the level of lead dust in the housing unit and potentially in the soil, thereby increasing the risk of lead 

ingestion in young children. 
§402(c) Economic Analysis Chapter 3 2 

Occupational exposure is the primary exposure pathway to lead for adults. Several occupations put adults 

in direct contact with lead including: plumbing, lead mining, auto repair, glass manufacturing, 

shipbuilding, printing, lead smelting and refining, battery manufacturing, and bridge reconstruction work. 

Other common exposure pathways for teenagers and adults include gardening, housework, drinking water 

and certain hobbies such as creating objects from stained-glass and making pottery. 

Individuals (children, teenagers and adults) are also exposed to a variety of other lead sources, some of 

which are localized in nature. Airborne lead is present in emissions from lead smelters, battery 

manufacturing plants, and solid waste incinerators. The phase-out of leaded gasoline has substantially 

reduced airborne lead. Drinking water may become contaminated with lead after it leaves the treatment 

plant. Although lead levels in drinking water generally do not have a statistically significant effect on 

blood-lead concentrations as a result of the 1986 Safe Drinking Water Act, water is still considered an 

important localized exposure source where lead solder and/or brass plumbing fixtures are present because 

of the high absorption rate of lead in water. Lead exposure through food ingestion has declined greatly in 

importance due to the phase-out of lead-soldered food cans and public education. With these 

improvements in exposure from air, water, and food, lead-based paint remains as the largest wide-spread 

source of lead exposure. 

3.1.2 Health Effects of Lead Exposure 

Most studies of the health effects of lead use body-lead burden as a biomarker for lead exposure. 

Although blood lead level reflects a mixture of recent and past exposure, it has the advantage of being 

easily and inexpensively measured. Other measures of body-lead burden include lead in bones, teeth, and 

hair. Each of these options, however, has disadvantages as measures of lead in the body, including poor 

sensitivity and external surface contamination problems. 

Increased blood lead levels are associated with an assortment of deleterious health effects. See Appendix 

5A for a discussion of the adverse health effects resulting from lead exposure.

EPA exposure data (EPA 1997) indicate that renovation activities potentially increase both short-term and 

long-term lead exposure levels. Lead concentrations are greatest in the area where the renovation work is 

performed, but lead does settle into other areas of the housing unit and potentially the surrounding 

housing units, causing longer-term exposure. The study found that, with the exception of carpet removal 

and drilling into plaster, all renovation activities examined deposited significant amounts of lead onto the 

floors in the area where the work was being performed, ranging from 480 micrograms per square foot for 

sawing to 15,500 micrograms per square foot for paint removal. This lead may be ingested or inhaled by 

occupants if proper containment and clean-up practices are not used. The study found that sweeping and 

shop-vacuum clean-up, considered to be standard practice in the industry, reduced the total amount of 

lead available to occupants. However, as the distance from the activity increased, the cleanup left more of 

the lead behind so that lead hazards remained following cleanup. These findings demonstrate that these 

practices do not adequately reduce risks from lead dust generated by renovation activities. Lead dust 

settled in carpeted areas or in soil is the most difficult to remove with simple broom and vacuum clean-up 

and thereby creates the longest lasting exposure pathway for household occupants. 
§402(c) Economic Analysis Chapter 3 3 

3.2 Justification for Federal Regulations of Lead Exposure during Renovation 

Executive Order 12866 calls for three findings to justify the need for a federal regulation. First, there 

should be a description of the market failure that can be corrected or other social purpose that can be met 

through regulation. Second, there should be n explanation of why the regulation should be carried out at 

the federal level. Finally, there should be a discussion of why current regulatory initiatives are not 

sufficient to correct the market failure. 

3.2.1 Market Failure 

From an economic perspective, a necessary condition for regulations is the existence of an inefficiency in 

the allocation of resources. This inefficiency is commonly labeled a market failure since the market is the 

mechanism assumed to make efficient resource allocations possible. A market failure can come from one 

or more of several sources. These include poorly defined property rights (such as negative externalities, 

common property resources, and public goods); imperfect markets for trading property rights (because of 

a lack of perfect information or of contingent markets; monopoly power; distortionary taxes and subsidies 

and other inappropriate government regulations); and the divergence of private and social discount rates. 

The occurrence of any of these conditions justifies further inquiry into the need for government regulation 

to reduce inefficiencies in the allocation of society’s resources. This section considers whether any of 

these conditions are linked to excess exposures from lead contamination resulting from renovation in 

target housing. If so, understanding the nature of the inefficiencies involved facilitates the design of more 

effective regulations. The specific regulatory approach considered here involves the promulgation of 

certification, training and accreditation requirements for firms that perform renovations that disturb leadbased paint in certain types of housing, as well as the establishment of containment, clean-up and cleaning 

verification practices to be used during regulated renovation projects. 

Economic efficiency suggests that “lead-safe” renovation will occur as long as the property owners’ 

willingness-to-pay for reduced lead risks exceeds the cost of reducing these risks. If the property owners 

are aware of the risks and are aware of the availability and costs of reducing these risks, then arguably 

they will be able to accurately trade off risk and cost without the aid of government regulation. However, 

there are two arguments for why individual households may not trade off risk and cost efficiently. 

Incomplete/Incorrect Information 

The strongest case for the existence of a market failure can be built on the lack of reliable information. 

Correct information is an important prerequisite to the demand for containment and clean-up practices 

that reduce lead exposure during renovation projects. In deciding whether lead-safe work practices or 

well-trained contractors are worth the extra cost, the property owner has to know whether there is lead in 

the work area, what risks are implied by having renovation done in areas with lead-based paint, the 

significance of these risks, what can be accomplished in reducing those risks through specific 

containment and clean-up practices, and how much these practices cost. 

Misinformation can lead to inefficient outcomes. Without knowing there is a lead problem, or how 

renovation might create lead hazards, the owner will have too low a demand for proper work practices 

and may be unwilling to pay additional costs for contractors who voluntarily abide by these containment 

and clean-up standards. Furthermore, a great deal of uncertainty can exist if the consumer is unsure about 

the quality of lead-safe renovation services being purchased and their likely benefits. If consumers do not 
§402(c) Economic Analysis Chapter 3 4 

have any guarantee that the contractor is qualified to identify and control lead-based paint hazards, his/her 

demand for these services is likely to be lower than in the presence of such a guarantee. On the supply 

side, contractors may be unaware of the risks they are creating and/or the methods they can use to reduce 

risks of lead exposure. 

External Costs and Public-Good Characteristics of Lead-Safe Renovation 

Another major cause of market failure stems from the external cost of poorly performed renovation 

projects in housing units with lead-based paint. An efficient outcome is achieved when the marginal 

willingness-to-pay for a service is equivalent to the marginal cost of providing that service. Because the 

use of lead-safe work practices is likely to benefit not only the consumer of the renovation (the head of a 

household, for example) but his/her children, neighbors and/or tenants, lead-safe renovation services are, 

in part, a public good. As such, even with perfect information, the maximum amount that the individual 

consumer of the renovation would be willing to pay for lead-safe work is likely to be lower than the total 

amount that that particular consumer plus the other beneficiaries (including children, neighbors, etc.) 

would be willing-to-pay for the service. Children, for example, cannot testify to their willingness-to-pay 

for risk reduction and thus rely on their parents’ or the property owners’ willingness-to-pay. Similarly, 

neighboring housing units may also experience an increased exposure to lead and may be willing-to-pay 

to reduce or eliminate this exposure but may not be consulted by the property owner making the decision. 

A typical external cost market failure example is that of a landlord’s decision to hire contractors to 

perform renovation in his/her rental units. Contractors that provide lead-safe renovation services are 

likely to charge more for their work than establishments that do not use lead-safe practices. Lead-safe 

work practices may also increase the duration of the project because contractors need to take additional 

steps to prevent the spread of lead dust. Since a landlord pays for the renovation, but not necessarily for 

the consequences of a tenant’s lead exposure, he is faced with powerful short-term incentives (lower cost 

and a faster turn-around) to hire a contractor that does not use lead-safe work practices. Because the 

tenant, and not the landlord (the decision maker in this situation) pays for the consequences lead 

exposure, this scenario is likely to result in a socially inefficient outcome of too little lead-safe renovation 

services provided. 

A similar external cost problem also leads to inefficiencies on the supply side of this market. Renovators 

that use lead-safe work practices incur higher costs than other contractors and contractors are faced with 

the incentives to keep their costs as low as possible. Similar to landlords, contractors may not incur the 

costs of consumer lead exposure resulting from unsafe renovation work. Because the legal/liability system 

is not perfect, the landlord’s and contractor’s financial responsibilities in terms of costs related to 

tenant/customer lead exposure are not clear and consistently enforced. This, in turn, may result in an 

inefficient outcome of either too much or too little lead-safe renovation services, depending on the riskaverseness of the landlord or contractor and his/her understanding of the risks and responsibilities 

involved. Given the other factors confronting landlords and contractors, there is likely to be too little 

lead-safe services. 

Impacts of the Regulation on Demand for Lead-Safe Renovation Services 

The general market failure relationships discussed above are illustrated in Exhibit 3-1 as three markets for 

close substitutes. A consumer’s demand for renovation services is a function of the price of these 

services, the characteristics of the services (e.g., quality, lead safety etc.), and the characteristics of 

consumers. Assume that all renovation services are identical except that some are performed using leadsafe containment and clean-up practices and some are not. Assume for illustration purposes that there is 

only one consumer and one supplier in the market. Of the services that are performed not using these 
§402(c) Economic Analysis Chapter 3 5 

lead-safe practices, some are done by the supplier, while others are do-it-yourself projects performed by 

the consumer. Figure (a) represents the market for lead-safe renovation projects, Figure (b) represents the 

professional market for “standard or non-lead-safe practice” renovation, and Figure (c) represents the doit-yourself market for “standard practice” renovation. In each market, S0 represents the supply of 

renovation services and D0 represents the demand for renovation services in the baseline with incomplete 

information. Note that, moving from left to right, each supply curve is lower than the prior one, 

corresponding to the lower cost in terms of materials and time combined. The area under the demand 

curve in each market represents the consumer’s willingness-to-pay for renovation services. 
§402(c) Economic Analysis Chapter 3 6 

Exhibit 3-1: Impact of Proposed Regulation on Markets for 

Renovation/Remodeling Services 

The proposed regulatory options alter the nature of these three markets by providing information to the 

consumer and contractor about the risk associated with lead-based paint renovation activities and by 

requiring lead-safe containment and clean-up practices for professional projects. EPA’s §406(b) 

regulations already require that compensated renovators distribute a lead awareness pamphlet to owners 

and occupants of most pre-1978 target housing before beginning renovations. The proposed RRP rule 

builds on §406(b) by providing additional information to the consumer that will help to establish a more 

structured market for lead-safe renovation services. As discussed earlier in this section, prior to the rule, 

consumers of renovation services had no guarantee that a contractor who claimed to provide lead-safe 

renovation services would actually perform the project in a lead-safe manner. The implementation of 

work practice standards and training/certification requirements is likely to increase consumer confidence 

in the quality of the work provided by certified contractors, increasing their willingness-to-pay for these 

services. 

EPA’s targeted outreach program is also likely to increase demand for lead-safe renovation services by 

raising consumer awareness about the dangers of unsafe work. Although contractors that currently 

provide well-trained staff and perform lead-safe work practices are expected to find it in their vested 

interest to provide the kinds of information cited above, this possibility has not closed the information 

gaps for the public. One impediment may be public uncertainty about the reliability of information that 

contractors themselves provide. Their information may be considered unreliable because they are not 

fully competent to assess the lead contamination and what needs to be done, because the businesses are 

subject to moral hazard (which occurs, for example, when a firm tells a homeowner that there is a lead 

problem that warrants certain practices at an additional cost), or both. Since many property owners may 

lack easy access to independent sources of information to motivate their decisions, doing nothing may be 

the likely response. When provided with reliable information, however, consumers are likely to avoid the 

dangers posed by unsafe renovation and hire a qualified contractor to perform the work in a lead-safe 

manner. 

The increased demand discussed above is shown by an upward shift of the demand curve in Figure (a) 

from D0 to D1 and an associated increase in price. Simultaneously, the demand for “standard practice” 

S0

D1

Work Practices

Figure (b) Professional Market with 

“Standard” Work Practices

QLead-Safe QStandard Professional

PLead-Safe PStandard Professional

D0

S0

Q Standard Do-it-yourself

?

Figure (c) Do-it-Yourself Market with

“Standard” Work Practices

P0

PStandard Do -it-yourself

D0

S1

D0

D1

S0

S1

Q0 Q1

P0

P1

Q0

P0

P1

Figure (a) Market with Lead-Safe 

Q1 Q0

S0

D1

Work Practices

Figure (b) Professional Market with 

“Standard” Work Practices

QLead-Safe QStandard Professional

PLead-Safe PStandard Professional

D0

S0

Q Standard Do-it-yourself

?

Figure (c) Do-it-Yourself Market with

“Standard” Work Practices

P0

PStandard Do -it-yourself

D0

S1

D0

D1

S0

S1

Q0 Q1

P0

P1

Q0

P0

P1

Figure (a) Market with Lead-Safe 

Q1 Q0
§402(c) Economic Analysis Chapter 3 7 

renovation services decreases with an associated decrease in price. Given scarce resources for 

enforcement, it is expected that some “standard practice” professional work will continue, even in homes 

where there is the potential for lead exposure. The effect of the regulation on the do-it-yourself market is 

ambiguous. Some households that might have hired a professional to perform “standard practice” 

renovation work in the baseline may decide to perform this work themselves rather than pay the 

additional costs for lead-safe work practices. This would increase demand in Figure (c). However, some 

households that would have performed do-it-yourself “standard practice” renovation in the baseline may 

decide to either forgo renovation altogether or hire a lead-safe professional rather than incur the risk of 

lead exposure, thus reducing do-it-yourself demand. 

Impacts of the Regulation on the Supply of Lead-Safe Renovation Services 

The proposed regulation will increase both the costs of supplying lead-safe services and standard services. 

In Figures (a) and (b), S1 represents the supply of services with the proposed regulations. A contractor 

that already uses lead-safe practices will also incur the costs of training, certification and cleaning 

verification. A contractor that continues to provide standard (not lead-safe) renovation services will have 

higher costs of operation due to potential enforcement actions, and potentially higher liability. The 

relative size of the shifts in the two submarkets will affect the final changes in quantity and price of both 

lead-safe and standard renovation services. 

The net impact on the quantity of renovation projects performed is also ambiguous. If all households are 

willing to pay the full amount for lead-safe work practices, then the total quantity performed across all 

three markets will remain constant but the average price will rise. However, if some households are not 

willing to pay for the risk reduction they may chose to forgo renovation services altogether, resulting in a 

net decline in renovation services provided after regulation.1

Conclusions

As demonstrated in this review, due to the lack of perfect information and the existence of externalities, 

the quantity of lead-safe RRP services currently provided is likely to be inefficiently low. The results of 

the market failures discussed in this review are significant in both qualitative and quantitative terms. 

Childhood lead exposure continues to be a major public health problem among young children in the 

United States. During 1999 through 2002, approximately 310,000 children aged 1 to 5 years , had bloodlead levels greater than 10 μg/dL, despite the removal of lead from gasoline and the banning of lead-based 

paint in 1978 (CDC 2005). Most children with blood-lead levels in excess of CDC’s current level of 

concern have been exposed to lead in non-intact paint, interior settled dust, and dust and soil in and 

around deteriorating older housing. According to the Center for Disease Control (CDC), “renovation and 

remodeling activities that disturb lead-based paint can create substantial amounts of lead dust in the 

home; such dust can then be inhaled or ingested by children” (CDC 1997). An insufficient number of 

lead-based paint interventions have occurred to remove the dangers posed by uncontrolled renovation 

activities; renovation activity thus continues to pose a significant risk of lead exposure. 

3.2.2 Justification for Regulation at the Federal Level 

In the Residential Lead-Based Hazard Reduction Act of 1992 (Title X), the United States Congress stated 

that the elimination of lead-based paint hazards was a national goal. Congress found that the Federal 

 

1 The amount by which price and quantity change in each of these markets is a function of both the amount by 

which the supply and/or demand functions shift and the relative elasticities of the two functions. See Appendix 3A 

for a discussion of how these factors affect the price of renovation services and the quantity provided by the market. 

Appendix 3B presents price elasticity estimates for construction and RRP.
§402(c) Economic Analysis Chapter 3 8 

Government must take a leadership role in building the required infrastructure, including an informed 

public, State and local delivery systems, certified inspectors, contractors, and laboratories, and trained 

workers (§1002(8)). The proposed rule under the authority of §402(c) helps the Federal Government 

achieve these objectives by establishing training, certification and accreditation requirements plus 

containment and clean-up standards for renovation work. 

As written by Congress, various sections of Title X address different parts of the imperfect information 

problem. By setting hazard standards, §403 helps consumers identify situations that subject them to risk. 

Without this information, consumers are more likely to not value an intervention properly. They may 

either underestimate or overestimate its value. Hazard standards provide necessary, although not 

sufficient, information for making an informed choice. In addition, the consumer needs information on 

the cost and effectiveness of the various lead hazard control options available (e.g. removal of lead-based 

paint or lead contaminated soil, encapsulation of lead-based paint, dust clean-up). This information need 

is addressed by the RRP rule, which assures that trained and certified personnel are qualified to identify 

and control lead-based paint hazards, including hazards resulting from renovation activities. In addition, 

§1018 and §406 provide information about lead-based paint hazards to the population in general and in 

particular at the time of property transactions and prior to compensated renovations. Finally, the RRP 

rule reduces transaction costs by assuring consumers that the information provided to them about their 

particular situation will be accurate and complete. The RRP rule addresses a special case – renovation

activities that may disturb lead-based paint and thus expose the workers, occupants and potentially their 

neighbors to lead. 

Lead hazards are found in residences in all parts of the nation, and renovation activities which disturb 

lead-based paint will likely create lead hazards. Federal regulations can promote cost savings by 

encouraging coordination among jurisdictions with resulting economies of scale. For example, training 

and certification costs are reduced where states share the same requirements and provide for certification 

reciprocity. Federal regulations also promote partnerships in developing the most cost-effective ways to 

address lead-paint hazards. Establishing training, certification and accreditation requirements, as well as 

containment and clean-up standards, at the federal level does not preempt states from addressing needs 

peculiar to their situation. States are granted the power to administer and implement the federal 

guidelines and are encouraged to do so. It is the Agency’s belief that states and localities are in a better 

position to determine how the hazard standards are used and how to adapt their implementation to local 

circumstances. In addition, states have the option of imposing requirements that are more stringent than 

the federal procedures. 
§402(c) Economic Analysis Chapter 3 9 

3.2.3 Regulatory Background 

This section outlines the extensive history of lead-based paint regulations at the federal, state and local 

levels and shows that current regulations are not sufficient to correct the market failure outlined in Section 

3.2.1. While these regulations cover a wide-range of lead-related issues, no single regulation, nor 

combination of regulations, adequately closes the information gap for lead exposure from renovation 

projects. 

The Federal Lead-based Paint Program. 

Title X and the Federal goal 

Primarily in response to the persistent health threat posed by lead-based paint, in 1992 Congress enacted 

Title X. Congress found that low-level lead poisoning was widespread among American children, 

affecting, at that time, as many as 3,000,000 children under age 6; that the ingestion of household dust 

containing lead from deteriorating or abraded lead-based paint was the most common cause of lead 

poisoning in children; and that the health and development of children living in as many as 3,800,000 

American homes was endangered by chipping or peeling lead paint, or excessive amounts of leadcontaminated dust in their homes. Congress determined that the prior Federal response to this crisis was 

insufficient and established, in Title X, a national goal of eliminating lead-based paint hazards in housing 

as expeditiously as possible. Congress decided that the Federal government would take a leadership role 

in building the infrastructure necessary to achieve this goal. 

The stated purposes of Title X are:

• To develop a national strategy to build the infrastructure necessary to eliminate lead-based paint 

hazards in all housing as expeditiously as possible. 

• To reorient the national approach to the presence of lead-based paint in housing to implement, on 

a priority basis, a broad program to evaluate and reduce lead-based paint hazards in the Nation’s 

housing stock. 

• To encourage effective action to prevent childhood lead poisoning by establishing a workable 

framework for lead-based paint hazard evaluation and reduction and by ending the current 

confusion over reasonable standards of care. 

• To ensure that the existence of lead-based paint hazards is taken into account in the development 

of Government housing policies and in the sale, rental, and renovation of homes and apartments. 

• To mobilize national resources expeditiously, through a partnership among all levels of 

government and the private sector, to develop the most promising, cost-effective methods for 

evaluating and reducing lead-based paint hazards. 

• To reduce the threat of childhood lead poisoning in housing owned, assisted, or transferred by the 

Federal Government. 

• To educate the public concerning the hazards and sources of lead-based paint poisoning and steps 

to reduce and eliminate such hazards (Residential Lead-Based Paint Hazard Reduction Act of 

1992). 

To accomplish this ambitious goal, a number of agencies were assigned specific responsibilities under 

Title X, including HUD, CDC, OSHA, the National Institute for Occupational Safety and Health 

(NIOSH), and EPA. 
§402(c) Economic Analysis Chapter 3 10 

The elimination of lead-based paint hazards in the nation’s housing remains an important goal for the 

Federal government. In 1997, President Clinton created the President’s Task Force on Environmental 

Health Risks and Safety Risks to Children in response to increased awareness that children face 

disproportionate risks from environmental health and safety hazards. Co-chaired by the Secretary of HHS 

and the Administrator of the EPA, the Task Force consisted of representatives from 16 Federal 

departments and agencies. The Task Force set a Federal goal of eliminating childhood lead poisoning by 

the year 2010. This proposed rule is an important component of the Federal strategy for achieving this 

goal. In October 2001, President Bush extended the work of the Task Force for an additional 18 months 

beyond its original charter (President’s Task Force on Environmental Health Risks and Safety Risks to 

Children 2000). Reducing lead poisoning in children was the Task Force’s top priority. 

Childhood lead exposure continues to be a major public health problem among young children in the 

United States. Most children with blood lead levels in excess of CDC’s current level of concern have 

been exposed to lead in non-intact paint, interior settled dust, and dust and soil in and around 

deteriorating older housing (CDC 2004). The nature and extent of the problems associated with 

residential lead-based paint have been thoroughly investigated. Approximately 40% of all U.S. housing 

units (about 38 million homes) have some lead-based paint. Use of leadsafe work practices during 

renovation can advance the goal of primary prevention of lead poisoning (CDC 2004). 

EPA’s lead-based paint program 

Under Title X, EPA is directed to take actions that can be divided into 4 key categories: 

• Establishing a training and certification program for persons engaged in lead-based paint 

activities, accrediting training providers, establishing work practice standards for the safe, 

reliable, and effective identification and elimination of lead-based paint hazards, and developing a 

program to address exposure to lead-based paint hazards from renovation and remodeling 

activities. 

• Ensuring that, for most housing constructed before 1978, lead-based paint information flows from 

sellers to purchasers, from landlords to tenants, and from renovators to owners and occupants. 

• Establishing standards for identifying dangerous levels of lead in paint, dust and soil. 

• Providing information on lead hazards to the public, including steps that people can take to 

protect themselves and their families from lead-based paint hazards. Each of these categories is 

discussed in more detail in the following sections.

a. Training and certification, accreditation, and work practice standards. Title X added a new title to 

TSCA entitled ‘‘Title IV Lead Exposure Reduction.’’ Most of EPA’s responsibilities for addressing leadbased paint hazards can be found in this title, with section 402 being one source of the rulemaking 

authority to carry out these responsibilities. TSCA section 402(a) directs EPA to promulgate regulations 

covering lead-based paint activities to ensure persons performing these activities are properly trained, that 

training programs are accredited, and that contractors performing these activities are certified. These 

regulations must contain standards for performing lead-based paint activities, taking into account 

reliability, effectiveness, and safety. 

On August 29, 1996, EPA promulgated final regulations under TSCA section 402(a) governing leadbased paint inspections, lead hazard screens, risk assessments, and abatements in target housing (U.S. 

EPA 1996). TSCA section 401 defines ‘‘target housing’’ as any housing constructed prior to 1978, 

except housing for the elderly or persons with disabilities (unless any child who is less than 6 years of age 

resides or is expected to reside in such housing for the elderly or persons with disabilities) or any 0-
§402(c) Economic Analysis Chapter 3 11 

bedroom dwelling. These regulations also apply to ‘‘child-occupied facilities,’’ which are defined at 40 

CFR 745.223 as buildings constructed before 1978, or portions of such buildings, where children under 

age 6 are regularly present. TSCA section 402 defines lead-based paint activities in target housing as 

inspections, risk assessments and abatements. The 1996 regulations cover lead-based paint activities in 

target housing and child-occupied facilities, along with limited screening activities called lead hazard 

screens. The regulations also established an accreditation program for training providers and a 

certification program for individuals and firms performing these activities. Training providers who wish 

to provide lead-based paint training for the purposes of the Federal lead-based paint program must be 

accredited by EPA. Implementing regulations at 40 CFR 745.225 describe in detail the requirements for 

each course of study, how training programs must be operated, and the process for obtaining 

accreditation. Training programs must have a training manager with experience or education in a 

construction or environmental field, and a principal instructor with experience or education in a related 

field and education or experience in teaching adults. Training programs must also have adequate facilities 

and equipment for delivering the training. To become accredited, an application for accreditation must be 

submitted to EPA on behalf of the training program. The application must either include the course 

materials and syllabus, or a statement that EPA model materials or materials approved by an authorized 

State or Tribe will be used. The application must also include a description of the facilities and equipment 

that will be used, a copy of the test blueprint for each course, a description of the activities and procedures 

that will be used during the hands-on skills portion of each course, a copy of the quality control plan, and 

the correct amount of fees. If EPA finds that the program meets the regulatory requirements, it will 

accredit the training program for 4 years. To maintain accreditation, the training program must submit an 

application and the correct amount of fees every 4 years. 

Individuals and firms that perform inspections, lead hazard screens, risk assessments, or abatements in 

target housing or child-occupied facilities must be certified. Certification requirements and the process for 

becoming certified are described in 40 CFR 745.226. A firm that wishes to become certified must submit 

an application, along with the correct amount of fees, attesting that it will use only certified individuals to 

perform lead-based paint activities and that it will follow the work practice standards in 40 CFR 745.227. 

An individual who wishes to become certified must take an accredited training course in at least one of 

the certified disciplines: Inspector, risk assessor, project designer, abatement worker, and abatement 

supervisor. The risk assessor, project designer, and abatement supervisor disciplines have additional 

requirements for education or experience in a construction or environmental field. The inspector, risk 

assessor, and abatement supervisor disciplines also require the applicant to pass a certification 

examination administered by a third party. 

The regulations at 40 CFR part 745, subpart L, also contain work practice standards for performing 

inspections, lead hazard screens, risk assessments and abatements in target housing and child-occupied 

facilities. The regulations contain specific requirements for conducting paint sampling during an 

inspection and specify information that must be gathered and samples that must be taken as part of a lead 

hazard screen or risk assessment. The requirements for abatements are also set forth in the regulations. 

When conducting abatements, an occupant protection plan must be prepared by a certified supervisor or 

project designer; certain work practices such as open-flame burning, machine sanding or abrasive blasting 

without high-efficiency exhaust control, dry scraping, and heat guns at high settings are prohibited; and a 

visual inspection and dust clearance sampling must be performed after the abatement is finished to ensure 

that the area is ready for re-occupancy. Any samples collected during any of these regulated lead-based 

paint activities must be analyzed by a laboratory recognized by EPA as being capable of analyzing paint 

chips, dust, and soil for lead. Requirements for inspection, lead hazard screen, risk assessment or 

abatement reports are also described in this section. 
§402(c) Economic Analysis Chapter 3 12 

Recognizing the importance of States and Territories in achieving the goal of eliminating lead-based paint 

hazards in housing, Congress specifically directed EPA to establish a model State program and a process 

for authorizing States to operate such programs in lieu of the Federal program. Concurrently with the 

subpart L rulemaking in 1996, EPA codified, at 40 CFR part 745, subpart Q, a model training and 

certification program and a process for enabling States, Territories, and Tribes to apply for authorization 

to administer their own lead-based paint activity programs. Providing Indian Tribes with this opportunity 

is consistent with EPA’s Policy for the Administration of Environmental Programs on Indian 

Reservations (U.S. EPA 1984). EPA also provides grants under TSCA section 404 to States, Territories, 

and Tribes to assist them in developing and administering these programs, as well as programs 

implementing TSCA section 406(b), discussed in this Unit. On June 9, 1999, the subpart L regulations 

were amended to include a fee schedule for training programs seeking EPA accreditation and for 

individuals and firms seeking EPA certification (U.S. EPA 1999). These fees were established as directed 

by TSCA section 402(a)(3), which requires EPA to recover the cost of administering and enforcing the 

lead-based paint activities requirements in unauthorized States. The most recent amendment to the subpart 

L regulations occurred on April 8, 2004, when notification requirements were added to help EPA monitor 

compliance with the training and certification provisions and the abatement work practice standards (U.S. 

EPA 2004a). 

As of December 2005, 44 programs comprised of 39 States, 3 Tribes, Puerto Rico, and the District of 

Columbia were authorized to administer lead-based paint activity programs. In the remaining 

jurisdictions, where EPA is responsible for administering the subpart L regulations, there were 

approximately 55 accredited training course providers, 1,300 certified firms, 500 certified inspectors, 

1,400 certified risk assessors, 60 certified project designers, 1,000 certified abatement supervisors, and 

2,800 certified abatement workers. EPA believes that, in most areas of the country, there is an adequate 

supply of accredited courses and certified firms and individuals available to meet the demand for 

leadbased paint services. This is a significant part of the national infrastructure necessary to achieve the 

goal of eliminating lead-based paint hazards in housing. 

In addition, Congress directed EPA, in TSCA section 405, to establish protocols, criteria, and minimum 

performance standards for analysis of lead in paint, dust, and soil. TSCA section 405 further directed 

EPA, in consultation with HHS, to develop a program to certify qualified laboratories. The National Lead 

Laboratory Accreditation Program (NLLAP) provides the public with a list of laboratories that have met 

EPA requirements and demonstrated the capability to accurately analyze paint chip, dust, or soil samples 

for lead. All laboratories recognized by NLLAP must pass on-site audits conducted by one of the two 

accrediting organizations currently participating in NLLAP, the American Industrial Hygiene Association 

(AIHA), and the American Association for Laboratory Accreditation. Recognized laboratories must also 

perform successfully on a continuing basis in the Environmental Lead Proficiency Analytical Testing 

(ELPAT) Program established by NIOSH, AIHA, and EPA. 

b. Lead-based paint information for purchasers, renters, owners, and occupants of target housing. 

Another of EPA’s responsibilities under Title X is to require that purchasers and tenants of target housing 

and occupants of target housing undergoing renovation are provided information on lead-based paint and 

lead-based paint hazards. As directed by TSCA section 406(a), CPSC, HUD, and EPA, in consultation 

with CDC, jointly developed a lead hazard information pamphlet entitled ‘‘Protect Your Family From 

Lead in Your Home’’ (‘‘PYF’’) (U.S. EPA et al 2003). The availability of this pamphlet was announced 

on August 1, 1995 (U.S. EPA 1995). This pamphlet was designed to be distributed as part of the 

disclosure requirements of section 1018 of Title X and TSCA section 406(b), to provide home purchasers, 
§402(c) Economic Analysis Chapter 3 13 

renters, owners, and occupants with the information necessary to allow them to make informed choices 

when selecting housing to buy or rent, or deciding on home renovation projects. The pamphlet contains 

information on the health effects of lead, how exposure can occur, and steps that can be taken to reduce or 

eliminate the risk of exposure during various activities in the home. 

Pursuant to the authority provided in section 1018 of Title X, on March 6, 1996, HUD and EPA jointly 

promulgated regulations requiring persons who are selling or leasing target housing to provide the PYF 

pamphlet and information on known lead-based paint and lead-based paint hazards in the housing to 

purchasers and renters (HUD and U.S. EPA 1996). These joint regulations, codified at 24 CFR part 35, 

subpart A, and 40 CFR part 745, subpart F, describe in detail the information that must be provided 

before the contract or lease is signed and require that sellers, landlords, and agents document compliance 

with the disclosure requirements in the contract to sell or lease the property. Title X does not provide for 

these requirements to be administered by States or Tribes in lieu of the Federal regulations. Therefore, 

HUD and EPA are responsible for administering and enforcing these disclosure obligations. 

TSCA section 406(b) directs EPA to promulgate regulations requiring persons who perform home 

renovations for compensation to provide a lead hazard information pamphlet to owners and occupants of 

target housing being renovated. These regulations, promulgated on June 1, 1998, are codified at 40 CFR 

part 745, subpart E (U.S. EPA 1998). The term ‘‘renovation’’ is defined, at 40 CFR 745.83, as the 

modification of any existing structure, or portion of a structure, that results in the disturbance of painted 

surfaces. Lead-based paint abatement projects are specifically excluded, as are small projects that disturb 

2 square feet (ft2) or less of painted surfaces, emergency projects, and renovations affecting components 

that have been found to be free of lead-based paint, as that term is defined in the regulations, by a 

certified inspector or risk assessor. Like the regulations regarding disclosure during sales or leases, these 

regulations require the renovation firm to document compliance with the requirement to provide the 

owner and the occupant with the PYF pamphlet. One important difference from the disclosure 

requirements in section 1018 of Title X is that TSCA section 404 allows States to apply for, and receive 

authorization to administer, the TSCA section 406(b) requirements. Two States are currently authorized 

to operate this program.

c. Standards for lead in paint, dust, and soil. Another responsibility assigned to EPA by Title X is the 

development of standards for identifying dangerous levels of lead in paint, dust and soil. These standards, 

promulgated pursuant to TSCA section 403 on January 5, 2001 and codified at 40 CFR part 745, subpart 

D, provide various Federal agencies, including HUD, and State, local and Tribal governments with 

uniform benchmarks on which to base decisions on remedial actions to safeguard children and the public 

from lead-based paint hazards (U.S. EPA 2001b). These standards also allow certified inspectors and risk 

assessors to easily determine whether a particular situation presents a lead-based paint hazard and whether 

to recommend remedial actions such as lead-based paint abatement, cleaning of dust, or removal of soil. 

The standards define lead-based paint hazards in target housing and child-occupied facilities as paint-lead, 

dust-lead, and soil-lead hazards. A paint-lead hazard is defined as any damaged or deteriorated lead-based 

paint, any chewable lead-based painted surface with evidence of teeth marks, or any lead-based paint on a 

friction surface if lead dust levels underneath the friction surface exceed the dust-lead hazard standards. A 

dust-lead hazard is surface dust that contains a mass-per-area concentration of lead equal to or exceeding 

40 micrograms per square foot (μg/ft2) on floors or 250 μg/ft2 on interior window sills based on wipe 

samples. A soil-lead hazard is bare soil that contains total lead equal to or exceeding 400 parts per million 

(μg/ g) in a play area or average of 1,200 parts per million of bare soil in the rest of the yard based on soil 

samples. 
§402(c) Economic Analysis Chapter 3 14 

d. Public outreach and education. Among other things, TSCA section 405(d) directs EPA, along with 

the Agency for Toxic Substances and Disease Registry (ATSDR) and HUD, to sponsor public education 

and outreach activities to increase public awareness of the health effects of lead, the potential for 

exposures, the importance of screening children for elevated blood lead levels, and measures that can be 

taken to reduce or eliminate lead-based paint hazards. Accordingly, EPA has worked to provide the public 

with information and increase public awareness of such matters. To date, these activities have included 

web site management, development of public outreach strategies, development of partnership agreements, 

distribution of materials, participation in national conferences and exhibits, and developing hazard 

information documents (and other media, such as videos), as necessary to implement Title X. EPA has 

collaborated closely with other Federal agencies and its State, Tribal, and local government partners in 

developing outreach campaigns targeted for the Women, Infants and Children (WIC) program, Little 

League Baseball, and Spanish-speaking populations. Recently, EPA worked with the National Head Start 

Association to develop a lead poisoning prevention campaign entitled ‘‘Give Your Child a Chance of a 

Lifetime.’’ The campaign consisted of a number of lead awareness documents, including a brochure for 

parents, fact sheets for Head Start staff, and a curriculum for Head Start teachers. Lead awareness 

outreach materials were provided to Head Start Centers in New York, Chicago, Philadelphia, Houston, 

and Los Angeles. The material was also distributed at the National Head Start Association Training 

Conferences. EPA has also been involved in developing model tool kits of various educational tools to 

provide to partners, such as slogans and graphic materials for public buses, trains, and mass transit 

stations. 

EPA has used its authority under TSCA section 10 to award grants to Tribes to support Tribal educational 

outreach and to conduct baseline assessments of Tribal children’s existing and potential exposure to lead. 

In fiscal year 2005, EPA began a new targeted grant program aimed at reducing the incidence of 

childhood lead poisoning in vulnerable populations (U.S. EPA 2004b). These grants are providing 

funding for proven or innovative programs in areas with high rates of childhood lead poisoning, and in 

areas where rates are unknown but other conditions suggest high rates may exist. 

TSCA section 405(e) further directs EPA to establish, in connection with HUD, CDC, other Federal 

agencies, and State and local governments, a clearinghouse for information on lead-based paint and a 

hotline for the public to use for questions and requests for information on lead-based paint. This 

clearinghouse, the National Lead Information Center, handles approximately 50,000 calls per year, and 

disseminates up to 500,000 documents per year to the public. 

Lead-based paint programs at other Federal agencies 

In addition to EPA, other Federal agencies have important roles in achieving the goals of reducing or 

eliminating lead-based paint hazards in housing, as well as the national goal of eliminating childhood lead 

poisoning by 2010. Other agencies specifically assigned tasks in Title X include HUD, CDC, and OSHA. 

The Federal agencies have long realized that they must work together to develop and implement Federal 

strategies for addressing lead-based paint hazards in order to be efficient and effective. In 1989, HUD and 

EPA formed an inter-agency task force to work through issues associated with lead-based paint 

abatement. The Federal Interagency Lead Based Paint Task Force has remained active throughout the 

years and continues to meet on a quarterly basis. Participating agencies include the Department of 

Defense, the Veterans Administration, the National Institute of Standards and Technology (NIST), the 

U.S. Public Health Service, the National Aeronautics and Space Administration (NASA), the United 

States Department of Agriculture (USDA), the Government Accountability Office (GAO), the National 
§402(c) Economic Analysis Chapter 3 15 

Institute for Environmental Health Sciences (NIEHS), ATSDR, CDC, CPSC, NIOSH, OSHA, HUD, and 

EPA. This Task Force serves as an important forum for coordinating the strategic plans of the Federal 

agencies who have responsibilities under Title X or who have responsibilities for maintaining and 

disposing of property that may contain lead-based paint. 

Title X assigned certain responsibilities to HUD. One of HUD’s functions is the administration of the 

Lead-Based Paint Hazard Control Grant Program established by the Act. This program provides grants of 

$1 million to $3 million to State and local governments for control of lead-based paint hazards in 

privately-owned, low-income owner-occupied and rental housing that is not receiving federal assistance. 

These grants are also designed to stimulate the development of a trained and certified hazard evaluation 

and control industry. Evaluation and hazard control work funded by the program must be conducted by 

either contractors who are certified by EPA or an EPA-approved State or Tribal program, or by 

contractors trained in lead-safe work practices, in the case of interim controls. Through these 

requirements, HUD hopes to create infrastructure that will last beyond the life of the grant. In awarding 

grants, HUD promotes the use of cost-effective approaches to hazard control that can be replicated across 

the nation. Since 1993, approximately $971 million has been awarded to over 200 local and State 

jurisdictions across the country. The work approved to date will lead to the control of lead-based paint 

hazards in more than 70,000 homes where young children reside or are expected to reside. Other HUD 

lead grant programs include the Lead Hazard Reduction Demonstration program, the Lead Elimination 

Action Program (LEAP), the Lead Outreach program and the Lead Technical Studies program. 

HUD was also given regulatory authority over some aspects of leadbased paint hazard control. As noted 

previously, on March 6, 1996, HUD and EPA jointly promulgated regulations requiring the disclosure of 

lead-based paint information during sale or lease transactions involving target housing. The HUD 

disclosure regulations are codified at 24 CFR part 35, subpart A. Subparts B through R of 24 CFR part 35 

are known as the ‘‘Lead Safe Housing Rule,’’ initially promulgated on September 15, 1999, and updated 

in June 2004 (HUD 2004b). This rule was designed to protect young children from lead-based paint 

hazards in target housing that is being sold by the Federal government or receives financial assistance 

from the government. The requirements generally depend upon the level of assistance being provided, 

and may include such things as inspections, risk assessments, abatement, paint stabilization, or interim 

controls, which are temporary measures to reduce potential exposure to lead-based paint hazards. The 

emphasis is on reducing lead-based paint hazards, so, after paint is disturbed, a visual assessment for 

surface dust, debris, and residue and dust clearance testing is required to ensure that no dust lead hazards 

were created or left in the work area or, for rehabilitation projects of moderate or substantial scope, in the 

entire housing unit. More information on the Lead Safe Housing Rule is available on the HUD website at 

http:/ /www.hud.gov/offices/lead/leadsaferule/index.cfm or by calling (202) 755–1785, extension 104. 

Section 1017 of Title X required HUD to issue ‘‘guidelines for the conduct of federally supported work 

involving risk assessments, inspections, interim controls, and abatement of lead-based paint hazards.’’ In 

response to this directive, HUD completed the Guidelines for the Evaluation and Control of Lead-Based 

Paint Hazards in Housing (Guidelines), in June 1995 (HUD 1995). The Guidelines provide detailed, 

comprehensive, technical information on how to identify lead-based paint hazards in housing and how to 

control such hazards safely and efficiently. 

Other core activities of HUD’s lead-based paint program include providing technical assistance to 

housing authorities, nonprofit housing providers, local and State agencies, other Federal agencies, 

housing developers, inspectors, real estate professionals, contractors and financiers, and public health 

authorities; evaluating the hazard reduction methods used in the grant program to measure their 
§402(c) Economic Analysis Chapter 3 16 

effectiveness, cost and safety; and maintaining a community outreach program in coordination with the 

other Federal agencies involved in lead-based paint hazard reduction. 

CDC also provides significant funding for the prevention of childhood lead poisoning. CDC provides 

funding to support State, city and county programs in the areas of primary prevention, case management 

and screening, surveillance, strategic partnerships, and program evaluation. Since 2002, CDC has 

recommended that a blood lead level of 10 micrograms per deciliter (μg/dL) be used as a threshold for 

individual intervention (CDC 2002). Additional CDC recommendations address the type and intensity of 

individual intervention strategies that should be undertaken, depending upon the child’s blood lead level. 

These strategies range from nutritional and educational interventions, along with more frequent testing, 

for a child with a blood lead level of 10–14 μg/dL, to medical and environmental interventions for 

children with blood lead levels above 45 μg/dL (CDC 2002). CDC has established a national surveillance 

system for children with elevated blood lead levels. In addition, CDC works with HUD and EPA to 

coordinate outreach and education campaigns. 

OSHA is another agency with regulatory authority under Title X. As directed by the Act, OSHA 

promulgated an interim final standard on May 4, 1993, which regulates lead exposures in the construction 

industry (OSHA 1993). This standard, codified at 29 CFR 1926.62, limits worker exposures to 50 

micrograms of lead per cubic meter of air averaged over an 8–hour workday. Employers must use a 

combination of engineering controls and work practices to reduce employee exposure as much as 

possible, using appropriate respiratory protection where necessary to achieve the exposure limit. 

Employees must receive training on the health effects of lead and how to limit exposure through proper 

work practices and personal protective equipment. Exposure monitoring and medical monitoring, 

including blood lead testing, are also required. This standard remains in effect and OSHA retains the 

authority to protect workers from occupational exposure to lead. 

Many Federal agencies have been working to reduce or eliminate lead-based paint hazards in housing and 

to end childhood lead poisoning. EPA, HUD, and other Federal agencies have been working for many 

years on the problem of lead-based paint hazards that can be created during renovation and remodeling 

activities in housing. This rulemaking is an important component of the Federal strategy for eliminating 

childhood lead poisoning.

State Programs 

As of August of 2005, 44 states, territories and tribes administer their own lead-based paint abatement 

programs. The programs vary in terms of the stringency of training, work practice standards and 

notification requirements, although all must be at least as protective of citizen well-being as the federal 

§402/404 regulations. In general, the programs focus on the prevention of lead-based paint poisoning via 

blood-lead level screenings, regulation of lead-based paint inspection, risk assessment, abatement and 

post-abatement clearance procedures, educational outreach and funding for lead-hazard reduction 

activities. Different state agencies may handle different aspects of a lead-based paint poisoning 

prevention program. 

The majority of state lead-based paint regulations explicitly exclude renovation and remodeling activities 

from their training and work practice standards requirements. Several states, however, have promulgated 

regulations that require contractors to either take precautions when working with lead-based paint, or to 

be trained in and use lead-safe work practices when disturbing paint in certain types of housing. Other 

state programs include voluntary training and outreach initiatives meant to educate contractors on the 
§402(c) Economic Analysis Chapter 3 17 

importance of using lead-safe work practices. EPA identified eight states with state-level regulations that 

address RRP activities in pre-1978 housing, as well as several states that have implemented voluntary 

programs. These state regulations and programs are summarized in Table 3-1. Due to time limitations, it 

was not possible to survey all states in detail. There may thus be additional states that have regulations 

pertaining to RRP projects in pre-1978 housing. It is unlikely, however, that these states have regulations 

that are more stringent than those discussed in this section. In general, identified state regulations address 

RRP activities in one of four ways: by prohibiting the creation of a lead hazard or lead 

threat/contamination (California and Maine), by prohibiting the use of certain work practices (Indiana and 

Oregon), by requiring the use of certain work practices (Massachusetts and exterior renovations in Rhode 

Island), and by setting forth training and work practice requirements for jobs performed in some, but not 

all, target housing (Rhode Island, New Jersey and Vermont). In addition, states may address renovation 

work in rental units indirectly through rental housing standards. 
§402(c) Economic Analysis Chapter 3 18 

 Table 3-1: State RRP Regulations 

State 

Type of RRP 

Regulations and 

Applicabilitya

 Comments 

CA Cannot create 

lead hazard 

Applies to: All 

Pre-1978 

Housing 

Title 17 and SB 460 prohibit creation of lead hazard during RRP activity. Definition 

of lead hazard includes “disturbing lead-based paint without containment.” If lead 

hazard is discovered and reported, it will have to be abated/mitigated using trained 

personnel and following abatement work practices. Title 17 does not establish training 

or additional work practice requirements. Under CalOSHA regulations (Section 

1532.1), workers performing lead-related construction (which includes renovation of 

residential or public building) who are exposed to more than 50μg/m3 average over 8-

hour period must be trained and certified as abatement workers or supervisors. 

ME Cannot allow 

lead to enter 

environment 

Applies to: Pre1978 housing 

Title 38, Chapter 12-B requires RRP contractors to take precautions to prevent release 

of lead to the environment, “including cleanup, removal and appropriate disposal of all 

visible lead-based paint debris generated by the project.” Lists certain practices that are 

likely to result in release of lead to the environment. If lead dust or lead debris 

resulting from project creates a threat to public health, commissioner may order an 

immediate end to the project and may force responsible party to mitigate the risk. 

There are no training requirements for renovation contractors. 

IN Work Practices 

Prohibited 

Applies to: Pre1960 target 

housing 

326 IAC 23-5-2: Prohibits the use of certain methods of lead-based paint removal 

during RRP activities that disturb over 20 sq. ft. on the exterior of a building, or 2 sq. 

ft. in any room on the interior. Prohibited practices include open flame burning, 

abrasive blasting and machine sanding. Also, in case of exterior renovations, prohibits 

leaving any visible dust/debris on soil/surroundings for over 48 hours. There are no 

training requirements for renovation contractors. 

OR Work Practices 

Prohibited 

Applies to: Pre1978 housing 

OAR 333-069: Anyone removing or stabilizing (remodeling/painting) lead-based 

paint must apply to the Department of Human Services for a permit. The permit 

application requires firm/contractor to agree not to use prohibited work practices 

(including hydro/other power blasting without containment), to post warning sign, and 

to notify occupant of potential risks. There are no training requirements for renovation 

contractors. 

MA Work Practice 

Standards 

Applies to: All 

pre-1978 

residences 

454 CMR 22.11: Requires that in pre-78 housing where no inspection/risk assessment 

showing absence of LBP has been conducted, all workers must have undergone OSHA 

Lead in Construction Standard training. Sets forth work practice standards including 

posting of signs, shutdown and coverage of HVAC systems, and prohibition of certain 

lead-based paint removal techniques. 

Work practice 

standards and 

training 

requirements 

Applies to: 

Increased blood 

lead cases 

R23-24.6-PB: Owners of certain high-risk properties and owners of properties 

receiving HUD or other funding, who are disturbing more than 15 sq. ft. of paint in 

any unit, or 3 sq. ft. feet in any common area, must use a certified Lead Hazard 

Reduction Contractor or Lead Renovator/Remodeler unless an inspection/risk 

assessment conducted by a certified professional has shown that there is no LBP 

present. 

RI 

Work practice 

standards 

Applies to: All 

exterior 

renovations 

Air Pollution Control Regulation No. 24: Contractors or owners removing LBP from 

exterior of buildings or structures must notify owners and occupants of buildings and 

businesses within 50 ft. of structure as well as principal and chief administrative 

officer of schools within 50 ft. of structure. Must follow work practice standards that 

include containment, clean-up and the prohibition of certain paint removal techniques.
§402(c) Economic Analysis Chapter 3 19 

 Table 3-1: State RRP Regulations 

State 

Type of RRP 

Regulations and 

Applicabilitya

 Comments 

NJ Work practice 

standards and 

training 

requirements. 

Applies to: Pre1978 rental 

housing 

5:10-6.6: Requires that anyone disturbing over 2 sq. ft. of interior LBP or 20 sq. ft. of 

exterior LBP in multi-family housing be trained in and follow lead-safe work practices 

(including occupant protection, worksite preparation, avoidance of certain work 

practices and dust sampling). Dust sampling must be performed by a person trained as 

a Lead-Sampling Technician. 

VT Work practice 

standards 

Applies to: Pre1978 rental 

housing 

18 V.S.A. § 1759: Requires owners of rental target housing and child care facilities to 

“take all reasonable precautions to avoid creating lead hazards during... renovation, 

remodeling... or repair project.” Lists prohibited paint removal techniques and 

requires use of lead-safe work practices such as limiting work area access to workers, 

covering work area with plastic sheeting and requiring protective clothing. Requires 

clean-up of work area following renovation work. Rental property owners, managers 

and their employees must be trained in essential maintenance practices. 

OH Voluntary Renovation contractors can get trained and certified as Lead-Safe Renovators. There 

are currently no regulations requiring lead-safe work practices. 

WI Voluntary Owner may certify property as Lead-Safe to obtain immunity from civil and criminal 

liability on his/her property. Chapter HFS 163: RRP projects on Lead-Safe properties 

may only be performed by trained lead-safe renovators using lead-safe work practices. 

MI Voluntary Michigan Compiled Laws Service 333.5473a(2-3) “requires department to establish 

and conduct educational programs to educate homeowners and remodelers of lead-safe 

practices and methods of lead-hazard reduction activities.” 

IA Voluntary Iowa Code §135.105A requires creation of voluntary program for training of 

remodelers. a Some regulations may also apply to Child-Occupied facilities. Since only residential structures are subject to 

the RRP rule, this table focuses on the residential housing affected by the state rules. 

Sources: CA DHS 1999 and 2003; State of Maine 2004; Rhode Island Department of Health 1992; New Jersey 

Department of Community Affairs 2004; Lamberti 2005; Vermont Statutes Online 2005; Indiana State 

Department of Health 2001; The Commonwealth of Massachusetts 1999; Holston 2005; Wisconsin Department 

of Health and Family Services 2003; National Council of State Legislatures 2005; OR DHS; OR DHS 2003; RI 

DEM 

Prohibition of Lead Hazards or Lead Threats 

Emergency provisions of Maine’s Lead Abatement regulations require that “a person engaged in any 

renovation, remodeling... or repair project involving lead-based paint not subject to the licensing and 

certification requirements... shall take reasonable precautions to prevent the release of lead to the 

environment, including cleanup, removal and appropriate disposal of all visible lead-based paint debris 

generated by the project.” The regulations list examples of work practices that may result in the release 

of lead to the environment, and stipulate that if the commissioner finds that the location of lead dust or 

debris resulting from the project poses a danger to public health, the commissioner may order the 

responsible party to mitigate the threat, and may also order an immediate stop to the project (State of 

Maine 2004). 

Similarly to Maine, the state of California does not dictate specific work practice standards for renovation 

and remodeling projects. California’s Title 17 and Senate Bill 460, however, make it illegal to create a 
§402(c) Economic Analysis Chapter 3 20 

lead hazard on either the interior or the exterior of any residential or public building. A “lead hazard” as 

defined in Title 17 is “deteriorated lead-based paint, lead contaminated soil, disturbing lead-based paint... 

without containment, or any other nuisance which may result in persistent and quantifiable lead exposure” 

(CA DHS 1999). As such, similarly to EPA’s RRP regulations, California’s regulations require the use of 

containment when disturbing more than a small area of lead-based paint. A small area is defined as less 

than 2 sq. ft. of paint on the interior or less than 20 sq. ft. of paint on the exterior of a building. If RRP 

activity results in the creation of a lead hazard, local and state agencies can “issue orders to abate or 

otherwise correct” the hazard. They can also order an immediate stop to the project (CA DHS 2003). 

Local and state agencies depend primarily on citizen complaints to enforce these regulations (Frazier 

2005). 

While Title 17 and SB 460 do not require training for renovation workers, CalOSHA’s Construction 

Safety Orders (Section 1532.1) states that any employee performing lead-related construction work 

(which includes renovation of public or residential buildings) and is exposed to lead dust concentrations 

above the permissible exposure limit must be trained by an accredited training provider and certified by 

the California Department of Health Services. The permissible exposure limit (as specified in CalOSHA 

regulations) is equal to an average of 50μg/m3

 average over an 8-hour period. If an employee works more 

than 8 hours in a workday, the allowable exposure limit is reduced to 400μg/m3

 divided by the number of 

hours worked. Because little information is available on the dust concentrations generated during 

renovation, repair and painting projects, it is not possible to determine what percentage of California’s 

RRP contractors are required to be trained under the CalOSHA regulations. 

Prohibition of Certain Work Practices 

Unlike California and Maine regulations, which do not explicitly require the use or avoidance of 

particular work practices, Indiana and Oregon seek to protect workers and occupants through the 

prohibition of certain lead-based paint removal techniques. 

Indiana’s 326 IAC 23-5-2 regulations prohibit anyone disturbing over 20 sq. ft. of exterior paint or 2 sq. 

ft. of interior paint in pre-1960 target housing or child-occupied facilities from using various methods of 

removing lead-based paint. Prohibited practices include, but are not limited to, open flame burning and 

machine sanding/grinding or abrasive blasting/sandblasting without high efficiency particulate air local 

exhaust control. For exterior renovations, the regulations also require that all visible lead-based paint on 

soil or other horizontal exterior surfaces be removed within 48 hours after the end of activity (Indiana 

State Department of Health 2001). 

In Oregon, contractors hired to remove or stabilize lead-based paint must apply to the Department of 

Human Services for a permit. As part of the permit application, contractors pledge not to use prohibited 

work practices such as uncontained hydro/other power blasting or sanding and agree to post a sign 

warning the public of possible lead-based paint hazards. Other prohibited work practices include, but are 

not limited to open-flame burning/torching and dry-scraping unless combined with a heat gun (OR DHS, 

OR DHS 2003). 

Work Practice Requirements Applicable to All Target Housing 

Massachusetts regulations (454 CMR 22.11) also prohibit the use of open flame burning as a method of 

LBP removal during renovation projects. In addition, the state has promulgated work practice 

requirements that are relatively similar to EPA’s proposed RRP standards. For example, Massachusetts 

requires that the HVAC system be shut down during renovations that disturb LBP and that any HVAC 
§402(c) Economic Analysis Chapter 3 21 

ducts exposed to the work area be sealed off. All movable objects must be removed from the work area, 

while non-movable objects must be covered with plastic sheeting. Clean-up requirements include 

cleaning any surfaces contaminated with lead debris or dust using a HEPA vacuum, wet wiping or 

another acceptable method (Commonwealth of Massachusetts 1999). 

While Massachusetts does not require lead-safe work practice training for renovation workers, minors 

may not work on projects involving lead-based paint, and all workers must be trained according to OSHA 

Lead in Construction Standard (29 CFR Part 1926.26(1)). 

The Rhode Island Department of Environmental Management (DEM) regulates all work involving the 

removal of lead-based paint from the exteriors of buildings and structures. Air Pollution Control 

Regulation No. 24 establishes detailed work practice standards for exterior lead-based paint removal. 

Requirements include, but are not limited to, covering or removing any toys, furnishings or play 

equipment within 50 ft. of the structure, covering the ground within an impenetrable material to contain 

all debris, abrasives and paint, and using vertical containment if there is “visible movement of abrasive 

material, paint dust and/or other debris beyond ground sheeting.” The regulations state that certain paint 

removal techniques may only be used in conjunction with a HEPA vacuum unit and/or vertical 

containment, while others (open flame burning) may not be used at all. Furthermore, the regulations list 

clean-up procedures to be conducted at the end of each day and at the end of the project (RI DEM). 

In addition to these work practice requirements, DEM regulations require that anyone removing leadbased paint notify a) adults residing in or within 50 ft. of the structure from which the paint is being 

removed, b) the owner of the structure or of any building or business located within 50 ft. of the structure, 

and c) the principal and chief administrative officer of any school within 50 ft of the structure five days 

prior to the start of the project. The notification must provide the location, start and completion dates of 

the project, a description of lead-paint removal procedures, contact information for the firm conducting 

the project, and a warning statement regarding the dangerous nature of lead-based paint (RI DEM). 

Although DEM regulations do not require training or certification, in April 2005 the Department 

implemented a voluntary certification program for contractors involved in removing exterior lead-based 

paint. To participate in the program, the contractor must read a Certification Workbook, complete a 

Participation Form and Certification Checklist stating that he/she abides by the Air Pollution Control 

Regulation No. 24, and present a completed copy of a project checklist to the owner/occupant of each 

structure the contractor conducts work on. As of August 2005, approximately 20 contractors have 

become certified with DEM through this program (RI DEM 2005 a-c). 

Work Practice and Training Requirements for RRP in Certain Types of Housing 

In addition to work practice standards/prohibitions, New Jersey, Vermont and Rhode Island regulations 

require the use of trained contractors and in the case of New Jersey, post-renovation dust testing. In New 

Jersey and Vermont, however, these regulations apply only to multi-family housing. In Rhode Island 

they apply mainly in cases involving a child with an increased blood lead level. 

New Jersey regulations require that all work that may disturb painted surfaces (over 2 sq. ft. of paint on 

the interior and over 20 sq. ft. of paint on the exterior) in multi-unit housing (except owner-occupied 

units) be performed by trained workers in accordance with HUD rules 24 CFR 35. The regulations 

require that steps be taken to protect occupants and prepare the worksite, and prohibit the use of some 

work practices, including open flame burning, power sanding and uncontained water blasting. Training 
§402(c) Economic Analysis Chapter 3 22 

options include the HUD-EPA Lead Safety for Remodeling, Repair and Painting course. Furthermore, 

following any project which disturbs lead-based paint, the dust sampling must be performed by a person 

trained as a Lead-Sampling Technician (NJ DCA 2004, Lamberti 2005). 

Vermont requires owners and managers of rental target housing and child-care facilities be trained in and 

perform essential maintenance practices on their properties. These practices include “tak[ing] all 

reasonable precautions to avoid creating lead hazards during any renovation, remodeling, maintenance or 

repair project that disturbs a lead-based painted surface pursuant to guidelines issued by the department.” 

Guidelines include the prohibition of work practices such as “burning, water blasting, dry scraping, power 

sanding, or sandblasting, unless authorized by the department.” The regulations further require the use of 

good work practices, including, but not limited to “limiting access to work areas to workers, covering the 

work area with six mil polyethylene plastic ... protecting belongings of occupants by covering or 

removing them from the work area.” Finally, the regulations require specialized cleaning of the work area 

using recommended methods (Vermont Statutes Online 2005). 

In Rhode Island, the Department of Health regulates Lead Hazard Reduction and Lead Hazard Control 

activities as well as renovation, repair and painting projects on certain properties. 

Lead Hazard Reduction activities are defined as 

“any activity which reduces the risk of human exposure to lead-based paint or lead containing 

materials or substances in a regulated facility through environmental modification. Such activity 

includes, but is not limited to: repair, enclosure, encapsulation, removal and/or replacement of leadbased paint or painted surfaces, materials, or components in a building or structure (RI DOH 1992).” 

Lead Hazard Reduction activities may only be performed by licensed Lead Hazard Reduction 

Contractors, who require 40 hours of training for certification. The regulations stipulate a variety of work 

practice standards, clean-up and clearance inspection/dust testing requirements. The regulations exclude 

activities that disturb less than 15 sq. ft. of paint in any one unit, or 3 sq. ft. of paint in any common area. 

Note that a Lead Hazard Reduction Contractor is not required for exterior abatement activity (RI DOH 

1992). 

Lead Hazard Control activities include paint stabilization and treatments of friction and impact surfaces 

where the lead levels are above the permitted standard. Window and door removal may also qualify as a 

Lead Hazard Control activity as long as the process does not involve paint removal and all resulting 

dust/debris are immediately cleaned up. Lead Hazard Control activities may only be performed by Lead 

Renovators/ Remodelers, who require eight hours of training. The regulations stipulate notification, work 

practice standards, clean-up and clearance inspection/ dust sampling requirements for Lead Hazard 

Control activities. Again, regulations exclude activities that disturb less than 15 sq. ft. of paint in any one 

unit, or 3 sq. ft. of paint in any common area (RI DOH 1992). 

For the majority of residential units, Lead Hazard Reduction and Lead Hazard Control activities do not 

include renovation, repair and painting work (although Lead Hazard Reduction may be required if a 

renovation project results in the generation of lead dust). However, properties that: 

• Have received a Notice of Violation or Order; 
§402(c) Economic Analysis Chapter 3 23 

• Have been cited by the Department of Health for “significant childhood lead poisoning involving 

three or more children [under age 6] in the previous seven years at units in which the owner has 

or had a financial interest ”; 

• Receive funding from an agency that requires this level of protection; or 

• Request this level of protection 

and are disturbing more than the exempt amount of paint during an RRP project must either conduct an 

inspection to show that no lead-based paint is present, or assume that there is lead-based paint and 

conduct the renovation/remodeling activity as if it were a Lead Hazard Reduction activity, following all 

relevant regulations. 

Similarly, properties that: 

• Have received a Notice to Abate; 

• Must comply with lead-hazard control requirements dictated by HUD; 

• Receive funding from an agency that requires this level of protection; or 

• Request this level of protection 

and are disturbing more than the exempted amount of paint must either conduct an inspection to show that 

no lead-based paint is present, or assume that there is lead-based paint and conduct the 

renovation/remodeling project as if it were a Lead Hazard Control activity, following all relevant 

regulations (RI DOH 1992). 

Additional Regulations that may Affect RRP Projects 

In addition to the regulations discussed above, EPA identified two states (Rhode Island and Maryland) 

that have promulgated housing standards that may impact renovation events in rental units. In both states, 

owners of rental housing constructed prior to 1978 in Rhode Island and prior to 1950 in Maryland are 

required to bring their properties into compliance with certain standards for the maintenance of surfaces 

covered with lead-based paint. In addition, these owners are required to perform visual inspections and 

maintenance/clean-up at tenant turnover (RI HRC 2003, State of Maryland 1994). Maryland Housing 

Bill 760 also requires that if a repair project takes place while a unit is occupied, all children and pregnant 

women must be relocated and all other occupants must be kept out of the work area (State of Maryland 

1994). Neither of the laws, however, explicitly dictates any work practices or training requirements for 

renovation, repair or painting projects. Thus, although these state laws are likely to result in thorough 

clean-up at the end of a project (so as not to violate the housing standards, which prohibit the presence of 

chipped or deteriorating lead-based paint in rental housing), they do not regulate the manner in which a 

renovation is performed. 

State Voluntary Programs 

Whereas some states have promulgated regulations that may limit lead exposure from renovation and 

remodeling activities, others have turned to voluntary programs as a way of encouraging contractor 

training and the use of lead-safe work practices. 

In Ohio, for example, contractors may choose to take a 6-hour class and become trained as Lead-Safe 

Renovators. Lead abatement supervisors and lead abatement workers are automatically eligible for 

certification as lead-safe renovators. There are currently no work practice standards in place for certified 
§402(c) Economic Analysis Chapter 3 24 

lead-safe renovators and no enforcement activities to ensure that the renovations are in fact performed 

safely. In the past, some lead-safe renovators had to submit a notification prior to starting a renovation 

project. The notifications are no longer required, but some renovators submit them voluntarily. 

Currently, there are approximately 900 - 1,000 certified lead-safe renovators in Ohio (Holston 2005).

In Wisconsin, a property owner may choose to certify his or her property as lead-safe. Lead-safe status is 

granted following an inspection conducted by a certified inspector/risk assessor. The Lead Safe 

certificate “provides the listed "Property Owner" and his employees and agents immunity from civil and 

criminal liability on this property. Also, they may not be subject to a DHFS proceeding, except under 

circumstances cited in ch. 254.173(2), Wis. Stats.” Once a property is certified as lead-safe, however, any 

RRP activity performed on the property must be conducted by a trained Lead-Safe Renovator following 

lead-safe work practices (WI DHFS 2003). As of July 2004, the Wisconsin listing of lead-safe properties 

contained 39 residential structures (WI DHFS 2005).

Other voluntary initiatives include educational outreach in the form of suggested lead-safe work practices 

and periodic free training offered by health departments and housing agencies.

Local Initiatives 

Similar to state programs, local lead-poisoning initiatives have had limited resources with which to carry 

out their programs. Differences between typical state and city programs lie more in the extent than in the 

substance of the activities. In general, city programs are more focused and seem to receive higher 

priority, which may be due to the urgency of the lead-paint problem in larger cities (HUD 1990). 

In the Comprehensive and Workable Plan for the Abatement of Lead-Based Paint in Privately Owned 

Housing (HUD 1990), the Department of Housing and Urban Development outlined several 

distinguishing features of local programs as determined by studying ten selected cities: 

• A city that is governed both by local ordinances and state regulations for lead-poisoning 

prevention and detection activities usually has local laws that are more stringent than state laws 

and may supersede the state requirements. 

• In addition to providing intervention after cases of lead poisoning have been detected, local 

programs may require intervention as a result of targeted inspection of tenant complaints. Several 

cities, including Baltimore, Chicago, Louisville, New York, and Philadelphia, are authorized to 

take such preventive measures. 

• In general, the city programs show more cooperation and coordination between agencies. 

• City programs usually screen for high blood lead levels more systematically and target high-risk 

areas for screening. 

Several cities have promulgated regulations that affect renovation, remodeling, and painting activities. 

These regulations are summarized in Table 3-2. Once again, it is possible that there are additional cities 

with similar regulations. However, similarly to state-level regulations, these rules are likely to fall short 

of correcting the market failure discussed in Section 3.2.1. and thus do not substitute for the proposed 

federal Renovation Rule. 

Local regulations, which are most often promulgated as city ordinances, are similar to state regulations in 

that they address the dangers posed by RRP activities in pre-78 housing via prohibiting the creation of 
§402(c) Economic Analysis Chapter 3 25 

lead hazards or the use of certain paint removal techniques, requiring the implementation of work practice 

standards, or requiring lead-safe work practices for projects in certain types of housing. 

New York City currently has one of the most extensive local regulatory programs dealing with lead-based 

paint. The City recently promulgated a rule entitled Local Law 1, which applies to all units with a child 

under age 7 in pre-1960 multi-dwelling buildings and to common areas in these buildings. The 

regulations also apply to housing units in multi-dwelling buildings constructed between 1960 and 1978 

where children reside and where the owner knows there is lead paint, as well as to common areas in these 

buildings. When disturbing between 2 sq. ft. and 100 sq. ft. of paint in the interior of these buildings, the 

owner must hire workers trained in lead-safe practices. Work practices must be no less stringent than 

Health Code §173.14 and dust tests must be performed. If work disturbs over 100 sq. ft. or more than one 

window within the interior of the building, the owner must hire an EPA-certified firm and follow the 

same work practices as for the disruption of areas between 2 sq. ft. and 100 sq. ft. Furthermore, 

notification is required for projects disturbing over 100 sq. ft. Relocation may be required for any project 

where work cannot be performed safely. According to the Department of Housing Preservation and 

Development’s Local Law 1/2004 – Section by Section Analysis, it is not clear from the statute whether 

the over 100 sq. ft. project requirements apply to private dwellings (NYC DHPD 2004a-b). 

Chapter 36 of San Francisco’s Building Code, Work Practices for Exterior Lead-based Paint, is another 

example of a city-level regulation that addresses renovation and remodeling. It should be noted that 

Chapter 36 establishes far more detailed requirements than do California Title 17 and SB460. The San 

Francisco regulations apply to any work that disturbs over 10 sq. ft. of lead-based paint on the exterior of 

pre – 1978 buildings or steel structures. The regulations require the use of containment for all regulated 

jobs and prohibit the use of paint removal techniques such as “acetylene or propane burning and torching, 

hydroblasting or high pressure blasting without containment barriers [and] heat guns operating above 

1,100 degrees Fahrenheit.” The party responsible for the project must also perform a clean-up of all 

visible lead-based paint debris prior to finishing the project. The regulations further require that the 

owner notify all contract bidders of any paint inspection reports related to lead-based paint in the 

regulated area of the project. The owner or contractor must also notify the Department of Building 

Inspection and the tenants prior to the start of work, and must post a sign warning of the presence of leadbased paint (National Center for Healthy Housing, DBI 1999). 

Although Cleveland’s lead paint regulations focus primarily on lead abatement, they do provide 

requirements for safe work practices and clean-up during any type of lead-based paint removal. 

Ordinance 1027-04 applies to all pre-1978 buildings except residences of the elderly or disabled where 

children under six years of age do not and will not reside or any zero bedroom dwelling. The regulations 

prohibit all open flame burning as well as power-assisted paint removal techniques that do not 

immediately capture dust and debris in a closed container (this method is likely to involve power-assisted 

machines with HEPA vacuum attachments). The law requires that notification be given to occupants of 

the building and to any occupants of neighboring buildings within 30 ft. of the worksite. Preparation of 

an exterior worksite includes attaching plastic sheeting to the foundation of the structure and extending it 

10 ft. from the foundation. For an interior paint removal task, preparation consists of laying plastic 

sheeting over an area “sufficiently large” to protect the surrounding environment from contamination and 

to capture dust and debris. Clean-up entails the rolling up and disposal of plastic sheeting along with the 

removal of all paint debris and dust (City of Cleveland, 2004). 

The Kansas City Lead Ordinance (Article X: Lead Poisoning Control, Sec. 34-401 – 34-409) includes a 

general statement regarding renovations, remodeling projects, and demolitions. While it does not 
§402(c) Economic Analysis Chapter 3 26 

mandate detailed guidelines, the ordinance makes it illegal for workers involved in these activities to 

create lead hazards and expose themselves, occupants of the building, or occupants of adjacent properties 

to lead-containing debris and dust. The rule applies to all housing types but is particularly important in 

areas where children under the age of six are likely to be exposed (Kansas City Health Department). 

Similar to Kansas City, the Chicago Department of Public Health issued a nonspecific lead-based paint 

regulation. The law, as outlined in Control and Mitigation of Lead Bearing Substances, applies to 

facilities and premises that are frequented by children who are of age six or younger. It simply states that 

workers cannot create lead hazards while performing any work on lead bearing substances in these 

facilities and premises. This includes containing and removing “any visible dust, chips, or debris” from 

lead-based paint. The regulation further prohibits the use of certain work practices, as described in Table 

3-2. Similar to the California regulations, this ordinance implicitly requires renovators to contain leadbased paint dust and debris (City of Chicago Department of Public Health, 2004). 
§402(c) Economic Analysis Chapter 3 27 

Table 3-2: Local RRP Regulations 

City, 

State

Type of RRP 

Regulations and 

Applicability Comments 

New York 

City, NY 

Training and work 

practices

Applies to: All Pre1960 multiple 

dwellings; Multiple 

dwellings built between 

1960 and 1978 with 

knowledge of lead paint 

(interior work) 

NYC Local Law 1: Regulation applies to all units with a child under age 7 in 

pre-1960 (as well as buildings constructed between 1960 and 1978 where the 

owner knows there is lead paint) multi-dwelling buildings and to common areas 

in these buildings. When disturbing between 2 and 100 sq. ft. of LBP, owner 

must hire workers trained in lead-safe practices. Work practices must be no less 

stringent than Health Code §173.14 and dust tests must be performed. If work 

disturbs over 100 sq. ft., must hire EPA-certified firm and follow same work 

practices as for disruption of 2 to 100 sq. ft. Notification is required for projects 

disturbing over 100 sq. ft. The 100 sq. ft. regulations may or may not apply to 

private residential dwellings. 

San 

Francisco, 

CA 

Work practices 

prohibited 

Applies to: Pre-1978 

buildings (exterior 

work) 

Chapter 36 of the San Francisco Building Code: Regulation applies to any 

work disturbing over 10 sq. ft. of LBP on the exterior of buildings and steel 

structures. Requires containment barriers for all jobs disturbing more than the 

exempted amount of paint. Prohibits use of some paint removal techniques and 

requires clean-up of all visible LPB debris. Requires notification of the 

Department of Building Inspection and of tenants prior to start of work. 

Requires the postage of sign warning of presence of LBP. No specialized 

training is required. 

Chicago, 

IL 

Cannot create lead 

hazard 

Applies to: Pre-1978 

buildings frequented by 

children six years old 

and younger 

Chicago Department of Public Health prohibits the presence of lead hazards 

(definition of “Lead Hazard” includes uncontained lead dust or debris created 

during RRP activity) in residential housing and child-occupied 

facilities/premises. Prohibits use of work practices (including open flame 

burning, dry sanding, dry scraping, heat guns, mechanical paint removers 

without HEPA dust containment, uncontained hydro or abrasive blasting, and 

chemical strippers) that may create a lead hazard. City inspectors may order 

abatement or mitigation of any lead hazards. No specialized training is 

required. 

Kansas 

City, MO 

Cannot create lead 

hazard 

Applies to: Pre-1978 

buildings, particularly 

areas where children 

under age 6 may be 

exposed to lead paint 

Kansas City Lead Ordinance (Article X: Lead Poisoning Control, Sec. 34-401 – 

34-409) makes it illegal for any person to “repair, renovate or demolish any 

dwelling in such a manner that any occupant, worker or any person on any 

adjacent property(ies) may be exposed or have access to the resulting dust, 

contaminants or debris from lead-bearing substances.” No specialized training 

is required. 

New 

Orleans, 

LA 

Cannot create lead 

hazard 

Applies to: Pre-1978 

buildings or metal 

structures 

New Orleans City Ordinance No. 20345 regulates activities that disturb LBP on 

and in pre-1978 buildings and all steel structures. Prohibits the use of certain 

paint removal practices including scraping, hydro blasting or sandblasting 

without containment, heat removal and chemical removal. Requires 

containment for exterior work using power sanding. Requires notification of 

tenants and other affected parties and postage of signs if power sanding is used. 

Requires notification of the Director of the Department of Safety and Permits if 

power sanding is used on exterior of building or structure. No specialized 

training is required. 
§402(c) Economic Analysis Chapter 3 28 

Table 3-2: Local RRP Regulations 

City, 

State

Type of RRP 

Regulations and 

Applicability Comments 

Cleveland, 

OH 

Work practices and 

prohibitions for paint 

removal 

Applies to: Pre-1978 

target housing 

Cleveland Ordinance 1027-04 provides prohibitions and guidelines for paint 

removal. It prohibits open flame burning and power-assisted paint removal 

unless debris and dust are immediately captured in a closed container before 

being released into the environment. Plastic cloths are to be attached to the 

foundation and extended out 10 ft. for exterior paint removal and laid in an area 

"sufficiently large" for interior. Vents, windows, and ducts are to be closed. 

Upon completion of work, cloths are to be wet wiped, rolled up, and disposed 

of. All paint or paint dust is to be removed from the premises. The law requires 

that notification be given to occupants of the building and occupants within 30 

ft. of paint removal. No specialized training is required. a Some regulations may also apply to Child Occupied Facilities. Since only residential structures are subject to the 

RRP rule, this table focuses on the residential housing affected by the state rules. 

Sources: National Center for Healthy Housing; NYC DHPD 2004a-b; DBI 1999; CDPH 2004; Kansas City 

Health Department; City of New Orleans 2001; City of Cleveland 2004. 

Conclusions 

While the regulatory and non-regulatory initiatives undertaken at the federal, state, and local level to 

reduce exposure to residential lead are extensive, they are not sufficient to ensure that lead exposure 

resulting from renovation activities is reduced to the levels of the RRP regulations. Very few of the 

existing programs address renovation or consider the release of lead into the surrounding environment 

that frequently occurs during renovation. Even childhood blood-lead screening programs, which should 

act as a monitoring system by identifying exposure problems that do develop, are not universal — many 

states and communities have yet to institute such testing programs and even where they exist, they often 

miss many children. Even if these blood-lead screening programs were more uniformly applied across 

states and at risk children, such an ex-ante approach to limiting exposure would only address the issue 

after it becomes a significant health concern (i.e., children will suffer from increased blood-lead before 

intervention occurs). 

3.3 Regulatory Options for Reducing Lead Exposure Resulting from Renovation 

In drafting the Renovation, Repair and Painting Rule, EPA considered various regulatory approaches, 

including, but not limited to: (1) information provision and labeling, (2) required work practice standards, 

(3) bans or restrictions on use, and (4) economic incentives. The first and second of these instruments are 

most closely linked to the problems contributing to the market failure described in Section 3.2. 

Consequently, directly addressing the lack of adequate information and external costs through 

information provision, and the establishment of work practice standards are the focus of this section and 

the analysis presented in this report. 

3.3.1 Information Provision 

The objective of the proposed regulation is to reduce exposure to lead from renovation projects and 

thereby protect children and adults from health hazards posed by lead. Due to the nature of the problem, 
§402(c) Economic Analysis Chapter 3 29 

uncertainty currently exists on the part of consumers about the quality of lead-safe renovation services 

and their likely benefits. The lack of information regarding the benefits of and the lack of confidence in 

the quality of a good or service generally leads to a lower demand and a lower willingness-to-pay for that 

good or service. Thus, if consumers of renovation services (i.e. property owners) are not aware of the 

dangers posed by lead dust generated during renovation, or if they are not confident that a contractor who 

claims to use lead-safe work practices has been properly trained, they may not be willing to pay the 

additional costs of contractors who voluntarily abide by these work practice standards. The proposed rule 

will assure consumers that trained and certified personnel are qualified to control lead-based paint 

hazards. This provision of information will act as an important instrument in alleviating the problems 

contributing to undue lead exposure. An example of the market failure stemming from the lack of perfect 

information is presented in the previous section and is shown graphically in Exhibit 3-1. 

An additional information flow will occur under these regulations. The teaching of safe work practices to 

contractors will provide them with information they need to undertake renovation activities in ways that 

will not expose their clients. The training course will also provide information about the hazards 

associated with lead and renovation activities, which contractors will pass along to their clients. Thus 

provision of information is likely to increase the demand for lead-safe work practices and assist in 

eliminating the market failure that currently exists due to incomplete or misinformation. 

Information provision will occur in several ways under this rule, in conjunction with other sections of 

Title X. Consumers will be directly informed about lead-based paint hazards and risks associated with 

renovation work through educational programs. The aim of these programs will be to educate the 

property owner about the risks associated with lead-based paint hazards and having renovation work done 

in areas with such hazards, the significance of these risks, what can be accomplished to reduce those risks 

through specific work practices, and how much these practices cost. In addition, requiring training of 

professionals carrying out renovation projects will provide these individuals information about the 

hazards of lead exposure and the use of appropriate procedures to reduce exposure during their work. 

Similarly, the firm certification process will act as an indirect form of information provision to the 

consumer by assuring them that the services they are purchasing will reduce or eliminate lead exposure. 

All these forms of information provision will aid in reducing the extent of the market failure that currently 

exists for lead-safe renovation services. However, relying solely on information provision is unlikely to 

be enough because of the nature of the lead problem. The lead in lead-based paint cannot be seen on 

visual inspection, and thus the consumer does not know if lead is present and whether a lead exposure 

hazard actually exists. Likewise, the adverse health effects are not noticeable for several years, and the 

source may not be recognized. In such situations, education may not be sufficient and other mechanisms 

are needed to ensure that if a potential risk exists, it is suitably addressed. The current rule introduces 

other mechanisms for the elimination of lead-hazards during renovation work. These include training 

requirements for personnel engaged in renovation work and standard practices for the containment and 

cleanup of lead dust and debris generated during the project. 

3.3.2 Containment and Clean-up Work Standards 

Flexible and prescriptive standards are two alternative regulatory approaches that were considered for the 

work practice standards component of this rule. Both options require the use of specific containment, 

clean-up and cleaning-verification practices2

 within the work area. Under the prescriptive option, EPA 

 

2 Note that in the remainder of this discussion, the terms clean-up or clean is used to mean clean-up and cleaning 

verification work practices. Higher/lower level of containment/clean-up means the size of the work area that is 
§402(c) Economic Analysis Chapter 3 30 

would define certain renovation projects as small and allow a smaller area to be contained and cleaned for 

these events; the remaining projects would be considered large and all rooms where work is performed 

would have to be contained and cleaned. Flexible standards, on the other hand, allow the certified 

renovator to determine the size of the work area that needs containment and cleaning for each project 

he/she performs. 

The advantage of flexible containment work practices over prescriptive standards lie in higher efficiency 

and resultant cost savings. The expected superiority of flexible containment work practices rests on the 

assumption that the contractor on the site is a better judge of the dwelling area that might be exposed to 

lead dust (and should thus be contained and cleaned) than the rule writers. Contractors with perfect 

information would contain/clean the minimum area necessary to prevent the spread of lead dust and 

debris. This would lead to cost savings for some percentage of jobs where a greater level of containment 

is not required (but would have been prescribed), resulting an efficiency gain for society as a whole. 

Exhibit 3-2 provides a graphical example of the type of efficiency gain that could result from applying the 

flexible rather than the prescriptive option under conditions of perfect information. The incremental costs 

for each are calculated relative to a baseline where no protective measures are taken. 

 

contained and cleaned using the work practices specified in the RRP rule.
§402(c) Economic Analysis Chapter 3 31 

Exhibit 3-2: Example of Cost Savings with Flexible Standards 

Under Perfect Information

Efficiency Gain

Incremental Cost

of Work Practices

$100

$0

1,000,000

Events

400,000

Events

A

B

C

In this example, 40% of events are assumed to require the maximum prescribed area to be contained and 

cleaned. The remaining 60% require containment and clean-up of a smaller area.3

 For simplicity, a linear 

decrease in the size of the work area that should be contained and cleaned is assumed, so that at the top 

margin projects require nearly the maximum area identified by the prescriptive and at the lower margin 

clearance is obtained using current industry practices only. The shaded area ABC represents the cost 

savings to be gained under flexible standards as compared to prescriptive option. Note that because all 

projects are assumed to attain the same level of lead hazard reduction, the benefits of the regulation 

remain unchanged, the costs decrease and the net benefits increase. In the example shown in Exhibit 3-3, 

the efficiency gain from using flexible work practices is $30 million (Area ABC = 0.5 × 600,000 × $100). 

What if contractors do not have perfect information? If contractors cannot determine the exact area that 

should be contained and cleaned in a particular situation, then the full cost savings may not be realized. 

Depending on the type of imperfect information, the flexible, rather than prescriptive option may result in 

either smaller cost savings or result in greater costs savings with reduced benefits, as illustrated in the 

following two examples. 

 

3 Note that these percentages are assumptions only and are not based on housing data. 
§402(c) Economic Analysis Chapter 3 32 

Example 1: Imperfect information results in using work practices that are too stringent

In this imperfect information scenario, contractors believe that the work area is larger than it actually is, 

resulting in a greater level of containment/clean-up than necessary. This situation is demonstrated 

graphically in Exhibit 3-3 below. 

Exhibit 3-3: Cost Savings with Flexible Containment Standards under Imperfect Information 

Doing More than Necessary

Under the illustration of perfect information presented in Exhibit 3-2 above, 600,000 events 

contained/cleaned a smaller area than required under the prescriptive option to attain the hazard reduction. 

If contractors are risk-adverse, or believe that a greater level of containment is necessary, then the number 

of events using less costly work practices is reduced. In the example presented in Exhibit 3-3, only 

300,000 events contained/cleaned a smaller area. Because contractors are erring on the side of additional 

work practices, the benefits of the regulation are not reduced, the costs are reduced from the prescriptive 

option as represented by the area DBC and an efficiency gain occurs. Using the numeric example in 

Exhibit 3-3, the cost savings from applying the flexible option under imperfect information rather than the 

prescriptive option is $15 million, a smaller gain than would have occurred under perfect information 

(area ABC). 

Incremental Cost

of Work Practices

$100

$0

1,000,000

Events

400,000

Events

Efficiency Gain 

Under Imperfect

 Information

+ Efficiency Gain 

Under Perfect

 Information

700,000

Events

A

B

D C
§402(c) Economic Analysis Chapter 3 33 

Example 2: Imperfect information results in using work practices that are too lax 

Under the second scenario of imperfect information, it is assumed that contractors may err on the side of 

doing too little rather than too much. The effect of this scenario on the potential cost savings is 

demonstrated graphically in Exhibit 3-4 below. 

Exhibit 3-4: Cost Savings with Flexible Standards Under Imperfect Information 

Doing Less than Necessary

G

$100

E A C

F B

$0

300,000

Events

400,000

Events

750,000

Events

1,000,000

Events

Incremental Cost

of Work Practices

Cost-savings

that are not

accompanied by

a change in

benefits. A clear

efficiency gain.

Cost-savings that

are accompanied

by benefits losses.

No clear efficiency

impact.

The efficiency impact of using the flexible option instead of the prescriptive option under this type of 

imperfect information is less clear. There is still an efficiency gain that results from cost-savings for 

projects where the EPA-recommended level of containment/clean-up is not required (area ABC). There is 

an additional cost savings that occurs on all projects that contained a smaller work area than was actually 

needed to achieve the hazard reduction (area EABF). In these cases, however, there is also a loss of 

benefits because the level of containment/clean-up used is not sufficient to prevent lead exposure. The 

net impact depends on the amount of benefits lost relative to the cost savings. 

In conclusion, the conceptual framework outlined here can still be used to approximate the cost-savings 

from using the flexible option under an assumption of perfect information. Since EPA does not know the 

extent to which imperfect information will affect the efficiency of the flexible option, this approximation 

is made by estimating the percentage of events that that require containment/clean-up of a smaller area 

than prescribed by EPA and calculating the area of the efficiency gain as shown in Exhibit 3-2. However, 

qualitative information on the relative costs and benefits of the rule can be used to determine if the 

flexible costs savings might be outweighed by losses in benefits resulting from imperfect information. 
§402(c) Economic Analysis Chapter 3 34 

3.3.3 Alternative Regulatory Options 

In light of the prior discussion, the regulatory options analyzed attempt to provide flexibility while also 

providing information on what action contractors and property owners need to consider undertaking in 

order to contain and clean-up potential lead contamination. These work practices are combined with 

training to ensure that contractors will have the information they need to properly conduct RRP events in 

a protective manner. 

Several alternative regulatory options are considered. First, EPA considered whether the regulations 

should apply to all housing units or only the housing units where children under the age of six reside 

and/or rental units. A focus on children is appropriate because they have the highest risk of exposure and 

adverse health effects. A focus on rental units is appropriate to address the agent problem – the person 

selecting the contractor and the containment/clean-up activities (i.e. the property owner) is not the person 

who will be affected by the resulting lead exposure (i.e. the tenant). 

Perhaps the main difference among the options is the definition of the housing units subject to the 

regulation based on year built: between housing units built before 1978 and housing units built before 

1960 or before 1950. With the ban on the use of lead-based paint in 1978, housing units built after that 

date are highly unlikely to present lead hazards, and thus are not included in the statutory definition of 

“target housing”. Units constructed prior to 1978 make up 65 percent of the U.S. housing stock, while 

units constructed prior to 1960 and 1950 make up 34 and 22 percent of the housing stock, respectively. 

The use of lead-based paint declined rapidly during the 1950s and 1960s, so housing units built between 

1960 and 1978 are much less likely to have lead-based paint than those built before 1960 (See Section 

4.2.5 of Chapter 4 for further discussion). 

Limiting the regulation to the earlier homes reduces costs with a less than commensurate reduction in 

benefits. This discrepancy arises from the difficulties associated with testing for lead-based paint in order 

to determine whether or not a particular project will need to comply with the regulations, which is likely 

to result in over-compliance, particularly in units constructed between 1960 and 1978. The RRP Rule 

allows contractors to use a lead-based paint (LBP) test kit to determine whether lead-based paint is 

present in a home, but test kits that are currently on the market have false positive rates that range from 47 

to 78 percent. Because pre-1960 and pre-1950 units are more likely to contain lead-based paint than units 

constructed between 1960 and 1978, the LBP test kits will return more false positives for these newer 

units. EPA plans to develop a more accurate LBP test kit, which is expected to have a false positive rate 

of only 10 percent or less and to be available by the second year that the regulation is in effect. As such, 

by promulgating an option that applies only to older units in the first year and to all pre-1978 units in the 

second year, EPA can reduce the costs of the rule while incurring a significantly smaller reduction in 

benefits. EPA is thus considering several phase-in options, where the regulation will apply only to older 

renter-occupied target housing units or owner-occupied target housing units where children under the age 

of six reside in the first year and to all such pre-1978 units in the second year.

As discussed in Section 3.3.2, the third distinction among the options is the amount of flexibility given to 

contractors. Three of the regulatory options analyzed allow the contractor to exercise judgment as size of 

the work area that requires containment, clean-up and cleaning verification. The fourth option under 

consideration defines the size of the work area as either small or large and prescribes the amount of 

containment/clean-up accordingly. 
§402(c) Economic Analysis Chapter 3 35 

The result is four options. By the second year of the regulation, all four options cover RRP events in 

renter-occupied target housing units built before 1978 and owner-occupied target housing units built 

before 1978 where a child under the age of six resides. One of the options also covers these same units in 

the first year, the other options cover smaller sets of housing units in the first year (two cover pre-60 

housing and one covers pre-50 housing in the first year). Three of the options (flexible options) allow a 

certified renovator to define of the size of the work area while one option (prescriptive option) defines the 

area that must be contained and cleaned. More information on the options is provided in Chapter 4. 
§402(c) Economic Analysis Chapter 3 36

Appendix 3A: The Role of Elasticities in Determining the Impacts of a 

Rule 

EPA is often faced with deciding on a regulatory policy in the absence of good information about the 

likely effects of the policy on consumers and producers. In particular, data on the own-price elasticity of 

supply and demand often are uncertain. This appendix provides background information on the likely 

effects of own-price elasticity of demand and supply on the outcomes of EPA’s regulatory efforts. The 

bulk of the discussion focuses on the case of perfect competition, not because the majority of markets 

EPA is likely to affect will exhibit competitive behavior, but simply because the theory is clearly defined 

in this case. However, this appendix also examines the likely impacts of relaxing the assumption of 

perfect competition. It focuses on two general classes of regulatory options: regulations that alter the 

market outcome by imposing additional costs upon producers, and regulations that alter the market by 

providing information to consumers.

3A.1 Elasticities of Supply and Demand 

The market equilibrium for a commodity (e.g., purchasing renovation, remodeling or painting (RRP) 

work that uses lead-safe work practices) is determined by the intersection of the aggregate demand and 

supply curves. The aggregate demand curve depicts consumer behavior and is based on consumer income 

and preferences. Likewise, the aggregate supply curve describes the behavior of producers in the market, 

and is dependent upon the costs of production. At market equilibrium, the price is referred to as market 

clearing. In other words, at this price, the quantity demanded by consumers and supplied by producers 

are equal and neither the consumer nor producer has any incentive to move away from this steady state as 

long as current demand and supply conditions prevail. 

However, when demand and supply conditions do change, for example when new information causes 

consumers to adjust their preferences and thus shift the demand curve, or changes in input prices affect 

costs of production and shift the supply curve, the market gravitates to a new equilibrium. This new 

equilibrium is represented by a new combination of market clearing price and quantity. The magnitude of 

the change in price and quantity is dependent not only upon the extent of the shift in the demand or supply 

curve, but also on the own-price elasticity of demand and supply for the commodity. 

The own-price elasticity of demand is defined as the ratio of the percent change in quantity demanded to 

the percent change in price, and is reflected in the slope of the demand curve, similarly for the own-price 

elasticity of supply. By determining the level of change in price and quantity, the elasticities of the two 

curves also determine the distribution of the burden or benefit between the consumer and producer 

resulting from a change in equilibrium conditions. Analyzing changes in consumer and producer 

surpluses provides a means for quantifying such distributional changes. 

Figure 3A-1 below provides an hypothetical example of how the effects of regulation may impact 

consumer and producer surpluses. In the baseline, the supply curve is represented by S1, and producers 

supply Q1 at a price P1. On all the inframarginal units supplied, producers receive a price above the cost 

of production. The difference between the price and the cost of production represents the producer 

surplus resulting from supplying Q1 at price P1 (triangle P1CD). Similarly, in the baseline consumers 

demand quantity Q1 at price P1. For all the inframarginal units demanded, consumers would be willing to 

pay more than that price and thus receive a surplus. The difference between what consumers are willing 

to pay as measured by the height of the demand curve, and what they have to pay is the consumer surplus 

(triangle ACP1). 
§402(c) Economic Analysis Chapter 3 37

So what are the effects of regulation? In Figure 3A-1, the upward shift in the supply curve to S2 (say 

from a rise in production costs due to the implementation of the RRP rule which requires use of the more 

costly lead-safe work practices) results in a new equilibrium at the point B, with a new market price of P2

and quantity of Q2. Note that producer surplus decreases from P1CD to EBP2 and the consumer surplus 

also decreases from ACP1 to ABP2. Thus, in the arbitrary case drawn in Figure 3A-1, the social costs of 

the regulation are born by both consumers and producers of the pollution-generating good. This result 

turns out to be a function of the way the supply and demand curves have been drawn, and the distribution 

of costs between consumers and producers depends on the slope (elasticity) of the demand and supply 

curves. 

A

B

C

D

E

Q2 Q1

P1

P2

S2

S1

D

Figure 3A-1: Effect on consumer and producer surplus due to a supply curve shift 

In general, for a given production cost increase, the more elastic the demand curve, the greater the 

inability on the part of the producers to pass the additional costs of production on to the consumers. As 

shown in Figure 3A-2 (a) and 3A-2 (b) below, the differing slopes of the demand curve lead to 

differential impacts on the consumer and producer surplus. In Figure 3A-2 (a) demand for the good is 

relatively price elastic, while in Figure 3A-2 (b) the good has a relatively inelastic demand. Notice that 

when demand is less elastic, the price increase resulting from a shift in supply is greater and consumers 

bear a greater share of the loss in consumer surplus. On the other hand, with a more elastic demand, the 

overall price increase is smaller and the share of total costs born by producers is larger. 

S2

S1

D

Q2 Q1

P1

P2

Q2 Q1

P1

P2

D

S1

S2

 Figure 3A-2(a) Figure 3A-2(b) 

2(a): Effect of a change in input prices when demand is elastic 

2(b): Effect of a change in input prices when demand is inelastic 
§402(c) Economic Analysis Chapter 3 38

The elasticity of demand is determined in general by the existence of suitable substitutes for a 

commodity. If several commodities exist in the market that are considered to be close substitutes for each 

other, then a consumer is likely to have a great deal of choice available to him while making his 

consumption decision. This being the case, if the price of the commodity that he is presently consuming 

happens to rise, he is easily able to reduce his current consumption level of that commodity and switch 

over to consuming more of one of the substitutes. This flexibility limits the ability of the producer to pass 

on the burden of the cost increase on to the consumer. Thus, the availability of close substitutes in the 

market explains why the demand curve for a commodity will be relatively elastic, and why the rise in 

price will be relatively small. On the other hand, if substitutes are lacking for a commodity that 

experiences a price increase (and it is not a luxury good), then the consumer has little choice but to carry 

on consuming similar quantities of the same product. Thus, in this situation he will have to shoulder a 

larger share of the increased costs by paying a much higher price, and this rigidity in his consumption 

behavior explains the inelastic nature of the demand curve for that commodity. 

Recognizing that most markets are not perfectly competitive, product differentiation allows firms to 

charge prices higher than marginal costs and charge different prices for similar goods. The degree to 

which producers can pass on the cost of production depends heavily on the degree to which they can 

convince consumers that their product is different from other products. In its limit this argument is just a 

restatement of the fact that markets with lower elasticities of demand will experience higher price 

increases. If “market demand” is defined to be the demand for a single brand of good, then the number of 

substitutes for the good affects its demand elasticity and thus affects the degree to which the producer can 

pass on cost increases. If the firm can convince consumers that the product is distinct then it in essence 

lowers the elasticity of demand for its product. 

The own price elasticity of supply, on the other hand, is dependent on the degree of specialization of 

inputs. If the inputs are highly specialized or firms are locked into long term contracts then firms in this 

industry can be left with substantial sunk investments creating high transition costs which are reflected in 

an inelastic supply curve. However, if supply is highly elastic then firms can easily switch production to 

other uses and minimize the effect of the demand shock. In essence the elasticity of supply measures the 

amount of resources lost or tied up indefinitely when consumption patterns change suddenly. 

The EPA seeks to reduce hazards from lead-based paint under the RRP rule by two separate pathways of 

regulatory impact. First, it hopes to reduce exposure to lead-based paint by regulating the “method of 

production” of RRP work in pre-1978 homes by establishing standards for such activities and through 

requiring certifications and/or training. This is likely to result in an increase in the “costs of production” 

of RRP work thereby affecting the supply curve for such activities. Second, the RRP rule will provide 

information to consumers. In this case EPA is likely to alter the market outcomes by changing the 

demand for products (lead-safe and non lead-safe work practices). To the extent that the demand and 

supply of RRP work will be affected by the rule, one must consider the price elasticities involved to 

determine the distributive impact of the rule on consumers and producers. 

An important factor on which the price elasticity will depend is the number of substitutes that exist for the 

RRP service that is sought in the market. As previously explained, the greater the number of available 

substitutes, the more elastic the demand and lesser the burden of a production cost increase likely to fall 

on the consumer. Under this rule three classes of substitutes may be said to exist for RRP services. These 

are (1) professionals using lead-safe work practices, (2) professionals using non lead-safe work practices, 
§402(c) Economic Analysis Chapter 3 39

and (3) the do-it-yourself jobs. Thus, a certain amount of flexibility is available to the consumer when it 

comes to hiring RRP services. 

Currently a sizeable number of RRP firms may not necessarily be following lead-safe work practices 

thereby limiting the size of the class of firms that do so. However, with the implementation of the RRP 

rule, a much larger number of firms are expected to adhere to these practices in the future, thus enlarging 

the size of this class. In addition, this increase in the number of professionals using lead-safe work 

practices will also have a geographical impact. Presently, the limited number of professionals who use 

lead-safe work practices are concentrated in a select number of locations where state and local regulations 

have fostered their development. As a result, in many parts of the country the choice of hiring “lead-safe” 

professionals currently does not exist. But this situation will change as a larger number of firms switch to 

lead-safe work practices once the RRP rule comes into effect. 

However, if the increase in production costs from the rule is extremely high such a large transition of 

firms from using lead-unsafe to lead-safe work practices may not occur. This is because the cheaper 

option of using non-certified (non lead-safe work practice using) RRP workers or doing the work yourself 

will limit the ability of the certified (lead-safe work practice using) professional to charge the consumer 

for all or a large portion of this significant cost increase. In this situation a large number of lead-unsafe 

firms may remain in existence. Thus, one may assume that as long as an appreciable difference exists 

between “costs of production” of lead-safe and non lead-safe work practices, firms of both types will 

continue to exist. The continued existence of firms using non lead-safe practices also depends on the 

extent and effectiveness of enforcement activities. The greater the cost differential between lead-safe and 

non lead-safe practices, the greater the need for enforcement activities. 

In addition to the number of substitutes, the closeness of substitutes in their ability to replace one another 

needs to be judged. The important question is whether RRP work done by uncertified professionals and 

the do-it-yourself efforts are substantially less safe than the services of certified professionals. To the 

extent an appreciable difference exists between the quality of service (in terms of preventing or reducing 

lead-based paint hazards) provided by the two groups, they will not be perceived as close substitutes for 

each other and their demand curves will not be as elastic as they would have been if they were considered 

close substitutes. In such a situation, consumers feel that a sufficiently differentiated product is being 

offered by the two groups, and thus their choice is limited. 

This judgment on the degree of closeness of substitutes will to some extent depend upon the importance 

that lead safety holds with the homeowner compared to other priorities. To the extent that the priority 

assigned to lead exposure is relatively small, the uncertified professionals and do-it-yourself jobs will 

tend to be seen as closer substitutes for certified professionals, than if lead-based paint hazards are 

perceived as a larger threat by the household. Thus, the elasticity of demand will also vary according to 

homeowner priorities, and in this regard, the informational aspect of the RRP rule may in fact assist in 

raising more awareness, resulting in lead safety being assigned a higher priority. 

Of a related nature, the firm certification aspect of the rule is likely to increase consumer ability to 

differentiate between the services being offered by the three classes of substitutes. The certification 

process will create a distinct divide which will permit the homeowner to get a better appreciation of the 

varied benefits to be gained from the alternatives at hand. This is likely to reduce to some extent the 

perceived closeness of the substitutes and thereby make the demand more inelastic for each class of RRP 

service. 
§402(c) Economic Analysis Chapter 3 40

3A.2 How Price Elasticity of Demand Affects the RRP Rule

As discussed above, EPA foresees two separate pathways by which the RRP rule will take affect; 

increasing costs of production leading to a shift in supply and provision of information to consumers 

leading to a shift in demand. The way these two effects will play out and the role that price elasticities 

will play in the adjustment of prices and quantities under the two scenarios is discussed below. 

3A.2.1 Effect of RRP Rule on the Cost of Production (Supply Shift) 

EPA seeks to reduce exposure to lead-based paint hazards by the introduction of lead-safe work practices 

during RRP work. These practices involve the use of increased precautions in situations where lead-based 

paint hazards may potentially be created during RRP work, and as a result costs of RRP work are likely to 

increase above current levels. Since producers seek to maximize profits and in the baseline will produce 

goods using the lowest-cost combination of inputs, a rule requiring producers to change their input mix 

will necessarily increase the cost of production. Thus, one impact of the rule will be to increase the 

production costs, leading the supply curve to shift upward and to the left. 

Figures 3A-2(a) and 3A-2(b) demonstrate the distributional affects of such a hypothetical shift in supply 

in markets with different elasticities of demand. The price increase is much higher (P1 to P2) and the 

decrease in quantity demanded is much lower (Q1 to Q2) with a given shift in supply when demand is 

less elastic (as shown in Figure 3A-2(b)) as compared to the elastic demand scenario in Figure 3A-2(a). 

Thus, the consumers bear a higher share of the total social cost from the regulation (represented by the 

relatively larger decrease in the consumer surplus compared to that in the producer surplus). On the other 

hand, Figure 3A-2(a) shows that the higher the elasticity of demand, the lower the overall price increase, 

the larger the reduction in quantity demanded, and thus the larger the share of total costs to be born by 

producers (represented similarly by the larger decrease in producer surplus as compared to the consumer 

surplus). 

3A.2.2 Effect of RRP Rule on the Provision of Information to Consumers (Demand Shift)

The alternative regulatory approach is to provide information to consumers in the hopes that they will 

make more environmentally friendly consumption choices. In this case EPA alters the market outcomes 

by changing the demand for products. Figures 3A-3(a) and 3A-3(b) depict such a hypothetical example. 

In these cases the commodity in question (non lead-safe work practices) has negative environmental 

effects (byproducts). By educating consumers about these byproducts and alternative products that have 

lower levels of adverse effects (lead-safe work practices), EPA can change consumer preferences and 

shift demand for the “bad product” inward and to the left. This lower demand curve would more 

accurately reflect the true “social” marginal benefits of consuming the product. 

What are the likely distributional and efficiency effects of this type of regulatory policy? Figures 3A-3(a) 

and 3A-3(b) reveal that under both scenarios (for an elastic and inelastic supply curve), the downward 

shift in the demand curve will lead to a decrease in price and quantity demanded of the commodity. 

However, in the case of an elastic supply curve when the transition costs associated with switching to the 

production of other products is relatively low, the decrease in price of the commodity is smaller and the 

decrease in quantity demanded larger, as compared to the changes in the case of an inelastic supply curve 

involving high transition costs. Restated in terms of changes in producer and consumer surpluses, the 

producer surplus is reduced under each scenario, but the elastic supply curve causes a relatively smaller 
§402(c) Economic Analysis Chapter 3 41

burden to fall on the producer than the inelastic supply curve. Similarly, the consumer receives a 

reduction in social benefit under each scenario, however, the magnitude of this reduction is larger under 

the inelastic supply curve case. 

D1

D2

S

Q2 Q1

P1

P2

Q2 Q1

P1

P2

D2

D1

S

 Figure 3A-3(a) Figure 3A-3(b) 

3(a): Effects of a regulation-induced change in demand when supply is elastic 

3(b): Effects of a regulation-induced change in demand when supply is inelastic

3A.2.3 Application to Renovation 

In the Renovation, Repair and Painting Rule, EPA is both affecting production and providing information. 

The likely effects of the regulation on prices and welfare are difficult to discuss without more accurate 

information on the supply and demand elasticities. However, some general observations are warranted. 

The welfare effects of the regulation will likely be driven by the supply side rather than the demand side. 

This is because the elasticity of supply for RRP services is likely to be relatively higher than the elasticity 

of demand. Supply elasticities are expected to be relatively high because there are relatively few barriers 

to entering or leaving this industry. Little capital equipment or specialized labor skills are needed for 

RRP work, and what is needed is easily transferred from non-compliant renovation to “lead-safe” 

projects. On the demand side, there are two primary categories of RRP events – those of a maintenance 

character and those of an improvement character. Maintenance activities usually cannot be postponed 

and thus are not particularly sensitive to price. Improvement projects, however, can more easily be 

postponed and thus tend to be more price elastic. Complicating matters, however, are the existence of 

different categories of purchasers. Some place a high premium on quality and timeliness, while others 

actively seek low prices. Appendix 3B discusses some of the empirical evidence on elasticities of 

demand and supply. 

However, the analysis does not suggest that the education factor is unimportant. If the regulation is not 

accompanied by education efforts and enforcement, then EPA could unintentionally drive up demand for 

non-compliant renovation projects creating additional welfare losses. These losses are the result of the 

fact that if consumers were aware of the lead paint issues their true marginal valuation for the noncompliant projects is lower than the price of these projects. Thus, if enforcement is not perfect, education 

is essential. EPA can compensate for the fact that it is raising the costs of lead-free renovation on the 

supply side by educating consumers on the environmental effects of non-compliant renovations thereby 

making these cheaper, non-compliant projects less attractive. 
§402(c) Economic Analysis Chapter 3 42

Appendix 3B: Elasticities of Demand and Supply for Housing / 

Renovation Services 

As described in Chapter 3 and Appendix 3A, the impact of increases in the cost of RRP services on 

demand for RRP will depend on both the size of the cost increase and the elasticity of demand for these 

services. Likewise, the impact on the supply of RRP services will depend on both the size of the cost 

increase and the elasticity of supply for these services. These impacts are expressed in terms of changes 

in price and in the quantity of services purchased. Chapter 4 estimates the cost increases due to the 

requirements of the various regulatory options, based on the increased labor and materials costs of 

complying with the containment and clean-up requirements, as well as the training and certification costs 

imposed by the requirements. This appendix reviews the existing literature on residential demand 

elasticities. 

Unfortunately, RRP has received relatively little attention by housing economists. While there are many 

studies that estimate elasticities for new construction, these studies have only limited applicability to 

renovation and remodeling. The income elasticity of demand for housing is generally estimated to be 

somewhat inelastic (in the 1.0 to 0.8 range). This is consistent with housing being a necessity – 

expenditures on housing do not increase as rapidly as income (Green and Malpezzi 2003). Demand for 

housing is also considered to be somewhat price inelastic, with generally accepted values either in the 

range of -0.5 to -1.0 or -0.75 to -1.2 (Mayo 1981, Malpezzi and Maclennan 2001, Ellwood and Polinski 

1979). One study is available that estimated a renovation demand elasticity (Gyourko and Saiz 2003). 

This study found renovation demand to be very inelastic, with an elasticity estimated to be –0.28. 

On the other hand, housing supply appears to be very elastic – consistent with the highly competitive 

nature of the residential construction market and the large number of small contractors. Because it is very 

easy to enter (and to leave) the construction business, supply is very responsive to changes in prices, 

especially in the long run.1

 Based on the literature surveyed, estimates of housing supply elasticities tend 

to range from 1.0 to 4.0, but a couple of studies found elasticities as high as 13 or higher (DiPasquale and 

Wheaton 1994, Topel and Rosen 1988, Blackley 1999, Malpezzi and Maclennan 2001). No elasticity 

numbers specific to the supply of renovation services could be found. 

Several characteristics of RRP tend to make its demand more price elastic than the demand for housing in 

general. For example: 

• The existence of close substitutes to professional RRP. These substitutes include: 

o Do-It-Yourself RRP. One substitute for professional RRP (the regulated commodity) is 

Do-It-Yourself RRP (a non-regulated commodity) 

o Firms that do not complying with the regulations. These regulations may be difficult to 

enforce because of the large number of small contractors who may be hard to identify and 

monitor. If the regulations are not actively enforced, purchasers will be able to buy the 

services from non-compliant firms at a lower price. 

o Reductions in the scope of the projects to compensate for the price increase. Purchasers 

can reduce other RRP-related costs by substituting lower-priced appliances/fixtures 

and/or less extensive remodeling 

 

1

 Note – stock adjustment models give lower elasticities than flow models. Malpezzi and Maclennan (2001). 
§402(c) Economic Analysis Chapter 3 43

o Move instead of remodel. Purchasers can move to another dwelling that meets their 

needs/desires. 

• Many RRP projects are discretionary. The price elasticity of discretionary projects (e.g. new 

family room or updated/expanded kitchen) is likely to be higher than replacement projects (e.g. 

new roof).For discretionary RRP projects, it is relatively easy for the purchaser to reduce the 

scale/scope of the project, postpone the project, or never do it. 

Offsetting these characteristics that foster higher elasticities of demand, are ones that foster lower 

elasticities. The major one is that the product purchased cannot be separated from the firm providing the 

product, which is true of all services. In addition to the various RRP events analyzed in the subsequent 

chapters, RRP firms themselves are relatively differentiated. Some firms specialize in high-end, 

complicated projects (e.g. elaborate new kitchens) while other firms specialize in performing small 

routine tasks (repainting apartments at tenant turn-over). Some firms only work in historic or Victorian 

homes, while others will work on any type of home. Some firms do only one type of project (e.g. 

replacing siding) while other firms will do any and all types of RRP work. This differentiation results in 

lower demand elasticities, because producers are not considered particularly close substitutes. 

• To the extent that lead-safe work can be distinguished from non-lead-safe work, a higher price 

can be charged for it. 

• Many contractors already employ lead-safe practices (or at least control the dispersion of dust and 

clean well before leaving). The regulations will serve to reduce this differentiation. 

Second, the nature of RRP projects may also reduce price competition. For relatively small jobs, 

homeowners frequently will not get multiple bids – the assumed cost of the job does not warrant the 

effort. In this case, the compliance cost can be passed on without fear of losing the work. In the case of 

large jobs, where home owners will get bids, compliance costs will make up a relatively small proportion 

of the total cost and, again, passing on the costs may be easy. 

Characteristics of the purchaser of the RRP services may also affect their demand price elasticity. Highincome purchasers are likely to be less price sensitive than low-income purchasers. In addition, owners of 

rental properties may be more price sensitive than owner occupants because they have different objective 

functions. Owner-occupants operate so as to maximize their utility (their enjoyment of the house) and 

asset growth is likely to enter their decision as a secondary factor. Owners of rental housing, on the other 

hand, are assumed to be maximizing their profits. It is reasonable to expect that the optimal level of 

capital of an absentee landlord’s rental building is lower than that of an owner-occupier’s house, since the 

landlord’s marginal rent revenue from renovations is likely to be less than the homeowner’s marginal 

utility. 

Because of the lack of detailed price elasticity estimates for RRP, the analysis in the Chapters 4, 5 and 6 

do not incorporate any reduction in professional RRP activities in response to the cost increases resulting 

from the regulation. The sensitivity analysis presented in Chapter 7 and the small entity analysis in 

Chapter 8 addresses these issues. 
§402(c) Economic Analysis Chapter 3 44

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Housing Prices." Journal of Urban Economics, 35: 1-27. 
§402(c) Economic Analysis Chapter 3 45

Ellwood, David and Mitchell Polinski. 1979. “An Empirical Reconciliation of Micro and Grouped 

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§402(c) Economic Analysis Chapter 3 46

Rhode Island Department of Environmental Management Office of Technical and Customer Assistance 

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Conforming Amendments and Corrections. Federal Register (69 FR 34262, June 21, 2004). 
§402(c) Economic Analysis Chapter 3 47

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for Disclosure of Known Lead-Based Paint and/or Lead-Based Paint Hazards in Housing; Final 

Rule. Federal Register (61 FR 9064, March 6, 1996) 

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Exposure in Construction; Interim Final Rule. Federal Register (58 FR 26590, May 4, 1993). 

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39167, August 1, 1995). 

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Rule. Federal Register (63 FR 29908, June 1, 1998). 

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Activities Contractors; Final Rule. Federal Register (64 FR 31092, June 9, 1999). 

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and Enforcement. August 2005. 

Personal Communication with Paul Lamberti, Supervisor, Lead/Asbestos Unit at the New Jersey 

Department of Community Affairs. August 2005. 
§402(c) Economic Analysis Chapter 4 1 

4. Compliance Costs of the Renovation, Repair, and Painting Rule 

The costs associated with the regulatory impact of the §402(c) Renovation, Repair, and Painting (RRP) 

Rule are divided into three categories for the purposes of this analysis: (1) training costs, (2) work 

practice costs, and (3) certification costs (which include the firm’s paperwork burden and EPA 

administrative and enforcement costs). The general approach of the analysis is to first estimate the 

number of affected activities or entities, then estimate the incremental regulatory cost per-activity or 

entity affected. Finally, the incremental costs and the number of affected activities and entities are 

combined to estimate the total costs. The analysis first estimates the total costs associated with the first 

three years of regulation; then, the analysis extrapolates to the costs of the regulation over a fifty year 

period—estimated with three and seven percent discount rates. 

The chapter is organized as follows: Section 4.1 defines the regulatory options considered in this analysis; 

Section 4.2 estimates the number of regulated renovation, repair, and painting events under the various 

regulatory scenarios; Section 4.3 presents the estimated number of affected establishments and personnel; 

Section 4.4 presents the estimated incremental training costs; Section 4.5 presents the per-event work 

practice costs; Section 4.6 presents the administrative and enforcement cost estimates; and Section 4.7 

presents the total costs of the regulation. 

4.1 Definitions of Options 

The four options considered in this analysis differ by the type of housing units they affect and whether 

they are flexible or prescriptive. In each case, the differences in the types of housing units affected by the 

rule produces differences in the numbers of housing units affected by the rule. Table 4-1 summarizes the 

options considered in this analysis; they are described in more detail below. 

Options A, B, and C are described as flexible, which means that certified renovators can rely upon their 

training to determine how much containment is necessary and practical in any particular situation. Thus, 

when the analysis refers to the flexible options, it refers to Options A, B, and C together; these options 

differ in terms of the universe of housing units subject to the rule’s requirements during the first year of 

the rule. In addition to these three options, a more prescriptive option is considered, referred to as Option 

D. The containment, cleaning, and verification practices required under Option D are the same as those in 

the flexible options; however, Option D prescribes the size of the work area that must be contained, 

cleaned, and verified. Therefore, Option D is referred to as prescriptive. The proposed rule is Option B. 
§402(c) Economic Analysis Chapter 4 2 

4.1.1 Affected Universe, by Option 

The term “target housing” is defined in TSCA Section 401 as any housing constructed before 1978, 

except housing for the elderly or persons with disabilities (unless any child under 6 resides or is expected 

to reside in such housing) or any 0-bedroom dwelling. EPA is not proposing to modify this definition in 

any way. For Options B, C, and D, the type of housing units affected by the rule differs in the first year 

of the rule but are the same in all subsequent years of the rule thereafter. 

Option A 

During all years of the rule, the requirements in Option A would apply to renovation projects performed 

for compensation in: 

• All renter-occupied target housing. 

• All owner-occupied target housing, unless the firm performing the renovation obtains a statement 

signed by the owner that the renovation will occur in the owner’s residence and no child under 6 

resides there. 

Table 4-1: Summary of Options 

Option Universe 

Name Year 1 Years 2+ 

Containment, Cleaning, and 

Verification 

Option A All Pre-1978 renteroccupied target housing 

units and pre-1978 owneroccupied target housing 

units where a child under 

the age of six resides 

All Pre-1978 renteroccupied target housing 

units and pre-1978 owneroccupied target housing 

units where a child under 

the age of six resides. 

Flexible: 

Flexible containment practices, required 

cleaning and verification methods 

Option B All Pre-1960 renteroccupied target housing 

units and pre-1960 owneroccupied target housing 

units where a child under 

the age of six resides a

All Pre-1978 renteroccupied target housing 

units and pre-1978 owneroccupied target housing 

units where a child under 

the age of six resides. 

Flexible: 

Flexible containment practices, required 

cleaning and verification methods 

Option C All Pre-1950 renteroccupied target housing 

units and pre-1950 owneroccupied target housing 

units where a child under 

the age of six resides a

All Pre-1978 renteroccupied target housing 

units and pre-1978 owneroccupied target housing 

units where a child under 

the age of six resides. 

Flexible: 

Flexible containment practices, required 

cleaning and verification methods 

Option D All Pre-1960 renteroccupied target housing 

units and pre-1960 owneroccupied target housing 

units where a child under 

the age of six resides a

All Pre-1978 renteroccupied target housing 

units and pre-1978 owneroccupied target housing 

units where a child under 

the age of six resides. 

Prescriptive: 

Required containment practices, required 

cleaning and verification methods 

a. In Year 1, also includes all pre-1978 housing units where a child with an increased blood-lead level resides, 

where increased is defined as greater than or equal to 10 μg/dL or a State or local government level of concern, if 

lower. 

 The proposed rule is Option B. 
§402(c) Economic Analysis Chapter 4 3 

Option B 

During the first year, the requirements in Option B apply to renovation projects performed for 

compensation in: 

• All pre-1960 renter-occupied target housing. 

• All pre-1960 owner-occupied target housing, unless the firm performing the renovation obtains a 

statement signed by the owner that the renovation will occur in the owner’s residence and no 

child under 6 resides there. 

• All pre-78 target housing units where a child with an increased blood-lead level resides. 

For all subsequent years: 

• Option B is identical to Option A. 

Option C 

During the first year, the requirements in Option C apply to renovation projects performed for 

compensation in: 

• All pre-1950 renter-occupied target housing. 

• All pre-1950 owner-occupied target housing, unless the firm performing the renovation obtains a 

statement signed by the owner that the renovation will occur in the owner’s residence and no 

child under 6 resides there. 

• All pre-78 target housing units where a child with an increased blood-lead level resides. 

For all subsequent years: 

• Option C is identical to Option A. 

Option D 

During the first year of the rule: 

• The type of housing units affected during the first year of the rule under Option D is the same as 

the type of housing units affected during the first year of the rule under Option B. 

For all subsequent years: 

• The housing stock affected under Option D is identical to the housing stock affected during 

subsequent years of the rule under Option B. 

For each option, the proposal would apply to housing that is currently being rented, as well as housing 

being offered for rent and housing that the owner intends to offer for rent. Renovations to prepare 

housing for the rental market would have to be performed in accordance with this proposal. 

For the purposes of this proposal, children reside in the primary residences of their custodial parents, 

foster parents, and legal guardians. In addition, EPA is proposing to apply this regulation to housing 

where a child resides and sleeps most of the time, even if this housing is not the residence of the child’s 

legal custodians. This means that a child may have more than one residence; this requirement should 

ensure that the primary residences of all children under 6 are covered by the proposal. 
§402(c) Economic Analysis Chapter 4 4 

4.1.2 Proposed Containment, Cleaning, and Verification Standards, by Option 

The proposed containment, cleaning, and verification standards mentioned in this section are the same for 

all options. Options A, B, and C allow those who are performing the RRP activity to decide the extent of 

containment necessary. Contrastingly, Option D specifies the area to be contained. 

 Occupant protection 

Under proposed Section 745.85(a)(1), work areas must be clearly defined with signs warning occupants 

and other persons not involved in renovation activities to remain outside of the work area. These signs 

must be posted before beginning the renovation and must remain in place until the renovation has been 

completed and the work area has been verified to have been adequately cleaned. If warning signs have 

been posted in accordance with HUD’s Lead Safe Housing Rule (24 CFR §35.1345(b)(2)) or OSHA’s 

Lead in Construction Standard (29 CFR §1926.62(m)), additional signs are not required by this proposal. 

 Containing the work area 

Under proposed Section 745.85(a)(2), a firm must contain the work area so that no visible dust or debris 

leaves the work area while the renovation is being performed. Containment refers to methods of 

preventing leaded dust from migrating beyond the work area. It includes everything from the simple use 

of disposable plastic drop cloths to the sealing of openings with plastic sheeting. 

 Interior renovations 

When planning a renovation project, special consideration should be given to determining the type of 

work site preparation necessary to prevent dust and debris from leaving the work area. Renovation 

projects generate varying amounts of leaded dust, paint chips, and other lead-contaminated materials 

depending on the type of work, area affected, and applied work methods. For example, repairing a small 

area of damaged drywall would likely generate less lead-contaminated dust and debris than sanding a 

large area in preparation for painting. Similarly, a higher containment level would be necessary for 

demolition work than for scraping a small area. To address these differences, Option D specifies that all 

rooms where RRP is being performed must be contained except for events that are considered small. A 

small event is defined under Option D as an event where dust or debris from a disturbed painted surface 

are unlikely to migrate further than five feet from the disturbed area. The flexible options (Options A, B, 

and C) allow certified renovators to rely on their training and experience to determine the area that 

requires containment. The certified renovator is responsible for determining which level of containment 

is appropriate for a particular renovation. 

Under the current regulations for lead-based paint abatement activities, certain practices are prohibited. 

These practices are open flame burning or torching of lead-based paint; machine sanding, grinding, 

abrasive blasting, or sandblasting of lead-based paint except when done with HEPA exhaust control; dry 

scraping of lead-based paint except around electrical outlets or for any area no more than 2 square feet in 

any one room, hallway, or stairwell, or for any area no more than 20 square feet on exterior surfaces; and 

operating a heat gun at 1100 degrees Fahrenheit or higher. 

Unlike with abatement, EPA is proposing to allow the use of these practices during renovation activities. 

The Agency understands that, because these practices are commonly used during renovation work, 

prohibiting such practices could make certain jobs, such as preparing a surface for new painting, 

extremely difficult, if not impossible. For example, contractors have indicated there may be no practical 

way to restore old and historic millwork other than open flame burning, and that prohibiting dry scraping 

and sanding would cause many problems because wet sanding tends to raise the grain of wood surfaces 

preventing a smooth finish which consumers demand. The Agency believes that proper training, in 
§402(c) Economic Analysis Chapter 4 5 

combination with appropriate containment and cleanup requirements, adequately addresses the 

introduction of new hazards. 

 Exterior renovations 

For exterior projects, the firm preparing the work area would be required to close all doors and windows 

within and below the area undergoing renovation, and to cover the ground with plastic sheeting or other 

disposable impermeable material extending out from the edge of the structure a sufficient distance to 

collect falling paint debris. In addition, doors within the work area that must be used while the job is 

being performed would have to be covered with plastic sheeting to prevent dust and debris from entering 

the building. 

 Waste from renovations 

Renovation projects can generate a considerable amount of waste material. Lead-contaminated building 

components and work area debris must be handled carefully to prevent the release of lead-contaminated 

dust and debris. EPA is concerned that allowing the storage of lead contaminated waste where it may be 

accessible to residents could result in exposure to a lead-based paint hazard. Therefore, under proposed 

Section 745.85(a)(3), a firm would be required to contain the waste from renovation activities to prevent 

releases of dust and debris before the waste is removed from the work area for storage or disposal. If a 

chute is used to remove waste from the work area, it must be covered. At the conclusion of each work 

day and at the conclusion of the renovation, waste that has been collected from renovation activities must 

be stored under containment, or behind a barrier that prevents release of dust and debris out of the work 

area and prevents access to dust and debris. 

In addition, transporting lead-based paint waste in uncovered vehicles is a possible source of releases of 

paint chips or dust. Therefore, lead-based paint waste from RRP activities would be required to be 

transported under containment that prevents identifiable releases (e.g., inside a plastic garbage bag). 

 Cleaning the work area 

Under proposed Section 745.85(a)(4), a firm would be required to clean the work area until no visible 

dust, debris, or residue remains. EPA is also proposing to require more thorough cleaning, which would 

remove both visible debris and dust particles too small to be seen by the naked eye. All renovation 

activities that disturb painted surfaces can produce dangerous quantities of leaded dust. Because very 

small particles of leaded dust are easily absorbed by the body when ingested or inhaled, a small amount 

can create a health hazard for young children. Unless this dust is properly removed, a work area will be 

more hazardous after the work is completed than it was originally. Therefore, careful cleaning is 

required. Improper cleaning can increase the cost of a project considerably because additional cleaning 

may be necessary during post-renovation cleaning verification. Although it may not be possible to 

remove all leaded dust generated by the renovation, it is possible to reduce it below the EPA floor hazard 

level, 40 μg/ft2

. 

The special cleaning methods and procedures required by the proposed option are typically not standard 

operating procedures for general home improvement contractors. Therefore, this proposal seeks to train 

renovators and establish containment and cleaning procedures to ensure no lead-based paint hazards are 

introduced as a result of a renovation. 

 Cleaning verification 

EPA is proposing to require an additional cleaning verification step following the visual inspection. This 

step would involve wiping the windowsills and floors with specialized cleaning cloths and comparing 

them to a cleaning verification card developed and distributed, or otherwise approved, by EPA for the 
§402(c) Economic Analysis Chapter 4 6 

purpose of determining, through comparison of disposable cleaning cloths with the card, whether 

postrenovation cleaning has been properly completed. 

4.2 Estimating the Number of Regulated Renovation, Repair, and Painting Events 

To achieve the rule’s objective of controlling lead exposure through containment, cleanup, and 

verification, most of the compliance costs associated with the RRP rule’s work practices pertain to the 

room or area where the renovation work is performed. Therefore, this analysis defines a regulated event 

as any group of renovation tasks where two or more square feet of a painted surface are disturbed in a 

specific room or area of a housing unit. The 2003 American Housing Survey (AHS) is the primary data 

source for the estimates of regulated RRP events that occur in owner-occupied housing. The 1995 

Property Owners and Managers Survey (POMS) is the primary data source utilized for estimating the 

number of regulated events in renter-occupied housing. 

Event counts are estimated separately for single- and multi-family units since compliance costs for the 

two types of housing differ (primarily because the average unit size differs). In addition, the counts of 

exterior events for multi-family housing units are adjusted to correspond to building-specific compliance 

costs.1

Available renovation data do not include information specific enough to determine when a renovation 

task disturbs a painted surface, or when renovation tasks are performed together in the same room or area. 

Thus, it was necessary to make some assumptions about which types of renovation tasks are likely to 

disturb painted surfaces and which sets of tasks are likely to be performed together as part of one 

renovation project. 

4.2.1 Data Sources 

U.S. Census: American Housing Survey 

According to the U.S. Census (2005g): 

The survey is conducted by the Bureau of the Census for the Department of Housing and Urban 

Development (HUD). 

The American Housing Survey (AHS) collects data on the Nation's housing, including 

apartments, single-family homes, mobile homes, vacant housing units, household characteristics, 

income, housing and neighborhood quality, housing costs, equipment and fuels, size of housing 

unit, and recent movers. National data are collected in odd numbered years, and data for each of 

47 selected Metropolitan Areas are collected currently about every six years. 

The surveys utilized in this analysis, 1997 and 2003, have sample sizes of 45,932 and 55,452, 

respectively. Of the housing units sampled, 33,549 and 35,996, for the 1997 and 2003 surveys 

respectively, have at least one bedroom, are not public housing, receive no rent subsidies, and were built 

before 1980. The 2003 AHS groups housing units built in the 1970’s as units built between 1970-74 or 

1975-1979, so this analysis counts all housing units built before 1980 in the pre-1978 regulated universe. 

 

1

 For example, when siding is replaced on the outside of a three-unit building, the analysis accounts for this as one

siding replacement event rather than the siding replacement outside of three units. 
§402(c) Economic Analysis Chapter 4 7 

The sample weights provided by the U.S. Census for analyzing the AHS data were designed so that 

estimates using the provided sample weights would represent the population of housing in the nation. 

However, the U.S. Census weights were not designed to correct for underreporting within housing units—

such as information reported on occupants living in the housing units. Since there is underreporting 

within-housing units, estimates of the number of individuals calculated using the U.S. Census weights 

results in lower population estimates than those estimated using other U.S. Census population data 

sources. In addition, according to Harvard’s Joint Center for Housing Studies (personal communication 

with Kermit Baker August 2005), it appears that the 2003 survey labels too many housing units as vacant; 

these units are actually occupied by individuals that did not respond to the survey. To correct for this 

bias, the Joint Center for Housing Studies has adjusted the weights provided by the U.S. Census for the 

2003 AHS. These adjusted weights provided by the Joint Center for Housing Studies are utilized for all 

of the calculations using the 2003 AHS in this analysis; population estimates calculated from the AHS are 

more closely aligned with other U.S. Census population estimates when calculated with these adjusted 

weights. 

U.S. Census: Property Owners and Managers Survey

According to the U.S. Census (2005h): 

The Property Owners and Managers Survey (POMS) was designed to learn more about rental 

housing and the providers of rental housing. The purpose was to gain a better understanding of 

the property owners and managers on whom the nation depends to provide affordable rental 

housing and what motivates their rental and maintenance policies. Interviewing for the survey 

was done between November 1995 and June 1996. 

A nationwide sample of approximately 16,300 housing units which were rented or vacant-for-rent 

in the 1993 American Housing Survey National Sample (AHS-N) was selected, and a 

questionnaire was mailed to the property owner, manager, or other agent of the owner of each 

property containing a selected unit. Detailed information was collected on maintenance, 

management practices, tenant policy, financial aspects of rental property ownership, owner 

characteristics, and related topics. 

POMS Sample Areas 

The addresses included in the POMS sample were limited to counties and independent cities in 

the 438 sampling areas used for the Census Bureau's 1993 American Housing Survey (AHS) 

National Sample. 

Units Included 

A unit (and the property containing the unit) was included in the survey if it was a privately 

owned rental unit in the 1993 AHS-N, and was still rental at the time of the POMS (November 

1995 to June 1996). A unit was considered rental if it was either rented for cash rent, occupied by 

someone other than the owner without payment of cash rent, or vacant but available for rent. 

Since the POMS survey is relatively old (1995), this analysis first calculates the percentage of rentalhousing units performing renovations according to the POMS and then applies these percentages to the 

corresponding number of rental-housing units in 2003 according to calculations using the AHS. This is 

described in greater detail in the section below. 
§402(c) Economic Analysis Chapter 4 8 

4.2.2 Number of Regulated Events in Owner-Occupied Housing Units 

The 2003 AHS is the primary data source used for estimating the number of RRP events in owneroccupied housing for which compliance costs will be incurred. The 1997 AHS is also used for estimating 

the number of RRP events since it contains some more specific renovation information that was not 

included in the 2003 survey. AHS respondents report information about the ages of householders, who 

are defined by the survey as persons who live or sleep there most of the time. Thus, child-occupied 

households are defined as those households that report having a householder under the age of 6. This 

section describes how the numbers of events are estimated from the renovation module of the AHS and 

the methodology for estimating the number of Interior Painting and Exterior Painting events using data 

from the (one-time) 1997 lead paint module of the AHS. 

AHS Renovation Tasks 

The 2003 AHS allows respondents to report 40 different renovation tasks; this analysis categorized 24 of 

these 40 as tasks that may disturb more than 2 square feet of a painted surface. Since tasks performed 

within two years of the survey can be reported, it is assumed that half occurred in the first year and half 

occurred in the second (i.e. the total number of events counted for the two year period is divided by two). 

Table 4-2 lists these 24 renovation tasks by their event category. The seven event categories (bathroom 

event, kitchen event, addition event, non-room-specific window/door event, non-room specific 

wall/ceiling event, whole exterior event, contained exterior event) are defined based on the room or area 

where each renovation task is likely to be performed. When a household reports multiple tasks listed 

under the same event category, it is assumed that these tasks are performed together in the same area; 

therefore, one set of compliance costs are assumed to apply to each event. For example, a household 

reporting replacing their air conditioning system and replacing their heating system is assumed to incur 

the compliance costs associated with one Non-Room-Specific event.2

 Similarly, when a household 

reports a Non-Room-Specific task as well as a room-specific task—e.g. remodeling the kitchen (specific 

to the kitchen) and replacing water pipes (non-room-specific), the analysis accounts for the costs 

associated with one Non-Room-Specific event (rather than one Non-Room-Specific event plus one 

Kitchen event). In other words, when tasks specific to a room are reported together with tasks that are not 

specific to a room, it is assumed that the Non-Room-Specific work area includes the specific rooms where 

other tasks are reported. 3 However, if a household reports multiple room-specific events (such as 

remodeling the kitchen and bathroom), all of the room-specific events are counted. 

As shown in Table 4-2 and discussed above, some tasks are not necessarily confined to a specific room or 

area of the unit. In these cases, the tasks are assigned to a Non-Room-Specific event. Of the tasks that 

are not specific to any room, the analysis differentiates between tasks that are likely to only disturb 

painted surfaces on walls or ceilings and those that involve adding and/or replacing windows and/or 

 

2 A Non-Room Specific Event is an interior event that is not a bathroom, kitchen, or addition event.

3 When the compliance costs are estimated for Non-Room-Specific events, it is assumed that the work area that must 

be contained, covered with plastic sheeting, and cleaned makes up 50 percent of the housing unit. When a 

household reports adding/replacing windows/doors together with at least one Non-Room-Specific Wall/Ceiling task, 

this is counted as a Non-Room-Specific Window/Door event, which has the same large event compliance costs as a 

Non-Room-Specific Wall/Ceiling events, but higher small event compliance costs. The small event cost associated 

with Non-Room-Specific Window/Door events is based on specific window/door-removal practices used to remove 

windows and doors from the exterior of the unit. A small interior event is one that affects only one side of a room 

and a large interior event affects the entire work area, which could include one or more rooms. 
§402(c) Economic Analysis Chapter 4 9 

doors. This distinction is made because lead-based paint (LBP) is more likely to be found on windows 

and doors; therefore, a LBP test kit result is more likely to be positive for LBP when testing these 

surfaces. 

As stated above, the 2003 AHS did not explicitly ask respondents whether a renovation task involved 

disturbing a painted surface. Therefore, assumptions are made about which tasks might disturb paint in 

order to estimate the number of events subject to the rule’s requirements. In general, when a reported task 

will sometimes involve disturbing a painted surface, it is assumed that compliance costs are incurred each 

time that task is reported. For example, replacing internal water pipes will sometimes, but not always, 

require disturbing painted walls to access old pipes and replace them with new ones. However, the 

analysis makes no adjustment to account for the instances where no painted surfaces are disturbed (or 

when less than two square feet of a painted surface is disturbed). Sufficient data for making such an 

adjustment are not available. Thus, these assumptions may lead to an overestimate of the number of 

regulated events. 

In the case of adding or replacing heating equipment (AHS task 58) and/or central air conditioning 

equipment (AHS task 57)—Heating Ventilation and Air Conditioning (HVAC) tasks—it is assumed that 

only a fraction of these HVAC tasks require disturbing a painted surface. In addition, 18 percent of the 

households reporting tasks listed in Table 4-2 reported at least one HVAC task without reporting any 

other Non-Room-Specific task. Therefore, assuming that all HVAC work requires disturbing painted 

surfaces is likely to result in a substantial overestimate of regulated Non-Room-Specific Wall/Ceiling 

events. 

The percentages of HVAC tasks that are assumed to disturb painted surfaces are estimated using the 1997 

AHS. Unlike the 2003 AHS, the 1997 AHS distinguishes between installing new HVAC equipment and 

replacing existing equipment. Since disturbing a painted surface is most likely to occur while performing 

work on the HVAC ducts (which often are behind painted walls), it is assumed that this occurs when new 

systems are installed but not when existing systems are replaced.4

In summary, when a household’s only reported Non-Room-Specific tasks are HVAC tasks, it is assumed 

that this disturbs a painted surface some percentage of the time, depending on which combination of 

HVAC tasks are reported. For households reporting a HVAC task and a room specific task, it is assumed 

that a Non-Room-Specific event occurs when a new HVAC system is added, and the room event(s) 

occurs the remaining percentage of the time (since the analysis only counts the Non-Room-Specific event 

when both a Non-Room-Specific and a room specific task are reported). 

In addition to these seven event definitions, Interior Painting events and Exterior Painting events are also 

estimated. The remodeling module of the 2003 AHS data does not cover these types of activities, so data 

from the 1997 (one-time) lead module are utilized to estimate the number of these events. 

 

4

 When heating equipment work (but not air conditioning work) is reported, 7 percent and 9 percent of these tasks 

involve adding a new system for single- and multi-family units, respectively. When air conditioning equipment 

work (but not heating work) is reported, 36 percent and 17 percent of these tasks involve adding a new system for 

single- and multi-family units, respectively. When both heating and air-conditioning equipment work is reported, 52 

percent and 29 percent of the households install a new system for single- and multi-family units, respectively. 
§402(c) Economic Analysis Chapter 4 10 

Interior Painting Events 

In the 1997 AHS, respondents were asked two questions related to painting activities that are used to 

estimate the number of Interior Painting events. Respondents were asked: 

• Was there any painting done on the inside of the unit? 

• Before painting, did anyone sand or scrape off any of the old paint? 

Unfortunately, obtaining a count of the number of Interior Painting events is not as simple as adding up 

the number of respondents that answered yes to both of these questions. It is also necessary to estimate: 

(1) how many of the respondents that had painting done with sanding or scraping hired a professional to 

do the work, and (2) how many of these events occur in conjunction with other professional events 

Table 4-2: List of 2003 AHS Renovation Tasks, Grouped by Room or Area 

AHS Task ID Task Description 

Bathroom Event 

71 Remodeled bathroom 

 

Kitchen Event 

72 Remodeled Kitchen 

Addition Event 

7 Added Bathroom onto home 

8 Added Kitchen onto home 

9 Added Bedroom onto home 

10 Added other inside room onto home 

35 Bedroom created through structural changes 

36 Other room created through structural changes 

73 Bathroom created through structural changes 

Non-Room-Specific Window/Door Event 

45 Added/Replaced doors/windows to home 

Non-Room-Specific Wall/Ceiling Event

40 Added/replaced internal water pipes in home 

42 Added/replaced electrical wiring, fuse boxes, or breaker switches in home 

47 Added/Replaced plumbing fixtures in home 

55 Installed paneling or ceiling tiles 

57 Added/replaced central air conditioning 

58 Added/replaced built-in heating equipment 

64 Other major improvements or repairs (up to three could be reported) 

74 Added/replaced security system in home 

Whole Exterior Event 

38 Added/replaced siding on home 

Contained Exterior Event

11 Added attached garage onto home 

12 Added porch onto home 

13 Added deck onto home 

14 Added carport onto home 

69 Added/replaced shed, detached garage, or other building 
§402(c) Economic Analysis Chapter 4 11 

reported (so the analysis does not double count if, for example, someone painted with sanding or scraping 

in their kitchen and reported both painting with sanding or scraping and remodeling their kitchen). 

To avoid the double counting problem, the analysis only counts an interior painting job as an event if no 

other in-scope renovation task was reported. That is, if a household reports remodeling their kitchen and 

painting with sanding and scraping, it is assumed that this is one event. Therefore, this will result in 

undercounting when the room painted was not where the reported task occurred. 

More formally, the number of Interior Painting events is the number of professionally performed in-scope 

2003 RRP events multiplied by the 1997 ratio of [number of units reporting painting with sanding or 

scraping—includes do-it-yourself painting] to [number of lead-disturbing renovation events—includes 

do-it-yourself events]. Thus, there are two critical assumptions: (1) the ratio of exclusive interior painting 

renovations to other renovations is the same in 1997 and 2003, and (2) the professional share of interior 

painting work is the same as the professional share of other renovation work. Since painting is one of the 

more popular do-it-yourself jobs, this second assumption may lead to an overstatement of the number of 

Interior Painting events. 

Exterior Painting Events 

This analysis assumes that exteriors of 100 percent of homes with some paint on their exterior are painted 

with sanding or scraping every eight years.5

 Since data on the percentage of homes with some paint on 

their exteriors are not available, it is assumed that 75 percent of homes have some exterior paint; this 

assumption is based on data from HUD’s (2000) National Survey of Dust Lead Hazards and Allergens in 

Housing, which indicates that 70 percent of pre-1960 homes have some lead paint on their exterior. Since 

nearly all exterior painted surfaces on pre-1960 homes are likely to have some lead paint, it was assumed 

that slightly more, 75 percent, of all pre-1978 homes have exterior painted surfaces. The annual number 

of Exterior Painting events is estimated as one eighth of the number of regulated structures with exterior 

paint. 

4.2.3 Number of Regulated Events in Renter-Occupied Housing Units 

The 1995 POMS is the primary data source used for estimating the number of RRP events in renter 

occupied housing where compliance costs will be incurred. The 1997 and 2003 AHS are also used for 

estimating the number of renter-occupied RRP events, since these data contain more current estimates of 

the number of potentially regulated households as well as some other information not available from the 

POMS. 

This section first describes how the POMS data are used to obtain the annual percentage of renteroccupied housing units where there is a regulated RRP event. Second, it describes the methods employed 

for combining the percentages estimated from the POMS and the AHS data to obtain an estimate of 

regulated RRP events in renter-occupied units for the first year the rule is in effect. 

 

5

 According to the Painting and Decorating Council, exteriors of homes are usually painted every 4-12 years; thus, 

the analysis uses the midpoint, eight, for estimating the number of Exterior Painting events. 
§402(c) Economic Analysis Chapter 4 12 

POMS Data 

The POMS data generally has less detail then the AHS but is still the best source of renter-occupied 

renovation information available. The POMS asked property owners or managers about 12 or 13 types of 

maintenance and repair activities (for single-family and multi-family units respectively) and about 11 

types of capital improvements that may have been made to one of their units. It is likely that 12 of these 

maintenance, repair, or upgrade activities require disturbing painted surfaces; these activities are listed in 

Table 4-3 according to the event category that they are classified by in this analysis. 

The percentage of units where at least one of the RRP activities listed under each event was performed is 

calculated by type of unit (single- or multi-family). Similarly to the owner-occupied event estimate, if a 

Non-Room-Specific activity was reported together with a room specific activity, the Non-Room-Specific 

event was counted and the room specific event was not. Unlike in the AHS data, respondents were not 

asked whether sanding or scraping was performed before painting (and painting without sanding or 

scraping is not subject to the rule’s requirements). Therefore, it is assumed that 40 percent of the 

households reporting interior painting are subject to the rule’s requirements; this is based on the 

percentage of rental households that reported sanding or scraping before painting in the AHS.6

Since the POMS does not ask respondents about replacing windows or doors, the frequency that these 

tasks are performed is assumed to be the same in rental units as observed in owner-occupied units; 3.7 

and 3.4 percent of owner-occupied single- and multi-family units, respectively, replace windows or doors 

each year. Since these improvements are likely to be reported in the POMS data as ‘other major 

upgrades,’ the numbers of these tasks that are reported are adjusted downward to reflect this. In 

summary, 37 and 23 percent of ‘other major upgrades’ reported in the POMS are assumed to be window 

or door replacements, for single- and multi-family units respectively. 

In contrast to the methodology employed for estimating owner-occupied events, when Interior Painting is 

reported along with a room-specific activity, only the Interior Painting event is counted—only the roomspecific event is counted for the owner-occupied estimates. This distinction between owner- and renteroccupied units is made because interior painting is more likely to occur throughout the unit in rental units 

than in owner-occupied units— since painting in rental units is generally a maintenance-related activity, 

whereas painting in an owner-occupied unit is more likely to be part of an improvement. 

Similarly to the methodology for the owner-occupied RRP event estimates, it is assumed that HVAC 

related activities do not always incur compliance costs. The analysis assumes that compliance costs are 

incurred 28 percent and 15 percent of the time, for single- and multi-family units respectively, which is 

the percentage of the time new equipment is installed when HVAC work is performed in owner-occupied 

units according to the 1997 AHS. 

 

6

 The 40 percent of rental units that reported sanding or scraping before painting in AHS compares to the 35 percent 

of owner-occupied units units that reported sanding or scraping before painting. 
§402(c) Economic Analysis Chapter 4 13 

Extrapolating from the POMS and AHS Data 

After calculating the percentages of rental units that performed RRP in the event categories listed in Table 

4-3, the number of renter-occupied events in these categories are calculated by applying the percentages 

calculated with the 1995 POMS data to the number of rental-units according to the 2003 AHS. It is 

assumed that Whole Exterior events and Contained Exterior events occur in rental units with the same 

frequency as they do in owner-occupied units (since data on these types of events are not available in the 

POMS). Addition events are not estimated for rental units since these renovation activities in these rooms 

are fairly uncommon in rental units and likely to already be reported as ‘other major upgrade’ and 

counted as a Non-Room-Specific event. 

Table 4-3: List of 1995 POMS RRP Activities that are Grouped by a Room or Area 

Specific Event

 Interior Painting Event 

 Any Interior Painting in 1995 

 Bathroom Event 

 Upgraded Bathroom in 1995 

 Kitchen Event

 Upgraded Kitchen in 1995 

 Non-Room-Specific Wall/Ceiling Event

 Unit Rewired in 1995 

 Other major repairs in 1995a

 Upgraded Plumbing in 1995 

 Upgraded Security System in 1995 

 Other Major Upgrade in 1995 

 Repaired Heat or AC in 1995 

 Upgraded Heat in 1995 

 Upgraded AC in 1995 

Non-Room-Specific Window/Door Event

Other Major Upgrade in 1995a

 Exterior Painting Event

 Any Exterior Painting in 1995 (single-family units only) 

a Some ‘Other Major Upgrades’ are counted as Non-Room-Specific Wall/Ceiling events, others are 

counted as Non-Room-Specific Window/Door events. See text above for a description of how the 

task is apportioned. 
§402(c) Economic Analysis Chapter 4 14 

4.2.4 Number of Regulated Events in Compliance During First Year of Regulation 

Table 4-4 presents the estimated number of regulated events in compliance with the rule the first year the 

requirements come into effect. These are estimated using the methodology outlined above along with the 

assumption that 75 percent of the RRP events subject to the rule’s requirements comply with the 

requirements. This assumption is based on compliance rates observed for the Occupational Safety and 

Health Administration’s (OSHA) regulations for the construction industry (Gilkeya 2003 and Weil 1999). 

The variation in the number of regulated events in compliance under the different options reflects the 

variation in the regulated universe. Thus, Table 4-4 shows that the number of regulated events is highest 

under Option A, where all pre-1978 renter-occupied target housing units and pre-1978 owner-occupied 

target housing units where a child under the age of six resides are subject to the requirements. Under 

Options B and D, pre-1960 renter-occupied target housing units and pre-1960 owner-occupied target 

housing units where a child under the age of six resides are subject to the requirements in the first year. 

Under Option C, pre-1950 renter-occupied target housing units and pre-1950 owner-occupied target 

housing units where a child under the age of six resides are subject to the requirements in the first year. 

Note that since the regulated universe will be the same under all four options after the first year, the 

number of regulated events in compliance will be the same under all the options in subsequent years. 

Also, for Options B, C, and D, the estimated number of events covered by the rule does not account for 

the events that are regulated because a child with an increased blood-lead level is living in a unit built 

before 1978. It would be difficult to estimate this because triggers for increased blood lead levels vary 

from community to community. This provision of the rule is estimated to account for a very small 

number of events—less than 0.2 percent for Options B and D.7

Since it is assumed that certified renovators always use a test kit to detect the presence of LBP before 

performing any RRP, the number of events presented in Table 4-4 represents the estimated number of 

tests performed using LBP test kits during the first year the rule goes into effect. About 40 percent of all 

events include renovation tasks that disturb walls and/or ceilings, but are not specific to any room (NonRoom Specific Wall/Ceiling Events). Exterior Painting accounts for nearly 20% of all events (note that 

this is the number of buildings where exterior painting is performed, so the number of units where there is 

exterior painting is larger). Additions account for the smallest share of the events, which reflects the fact 

that they are not reported for rental-units where they are likely to occur only rarely. 

 

7

 For example, there are an estimated 310,000 children with blood-lead levels greater than 10 μg/dL, a common 

community action threshold, and only about 75,000 are aware of their condition (MMWR 2003). If these children 

were equally likely to reside in housing units built in any year pre-1978, then about 46 percent would reside in units 

built between 1960 and 1980, and of these about 30 percent would have an RRP event in a year. Thus, under these 

assumptions, 10,000 additional events would be covered in the first year. This is likely to be a substantial 

overestimate, however, since other data show that children with an increased blood lead level are more likely to be 

living in older homes. Based on NHANES data for 1991-1994, about 8.6 percent of children living in pre-46 

housing units had an increased blood lead level, while only 4.6% of children living in units built between 1946 and 

1973 did (MMWR 1997). Thus the actual number of events due to children with increased blood lead levels living 

in housing units built between 1960 and 1980 is likely to be well below 10,000. 
§402(c) Economic Analysis Chapter 4 15 

4.2.5 Number of Events Employing Lead-Safe Work Practices 

Likelihood of Positive Test Kit Result for LBP 

It is assumed that all certified renovators use a test kit for LBP before performing any RRP, because 

performing the relatively inexpensive test may allow the renovator to avoid the costs of using Lead-Safe 

Work Practices (LSWP) that are required when LBP is disturbed. Since LBP is most likely to be found 

on certain components of housing units—and therefore most likely to be disturbed during certain types of 

renovations—the analysis accounts for this by estimating LBP likelihoods specific to each event type. 

These LBP likelihoods are estimated using data from HUD’s 2000 National Survey of Lead and 

Allergens in Housing (HUD 2000).8

 These data include information on approximately 630 housing units 

built before 1978, including data on the presence of LBP in certain rooms (e.g. kitchen) and on certain 

components or surfaces (e.g. floors, walls, ceilings, doors and windows). 

The probability that LBP is disturbed during a RRP event is estimated as the probability of LBP in any of 

the rooms where RRP is performed or on any of the components that might be disturbed during the RRP 

 

8 In addition to the likelihood of lead-based paint varying by age of housing, there is evidence that the concentration 

of lead in the paint varies by the age of housing. A review of the data in HUD 2000 is presented in EPA 2005c. 

This document is available in the docket for this rulemaking.

Table 4-4: Number of Events where Compliance Costs Are Incurred, First Year of Regulation 

Event Type Option A Option B Option C Option D 

Kitchen 848,766 438,199 333,187 438,199 

Bathroom 582,256 305,193 229,762 305,193 

Additions 14,080 6,208 4,501 6,208 

Non-Room-Specific Wall/Ceiling 4,385,000 2,332,696 1,743,874 2,332,696 

Non-Room-Specific Window/Door 980,233 537,820 387,996 537,820 

Interior Painting 1,727,358 924,003 691,317 924,003 

Whole Exterior 207,960 118,542 82,005 118,542 

Contained Exterior 150,358 87,301 60,429 87,301 

Exterior Painting 1,831,884 1,069,018 765,265 1,069,018 

Total 10,727,895 5,818,980 4,298,336 5,818,980 

Note: Events where compliance costs are incurred include those that are: (1) subject to the rule’s requirements, and 

(2) in compliance. Thus, this includes some events where LSWP are not required because a test kit indicates that 

LBP is not present. It excludes the 25% of regulated events that are assumed to be noncompliant. 

Option Descriptions: Option A: All pre-1978 renter-occupied target housing units and all pre-1978 owner-occupied target 

housing units where children under the age of six reside are subject to the rule; WPS requirements are flexible. Option B: All

pre-1960 renter-occupied target housing units and all pre-1960 owner-occupied target housing units where children under the age

of six reside are subject to the rule in the first year it is in effect (Phase 1); in the second year (Phase 2), all pre-1978 renteroccupied target housing units and all pre-1978 owner-occupied target housing units where children under the age of six reside are 

subject to the rule; WPS requirements are flexible. Option C: All pre-1950 renter-occupied target housing units and all pre-1950 

owner-occupied target housing units where children under the age of six reside are subject to the rule in the first year it is in 

effect (Phase 1); in the second year (Phase 2), all pre-1978 renter-occupied target housing units and all pre-1978 owner-occupied 

target housing units where children under the age of six reside are subject to the rule; WPS requirements are flexible. Option D: 

All pre-1960 renter-occupied target housing units and all pre-1960 owner-occupied target housing units where children under the

age of six reside are subject to the rule in the first year it is in effect (Phase 1); in the second year (Phase 2), all pre-1978 renteroccupied target housing units and all pre-1978 owner-occupied target housing units where children under the age of six reside are 

subject to the rule; WPS requirements are prescriptive.

Source: U.S. Census Bureau 1997 and 2003; U.S. Census Bureau 1995; EPA Calculations.
§402(c) Economic Analysis Chapter 4 16 

event. This assumption leads to an upward bias in the estimates of the number of events where LSWP are 

required. For example, if there is LBP in the kitchen, it is assumed that a kitchen remodeling will disturb 

LBP. However, the LBP component(s) will not necessarily always be disturbed. For example, the LBP 

in the kitchen may be on the window trim, but the renovation may not disturb the window trim. 

Unfortunately, there is no reasonable basis for correcting this bias using currently available data. For the 

purposes of this analysis, data from HUD (2000) are used to estimate event-specific likelihoods of 

positive test kit results based on the estimated likelihood of disturbing LBP for each event type, as Table 

4-5 describes. 

Test kits for LBP that are currently available have false positive rates that range from 47 percent to 78 

percent; this analysis assumes a false positive rate of 63 percent, the midpoint, for the first year that the 

rule’s requirements are effective. By the end of the first year of regulation it is assumed that an improved 

test kit will be developed that will have a false positive rate of 10 percent or less.9

 Thus, the likelihood of 

a positive test kit result in the first year is estimated as the likelihood of LBP plus 63 percent of the 

percentage of homes without LBP. In the second year, the likelihood of a positive test kit result is 

estimated as the likelihood of LBP plus 10 percent of the percentage of homes without LBP. Table 4-6 

shows the likelihoods of LBP and positive test kit results that are used to estimate the percentage of 

events where LSWP will be employed. 

 

9

 EPA believes that the sensitivity of test kits can be adjusted so the results reliably correspond to one of the two 

Federal standards for lead-based paint (1.0 mg/cm2

 and 0.5% by weight). EPA is planning to conduct research to 

further the development of test kits that accurately identify both the presence and absence of lead in paint at levels 

that exceed the Federal standards. EPA is confident that improved test kits can be commercially available within the 

next three years, i.e., by the time the second stage of the rule becomes effective. This timing will coincide with the 

expansion of the regulatory universe to include housing units built between 1960 and 1978. Alternatives for the test 

kit costs described in Section 4.5.1 and the development time-frame for the improved test kits are considered in 

sensitivity analyses presented in Chapter 7.

Table 4-5: Types of Estimates Used for Calculating the Likelihood of Disturbing LBP for Each Event Type 

Event Type Estimate of Likelihood of Disturbing LBP 

Kitchen Likelihood of LBP in the kitchen 

Bathroom Likelihood of LBP in ‘other room’ (up to two ‘other rooms’ were inspected for LBP in 

each housing unit; these rooms might be bathrooms, living rooms, dens, or laundry rooms) 

Additions Likelihood of LBP on the interior or exterior of the unit (since these events typically 

require some demolition of the interior and exterior) 

Non-Room-Specific 

Wall/Ceiling 

Likelihood of LBP on any walls, floors or ceilings of the housing unit 

Non-Room-Specific 

Window/Door 

Likelihood of LBP anywhere on the interior or exterior of windows and doors 

Interior Painting Likelihood of LBP anywhere in interior of unit 

Whole Exterior Likelihood of LBP anywhere on exterior of unit 

Contained Exterior Likelihood of LBP anywhere on exterior walls of unit (since Contained Exterior events—

such as replacing a porch—are likely to disturb exterior walls, but not very likely to 

disturb other exterior components such as windows 

Exterior Painting Likelihood of LBP anywhere on exterior of unit 

EPA estimated LBP Likelihoods with room and component/surface specific data from HUD (2000). 
§402(c) Economic Analysis Chapter 4 17 

In cases where a household performed more than one interior event, the likelihood of disturbing LBP is 

estimated as the likelihood of LBP anywhere in the interior of the unit. There are two exceptions to this: 

(1) when one of the events is an Addition, the Addition likelihood is used, and (2) when the sum of the 

individual event probabilities is less than the likelihood of LBP anywhere in the interior of the unit, the 

sum of the event probabilities is used. These simplifying assumptions are necessary because the data are 

not sufficient for calculating the joint probabilities that would be necessary for relaxing this assumption. 

As a result, the estimates of the number of events where LSWP are used will be biased upward. That is, 

for a housing unit performing multiple interior events, it is assumed that if there is LBP in the housing 

unit, all the interior events in that unit require LSWP. However, the LBP component(s) may be disturbed 

only in certain areas throughout the house, requiring less containment than is assumed. Similar to the 

assumptions pertaining to households performing multiple interior events, for households performing 

multiple exterior events the likelihood of disturbing LBP is assumed to be the maximum likelihood for 

the events performed. Unlike for interior events, this is always the same as the largest and most costly 

exterior event that determines the housing unit’s exterior compliance costs. 

Number of Events Where Lead-Safe Work Practices are Employed When the First Year Rule is Effective 

Table 4-7 shows the estimated number of events where LSWP are used during the first year the rule is in 

effect. These estimates are calculated by applying the test kit likelihoods described above to the number 

of events presented in Table 4-4. The percentage of test kit results indicating the presence of LBP 

increases from Option A to Options B&D to Option C because the prevalence of LBP increases with the 

age of the housing. 

Table 4-6: Likelihood of LBP and Positive Test Kit Results for LBP 

Year Built Kitchen Bathroom Addition

Non-RoomSpecific 

Wall/ 

Ceiling 

Non-RoomSpecific 

Window/ 

Door 

Interior 

Painting

Whole 

Exterior 

Contained 

Exterior 

Exterior 

Painting

Likelihood of LBP 

Pre-1950 50% 31% 83% 35% 77% 74% 70% 47% 70% 

1950-1959 23% 12% 67% 16% 56% 38% 55% 27% 55% 

1960-1979 6% 4% 22% 5% 14% 14% 13% 10% 13% 

Likelihood of Positive Test Kit Result for LBP in First Year (63% False Positive Rate) 

Pre-1950 82% 75% 94% 76% 92% 90% 89% 80% 89% 

1950-1959 71% 67% 88% 69% 84% 77% 83% 73% 83% 

1960-1979 65% 65% 71% 65% 68% 68% 68% 67% 68% 

Likelihood of Positive Test Kit Result for LBP after First Year (10% False Positive Rate) 

Pre-1950 55% 38% 84% 41% 79% 77% 73% 52% 73% 

1950-1959 30% 21% 70% 24% 60% 44% 60% 34% 60% 

1960-1979 15% 14% 30% 14% 23% 23% 21% 19% 21% 

Source: EPA calculations using HUD (2000) 
§402(c) Economic Analysis Chapter 4 18 

Table 4-7: Number of Events where LSWP are Employed, First Year of Regulation 

Option A Option B 

Event Type 

SingleFamily 

OwnerOccupied 

SingleFamily 

RenterOccupied 

MultiFamily All Housing

Units 

SingleFamily 

OwnerOccupied

SingleFamily 

RenterOccupied 

MultiFamily All Housing

Units 

Kitchen 21,754 190,655 414,984 627,393 10,651 121,341 225,739 357,731

Bathroom 20,617 145,229 258,298 424,144 11,184 91,021 140,123 242,328

Additions 11,047 na 263 11,310 5,708 na na 5,708

Non-Room-Specific 

Wall/Ceiling 194,795 1,288,758 1,714,667 3,198,220 112,285 811,194 920,332 1,843,811

Non-Room-Specific 

Window/Door 137,571 338,687 307,125 783,383 87,967 220,341 172,497 480,805

Interior Painting 104,557 481,715 766,505 1,352,777 71,208 309,905 422,582 803,695

Whole Exterior 38,202 107,428 18,345 163,975 21,334 69,628 12,523 103,485

Contained Exterior 28,351 81,920 na 110,271 16,944 51,285 na 68,229

Exterior Painting 299,693 978,912 172,109 1,450,714 183,382 634,475 116,810 934,667

Total 856,587 3,613,304 3,652,296 8,122,187 520,663 2,309,190 2,010,606 4,840,459

Option C Option D 

Single-Family

OwnerOccupied 

SingleFamily 

RenterOccupied

MultiFamily All Housing

Units 

SingleFamily 

OwnerOccupied

SingleFamily 

RenterOccupied 

MultiFamily All Housing

Units 

Kitchen 6,779 89,695 184,816 281,290 10,651 121,341 225,739 357,731

Bathroom 6,887 66,964 114,820 188,671 11,184 91,021 140,123 242,328

Additions 4,212 na na 4,212 5,708 na na 5,708

Non-Room-Specific 

Wall/Ceiling 72,794 596,823 751,691 1,421,308 112,285 811,194 920,332 1,843,811

Non-Room-Specific 

Window/Door 54,443 160,573 140,353 355,369 87,967 220,341 172,497 480,805

Interior Painting 47,310 230,057 347,253 624,620 71,208 309,905 422,582 803,695

Whole Exterior 12,036 50,372 10,571 72,979 21,334 69,628 12,523 103,485

Contained Exterior 11,173 37,446 na 48,619 16,944 51,285 na 68,229

Exterior Painting 123,851 459,008 98,199 681,058 183,382 634,475 116,810 934,667

Total 339,485 1,690,938 1,647,703 3,678,126 520,663 2,309,190 2,010,606 4,840,459

Notes: It is assumed that test kits have a false positive rate of 63% in the first year of regulation. 

See Table 4-4 for option descriptions. 

Source: U.S. Census Bureau 1997 and 2003; U.S. Census Bureau 1995; EPA Calculations.
§402(c) Economic Analysis Chapter 4 19 

Number of Events Where Lead-Safe Work Practices are Employed During Second Year Rule is Effective 

Table 4-8 shows the estimated number of events where LSWP are used during the second year the rule is 

in effect; the number is the same across all options after the first year since the options do not differ from 

the second year forward in terms of the regulated universe of housing. The percentage of positive test kit 

results is substantially lower in the second year because it is assumed that tests with a lower false positive 

rate (10 percent) will be available at that time. 

Table 4-8: Number of Events where LSWP are Employed, Second Year of 

Regulation 

All Options 

Event Type 

SingleFamily 

OwnerOccupied 

SingleFamily 

RenterOccupied 

MultiFamily All Housing 

Units 

Kitchen 9,470 95,925 203,623 309,018 

Bathroom 8,405 64,255 124,186 196,847 

Additions 7,201 0 110 7,311 

Non-Room-Specific 

Wall/Ceiling 79,185 614,421 798,488 1,492,093 

Non-Room-Specific 

Window/Door 88,895 221,119 189,342 499,355 

Interior Painting 64,685 297,093 451,091 812,869 

Whole Exterior 21,790 66,881 11,883 100,554 

Contained Exterior 13,181 39,453 0 52,633 

Exterior Painting 180,468 609,434 111,102 901,004 

Total 473,281 2,008,580 1,889,823 4,371,683 

Notes: It is assumed that test kits have a false positive rate of 10% after the first 

year of regulation. 

Source: U.S. Census Bureau 1997 and 2003; U.S. Census Bureau 1995; EPA 

Calculations. 

4.2.6 Number of Regulated Events over 50-Year Period 

The stock of regulated housing units is expected to slowly decline over time as some older housing is 

demolished or destroyed by disasters and as housing units are merged or converted to nonresidential 

structures.10 Likewise, EPA expects the number of regulated events to decline as the regulated housing 

stock declines. EPA estimated the decline in the number of regulated events based on the decline in the 

pre-1980 housing stock according to 1990 and 2000 Decennial Census data from the U.S. Census Bureau 

(1990 and 2000c). Since the pre-1980 housing stock declined at an annual rate of 0.41 percent, it is 

assumed that the number of regulated events will decline at this rate as well.

 

10 Housing where lead abatements are performed also shrinks the stock of regulated housing; however, this is not 

accounted for in the analysis since its impact is negligible—less than .05% of the housing stock (EPA Calculations 

using the Federal Lead-Based Paint Program (FLPP) Database, the U.S. Census (2003b) American Community 

Survey Profile, data collected from 8 non-EPA administered states and the U.S. Department of Housing and Urban 

Development’s (2000) National Survey of Lead and Allergens in Housing). See Appendix 4A. 
§402(c) Economic Analysis Chapter 4 20 

4.3 Estimating the Number of Establishments and Personnel Seeking Certification and 

Training 

The RRP rule requires all entities that conduct RRP activities in regulated housing to become certified 

under the rule. The regulations also require firms to ensure that all persons performing renovation 

activities on behalf of the firm are either certified renovators or have been trained by a certified renovator 

in a manner specified by the rule. It is expected that two types of construction businesses will perform 

regulated RRP work – businesses with employees and non-employer, or self-employed, contractors. In 

addition, rental companies are likely to perform some, if not all of the RRP work on the properties they 

manage rather than hire an outside contractor. The regulation requires that a certified renovator be 

physically present when warning signs are being posted, the work site is being contained, and when the 

post-renovation cleaning is being done. The certified renovator must be available, either on-site or by 

telephone, at all other times when regulated renovation activities are being performed. In addition, only a 

certified renovator may perform the cleaning verification step required by the rule. As such, each 

certified establishment with employees will need to have at least one certified renovator on staff. All selfemployed contractors performing regulated RRP work will need to be trained as renovators, and upon 

satisfying the training requirements, will need to be certified as firms. 

4.3.1 Estimating the Number of Construction Establishments with Employees Seeking Certification 

The RRP rule requires firms that conduct RRP activities in regulated housing to become certified under 

the rule. Because the majority of firms involved in construction work are likely to be small, single 

establishment businesses, this analysis assumes that firms will seek certification at the establishment 

level. As demonstrated in Chapter 2, the eleven potentially affected construction sectors (Residential 

Remodelers and ten specialty contractor sectors: Plumbing and HVAC, Tile and Terrazzo, Painting and 

Wall Covering, Finish Carpentry, Glass and Glazing, Drywall and Insulation, Siding, Other Building 

Equipment, Other Building Finishing, and Electrical contractors) include over 357,000 establishments. 

Because these establishments are involved in a variety of construction and non-construction activities, in 

all likelihood only some of them will seek certification under the RRP rule. For example, only 54 percent 

of Residential Remodeling establishments specialize in residential work (i.e. derive at least 51 percent of 

their revenues from residential work). In addition, only 56 percent of the revenues of Residential 

Remodelers come from residential RRP activities. Establishments are likely to incur the cost of 

certification and of training their employees only if they derive a substantial portion of their revenues 

from residential Renovation, Repair, and Painting in housing affected by the regulations. Businesses that 

derive the majority of their revenues from new construction or from RRP activities in non-target housing 

are not likely to invest in certification. 

Unfortunately, the U.S. Economic Census does not provide data on the number of establishments that 

specialize in residential RRP. The number of establishments that will perform regulated residential RRP 

was estimated by applying each industry sector’s ratio of RRP residential revenues to total construction 

revenues (obtained from the U.S. Economic Census, see Table 2.6 of Chapter 2) to that industry’s total 

number of establishments. The resulting estimated number of RRP establishments was further reduced to 

account for the fact that only some of these entities will perform RRP work in regulated housing.11 The 

latter adjustment was made for each option based on data obtained from the American Housing Survey on 

the percent of U.S. households residing in regulated housing (by age of housing stock) and on the percent 

of RRP events that take place in renter-occupied housing units and in owner-occupied housing units 

 

11 This assumption is relaxed in a sensitivity analysis in Chapter 7.
§402(c) Economic Analysis Chapter 4 21 

where children reside.12 Thus, for each industry the estimated number of certified establishments in the 

first year was calculated as follows: 

Number of establishments seeking certification = 

[(number of establishments in industry) x (value of residential RRP/total construction revenues)] 

x (% of households living in regulated and compliant housing) 

It is worth noting that 25 percent of regulated renovations are assumed to be out of compliance (i.e., 

performed by firms and individuals without training and certification). It is also worth noting that after 

the first year, the total number of certified establishments in each industry will be the same under all 

options since all establishments performing work in pre-1978 renter-occupied target housing units and 

owner-occupied target housing units where a child under the age of six resides will need to be certified. 

In the first year, however, only those establishments working in pre-1960 and pre-1950 renter-occupied 

target housing units and owner-occupied target housing units where a child under the age of six resides 

are likely to seek certification under Options B (D) and C, respectively. 

The estimation methodology used in this analysis makes several assumptions regarding the number of 

establishments that perform RRP work in regulated residential housing. These assumptions imply that 

most certified firms will specialize in regulated renovations. Since there may be less specialization than 

these assumptions imply, the analysis considers, as part of the sensitivity analysis, higher estimates for the 

regulated universe of certified firms and renovators. 

The assumptions made in this analysis involve a significant amount of uncertainty. The estimation 

approach based on these assumptions may lead to an underestimate of the number of establishments 

involved in RRP since the proportion of businesses performing RRP may be greater than the portion of 

revenues derived from these activities. Furthermore, if residential RRP projects are less profitable than 

new construction or RRP projects in non-residential structures, then the marginal revenue of each RRP 

project would be lower than the marginal revenue derived from other projects. This implies that an 

industry would need to perform more RRP projects (and would thus devote a larger portion of the 

workforce to these projects) in order to obtain the same amount of revenues from RRP as from other 

activities. 

On the other hand, the numbers presented here may overestimate the number of establishments seeking 

certification under the regulations. The residential RRP revenue figure obtained for nine out of eleven 

affected sectors includes revenues from RRP activities in single-family homes and “Other buildings” – a 

category that may include apartment buildings as well as other non-residential (and thus not regulated) 

structures. As such, the ratio of residential RRP revenues to the total value of construction for these 

industries is likely to overstate the true amount of residential Renovation, Repair, and Painting work 

performed by the industry. 

The resulting estimates of the number of establishments with employees likely to seek certification in the 

first year under Options A, B, C and D are presented in Table 4-9. Estimates of the total number of 

 

12 About 65 percent of U.S. households reside in buildings constructed before 1980, 34 percent reside in buildings 

constructed before 1960 and 22 percent reside in building constructed before 1950. Approximately 58 percent of all 

RRP events in pre-1978 and pre-1960 housing take place in renter-occupied housing units and owner-occupied 

housing units where children reside. This percentage is slightly higher (about 63 percent) for RRP events in pre1950 housing.
§402(c) Economic Analysis Chapter 4 22 

establishments with employees certified in the second and third years are presented in Table 4-14. Note 

that the number of self-employed firms seeking certification is estimated similarly and described in 4.3.3. 

Table 4-9: Estimated First-Year Number of Establishments with Employees Seeking Certification Under the RRP Rule

Number of Establishments Certified 

NAICS 

Code Description 

Total Number 

of Establishments 

Residential 

RR as 

Percent of 

total value 

construction Option Aa Options 

B & Da Option Ca

236118 Residential remodelers 82,747 56 13,207 6,970 4,798 

238170 Siding contractors 6,632 50 945 499 344 

238350 Finish carpentry contractors 35,087 50 5,000 2,639 1,817 

238290 Other building equipment 

contractors 6,087 33 572 302 208 

238390 Other building finishing 

contractors 3,729 30 319 168 116 

238340 Tile and terrazzo contractors 8,950 28 714 377 260 

238220 Plumbing and HVAC 

contractors 87,501 27 6,734 3,554 2,447 

238150 Glass and glazing contractors 5,294 26 392 207 143 

238320 Painting and wall covering 

contractors 38,943 25 2,775 1,465 1,008 

238210 Electrical contractors 62,586 23 4,103 2,165 1,490 

238310 Drywall and insulation 

contractors 19,598 21 1,173 619 426 

Total 357,154 31 35,933 18,964 13,054 

a About 65 percent of U.S. households reside in buildings constructed before 1980, 34 percent reside in buildings constructed 

before 1960 and 22 percent reside in building constructed before 1950. Approximately 58 percent of all RRP events in pre1978 and pre-1960 housing take place in renter-occupied target housing units and owner-occupied target housing units where 

a child under the age of six resides. This percentage is slightly higher (about 63 percent) for RRP events in pre-1950 

housing. Of the regulated housing, 75 percent are assumed to comply with the regulations. 

See Table 4-4 for option descriptions.

Source: U.S. Census Bureau 2003; U.S. Census Bureau 2005b,d,f; EPA Calculations. 
§402(c) Economic Analysis Chapter 4 23 

4.3.2 Estimating the Number of People who will Seek Renovator and Worker Training 

The RRP rule requires certified firms to ensure that employees involved in RRP activities are trained as 

either certified renovators or workers. This section discusses the methodology used to estimate the 

number of construction workers employed by certified establishments that are expected to seek renovator 

or worker training under the rule. 

Estimating the Total Number of People Trained 

The number of employee establishment personnel expected to seek training as either certified renovators 

or workers was estimated by applying the same approach used for the estimation of the number of 

establishments that will seek certification under the regulations (note: employee establishment personnel 

does not include the self-employed). EPA assumed that the number of people who perform RRP work in 

each of the affected industries is proportional to the ratio of residential RRP revenues to the total 

construction revenues in that sector. In other words, it was assumed that since 28 percent of construction 

revenues in the Tile and Terrazzo contractor industry come from residential RRP, then 28 percent of the 

construction employees perform residential RRP work. EPA then adjusted the number of people who 

perform any type of residential RRP by the percent of U.S. households living in regulated and compliant 

housing to obtain the estimated number of construction employees who will be trained as either 

renovators or workers under each regulatory option. Estimates of the number of construction employees 

seeking training in the first year are presented in Table 4-10. Note that, similar to the number of certified 

firms, the total number of trained individuals in each industry will be equal under all options starting with 

the second year, when the regulations require all firms performing work in pre-1978 renter or child 

occupied housing to ensure that only trained employees are involved in these projects.13 

 

13 Note that alternative estimates of the number of individuals seeking training and certification are considered in 

sensitivity analyses in Chapter 7. 
§402(c) Economic Analysis Chapter 4 24 

Estimating the Number of People Trained as Renovators and Workers 

The RRP rule requires that a certified renovator be physically present when warning signs are being 

posted, the work site is being contained, and when the post-renovation cleaning is being done. The 

certified renovator must be available, either on-site or by telephone, at all other times when regulated 

renovation activities are being performed. In addition, only a certified renovator may perform the 

cleaning verification step required by the rule. This means that each establishment performing RRP work 

must employ at least one certified renovator per construction crew. To estimate the number of 

construction employees that will train to become certified renovators, EPA looked at the average number 

of construction employees in establishments performing residential RRP jobs. The average employment 

size was calculated by dividing the number of construction employees seeking training (Table 4-10) by 

the number of establishments certified (Table 4-9) in each industry. 

Table 4-10: Number Of Construction Employees That Will Seek Training Under The RRP Rule in the First Year 

Number of Construction Employees 

Performing RRP in Regulated Housing NAICS 

Code Description 

Number of 

Construct. 

Employees in 

Industry 

Number of 

Construct. 

Employees 

Performing 

RRP Option Aa Options 

B & Da Option Ca

236118 Residential remodelers 207,633 116,274 33,140 17,489 12,039 

238170 Siding contractors 30,284 15,142 4,316 2,278 1,568 

238350 Finish carpentry contractors 129,888 64,944 18,510 9,769 6,725 

238290 Other building equipment 

contractors 90,504 29,866 8,513 4,493 3,092 

238390 Other building finishing 

contractors 37,353 11,206 3,194 1,685 1,160 

238340 Tile and terrazzo contractors 44,729 12,524 3,569 1,884 1,297 

238220 Plumbing and HVAC 

contractors 712,452 192,362 54,826 28,934 19,918 

238150 Glass and glazing contractors 34,086 8,862 2,526 1,333 917 

238320 Painting and wall covering 

contractors 184,328 46,082 13,134 6,932 4,772 

238210 Electrical contractors 606,403 139,473 39,752 20,979 14,441 

238310 Drywall and insulation 

contractors 261,239 54,860 15,636 8,252 5,681 

Total 2,338,899 691,595 197,114 104,027 71,609 a About 65 percent of U.S. households reside in buildings constructed before 1980, 34 percent reside in buildings constructed 

before 1960 and 22 percent reside in building constructed before 1950. Approximately 58 percent of all RRP events in pre1978 and pre-1960 housing take place in renter-occupied target housing units and owner-occupied target housing units where 

a child under the age of six resides. This percentage is slightly higher (about 63 percent) for RRP events in pre-1950 

housing. Of the regulated housing, 75 percent are assumed to comply with the regulations. 

See Table 4-4 for option descriptions.

Source: U.S. Census Bureau 2003; U.S. Census Bureau 2005b,d,f; EPA Calculations. 
§402(c) Economic Analysis Chapter 4 25 

This analysis also assumed that establishments will employ one certified renovator per every five 

construction employees. In other words, establishments that have one to five construction workers on 

staff will employ one renovator, establishments with six to ten construction workers on staff will employ 

two renovators, and those with 11 to 15 construction workers on staff will employ three renovators. The 

average number of construction workers per establishment was no higher than 15 in any affected sector. 

To estimate the number of construction employees that would be trained as renovators, the estimated 

number of establishments seeking certification in each sector was multiplied by the expected number of 

renovators per establishment for that sector. Four of the affected sectors (Other Building Equipment 

Contractors, Other Building Finishing Contractors, Electrical Contractors and Drywall and Insulation 

Contractors) had, on average, between 10 and 15 construction employees per establishment and were 

assumed to have three renovators on staff each. The number of construction employees in each sector 

that will need to receive worker training was estimated by subtracting the number of people receiving 

renovator certification from the total number of people seeking training (see Table 4-10). The average 

establishment sizes, expected number of certified renovators per establishment, and the total first-year 

estimated numbers of certified renovators and workers in each industry are presented in Table 4-11.
§402(c) Economic Analysis Chapter 4 26 

 

4.3.3 Estimating the Number of Self-Employed Contractors that will Seek Certified Renovator 

Training 

Because all regulated RRP projects must be conducted under the direction of a certified renovator, all 

self-employed contractors performing regulated RRP work will be trained as renovators. Following 

training, these contractors will apply for firm certification. In this section, the number of non-employer 

establishments that will be trained as renovators and certified as firms is estimated. 

The number of self-employed (non-employer) contractors in each of the eleven affected industry sectors 

was estimated and presented in Section 2.2.2 of Chapter 2. This analysis assumes that the percentage of 

self-employed contractors that perform regulated RRP work and will thus seek renovator training is 

equivalent to the percentage of establishments with employees that will seek certification under the 

Table 4-11: Estimated First-Year Number of Construction Employees Seeking Renovator and Worker Training

Option Aa Options B & D a Option C a

Description

Avg. number of 

construction 

workers / estab. 

(Expected Number 

of Renovators 

Trained) 

Number of 

Certified 

Renovators 

Trained 

Number of

Workers 

Trained 

Number of 

Certified 

Renovators 

Trained 

Number of 

Workers 

Trained 

Number of 

Certified 

Renovators 

Trained 

Number of 

Workers 

Trained 

Residential Remodelers 3 (1) 13,207 19,933 6,970 10,520 4,798 7,241 

Siding Contractors 5 (1) 945 3,371 499 1,779 344 1,225 

Finish carpentry 

Contractors 4 (1) 5,000 13,510 2,639 7,130 1,817 4,908 

Other building equipment 15 (3) 1,718 6,794 907 3,586 624 2,468 

Other building finishing 10 (3)b 957 2,237 505 1,181 347 813 

Tile and terrazzo 

contractors 5 (1) 714 2,855 377 1,507 260 1,037 

Plumbing and HVAC 

contractors 8 (2) 13,467 41,359 7,107 21,827 4,892 15,026 

Glass and glazing 

contractors 6 (2) 785 1,742 414 919 285 633 

Painting and wall 

covering contractors 5 (1) 2,775 10,359 1,465 5,467 1,008 3,764 

Electrical contractors 10 (2) 8,206 31,547 4,331 16,649 2,981 11,460 

Drywall and insulation 

contractors 13 (3) 3,519 12,116 1,857 6,395 1,279 4,402 

Total 5 (2) 51,292 145,822 27,069 76,957 18,634 52,976 a About 65 percent of U.S. households reside in buildings constructed before 1980, 34 percent reside in buildings constructed 

before 1960 and 22 percent reside in building constructed before 1950. Approximately 58 percent of all RRP events in pre-1978 

and pre-1960 housing take place in renter-occupied target housing units and owner-occupied target housing units where a child 

under the age of six resides. This percentage is slightly higher (about 63 percent) for RRP events in pre-1950 housing. Of the 

regulated housing, 75 percent are assumed to comply with the regulations. b The average Other Building Finishing contractor establishment has slightly more than 10 construction employees on staff. 

See Table 4-4 for option descriptions.

Source: U.S. Census Bureau 2003; U.S. Census Bureau 2005b,d,f; EPA Calculations.
§402(c) Economic Analysis Chapter 4 27 

regulations. In other words, to estimate the number of self-employed contractors that will seek training, 

the estimated number of non-employer establishments in each industry was multiplied by that industry’s 

ratio of residential RRP revenues to total construction revenues, and reduced by the percentage of U.S. 

households living in regulated housing. The resulting first-year estimates are presented in Table 4-12. 

Similarly to the number of employer firms, the total number of certified self-employed contractors in each 

industry in the second year will be the same under all options since all establishments performing work in 

pre-1978 renter-occupied target housing units and owner-occupied target housing units where a child 

under the age of six resides will need to be certified. 

Table 4-12: Estimated First-Year Number of Non-Employers (Self-Employed Contractors) Seeking Renovator Training

and Firm Certification 

Number of Non-Employers Trained as 

Renovators and Certified as Firms 

NAICS Description 

Number of 

Non-Employer 

Estab. in 

Industry 

Residential RRP 

Revenues as 

Percent of Total 

Value of 

Construction Option Aa Options B 

&Da Option Ca

236118 Residential remodelers 82,747 56 30,993 16,356 11,259 

238170 Siding contractors 6,632 50 2,272 1,199 825 

238350 Finish carpentry 

contractors 35,087 50 26,381 13,922 9,584 

238290 Other building equipment 

contractors 6,087 33 914 482 332 

238390 Other building finishing 

contractors 3,729 30 1,682 888 611 

238340 Tile and terrazzo 

contractors 8,950 28 3,769 1,989 1,369 

238220 Plumbing and HVAC 

contractors 87,501 27 8,479 4,475 3,080 

238150 Glass and glazing 

contractors 5,294 26 943 497 343 

238320 Painting and wall covering 

contractors 38,943 25 14,640 7,727 5,318 

238210 Electrical contractors 62,586 23 6,701 3,536 2,435 

238310 Drywall and insulation 

contractors 19,598 21 6,189 3,266 2,249 

Total 357,154 31 102,961 54,337 37,403 

a About 65 percent of U.S. households reside in buildings constructed before 1980, 34 percent reside in buildings constructed 

before 1960 and 22 percent reside in building constructed before 1950. Approximately 58 percent of all RRP events in pre1978 and pre-1960 housing take place in renter-occupied target housing units and owner-occupied target housing units where 

a child under the age of six resides. This percentage is slightly higher (about 63 percent) for RRP events in pre-1950 

housing. Of the regulated housing, 75 percent are assumed to comply with the regulations. 

See Table 4-4 for option descriptions.

Source: U.S. Census Bureau 2003; U.S. Census Bureau 2005d,f; U.S. Small Business Administration 2005; EPA Calculations 
§402(c) Economic Analysis Chapter 4 28 

This analysis makes several assumptions in order to estimate the number of non-employers who will be 

trained as certified renovators. First, as discussed in Chapter 2, the analysis assumes that the distribution 

of non-employer establishments among the six-digit industry codes within each 4-digit sector is identical 

to the distribution of establishments with employees within each 4-digit industry group. The analysis also 

assumes that the proportion of self-employed contractors involved in regulated RRP is equivalent to the 

proportion of establishments with employees involved in these activities. The uncertainties surrounding 

the latter assumption were discussed in Section 4.3.1 of this chapter. In the case of non-employers, the 

uncertainty is even greater since there are no data on revenues that self-employed contractors derive from 

residential RRP work – this data is only available from the U.S. Census for establishments with 

employees. It is possible that self-employed contractors are hired for RRP projects more often than larger 

establishments. It is also possible that they are hired less often for larger projects that disturb more than 

two square feet of paint. No current data is available from the U.S. Census or other sources in the public 

domain on the amount of RRP work performed by non-employer establishments. 

4.3.4 Estimating the Number of Residential Property Management Establishments and Employees 

that will Seek Certification and Training 

Instead of hiring an outside contractor for RRP work on properties under their management, Residential 

Property Managers (NAICS 531311) and Lessors of Residential Buildings and Dwellings (NAICS 

531110) may choose to do the renovation work with their own staff. Since all firms performing RRP 

work in regulated housing must be certified, establishments that choose to perform their own RRP work 

will seek certifications under the regulations. 

The U.S. Economic Census does not present any data on the amount of RRP work performed by 

Residential Property Managers on their own properties. Due to this lack of data, this analysis assumes 

that all Residential Property Management and Lessors of Residential Buildings and Dwellings 

establishments that have paid employees and manage housing regulated by the Renovation, Repair, and 

Painting rule will seek certification and train their employees as certified renovators or workers. 

Although this assumption is likely to overestimate the number of establishments and personnel seeking 

certification and training, it is not unreasonable since performing minor renovation or maintenance work 

in-house is often less expensive than hiring an outside contractor. The vast majority of establishments 

that manage regulated housing may thus find certification worthwhile. Note that only establishments with 

employees are expected to seek certification; non-employers are unlikely to have the time or manpower to 

perform renovations themselves and are more likely to hire an outside contractor. 

To estimate the number of establishments that manage regulated units (and will thus seek certification), 

this analysis adjusted the total number of establishments in the Residential Property Manager and Lessors 

of Residential Buildings and Dwellings industries by the percentage of U.S. households residing in and 

the number of RRP events taking place in regulated housing. The total number of employees expected to 

seek training as certified renovators or workers was also estimated by adjusting the total number of 

personnel in the industry by the percentage of U.S. households residing in regulated and compliant 

housing units. Although based on 2002 U.S. Census Data, establishments in the Residential Property 

Manager industry employ about eleven people on average, it was estimated that each establishment will 

have only two (rather than three) certified renovators on staff; the remainder of the employees will be 

trained as workers. This estimate is based on the fact that Residential Property Manager establishments 

are involved in a variety of non-construction activities; it is thus highly unlikely that these businesses will 

have more than one ten-person construction crew on staff. Lessors of Residential Buildings and 

Dwellings establishments employ about five people on average, and will thus each have one certified 
§402(c) Economic Analysis Chapter 4 29 

renovator on staff. The remaining employees involved in RRP projects will be trained as workers. Table 

4-13 presents the estimated first-year number of NAICS 531311 and 531110 establishments and 

employees seeking certification and training, respectively. This is likely to overestimate the number of 

workers trained because only a portion of the establishment staff is likely to be involved in renovation 

work. 
§402(c) Economic Analysis Chapter 4 30 

4.3.5 Total Numbers of Establishments and Individuals that will Seek Certification and Training 

During the First Three Years 

Table 4-14 presents a summary of the estimated number of establishments that will seek firm 

certification, as well as the estimated number of employees that will need to be trained as renovators and 

workers in Years 1-3. The number of renovators and firms that seek training and certification in the first 

three years is estimated slightly differently for the options without a phase-in period (Option A) and those 

that phase-in regulated housing in the second year (Options B, C, and D). 

Options Without Phase-In (Option A): 

In the first year, it is assumed that the number of renovators and firms that seek training and certification 

is equal to the number that is necessary to meet the demand for lead-safe RRP services in that first year. 

Thus, under Option A, the stock of renovators and firms required to meet the demand for lead-safe RRP 

services in all pre-1978 renter-occupied target housing units and owner-occupied target housing units 

Table 4-13: Total Number of Residential Property Managers and Lessors of Real Estate Seeking 

Certification and Training

Option Aa

 Options B &Da Option Ca

NAICS 531310 - Residential Property Managers

Total Number of Establishments 19,667 19,667 19,667 

Total Number of Employees 217,403 217,403 217,403 

Number of Establishments Seeking Certification 7,474 3,944 2,715 

Total Number of Employees Seeking Training 82,617 43,601 30,014 

Number of Employees Seeking Renovator Training 14,948 7,889 5,430 

Number of Employees Seeking Worker Training 67,670 35,712 24,584 

NAICS 531110 - Lessors of Residential Buildings and Dwellings

Total Number of Establishments 46,340 46,340 46,340 

Total Number of Employees 219,304 219,304 219,304 

Number of Establishments Seeking Certification 17,610 9,294 6,398 

Total Number of Employees Seeking Training 83,339 43,982 30,276 

Number of Employees Seeking Renovator Training 17,610 9,294 6,398 

Number of Employees Seeking Worker Training 65,729 34,688 23,879 

Total: Residential Property Managers and Lessors of Residential Buildings and Dwellings

Total Number of Establishments Seeking Certification 25,084 13,238 9,113 

Total Number of Employees Seeking Training 165,956 87,582 60,290 

Number of Employees Seeking Renovator Training 32,558 17,183 11,828 

Number of Employees Seeking Worker Training 133,399 70,400 48,462 a About 65 percent of U.S. households reside in buildings constructed before 1980, 34 percent reside in 

buildings constructed before 1960 and 22 percent reside in building constructed before 1950. 

Approximately 58 percent of all RRP events in pre-1978 and pre-1960 housing take place in renteroccupied target housing units and owner-occupied target housing units where a child under the age of six 

resides. This percentage is slightly higher (about 63 percent) for RRP events in pre-1950 housing. Of the 

regulated housing, 75 percent are assumed to comply with the regulations. 

See Table 4-4 for option descriptions.

Source: U.S. Census Bureau 2003; U.S. Census Bureau 2004b; EPA Calculations.
§402(c) Economic Analysis Chapter 4 31 

where a child under the age of six resides seeks training and certification. After the first year, it is 

assumed that one third of the necessary stock of individuals, and firms will obtain training and 

certification each year (since refresher-training and re-certification is required every three years). 

Options With Phase-In (Options B, C, and D): 

In the first year, it is assumed that the number of renovators and firms that seek training and certification 

is equal to the number that is necessary to meet the demand for lead-safe RRP services in that first year. 

Thus, under Options B and D, the stock of renovators and firms required to meet the demand for lead-safe 

RRP services in all pre-1960 renter-occupied target housing units and owner-occupied target housing 

units where a child under the age of six resides seeks training and certification. Under Option C, the 

stock of renovators and firms required to meet the demand for lead-safe RRP services in all pre-1950 

renter-occupied target housing units and owner-occupied target housing units where a child under the age 

of six resides seeks training and certification. 

In the second year, this analysis makes the simplifying assumption that one third of the number trained 

and certified in the first year seek initial- or re-certification.14 In addition, the stock of individuals and 

firms required to meet the additional demand in the newly regulated housing stock obtain initial training 

and certification (1960-1978 and renter-occupied target housing units and owner-occupied target housing 

units where a child under the age of six resides for Options B and D, and 1950-1978 and renter-occupied 

target housing units and owner-occupied target housing units where a child under the age of six resides 

for Option C). In later years, it is assumed that one third of the necessary stock of individuals and firms 

will obtain training and certification each year (since refresher-training and re-certification is required 

every three years). 

Training and Certification after the Initial Years 

As indicated above, this analysis assumes a steady annual number of firm and individual certifications 

after the second year of regulation.15 If all the individuals and firms needed to meet the demand for leadsafe RRP were trained and certified in the first and second years, one might expect a drop in the level of 

training and certification in the third year, followed by a spike in the next year. That is, one might expect 

a cyclical pattern of training and certification to emerge. However, it is difficult to predict how cyclical 

training and certification demand might be, or how this cyclicality might diminish over time. Therefore, 

this analysis assumes that a typical amount of training and certification occurs each year after the first two 

years because modeling a cyclical component would add little to the analysis without being able to 

estimate the extent of any cyclicality more precisely. 

This analysis accounts for turnover in the regulated RRP industry by assuming a certain percentage of 

certifications each year are initial certifications. Specifically, after the first year, 52 percent of the 

renovators seeking training and certification are assumed to be seeking their initial certification; this is 

based on the relative number of Abatement Supervisors applying for certifications according to the 

Federal Lead-Based Paint Program (FLPP) database (EPA 2005). Similarly, 54 percent of firms seeking 

certification are assumed to be seeking their initial certification based on the relative frequency of initial 

certifications observed for abatement firms in the FLPP database. 

 

14 Adjusted for by 0.41 percent to reflect the decline in the pre-1978 housing stock. 

15 The number of certifications is assumed to decline by 0.41 percent to reflect the decline in the pre-1978 housing 

stock.
§402(c) Economic Analysis Chapter 4 32 

4.3.6 Sampling Technicians 

While the RRP rule creates the discipline of certified sampling technician, training and certification costs 

associated with this new discipline are not included in this analysis. It is expected that few individuals 

will seek sampling technician certification as a result of the RRP rule, and few RRP activities will use 

sampling technicians to conduct dust clearance tests following RRP activities because of the high cost of 

dust clearance testing relative to cleaning verification. A small number of individuals may seek 

certification as sampling technicians, however, primarily to perform dust clearance testing following 

interim control activities where clearance testing is required by HUD regulations. Interim controls are an 

activity where contractors reduce, but do not permanently eliminate, exposures to lead-based paint 

hazards. Rehanging windows in a manner that reduces friction-produced lead dust is one example of an 

interim control activity. 

Table 4-14: Estimated Number of Establishments Seeking Certification and Workers and 

Renovators Seeking Training 

Option Aa

 Options B &Da Option Ca

Year 1 

Total Number of Establishments (with Employees and 

without) Seeking Certification c 163,979 86,539 59,571 

Total Number of Renovators Trained b,c 186,811 98,588 67,866 

Total Number of Workers Trained b,c 279,221 147,357 101,437 

Year 2

Total Number of Establishments (with Employees and 

without) Seeking Certification c 54,436 105,851 123,756 

Total Number of Renovators Trained b,c 62,015 120,589 140,987 

Total Number of Workers Trained b,c 278,076 278,076 278,076 

Year 3

Total Number of Establishments (with Employees and 

without) Seeking Certification c 54,212 54,212 54,212 

Total Number of Renovators Trained b,c 61,761 61,761 61,761 

Total Number of Workers Trained b,c 276,935 276,935 276,935 a About 65 percent of U.S. households reside in buildings constructed before 1980, 34 percent reside in 

buildings constructed before 1960 and 22 percent reside in building constructed before 1950. 

Approximately 58 percent of all RRP events in pre-1978 and pre-1960 housing take place in renteroccupied target housing units and owner-occupied target housing units where a child under the age of six 

resides. This percentage is slightly higher (about 63 percent) for RRP events in pre-1950 housing. Of 

the regulated housing, 75 percent are assumed to comply with the regulations. b Components may not add up to totals due to rounding. c The number of firms and individuals certified and trained, respectively, are assumed to decline by 0.41 

percent annually to account for the decline in the size of the regulated housing stock over time, and thus 

the demand for lead-safe renovation services. 

See Table 4-4 for option descriptions.

Source: EPA calculations 
§402(c) Economic Analysis Chapter 4 33 

4.4 Training Costs 

Training costs include the cost of the time spent on training activities as well as the associated travel and 

tuition costs. Note that tuition costs are assumed to include the costs associated with training provider 

accreditation. In other words, it is assumed that accredited training providers pass along their 

accreditation fees and other administrative costs through their tuition. These accreditation fees and other 

administrative costs are estimated in the paperwork burden analysis but are only implicitly accounted for 

(as part of tuition costs) in the estimates of the total cost of the rule. 

4.4.1 Estimates of Wages 

The wages of certified renovators and Workers are estimated for this analysis in order to estimate the 

costs of proposed changes to their training burdens. Wages are based on U.S. Bureau of Labor Statistics 

(2005a) data, from the occupational employment statistics series. All wages are fully loaded to account 

for fringe benefits with an average fringe rate for the construction industry of 23.5 percent. Certified 

renovators’ fully loaded wages ($31.64/hour) are estimated from the wages earned by First-Line 

Supervisors/Managers of Construction Trades and Extraction Workers (Occupation 47-1011) who work 

in the residential building construction industry. Workers’ loaded wages ($16.94/hour) are estimated 

from the wages of Construction Laborers who work in the residential building construction industry 

(Occupation 47-2061). 

4.4.2 Tuition Rate Estimates 

The estimated tuition cost for an accredited certified renovator course is based on data collected on the 

tuition rates of courses accredited under the 402/404 Abatement Rule. Tuition rates for an accredited 

certified renovator course are expected to be similar to tuition costs for lead evaluation and abatement 

courses since they have similar accreditation requirements and have a similar mix of classroom and 

hands-on training. 

Tuition data were collected on the following accredited lead evaluation and abatement courses: Inspector, 

Risk Assessor, Abatement Supervisor, Abatement Worker, and Project Designer. Tuition rates were 

collected from a random sample of firms that offer one or more of the courses required for abatement 

certification. The National Lead Service Provider Listing System (Lead Listing), which was operated for 

HUD (2004),16 lists 194 accredited training providers. These 194 providers form the universe on which 

the sample for this analysis is based. Many of these establishments are certified in multiple states and 

offer training in various locations. 

The data sample consisted of 83 establishments selected from the Lead Listing directory of 194 training 

providers. The sample included all the establishments on the list that are certified to offer a Project 

Designer course (42 total), as well as a random sample of 41 establishments that are not certified to offer 

this class. Data were collected from company web sites (when available) and/or over the phone. 

Information was obtained from 68 training providers; a total of 15 providers could not be reached. Seven 

of the 68 contacted providers no longer offered lead hazard reduction training. 

 

16 The Lead Listing (HUD 2004) (www.leadlisting.org) website was run for the U.S. Department of Housing and 

Urban Development’s Office of Healthy Homes and Lead Hazard Control that contained a directory of lead service 

providers. It is no longer in operation (as of late 2004). 
§402(c) Economic Analysis Chapter 4 34 

To determine whether the 15 unreached firms created a non-response bias due to a lower response rate by 

a single type of provider, they were classified by type of establishment (private establishments, nonprofits, unions). The fifteen non-response entities contained a very similar mix of provider types to those 

for which data was available; thus, there was no evidence of non-response bias. 

Tuition Data Availability 

Tuition data were collected from a total of 50 providers, including 35 establishments that were identified 

as private for-profit providers, 11 identified as educational institutions and 4 non-profit providers. 

Weighted averages of the tuition rates for each course were then calculated to account for the differences 

in the probability of selection between the providers that were certified to offer the Project Designer 

course (PD-certified) and those that were not. 

Calculation of Tuition Rate Estimates 

The following steps were taken to calculate the tuition rates for each course required by EPA based on the 

data collected. 

a. Select tuition rates for courses that match EPA-mandated training hour requirements (listed in Table 4-

15). 

• All data were collected in 2004. Data include tuition rates for courses offered currently, 

previously, and in the future. Some of the tuition data are for courses that satisfy specific state 

requirements.17 Since certification from authorized State and Tribal programs satisfies EPA 

certification requirements, all tuition data that meet EPA course-hour demands were included in 

the estimates. Several providers offer classes that are longer than those required by EPA 

(presumably in compliance with state regulations), while several others offer combined Lead 

Inspector/Risk Assessor courses. Tuition rates for these longer and combined classes were not 

included in the estimates. However, estimates are similar if these longer and combined classes are 

included in the sample with time-adjusted rates. 

b. Assign a weight to each selected data element based on the probability of selection into the sample. 

• Since all providers certified to offer the Project Designer course were selected, the probability of 

selection for these providers is one. The probability of selection for providers not certified to 

offer this class is as follows: (Number of providers in the sample)/ (Total Number of Providers - 

Number of PD-Certified Providers) = 0.27 

• The weight assigned to each provider is equal to the inverse of the probability of selection. Thus 

each provider certified to offer the Project Designer course receives a weight of one while other 

providers receive a weight of 1/0.27, or approximately 3.71. 

c. Calculate the weighted average tuition rates for each course. 

Estimated Tuition Rates 

Table 4-15 presents the estimated hourly tuition rates, based on the data obtained from the training 

providers, for each type of EPA-required course. 

 

17 In California, for example, lead professionals must take a general refresher course every two years. 
§402(c) Economic Analysis Chapter 4 35 

4.4.3 Aggregated Incremental Cost of Training 

To estimate the incremental burden of training, several cost components are calculated, including tuition 

rates, wage rates, and travel and expense costs. Each certified renovator will participate in 8 hours of 

formal initial training. Refresher renovator certification training is required every three years; the 

refresher course is only four hours. Workers receive informal, on-the-job training; it is assumed that a 

certified renovator typically trains three Workers at a time and the training requires one hour. 

Tuition for the initial certified renovator training class is estimated to be $186; the corresponding 

refresher course tuition is estimated to be $93. This estimate relies on the assumption that the average 

hourly tuition is equal to the observed rates for the accredited lead abatement and evaluation courses 

($23.26).18 Additional travel and meal costs associated with training are assumed to be $121.19

The time burden to certified renovators for formal initial training is $253 (8 hours at a loaded wage rate of 

$31.64/hour); the refresher training is half this amount, or $127. Certified renovators may be selfemployed or might be employed by a larger company. Therefore, the incidence of the time burden is 

likely to represent a mix of lost wages and additional overhead to firms. Assuming one certified 

renovator trains three Workers at a time, and this informal training requires an hour, informal training is 

estimated to cost $27 per Worker trained. Thus, the aggregated incremental cost of training is $560 for 

initial certified renovator training, $341 for refresher certified renovator training and $27 for informal 

Worker training. 

After the first year, 52 percent of the renovators seeking training and certification are assumed to be 

seeking their initial certification; this is based on the relative number of Abatement Supervisors applying 

for certifications according to the Federal Lead-Based Paint Program (FLPP) database (EPA 2005). 

 

18 The average of the hourly tuition rates are used rather than picking a single similar course because no single 

course is similar enough to the renovator course. For example, the initial courses are the only courses with hands-on 

training, but they are also longer than the renovator course. The refresher courses are more similar in length, but 

have no hands on requirements. 

19 Travel costs include 2 hours of travel time ($63), meals ($9), and mileage costs (50 miles, $49).

Table 4-15: Average Hourly Tuition (2005$) 

Initial Course 

Inspector $20.14 

Risk Assessor $21.24 

Abatement Supervisor $18.83 

Project Designer $27.52 

Abatement Worker $19.64 

Refresher Course 

Inspector $23.77 

Risk Assessor $24.54 

Abatement Supervisor $22.36 

Project Designer $35.17 

Abatement Worker $19.42 

Average Hourly Tuition for All Courses 

$23.26 

Source: EPA Calculations.
§402(c) Economic Analysis Chapter 4 36 

4.5 Work Practice Compliance Costs 

RRP projects generate varying amounts of leaded dust, paint chips, and other lead-contaminated materials 

depending on the type of work, area affected, and work methods used. For example, repairing a small 

area of damaged drywall is likely to generate less lead-contaminated dust and debris than sanding a large 

area in preparation for painting. Because of this variability, the size of the area that must be isolated and 

the containment methods used will vary from project to project. Large renovation projects could involve 

one or more rooms and potentially encompass an entire home or building, while small projects may 

involve a portion of a room or a building’s exterior. The necessary work area preparations will depend on 

the size of the surface(s) being disturbed, the method used in disturbing the surface, and the building 

layout. The certified renovator assigned to a renovation would weigh all of these factors in determining 

the appropriate work area size and preparation level for that particular situation. For example, repairing a 

small area of damaged drywall would probably require a smaller work area and minimal preparation 

while demolition work would probably require a larger work area and extensive preparation in order to 

prevent the migration of dust and debris from the work area. 

Since available data are not sufficient for estimating a distribution of work area sizes, this analysis used a 

simplified approach to estimating the per-event containment costs. First, for each type of event, the 

containment and cleaning cost was estimated for a typical large event and a typical small event. For the 

prescriptive option (Option D), the rule would define certain events as small and allow a smaller work 

area to be contained and cleaned for these events; the remaining events would be considered large and all 

rooms where work is performed would have to be contained and cleaned. It is assumed that 75 percent of 

events require the large event containment and cleaning practices and 25 percent require the small event 

containment and cleaning practices. 

Under the flexible options (Options A, B, and C) the certified renovator may apply their training and 

experience to determine the size of the work area that must be contained and cleaned. This contrasts with 

Option D, which prescribes that the entire room or rooms where work is being performed must be 

contained and cleaned unless an event meets the small event criteria. For estimating the cleaning and 

containment costs under the flexible options, it is assumed that 25 percent of events require the small 

event cleaning and containment, 25 percent require the large event cleaning and containment, and the 

remaining 50 percent require something in between—with the containment and cleaning cost estimated as 

the average of the large event and the small event containment and cleaning costs.20

 

20 This is equivalent to assuming that the average containment and cleaning cost per-event is the average of the small 

event and the large event cost. 

Table 4-16: Incremental Training Costs (2005$) 

 Tuition Time Burden Travel and 

Meals 

Total 

Burden 

Initial Training 

Certified Renovator $186 $253 $121 $560 

Worker $0 $27 $0 $27 

Refresher Training 

Certified Renovator $93 $127 $121 $341 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 4 37 

4.5.1 LBP Test Kit Compliance Costs 

It is assumed that tests kits are used to test for LBP before each RRP event; they are inexpensive to use 

and a negative result will allow the renovator to forgo the more costly containment, cleaning and 

verification requirements. Lead test kits currently can be purchased in bulk at a cost of approximately 

$0.50 per test; it is assumed that testing four samples will require about 15 minutes of a certified 

renovator’s time. Thus, testing using the test kits is estimated to cost $10 per event.21

Alternatively, RRP purchasers may choose to have XRF testing conducted to detect the presence of LBP 

instead of using a test kit. XRF testing has the advantage of having lower false positive rates, but the 

testing cost per event is much higher than a test kit. 

The purchase price of XRF machines ranges from $14,000 to $21,000. In addition, there are maintenance 

costs associated with replacing the source material or x-ray tube (about $2,000 to $4,000 every one to five 

years) and the time spent completing the manufacturer’s training class for the XRF. For XRF devices 

using a radioactive source, the operator must apply for a state license, and may need to pay a fee and 

periodically reapply for the license. Because of these substantial costs, it is unlikely that renovation 

contractors will choose to buy and operate XRF machines. Instead, individuals who wish to have XRF 

testing conducted prior to a renovation will have to hire a certified inspector or risk assessor. 

Hiring a certified inspector or risk assessor to test for the presence of LBP would typically cost $100 to 

$300 for a single room and $300 to $500 for an entire house. Factors such as travel time, size of the work 

area, accessibility of the work area, and administrative costs will determine the cost for any individual 

job. In addition to the direct costs of XRF testing, scheduling an inspection may impose delays on the 

RRP work. In contrast, a contractor can test for LBP with a test kit while visiting the site to provide an 

estimate. 

The benefits of the lower false positive rates associated with XRF testing are likely to outweigh the higher 

testing costs only in a few cases.22 Thus, the expected savings from avoiding the RRP rule’s work 

practice costs are generally lower than the $100 to $500 cost of XRF testing. (If the XRF testing indicates 

that LBP is present, the purchaser would have to pay for the work practices in addition to the XRF testing 

costs.) 

Another portable approach to lead paint testing is ultrasonic extraction/anodic stripping voltammetry 

(UE/ASV). However, UE/ASV instruments are unlikely to be selected for testing by renovators, repair 

persons, and painters. The steps involved in use of the equipment are complicated, requiring collecting a 

paint sample, placing the sample in dry ice to embrittle it, grinding the sample, adding nitric acid to the 

sample, adding water at approximately 50 degrees centigrade to bath the sample, conducting sample 

sonication for 30 minutes (up to 7 samples can be done at a time) to further dissolve the sample, adding 

distilled water to the sample, pouring the sample into a separate vial with a crushed electrolyte tablet, 

placing a portion of the sample onto an electrode, and operating and interpreting instrumentation to obtain 

a lead level. Hence, it is unlikely that renovation contractors will choose to buy and operate a UE/ASV 

instrument themselves. Given that much of the cost for hiring a certified inspector or risk assessor to test 

 

21 Alternatives for test kit costs and the development time-frame for the improved test kits are considered in 

sensitivity analyses presented in Chapter 7.

22 The benefits of a lower false positive rate are increasing with the costs of using LSWP and decreasing with the 

likelihood of LBP (i.e., the larger the job and the newer the house, the more likely that a RRP purchaser can avoid 

paying extra for LSWP by having an XRF test).
§402(c) Economic Analysis Chapter 4 38 

for LBP is due to travel time, administrative costs, etc., the costs for scheduling an inspection using a 

UE/ASV are expected to be significantly higher than for a test kit. Since it is expected that few 

individuals will chose XRF or UE/ASV testing instead of the test kit prior to RRP events, this analysis 

assumes that all RRP purchasers use the test kit. 

4.5.2 Containment, Cleaning, and Verification 

The containment and cleaning practices covered in the cost estimates are:23

For large interior events: 

• Remove or cover all objects in the room where the renovation will be performed, including 

furniture, rugs, and window coverings. 

• Close and cover all ducts opening into the room with taped-down plastic sheeting or other 

impermeable material. 

• Close windows and doors in the work area. Doors must be covered with plastic sheeting or other 

impermeable material. Doors used as an entrance to the work area must be covered with plastic 

sheeting or other impermeable material in a manner that allows workers to pass through while 

confining dust and debris to the work area.24 

• Cover the floor with taped-down plastic sheeting or other impermeable material. Place a tack pad 

at the edge of the sheeting at the entrance to the room. Cover paths through the rest of the 

housing used by persons performing the renovation with plastic sheeting or other impermeable 

material. 

For small interior events: 

• Remove or cover all objects within five feet of the work area, including furniture, rugs, and 

window coverings. 

• Close all windows, doors, and ducts within five feet of the work area. Cover ducts with plastic 

sheeting or other impermeable material.

• Cover the floor within five feet of the work area with taped-down plastic sheeting or other 

impermeable material.

• Wear disposable shoe covers and vacuum clothes.

For large and small exterior events: 

• Cover the ground with plastic sheeting or other disposable impermeable material extending out 

from the edge of the structure a sufficient distance to collect falling paint debris. 

• Ensure that doors within the work area that must be used while the job is being performed are 

covered with plastic sheeting or other impermeable material in a manner that allows workers to 

pass through while confining dust and debris to the work area. 

For all events: 

• Post signs warning occupants and other persons not involved in renovation activities to remain 

outside of the work area. 

• Isolate the work area so that no visible dust or debris leaves the work area while the renovation is 

being performed. 

• Contain waste from renovation activities to prevent releases of dust and debris before the waste is 

removed from the work area for storage or disposal. 

 

23 For the purposes of simplifying the modeling of the costs, some of the work practices described here are slightly 

different than those practices required by the rule. The costs of these practices are expected to be representative of 

the practices required by the rule.

24 This analysis assumes that contractors will meet the entrance door requirement by creating an airlock using two 

sheets of plastic.
§402(c) Economic Analysis Chapter 4 39 

• At the conclusion of each work day, store waste from renovation activities under containment, in 

an enclosure, or behind a barrier that prevents release of dust and debris and prevents access to 

dust and debris. 

• Pick up all paint chips and debris. 

• Remove plastic sheeting from objects in the work area and the floor or ground. Mist the sheeting 

before folding it, fold the dirty side inward, and tape shut to seal. Dispose of the sheeting as 

waste. 

• Clean all objects and surfaces in and around the work area in the following manner, cleaning 

from higher to lower: 

Thoroughly vacuum all surfaces and objects in the work area, including furniture and 

fixtures, with a vacuum equipped with a high-efficiency particulate air (HEPA) filter. 

Where feasible, floor surfaces underneath a rug or carpeting must also be thoroughly 

vacuumed with a HEPA vacuum. 

Wipe all surfaces and objects in the work area with a damp cloth (except for walls, ceilings, 

carpeted surfaces and upholstered surfaces). 

Mop uncarpeted floors thoroughly, using a two-bucket mopping method that keeps the wash 

water separate from the rinse water, or using a wet mopping system. 

Post-renovation cleaning verification for interior events: 

• A certified renovator must perform a visual inspection to determine if visible amounts of dust, 

debris or residue are still present. If visible amounts of dust, debris or residue are present, these 

conditions must be eliminated by re-cleaning and another visual inspection must be performed. 

• After a successful visual inspection, a certified renovator must:

Wipe uncarpeted floors within the work area with a disposable wet cleaning cloth. The cloth 

must remain damp at all times while it is being used to wipe the floor for post-cleaning 

verification. If the floor surface within the work area is greater than 40 square feet, the 

floor within the area must be divided into roughly equal sections that are less than 40 

square feet. Wipe each such section separately with a new disposable cleaning cloth. If 

the cloths used to wipe each section of the floor within the work area match the cleaning 

verification card, that section of the floor has been adequately cleaned.

If the cloth used to wipe a particular section of floor does not match the cleaning verification 

card, re-clean that section of the floor using the two-bucket mopping method. Then wipe 

that section of the floor using a new wet cleaning cloth. If the cloth matches the cleaning 

verification card, that section of the floor has been adequately cleaned.

If the second cloth used to wipe a particular floor section does not match the cleaning 

verification card, re-clean that section of the floor using the two-bucket mopping method 

described above and allow the entire floor within the work area to dry completely. After 

the entire floor within the work area has completely dried, wipe the floor with 

electrostatic cleaning cloths until a cloth that has wiped the entire floor matches the 

cleaning verification card.25

Wipe the windowsills in the work area following the same protocol as used for floors, but 

with one wet-wipe per-windowsill.

When the area passes the post-renovation cleaning verification, remove the warning signs.

Post-renovation cleaning verification for exterior events: 

• A certified renovator must perform a visual inspection to determine if visible amounts of dust, 

debris or residue are still present. If visible amounts of dust, debris or residue are present, these 

 

25 It is assumed that a second cleaning is required 30 percent of the time and a third cleaning is required 2 percent of 

the time.
§402(c) Economic Analysis Chapter 4 40 

conditions must be eliminated by re-cleaning and another visual inspection must be performed. 

When the area passes the visual inspection, remove the warning signs. 

4.5.3 Cost of Each Containment and Cleaning Practice 

The primary source of information on the cost of containment and cleaning practices, equipment and 

materials was the Means CostWorks Repair & Remodeling Cost Data (R.S. Means 2005). The data is 

designed to help contractors estimate the cost of a renovation project. The database provides the total 

labor and material costs of different renovation components on a unit basis. Most of the costs used from 

the R.S. Means database are for an asbestos abatement project, which requires much more elaborate 

containment and clean up than required under the analyzed options. The R.S. Means labor estimates have 

been adjusted downwards based on conversations with industry experts to reflect the less stringent 

requirements of this proposed rule. Depending on the type of activity, the unit may be a square foot, each 

item, or some other measure. Table 4-17 and Table 4-18 show the unit costs, labor requirements and total 

cost for the containment and cleaning practices for interior events and exterior events, respectively. 
§402(c) Economic Analysis Chapter 4 41 

Table 4-17: Unit Costs of RRP Interior Activities (2005$) 

Cost Type Material Cost Units Labor Hours Total Costa

Sign $0.11b Ea. 0 $0.11 

Floors: Cover surfaces with polyethylene 

sheeting, each layer, 6 mil, incl. glue & tape $0.08c

 S.F. 0.006 $0.20 

Wallsd: Cover surfaces with polyethylene 

sheeting, each layer, 6 mil, incl. glue & tape $0.08c

 S.F. 0.008 $0.25 

Tack pad $0.51e Per sheet 0 $0.51 

Disposable shoe covers $0.38f Per pair 0 $0.38 

Roll down polyethylene sheeting $0.00 S.F. 0.002 $0.03 

Bag polyethylene sheeting $1.15 Ea. 0.05 $2.24 

HEPA vacuum for work area $0.63g,h Ea. 0 $0.63 

HEPA vacuum use $0.01 S.F. 0.002 $0.05 

Wet wipe, flat surfaces $0.01 S.F. 0.002 $0.06 

Electrostatic cloth sweeper $0.01g,i Ea. 0 $0.01 

Disposable wet/dry cloth $0.01j S.F. 0.002k $0.05 a Using a mean loaded wage rate of $20.62 (2005$) based on the wages of three construction laborers and one 

supervisor from the May, 2004 Occupational Employment Statistics data from the Bureau of Labor Statistics. b The cost of a 9”x12” aluminum sign is $10.99; assumed to be used 100 times. c Based on a web search which showed that duct tape costs $0.02 per square foot and 6 mil. polyethylene sheeting 

costs $0.06 per square foot. d Estimate used for plastic on the doors, windows, and ducts. e Based on a review of price lists on the web which showed that the average cost per disposable sheet is $0.51. f Based on a review of price lists on the web which showed that the average cost per pair of shoe covers is $0.38. g Assumes that it will be used for 1,000 events. 

h Based on a review of price lists on the web which showed that the average cost for a HEPA vacuum is $626. i Based on a review of price lists on the web which showed that the average cost of an electrostatic cloth sweeper is 

$13.60. 

j Based on a review of price lists on the web which showed that the average cost of a electrostatic cloth wet cloth is 

$0.46. Also based on clearance requirements that the work area must be divided into roughly equal sections that 

are 40 square feet, therefore it costs $0.01 per square foot. k Based on EPA’s (2005b) “Disposable Cleaning Cloth (DCC) Lead Clearance Field Study” document that it would 

take 5 minutes per cleaning cloth and clearance requirements that the work area must be divided into roughly equal 

sections that are 40 square feet which is equivalent to 0.125 minutes per square foot or 0.002 hours per square foot.

Abbreviations: S.F. = Square Feet; Ea. = Each Item 

Source: RS Means 2005; U.S. Bureau of Labor Statistics 2005b.
§402(c) Economic Analysis Chapter 4 42 

4.5.4 Baseline Work Practices 

Some of the containment and cleaning practice standards specified by EPA under the RRP rule are 

currently in use by some renovation contractors. The costs of work practices already in use are not 

incremental costs of the rule and are subtracted out of the cost estimates. In order to determine how often 

the proposed work practices are used without regulation, EPA work group members as well as other 

industry experts were contacted in 1999 to provide information on current industry practices. A series of 

questions were asked to determine if the listed work practices were currently in use and if they were, the 

frequency with which they occur. The questions were divided into four sections (1) Preparation, (2) 

Performing the Work, (3) Clean-Up, (4) Cleaning Verification. These industry experts were asked to 

check how frequently these work practices were used when performing work in units with known or 

suspected lead-based paint. The frequency categories and corresponding measures are listed in 

percentage terms as follows: 

• Never = less than or equal to 2% of projects 

• Rarely = 3%-29% of projects 

• Often = 30%-69% of projects 

• Usually = 70%-97% of projects 

• Always = greater than or equal to 98% of projects 

In order to use these data to revise the cost estimates, it was necessary to convert the ranges of frequencies 

into specific percentages. This percentage represents the percent of projects that already use a given work 

practice, and thus will not incur additional costs from the regulation. For example, if a response was 

“Rarely” for “Cover surfaces with polyethylene sheeting,” then it was assumed that 16 percent (midpoint 

of 3-29 percent range) of the projects performed by that respondent already employ this work practice. 

The average of responses for each question was calculated to determine the percent of projects that 

already use that work practice. Table 4-19 presents the percentage of projects that are already using the 

Table 4-18: Unit Costs of RRP Exterior Activities (2005$) 

Cost Type Material Cost Units Labor Hours Total Costa

Sign $0.11b Ea. 0 $0.11 

Floors: Cover surfaces with polyethylene 

sheeting, each layer, 6 mil, incl. glue & tape $0.06c

 S.F. 0.001 $0.08 

Wallsd: Cover surfaces with polyethylene 

sheeting, each layer, 6 mil, incl. glue & tape $0.08c

 S.F. 0.008 $0.25 

Roll down polyethylene sheetinge $0.00 S.F. 0.0005 $0.01 

a Based on a mean loaded wage rate of $20.62 (2005$) based on the wages of three construction laborers and one 

supervisor from the May, 2004 Occupational Employment Statistics data from the Bureau of Labor Statistics. b The cost of a 9”x12” aluminum sign is $10.99 and we assume that the sign will be used 100 times. c Based on a web search which showed that duct tape costs $0.02 per square foot and 6 mil. polyethylene sheeting 

costs $0.06 per square foot. Based on the EPA 2000a Model Renovation Training Course, duct tape will be used 

to tape the plastic to the building and rocks will be used to weight down the edges therefore we assume only 1⁄4 of 

the duct tape is needed for floors. d Estimate used for plastic on the doors, windows, and ducts. e Assume that for exterior events the contractor would tape the plastic up rather than bagging it. 

Abbreviations: S.F. = Square Feet; Ea. = Each Item 

Source: RS Means 2005; U.S. Bureau of Labor Statistics 2005a and 2005b. 
§402(c) Economic Analysis Chapter 4 43 

recommended work practices separately for remodeling and painting projects. Industry experts indicated 

that painting projects tended to employ greater containment than remodeling projects without painting. 

See section 5.5.3 for further details on the responses that were used to develop the percentages presented 

in Table 4-19. 

The analysis estimates incremental costs where work practices are not currently in use. In some cases, the 

work practices may be conducted in the baseline pursuant to other regulatory requirements. For example, 

OSHA’s Lead in Construction Standard (29 CFR 1926.62) applies to a variety of construction activities 

by firms with employees, including repair and renovation work involving lead-based paint. The Lead in 

Construction Standard requires that floors and other surfaces where lead accumulates be cleaned 

wherever possible by vacuuming or other methods that minimize the likelihood of lead becoming 

airborne. Where vacuuming methods are selected, the vacuums shall be equipped with HEPA filters and 

used and emptied in a manner that minimizes the reentry of lead into the workplace. To the extent that 

firms are already using these practices, they are accounted for in the baseline work practice estimates, and 

the cost (and benefit) estimates are adjusted accordingly. Thus, firms complying with the OSHA standard 

would be among the 41% of firms assumed to use a HEPA vacuum upon finishing a remodeling job in the 

baseline. 

4.5.5 Estimating the Size of Events 

The costs for most of the containment, cleaning, and verification practices vary with the size of the room 

or housing unit involved. Based on the 2003 AHS, average unit sizes for housing units built before 1978 

varied substantially across these categories of housing: 

• Single-family owner (2,016 sq. feet), 

• Single-family renter (1,471 sq. feet), and 

• Multi-family owner & renter (1,135 sq. feet). 

Table 4-19: Current Work Practices 

Current Work Practices (percent of events 

Work Practice Activity where the work practice is already taking place)

Remodeling Painting 

Post warning signs – interior events 13.2% 13.2% 

Post warning signs – exterior events 23.0% 23.0% 

Cover surfaces with polyethylene sheeting 41.2% 51.2% 

Use a tack pad 20.6%a 25.6%a

Wear disposable shoe covers 0.0%c 0.0%c

Roll down polyethylene sheeting 41.2% 51.2% 

Bag polyethylene sheeting 23.0% 23.0% 

HEPA vacuuming 41.2%b 51.2%b

Cleaning Verification with electrostatic cloth 0.0%c 0.0%c

a Not included in the 1999 survey. Set the frequency equal to half that of plastic sheeting. b Industry experts were asked whether they HEPA vacuumed at the end of each day, but not whether 

they did so upon finishing a job. The analysis assumed that more jobs perform HEPA vacuuming at 

the end of a job than daily and estimated the frequency of end of the job HEPA vacuum use as equal 

to that of the use of plastic sheeting. c Not included in the 1999 survey. 

Source: Work group members and other industry experts (1999). 
§402(c) Economic Analysis Chapter 4 44 

For interior events, the average square footage of particular rooms in a single-family owner-occupied 

home was determined by taking the average square footage of the whole unit from the 1997 AHS (approx. 

1,750 sq. feet) and reviewing house plans for homes of similar square footage.26 The average size of 

individual rooms was calculated as the average of all rooms of that type from a sample of five house 

plans. The average square footage of individual rooms in rental single-family units and multi-family units 

was scaled down from the single-family owner occupied values in proportion to their relative total square 

footage. 

Costs were estimated for a small event (i.e., affecting only one side of the room or house) and a large 

event (i.e., affecting the entire area) for each event type. Both Whole and Contained Exterior events are 

assumed to be large events. It was assumed that some Exterior Paint Events could be small events that 

only affect one side of the house. The cost analysis also assumes that the removal of windows and doors 

can either be performed from the interior or the exterior of the house. When interior work is performed 

on windows and doors, the task is assumed to be a large event. Further, it assumes that on average a nonroom-specific window and door removal event will require containment, cleaning, and verification 

methods for fifty percent of the housing unit. According to EPA’s (1997) Reducing Lead Hazards When 

Remodeling Your Home, the alternative (small event) is to remove the windows and doors from the 

exterior, in which case plastic would cover the inside surface of the window or door and be laid on the 

interior and exterior floors extending five feet from the wall and one foot on each end of the window or 

door. The analysis assumes that an average of two doors connect the interior and exterior; fifty percent 

(one, in this case) of doors will be removed during exterior work. In both interior and exterior door and 

window removal, damaged paint on the removed door and window components will be wrapped with the 

plastic sheeting that is used to cover the floors.

For room-specific events, the analysis assumes that a small event would affect only one side of the room, 

so doors would not be covered. Based on the EPA Model Renovation Training Course (EPA 2000a) and 

work-practice recommendations described above, plastic sheeting would extend five feet on all sides of 

the work area. As mentioned above, a large event was assumed to involve the entire room. Based on the 

containment and cleaning practices described above, for a large event, the door opening used as the 

entrance will be air-locked with two layers of plastic sheeting, all other doors will be covered with one 

layer of plastic sheeting, ducts will be covered with plastic sheeting, all windows will be closed, all 

movable objects will be removed and all floor space will be covered. It was assumed that on average an 

extra 10 percent of plastic would be needed to cover any unmovable furniture. It was necessary to 

estimate the size of an average door, window, and air duct to calculate how much plastic sheeting would 

be needed to cover them. Based on information in R.S. Means, an average door is 20 square feet 

(3’×6’8”), an average window is 6.8 square feet (2’×3’5”) and an average air duct is one square foot 

(0.5’×2’). For large events, a tack pad (sticky pad that removes dust from the soles of shoes) would be 

needed. A path through the rest of the house would be created which is assumed to be 60 square feet 

(2’×30’). 

To estimate the affected square footage of non-room-specific events and interior paint events, EPA 

assumed that a non-room-specific event and interior paint event would affect 50 percent and 25 percent, 

respectively, of the total square footage in the housing unit. The 2003 AHS data was used to estimate the 

number of rooms in each type of housing unit and therefore the number of affected doors, windows, and 

ducts. 

 

26 Reviewed house plans at http://www.store.homestyles.com/homestyles/plans/search (Homestyles.com 2002). 
§402(c) Economic Analysis Chapter 4 45 

Addition events include the events in which rooms are created through the demolition of an existing wall 

for a new addition or by structural changes in an existing room, such as the creation of a wall. For a large 

Addition event, it is assumed that the workers would have to lay plastic sheeting over and clean an area of 

floor equal to the average size of the room from which the work is being performed (i.e., kitchen, 

bathroom, bedroom, “other” room). Since kitchens, bedrooms, and “other” rooms are similar in size and 

bathrooms are much smaller, the average size of a room was estimated as the smallest average room size 

between kitchens, bedrooms, and “other” rooms. For a small Addition event, it is assumed that the 

workers would be required to prepare and clean along the affected wall of the room using the guidelines 

for a small event. Again, work is assumed to affect a portion of a wall equal to an average sized wall of 

the room being added. 

The square foot costs of an external event are estimated for both an event involving the whole of the 

exterior (e.g. replacing siding) and for one where just a contained section of the unit (e.g., replacing a 

deck) is involved. The structures in a Contained Exterior event are outside the main body of the house 

and the structural work and contamination is primarily outdoors. The perimeter of a contained exterior 

structure is estimated to be 60 feet (10’×20’). Containment is necessary along the entire perimeter of a 

detached structure. However, it is assumed that less containment is required for attached contained 

exterior structures, which are assumed to be attached to the main structure of the house along a 20 foot 

side of the detached contained exterior structure. The analysis averages the cost of an attached and 

detached structure to estimate the cost of a Contained Exterior Event. 

To calculate the relevant square footage of a Whole Exterior or Exterior Painting event, the perimeters of 

the typical single-family and multi-family housing unit were estimated. The perimeter estimate for a 

single-family unit was calculated following the procedure used in EPA’s Economic Analysis for the 

TSCA Section 403 rule (EPA 2000b). It was assumed that the home is rectangular with a front to side 

ratio of 2:3 and an average first floor area of 1,390 sq. feet.27 This assumption leads to a perimeter of 152 

feet for a single-family owner occupied home. The perimeter of a single-family renter unit was estimated 

to be 130 feet, which assumes that the proportion of a single-family renter unit has the same proportion of 

total square footage to square footage of the first floor of a single-family owner unit. The perimeter of a 

multi-family housing structure (which contains several multi-family units) was calculated assuming the 

first-floor area was three times as large as a single-family unit. This perimeter estimate is 264 feet. 

For an exterior event, based on the training manual instructions, plastic would be placed stretching out 10 

feet from the structure including rounded corners. Based on the containment and cleaning practices 

described above, for a large event, the door opening used as the entrance to the building during the work 

will be air-locked with two layers of plastic sheeting, all other doors will be covered with one layer of 

plastic sheeting, and all windows on the same floor and floors below will be closed. Based on the EPA 

Model Renovation Training Course, duct tape will be used to tape the plastic to the building and rocks 

will be used to weight down the edges. Therefore, only one-fourth of the duct tape that would be needed 

for an interior event is necessary. 

 

27 Estimated based on information from http://www.dreamhomesource.com (2005) on the average size of the first 

floor of nine 2,000 square foot two stories homes (1,280 sq. feet). The weighted average of a first floor was 

calculated using 2003 AHS data which shows that 85% of single-family housing units are two stories high and the 

remaining 15% of homes are one story (i.e., first floor is 2,016 sq. feet). 
§402(c) Economic Analysis Chapter 4 46 

4.5.6 Estimating Total Per Event Containment and Cleaning Costs 

For each event, containment and cleaning costs are estimated by multiplying the containment and 

cleaning unit costs listed in Table 4-17 and Table 4-18 by the square footage and units of material and 

labor required for each event. The number of units required for each event was estimated using the 

containment and cleaning standards and size assumptions detailed in Section 4.5.2 and Section 4.5.5, 

respectively. Table 4-20 shows the estimated per event containment and cleaning costs combined with 

the cleaning verification costs described in Section 4.5.7. These costs are not adjusted for noncompliance 

or baseline work practices. 

4.5.7 Cleaning Verification Costs 

The interior cleaning verification costs for all of the proposed options includes the cost of wiping the 

windowsills and uncarpeted floors with a disposable wet cleaning cloth until it matches the cleaning 

verification card as described in Section 4.5.2. It was assumed that 30 percent of windowsills and 

uncarpeted floors would fail the cleaning verification card test the first time and 6 percent of those 

failures would fail a second time. According to the requirements described above, after the first failure 

the uncarpeted floors would have to be cleaned again using the two-bucket mopping method. For both 

the windowsills and uncarpeted floor, a new disposable wet cleaning cloth would be needed to check 

against the cleaning verification card. If the second cloth used to wipe a particular floor section does not 

match the cleaning verification card, that section of the floor would have to be re-cleaned using the twobucket mopping method described above and the entire floor within the work area would need to dry 

completely. After the entire floor within the work area has completely dried, the floor would be wiped 

with a dry electrostatic cleaning cloth that would need to be checked against the cleaning verification card 

again. It is assumed that there would be no further failures. For all events it is assumed that visual 

clearance is attained as part of the cleaning activities. 

The cleaning verification costs are estimated by multiplying the unit compliance costs of the wet wipe, 

electrostatic cloth sweeper, and disposable wet/dry cloths from Table 4-17 by the square footage and units 

of material and labor required for an event. The costs are combined with the containment and cleaning 

costs of Section 4.5.6 and are listed in Table 4-20. These costs are not adjusted for noncompliance or 

baseline work practices. 

Note that households may choose to have a sampling technician perform dust clearance testing following 

a renovation instead of performing cleaning verification. Because dust clearance testing is substantially 

more expensive than the cleaning verification, EPA expects few households to have dust clearance testing 

performed. Since the frequency of dust clearance testing is expected to be low, and therefore not to have 

a significant impact on the total cost of the rule, this analysis assumes that cleaning verification is always 

performed. 

4.5.8 Summary of Containment, Cleaning, and Verification Costs 

The costs presented in Table 4-20 combine the total containment and cleaning costs with the cleaning 

verification costs based on the methods outlined in Sections 4.5.6 and 4.5.7, respectively. These are the 

total compliance costs associated with using the containment, cleaning, and verification procedures, 

without any adjustment for baseline work practices. Event costs primarily vary with the size of the area 

that requires containment and cleaning. That is, small events or events confined to smaller areas have 

lower costs because they require less containment and cleaning. 
§402(c) Economic Analysis Chapter 4 47 

Table 4-20 presents the full per-event costs that a contractor will incur if they use the required work 

practices. These costs presented in Table 4-20 indicate how much more a contractor could charge for 

using all the required LSWP compared to a contractor who was not going to use any of the required work 

practices—assuming a contractor can pass on the full cost of using LSWP. The costs presented in Table 

4-20 are not, however, the per-event work practice burden attributable to the rule, because some 

contractors are incurring the costs presented in Table 4-20 in the baseline. Table 4-21 subtracts the work 

practice costs that are incurred in the baseline from the costs in Table 4-20 to arrive at the incremental 

impact of the rule on work practice costs. 28 Therefore, the costs presented in Table 4-21 are the costs that 

are multiplied by the number of events where LSWP are used to arrive at the total costs of using LSWP 

that are attributable to the RRP rule. 

 

28 It is estimated that about 47 percent of the post-rule containment, cleaning, and verification costs would be 

incurred in the baseline scenario (assuming 75 percent compliance). 

Table 4-20: Summary of Housing Unit Containment, Cleaning, and Verification Compliance Costs: Not 

Adjusted for Compliance with the Rule or Baseline Work Practicesa (2005$) 

Single-Family Owner 

Occupied Housing Unit 

Single-Family Rental 

Housing Unit 

Multi-Family Housing 

Unit Event Type Small Event 

Cost 

Large Event 

Cost 

Small Event 

Cost 

Large Event 

Cost 

Small Event 

Cost 

Large Event 

Cost 

Kitchen Remodel $37.18 $132.23 $32.88 $110.26 $27.77 $87.77 

Bathroom Remodel $22.71 $63.28 $22.69 $63.20 $22.68 $63.17 

Additions $33.26 $117.13 $30.17 $101.77 $25.50 $65.04 

Non-Room-Specific Interior 

Wall $75.31 $527.97 $63.81 $396.52 $57.17 $317.25 

Non-Room-Specific 

Window/Door $117.60 $527.89 $97.54 $396.52 $57.90 $317.25 

Interior Paint $54.58 $284.92 $46.99 $218.68 $42.01 $176.73 

Whole Exterior Remodelb nab $180.85 nab $160.86 nab $281.15 

Exterior Remodel in 

Contained Areab nab

 $76.66 nab $76.66 nab $76.66 

Exterior Paint $46.66 $180.85 $41.66 $160.86 $71.73 $281.15 

a Assumes 100% compliance with the rule and 0% of work practices already in use in the baseline. b All whole exterior remodel events and exterior remodels in a contained area were assumed to be large events. 

Source: RS Means 2005; U.S. Census Bureau 2003. 
§402(c) Economic Analysis Chapter 4 48 

This analysis assumes that 75 percent of establishments and events will be in compliance with the rule. It 

is assumed that the contractors and events that are not in compliance with the rule are contractors that are 

not using any of the required work practices in the baseline. For example, 13 percent of contractors post 

signs in the baseline and 75 percent will post signs under the rule—it is assumed that the 13 percent of 

contractors posting signs in the baseline will all comply with the rule. In other words, 17.3 percent (13 

divided by 0.75) of compliant contractors do not incur any new costs due to the sign posting requirement, 

while 82.7 percent (62 divided by 0.75) incur new costs associated with posting a sign under the rule. 

Thus, the expected regulatory impact per compliant event associated with posting signs is estimated as 

follows: A sign costs 11 cents, and in 82.7 percent of the compliant events the costs of posting a sign 

would not have been incurred in the baseline. However, in 17.3 percent of the compliant events the costs 

of posting a sign would have been incurred both under the baseline and after the rule. Therefore, the 

expected cost of the requirement to post a sign averages 9 cents per compliant event—since 82.7 percent 

of 11 is 9. 

Table 4-21 shows the average expected per-compliant event costs, accounting for the relative number of 

small and large events, and for flexible options, the reduced per-event costs. Under the prescriptive 

requirements (Option D), it is assumed that 25 percent of events are small and 75 percent are large. 

Under the flexible options (Options A, B, and C), it is assumed that 25 percent of events are small, 25 

percent are large, and 50 percent will have expected compliance costs at the midpoint of the small and 

large event expected compliance costs. These are average expected costs so some individual events will 

be above the average and some will be below it.

Table 4-21: Summary of Per-Event Containment, Cleaning, and Verification Costs 

(Adjusted for Baseline Work Practices, Assumes 75 Percent Compliance) 

Flexible Options (A, B, and C) Prescriptive Option (D)

Event Type Single-Family 

OwnerOccupied 

Single-Family

RenterOccupied 

MultiFamily 

Single-Family 

OwnerOccupied 

Single-Family

RenterOccupied 

MultiFamily 

Kitchen $45 $38 $30 $56 $47 $37 

Bathroom $23 $23 $23 $27 $27 $27 

Additions $39 naa $24 $49 naa $28 

Non-Room-Specific 

Wall/Ceiling $155 $117 $96 $212 $159 $128 

Non-Room-Specific 

Window/Door $163 $124 $95 $216 $162 $128 

Interior Painting $69 $54 $44 $90 $69 $56 

Whole Exterior $82 $73 $127 $82 $73 $127 

Contained Exterior $35 $35 $35 $35 $35 $35 

Exterior Painting $36 $32 $56 $47 $42 $73 a For rental housing units, it was not possible to estimate the number of Additions. Renovation activities in these 

rooms are likely to be accounted for as Non-Room-Specific events. 

See Table 4-4 for option descriptions.

Source: RS Means 2005; U.S. Census Bureau 2003; EPA Calculations.
§402(c) Economic Analysis Chapter 4 49 

4.6 Certification Costs: Firm Paperwork Burden and EPA Administrative and 

Enforcement Costs 

Under the RRP Rule, states are given the option of administering the regulations as long as the state 

implementation plan is approved by EPA. EPA will directly administer programs in states that do not 

have an approved implementation plan. This section of the analysis estimates costs that EPA expects to 

incur while administrating and enforcing the RRP program under the assumption that EPA administers 

the program everywhere. States that choose to implement the rule themselves are expected to incur 

similar costs. 

EPA will perform three tasks as part of administering the RRP program: accrediting training providers, 

certifying firms, and processing training provider notifications. In addition to administrative costs, EPA 

will also incur costs to enforce the RRP rule. To reduce the burden on the regulated community, EPA has 

decided not to require formal certification for renovators and workers. 

Accreditation/certification cost estimates are based on responses from nine states to a phone survey 

conducted in support of the TSCA §402(a)(3) “Fees Rule.” Data were collected from California, Illinois, 

Maine, Massachusetts, New Hampshire, Ohio, Rhode Island, Vermont, and Virginia. States were asked 

to provide the number of hours per applicant required to perform a variety of administrative tasks under 

the broader §402(a) lead abatement training and certification regulation. While §402(a) defines training 

and certification requirements for five different categories of lead abatement professionals, the type of 

administrative activities associated with the §402(a) rule are similar to those expected for the Renovation, 

Repair, and Painting Rule. As a result of these similarities, the state-provided data were not adjusted 

unless specifically noted. 

The nine states provided information on the hours required to perform the following administrative 

activities: 

• Application Processing and Recordkeeping; 

• Fee Transactions and Waivers; 

• Issuance of Accreditation/Certification Papers; 

• Public Assistance/Outreach; 

• Reporting; 

• Management; and 

• Auditing Training Courses for Training Provider Accreditation Only. 

These data were used to estimate the costs of accrediting training providers and certifying firms. In each 

case, the amount of time necessary to implement the rule was calculated as the simple average of the 

hours reported by the nine states surveyed for the §402(a) rule. Hours are reported for three categories of 

workers: clerical, technical, and managerial. These hourly burden estimates were multiplied by wage 

rates for each job category to determine the per-entity cost of administering the rule. 
§402(c) Economic Analysis Chapter 4 50 

Wage rates for administrative staff vary from region to region. EPA used the Office of Personnel 

Management’s (2005a-c) General Salary Table 2005-GS to estimate government employee wage rates. 

The labor rates used were: $49.44 per hour for managerial staff (GS-13, Step 1), $34.69 per hour for 

technical staff (GS 11, Step 1), and $21.09 per hour for clerical staff (GS-6, Step 1)29. These wage rates 

were multiplied by the hourly time estimates to derive total unit costs for accreditation/certification. 

4.6.1 Costs for Accrediting Renovator Training Providers and Processing Training Notifications 

The task of accrediting training providers includes approving curricula and quality assurance/quality 

control (QA/QC) programs for instructors, and maintaining a database of accredited training providers. 

The Renovation, Repair, and Painting Rule requires that renovators receive formal training in lead-safe 

work practices from an accredited training provider. In addition, renovators are required to take a 

refresher course once every three years. EPA, in turn, must accredit training courses by reviewing the 

curriculum and ensuring that training providers have acceptable quality assurance/quality control 

(QA/QC) procedures in place to ensure quality instruction by every instructor. EPA will review and 

document all applications for accreditation, audit training courses, process fees and fee waivers, issue 

accreditation papers, perform public outreach/assistance, report to overseeing organizations or legislative 

bodies, and perform other general program management activities (i.e., budgeting). In addition, EPA will 

process notifications submitted by training providers prior to and following each course session. 

Data on the time required to perform training accreditation activities were available from eight of nine 

states. The time required to administer the §402(a) program varies widely by state. In particular, the 

amount of time spent auditing training courses differs substantially among respondents. EPA used the 

simple average of time estimates for all eight responding states to determine the time required to process a 

single application in a typical state. EPA then adjusted the number of hours spent on auditing training 

courses to account for the fact that the renovator course is shorter than the majority of initial abatement 

training courses. EPA estimates an average of 12 FTE hours will be spent on auditing each training 

course. 

The average time spent performing each of the seven administrative activities associated with accrediting 

training courses is shown in Table 4-22. Notification processing time is assumed to be included in the 

Reporting hours estimate. The total unit cost of accrediting a training course is $1,796 based on these 

estimates and the above labor rates. Note that the cost of accrediting training courses are not used to 

calculate the certification cost impact of the rule. This is because this analysis assumes that training 

providers will recover their accreditation fees (which in turn cover the administrative and enforcement 

costs of training provider accreditation) through the tuition they charge. Thus, the cost of accrediting 

training courses is accounted for in the tuition estimates. 

 

29 These wage rates are fully loaded, and were calculated using the standard government multiplier of 1.6 to cover 

overhead and fringe benefits. 
§402(c) Economic Analysis Chapter 4 51 

Based on the U.S. Department of Housing and Urban Development’s Lead Listing and on contacts with a 

randomly selected group of training providers, EPA estimates that there are approximately 168 

firms/organization currently accredited to offer lead abatement training. It is assumed that each training 

provider can teach 10 classes a month with an average class size of 25 students. As such, 168 providers 

can train 42,000 renovators each month, or 504,000 a year. EPA estimates that under Option A, only 

186,811 renovators will seek training in the first year; this number is lower for the other Options. Thus, 

this analysis estimates that under Option A, all 168 training providers will seek accreditation prior to the 

first year that renovators will need to be certified. For the remaining Options, the number of training 

providers accredited by or in the first year will be proportional to the number of renovators trained (and, 

as such, to the regulated housing stock). At the same time, EPA believes that there will be at least two 

accredited training providers per state, thus at least 100 providers will seek accreditation under each 

option. The estimated numbers of training providers accredited by or in the first year (by option) are 

presented in Table 4-23. In the long run, all 168 training providers will seek accreditation regardless of 

the option. 

Table 4-22: Per-Unit Cost of Accrediting Training Providers 

 

Clerical 

Hours 

 (GS-6, Step 1) 

($21.09/hr) 

Technical 

Hours 

 (GS-11, Step 1)

($34.69/hr) 

Managerial 

Hours 

 (GS-13, Step 1) 

($49.44/hr) 

Unit Cost 

Application Processing and Recordkeeping 1.94 17.3 0 $641 

Auditing Training Courses 0 12 0 $416 

Fee Transactions and Waivers 0.24 0 0 $5 

Issuance of Accreditation Documents 0.79 0 0 $17 

Public Assistance/Outreach 0 5.79 0 $201 

Reporting 0 2.16 0 $75 

Other Management 0 0 8.93 $441 

Total 2.97 37.25 8.93 $1,796 

Source: U.S. EPA 1999, U.S. OPM 2005a-c.
§402(c) Economic Analysis Chapter 4 52 

To estimate the total administrative cost associated with training provider accreditation and notification 

processing, EPA multiplied the accreditation cost per-provider by the number of providers accredited 

under each Option. The resulting first-year administrative costs range from $180 thousand (Options B, C 

and D) to $302 thousand (Option A). 

4.6.2 Costs of Certifying Renovation Firms 

The Renovation, Repair and Painting Rule will require renovation establishments to submit a completed 

application and fee. For the purpose of estimating costs, it is assumed that EPA will review the 

certification statement for completeness, review the firm’s environmental compliance history, record the 

establishment’s information in a database, and mail a certification form to the establishment. 

Data on the time required to perform establishment certification activities were available from six of nine 

states. The states of California, New Hampshire, and Ohio did not provide any information on the cost of 

certifying establishments under §402(a). The time required to administer the §402(a) program is 

reasonably consistent among states. The simple average of the six states’ data was used to determine the 

time required to certify an establishment in a typical state. 

Table 4-24 provides the average time spent performing six administrative activities associated with 

certifying establishments. The total unit cost of certifying establishments is $318 based on these 

estimates and the above labor rates. 

Table 4-23: Estimated Number of Training Providers Accredited in the First Year, by Regulatory Option 

A B C D

Number of training providers accredited 168 100 100 100 

a In the first year, the number of renovators seeking training under Option B (Option C, D) is equal to 54 percent 

(40 percent, 54 percent) of renovators seeking training under Option A. 

See Table 4-4 for option descriptions.

Source: U.S. HUD 2004; EPA Calculations. 
§402(c) Economic Analysis Chapter 4 53 

Table 4-25 presents the estimated first-year numbers of renovation establishments (employers and selfemployed contractors) expected to seek certification under each regulatory option and the associated 

administrative costs.30

4.6.3 Costs of Enforcement 

In addition to administering the accreditation and certification requirements, EPA will perform a variety 

of enforcement activities to ensure that the training and performance (including containment, cleaning, 

and verification) requirements of the rule are met. Based on previous experience with similar programs, 

EPA estimates that it will need 2 Headquarters and 10 Regional FTEs for enforcement activities under 

each regulatory Option. Headquarters enforcement costs were calculated by loading the 2005 

Washington/Baltimore area annual salary rates for a GS-12, Step 1 employee ($100,618). Regional 

enforcement costs were estimated using the GS-12, Step 1 employee salary listed in the 2005 General 

Schedule ($86,754). 31 Based on these salaries and the indicated numbers of FTEs, total annual 

enforcement costs are estimated at $1,068,776. EPA assumed that enforcement costs associated with 

training providers is equal to 0.4 percent of the total enforcement costs, or $4,275 per year. Thus, costs of 

 

30 Firms already certified to perform lead-based paint activities would be deemed certified to perform renovations 

and are not included in this calculation. 

31 These salaries are fully loaded, and were calculated using the standard government multiplier of 1.6 to cover 

overhead and fringe benefits. 

Table 4-24: Per-Unit Costs of Certifying Renovation Establishments 

 

Clerical 

Hours 

 (GS-6, Step 1)

($21.09/hr) 

Technical 

Hours 

 (GS-11, Step 1)

($34.69/hr) 

Managerial 

Hours 

 (GS-13, Step 1) 

($49.44/hr) 

Unit Cost 

Application Processing and Recordkeeping 0.21 1.49 0 $56 

Fee Transactions and Waivers 0.16 0 0 $3 

Issuance of Accreditation Documents 0.12 0 0 $3 

Public Assistance/Outreach 0 1.66 0 $58 

Reporting 0 1.58 0 $55 

Other Management 0 0 2.9 $143 

Total 0.49 4.73 2.9 $318 

Source: U.S. EPA 1999, U.S. OPM 2005a-c.

Table 4-25: First-Year Total Costs of Certifying Renovation Establishments by Regulatory Option 

 Number of Establishments Certified Total Certification Costs 

Option A 163,979 $52,145,322 

Option B 86,539 $27,519,402 

Option C 59,571 $18,943,578 

Option D 86,539 $27,519,323 

See Table 4-4 for option descriptions.

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 4 54 

ensuring certified firm compliance account for 99.6 percent of the enforcement burden, or $1,064,501 per 

year. 

4.6.4 Administrative and Enforcement Costs: Contribution to Total Costs 

Similar to the regulations governing abatement, EPA is likely to recover its administrative and 

enforcement costs from certified firms and Accredited Training Providers through their certification and 

accreditation fees, respectively. However, these fees will be set by a separate rulemaking and may be 

apportioned differently than assumed in this analysis. Thus, while the estimation of these fees is outside 

the scope of this analysis, EPA’s administrative and enforcement costs are considered a part of the 

regulatory impact estimated here. Simply adding these costs to the other cost components, however, will 

result in some double counting. Specifically, this analysis assumes that training providers will recover 

their accreditation fees (which in turn cover the administrative and enforcement costs of training provider 

accreditation) through the tuition they charge. Thus, only costs associated with certified firms are used to 

calculate the certification cost impact of the rule; EPA’s burden of administering and enforcing the RRP 

Rule will be higher. The EPA costs that will be recovered from RRP firms in a given year are thus 

calculated as follows:32

4.6.5 Firm Paperwork Burden 

In addition to EPA’s administrative and enforcement costs, annual firm certification costs also include the 

paperwork burden incurred by certified firms. Note that there is also a paperwork burden borne by 

Accredited Training Providers, but like the fees, these costs are also assumed to be recovered through 

tuition charges. The training provider paperwork burden is estimated in Chapter 8, however, where it is 

considered separately from the total costs of the rule. 

It is estimated that firms will spend a total of three hours to familiarize themselves with the RRP rule’s 

requirements and a half an hour to fill out and mail the one-page Application for renovator certification. 

In addition, firms will spend 5 minutes per-event keeping records that demonstrate compliance with the 

Renovation, Repair and Painting Rule training and work-practice requirements. At a loaded wage rate of 

$31.64, the time burden in the first year will be $276 per firm (see Table 4-26). Additional costs are 

minor; these costs include: one application printout, one photocopy for personal records, an envelope, and 

a stamp. The total first year information collection burden is estimated be $276 per firm. Firms applying 

for re-certification will incur all the costs of initial certification, less the time burden associated with 

learning about the rule, or $181 per firm. In years where firms will not need to apply for re-certification 

their information collection burden will only include the recordkeeping burden of $165. 

 

32 The administrative costs associated with firm certification are estimated to be $318 per firm seeking certification; 

the annual costs of ensuring certified firm compliance is estimated to be $1.06 million. 

EPA Administrative and 

Enforcement Costs that will be 

recovered from FirmsYear X

= $318 * # of Firms CertifiedYear X + $1,064,501 
§402(c) Economic Analysis Chapter 4 55 

4.6.6 Total Certification Costs: Firm Paperwork Burden and EPA Administrative and Enforcement 

Costs 

Table 4-27 shows the total certification costs for the RRP rule in the first, second, and third years. Total 

per-firm costs are the sum of EPA’s administrative costs per firm and the firm paperwork burden. This 

per-firm cost is multiplied by the number of establishments estimated to provide lead-safe RRP services 

(See Section 4.3.5). 

In the first year, all the firms listed in the number of establishments column are presumed to seek initial 

certification, paying their share of EPA’s administrative costs ($318 per firm, see Section 4.6.4) and their 

share of the enforcement costs ($1.06 million in total, see Section 4.6.3). In addition, they are subject to a 

paperwork burden of $276 (see Table 4-26). In the second year, EPA administrative costs per-firm and 

the firm paperwork burden are estimated based on the costs presented in Table 4-26 and the relative 

number of firms seeking initial-certification, re-certification, and not seeking certification. Section 4.3.5 

describes and presents these estimates. The number of establishments includes all firms, even those not 

seeking certification or recertification that year. Since one-third of the firms under Option A will seek 

recertification in the second year, the average cost over all firms is one-third of $318. Under Option B, 

over 100,000 firms are seeking initial certification in year two. In addition, one-third of the firms 

certified in the first year are seeking recertification. Thus, the average cost over all firms is $206. 

Finally, in the third year, the average firm’s share of the administrative costs is $106 ($318/3, since one 

third of firms are paying a certification fee), and the average firm’s paperwork burden is $187.33

 

33 After the first year, 54 percent of firms seeking certification are assumed to be seeking their initial certification 

based on the relative frequency of initial certifications observed for abatement firms in the FLPP database (EPA 

2005). 

Table 4-26: Costs to Firms Associated with Information Collection 

First Year/Initial 

Certification Year 

Re- Certification 

Year Other Years 

Rule familiarization (3 hours)b $94.93 $0 $0 

Certification form (half hour)b $15.82 $15.82 $0 

Recordkeeping (5 hours per firm)b $164.85 $164.85 $164.85 

2 photocopies $0.16 $0.16 $0 

1 envelope $0.02 $0.02 $0 

1 stamp $0.37 $0.37 $0 

Totala $276 $181 $165 a Rounded to nearest dollar. 

Source: EPA Calculations and (b) U.S. Bureau of Labor Statistics 2005a.
§402(c) Economic Analysis Chapter 4 56 

4.7 Total Costs 

This section presents the total costs of the regulation. Total costs are estimated for the first, second and 

third years of regulation and also calculated as total 50-year costs and 50-year annualized costs. 

Estimates are calculated using discount rates of 3 and 7 percent. 

4.7.1 Total Costs in the First Year of Regulation 

Table 4-28 presents the total first year costs of the Renovation, Repair, and Painting Rule. Total 

containment, cleaning, and verification costs are calculated by adding the cost of testing using the LBP 

test kits to the costs of containment, cleaning, and verification. The total costs of containment, cleaning, 

and verification are calculated by multiplying the number of events presented in Table 4-7 by the 

corresponding incremental costs in Table 4-21. The total cost of conducting LBP tests using test kits is 

estimated as the number of events presented in Table 4-4 by the cost of conducting the test, $10 (see 

Section 4.5.1). Total training costs are calculated by multiplying the number of workers presented in 

Table 4-14 by the corresponding incremental costs in Table 4-16. Total certification costs are calculated 

by multiplying the number of firms presented in Table 4-14 by the corresponding incremental costs in 

Table 4-27. 

The total costs in the first year of regulation are highest under Option A, the only option that requires all 

pre-1978 renter-occupied target housing units and owner-occupied target housing units where a child 

under the age of six resides to follow the rule’s requirements. Both Options B and D regulate the same 

universe of housing units in the first year, all pre-1960 renter-occupied target housing units and owneroccupied target housing units where a child under the age of six resides, but Option D has higher first year 

costs because of its more prescriptive containment requirements. Option C has the lowest first year costs 

Table 4-27: Average Firm Annual Certification Costs: Firm Paperwork Burden and Fees in the First, 

Second, and Third Years of Regulation (including EPA Administrative and Enforcement Costs) 

EPA 

Administrative 

Costs, Average 

per Firm 

Average 

Firm 

Paperwork 

Burden 

Total 

Average 

Cost per 

Firm 

Number of 

Establishments 

Annual 

Enforcement 

Costs, Total 

(millions 

2005$) 

Total 

Certification 

Costs 

(millions 

2005$) 

First Year of Regulation 

Option A $318 $276 $594 163,979 $1.06 $98 

Option B $318 $276 $594 86,539 $1.06 $52 

Option C $318 $276 $594 59,571 $1.06 $36 

Option D $318 $276 $594 86,539 $1.06 $52 

Second Year of Regulation 

Option A $106 $187 $293 163,307 $1.06 $49 

Option B $206 $229 $435 163,307 $1.06 $72 

Option C $241 $244 $485 163,307 $1.06 $80 

Option D $206 $229 $435 163,307 $1.06 $72 

Third Year of Regulation 

All 

Options $106 $187 $293 162,637 $1.06 $49 

See Table 4-4 for option descriptions.

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 4 57 

because the regulated universe is limited to all pre-1950 renter-occupied target housing units and owneroccupied target housing units where a child under the age of six resides. 

4.7.2 Total Costs in the Second and Third Years of Regulation 

From the second year forward, the universe of regulated housing units is the same under all four options; 

all pre-1978 renter-occupied target housing units and owner-occupied target housing units where a child 

under the age of six resides are subject to the rule. Thus, Table 4-29 shows that the work practice costs 

are the same for the flexible options (A, B, and C). Despite the second year expansion of the number of 

regulated events under Options B and D, the total work practice costs are lower than in the first year. 

This decline results from the improved effectiveness of the test kit, from a false positive rate of 63 percent 

to a 10 percent rate, which yields a larger savings than the cost increase associated with the larger 

universe of regulated events. Under Option C, however, the cost increase from the regulated universe 

expansion in the second year is large enough to overshadow the cost savings associated with the improved 

test kit. 

In the second year, the training and certification costs are highest under Option C, and are relatively 

higher under Options B and D. This reflects the delayed start-up costs associated with training and 

certifying the additional individuals and firms needed to meet the demand increase that corresponds with 

the expansion in the regulated universe (to include all pre-1978 renter-occupied target housing units and 

owner-occupied target housing units where a child under the age of six resides). From the third year 

forward, the training and certification costs are the same under all four options. 

Table 4-28: Total First Year Costs of the Renovation, Repair, and Painting Rule (millions 2005$) 

Option A Option B Option C Option D

First Year 

Total Work Practice Costs $713 $419 $315 $533 

Total Training Costs $112 $59 $41 $59 

Total Certification Costs $98 $52 $36 $52 

Total Costs $924 $531 $393 $645 

See Table 4-4 for option descriptions.

Source: EPA Calculations.
§402(c) Economic Analysis Chapter 4 58 

4.7.3 Total 50-Year and 50-Year Annualized Costs 

The total costs are also calculated discounted over a 50-year period. Discounting refers to the economic 

conversion of future costs (and benefits) to their present values, accounting for the fact that society tends 

to value future costs or benefits less than comparable near-term costs or benefits. Discounting is 

important when the values of costs or benefits occur over a multiple year period and may vary from year 

to year. Discounting enables the accumulation of the cost and benefit values from multiple years at a 

single point in time, accounting for the difference in how society values those costs and benefits 

depending on the year in which the values are estimated to occur. 

To estimate the 50-year costs of options considered, EPA first developed a profile, over the period of 

analysis, of the compliance costs associated with each option. EPA defined the period of analysis as a 

period of 50 years based on the economic analysis done for the TSCA Section 403 Lead-Based Paint 

Hazard Standards. 

EPA developed a profile of costs over time by estimating the decline in pre-1978 housing stock, 0.41 

percent per-year, and assumed that the regulated universe would decrease by that rate every year. To 

estimate that rate, EPA calculated the average annual compound rate of change in the pre-1980 housing 

stock using data from the 1990 and 2000 Decennial Census (U.S. Census Bureau 1990 and 2000c). This 

rate affects costs because it decreases the number of events and number of workers trained every year. 

As discussed above in Section 4.7.1 (Total Costs in the First Year of Regulation), the first year training 

and certification costs account for the training and certification of all certified renovators and the 

certification of all certified firms to meet the demand for lead-safe RRP services in the first year. 

Similarly for the phase-in options (Options B, C, D) in the second year, it is assumed that the additional 

individuals and firms needed to meet the demand increase associated with the larger regulated universe 

will obtain training and certification. In subsequent years, it is assumed that one third of the necessary 

Table 4-29: Total Second and Third Year Net Present Value Costs of the Renovation, Repair, and 

Painting Rule (millions 2005$) 

3 Percent Discount Rate 7 Percent Discount Rate 

Option 

A 

Option 

B 

Option 

C 

Option 

D 

Option 

A 

Option 

B 

Option 

C 

Option 

D 

Second Year 

Total Work Practice Costs $413 $413 $413 $510 $397 $397 $397 $490 

Total Training Costs $35 $70 $82 $70 $33 $67 $79 $67 

Total Certification Costs $47 $70 $78 $70 $46 $67 $75 $67 

Total Costs $495 $552 $572 $649 $476 $532 $551 $625 

Third Year 

Total Work Practice Costs $399 $399 $399 $493 $370 $370 $370 $457 

Total Training Costs $34 $34 $34 $34 $31 $31 $31 $31 

Total Certification Costs $46 $46 $46 $46 $43 $43 $43 $43 

Total Costs $479 $479 $479 $572 $443 $443 $443 $530 

See Table 4-4 for option descriptions.

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 4 59 

stock of individuals and firms will obtain training and certification each year (since refresher-training and 

re-certification is required every three years). 

In fact, if all the individuals and firms needed to meet the demand for lead-safe RRP are trained and 

certified in the first and second years, one might expect a drop in the level of training and certification in 

the third year, followed by a spike in the next year. That is, one might expect a cyclical pattern of training 

and certification to emerge. Thus, this analysis assumes a typical amount of training and certification 

occurs each year because modeling such a trend would add little to the analysis without being able to 

precisely estimate the extent of any cyclicality. 

The total 50-year costs and the 50-year annualized costs are discounted using rates of 3 and 7 percent. 

These discount rate values reflect guidance from the Office of Management and Budget regulatory 

analysis guidance document, Circular A-4 (OMB, 2003). 

EPA used the following formula to calculate the present value (PV) of the time stream of costs: 

PV = ( 1)

,

(1 ) − + t

x t

r

Cost

where: 

 Costt = Costs in year t; 

 r = Discount rate (3 percent and 7 percent); and 

 t = Year in which cost is incurred. 

This analysis also presents the 50-year annualized costs of the rule. Conceptually, the 50-year annualized 

cost is the level annual payment that one would have to make to pay off a debt equal to the present value 

total 50-year cost for a given interest rate (the discount rate). 

The following formula is used to calculate the 50-year annualized cost. 

(1 ) 1

(1 )

(50)

50

+ −

× + = ×

r

r r AC PVr

where: 

 AC = Annualized 50-Year Costs; 

 PVr = Present Value Total 50-Year Costs assuming a discount rate of r; and 

 r = Discount rate (3 percent and 7 percent) 

Table 4-30 shows the present value of the total 50-year costs and Table 4- 31 shows the annualized 50-

year costs for the options considered. The differences among the flexible options (A, B, and C) are driven 

by the differences in the regulated universe during the first year the rule is in effect. Because the test kits 

available for the first year have a high false positive rate, including the newer units in the regulated 

universe is relatively costly. This is because the high rate of false positives will require many units 

without LBP to use the more costly work practices. The difference between Option D’s total 50-year and 

50-year annualized costs compared with the other options’ costs is primarily due to the higher costs of 

Option D’s prescriptive containment and cleaning requirements. 
§402(c) Economic Analysis Chapter 4 60 

Table 4-30: Total Present Value 50 Year Costs of the Renovation, Repair, and Painting Rule 

(millions 2005$) 

3 Percent Discount Rate 7 Percent Discount Rate 

Option 

A 

Option 

B 

Option 

C 

Option 

D 

Option 

A 

Option 

B 

Option 

C 

Option 

D 

Total Work Practice 

Costs $10,785 $10,491 $10,388 $12,967 $6,280 $5,986 $5,882 $7,405 

Total Training Costs $959 $940 $934 $940 $580 $561 $554 $561 

Total Certification Costs $1,257 $1,234 $1,226 $1,234 $739 $715 $706 $715 

Total Costs $13,001 $12,666 $12,548 $15,141 $7,599 $7,261 $7,142 $8,680 

See Table 4-4 for option descriptions. Assumes 75 percent rate of Compliance.

Source: EPA Calculations.

Table 4- 31: Annualized 50 Year Costs of the Renovation, Repair, and Painting Rule 

(millions 2005$) 

3 Percent Discount Rate 7 Percent Discount Rate 

Option 

A 

Option 

B 

Option 

C 

Option 

D 

Option 

A 

Option 

B 

Option 

C 

Option 

D 

Total Work Practice 

Costs $419 $408 $404 $504 $455 $434 $426 $537 

Total Training Costs $37 $37 $36 $37 $42 $41 $40 $41 

Total Certification Costs $49 $48 $48 $48 $54 $52 $51 $52 

Total Costs $505 $492 $488 $588 $551 $526 $518 $629 

See Table 4-4 for option descriptions. Assumes 75 percent rate of Compliance.

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 4 61

Appendix 4A. Lead Abatement 

The analysis does not adjust for the decrease over time in the stock of housing regulated by the RRP rule 

due to lead paint abatements. The number of abatements is small compared to the universe of housing 

covered by the RRP rule. Furthermore, an abatement does not necessarily eliminate all the lead-based 

paint in a home. Not all lead-based paint is in hazardous condition. A home that has been abated may 

still contain intact lead-based paint. This intact lead-based paint could be disturbed during subsequent 

RRP events. 

This appendix reviews the annual rate of lead abatement in target housing using data on notifications from 

contractors conducting the abatements. The information is submitted by contractors directly to EPA in 

states where EPA administers the lead abatement program. In states that administer their own programs, 

the information is sent to the state, and EPA collected data from several of these states. Results for the 

two groups of states are discussed separately below. 

4A.1 Abatements in EPA Administered States 

At the time the information for this analysis was completed, EPA administered the lead abatement 

program in twelve states. The Agency promulgated a notification rule in April 2004 requiring contractors 

in states where EPA administers the lead abatement program to notify the Agency at least 10 days before 

performing an abatement.1

 EPA records this data in its Federal Lead Based Paint Program (FLPP) 

database. At the time the information was collected for this analysis, the FLPP database contained 

notification data from May 2004 to February 2005. The annual number of abatements was estimated by 

doubling the reported number of abatements for the six months between September 2004 and February 

2005. The results are shown in Table 4A-1. Only five of the twelve EPA administered states reported 

any abatement activity between May 2004 and February 2005.2

 

1

 69 FR 18489, found at 40 CFR 745.227(e)(4).

2 The states of Alaska, Idaho, Montana, Nevada, South Carolina, South Dakota, and Wyoming did not report any activity. 

According to the Department of Housing and Urban Development (HUD), all of these states except for South Carolina have a 

relatively small stock of housing with lead hazards.
§402(c) Economic Analysis Chapter 4 62

Table 4A-1: Target Housing Abatements in EPA Administered Statesa

State 

Target Housing 

Abatements 

May 2004 - 

February 2005 

Target Housing 

Abatements 

September 2004 - 

February 2005 

Estimated 

Annual Target 

Housing 

Abatements 

Arizona 79 32 64 

Florida 4 2 4 

Hawaii 1 0 1 

New Mexico 16 15 30 

New York 1,145b 979b 1,958b

Other EPA Statesc 0 0 0 

a

 Notifications reported for the six months between September 2004 and February 2005 were 

doubled to yield an annual estimate, except for Hawaii. All available months were included for 

Hawaii, which had one reported abatement during the time period. b

 The absolute number of abatements in New York is large relative to the number in other EPA 

administered states. However, as demonstrated later in the report, the percent of the housing 

stock abated in New York is comparable to other states. c

 Alaska, Idaho, Montana, Nevada, South Carolina, South Dakota, and Wyoming did not report 

any activity. 

Source: EPA FLPP database.

4A.2 Abatements in States Administering their Own Lead Programs 

EPA requested data from nine states that administer their own lead abatement programs; the data from 

seven of those states was incorporated into the analysis.3

 Table 4A-2 presents the abatement data 

collected from seven states that administer their own lead programs. 

Data on abatements was available online for Massachusetts. When the information was collected for this 

analysis, the data for 2002 and beyond were incomplete. Therefore, the analysis averaged the number of 

abatements in 2000 and 2001 (2,267 and 2,711), yielding an estimate of 2,489 target housing abatements 

per year in Massachusetts. The portion of the housing stock abated in Massachusetts is much higher than 

in any other state with available data, due to specific state requirements in Massachusetts for housing with 

lead-based paint. 

 

3

 Data collected from Minnesota was not comparable with data from other states since HUD funded abatements are not reported 

in Minnesota, so the reported data does not represent the total number of abatements in the state. One other state that was 

contacted did not provide any results.
§402(c) Economic Analysis Chapter 4 63

Table 4A-2: Target Housing Abatements in Seven States Administering their Own Lead Programs

State 2002 2003 2004 

Average for 

2002 to 2004 

Estimated Annual Target 

Housing Abatements 

Connecticuta 365 365 365 

Illinois 1,086 1,134 1,091 1,104 856b

Maine 132 123 131 129 129 

New Jersey 255 313 237 268 268 

Ohio 892 729 789 803 803 

Pennsylvania 770 637 518 642 642 

Texasc 457 277 498 411 411 

a Connecticut data was only available for 2002. b

 Illinois data included interim controls as well as abatements. The average for the reported data was multiplied by 

77.55%, since HUD data indicates that abatement accounts for 77.55% of all lead hazard reductions that utilized either 

interim control or abatement strategies. c

 Texas data included abatements in child occupied facilities (COFs) as well as target housing. COFs are thought to 

represent a small fraction of abatements; in EPA-administered states, COFs account for 1.34% of total abatements. 

4A.3 Percent of Housing Abated 

Table 4A-3 compares the estimated annual number of abatements for each state to the pre-1980 housing 

stock (some fraction of which contain lead-based paint) and the stock of housing with lead hazards. Not 

all lead-based paint is in hazardous condition. Therefore, housing with lead hazards is a subset of housing 

with lead-based paint, which is in turn a subset of all pre-1980 housing. The stock of housing with lead 

hazards was estimated by combining HUD data on the prevalence of lead hazards by the age of dwelling 

with data on the distribution of the housing stock by age and state. The percent of the pre-1980 housing 

stock abated annually for the total sample is 0.02%, and the percent of the hazardous housing stock abated 

annually is 0.06%. The percent of target housing with lead-based paint that is abated annually is 

somewhere between these two values. 
§402(c) Economic Analysis Chapter 4 64

Table 4A-3: Estimated Lead Abatements Compared to the Housing Stock 

(1) 

State 

(2) 

Estimated 

Number of 

Abatements 

Annually 

(3) 

Pre-1980 

Housing 

Stock 

(4) 

Stock of 

Housing 

with Lead 

Hazards 

(5) 

Percent of 

Pre-1980 

Housing 

Stock Abated 

Annually 

(6) 

Percent of 

Hazardous 

Housing 

Abated 

Annually 

EPA Administered States 

Arizona 64 977,504 170,813 0.01% 0.04% 

Florida 4 3,736,874 715,105 0.00% 0.00% 

Hawaii 1 309,754 61,453 0.00% 0.00% 

New Mexico 30 461,377 116,249 0.01% 0.03% 

New York 1,958 6,552,424 2,765,456 0.03% 0.07% 

Other EPA States 0 2,360,698 596,611 0.00% 0.00% 

States Administering their 

own Programs 

 

Connecticut 365 1,074,747 406,726 0.03% 0.09% 

Illinois 856 3,761,546 1,399,151 0.02% 0.06% 

Maine 129 461,431 194,431 0.03% 0.07% 

New Jersey 268 2,538,919 935,743 0.01% 0.03% 

Ohio 803 3,680,341 1,348,072 0.02% 0.06% 

Pennsylvania 642 4,222,021 1,794,770 0.02% 0.04% 

Texas 411 4,639,948 1,074,401 0.01% 0.04% 

Massachusetts 2,489 2,113,926 909,932 0.11% 0.27% 

Total Sample 8,020 36,891,510 12,488,913 0.02% 0.06% 
§402(c) Economic Analysis Chapter 4 65

REFERENCES 

Dreamhomesource.com. 2005. Available at: www.dreamhomesource.com. (Accessed 2005). 

Gilkeya, David; Jacob Hautaluomaa, Taslim Ahmeda, Thomas Keefea, Robert Herrona, Philip Bigelowb. 

2003. Construction Work Practices and Conditions Improved After 2-Years’ Participation in the 

HomeSafe Pilot Program. American Industrial Hygiene Association Journal, May/June 2003. 

Harrington, David, et. al. 2004. “Can Half-Day Training Motivate Small Contractors to Address Lead 

Safety?” Health Promotion Practice. 5(3), 297-305. 

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(Accessed 2002). 

Morbidity and Mortality Weekly Report (MMWR). 1997. Update: Blood Lead Levels – United States, 

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Morbidity and Mortality Weekly Report (MMWR). 2003. Surveillance for Elevated Blood Lead Levels 

Among Children – United States, 1997-2001. Center for Disease Control and Prevention. Sep 

12. . 

Personal Communication with Kermit Baker, Joint Center for Housing Studies (JCHS) at Harvard 

University, August 2005. 

Personal communication with work group members and other industry experts. 1999. 

Personal communication with the Painting and Decorating Council. 

RS Means, 2005, Means CostWorks Repair & Remodeling Cost Data 2005 CD-ROM, 7th Edition 

http://www.rsmeans.com/bookstore/detail.asp?sku=65045 

U.S. Bureau of Labor Statistics. 2005a. Occupational Employment Statistics Series. 

U.S. Bureau of Labor Statistics. 2005b. Consumer Price Index: All urban consumers; other goods and 

services. Bureau of Labor Statistics, Washington, DC. 

U.S. Census Bureau. 1990. "H025. Year Structure Built - Universe: Housing units." American Fact 

Finder. Available at: http://factfinder.census.gov/ (Downloaded 10/26/2005) 

U.S. Census Bureau. 2000c. "H34. Year Structure Built [10] - Universe: Housing Units." American Fact 

Finder. Available at: http://factfinder.census.gov/ (Downloaded 10/26/2005) 

U.S. Census Bureau. 1997 and 2003. American Housing Survey (AHS). 

U.S. Census Bureau. 2003b. American Community Survey Profile. 

U.S. Census Bureau. 1995. Property Owners and Managers Survey (POMS) 
§402(c) Economic Analysis Chapter 4 66

U.S. Census Bureau. 2004a. 2002 Economic Census: Industry Series (For NAICS 61, 54, 56 and 53). 

Available at: http://www.census.gov/econ/census02/guide/INDSUMM.HTM. (January 12, 

2004). 

U.S. Census Bureau. 2004b. “Sector 53: Industry Series: Summary Statistics for the US: 2002.” 

American Fact Finder. Available at: 

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&ds_name=EC0200A1&_lang=en&_ts=141736463723 (Downloaded 8/3/2005) 

U.S. Census Bureau. 2005b. “Sector 23: Industry Series: Detailed Statistics for Establishments: 2002.” 

American Fact Finder. Available at: 

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&ds_name=EC0200A1&_lang=en&_ts=141735361508 (Downloaded 6/30/2005) 

U.S. Census Bureau. 2005d. “Sector 23: Industry Series: Value of Construction for Establishments by 

Type of Construction: 2002.” American Fact Finder. Available at: 

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&ds_name=EC0200A1&_lang=en&_ts=141735361508 (Downloaded 6/30/2005) 

U.S. Census Bureau. 2005g. American Housing Survey –Overview. Available at: 

http://www.census.gov/hhes/www/housing/ahs/overview.html. 

U.S. Census Bureau. 2005h. Property Owners and Managers Survey (POMS) – Overview. Available at: 

http://www.census.gov/hhes/www/housing/poms/overview.html 

U.S. Department of Housing and Urban Development. 2000. National Survey of Lead and Allergens in 

Housing. 

U.S. Department of Housing and Urban Development. 2004. The National Lead Service Provider 

Listing System (The Lead Listing). 

U.S. EPA. 1997. Reducing Lead Hazards When Remodeling Your Home. EPA 747-K-97-001, 

September. 

U.S. EPA. 1999. Economic Analysis of the Final TSCA Section 402(a)(3) Lead-Based Paint 

Aaccreditation and Certification Fee Rule. Available at: http://www.epa.gov/lead/lead2-26-

99.pdf. 

U.S. EPA. 2000a. Model Renovation Training Course. EPA 747-B-00-005/6. Available at: 

http://www.epa.gov/lead/rrmodel.htm. 

U.S. EPA. 2000b. Economic Analysis of Toxic Substances Control Act Section 403: Lead-Based Paint 

Hazard Standards. December 21. 

U.S. EPA. 2005. Federal Lead Based Paint Program (FLPP) Database. 

U.S. EPA, 2005b. Disposable Cleaning Cloth (DCC) Lead Clearance Field Study. July. 

U.S. EPA, 2005c. Estimates of Concentration of Lead in Paint by Age of Housing. October. 

U.S. Office of Management and Budget. 2003. Circular A-4. 
§402(c) Economic Analysis Chapter 4 67

U.S. Office of Personnel Management. 2005a. 2005 General Schedule (Base, Annual). Available at: 

http://www.opm.gov/oca/05tables/pdf/gs.pdf (Annual) and 

U.S. Office of Personnel Management. 2005b. 2005 General Schedule (Base, Hourly). Available at: 

http://www.opm.gov/oca/05tables/pdf/gs_h.pdf (Hourly). 

U.S. Office of Personnel Management. 2005c. Salary Table 2005-DCB. Available at: 

http://www.opm.gov/oca/05tables/pdf/DCB.pdf. 

U.S. Small Business Administration. 2005. “Non-Employer Statistics.” Firm Size Data. Available at: 

http://www.sba.gov/advo/research/data.html. (Downloaded 8/3/2005). 

Weil, David. 1999. Assessing OSHA Performance: Evidence from the Construction Industry. Boston 

University, October 1999. 
402(c) Economic Analysis Chapter 5 1 

Draft - Do Not Cite or Quote 02-23-2006

5. Benefits

This chapter contains an analysis of the benefits associated with the proposed regulations under TSCA 

Section 402(c)(3). The proposed work practices, training and certification requirements will reduce lead 

exposure by increasing the containment and cleanup of dust generated by renovation, repair, and painting 

(RRP) activities. These reductions in exposure will in turn reduce the risks of adverse health and 

ecological effects in the vicinity of these activities. 

Given the uncertainty associated with many of the inputs underlying the estimate of benefits, a Monte 

Carlo approach was used to model the expected benefits. Conceptually, each uncertain parameter in the 

benefits model could be treated as a random variable and the functional form and moments of the 

distribution of expected benefits could be mathematically derived. In practice however, given the large 

number of uncertain parameters, this derivation is impossible. The Monte Carlo approach, however, 

approximates the true underlying statistical distribution of expected benefits. 

The chapter is organized around the analytical steps involved in estimating the benefits. These steps are 

outlined in Figure 5-1. Section 5.1 of this chapter presents an overview of these steps, including: (1) 

estimating the amount of lead contamination due to RRP events, (2) estimating the resultant changes in 

blood lead levels, (3) estimating the resultant adverse health effects, including reduction in IQ, and (4) 

estimating the dollar value of the reductions in adverse effects. Steps one through three are conducted for 

both the “without rule” situation (i.e. the baseline) and for the with rule situations. The difference 

between the number of cases of adverse health effects and loss of children’s IQ points avoided under the 

rule as compared to the baseline are the quantified benefits of the rule, and are assigned dollar values in 

Step four. Section 5.2 provides details on step one, the estimation of lead levels generated by RRP events 

and the effectiveness of cleaning. Section 5.3 presents the analytical details of steps two, three, and four 

as they relate to children. Section 5.4 presents analytical details on steps two, three, and four as they 

relate to adults. The final section (Section 5.5) describes the derivation of the underlying estimates of the 

number of RRP events and the number of children affected, as well as the parameters used in the Monte 

Carlo analysis and their assumed values or distributions. The final part of Section 5.5 presents the 

numerical estimates of the value of the benefits for both children and adult. Four appendices supplement 

this chapter. They are Appendix 5A: Lead-Related Health Effects and Ecological Effects, Appendix 5B: 

Adult Benefit Calculations, Appendix 5C: Identifying and Characterizing Lead Loadings for Interior RRP 

Tasks, and Appendix 5D: Distributions of Inputs and Results. Appendix 5A contains Chapters 5 and 6 of 

the Air Quality Criteria Document for Lead, First External Review Draft (EPA 2005). 
402(c) Economic Analysis Chapter 5 

Figure 5-1: Overview of Analytical Steps 

Amount of Lead Generated by 

RRP Activity (EPA Phase I 

Study – Appendix 3C)

Estimate Amount of Lead 

Generated by Each Type of 

RRP Event (Section 5.2)

Estimate Level of Lead 

Exposure due to RRP

Using Adult Dose-Response 

Functions, Estimate Likelihood 

of 4 Adverse Health Effects 

(Section 5.4)

Estimate Number of Adult 

Adverse Health Effects Cases 

Avoided due to Regulation 

(Section 5.4)

Estimate Value of Adverse Adult 

Health Effects Avoided (Section 

5.5)

Estimate Number of IQ Points 

Gained due to Regulation 

(Section 5.3) 

Estimate Value of IQ Points 

Gained (Section 5.5) 

Estimate Value of Quantified and 

Monetized Benefits (Section 5.5)

Cleaning Efficiencies for 

Contractor and Household 

Cleaning (Section 5.2)

Number of At-Risk 

Children (Chapter 4) 

Number 

Adults (C

Value of Av

Effect (Cos

Sectio

Using Children’s Blood-Lead 

Models and Relationship between 

Blood-Lead and IQ, Estimate 

Changes in IQ (Section 5.3) 

Value of IQ Point Gained 

(Life-time Earnings – Section 

5.3) 

Amount of Lead Generated by 

RRP Activity (EPA Phase I 

Study – Appendix 3C)

Estimate Amount of Lead 

Generated by Each Type of 

RRP Event (Section 5.2)

Estimate Level of Lead 

Exposure due to RRP

Using Adult Dose-Response 

Functions, Estimate Likelihood 

of 4 Adverse Health Effects 

(Section 5.4)

Estimate Number of Adult 

Adverse Health Effects Cases 

Avoided due to Regulation 

(Section 5.4)

Estimate Value of Adverse Adult 

Health Effects Avoided (Section 

5.5)

Estimate Number of IQ Points 

Gained due to Regulation 

(Section 5.3) 

Estimate Value of IQ Points 

Gained (Section 5.5) 

Estimate Value of Quantified and 

Monetized Benefits (Section 5.5)

Cleaning Efficiencies for 

Contractor and Household 

Cleaning (Section 5.2)

Number of At-Risk 

Children (Chapter 4) 

Number 

Adults (C

Value of Av

Effect (Cos

Sectio

Using Children’s Blood-Lead 

Models and Relationship between 

Blood-Lead and IQ, Estimate 

Changes in IQ (Section 5.3) 

Value of IQ Point Gained 

(Life-time Earnings – Section 

5.3) 
402(c) Economic Analysis Chapter 5 3 

5.1 Overview of Approach 

Lead exposure causes many adverse health effects; a great deal of information on the health effects of 

lead is available from decades of medical observation and scientific research. Because inhaled or 

ingested lead is initially distributed throughout the body and is toxic to many organ systems, it damages a 

wide range of systems and its toxicity manifests itself in the form of many different types of adverse 

health effects. A reduction in lead exposure resulting from the rule would lead to a reduction in these 

adverse health effects and the costs of treating them. Young children are particularly sensitive to lead, 

which impairs a child’s neuropsychological development (most commonly measured as reduced IQ). 

Increased blood-lead levels have also been associated with aberrant behavior in school-age children and a 

decrease in their growth rate and stature. These cognitive and behavioral effects are strongly related to 

their future productivity and expected earnings. Adverse health effects also include hypertension, 

coronary heart disease (CHD), stroke, blood disorders, kidney damage, thyroid hormone abnormalities, 

immune system damage, many types of neurological abnormalities, increased incidence of stillbirths and 

miscarriage, low sperm rates, abnormal sperm, and infertility (ATSDR 1999). It appears that some of 

these effects, particularly changes in the levels of certain blood enzymes and in aspects of children's 

neurobehavioral development, may occur at blood-lead levels so low as to be essentially without a 

threshold (IRIS 2004). Appendix 5A presents an assessment of the animal toxicology and human 

epidemiology data available for a range of health effects associated with lead. 

There are an assortment of health effects associated with exposure to lead (see ATSDR 1999 and 

Appendix 5A). This analysis is able to include only a subset of adverse health effects, due to limitations 

in understanding and quantifying the dose response relationships for some of the health effects. Even 

where the dose-response relationships are known, many cases are not included in the estimates because 

exposure levels cannot be estimated for all potentially affected individuals. Consequently, this benefits 

assessment focuses on two major categories of health effects: effects on cognitive function in young 

children (under the age of six) and cardiovascular disease (hypertension, coronary heart disease and 

stroke) and premature mortality in adults. There are additional uncertainties in the quantification of adult 

effects, which are addressed in Section 5.5.5. 

It should be noted that even for these two categories of effects, some potential cases of these health 

effects are not included in the benefits estimates. This is because exposures of some potentially affected 

individuals (for example, neighbors of households performing renovations) have not been estimated in 

this assessment. 

To estimate the benefits of the proposed rulemaking, the quantified adverse health effects associated with 

exposures to lead from RRP tasks in the baseline (i.e., without RRP regulation) are first calculated; then, 

health effects associated with exposures are calculated assuming the RRP regulations are in place. Since 

the rule requires actions intended to reduce contamination, fewer adverse health effects are expected with 

the rule. This reduction in adverse health effects is the rule’s major benefit. The most commonly used 

measure of the amount of lead in the body is blood-lead level (PbB), although lead also bioaccumulates in 

bone, hair, teeth, and other tissues. Published studies relate one or more of these measures to adverse 

health effects. Some studies have examined the question of whether the neurological effects of exposures 

in early childhood are ameliorated when blood-lead levels decline. The data are mixed on this issue. In a 

study that treated lead-exposed children with a chelating agent, Ruff (1993) found that children whose 

blood-lead levels had the greatest decline showed the most improvement in IQ. In contrast, Rogan (2001) 
402(c) Economic Analysis Chapter 5 4 

found that treatment with a chelation agent lowered blood-lead levels in children but did not appear to 

improve neurological function. Liu (2002) also found that chelation therapy, while lowering blood-lead 

levels, did not improve neurological function in children at 5 years of age. While the study did detect a 

relationship between declining blood-lead and improved neurological function, this association was 

observed only in the untreated group, leading the authors to speculate that some other factor besides 

declining lead levels from chelation therapy (such as greater parental involvement), led to the 

neurological gains. Dietrich (2004) had similar findings in the same cohort of children at 7 years of age. 

One study cited in ATSDR (1999) showed impaired motor and cognitive function at a current mean level 

of 2.9 μg/dL, about 20 years after exposure when blood-lead levels were 40-50 μg/dL (Stokes 1998). 

These studies suggest that medical interventions aimed at lowering blood-lead levels may not lead to 

dramatic improvements in neurological function, further supporting the concern that early exposures to 

lead (Pb) lead to irreversible damage, and supporting the benefits of regulatory interventions to prevent or 

reduce lead exposure. 

The estimation of the adverse health effects associated with renovation, repair, and painting projects 

involves four steps: 

1. Estimate the amount of lead contamination due to the renovation project under various 

assumptions about cleaning; 

2. Estimate the blood-lead levels resulting from this contamination; 

3. Estimate the adverse health effects (e.g., loss in IQ points, increased incidence of hypertension) 

due to increased blood-lead levels using dose-response functions; and 

4. Assign medical costs, reduced income, or another proxy for willingness-to-pay to avoid the 

adverse health effects. 

Each of these steps is briefly discussed below; methods for implementing these steps are described in 

detail in Sections 5.2 and 5.4. 
402(c) Economic Analysis Chapter 5 5 

Step 1: Estimate the amount of lead contamination due to the renovation project 

Most of the events covered by this rule are expected to generate lead dust levels that exceed the EPA floor 

hazard standard of 40 μg/ft2

 promulgated in 2001.1 As described in detail in Appendix 5C, all RRP 

events undertaken where lead-based paint is present have the potential to exceed the 40 μg/ft2

 hazard 

standard if precautions are not taken. In some cases contractors are already taking precautions even 

without the rule, and the number of RRP events where this is the case is estimated in Section 4.2 of this 

document. (Also see Section 5.5 of this chapter.) In addition, not all homes contain lead-based paint; the 

likelihood that lead-based paint occurs in a house is estimated in Section 4.2.5 of this document, and 

summarized in Table 4-6. In the majority of RRP events, however, contractors do not take these 

precautions. RRP events with precautions already in place are not included in the benefits calculations; 

only those RRP events performed without appropriate precautions are included in the calculations. 

Unless the appropriate safe work practices, containment, and cleanup are used, lead dust from the 

renovation activities can migrate throughout the residence and residents living in these units could be 

exposed to lead levels that are high enough to cause adverse health effects, even when accounting for 

normal household cleaning. 

Step 2: Estimate blood-lead levels from this contamination 

Several studies establish a strong correlation between lead dust levels and blood-lead concentrations in 

children. Dust caught in carpets that is later released due to vacuuming, as well as dust in window wells 

and on uncarpeted floors, can contribute to increased blood-lead levels among children. In a study of lead 

exposure among urban children, Lanphear (1998a) showed a dramatically rising probability of blood-lead 

levels exceeding 10 μg/dL,2

 with a probability of over 50 percent for lead dust greater than 100 μg/ft2. 

Another analysis that measured lead dust on multiple surfaces (carpeted and non-carpeted floors as well 

as window sills and window wells) found that lead dust was significantly correlated with the probability 

of increased blood-lead levels for every surface tested (Lanphear 1996). When compared against several 

other factors, window trough lead dust highly correlated with blood-lead levels in the Lead-Safe 

Cambridge program (Potula 2001). 

The studies discussed above evaluated the correlation between lead dust and blood-lead levels without 

specifying the activities that generated the leaded dust. Further, the studies either do not specify the 

duration of the exposure to the lead dust, since the dust and blood-lead measurements are concurrent, or 

in one case, specifically examined chronic lead dust exposure and excluded cases where there had been 

spikes of exposure such as renovation (Lanphear 1996). However, two other recent studies focused 

specifically on the impact of home renovation on lead exposure among children. In New York City, 

authors conducted a case-control study comparing children living in homes that had undergone renovation 

and/or repair (cases) to those children living in homes without these activities (controls). One criterion 

for including children in the study was that they had no prior history of increased blood-lead 

measurements; thus it is very unlikely that the renovations were carried out as abatements to reduce lead 

 

1

 The final lead hazard standards were established under the authority of Section 403 of the Toxic Substances 

Control Act. These standards were based in part on a benefit-cost analysis comparing clean-up costs to the value of 

IQ points lost in children without the cleanup. The objective of the Section 403 benefit-cost analysis was to identify 

a standard at which net benefits are maximized, assuming that all households with children under the age of seven 

undertake appropriate lead clean-up activities if their home exceeds the hazard standard. 

2 This is the CDC level of concern, which is intended to trigger community-wide prevention activities. It is not a 

threshold of effect.
402(c) Economic Analysis Chapter 5 6 

exposure to children living in the house (which could have biased the study). The study found that 

children with increased blood-lead levels were more likely to live in a house that had undergone 

renovations (1.2 times more likely), had interior surfaces prepared for painting (3.5 times more likely), or 

had work-related dust dispersed throughout the house (6.3 times more likely), as compared to control 

children (Reissman 2002). In a Department of Health study also from New York (but which excluded 

New York City), half of the families with a child with increased blood-lead levels reported more than one 

type of paint removal activity in their house (CDC 1997). Thus, the studies concluded that increased 

blood-lead levels are correlated with renovation activities. 

Decreases in lead dust have been shown to decrease blood-lead levels among children. Several studies 

have investigated the effectiveness of lead dust controls in conjunction with or in the absence of other 

lead-control activities. One intervention study, which trained families in home dust-control measures, 

found a reduction of up to 4.0 μg/dL after one year of the program (Hilts 1998). Thus, control of dust is 

an important element of any renovation and clean-up event. 

Step 3: Estimate the adverse health effects (e.g., loss in IQ points, increased incidence of 

hypertension) due to increased blood-lead levels 

As described above, this assessment estimates the adverse health impact of increased blood-lead levels on 

cognitive function and, more specifically, IQ function in young children as well as cardiovascular effects 

in adults. Appendix 5A provides a review of the recent literature related to the cognitive effects of lead in 

children. Young children are particularly sensitive to lead, which impairs a child’s neuropsychological 

development (most commonly measured as reduced IQ). Increased blood-lead levels have also been 

associated with aberrant behavior in school-age children and a decrease in their growth rate and stature. 

These cognitive and behavioral effects are strongly related to their future productivity and expected 

earnings. EPA believes there is essentially no threshold for adverse health effects of lead in children. 

Indeed dose-effect curves for lead effects on children’s IQs show a non-linear, inverse relationship with 

the greatest effects occurring at the lowest detectable blood-lead levels. In an effort to determine what a 

blood-lead level of concern should be, the Workgroup of the Advisory Committee on Childhood Lead 

Poisoning Prevention to the Centers for Disease Control and Prevention (CDC 2005a) found that the 

overall weight of available evidence supports an inverse association between blood-lead levels and the 

cognitive function of children in the low range of exposure (less than 10 μg/dL blood). The evidence for 

such an association is bolstered by the consistency across both cross sectional and longitudinal studies in 

varied settings. Further, the association is not weaker in studies where the populations’ mean blood-lead 

levels are relatively lower (CDC 2005a). Thus, this analysis assumes that there is no evidence of a 

threshold below which the adverse health effects of lead are not experienced. 

Similarly, U.S. EPA’s Integrated Risk Information System (IRIS 2004) concluded: “by comparison to 

most other environmental toxicants, the degree of uncertainty about the health effects of lead is quite low. 

It appears that some of these effects, particularly changes in the levels of certain blood enzymes and in 

aspects of children's neurobehavioral development, may occur at blood-lead levels so low as to be 

essentially without a threshold.” 

This assessment also considers the cardiovascular effects of lead on adults. In 1986, US EPA published 

an addendum to the Air Quality Criteria Document for Lead (EPA 1986); this addendum reviewed in 

detail the existing evidence for the relationship between blood lead and blood pressure. Based on the 

review of the evidence, the 1986 Addendum to the Air Quality Criteria document concluded that overall, 

two large-scale population studies, the British Regional Heart Study and the NHANES II, provide “highly 
402(c) Economic Analysis Chapter 5 7 

convincing evidence demonstrating small but statistically significant” relationships between blood lead 

and blood pressure in adult men. Another addendum was published in 1989 (EPA 1989). Much of the 

discussion in the new Addendum was based on an extensive peer review of the literature (the 

International Symposium on Lead-Blood Pressure Relationships; for more detail see 

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?PrintVersion=True&deid=38444). That document 

concluded that the data since the 1986 Addendum further supported the conclusions of that document, i.e. 

that there is strong evidence for a relationship between blood lead and blood pressure, based on data from 

four large scale population studies and several smaller scale studies. 

In 2005, EPA released an external review draft of another addendum to the Air Quality Criteria 

Document for Lead (EPA 2005c). This document, portions of which are included as Appendix 5A, 

provides a detailed weight of evidence review of all the animal toxicology and epidemiology studies on 

the relationship of lead exposure to blood pressure. The conclusions of the epidemiology studies can be 

found in section 6.5.6 (page 6-207), and are as follows: 

“The combined blood lead studies using blood pressure/hypertension as an outcome 

continue to support the conclusions of the 1990 Supplement that there is a positive 

association between blood lead and increased blood pressure. The occasional finding of 

significant negative associations of blood lead with blood pressure (e.g., the Cadmibel 

study, one NHANES III study, the postpartum phase of the Los Angeles pregnancy 

study) have not been adequately explained and require further confirmation and study. 

The reported meta-analysis succinctly characterizes the blood pressure findings with 

blood lead: 1.0 mm Hg systolic pressure increase with each doubling of blood lead; 0.6 

mm Hg diastolic pressure increase with each doubling of blood lead. Although females 

often show lower lead coefficients than males, and blacks higher lead coefficients than 

whites, where these differences have been formally tested, they are usually not 

statistically significant. The tendencies may well arise in the differential lead exposure in 

these strata, lower in women than in men, higher in blacks than in whites. The same sex 

and race differential is found with blood pressure. 

The most promising developments in this field since the 1990 Supplement have been the 

use of bone lead as a long-term cumulative lead exposure index and the introduction of 

genetic analysis into the studies as potential lead effect modifiers. With one exception, all 

studies using bone lead have found a consistently positive and significant effect on blood 

pressure and/or hypertension. The ability to estimate past exposure in cross-sectional 

studies is a significant advance. The results of the bone lead studies to date highlight the 

important role of accumulated lead exposure in the development of cardiovascular 

problems. 

Though the study of genetic polymorphisms is still in its infancy in this field, it too holds 

great promise in accounting for individual variability in development of cardiovascular 

disease and individual response to lead exposure.” 

The draft Air Quality Criteria Document (AQCD) for Lead has not yet been peer reviewed by the Clean 

Air Act Scientific Advisory Committee (CASAC). The report may be revised in response to the CASAC 

review. EPA intends to reflect revisions to the AQCD in the economic analysis for the final lead RRP 

rule. For more information on the AQCD, see Appendix 5A and Section 5.5.5. 
402(c) Economic Analysis Chapter 5 8 

Understanding the underlying biological mechanisms by which lead can induce hypertension strengthens 

the case for causation. A number of studies describe animal experiments designed to elucidate the 

mechanism of action by which lead exposure could cause hypertension (Goch and Goch, 2005; Durnsun 

et al 2005; Bagchi and Preuss, 2005; Zysko et al, 2004; Farmand et al 2005; Vaziri and Sica 2004; 

Apostoli et al 2004; Lustberg et al 2004)). A plausible mechanism proposed by several authors is that 

exposure to lead causes oxidative stress. As further evidence for this mechanism of action, Ni et al (2004) 

found that human endothelial and vascular smooth muscle cells exposed to lead had increased production 

of superoxide and hydrogen peroxide. Changes in angiotensin converting enzyme (ACE) (an enzyme 

involved in regulating blood pressure through the kidneys) may also be involved in the hypertensive 

effects of lead (Sharifi et al 2004). A detailed discussion of these studies can be found in section 5.5 of 

the 2005 external review draft of the addendum to the Air Quality Criteria Document for Lead. 

Changes in blood pressure has been related to changes in risk for hypertension, coronary heart disease, 

stroke, and premature mortality in adults, as discussed in Appendix 5B. This assessment first estimates 

the change in blood pressure to due lead exposure and then estimates the number of cardiovascular 

disease cases and premature mortality associated with the predicted change in blood pressure. 

Step 4: Assign medical costs, reduced income or other proxy for willingness to pay to avoid the adverse 

health effects 

In the following analysis, standard values from the economic literature are used for the benefits valuation. 

In lieu of willingness to pay, medical costs and reduced income are used as an estimate of the cost of 

chronic conditions. For potentially lethal outcomes, the statistical value of life used by EPA is included. 

5.2 Estimating Lead Dust Contamination Levels from RRP Activities 

The benefit estimates provided in this report reflect the following sequence of events. In the baseline, an 

RRP event occurs, generating lead dust in both the area where the work occurs and the adjacent area (e.g., 

the adjacent room). In the baseline (without rule), the contractor cleans the work area before he/she 

leaves by sweeping or vacuuming. While this contractor cleaning substantially reduces the lead dust in 

the work area, it rarely brings the lead levels down to the EPA hazard levels of 40 μg/sq.ft (Dixon 1999, 

Ettinger 2002). In most cases, this cleaning also does not address the lead dust that may have migrated 

into the rest of the house during the RRP event. Following the end of the RRP event, the household 

cleans the work area and the rest of the house on a regular basis. Periodic cleaning continues to reduce 

the lead dust levels over time. Under the rule, the same sequence of events occurs, but it is assumed that 

the containment, cleaning, and cleaning verification practices required by the rule reduce lead dust 

loadings to 40 μg/ft2

 or less after contractor cleaning. For the benefits analysis, exposures to both indoor 

dust and to soil contaminated from exterior painting are evaluated. 

5.2.1 Initial Dust Loadings from Interior RRP Activities 

EPA estimated the lead dust loadings associated with an interior RRP event using the U.S. Census 

Bureau’s 1997 and 2003 American Housing Survey (AHS), the 1995 Property Owners and Manager 

Survey (POMS), and EPA’s 1997 “Lead Exposure Associated with Renovation and Remodeling 

Activities: Environmental Field Sampling Study” (EFSS). The AHS and POMS provide information on 

the number of households in which renovation and repair tasks of various types are carried out during the 
402(c) Economic Analysis Chapter 5 9 

prior two years.3 EPA used this information to estimate the number of renovation and remodeling 

activities that could potentially generate lead dust. The AHS and POMS do not detail the amount of lead 

dust a particular RRP event could generate. As a result, EPA used data provided in the EFSS to estimate 

the lead dust loadings associated with each RRP task identified in the 1997 AHS. For a more detailed 

description of the approach and methods used to estimate the lead dust loadings for interior RRP tasks, 

see Appendix 5C. 

5.2.2 Effect of Cleaning on Interior Dust Loadings 

Cleaning by the contractor immediately after the RRP work is completed decreases the amount of residual 

lead dust on household surfaces. Following the contractor cleaning, the household is expected to 

undertake routine cleaning, further decreasing lead levels generated by the RRP event. This section 

describes the development of cleaning effectiveness estimates for various specific cleaning methods. 

Section 5.5 presents the modeling assumptions about the types of cleaning and the frequency of cleaning 

undertaken by contractors and households in the baseline and under the rule. 

The amount of lead present at any particular time is a function of the initial lead levels, the effectiveness 

of the cleaning and the number of times that cleaning has occurred in the intervening period, as 

represented by the formula: 

Pb Concentration at time t = [Pb concentration at time 0] * (1-Efficiency)Frequency

where: 

 Efficiency = the percent of lead dust removal associated with each cleaning activity; and 

 Frequency = the number of times the cleaning technique is employed between time 0 and time t. 

As described in more detail below, cleaning efficiency rates vary with the type of surfaced cleaned, the 

type of cleaning done and the amount of dust present. While cleaning efficiencies typically decline as the 

amount of dust declines (Yiin 2002, Rich 2004), this analysis assumes a constant rate for any particular 

situation, and thus overestimates the effectiveness of multiple cleanings. This in turn results in an 

underestimate of the benefits of the regulation. The model further assumes that successive cleaning by the 

householder will continue to reduce floor lead levels until the floor lead dust loading reaches a minimum 

of 1.1 μg/ft2

. At this point, lead levels will no longer decline. The 1.1 μg/ft2 level is the U.S. household 

geometric mean for floor lead dust (Jacobs 2002).4

 The length of time to reduce floor lead dust loadings 

from a particular RRP event is a function of the amount of lead generated by the RRP event, the type of 

cleaning method used, the frequency of cleaning, and whether the work practices specified in the 

proposed rule are used. 

EPA assumes that the contractor will initially clean the workspace and that the householder will perform 

subsequent cleanings using a normal household vacuum or broom. To estimate the efficiency of clean-up 

activities performed by the householder (i.e. non-HEPA portable or central vacuum and/or broom 

sweeping), EPA conducted a literature review of studies that performed clean-up activities after RRP 

events. Of the studies reviewed by EPA, the majority described clean-up activities consisting of 

 

3 Details are provided in Section 5.5 and Chapter 4 of this report. 

4 This value is used to represent the lowest lead level that cleaning can feasibly achieve over time. It is used in the 

analysis to indicate the background lead level before an RRP event was commenced, hence the lowest level one 

could expect to achieve after an event if all lead from the RRP event was eventually removed by cleaning.
402(c) Economic Analysis Chapter 5 10 

vacuuming, mopping, sweeping and/or using a wet clean-up method (i.e., phosphate detergent or water) 

on either a carpeted or non-carpeted surface. Of the studies selected, EPA only considered studies that 

described the effectiveness of clean-up activities associated with RRP events. 

The studies identified by EPA used a variety of clean-up methods and reported a wide range of cleaning 

efficiencies. To determine the most representative cleaning efficiency value, EPA analyzed each study 

and selected the studies with the most robust study design to establish a householder clean-up efficiency 

for both carpeted and non-carpeted surfaces. None of the studies, however, looked at cleanup of dust 

from the full range of activities that could occur during RRP activities. 

Rich 2002, Yiin 2004, Dixon 1999, and Ettinger 2002 each use a clean-up method consisting of a HEPA 

vacuum alone or a HEPA or non-HEPA vacuum in conjunction with either a tri-sodium phosphate (TSP) 

or non-TSP detergent. The HEPA studies were excluded from the analysis because normal householder 

clean-up activities do not employ a HEPA vacuum. Studies reporting efficiencies from the use of nonHEPA vacuuming combined with wet cleaning were eliminated because wet cleaning was not included as 

an initial cleaning method in the analysis. 5

Yiin 2002, Clemson Environmental Technologies Laboratory (CETL) 2001, and Figley and Makohon 

(Canadian Mortgage and Housing Corporation (CMCH)) 1992 and EFSS 1997 describe clean-up 

efficiencies on both carpeted and/or non-carpeted surfaces. The Yiin, CETL, and CMCH studies used 

similar non-HEPA vacuums with an agitator head while the CMCH also used a non-HEPA vacuum with 

a plain tool head. It would be expected that each type of vacuum would remove a similar amount of lead 

dust from a carpeted surface, but Yiin 2002 reported that non-HEPA vacuums remove 14.0%-36.6% of 

lead dust deposited after a RRP event, the CMCH 1992 study reported a non-HEPA clean-up efficiency 

of 23.7%-65.3%, and the CETL 2001 study reported a non-HEPA clean-up efficiency of 66%-84%. The 

large discrepancy between the clean-up efficiencies reported in each of these studies could be attributed to 

three factors: (1) the lead dust level applied to the carpet prior to clean-up, (2) whether the study 

accounted for the size of the dust particles, and (3) whether and how the study accounted for the 

redistribution/deposition of lead dust after clean-up. 

Yiin 2002 had both a lead dust level similar to those found in RRP events and accounted for 

redistribution/deposition of lead dust after cleanup. The study measured the efficiency of removing lead 

dust from carpet using a non-HEPA vacuum in two different experiments. The first experiment observed 

the clean-up efficiency of non-HEPA vacuums on carpets with low levels of lead dust (geometric mean: 

54.4 μg/ft2), while the second experiment measured the clean-up efficiency of non-HEPA vacuums on 

“soiled” or high levels of lead dust (geometric mean: 113 μg/ft2). After vacuuming the carpeted surface 

Yiin et al. waited at least 1 hour to allow for the redistribution/deposition of lead dust prior to measuring 

the amount of lead dust remaining in the carpet. This practice was intended to account for the remaining 

lead dust levels because under normal vacuuming conditions airborne lead dust will be generated as a 

result of the agitator action of the vacuum head. Using the clean-up efficiencies (as measured by vacuum) 

from both the low dust level and high dust level experiments, EPA calculated a cleaning efficiency range 

for Yiin 2002 of 14.0%-36.6% for non-HEPA vacuums on carpets. This is applied to both contractor and 

householder non-HEPA cleaning of carpets. 

 

5 While contractors can use wet cleaning methods under the rule, such methods are not appropriate for carpeted and 

upholstered surface. To simplify the benefits estimation, dry methods were assumed to always be used. 
402(c) Economic Analysis Chapter 5 11 

The CETL 2001 study measured the clean-up efficiency on carpeted and non-carpeted surfaces of a 

variety of non-HEPA vacuums by applying a defined amount of lead dust to either a carpeted or noncarpeted surface. Unlike the Yiin 2002 study in which the lead dust level applied to the carpeted surface 

is more indicative of what would be found in a “real world” situation, CETL applied extremely high 

levels of lead dust, 1,000,000 μg/ft2

, to both carpeted and non-carpeted surfaces. As a result, the clean-up 

efficiencies detailed within the study may be an overestimation because it is easier to reduce the 

percentage of lead dust found on a surface if there is more lead dust initially. Further, the CETL study 

does not take into account the redistribution/deposition of lead dust after clean-up. 

The CMCH 1992 study measured the clean-up efficiency of a variety of non-HEPA vacuums on carpeted 

and non-carpeted surfaces. Although the CMCH study used an extremely high level of dust to determine 

these clean-up efficiencies, 3,700,000 μg/ft2, the study did not use lead dust generated from RRP events. 

Instead the study used “a representative dust sample... produced by gathering floor debris including 

wallboard/plaster scraps, dust and paint chips from an existing building renovation.” To produce a dust 

sample containing lead, lead stearate was added to the sample, but it represents only a “very small mass 

component of the test dust... [and artificially skewed] the lead content analysis... towards the fine 

particle sizes.” EPA excluded the non-HEPA vacuum clean-up efficiencies detailed within the CMCH 

study for carpeted and non-carpeted surfaces because the study does not use lead dust generated from a 

RRP event and, therefore, it is unclear if the efficiencies detailed are consistent with what would be found 

if the experiment used lead dust generated from a RRP event. EPA did include the broom clean-up 

efficiencies in this analysis although the study did not use lead dust generated from a RRP event because 

the broom clean-up efficiencies are consistent with those reported in the EFSS. 

The EFSS 1997 study measured the clean-up efficiency of brooms on non-carpeted surfaces, i.e. 

linoleum. Unlike the other studies considered by EPA, the EFSS study performed the clean-up operations 

on lead dust generated from drilling and sanding activities on wood door surfaces covered with leadbased paint. After the generation of lead dust the lead loadings in the workroom were measured at 0 ft 

and 6 ft from the activity.6

 The study found that at distances from 0-1 ft from the activity the broom had 

clean-up efficiencies similar to non-HEPA vacuums for lead dust generated from work activities, 98.8 

percent for drilling and 99.5 percent for sanding. The study did wait one hour after each clean-up activity 

to allow for redistribution/deposition of lead dust prior to determining the clean-up efficiency. The broom 

clean-up efficiencies obtained in the EFSS are similar to those found in CMCH 1992 for the lead dust 

levels generated at 0-1 ft, which supports the clean-up efficiencies in Table 5-1. The main discrepancy 

with broom clean-up efficiencies reported in EFSS compared to those reported in CMCH exists at 5-6 ft 

from the work activity. EFSS found at 5-6 ft from the work activity broom clean-up efficiencies 

decreased to 25.1 percent - 38.3 percent. In using the higher clean-up efficiencies, the analysis produces 

lower benefit estimates than would be the case if the lower efficiency numbers had been used 

The values used in the benefits estimate are shown in Table 5-1. 

 

6 At 0 ft from the activity the geometric mean lead loading was 26,700 μg/ft2 for drilling and 653,000 μg/ft2 for 

sanding, while the geometric mean lead loadings at 6 ft from the activity were 65 μg/ft2 for drilling and 1,380 μg/ft2 

for sanding. 
402(c) Economic Analysis Chapter 5 12 

Table 5-1: Efficacy of Clean-up Activities for Contractor and Household Cleaning 

Clean-up Option Surface Reduction in Lead 

Dust Loadings Citation 

Portable and Central Vacuum. No 

HEPA, no washing Carpet 14% - 36.6% Yiin 2002 

Portable and Central Vacuum or 

Sweeping. No HEPA, no washing 

Non-carpeted 

surface 94.8% - 98.5% 

Clemson Environmental 

Technologies Laboratory 

(CETL) 2001; Figley and 

Makohon 1992. 

Because the cleaning efficiencies vary depending on whether floors are carpeted or not, it was also 

necessary to estimate the percentage of floors covered by carpet. The percent of single family and multifamily homes with any carpet is presented in HUD (2000). For homes with carpet, these data also 

provide the percentage of area of flooring (in square feet) that is covered in carpet. Using these two 

values, the analysis calculated the total percentage of the area of flooring covered in carpet among all 

single family homes and multi-family homes covered by the proposed regulation. This value ranges from 

33 to 38 percent. As described in detail in Chapter 4 of this document, the American Housing Survey 

(AHS) provides information on the number of RRP homes that are single family and multi-family. Using 

these values, a weighted average percent of area of flooring that is carpeting across all types of homes 

covered by the regulation was created. This weighted average is 36 percent. 

With the rule, EPA requires more containment, cleaning and cleaning verification than would be 

undertaken without the rule. EPA assumes that these activities taken together will result in lead dust 

levels at or below the clearance level of 40 μg/ft2

. The data in the literature do not support a quantitative 

assessment of the independent efficiency of containment, cleaning and cleaning verification. However, 

the NCHH review (Staes and Rinehart 1995) details two abatement studies by Farfel that follow most of 

the “HUD interim guidelines.”7

 These studies report a reduction in post-abatement floor lead dust levels 

when compared with pre-abatement levels. While these studies do not include dust from “prohibited 

practices", they do support the conclusion that the barriers, work practices and clean-up activities, taken 

together, are effective in reducing post-abatement lead levels. Further, in the preliminary study of six 

dwellings, Farfel (1991) showed that the geometric mean floor lead dust level at 6-9 months post 

abatement was 56 μg/ft2

; in the follow-up study of thirteen homes, Farfel (1994) showed that the 

geometric mean floor lead dust level was 37 μg/ft2 one and a half to three and a half years post-abatement. 

The results of the study are consistent with the assumption that the proposed regulatory controls will 

result in a floor lead dust level below the EPA clearance level of 40 μg/ft2

. Lange (1997) reported on the 

abatement of a single building where barriers such as one layer of polyethylene plastic were established 

for all openings to the outside environment and for applicable internal openings. All critical barriers were 

sealed using duct tape and spray glue. In addition, safe work practices such as a three-stage 

decontamination chamber to prevent release of lead dust and debris from personnel and materials and 

negative air pressure inside the regulated area were used. The study measured airborne lead 

concentrations and determined that they were below both the U.S. Department of Labor’s Occupational 

Safety and Health Administration (OSHA) action limit and the permissible exposure limit (PEL) for 

 

7 Lead abatement activities differ from renovation activities in that they are conducted with the intent to remove 

lead-based paint or otherwise permanently eliminate a lead-based paint hazard. Unlike abatement activities, 

renovation projects do not intend to remove lead-based paint, but may disturb it in the process of the renovation.
402(c) Economic Analysis Chapter 5 13 

airborne lead. The study supports the efficacy of barriers and safe work practices in reducing airborne 

lead dust, which would be the source of dust loading in homes. 

In order to model the effect of household cleaning on the levels of residual dust over time, it was 

necessary to estimate a frequency of cleaning. Simcox (1995) conducted a study of pesticide exposures 

from household dust. As part of this study, the authors surveyed families about the frequency of cleaning 

activities. The study reported 40 percent of survey respondents vacuumed more than once per week, 45 

percent vacuumed once per week and 16 percent vacuumed less often than once per week. For this 

analysis, 40 percent of households were assumed to vacuum twice per week; 45 percent were assumed to 

vacuum once per week and 15 percent were assumed to vacuum once every two weeks.8

5.2.3 Soil Loadings from Exterior RRP events 

According to the AHS survey, slightly over one-half of households who performed RRP conducted an 

exterior event; of these approximately 88 percent are exterior painting. However, estimates of lead 

loadings from exterior activities were not included as part of EPA’s 1997 Lead Exposure Associated with 

Renovation and Remodeling Activities: Environmental Field Sampling Study (EFSS). A more recent 

study done by the University of Illinois (2002) investigated five different methods used to remove lead 

paint from exterior surfaces of homes in preparation of painting these surfaces. This study contains data 

that can be used to estimate lead loadings from exterior painting. For the analysis of exterior events, only 

lead exposures resulting from exterior painting were evaluated. Other exterior events were not modeled. 

As a result, benefits of avoiding exposure to lead from these events may be underestimated. However, 

given that these un-modeled events constitute a relatively small proportion of the number of exterior 

events, and given that the area of lead paint disturbed in these events (e.g., replacing a deck) are relatively 

small compared to the amount disturbed by exterior painting, it is unlikely the benefits are significantly 

underestimated by this omission. 

To estimate exposures to lead resulting from exterior paint, the analysis first estimated the increase in lead 

concentrations in soil that could result from exterior RRP activities involving lead-based paint. In the 

University of Illinois study, lead loadings from the five paint removal methods were measured on six, 12-

inch by 12-inch collection plates evenly placed at designated intervals within a 6.5 foot by 11 foot area on 

the ground directly under, and centered on, the work area. Lead deposited to surface soils is mostly 

immobilized and is retained within the top 2 inches if left undisturbed. EPA (1986) documents that lead 

deposited from air is basically retained within 2-5 cm of topsoil. Therefore, in this analysis, the lead 

deposits are assumed to be distributed within the top 2 inches of soil. Transport of lead contaminated soil 

can occur through soil erosion, however, it is assumed that this erosion is negligible in residential areas 

due to appropriate land grading and good vegetative cover commonly found in these areas. Estimation of 

the concentration of lead in soils for a mass loading is a function of the dry density of the soil. Dry 

densities can vary from 1.1 g/cm3

 for clays to 1.6 g/cm3 for sands. This analysis assumes an average 

density of 1.36 g/cm3

 corresponding to a loam soil (EPA 1986). 

 

8 Note that the analysis modeled each cleaning as having the same level of efficiency. In fact, several studies have 

shown that cleaning efficiency is dependent on the lead concentration. Initial cleanings can be more efficient than 

later cleanings after much of the lead dust has been removed. Further, at least one study (Ewers 1994) showed that 

vacuuming could actually increase the surface lead dust level on carpets by bringing lead trapped in carpets to the 

surface. To the extent that this analysis overestimates baseline cleaning efficiencies, the benefits are 

underestimated. 
402(c) Economic Analysis Chapter 5 14 

By dividing the lead loading on the collection plates by the mass of soil, the analysis obtained the 

additional concentration of lead in soil that could be contributed by exterior paint from each of the five 

methods. In the analysis, the five values were used to represent a distribution (each value with equal 

probability) of possible soil lead concentrations from exterior paint removal. This additional lead was 

added to background levels of lead assumed to be present in soil around houses painted with lead based 

paint. This value, 490 μg/g, was derived from the National Survey of Lead and Allergens in Housing 

(HUD 2000) for all pre-1980 houses. 

The study data found that almost all (94.0 percent to 99.8 percent) of the lead fell on the front center 

plate, located directly beneath, and centered on, the work area. This 12-inch by 12-inch plate was placed 

so that its nearest edge was 6 inches from the base of the house. Therefore, the analysis assumed that the 

observed lead loading in this plate would fall over an area 18 inches around the perimeter of the house 

and calculated the resulting soil concentrations in this area. 

When adults or children are exposed to soil during outdoor play, yard work, gardening or other outdoor 

activities, they can be exposed to soil anywhere in the yard surrounding their homes. Therefore, the 

analysis averaged the concentration in the contaminated area with the background soil concentrations 

assumed to be present in the remainder of the yard. The perimeter and total yard areas of single and 

multi-family homes were calculated in the EPA Section 403 Economic Analysis (U.S. EPA 2001). 

The inputs used to calculate the soil concentrations from exterior paint activities are summarized in Table 

5-2. 
402(c) Economic Analysis Chapter 5 15 

Table 5-2: Soil Concentrations from Exterior Paint Activities 

Parameter Value Reference 

Alkaline Chemical 

Paste 10,242 mg/ft2

Heat Gun 58,218 mg/ft2

Paint Shaver 10,071 mg/ft2

Safe Stripper 46,556 mg/ft2

Lead loadings in 

front center plate 

Wet Scrape 43,328 mg/ft2

University of 

Illinois 2002 

Density of soil 1.36 g/cm3 U.S. EPA 1986 

Size of yard – single family home 2,988 ft2 U.S. EPA 2001 

Size of yard – multi-family home 6,417 ft2 U.S. EPA 2001 

Area within 18 inches of perimeter – single 

family home 

235.37 ft2 - owner 

201.92 ft2 - renter 

See Chapter 

4.5.5 

Area within 18 inches of perimeter – multifamily home 402.47 ft2 See Chapter 

4.5.5 

The analysis assumes that one-quarter of exterior paint jobs involve all sides of the building, one-quarter 

involve only one side of the building, and the other one-half involve areas in between one side and all 

sides. In calculating soil lead concentrations due to RRP events that involve all four sides of the building, 

the contaminated area is calculated as the entire area within 18 inches of the structure. These are the 

perimeter values presented in the table above. For exterior painting events that involve only one side of 

the structure, the soil concentration is calculated assuming that only one-quarter of the perimeter is 

contaminated, and the rest of the yard (including the other three sides of the structure) have background 

lead levels. The average of these two contamination levels are used to characterize contamination levels 

for the exterior painting events that are “in between.” 

For exterior renovations without the rule, it is assumed no cleaning or soil replacement occurs. 

Furthermore, no degradation of lead is assumed to occur over time. Under the rule, contractors place 

plastic sheeting on the ground 10 feet out around the perimeter of the house to catch the dust and debris, 

and they remove it prior to possible exposure. 

5.3 Benefits Assessment -- Children 

Research suggests that exposure to lead in children can have immediate and long term impacts on health 

including cognitive and other neurobehavioral deficits. Data suggests that the risk for lead effects in 

children is due both to a greater likelihood of exposure in young children who have a greater frequency of 

hand-to-mouth behaviors than older children and adults, and an increased sensitivity of the developing 

nervous system. Previous data supported adverse effects of lead on the nervous system in children from 

0-3 years of age. (Bellinger et al., 1991, 1992) based on a correlation of blood lead levels at 2 years of age 

with cognitive impairment at 57 months and 10 years of age. Recent data (Canfield et al., 2003, 2004, 

Chen et al., 2005; Dietrich et al., 1993; Lanphear et al., 2000, 2005; Tong et al., 1996; Wasserman et al., 

2000) demonstrate that the adverse effects of lead on the nervous system extend to school-age children 

and into adolescence and adulthood. Further data by Rice and Barone (2000) also demonstrate the longterm effects of childhood lead exposure in adults as a magnification of earlier exposure with aging. 

Furthermore, for exposures to dust and soil, young children are also at risk because of their behaviors 

(i.e., higher levels of dust and soil ingestion). 
402(c) Economic Analysis Chapter 5 16 

5.3.1 Estimation of the change in blood-lead levels resulting from lead contamination 

To estimate the change in blood-lead levels in children per change in lead dust loadings or soil lead 

concentrations, the analysis used two alternative approaches. In the first approach, the analysis used 

EPA’s Integrated Exposure Uptake Biokinetic (IEUBK) model (U.S. EPA 2005). The IEUBK model 

estimates age-specific lead intake from environmental media (air, water, soil, dust, diet) and then models 

absorption and excretion in a child’s body to estimate the level of lead in blood. The model can be used 

to predict age-specific blood-lead levels for children ages 6 months to 84 months. For dust exposures 

from interior RRP activities, exposures occur from the time that RRP activity is completed (including 

contractor clean-up) until the time that the dust falls to background levels due to routine household 

cleaning (background is around 1.1 μg/ft2, the typical background level of floor dust cited in Jacobs et al., 

2002). In the modeling exercise performed for this assessment, where contractor and household cleaning 

are assumed to reduce dust levels over time, the dust levels generally fall to background levels in less than 

one year. However, because IEUBK predicts blood-lead for children in one-year age brackets, the 

analysis calculated the average lead dust during the entire year when RRP activities take place and used 

this value to represent the average dust exposure during the year that a child is exposed. At all other 

times during early childhood (from ages 6 months to 6 years), children are assumed to be exposed to 

background levels of household lead dust, equal to 1.1 μg/ft2

. For soil exposures from exterior painting, 

the analysis assumes that lead loadings remain in the soil and are not cleaned up or abated after exterior 

painting work is completed. Therefore, children are assumed to be exposed to contaminated soil from the 

year when exposure begins until the age of 6 years. 

The IEUBK requires an estimate of dust concentration rather than loadings. To estimate the relationship 

between floor dust loadings and hand lead dust concentrations, this analysis used a regression equation to 

describe hand dust-lead measures (PbH, μg) as a function of floor dust-lead loading (PbF, μg/ft2

), 

estimated using geometric mean floor dust-lead loadings and mean hand dust loadings from Clark (1985, 

as cited in Battelle 2005). 

An alternative approach to the use of the IEUBK is to estimate the blood-lead level directly as a function 

of floor lead dust loadings. In fact, the Rochester Lead-in-Dust study (URSM and NCLSH, 1995) 

concluded that lead dust loading is a better predictor of children's blood-lead levels than is lead dust 

concentration. This analysis used a regression equation that directly links dust loadings and blood-lead 

levels, previously presented in U.S. EPA (2000a), which was based on data from the Rochester Lead-inDust Study. The regression model used (Model C) was: 

log(PbB) = 1.337 + 0.140 * log(PbF) + 0.004 * (PbP) + error 

where: 

 PbB = the blood-lead concentration, μg/dL; 

 PbF = the floor lead dust loading, μg/ft2; and 

 PbP = the percent of painted surfaces containing deteriorated lead-based paint, assumed to 

be 0% in this analysis. 

 Error = 0.580 

This model applies only to lead dust and is not used to describe blood-lead concentrations from soil lead 

exposures. Although the Rochester data were collected for young children (ages 1-22 months), the model 

is used in this analysis for both young children (2 years old) and for children up to 6 years old. 
402(c) Economic Analysis Chapter 5 17 

5.3.2 Estimation of the adverse health effects (e.g., loss in IQ points) due to increased bloodlead 

Numerous cross-sectional and longitudinal studies have estimated the decrement in IQ points associated 

with an increase in blood-lead levels. In cross-sectional studies, blood-lead levels are measured only 

once; usually in very early childhood between 6 and 24 months, when children’s mouthing behavior leads 

to relatively high rates of ingestion of dust and soil, and when children are believed to be particularly 

vulnerable to neurological effects from exposure to lead. In longitudinal studies, blood-lead levels are 

typically measured several times during the course of young childhood (around 6 months to around 6 

years) and may be presented in several ways: as the peak blood-lead concentration (typically occurring 

around 24 months of age), as the average “lifetime” blood-lead concentration (where lifetime is equal to 

the time of first measurement until the time of the administration of the IQ testing); and blood-lead levels 

concurrent to the time of testing. These metrics are, of course, closely correlated. The studies reviewed 

for this analysis are listed on Table 5-3. 
402(c) Economic Analysis Chapter 5 

Table 5-3: Association between Blood-lead Levels and IQ Study Metric 

Initial Blood-lead 

Levels of Study 

Participants 

Study Results 

Dietrich 1993, 1995 

Peak and concurrent blood-lead levels 

20 ug/dL or 

greater 

Concurrent blood-lead levels were more strongly associated levels 

Tong 1996 Peak and child lifetime average blood-lead levels 20 ug/dL or greater Child lifetime average blood-lead levels were more strongly 

peak-blood levels 

Chen 2005 Peak, average, concurrent blood-lead levels 20 ug/dL or greater Concurrent blood-lead levels always had the strongest assoc

association grew stronger with age 

Canfield 2003 

Child lifetime average, concurrent, average during infancy (6-24 months) and peak concentrations of blood-lead levels 

Child lifetime 

average of 7.4 

μg/dL; Peak value 

of 11.1 μg/dL 

All four measures were significantly related to IQ declines, 

average and concurrent blood-lead levels were more highly infancy and peak blood-lead concentrations 

Lanphear 2005 

Child lifetime average, concurrent, peak, and very early childhood blood-lead levels 

Meta-analysis 

Concurrent or child lifetime average blood-lead levels more IQ declines than peak or very early childhood blood-lead cowas significantly greater among children whose peak blood-

Schwartz 1994 

Peak Exposure:

Cross sectional studies: Bloodlead level measured once Longitudinal studies: integrated blood-lead up to age three and the 24-month blood-lead level 

Meta-analysis Overall decline in IQ points: 0.257 IQ points per 1 μg Pb/dL 

higher IQ point losses among children with blood-lead level

Canfield 2003 

Average Exposure:

Child lifetime average, concurrent, average during infancy (6-24 months) and peak concentrations of blood-lead levels 

7.4 μg/dL child lifetime average among all participants 

Overall: IQ points decreased by 0.46 per 1 μg/dL change in blood-lead Sub-analysis: Children with peak blood-lead level <10 μg/dloss per 1 μg/dL change in blood-lead than those with bloodLinear model: estimated a 1.37 reduction in IQ points for a

child lifetime average blood-lead concentrations Non-linear model: estimated a 7.4 reduction in IQ points fo

in child lifetime average blood-lead. Children with peak bloμg/dL have an estimated reduction of 2.5 IQ points as blood10 μg/dL to 30 μg/dL 
402(c) Economic Analysis Chapter 5 19 

Peak blood-lead levels typically occur when children are young (around 2 years of age), but neurological 

function is difficult to measure until children are older (at around age 4 years or more). The question 

remains whether peak levels of exposures early in life are the cause of neurological effects reflected later 

in life or if the effects are the result of cumulative effects of exposures during early childhood. 

Because of the difficulty in answering this question, different theories have emerged. Some researchers 

have argued that peak lead exposures occurring around the ages of 1 to 2 years will affect neurological 

development more critically than exposures at other ages. Before the age of 2 years, the neural network 

in the brain is still undergoing substantial development, and many basic cognitive functions form during 

this period (ATDSR 1999). In a longitudinal study of lead-exposed children in Boston, Bellinger (1992) 

found a significant relationship between IQ and blood-lead levels at 2 years of age, but not with bloodlead levels at 57 months or 10 years of age. 

Several more recent studies have found a stronger association with child lifetime average or with 

concurrent, rather than peak exposure, and have found an attenuation of association between peak bloodlead levels and IQ over time. Note that in this circumstance, “lifetime average” is defined as the mean 

blood lead from the first blood lead test (usually around 6 months) to concurrent blood lead tests. For 

clarity, this assessment will henceforth refer to this measure as “child lifetime average.” The “concurrent 

blood lead” test is the blood lead measurement made closest in time to the IQ tests, which are typically 

administered between 5 and 7 years of age. 

Dietrich (1995) and Dietrich (1993) found that concurrent blood-lead levels were more strongly 

associated with IQ than peak blood-lead levels, while Tong (1996) found that child lifetime average 

blood-lead levels were more strongly associated with IQ than peak blood-lead levels. Chen (2005) 

examined the question by following children from about 2 years until 7 years of age, and comparing peak, 

average and concurrent blood-lead levels to IQ at different ages. Chen found that concurrent blood-lead 

levels always had the strongest association with IQ, and this association grew stronger with age. This 

result suggests that peak exposures at the age of 2 did not fully account for the neurological effects seen 

in older children, and that lower level, concurrent exposures are also influential. 

All of the studies were generally conducted on children with higher blood-lead concentrations (around 20 

μg/dL or more). Other recent studies have examined the question whether these results applied to 

children with lower blood-lead levels. Canfield (2003) studied the relationship of blood-lead 

measurements throughout early childhood to IQ measured at 3 and 5 years of age, using a variety of 

regression models. Among children included in the Canfield (2003) data analysis, the average blood-lead 

level was relatively low (child lifetime average of 7.4 μg/dL and a peak value of 11.1 μg/dL). The 

authors evaluated child lifetime average, concurrent, average during infancy (6-24 months) and peak 

concentrations of blood-lead levels. Although all four measures were significantly related to IQ declines, 

even after adjustment for covariates, the authors found that the child lifetime average and concurrent 

blood-lead levels were more highly significant (as measured by the P-value) than average in infancy and 

peak blood-lead concentrations. In a recent meta-analysis, Lanphear et al. (2005) also found the 

concurrent or child lifetime average blood-lead levels to be more strongly associated with IQ decrements 

than peak or very early childhood blood-lead concentrations. 

It should be noted again that EPA currently assumes that any exposure of young children to lead may 

result in IQ reductions. EPA believes that some effects, particularly changes in aspects of children's 

neurobehavioral development, may occur at blood-lead levels so low as to be essentially without a 

threshold (IRIS 2004). 
402(c) Economic Analysis Chapter 5 20 

The appropriate blood-lead metric is an important consideration for this proposed rulemaking, because the 

exposure associated with RRP activities is not expected to be a chronic exposure. If, in fact, this shortterm lead exposure occurs during a critical window of development, where lead can cause permanent 

cognitive and neurobehavioral deficits, then the full IQ decrement can be attributed to this period of 

exposure, and the appropriate metric of exposure is the blood-lead concentration measured during this 

developmental period. If in contrast, the IQ decrement is associated with the cumulative exposure of the 

child, then the more appropriate blood-lead exposure metric is the child lifetime average blood-lead 

concentration, where the blood-lead levels resulting from exposures to RRP generated dust are averaged 

with blood-lead levels during the rest of early childhood. 

This analysis presents two different approaches to estimate the reduction in IQ associated with increased 

blood-lead levels. In the first case, peak exposures are assumed to be the most relevant exposures for 

predicting IQ point loss. In this case, the blood-lead levels associated with floor lead dust exposures from 

RRP activities are averaged over one year, and are assumed to represent a peak of exposure between the 

ages of 0 and 6 years old. The change in IQ from a 1 μg/dL increase in peak blood-lead concentration is 

predicted using the results from Schwartz (1994). This meta-analysis was based on the results of seven 

studies (three longitudinal and four cross-sectional). Blood-lead was only measured once in the crosssectional studies, and these point-in-time measures were used in the meta-analysis as the exposure metric. 

For two of the longitudinal studies, the integrated blood-lead up to age 3 was used, while for one of the 

longitudinal studies, the 24-month blood-lead was used. For the purposes of this analysis, the results of 

this meta-analysis are interpreted as the IQ loss associated with peak blood-lead. The overall estimated 

decrement in IQ was estimated to be 0.257 IQ points per 1μg Pb/dL increase in blood-lead. 

In the second approach, the analysis assumed that the IQ decrement is associated with the average 

exposure over the lifetime of the child between the ages of 6 months and 6 years old (that is, over the 

course of 5 and one-half years). The analysis then uses the results of Canfield (2003) to predict the loss 

of IQ associated with a change in child lifetime average blood-lead. Canfield measured blood-lead 

concentrations in 172 children at six-month intervals from the age of 6 months until the age of 2 years, 

and then at one-year intervals until the age of 5 years. They related blood-lead measurements to IQ 

measured at 3 and 5 years of age, using a variety of regression models. The authors evaluated child 

lifetime average, concurrent, average during infancy (6-24 months) and peak concentrations of blood-lead 

levels. The researchers estimated a change of -0.46 IQ points per 1 μg/dL change in child lifetime 

average blood-lead, based on analyses across the entire range of blood-lead levels found in the study. 

However, in a separate analysis, they found that children whose peak blood-lead remained below 10 

μg/dL exhibited greater IQ loss than those with peak blood-lead levels greater than 10 μg/dL. Using 

linear models, they estimated a loss of 1.37 IQ points for each increase of 1 μg/dL of child lifetime 

average blood-lead concentration among this subset of children. Using a nonlinear model, they estimated 

a loss of 7.4 points per 10 μg/dL increase in child lifetime average blood-lead. (Among children with 

peak blood-lead above 10 μg/dL, the estimated decrease was 2.5 IQ points as blood-lead increased from 

10 μg/dL to 30 μg/dL.) Note that this finding is consistent with Schwartz (1994) who found higher IQ 

losses among children with blood-lead levels less than 15 μg/dL. This finding was also consistent with 

Lanphear (2005) who used data from seven longitudinal studies and found that the IQ decrement per 

deciliter of change was significantly greater among children whose peak blood-lead was below 7.5 μg/dL. 

Because the blood-lead levels among children estimated in this analysis may range from below 10 μg/dL 

to above 10 μg/dL depending on the dust exposure level, this analysis used the Canfield (2003) overall 
402(c) Economic Analysis Chapter 5 21 

estimate of -0.46 IQ point per 1 μg/dL, derived using data across all blood-lead ranges observed in that 

study, rather than the greater IQ loss estimated for children with blood-lead levels below 10 μg/dL. 

5.3.3 Populations at risk 

Based on the epidemiological evidence discussed above and elsewhere in the extensive literature on the 

topic, children 0 to 6 years old are considered to be the population at highest risk from lead contaminated 

dust and soil. However, because the levels of lead dust generated from a single RRP event are expected 

to remain at increased levels for only a short period of time (generally less than a year), the exposure 

occurs only during a fraction of a child’s life between the ages of 0 and 6 years. Furthermore, due to the 

particular vulnerability of the nervous systems of very young children (around the age of 2 years old), the 

timing of the short-term exposure may also influence the magnitude of adverse health effects associated 

with the exposure. 

This analysis examines two possible scenarios: in the first scenario, the analysis evaluates risks to 

children 1 to 2 years old only. At this age, behaviors such as mouthing and crawling lead to relatively 

high levels of dust and soil exposure, and, as discussed earlier, nervous system structures are considered 

particularly vulnerable to adverse effects from lead exposures at this age. In this case the analysis 

calculates peak blood-lead and child lifetime average blood-lead concentrations, assuming that the child is 

exposed to RRP-contaminated dust between the ages of 1 and 2 years old, and to RRP-contaminated soil 

beginning at age 1 year. When calculating benefits, the size of the population of children ages 1 to 2 

years estimated to be living in regulated housing with RRP events was used. 

Children of other ages are assumed to be exposed to lead from RRP activities, and may have health 

effects associated with these exposures; however, it is not known if exposures of the duration associated 

with RRP events occurring only at these other ages will have the same influence on IQ as exposures that 

occur at around the age of 2 years. Therefore, in this first scenario, risks to other age groups are not 

assessed quantitatively. Thus, IQ benefits may be underestimated. 

In the second scenario, the analysis assumes that short-term lead exposures that occur at any age under 6 

years have the same magnitude of effect on neurological decrement as exposures that occur when children 

are around the age of 2 years. In this case, risks to all children under the age of 6 were assessed. Because 

exposures to lead in dust or soil for young children could occur at any age under 6 years old, the analysis 

calculated the effect on blood-lead for exposures occurring at different times during young childhood. To 

do so, the analysis first calculated the effect of a single year of exposure to lead-contaminated dust for 

each age group separately. That is, the analysis first calculated the peak and child lifetime average bloodlead for a child, assuming exposure to RRP dust occurred when the child was 6 months to 1 year old; then 

assuming the exposure occurred when the child was 1 to 2 years old; then assuming exposure occurred 

when the child was 2 to 3 years old, and so on, for each one-year age group until the age of 5 to 6 years. 

The peak and child lifetime average blood-lead values for each age group were then weighted by the 

proportion of children in each age group in the U.S. population, according to the 2000 Census to derive 

“population-weighted average” peak and child lifetime average blood-lead values associated with 

exposures to dust. Similar calculations were made for exposures to lead-contaminated soil for each oneyear age range, assuming exposures start at the beginning of the age range and continue until the age of 6 

years. All children under the age of 6 years within the populations for each regulatory option were then 

used to calculate benefits. Using a population-weighted average for benefits assessment assumes that 
402(c) Economic Analysis Chapter 5 22 

using a population average will yield equivalent results to calculating lost IQ points based on the bloodlead metrics derived for each age group separately. 

5.3.4 Assignment of a medical cost, reduced income or other proxy for willingness to pay to 

avoid the adverse health effects 

The estimated value of an IQ point is $12,953 (2005 dollars), which is derived from coefficients provided 

by Salkever (1995). The IQ value is modeled as the present value of a loss in expected lifetime earnings 

due to a one point IQ drop.9

 The present value is calculated assuming that while most people start 

working at age 18, average income in the early adult years is reduced because some are still in school. In 

addition, the present value assumes a retirement age of 67 years old, due to the revisions of the Social 

Security law that are incrementally increasing the retirement age so that it will be at age 67 by the time 

today's children are retiring. Further, the analysis assumed that children would be affected by lead at 3 

years of age, the median of the range when children are most susceptible to lead hazards. As a result, the 

value of an IQ point is only discounted back to age 3. Limiting the valuation estimation to reduced 

income underestimates the value of children’s neurological benefits. Additional measures of the impact 

on IQ are: additional education costs for special and remedial education, and medical costs to treat very 

high levels of lead. This analysis does not generate the information needed to estimate the number of 

such cases, so these measures are not included in the valuation of children’s benefits. 

5.4 Benefits Assessment - Adults 

In this section, the analysis estimates the exposure of adults to lead-contaminated dust and soil from RRP 

activities and uses existing dose response relationships to calculate increased risks of hypertension, 

coronary heart disease (CHD), stroke and premature mortality. (The uncertainties in the quantification of 

adult effects are addressed in Section 5.5.5.) Costs for treatment of each disease were then applied and a 

total cost of health effects for each option was calculated. The following describes the process and results 

of this analysis. 

5.4.1 Estimation of lead contamination levels and estimation of the change in blood-lead 

levels resulting from lead contamination 

The methods used to evaluate exposure and resultant changes in blood-lead levels differ for adults and 

children. For adults, the total daily lead exposure from incidental ingestion of soil and dust was calculated 

using an adaptation of Equation 1 from the U.S. EPA Adult Lead Methodology (U.S. EPA 2003): 

PbBadult, central = PbBadult, 0 + PbD * IRD * BKSF * AFs

where: 

PbBadult, central = Central estimate of blood-lead concentrations (μg/dL) in adults that have 

 exposures to lead dust (PbD) from RRP activities; 

PbBadult, 0 = Typical blood-lead concentration (μg/dL) in adults in the absence of 

 exposures to lead dust from RRP activities; 

PbD = lead dust concentration (μg/g); 

IRD = Intake rate of dust, including both outdoor soil and indoor soil-derived 

 dust (g/day); 

 

9

 Present value of earnings calculated at a 3 percent discount rate. 
402(c) Economic Analysis Chapter 5 23 

BKSF = Biokinetic slope factor relating (quasi-steady state) increase in typical 

 adult blood-lead concentration to average daily lead uptake (μg/dL blood 

 lead increase per μg/day lead uptake); and 

AFS = Absolute gastrointestinal absorption fraction for ingested lead in soil and 

 lead in dust derived from soil (dimensionless). 

The data sources and derivation of each of the parameters in this model are discussed below. 

PbBadult, 0 

For blood-lead values, the geometric mean blood-lead values for adult men and women ages 20-59 and 

ages 60 and greater were obtained from National Health and Nutrition Evaluation Study (NHANES) III 

data. These data are summarized in Table 5-4. 

Table 5-4: Summary of Geometric Means of Blood-lead (measured in μg/dL) for Adults, from 

NHANES 1999-2002

Age group (years) Geometric mean (:g/dL) 

all racial groups 95% confidence interval 

Men 20-59 2.0 1.9-2.0 

Men >=60 2.7 2.6-2.8 

Women 20-59 1.2 1.2-1.2 

Women >=60 1.9 1.8-2.0 

Source: CDC 2005b 

PbD 

For children, empirically derived relationships are available to estimate the concentration of lead in dust 

(in μg/g) based on floor lead dust loadings (in μg/ft2

). For adults, such empirical relationships are not 

available; therefore, the lead dust concentration must be calculated from the assumptions regarding the 

floor lead dust loadings and the amount of dust on surfaces in a household. The lead dust concentration is 

calculated using the following equation: 

PbD = (Dlead /Dtotal) * 1,000,000 

where: 

 PbD = Concentration of lead in dust (μg/g); 

Dlead = Lead dust loading (μg/m2

); 

Dtotal = Total household dust loading from all sources (μg/m2

); and 

1,000,000 = Conversion from μg to g. 

The interior dust loadings for adults, Dlead, are calculated in the same fashion as the dust loadings for 

children, as described in Section 5.2. For total dust loadings in a household from all sources, Dtotal, this 

analysis used the value given in Hawley (1985), which was estimated to be 560 mg/m2

. Hawley derived 

this value from studies of residential dustfall (Hunter and Howe 1969 and Corn 1968, as discussed in 

detail in Hawley (1985, p 290)). This value was consistent with overall floor dust loading estimates 

derived data reported in another study, which measured floor dust levels of cadmium and lead in homes 

(Solomon and Hartford, as discussed in Hawley, 1985, p. 290). Soil lead concentrations for adults are 

calculated in the same manner as for children, as described in Section 5.2 above. 
402(c) Economic Analysis Chapter 5 24 

IRD 

The Exposure Factors Handbook (U.S. EPA 1997b) recommends the use of a value of 50 mg/day to 

represent adult daily incidental ingestion rate of soil (which includes outdoor soil and indoor dust). 

However, as this value includes exposures from both indoor dust and outdoor soil, its relevance to 

exposures that are only related to lead-contaminated indoor dust is not certain. Hawley (1985) estimates 

the daily consumption of incidental consumption of dust from living spaces to be approximately 0.56 

mg/day. For exposures to indoor dust alone, the analysis uses this value. For exposures to soil 

contaminated by exterior painting, this analysis uses the 50 mg/day value. These represent the total 

amount of dust and soil ingested; lead represents a fraction of these amounts. 

BKSF 

The Adult Lead Methodology (EPA 2003) recommends using, as a default value, 0.4 μg/dL blood per μg 

lead absorbed per day for the BKSF parameter. This value is based on data reported by Pocock (1983) on 

the relationship between tap water lead concentrations and blood-lead concentrations for a sample of 

males and on estimates of the bioavailability of lead in tap water. 

AFS 

The Adult Lead Methodology (EPA 2003) recommends a value of 0.12 for the fraction of lead in soil 

ingested daily that is absorbed from the gastrointestinal tract. This value is based on the assumption that 

the absorption factor for soluble lead is 0.2, and the relative bioavailability of lead in soil compared to 

soluble lead is 0.6. 

5.4.2 Estimation of adverse health effects from changes in blood-lead levels 

Cases of hypertension are assumed to be related directly to an estimated change in blood-lead levels for 

adults. For CHD, stroke and premature mortality, the cases are calculated based upon the expected 

increase in blood pressure due to an increase in blood-lead levels, which leads to a change in the risk of 

each disease. (Dose-response equations for these diseases are summarized in Table 5-5 and described in 

detail in Appendix 5B. The uncertainties in the quantification of adult effects are addressed in Section 

5.5.5.)
402(c) Economic Analysis Chapter 5 

Table 5-5: Health Functions Used in the Renovation, Remodeling, and Painting (RRP) Analysis Health Endpoint Gender Study Age Group Notes Function PbB Levels and Hypertension Men Schwartz 1988 20-74 

Hypertension 

defined as 

diastolic 

blood 

pressure 

above 90 

mm Hg 

2.744 0.793*(ln ) 2

1 

1

1

1 Pr( ) PbB 

e e

Hyp − 

+

−

+

∆ =

PbB Levels and Blood Pressure Men Schwartz 1992 Variable 

Change in 

blood 

pressure 

associated 

with a 

decrease in 

blood-lead 

from 10 

:g/dL to 5 

:g/dL 

1.4 ln( )

2

1

PbB

PbB

∆DBPmen = ×

Blood Pressure and Coronary Heart Disease (CHD) 

Men 

Pooling 

Project 

Research 

Group 

(PPRG) 

1978 

40-59 

10-year 

probability 

of 

occurrence 

of CHD 

event 

40 59 4.996 0.030365*( ) 

1 

1

1

1 Pr( ) DBP 

e 

CHD

−

− 

+

−

+

∆ =

Blood Pressure and Coronary Heart Disease (CHD) 

Men Shurtleff 1974 60-64 

2-year 

probability 

of 

occurrence 

of CHD 

event 

60 64 5.19676 0.02351*( ) 

1 

1

1

1 Pr( ) DBP 

e 

CHD

−

− 

+

−

+

∆ =

Blood Pressure and Coronary Heart Disease (CHD) 

Men Shurtleff 1974 65-74 

2-year 

probability 

of 

occurrence 

of CHD 

event 

65 74 4.90723 0.02031*( ) 

1 

1

1

1 Pr( ) DBP 

e 

CHD

−

− 

+

−

+

∆ =
402(c) Economic Analysis Chapter 5 

Table 5-5: Health Functions Used in the Renovation, Remodeling, and Painting (RRP) Analysis Health Endpoint Gender Study Age Group Notes Function Blood Pressure and First-Time Stroke (Initial Cerebrovascular Accidents (CA)) 

Men Shurtleff 19742 45-74 2-year probability of CA 8.58889 0.04066*( ) 

1 

1 

1 1 Pr( ) men DBP 

e e CA − 

+ − + ∆ =

Blood Pressure and First-Time Stroke (Initial Atherothrombotic Brain Infarctions (BI)) 

Men Shurtleff 19742 45-74 2-year probability of BI 9.9516 0.04840*( ) 

1 

1 

1 1 Pr( ) men DBP 

e e BI − 

+ − + ∆ =

Blood Pressure and Premature Mortality 

Men 

Framingham 

Study 

(McGee and 

Gordon 

1976) 

40-54 

12-year 

probability 

of death 

40 54 5.3158 0.03516*( ) 

1 

1

1

1 Pr( ) DBP 

e 

MORT

−

− 

+

−

+

∆ =

Blood Pressure and Premature Mortality 

Men Shurtleff 1974 55-64 2-year probability of death 55 64 4.89528 0.01866*( ) 

1 

1 

1 1 Pr( ) DBP 

e 

MORT − − 

− + ∆ =

Blood Pressure and Premature Mortality 

Men Shurtleff 1974 65-74 2-year probability of death 65 74 3.05723 0.00547*( ) 

1 

1 

1 1 Pr( ) DBP 

e 

MORT − − 

− + ∆ =

PbB Levels and Hypertension Women Schwartz 1992 Variable 

Hypertension 

defined as 

diastolic 

blood 

pressure 

above 90 

mm Hg 

(1.4) ln( 

PbB

PbB ∆DBPwomen = ×

Blood Pressure and Coronary Heart Disease (CHD) 

Women Shurtleff 1974 45-74 

2-year 

probability 

of 

occurrence 

of CHD 

event 

6.9401 0.03072*( ) 

1 

1

1

1 Pr( ) women DBP 

e 

CHD

− 

+

−

+

∆ =
402(c) Economic Analysis Chapter 5 

Table 5-5: Health Functions Used in the Renovation, Remodeling, and Painting (RRP) Analysis Health Endpoint Gender Study Age Group Notes Function Blood Pressure and First-Time Stroke (Initial Cerebrovascular Accidents (CA)) 

Women Shurtleff 19742 45-74 2-year probability of CA 9.07737 0.04287*( ) 

1 

1 

1 1 Pr( ) women DBP 

e 

CA − 

+ − + ∆ =

Blood Pressure and First-Time Stroke (Initial Atherothrombotic Brain Infarctions (BI)) 

Women Shurtleff 19742 45-74 2-year probability of BI 10.6716 0.0544*( ) 

1 

1 

1 1 Pr( ) women DBP 

e 

BI − 

+ − + ∆ =

Blood Pressure and Premature Mortality 

Women Shurtleff 1974 45-74 2-year probability of death 5.40374 0.01511*( ) 

1 

1 

1 1 Pr( ) women DBP 

e 

MORT − 

− + ∆ =

1 For coronary heart disease (CHD) and stroke this analysis estimates the probability of only non-fatal CHD and stroke events. 2 Shurtleff (1974) estimates that 70% of strokes are non-fatal. 3 Non-fatal CHD events estimated by assuming two-thirds of estimated events were not fatal (Shurtleff 1974). 
402(c) Economic Analysis Chapter 5 28 

5.4.3 Blood pressure data 

Data on diastolic blood pressure (DBP) have not been reported recently in NHANES summaries; this 

analysis uses the values from NHANES, 1976-1980.10 Table 5-6 shows the values for age ranges relevant 

to this study. 

Table 5-6: Summary of Mean Diastolic Blood Pressure (measured in mm Hg) 1976-1980 for Adults, 

from NHANES 1976-1980

 Age 

Sex 45-54 55-64 65-74 

Men 85 85 83 

Women 82 82 82 

Source: HHS 1986 

Calculation of annual cases 

As indicated in the dose-response equations, some of the dose-response functions reflect probabilities of 

cases of disease and death occurring over multiple years. To estimate the number of cases occurring each 

year, the total number of cases was divided by the number of years over which the probability is 

estimated. The costs associated with the cases were discounted back to 2005 using a 3 percent discount 

rate. 

5.4.4 Assignment of medical cost or other proxy for willingness to pay to avoid the adverse 

health effects 

The benefits of preventing chronic cases of adverse health effects are estimated using the avoided cost of 

these effects. This approach is described in the U.S. EPA Cost of Illness Handbook (U.S. EPA 1999) and 

Appendix G of “The Benefits and Costs of the Clean Air Act: 1970 to 1990,” prepared for U.S. Congress 

by U.S. EPA, Office of Air and Radiation in 1997 (U.S. EPA 1997c). The costs cited by these two 

sources came from published economic and medical studies and are presented in Table 5-7 along with a 

brief description of their origin. 

 

10 EPA plans to investigate the use of more recent NHANES data in an expanded risk assessment it intends to 

perform for this rulemaking. 
402(c) Economic Analysis Chapter 5 29 

Table 5-7: Per-Case Direct Medical Costs of Lead-Related Adverse Health Effects 

Adverse 

Effect Gender 

Cost per 

Case 

(2005$)

Cost Description 

Male $14,613 

Hypertension 

Female $12,524 

The cost estimates were derived by taking Cropper and Krupnick's 

(1990) average annual per-person costs of hypertension and 

applying Hartunian's (1981) methods for calculating lifetime costs 

of treating hypertension using a 3% discount rate. The costs 

include physician charges, medication costs, hospitalization costs 

and lost work time. 

Male 

Coronary 

Heart Disease 

Female 

$79,161 

The costs were estimated (Wittels 1990) for 3 CHDs (acute 

myocardial infarction, uncomplicated angina pectoris, and unstable 

angina pectoris) for 5 years post-diagnosis using a 3% discount 

rate. The probability of a medical service was multiplied by the 

estimated price of the service and the average cost for the three 

CHD types was determined. Since the effect of increased bloodlead levels on CHD incidence rates is beyond the scope of this 

analysis, weighting factors were not used to account for the 

different probabilities of contracting the three types of CHD. 

Male $295,704 

Stroke 

Female $221,777 

The cost estimates (Taylor 1996) represent the expected lifetime 

cost of a stroke for males and females age 45-74, including the 

present discounted value of the stream of medical expenditures and 

the stream of lost earnings, using a 5% discount rate. 

Death – Any Male 

Effect Female 

$6.98 

Million 

A range of values taken from hedonic wage studies and/or 

contingent valuation studies of primarily middle aged adults was 

used (U.S. EPA 200b), and converted to 2005$. 

In addition to providing cost estimates for the medical treatment of each adverse effect, the benefit 

estimates include the number of deaths resulting from each disease, in terms of the value of a statistical 

life (VSL). The dollar value of VSL was taken from EPA’s 2000 Guidelines for Preparing Economic 

Analyses, which presents a VSL of $5.8 million (1997 dollars) (U.S. EPA 2000b). 

5.5 Results 

To summarize, the benefit estimates provided in this section reflect the following sequence of events. In 

the baseline an RRP event occurs, generating lead dust in both the area where the work occurs and the 

adjacent area (e.g., the adjacent room). In the baseline (without rule), the contractor cleans the work area 

before he/she leaves by sweeping and vacuuming. While this contractor cleaning substantially reduces 

the lead dust in the work area, it rarely brings the lead levels down to the EPA hazard levels of 40 

μg/sq.ft. In most cases, this cleaning also does not address the lead dust that may have migrated into the 

rest of the house during the RRP event. Following the end of the RRP event, the household cleans the 

work area and the rest of the house on a regular basis. Periodic cleaning continues to reduce the lead dust 

levels over time. Under the rule, the same sequence of events occurs, but it is assumed that the 

containment, cleaning, and cleaning verification practices required by the rule reduce lead dust loadings 

to 40 μg/ft2

 or less after contractor cleaning. 
402(c) Economic Analysis Chapter 5 30 

The blood-lead models used in the analysis require an estimate of the annual lead exposure to occupants 

of homes where RRP occurs. To obtain that value, the models perform the following calculations: 

1. Lead dust levels in the work area due to the RRP event are estimated as described in Section 5.2 

and Appendix 5C. 

2. Lead dust levels due to the RRP event in the room(s) adjacent to the work area are estimated to 

be 16 percent of the lead levels in the work area (i.e., before contractor cleaning). See Appendix 

5C for the derivation of this factor. 

3. Lead dust levels in the rest of the house are assumed to be zero.11

4. Average work area lead levels when the contractor leaves are estimated by applying normal 

contractor cleaning efficiencies to the lead levels estimated in step 1. See Section 5.2 and 

Appendix 5C and further discussions below in Section 5.5.3. 

5. Average household lead dust levels when the contractor leaves are estimated as the weighted 

average of the lead dust levels due to the RRP event in the work room after contractor cleaning, 

the adjacent room, and the rest of the house. Each of these three values is weighted by the 

relative square feet of the area involved. The average work area size is estimated for each type 

of RRP event in Chapter 4 and then expressed as a percentage of the total size of the housing 

unit12. The size of any household’s work area is the sum of percentages shown in Table 5-8 for 

the events that are performed. The maximum work area size for a household is calculated as the 

average size of the largest event (a Non-Room-Specific event), which is 30 percent of the unit.13 

The adjacent area is assumed to equal the work area in size 

Table 5-8: Work Area Size by Event Type (Percent of 

Housing Unit) 

Event Type 

Work Area 

Size 

Kitchen 6% 

Bathroom 3% 

Addition 5% 

Non-Room-Specific 30% 

Interior Painting 16% 

Average Household Work Area 24% 

Source: Calculated from the American Housing Survey, 

see Chapter 4 for details. 

 

11 It is likely that in some circumstances the lead dust from RRP events can contaminate other areas of the house 

beyond the work room and the adjacent room. Because no data were located specifically addressing lead dust levels 

in the rest of the house from RRP events, the level was assumed to be zero. However, this assumption is likely to 

understate the extent of lead dust contamination from RRP events, and to underestimate the benefits of the rule. 12 For large events, the work area size is estimated as the size of the room where the RRP work is performed (or 50 

percent and 25 percent of the housing unit for non-room specific and interior painting events, respectively); for 

small events the work area is estimated as an area the size of one wall by five feet (to reflect the spreading of plastic 

out 5 feet from the work). To maintain consistency with the assumptions regarding the mix of large and small 

events estimated for the cost analysis, the typical work area size is estimated as the midpoint between these two 

estimates. 

13 Note that 30 percent of the unit is the average work area of the largest event, a non-room-specific event. While 

some non-room-specific events are larger, and others are smaller; the average size is used in the benefits 

calculations. 
402(c) Economic Analysis Chapter 5 31 

5. Periodic household cleaning is applied to this weighted average and the decline in lead levels is 

tracked over time so that the yearly average can be calculated. 

6. The benefits are estimated based on exposure that starts when the contractor leaves, having 

performed his/her cleaning. Thus the exposure estimates used in the benefits estimation do not 

include any exposure to household occupants or neighbors (or the RRP workers) that might occur 

during the RRP event itself. While many RRP events only last for one day, some last for many 

days but information on the distribution of event lengths are not available at this time. 

5.5.1 The Monte Carlo Model 

A Monte Carlo modeling approach was used to estimate blood-lead (and thus health effect) levels in both 

the baseline and with the regulations in place. A Monte Carlo approach was used because it provides a 

means of incorporating the uncertainty around each input parameter, as long as the uncertainty can be 

described in terms of a statistical distribution. For each run of the Monte Carlo model, a single value for 

each uncertain parameter is drawn from the distributions describing the uncertain parameters. 

This analysis treats each input as a statistically independent parameter. The expected benefits are 

calculated given this set of values for the uncertain input parameters. This is done multiple times, 

keeping track of the expected benefits calculated at each model run. The result of the Monte Carlo 

approach is a distribution of values for expected benefits that is described by its mean, standard deviation 

and percentile values. 

Uncertainty distributions are incorporated into the benefits model for a number of key inputs. For 

example, the initial lead loadings used in estimating exposures are drawn from distributions developed 

based on the frequency of different RRP activities and associated lead dust and soil concentration 

estimates. 

Further, for indoor exposure, the frequency of household cleaning and the cleaning efficiency of vacuums 

on carpet and vacuuming/sweeping on non-carpeted floors are uncertain. Using values from the literature 

the analysis characterizes the uncertainty of these important inputs. 

Several inputs that are known to be uncertain are treated as point estimates in the benefits model because 

the data that are necessary to statistically describe the uncertainty are not available. Therefore, although 

the benefits model incorporates as much input uncertainty as feasible, the outputs described below 

underestimate the level of uncertainty in the estimation of the benefits associated with the rule options. 

5.5.2 Alternative Blood-lead Modeling Assumptions 

While the causal relationship between lead exposure and IQ reduction in children is well established (see 

section 5.3.2), there remains some uncertainty about the exact form of the dose-response functions and 

whether exposure should be measured in terms of peak exposure or average exposure over the first six 

years of life. This uncertainty is handled by using six alternative sets of assumptions that reflect 

alternative combinations of: blood-lead models, age of children exposed and exposure metrics. These 

differences are discussed in detail in Section 5.3.1 and Section 5.3.2 of this chapter. The six alternative 

sets of assumptions are presented in Table 5-9. Age Group refers to the age at which exposure has an 
402(c) Economic Analysis Chapter 5 32 

effect, and Lead Exposure Metric refers to whether exposure level is measured in terms of peak or sixyear average lead exposure. 

Table 5-9: Alternative Blood-Lead Assumptions 

Blood-lead 

Assumptions Age Group Blood-Lead Model Lead Exposure Metric 

Set 1a 1-2 years old IEUBK Peak (age 1-2 year old) 

Set 1b 1-2 years old IEUBK Average (age 0 thru 5 years old) 

Set 1c 1-2 years old Empirical Model Peak (age 1-2 year old) 

Set 1e 1-2 years old Empirical Model Average (age 0 thru 5 years old) 

Set 2a 0 thru 5 years old IEUBK Peak (at any age 0 thru 5 years) 

Set 2b 0 thru 5 years old IEUBK Average (age 0 thru 5 years old) 

The Empirical Model was not used for Assumption Sets 2a or 2b because these sets assume that the 

relevant age group is children from 0 through 5 years of age. The Empirical Model, however, was 

derived from observations of very young children (around 2 years old) and automatically incorporates the 

behaviors of these young children when estimating how floor dust relates to blood lead. Because older 

children have different behaviors than very young children, the Empirical Model does not represent the 

relationship between blood lead and floor dust lead in older children. 

5.5.3 Size of Population that Avoids Exposure After the Rule 

The size of the population that has a reduced exposure to lead because of the rule is estimated using the 

1997 and 2003 American Housing Surveys (AHS) and the 1995 Property Owners and Managers Survey 

(POMS). Four major steps are taken to estimate this population: (1) estimate the number of individuals 

living in housing where there is a regulated RRP event; (2) estimate the proportion of regulated RRP 

events where lead-based paint (LBP) is present; (3) adjust for the baseline use of containment and cleanup practices to account for individuals who would avoid exposure in the absence of regulation; and (4) 

adjust for compliance rates. The basic analysis presented in this chapter assumes a 75 percent compliance 

rate, based on analyses of compliance rates with OSHA construction regulations. Alternative compliance 

rates are presented in the Sensitivity Analyses shown in Chapter 7. 

The first three steps are described in more detail below. 

Number of Individuals Living in Housing Units with Regulated RRP 

The number of individuals living in owner-occupied households with regulated RRP is estimated directly 

from the 2003 AHS, which reports renovation data together with information on the occupants of owneroccupied housing. For rental-units, the percentage of units estimated to have had at least one regulated 

RRP event is estimated using the POMS. This percentage is applied to the total number of individuals 

living in regulated rental units, according to the 2003 AHS, to estimate the number of individuals living in 

units where there was a regulated RRP event. 

Proportion of Regulated RRP Events where LBP is Present 

The likelihood that a housing unit has LBP is estimated from HUD’s 2000 National Survey of Dust Lead 

Hazards and Allergens in Housing (HUD 2000). In this survey, samples were collected from a nationally 

representative sample of 750 housing units; lead samples include dust wipes, vacuum samples (carpets), 

soil, and in-situ XRF testing. Various components of each housing unit were sampled and these 
402(c) Economic Analysis Chapter 5 33 

component-specific lead probabilities are used to estimate event-specific lead likelihood values. This is 

described in more detail in Chapter 4. These probabilities are applied to the number of individuals living 

in housing units with regulated RRP to estimate the number who are at risk for lead exposure. 

Adjustment for Baseline Lead Safe Work Practices 

Even without the proposed regulation, contractors already perform some containment and clean-up. In 

order to determine how often various work practices are used in the baseline, nine industry experts were 

questioned. (The data collection effort is described in Section 4.5.4). The questions and responses on 

work site preparation (containment) and clean-up are summarized in Table 5-10. As shown in Table 5-

10, the baseline frequency varies widely across different work practices. For example, respondents 

indicated that floors, outdoor areas, and doorways were covered with impermeable material (e.g., 

polyethylene plastic) in approximately 40 percent of events, work areas were vacuumed daily with a 

HEPA-filtered vacuum on a daily basis in less than 20 percent of events, and that exterior debris was wet 

misted and the impermeable material was rolled and sealed with duct tape in less than 5 percent of events. 

While the survey did not ask about cleaning verification, there are probably few renovation contractors 

performing the cleaning verification required by the rule. 

Care must be taken in interpreting these data. First, there were only 9 respondents the survey. Second, 

the questions only asked how frequently each of the various activities or practices was used (e.g. rarely, 

often, usually), not how often they are used when needed. Thus it is not clear whether the relatively low 

value for some activities reflects situations where the activity is not needed, or situations where they 

should be but were not undertaken. Third, some of the activities might be considered substitutes (e.g. 

turning off HVAC system versus sealing HVAC vents). Fourth, the survey asked about individual 

practices, but a combination of practices is needed to provide adequate protection. Finally, the survey did 

not address whether the activities were being performed properly to protect occupants. For example, 

contractors using containment may not do so effectively unless they have been trained in how to properly 

lay, affix, and dispose of plastic sheeting. Improper containment can release lead dust and contaminate 

the housing unit. 

Table 5-10 and 4-19 differ, Table 5-10 presents the actual survey questions while Table 4-19 relates to the 

work practices required by the rule. Because the survey was completed before the current proposed rule 

was developed, some of the survey questions do not match the rule’s requirements. In these cases the 

survey results in Table 5-10 were used to develop an assumption about the percentage of events where 

some form of a work practice required by the rule is already in use. For example, the survey asked how 

often a HEPA vacuum was used on a daily basis (shown in Table 5-10 to be estimated at 18.8 percent of 

events), but the rule only requires the use of a HEPA vacuum when the renovation is completed. It was 

assumed that some events that are not cleaned with a HEPA vacuum on a daily basis are cleaned with a 

HEPA vacuum when the renovation is completed. It was further assumed that a HEPA vacuum was used 

at the end of the renovation with the same frequency that polyethylene sheeting was used, or in 

approximately 40 percent of renovation jobs (as shown in Table 4-19). 
402(c) Economic Analysis Chapter 5 34 

Because of uncertainties about the type of baseline containment and cleaning practices used, how often 

they are performed, whether they are carried out properly, and how these practices reduce lead levels, 

benefits are calculated under two different scenarios. The two scenarios both start with the assumption 

that the more common work practices required by the rule (such as cleaning with a HEPA vacuum at the 

completion of the renovation) are used in 30 to 40 percent of baseline events. 

The first scenario assumes that the equivalent of 20 percent of all at-risk occupants are protected in the 

baseline commensurate with the results of the rule. This could be because 40 percent of all at-risk 

occupants receive 50 percent of the full protection benefits provided by the rule, or 31 percent of all atrisk occupants receive 65 percent of the full protection benefits provided by the rule, 25 percent of all atrisk occupants receive 80 percent of the full protection benefits provided by the rule, 20 percent of all atrisk occupants receive the full protection benefits provided by the rule, or some other computational 

equivalent. This scenario is meant to cover all baseline activities. 

The second scenario also assumes that 20 percent of all at-risk occupants are protected in the baseline 

commensurate with the results of the rule. In this scenario, the 20 percent represents occupants receiving 

the full protection benefits of the rule, and there are additional occupants who may receive some partial 

Table 5-10: Summary of Current Practice Survey Results 

Activity 

Percentage of 

time the activity

is already 

taking place 

Preparation 

Restrict access to the work area by placing impermeable material (e.g. 

polyethylene plastic) over doorways 39.3% 

Turn off the HVAC systems and close vents 16.9% 

Seal off HVAC vents with impermeable material 29.6% 

Cover floor of work area with impermeable material 41.2% 

Create a runner of impermeable material between work area and outside door 29.1% 

Cover occupants belongings with impermeable material 61.9% 

Cover surrounding ground/soil with impermeable material during outdoor 

renovation projects 37.6% 

Place warning signs outside unit in a multi-unit building 13.2% 

Restrict access to outdoor work area by constructing barriers and/or placing 

warning signs 23.0% 

Clean-Up 

Sweep work area daily 74.6% 

Mop work area daily 21.1% 

Vacuum work area with a shop-vac daily 58.1% 

Vacuum work area with a two-stage high efficiency filtered vacuum daily 27.2% 

Vacuum work area with a HEPA-filtered vacuum daily 18.8% 

Wrap debris in impermeable material and duct tape shut prior to removal 23.0% 

Place removed carpet in impermeable material and duct tape shut prior to 

removal 4.8% 

Wet mist debris generated by outdoor projects; roll and seal with duct tape 

before disposal 4.8% 
402(c) Economic Analysis Chapter 5 35 

protection that may not be commensurate with the rule. Given that work practices such as cleaning with a 

HEPA vacuum at the completion of the job are assumed to be used in 30 to 40 percent of the events, this 

scenario assumes that additional cleaning activities are performed in another 10 to 20 percent of events. 

This additional cleaning goes beyond the efficiency of normal contractor or household cleaning, but does 

not necessarily reach the level of protection achieved by the rule. There are three such activities assumed 

in Scenario 2: 

• Additional contractor cleaning. In 15 percent of the baseline events, contractors are assumed to 

achieve dust reduction levels beyond those credited to normal contractor cleaning. This could be 

due to the use of a HEPA vacuum, or through a second cleaning with normal cleaning methods 

immediately after the RRP event. This is assumed to occur in both owner-occupied and rental 

housing. Computationally, the cleaning efficiency is calculated as two successive cleanings. 

The first cleaning yields normal contractor efficiencies (a 14 percent to 37 percent removal rate 

on carpets and a 94.8 percent to 98.5 percent removal rate on non-carpeted surfaces). The second 

cleaning for carpets is credited with the same cleaning efficiency (14 percent to 37 percent), while 

non-carpeted surfaces are credited with a 70 percent reduction. Thus, the 15 percent of events in 

this category achieve a 26 percent to 60 percent cleaning efficiency on carpets and a 98.4 percent 

to 99.6 percent cleaning efficiency on non-carpeted surfaces. These events are in addition to the 

baseline activities that protect 20 percent of the population described above. If there are any 

events where the lead loadings are sufficiently low so that the cleaning efficiency for this 

additional contractor cleaning reduces lead loadings to below the 40 μg/ft2

 level in the baseline, 

then the same level is used in the post-rule analysis. (That is, lead levels are generally assumed to 

be 40 μg/ft2

 post-rule, but are not assumed to increase from the baseline as a result of the rule.) 

Contractors are assumed to cease this additional contractor cleaning after the rule. 

• Contractor cleaning of adjacent room. In 10 percent of baseline events, contractors are 

assumed to clean the adjacent room as well as the work room. This is assumed to occur in both 

owner-occupied and rental housing. These events are independent of the additional contractor 

cleaning described above. To the extent that an event is in both the 15 percent of events that 

achieve dust reduction above normal levels and the 10 percent of events where the adjacent room 

is cleaned, the cleaning efficiency is assumed to be the same in the adjacent room as in the work 

room. If there are any events where the lead loadings are low enough that the cleaning efficiency 

for this contractor cleaning of the adjacent room is calculated to reduce lead levels to below 40 

μg/ft2

 in the baseline, the same level is used in the post-rule analysis. (That is, lead levels are 

generally assumed to be 40 μg/ft2

 post-rule, but are not assumed to increase from the baseline as a 

result of the rule.) Contractors are assumed to cease this cleaning of the adjacent room after the 

rule. 

• Additional household cleaning. In 15 percent of the events, households are assumed to achieve 

dust reduction levels beyond those credited to normal household cleaning in their initial cleaning. 

This could be due to the use of a HEPA vacuum, or through a second cleaning with normal 

cleaning methods immediately after the RRP event. This is assumed to occur in both owneroccupied and rental housing. Computationally, the cleaning efficiency is calculated as two 

successive cleanings. The first cleaning yields normal contractor efficiencies (a 14 percent to 37 

percent removal rate on carpets and a 94.8 percent to 98.5 percent removal rate on non-carpeted 

surfaces). The second cleaning for carpets is credited with the same cleaning efficiency (14 

percent to 37 percent), while non-carpeted surfaces are credited with a 70 percent reduction. 
402(c) Economic Analysis Chapter 5 36 

Thus, the 15 percent of events in this category achieve a 26 percent to 60 percent cleaning 

efficiency on carpets and a 98.4 percent to 99.6 percent cleaning efficiency on non-carpeted 

surfaces. These events are independent of the contractor cleaning assumptions. The additional 

household cleaning in this scenario is assumed to continue after the rule. 

The two scenarios are summarized in Table 5-11. 

Table 5-11: Scenarios for Benefits Analysis 

Category Scenario 1 

Assumption Scenario 2 Assumption 

Treatment of 

baseline protection 

commensurate with 

the rule 

Equivalent of 20% of 

at-risk occupants 

protected 

20% of at-risk occupants protected 

Cleaning by 

contractors in the 

baseline 

Normal contractor 

cleaning in all events. 

In addition to normal contractor cleaning in all events, in 15% of 

baseline events contractors are assumed to achieve dust reduction 

levels beyond those credited to normal contractor cleaning. Events 

in this category achieve a 26% to 60% cleaning efficiency on 

carpets and a 98.4% to 99.6% cleaning efficiency on non-carpeted 

surfaces. These events are in addition to the baseline events that 

protect 20% of the population as described above. 

Contractor cleaning 

of adjacent room in 

the baseline 

Contractor cleans the 

work room but does 

not clean the adjacent 

room. 

In 10% of events, contractors are assumed to clean the adjacent 

room as well as the work room. These events are independent of 

the additional contractor cleaning described above. The cleaning 

efficiency is assumed to be the same in the adjacent room as in the 

work room. 

Initial household 

cleaning 

Normal household 

cleaning for all events 

In addition to normal household cleaning, in 15% of the baseline 

events, households are assumed to achieve dust reduction levels 

beyond those credited to normal household cleaning. The 15% of 

events in this category achieve a 26% to 60% cleaning efficiency 

on carpets and a 98.4% to 99.6% cleaning efficiency on noncarpeted surfaces. These events are independent of the contractor 

cleaning assumptions. 

The resulting number of RRP events where the proposed regulation will provide benefits, and the number 

of individuals that will benefit from the rule (i.e. are protected by the rule) are shown in Table 5-12. 

Some of the RRP events and the associated individuals counted in Table 5-12 are not included in the 

benefit estimates due to data limitations. For example, data are not available on the amount of lead 

generated by exterior non-painting RRP events, and so they are excluded from the benefits estimations. 

Thus the populations used in the benefits estimations are smaller than the actual population benefiting 

from the rule. Because all proposed options cover the same set of housing units in the second year (and 

beyond), all four options cover the same number of events and protect the same number of children and 

individuals in the second year. 
402(c) Economic Analysis Chapter 5 37 

Table 5-12: Annual Number of RRP Events and Number of Individuals who will Benefit from the 

Proposed Regulations 

Number of Events (Millions) Number of Individuals Protected 

(thousands)* 

Children under 

the Age of Six All Individuals 

Option First 

Year 

First 

Year with 

LSWP 

Second 

Year 

Second 

Year with 

LSWP First 

Year 

Second 

Year 

First 

Year 

Second 

Year 

Option A 10.7 8.1 10.7 4.4 787 783 5,309 5,287

Option B 5.8 4.8 10.7 4.4 668 783 4,529 5,287

Option C 4.3 3.7 10.7 4.4 520 783 3,659 5,287

Option D 5.8 4.8 10.7 4.4 668 783 4,529 5,287

* Number is increment above those occupying units where LSWP are currently practiced in the baseline 

and assume 75% compliance rate. The number protected may be higher under Scenario 1. 

 Alternative estimates using different development time-frames for the improved test kits are considered 

in sensitivity analyses presented in Chapter 7. 

5.5.4 Summary of Inputs to the Monte Carlo Model 

The input parameters are listed in Table 5-13, along with their value (for those with a point estimate) or 

their distribution. Certain inputs to the Monte Carlo model account for variability by incorporating a 

range of possible values. Where all values in this series are assumed to have equal probability of 

occurring, for example different parameters for contractor cleaning efficiency, these are termed uniform 

distributions in Table 5-13. Other inputs given by a range of values consist of custom distributions, with 

specific probabilities for each value in the range. For example, for the variable of soil lead concentration 

outdoors without the rule, different concentrations are likely depending upon the unit type and the system 

of paint removal used. These values are not equally likely to occur because of the different frequencies of 

unit types. The specific distributions used for the custom distribution parameters are given in Appendix 

5D. Uncertainties in the quantification of adult effects, including the age of the data used, are addressed 

in Section 5.5.5. 
402(c) Economic Analysis Chapter 5 38 

Table 5-13: Monte Carlo Analysis Inputs 

Bloodlead 

Assumptions 

Units Value or 

Distribution 

Reference or 

Report Section 

Population Assumptions 

Populations Exposed All Number of People

Single value for 

each age and sex 

category 

Section 5.4.1 

Lead Loading Assumptions 

Soil Lead Concentration Outdoors 

without Rule All mg/kg 

Custom 

Distribution 

(Range = 571.6 to 

1,123.5) 

UIUC, 2002 

Soil Lead Concentration Outdoors with 

Rule All mg/kg 490 HUD, 2000 

Initial lead dust level in work area after 

indoor work All μg/ft2

Custom 

Distribution 

(Range = 1,800 to 

409,031) 

Appendix 5C 

Percentage of initial dust loading in 

rooms adjacent to the work area. All unit-less fraction 16% Derived from U.S. EPA, 1997a 

Initial lead dust level outside of work 

area and adjacent room for interior work. All μg/ft2

 0 Section 5.5 

Percentage of area of the home that is a 

work area All unit-less fraction 

Custom 

Distribution 

(Range = 3% to 

30%) 

Section 5.5 

Lead dust level indoors after contractor 

cleaning with rule All μg/ft2

40 maximum or 

concentration 

resulting from 

cleaning, 

whichever is lower 

Toxic Substances 

Control Act 

(TSCA) Section 

403 Rule 

Child Dose-Response Assumptions 

IEUBK Lead Dust to Blood Lead 

Relationship 

1-year 

Peak μg/dL per μg/ft2

Linear regression 

based on series of 

IEUBK model 

results (see Section 

5.3.1 for further 

explanation) 

U.S. EPA, 2005 

Empirical Lead to Blood Lead 

Relationship All μg/dL per μg/ft2

 See Section 5.3.1 U.S. EPA, 2000a 

IQ Reduction Parameter 1-year 

Peak 

IQ points per 1 

μg/dL 

Normal 

Distribution (mean 

= 0.25, s.d. = 0.04) 

Schwartz, 1994 

IQ Reduction Parameter 6-year 

average 

IQ points per 1 

μg/dL 

Normal 

Distribution (mean Canfield, 2003 
402(c) Economic Analysis Chapter 5 39 

Table 5-13: Monte Carlo Analysis Inputs 

Bloodlead 

Assumptions 

Units Value or 

Distribution 

Reference or 

Report Section 

= 0.46, s.d. = 0.15) 

Indoor Cleaning Assumptions 

Percentage of Floors Carpeted All unit-less fraction 0.36 Derived from 

HUD, 2000 

Normal Contractor Cleaning Efficiency 

on Carpet All unit-less fraction 

Uniform 

Distribution 

(Range = 14% - 

37%) 

Yin, 2002 

Additional Contractor Cleaning 

Efficiency on Carpet where Contractors 

Achieve Dust Reductions beyond those 

of Normal Contractor Cleaning 

All unit-less fraction Same as first carpet 

cleaning efficiency Section 5.5.3 

Normal Contractor Cleaning Efficiency 

on Non-Carpet All unit-less fraction 

Uniform 

Distribution 

(Range = 94.8% - 

98.5%) 

CETL, 2001 

Additional Contractor Cleaning 

Efficiency on Non-Carpet where 

Contractors Achieve Dust Reductions 

beyond those of Normal Contractor 

Cleaning 

All unit-less fraction 70 % Section 5.5.3 

Percent of RRP Events where 

Contractors Achieve Dust Reductions 

beyond those of Normal Contractor 

Cleaning in Work Area 

All unit-less fraction 15 % Section 5.5.3 

Percent of RRP Events where 

Contractors Clean the Adjacent Room All unit-less fraction 10 % Section 5.5.3 

Percent of RRP Events where 

Contractors Achieve Dust Reductions 

beyond those of Normal Contractor 

Cleaning in the Adjacent Room 

All unit-less fraction 

15 % of the 10% of 

Adjacent Rooms 

that are Cleaned by 

Contractors (= 

1.5%) 

Section 5.5.3 

Normal Household Cleaning Efficiency 

on Carpet All unit-less fraction 

Uniform 

Distribution 

(Range = 14% - 

37%) 

Yin, 2002 

Normal Household Cleaning Efficiency 

on Non-Carpet All unit-less fraction 

Uniform 

Distribution 

(Range = 94.8% - 

98.5%) 

CETL, 2001 

Percent of RRP Events where 

Households Achieve Dust Reductions 

beyond those of Normal Household 

Cleaning 

All unit-less fraction 15 % Section 5.5.3 
402(c) Economic Analysis Chapter 5 40 

Table 5-13: Monte Carlo Analysis Inputs 

Bloodlead 

Assumptions 

Units Value or 

Distribution 

Reference or 

Report Section 

Additional Household Cleaning 

Efficiency on Carpet where Households 

Achieve Dust Reductions beyond those 

of Normal Cleaning 

All unit-less fraction Same as first carpet 

cleaning efficiency Section 5.5.3 

Additional Household Cleaning 

Efficiency on Non-Carpet where 

Households Achieve Dust Reductions 

beyond those of Normal Cleaning 

All unit-less fraction 70 % Section 5.5.3 

Frequency of Household Cleaning per 

year All integer 

Custom 

Distribution 

(Range from 26 to 

104) 

Simcox, 1995 

Adult Exposure Assumptions 

Dust ingested per day (indoors) All mg/day 0.56 Hawley, 1985 

Dust ingested per day (outdoors) All mg/day 50 Hawley, 1985 

Loading of dust on surfaces (indoors) All mg/m2 560 Hawley, 1985 

Absorption rate for ingested soil lead All unit-less fraction 0.12 

Adult Lead 

Methodology, U.S. 

EPA, 2003 

Increase in blood lead per ug/day 

absorbed from ingestion All μg/dL per μg/day 0.4 

Adult Lead 

Methodology, U.S. 

EPA, 2003 

Adult Dose Response Functions 

Blood Lead to Blood Pressure All mm Hg per μg/dL

See Table 5-5 for 

range of 

relationships. 

Section 5.4: 

Appendix 5B 

Blood Lead to Hypertension All 

probability per 

μg/dL 

See Table 5-5 for 

range of 

relationships. 

Section 5.4: 

Appendix 5B 

Adult Health Endpoint Relationships 

Blood Pressure to CHD All probability per 

mm Hg 

See Table 5-5 for 

range of 

relationships. 

Section 5.4: 

Appendix 5B 

CHD Fatality Rates All unit-less fraction 33% Shurtleff, 1974 

Blood Pressure to Atherothrombotic 

Brain Infarction All probability per 

mm Hg 

See Table 5-5 for 

range of 

relationships. 

Section 5.4: 

Appendix 5B 

Atherothrombotic Brain Infarction 

Fatality Rate All unit-less fraction 30% Shurtleff, 1974 

Blood Pressure to Cerebrovascular 

Accident All probability per mm Hg 

See Table 5-5 for 

range of 

relationships. 

Section 5.4: 

Appendix 5B 

Cerebrovascular Accident Fatality Rate All unit-less fraction 30% Shurtleff, 1974 

Blood Pressure to Mortality All probability per 

mm Hg 

See Table 5-5 for 

range of 

Section 5.4: 

Appendix 5B 
402(c) Economic Analysis Chapter 5 41 

Table 5-13: Monte Carlo Analysis Inputs 

Bloodlead 

Assumptions 

Units Value or 

Distribution 

Reference or 

Report Section 

relationships. 

Adult Health Assumptions 

Average PbB - Men 20-59 All μg/dL 2 CDC, 2005b, Table 

2 

Average PbB - Men >60 All μg/dL 2.7 CDC, 2005b, Table 

2 

Average PbB - Women 20-59 All μg/dL 1.2 CDC, 2005b, Table 

2 

Average PbB - Women >60 All μg/dL 1.9 CDC, 2005b, Table 

2 

Average DBP - Men 45-54 All mm Hg 85 HHS, 1986, Table 

C 

Average DBP - Men 55-64 All mm Hg 85 HHS, 1986, Table 

C 

Average DBP - Men 65-74 All mm Hg 83 HHS, 1986, Table 

C 

Average DBP - Women 45-54 All mm Hg 82 HHS, 1986, Table 

C 

Average DBP - Women 55-64 All mm Hg 82 HHS, 1986, Table 

C 

Average DBP - Women 65-74 All mm Hg 82 HHS, 1986, Table 

C 

Economic Assumptions

Discount Rate All unit-less fraction 0.03 and 0.7% 

IQ cost per point lost All Dollars 12,953 Salkever, 1995 

Adult Value of Statistical Life All Dollars 6,980,000 EPA, 2000b 

Cost per case: hypertension - men All Dollars 14,613 

Cropper and 

Krupnick, 1990 

and Hartunian, 

1981 

Cost per case: hypertension women All Dollars 12,524 

Cropper and 

Krupnick, 1990 

and Hartunian, 

1981 

Cost per case: CHD - men 40-59 All Dollars 79,161 Wittels, 1990 

Cost per case: CHD - men 60-64 All Dollars 79,161 Wittels, 1990 

Cost per case: CHD - men 65-74 All Dollars 79,161 Wittels, 1990 

Cost per case: CHD - women All Dollars 79,161 Wittels, 1990 

Cost per case: stroke - men All Dollars 295,704 Taylor, 1996 

Cost per case: stroke - women All Dollars 221,777 Taylor, 1996 
402(c) Economic Analysis Chapter 5 42 

5.5.5 Uncertainties in Adult Benefit Estimates 

In the 1989 analysis of the health effects associated with lead exposure (US EPA, 1989), EPA concluded 

that there is a positive association between blood lead and increased blood pressure, as well as between 

blood lead and cognitive function as measured by intelligence quotient. Since then, new data have 

become available that are summarized in the 2005 external draft of the Air Criteria Document for Lead 

(US EPA, 2005c). The EPA draft document states that the data provide stronger evidence for a 

relationship between lead exposure and blood pressure for adults, and between lead exposure, IQ deficits 

and other neurobehavioral effects for children. The new data also provide more information on gender 

and race differences, and on the neurobehavioral effects of lead at lower blood lead levels. EPA believes 

that the newer data reduces the uncertainties in these health endpoints. EPA’s Science Advisory Board 

(SAB) plans to review these data in March 2006. EPA will revise the draft Air Criteria Document for 

Lead after the SAB peer review is completed. 

There is also some uncertainty associated with the calculations for cardiovascular effects and premature 

mortality. This analysis estimates these effects based on equations provided by Schwartz (1992), 

Shurtleff (1974), and McGee and Gordon (1976), and on blood pressure data from the 1976-1980 

NHANES. EPA (2005c) cites more recent studies that provide alternate equations. EPA plans to prepare 

an expanded risk assessment for the lead RRP rulemaking, and will explore the use of more recent 

equations and more recent NHANES data. The use of newer equations and data is expected to reduce 

some of the existing uncertainties. 

Quantitative Estimate of Benefits 

This analysis estimates the benefits of the proposed regulation in terms of IQ deficits in children and 

increased blood pressure and related health effects in adults. Quantitative estimates of benefits are 

provided in two scenarios. Scenario 1 quantifies benefits for both children and adults. Scenario 2 

quantifies benefits for children alone.14 This approach is in recognition of the relatively larger 

uncertainties associated with adult health effects, pending completion of the SAB review, as well as the 

particular concern about children expressed in Title X of the Residential Lead-Based Paint Hazard 

Reduction Act of 1992. The Agency is more confident in the estimates for children’s IQ effects then it is 

for the estimates of adult benefits. While recognizing that adults may also benefit from the training and 

practices required under the rule, Scenario 2 does not try to quantify these benefits due to the uncertainties 

that currently exist. 

5.5.6 Summary of Results 

The estimated benefits for this proposed rule are substantial, regardless of which scenario and which set 

of children’s blood-lead modeling assumptions are used. Benefits in the first year for Options B, C and D 

are somewhat lower than the benefits for Option A, due to the phasing in of coverage in Options B, C and 

D. Benefits are first presented in terms of number of cases of adverse health effects avoided and the 

number of IQ points gained, followed by the value of these benefits. 

 

14 Scenario 2 also assumes additional cleaning in the baseline, as discussed in Section 5.5.3. 
402(c) Economic Analysis Chapter 5 43 

The benefits displayed in Table 5-14 through Table 5-18 are annual benefits.15 They result from the 

avoided adverse health effects among adults and avoided reductions in IQ among children who are living 

in units where RRP events occur during a single year’s time. Because these benefits occur from avoiding 

exposure to lead from a single RRP event, and each year a new group of regulated RRP events occurs 

thus generating a new group of at-risk individuals potentially exposed, every year there will be benefits of 

approximately this magnitude.16

Table 5-14a and b show the number of cases of adverse health effects avoided and IQ points gained under 

each of the regulatory options, as calculated using Scenario 1 (Table 5-14a) and Scenario 2 (Table 5-14b). 

(Scenario 2 assumes additional contractor and household cleaning in the baseline, as described in Section 

5.5.3.) Due to the differences in assumptions about baseline levels of cleaning after RRP events, the 

number of cases is lower under Scenario 2 as compared to Scenario 1. Under Scenario 2, the number of 

cases of IQ points gained is from 78 to 88 percent of the equivalent number of IQ points gained under 

Scenario 1. Under either scenario, the number of IQ points gained varies widely depending on the bloodlead modeling assumptions used. Starting in Year 2, under Scenario 1, they range from the equivalent of 

76 to 429 thousand IQ points gained.17 Under Scenario 2, the estimate of the number of IQ points gained 

in Year 2 ranges from 62 to 350 thousand IQ points. 

 

15 Benefits for Option D are not displayed in the following tables because they are the same as those for Option B; 

Options B and D cover the same universe of households. 

16 As discussed in more detail in Chapter 4, the number of RRP events covered by the rule will decline slowly as 

the regulated housing stock declines due to demolitions. 

17 In all cases, these IQ points represent fractions of IQ points gained by a much larger population of children. 
402(c) Economic Analysis Chapter 5 44 

Table 5-14a: Total Cases of Avoided Adverse Adult Health Effects and Number of IQ Points Gained – Scenario 1 

Option A Option B Option C 

Year 1 Year 2 Year 1 Year 2 Year 1 Year 2 

 Exposure Mean Mean Mean Mean Mean Mean 

Adult Exposures -- Cases of Adverse Health Effects Avoided - Interior and Exterior 

Hypertension na 44,683 44,499 38,533 44,499 31,134 44,499 

CHD na 188 187 164 187 134 187 

Stroke na 43 42 37 42 30 42 

Premature Mortality na 285 284 249 284 203 284 

Child Exposure - IQ Points Gained (thousands) - Interior and Exterior 

 Children, age 1-2 years 

Using IEUBK model Peak 138 137 118 137 94 137 

For Interior Estimates 6-Year Average 76 76 66 76 52 76 

Using Empirical model Peak 94 94 81 94 64 94 

For Interior Estimates 6-Year Average 112 112 96 112 76 112 

 Children, age 0-5 years 

Using IEUBK model Peak 431 429 382 429 294 429 

For Interior Estimates 6-Year Average 218 217 187 217 150 217 

Based on post-rule compliance rate of 75%. 

Table 5-14b: Total Number of IQ Points Gained – Scenario 2 

Option A Option B Option C 

Year 1 Year 2 Year 1 Year 2 Year 1 Year 2 

 Exposure Mean Mean Mean Mean Mean Mean 

Child Exposure - IQ Points Gained (thousands) - Interior and Exterior 

 Children, age 1-2 years 

Using IEUBK Model Peak 108 109 93 109 74 109 

For interior estimates 6-Year Average 63 62 54 62 42 62 

Using Empirical Model Peak 83 83 71 83 57 83 

For Interior Estimates 6-Year Average 98 98 84 98 67 98 

 Children, age 0-5 years 

Using IEUBK Model Peak 352 350 301 350 240 350 

For interior estimates 6-Year Average 171 171 147 171 118 171 

Based on post-rule compliance rate of 75%. 

Scenario 2 assumes additional contractor and household cleaning in the baseline as described in Section 5.5.3. 
402(c) Economic Analysis Chapter 5 45 

Looking at first year benefits (either adults or children), Option A (which applies to all renter-occupied 

target housing units built before 1978 plus all owner-occupied target housing units built before 1978 if a 

child under the age of six resides there) provides the greatest benefits in terms of number of cases of adult 

adverse health effects avoided, regardless of which blood-lead assumptions and scenario is used. Under 

Option B (which applies to all renter-occupied target housing units built before 1960 plus all owneroccupied target housing units built before 1960 if a child under the age of six resides there and any pre1978 target housing units if a child under six with increased blood-lead resides there), first year benefits 

are about 14 percent smaller than first year benefits under Option A. Under Option C (which applies to 

all renter-occupied target housing units built before 1950 plus all owner-occupied target housing units 

built before 1950 if a child under the age of six resides there and any pre-1978 target housing units if a 

child under six with increased blood-lead resides there), first year benefits in terms of number of cases of 

avoided adverse adult health effects are about 30 percent smaller than first year benefits under Option A. 

These differences are attributable to the greater number of persons protected under Option A in the first 

year. These differences disappear in the second year when all three options cover the same housing units 

and thus the same number of people. 

Among the categories of adult benefits, by far the largest number of cases avoided is cases of 

hypertension. The next largest category of adult adverse health effects avoided is Premature Mortality. 

Stroke has the fewest number of cases avoided. These relative relationships between Scenarios 1 and 2 

are consistent across the adult health effect categories. 

The tables also show that estimating children’s IQ benefits using the IEUBK model yields somewhat 

higher results than the Empirical Model when considering peak exposures in 1-2 year olds; however, 

when considering the six-year average exposure, the Empirical Model yields a consistently higher 

estimate than IEUBK model. This result is likely due to the fact that the Empirical Model is based on 

data that describes the relationship between dust lead and blood lead in younger children (around the age 

of two). Using this model to characterize dust and blood lead averaged over the six-year period of ages 0 

through 5 assumes that the same behaviors exist and thus the same relationship between dust lead and 

blood lead exists in younger (up to approximately age two) and older children (ages two and over). In 

contrast, IEUBK model accounts for differences in behaviors in younger and older children (e.g., dust and 

soil ingestion rates are lower for children three and older) and yields age-specific blood-lead values for a 

given dust lead value. 

The highest benefits in terms of number of children’s IQ points are estimated using peak blood lead as the 

exposure metric, and attributing the same magnitude of neurological decrement associated with this peak 

to all children under the age of six years, regardless of the age at which exposure occurs. The lowest 

benefit in terms of number of children’s IQ points gained are derived using IEUBK model to estimate a 

six-year blood lead average for 1-2 year olds; however, this estimate almost certainly underestimates 

benefits because it assumes that there are no benefits in avoiding exposures to other age groups. 

As with the number of cases of adverse adult health effects avoided, the number of children’s IQ points 

gained in year 1 are highest for Option A and decline for Option B and decline still further for Option C. 

In the second year, the number of IQ points gained among children is approximately the same for all 

regulatory options. 

Table 5-15 presents the benefits in dollars. In terms of the value of the benefits of the proposed options; 

they closely track the total number of cases and number of IQ points. Scenario 1 has higher benefits, in 
402(c) Economic Analysis Chapter 5 46 

terms of dollar value, than Scenario 2; Option A first year benefits are greater than Option B first year 

benefits, which are greater than Option C first year benefits. Year 2 benefits are the same across all 

options within a scenario. Under Scenario 1 Option A, children’s IQ benefit estimates range from $0.99 

billion to $5.6 billion. For Scenario 2 the range of estimated values for Option A is from $0.81 billion to 

$4.6 billion. As with number of IQ points, the lowest value almost certainly underestimates benefits 

because it assumes that there are no benefits in avoiding exposures for children other than those age 1 to 2 

years. 

Year 2 adult benefits are approximately $2.4 billion under Scenario 1. Depending on the blood-lead 

modeling assumptions used, adult benefits make up 30 to70 percent of total benefits. While premature 

mortality account for only a few cases, they are the largest source of adult dollar benefits. 

Table 5-15a: Total Benefits of Avoided Exposures – Scenario 1 ($ millions) 

Option A Option B Option C 

Year 1 Year 2 Year 1 Year 2 Year 1 Year 2 

 Exposure Mean Mean Mean Mean Mean Mean 

Adult Exposure - Interior and Exterior 

Hypertension na $602 $599 $519 $599 $419 $599 

CHD na $13 $13 $12 $13 $10 $13 

Stroke na $11 $11 $9 $11 $8 $11 

Premature Mortality na $1,741 $1,734 $1,517 $1,734 $1,239 $1,734 

Total na $2,367 $2,357 $2,057 $2,357 $1,676 $2,357 

Child Exposure - Interior and Exterior 

 Children, age 1-2 years 

Using IEUBK Model Peak $1,783 $1,776 $1,526 $1,776 $1,220 $1,776 

for Interior Estimates 6-Year Average $990 $986 $849 $986 $668 $986 

Using Empirical Model Peak $1,222 $1,217 $1,047 $1,217 $833 $1,217 

for Interior Estimates 6-Year Average $1,455 $1,449 $1,247 $1,449 $989 $1,449 

 Children, age 0-5 years 

Using IEUBK Model Peak $5,583 $5,560 $4,945 $5,560 $3,810 $5,560 

for Interior Estimates 6-Year Average $2,828 $2,816 $2,419 $2,816 $1,945 $2,816 

Total Exposure - Interior and Exterior 

 Adult and Children (age 1-2 years) 

Using IEUBK Model Peak $4,150 $4,133 $3,583 $4,133 $2,896 $4,133 

for Interior Estimates 6-Year Average $3,357 $3,343 $2,906 $3,343 $2,344 $3,343 

Using Empirical Model Peak $3,589 $3,574 $3,104 $3,574 $2,509 $3,574 

For Interior Estimates 6-Year Average $3,822 $3,806 $3,304 $3,806 $2,664 $3,806 

 Adult and Children (age 0-5 years) 

Using IEUBK Model Peak $7,949 $7,917 $7,002 $7,917 $5,485 $7,917 

for Interior Estimates 6-Year Average $5,194 $5,173 $4,476 $5,173 $3,621 $5,173 

Based on post-rule compliance rate of 75%. 
402(c) Economic Analysis Chapter 5 47 

Table 5-16b: Total Benefits of Avoided Exposures – Scenario 2 ($ millions) 

Option A Option B Option C 

Year 1 Year 2 Year 1 Year 2 Year 1 Year 2 

 Exposure Mean Mean Mean Mean Mean Mean 

Child Exposure - Interior and Exterior 

 Children, age 1-2 years 

Using IEUBK Model Peak $1,403 $1,410 $1,201 $1,410 $959 $1,410 

or Interior Estimates 6-Year Average $810 $807 $695 $807 $545 $807 

Using Empirical Model Peak $1,075 $1,073 $921 $1,073 $733 $1,073 

For Interior Estimates 6-Year Average $1,274 $1,268 $1,091 $1,268 $865 $1,268 

 Children, age 0-5 years 

Using IEUBK Model Peak $4,555 $4,537 $3,901 $4,537 $3,105 $4,537 

or Interior Estimates 6-Year Average $2,220 $2,211 $1,899 $2,211 $1,526 $2,211 

Based on post-rule compliance rate of 75%. 

Scenario 2 assumes additional contractor and household cleaning in the baseline, as described in Section 5.5.3. 

The full range of monetized benefits from reducing lead exposure is shown in Table 5-16 for each 

analytic scenario and each regulatory option. In addition to the median values, this table presents the 5th

and 95th percentile values derived in the Monte Carlo analysis. The 5th and 95th percentile provide 

information on the range of the distribution of estimates by showing the benefit estimate below which are 

5 percent of the estimates (the 5th percentile) and above which are 5 percent of the estimates (the 95th 

percentile). For adult benefits, 95th percentile estimates are about 69-74 times higher than the 5th

percentile estimates. The range for children’s IQ benefits is even larger. These results reflect highly 

skewed distributions. In other words, the mean values are higher than the median values because there 

are a few very large values. This relationship holds for both Scenario 1 and 2. 
402(c) Economic Analysis Chapter 5 

Table 5-16a: Total Benefits for Adult and Child Exposure – Scenario 1 ($ billions) 

Option A Option B Option C 

Year 1 Year 2 Year 1 Year 2 Year 1 

 Percentiles Percentiles Percentiles Percentiles Perc

 Exposure Median 5th 95th Median 5th 95th Median 5th 95th Median 5th 95th Median 5th Adult Exposure - Interior and Exterior Total na $1.2 $2.16 $160.6 $1.2 $2.15 $160.0 $1.0 $1.868 $138.4 $1.2 $2.15 $160.0 $0.8 $1.4Child Exposure - Interior and Exterior 

 Children, age 1-2 years 

Using IEUBK Peak $0.7 $0.019 $4.0 $0.7 $0.019 $4.0 $0.6 $0.017 $3.4 $0.7 $0.019 $4.0 $0.5 $0.0Model 6-Year Average $0.4 $0.024 $2.6 $0.4 $0.024 $2.6 $0.3 $0.021 $2.2 $0.4 $0.024 $2.6 $0.3 $0.0Using Empirical Peak $1.2 $0.057 $2.8 $1.2 $0.057 $2.8 $1.1 $0.049 $2.4 $1.2 $0.057 $2.8 $0.9 $0.0Model 6-Year Average $1.2 $0.035 $4.1 $1.2 $0.035 $4.1 $1.1 $0.030 $3.5 $1.2 $0.035 $4.1 $0.9 $0.0

 Children, age 0-5 years 

Using IEUBK Peak $2.4 $0.073 $17 $2.4 $0.073 $17 $2.1 $0.063 $15 $2.4 $0.073 $17 $1.6 $0.0Model 6-Year Average $0.9 $0.0090 $6.9 $0.9 $0.0090 $6.9 $0.8 $0.0078 $5.9 $0.9 $0.0090 $6.9 $0.6 $0.0Total Exposure - Interior and Exterior 

 Adult and Children (age 1-2 years) 

Using IEUBK Peak $1.9 $2.18 $165 $1.9 $2.17 $164 $1.6 $1.885 $142 $1.9 $2.17 $164 $1.3 $1.4Model 6-Year Average $1.6 $2.18 $163 $1.6 $2.17 $163 $1.4 $1.89 $140.6 $1.6 $2.17 $163 $1.1 $1.4Using Empirical Peak $2.4 $2.21 $163 $2.4 $2.21 $163 $2.1 $1.92 $140.8 $2.4 $2.21 $163 $1.7 $1.Model 6-Year Average $2.4 $2.19 $165 $2.4 $2.18 $164 $2.1 $1.90 $142 $2.4 $2.18 $164 $1.7 $1.4

 Adult and Children (age 0-5 years) 

Using IEUBK Peak $3.6 $2.23 $178 $3.6 $2.22 $177 $3.1 $1.93 $153 $3.6 $2.22 $177 $2.5 $1.Model 6-Year Average $2.1 $2.17 $168 $2.1 $2.16 $167 $1.9 $1.88 $144 $2.1 $2.16 $167 $1.5 $1.4

Based on post-rule compliance rate of 75%.
402(c) Economic Analysis Chapter 5 

Table 5-16b: Total Benefits for Child Exposure – Scenario 2 ($ billions) 

Option A Option B Op

Year 1 Year 2 Year 1 Year 2 Year 1 

 Percentiles Percentiles Percentiles Percentiles Percentiles 

 Exposure Median 5th 95th Median 5th 95th Median 5th 95th Median 5th 95th Median 5th 95th 

Child Exposure - Interior and Exterior 

 Children, age 1-2 years 

Using IEUBK Peak $0.5 $0.017 $3.3 $0.5 $0.017 $3.3 $0.5 $0.015 $2.9 $0.5 $0.017 $3.3 $0.4 $0.011 $2.3 Model 6-Year Average $0.3 $0.022 $2.2 $0.3 $0.022 $2.2 $0.3 $0.019 $1.9 $0.3 $0.022 $2.2 $0.2 $0.014 $1.5 Using Empirical Peak $1.1 $0.033 $2.5 $1.1 $0.033 $2.5 $0.9 $0.029 $2.2 $1.1 $0.033 $2.5 $0.7 $0.022 $1.7 Model 6-Year Average $1.1 $0.027 $3.6 $1.1 $0.026 $3.6 $0.9 $0.023 $3.1 $1.1 $0.026 $3.6 $0.7 $0.017 $2.5 

 Children, age 0-5 years 

Using IEUBK Peak $2.4 $0.066 $14.3 $2.4 $0.066 $14.2 $2.1 $0.057 $12.2 $2.4 $0.066 $14.2 $1.6 $0.042 $9.7 Model 6-Year Average $0.9 $0.008 $5.7 $0.9 $0.008 $5.7 $0.8 $0.007 $4.9 $0.9 $0.008 $5.7 $0.6 $0.005 $3.9 Based on post-rule compliance rate of 75%. Scenario 2 assumes additional contractor and household cleaning in the baseline, as described in Section 5.5.3. 
402(c) Economic Analysis Chapter 5 50 

Another way to look at the benefits is in terms of what proportion is attributable to reductions in interior 

event exposures and what proportion is due to reductions in exterior event exposures. Table 5-17 presents 

the number of cases of adverse adult health events avoided, and the number of IQ points gained, due to 

the various regulatory options. The first table presents results for Scenario 1; the second presents 

Scenario 2. The majority of IQ points gained, under any option and either scenario, are due to reductions 

in interior event exposures. For adult adverse health effects, however, while the interior number is greater 

than the exterior number, the difference is smaller. In the case of hypertension, the number of cases 

avoided due to interior event reductions is only slightly greater than the number avoided due to exterior 

event reductions. For the other adult health effects, however, the number of interior cases avoided is 25 

to 30 percent greater than the number of exterior event cases. Table 5-19 presents the dollar values of 

these benefits. Again, the majority of the value of children’s IQ points gained is attributable to reductions 

in interior event exposures. For adult health effects, under all options and in any year, the benefits due to 

reductions in interior event exposures are somewhat greater than the value of benefits from reductions in 

exterior event exposures. 
402(c) Economic Analysis Chapter 5 

Table 5-17a: Total Cases of Avoided Adverse Adult Health Effects and Number of IQ Points Gained per Year – Scenario 1 

Option A Option B Op

Year 1 Year 2 Year 1 Year 2 Year 1 

 Exposure Mean Mean Mean Mean Mean  Interior Exterior Interior Exterior Interior Exterior Interior Exterior Interior ExterioAdult Exposures -- Cases of Adverse Health Effects Avoided Hypertension na 22,604 22,079 22,510 21,989 19,419 19,114 22,510 21,989 16,352 14,78CHD na 106 82 105 82 92 72 105 82 78 5Stroke na 25 18 24 18 21 16 24 18 18 1Premature Mortality na 160 125 159 125 140 109 159 125 118 8Child Exposure - IQ Points Gained (thousands)  Children, age 1-2 years Using IEUBK model Peak 121 17 120 17 104 14 120 17 83 1For Interior Estimates 

6-Year Average 51 25 50 26 44 22 50 26 35 1

Using Empirical model Peak 78 16 78 16 67 14 78 16 53 1For Interior Estimates 

6-Year Average 86 26 85 26 74 22 85 26 60 1

 Children, age 0-5 years Using IEUBK model Peak 361 70 359 70 322 60 359 70 249 4For Interior Estimates 6-Year Average 208 10 207 10 178 9 207 10 144 

Based on post-rule compliance rate of 75%. 
402(c) Economic Analysis Chapter 5 

Table 5-18b: Total Number of IQ Points Gained per Year – Scenario 2 

Option A Option B Opt

Year 1 Year 2 Year 1 Year 2 Year 1 

 Exposure Mean Mean Mean Mean Mean  Interior Exterior Interior Exterior Interior Exterior Interior Exterior Interior ExterioChild Exposure - IQ Points Gained (thousands)  Children, age 1-2 years Using IEUBK Model Peak 93 15 94 15 80 13 94 15 64 1For interior estimates 6-Year Average 39 24 39 23 34 20 39 23 27 1Using Empirical Model Peak 68 15 68 15 58 13 68 15 47 1For Interior Estimates 6-Year Average 75 23 75 23 64 20 75 23 52 1 Children, age 0-5 years 

Peak 288 64 286 64 246 55 286 64 198 4

Using IEUBK Model For interior estimates 

6-Year Average 162 9 162 9 139 8 162 9 112 

Based on post-rule compliance rate of 75%. Scenario 2 assumes additional contractor and household cleaning in the baseline as described in Section 5.5.3. 
402(c) Economic Analysis Chapter 5 

Table 5-19a: Total Benefits of Avoided Exposures per Year – Scenario 1 ($ millions) 

Option A Option B Opt

Year 1 Year 2 Year 1 Year 2 Year 1 

Exposure Mean Mean Mean Mean Mean 

 Interior Exterior Interior Exterior Interior Exterior Interior Exterior Interior Exterior Adult Exposure Hypertension na $304 $298 $303 $296 $261 $258 $303 $296 $220 $199 CHD na $7 $6 $7 $6 $7 $5 $7 $6 $6 $4 Stroke na $6 $5 $6 $5 $5 $4 $6 $5 $5 $3 Premature Mortality na $979 $762 $975 $759 $850 $667 $975 $759 $719 $520 Total na $1,297 $1,070 $1,292 1,065 $1,124 $933 $1,292 1,065 $949 $727 Child Exposure  Children, age 1-2 years Using IEUBK Model Peak $1,569 $214 $1,562 $214 $1,341 $185 $1,562 $214 $1,082 $138 for Interior Estimates 6-Year Average $657 $333 $655 $331 $562 $287 $655 $331 $454 $214 Using Empirical Model Peak $1,007 $215 $1,003 $214 $862 $185 $1,003 $214 $695 $138 for Interior Estimates 6-Year Average $1,122 $333 $1,118 $331 $960 $287 $1,118 $331 $775 $214  Children, age 0-5 years Using IEUBK Model Peak $4,675 $908 $4,656 $904 $4,166 $779 $4,656 $904 $3,226 $584 for Interior Estimates 6-Year Average $2,698 $130 $2,687 $129 $2,307 $112 $2,687 $129 $1,862 $83 

Based on post-rule compliance rate of 75%. 
402(c) Economic Analysis Chapter 5 

Table 5-20b: Total Benefits of Avoided Exposures per Year – Scenario 2 ($ millions) 

Option A Option B Opt

Year 1 Year 2 Year 1 Year 2 Year 1 

Exposure Mean Mean Mean Mean Mean 

 Interior Exterior Interior Exterior Interior Exterior Interior Exterior Interior Exterior Child Exposure  Children, age 1-2 years Using IEUBK Model Peak $1,206 $197 $1,213 $197 $1,031 $170 $1,213 $197 $832 $127 or Interior Estimates 6-Year Average $505 $305 $503 $304 $432 $263 $503 $304 $349 $196 Using Empirical Model Peak $878 $197 $880 $193 $751 $170 $880 $193 $606 $127 For Interior Estimates 6-Year Average $969 $305 $965 $303 $828 $263 $965 $303 $669 $196  Children, age 0-5 years Using IEUBK Model Peak $3,723 $832 $3,708 $829 $3,184 $717 $3,708 $829 $2,569 $536 For Interior Estimates 6-Year Average $2,101 $119 $2,093 $118 $1,797 $102 $2,093 $118 $1,450 $7

Based on post-rule compliance rate of 75%. Scenario 2 assumes additional contractor and household cleaning in the baseline, as described in Section 5.5.3. 
402(c) Economic Analysis Chapter 5 55 

Table 5-21 and Table 5-22 present total estimated benefits over a 50-year period and annualized benefits 

for both scenarios. Table 5-21 presents values calculated with a 3 percent discount rate and Table 5-22 

with a 7 percent discount rate. Because Year 1 is the only year in which there is a difference among the 

regulatory options in terms of in population covered and thus benefits, the annualized benefits are nearly 

the same across the options within a scenario. Using a 3 percent discount rate, Scenario 2 monetary 

benefits for children’s IQ point gained range from 75 to 88 percent of those gained under Scenario 1, 

depending on which blood-lead model and exposure assumptions are used. Using a 7 percent discount 

rate, the results are even closer, with the value of children’s IQ points gained ranging from 77 to 93 

percent of the value estimated under Scenario 1. 
402(c) Economic Analysis Chapter 5 

Table 5-21a: Total 50- Year and 50-Year Annualized Benefits for Adult and Child Exposure – Scenario 1 (3 Percent Discount Rate, $ bill

Option A Option B Op

Total 50-Year Benefit Annualized Benefit Total 50-Year Benefit Annualized Benefit Total 50-Year Benefit 

 Percentiles Percentiles Percentiles Percentiles Percentiles 

 Exposure Median 5th 95th Median 5th 95th Median 5th 95th Median 5th 95th Median 5th 95th 

Adult Exposure - Interior and Exterior Total Na $30 $53.1 $3,950 $1.2 $2.1 $154 $28 $52.8 $3,928 $1.1 $2.1 $153 29 $52.4 $3,90Child Exposure - Interior and Exterior 

 Children, age 1-2 years 

Using IEUBK Peak $17 $0.5 $99 $0.7 $0.0 $4 $17 $0.5 $98 $0.7 $0.0 $4 $17 $0.5 $97 Model 6-Year Average $10 $0.6 $63 $0.4 $0.0 $2 $10 $0.6 $63 $0.4 $0.0 $2 $10 $0.6 $62 Using Empirical Peak $31 $1.4 $70 $1.2 $0.1 $3 $30 $1.4 $69 $1.2 $0.1 $3 $30 $1.4 $69 Model 6-Year Average $31 $0.9 $101 $1.2 $0.0 $4 $31 $0.9 $100 $1.2 $0.0 $4 $30 $0.9 $99 

 Children, age 0-5 years 

Using IEUBK Peak $59 $1.8 $418 $2.3 $0.1 $16 $58 $1.8 $416 $2.3 $0.1 $16 $58 $1.8 $412 Model 6-Year Average $23 $0.2 $171 $0.9 $0.0 $7 $23 $0.2 $170 $0.9 $0.0 $7 $23 $0.2 $169 Total Exposure - Interior and Exterior 

 Adult and Children (age 1-2 years) 

Using IEUBK Peak $47 $53.5 $4,049 $1.8 $2.1 $157 $46 $53.2 $4,026 $1.8 $2.1 $156 $46 $52.8 $4,00Model 6-Year Average $40 $53.7 $4,013 $1.6 $2.1 $156 $39 $53.4 $3,991 $1.5 $2.1 $155 $39 $52.9 $3,96Using Empirical Peak $61 $54.5 $4,020 $2.4 $2.1 $156 $60 $54.2 $3,997 $2.3 $2.1 $155 $59 $53.7 $3,97Model 6-Year Average $61 $53.9 $4,051 $2.4 $2.1 $157 $60 $53.6 $4,028 $2.3 $2.1 $157 $59 $53.2 $4,00

 Adult and Children (age 0-5 years) 

Using IEUBK Peak $90 $54.9 $4,368 $3.5 $2.1 $170 $88 $54.6 $4,344 $3.4 $2.1 $169 $87 $54.1 $4,31Model 6-Year Average $4 $4.3 $330 $0.2 $0.2 $13 $4 $4.0 $306 $0.2 $0.2 $12 $4 $3.5 $280 Based on post-rule compliance rate of 75%. Scenario 2 assumes additional contractor and household cleaning in the baseline, as described in Section 5.5.3. 
402(c) Economic Analysis Chapter 5 

Table 5-21b: Total 50- Year and 50-Year Annualized Benefits for Child Exposure – Scenario 2 (3 Percent Discount Rate, $ billions) 

Option A Option B Op

Total 50-Year Benefit Annualized Benefit Total 50-Year Benefit Annualized Benefit Total 50-Year Benefit 

 Percentiles Percentiles Percentiles Percentiles Percentiles 

 Exposure Median 5th 95th Median 5th 95th Median 5th 95th Median 5th 95th Median 5th 95th 

Child Exposure - Interior and Exterior 

 Children, age 1-2 years 

Using Indoor Peak $14 $0.4 $82 $0.5 $0.0 $3 $13 $0.4 $82 $0.5 $0.0 $3 $13 $0.4 $81 IEUBK 6-Year Average $8 $0.5 $54 $0.3 $0.0 $2 $8 $0.5 $54 $0.3 $0.0 $2 $8 $0.5 $53 Using Indoor Peak $27 $0.8 $62 $1.0 $0.0 $2 $26 $0.8 $62 $1.0 $0.0 $2 $26 $0.8 $61 Empirical 6-Year Average $26 $0.7 $89 $1.0 $0.0 $3 $26 $0.6 $89 $1.0 $0.0 $3 $26 $0.6 $88 

 Children, age 0-5 years 

Using Indoor Peak $59 $1.6 $351 $2.3 $0.1 $14 $58 $1.6 $349 $2.3 $0.1 $14 $58 $1.6 $34IEUBK 6-Year Average $23 $0.2 $141 $0.9 $0.0 $5 $23 $0.2 $140 $0.9 $0.0 $5 $23 $0.2 $13Based on post-rule compliance rate of 75%. Scenario 2 assumes additional contractor and household cleaning in the baseline, as described in Section 5.5.3. 
402(c) Economic Analysis Chapter 5 

Table 5-22a: Total 50- Year and 50-Year Annualized Benefits for Adult and Child Exposure – Scenario 1 (7 Percent Discount Rate, $ bill

Option A Option B Op

Total 50-Year Benefit Annualized Benefit Total 50-Year Benefit Annualized Benefit Total 50-Year Benefit 

 Percentiles Percentiles Percentiles Percentiles Percentiles 

 Exposure Median 5th 95th Median 5th 95th Median 5th 95th Median 5th 95th Median 5th 95th 

Adult Exposure - Interior and Exterior Total Na $18 $30.3 $2,255 $1.3 $2.2 $163 $17 $30.0 $2,233 $1.2 $2.2 $162 $16 $29.6 $2,20Child Exposure - Interior and Exterior 

 Children, age 1-2 years 

Using Indoor Peak $10 $0.3 $56 $0.7 $0.0 $4 $10 $0.3 $56 $0.7 $0.0 $4 $9 $0.3 $55 IEUBK 6-Year Average $6 $0.3 $36 $0.4 $0.0 $3 $6 $0.3 $36 $0.4 $0.0 $3 $5 $0.3 $35 Using Indoor Peak $17 $0.8 $40 $1.3 $0.1 $3 $17 $0.8 $39 $1.3 $0.1 $3 $17 $0.8 $39 Empirical 6-Year Average $18 $0.5 $57 $1.3 $0.0 $4 $17 $0.5 $57 $1.3 $0.0 $4 $17 $0.5 $56 

 Children, age 0-5 years 

Using Indoor Peak $34 $1.0 $238 $2.4 $0.1 $17 $33 $1.0 $236 $2.4 $0.1 $17 $33 $1.0 $233 IEUBK 6-Year Average $13 $0.1 $98 $1.0 $0.0 $7 $13 $0.1 $97 $1.0 $0.0 $7 $13 $0.1 $95 Total Exposure - Interior and Exterior 

 Adult and Children (age 1-2 years) 

Using Indoor Peak $28 $30.6 $2,311 $2.0 $2.2 $167 $26 $30.3 $2,289 $1.9 $2.2 $166 $26 $29.8 $2,26IEUBK 6-Year Average $24 $30.6 $2,291 $1.7 $2.2 $166 $22 $30.3 $2,269 $1.6 $2.2 $164 $22 $29.9 $2,24Using Indoor Peak $36 $31.1 $2,295 $2.6 $2.3 $166 $34 $30.8 $2,272 $2.5 $2.2 $165 $34 $30.4 $2,24Empirical 6-Year Average $36 $30.8 $2,312 $2.6 $2.2 $168 $34 $30.5 $2,290 $2.5 $2.2 $166 $34 $30.1 $2,26

 Adult and Children (age 0-5 years) 

Using Indoor Peak $53 $31.3 $2,494 $3.9 $2.3 $181 $50 $31.0 $2,469 $3.6 $2.2 $179 $49 $30.6 $2,44IEUBK 6-Year Average $4 $4.2 $324 $0.3 $0.3 $23 $4 $3.9 $300 $0.3 $0.3 $22 $3 $3.5 $274 Based on post-rule compliance rate of 75%. Scenario 2 assumes additional contractor and household cleaning in the baseline, as described in Section 5.5.3.
402(c) Economic Analysis Chapter 5 

Table 5-22b: Total 50- Year and 50-Year Annualized Benefits for Child Exposure – Scenario 2 (7 Percent Discount Rate, $ billions) 

Option A Option B Op

Total 50-Year Benefit Annualized Benefit Total 50-Year Benefit Annualized Benefit Total 50-Year Benefit 

 Percentiles Percentiles Percentiles Percentiles Percentiles 

 Exposure Median 5th 95th Median 5th 95th Median 5th 95th Median 5th 95th Median 5th 95th 

Child Exposure - Interior and Exterior 

 Children, age 1-2 years 

Using Indoor Peak $8 $0.2 $47 $0.6 $0.0 $3 $8 $0.2 $47 $0.5 $0.0 $3 $7 $0.2 $46 IEUBK 6-Year Average $5 $0.3 $31 $0.3 $0.0 $2 $5 $0.3 $31 $0.3 $0.0 $2 $5 $0.3 $30 Using Indoor Peak $15 $0.5 $36 $1.1 $0.0 $3 $15 $0.5 $35 $1.1 $0.0 $3 $15 $0.5 $35 Empirical 6-Year Average $15 $0.4 $51 $1.1 $0.0 $4 $15 $0.4 $50 $1.1 $0.0 $4 $15 $0.4 $50 

 Children, age 0-5 years 

Using Indoor Peak $34 $0.9 $200 $2.4 $0.1 $15 $33 $0.9 $198 $2.4 $0.1 $14 $33 $0.9 $19IEUBK 6-Year Average $13 $0.1 $80 $1.0 $0.0 $6 $13 $0.1 $80 $1.0 $0.0 $6 $13 $0.1 $79 Based on post-rule compliance rate of 75%. Scenario 2 assumes additional contractor and household cleaning in the baseline, as described in Section 5.5.3.
402(c) Economic Analysis Chapter 5 60 

Table 5-23 summarizes the annualized benefit estimates presented in the prior tables. Using a 3 percent 

discount rate, children’s IQ benefits under Scenario 1 range from about $940 to $5,300 million; under 

Scenario 2 they range from about $700 to $4,300 million. Under Scenario 1, the adult benefits are 

estimated to be about $2,200 million, bring the sum of estimated adult and children’s benefits to a range 

of $3.2 to $7.6 billion. Using a 7 percent discount rate, all the annualized values are slightly higher than 

they are when a 3 percent discount rate is used. 

Table 5-23: Summary of the Range of Benefits Estimate, by Scenario 1 and Option, 

using 3 Percent and 7 Percent Discount Rates 

Scenario 1 Scenario 2

Children’s IQ 

Benefits – 

Annualized 

(millions 2005$)a 

Adult Health 

Benefits – 

Annualized 

(millions 2005$) a 

Sum of Children’s 

IQ and Adult 

Benefits -- 

Annualized 

(millions 2005$) 

Children’s IQ Benefits – 

Annualizeda 

(millions 2005$)

Annualized using 3 Percent Discount Rate 

Option A $947 - $5,336 $2,262 $3,209 - $7,599 $774 - $4,354 

Option B $941 - $5,311 $2,250 $3,191 - $7,562 $770 - $4,329 

Option C $934 - $5,267 $2,235 $3,170 - $7,503 $764 - $4,298 

Option D $941 - $5,311 $2,250 $3,191 - $7,562 $770 - $4,329 

Annualized using 7 Percent Discount Rate

Option A $1,008 - $5,680 $2,408 $3,415 - $8,087 $824 - $4,635 

Option B $997 - $5,633 $2,385 $3,383 - $8,019 $816 - $4,587 

Option C $984 - $5,551 $2,358 $3,342 - $7,909 $805 - $4,530 

Option D $997 - $5,633 $2,385 $3,383 - $8,019 $816 - $4,587 

a

 From Table 5-17 and Table 5-18 – range reflects alternative models for blood lead, exposure estimates and 

population of children 

As with the first year adult benefits, premature mortality contributes the largest amount to total annualized 

adult benefits, under both the 3 percent and the 7 percent discount rate. As can be seen in Table 5-24, the 

relative values of each of the adult health effects is relatively constant across the regulatory options. 

Table 5-24: Annualized Benefits from Adult Exposures Avoided - Interior and Exterior, 

by Adverse Health Effect Avoided – Scenario 1 ($ millions)

Option A Option B Option C 

3 Percent 7 percent 3 Percent 7 percent 3 Percent 7 percent 

 Exposure Mean Mean Mean Mean Mean Mean 

Hypertension na $575 $612 $572 $606 $568 $599 

CHD na $13 $14 $13 $14 $13 $13 

Stroke na $10 $11 $10 $11 $10 $11 

Premature 

Mortality na $1,664 $1,771 $1,655 $1,755 $1,645 $1,735 

Based on post-rule compliance rate of 75%. 

As shown above, regardless of which scenario is considered, the estimated benefits are substantial. In 

addition, in both scenarios a number of benefit categories have been excluded from the estimated benefits. 

Among the categories of benefits excluded from either scenario are: 
402(c) Economic Analysis Chapter 5 61 

• Other health and developmental effects for which there were not adequate data to develop a doseresponse curve, and thus a benefits estimate, 

• Benefits that accrue to much of the exposed population (e.g., teenagers, adults younger than 40 

years old, exposed individuals that do not live in the housing units with RRP events), 

• Adverse effects on plants and animals, and 

• Willingness-to-pay values – values based on medical costs and lost income are used instead. 
402(c) Economic Analysis Chapter 5 62 

Appendix 5A: Lead-Related Health Effects and Ecological Effects 

Most of this appendix consists of two chapters from the First External Review draft of EPA’s 2005 Air 

Quality Criteria Document (AQCD) for Lead. The chapters that are reproduced here are Chapter 5, 

“Toxicological Effects of Lead in Laboratory Animals, Humans, and in Vitro Test Systems” and Chapter 

6, “Epidemiologic Studies of Human Health Effects Associated with Lead Exposure.” This is followed 

by a summary of the ecological effects from renovation, repair, and painting activities involving leadbased paint. 

5A.1 Health Effects to Children and Adults, Excerpted from Chapters 5 and 6 of the First 

External Review Draft of EPA’s Air Quality Criteria Document for Lead 

The Clean Air Act mandates periodic review of the National Ambient Air Quality Standards (NAAQS) 

for six common air pollutants, including lead, referred to as criteria pollutants. Under the review process, 

EPA's Office of Research and Development develops a "criteria document" -- a compilation and 

evaluation by U.S. EPA scientific staff and other expert authors of the latest scientific knowledge useful 

in assessing the health and welfare effects of the air pollutant. In this case, the Lead Criteria Document 

presents the latest available pertinent information on atmospheric science, air quality, exposure, 

dosimetry, health effects, and environmental effects of lead. In developing criteria documents, EPA must 

consider the advice of its Clean Air Scientific Advisory Committee (CASAC). 

The following is a brief history of the development of the Air Quality Criteria Document for Lead. 

• 2004 - EPA begins the mandated periodic revision of the Lead Criteria Document. 

• 2005 - CASAC and the public review and comment on the Project Work Plan for the document. 

• 2005 - EPA conducts peer consultative workshops in August 2005. 

• 2005 - EPA releases the first external review draft of the Lead Criteria Document 

The AQCD was released for public comment and for review by CASAC in a Federal Register notice on 

December 2, 2005 (70 FR 72300). Comments were due by February 15, 2006 in order to be considered 

by CASAC during their review. 

CASAC will hold a public meeting to review the second external review draft of the Air Quality Criteria 

Document for Lead in March 2006. A Federal Register Notice will announce the date of the meeting and 

its location. EPA will then review their feedback and recommendations with plans to publish the second 

external review draft by May 2006. EPA intends to reflect revisions to the AQCD in the economic 

analysis for the final lead RRP rule. 

The full text for the draft AQCD is available at http://cfpub2.epa.gov/ncea/cfm/recordisplay.cfm?deid=141779

The docket for the external review of the draft AQCD is available at the Regulations.gov Web site under 

docket ID ORD-2005-0018. 
1 5. TOXICOLOGICAL EFFECTS OF LEAD IN 

2 LABORATORY ANIMALS, HUMANS, AND IN VITRO 

3 TEST SYSTEMS 

4 

5 5.1 INTRODUCTION 

6 As noted in Chapter 1, air quality criteria documents evaluate scientific knowledge of 

7 relationships between pollutant concentrations and their effects on the environment and public 

8 health. Chapters 2 and 3 of this document discussed the chemistry and physical properties of 

9 lead (Pb); sources, emissions, transport, and deposition of Pb; and environmental concentrations 

10 and pathways to human exposure. Chapter 4 discussed models of human exposure that predict 

11 tissue distribution of lead. This chapter (Chapter 5) assesses information regarding the 

12 toxicological effects of Pb in laboratory animals, humans, and in vitro test systems. Emphasis is 

13 placed here on qualitative characterization of various Pb-induced effects, with attempts to define 

14 dose-effect relationships for the key health effects that are thought to occur at ambient exposure 

15 levels encountered by the general population of the United States. Chapter 6 follows with a 

16 discussion of epidemiologic studies of ambient Pb-exposure effects. Chapter 7 provides an 

17 integrative synthesis of information on Pb exposures and health effects. The environmental 

18 effects of Pb are discussed in Chapter 8. 

19 The framework used here for presenting the toxicologic effects of Pb is subdivided mainly 

20 according to organ systems. As noted in the 1986 Pb AQCD, this facilitates presentation of the 

21 information, but it must be stressed that all systems are interdependent, functioning in delicate 

22 concert to preserve the physiological integrity of the whole organism. 

23 The information discussed in this chapter is derived from a very wide body of literature on 

24 studies in humans, laboratory animals, and in vitro test systems of animal cell lines and organ 

25 systems that may mimic responses in intact animals. This chapter is not intended to be a 

26 compendium of all that is known about lead; rather, it is an update of the reported biological 

27 effects from the last previous Pb AQCD (U.S. Environmental Protection Agency, 1986), the 

28 Addendum to that document (Lead Effects on Cardiovascular Function, Early Development, and 

29 Stature) (U.S. Environmental Protection Agency, 1986), and the Supplement to the 1986 

30 Addendum (U.S. Environmental Protection Agency, 1990). The historical Pb literature is briefly 

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summarized at the opening of each section or subsection and is intended as a very concise 

overview of previous work The reader should refer to the previous documents listed above for 

more detailed discussion of the literature prior to the late 1980s. Each section then continues 

with brief discussions of key studies published since 1986. Longer discussions of the newly 

available studies are included where warranted. Sections are ended with comparisons of data 

from the 1986 AQCD with new data, and basic conclusions are drawn. More detailed summaries 

of newly available studies and results are provided in tables in Annex AX5. 

5.2 EFFECTS OF LEAD ON HEME SYNTHESIS 

5.2.1 Effects of Lead on Erythrocyte Biology and Function 

Lead poisoning is one of the most common acquired environmental diseases, because of 

physical properties of the metal and its widespread distribution in the environment. It is a 

complex disorder affecting several organs in the body, including developing erythrocytes (red 

blood cells [RBCs]). Anemia is frequently observed with Pb poisoning and is thought to result 

from the shortening of erythrocyte life span and is also due to the effects of Pb on hemoglobin 

synthesis. However, the exact mechanisms by which Pb affects the red blood cell (RBC) life 

span and heme synthesis are not clear. It is postulated that the mechanisms may be due to the 

effects of Pb on iron uptake; Pb poisoning also causes an increased urinary excretion of 

porphyrins and 5-aminolevulinic acid (ALA), the first precursor for heme synthesis. In addition, 

the striking similarities between Pb poisoning and acute intermittent porphyria (the disease 

associated with lesions in the heme biosynthetic enzyme, porphobilinogen deaminase) strongly 

suggests that one of the major sites of Pb intoxication is the heme biosynthetic pathway. 

The 1986 Pb AQCD presented a concise summary of literature available at that time from 

both animal and human studies indicating potential effects of Pb intoxication on enzymes and 

precursors involved in heme synthesis, erythrocyte morphology and function as well as the 

influence of these perturbations on the nervous system and vitamin D metabolism and associated 

physiological process. In summary, these studies reported an association between increased Pb 

exposure and increased ALA-S activity (which is increased in kidney with acute exposure and in 

spleen with chronic exposure, while it decreased in liver tissue in both the exposure scenarios). 

The activity of ALA-D appeared to be inversely correlated to blood Pb values and was found to 

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be inhibited in several tissues. It was also inferred from several animal studies that the effect of 

Pb on heme formation involved both ferrochelatase inhibition and impaired mitochondrial 

transport of iron. Human studies indicated that occupational exposure to Pb results in decreased 

erythrocyte cell survival and alterations in erythrocyte membrane integrity and energetics. The 

vast scientific literature on the effects of Pb on various aspects of heme metabolism in diverse 

organ systems both in human and animals has accumulated over the past two decades. 

Recognizing the magnitude of this literature, this chapter is primarily concerned with discussions 

of data from animal and in vitro studies, while the human studies are dealt with in Chapter 6. 

5.2.2 Effects of Lead on Erythrocyte Functions 

The cellular membrane is one of the main targets for toxic effects of heavy metals, 

including Pb. Anemia, one of the clinical symptoms of Pb intoxication, can develop because of 

impairment of hemoglobin synthesis and damage of erythrocyte membranes by Pb ions. 

Although, erythrocyte membrane is not as specialized as other cell membranes are, it carries out 

important functions common to other cell membranes, such as active and passive transport and 

the production of ionic and electric gradients. Changes in erythrocyte membrane lipid and 

protein profiles can alter the membrane fluidity, potentially affecting enzymatic activity and the 

functionality of receptors and ion channels present on the plasma membrane and also can 

influence the ionic and molecular composition of intracellular spaces. 

Lead Uptake, Binding, and Transport 

Studies by Simons (1986a) indicated that the uptake of Pb into human RBCs is a passive 

process, i.e., it does not require the use of energy in the form of ATP. In addition, Pb may be 

able to cross the membrane passively in either direction. This process involves anion transport 

mechanisms, as the characteristic anion exchange inhibitors have been found to inhibit the 

passive uptake of Pb by RBCs (Simons, 1986a,b). It has also been demonstrated that the 

transport of Pb across the membrane depends on the presence of another anion, the bicarbonate 

ion, and is transported as Pb-carbonate (Simons, 1986a). When Pb enters the cell, it binds 

mainly to hemoglobin, and the ratio of bound to free Pb in cytoplasm has been estimated to be 

6000:1. Simons (1986a,b) carried out studies using citrate buffers, which may cause hemolysis 

of RBCs. To avoid the influence of a citrate buffer, Sugawara et al. (1990) measured the uptake 

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of Pb into human RBCs by adding Pb directly into plasma. These investigators also found that 

the transport of Pb across the erythrocyte membrane is energy-independent (passive) and carrier 

mediated. Little release of Pb from the cells was observed, suggesting absence of any hemolysis 

of the cells in this protocol. Furthermore, the progressive accumulation of Pb was not observed. 

More than 98% of the Pb was found accumulated in the cytoplasm in protein-bound form, while 

only 2% was found in the membrane fraction. Sugawara et al. (1990) also reported finding 

45 Pb-binding sites on human hemoglobin. On the other hand, studies reported by Bergdahl 

et al. (1997) using liquid chromatography coupled with inductive plasma mass spectrometry 

analysis suggested aminolevulinic acid dehydratase (ALAD), the enzyme involved in the heme 

synthesis pathway, to be the principle Pb-binding protein, not hemoglobin, as previously thought. 

Additional studies carried out by Simons (1993a) evaluated the transport of Pb into RBCs 

for cell Pb contents in the range of 1 to 10 μM and reported that 203Pb uptake was mediated by an 

anion exchanger and the efflux was mediated through a vanadate-sensitive pathway identified 

with the calcium pump (Simons, 1988). He further concluded that the high ratio of RBC to 

plasma Pb observed in vivo was due to a labile Pb-binding component within the cytoplasm. 

Simons (1993a) also observed that exit of Pb ions from the RBC was much lower than expected 

based on his earlier work with erythrocyte ghosts. Utilizing a group of drugs that modify anion 

exchange and thiol groups in the cytoplasm, Lal et al. (1996) showed that anion exchange 

mechanisms and thiol groups were critical factors in how Pb stimulates calcium-dependent 

processes in erythrocytes. Once the role of anion exchanger proteins had been implicated in Pb 

transport in erythrocytes, Bannon et al. (2000) investigated whether similar anion exchange 

processes are involved in the uptake and transport of Pb in other cells, such as Madin-Darby 

canine kidney epithelial cells. Based on a comparative in vitro study using human erythrocytes 

and canine kidney epithelial cells, these authors reported transport of Pb in kidney epithelial 

cells, suggesting similar anion exchange involvement. 

Erythrocyte Survival, Mobility, and Membrane Integrity 

It is well recognized that Pb intoxication interferes with RBC survival by shortening the 

life span and altering the mobility of the erythrocytes; however, the molecular mechanisms 

behind these effects of Pb on erythrocyte functions are not well understood. The shape and 

deformability of the human erythrocyte, or RBC is maintained by several factors including low 

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concentration of free intracellular Ca2+ (<0.1 μM) and a replenished ATP level. An elevated 

interfacial Ca2+ concentration inside the RBC activates the passive ion efflux via a K+

 selective 

(voltage independent ) channel and a concomitant water transport (Gordos effect). Low 

concentrations of Pb ions can mimic Ca2+ and activate the same channel in the RBC. 

Intraperitonially injected Pb significantly decreases rat erythrocyte membrane mobility 

(Terayama et al., 1986), an effect evident to some extent even below blood Pb concentration of 

100 μg/100 ml. This decrease in rat erythrocyte mobility was found simultaneous or prior to 

changes in hematological parameters such as hemoglobin (Hb) levels and hematocrits (Hct). The 

same group (Terayama and Muratsugu, 1988) also reported a significant decrease in erythrocyte 

membrane sialic acid content at the same levels of blood Pb with exposure to Pb (20 mM 

Pb-acetate once a week for 5 weeks). Additional studies by the same group reported that other 

hematological parameters, such as mean corpuscular volume (MCV), mean corpuscular 

hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC), were also 

significantly decreased upon Pb exposure, along with decreased mobility, sialic acid content, and 

deformability of rat RBCs. It was speculated that Pb-induced decreases in sialic acid content and 

deformability of RBCs shorten RBC survival time and may lead to anemia in Pb poisoning. 

Jehan and Motlag (1995) reported Pb exposure caused significant change in RBC membrane 

cholesterol and phospholipid contents along with sialic acid. Coexposure to Zn was found to 

reduce these alterations. 

Pb-induced morphological changes in human RBC were studied by Eriksson and Bering 

(1993) using electron paramagnetic resonance imaging. These authors reported that Pb ions 

(a) induced time-dependent changes in MCV and cell shrinkage and (b) inhibited the Gardos 

effect. Trialkyl-Pb compounds have also been reported to induce hemolytic activity in 

erythrocytes, with intensity increasing with hydrophobicity of the compounds (Kleszcynska 

et al., 1997). Serrani et al. (1997) reported that Pb ions confer protection against RBC lysis in 

hypotonic low ionic strength media, presumably be due to interaction of Pb with certain 

constituents in the cell membrane. This resistance to erythrocyte lysis was found to significantly 

increase with Pb (20 to 25 μM) compared to other metals such as Al, Cd, and Zn (Corchs et al., 

2001). The Pb-induced reduction in MCV (RBCs derived from umbilical cord) was found to be 

reversed when the cells were treated with quinidine, an inhibitor of a potassium channel 

activator, without any effect on resistance to cell lysis, suggesting changes in cell membrane 

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structure. This effect may also be involved in membrane deformability (Mojzis and Nistiar, 

2001). 

Heavy metals, including Cd, Zn, and Pb, have been found to alter RBC membrane 

microviscosity and fluidity (Amoruso et al., 1987). These authors labeled RBC membranes with 

fluorescent lipid probe all trans 1, 6-diphenyl-1,3,5-hexatriene (DPH) and demonstrated 

increased polarization with increased membrane lipid viscosity on exposure to heavy metals. 

They also postulated that such alterations in cell membrane lipid and possibly also protein 

fluidity may contribute to abnormal cellular function. Similar changes in RBC fluidity were 

observed in the RBC collected from workers exposed to Pb (Cook et al., 1987). The RBC ghost 

membranes isolated from Pb- exposed workers exhibited a significant increase in 

phosphotidylcholine to phosphotidylethanolamine ratio (an established correlate of membrane 

fluidity) along with an increase in RBC cholesterol levels, as also reported by Jehan and Motlag 

(1995) discussed above. These authors predict that such alterations in phospholipid composition 

of the membrane are responsible in biochemical instability of RBC in Pb-exposed workers. 

Zimmermann et al. (1993) investigated the potential of such membrane lipid alterations to cause 

resistance to oxidation. These authors induced hyperlipidemia by treating Pb-exposed Wistar 

rats with triton. They observed an increase in erythrocyte choline phospholipid levels together 

with a significant decrease in membrane lipid resistance to oxidation. These authors postulated 

that such a decrease in resistance might cause RBC fragility, and ultimate destruction, leading to 

anemic conditions. It has been also reported that exposure to Pb may also increase the levels of 

fatty acids, e.g., arachidonic acid, in the RBC membrane in humans exposed to Pb (Osterode and 

Ulberth, 2000). Based on the negative correlation between serum calcium and increased 

arachidonic acid content, these authors postulated that Pb ions might have substituted for calcium 

in the activation of phospholipase enzymes, leading to increased synthesis of arachidonic acid. 

Suwalsky et al. (2003) investigated the interaction of Pb with the RBC membrane, utilizing intact 

as well as isolated unsealed RBC membrane models (representing phospholipids present in the 

inner and outer layers of the membrane). Electron microscopy, fluorescence spectroscopy, and 

X-ray diffraction analyses of these models by the authors indicated that Pb particles adhere to 

both external and internal surfaces of the membrane. Pb ions also have been found to disturb the 

lamellar organization by causing considerable molecular disorder within lipid layers. 

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Recently, it has been shown that osmotic shock, oxidative stress, and/or energy depletion 

activate Ca2+-sensitive erythrocyte scramblase, leading to the exposure of phosphotidylserine at 

the cell surface. This exposure of phosphotidylserine had been implicated in the phagocytosis of 

RBC by macrophages that can be measured by annexin binding, as determined by fluorescence 

activated cell sorting analysis. Kempe et al. (2005) carried out experiments to investigate 

whether anemic conditions reported in Pb intoxication are the result of the decreased life span of 

RBCs due to the above mentioned mechanisms. These authors reported that when human RBCs 

were exposed to Pb-nitrate (above 0.3 μM), it caused a significant increase in Pb annexin 

binding, indicative of phosphotidylserine exposure. Using inhibitors for Ca2+- sensitive 

potassium channels and whole cell patch clamp experiments, these authors concluded that Pb 

exposure increased activation of potassium channels, leading to shrinkage of cells and also 

activation of scramblase, resulting in the exposure of phosphotidylserine on the cell membrane 

surface. These authors further postulated that this exposure of phosphotidylserine on the 

membrane might have led to them being engulfed by macrophages and the ultimately decreased 

life span of RBCs in Pb intoxication. 

Membrane Proteins 

Earlier studies by Fukumoto et al. (1983) reported the differential profile for RBCmembrane polypeptides determined by SDS-PAGE analysis. These investigators found 

decreased levels of polypeptides in band 3 and increases in the levels of four other bands (i.e., 

bands 2, 4, 6, and 7) in the RBCs of human workers exposed to Pb. From these observations, 

they postulated that such Pb-induced alteration in RBC membrane proteins may lead to 

membrane permeability changes. Apostoli et al. (1988) also observed similar changes in RBC 

membrane polypeptides in Pb-exposed workers and suggested that band 3 may represent an 

anion channel protein; they also found that these changes occurred at blood Pb levels of 

>50 μg/100 ml. 

Lead exposure has been known to increase the amount of membrane-bound protein 

kinase C in rat brain, endothelial, and glial cells. Belloni-Olivi et al. (1996) reported an 

increased phosphorylation of RBC membrane proteins on Pb exposure. When human RBCs 

were incubated with Pb-acetate (>100 nM) for 60 min, it was found to increase phosphorylation 

of membrane cytoskeletal proteins (120, 80, 52 and 45 kDa). This increase was accompanied by 

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increase in protein kinase C activity. Membrane proteins were not phosphorylated when treated 

with protein kinase C inhibitors. Calcium and diacylglycerol were found not to be involved in 

this process. The authors suggested that this activation of protein kinase was a direct interaction 

of the enzyme protein with Pb. Slobozhanina et al. (2005) reported that incubation of human 

RBCs with Pb-acetate (1 to 10 μM for 3 h) caused differential binding of fluorescent probes to 

the membrane, suggesting alterations in the physicochemical state of the membrane proteins and 

lipids. Based on these observations, the authors postulated that such alterations in membrane 

molecular composition may influence the activity of membrane enzymes and function of 

receptors and channels present on the membrane. These and other related studies are 

summarized in Annex Table AX5-2.1. 

5.2.3 Effect of Lead on Erythrocyte Heme Metabolism 

Enzyme studies of the heme pathway have shown that Pb is an inhibitor of several 

enzymes involved in heme synthesis, including 5-aminolevulinic acid dehydratase (ALAD), 

coproporphyrinogen oxidase, and ferro chelatase (see Figure 5-2.1 for a schematic representation 

of heme biosynthesis). ALAD is a cytoplasmic enzyme that catalyzes the second, rate-limiting 

step of the heme biosynthesis pathway; that is, ALAD catalyzes formation of porphobilinogen 

through the conjugation of two molecules of δ-aminolevulinic acid. ALAD is a Zn-dependent 

enzyme, and thiol groups are essential for its activity (Bernard and Lauwerys, 1987). Decreased 

erythrocyte ALAD is the most sensitive indicator of human Pb exposure, to the extent that 

measurement of ALAD activity reflects well Pb levels in the blood. Similarly, erythrocyte 

ALAD activity measurements have been used to assess Pb toxicity in other species. 

Erythrocyte ALAD 

Terayama et al. (1986) reported decreased ALAD activity in rat RBCs at blood Pb levels of 

100 μg/100 mL. Scheuhammer (1987) studied the usefulness of the ALAD ratio 

(activated/nonactivated enzyme activity) to study Pb effects in avian RBCs. The ALAD activity 

ratio is a sensitive, dose responsive measure of Pb exposure regardless of the mode of 

administration of Pb. For example, dietary Pb concentrations as low as 5 ppm (dry weight) can 

be estimated through the use of the ALAD enzyme activity ratio method. A highly significant 

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402(c) Economic Analysis Chapter 5 70
Figure 5-2.1. Schematic presentation of heme synthesis pathway. Potential lead (Pb) 

interacting sites are indicated by curved arrows (8 increased, 9 decreased). 

1 positive correlation was observed between dietary Pb concentration over the 5 to 100 ppm range 

2 and the ALAD activity ratio. The author concluded that RBC ALAD ratio may be a useful 

3 method for estimating average dietary concentrations of Pb over an environmentally relevant 

4 range, in situations where diet is the major source of exposure to Pb or where accurate 

5 estimations of dietary Pb are not possible. Redig et al. (1991) reported heme synthetic pathway 

6 alterations upon chronic exposure (3 or 11 weeks) to Pb in red-tailed hawks. This treatment 

7 resulted in a severe decrease in RBC ALAD activity, which did not return to normal levels until 

8 5 weeks after termination of Pb treatment. Lead exposure also decreased ALAD activity in the 

9 bone marrow and in the liver but did not alter aminolevulinic acid synthase activity. Dorward 

10 and Yagminas (1994), using comparative enzyme kinetic analysis of ALAD in Pb-exposed 

11 female cynomolgus monkeys and human erythrocyte ALAD, found similar inhibition profiles 

12 and concluded that ALAD could be a useful model for measuring the biological response in 

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monkeys. Santos et al. (1999) reported that rat RBC heme biosynthesis was affected by either Pb 

treatment alone or Pb in combination with ethanol, due to the inhibition of ALAD activity. 

Analysis of blood ALAD activity had been used as a powerful clinical biomarker in 

evaluating Pb toxicity in occupational exposure. Fontanellas et al. (2002) further suggested that 

this enzyme assay be used in identifying even subclinical Pb poisoning in chronic renal failure 

(see Section 5.7 for details). 

Other Heme Metabolism Enzymes 

Taketani et al. (1985) studied the heme synthesizing activity of ferric ion using purified 

ferrochelatase from rat liver mitochondria and reported that Pb reduced NAD(P)H-dependent 

heme synthesis by 50% at 10!5 M, but that it had no effect when ferrous ion was used as the 

substrate. Based on these results, the authors concluded that heme synthesis from ferric ion was 

more susceptible to Pb than the ferrous ion. These studies also revealed that the NAD(P)H 

oxidizing system reduces ferric ion to ferrous ion, which in turn was used for heme synthesis by 

ferrochelatase. 

The effect of various metals, including Pb, on RBC porphobilinogen synthase (PBG-S) 

was studied using human RBC hemolysate. Farant and Wigfield (1987) reported that the effect 

on the enzyme depends on the affinity of the metal for thiol groups at its active sites. Additional 

studies carried out by the same group utilizing rabbit erythrocyte PBG-S indicated that Pb acts as 

a potent effector of this enzyme both in vitro and in vivo (Farant and Wigfield, 1990). Human 

RBC porphobilinogen synthetase activity was found to be inhibited by Pb, while Zn ions 

activated this enzyme (Simons, 1995). Another enzyme involved in the heme synthetic pathway, 

porphobilinogen deaminase, was inhibited in human RBC by Pb-nitrate (100 mM) in in vitro 

studies, but had no effect in vivo (Tomokuni and Ichiba, 1990). Rossi et al. (1992) reported no 

inhibition of coproporphyrinogen oxidase activity in human lymphocytes on exposure to Pb. 

Heme synthesis can also be affected in Pb intoxication by interference with Fe transport into 

reticulocytes. Using a rabbit reticulocyte model, Qian and Morgan (1990) reported that 

inhibitory effects of Pb on transferrin endocytosis and iron transport across the membrane may 

also contribute to altered heme metabolism in RBCs. These and other related studies are 

summarized in Annex Tables AX5-2.2 and 5-2.3. 

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5.2.4 Effect of Lead on Other Hematological Parameters 

The RBC pyrimidine 5-nucleotidase (P5N) catalysis of the hydrolytic dephosphorylation 

of pyrimidine 5-monophosphates is sensitive to inhibition by Pb. Tomokuni et al. (1989) 

evaluated the activity of RBC and bone marrow 5-nucleotidase (P5N) and RBC ALAD in mice 

exposed to drinking water Pb (200 to 500 ppm) for 14 or 30 days. These authors reported that Pb 

exposure decreased both P5N and ALAD activities in erythrocytes. Additional studies from this 

group, using a similar exposure regimen, indicated no change in levels of urinary coporphyrins. 

Lead exposure (4 mg/kg and 6 mg/Kg body wt/30 days) in splenectomized rats was found 

to cause depletion of RBC Hb content, to increase numbers of reticulocytes in peripheral blood, 

and to increase urinary delta aminolevulinic acid excretion (Gautam and Chowdhury, 1987). 

These authors further reported that the increased number of reticulocytes found in the blood may 

be due to induced acceleration of the erythropoeitic cell series. Redig et al. (1991) reported 

biphasic effects of Pb on hematological parameters from their chronic exposure studies in redtailed hawks over 3 or 11 weeks. These authors observed a rapid and relatively brief increase in 

RBC free protoporphyrin and a slower, but more prolonged, increase in its Zn complex with 

3-week exposure to Pb (0.82 mg/kg body wt). On the other hand, exposure to a higher dose of 

Pb (1.64 mg/kg body wt) for a longer duration (11 weeks) resulted in a decrease in the Hct and 

Hb. Panemangalore and Bebe (1996) reported that Zn deficiency increased the Pb-induced 

accumulation of porphyrin in RBCs to a lesser extent compared to its accumulation in the liver in 

weaning rats. 

The effects of Pb on RBC number and other Hct parameters appear to be dose dependent. 

Iavicoli et al. (2003) investigated these effects by feeding mice with eight different doses of Pb 

below (0.6 to <2.0 μg/dL) and above (>2.0 to13 μg/dL) normal background levels. These 

authors reported that mice receiving below normal background levels of dietary Pb displayed 

enhanced RBC counts and increased Hb and Hct values, whereas a marked decrease in RBC 

number occurred when blood Pb levels approached 10 μg/dL. Sivaprasad et al. (2003) also 

reported significant reductions in RBC Hb content and Hct on Pb exposure (0.02% Pb-acetate in 

drinking water for 5 weeks). Toplan et al. (2004) observed significant decreases in RBC Hb 

content and Hct and increases in blood viscosity in Wistar rats after 5-week exposure to Pb. 

Studies cited above are summarized in Annex Table AX5-2.4. 

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5.2.5 Effects of Lead on Erythrocyte Enzymes 

The toxic effects of Pb on RBCs result from its complexation with the sulfhydryl, 

carboxyl, and imidazole groups of proteins, particularly enzymes, by competitive binding of Pb2+ 

with Zn2+ or Mg2+ in metalloenzymes. This binding of Pb to enzyme proteins can inhibit 

enzymes involved in the glycolytic and pentose phosphate pathway, both of which are sources of 

energy compounds and intermediates of purine conversion, thus causing a disruption of energy 

metabolism. Along with these changes, Pb-induced changes in the membrane integrity, as 

discussed earlier (Section 5.2.1), may also affect the enzymes’ associated ion channels and other 

transport mechanisms. 

Energy Metabolism 

Erythrocytes generate high-energy ATP by anerobic glycolysis and cycle oxidized and 

reduced nicotinamide adenine nucleotide phosphate (NADP) by the aerobic pentose phosphate 

pathway. Anemic conditions associated with Pb poisoning, along with the inhibitory effects of 

Pb on heme synthesis, may result in increased RBC destruction due to the inhibitory effects of 

Pb on the activities of the enzyme, pyramidine 5-nucleotidase (P5N). Deficiency of this enzyme 

is characterized by intracellular accumulation of pyramidine-containing nucleotides, leading to 

hemolysis. Inhibition of this enzyme along with the perturbations in heme metabolism create 

imbalances in the energy currency of the erythrocyte. Perturbations in energy metabolism can be 

followed by changes in the concentration of purine nucleotides. In erythrocytes, these 

compounds cannot be synthesized de novo, they can only be reconstructed from preexisting free 

purine bases on nucleosides through salvage type reactions. The cell energy content can be 

measured by adenylate (ATP + ADP + AMP) and guanylate (GTP + GDP + GMP) nucleotides, 

and by their sum total. The concentrations of nucleoside monophosphates increase in cases of 

cell energy deficit, but they quickly degrade to nucleosides and bases. 

Cook et al. (1987) compared P5N and deoxypyramidine-5-nucleotidase levels in the RBC 

of Pb-exposed workers and matched controls and reported significantly lower levels of P5N in 

Pb-exposed workers. Konantakieti et al. (1986) reported similar observations in neonatal rat 

RBCs. These authors further indicated that the low levels of nucleotides were due to inhibition 

of P5N activity by Pb, as the depression in enzyme activity was correlated with blood Pb levels. 

This was further validated by in vitro inhibition of P5N in a dose-dependent manner. Tomokuni 

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and Ichiba (1987) found similar results with human RBCs both in vitro and in vivo. They 

reported activation of Pb-exposed human RBCs. Antonowicz et al. (1990) observed significantly 

higher levels of glycolytic enzymes and increased production of lactic acid and 2,3-diphospho 

glycerol, when human RBCs were incubated with Pb. Based on their observations, these authors 

suggested that Pb exposure may result in anaerobic glycolysis activation in human RBCs. In 

contrast, Grabowska and Guminska (1996) reported that Pb exposure diminished the ATP levels 

in human RBCs by inhibiting aerobic glycolysis. 

Erythrocyte energy metabolism in workers exposed to heavy metals, but without clinical 

manifestations of toxicity, was found to intensify and become more pronounced when they were 

occupationally exposed to Pb. Nikolova and Kavaldzhieva (1991) measured the exposed 

workers and reported higher ratios of ATP/ADP in Pb-exposed workers. Because the RBC 

energy pool is perturbed due to Pb exposure, Morita et al. (1997) evaluated the effect of Pb on 

NAD synthetase and reported an apparent dose-dependent decrease in NAD synthetase activity 

in the erythrocytes of Pb exposed workers. 

Baranowska-Bosiacka and Hlynczak (2003) evaluated Pb effects on distribution profiles 

of adenine, guanine nucleotide pools and their degradation products in human umbilical cord 

RBCs. In vitro exposure equivalent (Pb-acetate; 100 to 200 μg/dL) to Pb exposure for 20 h were 

found to significantly lower the levels of nucleotide pools, including NAD and NADP, 

accompanied by a significant increase in purine degradation products (adenosine, guanosine, 

inosine, and hypoxanthine). Associated morphological RBC alterations were also observed, with 

marked significant increases in stomatocytes, spherocytes, and echinocytes. These investigators 

also observed similar alterations in the nucleotide pools in Wistar rat RBCs with short-term 

exposure to Pb (Baranowska-Bosiacka and Hlynczak, 2004). Based on these observations, the 

authors postulated that decreases in NAD and NADP concentrations in RBCs may be a good 

indicator of Pb-induced disturbance in the energy process and can serve as a useful marker for 

chronic Pb exposure. If NAD synthetase activity had been measured in these studies, it might 

have provided experimental support for the observation of inhibition of NAD synthetase reported 

by Morita et al. (1997). 

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Other Enzymes 

Lead-induced efflux of K+ from human RBCs had been recognized as being due to the 

ability of Pb to selectively increase the membrane permeability for this cation. Studying the 

efflux of 86Rb using inside-out RBC vesicles, Alvarez et al. (1986) demonstrated that Pb 

promoted the selective efflux of K+

 ions by altering the sensitivity of Ca2+ binding site on the 

membrane either by direct binding or by altering Mg2+-mediated modulation. Fehlau et al. 

(1989) indicated that this modulation of the Ca 2+-activated K+

 channel in human RBCs 

coincides with the activation of RBC membrane-bound oxidoreductase. These authors suggested 

that, even though these two are independent events, the oxidoreductase enzyme activity may 

influence K channel gating. 

Earlier studies by Mas-Oliva (1989) on the potential effects of Pb on the RBC membrane 

(using RBC ghosts) indicated that Pb has inhibitory effects on Ca2+-Mg2+-ATPase. Further 

investigations on the role of calmodulin in the inhibition of Ca2+-Mg2+-ATPase indicated that the 

inhibitory activity on the enzyme may be due either to the effect of Pb on sulfhydryl groups on 

the enzyme or by direct binding to calmodulin. 

Jehan and Motlag (1995) reported that when albino rats were administered Pb i.p (5 or 

20 mg/kg body wt) for 14 consecutive days either alone or in combination with Cu (2 mg/kg 

body wt) or zinc (5 mg/kg body wt), there were severe decreases in RBC membrane enzyme, 

acetylcholine esterase (AchE), NADH dehydrogenase, and Na+

-K+ ATPase levels along with 

decreases in phospholipid content, hexose, and hexosamine. Of the combined metal treatment 

exposure regimens, Zn was found to considerably reduce such changes. Grabowska and 

Guminska (1996) assayed three ATPase activities (i.e., Na+

-K+ ATPase, Mg2+-ATPase, and 

Ca2+-ATPase) in human RBC in vitro and reported RBC Na+

-K+ ATPase to be the only enzyme 

inhibited by Pb, while Ca2+ or Mg 2+ATPases were not sensitive to Pb. On the other hand, 

Sivaprasad et al. (2003) observed Pb-induced reductions in RBC activities of the three of those 

ATPase activities. 

Two reports by Calderon-Salinas et al. (1999a,b) indicated Pb effects on calcium transport 

in human RBC. Initial studies by this group indicated that Pb and Ca are capable of inhibiting 

the passive transport of other metals in a noncompetitive way. Inhibition studies using N-ethylmaleimide indicated that Pb and Ca share the same permeability pathway in human RBCs and 

that this transport system is electrogenic (Calderon-Salinas et al., 1999a). Additional studies by 

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the same group reported that Pb is capable of inhibiting Ca efflux by inhibiting Ca-ATPase 

(Calderon-Salinas et al., 1999b). These authors further suggested that under physiological 

conditions, Pb, via Ca 2+-ATPase, alters Ca influx, while chronic Pb intoxication inhibits Ca 

efflux by altering RBC calcium homeostasis. Silkin et al. (2001) reported Pb-induced activation 

of K channels in the RBCs of the teleost fish S. porcus. Exposure of teleost fish RBCs to 1 to 

2 μM Pb led to a minor loss in cellular K+

; but, at 20 to 50 μM Pb, about 70% of cellular K+ was 

lost. Based on their observations of Pb-induced K+

 efflux from RBCs under competitive and 

inhibitory regimens, these authors suggested that Pb activates RBC K+

 channels. 

Eder et al. (1990) and Loipfuhrer et al. (1993) investigated activity levels of Ca 2+-ATPase 

and calcium accumulation, respectively, in Pb-depleted rat RBCs. No alteration in Ca 2+-ATPase 

activity or Ca accumulation was observed in the P0 generation (Eder et al., 1990). On the other 

hand, significant reduction in Ca-ATPase activity was observed in the F1 generation. It was 

suggested that Pb-induced alterations in the metabolism of phospho- and glycoproteins result 

from Pb depletion and may be responsible for the reduced enzyme activity. Both of the groups 

postulated that the decreased MCV observed in Pb depleted rat RBCs could be due to reduced Ca 

2+-ATPase activity in the RBCs. These and other related studies are summarized in Annex 

Tables AX5-2.5 and 5-2.6. 

5.2.6 Erythrocyte Lipid Peroxidation and Antioxidant Defense 

Although several mechanisms have been proposed to explain Pb toxicity, no mechanisms 

have been defined explicitly. Recent literature on Pb toxicity suggests oxidative stress as one of 

the important mechanisms for toxic effects of Pb in various organs. Because RBCs accumulate 

major amounts of Pb compared to other tissues, oxidative stress may also result in the 

accentuation of lipid peroxidation with concomitant inhibition of antioxidant enzymes, such as 

superoxide dismutase (SOD), catalase, GSH peroxidase, GSH reductase, and simultaneous 

increases in oxidized GSH (GSSG) and reduced GSH/GSSG ratios. Pb-induced lipid 

peroxidation and the mitigating effects of experimental chelation therapy are discussed with 

relevance to each tissue or organ within this chapter. The discussion focuses on the available 

literature with reference to studies on erythrocytes. 

Patra and Swarup (2000) reported significant changes in RBC lipid peroxide levels and 

anti oxidant defense (SOD and catalase) levels in RBC hemolysates from male calves exposed to 

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Pb (7.5 mg/kg body wt for 28 days). These authors suggested the potential role for increased 

peroxide levels in Pb-induced alterations in RBCs. Mousa et al. (2002) investigated the levels of 

various antioxidant enzymes, thiols, lipid peroxide in erythrocytes, and total thiol status of 

plasma in goats exposed to Pb (Pb-acetate, 5.46 mg/kg body wt for 2 weeks). These authors 

reported that all the parameters referred above were significantly increased in RBCs by day 7 

and receded to normal levels by day 14, while peroxides remained significantly increased even 

by day 14. Based on these observations, it was suggested that Pb-induced lipid peroxide 

generation in RBCs appears to be a continuous process and can lead to persistent oxidative stress 

in RBCs with chronic exposure. 

Metal chelator agents have been used clinically to reduce internal Pb body burden. These 

agents form an insoluble complex with Pb and are excreted. Though the majority of studies on 

the clinical potential of various experimental agents, including certain antioxidants, have been 

extensively performed mainly in relation to toxicity associated with hepatic and kidney tissues, 

such studies have also considered their potential effects on heme metabolism and blood Pb levels 

(see Sections 5.7 and 5.10). In the following paragraphs, two recent representative studies in 

experimental animals that specifically assessed the protection conferred to erythrocytes are 

described. 

El-Missiry (2000) investigated the protective role of the pineal hormone, melatonin, on 

Pb-induced suppression of heme synthesis as a consequence of reduced antioxidant status. 

Intramuscular injection of Pb-acetate (10 mg/kg body wt for 7 days) caused a significant 

reduction in heme synthesis with decreased blood Hb levels and decreased RBC and liver 

ALAD. Pretreatment of rats with melatonin (30 mg/kg body wt) intragastrically prevented the 

suppressive effects of Pb on RBC heme metabolism by conferring protection to the antioxidant 

capacity of the cells and also by scavenging free radicals generated by Pb intoxication. 

Sivaprasad et al. (2003) studied the protective effects of dl-alpha-lipoic acid (LA, 

25 mg/kg body wt) and meso-2,3-dimercaptosuccinic acid (DMSA, 25 mg/kg body wt); and they 

found such treatments, either alone or in combination for a week, had an effect on alterations in 

RBC functions induced by Pb-acetate (0.02% in drinking water for 5 weeks). These authors 

reported that treatment with LA or DMSA, alone or in combination, reversed Pb-induced 

increased LPO and reductions in Hb and Hct, along with changes in other biochemical 

parameters affected by Pb treatment. These authors further concluded that combined treatment 

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was much more potent and effective. These and other related studies are summarized in Annex 

Table AX5-2.7. 

5.2.7 Summary 

• The 1986 Pb AQCD reported that the activity of ALAD appeared to be inversely 

correlated to blood Pb values and was found inhibited in several tissues. Human studies 

reviewed in 1986 Pb AQCD also indicated that occupational exposure to Pb results in 

decreased RBC survival along with alterations in RBC membrane integrity and energetics. 

• More recent studies reviewed in this AQCD indicate that the transport of Pb across the 

RBC membrane is energy-independent, carrier-mediated and that the uptake of Pb is 

mediated by an anion exchanger through a vanadate-sensitive pathway. 

• Lead intoxication interferes with RBC survival and alters RBC mobility. Hematological 

parameters, such as mean corpuscular volume (MCV), mean corpuscular hemoglobin 

(MCH), and mean corpuscular hemoglobin concentration (MCHC), are also significantly 

decreased upon exposure to Pb. These changes are accompanied by decreased membrane 

sialic acid content. 

• Morphological analyses using electron paramagnetic resonance imaging and spin labeling 

techniques indicate that changes occur in RBC morphology upon Pb exposure. 

• Lead-induced RBC membrane lamellar organization and decreases in membrane lipid 

resistance to oxidation in rats appear to be mediated by perturbations in RBC membrane 

lipid profiles. Similarly, Pb-induced altered phosphorylation profiles of RBC membrane 

proteins have been reported. 

• Erythrocyte ALAD activity ratio (ratio of activated/non activated enzyme activity) has 

been shown to be a sensitive, dose-responsive measure of Pb exposure, regardless of the 

mode of administration of Pb. Competitive enzyme kinetic analyses in RBCs from both 

human and Cynomolgus monkeys indicated similar inhibition profiles by Pb. 

• Consistent observation of Pb-mediated inhibition of pyramidine 5′-nucleotidase (P5N) 

suggests this enzyme as a potential biomarker for Pb exposure. 

• Significant reductions in levels of nucleotide pools (e.g., NAD and NADP) accompanied 

by significant increase in purine degradation products have been implicated in the Pbinduced altered energetics of RBCs. 

• Lead-induced increased permeability for K+

 in RBCs appears to be due to the selective 

efflux of K+

 ions on the RBC membrane due to altered sensitivity of the Ca2+-binding site 

on the membrane. Erythrocyte Na+

-K+ ATPase appears to be more sensitive to Pb-induced 

inhibition than Ca2+-Mg2+ ATPase. 

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1 • Chelation agents and the pineal hormone, melatonin, have been reported to confer 

2 protection against Pb-induced lipid peroxidation and increased antioxidant defense 

3 in RBCs. 

4 

The newly available (since 1986) scientific evidence presented in this section 

6 convincingly demonstrates deleterious effects of lead on erythrocyte cell morphology, function, 

7 lead uptake and alterations in certain enzymes involved in heme synthetic pathways. However, 

8 some of the interesting and important conclusions are derived mainly from in vitro studies, often 

9 using short time incubations. It would be useful to substantiate such findings further by more 

systematic studies employing meaningful experimental designs for in vivo evaluation of 

11 laboratory animal models. 

12 

13 

14 5.3 NEUROLOGICAL/NEUROBEHAVIORAL EFFECTS OF LEAD 

5.3.1 Neurotoxicological/Neurobehavioral Effects of Lead in Animals 

16 5.3.1.1 Introduction 

17 Since the initial description of Pb encephalopathy in the developing rat in the mid-1960s, 

18 (Pentschew and Garro, 1966), a continuing research focus has been on defining the extent of 

19 CNS involvement at subencephalopathic, environmentally relevant, levels of exposure. These 

efforts have primarily addressed the developing organism, consistent with the primary public 

21 health concerns for neurotoxicity from Pb during this period. While significant research 

22 advances have been made in animal studies over the last four decades, relating these findings to 

23 neurotoxicity in children has been challenging and difficult. The barriers to greater progress 

24 have primarily been due to Pb’s multiple toxic mechanisms of action in brain tissue, which 

encompasses variable, overlapping, and, at times, opposing dose-effect relationships. One goal 

26 of this section is to bring greater clarity to the current state of knowledge. 

27 The Pb neurotoxicity evidence available for assessment in the 1986 Lead AQCD was 

28 considerably different in character from current, newly available findings. The literature was 

29 dominated by various types of assessments of CNS biogenic amine function in exposed animals, 

with dopaminergic neuronal systems seeming the most sensitive to the metal and drawing the 

31 most attention. In addition, the prevailing wisdom was that the neuronal actions of Pb were best 

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elucidated by perturbing neurotransmitter systems with CNS agents of known mechanism of 

action and comparing the responses in exposed animals to those in control subjects, an approach 

of limited value. Only some of those studies reported blood and/or brain Pb concentrations along 

with the experimental findings, rendering interpretation of results across different laboratories 

difficult and somewhat unreliable. 

As of 1986, perhaps the most reliable evidence concerned the effects of acute exposure to 

Pb2+ in vitro on voltage-sensitive Ca2+ channel function in the nerve cell membrane, developed to 

a great extent by Cooper and co-workers (Kober and Cooper, 1976; Cooper and Manalis, 1984; 

Suszkiw et al., 1984). Using neuromuscular endplate or synaptosomal preparations, these studies 

demonstrated that Pb2+ interfered with Ca2+ influx through voltage-sensitive channels. These 

findings significantly advanced the field, though acute exposure in vitro bore little resemblance 

to environmentally relevant routes and magnitudes of exposure. 

In the ensuing two decades, the Pb neurotoxicity literature has reflected an increased 

focus on cognitive-related mechanisms and the refinement of approaches and methodologies. 

Exposure-induced alterations at glutamatergic synapses have become a primary substrate of 

attention. Synaptic plasticity models (e.g., long-term potentiation [LTP]) developed in the 1990s 

are used in Pb studies in laboratories around the world. Behavioral paradigms, refined to more 

consistently discriminate Pb effects, aided in identifying optimal testing conditions and 

developmental periods for exposure. The cumulative result of these advances has lead to clearer 

understanding of likely mechanisms underlying Pb-induced cognitive impairments found in 

Pb-exposed children. 

The Pb neurotoxicity evidence reviewed in this section is organized largely according to 

scientific discipline: neurochemical alterations involving glutamatergic, cholinergic, and 

dopaminergic function; mechanisms defined by neurophysiological approaches; changes in 

auditory and visual function; modifications in behavioral function; induced alterations in cellular 

morphology; and findings on cellular disposition of Pb. This type of organization permits a more 

focused analysis of a very extensive, broad literature. 

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5.3.1.2 Neurochemical Alterations Resulting from Lead Exposure 

The following areas of investigation have drawn the most attention in the Pb neurotoxicity 

field over the last 20 years. A summary of the key studies evaluating neurochemical alterations 

resulting from Pb exposure are listed in Table AX5-3.1. 

Lead and Neurotransmitter Release Processes 

By the mid-1980s, it was evident that acute exposure to Pb2+ in vitro reduced the 

magnitude of depolarization-induced transmitter release, apparently by inhibiting Ca2+ influx 

into the nerve ending through voltage-sensitive Ca2+ channels (Kober and Cooper, 1976; Cooper 

and Manalis, 1984; Suszkiw et al., 1984). Since then, several investigators utilizing various 

preparations (Shao and Suszkiw, 1991 [cortical synaptosomes]; Tomsig and Suszkiw, 1993 

[bovine chromaffin cells]; Braga et al., 1999a,b [cultured hippocampal cells]; Westerink and 

Vijverberg, 2002 [PC12 cells]), have demonstrated that, in the absence of Ca2+, Pb2+ exhibits 

Ca2+-mimetic properties in stimulating exocytosis and is substantially more potent in doing so. 

That is, in the absence of Ca2+ and depolarization, nM concentrations of Pb2+ alone stimulate 

transmitter release. Many investigators have proposed that this action, in conjunction with the 

ability of Pb2+ to suppress evoked release, produces a higher noise level in synaptic transmission 

in Pb-exposed animals. 

The ability of Pb to diminish stimulated transmitter release has been demonstrated in 

intact chronically exposed animals via the use of intracerebral microdialysis (Kala and Jadhav, 

1995; Lasley and Gilbert, 1996; Lasley et al., 1999). More recently, Lasley and Gilbert (2002) 

used Ca2+-free perfusate containing a Ca2+ channel antagonist for microdialysis to identify the 

Ca2+-independent component of release. These workers demonstrated that under these 

conditions high K+

-stimulated glutamate and GABA release were elevated in chronic high level 

Pb-exposed animals, suggesting a Pb2+-induced enhancement of evoked release. It was 

concluded that this pattern of results indicated the presence of two actions of Pb on transmitter 

release in vivo: (1) a more potent suppression of stimulated release seen at lower exposure levels 

(associated with blood Pb values of 27-62 μg/dL) combined with (2) Ca2+-mimetic actions that 

independently induce the exocytosis seen at higher exposure levels (associated with blood Pb 

values $62 μg/dL). Together, these two actions produce a biphasic dose-effect relationship (see 

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402(c) Economic Analysis Chapter 5 82
1 Figure 5-3.1). Thus, there is good correspondence between findings in in vitro and in vivo 

2 studies with respect to the actions of Pb on transmitter release. 

Figure 5-3.1. Time course of extracellular GLU concentration and GLU concentration in 

response to lead exposure. 

*** p<0.001; ** p<0.01 relative to the GLU concentration in control animals; #p<0.0001 relative 

to the GLU concentration in the 0.2% Pb group. 

Source: Lasley and Gilbert (2002). 

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Lead and Glutamatergic NMDA Receptors 

Because of the established importance of the NMDA subtype of glutamate receptor in 

synaptic plasticity and learning, these receptors have been a focus of intense interest in Pb 

neurotoxicity for the last 15 years. Using whole cell and single channel patch clamp 

methodologies, Alkondon et al. (1990) were the first to report that Pb2+ inhibited the function of 

the NMDA receptor channel complex. Guilarte and Miceli (1992) reported similar findings 

using nominal Pb2+ concentrations and receptor binding techniques, and drew parallels between 

Zn2+ Ca2+2- and Pb2+-induced inhibition of the channel. However, Lasley and Gilbert (1999), 

using free Pb2+ ion concentrations and radioligand binding, demonstrated that, despite the 

similarities, Pb2+ did not inhibit the NMDA receptor channel complex by binding to the Zn2+ 

allosteric site. Furthermore, they indicated that the Pb2+ IC50 of 0.55 μM for inhibition of the 

channel complex was likely approximately two orders of magnitude greater than the extracellular 

fluid concentrations of Pb2+ associated with environmentally relevant exposure. This does not 

mean that NMDA receptor function does not change after Pb exposure, but it strongly suggests 

that the alterations are not based on a direct Pb2+ action. 

Unfortunately, a consensus on the effects of chronic Pb exposure on NMDA receptor 

expression and function has not been achieved. Extensive effort has been invested to assess 

NMDA receptor subunit mRNA and protein expression in exposed animals (Guilarte and 

McGlothan, 1998; Nihei and Guilarte, 1999; Guilarte et al., 2000; Nihei et al., 2000; Toscano 

et al., 2002; Guilarte and McGlothan, 2003), but consistent findings have not emerged. An 

exception was perhaps the work of Nihei et al. (2000) who found decreases in hippocampal NR1 

subunit mRNA and protein expression deficits in LTP to be associated with impaired spatial 

learning in PB-exposed animals. Correlations of this type with functional measures are valuable 

in validating the biochemical observations. 

While exposure-induced alterations of NMDA receptor binding have been observed in 

multiple laboratories, there has not been uniform agreement as to the direction of change. 

Upregulation of NMDA receptor density has been observed in rats continuously exposed 

throughout development (Ma et al., 1997; Lasley et al., 2001), but receptor downregulation has 

also been reported when exposure was begun immediately postweaning (Cory-Slechta et al., 

1997a). The results of behavioral investigations are best explained by increases in NMDA 

receptor density. Cohn and Cory-Slechta (1993, 1994b), using a repeated learning component of 

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a multiple reinforcement schedule, observed enhanced performance sensitivity to exogenous 

NMDA administration and diminished sensitivity to MK-801, an NMDA receptor antagonist in 

exposed animals. The same findings resulted when the drug discrimination paradigm was 

utilized (Cory-Slechta, 1995a; Cory-Slechta et al., 1996b): enhanced sensitivity to NMDA and 

reduced sensitivity to MK-801 in Pb-exposed groups. A decreased sensitivity to MK-801 can 

result from either increased numbers of NMDA receptors or a diminished access of the 

antagonist to its binding site in the ion channel. Thus, all these behavioral observations may be 

accounted for by Pb-induced increases in NMDA receptor density resulting in increased 

sensitivity to agonists coupled with decreased sensitivity to antagonists. That is, the functional 

measures suggest that an NMDA receptor upregulation occurs. 

Pb2+ and Protein Kinase C 

Another important focus area for Pb neurotoxicity research has been the interactions of 

Pb2+ with protein kinase C (PKC) activity. Markovac and Goldstein (1988a) were the first to 

report that Pb2+ directly stimulated PKC activity at picomolar concentrations, thereby exhibiting 

greater potency for this action than Ca2+ by 4-5 orders of magnitude. Long et al. (1994) made 

similar observations using free Pb2+ and Ca2+ ion concentrations and nuclear magnetic resonance 

spectroscopy, resulting in an EC50 of 55 pM for Pb2+ stimulation of PKC. These workers also 

presented evidence suggesting that the maximal efficacy of Pb2+ was less than that of Ca2+, 

despite its greater potency. Tomsig and Suszkiw (1995) elegantly elucidated multiple 

interactions of Pb2+ with PKC, identifying both stimulatory (affinity in the pM range) and 

inhibitory (affinities in the nM and μM range) binding sites on the kinase. They also showed 

that, on the basis of these interactions, Pb2+ induced a peak efficacy for stimulation of PKC that 

was only ~40% of the maximal efficacy produced by Ca2+, leading to their terming Pb2+ a partial 

agonist of the kinase, as reflected in Figure 5-3.2. 

Subsequent studies have begun to examine the cellular impact of the Pb2+ effects on PKC. 

Kim et al. (2000) showed that acute Pb2+ exposure in vitro stimulated immediate early gene 

expression in cultured cells by a mechanism that requires PKC. Braga et al. (2004) have 

demonstrated that Pb2+ stimulation of PKC results in inhibition of nicotinic cholinergic 

modulation of glutamate and GABA synaptic transmission in cultured hippocampal cells. It is 

anticipated that future studies will further develop this line of investigation. 

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402(c) Economic Analysis Chapter 5 85
Figure 5-3.2. PKC activity as a function of Ca2+ and Pb2+ concentrations. 

Source: Tomsig and Suszkiw (1995). 

1 The effects of chronic Pb exposure on PKC signaling have been more difficult to 

2 discriminate. Most investigators have utilized broken cell preparations and measures of either 

3 kinase translocation or enzyme activity; however, a broken cell preparation has not been shown 

4 to simulate the intracellular milieu of a chronically exposed intact animal. In the preparation of a 

5 tissue extract for determination of kinase activity, the unbound Pb2+ is removed or greatly 

6 diluted, so that the resulting activity measure largely reflects changes in total PKC expression 

7 resulting from the exposure. That is, this measure does not identify a synaptic pool of PKC or 

8 necessarily represent the pool of kinase involved in signal transduction. Alternatively, the 

9 translocation of kinase from a cytosolic to membrane cellular fraction is a somewhat nonspecific 

10 measure and observed changes should be independently confirmed. From the effects of acute 

11 Pb2+ exposure in vitro it is abundantly clear that PKC is a toxicologically significant intracellular 

12 target for Pb2+. However, various investigators have been unable to define how this acute effect 

13 translates, if at all, to chronic exposure in the intact animal. Neither is it evident how one could 

14 discriminate inhibition of PKC activity (e.g., resulting from decreased efficacy relative to that 

15 associated with Ca2+) from downregulation of the enzyme from prolonged stimulation. 

16 Resolution of these issues awaits the development of more specific methodologies. 

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Pb2+-Ca2+ Interactions 

In general Pb2+-Ca2+ interactions have long been proposed as important factors in 

manifestations of cellular Pb toxicity and have been under investigation since before the 1986 

AQCD was prepared. The classical effects of Pb2+ mentioned earlier include inhibiting Ca2+ 

influx through cell membrane voltage-sensitive Ca2+ channels and exhibiting Ca2+-mimetic 

properties at multiple intracellular proteins. In addition, Pb2+ is known to disturb intracellular 

Ca2+ homeostasis (Simons, 1993b). Ca2+-dependent proteins whose actions have been reported 

to be stimulated by Pb2+ include calmodulin and calmodulin-dependent phosphodiesterase 

(Goldstein, 1993), calcineurin (Kern and Audesirk, 2000), and Ca2+-ATPase (Ferguson et al., 

2000). These actions of Pb2+ are thought to be the points of initiation of much of the metal’s 

cellular toxicity. 

Lead Exposure and Cholinergic Neuronal Systems 

The actions of chronic exposure have also been studied with respect to changes in CNS 

cholinergic systems, as another substrate thought to underlie cognitive function. Bielarczyk et al. 

(1996) reported (a) decreased functional cholinergic innervation in the hippocampus and (b) 

depression of choline acetyltransferase activity in hippocampus and cortex in young adult rats 

exposed to Pb only during early development. Similar changes were reported by Bourjeily and 

Suszkiw (1997), leading to the conclusion that perinatal exposure results in a loss of 

septohippocampal cholinergic projection neurons that persists until testing in young adulthood. 

Tian et al. (2000) exposed PC12 cells to Pb2+ for #48 h and found that the downregulation of 

choline acetyltransferase activity reflected the effects of the metal at the level of gene expression. 

Consistent with these other findings, Jett et al. (2002) employed a similar perinatal exposure 

protocol and observed increased nicotinic receptor binding in multiple brain regions. These 

reports reinforce the belief that Pb exposure during early development deleteriously affects 

cholinergic function and indicate that these actions are an important component of the cognitive 

impairment resulting from exposure to the metal. 

Summary 

In reviewing the Pb neurotoxicity literature of the last 20 years and the research focus 

areas presented above, it is evident that the effects of Pb exposure on components of 

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neurotransmitter release and Pb2+-Ca2+ interactions are closely intertwined. Exposure-induced 

decreases in glutamatergic, cholinergic, and dopaminergic transmission are most prominent 

because of the purported role of these neuronal systems in brain development and cognitive 

function. In contrast, the weight of the data suggest an upregulation of NMDA receptors 

resulting from chronic exposure, but a consensus on the effects of Pb on expression and function 

remains to be attained, and it is increasingly apparent that this glutamate receptor subtype may 

not be a primary target of chronic exposure in the intact animal. While the in vitro interactions 

of Pb2+ and PKC have been carefully described and are broadly relevant to cellular signaling 

pathways, meaningful and valid observations of the functional effects of these interactions in 

intact animals have not been achieved. 

5.3.1.3 Actions of Lead Exposure Defined by Neurophysiological Approaches 

One of the most significant advances in Pb neurotoxicity research over the last two 

decades is the widespread application of synaptic plasticity models to studies of the effects of 

exposure. Key studies are listed in Table AX5-3.2. The incorporation of these paradigms into 

Pb studies could be seen as a natural progression, and one might expect that they would receive 

greater use in neurotoxicology, as they have in the broader field of neuroscience. 

Chronic Lead and Models of Synaptic Plasticity 

Throughout the 1990s, the LTP model of synaptic plasticity was utilized in studies of Pb 

neurotoxicity in laboratories around the world, undoubtedly because it was widely accepted that 

the model invoked synaptic processes that also were involved in learning and cognitive function. 

These investigations resulted in large body of evidence that characterized the actions of chronic 

exposure across several experimental parameters (see Table 5-3.1). Furthermore, at least in the 

hippocampal subregions, CA1 and dentate gyrus, there was uniform agreement as to the 

alterations that resulted. 

Chronic developmental Pb exposure decreased the magnitude of LTP and increased the 

threshold for induction (Altmann et al., 1993; Gilbert et al., 1996; Gutowski et al., 1998; Ruan 

et al., 1998). Simultaneous assessments of paired-pulse functions also uncovered reductions in 

paired-pulse facilitation, indicative of reduced glutamate release (Lasley and Gilbert, 1996; 

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Table 5-3.1. Chronic Lead Exposure and LTP 

Recording Site 

Exposure 

Period1 Blood Pb2

 Brain Pb3 Preparation 

Effect of Exposure on 

LTP 

Hippocampal Dentate Gyrus 

Gilbert et al. (1996) P0 – P90-120 37.2 ND in vivo elevated induction threshold 

Ruan et al. (1998) P0 – P90-115 30.1 180 in vivo diminished magnitude 

Gilbert et al. (1999a) G16 – P130-210 40.2 378 in vivo elevated induction threshold 

P30 – P130-210 38.7 350 and diminished magnitude 

Gilbert et al. (1999b) G16 – P120-180 26.84 220 in vivo elevated induction threshold 

40.2 378 and diminished magnitude 

61.8 670 

Gilbert and Mack G16 – P210-540 ND ND in vivo accelerated decay 

(1998) 

Hippocampal CA1 

Altmann et al. (1993) G0 – P70-210 14.3 160 slices blocked, required exposure 

during early development 

Gutowski et al. (1998) G0 – P90-130 16.0 135 slices diminished magnitude 

Hippocampal CA3 

Gutowski et al. (1997) G0 – P13-140 28.5 180 slices no effect across 4 ages 

Gutowski et al. (1998) G0 – P90-130 16.0 135 slices no effect 

1

Exposure duration in terms of gestational (G) or postnatal (P) days of age; P0 = day of birth. 2

Values expressed as μg/100 ml. 

3

Values expressed as ng/g tissue. 

4

Different blood Pb values generated by differing levels of exposure. 

Ruan et al., 1998). It was also shown that the potentiation produced in Pb-exposed animals 

decayed more rapidly than in controls (Gilbert and Mack, 1998). 

Gilbert et al. (1999a) compared the effects on LTP when exposure occurred during 

different developmental periods. These workers found that animals whose exposure began 

shortly after weaning exhibited the same impairments in LTP as animals continuously exposed 

from late gestation when testing in both groups occurred well into adulthood. A smaller effect 

on potentiation was observed when exposure was restricted to the late gestation/weaning period. 

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402(c) Economic Analysis Chapter 5 89
1 Gilbert et al. (1999b) also examined the effects of Pb on LTP as a function of chronic 

2 exposure level, utilizing a range of 0.1–1.0% Pb in the drinking water (corresponding to blood 

3 Pb values of 26 to 117 μg/dL). A reduced capacity for LTP was found at all exposure levels 

4 except in the 1.0% groups, indicative of a biphasisc dose-effect relationship (Figure 5-3.3). 

5 The 1.0% Pb-exposure level was clearly less effective than the lower exposure groups in 

6 reducing LTP magnitude and did not differ significantly from control values. Blood Pb values 

7 were elevated as a function of increasing exposure and could not account for the lack of effect in 

8 the 1.0% exposure group. 

9 

Figure 5-3.3. I/O function difference score–PS amplitude. 

Source: Gilbert et al. (1999b). 

10 Zhao et al. (1999) utilized low frequency electrical stimulation in the paradigm of long11 term depression (LTD) and found that chronic Pb exposure depressed the magnitude of this form 

12 of synaptic plasticity in both hippocampal CA1 and dentate gyrus subregions. The authors also 

13 made the point that in combination with the reduced magnitude of LTP reported by other 

14 workers, the decrease in LTD magnitude results in a reduced range of synaptic plasticity in 

15 chronically exposed subjects. 

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While the effects of Pb on synaptic plasticity are quite similar in the CA1 and dentate 

gyrus regions, they are not uniformly present throughout this brain area. Gutowski et al. (1997, 

1998) were unable to find any effect of chronic Pb exposure on LTP in hippocampal CA3 (i.e., 

mossy fiber LTP), even when the investigation was extended across multiple ages. The bases for 

this distinction await future investigation. 

Lead Exposure, Glutamatergic Transmission, and Synaptic Plasticity 

Investigation of the synaptic processes underlying LTP has provided insight into the bases 

for Pb exposure-related impairment of potentiation and cognitive ability (Lasley and Gilbert, 

2000). Biochemical and neurophysiological approaches (Lasley and Gilbert, 1996; Gilbert et al., 

1996; Ruan et al., 1998) have found stimulated glutamate release to be diminished in 

hippocampus at blood Pb values where deficits in LTP have been observed. Multiple actions of 

Pb may be involved at this exposure level because animals exposed postweaning exhibited 

similar decrements in evoked glutamate release to those exposed continuously from conception 

(Lasley et al., 1999), similar to the observations for measures of LTP. A biphasic dose-effect 

relationship was also found in which stimulated glutamate release in hippocampus was decreased 

at intermediate exposures, but not at higher levels (Lasley and Gilbert, 2002). On the basis of 

these observations, it is apparent that decreases in stimulated glutamate release are a significant 

contributing factor to the Pb exposure-related changes seen in LTP. 

In comparison to the concordance across laboratories with regard to effects of chronic Pb 

exposure on LTP and the notable similarities to its actions on glutamate release, the effects of 

exposure on the NMDA receptor are relatively variable. That is, there is not widespread 

agreement as to the nature of the exposure-induced changes. Alterations in receptor function 

occur readily in response to externally applied treatments and might be expected to vary in a 

dynamic fashion as a function of exposure parameters (e.g., Lasley et al., 2001). However, most 

studies have involved measures of NMDA receptor integrity in adult animals exposed to constant 

levels of Pb for at least three, and more commonly 6 to 15, months, so that receptor-mediated 

effects should have stabilized. Consequently, the following alternative conclusions could be 

proposed regarding the actions of Pb exposure on the NMDA receptor that are related to its 

effects on LTP. First, changes in NMDA receptor function may depend on specific Pb exposure 

conditions. For example, a postweaning exposure protocol may not necessarily produce similar 

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effects to an exposure protocol initiated during earlier development. Alternatively, exposure 

effects on LTP may be produced at signal transduction or other cellular loci that exert regulatory 

influences on the NMDA receptor. This latter conclusion implies that changes in the NMDA 

receptor do not mediate the primary action of Pb on LTP. In addition, this indicates that 

identification of some site of direct Pb effect that has regulatory influence on the receptor would 

produce more consistently observable findings. 

Lead and Electrophysiological Changes in Dopaminergic/Cholinergic Systems 

Electrophysiological approaches have been employed to delineate other interesting 

findings in Pb-exposed animals not directly related to synaptic plasticity. Using standard 

extracellular recording methods, Tavakoli-Nezhad et al. (2001) identified an exposure-dependent 

decrease in the number of spontaneously active dopamine cells in the substantia nigra and ventral 

tegmental area, but they found no evidence that this decrease was related to a physical loss of 

cells. In subsequent work, Tavakoli-Nezhad and Pitts (2005) determined that the decrease in the 

number of active dopamine cells was not based on depolarization inactivation. However they 

were able to discern a reduced impulse flow in dopamine neurons and a diminished sensitivity of 

D1 receptors in the nucleus accumbens. 

The actions of Pb2+ on cholinergic nicotinic receptors have been investigated in acutely 

dissociated or cultured hippocampal cells using the patch clamp technique in whole cell mode 

(Ishihara et al., 1995). These workers found that Pb2+ potently inhibits activation of fastdesensitizing nicotinic currents in a noncompetitive and voltage-dependent manner. The 

nicotinic receptors affected (methyllycaconitine-sensitive) were more sensitive to Pb2+ than other 

nicotinic subtypes and are known to be highly permeable to Ca2+. This latter observation likely 

explains the potency for their inhibition by Pb2+. 

5.3.1.4 Lead Exposure and Sensory Organ Function 

Another focus area for Pb neurotoxicity research that has generated valuable and relevant 

scientific findings has been sensory organ function. Visual and auditory systems have received 

the most attention, have generated results closely resembling clinical observations, and have 

been successful in defining some of the mechanisms underlying the exposure-induced 

alterations. These studies are summarized in Table AX5-3.3. 

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Sensory Organ Assessments in Nonhuman Primates 

Lilienthal and Winneke (1996) tested monkeys continually exposed to Pb from gestation 

through 8 to 9 years of age and found increased latencies for waves I, II, and IV in brainstem 

auditory evoked potentials. These effects persisted for at least 18 months after exposure was 

terminated and blood Pb values had declined nearly to control levels, leading to the conclusion 

that these actions of Pb were not dependent on current exposure. Rice (1997) determined pure 

tone detection thresholds in monkeys exposed continually from birth to 13 years of age, and 

reported that half of the subjects exhibited thresholds outside of the control range at some 

frequencies. These findings are consistent with reported alterations in auditory function in 

humans exposed to Pb developmentally (Otto and Fox, 1993). 

Visual function was assessed in monkeys by Reuhl et al. (1989), who exposed a high- and 

a low-dose group from birth to 6 years of age. This investigation uncovered a decrease in 

neuronal volume density in cortical areas V1 and V2 in the high-exposure compared to the lowexposure group. These workers also found a decrease in dendritic arborization in pyramidal 

neurons in these brain areas, leading to the conclusion that chronic developmental Pb exposure 

produces changes in cytoarchitecture in visual projection areas. 

Retinal Function in Rodents 

The actions of Pb on retinal cells have been a focus of research for more than two 

decades. It has long been recognized that Pb2+ exhibits a selective effect on rod cells (Fox and 

Sillman, 1979) and, more recently, that the associated loss of rod and bipolar cells was due to 

exposure-induced apoptotic changes (e.g., Fox et al., [1997]). These observations have been 

linked with exposure-related alterations in rod-mediated visual function. In vitro studies 

utilizing free Pb2+ ion concentrations have done much to elucidate the mechanistic bases of these 

observations. 

These latter efforts have established the concentration-dependent inhibition of cyclic 

GMP (cGMP) hydrolysis by free Pb2+, in addition to increases in retinal cGMP and rod Ca2+ 

levels (e.g., Srivastava et al., [1995]). Kinetic studies utilizing purified rod cGMP 

phosphodiesterase have shown that pM Pb2+ concentrations competitively inhibit the enzyme 

relative to mM concentrations that are required for Mg+2 cofactor activity, thus binding with 104

-

106

-fold higher affinity than Mg+2 and preventing cGMP hydrolysis (Srivastava et al., 1995). 

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When retinas are incubated in Ca2+ and/or Pb2+ in vitro, the rods selectively die by apoptosis 

associated with mitochondrial depolarization, release of mitochondrial cytochrome c, and 

increased caspase activity (He et al., 2000). He et al. (2003) have proposed that apoptosis is 

triggered by Ca2+ and Pb2+ overload due to translocation of cytosolic Bax to the mitochondria, 

which likely sensitized the overloaded mitochondria to release cytochrome c. Subsequent work 

found the elevations in free Ca2+ and Pb2+ to be localized to photoreceptors and determined that 

the effects of the two ions were additive and blocked by a mitochondrial permeability transition 

pore inhibitor (He et al., 2000). This suggested that the two ions bind to the internal metal 

binding site of this pore and, thereby, initiate the apoptosis cascade. 

These mechanisms are entirely consistent with electroretinogram (ERG) changes observed 

in animals chronically exposed during early development: decreases in maximal ERG 

amplitude, decreases in absolute ERG sensitivity, and increases in mean ERG latency that were 

selective for rod photoreceptors (Fox and Farber, 1988). Also in agreement with these 

mechanisms are observed elevations in retinal cGMP levels and reductions in light-activated 

cGMP phosphodiesterase activity. Moreover, the exposure level-dependent degeneration of rod 

and bipolar cells exhibited the classical morphological features of apoptotic cell death (Fox et al., 

1997). Other measures of visual function in chronically exposed animals also have been found 

to be consistent with the mechanistic data. Long-term dose-dependent elevations in response 

thresholds are present but only at scotopic (i.e., rod-mediated) backgrounds, and dark adaptation 

is delayed (Fox et al., 1994). In addition, exposure-induced decreases in rhodopsin content that 

were proportional to the loss of rod cells have been reported (Fox et al., 1997) as well as dosedependent decreases in retinal Na+

, K+-ATPase activity (Fox et al., 1991). 

These studies investigating rod photoreceptors are perhaps the best examples of the ability 

to correlate data obtained in vitro with findings derived from in vivo exposure and with changes 

in visual physiology. In multiple instances, the same cellular mechanisms are affected with each 

approach and are consistent with ERG and rod-mediated functional measures. These 

relationships are summarized in Table 5-3.2. 

5.3.1.5 Neurobehavioral Toxicity Resulting from Lead Exposure 

The breadth of research examining Pb neurotoxicity utilizing behavioral approaches is 

quite diverse with respect to test paradigms, exposure parameters, test species, and 

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402(c) Economic Analysis Chapter 5 94
Table 5-3.2. Mechanisms of Pb-Induced Impairment of Retinal Function 

In Vitro Evidence In Vivo Evidence Physiological Changes 

Competitive inhibition of Increased retinal cGMP 

cGMP PDE 

Increased retinal cGMP Decreased stimulated cGMP PDE Decreased maximal ERG amplitude 

activity Decreased absolute ERG sensitivity 

Increased mean ERG latency 

Increased rod [Ca2+] 

Apoptosis from increased 

photoreceptor Ca2+/Pb2+ via 

Morphological features of apoptotic rod, 

bipolar cell death 

Increased response thresholds at 

scotopic backgrounds 

binding to mitochondrial Decreased rhodopsin proportional to Delayed dark adaptation 

permeability transition pore cell loss 

Translocated cytosolic Bax to the 

mitochondria, cytochrome c released 

Decreased retinal Na+ 

, Decreased retinal Na+,K+-ATPase 

K+

-ATPase activity activity 

Abbreviations: PDE, phosphodiesterase; ERG, electroretinogram. 

1 neuropharmacological agents used. This large literature, summarized in Table AX5-3.4, has 

2 permitted development of insightful generalizations while, at the same time, providing focused 

3 descriptions of specific behaviors. In addition, the accumulated evidence has supported the 

4 development of more effective and refined methodologies. 

5 

6 Lead-Induced Alterations of Behavior – Nonhuman Primates 

7 In reviewing the results of behavioral investigations of Pb neurotoxicity in nonhuman 

8 primates conducted over the last two decades, it is abundantly clear that the results are shaped by 

9 the nature of the test paradigm and the developmental exposure periods utilized. Thus, studies 

10 employing nonspatial discrimination reversal (Rice and Gilbert, 1990a), spatial delayed 

11 alternation (Rice and Gilbert, 1990b), and spatial discrimination reversal (Rice, 1990) produced 

12 observations that are distinctly different. Experimental groups continually exposed to Pb from 

13 birth to testing as adults typically exhibit learning deficits, but groups continually exposed 

14 beginning after weaning or whose exposure from birth is terminated during development may or 

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may not display differences from control animals depending on the sensitivity to exposure of the 

test paradigm. 

Nonetheless, some characteristics of experimental subjects can be gleaned from 

investigations of neurobehavioral toxicity in nonhuman primates. Modifications of experimental 

parameters that make task acquisition or retention more challenging (Rice and Gilbert, 1990b; 

Rice, 1990) are more likely to elicit exposure-related changes in responding. In test paradigms 

based on fixed interval reinforcement or differential reinforcement of low rate responding 

schedules, Pb-exposed subjects displayed decreased inter-response times and a greater ratio of 

responses per earned reinforcement (Rice, 1992a,b). Exposed animals also are less sensitive to 

changing reinforcement contingencies and, therefore, commit more perseverative errors in 

responding (Rice, 1992c; Newland et al., 1994). Not surprisingly, it has been noted that these 

experimental behavioral effects correspond reasonably well to epidemiologic observations in 

Pb-exposed children (Rice, 1996; Lasley and Gilbert, 2000), thus validating the use of this 

species as an exposure model. 

Lead-Induced Alterations of Behavior – Rodents 

The observations of Pb’s neurobehavioral effects in rodents in many ways resemble those 

conclusions attained with nonhuman primates. However, the test paradigms utilized for rats 

have been somewhat more refined, and the behavioral data have been subjected to more detailed 

analyses. As a result, valuable insights into the component mechanisms underlying the 

exposure-related changes have been achieved. 

An olfactory serial reversal paradigm was utilized to demonstrate Pb-induced impairments 

in learning reversals (Hilson and Strupp, 1997; Garavan et al., 2000). These workers found that, 

when presented with altered reinforcement contingencies for the reversals, rats whose exposure 

was limited to early development exhibited a shortened initial period of responding to the 

previously correct cue coupled with a prolonged postperseverative learning phase for the new 

task. Hilson and Strupp (1997) concluded that the impaired reversal learning was due to a 

deficiency of learning new contingencies of the task (i.e., an associative deficit), and not based 

on inflexibility or deficient inhibitory control. Subsequent work by Garavan et al. (2000) 

determined that this associative deficit was based on a response bias and an impaired ability to 

associate cues and/or actions with their affective consequences. 

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Employing a visual discrimination task, Morgan et al. (2000) found that as the level of Pb 

exposure restricted to early development increased, learning of the task slowed and the number 

of defined “impaired” animals increased. The authors concluded that the deficits were not 

limited to attentional function and that an associative deficit had resulted along with a tendency 

to respond more rapidly. Subsequent work with visual discrimination vigilance tasks found that 

animals exposed only during gestation and/or lactation exhibited impaired response initiation and 

increased omission errors, indicating a lasting deficiency in sustained attention and an increased 

reactivity to errors (Morgan et al., 2001). The authors concluded that the effects of exposure are 

determined not only by the paradigm, but also by the timing and intensity of exposure. CorySlechta (2003) came to a similar conclusion on the factors underlying the manifestation of Pb 

effects but suggested that the alterations in attention may be due to impulsivity or aversion to 

delays. 

The actions of early Pb exposure on memory appear to be task-dependent, but this issue 

has not been clearly defined. Alber and Strupp (1996) found that exposed rats performed more 

poorly on a series of spatial alternation tasks but that the deficit did not vary across intertrial 

delays, suggesting that memory was not impaired. Murphy and Regan (1999) used a one-trial, 

light/dark, passive avoidance paradigm and observed a decrease in recall latency on post-training 

day 5 in rats whose exposure was restricted to early development. Since there was no exposure 

effect evident during the first 48 h after training, these authors concluded that the impairment 

was associated with long-term memory storage. Further studies are needed to more clearly 

characterize the effects of chronic Pb on memory function. 

Interactions of Lead Exposure and Responding to Cocaine 

Behavioral responses to a number of neuropharmacological agents have resulted in 

important and useful insights into Pb neurotoxicity. One approach that has been unique and has 

produced scientifically important results has been investigation of the interactions of chronic Pb 

exposure and responses to cocaine. Chronic exposure of adult male rats has been shown to 

attenuate cocaine-induced locomotor activation (Grover et al., 1993) and result in a slower 

development and reduced magnitude of cocaine-induced sensitization of locomotor activity 

(Nation et al., 1996). The latter observations are consistent with other evidence of impaired 

synaptic plasticity that were presented earlier in this chapter. These actions of exposure are not 

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specific to cocaine, as a similar exposure regimen attenuated the reinforcing effect of brain 

stimulation of the medial forebrain bundle (Burkey and Nation, 1994), the nerve tract conveying 

nigrostriatal and mesolimbic dopaminergic neurons to forebrain regions. 

Using the drug discrimination paradigm, Miller et al. (2001) restricted Pb exposure to the 

gestational and lactational periods of early development and observed decreased sensitivity to 

dopamine D1 and D2 receptor agonists when the animals were tested as adults. These findings 

may be taken as evidence of receptor downregulation, but, in this behavioral task, subjects 

received chronic intermittent doses of the training drug, which in this study was a low dose of 

cocaine. Thus, the actions of exposure on dopaminergic systems may be confounded with the 

receptor changes induced by chronic drug administration. 

In contrast to the attenuating effects of chronic Pb administration to adults described 

above, exposure restricted to the gestational and lactational periods exerts potentiating effects on 

other types of responses to cocaine when animals are tested long after exposure is terminated. 

Nation et al. (2003) trained rats to self-administer cocaine intravenously, extinguished the 

response, and then used a systemically administered priming dose of the drug to initiate a relapse 

response. Exposed animals were found to have an increased sensitivity to cocaine relapse 

compared to identically treated controls. When multiple cocaine doses were provided, 

identically exposed animals were found to self-administer more of a low dose of the drug and 

less of a high dose than controls, again suggesting an enhanced sensitivity to the actions of 

cocaine (Nation et al., 2004). Finally, animals exposed to Pb in this manner were found to have 

an accelerated rate of acquisition of cocaine self-administration behavior (Rocha et al., 2005). 

Lead Exposure and the Stimulus Properties of Neuropharmacological Agents 

The drug discrimination paradigm has been utilized more widely in Pb neurotoxicity 

research to characterize postsynaptic receptor status for multiple neurotransmitter systems and 

has resulted in some useful findings. Rats chronically exposed beginning at weaning and tested 

as adults were trained to discriminate either a systemically administered D1 or D2 receptor 

agonist (Cory-Slechta and Widzowski, 1991). Exposed rats learned the discrimination task more 

rapidly than controls and exhibited greater levels of response to lower doses of the training drugs 

and less blockade by a D2 receptor antagonist, consistent with generalized dopaminergic receptor 

supersensitivity. In groups of animals exposed only from birth to weaning and trained to 

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discriminate the same drugs, the D2-D3 subtype receptor supersensitivity in exposed animals was 

again present, but no changes in responding to the D1 agonist were apparent (Cory-Slechta et al., 

1992). Further work with this test paradigm employing the postweaning exposure protocol failed 

to demonstrate any D1-D2 receptor interactions in the supersensitivity displayed by Pb animals 

(Cory-Slechta et al., 1996a). 

To test cholinergic sensitivity in animals chronically exposed after weaning, rats were 

trained to discriminate a muscarinic agonist (Cory-Slechta and Pokora, 1995) and were tested in 

the added presence of a muscarinic antagonist. The results suggest an increased sensitivity to at 

least one subtype of muscarinic receptor in Pb-treated rats. 

Glutamatergic functioning also has been assessed by use of the drug discrimination 

paradigm. Rats chronically exposed beginning at weaning and tested as adults exhibited 

diminished responsiveness to an NMDA subtype receptor antagonist (Cory-Slechta, 1995b) but 

enhanced responsiveness to lower doses of NMDA (Cory-Slechta et al., 1996b). When exposure 

was limited to the period between birth and weaning, the diminished sensitivity to the NMDA 

receptor antagonist was less evident, but still present (Cory-Slechta, 1997b). 

Thus, the drug discrimination paradigm appears to provide useful insights into the status 

of some neurotransmitter systems in chronically Pb-exposed animals. The reports cited above 

indicate an upregulation of dopaminergic, cholinergic, and glutamatergic receptors that are 

generally consistent with findings of diminished presynaptic function described earlier in this 

section of the current Lead AQCD. Nonetheless, this paradigm has some limitations. As all 

drugs in the cited studies were administered systemically, the results provide no evidence on 

brain regional sites of action. In addition, the chronic intermittent administration of the training 

drug has the potential to induce compensatory neuronal changes by itself, and thusly may mask 

or otherwise alter the manifestation of the effects of Pb exposure. Future use of this paradigm in 

Pb neurotoxicity studies must acknowledge this latter consideration. 

Other Effective Behavioral Test Paradigms 

Another test paradigm effectively utilized at least transiently to distinguish changes in 

chronically Pb-exposed animals is the repeated acquisition and performance schedule (Cohn 

et al., 1993). The purpose of this paradigm was to determine the selectivity of Pb-induced 

changes in learning, as distinct from nonspecific or performance effects, and to explore the 

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nature of the underlying error patterns contributing to any learning deficits. This schedule 

required completion of a sequence of three responses for reinforcement, with the correct 

sequence for the learning (i.e., repeated acquisition) component changing with each successive 

experimental session, while the performance component sequence remained constant across 

sessions. 

The use of this schedule in animals chronically exposed to Pb beginning at weaning 

uncovered significant decrements in accuracy on the learning component, but not on the 

performance component, in Pb groups compared to controls (Cohn et al., 1993). A detailed 

analysis of subjects’ behavior indicated that Pb exposure impaired learning by increasing 

perseverative responding on a single lever, even though such repetitive responding was not 

directly reinforced. In a subsequent study, dose-effect curves for the NMDA receptor antagonist 

MK-801 were determined in controls and animals tested in this paradigm in which chronic 

exposure began at weaning (Cohn and Cory-Slechta, 1993). The decline in learning accuracy 

and the increases in perseverative responding produced by MK-801 were attenuated by Pb 

exposure, and dose-effect curves relating MK-801 dose to changes in rates of responding were 

shifted to the right in exposed rats compared to control animals. These observations, therefore, 

demonstrated a subsensitivity of Pb-exposed animals to both the accuracy-impairing and 

response rate-altering properties of the antagonist. An additional investigation utilized the same 

Pb exposure protocol and administration of doses of NMDA as a receptor agonist to rats 

undergoing this test paradigm (Cohn and Cory-Slechta, 1994b). In control animals, NMDA was 

found to decrease accuracy of response in both the repeated acquisition and performance 

components of this multiple schedule and to suppress response rates as well. Lead exposure 

potentiated the accuracy-impairing effects of NMDA by further increasing the frequencies of 

errors and likewise potentiated the drug’s rate-suppressing effects. Thus, as stated earlier in this 

section, the Pb-induced potentiation of the agonist effects and reduced sensitivity to the 

antagonist effects in this test paradigm are consistent with an increased density or some other 

upregulation of NMDA receptors in exposed brain tissue. In other work, Cohn and Cory-Slechta 

(1994a) were unable to distinguish any evidence of dopaminergic modulation of responding in 

this behavioral paradigm. Thus, the repeated acquisition and performance schedule proved 

valuable not only in providing a finer dissection of the animal’s behavior, but in elucidating 

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important aspects of Pb neurotoxicity without some of the limitations inherent with drug 

discrimination or other behavioral test methods. 

Summary 

There is general agreement that the important factors in determining behavioral responses 

of Pb-exposed animals are (a) the nature of the test paradigm and its sensitivity to exposure and 

(b) the timing and intensity of the Pb exposure. Detailed analyses of responding have shown that 

Pb-exposed animals are less sensitive to the changing reinforcement contingencies that are 

integral to series of reversal tasks. They exhibit shortened initial periods of responding to the 

previously correct cue in combination with prolonged postperseverative learning phases for the 

new task. These have been proposed to be associative deficits based on deficiencies in learning 

new response contingencies. In addition, the impaired responding of Pb-exposed animals in 

vigilance tasks has been attributed to deficiencies in sustained attention and an increased 

reactivity to errors. 

Other test paradigms such as drug discrimination and repeated acquisition/performance 

tasks have provided useful assessments of the integrity of CNS neurotransmitter systems in 

Pb-exposed animals. Evidence from both paradigms has been in general agreement in indicating 

up-regulated neurotransmitter receptor systems. The timing of Pb exposure is critically 

important in determining the response to cocaine, and the potentiating action of perinatal Pb 

exposure is of potential importance for public health purposes. 

5.3.1.6 Lead-Induced Changes in Cellular Development and Disposition of the Metal 

Alterations in cellular differentiation and morphology can be important structural 

neuronal and glial components of the manifestations of Pb neurotoxicity. While these issues 

have not been thoroughly addressed by research investigations, there have, nonetheless, been 

important observations made. This subsection reviews studies concerned with various aspects of 

this topic. 

Lead Exposure and Neural/Glial Progenitor Cells 

Studies of the effects of Pb exposure on neural and glial progenitor cells are recent 

occurrences in the field of Pb neurotoxicity research. Chronic exposure in rats begun at postnatal 

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day 25 was found to significantly decrease proliferation of new cells in the dentate gyrus 

compared to the extent of this process in control animals (Schneider et al., 2005). Other workers 

initiated Pb exposure at birth and determined that continuous exposure to adulthood reduced the 

total number of labeled cells in the hippocampal dentate gyrus at 28 days, but not 24 h, after the 

last administration of a DNA synthesis marker (Gilbert et al., 2005). Rats whose exposure was 

terminated at weaning exhibited no changes in cellular labeling or survival, indicating that 

chronic exposure reduces the capacity for hippocampal neurogenesis. 

Studies have also been conducted to investigate the effects of exposure on glial progenitor 

cells. Deng et al. (2001) examined cultured oligodendrocytes and their progenitor cells acutely 

exposed to Pb2+ in vitro; they observed an exposure-induced delay in the differentiation of the 

progenitors, and that the progenitor cultures were more sensitive to Pb2+ than the mature 

oligodendrocytes. These findings suggested interference with the timely developmental 

maturation of the progenitor cells. A subsequent study found that a low concentration of Pb2+ in 

vitro inhibited proliferation and differentiation of these progenitors without affecting cell 

viability (Deng and Poretz, 2002). Proliferative capability was decreased and cell-intrinsic 

lineage progression was inhibited at a late progenitor stage. Thus, acute Pb2+ suppresses both the 

proliferation and differentiation of these cells. 

Lead Exposure and Neurite Outgrowth 

Neurite initiation is known to be highly sensitive to neurotoxic compounds and has been 

the focus of studies examining morphological alterations caused by exposure to Pb2+ in vitro. 

Kern and Audesirk (1995) found that 100 nM Pb2+ inhibited neurite initiation in cultured rat 

hippocampal neurons and, on the basis of results with kinase inhibitors, concluded that this 

occurred by inappropriate stimulation of protein phosphorylation by Ca2+-calmodulin-dependent 

or cyclic AMP-dependent protein kinases, possibly through stimulation of calmodulin. 

Intracellular free Ca2+ concentrations were not altered by up to 48 h exposure to nominal 100 nM 

Pb2+, leading these workers to propose that the stimulation of the above kinases or calmodulin 

were not via increased Ca2+ but, instead, were attributable to intracellular Pb2+ concentrations. 

Evidence of Pb2+-induced inhibition of neurite outgrowth is in general agreement with 

observations made after chronic exposure to Pb employing in vivo models. Cline et al. (1996) 

employed an exposure protocol of 0.1 nM–100 μM nominal Pb2+ for 6 weeks localized to the 

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retinotectal system of frog tadpoles, and observed a severely reduced area and branchtip number 

of retinal ganglion cell axon arborizations within the optic tectum at nM Pb2+ concentrations. 

Reuhl (1989) exposed primates to 2 mg lead/kg/day from infancy to 6 years of age and found 

that neuronal volume density was reduced in primary visual area V1 and in visual projection area 

V2 compared to a group exposed to 25 μg lead/kg/day. Moreover, a relative decrease in the 

number of arborizations among pyramidal neurons in both areas V1 and V2 was observed in the 

higher dose group. Thus, there is good correspondence between reports that acute Pb2+ exposure 

in vitro and extended exposure in animal models in vivo results in diminished neuronal growth 

and differentiation at Pb levels of apparent environmental relevance. Studies employing intact 

animals have not progressed to investigation of specific cellular mechanisms underlying these 

effects. 

Lead Exposure and Neural Stem Cells 

Given considerable contemporary interest in the use of neural stem cells to treat various 

neurological diseases, the efforts of Huang and Schneider (2004) to examine the actions of 

exposure to Pb2+ in vitro on these cells is worthy of note. Lead exposure produced no effect on 

neurosphere viability, but, it did cause a significant dose-dependent inhibition of proliferation. 

In addition, the number of neurons differentiated from Pb2+-exposed neurospheres was 

significantly decreased from control, as were the number of oligodendrocytes obtained. 

However, Pb exposure increased the number of astrocytes obtained. These observations suggest 

an important Pb2+-induced influence on stem cell proliferation and differentiation that has public 

health relevance to prenatal metal exposure. 

Accumulation of Lead in Brain 

Most studies of neurotoxicity involving chronic Pb exposure now report blood and brain 

Pb concentrations to quantify exposure magnitude and/or as quality control measures. Thus, a 

sizable amount of data is available on general aspects of Pb toxicokinetics. While brain Pb 

values vary monotonically with blood Pb concentrations and exposure levels, steady state 

accumulation/washout times are longer in tissue and are dependent on exposure magnitude and 

duration. The half-time for the decline of Pb in brain tissue when exposure is terminated is on 

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the order of 10 days to 2 weeks, while the value for blood leads would be a matter of a few days 

(Lasley, unpublished observations). 

The speciation and distribution of Pb in brain tissue is largely unknown except for indirect 

indications that only a small fraction of the divalent cation is present in tissue in extracellular 

fluid in the free ion state. The existence of a lead-binding protein in brain cytosol was reported 

by Goering et al. (1986) and was invoked to explain the relatively weak inhibition by Pb2+ of 

brain δ-aminolevulinic acid dehydratase activity. But the binding protein was not fully 

characterized or identified. Pb2+ is known to bind to various intracellular Ca2+ binding proteins, 

such as calmodulin, PKC, and synaptotagmin, particularly those with a C2 domain (Sun et al., 

1999), but these are low-volume sources that have been studied for their functional importance 

and would not serve any kind of tissue metal storage function. 

Pb2+ appears to be taken up into cultured cells by multiple ion channel-based mechanisms 

including influx through channels activated by depletion of intracellular Ca2+ stores, non-L-type 

Ca2+ channels, and NMDA receptor-associated channels (Kerper and Hinkle, 1997; Mazzolini 

et al., 2001). Astroglia are well known to act as a Pb sink and, in culture, accumulate up to 

24 times more of the metal than neuronal cells (Lindahl et al., 1999); and there is evidence that 

glutathione may regulate Pb uptake into these cells. Only recently has one astroglial protein 

been identified—a molecular chaperone in endoplasmic reticulum (Qian et al., 2000, 2005), 

glucose-regulated protein (GRP78). Intracellular levels of this protein are increased in cultured 

astroglia during one week’s exposure to Pb2+, suggesting that this protein is a component of the 

intracellular tolerance mechanism that handles high intracellular Pb accumulation through a 

direct interaction. GRP78 depletion significantly increased the sensitivity of cultured glioma 

cells to Pb2+ as indicated by the generation of reactive oxygen species. Thus, it appears that Pb2+ 

directly targets the protein and induces its compartmentalized redistribution, enabling it to play a 

protective role in Pb neurotoxicity. 

5.3.1.7 Integration of Research Findings 

It is evident that the Pb neurotoxicity literature is broad and varied and that many valuable 

observations have been made over the last 20 years. Nevertheless, a few general conclusions are 

in order so as to help integrate and concisely summarize evidence in at least a few focused areas. 

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• Lead-induced impairments in glutamatergic neurotransmission appear to underlie the 

deficits in synaptic plasticity and in learning or acquisition behavior. Cholinergic 

neurotransmission also serves an important role in impaired learning in exposed subjects, 

while deficits in dopaminergic function are manifested as alterations in rates of 

responding or incentive motivation. Exposure-related alterations in structural plasticity 

appear to be based on interference with Ca2+ signaling and/or glutamatergic transmission. 

• There is little if any support in the Pb neurotoxicity research community for the notion of 

thresholds for any of the toxic mechanisms that have been addressed in this section of the 

document. With the pressure to reduce experimental group sizes to the minimal number 

necessary and the unspecified notion that rats are somewhat more resistant to Pb than 

children, most studies performed with in vivo models report blood Pb values in the range 

of 15 to 35-40 μg/dL. Moreover, in view of the complex and undefined speciation 

equilibria and distribution of Pb in physiological milieus, there is no way to directly 

relate a blood Pb value to the levels of free Pb2+ ion or to any other complexed active 

form of the metal, either in extracellular or intracellular fluids. Generally accepted 

estimates of the free Pb2+ ion concentrations produced in brain extracellular fluid by 

environmentally relevant exposures fall in the low nanomolar range. 

• Susceptibility factors for Pb neurotoxicity are poorly defined in laboratory animals, and, 

thus, have not been studied. A compelling rationale for their investigation has not been 

provided. 

5.3.2 Neurotoxicological/Neurobehavioral Effects of Lead in Humans 

This section is divided into three sub-sections, based upon age and exposure scenarios. 

The sub-sections include (1) children with blood lead levels above and below 10 μg/dL, (2) adult 

manifestations of neurotoxicity and other disease states as a result of excessive exposure to lead 

as children, and (3) adults who were exposed to “ambient” levels of lead. In each of these subsections, wherever possible, discussion is focused on biochemical markers, bioclinical markers, 

and reversibility of lead’s neurotoxic effects. In addition, for each of the groups cited above, 

vulnerability to the neurotoxic effects of lead is considered. Topics in this area include 

developmental toxicology and growth and development in children. For children and adults, 

other aspects of vulnerability are considered, such as socioeconomic status, nutrition, and genetic 

polymorphisms. Based upon the body of studies discussed in each sub-section, it is reasonable 

to draw conclusions relating to dose-response paradigms and clinical extensions of 

epidemiological data to individual children. 

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5.3.2.1 Effects of Lead in Young Children to Mid-Adolescence 

Since EPA’s publication of the Air Quality Criteria Document and Addenda in 1986-

1990{EPA-600/8-83/028aF(1986); EPA/600/8-89/049F(1990)}, major studies with new and 

critical information have substantially extended previous hypotheses expressed by the EPA. 

These new data are the primary and major departure from EPA’s earlier lead criteria reviews. 

It is now recognized that lead has adverse effects on the developing central nervous system of 

young children and that these effects on cognition and behavior persist (at least) into the schoolaged years and beyond into mid-adolescence. While causal conclusions about effects of lead 

exposure on cognitive development are made with caution, collectively, the nature and 

abundance of the evidence is clear and compelling. This new information causally links 

detrimental effects of lead on behavior and cognition at blood lead levels both above and below 

10 μg/dL. Compared to the earlier EPA documents (cited above), there is solid evidence for 

detrimental effects of lead on neuropsychological functions such as fine motor skills, 

visual-spatial, and executive functioning and attention in large groups of children. Apparently, 

there is no threshold below which lead is without adverse effects on the central nervous system 

of young children to mid-adolescence. This conclusion is also related to dose-response 

paradigms of lead in children, as well as to extending the results of epidemiological studies to 

individual children. 

Biomarkers 

There are three generally recognized types of biomarkers (National Research Council 

[NRC], 1993; Lanphear and Bearer, 2005). The first of these is relevant to quantifying exposure 

and, thus, the internal dose of lead. This subject is covered in Section 6.1. The second type of 

biomarker focuses on effects. Biomarkers of effect are biochemical, physiological and/or 

clinically measurable alterations in normal functioning that reflect an impairment of health or a 

specific disease. Effects of this nature include early subclinical effects of lead that are of value 

in quantifying human health risks; as a result, such effects can lead to an understanding of 

mechanisms of lead toxicity at the cellular and organ level. An example of the latter are the 

impacts of lead on heme synthesis, which have been extensively studied as discussed in 

Section 5.2. Other examples include (in children) effects on the electrophysiology and 

architecture of the brain. In contrast, biomarkers of susceptibility or vulnerability are native, 

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inherent or acquired situational characteristics that alter the responses of children (and adults) to 

lead exposure. Examples of these biomarkers include socioeconomic status, nutrition, 

developmental aspects of brain functions, and genetic polymorphisms. Ultimately, these 

biomarkers, collectively, as a constellation, are considered to be contributing factors that assist in 

determining whether the cognitive effects of lead exposure in children are reversible. 

Biochemical Biomarkers 

In the AQCD of 1986, reported studies in lead-poisoned children (blood lead levels of 

12-120 μg/dL) revealed an inverse correlation (!0.88) between the entire range of blood lead 

concentrations and plasma levels of the vitamin D hormone (1, 25-dihydroxyvitamin D) in 

177 children from 1-16 years of age (Rosen et al., 1980; Mahaffey et al., 1982). These results 

suggested that lead impairs the biosynthesis of the Vitamin D hormone; and, as a result, calcium 

absorption, and possibly that of lead, could be inhibited. Because of 1,25-dihydroxyvitamin D’s 

roles in multiple cellular functions, including the calcium-messenger cascade, development and 

proliferation of multiple cell types, these clinical observations have substantial implications 

(NRC, 1993). These data from clinical studies were supported in experimental animals (Smith 

et al., 1981). In animals fed a low calcium or phosphate diet, oral administration of 0.82% lead, 

as the acetate, yielded plasma levels of 1,25-dihydroxyvitamin D that were substantially reduced. 

This effect of lead on circulating 1,25-dihydroxyvitamin D disappeared when either a high 

calcium or phosphate diet, including lead, was administered. Moreover, intestinal lead appeared 

to block the absorption of calcium in response to administration of 25-hydroxyvitamin D and 

1,25-dihydroxyvitamin D, although there was no influence on calcium mobilization neither from 

bone nor of mineralization of rachitic bone (Smith et al., 1981). 

More recently, in animals and children, this relationship has been examined further. 

Chicks fed lead concurrently on a low calcium diet replicated the findings in animals and 

children noted above. However, chicks fed a calcium sufficient diet coupled to dietary lead, 

failed to exhibit decreased plasma levels of the vitamin D hormone (Fullmer and Rosen, 1990; 

Fullmer, 1995, 1997). Similar findings were reported in lead poisoned children with adequate 

dietary intakes of calcium as those in experimental studies (Koo et al., 1991). Compared to the 

1980s, when dietary intakes of calcium were marginal (at best) in inner-city children, recent 

estimates of dietary calcium intakes in inner city children meet or exceed recommended daily 

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requirements of 1000 mg/day or greater (Markowitz et al., 2004). Thus, in calcium-sufficient 

children, plasma concentrations of 1,25-dihydroxyvitamin D are not biomarkers of lead’s effects 

on the vitamin D endocrine system. Nonetheless, in at-risk populations of children, whose 

dietary intakes of calcium are suboptimal, apparent biosynthesis of the vitamin D hormone, 

evidenced by decreased circulating levels of the hormonal form of the vitamin, 1,25-

dihydroxyvitamin D, is expected. 

Tang and co-workers (1999) assessed 244 infants on the Brunet-Lezine Scales at 

9 months of age to evaluate possible relationships between cord blood lead levels and plasma 

concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) at 

9 months of age. Cord blood lead concentrations were in the range of 2.5-7 μg/dL. At 9 months 

of age, 5-HIAA and HVA were negatively correlated with blood lead values and with all the 

neurodevelopmental functions, except for language, on the Brunet-Lezine Scales. The negative 

correlations between the serotonergic system, coupled to blood lead levels, were found in global 

scores, sociability, and coordination on the Brunet-Lezine Scales. Although further confirmation 

of these results is needed, these findings are consistent with the findings in experimental studies 

linking lead effects to impairments in neurotransmission (Section 5.3). 

Clinically Oriented Biomarkers of Effect 

Very little information was available in the time frame of 1986-1990 relating to clinically 

oriented biomarkers of lead’s effects on the central nervous system of children. Currently, there 

is a substantial body of knowledge which focuses on the functional status of the brain in 

excessively lead-exposed children. This new information includes functional (Bhattacharya 

et al., 1993; Rothenberg et al., 1995) and electrophysiological (Otto and Fox, 1993; Burchfiel 

et al., 1992; Poblano et al., 2001; Rothenberg et al., 2000) studies. The most relevant studies of 

functional and electrophysiologic data, relating to spectral analyses of EEGs, brainstem auditoryevoked potentials or responses (BAEP and BAER) are those based upon prospective designs of a 

well characterized cohort of children. Another line of important new information is based upon 

results from assessments of the biochemical and anatomical functions of the central nervous 

system in lead-exposed children carried out by magnetic resonance spectroscopy (MRS)(Trope 

et al., 2001; Meng et al, 2005). Some of these studies link observed results to cognitive 

impairments summarized in the general introduction to this chapter. Although there may be 

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some overlap in these reported studies, for the purposes of this discussion, studies are 

categorized as functional, electrophysiologic and biochemical-anatomical. 

A functional assessment of postural equilibrium was carried out in 109 children (in the 

Cincinnati Prospective Study) at 5.8 years of age when the mean blood lead was 5.8 μg/dL (the 

geometric mean blood lead for the first 5 years of life was 11.9 μg/dL). Postural sway was 

quantitated with a microprocessor-based platform. A negative correlation was found between 

blood lead levels and vestibular/proprioceptive systems, suggesting that lead exposure has 

detrimental effects on posture and balance. Although these data may have potential relevance to 

psychomotor deficits observed in lead poisoned children, this methodology has not been further 

developed, and its potential implications to psychomotor skills in children have not evolved 

(Bhattacharya et al., 1993). 

In the Mexico City Prospective Study, analyses of acoustical cries was carried out in a 

subset of healthy babies at 2, 15, and 30 days of life. The mean maternal blood lead at 12 weeks 

of pregnancy was 8.2 μg/dL, and the mean cord blood lead level was 7.8 μg/dL (range: 1­

38 μg/dL). The percent nasalization, produced by raising the velum of the velopharynx, 

decreased progressively over the cord blood lead range of 4-40 μg/dL, and the number of cries 

were inversely related to cord blood lead levels over the same range. In a subset of the babies, 

decreased nasalization was related to increased BAEP-evoked latencies. These findings 

suggested that altered baby cries and auditory functions may be associated with developmental 

delays affecting early communication. However, validation of infant cries as a predictor of 

subsequent infant development has not yet evolved. 

Burchfiel et al., (1992) studied a subset of the Philadelphia children reported on by 

Needleman et al. (1979). The method used was brain electrical activity mapping (BEAM) 

coupled to spectral analysis for each individual electrode. Nineteen children in the uppermost 

10th percentile for dentine lead (>24 ppm) were compared to children in the lowest 10th 

percentile (<6 ppm). The spontaneous resting EEG of the high lead children (n = 19) had higher 

percentages of low frequency delta activity and reduced percentages of alpha activity compared 

to the lower lead group of 12 children. Qualitatively, these EEG changes are similar to those 

observed in acute-severe lead poisoning, and, generally, such findings of diffusely increased 

slow frequency activity and reduced alpha are commonly found in toxic encephalopathies. 

These results, which are qualitatively similar to results from the Mexico City Prospective Study, 

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in which BAER were employed in a different age group, indicate that lead may induce 

neuropathological effects in a dose-response manner over a continuum of exposure (see 

Section 5.3). 

In the Mexico City Prospective Lead Study, 100-113 5 to7 year olds underwent testing by 

BAER (Rothenberg et al., 2000). The mean blood lead level at 5 years of age was 8 μg/dL. The 

results indicated that intervals I-V and III-V intervals of BEAR recorded at 5-7 years of age were 

related to maternal blood lead at 20 weeks of pregnancy, when the geometric mean blood lead 

was 7.7 μg/dL (range: 1-30.5 μg/dL). This specificity of the lead effect suggests that the CNS is 

exquisitely sensitive to lead when auditory structures are undergoing rapid development, and this 

effect appears to persist to 5 or more years later. As indicated in this study, lead-related 

alterations in auditory brain stem function may underlie verbal deficits in lead-exposed children, 

as well as impair auditory functions observed in lead-exposed animals (Section 5.3.1). Also, it 

becomes increasingly important to examine functional deficits in hearing and language 

development that may be associated with postnatal lead exposure. 

Nine to ten year-olds in the Mexico City Prospective Study were evaluated by 

determining relative theta activity across the scalp. These results, together with life time blood 

lead concentrations, were assessed by multiple regression models (Poblano et al., 2001). The 

most significant increases in theta power were associated with blood lead levels (geometric 

mean: 10.3 μg/dL) measured between 54 and 72 months of age. Spatially weighted regression 

showed that there was a significant anterior-posterior gradient in the lead-induced increase in 

relative theta activity associated with postnatal blood leads at 54-72 and 78-96 months. These 

lead effects occurred at an age during which relative theta power reaches its developmental 

maximum and then starts to decrease. These data have critical implications in understanding the 

neurotoxic and developmental impacts of lead exposure. If theta waves continue throughout 

childhood as one of the most dominant CNS rhythms, this could qualify as a developmental 

disorder and an “EEG soft sign.” Stated differently, persistence of theta activity reflects an 

‘immature” EEG pattern and/or brain injury. Neuropsychological testing concurrent with this 

electrophysiological methodology could add important information connecting direct measures 

of theta activity to CNS development indexed by neuropsychological outcomes (Lidsky, 2003, 

2005). 

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Using MRS, two studies (Trope et al., 2001; Meng et al., 2005) have provided new and 

important information. Both studies employed MRS with N-acetylaspartate (NAA). MRS has 

the capability to monitor brain metabolism by detecting NAA, a metabolite that is known to 

decrease during processes involving neuronal loss. Thus, this methodology provides both 

biochemical and anatomical information directly related to the neurotoxic effects of lead on the 

CNS. Trope et al. (2001) studied 16 lead-poisoned children (mean blood lead: 39.9 μg/dL; 

range: 23-69 μg/dL) who had a mean age of 8 years, 9 months. All of these children received 

medical attention before 5 years of age. The latter group was compared to 5 children (blood lead 

levels <10 μg/dL) who had a mean age of 8 years, 6 months. Both groups of children had 

normal MRIs. The lead-exposed group of children had significant reductions in NAA/creatine 

and phosphocreatine ratios in frontal gray matter compared to the nonexposed group. Review of 

medical records in the lead-exposed group failed to reveal an alternative or contributing etiology 

that could explain this demonstration of brain damage by MRS. These findings, in the regions of 

the frontal lobes, which are responsible for attention, executive functions and impulse control, 

are likely to be relevant to neurotoxic outcomes in lead exposed children, who may exhibit 

impairments in these areas. 

Using very similar techniques, Meng et al. (2005) evaluated 6 lead-exposed children 

(mean blood lead: 37 μg/dL) who lived near a lead-recycling industry for a period of at least 

5 years. These children had never been chelated. The lead-exposed children were compared to 

6 non-lead exposed children who had blood lead levels <10 μg/dL. On the Wechsler scale, the 

control children had a Full Scale IQ of 101 compared to 81 in the excessively exposed group. 

MRIs were normal in both groups of children. These data parallel those reported by Trope et al., 

(2001). However, Meng et al. (2005) reported decreased levels of NAA in the lead-exposed 

group in four brain regions: the left and right frontal areas and the left and right hippocampus. 

This study also found that MRS metabolites in the lead-exposed subjects were significantly 

reduced as compared with controls, thereby suggesting interference with neuronal functioning 

after lead exposure. 

Collectively, these electrophysiological and biochemical-anatomical data can assist in 

providing an understanding of the neurotoxicity of lead and neurophysiological outcomes in 

relatively “low” and “higher” level childhood lead exposure. Collectively, these data also appear 

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to provide evidence that lead interferes with the hard-wiring and differentiation of the central 

nervous system in children. 

Vulnerability and Susceptibility 

The unique susceptibility of children to the adverse health effects of lead were recognized 

previously by EPA in 1986-1990. Some of these aspects included the specific behaviors of 

children, including their metabolism of lead, physiological considerations that separate children 

from adults, greater potential absorption of lead per square meter of body surface, hand-to-mouth 

activity, and prevalence of nutritional factors that can enhance the absorption of lead from the GI 

tract. 

Since 1986-1990, an enlarged database is now available to construct a somewhat wider 

approach to understanding not only new information relating to children’s susceptibility, but also 

furthering characterizing interindividual variability as related to manifestations of lead’s adverse 

health effects in children. This section includes topics of developmental toxicology, growth and 

development, economic status, nutritional aspects of lead and children, and, finally, genetic 

considerations of children with possibly a biologically based genetic character interacting with 

exterior environmental realities. Considerations in this section also delve into risk assessment 

focused on some child-specific factors that affect health outcomes in populations as well as 

individual children. 

Moreover, as a general principle of toxicology and neurotoxicology, it is recognized that a 

variety of factors can either enhance or decrease an individual’s sensitivity to toxic exposures of 

lead. Besides individual children, there are factors that modify the selective neurotoxic 

responses of subgroups of children. Some of these variables that increase a child’s vulnerability 

are discussed below. 

Developmental Toxicology 

In addition to child-specific factors detailed above, it was concluded previously in 1986– 

1990 that the critical window of adverse health effects of lead in children was at less than 3 years 

of age, as briefly mentioned below and in greater detail in Section 6.3. This suggestion of age 

should be extended to children in their school-aged years to mid-adolescence (Chen et al., 2005; 

Ris et al., 2004; Dietrich et al., 2004) and into the adult years as well (Rice and Barone, 2000). 

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Developmental toxicity is usually defined by the occurrence of adverse effects on the 

developing organism prior to conception and/or during prenatal and postnatal development. 

Manifestations of developmental toxicity include death to the developing organism, structural 

abnormalities, impaired growth, and functional deficiencies. Moreover, developmental 

exposures can result in adverse health effects prenatally, postnatally, in childhood, into schoolaged years, and into adult age groups to the elderly (Selevan et al, 2000; Weiss, 2000; Rice and 

Barone, 2000). An important concept in risk management is to identify, whenever possible, 

developmental windows for evaluating dose-response relationships. Moreover, in risk 

management, identification of critical windows is aimed at recognizing especially susceptible 

sub-groups within the general population to provide specific interventions (Selevan et al., 2000). 

Information on critical windows of development is needed to assess real and potential 

environmental health risks (Weiss, 2000). 

To protect children’s health, it is necessary to understand their unique sensitivity to 

environmental toxicants, and, to further this understanding, functions of risk and exposure must 

be considered (Faustman et al, 2000). Risk is defined as the probability of an adverse outcome 

as a function of exposure and toxicity. It is evident that in development of the CNS, 

unidirectional inhibition at one developmental stage can cause substantial alterations in 

subsequent processes. In addition, stages of development occur in temporally distinct time 

frames across regions of the brain (Rice and Barone, 2000; Weiss, 2000). As a result, the CNS 

has a very limited capability to compensate for cell loss or other injury (Rice and Barone, 2000). 

Thus, exposure criteria should be based on information relevant to predicting risks and to 

accounting for toxicokinetic differences that occur during different stages of development 

(Faustman et al., 2000). 

Characterization of critical time frames of development in children are based, in large 

part, on the results of experimental studies discussed in Section 5.3.1. Initially, the critical time 

frame for adverse effects of lead on CNS development was considered to be in children <3 years 

of age (Bellinger et al., 1991, 1992) in that blood lead levels at 2 years of age were correlated 

with cognitive impairments at 57 months and 10 years of age. However, as indicated in Section 

6.3, the age range for time windows for lead’s adverse effects on the CNS has been significantly 

extended to school-aged children, into adolescence, and into adulthood (Dietrich et al., 1993; 

Tong et al., 1996; Wasserman et al., 2000; Canfield et al., 2003, 2004; Chen et al., 2005; 

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Lanphear et al., 2000, 2005). Moreover, recapitulation of synaptogenesis in the form of synaptic 

plasticity is modified by experience and the environment as children become adults and age into 

the elderly life phase (Rice and Barone, 2000). This concept provides a toxicological framework 

for identifying latent or persistent expressions of childhood lead exposure in adults as “growing 

into a lesion” (Ris et al., 2004) or magnification of an earlier insult with aging (Rice and Barone, 

2000). This toxicological recognition of latent or persistent expressions of childhood exposure in 

adults forms the basis of Section 5.3.2.2, discussed below. Additional areas of concern for 

children related to risk assessment include consideration of lead’s deleterious effects on somatic 

growth, socioeconomic status, nutritional correlates of lead exposure and interactions between 

biologically inherent genetics and the external environment (discussed below). 

Growth and Development 

In the Supplement to the 1986 Addendum (EPA/600/8-89/049F), early results from 

prospective studies in Cincinnati, Boston, Port Pirie, and Yugoslavia were noted in terms of 

lead’s effects on perinatal and postnatal growth and development. However, evidence regarding 

physical growth effects related to prenatal or early postnatal exposure were inconsistent. 

Limitations in these early data from prospective studies included definitions of the length of 

gestation, racial makeup, maternal age, sample sizes, and levels of lead exposure. It appeared 

likely that prenatal lead exposure did pose a potential hazard to the developing fetus as related to 

reduced gestational length and possibly other aspects of fetal growth. It proved difficult, 

however, to define a definite dose-response relationship for fetal outcomes, although there were 

some indications that pointed to adverse effects on the fetus at blood lead levels of 10-15 μg/dL. 

More recently reported data have extended assessments of impacts of lead on early 

postnatal outcomes (birth weight, early weight gain to 1-month of age, birth length and head 

circumference) to measurements of maternal bone lead post-delivery by K-XRF. Additional 

studies have analyzed national data (NHANES III) in terms of the growth patterns of children 1 

to 7 years of age. From the same national survey, other studies have focused on sexual 

maturation as a function of blood lead concentrations. 

Gonzalez-Cossio et al. (1997) assessed the possible relationship of blood lead levels in 

cord blood and maternal bone lead to birth weight in Mexico City. Two hundred seventy-two 

mother-infant pairs were studied, and the cord and maternal blood lead levels were, on average, 

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7.1 and 8.9 μg/dL, respectively. Tibial lead (not patellar lead), measured 1-month postpartum by 

K-XRF, was the only marker related to birth weight, such that, at the highest quartile of bone 

lead (15.15 μg/g bone mineral), infants were, on average, 156 grams lighter at birth. Although 

these data appear to extend previously reported information from prospective studies, some 

caution in the interpretation of these data is indicated: 10% of tibial lead values and 13% of 

patellar lead levels were below the instrument’s detection limit (as defined by the authors), but 

these negative values were included in the statistical analysis. By necessity, the study design 

was cross-sectional, because, for ethical reasons, bone lead measurements are precluded during 

pregnancy due to radiation exposure, and, for unexplained reasons, there were no statistically 

significant relationships with blood lead values in mothers or infants. 

Sanin et al. (2001) studied a similar population in Mexico City comprising 329 motherinfant pairs. The umbilical cord blood lead (mean) was 6.8 μg/dL and the mean value for the 

infants was 5.6 μg/dL at 1-month of age. A 10 μg/dL increase in infant blood lead levels at 

1-month was associated with a 142 gram decrease in weight gain. Thus, lead exposure 

postnatally had adverse effects on early perinatal weight gain. In addition, maternal patellar lead 

at 1-month was negatively associated with weight gain as well. The important finding in this 

study was the inverse correlation between postnatal blood lead and weight gain. However, the 

significance of maternal patellar lead by K-XRF is limited by the large standard deviation in the 

measurement of patellar lead (15.2 μg/g bone mineral) and a revised statistical method for 

calculating bone leads, which was not delineated in this article. Moreover, the failure of 

maternal blood lead concentration to predict early or subsequent birth weight was unexplained. 

In the third of this series of reports from Mexico City, 233 mother-infant pairs were 

evaluated as described above, but the outcome measures were birth length and head 

circumference. These results showed that bone lead biomarkers (tibia and patella) were 

associated positively and significantly with maternal and umbilical cord lead. However, only 

patellar lead was significantly and negatively associated with birth length and head 

circumference. These associations were independent of maternal venous blood lead levels, 

umbilical cord lead levels, and other predictors of birth size, including birth weight. Similar 

concerns apply here, as those above, relating to K-XRF measurements. Collectively, except for 

the relationship between postnatal blood lead concentrations and decreases in weight gain (Sanin 

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et al., 2001), the cumulative findings relating to perinatal and postnatal outcomes, as indexed by 

bone lead values, fail to provide a consistent or readily interpretable set of conclusions. 

Evaluation of 4391 children 1-7 years old was carried out using the nationally 

representative data from NHANES III. This population study included non-Hispanic white, nonHispanic African-American, and Mexican-American children, and the outcomes measured were 

stature, head circumference, weight and body mass index (Ballew et al., 1999). Blood lead 

levels were significantly and negatively related to stature and head circumference, yielding a 

predicted decrease of 1.57 cm in stature and a 0.52 cm decrease in head circumference for each 

10 μg/dL increase in blood lead values. There was no statistically relevant association between 

blood lead and weight and body mass index. These robust findings are of considerable 

importance, because the observations are very similar to those reported earlier for NHANES II 

by Schwartz et al. (1986). Thus, although blood leads declined substantially in the United States 

over two decades (NHANES II vs.NHANES III), lead exposure at considerably lower levels 

continued to affect the growth of some children. Stated differently, there was no attenuation of 

the negative association between blood lead levels and indices of growth in children despite a 

substantial decrease in national blood lead values in young children. Collectively, these crosssectional national surveys (Schwartz et al., 1986; Ballew et al., 1999) indicate the following 

negative associations with blood lead values: a 1.0-1.5 cm decrease in stature and a 0.50 cm 

decrease in head circumference coupled to modest increases in blood lead levels within the range 

of blood lead levels in children in the United States. Over the past two decades, these data 

provide the most compelling data sets related to the adverse effects of lead on growth patterns in 

young American children. 

Two studies, utilizing NHANES III data, have measured pubertal development, as related 

to blood lead concentrations, to determine whether sexual maturation may be affected by current 

environmental lead exposure (Wu et al., 2003; Selevan et al., 2003). In the study by Wu et al. 

(2003), pubic hair and breast development were evaluated in 1,706 8–16 year-old girls, and 

information on menarche was delineated in 1,235 girls 10–16 years of age. The blood lead range 

was 0.7–21.7 μg/dL. This population was categorized into three groups, according to blood lead 

values: 0.7–2.0, 2.1-4.9, and 5.0–21.7 μg/dL. Sexual maturation markers were self-reported 

attainment of menarche and physician-determined Tanner stage 2 pubic hair and breast 

development. The results indicated that girls who had not yet reached menarche or stage 2 pubic 

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hair had higher blood leads than those girls who had. Negative relationships were found for 

blood leads with attainment of menarche and stage 2 pubic hair after adjusting for covariates; no 

relationships were evident for breast development. 

Selevan et al. (2003) studied a subset of girls (8-18 years old) from NHANES III that 

included 600 non-Hispanic white, 805 non-Hispanic African-American, and 781 MexicanAmerican girls, who, collectively, had a geometric mean blood lead level of 3 μg/dL. For all 

girls who had blood lead levels of 3 μg/dL compared to those whose blood leads were 1 μg/dL, 

the higher lead group had a significant decrease in height after adjustment for confounders. 

Also, in the higher lead group of girls, there were significant delays in breast and pubic hair 

development, especially in non-Hispanic African-American and Mexican-American girls. Of the 

latter two groups, the most profound delays were observed in non-Hispanic African-American 

girls. The delays in reaching Tanner stages 2, 3, 4, and 5 (in all girls) was associated with those 

whose geometric mean blood lead was 3 μg/dL (as compared to all girls whose geometric mean 

blood lead level was 1 μg/dL) were 3.8, 5.3, 5.8, and 2.1 months, respectively, for breast and 

pubic hair development. There were no significant delays found in non-Hispanic white girls. 

These findings, within a narrow blood lead range, indicate that environmental lead exposure can 

delay growth and pubertal development in girls. Thus, analyses of these national surveys in 

children 1-7 years old and in girls 8-18 years old provide strong evidence for adverse effects of 

lead on the growth of young children and adolescent girls at blood lead concentrations 

commonly found in the U.S. population today. 

Socioeconomic Status 

In the U.S. EPA’s Supplement to the 1986 addendum (EPA/600/8-89/049F), very little 

information was discussed relating to socioeconomic status (SES) and the vulnerability of 

children to lead exposure and resulting deficits in cognitive skills. Primarily as a result of 

analyses of NHANES III, the importance of SES has reached its appropriate focus and attention. 

Additional peer-reviewed articles have also contributed to now well-documented interactions 

between SES and children’s vulnerabilities to the neurotoxic effects of lead. 

A child’s SES clearly has an important influence on the possibility of lead exposure in 

young children. Disadvantaged children may have an already compromised neuropsychological 

status that is further impaired by the toxic effects of lead. Although the exact mechanisms of the 

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impact of SES on lead’s neurotoxic effects on the central nervous system are unknown, poverty, 

pre-1960 housing in segregated communities, ethnicity, and nutritional deficiencies, collectively, 

can contribute substantially to increased vulnerability of individual children and subgroups of 

children. The peer-reviewed literature, discussed in this section and in the following section, 

provides support for these conditions contributing to children’s susceptibility to the toxic effects 

of lead. 

An analysis of the early phase (1988-1991) of NHANES III was carried out by Brody 

et al. (1994), in which 13,201 persons from 1 year of age through elderly adults were assessed 

via a multiple stage probability design. It was found that the prevalence of elevated blood lead 

levels for children in low-income families (16.3%) was about four times higher than the 

prevalence for children with high family incomes. Non-Hispanic African-American children 

from low-income families had the highest proportion of elevated blood lead values (28.4%). 

A comparison of results from NHANES II and NHANES III (Pirkle et al., 1994) extended 

data reported earlier (Brody et al., 1994). From 1976 to 1991 (NHANES II vs. early NHANES 

III) there was an overall decline in all children 1-5 years old from 15.0 to 3.2 μg/dL (geometric 

means). For non-Hispanic white children, the decline was from 13.7 to 3.2 μg/dL, whereas for 

non-Hispanic African-American children, the decline was from 20.2 to 5.6 μg/dL. Income levels 

were based upon those previously determined by the U. S. Census Bureau: income level was 

defined by the poverty-income ratio (PIR), so that the total family income was divided by the 

current poverty threshold. PIRs were divided into three categories: low (0 < PIR < 1.30; midrange (1.30 < PIR 3.0) and high (PIR > 3.00). Based upon PIRs, it is noteworthy that mean 

blood lead levels decreased by 60% (24.0 to 9.7) for African-American children from lowincome families living in central cities with populations of 1 million or more. The latter value 

for low-income African-American children was about 3 times the mean value for non-Hispanic 

white children. 

An analysis of phase 2 of NAHANES III showed that it becomes increasingly evident that 

SES factors, including sociodemographic factors, are closely related to average blood lead 

concentrations in young children (Pirkle et al., 1998). By phase 2, the average blood lead in all 

children 1–5 years old was 2.7 μg/dL. The prevalence of elevated blood lead levels in 

African-American children living in pre-1946 housing was 21.9%; the prevalence in all children 

of low-income families living in pre-1946 housing was 16.4% (demographic status was 

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determined by U.S. Department of Agriculture codes populations according to proximity to 

major metropolitan areas). Low incomes among all ethnic groups, defined by PIRs, were 

significantly associated with higher blood leads (details of these data were not provided in the 

article). It is reasonable to conclude that U.S. children, based on ethnicity, housing age, and 

income, are disproportionately exposed to excessive levels of lead in their environments. 

SES was further considered in NHANES III (1988-1994) based upon age and blood lead 

concentrations (Bernard and McGheehin, 2003). Overall, 25.6% of children 1-5 years old had 

blood leads equal to or greater than 5 μg/dL; but most of these children (76%) had blood leads 

less than 10 μg/dL. Of those children who had blood leads greater than 5 μg/dL, 46.8% were 

non-Hispanic African-American compared to 18.7% non-Hispanic white children. Housing 

status also played a significant role: 42.5% of children who had blood leads greater than 5 μg/dL 

lived in pre-1946 housing, 38.9% lived in housing built between 1946-1973, and 14.1% of 

children in this blood lead group lived in housing built after 1973. Compared to non-Hispanic 

white children, African-American children were 3 times more likely to have blood leads greater 

than 5 μg/dL, 7 times more likely to have blood leads of 10-20 μg/dL, and 13.5 times more 

likely to have blood leads equal to or greater than 20 μg/dL. Low-income families, defined by 

PIRs, were at substantially elevated risk for having children with blood lead levels above 5 

μg/dL, and the odds ratios in these families were the highest when comparing the 10-20 μg/dL 

group to those children with blood leads <5 μg/dL. 

Among Native American children, 1 to 6 years old, living near a Superfund site in 

Oklahoma, strong interactions were observed between blood lead levels and poverty, suggesting 

that poor children were especially vulnerable to the toxic effects of lead (Malcoe et al., 2002). 

Moreover, blood lead levels were significantly higher in 52,407 WIC-enrolled families between 

1996-2000 compared to non-WIC-enrolled families indicating the vulnerability of children with 

low incomes and poorer nutritional status (Zierold et al., 2004). 

Similar findings have been reported from the Port Pirie prospective study (Tong et al., 

2000); 375 children, 11-13 years of age, were assessed by Daniel’s Scale of Occupational 

Prestige, which is a surrogate for SES. With adjustment for confounders, Wechsler-derived IQ 

scores were reported in three groups of children according to their lifetime blood lead values of 

<12, 12.1-17, and >17 μg/dL, respectively. For the less than 12 μg/dL group, the IQ in the high 

SES children was 105.6 vs. 103.1 in the low SES group. In the mid-range blood lead group 

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(12.1-17 μg/dL), the IQ score for the high SES group was 104.4 vs. 100.6 in the low SES group. 

For the higher lead group, the largest differential in IQ scores was apparent: high SES, 101.5 vs. 

90.9 in the low SES group. Poor children were especially vulnerable to the neurotoxic effects of 

lead. 

Familial and nonfamilial factors were discerned in 717 children, some of whom lived in 

Detroit (urban group-low SES) compared with a group of suburban-based middle class children 

(Breslau et al., 2001) who lived outside Detroit. Children were prospectively tested via the 

Wechsler at 6 and 11 years of age. Although blood lead levels were not included in this study, 

the results are of interest. On average, in the urban children, over time, there was a downward 

shift of 5 IQ points in the disadvantaged children while a negligible change was found in the 

suburban-middle class group. Income and demographic data for the two groups of children were 

defined by the 1990 U.S. Census data. Despite the absence of blood lead concentrations, it is 

reasonable to suggest that compared to the suburban children (according to the 1990 U. S. 

Census data utilized), that urban Detroit children were more likely to be exposed to lead based 

paint in their home environments. Familial determinants of IQ, such as maternal IQ, education, 

and marital status, exerted stable and uniform influences on children’s IQ scores across age in 

both communities; none of these variables were associated with change in IQ scores. Although 

family factors (maternal IQ specifically) explained about two-thirds of the initial 14 point 

disparity in IQ scores between urban vs. suburban children, such factor(s) did not account for 

any part of the IQ decline of 5 points (on average). These authors concluded that IQ is a “joint” 

product of “genetics” and the environment. The authors emphasized that the disadvantages of 

inner city children, including ethnicity, housing, segregation, and educational opportunities 

underscores the need to fully examine extrafamilial factors, including a community’s economic 

resources, to understand predictors of children’s IQs. Although family and community factors 

are not completely separable, these observations reflect, in part, the legacy and vulnerability of 

children growing up is socioeconomically disparate communities. 

Based upon the studies discussed above, there is conclusive evidence that SES has a 

profound influence on children’s vulnerability and susceptibility to the neurotoxic effects of lead 

exposure. 

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Nutrition 

There was little discussion of nutritional factors and their impacts on children’s 

vulnerability to lead in earlier EPA documents, because very little, if any, information was 

available at that time. It has become evident that the dangers of lead exposure in children are 

substantially enhanced by diet deficient in calcium, iron, zinc and other essential nutrients; 

specific dietary deficiencies are not infrequently coupled to increased susceptibility to lead in 

low SES children. 

In 205 one-year olds, who were low SES infants and who were living in old housing, 

blood lead levels were measured and related to nutrient intake (primarily of fat). This sample 

was stratified so that excessive exposure to lead could be analyzed as an independent or 

dependent variable to account for changes in blood lead values (Gallicchio et al., 2002). 

Exposure to environmental lead was assessed by measurements of lead in household dust. The 

authors reported a positive association between household dust levels and blood lead 

concentrations, and positive associations were also found between dietary intake of total calories 

and fat. The latter dietary observations were found to be independent of environmental exposure 

to lead at dust lead values above the 2001 EPA Guideline (Federal Register, 2001). These results 

implied that dietary control of fat and total caloric intake could have a beneficial effect on 

children’s blood lead levels independent of environmental exposure, although the authors 

cautioned that control of the external environment was also a critical factor in modulating 

children’s blood lead levels. Similar findings were reported by Lucas et al. (1996). The 

relationships between blood lead levels and nutritional factors were studied in 296 children who 

ranged in age from 9 to 72 months from low-SES families in Baltimore. When environmental 

lead exposure was statistically controlled, dietary fat intake had a positive association with blood 

lead levels, particularly in children who had blood leads >15 μg/dL. 

Several studies have established a negative association between dietary iron intake 

(as well as biochemical assessments of iron status). Hammad et al. (1996) evaluated 

299 children (9 months to 5 years of age) in a cross-sectional study design. The mean blood lead 

in this group was 11.4 μg/dL, and the mean age of the entire group of children was 26.2 months. 

After adjustment for confounders, the authors reported that the highest quartile of dietary iron 

intake had the lowest blood lead values. Bradman et al. (2001) studied 319 1-5 year-old children 

in Sacramento, CA in terms of iron status as measured by serum levels of ferritin, and 

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environmental exposure to lead from soil and lead-based paint. 24% of this sample was iron 

deficient defined as a serum ferritin level <12 ng/dL. Blood lead levels were higher for each 

tertile of iron-deficient children who were also experiencing excessive exposure to exogenous 

lead; and the greatest difference between iron-deficient compared to iron-replete children 

(a mean difference of 3 μg/dL) was in children who had on-going excessive exposure to lead. 

It was concluded that improvement of iron status, coupled to control of environmental lead 

sources led to a significant decline in blood lead concentrations. 

An important study was carried out in an urban (Boston) primary care setting of 3,650 

9-48 month-old children, and comparisons were made between iron status and “low-level” lead 

exposure. Iron deficiency was defined according to red blood cell indices, including mean 

corpuscular volume (MCV) and red cell distribution (RDW). During the study period of 1994­

1996, 9.9% of the children were iron deficient, defined by cut-offs for MCV and RDW, and 

9.4% of these children had blood lead concentrations of 10 μg/dL or greater (Wright et al., 

1999). Among lead-poisoned children, 11.6% were iron deficient. Blood lead levels ranged 

from less than 5 to 44 μg/dL. More than 50% of the children screened had blood lead 

concentrations below 5 μg/dL; and the median blood lead was 5 μg/dL. Blood lead levels were 

stratified into 3 categories: less than 5 μg/dL, 5–9 μg/dL, and greater than 10 μg/dL. Chi-square 

analysis showed a significant association between rising blood lead levels and iron deficiency, as 

previously defined. In group comparisons, the mean ages of the patients with blood lead levels 

less than 5 μg/dL and 10 μg/dL or greater differed significantly from each other, as did those of 

patients with blood lead levels of less than 5 μg/dL and 5-9 μg/dL. In contrast, there was no 

significant difference in the mean age for patients with blood lead levels of 5-9 μg/dL and those 

with blood lead values of 10 μg/dL or greater. Odds ratios were calculated based upon the 

postulate of iron deficiency as a predictor of blood lead levels after controlling for age, 

hemoglobin, and insurance status. The odds ratios were 1.63 for a blood lead concentration of 

5 μg/dL or more and 1.44 for a blood lead concentration of 10 μg/dL or more among iron 

deficient children. This study concluded that the combination of increased RDW and decreased 

MCV (markers of iron deficiency) is associated with blood lead concentrations of more than 5 

and more than 10 μg/dL. Thus, this important study demonstrated that iron deficiency is 

associated with even lower blood lead levels than currently found in the United States. 

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However, it is important to point out that the associations is not as strong as reported in children 

with more severe lead poisoning, as discussed above. 

In this study (Wright et al., 1999), the combined prevalence of lead poisoning and iron 

deficiency was present in 1.1% of the children tested. Therefore, secondary preventive measures 

of childhood lead poisoning, such as selective dietary interventions (iron supplementation), to 

reduce the intestinal absorption of lead can be simultaneously pursued in tandem with primary 

preventive efforts (Rosen and Mushak, 2001). 

Kordas et al. (2004) examined whether iron status could account in part or for all of the 

negative relationship between cognitive performance and lead exposure in 602 6-8 year old 

children living near a metal foundry in Torreon, Mexico. The average blood lead level was 

11.5 μg/dL with a standard deviation of 6.1, and 50% of this group had blood lead levels above 

10 μg/dL. The results showed that the relation between blood lead and cognition was not 

strongly affected by nutritional status (iron and zinc), indicating that the association between 

blood lead and cognition was not explained by the presence of iron deficiency in a relatively 

intact group of children from the standpoint of nutrition (21.7% were iron deficient). However, 

low serum ferritin values were more prevalent in children who had blood lead concentrations 

above 15 μg/dL than those below 15 μg/dL (33.0 vs. 18.4%, p<0.001). Furthermore, successive 

addition of iron status did not attenuate lead’s negative association with several cognitive 

outcomes. 

Based upon these reports, it is reasonable to conclude that caloric and fat intake have 

important effects on blood lead levels in children. Furthermore, based on the above evidence, 

the inverse association between iron status and blood lead levels is clearly documented in 

children with low-level lead exposure to more severely elevated blood lead values. 

Limited information is available concerning effects of iron supplementation on blood lead 

levels. Rico et al. (2005) have tested the efficacy of iron (and zinc) supplementation in 515 

6-8 year-old children living in close proximity to the lead metal foundry in Torreon, Mexico. 

This was a randomized, double blind, placebo-controlled study with about 125 subjects in each 

treatment/placebo group. In addition to supplements or placebo paradigms, selective tests of 

cognitive functioning were also administered at baseline and 6 months later. The overall 

prevalence of iron and zinc deficiency was 21.7 and 28.9%, respectively. Thus, in relative terms, 

this was a reasonably well off population from a nutritional standpoint, with a group of children 

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many of whom had been excessively exposed to lead since birth. The mean blood lead level was 

11.5 μg/dL (SD of 6.1). Cognitive improvements were not discerned in any of the 11 measures 

employed, and there was a very modest decrease in blood lead levels of only 2.6% (or about 

0.30 μg/dL) for the iron supplemented group. These negative findings can be explained by the 

relatively intact iron status in the majority of children at baseline, and the negative results of 

cognitive testing can be attributed to a population of children who had been excessively exposed 

to lead for long timeframes. In contrast, 191 children from a community project in Costa Rica, 

divided into five treatment groups, had an average blood lead level of 10.98 μg/dL (Wolf et al., 

2003). Oral iron supplementation led to a mean decrease in blood lead levels of 1.2 μg/dL over 

3 months. These authors concluded that iron therapy can have a substantial effect on decreasing 

blood lead levels, particularly in children whose iron status is the most compromised and if 

treated promptly. Interpretation of the results of this study require some degree of caution, 

because of the limited sample size in each of the five groups. 

Mahaffey et al. (1986) analyzed calcium intakes in comparison with blood lead levels in 

NHANES III. The MEAN and 25th, 50th and 75th percentiles for blood lead concentrations in 

2,926 children were, respectively, 15.7, 11, 14, and 19 μg/dL, Corresponding dietary calcium 

intakes were, respectively, 851, 522, 789, and 1,110 mg/day. Dietary calcium intake was a 

significant explanatory variable for blood lead, and this relationship was inverse. Thus, in this 

national survey, a significant and independent inverse association was observed between dietary 

calcium intake, assessed by the 24-h recall method, and blood lead levels. 

One hundred sixty-nine Albany-based mother-infant pairs were evaluated every 3 months 

during the first year of life according to calcium intakes measured by 24-h recall (Schell et al., 

2004). The geometric mean value for blood leads in infants at birth was 1.6 μg/dL; this value 

rose to 5.1 μg/dL by 12 months of age, when 18% of the sample had elevated blood lead levels 

(Schell et al., 2004). A significant inverse relationship between calcium intake and blood lead 

values was found at 6 months; but only the inverse relationship with iron and blood leads 

persisted to 12 months. The majority of infants in this study met the recommended daily 

allowances for calcium. 

Recent studies that have assessed the impact of calcium on blood lead levels have yielded 

reasonably consistent results. Sargent et al. (1999) studied 103 children 3.5 to 6 months of age; 

these infants were followed for 9 months, receiving either no treatment of calcium supplements 

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or treatment to increase daily calcium intake from about 450 mg/day to a supplemented intake of 

about 1700 mg/day. Through 4 months of supplementation, the median increase in blood leads 

was 57% compared to the control group. However, beyond 4 months of treatment, the effect on 

calcium was attenuated. Up to that time, coupled to measurements of household dust lead, 

calcium supplementation appeared to impair the absorption of lead from the GI tract; but this 

apparent effect was not sustained. 

In a randomized, double blind, placebo-controlled study, 67 children (1-6 years old), 

whose blood lead values ranged from 10-45 μg/dL, were given a placebo or a calcium 

supplement to reach a daily intake of about 1800 mg/day. The mean blood lead levels at baseline 

were 21.4 and 20.7 μg/dL in the placebo and treatment groups, respectively. All children in this 

study, from an inner-city group of children in the Bronx, NY, were at or above the daily 

recommended allowance (RDA) for calcium. Blood lead levels declined similarly in placebo vs. 

treated groups over the 3-month study period without a differential in final blood lead 

concentrations between the two groups. It appears that there is a negative association between 

blood lead levels and calcium intake, particularly, in children who fall below the RDA for 

calcium. However, even in inner-city children, current calcium intakes appear to readily meet 

expected RDAs, most likely accounting for the failure of calcium supplements to have effects on 

blood lead values. 

Genetic Polymorphisms 

A paucity of information was previously available in EPA’s documents in the time frame 

of 1986-1990. Since that time, at least three genes have been identified that may affect the 

accumulation and toxicokinetics of lead in children and adults. The three genes are ALAD, the 

vitamin D receptor gene (VDR), and the hemochromatosis gene (HFE). Relatively few studies 

relating to genetic polymorphisms have been reported in children compared to a substantial body 

of clinical research studies reported especially in excessively exposed adults. ALAD, VDR and 

HFE are discussed here in detail to serve as an introduction for clinical research reports in adults. 

The primary importance of incorporating a discussion of genetic polymorphisms in the 

field of environmental health is their usefulness in detecting differences in levels of risk within 

specific populations (Kelada et al, 2003). The range of responses to toxic environmental 

exposures can vary, and population attributable risk may be substantial. Furthermore, 

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understanding the possible role of genetic polymorphisms in risk assessment can lead to an 

enhanced delineation of mechanisms underlying toxic exposures. 

The ALAD gene (chromosome 9q34) encodes for ALAD, which catalyzes the second step 

of heme synthesis and is polymorphic. This polymorphism yields two codominant alleles, 

ALAD-1 and ALAD-2, and these have been differentially implicated in some clinical research 

studies to lead toxicity (Kelada et al., 2001). It is evident that genotypic frequencies differ by 

ethnicity and geography; and these considerations require careful assessment in the interpretation 

of research results. It has been suggested in some studies that ALAD-2 may possibly offer some 

level of “resistance” to the toxic effects of lead by generating a protein that avidly binds to lead, 

perhaps sequestering lead from its toxic expressions at various tissue sites. Other studies suggest 

that the rarer ALAD-2 allele has been associated with higher blood lead levels and may, thereby 

increase the risk of lead toxicity by producing a protein that binds more tightly than the ALAD-1 

protein. Some recent studies in adults have reported that individuals homozygous for the 

ALAD-1 allele have higher cortical bone lead concentrations and may be at higher risk for longterm adverse effects of lead. Occupationally exposed adults have been most frequently studied 

in terms of the possible interaction of ALAD polymorphism and adverse health outcomes. As 

discussed below, reports in children concerning ALAD polymorphism and risk assessment are 

limited. 

The vitamin D receptor (VDR) is a ligand-activated transcription factor that modulates the 

genomic effects of the vitamin D hormone, 1,25-dihydroxyvitamin D, in a wide variety of 

tissues. The gene encoding for VDR is on chromosome 12q and has common allelic variants 

(Zmuda et al., 2000). The allelic variants and their halotypes have been extensively studied with 

regard to osteoporosis susceptibility. Studies involving other disease states, such as breast and 

prostate cancer, diabetes, coronary artery disease, and primary hyperparathyroidism, have also 

focused on the role(s) of VDR gene variants. Consideration of VDR gene variants have also 

been extended to populations with increased lead exposure, particularly within an occupational 

setting. Very little information is available on these gene variants and lead exposure in the 

pediatric age group. 

Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron 

metabolism characterized by an increase in iron absorption and deposition in the liver, heart, 

pancreas, joints, and pituitary gland. HFE, the gene for HHC, has been mapped to the short arm 

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of chromosome 6 (Hanson et al., 2001). Two of the 37 allelic variants of HFE, described to date, 

C282Y and H63D have been significantly correlated with HHC. Homozygosity for the C282Y 

mutation has been found in the majority of patients and their probands diagnosed with HHC. 

Implications of HFE polymorphism have been proposed in studies of adults excessively exposed 

to lead, particularly in occupational settings. No studies of HFE have been reported in children 

with varying blood lead concentrations. 

As yet, studies have failed to evaluate arylsulfatase (ASA) polymorphisms in lead 

exposed children and adults. ASA is recognized as playing a significant role in regions of the 

brain known to be affected by lead, and it has been established in experimental studies that lead 

produces low levels of ASA at sensitive stages of nervous system development (Poretz et al., 

2000). Studies of ASA in children and adults may yield important information that may explain 

some of the neurocognitve effects of lead in pediatric and adult populations. As yet, no studies 

of this nature are available. 

A group of 142 lead-poisoned children (mean blood lead: 27.1 μg/dL; SD: 15.2) in New 

York City children who expressed the 2-2 or 1-2 isozyme phenotype were reported to have blood 

lead levels 9-11 μg/dL higher than children who were homozygous for the ALAD-1 allele 

(Wetmur et al., 1991). These authors suggested the possibility that, because the ALAD-2 

polypeptide binds lead more effectively, these individuals may be more susceptible to lead 

poisoning. At the time of publication, the lead binding properties of purified ALAD1-1 and 2-2 

proteins and tissue distribution of these alleles were unknown. 

The relationship was investigated between ALAD isozymes and blood lead levels in 

229 Chinese children within the age range of 6-10 years old (Shen et al., 2000). The mean blood 

lead value was 10.3 μg/dL (SD: 3.3) and for the 92% of children homozygous for ALAD-1, the 

mean blood lead was 9.7 μg/dL compared with the 8% of children who were heterozygous 

(ALAD-1-2) and who had a mean blood lead level of 11.7 μg/dL (p<0.05). Using step-wise 

multiple regression, children who had the ALAD-2 allele were shown to be more likely to have 

higher blood leads compared to children who had the ALAD-1 allele. 

In the only published article to date, environmental samples, blood lead levels, and 

nutritional factors were assessed together with determinations of VDR-Fok1 genotype (Haynes 

et al., 2003). A significant interaction was found between dust lead, such that at a 1 μg/ft2 

increase in floor dust lead, children with VDR-FF genotype had a 1.1% increase in blood lead; 

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VDR-Ff, a 0.53% increase; and VDR-ff; a 3.8% increase. At floor dust levels less than 

10 μg/ft2

, children with VDR-ff had the lowest blood lead concentrations. It is noteworthy that 

only 17 children in this study were homozygous for the ff allele. Nonetheless, the authors 

suggested that VDR-Fok1 is an effect modifier for the relationship of floor dust lead exposure 

and blood lead concentrations. 

The implications for risk assessment and health significance in these three pediatric 

studies are limited. Far more detailed studies in this area of investigation are needed before any 

firm conclusions can be reached. 

Dose-Response Paradigms 

The aim of this discussion is to bridge the gap between basic neurotoxicology findings 

assessed in Section 5.3.1 and the neurobehavioral consequences of lead discussed in Section 6.3. 

Based upon current neurotoxicological studies in vivo and in vitro (Section 5.3.1) and 

based upon epidemiological studies of children (Section 6.3), it is biologically implausible that 

neurotoxic effects of lead do not occur at blood lead concentrations in children above and below 

10 μg/dL. Although it is difficult to extrapolate from experimental studies to investigations in 

children (Manton et al., 2001), some examples are revealing. 

In experimental systems, lead dose is typically employed in molar concentrations 

(Section 5.3.1); 10 μg/dL of lead in whole blood of children is equivalent to a molar 

concentration of 0.48 μM. In vitro studies have reported effects of lead on cellular regulatory 

systems in neurons (and other tissues) far below 0.48 μM. Whereas most or all of the lead used 

in neurochemistry experimental systems can participate in a reaction, only a small fraction of 

circulating lead in blood enters specific metabolic pathways. It is recognized that the major 

portion of lead in whole blood is carried by erythrocytes and that the most accessible fraction of 

circulating lead to other tissues is in plasma. It has been estimated that 0.24 to 0.29% of lead in 

whole blood is in plasma (Smith et al., 2002) and that the concentration in CSF is about half of 

the plasma concentration (Manton and Cook, 1984). Thus, a calculation of the latter 

concentrations in plasma and CSF in 10 μg/dL of whole blood yields concentrations in the low 

nanomolar range. 

It is very unlikely that the plasma concentration of lead in the low nanomolar range is the 

“dose” that impacts upon the CNS of children at blood lead levels less than 10 μg/dL. The 

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“dose” that perturbs the central nervous system of children at “low” blood lead levels is likely to 

be much higher. Lead’s half-lives in various tissues is a function of the site of deposition and 

degree of on-going exposure. In blood (absent excessive external exposure), the half-life is 

about 30 days and in brain, the half-life is about 2 years (Leggett, 1993). However, in the 

absence of on-going external exposure, blood lead levels can remain elevated for relatively 

extended periods of time due to mobilization from internal stores (Roberts et al., 2001; Manton 

et al., 2000). As a result, lead, which readily penetrates the blood-brain barrier, can continuously 

enter neural tissue from the blood compartment (Leggett, 1993). 

Active transport mechanisms are also important to consider, and these mechanisms cause 

differential concentrations of lead in the systemic circulation compared to those in neuronal 

compartments. Metabolic pumps increase concentrations of ions within intracellular organelles 

to levels that exceed those in the cytosol. Mechanisms affecting Ca2+ distribution are the most 

critical (Section 5.3.1). Lead’s toxic effects in the brain and other tissues are based, in large part, 

on its ability to “mimic” Ca2+ in intracellular processes, coupled to its actions to perturb the Ca2+ 

messenger system (Schanne et al., 1989; Lidsky and Schneider, 2003). For example, lead enters 

neurons and glia by channels that, under physiological conditions, permit the passage of Ca2+ 

(Kerper and Hinkle, 1997; Legare et al., 1998). Lead enters and damages mitochondria via 

cellular mechanisms that bring calcium into this organelle (Chavez et al., 1987). Thus, transport 

mechanisms bring about variations in local concentrations of Ca2+ and, presumably, lead as well 

(Schanne et al., 1989). 

Based upon these considerations, it is concluded that brain cells in children are likely 

exposed to concentrations of lead, in the context of “low” blood lead levels, in the midnanomolar range and possibly higher, particularly in organelles that depend upon the calcium 

messenger system for their physiological activities. The experimental literature clearly 

demonstrates perturbations in fundamental cellular processes in the nanomolar range and 

considerably lower (Section 5.3.1). 

The shape of the dose-response curve(s) of IQ and blood lead concentrations in children 

below blood lead levels of 10 μg/dL may be considered to be unexpected. However, the above 

considerations provide a different and reasonable explanation. It is accepted that lead achieves 

its neurotoxic effects on multi-neuronal targets, and the threshold concentrations of lead to 

perturb multiple CNS targets differ by orders of magnitude (Lidsky and Schneider, 2003). 

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For instance, second messenger systems are affected at picomolar to nanomolar concentrations 

(Schanne et al., 1989; Lidsky and Schneider, 2003). These perturbations can mediate a variety 

of toxic consequences of lead by perturbing the temporal and spatial resolution of Ca2+. As a 

result, several loci within the complex Ca2+ messenger system may be impaired, thereby 

explaining toxic effects of lead on multiple cellular processes affecting brain functioning at 

differential intracellular concentrations. At somewhat higher lead concentrations in the 

circulation, other critical subcellular processes will be affected and impaired (e.g., heme 

synthesis and cellular energy metabolism). Thus, based upon various targets in the CNS affected 

by lead at widely different concentrations, the dose-response curve would tend to be steeper at 

lower lead “doses,” as may be seen when inspecting the relationships between blood lead and IQ, 

particularly at blood lead levels less than 10 μg/dL. 

Neuro-Epidemiological Studies: Implications for Individual Children 

Bellinger (2004) pointed out that the clinically evident cognitive outcomes applicable to 

attributing specific neurobehavioral outcomes to childhood lead poisoning differ from those that 

are employed more typically to characterize risk in a population of children. The latter type of 

epidemiological studies have been applied to setting public health standards in children by the 

EPA and the U.S. Centers for Disease Control and Prevention. However, the clinical 

presentation of and ultimately the diagnosis of cognitive outcomes caused by excessive exposure 

to lead in individual children have received little attention. Moreover, the clinical presentation of 

lead exposure in the individual child cannot be clearly recognized or ascertained from 

epidemiological data (Lidsky and Schneider, 2005). 

The majority of risk assessment studies have reported the averaged performance of large 

cohorts of children on a traditional IQ test as the neurobehavioral outcome measure. Such 

studies, after adjustment for appropriate confounders, have consistently reported an inverse 

correlation between blood lead concentrations and IQ scores (Schwartz, 1994). In addition to IQ 

as the outcome index, children who have elevated blood lead levels have been shown to lack 

skills in basic academic subjects (Needleman et al., 1990; Fergusson et al., 1997; Lanphear et al., 

2000). As adolescents, such children are at risk for anti-social behavior (Dietrich et al., 2001; 

Needleman et al., 2002). These reports indicate that the outcomes in a lead-exposed child focus 

on impairments in intellectual achievement, academic performance, and problematic behavior. 

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These nonspecific outcomes are of extremely limited diagnostic utility for a pediatrician to 

understand what measurable outcomes may or may not be attributable to childhood lead 

exposure in an individual child. 

Because lead has neurotoxic effects on a child’s developing brain (Bressler et al., 1999; 

Lidsky and Schneider, 2003; Finkelstein et al., 1998), diagnostic methods are necessary to 

uncover manifestations of brain dysfunction. IQ tests were not designed to evaluate brain 

dysfunction; IQ tests are insensitive to the symptoms of brain dysfunction resulting from brain 

injury (Lezak, 1995). Manifestations of brain injury are manifested by highly specific aspects 

of impaired functions that involve language, memory, and executive skills (Lezak, 1995). 

In contrast, IQ is an aggregate, based on the summed performance of several sub-tests that assess 

an array of cognitive functions, and this array fails to tap into focal deficits that are the stigmata 

of brain injury. Given the lack of sensitivity of IQ scores to assess the presence of brain damage, 

the generally consistent findings of lead’s adverse affects on IQ reflect the robustness of the 

reported data (Hill, 1965; Chen et al., 2005; Lanphear, 2005). Whereas the mean IQ in a large 

group of children has often shown a decrease as a result of brain damage, the size of the decrease 

fails to reflect the failures of a child’s abilities to carry out daily living activities, which are 

typically brought to the attention of a pediatrician for treatment and management. 

Neuropsychology is an applied science focused on the neurobehavioral manifestations of 

brain dysfunction (Lezak, 1995). Neuropsychological test batteries focus on testing paradigms 

that are controlled by specific neural systems to detect functional effects of brain injury. Several 

studies (noted above) have reported impairments in groups of children that have carried out 

neuropsychological tests of fine motor skills, executive abilities, language, and aspects of 

learning and memory (Bellinger et al., 1994; Faust and Brown, 1987; Stiles and Bellinger, 1993; 

Dietrich et al., 1992; Walkowiak et al., 1998; Wasserman et al., 2000; Campbell et al., 2000; 

Winneke and Kramer, 1997; Canfield et al., 2004; Ris et al., 2004). 

Because diffuse neurocognitive “dulling” is not a typical outcome of childhood lead 

exposure and because a specific pattern of cognitive deficits (“signature injury or injuries”) is not 

apparent in individual children, the clinical-pediatric presentation is specific to each individual 

child. Thus, a child’s specific deficits evidenced by neuropsychological testing are of little 

assistance in making a clinical diagnosis of past or present exposure to lead and the lack of a 

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neurobehavioral “signature” is common to other neurotoxic agents that can cause brain injury 

(Hartman, 1995). 

Neuropsychological testing within a clinical framework is designed to measure cognitive 

and behavioral manifestations of normal and abnormal brain function to arrive at a diagnosis of 

brain injury, when present. Decisions arriving at evidence for abnormality are based on a pattern 

of test results tapping specific neural systems, with the understanding that some systems will be 

affected and diminished as a result of brain injury whereas others will be unaffected (Lezak, 

1995; Lidsky and Schneider, 2003, 2005). 

From this discussion, it is reasonable to conclude that neuropsychological assessments 

provide additional and important information to the clinical understanding of an individual child 

compared to what a pediatrician and neuropsychologist can ascertain from epidemiological data. 

Clinical neuropsychological evaluations can lead to an etiological conclusion, together with a 

pediatrician’s differential diagnosis, whether a child’s cognitive deficits are typical of brain 

injury and whether, if present, that injury can be diagnostically attributed to lead exposure. 

When impairments are detected, it is then the task of the pediatrician to carry out a physical 

examination and to review medical records, radiographs, laboratory data, and environmentalexposure information. Based upon review of all this information and a differential diagnosis to 

rule out other causes of brain damage, a clinical determination can be made as to the etiology of 

an individual child’s impairments and whether such deficits can be the result of lead exposure. 

Once alternative or contributing etiologies have been ruled out as the cause of brain damage, a 

diagnosis can be made causally linking lead exposure to brain damage in an individual child. 

This describes the collaborative roles of the neuropsychologist and pediatrician in determining 

the role of lead as the etiological factor (or not) in producing manifestations of brain damage in 

the context of different patterns of neuropsychological deficits in each individual child. 

5.3.2.2 Clinical Manifestations in Adults with Childhood Lead Poisoning 

It is reasonable to conclude from the studies discussed in this section that clinical 

manifestations become manifest in adults as persistent or latent consequences of earlier 

childhood lead poisoning. Specific effects of lead in this section include impairments in 

cognitive abilities that directly involve the central nervous system (White et al., 1993). These 

data have been applied to cognitive outcomes (White et al., 1993) and mortality rates in adults 

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following severe childhood lead poisoning (McDonald et al., 1996). Data from these analyses 

also indicate the presence of long-term latent and/or persistent effects on blood pressure in adults 

several decades after severe childhood lead poisoning (Hu, 1991). These data have been 

extended to more recent studies of lead’s impacts on adults from early excessive childhood 

exposure, in terms of adverse health impacts on the central and peripheral nervous systems. 

With current analytical techniques, these data have been applied and connected to bone lead 

concentrations, as well as to the development of hypertension (Stokes et al., 1998; Gerr et al., 

2002). 

This section includes new concepts of health impacts of lead on adults from lead exposure 

during childhood, concepts that were not expressed in the previous 1986 EPA Lead 

AQCD/Addendum and the 1990 Supplement to that Addendum. 

White et al. (1993) evaluated cognitive functioning in 33 adults (mean age of 54 years), 

all of whom had been admitted to Boston’s Children’s Hospital during 1930-1942. Because 

blood lead measurements were not available then, criteria for the diagnosis of lead poisoning 

included: (1) lead paint exposure and pica; (2) signs and symptoms of childhood lead poisoning 

(i.e., abdominal pain, vomiting, constipation, anorexia, irritability.) A latter subgroup of 

27 adults was considered to have the mildest lead poisoning. The second and third groups had 

more severe central nervous system symptoms of “nerve palsy” (n = 3) and encephalopathy 

(n = 3) as well as (3) positive lead lines on skeletal radiographs. The 33 retrieved adults from the 

Boston area were generally characterized as to the severity of their childhood lead poisoning into 

three groups (according to the above symptoms) and according to blood lead concentrations 

estimated as 60–100, 90–120, and greater than 120 μg/dL, respectively. Each adult underwent a 

90-m neuropsychological test battery. Compared to matched controls, the 33 adults evidenced 

widespread cognitive deficits in attention, memory, reasoning, motor speed, visual-spatialconstructional skills, and coordination; previously leaded subjects were lower (compared to 

controls) in lifetime occupational status. These observations were consistent with the onset of 

brain damage as children with persistence 50 years later. Exposure of the CNS during their adult 

years could also have occurred from release of lead from bone stores (Tsaih et al., 2001). 

This is the first retrospective report that systematically addressed cognitive outcomes in 

adults from childhood lead poisoning. Nonetheless, these data are limited by their observational 

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context, lack of blood lead measurements, the long interval between childhood to the point of 

study as adults, the limited number of subjects, and the retrospective nature of the design. 

McDonald and Potter (1996) assessed ratios of observed (O)/expected (E) deaths in a 

cohort of 454 adults admitted as lead-poisoned children to Boston Children’s Hospital from 1923 

to 1966 and traced through December, 1991. These are the only such data reported. As children, 

the criteria for lead poisoning was based upon the following: (1) a history of “paint pica” or 

other sources of exposure; (2) positive bone radiographs for lead lines; and (3) GI, neurologic 

and/or hematologic signs and symptoms. Seventy-six percent of this group met all three criteria 

and 24% met at least two out of the three criteria for diagnostic inclusion. Data were adjusted 

for confounders such as age, sex, ethnicity, and calendar period but not for socioeconomic status. 

As noted, observed deaths were compared to expected deaths; and O/E ratios were computed for 

hematological deaths (O/E = 9.7), for seizure disorder deaths (O/E = 5.0), for cardiovascular 

disease deaths (O/E = 2.1), and for cerebrovascular disease deaths (O/E = 5.5). This unique 

study also has limitations. It was retrospective in design, deaths may have been underestimated, 

there was an excess of cases dating back to the 1930s, and blood lead measurements did not 

begin at Boston Children’s Hospital until 1963. Moreover, 153 of the original cohort of 454 

were lost to follow-up. However, the authors pointed out that (1) blood lead levels measured 

post-1963 were generally consistent with the classification of the severity of lead poisoning pre1963; (2) although 153 of the original group were lost to follow-up, the remaining cohort was 

followed for a total period of 29.5 years; (3) if deaths were missed, this would have artificially 

lowered the observed O/E ratios; (4) interpretation of these results could be limited by the 

relatively small number of deaths; but, for each of the mortality outcomes, less than one death 

was expected. Overall, in this cohort, mortality from all causes was about 70% higher than 

expected. 

Collectively, although the studies reported by White et al. (1993) and McDonald and 

Potter (1996) have limitations, these are the first reported data to indicate that severe lead 

poisoning causes brain damage and impacts on mortality in adults from childhood lead 

poisoning. 

Recent reports, utilizing current methodologies, have extended the above data relating to 

cognitive outcomes (Stokes et al., 1998), as well as hypertension (Gerr et al., 2002) in a cohort of 

257 adults (19-29 years old) who had childhood lead poisoning at 9 months to 9 years of age 

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from lead smelters in Idaho’s Silver Valley. In 1974-1975, the mean blood lead level in young 

children at each of five towns near the smelter activities was in the range of 40 to 65 μg/dL and 

the standard deviations of the blood lead levels in the five towns ranged from 13.5 to 28 μg/dL 

(Gerr et al., 2002). Of the 257 adults excessively exposed as children, 43 individual blood lead 

values were traced back to 1974-1975, and the mean level was 49 μg/dL. The referent cohort 

was in the Spokane, WA area. The exposed and nonexposed groups were compared in terms of 

electrophysiological and neuropsychological testing, and the latter results were evaluated with 

concurrent K-XRF tibial lead measurements. 

Fine motor and cognitive outcomes in the exposure group, after adjustment for 

confounding, were significantly associated with poorer performance on hand-eye coordination, 

reaction time, trails B, symbol digit, serial digit learning, Raven progressive matrices, and 

vocabulary tests. The estimated effect of being in the exposed group was negative for all 12 of 

the motor and cognitive outcomes. Among tests of peripheral nerve function, vibrotactile 

thresholds of the fingers and standing steadiness were significantly different between the 

exposed and nonexposed groups; sural sensory amplitude and peroneal motor amplitude were 

significantly related to the exposure group. Tibial bone lead measurements failed to reach a 

p value <.05 in any of the test paradigms, although there was a trend towards significance in 

vocabulary and vibrotactile thresholds for fingers and toes in the exposed group. This apparent 

insensitivity of bone lead measurements to various outcome measures was probably related to 

the modest precision of K-XRF determinations. 

Based on this study, it is reasonable to conclude that excessive accumulation of lead in 

childhood has latent and/or persistent adverse health effects on both the peripheral and central 

nervous systems of adults assessed 19-29 years later. The latter report, using currently available 

methods, is generally consistent with the earlier study by White et al. (1993). Information is 

needed in less severely exposed children followed longitudinally into adolescence and the adult 

age group. 

5.3.2.3 Adults with Ambient Exposures to Lead 

In the previous 1986 EPA AQCD/Addendum, the focus was on adverse health effects in 

adults at blood lead levels in the range of 30-50 μg/dL. The studies reviewed focused on slowed 

nerve conduction velocities, altered testicular function, reduced Hg production, and other signs 

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of impaired heme synthesis evident at somewhat lower blood lead levels. These effects pointed 

to a generalized impairment of normal physiological functioning as adult lead levels exceeded 

30-40 μg/dL. The lowest observed effect levels of 15-30 μg/dL were related to impairments in 

heme synthesis. In contrast, in the 1990 Supplement to the 1986 Addendum, it was concluded 

that the relationship between lead and blood pressure held across a wide range of blood lead 

values, possibly extending down to 7 μg/dL for middle-aged men. In brief, except for effects of 

lead on heme synthesis down to adult blood lead values of about 15 μg/dL, EPA’s emphasis was 

on adverse health effects in the 30-40-50 μg/dL blood lead range (1986-1990). 

Since that time, studies have shown lead’s effects in terms of biomarkers and indices of 

vulnerability and susceptibility in adult populations with blood lead concentrations, on average, 

less than 10 μg/dL. The number and strength of these studies are limited (see below). Several of 

these recent studies have also included K-XRF measurements of lead in bone which should be 

cautiously interpreted. 

Biochemical Biomarkers 

Plasma total homocysteine (tHcy) is recognized as an independent risk factor for 

atherosclerosis and cardiovascular disease and has both environmental and genetic risk factors. 

Homocysteine is an intermediate metabolite in the trans-sulfation pathway that converts 

methionine to cysteine. Moreover, the addition to homocysteine of serine by the pyridoxal 

phosphate-dependent enzyme cystathionine $eta-synthase produces cystathionine, which in turn 

is converted to cysteine by cystathionine gamma-lyase (CTH) (Mudd et al., 1995). 

Homocysteine can either be methylated back to methionine by the enzyme methionine synthase 

(MTH) or can undergo trans-sulfuration to produce cystathionine (Mudd et al., 1995). As a 

result, many enzymes can affect plasma tHcy concentrations, and each enzyme can identify a 

potential candidate gene for evaluating the genetic determinants of plasma tHcy. Of common 

gene variants, the thermolabile variant in MTHFR encoding methylenetetrahydrofolate has been 

associated with elevated plasma tHcy. This and other variants have been connected to the 

disease states noted above (Weisberg et al., 2003). In this regard, a study of 496 Caucasian 

adults found that common variants in CTH can be a determinant of plasma tHct levels (Wang 

et al., 2004). 

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In view of these interactions and the associations of plasma tHcy with environmental 

factors, cardiovascular disease and cognitive dysfunction, Schafer et al. (2005) evaluated the 

possible relationship between blood lead levels, tibia lead (by K-XRF), and tHcy in a 

longitudinal study carried out within the context of the Baltimore Memory Study. In this study, 

1,140 randomly selected adults were assessed. They had a mean age of 59.3 years, an average 

(SD) blood lead level of 3.5 (2.4) μg/dL, and a mean (SD) tibia lead (μg of Pb/g bone mineral) 

concentration of 18.9 (12.5). After adjustment for age, sex, ethnicity, educational level, and 

tobacco and alcohol use, plasma tHcy levels were found to have increased 0.35 μmol/L per 

1 μg/dL increase in blood lead concentration. No relationship was found between plasma tHcy 

and tibia lead levels, perhaps because of the wide standard deviation among the subjects and the 

modest precision of the K-XRF methodology. At blood lead levels, on average, under 10 μg/dL, 

these results provide some initial evidence suggesting that tHcy could be a mechanism 

underlying lead effects on the cardiovascular and central nervous systems. Whether lead directly 

elevates plasma tHcy, whether lead kinetics may be modified by tHcy, and/or whether one of 

homocysteine’s polymorphic variants may have specific binding properties for lead are all open 

questions for which further investigation is required. 

Vulnerability and Susceptibility 

Socioeconomic Status 

There was very little information on socioeconomic status (SES) in ambiently exposed 

adults in previous EPA Documents (1986-1990). Although some data have been published since 

1990, it is limited to investigations of a female population in Mexico City (Farias et al., 1996), of 

male populations from the Normative Aging Study in Boston (Elreedy et al., 1999), and of a 

minority group of men in the Boston area (Lin et al., 2004). 

Determinants of blood lead levels were evaluated in 513 pregnant women in Mexico City: 

one group of women was enrolled from a public general hospital, and was considered to be low 

SES. The second group, a high-SES cohort, was enrolled from a private hospital. The geometric 

mean blood lead values were 6.6 and 11.12 μg/dL from the high and low SES groups, 

respectively (Farias et al., 1996). The entire population of pregnant women was enrolled in this 

study during January 1994 to August 1995 and, beside different exposure paradigms, seasonality 

played an important role in differentiating blood lead concentrations between the high and low 

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SES groups. The primary determining factor for blood lead levels in the low SES population 

was the use of lead-glazed ceramics in women from the public hospital; and seasonality was the 

main factor influencing blood lead levels in the women from the private hospital. A predictive 

model, fitted to milk consumption, dietary supplements of calcium plus gestational age, was 

predictive of a 14 μg/dL difference between the best and worst scenarios in women from the 

public hospital. Seasonal differences in blood lead concentrations, which ranged, on average, 

from 4.7 to 12.7 μg/dL, from summer to winter, respectively, in the high SES-private hospitalbased women, focused on airborne lead as their primary source of exposure, although 

measurements of air lead levels were not reported. 

Elreedy et al. (1999) investigated various factors related to SES in 538 white males (ages 

50-92) in the Normative Aging Study or Boston-based adults. Questionnaire data were collected 

regarding educational and occupational status, and these data were further analyzed using 1990 

Census Block Group Data. Men who had four years of college, compared to others who did not 

graduate from high school, had, on average, lower bone lead levels. These data suggested the 

possibility of individual SES as having an affect on cumulative lead exposure. Detailed 

information on the health status of these two groups of Boston men was not provided. 

Eighty-four minority individuals living in the Boston area were compared by bone lead 

measurements to previously studied Caucasian subjects: the mean values for blood lead (SD), 

tibia lead (SD) and patella lead (SD) for the minority group of males were 3.0 μg/dL, 11.9 μg/g 

(11), and 14.9 μg/g (15.3), respectively. These results suggest disparities in body burdens of 

lead in the minority group of men, particularly in those older than 55 years of age. However, the 

high standard deviations in the bone lead data, the modest precision of the utilized K-XRF 

system, and lack of information on the health status within the minority group of men require a 

level of caution in evaluating these outcomes, which, in themselves, based upon the NHANES 

data from childhood national data, are not surprising. 

Nutrition 

Studies reported in populations from Mexico City, Boston and Rio de Janeiro provided 

new information on nutritional parameters in subjects with mean blood and erythrocyte lead 

levels less than 10 μg/dL. These three studies examined the effects of calcium and vitamin D 

nutrition in various populations. 

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Erythrocyte lead concentrations were evaluated in 68 pregnant and 45 lactating Rio de 

Janeiro women whose dietary intakes of calcium were low on a chronic basis (400-600 mg/day). 

Whole blood lead concentrations were less than 10 μg/dL in these women, including 33 controls 

(Pires et al., 2001). Lactating women had significantly higher erythrocyte lead values compared 

to both pregnant and control subjects. Indices of bone resorption (urinary d-pyridinoline) and 

formation (plasma bone alkaline phosphatase) were significantly higher in pregnant and lactating 

women, suggesting that RBC lead was elevated in the ambiently exposed women during 

lactation with low dietary intakes of calcium. 

A larger group of lactating women (617) in Mexico City were examined from 1994-1995 

to further understand the potential effects of lowering blood lead levels through dietary calcium 

supplements (Hernandez-Avilla et al., 2003). The average age was 24 years; the mean blood 

lead level at baseline was 8.5 μg/dL. Women were randomly assigned to receive either calcium 

carbonate (1200 mg/day) or placebo in a double-blind study, and blood lead concentrations were 

measured at 3 and 6 months into the study. A modest decrease of 1.16 μg/dL (mean) was 

observed at 6 months in the calcium-supplemented group. This relatively small decrease in 

blood lead values may be explained, in part, by relatively high lead burdens in this Mexico City 

population, although blood lead levels did not exceed 8.5 μg/dL initially. 

A cross-sectional assessment was carried out by Cheng et al. (1998) in 747 males in the 

context of the Boston Aging Study. In 67-year-old men (average age) the mean (SD) blood lead, 

tibia lead and patella lead were 6.2 (4.1) μg/dL, 21.9 (13.3) μg/g, and 32 (19.5) μg/g, 

respectively. After adjusting for age, education, cigarette use, and alcohol consumption, men in 

the lowest quintile of total dietary intakes of vitamin D (179 IU/day) had higher bone lead 

content compared to men in the highest quintile for vitamin D intake (IU 589/day). These data 

are consistent with those discussed above, in that low dietary intakes of vitamin could be 

expected to decrease calcium and increase lead absorption from the GI tract. However, dietary 

calcium intakes were not measured in this study. 

Genetic Polymorphisms 

Since 1986-1990, two reports have been published relating to genetic polymorphisms in 

ambiently exposed adults: one of these is related to ALAD and the other to HFE. Both of these 

studies were carried out in the Boston Normative Aging Study in adult males. Hu et al. (2001) 

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investigated whether ALAD polymorphism may be associated with blood and bone lead values 

in 726 middle-aged and elderly men from the Boston area. In this group of men, the mean (SD) 

of blood lead concentrations, tibia lead and patella lead were 6.2 (4.1) μg/dL, 22.1 (13.5) μg/g, 

and 30.4 (17.2) μg/g, respectively. The ALAD 1-1 genotype was associated with an increase of 

2.55 μg/g in cortical bone (tibia), thereby suggesting the possibility that the ALAD 2 allele may 

decrease the accumulation of lead in bone. Whether this difference of 2.55 μg/g bone mineral 

was above or below the precision and/or the minimum detection limits of the K-XRF method 

was not addressed in this report. 

Within the same Boston population, Wright et al. (2004) evaluated potential relationships 

between the HFE gene and bone lead values in 730 men. Of this population, 13 and 25% had the 

C282Y and H63D variants of HFE, respectively. After adjusting for age, smoking, and 

education, carriers of the HFE variant allele(s) had lower patella bone lead concentrations 

compared to all groups by polymorphism analyses. Caution in interpreting these data are 

expressed, as in other data reported from the Boston Normative Aging Study. 

Neurotoxicology of Lead 

One study has been reported since 1986-1990 that assessed aspects of cognitive 

functioning in the Normative Aging Study in Boston within a group of 466 males who had lowlevel or ambient lead exposure. The purpose was to evaluate whether biomarkers of lead were 

related to cognitive functioning, and the latter was indexed by the Mini-Mental State 

Examination (MMSE) (Weisskopf et al., 2004a). On two occasions, 3.5 years apart, MMSE 

scores were obtained during 1993–2002 in men whose age averaged 67.4 years. Bone lead 

measurements by K-XRF were assessed on two occasions between 1993–2002. The presented 

results indicated that a one-interquartile range (20 μg/g) increase in patella lead was associated 

with a decline in the MMSE equivalent to that of aging 5 years in relation to baseline MMSE 

scores. Associations were not observed in values for blood lead or tibia lead levels. The authors 

suggested that this steeper decline in MMSE scores was thus related to lead that is mobilizable 

from skeletal store (patella lead). These data reflect an important beginning to define effects of 

ambient lead exposure on cognitive functioning in adults. Although the MMSE has been 

employed in epidemiological population-based research, it is evident that a comprehensive 

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neuropsychological test battery has the potential to provide more definitive information related to 

understanding further the impact of ambient lead exposure on cognition in adults. 

5.4 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS OF LEAD 

5.4.1 Summary of Key Findings on the Developmental and Reproductive 

Effects of Lead in Animals from the 1986 Lead AQCD 

The 1986 Pb AQCD presented unequivocal evidence for effects of Pb on reproduction and 

development in laboratory animals, derived principally from studies of rodents. Fetotoxic effects 

(spontaneous abortion and fetal death) were reported following chronic exposures to relatively 

high doses (600 to 800 ppm inorganic lead) in the diet, and more subtle effects (such as changes 

in ALA-D activity or hematocrit) at lower doses (5 to 10 ppm in drinking water and 10 μg/m3

 in 

air). The 1986 Pb AQCD reported that the lowest observed adverse effect level (LOAEL) for 

reproductive and developmental effects was 64 μg/kg per day (multiple exposures by gavage). 

The 1986 Pb AQCD also reported evidence for a variety of sublethal effects on 

reproduction and development in experimental laboratory animals following Pb exposure. 

Sublethal effects included changes in levels or function of reproductive hormones as well as 

effects on the gonads (both male and female) and conception. The animal data also suggested 

more subtle effects on hormone metabolism and reproductive cell structure. Stowe and Goyer 

(1971) classified the reproductive effects of Pb as gametotoxic, whether intrauterine or 

extrauterine. 

The data reported in the 1986 Pb AQCD, and more recent studies conducted in 

experimental animal models, provide convincing evidence that Pb induces temporary and longlasting effects on male and female reproductive and developmental function. The newer 

literature supports the earlier conclusions presented in the 1986 Pb AQCD that Pb disrupts 

endocrine function at multiple points along the hypothalamic-pituitary-gonad axis (Sokol et al., 

1985; Stowe and Goyer, 1971; Vermande Van Eck and Meigs, 1960; Junaid et al., 1997; 

McGivern at al., 1991; Ronis et al., 1996, 1998b,c; Sokol, 1987; Sokol et al., 1985, 1994, 1998; 

Sokol and Berman, 1991; Kempinas at al., 1988, 1990, 1994; Tchernitchin et al., 1998b; Sant’ 

Ana et al., 2001; Srivastava et al., 2004). A schematic representation of the hypothalamicpituitary-gonadal axis is shown in Figure 5-4.1. 

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402(c) Economic Analysis Chapter 5 141
Figure 5-4.1. Data from male and female experimental animals suggests that Pb 

has multiple targets in the hypothalmic-pituitary-gonadal axis. 

1 The majority of the experimental animal studies on developmental and reproductive 

2 effects of Pb examined effects due to inorganic forms of lead; very little is known about the 

3 reproductive and developmental effects due to organic forms. In general, the few available 

4 studies suggest that effects of organic forms of Pb are similar to those produced by inorganic 

5 forms. Administration of triethyl-Pb-chloride during early gestation reduces pregnancy rates in 

6 mice (Odenbro and Kihlström, 1977). Growth retardation following organolead exposure has 

7 been reported (Kennedy et al., 1975; McClain and Becker, 1972). More recent studies have 

8 demonstrated that exposure of mice to triethyl-Pb-chloride during late gestation reduces perinatal 

9 growth rate (Odenbro et al., 1988). 

10 This section summarizes the evidence for effects of Pb exposure in developing organisms 

11 exposed during the period from conception to maturity that has been reported since 1986. 

12 Effects on neurological, immunological, or renal endpoints in developing organisms are 

13 discussed in Sections 5.3, 5.9 and 5.7, respectively. 

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5.4.2 Effects on Male Reproductive Function 

The 1986 Pb AQCD reported convincing evidence based on experimental animal studies 

that Pb acts as an endocrine disruptor in males. Those studies demonstrated an association 

between reduced male fertility and repeat-dose Pb exposure. Lead exposure had been reported to 

alter sperm development and function; however, the mechanism underlying these effects was not 

completely understood. These effects were attributed to either alterations in testicular enzymes 

important for hormone production or to changes in the hormone receptors. More recent research 

supports the conclusion that the mechanisms for endocrine disruption in males involves Pb 

acting at multiple sites along the hypothalamic-pituitary-gonadal axis (see Figure 5-4.1). 

Reported effects of Pb on male reproduction differ substantially across studies, with some 

studies finding profoundly adverse effects and other studies finding no or minimal effects. The 

variable findings have been attributed to the complex mechanisms involved in hormone 

regulation and the multiple sites of action for lead. Sokol et al. (2002) suggested that differences 

in results among studies may be, in part, attributed to an adaptive mechanism in the 

hypothalamic-pituitary-gonadal axis that may render the expression of some toxic effects 

dependent on exposure duration. Sokol and Berman (1991) found that timing of exposure was 

critical to Pb-induced male reproductive toxicity in rats. Studies conducted in nonhuman 

primates supported the importance of timing, finding that the adverse effects of Pb on male 

reproduction are dependent upon age (i.e., developmental stage at time of exposure) and duration 

of exposure (Foster et al., 1993; Singh et al., 1993a). 

The adverse effects of Pb on male reproduction may be expressed as perturbations in 

sexual development and maturation, changes in fertility, endocrine disruption, and alterations in 

structure of reproductive cells or tissue. Each of these effects is discussed in greater detail in the 

sections that follow. 

5.4.2.1 Effects on Male Sexual Development and Maturation 

The 1986 Pb AQCD reported adverse effects of Pb on male sexual development and 

maturation. Experimental studies conducted in animals demonstrated that high-dose (e.g., 

dietary exposure to 0.08 to 1.0% Pb-acetate in mice and to 100 ppm in dogs) preadolescent Pb 

exposure can produce long-lasting detrimental effects on male sexual development. Numerous 

more recent studies conducted in experimental animals support the earlier findings that Pb 

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exposure during early development can delay the onset of male puberty and alter reproductive 

function later in life (McGivern et al., 1991; al-Hakkak et al., 1988; Chowdhuri et al., 2001; 

Dearth et al., 2002, 2004; Gandley et al., 1999; McGivern et al., 1991; Ronis et al., 1998a,c; 

Sokol et al., 1994; Yu et al., 1996). Studies that provide the strongest evidence for the doseresponse range for typical effects in rodents are discussed below (Table 5-4.1). 

McGivern et al. (1991) found that male rats born to dams that received Pb-acetate in 

drinking water beginning on gestation day 14 and through parturition (PbB 73 μg/dL) exhibited 

reduced sperm counts, altered male reproductive behavior, and enlarged prostates later in life. 

Prepubertal exposure of male Sprague-Dawley rats (age 24 to 74 days) to Pb-acetate in drinking 

water (PbB 30 to 60 μg/dL) resulted in significant reduction in testis weight and in the weight of 

secondary sex organs; however, these effects were not observed in rats exposed postpubertally 

(day 60 to 74; Ronis et al., 1996). A dose-dependent delay in sexual maturation was found in 

male rats, following prenatal Pb exposure that continued until adulthood (age 85 days) (Ronis 

et al., 1998a,b,c). In these studies, PbBs in the pups between the ages of 21 and 85 days were 

>100 μg/dL. Additional details concerning these studies are provided in Table 5-4.1. 

One possible explanation for the persistent effects of Pb exposure on the male 

reproductive system is a disruption in pulsatile release of sex hormones during early 

development (Ronis et al., 1998c). Lead effects on sex hormones are discussed in 

Section 5.4.2.3. 

5.4.2.2 Effects on Male Fertility: Effects on Sperm Production and Function 

The 1986 Pb AQCD presented evidence that Pb exposure affects male fertility in various 

animal species, including rabbits (Cole and Bachhuber, 1915), guinea pigs (Weller, 1915), rats 

(Ivanova-Chemishanska et al., 1980), and mice (Schroeder and Mitchener, 1971). 

Several more recent studies, conducted in various animal species, have demonstrated Pbinduced alteration of sperm parameters (e.g., count, motility, number of abnormal) (Sokol et al., 

1985; and eight other studies). These effects, however, have not been reproduced in all studies. 

For example, Foster et al. (1996a) reported that 15- to 20-year-old cynomolgus monkeys 

receiving Pb-acetate for their lifetime (mean PbB 56 μg/dL) showed no significant alterations in 

sperm parameters (i.e., sperm count, viability, motility, and morphology) or circulating levels of 

testosterone (see Section 5.4.2.3 for discussion of lead-induced changes in testosterone levels). 

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December 2005 5-83 DRAFT-DO NOT QUOTE OR CITE Table 5-4.1. Selected Studies Showing the Effects of Lead on Reproductive Function in M

Citation Species/ Strain Dose/Route/Form/Duration/Group Size Endpoint/Magnitude of Effect/p-value Blood LeaFoster et al. (1993) Monkey/ Cynomolgus 0–1500 μg Pb-acetate/kg-d in gelatin capsules p.o. for various durations: 9 control monkeys, 4 monkeys in lifetime group (birth to 9 years), 4 in infancy group (first 400 days of life), 4 in post-infancy exposure (from 300 days to 9 years) Suppressed LH response to GnRH stimulation in the lifetime group (p = 0.0370); Sertoli cell function (reduction in the inhibin to FSH ratio) (p = 0.0286) in lifetime and post-infancy groups. Lifetime gr

years Infancy grodays, 3–3 μPost-infanc

Foster et al. (1996a) Monkey/ Cynomolgus 0–1500 μg Pb-acetate/kg-d in gelatin capsules p.o. from birth until 9 years of age 8 control monkeys, 4 monkeys in low group (6–20 μg/dL), 7 monkeys in high group (22–148 μg/dL) Mean PbB of 56 μg/dL showed no significant alterations in parameters of semen quality (count, viability, motility, or morphology). PbB 10±3 o

Foster et al. (1998) Monkey/ Cynomolgus 0–1500 μg Pb-acetate/kg-d in gelatin capsules p.o. for various durations: birth to 10 years (lifetime); PND 300 to 10 years (post-infancy); birth to 300 days (infancy); 3 control monkeys, 4 lifetime, 4 infancy, 5 post-infancy Circulating concentrations of FSH, LH, and testosterone were not altered by treatment; semen characteristics (count, motility, morphology) were not affected by treatment possibly because not all Sertoli cells were injured; degeneration of seminiferous epithelium in infancy and lifetime groups (no difference in severity between these groups); ultrastructural alterations in seminal vesicles, most prominent in infancy and post-infancy groups. PbB ~35 μ

McGivern et al. (1991) Rat/Sprague- Dawley 0.1% Pb-acetate in drinking water from GD 14 to parturition; 8 control litters; 6 Pb-acetate litters (5 males per litter) Decreased sperm count (21% at 70 days and 24% at 165 days, p<0.05); reduced male behavior (p < 0.05); enlarged prostate (25% increase in weight; p<0.07); irregular release patterns of both FSH and LH (p<0.05). Control Pb

Maternal PPup PbB 64 

Ronis et al. (1996) Rat/Sprague- Dawley 0.6% Pb-acetate in drinking water for various durations: PND 24–74 (pubertal exposure); PND 60–74 (post pubertal exposure); 11 males and 

females in pubertal exposure group (10 each in control pubertal group); 6 males and females post-pubertal exposure and control groups 

PbB >250 μg/dL reduced circulating testosterone levels in male rats 40–50% (p < 0.05); reduction in male secondary sex organ weight (p < 0.005); delayed vaginal opening (p<0.0001); disrupted estrous cycle in females (50% of rats); increased incidence of stillbirth (2% control vs. 19% Pb) (p < 0.005). 

Pubertal PbPost-pubertMean PbBs respectively 

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Species/ Citation Strain Dose/Route/Form/Duration/Group Size Endpoint/Magnitude of Effect/p-value Blood Lea

Ronis et al. Rat/Sprague- 0.6% Pb-acetate in drinking water ad libitum for Suppression of adult mean serum testosterone Group (1998a) Dawley various durations as follows: GD 5 to PND 1; levels was only observed in male pups exposed GD 5 to weaning; PND 1 to weaning; 3 control litters, 2 gestation exposure litters, 2 lactation to Pb continuously from GD 5 throughout life (p < 0.05). Naïve 

exposure litters, 2 gestation and lactation exposure litters, 2 postnatal exposure litters, Control 2 chronic exposure litters; 4 male and 4 female pups per litter Gest 

Lact 

Gest+La

Postnata

Chronic 

Ronis et al. Rat/Sprague- Lead acetate in drinking water (0.05% to 0.45% Dose-response reduction in birth weight Mean PbB (1998b) Dawley w/v); dams exposed until weaning; exposure of (p < 0.05), more pronounced in male pups; 49±6 μg/dL pups which continued until PND 21, 35, 55, or 85; 5 control litters (0%), 10 low-dose litters (0.05%), 8 mid-dose litters (0.15%), 9 high-dose decreased growth rates in both sexes (p < 0.05) were accompanied by a statistically significant decrease in plasma concentrations of IGF1 Mean PbB 

126 ± 16 μ

litters (0.45%); 4 male and 4 female pups per litter through puberty PND 35 and 55 (p < 0.05); increase in pituitary growth hormone during puberty (p < 0.05). Mean PbB 

263 ± 28 μ

Ronis et al. Rat/Sprague- Lead acetate 0.05, 0.15, or 0.45% in drinking Dose-responsive decrease in birth weight Dams: 0, 4(1998c) Dawley water beginning GD 5 continuing until PND 21, (p < 0.05); dose-responsive decrease in crown- Pups PND 

35, 55, or 85; 5 control litters (0%), 10 low-dose to-rump length (p < 0.05); dose-dependent delay Pups PND litters (0.05%), 8 mid-dose litters (0.15%), 9 in sexual maturity (p < 0.05); decrease in 236 μg/dL high-dose litters (0.45%); 4 male and 4 female prostate weight (p < 0.05); decrease in plasma Pups PND pups per litter concentration of testosterone during puberty 278 μg/dL (p < 0.05); decrease in plasma LH (p < 0.05); Pups PND 

elevated pituitary LH content (p < 0.05); 379 μg/dL decrease in plasma testosterone/LH ratio at high Pups PND dose (p < 0.05). 214 μg/dL 

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Species/ Citation Strain Dose/Route/Form/Duration/Group Size Endpoint/Magnitude of Effect/p-value Blood Lea

Singh et al. Monkey/ 0–1500 μg Pb-acetate/kg-d in gelatin capsules for Degeneration of seminiferous epithelium in all Chronic Pb(1993a) Cynomolgus various durations: 3 control monkeys, 4 monkeys exposed groups (frequency not specified); <40–50 μg/

in infancy group (exposure first 400 days), 5 in ultrastructural alterations in seminal vesicles, post-infancy group (exposure 300 days to 9 years most prominent in infancy and post-infancy of age), 4 in lifetime group (exposure from birth groups (frequency not specified). until 9 years) Sokol and Rat/Wistar 0, 0.1, or 0.3% Pb-acetate in drinking water for Dose-related suppression of spermatogenesis Group 

Berman (1991) 30 days beginning at 42, 52, or 70 days old; 8–11 control rats for each age, 8–11 rats for each age in (decreased sperm count and sperm production rate) in the exposed rats of the two highest age 0% 

0.1% group, 8–11 rats for each age in 0.3% group groups (p < 0.05); dose-related suppression of serum testosterone in 52-day old rats (p = 0.04) 

and in 70-day old rats (p < 0.003). 0.1% 

0.3% 

FSH, follicle stimulating hormone; GD, gestational day; GnRH, gonadotropin releasing hormone; IGF1, insulin-like growth factor 1; LH, luteinizing 

concentration; PND, post-natal day 

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Sokol et al. (2002) provided evidence of an adaptive mechanism in the hypothalamicpituitary-gonadal axis in response to prolonged exposure to lead. The existence of this adaptive 

mechanism would explain the apparent inconsistency in reported effects on circulating 

testosterone levels, sperm count, and sperm production following Pb exposure. Because of this 

adaptive mechanism, changes in testosterone levels and certain sperm parameters may not 

always serve as reliable endpoints for assessing the effects of Pb on male fertility and 

reproductive function for all exposure durations. 

Although gross changes in sperm parameters were not observed in monkeys in which 

chronic PbB was approximately 56 μg/dL, Foster et al. (1996a) reported that monkey sperm 

exhibited a statistically significant, dose-related reduction in chromatin structure (as determined 

by susceptibility to weak acid denaturation). These changes may have adverse impacts on 

fertility, and they are thought to be related to dominant lethal effects of Pb (similar to the effects 

reported by al-Hakkak et al. [1988] in mice). Additional details concerning Foster et al. (1996a) 

are provided in Table 5-4.1. 

The data from Foster et al. (1996a), demonstrating a change in monkey sperm chromatin 

suggestive of a subtle lead-induced reduction in male fertility (in the absence of gross changes 

sperm parameters), are consistent with observations of reduced in vitro fertilization capacity of 

sperm collected from other mammalian species. Sokol et al. (1994) reported that exposure of 

adult male rats to Pb-acetate in drinking water for 14 to 60 days (PbB 33 to 46 μg/dL) resulted in 

reduced in vitro fertilization of eggs harvested from unexposed females. No differences were 

observed in sperm ultrastructure or in the DNA histogram of sperm obtained from lead-exposed 

rats compared to controls. Consistent with this finding are reports of reduced fertilization 

capacity of rabbit sperm exposed to high concentrations (25 μM) of Pb chloride in vitro (Foote, 

1999) and reduced in vitro fertilization capacity of sperm from mice exposed to Pb in drinking 

water at 1 g/L for 4 months (PbB not reported) (Johansson et al., 1987). 

Two modes of action have been proposed for lead-induced alterations in sperm capacity 

for fertilization. The affinity of Pb for sulfhydryl groups may explain some of the lead-induced 

alterations in sperm structure and function. Mammalian sperm possess high concentrations of 

sulfhydryl groups, which are critical for maintaining normal function (Johansson and Pellicciari, 

1988). Reyes et al. (1976) demonstrated that binding of Pb to membrane thiols inhibits sperm 

maturation. In addition, recent experimental data also suggest that lead-induced generation of 

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reactive oxygen species (ROS) may contribute to the injury of tissues responsible for sperm 

formation (see Section 5.4.2.4). 

5.4.2.3 Effects on Male Sex Endocrine System 

The 1986 Pb AQCD reported that, although the mode of action for the adverse effects of 

Pb on the male reproductive system was not understood, effects on hormone production or 

hormone receptors were likely contributors. More recent studies provide convincing evidence 

that Pb acts as an endocrine disruptor in males at various points along the hypothalamicpituitary-gonadal axis (Figure 5-4.1). In rats, Pb exposures that decreased serum testosterone 

levels increased mRNA levels of GnRH and LH in the hypothalamus and pituitary, respectively, 

and increased levels of LH in pituitary; these changes can occur in the absence of a change in 

serum gonadotropin levels (Klein et al., 1994; Ronis et al., 1998c; Sokol et al., 2002). 

In monkeys, chronic Pb exposures (PbB 20 to 35 μg/dL) suppressed GnRH-induced secretion of 

LH and decreased serum testosterone:LH and inhibin:FSH ratios (Foster et al., 1993). The 

mechanisms underlying the effects on the hypothalamic-pituitary-gonadal axis have not been 

elucidated but may involve a suppression of GnRH secretion (Bratton et al., 1994; Sokol, 1987; 

Sokol et al., 1998). 

Although there is evidence for a common mode of action, consistent effects on circulating 

testosterone levels are not always observed in lead-exposed animals. Rodamilans et al. (1988) 

and Kempinas et al. (1994) attributed these inconsistencies to the normal biological variation 

(circannual and seasonal) of testosterone secretion in rats and monkeys. Observations of 

lead-induced reductions in testosterone levels in some studies, but not others, may be due to 

enhanced sensitivity to inhibition of the testosterone secretory system during certain periods of 

development. In addition, the hypothalamic-pituitary-gonadal axis exhibits compensatory 

mechanisms that may attenuate the effects of Pb during prolonged Pb exposure (Sokol et al., 

2002). Taken together, the sensitivity of testosterone secretion during certain periods and 

potential for modulation of the effects during long-term exposures studies, may explain some of 

the apparent inconsistencies in the reported effects of Pb exposure on circulating testosterone 

levels. 

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5.4.2.4 Effects on Morphology and Histology of Male Sex Organs 

The 1986 Pb AQCD reported evidence for histological changes in the testes or prostate in 

rats, in association with relatively high doses of Pb (Chowdhury et al., 1984; Hilderbrand et al., 

1973; Golubovich et al., 1968). More recent studies conducted in animal models provide 

persuasive support for testicular damage (i.e., ultrastructural changes in testes and cytotoxicity in 

Sertoli cells) following lower level lead exposure (Foster et al., 1998; Singh et al., 1993a; Batra 

et al., 2001; Chowdhury et al., 1986, 1987; Corpas et al., 1995; Pinon-Lataillade et al., 1993; 

Saxena et al., 1990). Studies conducted in nonhuman primates warrant particular attention. 

These studies found ultrastructural changes in the testes (Sertoli and other spermatogenic cells) 

of monkeys at PbB 35 to 40 μg/dL (Foster et al., 1998; Singh et al., 1993a). 

Foster et al. (1998) reported that chronic Pb exposure (PbB ~35 μg/dL), beginning in 

infancy, resulted in persistent ultrastructural changes in the testes of cynomolgus monkeys. 

Electron microscopy showed disruption of the general structure of the seminiferous epithelium 

involving Sertoli cells, basal lamina, and spermatids in the groups exposed for lifetime and 

during infancy (with no duration difference in severity). Chronic exposures to Pb beginning 

after infancy, that achieved similar PbBs, did not produce these effects. 

Similarly, Singh et al. (1993a) demonstrated ultrastructural changes in testicular basement 

membrane and Sertoli cell morphology (seminiferous tubules) in cynomolgus monkeys exposed 

chronically to Pb (PbB <40 to 50 μg/dL); the effects were most prominent when dosing began in 

infancy or post-infancy. These results suggest that, in monkeys, Pb exposure during certain 

periods of development produces persistent testicular alterations. Additional details concerning 

Foster et al. (1998) and Singh et al. (1993a) are provided in Table 5-4.1. 

A possible mode of action for lead-induced testicular injury is oxidative stress. Foster 

et al. (1998) suggested that lead-induced oxygen free radical generation was a plausible 

mechanism of testicular injury in primates. This oxygen radical hypothesis is supported by 

studies conducted in rodents (Chowdhury et al., 1984; Acharya et al., 2003; Adhikari et al., 

2001; Batra et al., 2001; Bizarro et al., 2003; Chowdhury et al., 1984; Gorbel et al., 2002; Mishra 

and Acharya, 2004). Also supporting the oxidative stress hypothesis are observations of 

increases in the percentage of apoptotic cells in the testes of rodents in response to Pb exposure 

(Pace et al., 2005; Gorbel et al., 2002; Adhikari et al., 2001). 

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5.4.3 Effects on Female Reproductive Function 

Lead has been shown to disrupt the hypothalamic-pituitary-gonadal axis and to produce 

ovarian atrophy and reproductive dysfunction in females (Figure 5-4.1). The 1986 Pb AQCD 

reported that Pb exposure was associated with inhibition of menstruation, ovulation, and 

follicular growth in monkeys (Vermande-Van Eck and Meigs, 1960), and in rodents Pb exposure 

delayed vaginal opening, decreased frequency of implantation, and reduced rates of pregnancy 

(Kimmel et al., 1980; Odenbro and Kihlström, 1977, respectively). 

Data from more recent experimental animal studies support these findings. Lead effects 

on female reproduction may be classified as alterations in female sexual maturation, effects on 

fertility and menstrual cycle, endocrine disruption, and changes in morphology or histology or 

female reproductive organs as well as the placenta. Recent literature concerning each of these 

effects is summarized below. 

5.4.3.1 Effects on Female Sexual Development and Maturation 

The 1986 Pb AQCD reported that Pb exposure in rodents produced delays in sexual 

maturation. Grant et al. (1980) reported delayed vaginal opening in female rats exposed in utero 

and during lactation and maturation (PbB ~20 to 40 μg/dL). More recent studies in experimental 

animals (primarily rodent studies) provide convincing evidence that Pb exposure before puberty 

(particularly prenatal and early postnatal exposure) delays the maturation of the female 

reproductive system (Dearth et al., 2002, 2004; Ronis et al., 1996, 1998b,c). 

Dearth et al. (2002) is of particular interest, because it employed a cross-fostering design 

(to allow comparison of pups exposed during gestation only, lactation only, or both) and because 

maternal and offspring PbBs were monitored throughout gestation and lactation. Fisher 344 

dams were exposed to Pb by gavage beginning 30 days before mating until weaning of the pups 

at 21 days of age (gavage exposure removes possible confounding of exposure by consumption 

of Pb in drinking water by pups in those studies where drinking water is the route of exposure for 

dams). Mean maternal PbB was approximately 40 μg/dL. Pups exposed during gestation and 

lactation had the highest PbB (38.5 μg/dL) on day 10; at this time, the PbBs in pups exposed 

during gestation only or lactation only were 13.7 and 27.6 μg/dL, respectively. By postnatal day 

(PND) 30, all three groups had PbB #3 μg/dL. Dearth et al. (2002) reported a statistically 

significant delay in the onset of puberty (vaginal opening and days at first diestrus) in rats 

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exposed during lactation, gestation, or during lactation and gestation (with no differences among 

the groups). In addition, a statistically significant reduction in the circulating levels of insulinlike growth factor 1 (IGF1), LH, and estradiol (E2) were reported on PND 30 in all three 

treatment groups (with no differences among treatment groups). Additional details concerning 

Dearth et al. (2002) are provided in Table 5-4.2. 

A subsequent study in both Sprague-Dawley and F344 rats (Dearth et al., 2004) showed 

that the F344 strain is more sensitive to maternal Pb exposure than Sprague-Dawley rats to leadinduced delayed puberty, which could, in part, explain the inconsistencies with effect levels 

observed in Sprague Dawley rats (e.g., Ronis et al., 1998a,b,c; McGivern et al., 1991). Ronis 

et al. (1998c) suggested that the delayed onset of puberty may arise from a lead-induced 

disruption of pulsatile release of sex hormones (see Section 5.4.3.3). 

5.4.3.2 Effects on Female Fertility 

The 1986 Pb AQCD reported convincing evidence from experimental animal studies for 

lead-induced alterations in female fertility, including interference with implantation and 

pregnancy (Odenbro and Kihlström, 1977; Wide and Nilsson, 1977). More recent studies have 

confirmed these effects. In general, Pb exposure does not produce total sterility, although Pb 

exposure clearly disturbs female fertility (Taupeau et al., 2001). Studies in nonhuman primates 

and rodents have shown that exposure of gravid females to Pb produces implantation dysfunction 

and reduces litter size and newborn survival (Lögdberg et al., 1987; Flora and Tandon, 1987; 

Johansson and Wide, 1986; Pinon-Lataillade et al., 1995; Piasek and Kostial, 1991; Ronis et al., 

1996). See Section 5.4.4.1 for details. 

5.4.3.3 Effects on the Female Sex Endocrine System and Menstrual Cycle 

The 1986 Pb AQCD described numerous studies that found effects of Pb on the female 

endocrine system and menstrual cycle in various species, including nonhuman primates, and that 

supported the conclusion that Pb was an endocrine disruptor in females (Grant et al., 1980; 

Maker et al., 1975; Vermande-Van Eck and Meigs, 1960). Observations of delayed vaginal 

opening (see Section 5.4.3.1) were attributed to the endocrine disruption effects of Pb on the 

hypothalamic-pituitary-gonadal axis (Stowe and Goyer, 1971; Vermande Van Eck and Meigs, 

1960). 

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Species/ Dose/Route/Form/Duration/ Endpoint/Magnitude of Effect Blood 

Citation Strain Group Size (% or incidence) /p-value (PbB) Dearth Rat/Fisher et al. 344 (2002) Foster Monkey/ (1992) Cynomolgus Foster et al. Monkey/ (1992) Cynomolgus Foster et al. Monkey/ (1996b) Cynomolgus 12 mg/mL Pb-acetate gavage from 30 days prior breeding until pups were weaned 21 day after birth; 10–32 litters per group, control group, gestation and lactation exposure, gestation only exposure, lactation only exposure Daily dosing for up to 10 years with gelatin capsules containing Pb-acetate (1.5 mg/kg); 8 control group monkeys, 8 lifetime exposure (birth–10 years), 8 childhood exposure (birth–400 days), and 8 adolescent exposure (PND 300-10 years of age) Daily dosing for up to 10 years with gelatin capsules containing Pb-acetate (1.5 mg/kg); 8 control group monkeys, 8 childhood (birth–400 days), 7 adolescent (PND 300–10 years), 7 lifetime (birth–10 years) Chronic exposure to Pb-acetate 50 to 2000 μg/kg-day p.o. beginning at birth for 15–20 years; 20 control monkeys, 4 monkeys in 50 μg/kg-d group, 3 monkeys in 100 μg/kg-d, 2 monkeys in 500 μg/kg-d group, and 3 monkeys in 2000 μg/kg-d group Delay in onset of puberty (p < 0.05); reduced serum levels of IGF1 (p < 0.001), LH (p < 0.001), and E2 (p < 0.001). Statistically significant reductions in circulating levels of LH, (p < 0.042), FSH (p < 0.041), and 

E2 (p < 0.0001) during menstrual cycle; 

progesterone concentrations were unchanged and menstrual cycle was not significantly affected. 

No effect on endometrial response to gonadal steroids as determined by ultrasound. 

Reduced corpora luteal production of progesterone (p = 0.04), without alterations in E2, 20-alpha-hydroxyprogesterone, or menstrual 

cyclicity. 

MaternPups PGest+lGest+lGest+lGest ~Gest ~Gest ~Lact ~Lact ~Lact ~

PbB <

PbB <

PbB 10(50 or PbB 25group 

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Citation Species/ Strain Dose/Route/Form/Duration/ Group Size Endpoint/Magnitude of Effect (% or incidence)/p-value Blood 

(PbB) Franks et al. (1989) Monkey/ Rhesus Lead acetate in drinking water (2–8 mg/kg-d) for 33 months; 7 control and 10 Pb monkeys Reduced circulating concentration of progesterone (p < 0.05); treatment with Pb did not prevent ovulation, but produced longer and more variable menstrual cycles and shorter menstrual flow. PbB 6

Laughlin et al. (1987) Monkey/ Rhesus Lead acetate in drinking water at 3.6, 5.9, or 8.1 mg/kg-day for 1–2 years 7 control and 10 experimental monkeys per group Reductions in cycle frequency (p<0.01); fewer days of flow (p<0.01); longer and more variable cycle intervals (p<0.025). PbB 44

51.2 μ80.7 μ88.4 μ

Lögdberg et al. (1988) Monkey/ Squirrel Lead acetate (varying concentrations 

≤0.1% in diet) maternal dosing from 5-8.5 weeks pregnant to PND 1 11 control monkeys, 3 low Pb exposure group (PbB 24 μg/dL), 7 medium Pb group (PbB 40 μg/dL, 5 high Pb group (PbB 56 μg/dL) 

Dose-dependent reduction in placental weight (p<0.0007); various pathological lesions were seen in the placentas (n = 4), including hemorrhages, hyalinization of the parenchyma with destruction of the villi and massive vacuolization of chorion epithelium. 

Mean (22-82 24 (2240 (3556 (43

E2, estradiol; FSH, follicle stimulating hormone; GD, gestational day; IGF1, insulin-like growth factor 1; LH, luteinizing hormone; Pb

concentration; PND, post-natal day 

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More recent studies have provided convincing support for endocrine-mediated alterations 

of the female reproductive system in rats (Srivastava et al., 2004; Dearth et al., 2002; Ronis 

et al., 1998a,b,c; Junaid et al., 1997; Ronis et al., 1996), guinea pigs (Sierra and TiffanyCastiglioni, 1992), and nonhuman primates (Foster et al., 1992, 1996b; Foster, 1992; Franks 

et al., 1989; Laughlin et al., 1987). The nonhuman primate studies are particularly relevant to 

extrapolations to humans and provide dose-response information for effects of Pb on female sex 

hormones and menstrual cycle. 

Laughlin et al. (1987) found that exposure to Pb (PbB 44 to 89 μg/dL) alters menstrual 

cycles (specifically, causing reductions in cycle frequency, fewer days of menstrual flow, and 

longer and more variable cycle intervals) in female rhesus monkeys. Consistent with these 

observations, Franks et al. (1989) found that chronic exposure to Pb in the drinking water (PbB 

70 μg/dL) reduced circulating concentrations of progesterone (suggesting impaired luteal 

function), produced longer and more variable menstrual cycles and temporally shorter menstrual 

flow in female rhesus monkeys. Additional details concerning these studies are provided in 

Table 5-4.2. 

At lower blood Pb levels (PbB <40 μg/dL), female cynomolgus monkeys exhibited 

statistically significant reductions in circulating levels of LH, FSH, and E2 during the menstrual 

cycle; however, serum progesterone concentrations were unchanged and menstrual cycle was not 

significantly affected (Foster, 1992). Similar exposures and PbB were shown to have no effect 

on endometrial response to gonadal steroids in cynomolgus monkeys as determined by 

ultrasound analysis (Foster et al., 1992). At lower blood lead concentrations (25 to 30 μg/dL), 

reduced corpora luteal production of progesterone occurred in the absence of alterations in E2, 

20-alpha-hydroxyprogesterone, or menstrual cyclicity (Foster et al., 1996b). In contrast to Foster 

et al. (1992), this study (Foster et al., 1996b) found no statistically significant effect of Pb on 

serum progesterone levels in cynomolgus monkeys that had lower PbB (10 to 15 μg/dL). 

Additional details concerning these studies are provided in Table 5-4.2. 

Several modes of action for lead-induced, endocrine disruption-mediated alterations in 

female reproduction have been proposed, including changes in hormone synthesis or metabolism 

at the enzyme level (Wiebe and Barr, 1988; Wiebe et al., 1988) and changes in hormone receptor 

levels (Wiebe et al., 1988; Wide and D’Argy, 1986). In addition, Pb may alter sex hormone 

release and imprinting during early development (Ronis et al., 1998c; Tchernitchin et al., 

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1998a,b). The latter effects would be consistent with observations of persistent changes in 

estrogen receptor levels in the uterus (Wiebe and Barr, 1988) and LH function in the ovary 

(Srivastava et al., 2004) in lead-exposed animals. 

5.4.3.4 Effects on Morphology and Histology of Female Sex Organs and the Placenta 

Lead-induced changes in morphology or histology in female sex organs and the placenta may 

explain reduced fertility and impaired female reproductive success (see Sections 5.4.3.2 and 

5.4.4.1.). Lögdberg et al. (1988) reported a dose-dependent reduction in placental weight and an 

increase in pathological lesions of the placenta in squirrel monkeys that received oral doses of 

Pb-acetate (0.001 to 0.1% in diet) during the last three-fourths or two-thirds of pregnancy (mean 

maternal PbB 37 μg/dL; range: 22 to 82 μg/dL). These effects occurred without overt toxicity in 

the mothers. Additional details concerning Lögdberg et al. (1988) are provided in Table 5-4.2. 

Similar effects on placental weight and histology were observed in mice (Fuentes et al., 

1996; Nayak et al., 1989). These effects on the placenta may explain the reduced birth weight 

that has been associated with prenatal Pb exposure (see Section 5.4.5). Exposure to Pb in early 

pregnancy also produces structural changes in the epithelium of the uterus of mice (Nilsson 

et al., 1991; Wide and Nilsson, 1979). These changes in uterine tissue may impair successful 

implantation of the blastocysts (see Section 5.4.4.1). 

5.4.4 Effects on Embryogenesis 

Lead exposure can increase fetal mortality, produce a variety of sublethal effects, and 

disrupt the growth and development of the offspring. Many of the lead-induced sublethal 

developmental effects occur at maternal PbB levels that do not result in clinical toxicity in the 

mothers. 

5.4.4.1 Embryo/Fetal Mortality 

The 1986 Pb AQCD concluded that that acute exposure to high doses of Pb interfered 

with implantation and pregnancy (Wide, 1985; Odenbro and Kihlström, 1977; Wide and Nilsson, 

1977; Vermande-Van Eck and Meigs, 1960). This conclusion is supported by results of more 

recent studies (Lögdberg et al., 1987; Giavini et al., 1980; Jacquet, 1976, 1977; Jacquet et al., 

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1975, 1976; Johansson and Wide 1986; Johansson et al., 1987; Johansson, 1989; Maisin et al., 

1978; Pinon-Lataillade et al., 1995; Wide and Nilsson, 1977, 1979). 

Lögdberg et al. (1987) reported an increase in pre- and perinatal mortality in squirrel 

monkeys that received Pb-acetate orally during the last two-thirds of pregnancy (45% versus 7 to 

8% among controls). Mean maternal PbB was 54 μg/dL (39 to 82 μg/dL). These fetotoxic 

effects occurred without overt toxicity in the mothers. Additional details concerning Lögdberg 

et al. (1987) are provided in Table 5-4.3. These effects are consistent with data from rodent 

studies, wherein gestational exposure to Pb (PbB 32 to >70 μg/dL) resulted in smaller litters and 

fewer implantation sites (e.g., Pinon-Lataillade et al., 1995; Singh et al., 1993b; Piasek and 

Kostial, 1991). 

Numerous studies have been performed to elucidate the mechanisms by which Pb causes 

prenatal death (Maisin at al., 1978; Jacquet, 1977, 1976; Jacquet et al., 1976, 1975). The 

available data suggest that Pb may alter blastocyst development and impair implantation. Hanna 

et al. (1997) demonstrated that in vitro exposure of 2- and 4-cell mouse embryos to 200 μM 

Pb-acetate resulted in reduced cell proliferation and blastocyst formation. Additional evidence 

for an effect on blastocysts is provided by data from in vitro fertilization studies (Chowdhuri 

et al., 2001; Johansson, 1989; Johansson et al., 1987). Johansson and co-workers (1989, 1987) 

reported that Pb delayed the timing of escape from the zona pellucida and induced a premature 

acrosome reaction. These effects could disrupt attachment and implantation of the blastocyst if 

they were to occur in vivo. 

5.4.4.2 Effects on embryo/fetal morphology 

The 1986 Pb AQCD summarized numerous reports that found associations between 

prenatal exposure to high doses of Pb and increased incidences of teratogenic effects 

(particularly tail stunting) in rodents (Ferm and Carpenter, 1967; Dey et al., 2001; Flora and 

Tandon, 1987; Ronis et al., 1996; Wide, 1985). More recent studies provide additional support 

for teratogenic effects of Pb in experimental animals (Flora and Tandon, 1987). Flora and 

Tandon (1987) demonstrated a dose-dependent effect on the incidence of tail malformations at 

$10 mg/kg i.v. on days 9 to 11 of gestation (PbB 13 to 45 μg/dL) that occurred only in those 

dams exhibiting “observable maternal toxicity” (not otherwise specified in the report). The few 

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Citation Species/ Strain Dose/Route/Form/Duration/Group size Endpoint/Magnitude of Effect/p-value Blood Le

(PbB) Cory-Slechta et al. (2004) Rat/Long- Evans Lead acetate in drinking water (150 ppm); 2 months before breeding until the end of lactation; 14 rats no maternal stress with Pb exposure, 15 rats no maternal stress with Pb exposure, 18 rats maternal stress without Pb exposure, 23 rats maternal stress and Pb Pb alone (in male) (p<0.05) and Pb plus stress (in females) (p<0.05) permanently elevated corticosterene levels in offspring PbB 30–40 

exposure Dearth et al. (2002) Rat/Fisher 344 12 mg/mL Pb-acetate gavage during gestation and lactation exposure 4 groups: control group, gestation and lactation exposure, gestation only exposure, lactation only exposure 10–32 litters per group (NOS) Delayed onset of puberty (p<0.05); suppressed serum levels of IGF1, LH, and E2 (p<0.001); Pb altered translation and/or secretion of IGF1 (p<0.001). Maternal P

Pups PbB Gest+lact ~Gest+lact ~Gest+lact ~Gest ~14 μGest ~3 μgGest ~1 μgLact ~28 μLact ~15 μLact ~3 μg

Flora and Tandon (1987) Rat/Albino (NOS) Lead nitrate dissolved in water 2–20 mg/kg-d i.v. on day 9, 10, 11 of gestation; 6 rats in each group (0, 5, 10 , 20, 40 mg/kg lead) Dose-dependant increase in external malformations at all doses (p<0.001), particularly tail defects; dose-dependant decrease in number of live births at 20 and 400 mg/kg (p<0.001); dose-dependent increase in number of resorptions per dam at 

≤10 

mg/kg (p<0.01). 

PbB 4.13±PbB 10.21PbB 13.13PbB 29.41PbB 45.03

Fox et al. (1991a) 

Rat/LongEvans hooded 

Lactation exposure via dams exposed to 0.02 or 0.2% Pb in drinking water from PND 1 through weaning (PND 21); 8 female pups per litter (number of litter unspecified) control pups, 8 pups for litter (number of litter unspecified) low-level exposure pups, 8 pups per litter (number of litter unspecified) moderate level exposure pups 

Long-term, dose-dependent decreases retinal Na/K ATPase activity in the female offspring (only female pups were used) (-11%; -26%) (p<0.05). 

PbB 18.8 μ59.4 μg/dL 

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Species/ Blood Le

Citation Strain Dose/Route/Form/Duration/Group Size Endpoint/Magnitude of Effect/p-value (PbB) Fox et al. Rat/Long- 0.02 or 0.2% Pb-acetate in drinking water (1997) Evans from PND 0–PND 21; 8 female pups per litter hooded control pups; 8 pups per litter low-level exposure; 8 pups per litter moderate level exposure (number of litters per dose unspecified) Iavicoli et al. Mouse/Swiss Lead acetate in food (0.02, 0.06, 0.11, 0.2, 2, (2003) 4, 20, 40 ppm); exposure began 1 day after mating until litter was 90 days old; one litter of mice exposed to each dietary concentration Developmental and adult Pb exposure for 6 weeks produced age and dose-dependent retinal degeneration such that rods and bipolar cells were selectively lost; at the ultrastructural level, all dying cells exhibit the classical morphological features of apoptotic cell death; decrease in the number of rods was correlated with the loss of rhodopsin content per eye confirming that rods were directly affected by Pb (p < 0.05); single- flash rod ERGs and cone ERGs obtained from lead-exposed rats demonstrated that there were age- and dose-dependent decreases in the rod a- wave and b-wave sensitivity and maximum amplitudes without any effect on cones; in adult rats exposed to Pb for three weeks, qualitatively similar ERG changes occurred in the absence of cell loss or decrease in rhodopsin content (p < 0.05); developmental and adult Pb exposure for three and six weeks produced age- and dose- dependent decreases in retinal cGMP phosphodiesterase (PDE) activity resulting in increased cGMP levels (p<0.05); retinas of developing and adult rats exposed to Pb exhibit qualitatively similar rod mediated ERG alterations as well as rod and bipolar apoptotic cell death (p<0.05) Similar biochemical mechanism such as the inhibition of rod and bipolar cell cGMP PDE, varying only in degree and duration, underlies both the lead-induced ERG rod-mediated deficits and the rod and bipolar apoptotic cell death (p<0.05). Low-level Pb exposure (PbB 2–13 μg/dL) reduced red cell synthesis (p<0.05); high-level exposure (PbB 0.6-2 μg/dL) enhanced red cell synthesis (p < 0.05). PbB weanl

or 59±8 μgadult 7±2 μPbB 0.6 to >2.0–13 μ

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Dose/Route/Form/Duration/Group Blood Le

Citation Species/ Strain size Endpoint/Magnitude of effect/p-value (PbB) Lögdberg Monkey/ Squirrel Lead acetate (5–20 mg/kg daily to maintain Increase in pre- and perinatal mortality among PbB 54 μget al. PbB) maternal dosing from 5–8.5 weeks squirrel monkeys receiving Pb-acetate p.o. during 82 μg/dL) (1987) pregnant to PND1 20 control; 11 lead- the last two-thirds of pregnancy (45% vs. 7–8% exposed monkeys among controls). Statistically significant reductions in mean birth weight (p<0.05) were observed in Pb exposed monkeys as compared to controls. Effects occurred without clinical manifestation of toxic effects in the mothers. Ronis Rat/Sprague- 0.6% Pb-acetate in drinking water for Reduction in serum testosterone levels in male, not In utero Pbet al. Dawley various durations: PND 24–74 (pubertal female; in female suppression of circulating E2 300 μg/dL (1996) exposure); PND 60–74 (post pubertal (p<0.05) and LH (p<0.05); reduction in male pre-pubert

exposure); 11 males and females in pubertal secondary sex organ weight (p<0.0005); delayed 30–60 μg/exposure group (10 each in control pubertal vaginal opening and disrupted diestrous in females post pubergroup) (p<0.005); increased incidence of stillbirth (2% 30–60 μg/6 males and females post-pubertal exposure control vs. 19% Pb) (p<0.005). PbBs in thand control groups and offspri

experimen>200 μg/d

Ronis Rat/Sprague- 0.6% Pb-acetate in drinking water ad libitum Dose-dependent delay in sexual maturation Groet al. (1998a) Dawley for various durations; GD 5 to PND 1; GD 5 to weaning; PND 1 to weaning; 3 control (delayed vaginal opening) (p<0.0002) following prenatal Pb exposure that continued until Naï

litters, 2 gestation exposure litters, 2 lactation exposure litters, 2 gestation and adulthood (85 days old); reduced birth weight (p<0.05), more pronounced among male pups. Conlactation exposure litters, 2 postnatal litters, 2 chronic litters (4 male and 4 female pups Geper litter) La

Gest+

Postn

Chro

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(PbB) Ronis et al. (1998b) Rat/Sprague- Dawley Lead acetate in drinking water (0.05% to 0.45% w/v); dams exposed until weaning; exposure of pups which continued until PND 21, 35, 55, or 85 Prenatal Pb exposure that continues until adulthood (85 days old) delays sexual maturation in female pups in a dose-related manner (p<0.05); birth weight reduced (p<0.05), more pronounced among male pups; PbBs in th

21 and 85 reached up 

5 control litters (0%), 10 low-dose litters (0.05%), 8 mid-dose litters (0.15%), 9 high- dose litters (0.45%) decreased growth rates (p<0.05) in both sexes accompanied by decrease in plasma concentrations of IGF1 through puberty (p<0.05) and a significant (4 male and 4 female pups per litter) increase in pituitary growth hormone during puberty (p<0.05). Ronis et al. (1998c) Rat/Sprague- Dawley Lead acetate 0.05, 0.15, or 0.45% in drinking water beginning GD 5 continuing until PND 21, 35, 55, or 85; 5 control litters (0%), 10 low-dose litters (0.05%), 8 mid-dose litters (0.15%), 9 high-dose litters (0.45%) Dose-responsive decrease in birth weight (p<0.05), and crown-to-rump length (p<0.05); dose-responsive delay in sexual maturity in male (p<0.05) and female (p<0.05); neonatal decrease in sex steroids (p<0.05); pubertal decrease in testosterone (male) (p<0.05), and Dams: 0, 4

Pups PND >120 μg/dPups PND ~237 μg/d

(4 male and 4 female pups per litter) 

E2 (female) (p<0.05); decrease estrous cyclicity at high 

dose (p<0.05). 

Pups PND >278 μg/dPups PND ~380 μg/d

Ronis et al. (2001) 

Rat/SpragueDawley Lead acetate in drinking water to 825 or 2475 ppm ad libitum from GD 4 to GD 55 

postpartum; 1 male and female pup/litter (5 litters per group) control group, 1 male and female pup/litter (5 litters per group) 825 ppm Pb-acetate group, 1 male and female pup/litter (5 litters per group) 2475 ppm Pb-acetate 

Dose-dependent decrease of the load of failure in male (p<0.05); no difference in plasma levels of vitamin D metabolites; reduced somatic growth (p<0.05), longitudinal bone growth (p<0.05, and bone strength during the pubertal period (p<0.05); sex steroid replacement did not restore skeletal parameters in Pb exposed rats; L-Dopa increased plasma IGF1 

Pups PND >214 μg/d

PbB at 825 PbB at 247

group concentrations, rates of bone growth, and bone 

strength measures in controls while having no effect in Pb exposed groups; DO gap x-ray density and proximal new endostreal bone formation were decreased in the distration gaps of the lead-treated animals (p < 0.01); distraction initiated at 0.2 mm 30 to 60 days of age. 

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Species/ Blood Le

Citation Strain Dose/Route/Form/Duration/Group Size Endpoint/Magnitude of Effect/p-value (PbB) Rat/Sprague- Lead in drinking water at 34 ppm from Reduced body weight (p = 0.04); parotid function was PbB 48±13 

Dawley weaning of mothers through gestation and decreased by nearly 30% (p = 0.30); higher mean weaning of offspring until birth; 6 pups caries scores than the control pups (p = 0.005); pre- control group, 6 pups experimental group and perinatal Pb exposure had significantly increased susceptibility to dental caries (p = 0.015). GMP, cyclic guanosine--3',5'-monophosphate; DO, distraction osteogenesis; E2, estradiol; ERG, electroretinographic; GD, gestational day; IGF1, ins

LH, luteinizing hormone; NOS, not otherwise specified; PbB, blood Pb concentration; PDE, phosphodiesterase; PND, post-natal day 

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studies (including those described in the 1986 Pb AQCD and more recent reports) that have 

demonstrated teratogenic effects of Pb exposure are confounded by maternal toxicity. 

5.4.5 Effects on Growth and Endocrine Regulation of Growth 

Studies conducted in rodents provide convincing evidence for an association between gestational 

Pb exposure and reduced birth weight and postnatal growth at doses that produce no clinical 

toxicity in the mothers (Dearth et al., 2002; Hamilton et al., 1994; Lögdberg et al., 1987; Piasek 

and Kostial, 1991; Pinon-Lataillade et al., 1995; Ronis et al., 1998a,b,c; Singh et al., 1993b; 

Watson et al., 1997). In squirrel monkeys, Lögdberg et al. (1987) reported a statistically 

significant reduction in mean birth weight following oral exposure to Pb-acetate during the latter 

trimesters of pregnancy (mean maternal PbB 54 μg/dL [39 to 82 μg/dL]). Additional details 

concerning Lögdberg et al. (1987) are provided in Table AX5-4.3. 

In addition, the literature provides convincing support for lead-induced impairment of 

postnatal growth. Although some early studies (Minnema and Hammond, 1994; Hammond 

et al., 1993, 1990) ascribed the reduction in postnatal growth to reduced food consumption 

(suggesting an effect of Pb on the satiety endpoint), more recent studies report impaired growth 

unrelated to changes in food consumption. Ronis et al. (1996, 1998a,b,c) reported lead-induced 

reductions in birth weight and postnatal growth that occurred in the absence of a significant 

alteration in food consumption. Han et al. (2000) found a reduction in the birth length of pups 

(pup PbB ~16 μg/dL on PND 1) whose mothers had been exposed to Pb up to 1 month before 

mating (maternal PbB on GD 9, 16, and 21 <40 μg/dL). Berry et al. (2002) reported depressed 

growth in rats exposed to lead, even though food consumption was higher in the lead-exposed 

rats. 

Ronis et al. (2001) showed that in rats, pre- and postnatal (through PND 55) exposure to 

Pb reduced somatic longitudinal bone growth and bone strength during the pubertal period (PbB 

>67 μg/dL). These effects could not be reversed by stimulation of the growth hormone axis by 

supplemental sex hormone. These results suggest that Pb exposure may impair growth through a 

mechanism that involves a suppressed pituitary response to hypothalamic stimulation. The 

mechanism may be related to a reduction in plasma concentrations of IGF1 following Pb 

exposure (Dearth et al., 2002; Ronis et al., 1998b). Dearth et al. (2002) exposed F344 rats to Pb 

by gavage beginning 30 days before mating and continuing until weaning of the pups at 21 days 

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of age. By PND 30, all three groups had PbB #3 μg/dL and all lead-exposed groups exhibited 

decreased serum levels of IGF1, LH, and E2. Since liver IGF1 mRNA was not affected, it 

appeared that Pb altered the translation and/or secretion of IGF1, which in turn decreased LHreleasing hormone at the hypothalamic level. Additional details concerning Dearth et al. (2002) 

are provided in Table AX5-4.3. An effect on IGF1 also been demonstrated by Ronis et al. 

(1998b). 

5.4.6 Effects on Other Endocrine Systems during Development 

Recent experimental animal studies provide evidence for an interaction between Pb 

exposure and stress hormones, including glucocorticoids and catecholamines (Cory-Slechta 

et al., 2004; Yu et al., 1996; Vyskocil et al., 1991; Saxena et al., 1990). Lead has been reported 

to increase stress hormone levels (Vyskocil et al., 1991). 

Cory-Slechta et al. (2004) reported a persistent effect of combined environmental stress 

(administered as restraint) and maternal Pb exposure (PbB 30 to 40 μg/dL) on corticosteroid 

levels in adult offspring. Female adult offspring born to these dams exhibited elevated 

corticosteroid levels only when Pb exposure was combined with environmental stress, whereas 

their adult male siblings exhibited elevated corticosteroid levels from Pb exposure alone. These 

data suggest that brief exposures to Pb and stress during development may result in persistent 

changes in the hypothalamic-pituitary-adrenal axis. Additional details concerning Cory-Slechta 

et al. (2004) are provided in Table AX5-4.3. 

The interplay between Pb and stress hormones is consistent with the findings of Yu et al. 

(1996) wherein neonatal exposure to Pb (PbB 70 μg/dL) decreased cold-water swimming 

endurance (a standard test for stress endurance). The enhancement of lead-induced toxicity by 

stress was also reported by Saxena et al. (1990) in adult male rats. Saxena et al. (1990) reported 

enhanced testicular injury when rats were exposed to immobilization stress in combination with 

Pb exposure (PbB >200 μg/dL). 

5.4.7 Effects on Other Organ Systems during Development 

5.4.7.1 Developmental Effects on Blood and Liver 

Recent data provides evidence for lead-induced alterations in developing hematopoietic 

and hepatic system. The data concerning the effect of Pb exposure on the developing 

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hematopoietic system are limited. The 1986 Pb AQCD proposed that alterations in blood ALAD 

activity and erythrocyte protoporphyrin were possible biomarkers for subtle, prenatal effects of 

Pb on heme synthesis (Hayashi 1983a,b; Jacquet et al., 1977; Prigge and Greve, 1977; 

Hubermont et al., 1976). A more recent study (Iavicoli et al., 2003) of Pb effects on RBC 

production, HB concentration, and Hct was not able to clearly establish a dose-response 

relationship for these endpoints. Although limited by small group size (one litter per dose), 

subchronic dietary exposure to low levels of Pb (PbB 0.6 to 2 or 2 to 13 μg/dL) revealed that Pb 

exposure reduced red cell synthesis, hemoglobin concentration, and hematocrit at PbB 2 to 

13 μg/dL and increased RBC synthesis, Hb concentration, and Hct at PbB 0.6 to 2 μg/dL. More 

data are needed to clarify the effect of low-dose Pb exposure on blood endpoints. 

Two rodent studies provide limited suggestive evidence that Pb exposure during 

development produces changes in hepatic enzymes and other biomarkers of hepatic function. 

Pillai and Gupta (2005) reported that long-term exposure of rats (pre-mating, gestation, and 

lactation) to moderate levels of Pb-acetate (subcutaneous injections of 0.05 mg/kg-day; PbB not 

reported) resulted in reduced activities of hepatic steroid (E2) metabolizing enzymes (17-ßhydroxy steroid oxidoreductase and UDP glucuronyl transferase) and decreased hepatic CYP450 

content. Corpas (2002) reported that exposure to Pb in drinking water exposure during gestation 

and lactation (pup PbB ~22 μg/dL at PND 12 and PND 21) resulted in alterations in the hepatic 

systems of neonates (PND 12) and pups (PND 21). The effects manifested as alterations in 

several biochemical indicators of hepatic toxicity: reductions in Hb, iron, alkaline and acid 

phosphatase levels, and hepatic glycogen, and elevated blood glucose. These data suggest that 

Pb may alter hepatic function during development; however, more data are needed to determine 

whether these effects are persistent. 

5.4.7.2 Developmental Effects on Skin 

Recent data provides limited evidence of altered soft tissue development resulting from 

Pb exposure. The literature includes one report of lead-induced abnormalities in skin 

development. Dey et al. (2001) reported that the pups of mice exposed orally to Pb citrate 

(5 μg/kg-day) throughout gestation exhibited a variety of skin anomalies, including perforations, 

cell deformity, and disordered collagen bundles. The PbB levels for mothers and pups were not 

provided. Although detailed biochemical studies are required to elucidate the mechanism for 

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structural abnormalities, it appears that covalent binding of Pb ions to the sulfate group of 

glycosaminoglycans may be involved. 

5.4.7.3 Developmental Effects on the Retina 

Several studies have found that Pb exposure during early postnatal development impairs 

retinal development in female Long-Evans hooded rats (Fox et al., 1997, 1991a,b; Fox and 

Rubenstein, 1989; Fox and Chu, 1988). Of these, two studies are particularly important. Fox 

et al. (1991a) demonstrated that lactation exposure to Long-Evans hooded rats (PbB 18.8 or 

59.4 μg/dL) resulted in long-term, dose-dependent decreases retinal Na/K ATPase activity in the 

female offspring (only female pups were used). Fox et al. (1997) subsequently demonstrated that 

lactation exposure to female Long-Evans hooded rats (PbB 19 ± 3 or 59 ± 8 μg/dL) or drinking 

water exposure to adult females (PbB 56 ± 9 μg/dL) resulted in differential age- and dosedependent alterations in retinal structure and function following low (PbB <20 μg/dL) and 

moderate (PbB <60 μg/dL) exposures during lactation or long-term (~60 days) exposure during 

adulthood. The mode of action for the effects of Pb on retinal development may be related to 

impaired Na/K ATPase activity (Fox et al., 1991a). The observation of reduced enzyme activity 

in the retina, but not in the kidney, suggests specificity for the retinal alpha-3 isozyme of Na/K 

ATPase, rather than the renal alpha-1 isozyme of Na/K ATPase. The authors suggested that this 

specificity may play a role in the target organ-specific toxicity of Pb (Fox et al., 1991a). 

5.4.8 Conclusions 

The 1986 Pb AQCD presented unequivocal evidence (derived principally from studies of 

rodents) for effects of Pb on reproduction and development in laboratory animals. This included 

evidence for lethal effects in developing organisms exposed to Pb during gestation and in the 

neonatal period, as well as a variety of sublethal effects on reproduction and development. 

Sublethal effects included changes in levels or function of reproductive hormones, effects on 

maturation of reproductive systems, persistent toxic effects on the gonads (both male and 

female), and adverse effects on the conceptus. More subtle effects on hormone metabolism and 

reproductive cell structure of developing organisms were also documented. 

More recent studies support earlier conclusions, presented in the 1986 Pb AQCD, that Pb 

can produce temporary and persistent effects on male and female reproductive function and 

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development and that Pb disrupts endocrine function at multiple points along the hypothalamicpituitary-gonadal axis. 

Effects on Male Reproduction. Studies in experimental animals (presented in the 1986 Pb 

AQCD and others published subsequent to the 1986 Pb AQCD) provide convincing evidence 

that Pb acts as an endocrine disruptor in males. The majority of studies support the conclusion 

that endocrine disruption in males involves Pb acting at multiple sites along the hypothalamicpituitary-gonadal axis. The adverse effects of Pb on male reproduction include perturbations in 

sexual development and maturation, changes in fertility, changes in male sex hormone levels, 

and alterations in gonad tissues and cell structure. 

Studies conducted in male experimental animals unequivocally demonstrate that Pb 

exposure during early development (PbB >30 μg/dL) can delay the onset of puberty and alter 

reproductive function later in life. Persistent effects of Pb exposure on the male reproductive 

system may derive from disruption in pulsatile release of sex hormones during early 

development (Ronis et al., 1998c). 

The 1986 Pb AQCD reported evidence that Pb exposure affects male fertility in various 

animal species, including rabbits (Cole and Bachhuber, 1915), guinea pigs (Weller, 1915), rats 

(Ivanova-Chemishanska et al., 1980), and mice (Schroeder and Mitchener, 1971). More recent 

studies, conducted in various animal species, have demonstrated lead-induced alteration of sperm 

parameters (e.g., count, motility, number of abnormal sperm) (Sokol et al., 1985; Acharya et al., 

2003; Adhikari et al., 2000; Foster et al., 1998; Graca et al., 2004; McGivern et al., 1991; Mishra 

and Acharya, 2004; Sokol and Berman, 1991). These effects, however, have not been observed 

in all studies; the response may be modified by an adaptive mechanism in the hypothalamicpituitary-gonadal axis. Lead has also been shown to alter the stability of sperm chromatin in 

monkeys (PbB 56 μg/dL) in the absence of gross changes in sperm parameters, a finding which 

may contribute to a reduction in male fertility (Foster et al., 1996a). These results are consistent 

with observations of reduced in vitro fertilization capacity of sperm collected from rats, rabbits, 

or mice previously exposed to Pb (Sokol et al., 1994; Foote, 1999; Johansson et al., 1987, 

respectively). Two modes of action have been proposed for lead-induced alterations in sperm 

capacity for fertilization: (1) Pb complexation with sulfhydryl groups in sperm, and (2) leadinduced generation of ROS in testes. 

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Experimental animal studies provide convincing evidence that Pb acts as an endocrine 

disruptor in males at various points along the hypothalamic-pituitary-gonadal axis. Although 

there is evidence for a common mode of action, consistent effects on circulating testosterone 

levels are not always observed in lead-exposed animals. The inconsistency in the reports of 

circulating testosterone levels complicates the derivation of a dose-response relationship for this 

endpoint. 

The 1986 Pb AQCD reported evidence for histological changes in the testes and prostate 

in rats in association with relatively high doses of Pb (Chowdhury et al., 1984; Hilderbrand et al., 

1973; Golubovich et al., 1968). More recent studies in animals provide additional support for 

testicular damage (i.e., ultrastructural changes in testes and cytotoxicity in Sertoli cells) 

following exposure to Pb (Foster et al., 1998; Singh et al., 1993a; Batra et al., 2001; Chowdhury 

et al., 1986, 1987; Corpas et al., 1995; Graca et al., 2004; Pinon- Lataillade et al., 1993; Saxena 

et al., 1990). Foster et al. (1998) and Singh et al. (1993a) demonstrated ultrastructural changes in 

testes of monkeys at PbB 35 to 40 μg/dL. Lead-induced oxygen free radical generation is the 

plausible mechanism of testicular injury in primates (Foster et al., 1998) and rodents 

(Chowdhury et al., 1984; Acharya et al., 2003; Adhikari et al., 2001; Batra et al., 2001; Bizarro 

et al., 2003; Chowdhury et al., 1984; Gorbel et al., 2002; Mishra and Acharya, 2004). 

Effects on Female Reproduction. In females, Pb exposure has been consistently shown to 

disrupt the hypothalamic-pituitary-gonadal axis and to produce reproductive dysfunction. The 

1986 Pb AQCD reported that Pb exposure was associated with inhibition of menstruation, 

ovulation, and follicular growth in monkeys (Vermande-Van Eck and Meigs, 1960) and, in 

rodents, delayed vaginal opening, decreased frequency of implantation, and reduced rates of 

pregnancy (Kimmel et al., 1980; Odenbro and Kihlström, 1977). Observations from more recent 

experimental animal studies support these findings. The effects of Pb on female reproduction 

may be classified as alterations in female sexual maturation, effects on fertility and menstrual 

cycle, alterations in levels of female sex hormones, and changes in morphology or histology of 

female reproductive organs as well as the placenta. 

The 1986 Pb AQCD reported that Pb exposure (PbB 20 to 40 μg/dL) in rodents produced 

delays in sexual maturation. More recent studies in experimental animals (primarily rodent 

studies) provide convincing evidence that Pb exposure before puberty (prenatal and early 

postnatal PbB ~40 μg/dL) delays maturation of the female reproductive system (Dearth et al., 

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2002, 2004; Iavicoli et al., 2004; McGivern et al., 1991; Ronis et al., 1998a,b,c,). Ronis et al. 

(1998c) suggested that lead-induced disruption of pulsatile release of sex hormones may result in 

delayed onset of puberty. 

Numerous studies were described in the 1986 Pb AQCD that supported the conclusion 

that Pb was an endocrine disruptor in females. More recent studies in various mammalian 

species provide convincing support for endocrine-mediated alterations of the female reproductive 

system. The nonhuman primate studies provide dose-response information concerning the 

effects of Pb on female sex hormones and menstrual cycle (Foster et al., 1996b; Foster, 1992; 

Foster et al., 1992; Franks et al., 1989; Laughlin et al., 1987). Exposures of monkeys to Pb 

resulting in chronic PbB <20 μg/dL produce few effects on circulating hormone levels and do 

not alter the menstrual cycle. Higher exposures of monkeys to Pb (PbB >40 μg/dL) alter 

circulating hormone levels and the menstrual cycle, with more marked changes in these 

endpoints occurring at higher PbB levels. Several modes of action for lead-induced alterations in 

female reproduction have been proposed, including changes in hormone synthesis or metabolism 

(Wiebe and Barr, 1988; Wiebe et al., 1988) and changes in hormone receptor levels (Wiebe 

et al., 1988; Wide and D’Argy, 1986). In addition, Pb may alter sex hormone release and 

imprinting during early development (Ronis et al., 1998c; Tchernitchin et al., 1998a,b). 

The 1986 Pb AQCD presented convincing evidence from experimental animal studies for 

lead-induced alterations in female fertility, including interference with implantation and 

pregnancy. More recent studies have confirmed that Pb exposure disturbs female fertility; 

however, Pb exposure does not generally produce total sterility. Studies in nonhuman primates 

and rodents have also demonstrated reductions in litter size, implantation dysfunction, and 

decreased postnatal survival following Pb exposure of gravid female experimental animals (PbB 

>30 μg/dL) (Lögdberg et al., 1987; al-Hakkak et al., 1988; Flora and Tandon, 1987; Piasek and 

Kostial, 1991; Pinon-Lataillade et al., 1995; Ronis et al., 1996; Singh et al., 1993b; Wide, 1985). 

Lead-induced changes in morphology or histology in female sex organs and placenta may 

explain reduced fertility and impaired female reproductive success. Lögdberg et al. (1988) 

reported a dose-dependent reduction in placental weight and an increase in pathological lesions 

of the placenta in squirrel monkeys that consuming Pb-acetate in their diet during the last threefourths or two-thirds of pregnancy (maternal PbB 37 μg/dL). Exposure to Pb in early pregnancy 

also produces structural changes in the epithelium of the uterus of mice (Nilsson et al., 1991; 

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Wide and Nilsson, 1979). These changes in uterine tissue may impair successful implantation of 

the blastocysts. In addition, the histological and morphological effects on the uterus and placenta 

may explain the reduced birth weight that has been associated with prenatal Pb exposure 

(possibly due to placental insufficiency). 

Developmental Effect. Pre- and postnatal exposure to Pb has been demonstrated to result 

in fetal mortality and produce a variety of sublethal effects in the offspring. Many of these leadinduced sublethal developmental effects occur at maternal PbB that do not result in clinical 

(overt) toxicity in the mothers. The few studies that have reported teratogenic effects resulting 

from Pb exposure are confounded by maternal toxicity. 

Studies conducted in rodents and primates provide convincing evidence for an association 

between Pb exposure and reduced birth weight and postnatal growth at doses that produce no 

clinical toxicity in the mothers (maternal PbB >40 μg/dL) (Dearth et al., 2002; Lögdberg et al., 

1987; Berry et al., 2002; Bogden et al., 1995; Camoratto et al., 1993 Hamilton et al., 1994; 

Hammond et al., 1989, 1990, 1993; Minnema and Hammmond 1994; Han et al., 2000; Ronis 

et al., 1996, 1998a,b,c; Piasek and Kostial, 1991; Pinon-Lataillade et al., 1995; Sant’Ana et al., 

2001; Singh et al., 1993b; Watson et al., 1997). The available data suggest that the mode of 

action for lead-induced growth suppression involves a reduction in the plasma concentration 

of IGF1. 

Recent experimental animal studies provide evidence for an interaction between Pb 

exposure during development (PbB 30 to 40 μg/dL) and stress hormones, including 

glucocorticoids and catecholamines (Cory-Slechta et al., 2004; Yu et al., 1996; Vyskocil et al., 

1991; Saxena et al., 1990). Lead exposure during early postnatal development (PbB ~20 μg/dL) 

impairs retinal development in female Long-Evans hooded rats (Fox et al., 1997, 1991a,b; Fox 

and Rubenstein, 1989; Fox and Chu, 1988). 

In addition, recent studies provide limited evidence for lead-induced alterations in 

developing skin, and hematopoietic and hepatic systems; however, more data are needed to 

clarify the effect of low-dose Pb exposure on these endpoints. 

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5.5 CARDIOVASCULAR EFFECTS OF LEAD 

5.5.1 Introduction 

Numerous large and small epidemiological studies have attempted to examine the link 

between Pb exposure and development of hypertension (HTN) in the general population and 

occupationally-exposed individuals. In addition, a number of studies have reported on other 

cardiovascular effects of Pb in Pb-exposed humans (U.S. Environmental Protection Agency, 

1990). While several studies have demonstrated a positive correlation between blood pressure 

and blood Pb concentration, others have failed to show such association when controlling for 

confounding factors such as tobacco smoking, exercise, body weight, alcohol consumption, and 

socioeconomic status. Thus, the studies that have employed blood Pb level as an index of 

exposure have shown a relatively weak association with blood pressure. In contrast, the majority 

of the more recent studies employing bone Pb level have found a strong association between 

long-term Pb exposure and arterial pressure (Chapter 6). Since the residence time of Pb in the 

blood is relatively short but very long in the bone, the latter observations have provided 

compelling evidence for the positive relationship between Pb exposure and a subsequent rise in 

arterial pressure. This section reviews the published studies pertaining to the cardiovascular 

effects of Pb exposure in experimental animals, isolated vascular tissues, and cultured vascular 

cells. 

5.5.2 Lead Exposure and Arterial Pressure in Experimental Animals 

Numerous studies have shown that exposure to low levels of Pb for extended periods 

results in a delayed onset of arterial HTN that persists long after the cessation of Pb exposure in 

genetically normal animals (see Tables AX5-5.1 to AX5-5.5). In addition, Pb exposure during 

gestation has been reported to significantly raise arterial pressure in the third trimester of 

pregnancy in SD rats given a low calcium diet (Bogden et al., 1995). Taken together, these 

observations provide irrefutable evidence that extended exposure to low levels of Pb can result in 

the subsequent onset of HTN in experimental animals. 

Many studies have been conducted to explore the mechanisms by which chronic Pb 

exposure may cause HTN. Most of these studies have examined various blood-pressure 

regulatory and vasoactive systems in animal models of Pb-induced HTN. In addition, several 

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studies have investigated the direct effect of Pb on vascular tone or the ability of Pb to modify 

the response to vasoconstrictor/vasodilator agents in isolated vascular tissues. Finally, a number 

of studies have explored the effect of Pb on cultured endothelial and vascular smooth muscle 

cells. An overview of the findings of these studies is provided below: 

5.5.2.1 Effect of Lead on Production of Reactive Oxygen Species and Nitric 

Oxide Metabolism 

Reactive oxygen species (ROS), such as, superoxide (O2 

!

), hydroxyl radical (OH) and 

hydrogen peroxide (H2O2) are normally produced in the course of metabolism and are safely 

contained by the natural antioxidant defense system. Excess production and/or diminished 

containment of ROS can lead to oxidative stress in which uncontained ROS can attack and 

denature functional/structural molecules and, thereby, promote tissue damage, cytotoxicity, and 

dysfunction. In fact, oxidative stress has been implicated in the pathogenesis of HTN, 

atherosclerosis, neurodegenerative disorders, aging, and neoplasm among other afflictions. 

During the past decade, several studies have demonstrated that Pb exposure causes oxidative 

stress, particularly in the kidney and cardiovascular tissues, as well as in cultured endothelial and 

vascular smooth muscle cells (VSMC). The in vivo studies have further shown that Pb-induced 

oxidative stress is, at least in part, responsible for the associated HTN in experimental animals. 

Relevant published studies pertaining to this issue are summarized below and listed in Annex 

Table AX5-5.1. 

Khalil-Manesh et al. (1994) were among the first to suggest that oxidative stress may be 

involved in the pathogenesis of Pb-induced HTN. This assumption was based on the observation 

that chelation therapy with dimethyl succinic acid (DMSA) rapidly ameliorated HTN and raised 

plasma cGMP level in rats with Pb-induced HTN. They further demonstrated that DMSA 

possesses strong antioxidant properties in vitro. Accordingly, they theorized (a) that Pb exposure 

may increase the generation of ROS, which, in turn, elevate arterial pressure by reacting with and 

inactivating endothelium-derived-relaxing factor (EDRF), and (b) that by scavenging ROS, 

DMSA rapidly lowers blood pressure prior to significantly affecting body Pb burden. 

In a subsequent study, Gonick et al. (1997) showed a marked increase in renal tissue 

content of lipid peroxidation product malondialdehyde (MDA) coupled with significant 

upregulations of endothelial (eNOS) and inducible (iNOS) nitric oxide synthases. Thus, the 

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study provided evidence for the occurrence of oxidative stress and compensatory upregulation of 

NOS isotypes in the kidney of animals with Pb-induced HTN. 

In another study, Ding et al. (1998) showed that infusion of NOS substrate, L-Arginine, 

lowers blood pressure to a much greater extent in rats with Pb-induced HTN than that seen in 

either control animals or DMSA-treated Pb-exposed animals. The data, therefore, provided 

indirect evidence for the role of depressed NO availability in the pathogenesis of Pb-induced 

HTN. The study further suggested that oxidative stress may be responsible for diminished NO 

availability in this model. It should be noted that administrating cell-impermeable native SOD 

did not lead to a further reduction of blood pressure beyond that seen with L-Arginine alone. 

As with the previous study (Khalil-Manesh 1994), oral DMSA therapy for 2 weeks significantly 

lowered blood pressure in the Pb-exposed animals. This was accompanied by a significant 

reduction of blood Pb concentration. In an attempt to explore whether the observed amelioration 

of Pb-induced HTN was due to the reduction of Pb burden or alleviation of oxidative stress by 

DMSA, Vaziri et al. (1997) carried out a study in which rats with Pb-induced HTN were treated 

with a lazaroid compound, a potent, non-chelating antioxidant. The study revealed marked 

elevation of blood pressure and oxidative stress (increased lipid peroxidation) and reduced NO 

availability (depressed urinary NO2 + NO3 excretion) in the untreated rats with Pb-induced HTN. 

Antioxidant therapy with the lazaroid compound resulted in a significant alleviation of oxidative 

stress, improved NO availability, and a marked attenuation of HTN without affecting blood Pb 

concentration. Thus, the latter study provided convincing evidence for the role of oxidative 

stress as a major mediator of Pb-induced HTN. The study further demonstrated that Pb-induced 

HTN is associated with diminished NO availability and that the latter was mediated by oxidative 

stress. The reduction in NO availability observed in rats with Pb-induced HTN (Pb-acetate, 

100 ppm in drinking water for 12 weeks) was recently confirmed by Dursun et al. (2005) in rats 

treated with daily IP injection of Pb-acetate (8 mg/Kg) for 2 weeks. The authors showed that the 

rise in arterial pressure was accompanied by a significant reduction of urinary NO2 + NO3 

excretion and a significant fall in renal blood flow (indicating increased renal vascular 

resistance), mimicking the effect of the NOS inhibitor LNAME. 

To further explore the cause for the observed reduction of NO availability, Vaziri et al. 

(1999a) subsequently studied the expression of eNOS and iNOS in the kidney and cardiovascular 

tissues of rats with Pb-induced HTN. The study showed that the reduction in NO availability is 

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paradoxically associated with a significant upregulation of NOS isotypes. Moreover, in vitro 

incubation experiments revealed no significant change in NOS activity in the presence of lead. 

Interestingly, antioxidant therapy with pharmacological doses of vitamin E and ascorbic acid 

reversed the upregulation of NOS isotypes and paradoxically raised NO availability in the 

subgroup of rats with Pb-induced HTN (Vaziri et al., 1999a). These observations were 

subsequently confirmed by Vaziri and Ding (2001) who showed marked reduction of NO 

availability despite significant upregulations of eNOS, nNOS, and iNOS in the aorta, heart, 

kidney, and brain of rats with Pb-induced HTN and their normalization with the administration 

of superoxide-scavenger tempol (15 mg/Kg IP/day) for 2 weeks. It is noteworthy that tempol 

administration had no effect on the measured parameters in the control animals. Taken together, 

these observations indicated that ROS-mediated NO inactivation and, hence, depressed NO 

availability, results in a compensatory upregulation of NOS isotypes in animals with Pb-induced 

HTN. This phenomenon is consistent with other studies from this group, which have 

demonstrated the presence of a negative-feedback regulation of eNOS by NO (Vaziri and Wang, 

1999; Vaziri et al., 2005). 

The occurrence of compensatory upregulation of NOS by oxidative stress in Pb-exposed 

intact animals described above was subsequently replicated by Vaziri and Ding (2001) in 

cultured human endothelial cells incubated in media containing different concentrations of Pbacetate (versus control media containing sodium acetate). Once again, co-incubation with 

tempol prevented this phenomenon. This study confirmed the ability of Pb to affect endothelium 

independently of its effects on humoral or hemodynamic factors, which are operative in vivo. 

Taken together, these observations suggest that Pb-induced reduction of biologically-active NO 

is not due to the reduction of NO-production capacity. Instead, it is linked to oxidative stress. In 

an attempt to explore this supposition, in a separate study, Vaziri et al. (1999b), tested the 

hypothesis that avid inactivation and sequestration of NO by ROS may be, in part, responsible 

for the reduction of NO availability in animals with Pb-induced HTN. To this end, they tested 

for the presence of immunodetectable nitrotyrosine in kidney, brain, and cardiovascular tissues 

harvested from untreated and antioxidant-treated (vitamin E + vitamin C) rats with Pb-induced 

HTN and normal control rats. Nitrotyrosine was used as a marker of NO oxidation by ROS (NO 

+ O2 

• → ONOO!

, ONOO! + tyrosine → nitrotyrosine). The study showed an overabundance of 

nitrotyrosine in all plasma and tested tissues in the untreated rats with Pb-induced HTN. 

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Antioxidant therapy reduced nitrotyrosine abundance, attenuated HTN, and simultaneously 

raised NO availability in the subgroup of rats with Pb-induced HTN but had no effect on the 

normal control group. These observations provided compelling evidence that Pb-induced HTN 

causes oxidative stress, which, in turn, promotes functional NO deficiency via ROS-mediated 

NO inactivation. The latter, in turn, participates in the development and maintenance of HTN 

and cardiovascular abnormalities. In addition, the formation of the highly cytotoxic reactive 

nitrogen species, peroxynitrite (ONOO!

), from the NO-ROS interaction and the associated 

nitrosative stress could potentially contribute to the long-term cardiovascular, renal, and 

neurological consequences of Pb exposure. 

In a series of subsequent studies Vaziri et al. (2003) explored the expression of NAD(P)H 

oxidase (which is a well-recognized source of ROS in, not only, the immune cells but also in 

renal, cardiovascular, and neuronal tissues) in animals with Pb-induced HTN. In addition, 

expression of the main antioxidant enzymes, namely Mn and CuZn-superoxide dismutases 

(SOD), catalase and glutathione peroxidase were investigated. The study revealed significant 

upregulation the gp91phox subunit of NAD(P)H oxidase in the brain as well as a trend for higher 

levels in the renal cortex and left ventricle of rats with Pb-induced HTN. This was accompanied 

by a significant compensatory upregulation of CuZn SOD in the kidney and brain, and of Mn 

SOD in the heart, of rats with Pb-induced HTN. In contrast, despite the presence of oxidative 

stress, catalase and glutathione peroxidase activity levels were unchanged. In a more recent 

study, Farmand et al. (2005), showed a significant increase in CuZn SOD activity with no change 

in either catalase or glutathione peroxidase activity in the aorta of rats with Pb-induced HTN 

compared with control animals. Since the latter enzymes are responsible for the reduction of 

H2O2 and lipoperoxides, the lack of an appropriate rise in their tissue levels may contribute to the 

severity of oxidative stress in Pb-exposed animals. 

The contribution of oxidative stress in the pathogenesis of HTN in this model was 

confirmed by experiments which demonstrated normalization of arterial pressure with the 

infusion of superoxide-scavenger, tempol, in rats with Pb-induced HTN (but no change was 

observed in the blood pressure in the control rats) (Vaziri et al., 2003). As noted above, the 

relative reduction of tissue catalase and glutathione peroxidase, which are responsible for the 

CAT reduction of H2O2 to water and molecular oxygen (2H2O2 ⎯ ⎯ →⎯ 2H2O + O2) , can result in

GPX 

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accumulation of H2O2. H2O2 serves as a cellular growth signal, as well as a substrate for 

hydroxyl radical (·OH) generation. The former action can potentially contribute to 

cardiovascular remodeling, whereas the latter can promote oxidative injury. In a recent study, 

Ni et al. (2004) demonstrated a transient rise in O2 

!

 production followed by a sustained rise in 

H2O2 production by human coronary endothelial and vascular smooth muscle cells cultured in 

media containing Pb-acetate versus the control media containing Na-acetate. This was 

accompanied by, and primarily due to, upregulation of NAD(P)H oxidase and SOD together with 

reduced or unchanged catalase and glutathione peroxidase levels. Accordingly, the results of this 

in vitro study confirmed the findings of the in vivo studies and validated the anticipated 

accumulation of H2O2. 

As noted above, H2O2 is the substrate for the Fenton and Haber-Weiss reactions, which 

culminate in formation of the highly cytotoxic·OH (H2O2 + e! → OH + OH!

). Thus, 

accumulation of H2O2 in animals with Pb-induced HTN can facilitate·OH production and, 

thereby, promote oxidative stress and tissue injury. This supposition was confirmed in a series 

of studies by Ding et al. (2001), who showed increased hydroxyl radical production in rats with 

Pb-induced HTN. Oxidative stress, HTN, and excess hydroxyl radical production were all 

reversed with IV infusion of the reputed hydroxyl radical scavenger, DMTU, in the Pb-exposed 

animals. Increased hydroxyl radical production observed in intact animals with Pb-induced HTN 

was confirmed in lead-treated cultured endothelial cells (Ding et al., 2000). The role of oxidative 

stress in the pathogenesis of HTN and endothelial dysfunction (depressed NO availability) has 

been substantiated by a number of other investigators. For instance, Attri et al. (2003), 

demonstrated that exposure to Pb for up to 3 months resulted in a significant rise in arterial 

pressure, which was substantially ameliorated by coadministration of the antioxidant vitamin 

ascorbic acid (20 mg/rat) in Wistar-Kyoto rats. The rise in arterial pressure in lead-treated rats 

was accompanied by diminished NO availability (low plasma NO2 + NO3) and biochemical 

evidence of oxidative stress, i.e., elevations of plasma MDA, a DNA oxidation product 

(8-hydroxyguanosine), and diminished ferric-reducing antioxidant power, as well as 

electrophoretic evidence of DNA damage. Amelioration of HTN by antioxidant therapy was 

accompanied by improved NO availability (plasma NO2 + NO3), marked attenuation of oxidative 

stress, and partial reduction of DNA damage in this model. In another study, Malvezzi et al. 

(2001) showed partial amelioration of HTN in Pb-exposed rats with the administration of either 

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DMSA or L-arginine and showed a much greater response with the combination thereof. These 

observations support the role of interaction of ROS and NO in the pathogenesis of Pb-induced 

HTN in the rat. 

As cited above, Pb-induced HTN is associated with and is, at least in part, due to ROSmediated inactivation and hence, reduced availability of biologically active NO. Many of the 

biological actions of NO are mediated by cGMP, which is produced from the substrate GTP by 

the cytosolic enzyme soluble guanylate cyclase (sGC). sGC is expressed in VSMC and several 

other cell types. The enzyme is activated by NO to produce cGMP, which, in turn, promotes 

vasorelaxation by lowering cytosolic Ca2+ concentrations. In an earlier study, Khalil-Manesh 

et al. (1993) demonstrated a significant reduction of plasma and urinary cGMP in rats with Pbinduced HTN. These observations prompted a number of studies to evaluate the effect of Pb on 

sGC expression and cGMP production in vascular tissues obtained from rats with Pb-induced 

HTN or in normal vascular tissues incubated in Pb-containing media. For instance, Marques 

et al. (2001) found significant reductions of acetylcholine- and Na-nitroprusside-induced 

vasorelaxation, despite upregulation of eNOS, in the aorta of rats with Pb-induced HTN. This 

was associated with marked downregulation of sGC abundance and diminished cGMP 

production in the aorta. In an attempt to explore the possible role of oxidative stress in Pbinduced downregulation of sGC, they included a group of rats that were co-treated with Pb and 

the antioxidant vitamin ascorbic acid. Antioxidant therapy ameliorated HTN, restored 

vasorelaxation response to acetylcholine and Na-nitroprusside, and normalized sGC expression 

and cGMP production. The authors, therefore, identified diminished sGC as another mechanism 

by which Pb exposure can promote endothelial dysfunction and HTN. They further showed that 

Pb-induced downregulation of sGC is mediated by oxidative stress, as evidenced by its 

prevention with antioxidant therapy. Downregulation of sGC protein abundance in the aorta of 

Wistar rats with Pb-induced HTN was recently confirmed by Farmand et al. (2005) in the 

Pb-exposed Sprague-Dawley rats. In another study, Courtois et al. (2003) showed that 24-h 

incubation of normal rat aorta in the lead-containing media resulted in a concentration-dependent 

downregulation of sGC (beta subunit), with the maximum effect observed at 1 ppm 

concentration. This was associated with increased O2 

!

 production and upregulation of 

cyclooxygenase-2 (COX-2) expression. Co-incubation with ascorbic acid reduced COX-2 

expression and O2 

!

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downregulation of sGC. Similarly, addition of COX-2 inhibitor Rofecoxib or of protein kinase 

A inhibitor (H-89) partially mitigated the Pb-induced downregulation of sGC in vitro. However, 

the COX-2 inhibitor failed to reduce O2 

!

 production in Pb-exposed vascular tissues. Based on 

these observations, the authors concluded that Pb exposure downregulates vascular tissue sGC 

abundance via induction of oxidative stress and upregulation of COX-2. 

Oxidative stress and altered NO metabolism can potentially trigger a cascade of events 

that work in concert to promote HTN and cardiovascular disease in Pb-exposed organisms. 

Some of these potential links are illustrated in Figure 5-5.1. 

5.5.2.2 Protein Kinase C, Inflammation, NFκB Activation and Apoptosis 

Protein kinase C (PKC) isoforms belong to a family of serine-threonine kinases, which 

serve numerous diverse cellular functions. For instance, PKC is involved in regulating vascular 

contractility, blood flow, permeability, and cell growth. In this regard, the activation of PKC has 

been shown to cause vascular contraction and Pb exposure has been found to raise PKC activity. 

For example, Hwang et al. (2002) found increased PKC activity in the erythrocytes of a group of 

Pb-exposed Korean workers, and Markovac and Goldstein (1988b) showed a significant increase 

in PKC activity in rat brain micro vessels following exposure to micromolar concentrations of 

Pb. Also, Watts et al. (1995) demonstrated that Pb-acetate (10!10 to 10!3

 M) caused contraction 

in an isolated rabbit mesenteric artery preparation. This Pb-induced vasoconstriction was 

unaffected by denudation of endothelium, while it was significantly potentiated by PKC agonists 

and attenuated by a PKC inhibitor. Calcium channel blockade with verapamil attenuated, but did 

not abolish, Pb-induced vasoconstriction. These findings were considered to indicate that 

activation of PKC is, in part, responsible for Pb-induced vasoconstriction, independently of 

endothelium or extracellular influx of calcium. Taken together, these observations suggest that 

the activation of PKC in the vascular smooth muscle cells may, in part, contribute to the 

pathogenesis of Pb-induced HTN by enhancing vascular contractility. It should be noted, 

however, that Pb-induced contraction has been shown to be unaffected by a PKC inhibitor in the 

rat aorta rings (Valencia 2001). Thus, the contribution of PKC activation to the Pb-induced 

alteration of vascular contractility appears to be both vessel- and species-specific. It is of note, 

that at high concentrations, Pb can reduce PKC activity in certain cell types, including mouse 

macrophages and rat brain cortex (reviewed by Watts et al. [1995]). 

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402(c) Economic Analysis Chapter 5 178
Figure 5-5-1. This illustration depicts some of the potential mechanisms by which 

oxidative stress may participate in the pathogenesis of Pb-induced HTN 

and cardiovascular complications. In the presence of oxidative stress, 

uncontained reactive oxygen species (ROS) inactivate nitric oxide (NO), 

deplete NO synthase cofactor (tetrahydrobiopterin), uncouple eNOS, 

promote generation of isoprostanes by oxidizing aracidonic acid, and 

activate the redox-sensitive transcription factor NFκB. Together, these 

events can cause vasoconstriction, salt retention, sympathetic system 

activation, renin-angiotensin system stimulation, platelet adhesion, and, 

thereby, endothelial dysfunction, hypertension (HTN), inflammation, 

arteriosclerosis, and thrombosis. 

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As noted earlier, Pb exposure results in oxidative stress in cultured VSMC and endothelial 

cells, as well as in intact animals. Oxidative stress can promote the activation of the nuclear 

transcription factor Kappa B (NFκB) and, thereby, trigger inflammation and apoptosis. In this 

context, Ramesh et al. (2001) showed that exposure to low Pb levels (50 ppm in drinking water) 

for 90 days activates NFκB and capsases in the rat brain. It is of note that several studies have 

revealed the presence of renal tubulointerstitial infiltration of activated T cells, macrophages, and 

angiotensin II (Ang-II) producing cells in various forms of genetic and acquired HTN in 

experimental animals. Moreover, the associated tubulointerstitial inflammation has been shown 

to contribute to the pathogenesis of HTN in these disorders (Rodriguez-Iturbe, 2004). These 

abnormalities are accompanied by activation of the redox-sensitive NFκB, which can account for 

the associated inflammation (reviewed by Rodriguez-Iturbe et al. [2004]). The NFκB activation, 

the accompanying inflammation, and HTN are ameliorated by antioxidant therapy in these 

models, pointing to the role of oxidative stress in this process. In a recent study, RodriguezIturbe, et al. (2005) observed marked activation of NFκB coupled with tubulointerstitial 

accumulation of activated T-cells, macrophages, and Ang-II-producing cells, as well as increased 

apoptotic cells in the kidneys of Pb-exposed rats (100 ppm Pb-acetate in water for 3 months). 

This was associated with increased nitrotyrosine staining (a marker of NO/ROS interaction) in 

the kidney tissue. Since tubulointerstitial inflammation plays a crucial role in the pathogenesis 

of HTN in various other models of HTN, its presence in the Pb-exposed animals may contribute 

to the associated HTN. Inflammation in Pb-induced HTN is not limited to the kidney. In fact, 

lymphocyte infiltration is reported in the periaortic tissues in rats with Pb-induced HTN 

(Carmignani et al 2000). The inflammatory response to Pb exposure in the renal and vascular 

tissues outlined above parallels the observations reported with immune system in Section 5.9 of 

this chapter. 

5.5.2.3 Effect of Lead Exposure on the Adrenergic System 

The adrenergic system plays an important role in regulating arterial pressure, renal and 

systemic hemodynamics, and cardiac function in health and disease. For this reason, a number 

of clinical and animal studies have focused on the sympathetic system as a possible mediator of 

Pb-induced HTN and cardiovascular abnormalities. For instance, in a study of a group of Pbexposed workers, Chang et al. (1996), found elevated plasma norepinephrine (NE), but normal 

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plasma dopamine and epinephrine, levels. The constellation of these biochemical abnormalities 

points to increased sympathetic nervous system activity in Pb-exposed humans. The impact of 

Pb exposure on the sympathetic nervous system activity has been substantiated in experimental 

animals. For example, Chang et al. (1997) showed that administration of Pb (Pb-acetate 0.5% in 

drinking H2O) for 2 months resulted in significant rises in arterial pressure and plasma NE (but 

not epinephrine) in Wistar rats. This was coupled with significant reductions of the aorta β

adrenergic receptor density and isoproterenol (β agonist)-stimulated cAMP production. In a 

subsequent study Tsao et al. (2000) reported a significant rise in plasma NE coupled with marked 

reductions of β receptor density as well as diminished basal and isoproterenol-stimulated cAMP 

productions in the aorta and heart of Wistar rats with Pb-induced HTN. In contrast to the heart 

and aorta, β receptor density as well as basal and β agonist-stimulated cAMP production were 

increased in the kidneys of Pb-exposed animals. 

In another study, Carmignani et al. (2000) found significant elevations of blood pressure, 

plasma catecholamines, and cardiac contractility (dP/dt), together with reduced carotid blood 

flow in rats with Pb-induced HTN. The effect of Pb on the sympathetic nervous system activity 

was examined by Lai et al. (2002) who tested the rapid response to intrathecal (IT) injection of 

PbCl2 in vivo and its addition to the thoracic cord slices in vitro in the rats. They found 

significant rises in arterial pressure and heart rate with IT injection of Pb-chloride. These effects 

of Pb were abrogated by the administration of ganglionic blockade using hexomethonium. The 

in vitro studies revealed a significant rise in excitatory and significant fall in inhibitory postsynaptic potentials with the addition of Pb to the bathing medium and their reversal with saline 

washout. 

In a recent study, Chang et al. (2005) showed a gradual decline in blood, kidney, heart, 

and aorta Pb contents toward the control values within 7 months following cessation of exposure 

in rats with Pb-induced HTN. This was coupled with a parallel declines in arterial pressure, 

plasma NE and renal tissue β receptor density as well as parallel rises in the aorta and heart β

receptors densities during the 7-month period following cessation of Pb exposure. However, 

while HTN and β receptor abnormalities were significantly improved, they were not completely 

reversed. It should be noted that bone Pb contents were not measured in this study and were 

most likely elevated despite normalization of blood and soft tissue levels. These findings 

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provided evidence for the stimulatory effect of Pb on the sympathetic nervous system and for its 

contribution to the cardiovascular effects of Pb exposure. 

5.5.2.4 Effects of Lead on the Renin-Angiotensin-Aldosterone (RAAS) and 

Kininergic Systems 

The available data on the effects of Pb exposure on the RAAS are contradictory. This 

appears to be primarily due to variability in the dosage and duration of Pb exposure, as well as 

the age at which exposure is initiated or the animals studied. In addition, when present, 

nephropathy can potentially affect the RAAS profile of Pb-exposed animals or humans. The 

majority of animal studies of the effects of Pb on RAAS were conducted and published in the 

late 1970s and 1980s. In a meta-analysis of the studies published in that period, Vander (1988) 

found increased plasma renin activity and renal tissue renin content in young rats after several 

weeks of Pb exposure sufficient to achieve blood Pb concentrations in the range of 30 to 

40 μg/dL. Similar results were found in rats exposed to Pb in utero and for 1 month after birth. 

In contrast, plasma renin activity and renal renin contents were generally unchanged or even 

reduced in older rats whose Pb exposure had commenced in utero. 

In a more recent study, Carmignani et al. (1999) showed a significant increase in plasma 

angiotensin converting enzyme (ACE) activity in the rats exposed to Pb (60 ppm Pb-acetate in 

water) for 10 months beginning at an early age (weaning). This was accompanied by a 

significant increase in plasma kininase II, kininase I, and kallikrein activities. In a subsequent 

study, Sharifi et al. (2004) examined plasma and tissue ACE activity in young adult rats 

(weighing 200 g) exposed to Pb (100 ppm Pb-acetate) for 2 to 8 weeks. They found significant 

rises in plasma, aorta, heart, and kidney ACE activities, peaking at 2 to 4 weeks. This was 

followed by a decline in plasma and tissue ACE activity to subnormal values by 8 weeks, at 

which point arterial pressure was markedly elevated. The authors concluded that the elevated 

ACE activity is involved in the induction of HTN but may not be necessary for maintaining HTN 

in Pb-exposed animals. Finally, in a recent study, Rodriguez-Iturbe et al. (2005) demonstrated a 

marked increase in the number of Ang-II positive cells in the kidneys of rats treated with leadacetate (100 ppm in water) for 3 months. This observation points to heightened intra-renal AngII generation in rats with Pb-induced HTN. 

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Taken together, the data point to activation of the RAAS at some point in the course of 

Pb-induced HTN. Further studies are needed to fully elucidate the effects of Pb exposure on 

various other RAAS components. 

5.5.3 Effects of Lead Exposure on Vasomodulators 

In a study of a group of Pb workers with elevated blood Pb concentration, Cardenas et al 

(1993) found a significant increase in urinary excretion of the metabolite of vasoconstrictive 

prostaglandin, thromboxan (TXB2), and significant reduction of the vasodilatory prostaglandin, 

6-keto-PGF1, when compared with the control workers. Subsequently, Hotter et al. (1995) 

confirmed the elevation of urinary TXB2 in another group of Pb-exposed workers. Based on 

these observations, the authors suggested that Pb can alter the balance between vasoconstrictive 

and vasodilatory prostaglandins in a way which may contribute to HTN and cardiovascular 

disease. In an attempt to examine such possible effects of Pb exposure in experimental animals, 

Gonick et al. (1998) measured urinary excretion of the above metabolites in the rat model of Pbinduced HTN. The study showed no significant difference in urinary excretion of the given 

prostaglandin metabolites between the Pb-exposed and control rats. However, in a recent in vitro 

study, Dorman and Freeman (2002) demonstrated that Pb promotes the release of arachidonic 

acid by vascular smooth cells via activation of phospholipase A2. They further showed that, at 

low concentrations, Pb augments Ang-II-induced VSMC proliferation, whereas at a high 

concentration it reduces viability and cell count in unstimulated cells and reduces DNA 

synthases in Ang-II and Fetal Calf Serum (FCS)-stimulated VSMC. Thus, Pb can increase the 

release of arachidonic acid (the substrate for prostaglandins) via activation of phospholipase A2. 

Given the limited and contradictory nature of the published data, further in-depth studies 

are needed to clarify the effects of Pb on regulation of arachidonic acid metabolism and the 

synthesis of various classes of prostaglandins. 

Endothelin 

Endothelins (ET) represent a family of potent vasoconstrictive peptides that are produced 

by endothelium and a number of other cell types. Excess production or increased sensitivity to 

ET can raise arterial pressure. In an attempt to explore the possible contribution of ET to the 

pathogenesis of Pb-induced HTN, Khalil-Manesh et al. (1993) studied the effects of exposure to 

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low and high levels of Pb (100 ppm versus 5000 ppm) in the drinking water for 1 to 12 months in 

rats. Rats exposed to low (but not high) levels of Pb exhibited HTN and a significant increase in 

plasma ET-3 concentration. These findings were confirmed by these investigators in a 

subsequent study of rats with Pb-induced HTN (Khalil-Manesh et al., 1994). Similarly, Gonick 

et al. (1997) demonstrated a significant elevation of plasma concentration and urinary excretion 

of ET-3 in rats with Pb-induced HTN. In a recent study, Martin et al. (2005) showed that 

incubation in the lead-containing media resulted in the downregulation of soluble guanylate 

cyclase and cGMP production in the isolated artery segment of normal rats. They further found 

that co-incubation with an ET-A receptor antagonist can partially reverse this effect of lead. 

These findings suggest that the adverse effect of Pb exposure on cGMP production in the 

vascular tissue is, in part, mediated by its ability to raise ET activity. It, thus, appears that 

exposure to low-levels of Pb can raise activity or production of ET, which can, in turn, play a 

part in the pathogenesis of Pb-induced HTN in the rat. Further studies are required to carefully 

explore the effects of Pb on various components of the ET system. 

Atrial Natriuretic Factor 

Atrial natriuretic factor (ANF) is produced and secreted by cardiac myocytes. Plasma 

concentration of ANF rises with volume expansion and declines with volume contraction. ANF 

serves as a vasodilator and a natriuretic agent and, as such, plays a role in regulating blood 

volume, vascular resistance, and, hence, arterial pressure. Giridhar and Isom (1990) measured 

ANF in rats treated with IP injection of Pb-acetate (0.0 to 1.0 mg/kg/twice weekly for 30 days). 

The Pb-exposed animals exhibited fluid retention, which was coupled with a paradoxical dosedependent decline in plasma ANF concentration. Based on these findings, they suggested that 

Pb may interfere with the hormonal regulation of cardiovascular system, which may, in turn, 

relate to the cardiovascular toxicity of this metal. 

5.5.4 Effects of Lead on Vascular Reactivity 

Addition of Pb-acetate to the bathing medium has been shown to elicit a cumulative 

concentration-dependent vasoconstriction in isolated rabbit mesenteric artery (Watts et al., 

1995). This effect was reported to be partly mediated by activation of PKC. In a more recent 

study, Valencia et al. (2001) found a concentration-dependent vasoconstrictive response to 

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Pb-acetate (0.1 to 3.1 mM) in Wistar rat thoracic aorta rings. The contractile response was 

observed in both intact and endothelium-denuded rings. Likewise, Pb-induced vasoconstriction 

was preserved in calcium-free medium and was unaffected by either α-1 blockade (prazosin), 

PKC inhibition (Calphostin) or L-type calcium channel blockade (verapamil). However, Pbinduced vasoconstriction was inhibited by lanthanum, which is a general calcium-channel 

blocker. These observations suggest that Pb can promote an endothelium-independent 

vasoconstriction by a direct effect on the vascular smooth muscle cells. The data further 

suggests that the effect of Pb is Ca-independent and may depend on the entry of Pb to the cell via 

a lanthanum-blockable channel. In contrast to the latter studies, addition of Pb-acetate did not 

cause vasoconstriction in the rat aorta rings used in a study reported by Shelkovnikov and 

Gonick (2001). Moreover, Pb-acetate at either high (10!4

m) or low (10!8m) concentrations did 

not modify the response to NE, phorbol ester, or isoproterenol. However, at 10!4M, Pb-acetate 

augmented the contractile response to submaximal concentrations of calcium. Thus, the rapid 

action of Pb on vascular reactivity in vitro seems to vary depending on the type of the vessel 

used, the Pb concentration employed, and the animal species being studied. 

A number of studies have endeavored to discern possible differences in vascular reactivity 

to various agonists between animals with Pb-induced HTN and control animals. For instance, 

Purdy et al. (1997) found no significant difference in vasoconstrictive response to NE and 

phenylephrine or vasodilatory response to acetylcholine or nitroprusside in the aorta rings 

obtained from Sprague-Dawley rats with Pb-induced HTN. In contrast, Marques et al. (2001) 

showed a significant reduction of vasodilatory response to both acetylcholine and nitroprusside 

in Wistar rats with Pb-induced HTN. It should be noted that the Wistar rats employed in the 

latter study had been treated with 5 ppm Pb-acetate in the drinking water for 1 month, whereas 

those reported by Purdy et al. (1997) had been given a higher dosage (100 ppm) for a longer 

period (3 months). Therefore, the magnitude and duration of exposure may account for the 

differences observed between the two reports. Also, the effect of Pb on vascular reactivity may 

vary from one tissue to the next, as clearly exemplified by studies (Oishi et al., 1996) that 

showed significant endothelium-dependent vasorelaxation of mesenteric artery response to 

acetylcholine in the presence of the NOS inhibitor L-NAME in tissues from rats exposed to 

Pb-acetate for 3 months. These observations suggest that chronic Pb exposure may impair 

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endothelium-dependent hyperpolarization in the rat mesenteric artery. However, no such effect 

was noted in the aorta obtained from the same animals. 

5.5.5 Lead-Calcium Interactions in Vascular Tissue 

Changes in cytosolic Ca2+ concentrations are intimately involved in regulating vascular 

tone and vascular smooth muscle contraction. Consequently, several studies have focused on the 

interaction of Pb with cellular Ca2+ and Ca2+-dependent signaling pathways as a means to gain 

insight into the pathogenesis of Pb-induced HTN (Piccini et al 1977; Favalli et al 1977; Webb 

et al 1981; Goldstein 1993; Watts et al 1995). Lead can potentially compete with Ca2+ in 

transport systems (i.e., channels and pumps) involved in physiological movements of ions, 

particularly Ca2+, into and out of the cell (Simons 1993a,b). Moreover, Pb can alter the 

intracellular distribution of Ca2+ between cytoplasm, endoplasmic reticulum, and mitochondria, 

which normally regulates cytosolic Ca2+ concentration, (Simons 1993a,b). In addition, Pb can 

serve as a substitute for calcium in Ca2+-dependent signaling pathways by interacting with 

calmodulin, PKC, and calcium-dependent potassium channels (Haberman, 1983; Richardt, 1986; 

Chai and Webb, 1988; Simons, 1993a,b; Watts, 1995). Thus, interactions of Pb with cellular 

Ca2+ via these complex mechanisms in the vascular cells may contribute to alterations of 

vascular resistance and HTN. For example, Piccini et al. (1997) and Favalli et al. (1977) showed 

that Pb exposure increases calcium content in the tail artery in rats. The authors attributed this 

phenomenon to a possible Pb-induced inhibition of Ca2+ extrusion from the vascular cells. Using 

rabbit mesenteric artery preparations, Watts et al. (1995), showed that blockade of either PKC or 

voltage-gated Ca channels by verapamil substantially attenuated Pb-induced vasoconstriction in 

both intact and endothelium-denuded preparations. Based on these observations, the authors 

suggested that Pb promotes a vasoconstrictive response in rabbit mesenteric artery via a Ca2+-

dependent activation of PKC. In contrast, Valencia et al. (2001) using rat aorta rings reported a 

vasoconstrictive response to Pb-acetate in rat aorta rings bathed in either Ca2+-free or Ca2+-

containing media and in the presence or absence of the L-type calcium-channel blocker 

verapamil or of the PKC inhibitor calphostin. Moreover, depletion of intracellular Ca2+ stores by 

preincubation of rings in EGTA, while diminishing the intensity, did not abrogate Pb-induced 

vasoconstriction in this system. In contrast, Pb-induced vasoconstriction was prevented by 

lanthanum (a general blocker of calcium channels) in both Ca2+-containing and Ca2+-free media. 

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Based on these observations, the authors concluded that Pb can elicit a PKC-independent 

contractile response in the rat aorta by entering VSMC via a non-voltage-gated Ca2+ channel and 

mimicking the action of Ca2+. It, thus, appears that Pb exerts its effect by mechanisms that are 

species- and vessel-specific. 

5.5.6 Cardiotoxicity and Atherogenesis 

Acute Pb exposure has been reported to affect cardiac function, and chronic exposure has 

been linked to atherosclerosis and increased cardiovascular mortality by some, but not by all 

investigators, in humans (See Chapter 6). In an attempt to assess the cardiotoxicity of lead, 

Prentice and Kopp (1985) carried out the in vitro perfusion of isolated rat heart preparations with 

a perfusate containing 0.3 and 30 μM Pb-acetate for up to 60 min. At 30 μM concentration, Pb 

prolonged the AV node and His bundle conduction times, reduced coronary blood flow and heart 

rate, and altered cardiac energy metabolism. Milder, and statistically insignificant, changes were 

also observed at 0.3 μM Pb concentration in this model. These observations illustrate the direct 

cardiotoxicity of Pb independently of its systemic and neuroendocrine actions in acute 

intoxication. In an attempt to determine whether chronic exposure to Pb or cadmium can cause 

atherosclerosis, Revis et al. (1981), studied male white pigeons that were exposed to Pb (0.8 ppm 

in drinking water) for extended periods. Long-term low-level Pb exposure in this model resulted 

in a significant rise in arterial pressure and a near doubling of the number of atheromatous 

plaques in the aorta. These observations demonstrate the proatherogenic effects of chronic 

exposure to low levels of Pb in pigeons. 

5.5.7 Effects of Lead on Endothelial Cells 

Endothelium is an important constituent of the blood vessel wall and regulates 

macromolecular permeability, vascular smooth muscle tone, tissue perfusion, and blood fluidity. 

Endothelial damage or dysfunction results in atherosclerosis, thrombosis, and tissue injury. 

Chronic Pb exposure has been shown to promote atherosclerosis in experimental animals (Revis 

et al., 1981). Given the central role of endothelial injury/dysfunction in the pathogenesis of 

atherosclerosis, numerous studies have explored the effect of Pb on cultured endothelial cells. 

These studies have searched for evidence of Pb-mediated endothelial cell injury and the effects 

of Pb on endothelial cell proliferation, tube formation (angiogenesis), monolayer wound repair, 

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and production of heparansulfate proteoglycans, plasminogen activator (tPA), and plasminogen 

activator inhibitor-1 (PAI-1). 

Using cultured bovine aorta endothelial cells, Kaji et al. (1995a) showed that incubation 

with Pb-nitrate at concentrations equal to or below 50 μM for 24 h, results in mild deendothelialization of endothelial monolayers in vitro. They further showed that adding Pb at 

10 μM concentration markedly increased cadmium-induced endothelial injury. 

Proliferation of endothelial cells is a critical step for the repair of injured endothelium. 

Failure of the repair process can result in thrombosis, VSM cell migration and proliferation, and 

atherosclerosis. In this regard, Pb (Pb-nitrate 0.5 to 5 μM) has been shown to significantly 

reduce DNA synthesis and cell proliferation in growing cultured bovine aorta endothelial cells 

(Kaji, 1995a). Similarly, the proliferative response to βFGF and αFGF is significantly attenuated 

by Pb in this system (Kaji, 1995b). The reported inhibition of endothelial cell proliferation by Pb 

can potentially diminish the repair process in response to endothelial injury. This supposition 

has been confirmed by Fujiwara et al. (1998) who showed that at 5 to 10 μM concentrations, Pb 

markedly inhibited the repair of the wounded endothelial monolayer in vitro. Moreover, Pb 

severely mitigated the zinc-stimulated endothelial cell proliferation and repopulation of the 

denuded sections in this system. 

Endothelial cell proliferation is the primary step in angiogenesis, a phenomenon that is 

essential for numerous physiological functions such as growth, development, wound repair, and 

menstrual cycle as well as certain pathological events including diabetic retinopathy and tumor 

growth. In view of the demonstrated inhibition of endothelial cell growth by lead, it has been 

postulated that Pb may impair angiogenesis. This assumption has been confirmed by a number 

of studies testing the effect of Pb by angiogenesis assay (tube formation) in endothelial cells 

cultured on matrigel (a laminin-rich basement membrane product) matrix in vitro. For instance, 

Ueda et al. (1997) and Kishimoto et al. (1995) have shown that Pb-acetate (1 to 100 μM) results 

in a concentration- and time-dependent inhibition of tube formation by human umbilical vein 

endothelial cells cultured on a matrigel matrix. 

Endothelial cell migration and proliferation are critical for angiogenesis and repair of the 

damaged endothelium. βFGF is a powerful mitogen for endothelial cells as well as several other 

cell types. Endothelial cells synthesize βFGF, which is released following injury or spontaneous 

death of endothelial cells and acts in an autocrine fashion to facilitate the repair process by 

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promoting endothelial cell migration and proliferation. Binding of βFGF to its receptor on the 

endothelial cell is facilitated by heparan sulfate proteoglycans (HSPGS) that are normally 

produced and released by the endothelial cells for attachment to the cell surface as well as 

incorporation in the extracellular matrix. As noted above, Pb significantly attenuates βFGF and 

αFGF-mediated DNA synthesis and proliferation in cultured endothelial cells (Kaji et al., 

1995b). In this regard, Pb has been shown to reduce βFGF binding to the cell surface HSPGs 

without changing the biosynthesis or intracellular abundance of βFGF in cultured bovine 

endothelial cells (Fujiwara and Kaji, 1999a). Moreover, Pb has been shown to significantly 

reduce the synthesis of glycosamino-glycans (GAG, measured by sulfate incorporation into 

heparan sulfate) in the growing endothelial cells. 

The above observations suggest that Pb-induced reduction of βFGF-mediated proliferative 

response in cultured endothelial cells is largely due to impaired production of HSPGs. This 

supposition is further supported by observations that DNA synthesis can be restored by adding 

heparin in lead-treated growing endothelial cells (Fujiwara et al., 1995). The reduction in the 

production of GAGs by Pb in the growing endothelial cells (Fujiwara et al., 1995) is also seen in 

confluent (quiescent) cells. For instance, Kaji et al. (1991) demonstrated a marked reduction of 

GAG production following incubation with 10 μM Pb nitrate in confluent endothelial cells in 

vitro. The Pb-induced reduction of heparan sulfate production was more severe than that of the 

other GAGs. Moreover, the reduction in the cell surface-associated GAGs was more severe than 

that of the newly synthesized GAG found in the incubation media. GAGs combine with a series 

of specific core proteins to form anionic macromolecular complexes known as proteoglycans, 

which are widely distributed in the extracellular matrix of the mammalian tissues. Endothelial 

cells produce two types of HSPGs, i.e., the high-molecular weight and low-molecular weight 

classes. Perlecan is a high-molecular weight heparan-sulfate proteoglycan which is a component 

of the basement membrane. Syndecan, glypican, ryudocan, and fibroglygan are among the lowmolecular weight subclass and are primarily associated with the cell surface. Proteoglycans play 

an important role in regulating vascular function and structure. For instance, by providing a 

negative electrostatic charge, these molecules constitute a major barrier against extravasations of 

negatively-charged plasma proteins. In addition, by interacting with antihthrombin-III and tPA, 

these molecules serve as important endogenous anticoagulants. Moreover, perlecans facilitate 

βFGF binding to its receptor on endothelial cells and, thus, contributes to the endothelial growth 

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and repair processes. In contrast, these molecules tend to inhibit migration and growth of 

vascular smooth muscle cells and, thereby, help to prevent athero- and arteriosclerosis. Another 

important function of HSPGs is their role in stabilizing and anchoring lipoprotein lipase and 

VLDL receptors on the endothelial surface. Consequently, they play an important indirect part 

in the clearance of VLDL and chylomicrons from the circulation, a process which has major 

implications for energy metabolism and cardiovascular protection. 

In a study of cultured bovine endothelial cells, Kaji et al. (1997) found that Pb-chloride, at 

10 μM concentration, markedly lowers incorporation of precursors (glycosamine and sulfate) 

into HSPG in confluent bovine aorta endothelial cells. The effect of Pb was more severe on 

low-molecular than high-molecular weight HSPGs. However, Pb did not change the length of 

heparan sulfate chains. It is of note that Pb slightly increased the abundance of the HSPG core 

proteins. This observation excluded a reduction in core protein synthesis as a cause of 

diminished HSPGs in the lead-treated confluent endothelial cells. In a subsequent study, 

Fujiwara and Kaji (1999) investigated the effect of Pb-nitrate on production of high- and lowmolecular weight subclasses of HSPGs in growing bovine aorta endothelial cells. In contrast to 

the quiescent cells, lead-treated growing cells exhibited a marked reduction in the highmolecular weight with no change in production of low molecular weight (~50KD) HSPGs. They 

further showed a significant reduction of the core protein of perlecan, which is a high-molecular 

weight (400 KD) HSPG. Thus, Pb appears to affect productions of subclasses of HSPGs 

differently depending on the cells’ growth cycle. Accordingly, in the growing endothelial cells 

(a condition which simulates the response to injury), Pb downregulates perlecan, which is 

involved in βFGF-mediated migration and proliferation of endothelial cells and inhibition of 

migration and proliferation of VSMC. This phenomenon may adversely affect endothelial repair 

and promote athero- and arteriosclerosis. On the other hand, Pb-induced reduction of the cell 

surface-associated low-molecular weight HSPGs (which are predominantly involved with 

lipolytic, anticoagulant, and other functions of confluent endothelial cells (simulating intact 

endothelium) can contribute to hyperlipidemia and thromboembolism, among other disorders. 

One of the major properties of normal endothelium is its ability to prevent coagulation. 

Several factors contribute to the thromboresistance of the endothelial lining. These include the 

surface coating of HSPG (which confers heparin-like properties), nitric oxide (which inhibits 

platelet adhesion and activation), and tPA (which promotes thrombolysis), thrombomodulin, and 

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prostacycline. As noted earlier, Pb exposure reduces HSPG-production (Kaji et al., 1995b, 1997) 

and diminishes nitric oxide availability via ROS-mediated NO inactivation (Vaziri 1999). In 

addition, Kaji et al. (1992) showed that incubation of confluent human umbilical vein endothelial 

cells with Pb nitrate, at 0.01 to 1.0 μM concentrations, significantly reduced basal and thrombinstimulated tPA release. It thus, appears that Pb exposure may confer a thrombophilic diathesis. 

5.5.8 Effects of Lead on Vascular Smooth Muscle Cells 

Lead has been shown to stimulate proliferation of bovine aorta VSMCs in a 

concentration-dependent manner (Fujiwara et al., 1995). Moreover, the combination of Pb and 

βFGF results in an additive effect on VSMC proliferation. As with bovine aorta VSMCs, 

cultured rat aorta VSMCs exhibit hyperplasia in response to a low concentration of (100 μg/L) of 

Pb-citrate (Carsia, 1995). The reported hyperplasia is accompanied by phenotypical 

transformation of cells from the spindle or ribbon shape to cobblestone shape, simulating the 

neointimal cell morphology. This was accompanied by a significant reduction in Ang-II receptor 

but no change in α, β, or ANP receptor densities. It is of note that, in contrast to the low 

concentration, a high concentration (500 μM/L) of Pb resulted in growth arrest in this system. 

Thus, the effect of low concentration of Pb on VSMC proliferation is opposite of its action on the 

endothelial cells. 

Under normal conditions, intact endothelial lining shields the cells residing in the 

subendothelial tissue, i.e., fibroblasts and VSMCs, from coming into contact with the circulating 

blood. However, this barrier is lost when the endothelium is injured, an event which can lead to 

platelet adhesion and fibrin thrombosis formation. Propagation of fibrin thrombus is limited by 

activation of the fibrinolytic system, which, in turn, depends on the balance between tPA and 

plasminogen activator inhibitor-1 (PAI-1). In addition to endothelial cells, VSMCs and 

fibroblasts express tPA and PAI-1. Using cultured human aorta VSMCs and fetal lung 

fibroblasts, Yamamoto et al. (1997) investigated the effect of Pb chloride on the release of tPA 

and PAI-1 in vitro. The authors found that Pb causes a significant inhibition of tPA release and a 

significant increase in PAI-1 release in cultured fibroblasts in a dose-dependent manner. The 

lead-treated VSMC exhibited a significant dose-dependent decline in tPA release and to a lesser 

extent of PAI-1 release. Taken together, exposure to Pb appears to evoke a negative effect on 

fibrinolytic process by the cellular constituents of the subendothelial tissue. 

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5.5.9 Summary/Conclusion 

In vivo and in vitro studies published during the past 15 years have considerably 

expanded our knowledge of the effects of Pb exposure on the cardiovascular system. However, 

many questions remain unanswered and await further investigation. 

A number of in vivo and in vitro studies conducted during the review period have 

provided compelling evidence for the role of oxidative stress in the pathogenesis of Pb-induced 

HTN. Moreover, the effect of oxidative stress on blood pressure has been shown to be, in part, 

mediated by avid inactivation of NO and downregulation of sGC. In addition, a limited number 

of in vitro studies have provided indirect evidence that, via activations of PKC and NFκB, Pb 

may raise vascular tone and promote inflammation. 

The adrenergic system plays a major role in regulating cardiovascular function and 

structure and, as such, has been the focus of several studies during the review period. Based on 

these studies, chronic low level lead exposure appears to increase central sympathetic activity, 

reduce cardiac and vascular and raise kidney β adrenergic receptor density. These events can, in 

turn, increase peripheral vascular resistance and renal renin release/production and, thereby, 

arterial pressure. Since sympathetic outflow is inhibited by NO, inactivation of NO by oxidative 

stress may be, in part, responsible for the increased sympathetic activity in Pb-exposed animals. 

The renin-angiotensin-aldosterone system (RAAS) plays an important role in regulating 

blood pressure and cardiovascular function and structure. The available data published during 

the review period suggest that Pb exposure can raise plasma ACE and kininase activities at 

different points in the course of Pb-induced HTN in experimental animals. This can, in turn, 

contribute to the genesis and/or maintenance of HTN. Since renin release (which is responsible 

for production of ACE substrate, i.e., Ang-1) is, in part, driven by β adrenergic activation, 

upregulation of renal β adrenergic activity may, in part, account for increased RAAS activity in 

the Pb-exposed animals. 

The balance in production of vasodilator and vasoconstrictor prostaglandins plays an 

important role in regulation of blood pressure and cardiovascular function. Studies of the Pb 

exposed humans have revealed an imbalance in production of prostaglandins favoring a rise in 

arterial pressure. However, the animal and in vitro studies published during the review period 

have been limited and inconsistent. Further studies are needed to address this issue. 

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Based on the available studies, Pb exposure appears to increase endothelin production in 

experimental animals. This phenomenon can, in part, contribute to the rise in blood pressure in 

the Pb-exposed animals. A number of studies have explored the effect of Pb on vascular tone as 

well as vascular response to vasoconstrictor and vasodilator agents. For instance, Pb has been 

shown to cause vasoconstriction and to attenuate acetylcholine- and NO-mediated vasodilatation 

in some, but not all vascular tissues and in some, but not all, studies. These effects have been 

variably attributed to lead-mediated activation of PKC and Ca2+-mimetic action of Pb, among 

other possibilities. 

Finally, a number of studies have explored the effects of endothelial and vascular smooth 

muscle cells to explore the possible atherogenic effect of Pb exposure. In this context, Pb has 

been found to inhibit proliferation of the growing (non-confluent) endothelial cells (mimicking in 

vivo response to injury), impair tube formation (angiogenesis), and the repair of wounded 

endothelial monolayer in vitro. Likewise, Pb exposure was shown to reduce production of 

HSPGs and tPA by confluent endothelial monolayers, events that may favor thrombosis and 

hyperlipidemia. Lead exposure has been also shown to promote vascular smooth muscle cell and 

fibroblast proliferation and phenotypic transformation in ways that seem to favor arteriosclerosis 

and vascular remodeling. 

Among many questions awaiting clarification, a few are of particular interest. For 

instance, it is not clear as to why low, but not high, levels of Pb exposure cause HTN in 

experimental animals. Similarly, it is uncertain as to why HTN occurs long after the onset of Pb 

exposure in the intact animals, whereas the effects on cultured cells and isolated tissues are 

manifested within short periods of time. 

5.6 GENOTOXIC AND CARCINOGENIC EFFECTS OF LEAD 

5.6.1 Introduction 

The 1986 Pb AQCD (U.S. Environmental Protection Agency, 1986) and its 1990 

Supplement (U.S. Environmental Protection Agency, 1990) concluded that, at relatively high 

concentrations, Pb may be carcinogenic to laboratory animals, particularly the rat. Cell culture 

studies were considered to be supportive of these observations, but also indicated that Pb was not 

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particularly potent. Human data were considered to be of concern, but not definitive, and given 

the animal data, the prudent choice was to consider Pb to be a possible human carcinogen. 

This section reviews reports of Pb-induced carcinogenesis and DNA damage published 

since 1986. More than 200 publications were read and considered and those that reported any 

effect related to carcinogenesis or genotoxicity that was attributable to Pb are presented below. 

This report follows the same format as the previous one (1986) and the explanations for 

the relative importance of the various types of studies (e.g. epidemiology, animal and cell 

culture) can be found in the original report and are not repeated here. Carcinogenesis studies are 

presented first, followed by genotoxicity studies. Each of these sections is further subdivided 

into human studies (considering adults and then children), animal studies, and then cell culture 

studies (considering human, mammalian, and then nonmammalian). When appropriate, these 

sections are followed by a section describing acellular (cell-free) model studies. 

There are some differences with this new report. For one, each section is more distinctly 

broken out. The epidemiology has been reviewed in more detail in Chapter 6 (Section 6.7) in 

this document and, so, only a brief summary is presented here. Because of more recent concerns 

about effects on childhood development, this issue was specifically considered in a separate 

section. Following advances in hypotheses and technology, much more specific sections about 

the possible epigenetic effects of Pb have also been added. 

5.6.2 Carcinogenesis Studies 

5.6.2.1 Human Studies 

The human carcinogenesis studies are only briefly reviewed in this section; for a more 

detailed review, see Chapter 6 (Section 6.7) in this document. 

Adults 

The assessment of the carcinogenicity of Pb through human epidemiological studies 

remains ambiguous. Several reports state that occupational exposure to Pb increases the risk of 

lung, kidney, brain, stomach, and liver cancer (Fu and Boffetta, 1995; Kauppinen et al., 1992; 

Gerhardsson et al., 1995a; Ades and Kazantzis, 1988; Wicklund et al., 1988; Steenland et al., 

1992; Englyst et al., 2001; Gerhardsson et al., 1986; Antitila et al., 1995, 1996; Cocco et al., 

1998; Shukla et al., 1998). However, a full interpretation of the data in these studies is 

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complicated by the fact that the study participants also incurred coexposure to other known 

carcinogens, such as arsenic, cadmium, and hexavalent chromium. Thus, it is difficult to 

determine if the excess cancers observed were due to exposure to Pb, one of these other 

carcinogens, or some combination of the various chemicals. In addition, other reports indicate 

that occupational or environmental exposure to Pb did not alter cancer risk (Cocco et al., 1996; 

Fanning, 1988; Jemai et al., 2002). Consequently a definitive assessment of the carcinogenicity 

of Pb from human studies cannot be made at this time. 

Children 

There have been no recent studies of Pb-induced cancers in children. This lack of data is 

not unexpected and is largely because Pb has not been considered a likely cause of childhood 

cancers. There have, however, been studies of cancers in children resulting from paternal 

exposure. Here again, the same confounding problems encountered are as seen in the adult 

population studies, and it is difficult to draw any definitive conclusions. For example, two 

studies reported elevated childhood tumors (Wilm’s tumor and acute nonlymphocytic leukemia) 

in children whose fathers worked in Pb-related industries, such as welding, painting, and auto 

repair (Buckley et al, 1989; Olshan et al., 1990). However, workers in these occupations also 

experienced coexposure to arsenic, cadmium, and hexavalent chromium, and so the cancers 

observed cannot be solely linked to Pb exposure. In addition, a report from the printing industry 

in Norway found no link between paternal exposure and childhood cancers and, perhaps, even 

found a possible reduction in the incidence of childhood cancers with paternal Pb exposure 

(Kristensen and Andersen, 1992). 

The possible interaction of paternal occupation and childhood cancer is an important area 

of concern. However, a definitive assessment of paternal exposure to Pb cannot be made at this 

time and more research is needed. 

5.6.2.2 Laboratory Animal Studies 

Lead is a well-established animal carcinogen, as noted in the 1986 Lead AQCD. 

Consequently, limited tumorigenesis studies have been conducted in animal models and the 

focus has been more on the mechanism of neoplasia (e.g., the roles of calcium and 

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metallothionein) and possible immunomodulatory effects of Pb in the promotion of cancer. 

These studies are summarized in Table AX5-6.1. 

All of the studies exposed animals to Pb-acetate except one, which focused on Pbchromate. One study investigated the carcinogenicity of a series of chromate compounds, i.e., 

Pb-chromate and several Pb-chromate-based compounds were included as part of the group of 

chromate compounds. The Pb-chromate was administered by implantation into the lung after 

being embedded within a cholesterol pellet. The authors indicated that in this design, Pbchromate was not carcinogenic, but that 4 of the Pb chromate compounds did induce a very rare 

tumor in the mice. Thus, there is some ambiguity about the carcinogenicity of Pb-chromate in 

the study, as the statistics calculated an expected tumor level based on any tumor and were not 

based on the occurrence of this very rare (for rats) tumor. It is likely that had the expected value 

been adjusted for the rare tumor, a conclusion would have been reached that either Pb-chromate 

was tumorigenic or that the study lacked the power to make any determination. The previous 

EPA report had concluded that Pb-chromate is tumorigenic. Thus, it is difficult to draw a firm 

conclusion from this study. 

The remaining five studies focused on Pb-acetate (Schrauzer, 1987; Blakley, 1987; Teraki 

and Uchiumi, 1990; Bogden et al., 1991; Waalkes et al., 2004). In most studies, this compound 

was administered in drinking water at concentrations from 0.5 to 4000 ppm, but one study 

considered effects from a subcutaneous (SC) injection both in mice and in rats. Consistent with 

the findings in the 1986 Pb AQCD, Pb not only induced renal tumors, but also induced other 

tumors, although the possible effect on mammary tumors is difficult to interpret, as important 

study details were omitted, as discussed below. In a surprising development, during one lifetime 

exposure study, Pb suppressed liver tumors (Waalkes et al., 2004). 

The key study in this group of studies was a lifetime exposure study that investigated 

mice exposed to drinking water concentrations of 1,000 to 4,000 ppm Pb and also considered the 

role of metallothionein. In wild-type mice, Pb-acetate induced a low frequency of renal tumors, 

but hyperplasia was common and exhibited overexpression of cyclin D1. Lead inclusion bodies 

were also common. Lead also suppressed liver tumors in this study. 

By contrast, in metallothionein-deficient mice, Pb-acetate induced a high frequency of 

kidney tumors and severe inflammation. Both the tumors and the regions of inflammation 

exhibited cyclin D1 overexpression. Lead also suppressed liver tumors in these animals. In 

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contrast to the wild-type mice, Pb inclusion bodies were not seen in these animals. Thus, the 

data convincingly indicate that metallothionein binds Pb as part of an inclusion body and 

prevents the formation of tumors. 

Another study focused on the ability of Pb to induce tumors in rats after SC injection of 

Pb-acetate (Teraki and Uchiumi, 1990). Tumors formed at the site of injection, and Pb 

accumulated in the tumors, indicating that Pb is tumorigenic. However, full interpretation of the 

data is complicated by the absence of data on control animals and the fact that only a single dose 

was considered. 

Three studies investigated compounds that might reduce or prevent Pb-induced cancers, 

specifically selenium and calcium compounds (Schrauzer, 1987; Bogden et al., 1991). The first 

study used a rather complex approach to study the possibly protective effects of selenium 

(Shrauzer, 1987). In this study, mice were infected with the murine mammary tumor virus, 

because they are known to develop mammary adenocarcinomas when maintained on a lowselenium diet. The data indicated that Pb can induce tumors in these mice even when they are 

maintained on a high-selenium diet. However, the data are difficult to interpret and the impact of 

the study is uncertain, as the methods are incomplete, the data on control animals are not 

provided, and the experimental results are stated but not presented in tables or figures. 

The second study investigated the effect of calcium (Bogden et al., 1991). The main 

focus of this study appeared to be blood pressure, but tumorigenesis was also considered. 

It might be anticipated that calcium might reduce Pb tumorigenesis by competing for its binding 

sites or blocking its uptake. However, in this study, calcium did not affect Pb levels in tissue and 

actually exacerbated Pb-induced carcinogenesis. The full impact of this study is also difficult to 

assess, as the calcium-treated animals incurred profound nephrocalcinosis. 

The remaining study considered Pb-induced immunosuppression as a possible factor 

contributing to the tumorigenesis induced by other agents, including viruses or chemicals 

(Blakley, 1987). The results indicated that Pb may suppress humoral immunity but not cellular 

immunity. However, this is the only study of its kind and the results need to be repeated in other 

settings. In addition, it is difficult to determine if these data are specific to the agents used (e.g., 

murine lymphocytic leukemia virus) or if they represent a class of agents (e.g., viruses in 

general). 

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Overall, the above studies confirm that Pb is an animal carcinogen and extends our 

understanding of mechanisms involved to include a role for metallothionein. Specifically, the 

recent data show that metallothionein may participate in Pb inclusion bodies and, thus, serves to 

prevent or reduce Pb-induced tumorigenesis. Much more work is needed to determine the 

potential exacerbating or ameliorating roles of calcium and selenium and to determine what role 

Pb-induced immunomodulation may play in the promotion of tumors. 

5.6.2.3 Cell Culture Studies 

Carcinogenesis is measured in cell culture systems through studies of neoplastic 

transformation, where morphologically transformed cells are injected into athymic mice to see if 

the cells can form a tumor in the host animal. Morphological transformation refers to cells that 

incur a change in morphology, such as formation of a focus (or foci) of cell growth. In addition, 

for faster study results and as a screening tool, the ability of cells to grow in agar without a 

surface to attach to (anchorage independence) is often used as a short-term substitute measure for 

transformation. 

Human Cell Cultures 

Since the 1986 Pb AQCD, only four studies have used human cell culture systems to 

study the carcinogenesis of Pb compounds. One found that Pb-acetate induced anchorage 

independence in primary human foreskin fibroblasts (HFF) (Hwua and Yang, 1998). The full 

impact of these data is uncertain, as previous studies of known metal carcinogens in primary 

HFF found that these carcinogens induced anchorage independence, but those anchorageindependent cells ultimately senesced. These studies are summarized in Table AX5-6.2. Further 

study is needed to confirm that Pb can induce anchorage independence and to see if these cells 

can progress to full neoplastic transformation. 

In an effort to explore the importance of oxidative metabolism in inducing anchorage 

independence, Hwua and Yang (1998) also co-treated some cells with 3-aminotriazole, a known 

catalase inhibitor. This co-treatment had no effect on Pb-acetate-induced anchorage 

independence, suggesting that catalase was not involved in this effect. It would be premature to 

conclude that oxidative metabolism is not involved in anchorage independence, as these are the 

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only data available and are limited to catalase only. More data are needed to elucidate whether 

oxidative metabolism is involved in this lead effect. 

The remaining three studies focused on Pb-chromate (Beiderman and Landolph, 1987, 

1990; Sidhu et al., 1991). Two used similar HFF cells and found that Pb-chromate induced 

anchorage independence (Beiderman and Landolph, 1987, 1990). However, these anchorageindependent cells ultimately underwent senescence, suggesting that anchorage independence 

may not be a suitable short-term marker for neoplastic transformation in primary HFF. It should 

be noted that these studies were focused on the chromate component of this compound and the 

potential contribution of Pb was not investigated or discussed. By contrast, Sidhu et al. (1991) 

found that Pb-chromate did not induce anchorage independence in a human osteosarcoma cell 

line, while it did induce full neoplastic transformation of these cells and the transformed cells did 

grow in agar. It should be noted that this study was also focused on the chromate component of 

this compound and that the potential contribution of Pb was not investigated or discussed. 

The 1986 Pb AQCD did not include any studies of transformation in human cells. Given 

that other chromate compounds have been shown to induce anchorage independence, it seems 

quite possible that the data from Pb-chromate exposures may represent effects from chromate 

and not from Pb. Thus, the data currently seem to indicate that Pb can induce anchorage 

independence in human cells, but its ability to induce neoplastic transformation of human cells is 

uncertain. Further study of different Pb compounds and the full assessment of their neoplastic 

potential (i.e., including studies of the ability of treated cells to form tumors in experimental 

animal models) are needed before definitive conclusions can be drawn. 

Animal Cell Cultures 

The 1986 Pb AQCD presented several studies demonstrating that Pb compounds could 

induce anchorage independence and morphological and neoplastic transformation in rodent cell 

culture systems. Since that report, six studies have further considered the ability of Pb 

compounds to induce these effects. Three focused on Pb-chromate and three on Pb compounds 

without the confounding factor of chromate; and these studies are summarized in Table AX5-6.3. 

Four studies considered Pb-acetate, Pb-chloride, or Pb-nitrate in Syrian hamster embryo 

and C3H10T1/2 mouse embryo cells (Zelikoff et al., 1988; Patierno et al., 1988; Patierno and 

Landolph, 1989; Elias et al., 1991). Three found that Pb compounds did not induce 

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transformation (Patierno et al., 1988; Patierno and Landolph, 1989; Elias et al., 1991); but the 

third study (Zelikoff et al., 1988) indicated that Pb was weakly positive, though no statistics were 

performed to validate this conclusion. Zelikoff et al. (1988) indicated that the observations were 

repeated several times, but only showed data from one experimental run. It is unclear why the 

studies were not averaged together, as multiple repeats would likely have provided the power to 

detect whether the observed weak increase was significant. 

Five studies considered Pb-chromate, which induced neoplastic and morphological 

transformation of Syrian hamster and mouse C3H10T1/2 embryo cells, as well as enhancing 

viral transformation (Patierno et al., 1988; Patierno and Landolph, 1989; Schectman et al., 1986; 

Elias et al., 1989, 1991). The focus on Pb-chromate was based largely on concern about 

chromate; but these studies found that Pb-chromate was more potent than other chromate 

compounds, suggesting that Pb may enhance or contribute to the carcinogenicity. Indeed, one 

study found that combining Pb-nitrate with soluble chromate was as potent as Pb-chromate and 

greater than soluble chromate alone (Elias et al., 1991). 

Thus, all together, these studies suggest that Pb ions alone cannot transform rodent cells; 

however, they may be co-carcinogenic or promote the carcinogenicity of other compounds. 

These data are in contrast to findings described in the1986 Pb AQCD that included a positive 

study. One possible factor may be exposure duration; the study in question indicated that the 

Pb-transformed cells were exposed for 9 days. The studies discussed here all exposed cells for 

7 days or less. Further careful study of a time course of exposure is necessary to determine 

whether Pb actually induces transformation in cultured rodent cells. 

Nonmammalian Cell Cultures 

No carcinogenesis studies were located that used nonmammalian cell culture models. 

5.6.2.4 Organ-Specific Studies 

No organ-specific or organ culture studies concerning Pb carcinogenesis were located. 

5.6.2.5 Carcinogenesis Summary 

It still remains difficult to conclude whether Pb is a human carcinogen. The assessment 

of the carcinogenicity of Pb through human epidemiological studies remains ambiguous. 

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By contrast, the studies confirm that Pb is an animal carcinogen and further extend our 

understanding of the mechanism to include a role for metallothionein. The cell culture data 

suggest that Pb can induce anchorage independence, but whether it can induce full neoplastic 

transformation of human cells is uncertain. 

5.6.3 Genotoxicity Studies 

The human genotoxicity studies are only briefly reviewed in this section. For a more 

detailed review, see Chapter 6 (Section 6.7) in this document. 

5.6.3.1 Human Studies 

Adults 

A number of studies investigating the potential genotoxicity of Pb have been conducted in 

human populations. Endpoints considered include chromosome aberrations, sister chromatid 

exchanges (SCE), micronuclei formation, DNA strand breaks, and hypoxanthine guanine 

phosphoribosyl transferase (HPRT) mutations. In general, these studies were much more 

specific than the carcinogenesis studies, as correlations with blood-Pb levels could be made, 

other confounders could be ruled out, and the endpoints were more short-term. 

The chromosome damage studies are ambiguous and contained some methodological 

flaws. Four studies were positive (Xupei et al., 1988; De at al., 1995; Bilban, 1998; Pinto et al., 

2000), while two were negative (Anwar and Kamal, 1988; Rajah and Ahuja, 1996). Moreover, 

the four positive studies included two that could not rule out potential contributions from other 

genotoxic metals and one that found a correlation only at very high blood Pb levels (>52 μg/dL). 

By contrast, the studies of micronucleus formation (Bilban, 1998; Vaglenov et al., 1998; 

Pinto et al., 2000; Palus et al., 2003; Minozzo et al., 2004), SCE (Xupei et al., 1988; Bilban, 

1998; Pinto et al., 2000; Duydu et al., 2001; Palus et al., 2003), DNA strand breaks (Restrepo 

et al., 2000; Fracasso et al., 2002; Hengstler et al., 2003; Danadevi et al., 2003; Palus et al., 

2003) all consistently found clear correlations between Pb and genotoxicity. It should be noted 

that there were two negative studies for SCE (Rajah and Ahuja, 1995, 1996), but both were by 

the same group and considered the same very small population of workers (only 5 Pb-exposed 

workers) and, thus, may not have had enough power to detect potential differences. 

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1 It is notable that one study found an interesting correlation of HPRT mutation rates and 

2 blood Pb levels from environmental Pb exposure in Belgian women (Van Larebeke et al., 2004). 

3 This study is the first and only one to consider Pb-induced mutations. Further research is needed 

4 to assess the validity of these data. 

5 Thus, it appears from these studies that Pb is genotoxic to humans, although it may not 

6 induce substantial amounts of chromosome damage. This conclusion is consistent with the 

7 laboratory studies discussed below. For more in-depth consideration of the epidemiology studies 

8 see Chapter 6, Section 6.7. 

9 Children 

10 Two recent studies of Pb-induced genotoxicity in children have been published. One 

11 study of children living in a high Pb contamination area of Czechoslovakia found no increase in 

12 chromosome damage in white blood cells compared with children living in an area with lower Pb 

13 contamination (Smejkalova, 1990). Comparisons were not done with children living in an area 

14 with little or no Pb contamination. Measurements of blood Pb levels indicated a statistical 

15 difference in blood levels between the two groups but not necessarily a substantial, or 

16 biologically significant, difference between them. (Typically the control group levels were in the 

17 high 20’s compared to the low 30’s μg/dL in the exposed group). Thus, the possibility that each 

18 group was exposed to a Pb level that could induce a baseline level of damage cannot be ruled out 

19 and, thus, it cannot be conclusively stated that Pb was not clastogenic in this study. 

20 The other study found an increase in Pb-induced strand breaks in white blood cells from 

21 children living in an area of Mexico with high Pb contamination compared to children living in 

22 an area with lower Pb contamination (Yanez et al., 2003). Blood Pb levels confirmed a 

23 difference in exposure to Pb, but urinary arsenic levels confirmed that these children were 

24 exposed to higher levels of arsenic, too; and, thus, it cannot be determined which chemical was 

25 responsible for the damage. 

26 The possible genotoxicity of Pb for children is an important concern. However, there are 

27 simply too few data to draw definitive conclusions, and more research is needed. See Chapter 6 

28 (Section 6.7) for more in-depth discussion of the epidemiology of Pb in human populations. 

29 

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5.6.3.2 Laboratory Animal Studies 

Fourteen studies evaluated the genotoxicity of Pb compounds in animal models. The 

majority of these studies focused on mice, and the Pb was administered by intraperitoneal (IP) or 

intravenous (IV) injection. Several endpoints were considered including chromosome 

aberrations, SCE, micronucleus formation, and DNA strand breaks. Overall, the results are 

ambiguous, due in part to study design and the various endpoints considered. These studies are 

summarized in Table AX5-6.4. 

Lead compounds appear to be able to damage chromosomes, if only weakly. Two studies 

with well-performed analyses were positive (Fahmy, 1999; Aboul-Ela, 2002). The other positive 

studies observed that Pb could induce karyotypic arrangements, indicating a possible clastogenic 

response; however, these studies did not analyze very many cells (Chakraborty et al., 1987; 

Nayak et al., 1989a,b; Dhir et al., 1990, 1992a,b; Nehez et al., 2000). Some found chromosome 

damage, but it did not increase with dose (Chakraborty et al., 1987; Nayak et al., 1989a,b; Dhir 

et al., 1990). Altogether, the data do suggest some role for Pb in inducing chromosome damage, 

but it may be a weak effect. 

Similarly, the data for micronuclei and DNA damage are ambiguous. One study found 

that Pb induced micronucleus formation in a dose-associated manner, but only considered two 

doses (Roy et al., 1992). The other study found that Pb induced micronucleus formation but not 

in a dose-dependent manner (Jagetia and Aruna, 1998). This difference may reflect the 

somewhat shorter exposure time in the second study. 

One DNA damage study found that Pb nitrate could induce DNA strand breaks in the 

white blood cells of mice (Devi et al., 2000); however, the damage was not dose-dependent. 

Another found DNA damage in a number of organs, but only one dose was considered and the 

authors described the effect as weak (Valverde et al., 2002). In both studies, the highest doses 

caused less damage than the moderate- to low-doses. These data again suggest that Pb is only 

weakly causing damage. 

By contrast, the results for SCE are consistently positive. The three studies that were 

positive found that SCEs were induced in a dose-dependent manner (Fahmy, 1999; Nayak et al., 

1989a; Dhir et al., 1993). 

The route of administration complicates the interpretation of all of these genetic studies. 

All of the studies, except for three chromosome damage studies, used injection-based exposures. 

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It is unknown if exposures that reflect more realistic scenarios (e.g., from drinking water) would 

cause any of these effects. Only one study of DNA strand breaks used a physiologically relevant 

exposure (inhalation). 

Four studies exposed animals by gavage, which is still a somewhat artificial exposure. 

One was a DNA damage study that found weak activity (Devi et al., 2000). The other three 

considered chromosome damage (Aboul-Ela, 2002; Dhir et al., 1992b; Nehez et al., 2000). 

Two found a dose-response for a 24 h-exposure to Pb nitrate-induced chromosome aberrations in 

mice (Aboul-Ela, 2002; Dhir et al., 1992b). The other found that a 4-week exposure to Pbacetate induced aneuploidy, but not chromosome aberrations, in rats (Nehez et al., 2000). It is 

difficult to reconcile these two studies, as they use different exposure times, chemicals, and 

species. More work is needed using relevant doses and exposure conditions to Pb compounds in 

multiple species to determine if Pb induces chromosome aberrations. 

Some studies also tried to offset the effects of Pb with a variety of compounds. Potential 

modulators included fruit extract from Phyllanthus emblica, ascorbic acid, calcium, and iron 

(Aboul-Ela, 2002; Dhir et al., 1990, 1992a, 1993; Roy et al., 1992). Other studies sought to 

determine if coexposure to other toxicants would potentiate the effects of Pb (Dhir et al., 1992b; 

Nehez et al., 2000) and considered both zirconium and cypermethrin. The data indicated that the 

fruit extract could block the toxic effects of Pb, an effect which may, in part, be attributable to 

ascorbic acid, but that other components must also be involved, because ascorbic acid alone 

produced variable results. Iron also had an effect, but only if given just before, or with, the Pb 

compound; post treatments with iron had no effect. Calcium had a strong effect. 

The effects with zirconium and cypermethrin are less clear. Both were reported to 

exacerbate the effects of Pb, but the effects for both are complicated by experimental design 

problems. For example, zirconium only exacerbated Pb’s effects when given simultaneously and 

not when given 2 h before, or after, Pb. This seems rather unusual as the total exposure to each 

was 24 h and, thus, simultaneous exposure occurred in every circumstance. Thus, the data would 

seem to suggest that a 22-h coexposure had no effect, but that a 24-h exposure did. 

Alternatively, there may have been some interaction of the two chemicals in the gut during 

coexposure, creating a more toxic species. 

Interpretation of the cypermethrin study is complicated by its design and the results. Only 

20 metaphases were analyzed for each animal, instead of the recommended 100. In addition, the 

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statistical analyses were done relative to untreated controls and not to animals treated with Pb or 

cypermethrin alone. Careful inspection of the tables reveals that actual exposure to Pb plus 

cypermethrin induced less damage than that induced by Pb alone. Thus, the effects of them 

together appear to be less than additive. More work is needed to explore the meaning of these 

data and the importance of Pb mixtures. 

The previous report found a similar amount of ambiguity; some animal studies were 

positive for chromosome damage and others were negative. Other endpoints were not described 

after Pb exposure in experimental animals. These data suggest that Pb can induce SCE but that it 

can induce chromosome damage, DNA damage, or micronuclei either weakly or not at all. 

5.6.3.3 Cell Culture Studies 

Few cell culture studies were reported in the 1986 Pb AQCD. Since 1986, a great deal of 

theoretical and technological progress has allowed for a large number of cell culture studies to be 

performed, as discussed below. 

Human Cell Culture 

Mutagenicity 

Two studies considered Pb-acetate-induced mutagenesis in human cells. Both considered 

mutations at the HPRT locus, with one using keratinocytes and the other skin fibroblasts (Ye, 

1993; Hwua and Yang, 1998). These studies are summarized in Table AX5-6.5. 

One study reported no lead-induced mutagenesis (Hwua and Yang, 1998) but sought to 

explore the importance of oxidative metabolism in lead-induced mutagenesis by co-treatment 

with 3-aminotriazole, a known catalase inhibitor. This co-treatment did not increase Pb-acetateinduced mutagenesis, suggesting that either catalase was not involved in this effect or that Pb is 

truly not mutagenic. It would be premature to conclude that oxidative metabolism is not 

involved in anchorage independence, as these are the only data and are limited to catalase. 

Further data is needed to elucidate whether oxidative metabolism is involved in this effect of Pb 

as well as further studies of lead-induced mutagenesis. 

The other study reported that Pb-acetate induced mutagenesis (Ye, 1993). However, 

interpretation of this study is hampered by its methodology. The study did not actually measure 

HPRT mutations or colony formation, but rather it attempted a quicker methodology that 

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measured tritium incorporation. Although a shorter assay is highly desirable, the study did not 

verify the observed effects with standard methods, and, thus, it is uncertain if the tritium 

incorporation actually reflected lead-induced mutations. 

One study considered Pb-chromate and found that it was not mutagenic (Biedermann and 

Landolph, 1990). 

There are insufficient data at this point to conclude whether Pb is mutagenic in human 

cells, although the few data that exist are largely negative. 

Clastogenicity 

Ten studies investigated the ability of Pb compounds to induce chromosome damage in 

cultured human cells. All but one were essentially from the same research group, and all but two 

considered Pb-chromate. All were done using normal, or nearly normal, human cells. These 

studies are summarized in Table AX5-6.6. 

Only two of those studies focused on the clastogenicity of Pb itself (Wise et al., 2004b, 

2005), the remainder used Pb compounds but focused on either chromate or radioactive particles 

as the clastogenic species. These studies found that Pb-glutamate was not clastogenic. 

All of the Pb-chromate studies found that Pb-chromate induced chromosome damage in a 

concentration-dependent manner. However, the effects were either attributed or demonstrated to 

be caused by chromate ions. Lead ions were produced by Pb-chromate, but they were not 

clastogenic. 

There was one study of radioactive Pb (Martins et al., 1993). The focus was on the 

clastogenic activity of alpha particles, and the identity of the specific Pb salt was not provided. 

The alpha particles were able to induce chromosome damage. 

Overall, the data appear to indicate that Pb does not induce chromosome damage in 

human cells, although more investigation of different compounds is needed. 

DNA Damage 

Studies of DNA damage in cultured human cells have considered DNA strand breaks, 

Pb-DNA adducts, and DNA-protein crosslinks for a variety of Pb compounds. The only clear 

positive damage induced by Pb was Pb-DNA adducts following Pb-chromate exposure, although 

the authors referred to them as Pb associated with DNA (Singh et al., 1999). It is uncertain if 

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these represent actual adducts or some weaker association. Two studies found no DNA strand 

breaks induced by Pb (Hartwig et al., 1990; Snyder and Lachmann, 1989), and one study 

involving several laboratories found no DNA-protein crosslinks after Pb exposure (Costa et al., 

1996). The other study found DNA double-strand breaks, but these were attributed to chromate 

and not Pb (Xie et al., 2005). These studies are summarized in Table AX5-6.7. 

One other study was positive (Wozniak and Blasiak, 2003), but the results were unusual 

and their impact uncertain. Specifically, this study found that Pb-acetate induced DNA singlestrand breaks but that the amount of damage decreased with concentration, and ultimately the 

highest concentration had less damage than the control. DNA double-strand breaks were 

observed, but were lowest at the highest concentration. DNA-protein crosslinks were seen only 

at the highest concentration, and the authors attempted to explain the decrease in strand breaks 

with this effect. This explanation may partially correct, but it does not entirely explain the 

decreased amount of damage at the middle concentration. These data need to be repeated by an 

independent group before they can be fully assessed. 

Together, these data suggest that Pb likely does not induce DNA damage; however, the 

data are still too limited to allow any definitive conclusions. 

Human Cell Genotoxicity Summary 

The cumulative data suggest that Pb is not mutagenic and does not induce chromosome 

aberrations or DNA damage in cultured human cells. It is interesting to note that Pb-induced 

SCEs have not been considered in human cells. 

5.6.3.4 Animal Cell Cultures 

Mutagenicity 

The potential mutagenicity of Pb compounds in rodent cells was considered in six studies. 

In particular, three mutagenesis systems were considered: mutagenesis at the HPRT locus, the 

gpt locus, and mutations in sodium-potassium ATPase. The results are highly variable and may 

be specific to the Pb compound considered in each case. In particular, Pb-chromate and Pbacetate appear to be nonmutagenic. Lead acetate was positive but only at highly cytotoxic 

concentrations. By contrast, Pb-chloride and Pb-sulfate appeared to be mutagenic at relatively 

nontoxic concentrations. These studies are summarized in Table AX5-6.8. 

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Insufficient data exist at this point to conclude whether or not Pb is mutagenic in animal 

cells. 

Clastogenicity 

Seven studies investigated the ability of Pb compounds to induce chromosome aberrations 

in cultured mammalian cells (Table AX5-6.9). Four of these studies considered Pb-chromate 

and further investigation revealed that chromate was responsible for the clastogenic effect (Wise 

et al., 1992, 1993; Blankenship et al., 1997). Three of these studies considered other leadcontaining compounds (Wise et al., 1994; Lin et al., 1994; Cai and Arenaz, 1998). All but one 

were negative and that one only found a small response at a single high dose (Wise et al., 1994). 

Lower doses had no effect. Considered together, the studies indicate that Pb does not induce 

chromosomal aberrations in cultured mammalian cells. 

Only two studies considered Pb-induced micronuclei in cultured mammalian cells. One 

was negative (Lin et al., 1994) and the other positive (Bonacker et al., 2005). 

Four studies considered Pb-induced SCE in cultured mammalian cells. The results were 

predominately negative (three studies [Hartwig et al, 1990; Lin et al., 1994; Zelikoff et al., 

1988]). Interpreting these studies, however, is complicated by the fact that too few metaphase 

cells (less than 30 per concentration) were analyzed in each study. The one positive study 

considered 100 metaphases per concentration, making those data more reliable (Cai and Arenaz, 

1998). 

DNA Damage 

Several measures of DNA damage in cultured human cells have been investigated, 

including DNA single-strand breaks and DNA-protein crosslinks. Most Pb compounds did not 

induce DNA single-strand breaks. The exception was Pb-chromate, which did induce DNA 

strand breaks, but this effect was likely a result of the chromate ion. These studies are 

summarized in Table AX5-6.10. 

Both Pb-chromate and Pb-nitrate induced DNA-protein crosslinks in cultured mammalian 

cells. These data suggest that Pb is genotoxic in this manner; however, it is thought that the Pbchromate-induced DNA-protein crosslinks result from the chromate and that the method used for 

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402(c) Economic Analysis Chapter 5 208
1 Pb-nitrate is not sufficiently rigorous. Thus, while the data are certainly suggestive, they are 

2 insufficient to make any definitive conclusion. 

3 Nonmammalian Cell Cultures 

4 Only one study was located considering Pb in a nonmammalian model (Table AX5-6.11). 

5 This study found that Pb-chromate was not mutagenic in a bacterial assay. The compound was 

6 studied because of its chromate content and, given that it is the lone study, no definitive 

7 conclusions can be reached. 

8 

9 5.6.3.5 Cell-Free Studies 

10 No cell-free studies concerning Pb carcinogenesis or genotoxicity were located. 

11 

12 5.6.3.6 Organ-Specific Studies 

13 One study (Valverde et al., 2002) considered organ-specific effects (see Table AX5-6.4). 

14 That study found a different pattern of DNA strand breaks in mice after inhalational exposure to 

15 Pb-acetate. DNA in the brain and lung were damaged the most, kidney and liver next, then nasal 

16 epithelia and leukocytes, with no damage in testicle DNA. These data are intriguing, as they 

17 suggest organ-specific responses after a physiologically relevant exposure (inhalation). More 

18 research is needed, however, to fully assess the impact of these findings. Moreover, while the 

19 damage was statistically significant, the authors described the effects as weak. 

20 

21 5.6.3.7 Genotoxicity Section Summary 

22 There is some ambiguity in the genotoxicity results, as some endpoints were positive 

23 while most were negative. Consistent with the animal study data, Pb can induce SCE in rodent 

24 cells, but it is unknown if it can do so in human cells because this has not been tested. Lead also 

25 seems to induce DNA-protein crosslinks in rodent cells. 

26 

27 5.6.4 Genotoxicity as it Pertains to Potential Developmental Effects 

28 The human genotoxicity studies are only briefly reviewed in this section. For a more 

29 detailed review, see Chapter 6 (Section 6.7). Only limited animal data and no cell culture studies 

30 focused on this issue as a concern. The available data are described below. 

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402(c) Economic Analysis Chapter 5 209
1 Adults

2 One study was located that considered the effects of Pb on sperm quality and quantity.

3 This study considered Pb, cadmium, and selenium levels in 56 nonsmoking volunteers (Xu et al., 

4 2003). No effects on sperm quality were correlated with Pb exposure up to 10 μg/L. 

5 Two studies were located on the effects of Pb on sperm morphology in animals (Fahmy, 

6 1999; Aboul-Ela, 2002). Both were positive, indicating that Pb may have an effect on sperm.

7 They also found that Pb induced DNA damage in the sperm (See Table AX5-6.4). These studies 

8 are summarized in Table AX5-6.12. 

9 Children 

10 No studies were analyzed that considered the genotoxic effects of Pb in children as a 

11 developmental hazard. There are two studies that considered the genotoxic effects of Pb in 

12 children. They were discussed in Section 5.6.3.1. 

13 Three studies were located on the fetal effects of Pb-nitrate on the fetus (Kristensen et al., 

14 1993; Nayak et al., 1989a,b). Lead induced an increase in resorptions and there were hints of 

15 possible fetal chromosome damage, but the methods were poorly described and much more work 

16 is needed before conclusions can be drawn. These studies are summarized in Table AX5-6.13. 

17 

18 5.6.5 Epigenetic Effects and Mixture Interactions 

19 Lead has been proposed to be a co-mutagen or possibly a promoter. Thus a number of 

20 epigenetic mechanisms have been proposed. Epigenetic effects occur when a compound such as 

21 Pb induces changes in cellular processes that do not result from changes in DNA sequence. In 

22 other words, Pb has been proposed to alter cells in ways that may change the cell without 

23 breaking or mutating DNA. There are three possible mechanisms: (1) alterations of gene 

24 expression that can stimulate cells to grow (mitogenesis) and/or can interfere with DNA repair; 

25 (this possibility has been investigated in several studies); (2) interaction with other metals; and 

26 (3) alteration of oxidative metabolism. Neither of the latter two have been extensively 

27 investigated. 

28 

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5.6.5.1 Gene Expression 

It has been argued that Pb may induce or co-induce carcinogenesis by altering cellular 

metabolism or by altering the metabolism of another chemical. Both whole animal and cell 

culture studies have been conducted to address this question and are described below. 

Animal 

Animal studies indicate that Pb can induce the expression of some phase I metabolizing 

enzymes, such as cytochrome P4501A1, and phase II metabolizing enzymes, such as glutathione 

and glutathione-S-transferase. These studies are summarized in Table AX5-6.14. 

Thus, it is plausible that through this mechanism, Pb may act as a co-carcinogen by 

affecting the metabolism of other chemicals or possibly as a direct carcinogen by enhancing 

endogenously-induced damage. However, no studies have directly shown that such Pb effects 

are linked to cancer or alter the potency of another chemical; and, thus, it remains only a 

plausible hypothesis. 

Human Cell Culture Studies 

A few human cell culture studies have been done, and these generally confirm the animal 

studies. These studies are summarized in Table AX5-6.15. 

Lead has been shown to affect the induction of some phase I metabolizing enzymes (such 

as cytochrome P4501A1) and phase II metabolizing enzymes (such as glutathione and 

glutathione-S-transferase and NAPDH oxidase). These experiments also indicate that Pb can 

affect the metabolism of other carcinogenic compounds, although they do not show that the 

genotoxic or carcinogenic effects change as a result of these effects; and, thus, more work 

remains to make this more than just a plausible explanation. 

Animal Cell Culture Studies 

No animal cell culture studies concerning the effects of Pb on the expression of metabolic 

genes were located. 

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1 5.6.5.2 DNA Repair 

2 It has been argued that Pb may induce or co-induce carcinogenesis by altering the repair 

3 of DNA lesions induced by another agent. The greatest focus has been on damage induced by 

4 ultraviolet (UV) light. Only cell culture and cell-free studies have been conducted to address this 

5 question and are described below. 

6 Human 

7 Only one study considered Pb-induced effects on DNA repair in cultured human cells (see 

8 Table AX5-6.16). This study found that coexposure to Pb caused persistence of strand breaks 

9 induced by UV light. This persistence suggests that Pb interfered with the repair of these lesions, 

10 but direct evidence of that interference was not provided. These are the only data in human cells 

11 and, thus, it cannot be determined if Pb inhibits DNA repair in human cells. 

12 

13 Mammalian Cell Culture Models 

14 Two studies considered Pb-induced effects on DNA repair in cultured mammalian cells. 

15 These studies are summarized in Table AX5-6.17. Both found that Pb-acetate increased UV16 induced DNA damage including SCE, mutagenesis, and cytotoxicity. Lead did not affect strand 

17 breaks induced by UV. These data suggest that Pb may indeed inhibit repair, although direct 

18 interactions with repair proteins were not demonstrated. 

19 

20 Cell Free Systems 

21 One study considered the effects of Pb on DNA repair proteins (McNeill et al., 2004). 

22 That study found that Pb can inhibit APE nuclease in cell-free systems. 

23 

24 5.6.5.3 Mitogenesis 

25 It has been argued that Pb may induce or co-induce carcinogenesis by inducing cells to 

26 grow when they should not. Both animal and cell culture studies have been conducted to address 

27 this question and are described below. 

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29 5.6.5.3.1 Animal 

30 Several studies have considered Pb-induced mitogenesis in animal models. These studies 

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are summarized in Table AX5-6.18. These studies found that Pb can stimulate cell growth, but 

primarily in the liver. One study did consider TNF-α expression in brain cells, but it was not 

demonstrated whether these effects were mitogenic. The interpretation of many of the studies is 

complicated by the exposure method (IV injection), which does not reflect human exposure. In 

general, the data indicate that Pb is mitogenic to the liver. 

Human Cell Culture Studies 

A number of studies have considered the potential growth-stimulatory effects of Pb in 

cultured human cells (Table AX5-6.19). These studies all found that Pb did not stimulate cell 

growth. Thus, mitogenesis is not a likely epigenetic effect for Pb in human cells. 

Mammalian Cell Culture Studies 

A number of studies have considered the potential growth-stimulatory effects of Pb in 

cultured mammalian cells other than the kidney. These studies all found that Pb did not 

stimulate cell growth. Thus, mitogenesis is not a likely epigenetic effect of Pb in human cells. 

One study found an increased mitotic index; however, it did not consider possible cell cycle 

arrest (Lin et al., 1994). Indeed, another study found that Pb increased the mitotic index, because 

it induced M-phase arrest (Wise et al., 2005). 

Other 

Lead-induced oxidative damage has been investigated as a potential cause of genotoxic or 

carcinogenic effects. Generally, the results suggest that Pb only produces low levels of reactive 

oxygen species, but that it may inhibit some enzymes involved in oxidative metabolism (Table 

AX5-6.20). Thus, Pb may affect oxidative metabolism, but more work is needed to draw 

meaningful conclusions. 

5.6.5.4 Epigenetic Mechanisms Summary 

The collective data support the hypothesis that Pb can induce an epigenetic effect. Lead 

can alter the expression of metabolic genes in cultured cells and may alter DNA repair, although 

much more study is needed. Lead may also affect oxidative metabolism or interact with other 

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metals, but again more study is needed. By contrast, it is unclear if Pb is mitogenic. It is 

mitogenic to the liver in animals, but it is not mitogenic in cultured cells. More study is needed 

to determine if this difference reflects differences between in vivo and cell culture models or if 

this property is specific to only certain organs, e.g., the liver. 

5.6.6 Overall Conclusions 

The overall conclusions have not changed much from the 1986 Pb AQCD. Lead remains 

an ambiguous carcinogen in humans and a clear carcinogen in animals. Cell culture studies 

support both of these conclusions, as effects in rodent cells were not seen in human cells. Lead 

does appear to be genotoxic in human epidemiology studies. By contrast, the laboratory studies 

are more ambiguous in both animal and cell culture studies. In these systems, the genotoxicity in 

culture is limited to SCE and, perhaps, to DNA-protein crosslinks. For other endpoints, it is only 

weakly active, if at all. Lead has not been evaluated sufficiently as a potential genotoxic hazard, 

but this probably stems from the fact it appears to be weakly genotoxic. The available data 

suggest that Pb can damage sperm and affect fetuses. More work is urgently needed on this 

topic. Cell culture studies do support a possible epigenetic mechanism or co-mutagenic effects. 

5.7 LEAD AND THE KIDNEY 

5.7.1 Review of Earlier Work 

This section summarizes key finding from the 1986 Pb AQCD on the effects of Pb on the 

kidney in animals. Human studies published since 1986 are then reviewed in Section 6.4. 

Both in vivo and in vitro studies on several different animal species revealed that renal 

accumulation of Pb is an efficient process that occurs in both proximal and distal portions of the 

nephron and at both luminal and basolateral membranes (Victery et al., 1979a; Vander et al., 

1977). The transmembrane movement of Pb appears to be mediated by an uptake process that is 

subject to inhibition by several metabolic inhibitors and the acid-base status of the organism. 

Alkalosis increases Pb entry into tubule cells via both the luminal and basolateral membranes 

(Victery et al., 1979b). 

Goyer et al. (1970a) were principally responsible for defining the role of renal proximal 

tubular nuclear inclusion bodies in the response to Pb intoxication. In addition to the early 

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reports of nuclear inclusion bodies appearing in the proximal tubule following Pb exposure 

(Goyer et al., 1970b), biochemical studies on the protein components of isolated rat kidney 

intranuclear inclusion bodies have shown that the main component has an approximate molecular 

weight of 27 kDa (Moore et al., 1973) or 32 kDa (Shelton and Egle, 1982) and is rich in 

glutamate and aspartate. Goyer et al. (1970c) suggested that the intranuclear inclusion body 

sequesters Pb, to some degree, away from sensitive renal organelles and metabolic pathways. 

Goyer et al. (1975, 1978) also showed that single or repeated administration of CaNa2EDTA 

leads to the disruption of the nuclear inclusion bodies and their removal from the nuclei. Rats 

treated for 24 weeks with both Pb and CaNa2EDTA had no inclusion bodies, but showed early 

interstitial nephropathy. As an extension of this study, Cramer et al. (1974) examined renal 

biopsies from 5 Pb workers with 0.5 to 20 years of exposure. The two workers with normal 

GFRs, and shortest exposure duration, showed intranuclear inclusion bodies, whereas the 

remaining three workers had no intranuclear inclusions but showed peritubular fibrosis. 

Formation of intranuclear inclusion bodies was a common pathognomic feature for all 

species examined. In addition, proximal tubular cytomegaly and swollen mitochondria with 

increased numbers of cytosomes were also observed (Fowler et al., 1980; Spit et al., 1981). The 

morphological changes were principally localized in the straight (S3) segments of the proximal 

tubule. Goyer (1968) and Goyer et al. (1968) had demonstrated earlier that, after lead exposure, 

mitochondria were not only swollen but had decreased respiratory control ratios (RCRs) and 

inhibited state-3 respiration. 

Aminoaciduria has been reported in several studies (Studnitz and Haeger-Aronson, 1962; 

Goyer et al., 1970b; Wapnir et al., 1979). Other studies have reported increased urinary 

excretion of electrolytes (e.g., sodium, potassium, calcium, water) following Pb administration 

(Mouw et al., 1978). Victery et al. (1981, 1982a,b, 1983) found that zinc excretion was 

increased following injection of lead. 

Wapnir et al. (1979) observed that Pb-acetate administration caused a reduction in renal 

alkaline phosphatase activity and an increase in Mg-ATPase activity, but no significant changes 

in NaK-ATPase activity. On the other hand, Suketa et al. (1979) found marked a decrease in 

renal NaK-ATPase activity following a single oral administration of Pb-acetate at a dose of 

200 mg/kg, but no change in Mg-ATPase. 

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Renal ALAD was found to be inhibited by Pb in both acute and chronic experiments 

(Silbergeld et al., 1982). Renal ALAD was similar to control levels when GSH was present but 

was significantly reduced in the absence of GSH (Gibson and Goldberg, 1970). Accumulation of 

both ALA and porphobilinogen was also observed in kidney tissue of Pb-treated rabbits, 

compared to controls. Other studies have not shown a reduction in renal ALAD following Pb 

exposure (e.g., Fowler et al., 1980). Higher levels of Pb may be required to cause the reduction 

in ALAD reported by Silbergeld et al. (1982), and it may possibly involve Pb-binding proteins in 

the kidney. 

5.7.2 Markers of Renal Toxicity 

The establishment and validation of new screening tests for nephrotoxic effects have been 

principally due to the efforts of the Belgian group (Price et al., 1996; Price, 2000; Lauwerys 

et al., 1992). They proposed the following battery of tests be used to screen both 

environmentally exposed and occupationally exposed individuals: (1) measures of glomerular 

integrity, i.e., urinary high-molecular weight proteins (albumin, IgG, transferrin); (2) measures 

of tubular absorption and secretion, i.e., low-molecular weight proteins (retinol binding protein, 

α-1-microglobulin; (3) measures of tubular integrity, i.e., enzymes, lysosomal N-acetyl 

$-D-glucosaminidase (NAG), brush border alanine aminopeptidase, brush border intestinal 

alkaline phosphatase, nonspecific alkaline phosphatase, α-glutathione-S-transferase (GST), and 

brush border antigens (BB50, BBA, HF5); (4) measures of glomerular and distal tubular 

function, i.e., prostanoids (thromboxane B2, prostaglandin F2 alpha, 6-keto prostaglandin 

F1alpha) ; (5) measures of glomerular structural proteins (fibronectin and laminin fragments); 

and (6) measures of distal tubular function, i.e., Tamm-Horsfall protein and π-GST. Other useful 

markers include urinary $2-microglobulin, as a marker of proximal tubular integrity; PGE2 and 

PGF2, distal nephron markers; kallikrein, a marker of the distal tubule; lysozyme, ribonuclease, 

and γ-glutamyl transferrase, enzymes reflecting proximal tubule integrity; and sialic acid, an 

extracellular matrix marker (Fels et al., 1994; Pergande et al., 1994; Taylor et al., 1997). One or 

several of these urinary markers have been used in screening tests for human Pb workers and in 

animal studies of renal nephrotoxicity. 

Questions have been raised about the usefulness of urinary NAG due to the absence of 

light or electron microscopic changes in low-dose Pb-treated animals who showed substantial 

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increases in NAG (vide infra) (Khalil-Maesh et al., 1993). Furthermore, Chia et al. (1994) found 

that urinary NAG in workers exposed to Pb correlated best with recent blood lead changes, 

suggesting that the increased urinary NAG activity reflected an acute response to a sharp 

increase in the renal Pb burden rather than to exocytosis. Questions have also been raised about 

the value of measuring the vasoconstricting prostariod cytokine thromboxane B2 (TXB2) and the 

vasodilating prostanoid 6-keto prostaglandin F1 alpha (PGF1 alpha). Conflicting results have 

been reported in human Pb-exposed workers. Cardenas et al. (1993) reported an elevation in 

TXB2 and a diminution in PGF1 alpha in 41 Pb-exposed workers in contrast to 41 controls. 

Hotter et al. (1995), on the other hand, reported that both substances were increased in 69 Pbexposed workers in contrast to 62 controls. Blood Pb levels in the two worker groups were 

comparable, i.e., 48 μg/dL in the first group and 43 μg/dL in the second. In animal experiments 

(Gonick et al., 1998), the excretion of both prostanoids was equal in low-Pb (100 ppm)-fed rats 

as contrasted to normal controls after 3 months, despite an elevation in blood pressure in the Pbfed rats. Blood Pb in the Pb-fed rats averaged 12.4 μg/dL compared to 1 μg/dL in the controls. 

Thus, measurements of these prostanoids remain of questionable value. 

Attempts to validate nephrotoxic markers were conducted by Pergande et al. (1994), 

utilizing Pb-exposed workers as contrasted to normal controls. They found that about 30% of the 

Pb workers showed an increased excretion of α1-microglobulin, NAG, ribonuclease, and/or 

Tamm-Horsfall protein, with positive correlations between these tubular indicators and blood Pb 

concentration. 

5.7.3 Biochemical Mechanisms of Lead Toxicity 

Nolan and Shaikh (1992) summarized what was known about biochemical mechanisms 

underlying Pb-induced toxicity at that time. A more detailed description based on recent animal 

studies follows in the next section. 

The initial accumulation of absorbed Pb occurs primarily in the kidneys. This takes place 

mainly through glomerular filtration and subsequent reabsorption, and, to a small extent, through 

direct absorption from the blood. Lead may be taken up by the renal tubular epithelial cells from 

the basolateral side by active transport of the free ion. Smaller amounts can also cotransport 

with low molecular weight organic anions. The uptake of Pb through the renal brush border does 

not appear to occur via any specific carriers. Instead, the process may involve binding of Pb to 

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nonspecific surface sites on the brush border membrane, followed by internalization via 

endocytosis. Acute kidney damage due to Pb manifests primarily in the proximal tubules. The 

ultrastructural changes observed in acute experimental Pb nephropathy include both specific and 

nonspecific effects on the proximal tubular epithelium, e.g., dilation of the endoplasmic 

epithelium, blebbing of the nuclear membrane, enlargement of the autophagosomes, changes in 

mitochondrial structure, formation of inclusion bodies. Chronic exposure to Pb affects 

glomerular filtration, renal clearance, and tubular reabsorption and can lead to renal failure from 

interstitial nephritis. 

Kidneys of chronically exposed individuals often show fewer or no nuclear inclusion 

bodies compared to kidneys of acutely exposed individuals. The specific ultrastructural changes 

associated with Pb nephropathy are the formation of cytoplasmic and nuclear Pb inclusion bodies 

(discussed at greater length below). These inclusion bodies are not limited to the proximal 

tubular epithelium, and have also been observed in peritoneum, astrocytes, neuroblastoma cells, 

and osteoclasts upon Pb exposure. The inclusion bodies are roughly spherical and typically 

consist of an electron-dense core, with a fibrillary network at the periphery. Research has 

revealed that the formation of the nuclear inclusion bodies is preceded by the synthesis of 

cytoplasmic inclusion bodies with a very similar structure. A protein unique to these structures 

is rich in acidic amino acids and has an isoelectric point of 6.3 and a molecular weight of 

32 kDa. Two additional proteins with apparent molecular weights of 11.5 kDa and 63 kDa have 

been identified in kidney extracts. Both of these proteins have a high affinity, but little capacity, 

for binding lead. A Pb-binding protein of 12 kDa molecular weight was identified in the 

supernatant of brain homogenate from Pb-treated rats. A Pb binding protein of 10 kDa has also 

been isolated from the erythrocytes of Pb-exposed workers. 

Mitochondrial function, in addition to structure, is very sensitive to lead. Changes include 

the uncoupling of oxidative phosphorylation, decreased substrate oxidation, and modification of 

ion transport processes. Other effects of Pb on cellular energetics include chelation of ATP and 

inhibition of microsomal NaK-ATPase. These changes may account for the proximal tubular 

dysfunction seen with acute Pb poisoning in children. 

A new area of investigation of the mechanism of Pb toxicity was initially proposed by 

Quinlan et al. (1988) and Hermes-Lima et al. (1991). Both investigators proposed that free 

radicals, or ROS, stimulated by lead, may accelerate iron-dependent lipid peroxidation, causing 

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tissue injury. Hermes-Lima et al. (1991) stated further that ALA, which is formed in large 

amounts in Pb toxicity, may undergo enolization and autoxidation, yielding ROS. Autoxidation 

of ALA, in the presence or absence of iron complexes, yields superoxide, peroxide, and hydroxyl 

radicals. Gurer and Ercal (2000), based on several animal studies to be discussed below, have 

proposed that antioxidant supplementation following Pb exposure may provide a partial remedy 

by restoring the cell’s antioxidant capacity. 

5.7.4 Animal Studies 

Two excellent review articles have been written about the effects of heavy metals on, and 

their handling by, the kidney (Barbier et al., 2005) as well as the mechanisms of kidney cell 

injury from metals (Fowler, 1992). The interested reader is directed to these reviews, although 

individual effects and mechanisms will be discussed subsequently. 

5.7.4.1 Lead Toxicokinetics 

deVries et al. (1998) published a model for Pb toxicokinetics to be used in planning 

treatment. The model is a four-compartment model with first-order kinetics. The four 

compartments of this model are blood, bone, liver, and kidney. Soft tissues are represented by 

the kidney and liver compartments. In addition, intake and excretion are included in the model. 

Excretion of Pb is mainly via the kidneys (70 to 80%), via bile and feces (15%), via nails, hair, 

and sweat (8%). The blood makes up the central compartment from which Pb is distributed after 

uptake in the body. The blood compartment contains about 4% of the total body burden of lead, 

and within this compartment, the Pb is mainly taken up by erythrocytes. The half-life of Pb in 

blood is about 30 days. From the blood, Pb is distributed relatively quickly to the soft tissues 

and bone. The distribution constant from blood to bone is much higher than the one from bone 

to blood, resulting in the accumulation of Pb in bone. The half-life in the soft tissues is about 

30 to 40 days. Most of the body burden of Pb can be found in the bone compartment (~94%), 

where the half-life of Pb is several decades. Because of the vast amount of Pb in bone, a 

rebound in blood Pb usually occurs after chelation therapy. This model can be compared with a 

toxicokinetic model developed by Marcus (1985a,b,c) and further explored by Hogan et al. 

(1998), as discussed in Chapter 4 of this document. 

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Dieter et al. (1993) examined the effect of the nature of the Pb salt on the oral intake of Pb 

in male F344 rats. For 30 days, they administered doses of 0, 10, 30, and 100 ppm Pb in the 

form of soluble Pb-oxide, Pb-acetate, Pb-sulfide, and Pb-ore. At 100 ppm of Pb-acetate or 

soluble Pb-oxide, the rats developed ~80 μg/dL of blood and ~200 μg/g of bone Pb levels, 

whereas rats fed Pb-sulfide or Pb ore developed ~10 μg/dL of blood Pb and 10 μg/g of bone 

lead. In rats fed Pb-acetate or soluble Pb-oxide, blood Pb progressively increased with 

increasing dose, while in the other two groups measurable levels of Pb were observed only at the 

highest dose (100 ppm). 

5.7.4.2 Pathology, Ultrastructural, and Functional Studies 

Two important series of studies contrast the pathological and functional changes in the 

kidney after prolonged exposure to lead, with and without chelation therapy (i.e., DMSA or 

CaNa2EDTA). In the first series of 3 long-term studies, Khalil-Manesh et al. (1992a,b, 1993a) 

described the effects of Pb-acetate on renal function and morphology in male Sprague-Dawley 

rats fed a low-calcium diet. Lead acetate was used in concentrations of 0.5% (high dose) and 

0.01% (low dose) in drinking water for periods from 1 to 12 months, and then Pb-exposed 

animals were compared to pair-fed controls (12 rats in each group). In all studies GFR was 

measured as 125I-iothalamate clearance by a single injection technique. Urinary markers 

included NAG, GST, and brush border antigens (BB50, HF5, and CG9) and were expressed as 

units/g creatinine. Blood and urine Pb were measured prior to sacrifice in each group of animals. 

Wet and dry weights of kidneys were determined, then the kidneys were processed for light, 

electron, and immunofluorescent microscopy. 

In the first study (Khalil-Manesh et al., 1992a), animals treated with continuous high-dose 

Pb for 12 months reached a maximum blood Pb of 125.4 ± 10.1 μg/dL after 6 months, at which 

time the dose of Pb was reduced from 0.5% to 0.1%. Blood Pb at the end of 12 months averaged 

55 μg/dL. Urine Pb remained above 100 μg/g creatinine at all times, but it was highest at 

3 months, averaging 340 μg/g creatinine. In the Pb-treated animals, GFR was increased above 

controls at 3 months (1.00 ± 0.14 vs. 0.83 ± 0.26 mL/min/ 100 g body wt, p = 0.05), then 

declined after 6 months to 0.78 ± 0.16 vs. 0.96 ± 0.08 mL/min/100 g body wt in controls 

(Figures 5-7.1 and 5-7.2). As indicated by the ratio of kidney dry/wet weight, increased kidney 

tissue mass was observed during the first 3 months of Pb exposure, but decreased tissue mass 

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402(c) Economic Analysis Chapter 5 220
Figure 5-7.1. Changes in GFR of experimental high-dose lead and control animals with 

duration of exposure to lead. Open and closed bars represent GFR in 

experimental and control rats, respectively. 

Source: Khalil-Manesh et al. (1992a), with permission. 

Figure 5-7.2. Correlation between GFR and blood lead during the first 6 months of 

high-dose lead exposure. 

Source: Khalil-Manesh et al. (1992a), with permission. 

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was observed by 12 months. With regard to urinary markers, NAG was elevated above control 

levels at 3, 6, and 9 months of Pb exposure; GST was elevated at 3, 6, and 12 months of Pb 

exposure; and no significant differences were observed in the brush border antigens. Proximal 

tubular nuclear inclusion bodies were present at all time periods in Pb-treated animals. 

Enlargement of proximal tubular cells and nuclei were seen beginning at 3 months. At 6 months, 

focal tubular atrophy and interstitial fibrosis appeared, increasing in extent up to 12 months. 

Mitochondrial alterations, consisting of rounding and elongation, appeared by 1 month and were 

persistent. Glomeruli were normal through 9 months, but, at 12 months, they showed focal and 

segmental sclerosis. There were no electron-dense deposits and immunofluorescent studies were 

negative. Renal arteries and arterioles were normal at all time point examined. 

The second study (Khalil-Manesh et al., 1992b) consisted of the discontinuation of both 

the high- and low-dose Pb exposure after 6 months, then treatment with three courses of DMSA 

or discontinuation of high-dose Pb alone after 1, 6, and 9 months of Pb feeding. Controls were 

pair-fed, exposed to Pb for 6 months, then removed from exposure for 6 months without 

receiving DMSA. Low-dose Pb-treated rats showed no significant pathologically with or 

without DMSA treatment but exhibited a significant increase in GFR after DMSA treatment 

(1.09 ± 0.19 vs. 0.88 ± 0.22 mL/min/100 g body weight; P < 0.03) (Figure 5-7.3). Urinary 

markers remained unchanged, and there were no structural alterations by light or electron 

microscopy. High-dose Pb-treated animals showed no functional or pathologic changes when Pb 

exposure was discontinued after 1 month. However, when the duration of exposure was 6 or 

9 months, GFR was decreased and serum creatinine and urea nitrogen were increased compared 

to controls. Tubulointerstitial disease was severe. Administration of DMSA resulted in an 

improvement in GFR (Figure 5-7.3) and a decrease in albuminuria, together with a reduction in 

size and number of nuclear inclusion bodies in proximal tubules. However, tubulointerstitial 

scarring was only minimally reduced. In conclusion, except for a brief initial exposure, 

discontinuation of high-dose Pb exposure failed to reverse Pb-induced renal damage. Treatment 

with the chelator, DMSA, improved renal function but had less effect on pathologic alterations. 

Because GFR improved after DMSA treatment in both low- and high-dose Pb-treated animals, 

irrespective of the degree of pathologic alterations, it may be concluded that the DMSA effect is 

most likely mediated by hemodynamic changes. 

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402(c) Economic Analysis Chapter 5 222
Figure 5-7.3. GFR in high-lead and low-lead experimental discontinuous (ED6) and 

DMSA-treated rats (DMSA) as compared to controls (C12). All rats 

were studied at 12 months. 

 *p < 0.01 when compared to ED6 and C12. 

**p < 0.05 when compared to ED6. 

Source: Khalil-Manesh et al. (1992b), with permission. 

1 The third study (Khalil-Manesh et al., 1993a) examined the course of events over 

2 12 months in continuous low level Pb-exposed animals. Maximum blood Pb levels in 

3 experimental animals were reached at 3 months, averaging 29.4 ± 4.1 μg/dL. GFR was found 

4 to be significantly increased above pair-fed controls at 1 and 3 months, but it was normal at 

5 other time periods (1 month experimental, 1.18 ± 0.12 vs. control, 0.76 ± 0.15mL/min/100 g; 

6 p < 0.001; 3 month experimental, 1.12 ± 0.16 , vs. control, 0.86 ± 0.10 mL/min/100 g; p < 0.001) 

7 (Figure 5-7.4). Levels of urinary NAG in Pb-exposed rats exceeded control levels at all time 

8 periods, except at 12 months, when the normal increase with aging obscured differences between 

9 experimental animals and controls (Figure 5-7.5). In contrast, urinary GST, a more specific 

10 marker of metal-associated proximal tubular injury, was normal at all time periods. Proximal 

11 tubular nuclear inclusion bodies were sparse and were observed only at 1 and 3 months. 

12 

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402(c) Economic Analysis Chapter 5 223
Figure 5-7.4. Changes in GFR in experimental and control rats, at various time periods. 

Source: Khalil-Manesh et al. (1993a). 

Figure 5-7.5. Urinary NAG concentration in experimental and control rats at various 

time periods. 

Source: Khalil-Manesh et al. (1993a). 

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No other pathologic alterations were found in the kidneys until 12 months of exposure, 

when mild tubular atrophy and interstitial fibrosis were seen. The absence of changes in urinary 

GST accorded with the relative absence of morphologic changes, whereas the observed increases 

in urinary NAG suggest that this enzyme may be an overly sensitive indicator of tubular injury, 

more probably reflecting upregulation of the enzyme even in the absence of tubular injury. 

It should be noted that both low-dose Pb-treated animals and high-dose Pb-treated animals 

showed a “hyperfiltration” phenomenon during the first 3 months of Pb exposure. This 

observation could be invoked as a partial explanation for the late changes of glomerulosclerosis 

in the high-dose animals, but it cannot explain the lack of glomerular changes in the low-dose 

animals. Thus, these studies join those of Roels et al. (1994) and Hu (1991) in humans that 

indicate that Pb nephropathy should be added to diabetic nephropathy as diseases that lead to 

early hyperfiltration. 

The second series of studies were performed by Sanchez-Fructuoso et al. (2002a,b). 

Sanchez-Fructuoso et al. (2002a,b) evaluated the effect of CaNa2EDTA on tissue mobilization of 

Pb in Wistar rats initially treated with 500 ppm Pb-acetate for 90 days, followed by treatment 

with three courses of CaNa2EDTA 50 mg/kg/day for 5 days, separated by 9 days, or placebo. 

Lead levels were measured in blood, urine, kidney, liver, brain, and femur. There was no change 

in bone Pb after CaNa2EDTA compared to placebo, but Pb levels were significantly reduced in 

all other tissues (Figure 5-7.6). The authors emphasized that there was no redistribution to brain. 

Cory-Slechta et al. (1987) had originally reported that with CaNa2EDTA chelation in rats Pb is 

preferentially mobilized from bone and then redistributed to other organs, including brain. The 

Sanchez-Fructuoso et al. (2002a,b) findings stand in contrast, explained by the authors as due to 

a 3-fold higher level of CaNa2EDTA used by Cory-Slechta et al. (1987). 

Sanchez-Fructuoso et al. (2002b) also evaluated pathologic changes, as well as the 

response of ALAD activity before and after CaNa2EDTA treatment in the same rats. In the 

90-day Pb-treated animals, the main findings were hypertrophy and vacuolization of medium and 

small arteries (Figure 5-7.7); mucoid edema and muscular hypertrophy in arterioles; loss of cell 

brush borders, cell loss, and intranuclear inclusion bodies in the proximal tubule; and fibrosis and 

the presence of infiltrates in the interstitial component. Treatment with CaNa2EDTA slowed the 

progression of most alterations (Figure 5-7.8) and resulted in a diminution in nuclear inclusion 

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402(c) Economic Analysis Chapter 5 225
Figure 5-7.6. Kidney, liver, brain, and bone Pb levels in 56 Pb-exposed rats. 

After 90 days of poisoning, animals were administered serum saline 

(solid line) or calcium disodium EDTA (broken line). 

Source: Sanchez-Fructuoso et al. (2002a), with permission. 

Figure 5-7.7. Percentage of moderate and severe hypertrophy and vacuolization lesions in 

small and medium sized arteries in the kidney of lead-exposed rats. 

Source: Sanchez-Fructuoso et al. (2002b), with permission. 

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402(c) Economic Analysis Chapter 5 226
Figure 5-7.8. Percentage of moderate and severe muscular hypertrophy lesions in 

arterioles of the kidney in lead-exposed rats. 

Source: Sanchez-Fructuoso et al. (2002b), with permission. 

1 bodies. ALAD activity was reduced from 3.18 ± 0.52 U/mL in controls, to 0.82 ± 0.16 U/mL in 

2 the Pb-exposed rats. In the rats treated with CaNa2EDTA, ALAD returned to near control levels 

3 (2.98 ± 0.41 U/mL) at 137 days. It is surprising that such remarkable vascular changes were 

4 noted in this study, while none were noted in Khalil-Manesh et al. (1992a), even with high-dose 

5 Pb for longer periods of time. The kidney content of Pb (mean 74.6 μg/g) was also lower than 

6 the mean kidney content at 12 months (294 μg/g) in the Khalil-Manesh et al. (1992a) study. 

7 The only explanation for these striking differences that can be offered is that different strains of 

8 rats were employed, i.e., Wistar in the Sanchez-Fructuoso (2002b) study and Sprague-Dawley in 

9 the Khalil-Manesh et al. (1992a) study. The presence or absence of hypertension cannot be 

10 invoked as an explanation, because in another Khalil-Manesh et al. (1993b) study the low-dose 

11 Pb animals became hypertensive while the high-dose animals did not. These and other related 

12 studies are summarized in Table AX5-7.1. 

13 5.7.4.3 Biochemical Mechanisms of Lead Toxicity 

14 Role of Free Radicals (Reactive Oxygen Species) 

15 Since the early 1990s, it has been appreciated that free radicals, now known as reactive 

16 oxygen species (ROS), are involved in the manifestations of Pb poisoning, presumably via their 

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adverse effects on tissue integrity and/or their vasoconstrictive effects on vascular endothelium. 

Wolin (2000) produced an extensive review of individual ROS, and their interactions with NO, 

the major endogenous vasodilator, which acts via a second messenger, cGMP. The production 

of ROS often begins with a one-electron reduction of molecular oxygen to superoxide anion 

(O2 

!

) by various oxidases. NAD(P)H oxidases are the principal enzymes involved. Superoxide 

anion is a negatively charged free radical that can be broken down to hydrogen peroxide (H2O2) 

by superoxide dismutase (SOD) or can interact with NO to form the highly reactive peroxynitrite 

ion (ONOO!

), which, because of its extremely short half-life, is measured as its reaction product, 

tissue nitrotyrosine. Catalase and glutathione (GSH) peroxidase (GSHRx) metabolize H2O2 to 

Compound I and oxidized glutathione (GSSG), respectively, while myeloperoxidase metabolizes 

H2O2 to hypochlorous acid (HOCl). The reaction of H2O2 with ferrous ion results in the 

formation of hydroxyl ion (•

OH). ROS can be scavenged by endogenous thiols (e.g., GSH) or 

exogenous thiol, e.g., N-acetylcysteine (NAC). ROS can be measured as the concentration of the 

lipid peroxidation product, malondialdehyde-thiobarbituric acid (MDA-TBA) or by the more 

recently introduced F-2 isoprostanes. 

Kumar and Das (1993) explored the involvement of ROS in the pathobiology of human 

essential hypertension. They found that plasma levels of lipid peroxides were higher in subjects 

with uncontrolled essential hypertension compared to normal controls. Angiotensin II, a potent 

vasoconstrictor, was found to stimulate free radical generation in normal leukocytes, which was 

thought to inactivate NO, and possibly prostacyclin, which can lead to increased peripheral 

vascular resistance and hypertension. 

Hermes-Lima et al. (1991) also explored the involvement of ROS in Pb poisoning. They 

described the process of autoxidation of ALA in the presence or absence of iron complexes, 

which yields free radicals. Free radicals are also produced by Pb-stimulated iron-dependent lipid 

peroxidation, as determined by quantification of thiobarbituric acid-reactive species (TBARS). 

Pereira et al. (1992) demonstrated that chronically ALA-treated rats (40 mg/kg body weight 

every 2 days for 15 days) under swimming training reached fatigue significantly earlier than the 

control group, as well as demonstrating decreased mitochondrial enzymatic activities. In vivo 

prooxidant properties of ALA were also suggested by the observed increase of CuZnSOD in 

brain, muscle, and liver of untrained rats submitted to chronic treatment with ALA. 

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Ercal et al. (1996) contrasted the effects of treatment with DMSA or NAC in Pb-exposed 

C57BL/6 mice. Five weeks of Pb exposure was found to deplete GSH levels, increase GSSG, 

and promote MDA production in both liver and brain samples. Glutathione levels increased and 

GSSG and MDA levels decreased in groups of Pb-exposed mice that received 1 mmol/kg DMSA 

or 5.5 mM/kg NAC for 7 days prior to sacrifice. Treatment with DMSA caused reduction in 

blood, liver, and brain Pb levels consistent with its function as a chelating agent, while treatment 

with NAC did not reduce these Pb levels. However, NAC treatment reduced indices of oxidative 

stress in both brain and liver samples. Concentrations of blood Pb in controls were 0.5 ± 

0.5 μg/dL; in Pb-treated mice, were 36.5 ± 2.4 μg/dL; in Pb + DMSA-treated mice, were 13.7 ± 

1.3 μg/dL; and in Pb + NAC-treated mice, were 36.0 ± 3.5 μg/dL. Thus both DMSA and NAC 

acted as antioxidants, presumably via their thiol groups, but only DMSA reduced the 

concentration of lead. 

Vaziri and co-workers (Gonick et al., 1997; Ding et al., 1998, 2000, 2001; Vaziri et al., 

1997, 1999a,b, 2000, 2001a,b, 2003; Zhou et al., 2002; Ni et al., 2004) have published a number 

of articles relating to the production of ROS and alterations in enzymatic activities in Pb-induced 

hypertension. These were discussed in detail in Section 5.5 but are described briefly here. In the 

majority of studies, Pb-induced hypertension was produced by the administration of Pb-acetate, 

100 ppm in drinking water, for 3 months to male Sprague-Dawley rats. Early studies (Gonick 

et al., 1997) revealed that hypertension could occur in the absence of changes in NO or cGMP 

but with an attendant rise in plasma and kidney MDA-TBA, indicating an increase in ROS. In a 

second study, Ding et al. (1998) showed that infusion of arginine, the precursor of NO, or 

DMSA, a thiol Pb chelator and antioxidant, reduced blood pressure to or towards normal, while 

simultaneously increasing depressed urinary NO and decreasing an elevated MDA-TBA. Ding 

et al. (2000, 2001) further showed that the ROS species, •

OH, measured as salicylate-trapped 

2,3 dihydroxybutyric acid, was increased in plasma and cultured rat aortic endothelial cells after 

exposure to lead, and that dimethylthiourea, a reputed scavenger of •

OH, returned blood pressure, 

MDA-TBA, •

OH, and nitrotyrosine to or towards normal. Ni et al., in 2004, demonstrated in 

both human coronary endothelial (EC) and vascular smooth muscle cells (VSMC) that Pb-acetate 

also increased superoxide (demonstrated by flow cytometry using hydroethidine) and H2O2 

(demonstrated with dihydrorhodamine) production. After long-term (60-h) exposure, detectable 

superoxide levels fell to near normal while H2O2 production remained high. 

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Vaziri et al. (1997) showed that lazaroids, a class of non-thiol antioxidant, also restored 

blood pressure, NO, and MDA-TBA to normal. Vaziri et al. (1999a) studied rats treated for 

12 weeks with either Pb-acetate alone or Pb-acetate + vitamin E-fortified food (5000 units/kg rat 

chow). They measured urinary excretions of stable NO metabolites (NOx) and plasma and tissue 

abundance of nitrotyrosine, the footprint of NO oxidation by ROS. The Pb-treated group showed 

a marked rise in blood pressure; a significant increase in plasma and kidney, heart, liver, and 

brain nitrotyrosine abundance; and a substantial fall in urinary NOx excretion. Concomitant 

administration of high-dose vitamin E ameliorated hypertension and normalized both urinary 

NOx excretion and tissue nitrotyrosine without altering tissue Pb content. Vaziri et al. (1999b) 

also measured eNOS and iNOS in the aorta and kidney of Pb-treated and Pb + vitamin E-treated 

rats. Lead treatment increased both isotypes in aorta and kidney, signifying increased NO 

production, while Pb + vitamin E lowered aortic, but not kidney, expression of eNOS and iNOS. 

Vaziri and Ding (2001) tested the effect of lead, 1 ppm, on cultured human EC cells. Lead was 

tested alone or with either the SOD-mimetic agent, tempol, or a potent antioxidant lazaroid 

compound (both at 10-8 or 10-7mol/L) on eNOS expression and NO production. Lead-treated 

cells showed a significant upregulation of endothelial eNOS, increase in protein abundance, and 

increase in the production of NO metabolites. Treatment with either tempol or lazaroids 

abrogated the Pb-induced upregulation of eNOS protein and NOx production. Vaziri et al. 

(2001) also studied increases in NOS isoforms in vivo in Pb-induced hypertension and reversal 

by tempol. Both eNOS and iNOS were increased in kidney, aorta, and heart, while NOS was 

increased in cerebral cortex and brain stem, of Pb-treated rats; blood pressure and NOS isoforms 

were returned to normal by tempol. Vaziri et al. (2003) determined whether the oxidative stress 

in animals with Pb-induced hypertension is associated with dysregulation of the main antioxidant 

enzymes (i.e., SOD, catalase, and GSHPx), or increases in the superoxide-producing enzyme 

NAD(P)H oxidase. At the conclusion of the experiment, immunodetectable CuZnSOD, 

MnSOD, catalase, GSHPx, and the gp91phox subunit of NAD(P)H oxidase were measured by 

Western analysis in the kidney, brain, and left ventricle of control and Pb-exposed rats. Lead 

exposure resulted in a significant increase in kidney and brain CuZnSOD with a significant 

increase in brain, and insignificant increase in kidney and heart, gp91phox. In contrast, MnSOD, 

catalase, and GSHPx in the kidney, brain, and left ventricle were unchanged. Incubation with 

Pb-acetate did not alter SOD activity in vitro. Thus, animals with Pb-induced hypertension 

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exhibited oxidative stress, which was associated with mild upregulation of the superoxidegenerating enzyme NAD(P)H oxidase, with no evidence of quantitative SOD, catalase, or 

GSHPx deficiencies. 

Vaziri et al. (2000) demonstrated that induction of oxidative stress in normal animals 

(by feeding the GSH synthase inhibitor, buthionine sulfoximine, 30 mmol/L in drinking water 

for 2 weeks) led to an increase in blood pressure, a reduction of urinary NOx, a 3-fold decrease in 

liver GSH, and an increase in nitrotyrosine in kidney, aorta, heart, liver and plasma. 

Administration of vitamin E + ascorbic acid ameliorated hypertension and mitigated 

nitrotyrosine accumulation despite persistent GSH depletion. This experiment demonstrated the 

importance of GSH in protecting against the adverse effects of ROS accumulation in normal 

animals. Majority of the studies reported by Vaziri and co-workers indicated that low Pb 

exposure induced hypertension to be primarily mediated by ROS-induced depletion of NO. 

NO production, on the other hand, is stimulated, as shown by the increase in eNOS and iNOS. 

Enzymatic control of ROS levels by low Pb is achieved by upregulation of NAD(P)H oxidase 

with no decrease in SOD, catalase, or GSHPx, i.e., the enzymes that breakdown ROS. 

Scavengers of ROS ameliorate the elevated blood pressure, while the depletion of the 

endogenous methyl scavenger, GSH, increases blood pressure in normal animals. No studies 

have been done to date to address the question of why high-dose Pb administration does not lead 

to hypertension. 

Farmand et al. (2005) pursued enzymatic studies by activity measurements and measures 

of protein abundance in the rat kidney and aorta following the protocol of Gonick et al. (1997) 

whereby rats are fed Pb-acetate 100 ppm for 12 weeks. They demonstrated that the activities of 

CuZnSOD and catalase were increased by Pb administration in renal cortex and medulla, 

whereas GSHPx was unchanged. In the thoracic aorta, Pb exposure resulted in significant 

upregulation of CuZnSOD activity, while catalase and GSHPx activities were unchanged, 

CuZnSOD, MnSOD, and catalase protein abundance were likewise unchanged. However, 

guanylate cyclase protein abundance in the thoracic aorta was decreased. The authors suggested 

that the Pb-induced compensatory upregulation of CuZnSOD and catalase and the decrease in 

aortic guanylate cyclase may be related to Pb-induced hypertension. 

Gurer et al. (1999a) evaluated whether captopril, an ACE inhibitor, acted as an 

antioxidant in Pb-exposed F344 rats. Lead acetate was given in drinking water for 6 weeks. 

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Group I were the controls; group II received 1100 ppm Pb for 5 weeks and plain water during the 

week 6; group III received 1100 ppm Pb for 5 weeks and, during the week 6, received water 

containing captopril (10 mg/day). Blood Pb concentrations in the control group measured 

0.8 μg/dL; in the Pb treated group, 24.6 ± 20 μg/dL; in the Pb + captopril group, 23.8 ± 

1.6 μg/dL. MDA concentrations in liver, brain, and kidney were increased by Pb administration 

and reduced to or towards normal by the Pb + captopril treatment. GSH concentrations were 

decreased by Pb administration and restored by Pb + captopril treatment, whereas GSSG 

concentrations were increased by Pb administration and reduced by Pb + captopril treatment. 

Thus, this study showed that captopril was capable of augmenting the reducing capacity of the 

cells by increasing GSH/GSSG ratios without affecting blood Pb concentrations. 

McGowan and Donaldson (1987) examined total nonprotein sulfhydryl and GSH 

concentrations in liver and kidney as well as GSH-related free amino acid concentrations in liver, 

kidney, and plasma in 3-week-old Pb-treated (2000 ppm dietary lead) chicks. Cysteine, 

converted from methionine, is the rate-limiting amino acid in GSH formation. The availability 

of glutamate, cysteine, and glycine becomes important in the restoration of depleted GSH. 

GSH, nonprotein sulfhydryl groups, glycine, and methionine were increased versus controls in 

the liver, but only nonprotein sulfhydryl, glycine, cysteine, and cystathionine increased in the 

kidney. Plasma levels of cysteine, taurine, and cystathione were reduced. Thus, Pb, for 

short periods of time, increases GSH turnover. These and other studies are summarized in 

Table AX5-7.2. 

Effect of Lead on Selective Renal Enzyme Levels 

Effects of Lead on Renal NAG 

Dehpour et al. (1999) studied NAG release by the rat kidney perfused with Pb-acetate at 

10, 20, and 50 μg/dL for 120 min, or Pb + arginine (the substrate for NO), or Pb + L-NAME 

(an inhibitor of NOS). Lead acetate caused a time and concentration-dependent increase in 

enzymuria. Addition of arginine decreased, while addition of L-NAME increased, Pb-induced 

NAG release. Histologic studies showed damage to some of the proximal tubule epithelial cells 

in rats treated with 50 μg/dL Pb-acetate, damage that which was increased further by the addition 

of L-NAME. 

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Effect of Lead on Renal GST 

Two studies (Moser et al., 1995; Oberley et al., 1995) reported the effects of Pb 

administration on GST isoforms in developing rat kidney. In the first study (Moser et al., 1995), 

rats were treated either acutely (14- and 50-day old rats given three daily injections of Pb-acetate, 

114mg/kg) or chronically (Pb levels of 0, 50, 250, and 500 ppm in drinking water for 1, 2, 3, 4, 

and 7 weeks postnatal). Chronic treatment rats were also given a 0.66% low calcium diet or 

standard rat chow. Essentially all kidney cytosolic GSTs (Yb1, Yb2, Yp, Yc1, Yl, Yb3, Ya1, 

Ya2, Yk) increased in the acute experiment (1.1- to 6.0-fold). In the chronic experiment, all but 

one isoform (Yb3) increased, and these results were markedly exacerbated by placing the rats on 

a low-calcium diet (Yb1 and Yp increased >25-fold). In the second study (Oberley et al., 1995), 

pregnant rats were given 250 ppm Pb from conception until weaning, then pups received 500 

ppm from weaning until termination at either 3 or 7 weeks of age. By 7 weeks, proximal tubular 

cells showed intranuclear inclusions, tubular injury, and interstitial fibrosis. Creatinine 

clearances were reduced (0.55 + 0.05 versus 1.05 + 0.07 mL/min/100g; P< 0.001). Treatment 

with Pb also caused large increases in the immunoreactive protein of Yc, Yk, Yb1, and Yp GST 

subunits in proximal tubules but did not increase in the antioxidant enzymes CuZnSOD, catalase, 

and GSHPx. 

Another experiment that examined the effect of an acute dose of Pb as Pb-nitrate 

(100 μmol/kg IV) on GST levels in rat liver and kidney was reported by Planas-Bohne and 

Elizade (1992). Seventy hours after injection, there was a marked increase in GST activity in 

both organs, accompanied by induction of the isoenzyme GST 7-7 in the liver. 

The relationship between GST induction by acute exposure to Pb-acetate and oxidative 

stress was explored by Daggett et al. (1998). Rats in the 72-h and 7-day experimental groups 

received three consecutive daily injections of 114 mg/kg body weight of Pb-acetate. The level of 

kidney GST was increased at 3, 6, 12, and 24 h after injection, but MDA levels remained 

unchanged. Immunohistochemical markers of oxidative stress and NO production (MnSOD, 

eNOS, iNOS, and 4-hydroxy-2-nonenal) also did not change. The authors concluded that the 

GST changes were not the result of oxidative stress. 

Witzman et al. (1998) and Kanitz et al. (1999) utilized two-dimensional (2-D) gel 

electrophoresis to explore protein markers of Pb exposure. Witzman et al. (1998) gave three 

consecutive IP injections of Pb-acetate (114 mg/kg) to Sprague-Dawley rats, sacrificed them on 

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the fourth day, and subjected the cytosolic fraction of kidney homogenate to 2-D gel 

electrophoresis. Lead exposure caused detectable inductions in both GSTP1 and GSTM1 and 

caused quantifiable charge modifications in GSTP1. Kanitz et al. (1999) examined kidney 

protein expression in male rabbits injected with Pb-acetate (260, 360, or 100 μg/kg) designed to 

produce blood levels of 20, 40, or 80 μg/dL. Injections were given during weeks 6 to 10, 

followed by maintenance doses during study weeks 11 to 20. Kidney homogenates were 

subjected to 2-D electrophoresis. Significant quantitative changes occurred in 12 proteins in a 

dose-related manner. Four proteins cross-reacted with anti-rat GSTp1 (π-GST). Thus, both 

studies confirmed GST induction by lead. 

Daggett et al. (1997) examined the effects of triethyl Pb administration on the expression 

on GST isoenzymes and quinone reductase in rat kidney and liver. Fischer 344 rats were given 

one IP injection of triethyl Pb chloride (10 mg/kg body weight) and subsequent changes in 

enzyme expression were measured. There was a significant increase in GST activity in kidney; 

all GST subunits were significantly elevated, the largest increase being a 3.2-fold increase in 

GST Yb1. In the liver, injection of triethyl Pb-chloride resulted in decreased GST activity. 

The largest decrease in subunits was a 40% reduction in GST Ya1. The activity of quinone 

reductase was elevated 1.5-fold in kidney and 2.7-fold in liver within 14 days after the injection 

of triethyl Pb chloride. 

Effects of Lead on Renal Heme Enzymes 

Vij et al. (1998) explored Pb-induced alterations in male rats in the heme synthesizing 

enzymes, ALAD, and uroporphyrinogen I synthetase, and the effect of ascorbic acid 

supplementation in reversing these alterations. Lead-treated rats were injected IP with 20 mg/kg 

of Pb-acetate for 3 consecutive days and sacrificed 4 days later. A separate group of animals 

were administered 100 mg/kg ascorbic acid PO for 3 days following Pb administration. Blood 

Pb concentration was 4.67 ± 1.49 μg/dL in control rats, 16.59 ± 4.65 μg/dL in Pb-treated rats, 

and 7.83 ± 2.03 μg/dL in the Pb + ascorbic acid treated rats. Lead content of liver and kidney 

followed the same pattern. Blood ALAD activity was diminished in the Pb-treated rats but was 

restored in the Pb + ascorbic acid-treated rats. Uroporphyrinogen I synthetase activity followed 

the same pattern in blood but was not restored by ascorbic acid in liver. Total and nonprotein 

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sulfhydryl concentrations in blood were depressed by Pb administration and were not restored by 

ascorbic acid. However, levels in liver and kidney were restored by ascorbic acid. 

ALAD levels following administration of Pb were also investigated by Rodrigues et al. 

(1996) and Peixoto et al. (2004). The study by Rodrigues et al. (1996) examined rats from Pbexposed mothers that were maintained after weaning on either 0.5 or 4.0 mM Pb-acetate in 

drinking water for 21 days or 6 months. At sacrifice, ALAD activity was measured in kidney, 

forebrain, and cerebellum. Both 6-month-old Pb-exposed groups showed an increase in the 

kidney-to-body weight ratio, suggesting Pb-induced cell proliferation in the kidney. Blood Pb 

increased from 6.53 to 7.61 μg/dL in the 21-day-old exposed rats compared to 6-month-old 

controls. In the 0.5 mM Pb-treated group, blood Pb was 9.77 μg/dL in the 21-day-old and 

41.63 μg/dL in 6-month-old rats, while in the 4.0 mM group, blood Pb was 44.35 μg/dL in the 

21-day-old and 116.91 μg/dL in the 6-month-old group. ALAD activity was reduced at 

6 months in the forebrain of the 4.0 mM Pb-treated group, and in the kidneys at 6 months in both 

the 0.5 mM and 4.0 mM Pb-treated groups. The study by Peixoto et al. (2004) examined the in 

vitro sensitivity (IC50) to Pb of ALAD activity of brain, kidneys, and liver from suckling rats 

aged between 1 and 5, 8 and 13, or 17 and 21 days. The metal concentrations ranged from 0 to 

50 μM for Pb-acetate. Rats in the first age group showed the greatest sensitivity in all three 

organs. Liver was the least sensitive to ALAD inhibition by lead, while brain was the most 

sensitive. 

Effects of Lead on NaK-ATPase 

Fox et al. (1991) explored the effect of in vivo Pb exposure on adult rat retinal and kidney 

NaK-ATPase. Pups, exposed to Pb through the milk of dams consuming 0, 0.02, or 0.2% Pb 

solutions, had mean blood Pb concentrations of 1.2, 18.8, and 59.4 μg/dL at weaning, 

respectively, and 5 to 7 μg/dL as 90 to 100-day-old adults. Prior Pb exposure produced 

significant dose-dependent decreases in isolated retinal NaK-ATPase activity (!11%; !26%), 

whereas activity in the kidney was unchanged. In contrast, NaK-ATPase from both isolated 

control tissues was inhibited by Pb in vitro. The half-maximal inhibitory dose of Pb for retinal 

and renal NaK-ATPase was 5.21 H 10!7

 and 1.25 H 10!5 M, respectively. Retinal and renal NaKATPase were 20-fold and 1.1-fold more sensitive to inhibition by Pb than calcium. The 

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increased sensitivity of retinal, compared to renal, NaK-ATPase to inhibition following in vivo 

or in vitro Pb exposure may be related to their different α subunit composition. 

Kramer et al. (1986) had also explored the half-maximal inhibitory dose for Pb-chloride 

on renal cortical homogenate NaK-ATPase, and found it to be 7 H 10!5

 M. There was a 

competitive inhibition with regard to the substrate, ATP. Of several metals tested, Pb was 

second only to Hg in potency as a NaK-ATPase inhibitor. 

Weiler et al. (1990) studied the effect of Pb on the kinetics of purified (from hog cerebral 

cortex) NaK-ATPase and potassium-stimulated p-nitrophenylphosphatase (K-pNPPase), which is 

referred to as the E2 configuration of the NaK-ATPase system. IC50 for Pb was found to be 

8.0 H 10!5

 M for NaK-ATPase and 5.0 H 10!6 M for K-pNPPase. Inhibition of NaK-ATPase by 

Pb was found to be noncompetitive with respect to K, but competitive with respect to Na and 

MgATP. Inhibition of K-pNPPase by Pb was competitive with respect to K. 

Effects of Lead on Cardiovascular Hormones 

Effects of Lead on Endothelin 

Khalil-Manesh et al. (1993a) examined the role of endothelial factors in Pb-induced 

hypertension. They found that low Pb administration (0.01%), but not high Pb administration, 

(0.5%) resulted in increased blood pressure in rats treated for 12 months. In the low-Pb-treated 

rats, measurement of plasma endothelins-1 and -3 revealed that endothelin-3 concentration 

increased significantly after both 3 months (lead, 92.1 ± 9.7 vs. control, 46.7 ± 12.0 pmol/ml; 

p < 0.001) and 12 months (lead, 105.0 ± 9.3 vs. control, 94.1 ± 5.0 pmol/ml; p < 0.01), while 

endothelin-1 was unaffected. Plasma and urinary cyclic GMP concentrations, as a reflection of 

endothelium-derived relaxing factor (EDRF), decreased significantly at 3 months (plasma lead, 

1.8 ± 0.9 vs. control, 4.2 ± 1.6 pmol/ml; p < 0.001) and 12 months (plasma Pb 2.2 ± 0.7 

vs.control, 4.2 ± 0.9 pmol/ml; p < 0.001). High levels of Pb exposure did not result in 

hypertension, perhaps related to the fact that plasma concentrations of endothelin-1, endothelin3, and cyclic GMP were unaltered at 3 months, while their concentrations were significantly 

decreased at 12 months (plasma cyclic GMP at 12 months, 2.2 ± 0.7, lead, vs. 4.2 ± 0.9 pmol/ml, 

control; p < 0.001). Thus, the path to development of hypertension in low-Pb rats was thought to 

be through an increase in the concentration of the vasoconstrictor, endothelin-3, and a decrease 

in the vasodilator hormone, endothelium-derived relaxing factor or NO. 

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Novak and Banks (1995) studied the effects of Pb on the actions of endothelin. They 

measured renal clearances and mean arterial pressure in rats in which endothelin-1 was infused at 

110 ng/kg/min for 30 min. Lead was infused as Pb-acetate throughout the experiment at 0.48, 

4.8, and 24 nmoles/min. At the two higher doses, Pb significantly attenuated the endothelininduced increase in mean arterial pressure; Pb infused as 0.48 nmoles/min had no effect. 

An endothelin-induced decrease in GFR in control rats was completely blocked at the higher 

doses of lead. In additional experiments, calcium chloride was infused at 500 nmoles/min for 

105 min, and then calcium + Pb (4.8 nmoles/min) were infused for another 105 min. In these 

experiments, there was no Pb-induced inhibition of the mean arterial pressure response to 

endothelin. However, the GFR response to the peptide remained blocked. These data illustrate 

that Pb inhibits the cardiorenal actions of endothelin and that a calcium-related process is 

involved in the systemic, but not the renal, component of this inhibition. 

Effects of Lead on the Catecholamine System 

Carmignani et al. (2000) studied the effects of low Pb exposure (60 ppm of Pb-acetate), 

given for 10 months, on catecholamine and monoaminoxidase (MAO) levels. Plasma 

catecholamines were measured by HPLC and MAO in aorta, liver, heart, kidney, and brain by a 

histochemical technique. Plasma norepinephrine (NE) was increased by 104% and adrenaline by 

81% with no changes noted in L-DOPA and dopamine levels. MAO activity was increased in all 

organs. These workers ascribed the low Pb-induced hypertension in part to raised 

catecholamines levels. 

Tsao et al. (2000) and Chang et al. (2005) measured changes in the $-adrenergic system in 

Wistar rats during and following Pb exposure. In Tsao et al. (2000), rats were chronically fed 

with 0.01, 0.05, 0.1, 0.5, 1.0, and 2.0% Pb-acetate for 2 months. Plasma catecholamine levels 

were measured by HPLC; cAMP levels in heart, kidney, and aorta by radioimmunoassay; and 

$-adrenergic receptors in heart, kidney, and aorta membranes by a radio ligand binding assay. 

Blood Pb increased from 0.05 ± 0.05 μg/dL in controls to 85.8 ± 4.1 μg/dL in the 2.0% 

Pb-treated group. Plasma NE, but not E, levels increased with increasing Pb dosage. 

$-Adrenoreceptor density of heart and kidney decreased progressively with increasing Pb 

dosage, whereas kidney β-adrenoreceptor density increased up to the 0.5% Pb group and then 

remained constant. Unstimulated cAMP was constant in all tissues, but cAMP stimulated by 

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isoprotorenol was lowered progressively in aorta and heart and increased in kidney. Chang et al. 

(2005) continued these measurements in rats fed 2% Pb-acetate for 2 months then withdrawn 

from Pb for periods of 1, 2, 3, 4, 5, 6, and 7 months. Blood Pb levels, systolic and diastolic 

blood pressure levels, and plasma NE were reduced after cessation of Pb exposure. This 

occurred in conjunction with an increase in β-adrenoreceptor density in heart and aorta and a 

decrease in $-adrenoreceptor density in kidney. (See Table AX5-5.5 for experimental details on 

these studies). 

Effects of Chelators (Single or Combined) on Lead Mobilization 

Effects of DMSA Alone 

Cory-Slechta (1988) studied the mobilization of Pb by DMSA, following a 3- to 4-month 

exposure to 50 ppm of Pb-acetate in rats. These rats received an IP injection of saline or 25 or 

50 mg/kg of DMSA once daily for either 1, 2, 3, 4, or 5 days. Tissue analyses indicated that 

DMSA mobilized Pb from blood, brain, kidney, and liver with no loss noted from femur. 

Pappas et al. (1995) reported on Sprague-Dawley rats exposed to 550 or 1100 ppm Pbacetate for 35 days and treated either with Pb + DMSA or DMSA alone at varying dosage for 

21 days. Animals showed a dose-related reduction in Pb content of blood, brain, femur, kidney, 

and liver whether they received DMSA alone or Pb + DMSA. 

Smith and Flegal (1992) studied the influence of DMSA on the mobilization and 

redistribution of Pb in skeletal and soft tissue compartments of low-Pb-exposed female rats, 

using stable Pb isotope tracer techniques. Rats reared on a low-Pb diet received 206Pb-enriched 

drinking water for 1.5 days and then were chelated with a single IP injection of 0.11 mmol/kg 

dose of DMSA. Blood, kidney, brain, tibia, urine, and feces were collected 24 h after chelation 

and analyzed for Pb concentrations and for Pb isotope compositions. DMSA chelation 

significantly increased the diuresis of labile soft tissue Pb but not skeletal Pb. DMSA also 

appeared to cause the redistribution and input of a comparable amount of Pb to the skeleton and 

smaller relative amounts of Pb to the soft tissues of the chelated animals. 

Varnai et al. (2001) determined whether ongoing Pb exposure influenced the mobilization 

of Pb in suckling rats. Six-day-old Wistar rats were given Pb-acetate in a dose of 2 mg/kg/day 

for 8 consecutive days. A treated group received a daily dose of 0.5 mmol/kg of DMSA PO six 

times on days 1 to 3 and 6 to 8. DMSA efficiently reduced Pb concentration in carcass, liver, 

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kidneys, and brain by approximately 50% versus with untreated controls. The results indicate 

that DMSA is an efficient oral chelator, even when challenged with ongoing Pb exposure. 

Effects of Combined Chelators 

Flora et al. (1994) compared the combined use of CaNa2EDTA with DMSA on the 

distribution of Pb and Pb-related biochemical effects with the influence of each chelator used 

alone. Wistar rats were given 1000 ppm Pb as Pb-acetate in drinking water for 4 months. They 

were then treated for 5 days with either saline, DMSA, 25 mg/kg PO twice daily; CaNa2EDTA, 

75 mg/kg once daily; or DMSA, 25 mg/kg twice daily, all followed by a single daily IP injection 

of 75 mg/kg of CaNa2EDTA. Blood ALAD was reduced from 6.54 ± 0.18 nmol/min/ml in 

controls to 0.84 ± 0.10 in Pb-treated animals, with restoration to 3.03 ± 0.29 after combined 

treatment. Lead content in blood, liver, kidney, brain, and femur followed the same pattern: 

controls had 2.11 ± 0.23 μg/dL; Pb-treated, 46.0 ± 4.1 μg/dL; combined chelator-treated, 12.8 ± 

0.3 μg/dL. Treatment with either DMSA or CaNa2EDTA alone produced intermediate results. 

Tandon et al. (1994) reported similar results. 

Jones et al. (1994) compared the effects of DMSA, CaNa2EDTA, ZnNa2EDTA, and 

ZnNa3DTPA on Pb mobilization in mice. Mice were given 10 IP injections of Pb-acetate, 

5.0 mg/kg per injection. Three days after the final Pb injection, mice received one of the 

chelators. Injections were given at a dose of 1 mmol/kg/day IP for either 4 days or 8 days. 

At 8 days, DMSA was the most effective chelator in removing Pb from kidney and bone. 

CaNa2EDTA was more effective in removing brain lead. When animals were loaded with 

100 mg of Pb per kg body weight, DMSA remained more effective in removing Pb from kidney 

and bone while CaNa2EDTA was more effective in brain. 

Kostial et al. (1999) evaluated the efficacy of three chelating agents, administered either 

as monotherapy or as combined treatments, in suckling rats. Lead acetate (5 mg Pb/kg IP) was 

administered to 7-day-old rat pups on experimental day 1, and chelating agents was administered 

on experimental days 2 and 3. The pups were divided into untreated control, EDTA-treated, 

meso-DMSA-treated, racemic DMSA-treated, EDTA plus meso-DMSA-treated, and EDTA + 

plus racemic DMSA-treated. Rats were killed on experimental day 5 and tissue analyses were 

done for lead, zinc, and copper. Treatment with EDTA did not affect tissue lead, but it reduced 

zinc in the carcass and liver. Meso-DMSA reduced Pb in the kidneys and brain and did not 

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affect organ essential elements. Racemic DMSA most efficiently reduced Pb concentrations in 

the carcass, kidneys, and brain, but it also reduced zinc and copper in the liver and zinc in the 

kidneys. Combined treatments with EDTA did not improve the efficiency of either DMSA 

isoform in decreasing tissue lead, but they did reduce tissue zinc concentrations. The results 

suggest that meso-DMSA may be the treatment of choice in acute Pb poisoning in infants, 

reducing Pb without affecting trace elements. 

Malvezzi et al. (2001) evaluated the effects of DMSA, L-arginine (a precursor of NO), 

and the association of L-arginine and DMSA on tissue Pb mobilization and blood pressure levels 

in Pb-intoxicated rats. Tissue Pb levels and blood pressure evolution were evaluated in rats 

exposed to Pb (750 ppm in drinking water for 70 days), Pb + water for 30 more days , Pb + 

DMSA (50 mg/kg day, PO), L-arginine (0.6% in drinking water), the combination of L-arginine 

+ DMSA for 30 more days, and their respective matching controls. Lead exposure increased Pb 

levels in the blood, liver, femur, kidney, and aorta. Lead levels in tissue decreased after 

cessation of Pb administration, except in the aorta. Blood Pb decreased from 67.8 μg/dL to 

11.2 μg/dL in those subsequently treated with water, to 13.8 μg/dL in animals treated with 

Pb + DMSA, to 11.6 μg/dL in animals treated with Pb + L-arginine, and to 6.1 μg/dL in animals 

treated with Pb + L-arginine + DMSA. Lead mobilization from the aorta was only effective with 

the L-arginine/DMSA treatment. Lead administration increased blood pressure starting from the 

week 5, while L-arginine and DMSA treatments and the combination of L-arginine + DMSA 

decreased blood pressure levels of intoxicated rats; but these levels did not reach those of 

nonintoxicated rats. Treatment with L-arginine + DMSA was more effective than individual 

treatments in mobilizing Pb from tissues and in reducing the blood pressure of intoxicated rats. 

This paper lacks measurements of NO, which would have allowed the reader to more properly 

judge the mechanism of the effects of L-arginine administration. Furthermore, the dose of Pb 

was higher than in earlier studies that showed that DMSA was effective in lowering blood 

pressure. These and other studies are summarized in Tables AX5-7.3 and AX5-7.4. 

Effects of Other Metals on Lead Distribution 

Lead and Calcium 

Fullmer (1992) published a review of intestinal interactions of Pb and calcium. High 

affinity Pb binding to intracellular calcium receptors and transport proteins, as well as the 

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involvement of Pb in calcium-activated and calcium-regulating processes, are thought to provide 

a partial molecular basis for the cellular and systemic effects of lead. 

Maldonado-Vega et al. (1996) examined the intestinal absorption of Pb and bone 

mobilization during lactation. All experiments were started with 3-week-old female Wistar rats. 

Rats were impregnated at 16 weeks and were fed a 100 ppm solution of Pb-acetate for 158 or 

144 days (mid-lactation or before lactation). Rats were also exposed for only 14 days, from 144 

to 158 days (i.e., only during lactation). Nonpregnant rats from the same litter were exposed to 

Pb for periods equivalent to each of these groups. In the nonpregnant rats, blood Pb increased to 

27.3 μg/dL from 5.2 μg/dL in controls. Similarly, kidney Pb increased to 13.2 nmol/g from 

0.5 nmol/g, and bone Pb increased to 88.9 nmol/g from 0.9 nmol/g. ALAD activity decreased to 

410 nmol/h/ml from 1004 nmol/h/ml. Compared to nonpregnant rats, there was a moderate 

increase in blood Pb in the lactating animals whether the Pb was given to mid-lactation or up to 

the period before lactation. Similarly, when Pb was administered only during lactation, there 

was a much higher increase in blood Pb in the pregnant rats than in the nonpregnant rats. Bone 

Pb concentration increased when Pb was given only during lactation, whereas bone Pb decreased 

(compared to Pb-treated nonpregnant rats) when the Pb was given either before lactation or 

before and during lactation. The authors considered that resorption of Pb from bone was the 

main additional source of Pb during lactation. The data indicate that Pb stored in bone as a result 

of prior maternal exposure should be considered as a major source of self intoxication and of Pb 

in milk available to suckling pups. 

Lead and Cadmium 

Skoczynska et al. (1994) compared the effects of the combined exposure to Pb and 

cadmium to each metal singly on tissue composition of trace metals. Experiments were 

performed on 5- to 6-week-old male Buffalo rats given Pb-acetate (70 mg lead/kg body weight 

twice a week) and cadmium chlorate (20 mg Cd/kg body weight once a week) intragastrically for 

7 weeks either singly or in combination. Blood Pb in the control group was 5.1 μg/dL, compared 

to 29.6 μg/dL in the Pb-treated group. In contrast, the Pb + cadmium group showed a blood Pb 

of 37.4 μg/dL. After combined exposure to Pb and cadmium, the level of these metals in the 

liver and kidney was lower than after the single administration of Pb or cadmium. Exposure of 

the rats to cadmium resulted in an increase of kidney zinc and copper and liver zinc 

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concentrations; combined exposure to Pb + cadmium did not produce more extensive changes in 

tissue zinc and copper concentrations. 

Lead and Selenium 

Othman and Missiry (1998) examined the effect of selenium against Pb toxicity in male 

rats. Male albino rats were given a single dose of Pb-acetate (100 μmol/kg body weight) and 

sacrificed 3 or 24 h later. Another group of animals was pretreated with sodium selenite 

(10 μmol/kg body weight) 2 h before receiving Pb-acetate and sacrificed 24 h later. Selenium is 

well known as an antioxidant and cofactor for GSHPx. In this experiment, GSH content, 

GSHPx, SOD activities, and the products of lipid peroxidation (i.e., TBARS) were determined. 

It was found that lipid peroxidation was prevented and the reduction in GSH caused by Pb in 

liver and kidney was diminished by selenium. Lead-induced diminution in SOD activity and 

GSHPx activity was also returned to normal by selenium. 

Tandon et al. (1992) studied the effect of selenium supplementation during chelation of 

Pb with CaNa2EDTA. Rats were given Pb-acetate 10 mg/kg/day by gastric gavage for 6 weeks. 

This was followed by a 5-day treatment course of CaNa2EDTA, 0.3 mmol/kg IP or of 

CaNa2EDTA + sodium selenite, 0.5 mg/kg PO. Selenium had marginal effects on Pb removal 

by CaNa2EDTA in blood, liver, and kidney and similar effects on ALAD activity. 

Lead and Zinc 

Flora et al. (1989) examined the role of thiamine, zinc, or their combination in the 

prevention or therapy of Pb intoxication. Albino rats received the following treatments daily 

through gastric gavage for 6 days each week over a six-week period, 10 mg/kg of Pb as Pbacetate; or the same dose of Pb-acetate + thiamine (25 mg/kg) zinc sulfate (25 mg/kg) or 

Pb + thiamine and zinc. Rats that had been exposed to Pb only were additionally divided into 

four groups treated by gastric gavage daily for 6 days as follows: group I, water only; group II, 

thiamine only; group III, zinc only; and group IV, combined zinc + thiamine. The activities of 

blood ALAD, blood ZPP, blood lead, and urine ALA were determined. Blood Pb concentrations 

increased from 6.2 to 120.9 μg/dL, contrasting normal controls with Pb-treated animals. There 

was a slight reduction in blood Pb in animals treated with either thiamine or zinc and a greater 

reduction in animals treated with thiamine + zinc. In the post-Pb-exposure treatment group, 

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thiamine + zinc was also the most effective treatment. Liver and kidney Pb levels followed the 

same course but brain Pb was not reduced by treatment. Blood ALAD activity was decreased 

from a normal level of 7.63 μmol ALA/min/L to 0.69 in Pb-treated animals and restored to 7.52 

in Pb + thiamine + zinc-treated rats. ZPP was increased from 1.78 μg/g hemoglobin to 4.22 in 

Pb-treated animals and reduced to 2.50 in Pb + thiamine + zinc-treated animals. Urine ALA was 

increased from 0.07 to 0.24 mg/dL in Pb-treated animals and decreased to 0.17 in Pb + thiamine 

+ zinc-treated rats. Prevention was more effective than post-Pb-exposure treatment. This was 

thought to be due mainly to the decrease in the absorption of Pb in the GI tract in the presence of 

thiamine and/or zinc. 

Flora et al. (1994) explored the dose-dependent effects of zinc supplementation during 

chelation of Pb in rats. The chelator employed was CaNa2EDTA, whose toxic effects are known 

to be mainly due to the depletion of endogenous zinc and, possibly, copper and manganese. 

In this experiment, male Wistar rats were started on exposure to Pb-acetate, 10 mg/kg, 

administered through gastric gavage once daily for 56 days. Twenty-four hours later, the 

Pb-exposed animals were treated daily for 5 days as indicated: group I, saline ; group II, 

CaNa2EDTA 0.3 mmol/kg, IP, once daily for 5 days; group III, CaNa2EDTA + zinc sulfate, 

10 mg/kg, PO once daily for 5 days; and group IV, CaNa2EDTA + zinc sulfate, 50 mg/kg, 

PO once daily for 5 days. Blood ALAD decreased from 6.30 to 1.44 nmol/min/mL erythrocyte 

in Pb-exposed animals, with no change after CaNa2EDTA treatment and partial restoration after 

the CaNa2EDTA + zinc, 10 mg/kg treatment. There was no improvement following zinc, 

50 mg/kg. Lead concentration in blood increased from 4.6 μg/dL to 43.0 μg/dL in Pb exposed 

animals, decreasing to 22.5 μg/dL in CaNa2EDTA-treated animals and decreasing further to 

16.5 μg/dL in CaNa2EDTA plus zinc-treated animals. Zinc at 50 mg/kg led to an increase in 

blood Pb to 56.1 μg/dL. Changes in the liver follow the same pattern, while in the kidney, zinc 

increased the Pb levels further, and in the femur, zinc had no influence on Pb content. Blood 

zinc decreased from 6.1 to 5.7 μg/ml in Pb-exposed rats and further to 5.0 μg/ml in 

CaNa2EDTA-treated animals. There was an increase to levels of 6.6 μg/ml on the 10 mg/kg 

supplement of zinc and a further increase to 8.1 μg/ml on the 50 mg/kg zinc supplement. 

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Lead and Iron 

Hashmi et al. (1989) examined the influence of dietary iron deficiency, Pb exposure, or 

the combination of the two on the accumulation of Pb in vital organs of rats. Animals fed an iron 

deficient diet for 2 weeks were also subjected to orbital plexus puncturing twice a week to allow 

a Hb levels to decrease to 7 to 8 g/dL. Animals were thereafter treated for the next 6 weeks with 

iron deficient diets or iron-deficient diets + 0.1% Pb-acetate in drinking water. At the end of 

3 and 6 weeks, animals from each group were sacrificed. Feeding of an iron-deficient diet 

during Pb exposure enhanced the accumulation of Pb in soft tissues and flat bones. For example, 

liver Pb content was 0.75 μg/g in control animals, 8.43 in Pb treated animals, and 12.93 in irondeficient and Pb-treated animals. The sequence of events was similar in kidney, spleen, and 

femur except that the Pb content in femur was reduced in the iron deficient and Pb-treated group. 

Singh et al. (1991) conducted a study to ascertain the role of iron deficiency during 

pregnancy in inducing fetal nephrotoxicity in mothers exposed to lead. Rats were fed either a 

normal iron diet or an iron free synthetic diet for 15 days, followed by a diet containing half of 

the daily required iron (47 mg/100 g ferrous ammonium sulfate) for a further 15 days. Female 

animals were mated with healthy adult males. Lead doses of 250, 500, 1000, and 2000 ppm 

were given in drinking water during pregnancy and lactation. Fetuses were removed by 

Caesarean section on the 21st day. Maternal blood Pb levels in rats on an iron deficient diet 

were higher than those in rats on a normal iron diet at all levels of Pb dosing. Similarly, 

placental Pb levels were higher in animals on an iron-deficient diet as compared to a normal diet. 

Lead content in the fetuses were higher on the iron-deficient diet. Lead administration resulted 

in dose-dependent hydropic degeneration of renal proximal tubular cells in the fetuses. At a dose 

of 2000 ppm Pb with iron deficiency, more Pb accumulated in maternal blood, placenta, and 

fetuses and maximum pathological changes were seen in the fetal kidney as compared to other 

doses. 

Lead and Aluminum 

Shakoor et al. (2000) reported beneficial effects of aluminum on the progression of Pbinduced nephropathy in rats. Male albino rats were treated with water only or Pb-acetate 

(125 mg/kg) and/or aluminum chloride (50 mg/kg or 100 mg/kg) for a period of 90 days. 

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dependent manner. Aluminum also prevented Pb-induced increases in plasma creatinine levels 

of Pb- treated animals. The net deposition of Pb in kidneys was lower in animals that were given 

both Pb-acetate and aluminum chloride simultaneously. By day 90, plasma creatinine was 

1.26 mg/dL in control animals, 1.88 mg/dL in Pb-treated animals, and 1.34 and 1.44 mg/dL in Pb 

and aluminum-treated animals. Similarly, kidney Pb increased from 5.4 μg/g in control animals 

to 220.0 μg/g in Pb-treated animals and decreased to 138.5 and 98.9 μg/g in Pb and aluminum 

treated animals. These and other studies are summarized in Table AX5-7-5. 

5.7.4.4 Effect of Age on Lead Toxicity 

Han et al. (1997) examined the hypothesis that the high rate of bone remodeling during 

childhood and the consequent high calcium and Pb turnover would result in a substantial 

reduction in bone Pb stores, so that much of the Pb incorporated in bone during childhood does 

not persist into adulthood. They treated female Sprague-Dawley rats with 250 ppm of Pb in 

drinking water for 5 weeks beginning at 5, 10, or 15 weeks of age. Organ harvesting occurred 

4 weeks after the end of Pb exposure for all groups, as well as 8 and 20 weeks after cessation of 

Pb ingestion in the rats exposed beginning at 5 weeks of age. Organs examined were brain, 

kidney, liver, femur, and spinal column bone. Blood and organ Pb concentrations were 

significantly higher in the rats exposed beginning at 5 weeks of age than in those exposed 

beginning at 10 or 15 weeks of age. The results of this experiment rejected the hypothesis and 

suggested instead that a younger age at Pb exposure is associated with greater Pb retention and 

toxicity, even in the absence of continued Pb exposure. 

Garcia and Corredor (2004) examined biochemical changes in the kidneys after perinatal 

intoxication with Pb and/or cadmium. Lead acetate (300 ppm) and/or cadmium acetate (10 ppm) 

were administered in drinking water to pregnant Wistar rats from day 1 of pregnancy to 

parturition (day 0) or until weaning (day 21). The following kidney enzyme activities were 

determined: alkaline and acid phosphatases, Mg-ATPase, and NaK-ATPase. Blood Pb was 

measured in control pups as well as in pups exposed to lead at parturition and at weaning. 

Control pups showed 1.43 μg/dL of blood Pb compared to 31.5 μg/dL at day 0 and 22.8 μg/dL 

at day 21 in pups exposed to lead. In those rats receiving both cadmium and Pb, the blood Pb 

concentration was 23.2 μg/dL at day 0 and 13.2 μg/dL at day 21. Lead caused a significant 

inhibition of kidney alkaline phosphatase and kidney acid phosphatase. At parturition, Pb 

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intoxication produced a strong inhibition of NaK-ATPase (~80%) as well as of Mg-ATPase 

activities (~24%); whereas, when Pb was given in combination with cadmium, these inhibitory 

effects were attenuated. At weaning, Pb continued to produce a significant inhibition of MgATPase but had no effect on NaK-ATPase. Thus, simultaneous perinatal administration of both 

Pb and cadmium seemed to protect against the toxicity produced by Pb separately. 

Cory-Slechta (1990a,b) published two articles on the effects of old age on the disposition 

of lead. In the first study (1990a) male F344 rats, at the ages of 8 months (adult) and 16 months 

(old) were exposed to concentrations of 0, 250, or 500 ppm Pb-acetate in drinking water for 

7 months. At these Pb doses, prior studies had indicated that blood Pb levels ranged from 60 to 

90 μg/dL. Blood lead, ZPP, and urinary ALA levels were determined after both 3 and 7 months 

of exposure. Organ weights, tissue Pb concentrations, and urinary excretion of lead, calcium, 

copper, and zinc were examined after 7 months of exposure. Tissue Pb distribution was 

markedly altered in old rats: in bone and kidney, Pb levels were reduced while liver Pb was 

substantially increased. Blood Pb levels in adult and old rats were comparable at both 

measurement intervals, as was urinary Pb excretion at 7 months. Lead-induced elevation of ZPP 

exhibited differential changes between 3 and 7 months; values in adults declined while levels in 

old rats increased or remained unchanged. In the adult group, Pb exposure increased calcium 

excretion primarily at the 500 ppm exposure level. In contrast, Pb exposure decreased urinary 

calcium excretion in old animals at the higher exposure level. No effects of either age or Pb 

exposure were detected in the comparison of adult versus old urinary excretion of zinc or copper. 

In the second study, Cory-Slechta (1990b), young (21 days old), adult (8 months old), and 

(16 months old) rats exposed to 0, 2, or 10 mg of Pb-acetate/kg per day for a period of 

9.5 months were evaluated. Differences in the tissue distribution of Pb with age included lower 

bone levels, but increased concentrations in brain, liver, and kidney. Differences in blood Pb 

levels over the course of exposure were not remarkable. Thus, these effects did not appear to 

reflect an enhanced Pb absorption from the GI tract with age. Instead, the bone changes may 

reflect enhanced bone resorption with a concurrent decline in bone apposition with age, 

combined with altered patterns of urinary Pb excretion over time, i.e., elevated urinary Pb at 3 

and 6 months, but comparable Pb excretion at 9.5 months, as compared to young and adult rats. 

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5.7.5 Summary 

Highlights of the previous 1986 Pb AQCD and of studies done between 1986 and the 

present are outlined in this section. 

1986 Document 

• In animal studies, nuclear inclusion bodies were found in proximal tubules, identified as 

27 kDa or 32 kDa proteins in combination with lead. Subsequently, a 63 kDa Pb-binding 

cytosolic protein was described in kidney. 

• Swollen mitochondria, with diminished mitochondrial function, were found in the 

proximal tubules. 

• Renal ALAD was the same in Pb-treated animals as in controls when GSH was present, 

but was reduced when GSH was absent. 

Newer studies 

• Hyperfiltration, when compared to age- and sex-matched normal controls, was found in 

adults who had suffered from childhood Pb poisoning, in young occupationally exposed 

Pb workers in Korea, and in both low-Pb-treated rats and high-Pb-treated rats up to 

3 months of exposure. This is paralleled in animal experiments by an increase in 

kidney weight. 

• Various new urinary markers for Pb toxicity have been described. These include NAG, 

$2-microglobulin, α1-microglobulin, retinol binding protein, GST, lysozyme, γ-glutamyl 

transferase, alanine aminopeptidase, prostanoids, and brush border antigens. The 

literature on these markers is voluminous, but, on review, only GST and α1-

microglobulin seemed to be appropriate urinary markers. NAG, which has been most 

extensively investigated, appears in detailed-animal studies to be overly sensitive, 

increasing in low-Pb-treated animals, despite an absence of pathological changes on 

ultrastructural study. $2-Microglobulin, and possibly retinol binding protein, which are 

low-molecular weight proteins reabsorbed by the proximal tubule, appeared to be 

elevated only with high levels of blood Pb (>80 μg/dL). 

• Animal studies have implicated free radicals in the pathogenesis of Pb-induced 

hypertension and renal disease. A sequence of free radicals can be demonstrated in 

Pb-induced disease, as evidenced by an increase in superoxide radicals, hydroxyl 

radicals, hydrogen peroxide, and peroxynitrite, together with a diminution in GSH in 

liver, brain, and aorta. Nitric oxide is most commonly decreased (by free radicals) as is 

urinary cyclic GMP. Aortic guanylate cyclase is decreased. The enzyme responsible for 

an increase in the production of free radicals, NAD(P)H oxidase, is increased by Pb, 

whereas eNOS and iNOS, the enzymes involved in the production of nitric oxide, are also 

increased, attesting to the importance of free radical destruction of nitric oxide. 

Antioxidants reverse these changes and diminish blood pressure. 

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402(c) Economic Analysis Chapter 5 247
1 • Norepinephrine and epinephrine are increased by Pb administration, whereas 

2 $-adrenoreceptor density of heart and kidney are decreased. In a second study, 

3 norepinephrine, but not epinephrine, was increased by Pb. 

4 • Various antioxidants have been used in conjunction with chelators, to both remove Pb 

5 from tissue and to diminish free radicals. Taurine, lipoic acid, arginine, ascorbic acid, 

6 vitamin E, thiamine, tempol, and lazaroids have been used in conjunction with DMSA, 

7 all improving free radical diminution. 

8 • Metal combinations have also been employed to reduce tissue Pb and/or affect free 

9 radicals. Cadmium increases Pb in blood when both are given, but diminishes Pb in liver 

10 and kidney. Selenium, an antioxidant, improves both parameters, as does thiamine or 

11 L-lysine plus zinc. Iron deficiency increases intestinal absorption of Pb and the Pb 

12 content of soft tissues and bone. Aluminum decreases kidney Pb content and serum 

13 creatinine in Pb-intoxicated animals. 

14 • Age also has an effect on Pb retention. There is higher Pb retention at a very young age 

15 and lower bone and kidney Pb at old age, attributed in part to increased bone resorption 

16 and decreased bone accretion. 

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19 5.8 EFFECTS ON BONE AND TEETH 

20 5.8.1 Biology of Bone and Bone Cells 

21 By weight, bone is composed of 28% collagen fibers (predominantly type I collagen) and 

22 5% noncollagenous proteins (osteocalcin, osteonectin, and other proteoglycans), with crystals of 

23 hydroxyapatite [Ca10(PO4)6(OH)2] making up the remaining 67%. In addition to providing 

24 mechanical support for the body and protection of vital organs, the skeletal system also functions 

25 in a metabolic capacity. Historically, bones have been classified as either long or flat based on 

26 their appearance, with long bones including limb bones, e.g., the femur and humerus, and flat 

27 bones including the bones of the skull, sternum, pelvis, and scapula. Long and flat bones 

28 originate by distinct methods of formation, endochondral and intramembranous, respectively, 

29 with long bones eventually using both processes. In endochondral bone formation, a 

30 mineralized, cartilaginous matrix precedes the transition into true bone, while in 

31 intramembranous formation, the bone forming cells create bone directly without the cartilaginous 

32 template. 

33 Bone cells responsible for producing the bone matrix of collagen and ground substance 

34 are called osteoblasts. Several signaling factors including growth factors and hormones 

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influence pre-osteoblastic cells to differentiate into mature osteoblasts and subsequently 

synthesize and mineralize the extracellular matrix to form mature bone. It is during the process 

of bone mineralization that the Pb ion (Pb2+) can become incorporated by substituting for the 

calcium ion (Ca2+). The bone cells responsible for bone resorption are the osteoclasts. 

Osteoclasts, which are large and multicellular (4 to 20 cells), dissolve bone matrix and 

hydroxyapatite by synthesizing and releasing lysosomal enzymes and acidifying the extracellular 

surroundings. It is during the process of dissolving bone, or demineralization, that Pb stored in 

bone can be released locally and into the general system. 

Bone cell function may be compromised both directly and indirectly by exposure to Pb. 

Regulation of bone cells occurs by numerous local and systemic factors, including growth 

hormone (GH), epidermal growth factor (EGF), transforming growth factor-beta 1(TGF-$1), and 

parathyroid hormone-related protein (PTHrP). As discussed further below in this section, the 

presence of lead can potentially interfere with each of these factors. The bones of the skeleton 

serve as the primary reservoir for calcium and phosphate in the body and help to maintain 

homeostasis of these ions in the serum through bone turnover or remodeling. Vitamin D 

[1,25-(OH2)D3] maintains the normal range of calcium in the serum by increasing the efficiency 

of calcium absorption in the intestines and facilitating differentiation of stem cells into 

osteoclasts, which break down bone and mobilize calcium (and lead) stores. Parathyroid 

hormone (PTH), in turn, regulates the production of vitamin D in the kidney. Lead has been 

shown to interfere with the action of both of these hormones. Other substances influenced by 

lead and discussed in this section are alkaline phosphatase, an enzyme necessary for 

mineralization of bones and teeth, and osteocalcin, a noncollagenous protein whose spatial and 

temporal pattern of expression suggests a role in bone mineralization. Both substances are also 

markers for osteoblast activity and, by default, bone formation. Alkaline phosphatase is a 

potential carrier of ionic calcium and is capable of hydrolyzing inhibitors of mineral deposition 

such as pyrophosphates. 

5.8.2 Summary of Information Presented in the 1986 Lead AQCD 

Lead has been shown to become localized and accumulate in bones and teeth, with 

accumulation beginning as early as fetal development. Lead administered to rats as a single dose 

results in blood lead concentrations that are initially elevated, but rapidly fall as Pb is transferred 

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to bone or excreted. The dose of Pb administered does not apparently affect distribution to the 

various body compartments; however, the rate-limiting step in the clearance of Pb from rats and 

mice involves absorption into/clearance from the skeletal system. The loss of Pb from various 

organs and tissues follows first-order kinetics, except from bone. More absorbed Pb is retained 

by young animals compared with adult animals, leading to higher tissue levels. Moreover, once 

Pb is incorporated into the young animal’s body, the long-term rate of retention is greater than 

that of adults. In Pb-exposed animals, Pb is distributed subcellularly, preferentially to the 

nucleus and mitochondrial fractions. 

During lactation in mice, a redistribution of tissue Pb occurs (mobilization), resulting in 

the transfer of Pb and calcium from mother to pups via the milk, and subsequent overall loss of 

Pb in the mothers. Lead transfer to suckling rats via mother’s milk has been reported to be 

approximately 3% of the maternal body burden or more, if Pb exposure continues during 

lactation. Eight days after a single injection of Pb, the content of Pb in rabbit’s milk was 8-fold 

higher than the maternal blood level, suggesting Pb transfer can occur against a concentration 

gradient. Transplacental transfer of Pb from mother to fetus also occurs in various animals. 

In rats, a significant reduction of calcium in the diet leads to enhanced uptake of lead into 

the bones and other tissues. In general, an enhanced uptake of Pb into tissues is also seen in rats 

fed diets deficient in iron, zinc, copper, or phosphorus, and in the presence of low or excess 

vitamin D. 

5.8.3 Bone Growth in Lead-Exposed Animals 

Lead is readily taken up and stored in the bone of experimental animals, where it can 

potentially manifest toxic effects that result in stunted skeletal growth. In experiments reported 

since the 1986 Pb AQCD, Hac and Krechniak (1996) determined uptake and retention of Pb in 

bone from rats exposed to plain water or water containing Pb-acetate (41.7 to 166.6 mg/L) for 12 

to 16 weeks. After 4 weeks, the skeletal Pb in animals receiving the lowest dose was almost 

5 times higher than control animals (5.9 versus 1.2 μg Pb/g bone, respectively). Lead levels in 

bones from animals receiving 83.3 mg/L and 166.6 mg/L were dose-dependently higher at 11.7 

and 17.0 μg Pb/g bone, respectively, after 4 weeks of exposure. All bone Pb levels were 

maintained essentially in a steady state until the completion of exposure, when all animals were 

placed on control water. Approximately 64% of Pb remained in the bones of rats in the 

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83.3 mg/L exposed group at 64 days postexposure. Similarly, airborne Pb can be inhaled and 

subsequently incorporated into bone. Grobler and co-workers (1991) exposed 6-week-old rats to 

either “clean air” (0.05 μg Pb/m3

) or air containing 77 μg Pb/m3 and found significant 

differences in the amount of Pb incorporated into the alveolar bones of the animals. After 

70 days, a mean of only 0.2 μg Pb/g of bone dry mass was found in bone from control animals, 

while 16.9 μg Pb/g was present in bone from the 77 μg Pb/m3

 exposure group. Exposure to air 

containing 249 μg Pb/m3

 for 28 days or 1,546 μg Pb/m3 for 50 days, resulted in mean values of 

15.9 and 158 μg Pb/g dry weight of Pb incorporation into the bone, respectively, highlighting the 

fact that dose and length of exposure are determinates of amount of Pb contained in the bones of 

these animals. The uptake of Pb by bone has the potential for immediate toxic effects on the 

cellular processes occurring during bone growth, development, and maintenance, with the 

additional potential for delayed toxicity from release of stored Pb during periods of normal or 

accelerated bone remodeling. 

Numerous studies have examined growth suppression associated with developmental Pb 

exposure. Hamilton and O’Flaherty (1994) examined the effects of Pb on growth in female rats, 

and subsequently, on growth and skeletal development in their offspring. Administration of 

drinking water containing either 250 or 1,000 ppm lead to weaning female rats for 49 days 

produced no alteration in growth rate in these future dams. The rats were then bred, with Pb 

exposure continuing through parturition and lactation. Lead did not affect gestation time nor 

Day 1 suckling body weight, however, pup body weight and tail length were subsequently 

decreased in both exposure groups. A 10% increase in tibial growth plate width and disruption 

of chondrocyte organization were observed in offspring from the high exposure group. 

In male rats exposed to 100 ppm Pb in drinking water and a low calcium diet for up to one 

year, bone density was significantly decreased after 12 months, while rats exposed to 5,000 ppm 

Pb had significantly decreased bone density after 3 months (Gruber et al., 1997). Pb content of 

femurs was significantly elevated over the content of control rats at all time points (1, 3, 6, 9, 12 

months). Trabecular bone from the low dose animals was significantly decreased from 3 months 

forward. Young female rats exposed to 17 mg of Pb-acetate per kg of feed for 50 days showed 

no differences in the length of the femurs, but the mean length of the 5th lumbar vertebra was 

significantly decreased (Gonzalez-Riola et al., 1997; Escribano et al., 1997). The mean length of 

the femur growth plate cartilage was also significantly decreased in Pb-exposed animals. 

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In a dose-response study, Ronis et al. (1998a, 1998b) exposed pregnant rats to Pb-acetate 

in drinking water (0.05% up to 0.45% w/v) beginning at gestation Day 5 and continuing through 

weaning of offspring at Day 21. Early bone growth was significantly depressed in a dosedependent fashion in pups of all Pb-exposed groups, with growth suppression in male offspring 

considerably greater than in females. Significant decreases in plasma insulin-like growth factor 

and plasma sex steroids and increased pituitary growth hormone were also observed. This is 

somewhat in contrast to the findings of Camoratto and coworkers (1993), who reported low 

exposure to 0.2% Pb nitrate (125 ppm Pb) did not significantly affect growth, though males 

weighed significantly less than females. Between age 57 and 85 days Ronis et al. (1998b) noted 

that growth rates were similar in control and Pb-exposed pups, suggesting exposure at critical 

growth periods such as puberty and gender may account for differences in growth reported by 

various investigators. In a series of follow-up experiments (Ronis et al., 2001) reported a dosedependent decrease in load to failure in tibia from Pb-exposed (0.15% and 0.45% Pb-acetate in 

drinking water) male pups only. Hormone treatments (estradiol in females or L-dopa, 

testosterone or dihydrotestosterone in males) failed to attenuate Pb deficits during the pubertal 

period. Distraction osteogenesis experiments performed after stabilization of endocrine 

parameters (at 100 days of age) found decreased new endosteal bone formation and gap x-ray 

density in the distraction gaps of Pb-exposed animals (Ronis et al., 2001). 

Hamilton and O’Flaherty (1995) found Pb disrupted mineralization during growth when 

they implanted demineralized bone matrix subcutaneously into male rats. In the matrix that 

contained 200 μg Pb/g of plaque tissue, alkaline phosphatase activity and cartilage 

mineralization were absent, though calcium deposition was enhanced. Separate experiments 

found enhanced calcification and decreased alkaline phosphatase activity in rats implanted with a 

control (no Pb) matrix and given 1,000 ppm Pb in drinking water for 26 days. 

In summary, results from animal studies suggest Pb exposure is capable of adversely 

affecting bone growth and density, potentially manifesting its action through interference with 

growth and hormonal factors as well as toxic effects directly on bone. 

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5.8.4 Regulation of Bone Cell Function in Animals – Systemic Effects 

of Lead 

Lead may exhibit multiple complex systemic effects that ultimately could influence bone 

cell function. As discussed in the animal studies below, Pb can modulate alterations in calcium 

binding proteins and in calcium and phosphorus concentration in the blood stream, in addition to 

potentially altering bone cell differentiation and function by altering plasma levels of growth 

hormone and calciotropic hormones such as vitamin D3 [1,25-(OH2)D3] and parathyroid 

hormone. 

5.8.4.1 Hypercalcemia/Hyperphosphatemia 

Intravenous injection of Pb has been shown to produce both an acute hypercalcemia and 

hyperphosphatemia in rats (Kato et al., 1977). Injection of a relatively high dose of 30 mg/kg Pb 

resulted in maximum values of calcium (17 mg%) after one hour and maximum values of 

phosphorus (13.5 mg%) after 30 minutes. After 12 hours the levels of both calcium and 

phosphorus had returned to baseline levels. Histochemical examination demonstrated deposition 

of Pb into bone and dentin in the rats, suggesting a direct action of Pb on bone and/or teeth, 

ultimately displacing calcium and phosphorus and thereby producing hypercalcemia and 

hyperphosphatemia. 

5.8.4.2 Vitamin D [1,25-(OH2)D3] 

As discussed above, vitamin D [1,25-(OH2)D3] modulates the normal range of calcium in 

serum. In rats fed a low calcium or low phosphorus diet, ingestion of 0.82% Pb in the diet 

reduced plasma levels of 1,25-(OH2)D3; however, this effect is lost when a high calcium or 

normal phosphorus diet is given (Smith et al., 1981), suggesting a high calcium/phosphorus diet 

reduces the susceptibility of vitamin D system to the effect of Pb. No mobilization of calcium 

from bone or elevation of inorganic phosphorus was seen. Ronis et al. (2001) also reported no 

effects of Pb on plasma concentrations of vitamin D metabolites, 25-OH D3 or 1,25-(OH2)D3, in 

pubertal male rats exposed to either 0.15% or 0.45% Pb acetate in drinking water and maintained 

on an adequate diet. Fullmer (1995) found vitamin D function was severely compromised in 

young growing chicks given a diet low in calcium (0.1% calcium) for two weeks and then 

exposed to 0.2% or 0.8% Pb in their diet for an additional one or two weeks. In chicks 

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maintained on an adequate diet (1.2% calcium), exposure to 0.2% or 0.8% Pb in the diet resulted 

in increased plasma levels of 1,25-(OH2)D3 as well as significantly increased intestinal 

Calbindin-D protein [a calcium binding protein induced by 1,25-(OH2)D3] and its associated 

mRNA, when compared with unexposed control chicks. Levels of intestinal Calbindin-D mRNA 

and protein and plasma levels of 1,25-(OH2)D3 were elevated during the first week of Pb 

exposure to chicks fed a diet deficient in calcium, but were significantly decreased by the second 

week of Pb exposure. The study suggested Pb was mediating its effect through 1,25-(OH2)D3, 

rather than via a direct action on the Calbindin-D protein. Follow up studies by Fullmer et al. 

(1996) confirmed dose dependent increases in serum 1,25-(OH2)D3 levels (and Calbindin-D 

protein and mRNA) with increasing dietary Pb exposure (0.1% to 0.8%) in similar experiments 

performed on Leghorn cockerel chicks fed an adequate calcium diet. 

5.8.4.3 Parathyroid Hormone 

At least one animal study has associated experimental Pb exposure with secondary 

hyperparathyroidism. Szabo et al. (1991) exposed Wistar Kyoto rats to either 1% Pb acetate in 

water for a short term (10 weeks) or varying concentrations (0.001 to 1% Pb acetate) for a longer 

term (24 weeks) to assess the influence of Pb on the interaction of the parathyroids with 

1,25-(OH2)D3. Short term administration of 1% Pb resulted in significant increases in bone Pb; 

however, total serum calcium and ionized serum calcium were significantly decreased, as 

compared to controls. Circulating levels of 1,25-(OH2)D3 were also decreased, though the rats 

were maintained on a normal calcium diet (0.95%). Parathyroid glands from rats exposed short 

term to Pb were significantly increased in size over those in control animals (178 μg per gland 

versus 96 μg per gland) and specific binding of 1,25-(OH2)D3 to parathyroid and intestinal tissue 

was increased. Likewise, long term administration of 1% Pb resulted in significant increases in 

bone Pb and normalized parathyroid gland weights, and a significant decrease in the level of 

1,25-(OH2)D3. In the long term study, a dose-dependent increase in parathyroid weight occurred 

with increasing exposure to Pb in drinking water. The authors concluded the secondary 

hyperparathyroidism was associated with, and/or a result of, the hypocalcemia and decreased 

1,25-(OH2)D3 levels secondary to Pb exposure. 

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5.8.4.4 Growth Hormone 

As discussed in Section 5.8.3, exposure to Pb has been associated with altered bone 

metabolism and decreased growth and skeletal development (Hamilton and O’Flaherty, 1994, 

1995; Gruber et al., 1997; Gonzalez-Riola et al., 1997; Escribano et al., 1997; Ronis et al., 

1998a,b, 2001; Camoratto et al., 1993), suggesting perturbation of one or more endocrine factors 

such as growth hormone. To examine the effect of exposure to low-level Pb on pituitary growth 

hormone release, Camoratto et al. (1993) exposed pregnant female rats to 0.02% Pb nitrate 

(125 ppm Pb) beginning on gestational day 5 and continuing in pups through postnatal day 48. 

Basal release of growth hormone from control and Pb-exposed pups at age 49 days was not 

significantly different. Growth hormone releasing factor-stimulated release of growth hormone 

from pituitaries of Pb-exposed pups was smaller than the stimulated release of growth hormone 

from pituitaries of control animals (75% increase over baseline vs. 171% increase, respectively), 

but the difference did not achieve significance (p = 0.08). Growth hormone content of the 

pituitary glands was also not influenced by Pb exposure. Ronis et al. (1998b) reported similar 

findings in rat pups exposed to 0.05%, 0.15%, or 0.45% Pb acetate in drinking water from 

gestation day 5 through postnatal day 85, with the exception being significantly elevated 

pituitary growth hormone levels at postnatal day 55. Taken together, these rat studies suggest 

that differences in growth seen with Pb exposure may not necessarily be the result of alterations 

in secretion of growth hormone. 

5.8.5 Bone Cell Cultures Utilized to Test the Effects of Lead 

5.8.5.1 Bone Organ Culture 

In an early bone organ culture study utilizing incorporated radioactive Pb into fetal radii 

and ulnae, Rosen and Wexler (1977) reported release of Pb as the concentration of calcium in the 

media was reduced or with addition of parathyroid hormone, but that calcitonin inhibited the 

release of Pb as expected, verifying the capacity of this model system. The bone organ system 

was subsequently used to evaluate the efficacy of Pb chelating agents, such as D-Penicillamine 

and CaNa2EDTA (Rosen and Markokwitz, 1980; Rosen et al., 1982). 

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5.8.5.2 Primary Cultures of Osteoclasts and Osteoblasts 

The ability to isolate primary cultures of osteoclasts and osteoblasts from mouse calvaria 

provided an additional experimental model system to study the effects of Pb on specific bone 

cells. Using isolated osteoclasts and osteoblasts, Rosen (1983) reported that uptake of 

radioactive Pb by osteoclasts was rapid, almost linear, while osteoblasts showed very little 

increase in uptake of Pb at increasing media concentrations. Physiological concentrations of 

parathyroid hormone markedly increased uptake of Pb and calcium by osteoclast cells and, once 

loaded with Pb, osteoclasts were capable of releasing Pb slowly into the media. Further kinetic 

analysis of cultured osteoclastic bone cells indicated that cellular Pb is primarily associated with 

the mitochondrial fraction (~78%) and that this Pb is readily exchangeable with the outside 

media (Pounds and Rosen, 1986; Rosen and Pounds, 1988). Experiments conducted to 

characterize the steady-state kinetic distribution and metabolism of calcium and Pb supported the 

concept that the two elements are metabolized similarly in the osteoclasts cells (Rosen and 

Pounds, 1989). 

5.8.5.3 Rat Osteosarcoma Cell Line (ROS 17/2.8) 

In recent years, the rat osteosarcoma cell line ROS 17/2.8 has been used extensively to 

investigate the influence of Pb on various cellular processes and kinetics within these osteoblastlike cells. The ROS 17/2.8 cell model is useful in that the cells are capable of producing 

osteocalcin (a bone protein important for proper bone mineralization), have high alkaline 

phosphatase activity (an enzyme normally associated with mineralization of cartilage), possess 

vitamin D receptors, and respond to parathyroid hormone. In comparisons of cellular lead 

toxicity and metabolism between primary cell culture from mouse calvaria and the rat 

osteosarcoma cell line, Long and coworkers (1990a) reported remarkable similarities in the 

profile of radiolabeled Pb kinetics and intracellular Pb distribution. Using this cell line, Schanne 

and coworkers (1989) simultaneously measured intracellular Pb and calcium concentrations and 

found 5 and 25 micromolar Pb produced sustained 50% and 120% (respectively) increases in 

intracellular calcium over a 5 hour period, and that measurable entry of Pb into the cells could be 

demonstrated at the higher concentration. These findings advanced the hypothesis that 

perturbation of intracellular calcium concentration may be the mechanism of Pb bone toxicity. 

Schirrmacher and coworkers (1998) reported that calcium homeostasis is upset within 

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20 minutes of its addition to calvarial bone cell culture. Their results suggested that the calciumATPases of intracellular stores were potentially poisoned by Pb entering the cells. Wiemann et 

al. (1999) demonstrated that Pb was also capable of interfering with the calcium release activated 

calcium influx (CRAC) in calvarial bone cell cultures. Pb was found to partially inhibit the 

influx of calcium into the bone cells, plus influx of Pb into the cells was greatly enhanced 

(2.7 fold) after CRAC had been induced. These effects of Pb were found to be independent of 

any inhibitory effect on calcium-ATPase. 

Miyahara et al. (1995) performed a series of experiments in 45Ca-labeled bone organ 

culture to determine whether the Pb-induced hypercalcemia was the result of the active process 

of biological bone resorption or simply physiochemical mineral dissolution. Lead introduced 

into the culture at concentrations of 50 μM and above stimulated the release of calcium and 

hydroxyproline into the medium, however no release was elicited from bones inactivated by 

freezing and thawing. Pb-stimulated 45Ca release was inhibited by eel calcitonin, bafilomycin 

A1, and scopadulcic acid B, suggesting the release was secondary to osteoclastic bone resorption. 

Further evidence to support this conclusion came from experiments examining the influence of 

two inhibitors of cyclooxygenase on Pb-induced bone resorption. Lead was found to stimulate 

prostaglandin E2 release and in cultures, there was a high correlation between prostaglandin E2 

released into the media and 45Ca release. In the presence of cyclooxygenase inhibitors (blocking 

prostaglandin synthesis), Pb-stimulated 45Ca release was inhibited suggesting the mechanism of 

bone resorption in this instance was via a prostaglandin E2-mediated mechanism. 

Lead has been demonstrated to directly impair production of osteocalcin by ROS 17/2.8 

cells by 70% after 24 hours of exposure to 25 micromolar Pb (Long et al., 1990a). The resulting 

decrease in cell proliferation is in agreement with similar studies by Sauk et al., 1992). 

Interestingly, exposure of dental pulp cells, which also produce osteocalcin, to a similar 

concentration of Pb reduced osteocalcin production by 55% after 12 hours of exposure 

(Thaweboon et al., 2002). Vitamin D has been shown to increase osteocalcin production in ROS 

17/2.8 cells; however, Pb inhibited the vitamin D-stimulated osteocalcin production in a dosedependent manner from 0 up to 25 micromolar concentrations, plus was shown to be capable of 

attenuating basal (non-vitamin D-stimulated) osteocalcin production (Long et al., 1990a). Lead 

(5 to 20 micromolar) inhibition of vitamin D stimulation of osteocalcin in ROS cells was also 

reported by Guity and coworkers (2002). Later studies suggested that Pb acts by inhibiting 

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vitamin D activation of calcium channels and interferes with regulation of calcium metabolism 

(Schanne et al., 1992), though apparently this effect is not mediated via PKC (Guity et al., 2002). 

Angle and coworkers (1990) reported that 24 hours of incubation with vitamin D (10 nM) was 

capable of evoking a 4 to 5 fold increase in osteocalcin production and a 100% increase in 

cellular alkaline phosphatase activity in ROS cells. Osteocalcin production and cellular DNA 

contents were increased 100% and 20% respectively by addition of insulin-like growth factor 

(92.5 ng/mL). Consistent with a toxic effect of Pb on osteoblast function, the addition of 1 to 

10 μM Pb to the system inhibited both basal and stimulated osteocalcin secretion, alkaline 

phosphatase activity and DNA contents (Angle et al., 1990). Dose- and time-dependent 

reduction in alkaline phosphatase activity with Pb exposure (2 to 200 micromolar) has also been 

reported in osteosarcoma cells, along with parallel reductions in steady state levels of alkaline 

phosphatase mRNA levels (Klein and Wiren, 1993). No effect on cell number or DNA and 

protein synthesis was seen at these levels of Pb exposure. 

Though the exact mechanism of Pb toxicity on osteocalcin was unclear, Pb was known to 

inhibit some of the functional properties of osteocalcin including inhibition of osteocalcin 

adsorption to hydroxyapatite. An investigation by Dowd and coworkers (1994) utilized the 

ability of osteocalcin added to a solution of 43CaCl2 to broaden 43Ca resonance, as a method to 

examine binding of calcium to osteocalcin and the influence of Pb on calcium binding. It was 

determined that the dissociation constant of calcium for osteocalcin was 7 micromolar, while the 

dissociation constant for Pb was determined by competitive displacement to be 2 nM, indicating 

more than three orders of magnitude tighter binding of Pb than calcium to osteocalcin and the 

likelihood that even submicromolar levels of free Pb would significantly inactivate osteocalcin. 

Circular dichroism indicated that upon binding, Pb induces a similar structural change in 

osteocalcin to that found with calcium binding, but the binding with Pb occurs at 2 orders of 

magnitude lower than with calcium (Dowd et al., 2001). Similarly, hydroxyapatite binding 

assays indicated Pb causes an increased absorption to hydroxyapatite that is similar to calcium, 

but again at 2 to 3 orders of magnitude lower concentration, potentially leading to low bone 

formation rates and/or density (Dowd et al., 2001). 

Besides perturbation of calcium metabolism, Pb has been shown to reduce intracellular 

free magnesium concentrations by 21% in osteosarcoma cells incubated in 10 micromolar Pb for 

2 hours (Dowd et al., 1990). Under these same conditions, the unidirectional rate of ATP 

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synthesis (i.e. Pi to ATP) was reduced by a factor greater than 6 over control cultures. 

Impairment of both of these processes by Pb could ultimately influence bone growth and 

development. 

Lead has also been show to perturb Epidermal Growth Factor’s (EGF) control of 

intracellular calcium metabolism and collagen production in ROS cells (Long and Rosen, 1992). 

EGF is known to activate protein kinase C (PKC), resulting in increased calcium influx and 

through this mechanism, decreased collagen synthesis. Incubation of ROS cells with 

5 micromolar Pb and 50 ng/mL EGF for 20 hours resulted in a 50% increase in total cell calcium 

versus the calcium increase seen in cells treated with EGF alone, suggesting more than one site 

of action is involved in calcium messenger perturbation. A similar finding was reported by Long 

and coworkers (1992) who found that treatment of Pb (25 micromolar) intoxicated osteosarcoma 

cells with parathyroid hormone (PTH, 400 mg/mL) resulted in a greater increase in cell calcium 

than with either treatment alone. Supplementary inhibition of collagen synthesis has also been 

reported with the addition of 25 micromolar Pb plus 50 ng/mL EGF, suggesting more than one 

site of action for the effect of Pb on collagen synthesis (Long and Rosen, 1992). Additional 

study has since suggested that Pb activates PKC in ROS cells and that PKC mediates the rise in 

intracellular calcium (Schanne et al., 1997). The observation that calphostin C, an inhibitor of 

PKC, prevented the Pb-induced elevation of intracellular calcium supported this hypothesis, as 

did the fact that free Pb at concentrations of 10-11 to 10-7 M directly activated PKC in the absence 

of activating concentrations of calcium. This would suggest Pb is capable of activating PKC at 

concentrations approximately 3,000 times lower than calcium. 

Finally, Pb has been shown to be capable of inhibiting secretion of osteonectin, a bone 

related protein found in areas of active morphogenesis (Sauk et al., 1992). Treatment of ROS 

17/2.8 cells with lead (4.5 X 10-6 M to 4.5 10-7 M) demonstrated that intracellular osteonectin 

levels were actually enhanced; however, the secretion of osteonectin into the media was delayed 

or inhibited. Protein production of collagen and the endoplasmic reticulum protein, Asp47, were 

relatively unaffected by Pb at these concentrations. The intracellular retention of osteonectin 

coincided with a decrease in levels of osteonectin mRNA, suggesting the processes associated 

with translation and secretion of osteonectin are sensitive to Pb. 

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5.8.5.4 Human Osteosarcoma Cells (HOS TE 85) 

Evidence exists that Pb is directly osteotoxic to bone cells in culture. Studies examining 

the sensitivity of human osteosarcoma cells (HOS TE 85) to Pb found proliferation of the cells 

was inhibited at Pb concentrations of 4 μmol/l, while cytotoxicity occurred at the 20 μmol/l Pb 

concentration (Angle et al., 1993). In parallel experiments, rat osteosarcoma cells (ROS 17/2.8) 

were found to be somewhat less sensitive to the effects of Pb with inhibition of proliferation 

occurring at 6 μmol/l Pb concentration and cytotoxicity at Pb concentrations over 20 μmol/l. 

5.8.5.5 Chick Chondrocytes 

The effects of Pb on cartilage biology have been examined in isolated avian chondrocytes 

obtained from 3 to 5 week old chicks (Hicks et al., 1996). Exposure to media containing 0.1 to 

200 μM Pb acetate or chloride were found to decrease thymidine incorporation, suppress alkaline 

phosphatase, and suppress both type II and type X collagen expression at the mRNA and protein 

levels. Cytotoxicity of the cultures from Pb exposure was dismissed as proteoglycan synthesis 

was found to be augmented, suggested Pb selectively inhibits specific aspects of the chondrocyte 

growth plate. Using the avian chondrocyte model, Zuscik et al. (2002) similarly reported Pb 

exposure (1 to 30 μM) causing a dose-dependent inhibition of thymidine incorporation into the 

growth plate, with a 60% reduction in proliferation at the highest concentration. Addition of 

TGF-$1 and PTHrP, regulators of growth plate, both separately stimulated thymidine 

incorporation, an effect that was dose-dependently blunted in the presence of Pb. At the highest 

Pb concentration (30 μM), inhibition was significantly less in the chondrocytes treated with Pb + 

TGF-$1 (24%) and Pb + PTHrP (19%) than for Pb alone (60%), suggesting the interaction of Pb 

with these growth factors may be independent of its primary action on the chondrocyte cells. 

Support for a direct action of Pb on these growth regulators is supported by the finding that 

normal TGF-β1 and PTHrP suppression of type X collagen expression is significantly reversed 

in a dose-dependent fashion in the presence of Pb. This effect evidently was not mediated by 

BMP-6 (Bone Morphogenic Protein), an inducer of terminal differentiation known to partially 

reverse the inhibitory effect of PTHrP, because in the presence of Pb, PTHrP significantly 

suppressed BMP expression, while combined exposure to Pb and TGF-β1 increased BMP 

expression approximately 3-fold. Further experiments performed on chick sternal chondrocyte 

cultures, utilized PTHrP responsive (AP-1) and non-responsive (NF-қB) reporter constructs to 

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examine potential effects of Pb on signaling. While having no effect on the basal activity of the 

AP-1 reporter, Pb dose-dependently enhanced PTHrP induction of the responsive AP-1 reporter. 

Lead dose-dependently inhibited the basal activity of the non-PTHrP responsive, NF-қB 

reporter. Taken together, these studies demonstrate that Pb has an inhibitory effect on the 

process of endochondral bone formation and that the effects of Pb are likely from its modulation 

of growth factors and second messengers involved in cell signaling responses. 

5.8.6 Bone Lead as a Potential Source of Toxicity in Altered 

Metabolic Conditions 

Lead is avidly taken up by bone and incorporated into bone matrix, where a substantial 

amount can remain over the lifetime of an organism. The uptake and incorporation of Pb into 

bone during acute exogenous exposures may be of short term benefit by limiting the exposure of 

other, more sensitive tissues; however, this does not eliminate Pb from the system. Subsequent 

release of Pb from this endogenous storage can produce a lifetime of steady, low level Pb 

exposure during periods of normal bone remodeling, while elevated Pb release during times of 

increased bone metabolism and turnover (i.e., pregnancy, lactation, menopause, and 

osteoporosis) can elevate blood levels of Pb significantly, potentially to toxic concentrations. 

This is especially relevant when there is concurrent exogenous exposure to Pb, as current blood 

Pb levels are a composite of current and past Pb exposure. Of greater concern is the mobilization 

of Pb during pregnancy and subsequent transfer to the developing brain of the fetus across the 

poorly developed blood:brain barrier. Maternal Pb also appears in breast milk, providing further 

exposure of the infant to Pb during lactation. Currently, the majority of animal studies 

examining mobilization of Pb from bone stores have focused principally on elevation of Pb 

levels or transfer of Pb, rather than reporting toxic effects associated with these exposures. Note 

that in most instances the mobilization and elimination of Pb is much faster in laboratory animals 

than in humans. For example, as discussed in Section 5.8.3, Hac and Kruchniak (1996) reported 

approximately 64% of Pb given over a 12 week period remained in the bones of rats 64 days post 

exposure. Therefore, the caveats of experiments performed in small animals, especially when 

examining mobilization of Pb stores, must be taken into consideration. 

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5.8.6.1 Pregnancy and Lactation 

Pregnancy, and to a much greater extent, lactation, place significant calcium demands on 

the mother as she provides all the necessary calcium requirements of the developing fetus/infant. 

During these times of metabolic stress, increased demineralization of maternal bone occurs to 

supplement demand, unfortunately accompanied by the concurrent mobilization and release of 

Pb stored in the maternal skeleton from past exposure. Studies in several animal models have 

shown that maternal bone Pb can be mobilized during pregnancy and lactation, ultimately being 

transferred to the fetus during gestation and breast feeding. Keller and Doherty (1980) 

administered radiolabeled Pb drinking water (200μg/mL) to female mice for 105 days prior to 

mating or 105 days prior to mating and during periods of gestation and lactation (total 160 days 

of exposure). The results suggested very little Pb was transferred from mother to fetus during 

gestation, however, Pb transferred in milk and retained by the pups accounted for 3% of the 

maternal body burden of those mice exposed to Pb prior to mating only. The amount of Pb 

retained in these pups exceeded that retained in the mothers, suggesting lactation effectively 

transfers Pb burden from mother to suckling offspring. Transfer of Pb from mothers was 

significantly higher when Pb was supplied continuously in drinking water, rather than terminated 

prior to mating. Considerably higher lactational transfer of Pb from rat dams compared to 

placental transfer has also been reported (Palminger Hallén et al., 1996). Continuous exposure 

of rat dams to Pb until day 15 of lactation resulted in milk Pb levels 2.5 times higher than in 

whole blood, while termination of maternal Pb exposure at parturition yielded equivalent blood 

and milk levels of Pb, principally from Pb mobilized from maternal bone. 

Using rats chronically exposed to Pb in drinking water, Maldonado-Vega et al. (1996) 

studied intestinal absorption of Pb, its mobilization, and redistribution during lactation. In rats 

exposed to Pb 144 days prior to lactation, the process of lactation itself elevated blood Pb and 

decreased bone Pb, indicating mobilization of Pb from bone as there was no external source of 

Pb during the lactation process. Rats exposed to Pb for 158 days (144 days prior to lactation and 

14 days during lactation) also experienced elevated BLLs and loss of Pb from bone. Lead 

exposure only during the 14 days of lactation was found to significantly increase intestinal 

absorption and deposition (17 fold increase) of Pb into bone compared to non-pregnant rats, 

suggesting enhanced absorption of Pb takes place during lactation. As in other previous studies, 

the highest concentration of Pb in bone was found in non-pregnant non-lactating control animals, 

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with significantly decreased bone Pb in lactating rats secondary to bone mobilization and transfer 

via milk to suckling offspring. Follow-up studies examining the influence of dietary calcium 

found when calcium was altered from the normal 1% to 0.05%, bone calcium concentration 

decreased by 15% and bone Pb concentration decreased by 30% during the first 14 days of 

lactation (Maldonado-Vega et al., 2002). In non-lactating rats on the 0.05% calcium diet, there 

were also decreases in bone calcium, but neither incremental bone resorption nor Pb efflux from 

bone, suggesting the efflux from bone during lactation was related to bone resorption. Of 

interest, enhancement of calcium (2.5%) in the diet of lactating rats increased calcium 

concentration in bone by 21%, but did not decrease bone resorption, resulting in a 28% decrease 

in bone Pb concentration and concomitant rise in systemic toxicity. In both studies, the authors 

concluded that Pb stored in bone should be considered a major source of self-intoxication and of 

exposure to suckling offspring. 

In one of few studies showing a toxic effect, Han et al. (2000) demonstrated adverse 

effects in rat offspring born to females whose exposure to Pb ended well before pregnancy. Five 

week-old-female rats had been given Pb-acetate in drinking water (250 mg/mL) for five weeks, 

followed by a one month period without Pb exposure before mating. To test the influence of 

dietary calcium on Pb absorption and accumulation, some pregnant rats were fed diets deficient 

in calcium (0.1%) while others were maintained on a normal calcium (0.5%) diet. As expected, 

all Pb-exposed dams and pups had elevated blood Pb levels; however, pups born to dams fed the 

diet deficient in calcium during pregnancy had higher blood and organ Pb concentrations 

compared to pups from dams fed the normal diet. Significantly, pups born to Pb-exposed dams 

had lower mean birth weights and birth lengths than pups born to non-Pb-exposed control dams 

(p < 0.0001), even after confounders such as litter size, pup sex, and dam weight gain were taken 

into account. The authors concluded that while increases in dietary calcium during pregnancy 

are capable of reducing Pb accumulation in the fetus, they cannot prevent the decreases in birth 

weight and length associated with pre-maternal Pb exposure and subsequent mobilization. This 

has relevance in human pregnancy, as many women experience exposure to Pb during their 

lifetimes (especially during childhood) and mobilization of the Pb from bone stores during 

pregnancy could present toxic complications. 

Within the last decade, an invaluable method to explore the kinetics of Pb transfer from 

bone to blood has been developed and evaluated (Inskip et al., 1996; O’Flaherty et al., 1998). 

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The method utilizes recent administration of sequential doses of Pb mixes enriched in stable 

isotopes ( 204Pb, 206Pb, and 207Pb) to female cynomolgus monkeys (Macaca fascicularis) that 

have been chronically (1,300 to 1,500 μg Pb/kg body weight per day for ten years or greater) 

administered a common Pb isotope mix. The stable isotope mixes serve as a marker of recent, 

exogenous Pb exposure, while the chronically administered common Pb serves as a marker of 

endogenous (principally bone) Pb. From thermal ionization mass spectrometry analysis of the 

Pb isotopic ratios of blood and bone biopsies collected at each isotope change, and using endmember unmixing equations, it was determined that administration of the first isotope label 

allows measurement of the contribution of historic bone stores to blood Pb. Exposure to 

subsequent isotopic labels allowed measurements of the contribution from historic bone Pb 

stores and the recently administered enriched isotopes that incorporated into bone (Inskip et al., 

1996). In general the contribution from the historic bone Pb (common Pb) to blood lead level 

was constant (~20%), accentuated with spikes in total blood Pb due to the current administration 

of the stable isotopes. After cessation of each sequential administration, the concentration of the 

signature dose rapidly decreased. Initial attempts to apply a single-bone physiologically based 

model of Pb kinetics were unsuccessful until adequate explanation of these rapid drops in stable 

isotopes in the blood were incorporated (O’Flaherty et al., 1998). Once revisions were added to 

account for rapid turnover of the trabecular bone compartment and slower turnover rates of 

cortical bone compartment, an acceptable model evolved. From this model it was reported that 

historic bone Pb from 11 years of continuous exposure contributes approximately 17% of the 

blood Pb concentration at Pb concentration over 50 μg/dL, reinforcing the concept that the length 

of Pb exposure and the rates of past and current Pb exposures help determine the fractional 

contribution of bone Pb to total blood Pb levels (O’Flaherty et al., 1998). The turnover rate for 

cortical (~88% of total bone by volume) bone in the adult cynomolgus monkey was estimated by 

the model to be ~4.5% per year, while the turnover rate for trabecular bone was estimated to be 

33% per year. 

Using the method of sequential stable isotope administration, Franklin et al. (1997) 

examined flux of Pb from maternal bone during pregnancy of 5 female cynomolgus monkeys 

who had been previously exposed to common Pb (approximately 1,100 to1,300 μg Pb/kg body 

weight) for about 14 years. In general, lead levels in maternal blood attributable to Pb from 

mobilized bone were reported to drop 29 to 56% below prepregnancy baseline levels during the 

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first trimester of pregnancy. This was ascribed to the known increase in maternal fluid volume, 

specific organ enlargement (e.g., mammary glands, uterus, placenta), and increased metabolic 

activity that occurs during pregnancy. During the second and third trimesters, when there is a 

rapid growth in the fetal skeleton and compensatory demand for calcium from the maternal 

blood, the Pb levels increased up to 44% over pre-pregnancy levels. With the exception of one 

monkey, blood Pb concentrations in the fetus corresponded to those found in the mothers, both in 

total Pb concentration and proportion of Pb attributable to each isotopic signature dose (common 

= 22.1% vs. 23.7%, 204Pb = 6.9% vs. 7.4%, and 206Pb = 71.0% vs. 68.9%, respectively). From 7 

to 25% of the Pb found in fetal bone originated from maternal bone, with the balance derived 

from oral dosing of the mothers with isotope during pregnancy. Of interest, in offspring from a 

low Pb exposure control monkey (blood Pb <5 μg/100 g) ~39% of Pb found in fetal bone was of 

maternal origin, suggesting enhanced transfer and retention of Pb under low Pb conditions. 

Clearly, the results of these studies show that Pb stored in bone is mobilized during 

pregnancy and lactation, exposing both mother and fetus/nursing infant to blood/milk Pb levels 

of potential toxicity. Of equal concern, a significant proportion of Pb transferred from the 

mother is incorporated into the developing skeletal system of the offspring, where it can serve as 

a continuing source of toxic exposure. The above study by Franklin et al. (1997) illustrates the 

utility of sequentially administered stable isotopes in pregnancy; however, its use may also be 

applicable in studies of lactation, menopause, osteoporosis, and other disease states where 

mobilization of bone and release of Pb stores occurs. Furthermore, given that isotopic ratios of 

common Pbs vary by location and source of exposure, when humans migrate from one area and 

source of exposure to another, it is possible to document changes in mobilized Pb, especially 

during times of metabolic stress. 

5.8.6.2 Age/Osteoporosis 

The age of an animal at the time of exposure to Pb has been shown to influence the uptake 

and retention of Pb by bone. In experiments to determine the influence of age on this process, 

Han et al. (1997) exposed rats for five weeks to 250 mg/L Pb-acetate in drinking water beginning 

at 5 weeks of age (young child), 10 weeks of age (mid-adolescence), or 15 weeks of age (young 

adult), followed by a 4 week period of without Pb exposure. An additional group of rats were 

exposed to Pb beginning at 5 weeks, but examined following an 8 or 20 week period after 

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cessation of Pb. Significantly lower blood and bone Pb concentrations were associated with 

greater age at the start of Pb exposure and increased interval since the end of exposure. 

However, young rats beginning exposure to Pb at 5 weeks and examined 20 weeks after 

cessation of exposure, still had bone Pb concentrations higher than those found in older rats only 

4 weeks after cessation of exposure. This demonstrated that exposure to Pb at a young age leads 

to significant skeletal Pb accumulation and retention, despite the high rate of bone remodeling 

that occurs during growth and development at that time. 

At the opposite end of the spectrum, Cory-Slechta et al. (1989) studied differences in 

tissue distribution of Pb in adult and old rats. Adult (8 months old) and old (16 months old) rats 

were exposed to 50 ppm Pb-acetate in drinking water for 11 months, at which time the 

experiment was completed. Bone (femur) Pb levels in older rats were found to be less than those 

in younger rats; however, blood lead levels were higher in the older rats. Of interest, brain Pb 

concentrations in the older rats exposed to Pb were significantly higher, and brain weights were 

significantly less than the brain Pb concentration and weights of unexposed older control rats or 

adult rats exposed to Pb, suggesting a potential detrimental effect. The authors suggested that a 

possibility for the observed differences in tissue concentrations of Pb was due to changes in the 

capacity of bone to store Pb with advanced age. In a subsequent study, Cory-Slechta (1990b) 

examined kinetic and biochemical responses of young (21 day old), adult (8 months old), and old 

(16 months old) rats exposed to Pb at 0, 2, or 10 mg Pb acetate/kg/day over a 9.5 month 

experimental period. Results suggested that older rats may have increased vulnerability to Pb 

due to increased exposure of tissues to Pb and greater sensitivity of the tissues to the effects of 

Pb. As in the previous study (Cory-Slechta et al., 1989), lower bone levels of Pb were present in 

older rats with concomitant elevated levels of Pb in brain and other tissues, supporting the 

hypothesis that exposure to Pb over a lifetime may contribute to deterioration of health in old 

age, potentially during times of heightened bone remodeling such as occurs during osteoporosis. 

In studies of bone Pb metabolism in a geriatric, female nonhuman primates exposed to Pb 

approximately 10 years previously, McNeill et al. (1997) reported no significant changes in bone 

Pb level over a 10 month observation period as measured by 109Cd K X-ray fluorescence. The 

mean half-life of Pb in bone of these animals was found to be 3.0 ± 1.0 years, consistent with 

data found in humans, while the endogenous exposure level due to mobilized Pb was 0.09 ± 

0.02 μg/dL blood. Results examining Pb accumulation in the bones of aging male mice suggest 

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low levels of bone Pb contributing to the osteopenia observed normally in C57BL/6J mice 

(Massie and Aiello, 1992). The mice were maintained on regular diet (0.258 ppm Pb) and water 

(5.45 ppb Pb) from 76 to 958 days of age. While the Pb content of femurs increased by 83%, no 

significant relationship was found between Pb and bone density, bone collagen, or loss of 

calcium from bone. 

5.8.6.3 Weight Loss 

The relationship between body mass and bone mass is highly correlated and during times 

of loss of body weight, such as dietary restriction, a concomitant loss of bone mass also occurs. 

It is therefore possible that Pb stored in bone from prior exposures could be released into the 

system as skeletal bone is mobilized and result in Pb toxicity. To examine the influence of 

weight loss on release of stored Pb, Han et al. (1996) first exposed rats to Pb in drinking water 

(250 mg/l of Pb as acetate) for 5 weeks, followed by a 4 week washout period without Pb to 

allow primarily accumulation in the skeleton. Rats were then randomly assigned to a weight 

maintenance group, a moderate weight loss group (70% of maintenance diet), or a substantial 

weight loss group (40% of maintenance diet) for a four week period. At the end of this 

experimental period the blood and bone levels of Pb did not differ between groups, however, the 

amount and concentration of Pb in the liver increased significantly. A follow up study in rats 

previous exposed to Pb for two weeks was undertaken to determine the effect of weight loss and 

exercise on the distribution of Pb (Han et al., 1999). They found weight loss secondary to 

dietary restriction to be the critical factor elevating organ Pb levels and, contrary to their first 

study, elevated blood levels of Pb. No significant difference in organ or blood Pb concentrations 

were reported between the exercise vs. no exercise groups. These studies suggest Pb toxicity 

could occur in those previously exposed to Pb during times of dietary restriction. 

5.8.7 Bone and Lead Summary 

Lead substitutes for calcium and is readily taken up and stored in the bone of experimental 

animals, potentially allowing bone cell function to be compromised both directly and indirectly 

by exposure. In general, relatively short term exposure of mature animals to Pb does not result 

in significant growth suppression, however, chronic Pb exposure during times of inadequate 

nutrition have been shown to adversely influence bone growth, including decreased bone density, 

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decreased trabecular bone, and growth plates. Exposure of developing animals to Pb during 

gestation and the immediate postnatal period has clearly been shown to significantly depress 

early bone growth in a dose-dependent fashion, though this effect is not manifest below a certain 

threshold. Numerous mechanisms for the toxic effect of Pb on bone have been explored using 

various animal models. Systemically, Pb has been shown to disrupt mineralization of bone 

during growth, to alter calcium binding proteins, and to increase calcium and phosphorus 

concentration in the blood stream, in addition to potentially altering bone cell differentiation and 

function by altering plasma levels of growth hormone and calciotropic hormones such as vitamin 

D3 [1,25-(OH2)D3]. 

Bone cell cultures of both animal and human derivation have substantially contributed to 

the general understanding of the adverse effects of Pb on bone cell metabolism directly and its 

indirect effect on bone and bone cells by perturbation of numerous local and systemic factors. 

These in vitro studies have indicated that Pb is primarily taken up by osteoclasts and likely 

perturbs intracellular calcium homeostasis secondary to osteoclastic bone resorption. Bone cell 

proliferation is also inhibited. Exposure of bone cell cultures to Pb has been shown to impair 

vitamin D-stimulated production of osteocalcin, inhibit secretion of bone-related proteins such as 

osteonectin and collagen, and suppress bone cell proliferation, potentially by interference with 

such factors as GH, EGF, TGF-β1, and PTHrP. 

Finally, several animal studies have suggested Pb stored in bone can serve as a 

continuing, endogenous source of exposure for an individual or can be transferred from mother 

to offspring during pregnancy and/or lactation, with potentially toxic consequences. Periods of 

extensive bone remodeling, (i.e., during weight loss, advanced age, altered metabolic state, and 

pregnancy and lactation) are all associated with mobilization of Pb stores from bone of animals. 

During pregnancy, transfer of Pb from mother to offspring has been documented, however, 

available evidence suggests a more significant transfer from mother to offspring occurs during 

lactation when the concentration of Pb in mother’s milk can be several times higher than 

corresponding blood levels. Despite the extensive remodeling of bone that occurs during growth 

and development of young animals, a significant amount of Pb can be accumulated and retained 

during times of exposure. 

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5.8.8 Teeth – Introduction 

There was little information in the prior 1986 AQCD relating lead exposure to adverse 

outcomes in the teeth of animals. At that time, the incorporation of Pb into teeth was recognized 

as was the fact that tooth Pb increased with age, proportional to the rate of exposure and roughly 

proportional to the blood Pb concentration. 

Teeth consist of a hard outer layer of enamel, supported by an underlying layer of dentin, 

which itself is supported by a connective tissue known as the dental pulp. Enamel is the hardest 

substance in the body and the most highly mineralized, consisting of ~96% mineral (calcium 

hydroxyapatite substituted with carbonate ions) and 4% other organic materials, while dentin is 

only ~70% mineral. The formation of enamel (amelogenesis) occurs as a two stage process of 

organic matrix production with ~30% mineralization, followed by removal of water and proteins 

from the matrix with concurrent further mineralization. As in bone, Pb ions are apparently 

capable of substituting for calcium ions in the mineralizing tooth, becoming essentially trapped. 

However, unlike bone, the tooth, with subtle exceptions, does not undergo a remodeling process. 

Dentin formation (dentinogenesis) can be likened to endochondral bone formation, in that an 

unmineralized matrix (predentin, rather than cartilage) is laid down first, followed by 

mineralization to mature dentin. The cells responsible for amelogenesis and dentinogenesis, 

called ameloblasts and odontoblasts respectively, are similar to osteoblasts in that they respond 

to various signaling factors, secrete matrix proteins, and create an environment favorable to 

deposition of minerals. After enamel formation on a specific tooth is completed, ameloblasts are 

lost and no additional enamel is laid down with the exception of certain teeth in rodents. These 

teeth, typically incisors on rats, mice, and most other rodents, continuously erupt to offset the 

attrition that occurs with daily use. Therefore, the process of amelogenesis is ongoing, albeit 

confined to a localized area, throughout the life of the animals. For this reason rodents have 

been utilized extensively to examine the processes of amelogenesis and the influence of various 

toxic agents, such as Pb, on tooth development. Ameloblasts are especially sensitive to toxins 

and altered metabolic conditions and respond to such insults with disruption of enamel 

formation. When disruption occurs, defects in the enamel can occur, typically as a band of 

malformed or altered enamel. As described below, exposure of animals to various 

concentrations of Pb during tooth development is not only capable of creating distinctive 

marking of enamel (“Pb lines”), but may influence the resistance of the enamel to dental decay. 

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Within the dental pulp, a layer of odontoblasts continue to reside against the inner layer of the 

primary dentin for the life of the tooth. During this time the odontoblasts are systematically 

slowly putting down thin layers of secondary dentin, slowly decreasing the size of the pulp 

chamber with age. Lead present during this process has been shown to be readily taken up by 

this dentin layer, providing a potential marker of historic Pb exposure. Though the enamel is a 

non-living substance, it is not entirely inert. The external surface of enamel is more or less in a 

continuous state of flux or turnover as it chemically demineralizes from acids consumed or 

produced in the mouth by bacteria, followed by remineralization of demineralized enamel when 

contact with saliva supersaturated with calcium and phosphate ions occurs. Lead present during 

this process can easily be released from enamel and/or incorporated initially or back into it 

depending on the circumstances. 

In summary, Pb has the potential to disrupt the various processes associated with 

formation of teeth, plus incorporate itself into all mineralized tooth tissues during formation. 

Posteruptively, Pb can become incorporated into the secondary dentin, and can be taken up or 

released from the outer surface layer of enamel during times of remineralization/ 

demineralization. As described below, exposure of animals to Pb has been associated with 

adverse dental outcomes. 

5.8.9 Uptake of Lead by Teeth 

As seen with bone, uptake of Pb into the teeth of animals has been demonstrated in a 

number of studies and by multiple routes of administration. Twenty four hours after a single 

intraperitoneal injection of radioactive Pb-203 (203Pb, 1 μg/kg) to young (15 day suckling rats) 

and old (120 day) female rats, 0.7% of the injected dose was present in the four incisor teeth of 

the younger animals and 0.6% was present in the same teeth of the older animals (Momcilovic 

and Kostial, 1974). These percentages jumped to 1.43% and 0.88%, respectively, 192 hours 

after the injection, suggesting incorporation and retention of Pb by teeth is greater in younger 

animals than in adults, as found in bone. Lead has also been shown to be incorporated into 

incisors of rats exposed to airborne Pb. Grobler and coworkers (1991) exposed 6 week old rats 

to either “Clean Air” (0.05 μg Pb/m3

) or air containing 77 μg Pb/m3 and found significant 

differences in the amount of Pb incorporated into the incisors of the animals. After 70 days, a 

mean of only 0.8 μg Pb/g of incisor dry mass was found in incisors from control animals, while 

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11.0 μg Pb/g was present in incisors from the 77 μg Pb/m3 group. Exposure to air containing 

249 μg Pb/m3

 for 28 days or to 1,546 μg Pb/m3 for 50 days resulted in mean values of 13.8 and 

153 μg Pb/g incisor dry weight of Pb incorporation, respectively, highlighting the fact that dose 

and length of exposure are determinates of amount of Pb contained in the teeth of these animals. 

Lead has also been shown to be taken up into the teeth of weanling rats whose mothers were 

exposed to Pb in drinking water. The offspring of pregnant rats exposed during gestation and 

lactation until 21 days post partum to water containing 0, 3, or 10 ppm Pb showed dosedependent, significant increases in the Pb content of incisors, first molars, and second molars 

(Grobler et al., 1985). Taken together, these studies confirm the uptake of Pb into teeth as 

delivered by various means and suggest that maternal exposure can result in uptake in offspring, 

during gestation and/or lactation. 

5.8.10 Effects of Lead on Enamel and Dentine Formation 

Early microscopic studies by Eisenmann and Yaeger (1969) confirmed alterations in rat 

incisor enamel formation 7 days after a single SC dose of Pb (0.15 or 1.5 mM/100g animal 

weight); however, no effect was seen at the 0.075 mM/100g dose. Lead was found to have 

inhibited mineralization of both enamel and dentin, but only to a “mild to moderate” extent with 

the mineralization of dentin more affected. It was speculated at the time that Pb could affect the 

production of normal, mineralizable organic matrix; affect enzymes specific to enamel or dentin 

formation; affect crystal structure and/or growth; or affect a combination of these factors. In 

studies of dentinogenesis, incubation of fixed rat molar germs with Pb-pyrophosphate has shown 

localization of Pb to the mineralization front of dentin (i.e., the area of recently formed dentin), 

to the stratum intermedium, and to subodontoblastic cells, suggesting Pb may react with mineral 

components located in the mineralization zone or have a high affinity for these incompletely 

mineralized areas (Larsson and Helander, 1974). Localization of Pb was also seen at the area of 

the dentino-enamel junction. Similar examination of first molar germs from 3-day-old rats 

showed that Pb also localized to the periphery of dentinal globules (Larsson, 1974). A single 

injection of Pb-acetate (30 mg/kg body weight) produces an immediate (within 6 h) response in 

the growing dentin of the rat incisor, leading to the formation of a so-called “Pb line” (Appleton, 

1991). A transient rise in serum calcium and phosphorus accompanied the injection, leading to 

speculation that lead may have been replacing these minerals in the apatite structure. However, 

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backscattered electron imaging of the Pb line showed it to be composed of continuous 

hypomineralized interglobular dentin with some incomplete fusion of calcospherites resulting in 

uneven mineralization, but no localized concentration of Pb was detectable. This is consistent 

with Featherstone and co-workers (1981) who reported that Pb incorporation during apatite 

synthesis was widely dispersed, rather than concentrated in areas of calcium deficiency. Once 

synthesis is complete, however, Pb is capable of entering calcium deficient areas in enamel, 

substituting for calcium (Featherstone et al., 1979). This is essentially the process that occurs 

during demineralization/remineralization of enamel. Appleton (1991, 1992) suggested that Pb 

has a direct effect on odontoblasts, creating a local disturbance of calcium metabolism, a process 

similar to that described in bone (Pounds et al., 1991). Interestingly, no ultrastructural changes 

in ameloblasts from rat pups whose mothers had been drinking water containing Pb was 

observed. 

During the normal process of amelogenesis, water and proteins contained within the 

organic matrix are lost, leaving densely mineralized enamel. The removal of enamel proteins 

during this phase is facilitated by enamel proteinases, which are believed to degrade the proteins 

into smaller units capable of diffusing from the matrix. Using crude extracts from scrapings of 

rat incisor teeth, Gerlach and co-workers (2000a) demonstrated that Pb inhibited these 

proteinases in vitro at micromolar concentrations. In rats given drinking water containing Pb at 

either 0, 34, or 170 mg/L as Pb-acetate for 70 days, increased amounts of proteins were found in 

enamel matrix from animals exposed to Pb (Gerlach et al., 2002). Moreover, enamel 

microhardness analysis of upper incisors revealed a significant decrease in microhardness in 

regions of enamel maturation, but not in areas of fully mature enamel, suggesting Pb exposure 

mediates a delay in enamel mineralization. In adult rats with incisors trimmed to remove 

occlusal (biting) contact, a single IP dose of Pb-acetate (40 mg/kg) significantly delayed the 

continuous eruption of the incisor at all time points between 8 and 28 days after dosing, 

compared with controls (Gerlach et al., 2000b). It is of interest that delayed eruption of teeth in 

children living in areas of heavy metal contamination (Pb and zinc) has been reported previously 

(Curzon and Bibby, 1970). 

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5.8.11 Effects of Lead on Dental Pulp Cells 

Hampered by a general lack of cell cultures specifically for teeth, there remains a paucity 

of information regarding both the cultures themselves and the effect of Pb upon such cultures. In 

a single in vitro study using a human dental pulp cell culture obtained from teeth extracted for 

orthodontic purposes, Thaweboon and co-workers (2002) examined the effects of three 

concentrations (4.5 H 10-5 M, 4.5 H 10-6 M, 4.5 H 10-7 M) of Pb-glutamate on cell proliferation, 

protein production, and osteocalcin secretion. Under serum free conditions (DMEM only) all 

concentrations of Pb significantly increased cell proliferation on day 1, day 3 and day 5 of 

exposure, as measured indirectly by mitochondrial dehydrogenase enzyme assay. In the 

presence of 2% fetal bovine serum only, the higher concentration of Pb significantly increased 

protein production, suggesting an influence of serum constituents on cell growth or binding of 

free Pb in the medium. Similar results were reported when rat osteosarcoma cells (ROS 17/2.8) 

were exposed to identical concentrations of Pb over 2-, 4-, and 6-day time points (Sauk et al., 

1992). Concentrations of Pb less than 4.5 H 10-5 M concentration did not affect osteosarcoma 

cell proliferation in the presence of serum, but in the absence of serum 4.5 H 10-7 M Pb increased 

cell proliferation at day 4, while at day 6, 4.5 H 10-6 M Pb inhibited proliferation. Further testing 

of human dental pulp cells in serum-free conditions showed that Pb exposure caused dosedependent decreases in intracellular protein and procollagen type I production over the 5-day 

period experimental period (Thaweboon et al., 2002). Short-term exposure of the cells to Pb 

significantly decreased osteocalcin production in a dose-dependent manner at 8- and 12-h 

exposure time points. These results suggest that Pb is capable of exerting multiple toxic effects 

on cells derived from human dental pulp. 

5.8.12 Adverse Effects of Lead on Teeth—Dental Caries 

In a recent review, Bowen (2001) highlighted 12 epidemiological studies that examined 

the association between Pb exposure and dental caries (decay), reporting that 8 studies supported 

the concept that Pb is a caries-promoting element. Unfortunately, the source and actual exposure 

to Pb and measurement of prevalence of caries varied greatly, providing less than completely 

satisfactory evidence in the opinion of the author. There is also a paucity of well-controlled 

animal studies examining this issue. 

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In an early study examining the effect of drinking solutions containing various metallic 

ions on dental caries in hamsters, Wisotzky and Hein (1958) reported post-eruptive ingestion of 

drinking water containing 0.5 mEq of Pb significantly increased caries scores in molar teeth of 

males after 84 days, but, perplexingly, not in females after 98 days of exposure. It should be 

noted that in animal studies such as these it is routine to maintain the animals on cariogenic or 

caries-promoting diets high in fermentable sugars. Clear evidence supporting Pb’s role in 

enhancing susceptibility to dental caries was reported by Watson and co-workers in 1997. In 

their study, female rats were exposed to Pb in drinking water (34 ppm as Pb-acetate) as young 

adults, during pregnancy, and during lactation. Lead exposure of the subsequent offspring from 

the dams was, therefore, from transfer of endogenous Pb from dam to pup during gestation and 

lactation, with no further exposure after weaning. This pre- and perinatal exposure to Pb resulted 

in a significant, almost 40%, increase in the prevalence of dental caries over control animals. 

The study was significant for other reasons, as it mimicked the conditions found in many inner 

cities where young females are exposed to Pb in their environment and later transfer this Pb to 

their own fetuses during the extensive bone remodeling that occurs during pregnancy and 

lactation. The mean blood Pb level in the dams upon weaning was 48 μg/dL, which is not unlike 

upper levels reported in humans. 

The mechanisms by which Pb enhances susceptibility to caries remain uncertain, though 

clearly altered mineralization and/or incorporation of Pb into enamel as described above could 

enhance its solubility in acid. Lead also appears in the saliva of rats at about 5% of the whole 

blood level and at about 61% of the plasma filtrate Pb level (Mobarak and P’an, 1984), providing 

an avenue for post-eruptive interaction with the exposed enamel in the oral cavity. Notably, 

decreased salivary flow has been reported in rats exposed to Pb, and decreased salivary function 

is known to increase caries risk. Stimulated parotid function was decreased by nearly 30% in the 

Pb-exposed offspring in the study by Watson and co-workers (1997), an effect that could have 

been mediated by the salivary gland requirement of intact parasympathetic and sympathetic 

nervous systems for normal development (Schneyer and Hall, 1970) and Pb’s known adverse 

effect on neurotransmitters (Bressler and Goldstein, 1991). Acute infusion of 4 μg of Pb per min 

has been reported to significantly reduce pilocarpine-stimulated salivary secretion in rats over a 

50-min period (Craan et al., 1984), while 24-day administration of 0.05% Pb-acetate 

significantly reduced the concentration of protein and calcium in pilocarpine-stimulated rat 

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submandibular saliva (Abdollahi et al., 1997). Of potential interest, postnatal exposure of rats to 

Pb (10 or 25 ppm in drinking water) and a caries-enhancing diet containing fluoride (sucrose 

containing 15 ppm fluoride) was not associated with an increased risk of dental caries, 

suggesting that Pb does not interfere with the protective effect of fluoride (Tabchoury et al., 

1999). Clearly though, the effect of Pb exposure on salivary gland function and the mechanism 

by which Pb exposure enhances caries risk needs to be further explored. 

5.8.13 Lead from Teeth as a Potential Source of Toxicity 

Although no studies currently document the contribution of Pb incorporated into teeth as a 

source of endogenous Pb exposure, the potential exists during the process of exfoliation of the 

primary dentition. As described above (Section 5.8.9) Pb is avidly incorporated into the 

developing dentin and enamel components of teeth. Like bone, the uptake and incorporation of 

Pb into teeth during acute exogenous exposures may be of short-term benefit by limiting the 

exposure of other, more sensitive tissues, but, unlike bone, teeth do not undergo a gross 

remodeling process (the continuous, superficial demineralization/remineralization of the exposed 

tooth surfaces, principally enamel, are assumed here to be insignificant). However, during the 

exfoliative process, the erupting secondary tooth erodes away the root (composed of cementum 

and dentin) of the overlying primary tooth along with some surrounding alveolar bone. Any Pb 

incorporated into these portions of bone and primary tooth would be released by the erosive 

process, with the potential to produce highly elevated local concentrations of Pb in the proximity 

of remodeling alveolar bone and developing secondary teeth. A more modest contribution to 

circulating blood Pb would be predicted. Animal research in this area has been hampered, as 

most common rodents (i.e., rats, mice) are monophyodonts (have only one set of teeth). 

Although monkeys are an acceptable model, it is problematic how release of Pb stored in teeth 

could be differentiated from that of remodeling skeletal bones formed at a similar time point, 

plus the disproportionate size of the skeletal mass compared to the dentition may mask any 

contribution of Pb mobilized by exfoliation. 

5.8.14 Teeth and Lead Summary 

As found with bone, Pb substitutes for calcium and is readily taken up and incorporated 

into the developing teeth of experimental animals. Unlike bone, teeth do not undergo 

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remodeling per se and, with few exceptions, most Pb incorporated into tooth structure remains 

essentially in a state of permanent storage. Administration of high doses of Pb to animals has 

demonstrated the formation of a Pb line, visible in both the enamel and dentin and localized to 

areas of recently formed tooth structure. Within this Pb line, areas of inhibition of mineralization 

are evident in enamel and dentin. Lead has been shown to decrease cell proliferation and 

production of intracellular protein, procollagen type I, and osteocalcin in human dental pulp cells 

in culture. Studies of Pb exposure in adult rats have reported inhibition of post-eruptive enamel 

proteinases, delayed teeth eruption times, and decreased microhardness of surface enamel. 

During the process of enamel formation, Pb is apparently widely dispersed when first 

incorporated into the developing apatite crystal; however, post-formation, Pb is capable of 

entering and concentrating in calcium-deficient areas within the enamel. Whether Pb 

incorporation into the enamel surface compromises the integrity and resistance of the surface to 

dissolution, and ultimately increases risk of dental decay, is unclear. Numerous epidemiologic 

studies suggest Pb is a caries-promoting element. Animal studies (both post-eruptive Pb 

exposure and pre- and perinatal Pb exposure studies) support this concept, although the exact 

mechanism of action remains elusive. No animal studies have examined the role exfoliation of 

the primary dentition in release of Pb previously stored in tooth structure, though it is likely this 

process could serve as an additional source of Pb exposure in childhood. 

5.9 EFFECTS OF LEAD ON THE IMMUNE SYSTEM 

The immune system, along with the neurological system, has emerged as one of the more 

sensitive targets of Pb-induced toxicity. However, because Pb exposure at low to moderate 

levels does not produce overt cytotoxicity of immune cells, immune-associated health effects 

result from misregulation and shifts in functional capacity rather than profound lymphoid 

deficiencies. As a result, the most sensitive biomarkers of Pb-induced immunotoxicity are those 

associated with specific functional capacities as opposed to measures of cell enumeration and/or 

lymphoid organ pathology. This distinguishes Pb from some other types of immunotoxicants. 

The following sections provide a survey of the reported immune effects resulting from exposure 

to Pb in humans and animal models. In general, the focus is on those studies that have been 

reported since the 1986 AQCD (U.S. Environmental Protection Agency, 1986) was prepared and 

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have altered our understanding of lead-induced immunotoxicity and the associated immunerelated health risks. 

5.9.1 Introduction 

The comparative development of the immune system in humans and animal models used 

for immunotoxicology was reviewed in recent years by Payne and Crooks (2002) and Holsapple 

et al. (2003). Pluripotent hematopoietic stem cells arise from uncommitted mesenchymal stem 

cells located in the spanochnopleure area near the heart and appear in the yolk sac (Holsapple 

et al., 2003). During human gestation, these stem cells first migrate at approximately 5 weeks 

and produce lymphoid and myeloid stem cells. Lymphoid stem cells can be found in the liver at 

approximately 7–8 weeks of gestation. In the mouse, the hematopoietic stem cells migrate to the 

liver on gestational day (GD) 10. 

Migration of stem cells to the thymus occurs in humans about the 9th week of gestation 

and in mice on GD 11. The equivalent migration probably happens in the rat at GD 13 or later. 

Bone marrow lymphopoieis begins in humans about week 12 of gestation and in mice about GD 

18. Immune development continues postnatally in humans as well as rodents. During 

embryonic development, immune maintenance of the pregnancy is important, and Th2 

development is favored over Th1. Among other things, the capacity of dendritic cells to promote 

Th1 activity is dramatically suppressed in the newborn (Langrish et al., 2002). However, Th1 

cytokines can be stimulated shortly after birth in humans (Malamitsi-Pichner et al., 2005). 

However, it is clear that, at birth, rodents lag behind in immune development compared with 

humans (Dietert et al., 2000; Holsapple et al., 2003). 

Immune maturation continues in the thymus and bone marrow to give rise to the broad 

spectrum of myeloid and lymphoid cells that contribute to host defense and tissue homeostasis. 

The thymus-derived (T) lymphocytes provide regulatory cells facilitating a wide range of 

acquired immune responses and also produce cytotoxic T lymphocytes capable of attacking 

tumor and virally infected cells. Among regulatory T lymphocytes are at least two types of 

helper populations termed T helper 1 (Th1) and T helper 2 (Th2). The former regulatory cells 

promote immune responses helpful against intracellular pathogens, while the latter are important 

in defense against extracellular pathogens. However, skewing of the Th1/Th2 balance too far in 

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either direction is problematic in terms of health risk. Such skewing is a large factor in the 

consideration of lead-induced immunotoxicity (see Sections 5.9.2, 5.9.4, and 5.9.8). 

B lymphocytes are named for the Bursa of Fabricius, an organ important in their 

development in avian species. They constitute the other major lymphoid cell type important in 

acquired immunity. B lymphocytes produce first membrane-bound and then secreted 

immunoglobulins (antibodies) that are a significant part of humoral immunity. Different classes 

of immunoglobulins produced during class switching, and promoted by different T lymphocyte 

cytokines, are tailored to be effective against different types of pathogens (e.g., viruses vs. extracellular parasites). The potential of Pb on B lymphocytes is discussed along with humoral 

immunity in Section 5.9.3.1. 

Another lymphoid cell type is the natural killer (NK) cell. These cells function during 

innate immunity as a front line defense against tumor cells and virally infected cells. NK cells 

have the capacity to recognize a limited number of receptors on target cell surfaces, including the 

loss of Class I (major histocompatibility complex) proteins. Such self-protein identity loss is 

usually associated with viral infection of host cells. NK cells also produce cytokines capable of 

regulating macrophage and T cell activity and, in turn, NK cells can be activated by 

lymphoid-produced cytokines. Consideration of the effect of Pb on NK cells is presented in 

Section 5.9.8. 

Myelomonocytic cells such as macrophages and polymorphonuclear leukocytes 

(neutrophils) are also important in innate immunity. Neutrophils are usually short-lived cells that 

are capable of leaving the circulation and migrating into tissues. From there they can 

phagocytize pathogenic targets, utilize phagolysosomes to destroy bacteria, and secrete 

significant quantities of reactive oxygen intermediates (ROIs) into the local environment. They 

are also capable of producing nitric oxide (NO) in most species. The impact of Pb on neutrophils 

is presented in Section 5.9.7. 

Macrophages are much longer-lived and can perform many of the same functions as 

neutrophils. Unlike neutrophils, macrophages can inactivate much of the ROIs they produce 

internally. However, they can produce vast quantities of NO and have major functional roles in 

tissue homeostasis, lymphoid regulation, and antigen presentation. In fact, macrophages reside 

in virtually every tissue, although their morphology can vary widely and their function spectrum 

can be quite distinct among different specialized organs. Kupffer cells in the liver and alveolar 

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macrophages in the lungs are two examples of highly specialized forms of macrophages. 

Misregulated or misdirected macrophage activity is a major cause of immune-inflicted tissue 

damage. When the cells are activated within tissues and chronically overproduce 

proinflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), 

and interleukin-6 (IL-6) in addition to NO and ROIs, the result is usually tissue damage and loss 

of function, if not ultimately cancer. A classic example of the potentially destructive role of 

misregulated macrophages is found in the case of asbestos-induced pathology of the lung (Holian 

et al., 1997; Driscoll, 2000). Misregulation of macrophages is a major consideration in the case 

of Pb (discussed in Section 5.9.6). 

Dendritic and Langerhans cells are related in lineage to macrophages. These cells are 

vitally important in antigen trafficking and presentation, particularly in lymph nodes and skin. 

However, far too little is known about their potential sensitivity to lead, largely because their 

isolation, complete phenotypic and functional characterizations, and inclusion in assessment 

methodologies are relatively recent developments within immunology. 

The other major cell types important in a consideration of lead-induced immunotoxicity 

are basophils, eosinophils, and mast cells. Basophils are involved in various inflammatory 

reactions, but little is known about the direct effect of Pb on this cell population. Mast cells are 

fixed tissue cells surrounding the vasculature in many organs. These cells can secrete preformed 

highly vasoactive products with inflammatory potential (e.g., kinins and histamine) in response 

to cell-surface-initiated signals. Mast cells can be triggered by numerous signals including both 

substance P and immunoglobulin E (IgE). Because mast cell-induced inflammation is associated 

with IgE-mediated allergic reactions, these cells are important in the clinical ramification of leadinduced immunotoxicity. Eosinophils are a granulocytic cell type associated with Th2-driven 

inflammatory reactions. They frequently appear in association with allergic reactions and are 

regulated by numerous lymphoid cells as well as by mast cells. Remarkably little is known 

about the direct effects of Pb on eosinophil function despite the probable role of these cells in 

certain allergic manifestations following exposure to lead. 

Life-stage related differences in immunotoxicological risk have been reviewed by several 

authors (Barnett 1996; Holladay and Smialowitz, 2000; Dietert et al., 2002; Holladay, 2005), and 

it seems clear that the vulnerability of the developing immune system to immunotoxic insult is 

significantly greater than that of the fully-matured and dispersed immune system for the vast 

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majority of immunotoxicants (Luebke et al., 2005). Dietert et al. (2000) and Holsapple et al. 

(2003) have considered the likely existence of critical windows during immune development 

when the immune system as a target may have increased sensitivity or increased resistance to 

xenobiotic-induced immunotoxic alteration. These windows correspond to different dynamic 

stages of functional development within the embryonic, fetal, and early neonatal immune system. 

One issue of immune development particularly pertinent to Pb is the fact that Th1 and Th2 

functional capacities do not develop at the same time in either humans or rodents. The need to 

protect against maternal-fetal allogeneic reactions results in Th1 function being acquired largely 

after birth. Therefore, any environmental exposure that interferes with the rapid development of 

Th1 function might leave the individual with a Th2-biased immune system. The heavy metal Pb 

apparently represents one of the xenobiotics that are capable of suppressing Th1 capacity, 

resulting in dysregulated immune balance. This is discussed further in Sections 5.9.4, 5.9.8, and 

5.9.10. 

5.9.2 Host Resistance 

Host resistance to disease has been used as an effective measure of the impact of 

environmental toxicants on immune function. Because different diseases require different 

combinations of immune effector functions for host protection, analysis of environmental 

modulation of host resistance across a spectrum of diseases can help identify clinically relevant 

immunotoxicity. 

The 1986 AQCD presented a range of studies in which exposure to Pb inhibited host 

resistance to disease. Since the time of that report, few new infectious diseases have been added 

to the list of those that Pb is known to influence. Instead, a much broader understanding of the 

likely basis for the increased disease susceptibility to these pathogens has become evident. 

Additionally, recognition of an increased risk for some atopic and autoimmune diseases arising 

from lead-induced immunotoxicity has occurred in recent years. This is discussed under Section 

5.9.8. Lead-induced alterations of host resistance against infectious and neoplastic diseases are 

considered in the following sections. 

To date, there has been either no effect or an increased susceptibility to disease resulting 

from exposure to lead for virtually every infectious agent examined. Given the capacity of Pb to 

shift immune responses toward Th2, one might expect that enhanced resistance might occur for 

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diseases where robust Th2 responses were required. For example, an increased resistance 

against helminth parasitic disease might be hypothesized. However, this possible association has 

not been widely examined to date. 

5.9.2.1 Viral Diseases 

In general, exposure to Pb increases the susceptibility to viral infections. Studies include 

host resistance directed against the encephalomyocarditis virus (Gainer, 1977; Exon et al, 1979), 

Langat virus (Thind and Khan, 1978), and Semliki Forrest virus (Gupta et al., 2002). In the last 

example, oral dosing of Swiss mice with Pb-acetate (250 mg/kg for 28 days) significantly 

increased mortality to sublethal doses of the virus. Ewers et al. (1982) reported that occupational 

exposure to Pb resulted in an increased incidence of influenza cases among workers. In chickens 

administered Pb-acetate orally (20 and 40 mg/100g body weight) for 56 days, antibody 

production against Newcastle virus vaccine was reduced, while mortality against viral challenge 

was increased (Youssef et al., 1996). It seems likely that the reduced Th1 capacity (including 

effective CTL generation) combined with increased TNF-α, ROI, and prostaglandin E2 (PGE2) 

production by responding macrophages would contribute to increased tissue pathology but 

reduce viral clearance for many infections. 

5.9.2.2 Bacterial Diseases 

Most of the lead-associated host resistance research has been conducted on bacterial 

diseases. Hemphill et al. (1971) first described the increased susceptibility of mice exposed to 

Pb (250 μg given i.p. for 30 days) to Samonella typhimurium, while Selye et al. (1966) reported 

increased susceptibility of rats to bacteria endotoxins. Cook et al. (1975) found increased 

susceptibility of lead-exposed rats (2 mg/100g body weight given i.v. once) to both Eschrichia 

coli and Staphylococcus epidermidis. 

The vast majority of studies have been conducted using the intracellular bacterium, 

Listeria monocytogenes, in mice. Listeria infection and host resistance to the disease have been 

well characterized. Essentially, this infection requires an effective antigen presentation 

(probably involving toll-like receptor 2 involvement), a robust response by activated 

macrophages leading to interlukin-12 (IL-12) and interferon-γ (IFN-γ) production and robust Th1 

driven host protection (Torres et al., 2004; Lara-Tejero and Pamer, 2004). Ideally, activated 

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macrophages would produce NO in an effective response against Listeria (Ito et al., 2005). In 

the case of lead-induced immunotoxicity, everything works against this type of response. First, 

macrophages have severely suppressed NO production. Yet, overproduction of TNF-α, ROIs 

and PGE2 leads to tissue inflammation and damage. The skewing of the response toward Th2 

means that both IL-12 and IFN-γ are lacking. Excessive production of IL-6 and other proinflammatory cytokines results in what has been termed “sickness behavior” which involves both 

the immune and central nervous systems (Dantzer et al., 1998; Dyatlov et al., 1998a,b; Lawrence 

and Kim, 2000; Dyatlov and Lawrence, 2002). Lead-induced impairment in host resistance to 

listeria was reported by Lawrence (1981). CBA/J mice exposed orally to 80 ppm or greater of 

Pb-acetate for 4 weeks had 100% mortality (after 10 days) compared with no mortality for mice 

exposed to 0 or 16 ppm lead. 

In an important study concerning individual variation to lead-induced immunotoxicity and 

host resistance, Kim and Lawrence (2000) demonstrated that neurological circuitry as it pertains 

to brain lateralized behavior could impact the effect of Pb on immune responses and host 

resistance to Listeria. Not surprisingly, this suggests that host genotype and epigenetic factors 

can be influenced by Pb exposure to the individual. Using female BALB/c mice, Kishikawa and 

Lawrence (1997) demonstrated that exogenously administered recombinant IL-12 (1 μg each for 

three days i.p.) could enhance production of IFN-γ as well as host resistance to Listeria in leadexposed (2 mM in water for 3 weeks) mice. However, lead-exposed mice continued to have 

excess IL-6 production (part of the sickness behavior phenotype). The result with IL-12 

validates the importance of the Th skewing and macrophage impairment induced by Pb on host 

resistance to certain diseases. 

Additional bacterial infections in which Pb exposure has been reported to reduce host 

resistance include Serratia marcesens (Schlipkopter and Frieler, 1979) and Pasteurella 

multocida (Bouley et al., 1977). 

5.9.2.3 Parasitic Diseases 

Few studies have been conducted to date regarding the effects of Pb on host resistance to 

parasitic diseases. This is unfortunate as some parasitic disease challenges require effective Th2 

responses for optimal resistance. Hence, it is not clear that Pb exposure would depress host 

resistance in every case (e.g., for helminth parasites). Since the AQCD in 1986, one study was 

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conducted examining the effect of Pb on the killing ability of Leishmania enriettii parasites in 

vitro by mouse macrophages (Mauel et al., 1989). The authors found that 30–100 mM Pbacetate interfered with the killing ability of macrophages without producing macrophage 

cytotoxicity. 

5.9.2.4 Tumors 

The primary study concerning tumor immunity/tumor growth and Pb was already known 

at the time of the 1986 AQCD. In this study, male C57Bl/6 mice were exposed to Pb-acetate in 

the drinking water at concentrations of 0, 13, 130, or 1300 ppm. Moloney sarcoma virus (MSV)-

induced tumor formation and growth were compared following the exposure of mice to Pb for 

10-12 weeks. MSV-induced transplantable tumors were also used in this study. Primary tumor 

growth was enhanced in animals that received 130 and 1300 ppm of Pb vs. the control. 

However, all tumors regressed eventually. Most other studies involving Pb exposure and tumors 

describe the fact that Pb can exacerbate the ability of other toxins to promote tumor formation 

(Kobayashi and Okamoto, 1974; Hinton et al., 1979). Much of the tumor-promoting activity of 

Pb would seem to involve depressed Th1 and macrophage function as well as the promotion of 

excessive ROI release into tissues. 

5.9.3 Humoral Immunity 

The irony of Pb as an immunotoxicant is that the overall effects on humoral immunity are 

reasonably modest compared to those reported for macrophages and T lymphocytes (McCabe 

1994). McCabe et al. (1991) discussed the fact that Pb is not profoundly cytotoxic for most 

immune cells yet can cause major functional shifts within the immune system as well as 

decreased host resistance to disease. In many cases, antibody production can remain robust in 

lead-exposed animals and humans. However, the nature and spectrum of the antibodies 

produced is the more significant cause for concern. Lead appears to alter the course of T 

lymphocyte-driven B cell maturation such that class switching may be skewed in lead-exposed 

animals and humans. If Pb dosage and duration of exposure is sufficient, antibody production 

may be depressed overall. However, with low-level Pb exposure, skewed isotype production is 

the greater health risk. 

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5.9.3.1 General Effects on B lymphocytes and Immunoglobulins 

Despite the fact that T lymphocytes and macrophages appear to be the more sensitive 

targets of lead, the metal can alter B lymphocyte maturation and shift immunoglobulin 

production. The 1986 AQCD describes the fact that some early studies reported no effect of Pb 

on antibody production (Reigart and Graber, 1976; Ewers et al., 1982), while others reported a 

significant decrease in the humoral immune response (Koller, 1973; Koller and Kovaic, 1974; 

Blakley et al., 1980). In retrospect, this apparent discrepancy may have been caused by the 

various concentrations of Pb administered as well as variations in the duration of exposure. 

Additionally, as mentioned in the 1986 AQCD, the temporal relationship of Pb exposure to 

antigen challenge may be important. 

In studies measuring generation of plaque forming cells (PFCs) against sheep red blood 

cells (SRBCs), Pb incubation with lymphocytes in vitro caused an increased response (Lawrence, 

1981). In a comprehensive study using several strains of mice, Mudzinski et al. (1986) reported 

that Pb-acetate administered in the drinking water (10 mM for 8 weeks) elevated the response in 

the one strain (BALB/c mice) but failed to alter the humoral response to SRBCs (either PFCs or 

antibody titers) in all other strains. McCabe et al. (1990) reported that Pb caused an elevation in 

B cell expression of Class II molecules, thereby influencing B cell differentiation. Lead seemed 

to impact Class II molecule density at the cell surface via the levels of mRNA translational 

and/or the posttranslational stages of cell surface protein synthesis (McCabe et al., 1991). 

Some human epidemiological and occupational studies have reported lead-associated 

differences in levels of circulating immunoglobulins. However, Tryphonas (2001) discussed the 

pitfalls of relying on total serum immunoglobulin in assessing immunotoxic effects in humans. 

Sun et al. (2003) reported that immunoglobulin M (IgM) and immunoglobulin G (IgG) were 

lower but that IgE was higher among females within their high-Pb group. Basaran and Undeger 

(2000) found that IgM, IgG, and some complement proteins were reduced among battery 

workers with high Pb exposure. Results of Undeger et al. (1996) were similar as well. In 

contrast, Sarasua et al. (2000) reported an elevation in immunoglobulin A (IgA), IgG, and IgM 

associated with environmental Pb exposure. Pinkerton et al. (1998) found no major effects but 

reported a significant lead-associated decline in serum IgG and an elevation in B cell percentage. 

In a human in vitro study, Borella and Giardino (1991) showed that Pb exposure caused an 

increased IgG production following stimulation of cells with pokeweed mitogen. 

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In more recent animal studies, Miller et al. (1998) and Chen et al. (1999) reported no 

effect on antigen-specific IgG titers against keyhole limpet hemocyanin (KLH) protein in F344 

strain rats that had been exposed in utero to Pb (0–500 ppm Pb-acetate in drinking water). 

It seems likely that Pb exposure may be capable of reducing serum immunoglobulin levels 

given sufficient dose and duration of exposure. However, the more critical issue pertains to the 

distribution of class and subclass of immunoglobulins produced after exposure to lead. Because 

Pb can alter the development of T cells involved in specific antigen responses, this can impact 

the spectrum of immunoglobulins produced in response to T-dependent antigens. As discussed 

in the following section, production of IgE (a class of immunoglobulin that is poorly represented 

in serum but of great clinical significance) is a central issue for lead-induced immunotoxicity. 

One additional health concern is the potential for Pb to enhance the likelihood of autoantibody 

production (Lawrence and McCabe, 2002; Hudson et al., 2003). This latter concern is discussed 

under Section 5.9.8. 

5.9.3.2 IgE Alterations 

One of the three predominant hallmarks of lead-induced immunotoxicity is an increase in 

IgE production. This can occur in the context of antigen-specific responses or as measured by 

total serum IgE. For this endpoint, the human and animal findings are very similar. Virtually all 

of the information concerning the capacity of Pb to elevate IgE production in humans and 

animals has been obtained since the 1986 AQCD. As a result, this represents a relatively new 

biomarker for lead-induced immunomodulation, and one not included in most animal or human 

studies conducted prior to 1990 (e.g., Wagerova et al., 1986). 

Table 5-9.1 lists the studies reporting lead-induced elevation of IgE. The disease 

implications of lead-induced increases in IgE production are potentially significant and may help 

to address, in part, the allergy epidemic that has occurred in the last several decades (Isolauri 

et al., 2004). A relationship has been established between relative Th2 cytokine levels, serum 

IgE levels, and the risk of allergic airway inflammation (Maezawa et al., 2004; Cardinale et al., 

2005). In fact, attempts to manage allergic inflammation use IgE as one of the major targets 

(Stokes and Casale, 2005). IgE levels are directly related to the production of Th2 cytokines 

such as interlukin-4 (IL-4), among others (Tepper et al., 1990; Burstein et al., 1991; Carballido 

et al., 1995; Takeno et al., 2004; Wood et al., 2004). The relationship between Th2 cytokines 

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Table 5-9.1. Recent Studies Reporting Lead-Induced Increase in IgE 

In vivo Lowest Exposure 

Species Strain/Gender Age Ex vivo Effective Dose Duration Reference 

Human Both genders Children Yes Not available Not Available Karmous et 

al. (2005) 

Human Both genders, Adult Yes Not Available Not Available Heo et al. 

91% males (2004) 

Human Females Children Yes Not Available Not Available Sun et al. 

(2003) 

Mouse Balb/c males Fetal Yes 0.1 mM 3 days Snyder et al. 

and females (2000) 

Human Both genders, Juvenile Yes Not Available Not Available Lutz et al. 

56% male (1999) 

Rat F344 females Embryo – Yes 100 ppm 5 weeks to dam (2 Miller et al. 

fetal and 3 gestational) (1998) 

Mouse Balb/c females Adult Yes 50 μg 3x per 

week s.c. 

3 weeks Heo et al. 

(1996) 

Human Males Adult Yes Not Available Not Available Horiguchi et 

al. (1992) 

1 (e.g., IL-4), IgE levels, and allergic airway disease is supported through various pharmacological 

2 interventions in both animals and humans that either induce Th2 cytokine and promote allergic 

3 airway disease (Wu et al., 2004) or interfere with Th2 cytokine-driven IgE production and inhibit 

4 allergic inflammation (Holgate et al., 2005; Ban and Hettich, 2005). The production of IgE is of 

5 importance in terms of potential inflammation. Not only is the level of IgE a consideration, but 

6 also the expression of the Fc receptor for the epsilon (ε) chain of IgE on mast cells and basophils. 

7 In humans, Karmaus et al. (2005) reported a positive association of blood Pb levels with 

8 serum IgE concentration among second grade children living near a waste incinerator or other 

9 lead-emitting industries. Sun et al. (2003) also found a positive association of blood lead and 

10 serum IgE levels among children in Taiwan. Lutz et al. (1999) reported a correlation of blood 

11 lead levels and serum IgE levels in children in Missouri from 9 months–6 years of age. This 

12 association appears to hold not only for children but also for adults. Heo et al. (2004) recently 

13 showed that battery workers with blood leads > 30 μg/dL differed significantly in serum IgE 

14 levels from those with blood leads < 30 μg/dL. Additionally, serum IgE concentration correlated 

15 with blood lead among the populations examined (r = 0.0872). 

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Animal data support this relationship between blood lead concentration and IgE level and 

further suggest that even very low-level Pb exposure early in development may produce elevated 

IgE production in the juvenile offspring. Miller et al. (1998) found that gestational exposure of 

rats to 100 ppm Pb-acetate in the drinking water could produce elevated IgE in the adult 

offspring. Snyder et al. (2000) showed that gestational and/or neonatal exposure of mice to Pbacetate produced neonatal blood lead levels not above background (5.0 μg/dL), but nevertheless, 

could result in elevated IgE production in the juvenile mouse. In most cases, Pb exposures 

associated with elevated IgE were also associated with increases in IL-4 production by T cells 

(Chen et al., 1999; Snyder et al., 2000). This is consistent with the fact that high IL-4 production 

can predispose B lymphocytes to undergo a specific class switch for the production of IgE. 

One importance of these findings is that, in each case, the elevation in IgE persisted long 

after blood Pb levels had returned to normal. This means that Pb exposure could occur early in 

life and produce an increased risk of later-life allergic disease with no residual evidence that the 

individual had ever been exposed to lead. This should provide a cautionary note for future 

human studies examining Pb body burden and immune function. 

5.9.4 Cell-Mediated Immunity 

Cell-mediated immunity (CMI) essentially involves all host resistance beyond the soluble 

components of defense, i.e., antibody and complement. CMI includes any action of the immune 

system that is a direct effect of leukocytes on neoplastic or virally-infected cells or against 

extracellular targets such as bacteria. Even macrophage functional processes involving 

antibodies, such as antibody-dependent cellular cytotoxicity (ADCC), are considered to be CMI. 

One of the hallmarks of CMI is that cellular activation is usually required for the effector cells to 

attack the target. In the case of macrophages, this is usually activation with the Th1-associated 

cytokine, IFN-γ. 

For NK cells, activation can occur through various pathogenic components such as double 

stranded RNA. However, recently Borg et al. (2004) showed that mature dendritic cells 

produced a Th1-promoting cytokine, IL-12, and this in turn activates NK cells to produce the 

further Th1-promoting cytokine, IFN-γ. Interleukin-18 (IL-18) produced by macrophages is also 

an activator of NK cells, facilitating Th1-promoting cytokine release while interleukins-2 and 

-15 (IL-2, IL-15) are growth factors for NK cells. NK cells would appear to be relatively 

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resistant to the effects of Pb compared to some T lymphocytes and macrophages. For a detailed 

consideration of the effects of Pb on NK cells, see Section 5.9.7. 

Cytotoxic T lymphocytes are generated in response to antigen presentation delivered with 

Th1 cytokines. These cells are capable of mediating antigen specific destruction of neoplastic 

and virally-infected cells via binding and release of cytolytic proteins into the intracellular space. 

Frequently, the most effective antigen targets of CTLs are the early viral proteins produced in the 

first phase of host cell infection by viruses. IL-12, produced largely by dendritic cells, appears to 

be important in the generation of antigen CTL cells and IFN-γ produced by Th1 lymphocytes. 

NK cells are a potent regulator of CTL activity. Cell signaling via certain toll-like receptors on 

antigen presenting cells seems to have a role in determining the nature of the Th activation (Th1 

vs. Th2) and can, therefore, influence the extent of CTL production. 

Because T lymphocytes and their regulator and effector functions are so critical in CMI, 

the maturation of thymocytes within the thymus microenvironment and the selection of 

repertoire among the maturing T lymphocytes are crucial issues for potential developmental 

immunotoxicants. In fact, lead seems to be capable of disrupting several aspects of T cell 

maturation, activation, and repertoire usage (McCabe and Lawrence, 1991; Heo et al., 1998; 

Miller et al., 1998; McCabe et al., 2001, Lee and Dietert, 2003). 

5.9.4.1 General Effects on Thymocytes and T lymphocytes 

In general, cells of the T cell lineage appear to be relatively sensitive to the toxic effects 

of Pb compared to other lymphoid populations. At the time of the 1986 AQCD, there was some 

understanding of this sensitivity. However, there appear to be considerable differences in 

sensitivity across various T cell subpopulations (McCabe and Lawrence, 1991; Heo et al., 1996; 

1997; 1998). This was largely unknown when the prior AQCD was prepared as the partitioning 

of T helper cells into functionally distinct subpopulations (e.g., Th0, Th1, and Th2) was not 

known until the latter part of the 1980s. The differential impact of Pb on T helper cell 

populations and on immune balance was established during the 1990s. This has become one of 

the four hallmarks of lead-induced immunotoxicity. 

Original observations of both in vivo and in vitro T-dependent immune responses in the 

presence of Pb suggest that T helper function, as well as the spectrum of cytokines produced, are 

skewed toward the Th2. The cytokine skewing is discussed as well in Section 5.9.5.3. Smith 

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and Lawrence (1988) have shown that Pb can inhibit antigen presentation and stimulation of a 

T cell clone of the Th1 phenotype. McCabe and Lawrence (1991) were the first to show that this 

was caused by the novel capacity of Pb to inhibit Th1 stimulation while promoting presentation 

to Th2 clones. Heo et al. (1996) provided both in vitro and in vivo results supporting this 

immunomodulation of lead. Cytokine skewing accompanied the differential stimulation of Th 

cells. 

Using naïve splenic CD4+ T cells derived from D11.10 ovalbumin-transgenic mice, Heo 

et al. (1998) developed T cell clones in vitro in the presence of lead. The authors found the 

T cells that developed from the naïve precursors were significantly skewed toward the Th2 

helper phenotype and away from the Th1 phenotype. If IL-4 was inhibited with the addition of 

anti-IL-4 to the cultures or if the Th1- promoting cytokine IL-12 was added exogenously to the 

culture, the effects of Pb could be largely overcome. This study provided firm evidence that Pb 

can directly promote Th2 development among precursor Th(0) cells and impair development of 

Th1 cells. Among its effects, Pb enhanced adenyl cyclase activity and increased the levels of 

cAMP. The authors suggested that Pb may influence cell signaling in such as manner as to 

promote the Th2 pathway. 

Beyond the biasing of immune responses at the level of the T lymphocyte based on 

Th1/Th2 balance, Pb has the capacity to bias usage of certain V$ genes (Vβ 5, Vβ 7, and V$ 13) 

among T lymphocyte clones in mice (Heo et al., 1997). This is of concern, as it suggests that 

exposure to Pb may alter the T cell repertoire and skew its representation. Heo et al. (1997) 

discussed the fact that many autoimmune diseases are characterized by a disproportionate usage 

of certain Vβ genes. Different autoimmune conditions are associated with the differential 

overabundant usage of a specific V$ gene. They suggest that this feature of lead-induced 

T lymphocyte immunotoxicity may contribute to and enhance the risk of autoimmunity. 

Lee and Dietert (2003) exposed the developing thymus of embryonic day 12 (E12) 

chickens to Pb-acetate (single injection of 400 μg) and evaluated the capacity of thymocytes (ex 

vivo) from juvenile chickens to produce IFN-γ . They found that embryonic exposure at doses 

that impair juvenile delayed type hypersensitivity (DTH) also inhibit IFN-γ production. 

Similarly, IFN-γ production was decreased when thymocytes from juvenile chickens were 

exposed to Pb in vitro (0.45 μΜ). However, in vitro exposure of thymic stroma to Pb did not 

result in suppression of control thymocyte IFN-γ production in co-cultures. There is a suggestion 

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that the balance of reproductive hormones in early life may influence the impact of Pb on 

developing thymocytes (Hussain et al., 2005). 

5.9.4.2 Delayed Type Hypersensitivity 

The DTH assay is an in vivo assay requiring antigen-specific T lymphocytes to be primed, 

expanded, and then recruited to a local site of antigen deposition. The most common application 

of the DTH is the tuberculin assay for TB in humans. The assay has a long history of application 

in immunotoxicology, and its utility within the national toxicology program assessment in the 

mouse has been previously reported (Luster et al., 1992). The assay is known to depend largely 

on Th1 participation and is, therefore, an effective measure of Th1-dependent function. 

However, there are at least two different portions of the response that are under somewhat 

separate control. Priming and expansion of the antigen-specific T lymphocytes is largely Th1 

dependent. However, recruitment of T lymphocytes to the periphery involves a variety of 

locally-produced chemotactic signals that may not be under the same regulation. In fact, Chen 

et al. (1999) showed that a commonly used chelator for Pb poisoning (succimer, 

meso-2,3-dimercaptosuccinic acid [DMSA]) fails to restore lead-induced suppression of DTH in 

rats, because the chelator itself somehow interferes with the production of chemotactic factors 

necessary for T lymphocyte recruitment. The DTH assay is also generally useful in questions of 

possible developmental immunotoxicity, because of the natural skewing toward Th2 that occurs 

during gestation through birth and the issue of effective Th1 functional acquisition in the 

newborn. 

Lead-induced suppression of the DTH response is one of the four hallmarks of leadinduced immunotoxicity. At the time of the 1986 AQCD, the capacity of Pb to suppress DTH 

function was already known from two studies conducted during the late 1970s. However, the 

association of the function with Th1 help had not been established. Muller et al. (1977) were 

among the first to demonstrate lead-induced suppression of DTH. Using mice, these 

investigators administered Pb-acetate i.p. for 30 days prior to assessment of primary and 

secondary DTH responses against SRBCs. Both primary and secondary responses were severely 

depressed following exposure to Pb, even at the lowest dose tested (0.025 mg). Faith et al. 

(1979) exposed developing Sprague-Dawley rats to Pb-acetate in the drinking water (lowest dose 

at 25 ppm) first via the dams during gestation and through weaning and then with direct exposure 

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of the offspring until 6 weeks of age. In this case, the purified protein derivative (PPD) of 

tuberculin was used as the antigen compared against the saline injection control. Rats 

administered the lowest dose of Pb evaluated (producing a BLL of 29.3 μg/dL) had a 

significantly reduced DTH response. Laschi-Loquerie et al. (1984) measured the contact 

hypersensitivity reaction against picryl chloride in mice that had received 0.5 mg/Kg Pb via s.c. 

administration. Lead administration was given from 3-6 days in duration at varying times 

relative to the sensitization period. These investigators reported that Pb suppressed the DTH 

type of response regardless of the window (before or during sensitization) in which it had been 

administered. 

More recently, Miller et al. (1998) found that female F344 rats gestationally exposed to 

250 ppm of Pb-acetate in drinking water had a persistently reduced DTH reaction against KLH 

protein. Chen et al. (1999), Bunn et al. (2001a,b,c) and Chen et al. (2004) had similar findings in 

studies that included both the F344 and CD strains of rats. In the last study conducted in F344 

rats, a BLL of 6.75 μg/dL at 4 weeks of age, postgestational exposure to Pb-acetate (250 ppm in 

drinking water) was associated with depressed DTH against KLH in the 13-week-old adult 

female offspring (Chen et al., 2004). McCabe et al. (1999) were among the first to draw 

attention to the relationship between lead-induced suppression of DTH and the prior observations 

of lead-induced Th skewing. These authors gave varying doses of Pb-acetate in drinking water 

(32,128, 512, 2048 ppm) to female BALB/c mice for 3 weeks prior to measuring the DTH 

against SRBCs. They found that the 512 ppm dose producing a BLL of 87 μg/dL significantly 

impaired the DTH response. Antigen routes proved to be important as Pb depressed DTH when 

an i.v. primed with SRBCs was used, but not when SRBCs were administered i.p. Timing of Pb 

administration was found to be important relative to the capacity to depress the DTH response. 

Lee et al. (2001) showed that Pb-acetate (200 μg) administered in ovo to chicken embryos at 

9 days of incubation failed to depress juvenile DTH against bovine serum albumin (BSA), but 

when the same dose of Pb was administered 3 days later producing the same BLL, juvenile DTH 

was severely reduced. Using the latter model, embryonic administration of exogenous thymulin 

was found to partially restore juvenile DTH function following embryonic exposure to Pb (Lee 

and Dietert, 2003). 

Regarding developmental sensitivity of the DTH response to lead-induced 

immunosuppression, parallel findings were obtained in the developing rat (CD strain females) 

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1 (Bunn et al., 2001c) in agreement with those found in the chicken. Administration of 500 ppm 

2 Pb-acetate during gestational days 3 to 9 or 15 to 21 produced no DTH effect compared with 

3 DTH suppression in the corresponding adult offspring. As shown in Figure 5-9.1, the sensitivity 

4 of the DTH response to Pb appears to develop sometime between days 9 and 15 of rat embryonic 

5 development. Apparently, the status of the developing thymus may be a consideration in the 

6 capacity of Pb to impact the subsequent DTH response. This is discussed further in 

7 Section 5.9.10. 

Figure 5-9.1. Windows during prenatal development (days postconception for rat) or 

embryonic development (days postincubation initiation for chicken) during 

which sensitivity of DTH to lead emerges. 

8 It should be noted that in several studies, lead-induced suppression of the DTH response 

9 was associated with reduced capacity to produce the Th1 cytokine, IFN-γ (Chen et al., 1999; Lee 

10 et al., 2001). 

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5.9.4.3 Other T-Dependent Cell-Mediated Immune Changes 

The in vitro response of T lymphocyte populations to various mitogens (e.g., 

Concavavalin A [ConA], Phytohemagglutinin A [PHA]) has been used as a surrogate measure of 

antigen-driven T lymphocyte stimulation. The impact of Pb on these parameters is presented in 

Section 5.9.5. Another T cell response altered by exposure to Pb is the mixed lymphocyte 

response (MLR). This in vitro assay is a measure for the responsiveness of T cells to the 

presentation of allogeneic major histocompatibility complex (MHC) molecules by antigen 

presenting cells. The in vivo correlate of the MLR is usually considered to be the graft vs. host 

(GvH) reaction. Several investigators have reported Pb alteration of the MLR as summarized in 

Table AX5-9.4. 

McCabe et al. (2001) demonstrated that Pb at very low physiological concentrations 

(0.1 μM or approximately the equivalent of 10 μg/dL) in vitro significantly enhanced the 

proliferation and expansion of murine alloreactive CD4+ T lymphocytes in the MLR reaction. In 

fact, the resulting population was found to have a high density of CD4 molecules on the cell 

surface-making them phenotypically similar to memory T lymphocytes. The authors 

hypothesized that lead-induced creation of an exaggerated pool of memory-type T lymphocytes 

(possessing a lower threshold required for subsequent activation) would be problematic for the 

host. In a study using Lewis strain rats, Razani-Boroujerdi et al. (1999) also found evidence for 

lead-induced stimulation of the in vitro MLR response. In this case, both the alloreactive 

mixtures of cells as well as syngeneic mixtures were elevated in proliferation when cultured in 

the presence of Pb-acetate (e.g., 50 ppm or approximately 131 μM). When concentrations of Pb 

were significantly higher (200 ppm or greater), proliferation was inhibited in these cultures. 

Figure 5-9.1 illustrates the developmental appearance of initial sensitivity for Pb-induced 

suppression of the DTH function. The mid-embryonic developmental window is the time during 

which the capacity of Pb to impair later-life DTH responses first emerges. Earlier pulsed 

exposure to Pb fails to impair juvenile and/or adult DTH despite the continuing of presence of Pb 

in the embryo. However, during the second half of embryonic development the embryo becomes 

remarkably sensitive to lead-induced suppression of DTH. Both the rat and chicken are similar 

in this window of emerging Th1-dependent functional sensitivity. Thymus-related 

developmental events are indicated along with the emergence of DTH functional sensitivity to 

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lead. Information was derived from Gobel (1996), Vicente et al. (1998), Dunon et al. (1999), 

Dietert et al., (2000), Bunn et al. (2001c), Lee et al. (2001) and Holsapple et al. (2003). 

5.9.5 Lymphocyte Activation and Responses 

Many of the broader functional ramifications of Pb exposure on lymphocytes are 

discussed under Sections 5-9.3 and 5-9.4. However, the capacity of Pb to directly alter lymphoid 

responses is a significant component of lead-induced immunotoxicity and is summarized within 

the present section. Lymphoid responses are usually assessed in terms of proliferation and 

activation (functional changes). One of the recent endpoints reflecting functional status is the 

production of cytokines. These both autoregulate the producing cells and significantly impact 

the activity of other immune and nonimmune cells carrying the appropriate receptors. The 

spectrum and levels of cytokines produced by a population of immune cells tends to reflect their 

capacity to regulate the host immune response. 

5.9.5.1 Activation by Mitogens 

The capacity of certain plant- and bacterially derived products to stimulate lymphoid 

populations to enter the cell cycle and undergo mitogenesis has been used for decades to assess 

the potential capacity of lymphocytes to receive proliferation signals and expand their 

population. Among the mitogens employed within the Pb exposure studies are the T lymphocyte 

subpopulation mitogens, PHA and Con A; the dual T and B cell mitogen, pokeweed mitogen 

(PWM; the B lymphocyte mitogen derived from gram-negative bacteria, lipopolysaccharide 

(LPS), and the B cell mitogen, Staphylococcus aureus enterotoxin (SE). It should be noted that 

these mitogens do not necessarily stimulate all T lymphocytes or all lymphocytes but, instead, 

stimulate selected populations of the cells. The mitogens react with a large array of cell surface 

molecules producing cross-linking and appropriate signal transduction to initiate mitogenesis. 

In the case of the plant-derived mitogens, lectins, numerous glycoproteins and glycolipids 

carrying the correct carbohydrate residues serve as the cell surface binding sites for crosslinking. Mitogen stimulation in vitro has been used as a surrogate for antigen-driven stimulation 

and proliferation of antigen-specific T and B cell clones. However, it should be noted that while 

the assays have been used for decades, there are now more specific assays utilizing more 

functionally relevant cell surface receptors to assess lymphoid activation potential. 

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The 1986 AQCD has an extensive review of mitogenic responses of lymphocytes 

following both in vivo and in vitro treatment by lead. The results at that time showed no clear 

pattern. At low to moderate levels, Pb was potentially co-mitogenic for some cells and at very 

high concentrations could suppress proliferation. Little has changed in conclusions for this 

assessment measure since the 1986 report. The most significant findings from the mitogenic 

studies are that at doses encountered physiologically Pb is not a potent cytotoxic agent for most 

immune cells. At low concentrations, it can marginally stimulate lymphoid mitogenesis. 

However, as one examines more refined subpopulations of lymphocytes than what were able to 

be identified prior to 1986 (e.g., Th1 vs. Th2 clone of T lymphocytes), it becomes clear that Pb 

can promote expansion of some lymphoid populations while suppressing others. 

Annex Table AX5-9.5 for this section summarizes results of Pb effects on mitogenstimulated proliferation of lymphoid populations. 

5.9.5.2 Activation via Other Receptors 

In recent years, lymphoid activation and population expansion has been measured using 

the triggering of specific T and B cell surface receptors (e.g., CD3 on T cells) as well as antigendriven proliferation of T cell clones known to be specific for the antigen in question. The latter 

has provided the opportunity to simulate in vivo lymphoid activation and antigen-driven 

proliferation by using receptors in vitro, which are more physiologically relevant than those 

activated by plant lectins. Because Pb does not cause profound population loss across the entire 

population of T or B lymphocytes, these more refined and functionally-relevant assay systems 

have enabled a much clearer picture to emerge concerning lead-induced changes in lymphoid 

population than was available for the 1986 AQCD report. 

Smith and Lawrence (1988) and McCabe and Lawrence (1991) utilized antigen-specific 

mouse T clones. They found that Pb directly promoted antigen presentation and stimulation of 

the T cell clones when these clones were Th2 cells. However, when the Th1 clones were used, 

Pb suppressed the antigen-specific presentation signal. In the McCabe and Lawrence study, 

direct comparisons were made between Th1 and Th2 clones specific for mouse allogeneic MHC 

molecules. These studies provided the first clear picture of the differential effects of Pb on Th1 

vs. Th2 cells. Several studies since these have verified this major effect of Pb (Heo et al., 1996; 

1997, 1998). Many of these later studies utilized the transgenic mouse strain (DO11.10 OVA-tg) 

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that carries T cells specific for a peptide fragment of ovalbumin. These enabled the same 

comparisons to be made with the presentation of a soluble protein antigen as the stimulating 

signal. Heo et al. (1998) showed that Pb not only selectively stimulates Th2 cells and suppresses 

Th1 cells but that it preferentially causes precursor Th0 cells to mature into Th2, rather Th1 cells, 

as well. Additionally, the T cell clones in the presence of Pb are skewed in terms of their usage 

of V$ genes (as reflected in their cell surface receptors) (Heo et al., 1997). This is of particular 

concern relative to the risk of autoimmunity. More recently, McCabe et al. (2001) examined Pb 

exposure in the context of the allogeneic MLR against allogeneic MHC molecules. In vitro 

exposure to Pb (as low as 1.0 μM) enhanced the primary MLR response, but not the secondary 

MLR response and not the mitogenic response using PHA. Significantly, the T cell clones that 

emerged from the primary MLR were in greater proportion than normal and were of the 

specialized phenotype CD4-plus high density (CD4+high). Because these fit the phenotype of 

memory cells, it is likely that an overabundance of memory cells was produced during the 

primary response, where the antigen may be of lesser biological significance than in a secondary 

response. The authors discussed the fact that Pb may cause T cells to respond under conditions 

of low antigen concentration, which could waste valuable and limited resources by generating 

T memory cell clones when they are not needed (against unimportant antigens) or even increase 

the risk of autoimmune responses by altering the threshold requirements for stimulation. The 

putative mechanisms suggested for the differential effects of Pb on Th cells are presented in 

Section 5.9.9. 

5.9.5.3 Cytokine Production 

At the time of the 1986 AQCD, immune cytokines were essentially absent from the 

information available for consideration. Only the antiviral interferons (α,$) had been examined 

among studies available for that report. Therefore, one of the most important effects of Pb on the 

immune system, i.e., Pb-induced cytokine production was not known at that time. 

Most studies since 1986 have shown that Pb exposure at low to moderate levels causes a 

significant shift in the production of Th1 vs. Th2 cytokines with the bias toward the latter. 

Hence, production of IFN is decreased and IL-12 is inadequate for effective host resistance. 

In contrast, production of IL-4, IL-6, and, frequently, interlukin-10 (IL-10) is elevated. 

Table 5-9.2 illustrates the studies reporting shifts in cytokine production induced by lead. 

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December 2005 5-235 DRAFT-DO NOT QUOTE OR CITE Table 5-9.2. Studies Reporting Lead-Induced Shifts in Th1 vs. Th2 Cytokines In vivo/ Lead Dose/ Duration of Species Strain/ Gender Age Cytokine Alterations Ex vivo Concentration Exposure 

Rat F344 Females Embryo-fetal KIL-4 Yes 250 ppm in water 2 weeks prior 

LIFNγ splenic lymphocytes to dams week of gesta

dam 

Human Males Adults K IFN-γ Yes Not available Not available 

PHA stimulated peripheral blood lymphocytes 

Chicken Cornell K females Embryonic LIFN-γ 

stimulated thymocytes 

Yes 400 

μg Single injectio

Mouse Balb/c Neonatal/ KIL-6 Yes 0.5 mM in water to 4 weeks (3 via 

Juvenile serum during infection dams and their pups 

Rat CD females Fetal KIL-10 Yes 550ppm in water to 6 days via ges

dams of dam 

Chicken Cornell K females Embryonic LIFN-γ Yes 50 

μg Single injectio

Mouse Balb/c male Adults KIL-6 Yes 2 mM 8 weeks 

serum during infection in certain groups 

Mouse NOD 

Autoimmune strain 

Adult LIFN-γ, 

term 

no change long Yes Oral 10 mM and 

ovalbumin antigen 

10 days 

adult LTGFβ intestinal levels 

Mouse C57 Bl/6 females Adult No effect on gut balance in Yes 0.5 mg/kg injection 6 injections ov

NOD autoimmune normal mice and oral ovalbumin 2 weeks strain females LTGFβ in autoimmune mice 

Rat F344 females Embryofetal 

LIFN-γ KIL-10 

Yes 250 ppm to dams 2 weeks befor

3rd week of ge

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December 2005 5-236 DRAFT-DO NOT QUOTE OR CITE Table 5-9.2 (cont’d). Studies Reporting Lead-Induced Shifts in Th1 vs. Th2 Cytokine

In vivo/ Lead Dose/ Duration of Species Strain/ Gender Age Cytokine Alterations Ex vivo Concentration Exposure 

Mouse DO11.10 ova-tg, ova mice and RAG Adult LIFN-γ No 25 

μM 3 days 

knockouts 

Rat F344 females Embryofetal 

LIFN-γ Yes 500 ppm to dams 2 weeks befor

3rd week of ge

Mouse Balb/c ByJ females Adult LIFN-γ Yes 2 mM 3 weeks 

KIL-6 

Mouse Balb/c and 

DO11.10 ova-tg mice 

Adult LIFN-γ 

LIFN-γ/IL-4 

Yes 50 

μg each 

injection (s.c.) 3 per week 

2 weeks 

ratio 

Mouse Balb/c ByJ female 

or male 

Adult LIFN-γ 

KIL-4 

Yes 50 

μg each 

injection (s.c.) 3 per week 

2 weeks 

Mouse Balb/c ByJ female 

or male 

Adult LIFN-γ 

KIL-4 

No 10 

μM – 50 

μM 2 days 

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(Please note that TNF-α production is considered in the macrophage section, Section 5.9.6). 

These shifts in cytokine production are remarkably consistent, occur even at low levels of 

exposure, and are reported following both in vivo and in vitro exposure to lead. Furthermore, the 

effects are persistent even when exposure to Pb was restricted to early development and cytokine 

assessment was performed in the subsequent juvenile or adult (Miller et al., 1998; Bunn et al., 

2001c; Lee et al., 2001; Chen et al., 2004). 

The only exceptions to lead-induced biasing in favor of Th2 occur in the reports by 

Goebel et al. (2000) and Mishra et al. (2003). In the latter case, the authors attributed this 

difference (in humans) to the very high Pb levels considered in the study. In the prior case, 

Goebel et al. (2000) saw a local bias to Th1 in the intestinal tract of a specialized autoimmune 

diabetes-prone strain of mice (NOD) but not in normal mice. Initially, the Pb-induced cytokine 

skewing favored Th2 (after 1 day), but this shifted to Th1 with more prolonged Pb exposure 

(after 10 days). Loss of oral tolerance accompanied this long-term shift. These results suggest 

that in most cases, lead-induced skewing would favor Th2. But with some genotypes or 

additional disease conditions, an imbalance may occur in the direction of a gut-associated Th1 

environment, increasing risk for loss of oral tolerance and the potential for increased food 

allergies. 

One ramification for the capacity of Pb to promote Th2 cells is the impact of elevated 

IL-4 on IgE. It seems clear that lead-induced overproduction of IgE (seen in virtually all animal 

models examined as well as humans) is directly linked with the overproduction of IL-4. 

Excessive IL-4 and the resulting IgE production increases the risk for IgE-mediated atopy and 

asthma. 

Additionally, Kishikawa et al (1997) demonstrated that administration of the potent 

Th1-promoting cytokine, IL-12, to lead-exposed mice can restore the balance of Th1 (IFN-γ) vs. 

Th2 cytokines (e.g., IL-6), reduce corticosterone levels, and enhance host resistance in Listeriainfected mice. This observation supports the critical role of Th1/Th2 balance in overall risk to 

host resistance against disease presented by Pb disruption of that balance. 

5.9.6 Macrophage Function 

Macrophages represent a diverse population of cells that play critical roles in both host 

defense and tissue homeostasis. Macrophage subpopulations provide a front line of defense 

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against bacteria, parasites, viruses, and tumors via the innate immune response. Additionally, 

they are important in tissue repair and remodeling as well as in the removal of senescent cells. 

Some forms of macrophages are efficient in the processing of antigens and the presentation of 

antigen fragments to T lymphocytes. Additionally, macrophages can regulate lymphoid activity 

through the secretion of a variety of cytokines and through the production of various 

immunomodulatory metabolites (e.g., NO, ROIs) and the products of the cyclooxygenase and 

lipoxygenase pathways. 

Because macrophages can be found residing in most tissues, lead-induced modulation of 

macrophage functional capacity has the potential to alter overall organ function. Macrophages 

originate in the bone marrow from pluripotent stem cells that give rise to both the monocytemacrophage lineage as well as polymorphonuclear leukocyte populations. Bone marrow-derived 

macrophages mature under the influence of various cytokine growth factors to become the full 

array of mature cell subpopulations. Various investigators have examined the effects of lead on 

the maturation of macrophages in vitro as well as on the functional capacity on fully mature cells 

both in vitro and in vivo. Blood monocytes represent a functional, yet not fully specialized, form 

of macrophage. As a result the influence of environmental toxicants on monocytes may not be 

fully predictive of the effects of the same toxicants on splenic or alveolar macrophages, glial 

cells, or Kupffer cells. 

Because macrophages give rise to several specialized populations, e.g. Kupffer cells in the 

liver, glial cells in the brain, and various skin macrophage populations, it is important to realize 

that different specialized macrophage populations are likely to have somewhat different 

sensitivities to lead, as well as potentially different responses following exposure. Not 

surprisingly, blood monocytes may not always be an appropriate model to accurately predict the 

outcome of lead-induced immunotoxicity for alveolar macrophages following an inhalation 

exposure. 

The 1986 AQCD identified macrophages as a significant target for lead-induced 

immunotoxicity. Research since the mid-1980s has served to underscore this point. The 

understanding of lead-induced alterations in macrophage function has increased significantly 

since the prior AQCD report. The following sections describe the reported immunotoxic effects 

of lead on macrophages. It should be noted that for a number of endpoints, such as lead-induced 

alterations in the production of NO, ROIs and TNF-α, there is a general consensus among a 

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majority of immunotoxicology studies and agreement with the effects described for the 

cardiovascular system (see Chapter 5.5). 

5.9.6.1 Nitric Oxide (NO) Production 

Nitric oxide is a short-lived metabolite produced in large quantities by macrophages 

during cellular activation. The enzyme responsible is an inducible form of nitric oxide synthase 

(iNOS), which, utilizing a bioptrin cofactor, converts the amino acid arginine into NO and 

citrulline. A competing alternative pathway utilizing arginine leads to the production of 

polyamines, which themselves are immunomodulatory for lymphocytes. Nitric oxide is critical 

in the defense against certain infectious agents, including various bacteria. 

Among the most sensitive immunomodulatory effects of Pb exposure is the capacity to 

impair NO production by macrophages (Table AX5-9.6). Several research groups have shown 

that in vitro as well as in vivo exposure to Pb results in significantly reduced production of NO 

(Tian and Lawrence, 1995, 1996; Chen et al., 1997; Lee et al., 2001; Pineda-Zavaleta et al., 2004 

[also reviewed in Singh et al., 2003]). Similar results were obtained in human, mouse, rat and 

chicken. Depression of NO production capacity usually occurs shortly after exposure to lead. 

However, the long-term effects of Pb on NO production following very early life exposure are 

less clear (Miller et al., 1998; Chen et al., 1999; Bunn et al., 2001a). 

Tian and Lawrence (1996) have hypothesized that because very low Pb concentrations (in 

vitro equivalents to 10 μg/dL) can impair NO production, impaired NO production may be 

responsible for reduced host resistance to Listeria seen among lead-exposed rodents as well as 

for lead-induced hypertension among humans (Pirkle et al., 1985). Indeed, impaired NO 

production by macrophages seems to be one of the more sensitive endpoints for immediate leadinduced immunotoxicity. 

5.9.6.2 Other Functional Alterations 

TNF-α Production 

Early studies identified the fact that Pb exposure could predispose animals for a 

dramatically increased sensitivity to bacterially-derived endotoxin (Trejo et al., 1972; Filkins and 

Buchanan, 1973; Schlick and Friedberg, 1981). 

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It is now known that the increased sensitivity to endotoxin is linked to the capacity of Pb 

to increase production of TNF-α among macrophages (Dentener et al., 1989; Zelikoff et al., 

1993; Guo et al., 1996; Miller et al., 1998; Chen et al., 1999; Krocova et al., 2000; Flohe et al., 

2002). Studies in mouse, rat, rabbit, and human provide a clear indication that one effect of Pb 

on macrophages is to boost production of the proinflammatory cytokine TNF-α. While most 

studies examined the immediate effects of Pb exposure on TNF-α production, studies by Miller 

et al. (1998) and Chen et al. (1999, (2004) showed that the effects of early gestational exposure 

to Pb on macrophages could persist well into later life, including adulthood. Additionally, Chen 

et al. (1999) showed that chelation of Pb with succimer in developing female rats in utero could 

eliminate the persistent effect of elevated TNF-α production in the adult offspring. Flohe et al. 

(2002) found evidence that lead-induced elevation in TNF-α production is sensitive to both PKC 

signaling as well as to protein production. While the production of TNF-α can be elevated 

following exposure to lead, the expression of the receptor for TNF-α (ΤΝF-R) was also increased 

during the in vitro exposure of human blood monocytes to Pb-chloride (Guo et al., 1996). 

Therefore, the combined effect of elevated cytokine production by macrophages as well as 

increased receptor expression would be expected to contribute to problematic inflammatory 

responses. 

Production of Other Proinflammatory Cytokines 

Several studies have indicated that macrophage production of cytokines (or that levels of 

cytokines known to be produced primarily by macrophage populations) is altered after exposure 

to lead. These vary somewhat, depending upon the exposure protocol and the source of 

macrophages examined. In addition to the previously discussed elevation of TNF-α by lead, the 

most significant and consistent lead-induced effects seem to involve elevated production of the 

other major proinflammatory cytokines, interleukin-1$ (IL-1β) and IL-6. Increased production 

of IL-6 following exposure to Pb has been reported by Dyatlov and Lawrence (2002), Flohe et al. 

(2002), Kim and Lawrence (2000), Krocova et al. (2000), Kishikawa and Lawrence (1998) and 

Kishikawa et al. (1997). Because IL-6 is a proinflammatory cytokine, its increased production 

following Pb exposure has the potential to influence many different tissues. Dyatlov et al. 

(1998a,b) provided evidence that lead, IL-6 and LPS can combine to exert a significant impact 

on the permeability of the blood brain barrier as well as the properties of brain neurons and 

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endothelial cells. Lead-induced elevation of IL-1β production has been reported by Dyatlov and 

Lawrence (2002). It is probable that enhanced co-production of IL-1$ and IL-6 would increase 

the likelihood of local tissue inflammation. 

Production of Reactive Oxygen Intermediates (ROIs) 

Reactive oxygen intermediates (ROIs) are important metabolites in the capacity of 

macrophages and other inflammatory cells to kill invading bacteria and to attack cancer cells. 

However, increased overall production or inappropriate triggering of ROI release by 

macrophages can be a major contributor to tissue damage and the oxidation of cell surface lipids 

as well as DNA. The latter is one mechanism through which improperly regulated macrophages 

can actually increase the incidence of cancer. Results from many studies suggest that leadexposure of macrophages can increase the release of superoxide anion and/or hydrogen peroxide 

at least shortly after exposure. Key studies are summarized in Table AX5-9.6. 

In a recent study on environmentally exposed children in Mexico, Pineada-Zavaleta et al. 

(2004) reported that production of superoxide anion by directly activated (interferon-gamma + 

LPS) monocytes was directly correlated with blood Pb level. This was in contrast with the effect 

of arsenic, which had a negative association. In other studies involving low levels of exposures, 

Zelikoff et al. (1993) demonstrated that rabbits exposed to Pb via inhalation had pulmonary 

macrophages that produced elevated levels of both H2O2 and superoxide anion upon stimulation 

in vitro. In an in vitro study, Shabani and Rabani (2000) reported that Pb nitrate exposure 

produced a dose dependent increase in superoxide anion by rat alveolar macrophages. Baykov 

et al. (1996) fed BALB/c mice dietary Pb and found that peritoneal macrophages had an 

increased spontaneous release of H2O2. 

Other studies have reported no effects of Pb on superoxide anion production when a long 

recovery period was included following in vivo exposure (Miller et al., 1998) as well as negative 

effects of Pb on oxidative metabolism by certain macrophages or macrophage cell lines 

(Castranova et al., 1980; Hilbertz et al., 1986; Chen et al., 1997). These somewhat different 

results suggest that the subpopulations of macrophages examined (e.g., alveolar vs. splenic vs. 

peritoneal) and the timeframe of assessment relative to exposure may be important factors in the 

effect of Pb on ROI production. 

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The biological importance of increased ROI production by lead-exposed macrophages 

should not be underestimated. Fernadez-Cabezudo et al. (2003) demonstrated that the potent 

antioxidant, vitamin E could protect TO strain mice against some lead-induced 

immunosuppressive alterations. Hence, macrophage-associated oxidative damage following 

exposure to Pb may be a mitigating factor in nonlymphoid organ lead-induced pathologies. 

Arachidonic Acid Content and Prostaglandin Production 

Archidonic acid (AA) is a major surface component of many cells, including 

macrophages, and is the precursor of cyclooxygenase and lipoxygenase metabolites. As a result, 

the specific AA content of membranes and the capacity of macrophages to produce 

immunomodulatory metabolites from AA are important to overall health of the individual. One 

of the findings since 1986 concerning lead-induced modulation of macrophage function is the 

impact of Pb on PGE2 production. One study (Knowles and Donaldson, 1990) reported that diets 

supplemented with Pb at 500 ppm and fed to chicks produced an increase in the percentage of 

AA included in cell membranes. Such an increase would be expected to raise the risk of overall 

inflammation. 

Several groups have reported that Pb exposure increases macrophage production of the 

immunosuppressive metabolite PGE2. Lee and Battles (1994) reported that mouse macrophages 

exposed to Pb (10 μM) in vitro had elevated basal PGE2 production, but under some stimulatory 

conditions, had decreased production of PGE2. When Knowles and Donaldson (1997) fed Pb to 

turkey poults in the diet at a level of 100 ppm, macrophage production of prostaglandin F2 

(PGF2), PGE2 and thromboxane production were all significantly elevated vs. the control. Flohe 

et al. (2002) showed that exposure of mouse bone marrow-derived macrophages to Pb-chloride 

resulted in increased production of PGE2 that correlated with increased mRNA production for the 

necessary enzyme, prostaglandin H synthase type-2. 

Tissue Homeostasis 

In an important observation reflecting the impact of lead-induced immunotoxicity on 

nonlymphoid tissues, Pace et al. (2005) showed that neonatal exposure of mice to Pb-acetate via 

drinking water (0.1 ppm for 6 weeks, both through maternal nursing and direct) produced a 

significant reduction in the testicular macrophage population. This correlated with increased 

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estradiol levels in the testis and reduced male reproductive performance. The authors 

hypothesized that lead-induced alteration among testicular macrophages is linked to an impaired 

tissue environment that likely includes increased oxidative stress, apoptotic somatic cells, and 

reduced fertility of males. 

Colony Formation and Population Distribution 

The ability of bone marrow-derived macrophages (BMDM) to form colonies in response 

to certain growth factors (e.g., colony stimulating factor-1 [CSF-1]) is a property related to the 

growth and differentiation of subsequent macrophage populations. Kowelenko et al. (1991) 

found that exposure to CBA/J female mice to Pb-acetate (0.4 mM in drinking water for 2 weeks) 

reduced colony formation of macrophages in response to CSF-1. Infection of the mice with 

Listeria only exacerbated this effect of lead. The same authors (Kowelenko et al., 1989) had 

previously demonstrated that when BMDM were cultured in vitro with Pb-chloride (0.1 μM), 

colony formation was significantly impaired. These combined results suggest that exposure to 

Pb can impair the generation of macrophage populations as well as modulate the functional 

spectrum of fully matured macrophages. Bunn et al. (2001a) reported that gestational exposure 

of CD rats to 50 ppm Pb-acetate via the drinking water of the dams resulted in female adult 

offspring with a significantly decreased percentage (58% reduced) of circulating monocytes. 

A 100 ppm dose of Pb-acetate produced a significant reduction (74% reduced) in the absolute 

numbers of monocytes as well. The blood lead level at birth associated with the decreased 

percentage of macrophages in the adult offspring was 8.2 μg/dL. In general agreement, Lee 

et al. (2002) reported a significant decrease in the absolute numbers of circulating monocytes and 

polymorphonuclear leukocytes (PMNs) in juvenile female chickens exposed in ovo on 

embryonic day (E) 12 to 200 μg Pb-acetate. The corresponding blood lead level at hatching was 

11.0 μg/dL. However, in this case, the lead-induced reduction in monocytes and PMNs was only 

seen in concert with an airway viral infection (viral stressor) and not in the resting uninfected 

animal. 

Antigen Presentation and Lymphoid Stimulation 

Exposure to Pb influences the interaction between macrophages and T lymphocytes, and 

as a result, the capacity of macrophages to support T lymphocyte proliferation and activation can 

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be altered as well. Kowelenko et al. (1988) found that mouse macrophages exposed to Pb (both 

in vivo and in vitro) can induce an increased proliferative response of T lymphocytes in coculture but that antigen-specific stimulation of primed T cells is significantly reduced. 

Lead-suppressed antigen presentation capabilities of mouse macrophages were also reported by 

both Smith and Lawrence (1988) and Blakley and Archer (1981). 

Chemotaxis 

Chemotactic activity of macrophages is an important function required for the directed 

migration of macrophages to sites of infection and tumor growth. However, it is a functional 

capacity that has not been systematically examined within the lead-immune literature. Using 

female Moen-Chase guinea pigs, Kiremidjian-Schumacher et al. (1981) showed that Pb chloride 

exposure of peritoneal macrophages in vitro (10-6 μM) inhibited the electrophoretic mobility of 

the cells. 

Phagocytosis and Clearance of Particles 

Phagocytosis of targets and removal/clearance of dead cells and particles are major 

functions of macrophages. However, phagocytosis can involve a variety of different cell surface 

receptors on macrophages, depending upon both the nature of the target encountered and the 

subpopulation of macrophages examined. In general, phagocytic capacity of macrophages seems 

to be relatively insensitive to lead-induced immunomodulation compared with the effects on NO 

and TNF-α production. 

However, differences in outcome in phagocytosis evaluations are likely to be based on the 

differences in the source of macrophages used and their relative activation state at the time of 

assessment. A few studies have described significant effects on phagocytosis, but these have 

usually relied upon phagocytosis mediated through the Fc receptor on macrophages. Because 

cell adherence to surfaces may be influenced negatively by Pb (Sengupta and Bishali, 2002), 

impairment of phagocytosis may also involve some lack in efficiency with macrophage 

anchoring to substrates. De Guise et al. (2000) reported no effect on bovine macrophage 

phagocytosis of latex beads by Pb at in vitro treatment concentration of 104 M. This was in 

contrast with suppressive effects of both cadmium and mercury. Using Sephadex-elicited 

peritoneal macrophages derived from young turkeys fed 100 ppm Pb in the diet, Knowles and 

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Donaldson (1997) found a 50% reduction in the percentage of phagocytic macrophages using 

SRBC targets. The activity per phagocytic macrophage was also reduced. 

Kowolenko et al. (1988) studied the effect of Pb-acetate at 10 mM in the drinking water of 

CBA/J mice. They reported no effect on phagocytosis of Listeria monocytogenes targets, yet 

they found an overall decreased resistance to Listeria. When the same investigators exposed 

peritoneal and splenic macrophages to Pb in vitro (100 μM), they also found no significant effect 

of Pb on phagocytic activity. Jian et al. (1985) reported that New Zealand white rabbit-derived 

alveolar macrophages exposed to Pb in vitro at 10-5 M concentration were significantly impaired 

in the phagocytosis of opsonized chicken erythrocytes (Fc receptor-mediated phagocytosis). 

Trejo et al. (1972) reported that a single i.v. injection of Pb (5 mg/rat) into male Sprague Dawley 

(SD) strain rats produced an inhibition in the phagocytic capacity of Kupffer cells. 

Several studies have reported a decreased clearance capacity of the reticuloendothelial 

system following in vivo exposure to lead. Filkins and Buchanan (1973) found that injection of 

5 mg of Pb-acetate i.v. into male Holtzman strain rats produced reduced carbon clearance. 

Similarly, Trejo et al. (1972) reported that a single i.v. injection of Pb (2.5 mg) into male SD 

strain rats significantly reduced clearance of colloidal carbon. 

In contrast, Schlick and Friedberg (1981) found that 20 μg/kg Pb-acetate in a single i.p. 

injection of NMRI strain mice significantly increased the clearance of India ink. Ironically, oral 

administration of Pb for 10, but not 30, days of 10 μg/kg resulted in an increase in clearance 

activity. Difference in route of Pb administration may be a factor in the different results 

obtained. 

Induction of Heat Shock Proteins 

One study (Miller and Qureshi, 1992), using a macrophage cell line, reported that 

exposure of macrophages (MQ-NCSU) in culture to Pb-acetate (1000 μM) induced the same set 

of four heat shock proteins as when the macrophages were subjected to thermal stress. This 

result fits the hypothesis that Pb produces a profound immunomodulatory effect in macrophages 

that has similarities with the exposure of macrophages to certain pathogens. 

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Apoptosis 

Significant differences exist in the literature concerning the potential role of Pb in the 

apoptosis of macrophages. The difference may be based on the exposure methodologies (in vivo 

vs. in vitro) as well as the source of macrophages utilized. De la Fuente et al. (2002) found that 

human monocytes exposed to Pb in vitro at high concentrations did not undergo apoptosis. This 

was in direct contrast with the apoptosis-promoting effects of cadmium in the same assessment 

protocol. In contrast, Shabani and Rabibani (2000) exposed rat alveolar macrophage to Pb 

nitrate in vitro and found that 60 μM concentration produced a significant increase (2x) in DNA 

fragmentation after 3 to 24 h in culture. 

5.9.7 Granulocytes and Natural Killer (NK) Cells 

Other cell types important in innate immunity, as well as in immunoregulation, are the 

lymphoid population of natural killer cells and granulocytes, including PMNs (i.e., neutrophils). 

Neither population appears to be a major target for lead-induced immunotoxicity, although both 

may be influenced indirectly via immune cell-cell interactions as well as by changes in cytokine 

production. Among the two, neutrophils may be the more sensitive cell type based on assays 

conducted to date. For neutrophils, several groups have reported alteration in chemotactic 

activity following exposure to lead. Queiroz et al. (1993) found impaired migration ability of 

neutrophils from battery workers occupationally exposed to lead. Likewise, Valentino et al. 

(1991) had a similar observation among male occupationally exposed workers. Lead exposure of 

young SD strain rats can increase the population of neutrophils (Villagra et al., 1997), although, 

as the authors indicated, this does not necessarily afford enhanced host protection against 

disease. Baginski and Grube (1991) reported that human neutrophils exposed to Pb had 

increased killing capacity, probably via increased release of ROIs despite having reduced 

phagocytic capacity. This would fit the same general profile as the effects of Pb on 

macrophages. Therefore, neutrophils may contribute to lead-induced tissue inflammation and 

damage via increased ROI release. Yet, their effectiveness in protection against disease 

challenge may be no greater following exposure to Pb, because some impairment in chemotaxis 

and phagocytosis has been reported as well. 

Yucesoy et al. (1997) reported that either Pb exposure or simultaneous exposure to Pb and 

cadmium in human workers did not impair NK cytotoxicity activity. This finding was supported 

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by studies using in vivo exposure to Pb in rats (Kimber et al., 1986) and mice (Neilan et al., 

1983). Therefore, it would appear that NK cells are not a prime target associated with leadinduced immunotoxicity, although more subtle effects may certainly exist within the cell type. 

Eosinophils represent an important granulocytic cell type in type 2 associated 

inflammatory and allergic reactions. However, few studies have examined Pb exposure and 

eosinophil activity. Villagra et al. (1997) reported that exposure of female juvenile SD rats to Pb 

[four alternate-day s.c. injections of 172 mg/g body wt Pb-acetate] increased the degranulation of 

eosinophils (in animals given estrogen 1 day later). Such a response would be expected to 

contribute to increased inflammation. 

5.9.8 Hypersensitivity and Autoimmunity 

At the time of preparation of the 1986 AQCD, little was known about the potential for Pb 

to influence the risk of allergic and autoimmune diseases. However, since the early 1990s, a 

significant number of studies have all pointed toward the fact that Pb causes a profound 

dysregulation of the immune system. It skews the balance of responses in directions that reduce 

certain host defenses against infectious diseases while enhancing the risk of allergic and 

autoimmune disease. Lead exposure at low to moderate levels appears to alter T lymphocyte 

responses in such a way as to increase the risk of atopy, asthma, and some forms of 

autoimmunity. Increased IgE production following exposure to Pb is among the most frequently 

reported immune alterations. Elevated IgE levels would be an associated risk factor for atopy 

and allergic disease. Several investigators have discussed the fact that Pb is a likely risk factor 

associated with the increased incidence of childhood allergic asthma (Miller et al., 1998; Heo 

et al., 1998; Snyder et al., 2000; McCabe et al., 2001; Dietert et al., 2004; Transande and 

Thurston, 2005) as well as later life allergic disease (Heo et al., 2004). Joseph et al. (2005) 

observed no association for childhood BLL and risk of asthma among an African-American 

population. However, results on other populations from this study, including those involving 

Caucasian children with BLLs above 5 μg/dL, led the authors to call for further studies into the 

possible linkage of early life lead exposure and risk of asthma (Joseph et al., 2005). 

As described by McCabe et al. (1991) and discussed by Dietert et al. (2004), lead-induced 

immunotoxicity is novel in that profound cellular toxicity is not evident following exposure at 

low to moderate exposure concentrations. In fact, antibody responses overall are usually 

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unaffected or may be increased depending upon the class/isotype measured. However, the 

functional responses mounted following Pb exposure do not reflect the normal immune balance 

that would otherwise occur. This dysregulation can alter the risk of certain autoimmune diseases 

based on several observations. Holladay (1999) has considered the importance of the timing of 

exposure and the fact that early life exposure may establish the immune profile that then 

contributes to later disease including autoimmunity. 

Hudson et al. (2003) reported that exposure to Pb can exacerbate systemic lupus 

erythmatosus (SLE) in lupus-prone strains of mice. In contrast with the effect of mercury, these 

authors found that for lupus, Pb exposure would not induce this autoimmune condition in 

genetically resistant mice but would increase severity of the disease in genetically prone animals. 

The authors noted some gender effects within certain strains (e.g., NZM88). Using early in ovo 

exposure to Pb (10 μg/egg), Bunn et al. (2000) found that Pb-acetate-exposed male chicks could 

be induced to produce autoantibodies against thyroglobulin, which were not present in acetateexposed controls. No lead-induced alteration was observed in females that were predisposed to 

mount anti-thyroglobulin responses. The gender effect is intriguing in that autoimmune 

thyroiditis in genetically predisposed strains is always more severe in females than in males. 

Two lines of evidence suggest that the capacity of Pb to influence the risk of 

autoimmunity is not always associated with simply a strict shift from Th1 to Th2 responses. 

Hudson et al. (2003) discussed the fact that lupus is not purely a Th2-mediated disease, but rather 

seems to occur under conditions associated with skewing in either direction. McCabe et al. 

(2001) found that Pb can increase the stimulation of alloantigen reactive T cells (where 

macrophage processing of antigen is required) but not enhancement of T cell clonotypic 

responses against either mitogens or superantigens (where processing is not required). This 

suggests that the role of Pb in influencing risk of autoimmune disease goes beyond a simple 

consideration of Th1/Th2 balance. In fact, Goebel et al. (2000), studying mucosal immunity, 

reported that administration of Pb-chloride to NOD strain mice produced a gut cytokine 

microenvironment that was skewed toward Th2 over the short run, but later was shifted toward 

Th1 with increased production of IFN-γ. This shift to Th1 was accompanied by a loss of 

tolerance and capacity to mount an immune response against a diet-associated protein (chicken 

ovalbumin). The authors proposed that reduction of the capacity for oral tolerance would 

predispose an individual toward autoimmune disease. 

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Finally, Waterman et al. (1994) and El-Fawal et al. (1999) have described the production 

of autoantibodies against neural proteins in both battery workers and rats exposed to low levels 

of Pb via drinking water. These authors have suggested that exposure to Pb may precipitate the 

autoimmunity by altering antigen immunogenicity and/or the capacity of the immune system to 

respond to certain antigens. This, in turn, may contribute to the eventual lead-associated 

neurological disease. 

5.9.9 Mechanism of Lead-Based Immunomodulation 

In the 1986 AQCD, there was little direct information available about the immune system 

regarding the molecular mechanism(s) of lead-induced immunotoxicity. Binding to thiol groups 

and altering cell surface receptors were indicated as possible factors in altered immune function. 

Since that time, some additional information has been generated through a variety of studies on 

human and animal immune cells. However, a clear or simple explanation remains to be 

determined. Table 5-9.3 lists studies on the immune system that have contributed to a better 

understanding of potential mechanisms or have forwarded potential hypotheses with some 

supporting data. 

At the level of cell-cell interactions, it seems clear that Pb alters metabolism and cytokine 

production by macrophages and antigen presenting cells. It also reduces their capacity to 

respond to growth factors such as CSF-1 (Kowelenko et al., 1989). Pace et al. (2005) discussed 

the hypothesis that reduced populations of functionally altered macrophages (because of leadinduced unresponsiveness to CSF-1and over production of ROIs) in tissues can produce 

nonimmune problems. The model they used is the homeostatic presence of testicular 

macrophages and the likelihood that lead-induced macrophage immunotoxicity contributes 

directly to lead-associated reduction in male fertility. 

Additionally, Pb is known to selectively alter cell signaling to CD4+ T cell 

subpopulations, promoting proliferation in some but not others. The outcome is enhanced tissue 

inflammation, reduced CMI, and increased production of atopy-inducing antibodies. Risk of 

autoimmune reactions is increased in some models of lead-induced immunotoxicity. For 

example, Heo et al. (1997) reported that lead-exposed murine T lymphocytes are biased in 

expression of V$ genes. This is potentially problematic as this phenotype is common among a 

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Table 5-9.3. Suggested Mechanisms of Lead-Induced Immunotoxicity 

Associated Lowest 

Species Strain/Gender 

Suggested 

Endpoints 

Functional 

Alteration 

Effective 

Dose Duration References 

Mouse Balb/c CSF-1 

Responsiveness of 

Macrophages 

LTesticular 

macrophages 

LFertility 

0.1 ppm 6 weeks Pace et al. 

(2005) 

Mouse TO strain males Vitamin E 

protection against 

lead-induced 

splenomegaly 

KPutative ROI 

associated 

splenomegaly 

1 mg/kg 2 weeks FernandezCabezudo 

et al. (2003) 

Chicken Cornell K Strain Thymulin partial 

reversal of Th 

skewing 

LLead-induced 

DTH 

suppression 

400 μg Single in 

ovo 

injection 

Lee and 

Dietert, 

(2003) 

Mouse Balb/c females 

C57 Bl/6 

females 

Lead disruption of 

antigen 

processing and 

presentation 

signals 

KAlloreactive 

CD4+ high cells 

KRisk of 

autoimmunity 

0.5 μM in 

vitro 

4 days McCabe et 

al. (2001) 

Mouse C 57Bl/6 PKC activation KTNF-α, KIL-6 

KPGE2 

20μM in 

vitro 

4.5 hrs Flohe et al. 

(2002) 

Rat PC-12 cells NF-κB activation 

AP-1 induction 

C-Jun kinase 

KROI 1 μM in 

vitro 

5-120 min Ramesh et 

al. (1999) 

induction 

Mouse DO11.10 ovamice Adenylcyclase 

activation with 

elevated cAMP 

KTh skewing 2.5 μM in 

vitro 

15 mins6 hrs Heo et al. 

(1998) 

levels 

Mouse DO11.10 ova-tg 

mice 

Vβ gene usage KRisk of 

autoimmunity 

50 μg 

2x/week 

8 weeks Heo et al. 

(1997) 

s.c. 

Human - NF-κB activation 

in CD4+ cells 

KRisk of 

autoimmunity 

and 

1 μM 30 min Pyatt et al. 

(1996) 

hypersensitivity 

Mouse CBA/J females KImmunogenicity 

of neural proteins 

KAutoimmune 

mediated 

neurological 

damage 

Leadaltered 

proteins 

used as 

antigens 

3 injections 

of leadmodified 

neural 

proteins 

Waterman, 

et al. (1994) 

Mouse Swiss Females KTNF-α 

production 

KSensitivity to 

endotoxin 

5 mg Single i.p. 

injection 

Dentener et 

al. (1989) 

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variety of human and animal model autoimmune conditions. A variety of exogenous factors 

have been reported to partially ameliorate the immunotoxic effects of lead. Chelation of Pb in 

lead-exposed dams corrected some lead-induced immunotoxic problems in the rat female 

offspring, but it left the animals with some DMSA-induced immune alterations (Chen et al., 

1999). Other exogenously administered factors that have been reported to partially restore 

lead-suppressed immune function are vitamin E (Fernandez-Carbezudo et al., 2003) and 

thymulin (Lee and Dietert, 2003). 

At the subcellular level, the bases for immunotoxic changes remain speculative. McCabe 

et al. (2001) suggested that altered antigen processing and subsequent cell signaling to T cells 

may be an explanation for the capacity of Pb to selectively increase CD4+ (high density) cells. 

Certainly Pb appears to alter signal transduction. It appears to elevate expression of the nuclear 

transcription factor NF-κB (Pyatt et al., 1996; Ramesh et al., 1999) as well as increase 

expression of AP-1 and cJun (Ramesh et al., 1999). Flohe et al. (2002) found evidence that Pb 

can elevate the activation of PKC. The authors speculated that this might be involved in leadinduced increases in TNF-α production. Additionally, Heo et al. (1998) reported that Pb 

increases adenyl cyclase activity among T lymphocytes, generating elevated cAMP levels. The 

authors hypothesized that this effect, in conjunction with differences in cell signaling pathways 

for promoting Th1 vs. Th2 cells, may be involved in the capacity of Pb to skew Th0 helper cells 

toward Th2. 

5.9.10 Age-Based Differences in Sensitivity 

With the literature available at the time of the 1986 AQCD, it was virtually impossible to 

evaluate age-based differences in susceptibility to lead-induced immunotoxicity. However, in 

recent years, this has become a major topic of study for many toxicants including lead. Several 

studies have added to the available data assessing the developmental immunotoxicity of Pb 

(reviewed in Barnett [1996], Dietert et al. [2000, 2004], Lee and Dietert [2005]). Several 

patterns have emerged from exposure data using animals of different ages. 

First, it seems clear that blood Pb levels at or near birth of below 10 μg/dL can be 

associated with juvenile and/or adult immunotoxicity. Several studies reported effects in the 

range of 5-8 μg/dL. These low levels would seem to place the immune system on par with the 

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402(c) Economic Analysis Chapter 5 313
1 neurological system in terms of potential sensitivity to lead. Table 5-9.4 shows examples of 

2 studies in which low blood lead levels were linked with immunotoxicity. 

Table 5-9.4. Immunomodulation Associated with Low Blood Lead Levels 

in Animals 

Blood lead Age at Age at 

Species (μg/dL) Measurement Immune Parameter(s) Assessment Reference 

Mouse ~5.0 1 week KIgE, 2 weeks Snyder et al. 

L Splenic (2000) 

T Cell Populations 

Rat 8.2 1 day Lmonocytes 13 weeks Bunn et al. 

(2001a) 

Rat 6.75 4 weeks LDTH, 13 weeks Chen et al. (2004) 

LIFN-γ, 

KIL-4 

Rat 8.0 4 weeks KTNF-α 13 weeks Lee et al. (2002) 

KRel. Spleen weight 

Chicken 8.2 1 day Lcirculating lymphocytes post 5 weeks Lee et al. (2002) 

infection 

Chicken 11.0 1 day LDTH and LTLC, monocytes, 5 weeks Lee et al. (2001) 

PMNs post infection 

Chicken 7.0 1 day Kautoantibody production 10 weeks Bunn et al. (2000) 

3 A second finding is that the immunotoxic effects induced by Pb are persistent long after 

4 blood levels and potential body burdens of Pb are significantly reduced. Miller et al. (1998), 

5 Chen et al. (1999), Snyder et al. (2000), and Lee et al. (2001) all emphasize this latter point. 

6 In fact, in most of these studies immunotoxic alterations were present when Pb levels in exposed 

7 animals were not distinguishable from control levels. This should provide a cautionary note 

8 regarding studies in humans. Data from adult exposures provides little insight into the potential 

9 persistence following adult exposure to lead. However, rather than the developing immune 

10 system being more regenerative postexposure and able to withstand immunotoxic insult, it 

11 appears that the non-dispersed developing immune system is a particularly susceptible target to 

12 many immunotoxicants (Dietert et al., 2002). 

13 A third, and somewhat surprising, finding concerning early exposure to Pb is that 

14 qualitative differences in the spectrum of immune alterations can exist, depending upon the 

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developmental window of exposure. Figure 5-9.1 illustrates this point. Early embryonic 

exposure of rats and chickens to Pb failed to alter juvenile DTH responses, despite significant 

effects on macrophage function. However, exposure to Pb after the mid-embryonic point of 

embryonic development readily suppressed subsequent DTH. As shown in Figure 5-9.1, the 

development window in which sensitivity to DTH suppression emerges is quite similar in the 

two species. This observation suggests that both quantitative (LOAELs) and qualitative (range 

of immune alterations) differences in sensitivity to Pb can exist across different age groups. 

Additionally, some studies in animals have noted gender differences in the effects of Pb 

following exposure (Bunn et al., 2000, 2001a,b, c; Hudson et al., 2003). Gender differences 

have also extended to results in humans as per lead-induced immune and inflammatory 

alterations (Karmaus et al., 2005; Fortoul et al., 2005). It seems feasible that, even in the 

embryo, hormonal differences among females and males may impact some outcomes of lowlevel Pb exposure. 

Table 5-9.5 shows comparisons of the lowest reported blood Pb levels at different ages 

associated with the same immunotoxic endpoint. From these limited comparisons, it would 

appear that different ages of rodents (e.g., embryonic vs. adult) differ in dose sensitivity for leadinduced immunotoxicity somewhere in the range of 3 to 12-fold. Clearly, additional direct 

comparisons would help to refine this estimate. 

A fourth observation from the early exposure studies is that exposure to even very low 

levels of Pb can predispose the immune system for unanticipated postnatal responses when the 

system is stressed. This general phenomenon is called latency. Lee et al. (2002) provided an 

example of this following the single in ovo exposure of embryonic day 5 chick embryos to low 

levels of Pb (10 μg; blood lead level 1 day post hatch of 8.2 μg/dL). The leukocyte profiles of 

the animals appeared to be completely normal. However, when these animals were exposed to a 

respiratory virus, their pattern of leukocyte mobilization was completely aberrant from controls. 

Therefore, some immunotoxic alterations following early exposure to low levels of Pb may only 

be evident during periods of postnatal stress. 

Several studies have reported the positive association of blood Pb levels in children with 

elevated serum IgE (Karmaus et al., 2005; Sun et al., 2003; Lutz et al., 1999). These 

observations are supported by the animal data in rats and mice (Miller et al., 1998; Snyder et al., 

2000) and suggest that lead-induced risk of atopy and asthma may be a particular health issue. 

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Table 5-9.5. Comparisons of Age-Based Sensitivity to Lead-Induced Immunotoxicity 

Species Altered Endpoint Embryo – fetal* Neonatal* Adult* References 

Mouse KIgE ~5μg/dL 12 μg/dL 38 μg/dL Snyder et al. 

(2000) 

Heo et al. (1996) 

Rat LDTH 34 μg/dL - >112 μg/dL Miller et al. 

(persistent effect assessed (measured at birth (1998) 

13 weeks post-exposure) for persistent Bunn et al. 

effect) (2001b) 

Mouse LDTH - 29 μg/dL 87 μg/dL Faith et al. (1979) 

McCabe et al. 

(1999) 

Rat KTNF - α 8 μg/dL − >112 μg/dL Miller et al. 

(persistent effect assessed (measured at birth (1998) 

13 weeks post-exposure) for persistent Chen et al. (2004) 

effect) 

* Lowest blood lead concentration reported with effect 

1 Trasande et al. (2005) recently discussed the fact that, despite progress in reducing the 

2 deposition of Pb in the environment, Pb continues to be a concern relative to asthma and 

3 children’s health. 

4 

5 5.9.11 Summary and Conclusions 

6 The immune system appears to be one of the more sensitive systems to the toxic effects of 

7 lead. The 1986 AQCD provided an excellent summary of the studies that had been conducted 

8 prior to that date. But knowledge of fundamental immunology has progressed greatly during the 

9 past 20 years. Not surprisingly, the large number of studies conducted since the mid-1980s 

10 provided a much clearer understanding of the immune-associated problems that can arise from 

11 problematic exposure to lead. Studies across humans and a variety of animal models are in 

12 general agreement concerning both the nature of the immunotoxicity induced by Pb as well as 

13 the exposure conditions that are required to produce immunomodulation. Figure 5-9.2 

14 summarizes the basic immunotoxic changes induced by Pb that result in Th skewing, impaired 

15 macrophage function, and increased risk of inflammation-associated tissue damage. 

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402(c) Economic Analysis Chapter 5 316
Figure 5-9.2. This figure shows the fundamental alterations to the immune system and to 

immunological response and recognition induced by exposure to lead. The 

functional shifts are disproportionate compared to the relatively modest 

changes among leukocytes with low to moderate exposure to lead. 

1 Lead is unlike many immunotoxicants in that, at low to moderate levels of exposure, it 

2 does not produce overt cellular cytotoxicity or lymphoid organ pathology. However, it can 

3 induce profound functional alterations that influence risk of disease. Lead preferentially targets 

4 macrophages and T lymphocytes, although effects have been reported in B cells and neutrophils 

5 as well. There are three major hallmarks of lead-induced immunotoxicity. First, Pb can 

6 dramatically suppress the Th1-dependent DTH response, as well as production of associated Th1 

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cytokines. Second, Pb can dramatically elevate production of IgE while increasing production of 

Th2 cytokines, such as IL-4. Third, and perhaps most sensitive, is the modulation of 

macrophages by Pb into a hyperinflammatory phenotype. After exposure to lead, macrophages 

significantly increase production of the proinflammatory cytokines TNF-α and IL-6 (and in some 

studies IL-1). Many studies also reported elevated release of ROIs and prostaglandins. 

Ironically, production of one of the most important host defense factors, NO, is consistently and 

severely suppressed by exposure to lead. This package of lead-induced changes among 

macrophages makes them more prone to promote tissue destruction but actually less capable of 

killing bacteria or possibly presenting antigens to T lymphocytes. The Pb-induced shift in 

phenotype explains the capacity of inhaled Pb to promote bronchial inflammation while bacterial 

resistance is severely depressed. 

Lead-induced skewing of Th activity (biasing responses toward Th2) across a population 

would lead to the expectation of a greater risk of atopy, asthma, and some forms of 

autoimmunity. Concomitantly, resistance to some infectious diseases could be reduced. This 

predicted change of risk might help explain some recent trends in the incidence of diseases, such 

as the epidemic rise in allergy and some forms of asthma in the United States. 

Sensitivity of the immune system to Pb appears to differ across life stages. Studies in rats 

and mice suggest that the gestation period is the most sensitive life stage followed by the early 

neonatal stage. But even during embryonic, fetal, and early neonatal development, critical 

windows of vulnerability are likely to exist. Compared to adults, the increased dose sensitivity 

of the embryo-fetus would appear to fall in the range of 3-10x depending upon the immune 

endpoint considered. Some studies have found evidence for gender differences in the impact of 

Pb on the immune system particularly with early life exposures. Potential gender differences in 

immunotoxic outcome may be important in the evaluation of those populations at greatest risk. 

Recent studies have suggested that exposure of embryos to Pb producing neonatal blood 

lead concentrations below 10 μg/dL can also produce later-life immunotoxicity (see 

Table 5-9.4). Furthermore, immunotoxicity persists long after any evidence of prior embryonic 

Pb exposure. This latter observation from several laboratories may have implications for the 

design of human epidemiological studies. 

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5.10 EFFECTS OF LEAD ON OTHER ORGAN SYSTEMS 

In the 1986 Pb AQCD, the discussion of other organ systems included cardiovascular, 

hepatic, gastrointestinal (GI), and endocrine systems. Due to our increased understanding on the 

effects of Pb on cardiovascular and renal systems and their contribution to potential health 

effects of Pb, separate sections (5.5, 5.7) were dedicated earlier in this chapter to detailed 

discussions on these aspects. Similarly, with our increased understanding on the effects of Pb on 

endocrine functions and its inherent role with respect to neurotoxicological, reproductive, and 

developmental effects, literature reviewed for Pb effects on the endocrine system is discussed in 

the respective sections. This section focuses on the discussion of Pb effects on the hepatic and 

GI systems. 

5.10.1 Effects of Lead on the Hepatic System 

The liver is a highly active metabolic tissue. Apart from its roles in fatty acid metabolism 

and limited heme synthesis function, the liver also has a major role in guarding other systems 

from the toxic effects of xenobiotic compounds using a huge complement of detoxification 

machinery referred to as phase I and phase II enzyme systems. Limited studies on experimental 

animals reported in the 1986 Pb AQCD indicated that Pb induced effects in the hepatic system. 

Laboratory animals, especially rats, exposed to Pb-nitrate have exhibited increased liver cell 

proliferation, DNA synthesis, cholesterol synthesis, and glucose -6-phosphate dehydrogenase 

(G6PD) activity indicative of Pb-induced hyperplasia. Further, the literature reviewed in the 

1986 Pb AQCD reported alterations in the levels of drug metabolizing enzymes in experimental 

animals given large doses of Pb. The evidence for such effects in humans was less consistent. 

The 1986 document also concluded that the effects on the liver occurred only at high exposure 

levels. The majority of studies on the effects of Pb on the hepatic system in experimental 

animals that are reviewed in this document report functional and biochemical changes in the 

liver, clearly pointing to metabolic perturbations in liver. For ease in understanding and 

integration of these functional changes, the discussion is divided into the following four 

subsections: hepatic drug metabolism, lipid and glycogen metabolism and lipid peroxidation, 

heme synthesis, and toxicity mitigation by chelation and other interventions. 

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5.10.1.1 Hepatic Drug Metabolism 

Approximately 75% of the hepatic blood comes directly from the gastrointestinal viscera, 

with the majority of drugs or xenobiotics absorbed coming directly to the liver in concentrated 

form. The liver is equipped with a huge complement of drug metabolizing enzymes that detoxify 

many of the xenobiotics but also activate the toxicity of others. Oxidation and conjugation of 

xenobiotics have historically been referred to as phase I and phase II reactions. The phase I 

enzymes include cytochrome P450 (CYP450) heme-containing monoxygenases, flavincontaining monoxygenases, and epoxide hydrolases. The phase II enzymes include glutathione 

(GSH) S-transferases (GST), UDP-glucuronyl transferases (UGT), N-acetyltransferases (NAT), 

and sulfotransferases (SULT). Xenobiotic metabolism by these two complements of enzyme 

systems are essential for catabolizing and eliminating of drugs; however, this process can also 

produce activated toxicants and carcinogens. A limited number of these CYP450s are involved 

in the biosynthetic pathways of steroid and bile acid production. It has been increasingly 

recognized that, under certain circumstances, CYP P450s can produce ROS that result in 

oxidative stress and cell death. 

Liver is an active tissue. In addition to xenobiotic metabolism, it also participates in 

gluconeogenesis, fatty acid metabolism, and cholesterol biosynthesis. Research concerning the 

effects of Pb on the hepatic system in the past 15 years has provided some preliminary 

indications of Pb-induced alterations in many of the hepatic functions described above. The 

following discussion presents, as much as possible, the effects of Pb on individual enzymes, but 

due to the multifarious interactions of many of these metabolic enzymes, there may be places 

such separation was not possible. 

Phase I Enzyme 

Earlier studies on the toxic effects of Pb on hepatic drug metabolizing enzymes 

demonstrated that acute exposure to Pb-acetate decreased rat hepatic CYP450s with increased 

levels of urinary *-aminolevulinic acid (ALA). Co-treatment with phenobarbitol, a CYP450 

inducer, was shown to reverse the decrease CYP450 levels, suggesting a Pb-acetate-mediated 

inhibition of heme synthetic enzymes. Decreased activities of estradiol-17 beta enzyme 

observed in rat liver treated with triethyl Pb-chloride (Odenbro and Arhenius, 1984) suggest that 

both Pb and organo-Pb compounds are capable of inhibiting CYP450 activities. Roomi et al. 

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(1986) also observed decreased levels of hepatic microsomal CYP450s and decreased 

aminopyrene-N-demethylase activity on exposure to a single dose of Pb-nitrate (5-10 mmol/kg 

body wt). This decrease in phase I enzymes was followed by increased levels of phase II 

components such as GSH, GST, and DT diaphorase, suggesting that Pb-nitrate and Pb 

compounds can induce biochemical properties characteristic of hepatocyte nodules. Subchronic 

(2-3 months) exposure to Pb-acetate (5-50 mg/kg body wt) had been found to induce CYP450s 

and cytochrome b5 in rat liver and kidney (Nehru and Kaushal, 1992). As described earlier, 

multiple isoforms of CYP450s exist in the liver. 

To identify the inhibitory effect of acute Pb exposure on specific isoform(s), Degawa 

et al. (1994) exposed male F344 rats to Pb nitrate (20,100 μmol/kg body wt) and evaluated liver 

CYP450s 24 h postexposure. Lead-nitrate exposure preferentially inhibited cytochrome 

P4501A2 enzyme activity in liver microsomal preparations as assayed for mutagenic conversion 

of substrates 2-amino-6-methyl-dipyridol [1,2-a; 3',2-d] imidazole and 3-amino-1-methyl-5Hpyridol[4,3,-b]indole. Lead-nitrate exposure also inhibited the induction of cytochrome 

P4501A2 by the inducers 3-methylcholanthrene and 2-methoxy-4-aminoazobenzene at both the 

protein and mRNA levels. The authors further concluded that the specific inhibition of P4501A2 

by Pb-nitrate observed may have been due to inhibition of heme synthesis, as Pb-nitrate was not 

found to inhibit P4501A2 activity in vitro. Additional studies carried out by the same group 

using various metal ions (e.g., Pb, Ni, Co, and Cd) found that the specific inhibition of P4501A2 

was unique to Pb-nitrate (Degawa et al., 1994, 1995). Degawa et al. (1996) also investigated the 

effect of Pb-nitrate-mediated inhibition of CYP1A gene activity in rat liver by specific inducers 

and reported that Pb-nitrate inhibited the induction of CYP1A mRNA by aromatic amines, but 

not by aryl hydrocarbons, suggesting the role of other cellular factors in the transcriptional 

activation of CYP1A genes. Lead-nitrate has been reported to induce the production of TNF-α

in rat liver (Shinozuka et al., 1994), a cytokine implicated in the suppression of constitutive 

expression of CYP1A2 mRNA in rat hepatocytes. Based on these findings, Degawa et al. (1996) 

concluded that the inhibition of constitutive and aromatic amine-induced expression of CYP1A2 

in rat liver caused by Pb-nitrate may occur at least in part by TNF-α-associated mechanisms. 

Lead-nitrate (0.33 mg/kg body wt) pretreatment-mediated protection conferred against carbon 

tetrachloride (0.3 mL/kg)-induced hepatotoxicity as reported by Calabrese et al. (1995) may be 

due to the inhibition of CYP450 activities in liver by Pb. 

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Jover et al. (1996) investigated the effect of heme deficiency on Pb-induced hepatic P450 

function and transcription. These authors concluded that the decrease in hepatic P450 resulting 

from Pb intoxication was mediated by two different mechanisms. One mechanism is involved 

inhibitory effects on P450 by Pb at the transcriptional level; the second was heme- dependent, as 

Pb-mediated inhibition of heme synthesis decreased the heme saturation of P450 and the apoP450 ratio. 

The effect of heavy metals (Cd, Co, Cu, Ni, Pb, and Zn) on 3-methylcholanthreneinduction of cytochrome P4501A and the activity of ethoxyresorufin-O-deethylase (EROD) were 

investigated in fish hepatoma cells (PLHC-1) by Brucshweiler et al. (1996). The authors 

reported that all the heavy metals tested had more pronounced effects on EROD activity 

compared to controls. The inhibitory potency of Pb was reported to be very low compared to 

cadmium or cobalt. A single treatment of Pb-acetate induced hepatic DT diaphorase activity 

(Sugiura et al., 1993). This induction of hepatic DT diaphorase by Pb-acetate has been reported 

to be decreased with concomitant administration of Dil, a calcium antagonist. Based on these 

observations, Arizono et al. (1996) suggested that DT diaphorase induction by Pb-acetate may 

occur de novo via protein synthesis mediated by increased cellular calcium. The potential 

interaction of metals, including Pb, on the induction of CYP1A1 and CYP1A2 by polycyclic 

aromatic hydrocarbons (PAHs) in human hepatocyte cultures was investigated by Vakharia et al. 

(2001). Lead-nitrate, like other metals such as Cd, Hg, and As, decreased the extent of CYP1A1 

and CYP1A2 induction by five different PAHs. The authors concluded from these studies that 

Pb (5 μM) diminished the induction of CYP1A1 and CYP1A2 in human hepatocytes by 

ultimately decreasing the levels of CYP1A1 protein that was normally attainable through PAH 

induction. Korashy and El-Kadi (2004) also investigated similar interactions of metals with aryl 

hydrocarbon receptor (AHR)-regulated gene expression and enzyme activities in wild-type 

murine hepatoma cells (Hepa 1c1c7) and AHR-deficient cells (C12). These studies indicated 

that metals alone (including Pb) did not significantly alter CYP1A1 proteins or activity, or 

change AHR ligand-induced enzyme activity. There was no change in mRNA levels. Lead, in 

the presence or absence of AHR ligand, increased the activity of NAD(P)H:quinone 

oxidoreductase and its mRNA levels. 

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Phase II Enzymes 

A single injection of Pb-nitrate (5-10 μM/100 g body wt) was found to increase GST 

activity levels (Roomi et al., 1986). Additional studies by the same group identified induction of 

a specific form GST-P by Pb-nitrate in rat liver (Roomi et al., 1987). Because a single injection 

of Pb-nitrate decreased phase I and increased phase II hepatic enzymes, these investigators 

concluded that Pb-nitrate treatment initiated a biochemical phenotype similar to carcinogeninduced hepatocyte nodules. Immunohistochemical analysis by the same group reported that Pbnitrate administration resulted in the appearance of GST-P in most of the hepatocytes, an enzyme 

that is otherwise undetectable in normal rat liver (Columbano et al., 1988; Roomi et al., 1987). 

On the other hand, Nakagawa (1991) reported inhibition of GST on acute exposure to Pb and 

that the inhibition of GST followed a reduction in liver GSH levels. Nakagawa (1991) 

concluded that the depletion of GSH was not necessarily a critical factor in inhibiting GST. 

Planas-Bohne and Elizdale (1992) reported that acute exposure to Pb-nitrate 

(100 μmol/kg) caused a significant increase in liver and kidney GST activity. Gel 

electrophoresis analysis to evaluate the contribution of various GST isoforms indicated that 

enhancement of liver GST activity was predominantly due to induction of GST isoform 7-7 in 

liver compared to all isoforms in kidney. Liver GST-P isoform was reported to be induced by 

both Pb-acetate and Pb-nitrate (Boyce and Mantle, 1993; Koo et al., 1994). This transient 

induction of GST-P has been regulated at transcription, post-transcription, and post-translational 

levels. Suzuki et al. (1996) utilized a transgenic approach to investigate the transcriptional 

regulation of GST-P induced by Pb and identified glutathione S-transferase P enhancer I (GPEI), 

an enhancer (whose core consists of two AP-1 site-like sequences) located at the 5' flanking 

region of this gene. The authors demonstrated that GPEI is an essential element in the activation 

of the GST-P by Pb and that the trans activating factor AP-1 is likely to be involved, at least in 

part, in the transcriptional activation of the GST-P gene by Pb via the GPEI sequence. 

Daggett et al. (1997, 1998) investigated the effect of inorganic and organic Pb on liver 

GST expression and other phase II detoxifying enzymes in rat liver and kidney. Triethyl Pb 

chloride (TEL) injection (10 mg/kg body wt) decreased liver GST activity, as well as levels of 

various other GST isoforms (Daggett et al., 1997), in contrast to significant induction of kidney 

GST activity, suggesting that a single compound, TEL, had opposite effects on the expression of 

GST isozymes and indicated the complexity of GST regulation. Similarly, this group also 

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reported that a single injection of Pb-acetate (114 mg/kg body wt) reduced GSH levels, increased 

production of malondialdehyde (MDA), and did not change the expression of various GST 

isoforms analyzed, except GST-p1 on repeated injection (Daggett et al., 1998). Similar to 

studies with TEL, Pb-acetate also increased the expression of GST enzyme activity and 

expression of various isoforms without changing GSH and MDA levels, suggesting that 

oxidative stress may not be mediating the toxicity in kidney. On the other hand, TEL exposure 

was found to decrease microsomal estradiol metabolism (Odenbro and Rafter, 1988). The 

suppression of GST expression reported by Daggett et al. (1997, 1998) is in contrast to the 

induction of GST reported by various other groups discussed earlier. Other GSH-dependent 

enzymes (i.e., GSH peroxidase, GSH reductase) have been found to be suppressed with a 

simultaneous increase in oxidized GSH (GSSG) and a reduction in GSH/GSSG ratio (Sandhir 

and Gill, 1995). More detailed information on these and related studies is summarized in 

Table AX5-10.1. 

5.10.1.2 Biochemical and Molecular Perturbations in Lead-Induced Liver Tissue Injury 

Oskarsson and Hellström-Lindahl et al. (1989) studied the cellular transport of Pb (203Pb), 

in rat hepatocytes using dithiocarbamate (DTC). Cells treated with Pb-acetate and Pb-DTC 

lipophylic complex demonstrated increased cytosolic Pb levels compared to Pb alone. This was 

further evaluated by measuring levels of ALAD. Cells treated with Pb-DTC complex showed 

rapid and stronger inhibition of ALAD compared to Pb-acetate, suggesting that this inhibition 

was due to increased mobilization of Pb into cells treated with Pb-DTC complex. Another report 

by the same group, Hellström-Lindahl and Oskarsson (1990), suggested that the increased 

inhibition of ALAD was due to the release of Pb from the Pb-DTC complex by decomposition. 

Using the mouse strain with a duplication of the ALAD gene (DBA), Claudio et al. (1997) 

reported increased accumulation of Pb in this strain by many fold as compared to mice with a 

single copy of the ALAD gene (C57). 

A single injection of Pb-nitrate was reported to cause hepatic hyperplasia correlating with 

hepatic de novo synthesis of cholesterol along with alterations in glucose and lipid metabolism 

leading to altered serum lipid profiles (Dessi et al., 1984; Pani et al., 1984). Mobilization of 

hepatic glycogen and altered gluconeogenic enzymes, including differential expression of G6PD, 

have been reported following Pb exposure (Batetta et al., 1990; Hacker et al., 1990). Chronic Pb 

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intoxication has also been reported to inhibit gluconeogenic enzymes, alterations that were 

implicated in Pb bio-transformation rather than liver cell proliferation in Wistar rats (Calabrese 

and Baldwin, 1992). Increased levels of serum lipid peroxide (LPO) were also observed in rats 

given SC injection of Pb-acetate, supporting similar increased levels of serum LPO in humans 

exposed to Pb (Ito et al., 1985). These initial studies suggest that alterations in liver intermediary 

metabolism occur on exposure to Pb with a role for Pb-induced LPO in hepatotoxicity and 

potential involvement of oxidative stress in Pb toxicity. 

Dessi et al. (1990 ) investigated the role of fasting on Pb-induced hepatic hyperplasia by 

monitoring the activities of enzymes involved in cholesterol synthesis and the hexose 

monophosphate shunt and reported that stimulation of these enzymes, even in Pb-acetate-treated 

fasting rats, supported the role of new endogenous synthesis of cholesterol and gluconeogenic 

mechanisms in Pb-induced hepatic cell proliferation. Chronic exposure to Pb was found to 

increase the arachidonate/linoleic acid ratio in liver and serum (Donaldson and Leeming, 1984; 

Donaldson et al., 1985) along with the GSG concentration (McGowan and Donaldson, 1987). 

As GSH and arachidonate are precursors for peptido-leukotrienes, Donaldson=s group 

investigated the potential effects of dietary Pb on levels of fatty acids, peptido-leukotrienes, and 

arachidonate/linoleic ratios in chicken fed with diets low in calcium and methionine. These 

investigations found similar increases in arachidonate/linoelic acid ratio and in GSH levels 

without bearing on peptido-leukotriene levels. The authors also found the influence of a low 

calcium and methionine diet on Pb-induced serum fatty acid profiles (Knowles and Donaldson, 

1990). 

Chronic sublethal exposure (5 ppm Pb-nitrate for 30 days) has been found to alter liver 

lipid profiles in blood and liver tissue of the fresh water fish Anabas testudineus (Tulasi et al., 

1992). These authors reported significant increases in liver total lipids, cholesterol, and free fatty 

acids. Tandon et al. (1994b) reported that iron deficiency enhanced the accumulation of Pb in 

liver and kidney and also increased liver calcium levels. Induced expression of metallothionein 

(MT) in renal and intestine was also observed in iron deficiency. Han et al. (1996) investigated 

the effect of Pb burden on weight loss using an energy restriction diet regimen on rats with prior 

Pb exposure. The authors reported that rats on a substantial weight loss regimen (40% of normal 

calories) exhibited a significant increase in the quantity and concentration of liver Pb and a 

decrease in the concentration of other metals (e.g., Ca, Cu, Mg, Zn). The authors concluded that 

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weight loss can increase the liver concentration of Pb, even in the absence of continued 

exposure. Combined exposure to Pb (70 mg/kg) and Cd (20 mg/kg) in Buffalo rats for 7 weeks 

was found to alter liver levels of Zn and Cu, with less accumulation of Pb and Cd, compared to 

individuals exposure to either Pb or Cd alone (Skoczynska et al., 1993). These authors also 

reported that a combined exposure regimen interfered with serum lipid profiles (Skoczynska and 

Smolik, 1994). 

Liu et al. (1997) utilized rat primary hepatocyte cultures to explore the protective effect of 

Zn-induced expression of metallothionein (MT) in Pb toxicity. These authors found that, in the 

control cells without prior Zn exposure, most of the Pb was found bound to high-molecular 

weight proteins in the cytosol, while in the Zn pretreated cells, a majority of Pb bound to MT, 

indicating a MT-mediated protection against Pb toxicity to hepatocytes. More details about these 

and related studies are summarized in Table AX5-10.2. 

5.10.1.3 Effects of Lead Exposure on Hepatic Cholesterol Metabolism 

Lead-nitrate-induced hyperplasia or liver cell proliferation involves simultaneous increase 

in both liver and serum total cholesterol levels. Recent studies have reported various molecular 

events associated with this process. Induction of gene expression for CYP51 (Lanosterol 

14α-demethylase), an essential enzyme for cholesterol biosynthesis, was reported in Pb-nitrateinduced liver hyperplasia, although other cytochrome P450 enzymes involved in drug 

metabolism have been reported as being suppressed, as discussed in earlier sections. This gene 

has various regulatory elements and its constitutive expression in liver is mediated by sterol 

regulatory element (SRE) and by the SRE binding proteins-1a, 2, and 1c. Kojima et al. (2002) 

reported that Pb-nitrate induced the expression of CYP51 in the livers of both immature (4-weekold) and mature (7-week-old) rats and that this induction appeared to be mediated by the 

upregulation of SRE binding protein-2. However, this increased synthesis of cholesterol 

observed in rat liver was not mediated by endogenous feedback regulation by sterols, as no 

decrease in serum total cholesterol was observed. To understand the molecular mechanisms 

involved in the Pb-nitrate-mediated development of hepatic hypercholesterolemia, Kojima et al. 

(2004) investigated the expression of various enzymes involved in cholesterol homeostasis, 

including some of the associated transcription factors in male rats exposed to Pb-nitrate 

(100 μmol/kg body wt). The authors reported that Pb-nitrate exposure caused a significant 

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402(c) Economic Analysis Chapter 5 326
1 increase in liver and serum total cholesterol levels at 3-72 h and 12-72 h, respectively. The 

2 enzymes involved in cholesterol biosynthesis viz. (i.e., 3-hydroxy-3methyglutaryl-CoA 

3 reductase, farnesyl diphosphate synthase, squalene synthase, CYP51) were all activated (3-24 h), 

4 while the enzymes involved in cholesterol catabolism such as 7α-hydroxylase were remarkably 

5 suppressed 3-72 h. Figure 5-10.1 shows the involvement of Pb at various stages of the 

6 cholesterol synthesis pathway. The induction of the cytokines interleukin-1α and TNF-α in rat 

7 liver prior to the induction of the genes for these synthesis enzymes suggested that Pb-nitrate8 induced cholesterol synthesis is independent of sterol homeostasis regulation. Following 

9 gestational and lactational exposure to Pb-acetate (0.05 mg/kg body wt), Pillai and Gupta (2005) 

10 reported that the activities of the hepatic steroid metabolizing enzyme 17-$-hydroxy steroid 

11 reductase, UDP glucouronyl transferase, and CYP450 levels decreased in rat pups on PND21. 

Figure 5-10.1. Flow diagram indicating the Pb effects on the cholesterol synthesis pathway. 

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402(c) Economic Analysis Chapter 5 327
1 Alterations in the hepatic system of neonates and pups (at PND12 and PND21) after 

2 gestational and lactational exposure to Pb-acetate (300 mg/L) have been reported by Corpas et al. 

3 (2002). The authors found significant reductions in the liver weight of pups and in hepatic 

4 glycogen that correlated with increased blood glucose levels. The authors also reported 

5 reductions in liver protein, lipid levels, and alkaline and acid phosphatase activities but did not 

6 find any gross structural alterations in liver tissue. These and other studies are summarized in 

7 Table AX5-10.3. 

8 

9 5.10.1.4 Effect of Chelation Therapy on Lead-Induced Hepatic Oxidative Stress 

10 Although several mechanisms have been proposed to explain Pb toxicity, no mechanism 

11 has been defined explicitly. Recent literature on Pb toxicity suggests oxidative stress as one of 

12 the important mechanisms of toxic effects of Pb in liver, kidneys, brain, and other organs. 

13 Schematic representation of the various mechanisms by which Pb induces lipid 

14 peroxidation is shown Figure 5-10.2. Lead toxicity to the liver has been found to be associated 

15 with significant accumulation of Pb in the liver. This results in the accentuation of lipid 

16 peroxidation with concomitant inhibition of antioxidant enzymes (i.e., SOD, catalase, GSH 

17 peroxidase, GSH reductase) and a simultaneous increase in GSSG with a reduction in 

18 GSH/GSSG ratio (Sandhir and Gill, 1995; Aykin-Burns et al., 2003). However, Furono et al. 

19 (1996) studied the potential of various redox-active metals to induce LPO in normal and alpha20 linolenic acid-loaded rat hepatocytes and suggested that Pb ions were not capable of inducing 

21 lipid peroxidation in such hepatocytes. 

Figure 5-10.2. Schematic diagram illustrating the mode of Pb-induced lipid peroxidation. 

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The currently approved clinical intervention method is to give chelating agents that form 

an insoluble complex with Pb and remove the same from Pb-burdened tissues. The efficacy of 

various chelating agents and antioxidants studied in experimental animals on Pb induced liver 

toxicity is discussed below. 

Chelation therapy with mono-3-methylbutane-1-yl (monoisomyl) ester of meso-2,3-

dimercaptosuccinic acid (Mi-DMSA) and meso-DMSA (meso-2,3-dimercaptosuccinic acid) was 

found to offer no protection to suckling rat pups as measured by liver Pb levels (Cory-Slechta, 

1988; Blanusa et al., 1995; Pappas et al., 1995; Smith et al., 2000). Similar studies by Kostial 

et al. (1999), using various isoforms of DMSA, EDTA, and combined therapy, did not find a 

chelator-mediated reduction in liver Pb levels except for meso-DMSA (0.5 mmol/kg), which 

caused significant reduction in Pb levels in kidney and brain. On the other hand, it decreased 

liver zinc and copper levels. The authors concluded that combined therapy may not be the best 

choice at this age, because infants are more sensitive to trace metal deficiency. Flora and Seth 

(1999) investigated the protective role of S-adenosyl-L-methionine (SAM) on acute Pb and 

Pb + thanol-induced hepatic toxicity in mice by monitoring hepatic GSH and MDA levels. The 

authors concluded that bioaccumulation of Pb in liver in both Pb- and Pb + ethanol-exposed 

groups were significantly decreased by SAM. 

To identify the efficacy of chelation therapy (mono or combined therapy) for acute Pb 

poisoning in infants, Kostial et al. (1999) utilized suckling rat pups and monitored tissue Pb 

levels. Monotherapy of either EDTA (0.3 mmol/kg), meso-DMSA (0.5 mmol/kg), rac-DMSA 

(racemic-2,3-meso-2,3-dimercaptosuccinic acid, 0.5 mmol/kg), or a combined therapy of 

EDTA + meso-DMSA, EDTA + rac-DMSO indicated differential effects on liver tissue Pb and 

other trace metal levels. The authors concluded that meso-DMSA was the more potent therapy 

for acute Pb poisoning in infants and suggested that combined therapy may not be the best 

choice, as at this age the infants are more sensitive to trace metal deficiency. 

Supplementation with sodium molybdate (1 mg/kg body wt) during the course of Pb 

exposure (0.1% Pb-acetate in water for 4 weeks) was found to provide significant protection 

from the uptake of Pb by blood, liver and kidneys and also from hepatic LPO (Flora et al., 1993). 

Similarly, supplementation with antioxidants and vitamins were explored to reduce the toxic 

effects of Pb on liver function and activity. Oral supplementation of vitamin C (100 mg/kg for 

3 days) has been reported to provide significant protection against Pb-induced declines in liver 

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heme synthesis, drug metabolism, tissue thiols, and vitamin C levels along with reduction in liver 

Pb levels (Vij et al., 1998). Similarly, simultaneous administration of vitamin E (5 mg/kg body 

wt) was reported to confer protection against Pb-induced decline in hepatic type-1 iodothyronine 

5'-monodeiodinase activity, inhibition of SOD and catalase activities, and increased lipid 

peroxidation (Chaurasia and Kar, 1997). Studies by Tandon et al. (1997) also suggested that Pb 

and Pb + ethanol-induced biochemical changes in mouse liver can be prevented by the 

simultaneous administration of lysine and zinc. This regimen was also reported to prevent the 

Pb-induced depletion of endogenous calcium and magnesium in liver. Two well-known 

antioxidants, N-acetylcysteine and lipoic acid, have been reported to reduce Pb-induced 

oxidative stress (OS) both in vitro in Chinese hamster ovary cells and in vivo in F344 rats (Ercal 

et al., 1996; Gurer et al., 1998, 1999b). The same group also investigated the protective effects 

of another antioxidant, taurine, against Pb-induced OS in the same systems both in vitro and in 

vivo. These authors reported that taurine was effective by increasing cellular GSH while 

simultaneously reducing malondiablehde (MAD) and catalase activity levels, offering protection 

against Pb-acetate-induced OS, without decreasing the liver or blood Pb levels (Gurer et al., 

2001). Patra et al. (2001) studied the ameliorative effects of antioxidants (i.e., ascorbic acid, 

vitamin E, L-methionine) alone and vitamin E + EDTA on Pb-induced OS in liver, kidney, and 

brain tissues of rats exposed to Pb-acetate (1 mg/kg body wt, 4 weeks) and found that all the 

antioxidants used conferred protection against OS without a significant decline in tissue Pb 

burden. The level of protection conferred exhibited tissue-specific differences. L-Methionine 

was also found to offer similar protection in mice exposed to Pb (Xie et al., 2003). Othman and 

El Missiry (1998) reported that administration of selenium (sodium selinite, 10 μM/kg body wt) 

prior to Pb-acetate (100 μM/kg body wt) produced pronounced prophylactic action against Pbinduced LPO in liver and kidney of male albino rats. 

In earlier combination chelation therapy using thiamine and Ca2+-EDTA, Kim et al. 

(1992) reported that regardless of the route of exposure, reduction in liver tissue retention of 

203Pb occurred, while thiamine alone reduced only the Pb content of kidney. Recent studies used 

a combination of chelators with antioxidants to reduce Pb-induced OS in liver and other tissues 

(i.e., kidney and brain). α-Lipoic acid, meso-DMSA, and their combination was found to reduce 

OS by increasing hepatic GSH levels and reducing GSSG and thiobarbituric acid reactive 

substances (Pande and Flora, 2002). The same group also studied the protective effect of the 

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combination of ascorbic acid, vitamin E, meso-DMSA, and miADMSA and found a significant 

reduction in hepatic OS by the combination therapy of ascorbic acid and thiol chelators (i.e., 

DMSA, miADMSA) in rat. The combination therapy also produced similar reduction in renal 

OS (Flora et al., 2003). Studies reported by Varnai et al., (2003) suggested that ascorbic acid 

supplementation did not improve the efficiency of meso-DMSA in reducing Pb-induced OS in 

suckling rats. On the other hand, combined treatment of ascorbic acid (1 mg/100 g body wt) and 

silymarian (1 mg/100 g body wt) has been reported (Shalan et al., 2005) to cause marked 

improvement of the biochemical, molecular and histopathological changes caused by Pb-acetate 

(500 mg/kg body wt). Similarly, combined treatment with lipoic acid + DMSA has been found 

to completely ameliorate Pb-acetate-induced oxidative damage. However, either lipoic acid or 

DMSA alone conferred partial protection against Pb-induced hepatic damage (Sivaprasad et al., 

2004). These and related studies are summarized in Table AX5-10.4. 

5.10.1.5 Lead-Induced Liver Hyperplasia: Mediators and Molecular Mechanisms 

The biochemical and molecular events associated with Pb-induced hyperplasia has been 

accumulating in the scientific literature. Lead-nitrate, a known mitogen, is also considered to be 

a carcinogen that induces liver cell proliferation in rats without any accompanying liver cell 

necrosis. It has been recognized that this proliferation is a transient process and that apoptosis 

plays a major role in the regression of Pb-nitrate-induced hepatic hyperplasia (Nakajima et al., 

1995). Columbano et al. (1996) studied the cell proliferation and regression phases by apoptosis 

in Wistar male rat liver by monitoring the incorporation of tritiated thymidine as a marker for 

increased DNA synthesis. These studies demonstrated the production of Pb-induced 

proliferation 3 days after a single injection of Pb-nitrate with complete regression of hyperplasia 

seen after 15 days. The authors suggested that the apoptosis process observed in the regression 

phase also involved newly initiated hepatocytes. On the other hand, Dini et al. (1999) reported 

the regressive or involutive phase as beginning 5 days post single injection of Pb-nitrate. 

Apostoli et al. (2000) evaluated the proliferative effects of various Pb salts (i.e., Pb-acetate, Pbchloride, Pb-monoxide, Pb-sulfate) using liver-derived REL cells. These authors reported that 

all the Pb compounds tested showed dose- and time-dependent effects on the proliferation of 

REL cells. Unlike other tumor promoters, Pb compounds did not exhibit effects on cell 

junctional coupling. Liver hyperplasia induced by Pb-nitrate has been shown to demonstrate 

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sexual dimorphism in all phases of the proliferation as well as in apoptosis (Tessitore et al., 

1995). Biochemical changes associated with liver hyperplasia in the intermediary metabolic 

pathways were discussed in earlier sections of this chapter; the present discussion focuses on 

other molecular characteristics of this process. As the numerous molecular networks involved in 

both the proliferation and apoptosis processes have many common mediators and pathways, it is 

very difficult to provide a discussion without an overlap. 

DNA hypomethylation has been recognized to play a major role in the proliferation of 

cells in regenerating and in hepatic pre-malignant lesions when compared to normal non-dividing 

liver cells. A single dose of Pb-nitrate (75 μM/kg body wt) has been found to cause extensive 

hypomethylation in rat liver (Kanduc et al., 1991). Additional investigations from the same 

group reported that this hypomethylation status of liver DNA by Pb-nitrate changed significantly 

with age and exhibited liver cell specificity (Kanduc and Prisco, 1992). 

Investigations of cell cycle-dependent expression of proto-oncogenes in Pb-nitrate 

(10 μM/100 g body wt)-induced liver cell proliferation by Coni et al. (1989) showed that peak 

DNA synthesis occurred at 36 h after a single injection of Pb-nitrate. In addition to DNA 

synthesis, induced expression of c-fos, c-myc, and c-Ha-ras oncogenes was also observed in rat 

liver tissue. Additional studies by the same group reported that Pb-nitrate-induced liver 

hyperplasia involved an increased expression of c-jun in the absence of c-fos expression (Coni 

et al., 1993). The induced expression of c-myc persisted up to 40 h post Pb-nitrate exposure. 

Pb-nitrate-induced liver proliferation and DNA synthesis, as monitored by 5-bromo-2- 

deoxyuridine immunohistochemistry, lead to DNA labeling in a few hepatocytes (Rijhsinghani 

et al., 1993). The observed DNA synthesis appeared to be due to the increased activity and 

expression of DNA polymerase-α observed at 8 h postexposure to a single injection of Pb-nitrate 

(Menegazzi et al., 1992). Along with DNA synthesis, poly (ADP-ribose) polymerase was also 

induced by Pb-nitrate (Menegazzi et al., 1990). Differential activation of various PKC isoforms, 

downregulation of PKC-α, and marked activation of PKC-, in Pb-nitrate-mediated liver 

hyperplasia suggested the involvement of these PKC enzymes in DNA synthesis and related 

signal transduction pathways (Tessitore et al., 1994; Liu et al., 1997). 

Coni et al. (1992) reported the proliferation of normal and pre-neoplastic hepatic cells 

treated with the plasma derived from male Wistar rats treated with a single injection of Pbnitrate; this was the first report on the secretion of biological cell proliferation signals in the liver 

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after Pb-nitrate treatment. These authors reported that DNA synthesis was detected as early as 

30 min and persisted up to 5 days after Pb-nitrate exposure. This observation has opened up the 

inquiry into the involvement of various growth factors and other biological mediators in hepatic 

hyperplasia. Shinozuka et al. (1994) investigated the expression of various growth factors (i.e., 

hepatocyte growth factor, TGF-α, TGF-$) in rat liver after a single injection of Pb-nitrate 

(100 μM/kg body wt) and reported the involvement of these growth factors in liver cell 

proliferation. Additional studies by this group to observe LPS sensitivity in rats given Pb nitrate 

reported that animals given a single injection of LPS up to 100 μg survived, whereas in the 

presence of Pb-nitrate, they tolerated only 6 μg of LPS, indicating that Pb-nitrate may sensitize 

the animals for LPS toxicity. 

Earlier studies by Honchel et al. (1991) reported that coexposure of rats to Pb-acetate 

(15 mg/kg) and LPS or TNF showed markedly increased serum levels for various liver injury 

parameters. They concluded that Pb may potentiate liver toxicity by LPS via a TNF-mediated 

pathway. The role of TNF-α in Pb-nitrate-induced liver cell proliferation was further 

investigated by (Ledda-Columbano et al., 1994) who demonstrated the inhibition of Pb-nitrateinduced cell proliferation by pretreatment with dexamethasone, an inhibitor of TNF-α

expression. Additional studies by the same group evaluated the liver cell specificity in Pbnitrate-induced cell proliferation (Shinozuka et al., 1996). They monitored the incorporation of 

5-bromo-2-deoxyuridine by immunohistochemical analysis on rat liver as induced by Pb-nitrate 

and TNF-α and observed 5-bromo-2-deoxyuridine incorporation in hepatocytes and nonparenchymal cells (i.e., Kupffer cells, endothelial cells, periportal nondescript cells), confirming 

that Pb-induced liver cell proliferation was mediated by TNF-α. Kubo et al. (1996) used various 

TNF-α inhibitors to further confirm the role of TNF-α in Pb-nitrate-induced hepatocyte 

proliferation. Menegazzi et al. (1997) reported that Pb-nitrate induced proliferation involved the 

induction of iNOS along with TNF-α and that appeared to be mediated by a strong, prolonged 

activation of NF6B but not activator protein-1 (AP-1). Nemoto et al. (2000) investigated the 

potential role of neurotrophins and their receptors in Pb-nitrate-induced hepatic hyperplasia. The 

expression profile of TNF-α, neurotrophins (i.e., nerve growth factor, brain-derived neurotrophic 

factor neurotrophin-3 and (their receptors), tyrosine kinase receptor (Trk) and neurotrophin 

receptor (p75NTR) were investigated in liver tissue after a single injection of Pb-nitrate 

(100 μM/kg body wt). The Pb-nitrate induced increased expression of TNF-α preceded the 

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expression of the neurotrophins and their receptors. Based on these results, the author=s 

suggested that neurotrophins and neurotrophin receptors are involved in mediating mitogenic 

signals related to hepatic hyperplasia. 

The regression phase of Pb-induced liver hyperplasia appears to be mediated by OS. 

As discussed earlier, this process involves LPO and other cytokine mediators, including TNF-α. 

Sieg and Billings (1997) reported that Pb potentiated cytokine-induced OS, producing a 

significant decline in intracellular ATP concentration in mouse hepatocyte culture studies. The 

authors suggested that cytotoxic interaction between Pb and cytokines (e.g., TNF-α and IFN) 

may be mediated by oxidative DNA damage resulting from OS. The potential role OS along 

with TNF-α has been implicated in the apoptosis of hepatocytes by Milosevic and Maier (2000). 

Using freshly isolated cultures of hepatocytes and Kupffer cells and their co-culture system 

exposed to Pb-acetate (2-50 μM) and LPS (0.1-1000 ng/mL), the authors reported that, in the 

co-culture system, the Pb-LPS-induced release of TNF-α from the Kupffer cells, increased nitric 

oxide levels by 6-fold and downregulated the acute phase protein, albumin, in hepatocytes. 

From these observations the authors concluded that Pb-induced Kupffer cell-derived signals 

promoted the toxicity of Pb in hepatocytes, resulting in hepatocyte death by proteolysis. The 

importance of the Kupffer cells role in Pb-nitrate-induced heptatocyte apoptosis was further 

demonstrated (Pagliara et al., 2003a,b). These authors reported that in vivo hepatic apoptosis 

including oxidative response induced by Pb-nitrate, was prevented by pretreatment with 

gadolinium chloride, a Kupffer cell toxicant that specifically suppresses Kupffer cell activity. 

When treated hepatocytes were exposed in vitro to Pb-nitrate, hepatocyte apoptosis was not 

observed. On the other hand, hepatocyte apoptosis was evident when the hepatocytes were 

incubated with culture medium derived from Kupffer cells that had been exposed to Pb-nitrate. 

Based on these studies, the authors concluded that heptocyte apoptosis was potentiated by 

soluble factors secreted by Pb-exposed Kupffer cells. The role of activated Kupffer cells, 

macrophages, and TNF-α in chemical-induced hepatotoxicity is presented schematically in 

Figure 5-10.3. 

Dini et al. (1993) investigated the expression of asialoglycoprotein receptors on the 

surface of hepatocytes and galactose-specific receptors of non-parenchymal cells during the 

apoptic phase of Pb-induced hepatic hyperplasia. A significant increase in asialoglycoprotein 

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402(c) Economic Analysis Chapter 5 334
Figure 5-10.3. Hypothesis of chemical-induced liver injury generated primarily on the 

basis of different types of inhibitors. 

1 receptor expression in hepatocytes coincided with massive apoptosis. Later studies from this 

2 group demonstrated that sinusoidal liver cells predominantly phagocytosed the Pb-nitrate3 induced apoptic hepatic cells and concluded that this process appeared to be mediated by the cell 

4 surface carbohydrate receptors (i.e., mannose and galactose receptors) (Ruzittu et al., 1999). 

5 Pretreatment of rats with gadolinium chloride, a kupffer cell toxicant, was also found to abolish 

6 the altered expression of galactose receptors (Pagliara et al., 2003b). 

7 The role of glucocorticoid-mediated signal transduction in the hepatotoxicity of Pb was 

8 evaluated by Heiman and Tonner (1995), using H4-IIE-C3 hepatoma cells (HTC). Acute 

9 exposure of cells to Pb (300 nM!1

 or 10 μM) was found to inhibit processes involved in 

10 glucocorticoid-mediated enzyme induction (e.g., tyrosine aminotransferase activity) in a dose11 dependent manner both at the transcriptional and translational level, without altering 

12 glucocorticoid receptor binding characteristics. Tonner and Heiman (1997) also reported 

13 Pb-induced hepatotoxicity by glucocorticoid-mediated signaling and its involvement in the 

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interference with calcium-mediated events as well as the differential modulation and 

translocation of protein kinase isoforms α and $ into the nucleus. More information on these and 

other related studies is summarized in Table AX5-10.5. 

5.10.1.6 Effects of Lead on Liver Heme Synthesis 

Effects of Pb on heme metabolism have been extensively investigated in major target 

tissues such as liver and erythrocytes. Section 5.2 described Pb effects on heme synthesis, with 

particular relevance to erythrocytes. The effects of Pb on heme synthesis in the liver and the role 

of chelation therapy in this process are discussed in this section. 

Fifteen percent of heme is produced in the liver. Heme metabolism in the liver is an 

essential component of various cytochrome P450s that participate in cellular redox reactions and 

xenobiotic detoxification pathways in the liver tissue and, hence, heme plays a vital role in liver 

function (Jover et al., 1996). Due to the important and critical role of heme in liver function, 

Pb-induced effects on hepatic heme metabolism are discussed below. 

Initial studies on the effects of Pb-nitrate on hepatic heme biosynthesis were reported by 

Lake and Gerschenson (1978) using the rat liver cell line (RLC-GAI). The effects of various 

organic metal compounds on ALAD activity have been studied by Bondy (1986). The authors 

reported that triethyl Pb-chloride has the same potency as Pb-nitrate in inhibiting ALAD both in 

vitro and in vivo, with liver and blood ALAD exhibiting similar sensitivities to Pb compounds. 

By measuring the conversion of ALA into heme, these authors showed that heme biosynthesis 

was inhibited by Pb in a dose dependent manner. Using a lipophilic complex of Pb-acetate + 

DTC to increase the cellular uptake of Pb, Osksarsson et al. (1989) demonstrated the inhibition 

of ALAD activity in primary rat hepatocytes cultures. Lead-acetate has been reported to inhibit 

ALAD activity in rabbit liver tissue without any effect on delta-aminolevulinic acid synthase 

(ALA-synthase) activity (Zereba and Chemielnicka, 1992). Exposure to Pb (500 ppm) in 

drinking water did not inhibit hepatic ALA-synthase, but did inhibit ALA-dehydratase activity in 

mice (Tomokuni et al., 1991). Exposure to Pb-acetate (20 mg/kg body wt for 3 days) has been 

reported to decrease hepatic ALAD and uroporphyrinogen activity (Satija and Vij, 1995). These 

authors also reported that IP injection of zinc (5 mg/kg body wt for 3 days) conferred protection 

against Pb-acetate effects in liver tissue. 

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Effects of Pb on hepatic porphyrins, intermediate metabolites of heme metabolism, were 

investigated by few researchers. Quntanilla-Vega et al. (1995) reported that 3T3-hepatocyte 

cultures, when incubated with a micromolar concentration of Pb-acetate increased cellular 

porphyrin content and excretion. This increased porphyrin production may have been due to an 

accumulation of protoporphyrin and coproporphyrin, as in coproporphyrinuria, a wellcharacterized sign of Pb intoxication (Ichiba and Tomokuni, 1987; Zereba and Chemielnicka, 

1992). Dietary supplementation of selenium and monensin increased Pb-induced accumulation 

of prophyrins in chicken liver (Khan and Szarek, 1994). Species-specific differences in the 

effects of Pb on protoporphyrins were reported by Jacobs et al. (1998). These authors 

investigated the effect of Pb on zinc protoporphyrin synthesis in cultured chick and rat 

hepatocytes and observed decreased levels of protoporphyrin in rat hepatocytes, but no effect on 

chick hepatocytes. Santos et al. (1999) also reported Pb-induced derangements (including 

porphyrin metabolism) in rat liver heme metabolism, but these effects were far less severe than 

those observed in erythrocytes. Their investigations on the effect of chronic alcoholism on Pb 

effects in hepatic heme metabolism suggested no potentiation by alcohol. 

Transferrin (TF) is the major iron-transport protein in serum and other biological fluids. 

Transferrin can also has the capacity to transport other metals. Lead was found to inhibit TF 

endocytosis and transport of iron across the cell membrane of rabbit reticulocytes (Qian and 

Morgan, 1990). The effect of Pb on TF gene expression was investigated by Adrian et al. (1993) 

using a transgenic mouse with the human TF gene. They found that Pb suppressed the 

expression of TF transgene in mouse liver at the transcriptional level; however, the same dose of 

Pb did not inhibit mouse endogenous hepatic TF gene expression. Lead exposure was also found 

to inhibit recombinant TF expression in human hepatoma hepG2 cells. Other studies by the 

same group found that Pb exposure suppressed the expression of endogenous TF in HepG2 cells 

(Barnum-Huckins et al., 1997). These authors further suggested that Pb effects on hepatic TF 

levels may also interfere with iron metabolism in humans. (See Annex Table AX5-10.6 for more 

information on these and related studies.) 

5.10.1.7 Summary 

Extensive in vivo and in vitro experimental evidence has accumulated over the past 

20 years and increased our understanding of the potential toxic effects of Pb in the hepatic 

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system. These studies ranged from simple biochemical studies to molecular characterizations of 

the induction of drug-metabolizing enzymes, liver hyperplasia, and the protective effects of 

chelation therapy. 

• Rat liver microsomal cytochrome P-450 levels were found to decrease with a single dose 

exposure of Pb nitrate. Inhibition of both constitutive and induced expression of 

microsomal P450 A1 and A2 activity occurred. Simultaneous induction of the activities 

of phase II drug metabolizing enzymes with decreased phase I enzymes with single 

exposure to Pb nitrate suggests biochemical properties similar to hepatic nodules. 

• Newer studies examined the induction of GST-P at both transcriptional and translational 

levels using in vitro systems and indicated a role for Pb-nitrate and Pb-acetate in the 

induction process. On the other hand, triethyl Pb compounds have been found to 

suppress the activity of various GST isoforms. 

• Studies on Pb-induced liver hyperplasia demonstrated de novo synthesis of cholesterol, 

alterations in the gluconeogenic mechanism, as well as DNA hypomethylation and 

subsequent changes in the expression of protooncogenes. 

• Lead-induced alterations in cholesterol metabolism appear to be mediated by the 

induction of several enzymes related to cholesterol metabolism and the decrease of 7 

α-hydroxylase, a cholesterol catabolizing enzyme. This regulation of cholesterol 

homeostasis is modulated by changes in cytokine expression and related signaling. 

• Studies using an inhibitor to block TNF-α have clearly demonstrated TNF-α as one of the 

major mitogenic signals that mediate Pb-nitrate-induced liver hyperplasia. Lead-induced 

hyperplasia also appears to be modulated by neurotrophins and their receptors. 

• In vitro co-culture systems with Kupffer cells and hepatocytes suggested liver cell 

apoptosis is mediated by Kupffer cell-derived signals and Pb-induced oxidative stress. 

• Newer experimental evidence suggests that Pb-induced alterations in liver heme 

metabolism involves perturbations in ALAD activity, and porphyrin metabolism, 

alterations in Transferrin gene expression, and associated changes in iron metabolism. 

• Limited experimental evidence on the role of weight loss on liver Pb burden in exposed 

animals indicate that liver Pb content increases even in the absence of prolonged 

continued exposure. 

• Extensive scientific evidence has accumulated over these two decades on the role of 

chelation therapy, both individual and combined. Studies using a combination of therapy 

regimens with chelators such as DMSA, Mi-DMSA, or DMSA+ EDTA did not prove 

beneficial in ameliorating the Pb-induced oxidative stress in infant/neonatal rats as the 

combination therapy in young rats resulted in essential mineral deficiencies. 

• Therapeutic intervention with S-adenosyl-L-methionine, L-acetyl cysteine, lipoic acid, 

and vitamin E conferred protection against Pb accumulation in the liver and Pb-induced 

lipid peroxidation. Intervention with ascorbic acid, on the other hand, has been found to 

confer protection against Pb-induced decrease in hepatic heme synthesis. 

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5.10.2 Gastrointestinal System and Lead Absorption 

Lead enters the body by many routes, but primarily via the GI tract. The intestinal 

epithelium serves as one of the body’s primary interfaces with the outside world. The 

transporting epithelia in the small intestine are characterized by layers of anatomically and 

biochemically polarized cells that are connected to each other by tight junctions and resting on a 

basement membrane. Classically, the intestinal epithelium is thought of primarily as a barrier, 

but it also is a highly reactive barrier. Even modest perturbations in its functions may lead to 

diarrhea, constipation, malnutrition, dehydration, and infectious diseases (i.e., ulcerative colitis, 

collectively referred as chronic intestinal inflammatory diseases) (Gewirtz et al., 2002). 

Abdominal colic and constipation are symptoms of Pb poisoning, but its mechanism is not fully 

understood. Studies have been carried out in the past decade to increase our understanding of the 

fundamental mechanism(s) in order to extrapolate the experimental observations to human 

health effects. 

The intestinal absorption of Pb is influenced by a variety of factors, including the 

chemical and physical forms of the element, age at intake, and various nutritional factors. 

Gastrointestinal absorption of Pb is thought to occur primarily in the duodenum. In the isolated 

rat intestine, absorption, and, in particular, serosal Pb transfer activity (net transfer of Pb from 

the small intestine lumen across the epithelium and into the serosal space) is highest in the 

duodenum. The mechanisms of absorption may involve active transport and/or diffusion through 

the intestinal epithelial cells. Both saturable and non-saturable pathways of absorption have been 

inferred from the studies in different animal models, although the understanding of the former is 

slightly more robust (Diamond et al., 1998). 

Transport of Pb as a complex with proteins via endocytosis or as a complex with amino 

acids are postulated as possible mechanisms. Direct evidence for transport of an organic Pb 

complex has not been provided, but it seems possible. 

In the cell, Pb interacts with a variety of intracellular ligands, including calcium-binding 

proteins and high-affinity Pb-binding proteins. Transfer across the cell or basolateral membrane 

(or both) involves a mechanism(s) that may be sensitive to vitamin D and iron status. Alternate 

transport mechanisms via a Ca2+-Na+

 exchanger, independent of regulation by vitamin D, are 

also possible. 

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5.10.2.1 Lead and In vitro Cytotoxicity in Intestinal Cells 

In vitro cytotoxicity of metal salts for 48 h was determined in the intestinal epithelial cell 

line I-407 by Keogh et al. (1994). The investigations identified rank order cytotoxicity in terms 

of LC50 values: HgCl2 (32 μM)>CdCl2 (53 μM) > CuCl2 (156 μM) > Ti2SO4 (377 μM) > Pb 

(NO3)2 (1.99 mM). Further studies using a noncytotoxic concentration of butathione 

sulphoxamine pretreatment for GSH depletion revealed that the cytotoxicity of Pb was 

unaffected by GSH depletion (see Table AX5-10.7). 

5.10.2.2 Alterations in Intestinal Physiology and Ultrastructure 

Karmakar et al. (1986) investigated the pathologic alterations that occur in the intestine, 

liver, and kidney of Pb-intoxicated rats upon short-term exposure to sublethal doses of Pb 

(44 mg/Kg body wt) and reported degeneration of intestinal mucosal epithelium leading to 

potential malabsorption. 

The effect of low-concentration Pb-acetate (0.1%) on the jejunal ultrastructure was 

studied by Tomczok et al. (1988) in young male rats. The studies revealed that the villi of 

jejunum of rats exposed to Pb for 30 days had a rough appearance on the surface, which could be 

associated with a distortion of glycocalyx layer. Areas of extensive degenerative lesions were 

also observed on the surface of most villi on the 60th day of exposure. All intestinal epithelial 

cells exhibited various degrees of glycocalyx disturbance, indicating that pronounced toxic 

effects of Pb were related to modifications of the biochemical properties of the surface coat of 

the cells. These authors also reported the appearance of goblet cells and of Pb deposition along 

the goblet cell membrane in blocks of tissue along the border between duodenum and jejunum. 

Continued treatment up to 60 days resulted in mucus droplets in the cytoplasm of goblet cells, 

along with deposition of silver salts indicative of Pb in these cells. These results demonstrated 

the significance of goblet cells in Pb detoxification. 

In another study on the ultrastructure of rat jejunum exposed to Pb-acetate (100 mg/kg 

body wt/day), Tomczok et al. (1991) found that 30-day treatment resulted in numerous small, 

rough-membraned vesicles and dilated golgi complexes in the cytoplasm. Continued treatment 

for 60 days resulted in vacuolated cytoplasm associated with the golgi complexes, roughmembraned vesicles, and dilated cisternae. Also, the surface of the intestinal epithelial cell 

microvilli showed evidence of Pb deposition, as evidenced by Timm sulfide silver reaction sites. 

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5.10.2.3 Intestinal Uptake and Transport 

Infants are a particularly susceptible population for Pb toxicity, possibly due to the 

immaturity of the digestive tract, feeding pattern, or source of Pb. To investigate these aspects, 

Henning’s group (Beach and Henning, 1988; Henning and Cooper, 1988) carried out a series of 

experiments using suckling rat pups and reported that Pb in rat and bovine milk and infant milk 

formula was primarily associated with casein micelles. Casein-bound Pb may be the most 

common form of Pb presented to the small intestine (Beach and Henning, 1988). Other studies 

by this group investigated potential differences in the mechanisms when Pb was presented in 

ionic or milk-bound form, using 203Pb as a tracer. These studies clearly showed that when 203Pb 

was administered intragastrically as a soluble salt, it was primarily accumulated in the 

duodenum, regardless of dose or vehicle used. In contrast, substantial accumulation of 203Pb was 

found in the ileal tissue following Pb administration in milk. These studies clearly indicated 

strikingly different patterns in the intestinal accumulation of ionic and milk-bound Pb and 

suggest a greater toxicity for Pb in drinking water compared to Pb ingestion via milk (Henning 

and Cooper, 1988). 

Dekaney et al. (1997) investigated the uptake and transport of Pb using intestinal 

epithelial cells (IEC-6). The authors observed that Pb accumulation in Pb-exposed (5-10 μM) 

IEC-6 cells was time- and dose-dependent up to 1 h and that reduction of the incubation 

temperature significantly reduced the total cellular Pb content of IEC-6 cells. Simultaneous 

exposure to Zn resulted in decreased cellular Pb content compared to cells exposed to Pb only. 

Exposure of cells to ouabin or sodium azide has been found to increase Pb accumulation in the 

cells compared to cells treated with Pb (5 μM) alone. These studies clearly demonstrate that Pb 

transport in IEC-6 cells is time- and temperature-dependent, involves the presence of sulfydryl 

groups, and competes with the uptake of Zn. 

Lead speciation and transport across intestinal epithelium in artificial human digestive 

fluid (chyme), both in vivo and in vitro, in Caco-2 cells were evaluated by Oomen et al. (2003). 

In vivo studies indicated that in chyme, Pb-phosphate and Pb-bile complexes are important 

fractions. The metal ions dissociated from these complexes can subsequently be transported 

across the intestinal epithelium or they may traverse the intestinal membrane. In vitro studies, on 

the transport of bioaccessible Pb across the intestinal epithelium in Caco-2 cells exposed to 

diluted artificial chyme for 24 h, indicated that 3% of the Pb was transported across the cell 

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monolayer. Lead associated with cells in a linear relationship to the total amount of Pb in the 

system. Bile levels were not found to affect the fraction of Pb associated with the cells. The free 

Pb2+ concentration in chyme was negligible. Extrapolating these results to the in vivo situation, 

the authors concluded that Pb species other than the free metal ion may have contributed to the 

Pb flux towards the cells, possibly involving the dissociation of labile Pb species, such as Pbphosphate and Pb-labile complexes and the subsequent transport of the released free metal ions 

toward the intestinal membrane. 

5.10.2.4 Alterations in Gastrointestinal Motility/Gastrointestinal Transit and Function 

The effect of Pb on contractility of rat duodenum was determined in vivo in rats given an 

oral dose of Pb-acetate (44 mg/kg per day, Pb as 53 mM/L for 4 weeks) to investigate the 

possible mechanisms associated with Pb-induced abdominal colic and constipation (Karmakar 

and Anand, 1989). Deodenal motility and the amplitude of contractility of rat duodenum were 

decreased significantly in the Pb-exposed rats, leading the authors to conclude that there was a 

fundamental change in the contractility of the intestinal tract due to Pb intoxication. 

Chronic Pb ingestion through drinking water (2-5 mg/mL, Pb-acetate for 55 days) caused 

a 20-fold increase in urinary excretion of D-ALA and an increase in blood Pb level (80 μg/dL), 

without any perturbations in propulsive motility of guinea pig colon (Rizzi et al., 1989). On the 

other hand, Lawrel et al. (1991) observed no changes in gastric contractions during ingestion in 

red-tailed hawks exposed to Pb-acetate (0.82 or 1.64 mg/kg body wt for 3 weeks). This low 

level of exposure has also been found to have no bearing on the regular passing of pellets of 

undigested material. Shraideh (1999) studied the effect of triethyl Pb-chloride on the rhythmic 

and peristalitic contractile activity of ileum isolated from Swiss mice. These authors observed 

no significant effect below 40 μM of TEL, while higher concentrations (40-120 μM) caused 

changes in contraction rhythm. These studies also reported that TEL above 120 μM induced 

irreversible changes in the ileal contractile activity. These and related studies are summarized in 

Table AX5-10.8. 

5.10.2.5 Lead, Calcium, and Vitamin D Interactions in the Intestine 

The complex biological interactions between Pb and calcium have been recognized and 

demonstrated in virtually every type of tissue. Studies of high-affinity Pb binding to intracellular 

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calcium receptors and transport proteins, as well as the involvement of Pb in calcium-activated 

and calcium-regulated processes, have added to our understanding of the effects of Pb on 

biological processes at the cellular level. The intestinal absorption of Pb is influenced by a 

variety of factors, including chemical and physical forms of the element, age at intake, and 

various nutritional factors. Work dating back to the 1940s established that the deposition of Pb 

in bone and soft tissue significantly increases under conditions of dietary calcium and 

phosphorus deprivation or by the administration of vitamin D to rachitic animals. Later, in the 

1970s, it was demonstrated that dietary calcium status was a major contributing factor 

determining relative susceptibility to Pb intoxication. 

Fullmer’s group (Fullmer and Rosen, 1990; Fullmer, 1991, 1992, 1997) carried out a 

series of studies to investigate the potential interaction between calcium and Pb in the ingestion 

and intestinal absorption of Pb. Various parameters, such as absorption kinetics for Ca and Pb, 

activity of alkaline phosphatase, expression of the clabindin D gene, and the potential role of 

endocrine function in this interaction (as assessed by cholecalciferol and its active hormonal 

form, 1, 25-dihydroxycholecalciferol levels) were investigated. Fullmer and Rosen (1990) 

observed that chicks fed with low (0.5%) and adequate (1.2%) dietary calcium and exposed to Pb 

(0-0.8%) exhibited differential effects on intestinal Ca absorption depending on their dietary Ca 

status. In the chicks fed a low-calcium diet, Pb inhibited intestinal Ca absorption and calbindin 

D and alkaline phosphatase synthesis in a dose-dependent fashion. On the other hand, chicks fed 

the normal diet, showed no inhibition of Ca absorption. Based on these results, the authors 

postulated that Pb-induced alterations in intestinal Ca absorption may involve cholecalciferol and 

the endocrine system. In an extension of this study using young growing chicks, Fullmer (1991) 

observed similar results in 2-week Pb-exposed, but not in 1-week exposed, chicks. 

As dietary Ca deficiency is associated with a marked increase in the body burden of Pb 

and in the susceptibility to Pb toxicity during chronic ingestion, Fullmer (1992) examined the 

effects of vitamin D supplementation on intestinal Pb and Ca absorption. When vitamin Ddeficient chicks received physiologic amounts of vitamin D (0.1mg/day), intestinal 203Pb and 

47Ca absorption rates were elevated by 4- and 8-fold, respectively. Along with this, calbindin D 

and alkaline phosphatase activities were also found to be significantly elevated. Ingestion of 

even the highest level of Pb (0.8 %) during the repletion phase had no effect on intestinal Ca 

absorption. To further understand the Pb-Ca interactions and the potential involvement of 

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vitamin D on intestinal absorption, Fullmer (1997) evaluated serum levels of 1, 25­

dihydroxyvitamin D. Lead ingestion and Ca deficiency alone, or in combination, generally 

increased serum 1, 25-dihydroxyvitamin D levels over most of the ranges of Pb or Ca studied. 

However, in severe Ca deficiency, Pb ingestion resulted in marked decreases in serum 1, 25­

dihydroxyvitamin D, intestinal Ca absorption, and calbindin D mRNA. From these studies using 

response surface models, Fullmer (1997) concluded that the interactions between Pb and Ca were 

mediated via changes in circulating 1, 25-dihydroxy vitamin D hormone, rather than via direct 

effects on the intestine. 

Similar to Ca deficiency, iron deficiency has also been found to increase intestinal 

absorption of Pb, as indicated by increased blood and kidney Pb levels in iron-deficient rats 

exposed to dietary Pb; but the mechanistic details are not known (Crowe and Morgan, 1996). 

These and other related studies are summarized in Table AX5-10.9. 

5.10.2.6 Lead and Intestinal Enzymes 

Differential effects of Pb on intestinal brush border enzyme activity profiles were reported 

by Gupta et al. (1994). Across a concentration range of 0.5-6.0 mM, Pb-acetate was found to 

significantly inhibit Ca-Mg-ATpase, g-glutamyl transpeptidase, and acetylcholineesterase 

activities in a dose-dependent manner without effects on alkaline phosphatase. 

Cremin et al. (2001) investigated the effects of oral succimer on the intestinal absorption 

of Pb in infant rhesus monkeys. These studies indicated that chelation therapy with DMSA for 

two successive 19-day periods significantly decreased GI absorption of Pb and increased urinary 

excretion of endogenous lead (see Table AX5-10.9). 

5.10.2.7 Summary 

• Gastrointestinal absorption of Pb is influenced by a variety of factors, including chemical 

and physical forms of the element, age at intake, and various nutritional factors. The 

degeneration of intestinal mucosal epithelium leading to potential malabsorption and 

alterations in the jejunal ultrastructure (possibly associated with distortion of glycocalyx 

layer) have been reported in the intestine of Pb-exposed rats. 

• Lead in rat and bovine milk and, also, infant milk formula was demonstrated to be 

primarily associated with caseine micelles. 

• Tracer studies using 203Pb indicated that intragastric administration of Pb as a soluble salt 

resulted in Pb primarily accumulating in the deuodenum, regardless of dose or vehicle 

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used, whereas Pb from milk was found to be taken up by ileal tissue. Studies also 

suggested Pb ingestion through water was more toxic than ingestion through milk. 

• Lead induced decreases in duodenal motility and amplitude of contractility of the 

intestinal tract has been reported for rats. 

• Nutritional studies using various levels of Pb, Ca, and vitamin D in the diet indicate 

competition of Pb with Ca absorption. Supplementation with vitamin D has been 

reported to enhance intestinal absorption of Ca and lead. Physiological amounts of 

vitamin D administered to vitamin D-deficient rats resulted in elevated Pb and Ca levels. 

In the case of severe Ca deficiency, Pb ingestion results in a marked decrease in serum 

1,25-hydroxy vitamin D. 

Overall, our understanding of Pb effects on hepatic and gastro intestinal systems using in 

vitro cell culture models and in vivo animal models has increased greatly compared to the 1986 

AQCD. Significant insights have emerged regarding the role of Pb in hepatic cholesterol 

synthesis, the role of inflammation in Pb-induced hepatotoxicity, and the contribution of newer 

chelation therapy in the amelioration of Pb-induced oxidative burden. Similarly, our knowledge 

has greatly enhanced as to the absorption, transport, and toxicity of Pb in the gastrointestinal 

tract. 

5.11 LEAD-BINDING PROTEINS 

Lead-binding proteins that are constitutively expressed within the cells and bind Pb can be 

classified into two types of protein. The first type of Pb-binding proteins are inducible, i.e., their 

concentration increases after exposure to Pb. The second type of Pb-binding proteins have 

binding sites that are saturable by Pb, but no discernible increase in protein content occurs after 

exposure to Pb. The second type is, perhaps, most pertinent to enzymes that can be inhibited by 

Pb. 

The history of research on Pb-binding proteins dates back to 1936, when the presence of 

intranuclear inclusion bodies in the liver and kidney as manifestations of Pb poisoning was first 

described (Blackman, 1936). Later, detailed studies of the composition of renal tubular 

intranuclear Pb inclusion bodies and consequent alterations in mitochondrial structure and 

function followed. 

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5.11.1 Lead-Binding Proteins Within Intranuclear Inclusion Bodies 

in Kidney 

Goyer (1968) examined the renal tubules of rats fed 1% Pb-acetate for up to 20 weeks, 

and found that dense, deeply staining intranuclear inclusions were located in the straight portion 

of the proximal tubules, accompanied by swollen, globular or ovoid, closely packed 

mitochondria with many marginated, irregular, or vesicular cristae. Accompanying these 

mitochondrial changes was the presence of generalized aminoaciduria. Goyer et al. (1968) also 

isolated mitochondria from Pb-exposed and control rats and demonstrated that mitochondria 

from the Pb-exposed rats showed reduced rates of respiration and oxidative phosphorylation. 

Lead within the kidneys in Pb-poisoned rats was found to be concentrated in the nuclei 

and, within nuclei, in the nuclear inclusion body (Goyer et al., 1970a,b). Choie and Richter 

(1972) showed that rapid induction of inclusion bodies by injections of Pb salts in the rat resulted 

in cytoplasmic inclusions, suggesting that they were precursors to the intranuclear inclusions. 

Lead-containing nuclear inclusions were also found in organs other than the kidney, including 

liver and glial cells of the central nervous system (Goyer and Rhyne, 1973). Moore et al. (1973) 

dissolved the rat renal intranuclear inclusions in strong denaturing agents and found that the 

protein in the inclusions is acidic, with high levels of aspartic acid, glutamic acid, glycine, and 

cystine. Moore and Goyer (1974) later characterized the protein as a 27.5 kDa protein, which 

migrates as a single band on acrylamide gel electrophoresis. Repeated intraperitoneal injections 

of CaNa2EDTA resulted in the disappearance of the inclusion bodies in Pb-exposed rats, together 

with a marked decrease in kidney Pb levels (Goyer et al., 1978). 

Shelton and co-workers have also explored the composition of Pb-binding proteins in the 

nuclear inclusion proteins of Pb-exposed rat kidneys. Shelton and Egle (1982) first described a 

32 kDa protein with an isoelectric point of 6.3, which was isolated from the kidneys of rats 

treated with 1% Pb-acetate in rat chow or 0.75% Pb-acetate in drinking water for 13-17 weeks. 

In contrast to Goyer and co-workers, they used two-dimensional gel electrophoresis to isolate the 

protein from the nuclear inclusion bodies and demonstrated that it was present in Pb-exposed, 

but not control, kidneys (hence, inducible). This protein has been termed p32/6.3. Inhibitor 

studies with cycloheximide and actinomycin D (McLachlin et al., 1980; Choie et al., 1975) had 

indicated earlier that protein synthesis was required for induction of the nuclear and cytoplasmic 

inclusion bodies. 

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Egle and Shelton (1986) unexpectedly found that p32/6.3, now characterized by a 

monoclonal antibody, was constitutively present in the cerebral cortex, both in neurons and 

astrocytes. The protein was concentrated in the insoluble nuclear protein, findings similar as for 

the Pb-exposed kidney. Brain p32/6.3 was detected in rat, mouse, dog, man, and chicken. In rat 

brain, adult levels were achieved in 1 to 2 weeks after birth, whereas only trace amounts were 

found at 3 days. Brain p32/6.3 increased between postnatal days 10 to 12 in the guinea pig and 

days 15 to 21 in the rat, suggesting that the increase may be related in part to exposure to the 

external environment (Shelton et al., 1993). When neuroblastoma cells were cultured after 1- 

and 3-day exposure to Pb, the abundance of p32/6.3 increased. Simultaneous incubation with Pb 

and cycloheximide or actinomycin D increased in p32/6.3, suggesting that Pb selectively retards 

the degradation of the brain protein (Klann and Shelton, 1989). The amino acid composition of 

partially purified p32/6.3 revealed a high percentage of glycine, aspartic and glutamic acid 

(Shelton et al., 1990). Thus, the inducible protein, p32/6.3, can be extracted from nuclear 

inclusion bodies from the Pb-exposed rat kidney, and a similar or identical protein from adult rat 

brain. Whether the brain protein is constitutive or inducible by exposure to environmental Pb 

has yet to be determined. 

Oskarsson and Fowler (1985) examined the influence of pretreatment with Pb by a single 

IP injection of Pb-acetate (50 mg Pb per kg) 1, 3, and 6 days before injecting 203Pb. Rats were 

sacrificed 24 h later and the kidneys were examined both microscopically and for the distribution 

of 203Pb. At 3 days, rat kidneys displayed fibrillar cytoplasmic inclusions, but at 6 days, these 

inclusions were less prominent and intranuclear inclusions were observed. 203Pb uptake at 6 days 

was maximal in the purified nuclear fraction and in the nuclear inclusion bodies (7H and 20H

control, respectively). 

5.11.2 Cytoplasmic Lead-Binding Proteins in Kidney and Brain 

The remaining studies of non-Pb-stimulated cytoplasmic kidney and brain Pb-binding 

proteins have been provided by Fowler and associates. 

The first study (Oskarsson et al., 1982) reported on the Pb-binding proteins in kidney 

postmitochondrial cytosolic fractions. Binding of 203Pb was found in two protein fractions of 

control kidneys with molecular weights of 11.5 and 63 kDa. Binding was markedly decreased 

after Pb pretreatment. The use of cadmium to stimulate metallothionein synthesis did not 

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increase 203Pb binding to the 11.5 kDa protein. The two binding proteins were also present in 

brain, but not in liver or lung. Subsequently, Mistry et al. (1985) demonstrated three Pb-binding 

proteins (11.5, 63, and >200 kDa) in rat kidney cytosol, which had binding characteristics of 

high affinity, low capacity with respective Kd values of 13, 40, and 123 nM. The 11.5 kDa and, 

possibly, the 63 kDa proteins were capable of translocating Pb into the nucleus as shown by 

uptake of 203Pb into nuclei incubated with tagged cytosolic proteins. Goering and Fowler (1984) 

showed that the 11.5 kDa protein, but not the 63 kDa protein was capable of reversing 

Pb-induced ALAD inhibition in liver homogenates. This effect was mediated both by chelation 

of Pb by the Pb-binding protein and by donation of zinc to ALAD (Goering and Fowler, 1985). 

Various divalent metal ions influence the binding of Pb to the rat kidney cytosolic binding 

proteins, with an order of displacement of Cd2+>Zn2+>Pb2+. Ca2+ had no effect, while Fe2+ had a 

cooperative effect (Mistry et al., 1985). These observations may account for the previously 

demonstrated effect of concomitant Pb and cadmium administration in reducing total kidney Pb 

(Mahaffey et al., 1981) and preventing the development of intranuclear inclusion bodies 

(Mahaffey and Fowler, 1977). 

Later studies by Fowler and Duval (1991) identified the rat renal Pb-binding protein as a 

cleavage product of α2-microglobulin, with a Kd of 10-8 M Pb. There are two forms of the 

protein in the kidney, differentiated by the cleavage of the first 9-N terminal residues from the 

higher-molecular weight form. Other studies by Smith et al. (1998) found two Pb-binding 

proteins in environmentally exposed human kidneys, identified as acyl-CoA binding protein 

(ACBP) or diazepam binding inhibitor (molecular weight 9 kDa) and thymosin β4 (molecular 

weight 5 kDa). These polypeptides have a high affinity for Pb (Kd~14 nM). 

In rat brain, Goering et al. (1986) and Duval and Fowler (1989) explored the effects of 

environmental Pb on Pb-binding proteins and the ability of rat brain Pb-binding proteins to 

diminish the inhibition of hepatic ALAD by Pb (liver does not contain the Pb-binding protein). 

In the first study, a brain protein of 12 kDa was described, in comparison to the kidney 

Pb-binding protein of 9 kDa. Both competition of Pb binding between the brain Pb-binding 

protein and ALAD and donation of zinc by the brain protein (shown by 65Zn uptake) were found 

to account for the decreased ALAD inhibition. In the second study the rat brain Pb-binding 

protein was described as having a molecular weight of 23 kDa, with significant levels of 

glutamic acid, aspartic acid, and cysteine. Polyclonal antibody to rat renal Pb-binding proteins 

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showed a lack of reactivity with the brain protein, indicating that the proteins are 

immunologically distinct. 

Fowler et al. (1993) examined monkey kidney and brain from non-Pb-treated animals and 

isolated Pb-binding proteins that also had a relatively high content of aspartic and glutamic 

amino acid residues and were similar in size to the rat Pb-binding proteins. Polyclonal 

antibodies to α-2 microglobulin and metallothionein did not cross-react with either monkey 

kidney or brain proteins. Quintanilla-Vega et al. (1995) isolated a thymosin $4 and a second, as 

yet unidentified, protein with a molecular weight of 20 kDa and a pI of 5.9 from brains of 

environmentally Pb-exposed humans. 

5.11.3 Lead-Binding Proteins in Erythrocytes 

Intra-erythrocytic Pb-binding was initially attributed primarily to hemoglobin, molecular 

weight 64 kDa (Barltrop and Smith, 1972; Raghavan and Gonick, 1977; Ong and Lee, 1980; 

Lolin and O'Gorman, 1988), but more recent studies have ascribed the major Pb binding to 

ALAD, molecular weight 240–280 kDa. In contrast to this protein, several studies have focused 

on an inducible low molecular weight protein in workers chronically exposed to Pb and which 

seems to have a protective effect. The first recognition of this protein was by Raghavan and 

Gonick (1977) who found an approximately 10 kDa protein in Pb workers but not in controls, 

following Sephadex G-75 fractionation (Figure 5-11.1). Upon subsequent SDS-polyacrylamide 

gel electrophoresis, the protein split into two bands, only the uppermost of which contained Pb 

(Figure 5-11.2). 

Raghavan et al. (1980) then went on to fractionate the erythrocyte Pb into a hemoglobin 

fraction, a 10 kDa fraction, free Pb, and a “residual Pb” fraction thought to be composed of 

membrane Pb and a high-molecular weight fraction. Lead workers manifesting toxicity at both 

high blood Pb and relatively low blood Pb levels showed high levels of residual Pb, attributed in 

the workers with toxicity at low blood leads to a very low quantity of the 10 kDa fraction. In a 

follow-up study, Raghavan et al. (1981) reported elevated levels of Pb in the high molecular 

weight fraction (pre-hemoglobin) and in the membrane fraction in workers with toxicity at both 

high and low BLLs. Again, those with toxicity at low blood Pb had low levels of the Pb bound 

to the 10 kDa protein. Membrane Pb was found to correlate inversely with membrane Na-KATPase; no correlation was seen with total blood Pb. 

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402(c) Economic Analysis Chapter 5 349
Figure 5-11.1. Sephadex G-75 gel filtration of RBC hemolysate from lead-exposed 

individual. Ultraviolet absorption and radioactivity of 210Pb are plotted 

against elution volume. The column was calibrated with ovalbumin (mol 

wt 45,000) and ribonuclease (mol wt 13,700). Also indicated is the locus of 

hemoglobin (Hb). Hemolysates from normal control individuals showed no 

UV absorption or radioactivity in the volume eluting between 130 and 

155 mL. 

Source: Raghavan and Gonick (1977) with permission. 

Figure 5-11.2. SDS-polyacrylamide gel electrophoresis of RBC hemolysates from normal 

control (A) and lead-exposed individuals (B), and of low-mol-wt. leadbinding protein (C). Stained with coomassie blue. 

Source: Raghavan and Gonick (1977) with permission. 

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Gonick et al. (1985) partially purified the 10 kDa protein by HPLC using a protein I-125 

column followed by isoelectric focusing on a sucrose gradient column. Three protein peaks 

resulted: one of 30 kDa, and two of 10 kDa. Only one of the latter peaks contained Pb. This 

peak had a pI of 5.3 and a molecular weight, determined by SDS-PAGE, of 12 kDa. The 

majority of Pb was found in this peak, which also contained calcium, zinc, and cadmium. Amino 

acid analysis showed a very high percentage of glycine (44%) and lower quantities of histidine, 

aspartic acid, and leucine. 

Ong and Lee (1980) studied the distribution of 203Pb in components of normal human 

blood. Ninety-four percent of 203Pb was incorporated into the erythrocyte and 6% remained in 

the plasma. SDS-PAGE of plasma showed that 90% was present in the albumin fraction. Within 

the erythrocyte membrane, the most important binding site was the high molecular weight 

fraction, about 130–230 kDa. Within the erythrocytic cytoplasm, the protein band associated 

with 203Pb had a molecular weight of 67 kDa as shown by the elution characteristics on G-75 

chromatography. This was thought to be hemoglobin. 

Lolin and O’Gorman (1988) and Church et al. (1993 a,b), following the same procedure 

as Raghavan and Gonick (1977), confirmed the findings of a low molecular weight protein in the 

erythrocytes of Pb workers, but not found in control patients. Lolin and O’Gorman (1988) 

quantitated the protein, which ranged from 8.2 to 52.2 mg/L RBC in Pb workers but found none 

in controls, again implying it to be an inducible protein. They found that the low molecular 

weight protein first appeared when the blood Pb concentration exceeded 39 μg/dL. A positive 

correlation was seen between the amount of the intra-erythocytic low molecular weight protein 

and dithiothreitol-activated ALAD activity but not the non-activated activity. Church et al. 

(1993a,b) also confirmed the findings of Raghavan et al. (1977). In 1993a, they described two 

patients with high blood Pb levels: an asymptomatic worker with a blood Pb of 180 μg/dL, and a 

symptomatic worker with a blood Pb of 161 μg/dL. In the first patient, approximately 67% of 

the erythrocyte Pb was bound to a low molecular weight protein of approximately 6–7 kDa. In 

the second patient, the protein only contained 22% of the total erythrocytic Pb. Church et al. 

(1993b) found that a sample of the low molecular weight protein purified from Pb workers, 

which they termed protein M, had characteristics of metallothionein, such as a molecular weight 

of 6.5 kDa, a pI between 4.7 and 4.9, and a greater UV absorbance at 254 nm than at 280 nm. 

Amino acid composition showed 33% cysteine but no aromatic amino acids. This composition 

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differed from that of the low molecular weight protein described by Gonick et al. (1985), which 

had a molecule weight of 12 kDa, a pI of 5.3, and amino acid analysis that showed no cysteine. 

This discrepancy might be explained by a combined Pb and cadmium exposure in the Church 

et al. (1993b) study, which may have produced a Pb-thionein. 

Xie et al. (1998) used a Biogel A column instead of Sephadex G-75 to separate 

Pb-binding proteins from erythrocyte hemolysates from a control patient and from Pb-exposed 

workers. They clearly showed that the major Pb-binding was associated with a large molecular 

weight protein, consistent with ALAD, in both the controls and Pb workers. When they added 

increasing amounts of Pb to the blood of the control patient, a second low molecular weight 

protein peak occurred, in which Pb binding was larger than the ALAD peak (Figure 5-11.3). 

This second peak was also seen in a chronically Pb-exposed worker (Figure 5-11.4) and was 

estimated to be less than 30 kDa in molecular weight. Thus these results are consistent with the 

aforementioned studies. 

5.11.4 Lead-Binding Proteins in Rat Liver 

Sabbioni and Marafante (1976) explored the distribution of 203Pb in rat whole tissue as 

well as in subcellular liver fractions. By far the largest quantity of Pb recovered was in the 

kidney, with lesser amounts in liver, spleen, and blood. Upon subcellular fractionation of the 

liver, the majority of 203Pb was found in the nuclei, and most of the Pb was detected in the 

nuclear membrane fraction, bound exclusively to membrane proteins. The intranuclear Pb was 

associated with histone fractions. As reported by Oskarsson et al. (1982), Pb binding proteins 

were found in the cytoplasm of the liver. 

5.11.5 Lead-Binding Proteins in Intestine 

Fullmer et al. (1985) showed in the chick and cow that although Pb does not directly 

stimulate Pb-binding proteins in the intestine, Pb can displace calcium from calcium-binding 

proteins; and, thus, calcium-binding proteins may play a role in intestinal Pb transport. Purified 

calcium-binding protein from chick and cow, as well as calmodulin, troponin C, and 

oncomodulin were dialyzed against added labeled and unlabeled Pb or calcium. Results 

disclosed high affinity binding sites, with greater affinity for Pb than for calcium. Similar results 

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402(c) Economic Analysis Chapter 5 352
Figure 5-11.3. Chromatographic profiles of protein, ALAD activity and Pb in human 

erythrocytes incubated with 5% glucose solution containing Pb acetate. 

Blood was incubated (a) without Pb (b) 10 μM Pb (final concentrations). 

Source: Adapted from Xie et al. (1998). 

1 were obtained with calmodulin, troponin C, and oncomodulin, all members of the troponin C 

2 superfamily of calcium-binding proteins. 

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Figure 5-11.4. Chromatic profiles of protein, ALAD activity, Pb, and Se in the 

erythrocytes of lead-exposed workers. (a) control, (b) subacute exposure, 

(c) chronic exposure. 

Source: Xie et al. (1998) with permission. 

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5.11.6 Relationship of Lead-Binding Protein to Metallothionein 

Similarities of Pb-binding protein to metallothionein have been discussed earlier. Maitani 

et al. (1986) commented that hepatic zinc-metallothionein could be induced by intravenous and 

intraperitoneal injections of Pb into mice, but not by subcutaneous injection. Ikebuchi et al. 

(1986) found that a sublethal dose of Pb-acetate injected intraperitoneally into rats induced the 

synthesis of a Pb-metallothionein in addition to zinc-metallothionein. The Pb-metallothionein 

contained 28% half-cysteine and cross-reacted with an antibody against rat zinc-thionein II. 

Goering and Fowler (1987 a,b) demonstrated that pretreatment of rats with zinc 48 and 

24 h prior to injection of 203Pb resulted in both zinc and Pb co-eluting with a zinc-thionein 

fraction on Sephadex G-75 filtration. In addition, both purified zinc-thionein-I and II bound 

203Pb in vitro. Gel filtration of incubates containing liver ALAD and 203Pb demonstrated that the 

presence of zinc-thionein alters the cytosolic binding pattern of Pb, with less binding to ALAD. 

Zinc-thionein also donates zinc to activate ALAD. Goering and Fowler (1987b) found that 

pretreatment of rats with either cadmium or zinc affected liver ALAD activity when incubated 

with Pb. Liver and kidney zinc-thioneins, and to a lesser extent, cadmium, zinc-thionein 

decreased the free pool of Pb available to interact with ALAD, resulting in attenuated ALAD 

inhibition. Liu et al. (1991) further showed that zinc-induced metallothionein in primary 

hepatocyte cultures protects against Pb-induced cytotoxicity, as assessed by enzyme leakage and 

loss of intracellular potassium. 

Qu et al. (2002) and Waalkes et al. (2004) have shown that metallothionein-null 

phenotypic mice are more susceptible to Pb injury over a 20-week period than wild type mice. 

Unlike the wild type mice, Pb-treated metallothionein-null mice showed nephromegaly and 

significantly decreased renal function after exposure to Pb. The metallothionein-null mice 

accumulated less renal Pb than wild type and formed no inclusion bodies. When the 

observations were extended to 104 weeks, renal proliferative lesions (adenoma and cystic tubular 

atypical hyperplasia) were more common and severe in metallothionein-null than in wild type 

mice. A metastatic renal cell carcinoma occurred in a metallothionein-null mouse, whereas none 

occurred in wild type mice. Such studies lend credence to the view that metallothinein, or a 

closely related gene, is involved in the formation of Pb-binding proteins in the kidney. 

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5.11.7 Is ALAD an Inducible Enzyme and is it the Principal Lead-Binding 

Protein in the Erythrocyte? 

The enzyme ALAD has been found to be the most sensitive indicator of Pb exposure and 

toxicity (Granick et al., 1973, Buchet et al., 1976). In the 1980s, two articles were presented 

appearing to show that ALAD is inducible after Pb exposure in humans. By comparing a 

nonexposed control population of Pb workers and assaying ALAD by means of immunoassay or 

as ‘restored’ ALAD activity (i.e., incubation with heat, zinc and dithiothreitol) both articles 

indicated that the amount of ALAD, as contrasted to ALAD activity, was increased by Pb 

exposure (Fujita et al., 1982; Boudene et al., 1984). Similar findings were reported for the rat 

(Fujita et al., 1981). Subsequent studies have focused on the effect of ALAD polymorphism on 

the susceptibility to Pb intoxication. ALAD is a zinc-containing enzyme, which catalyzes the 

second step of heme synthesis, i.e., catalyzes the condensation of two delta-aminolevulinic acid 

molecules into one molecule of porphobilinogen (Boudene et al., 1984). It is a polymorphic 

protein with three isoforms: ALAD-1, ALAD 1-2, and ALAD 2-2. Several studies have shown 

that, with the same exposure to Pb, individuals with the ALAD-2 gene have higher blood Pb 

levels (Astrin et al., 1987; Wetmur, 1994; Wetmur et al., 1991; Smith et al., 1995a; Bergdahl 

et al., 1997; Perez-Bravo et al., 2004; Kim et al., 2004). Initially it was thought that these 

individuals might be more susceptible to Pb poisoning (Wetmur et al., 1991), but it is now 

appreciated that the ALAD-2 gene offers protection against Pb poisoning by binding Pb more 

securely (Kelada et al., 2001). In support of this statement, it can be cited that individuals with 

the ALAD 1-2/2-2 genotypes, in comparison to those with the ALAD 1-1 genotype, have not 

only higher blood Pb but also decreased plasma levulinic acid (Schwartz et al., 1997), lower zinc 

protopophyrin (Kim et al., 2004), lower cortical bone Pb (Smith et al., 1995b), and lower 

amounts of DMSA-chelatable Pb (Schwartz et al., 1997, 2000). 

The significance of erythrocyte ALAD binding to Pb was initially confirmed by a study 

by Bergdahl et al. (1997) in which the authors used a FPLC Superdex 200 HR 10/30 

chromatographic column coupled to ICP-MS (for determination of Pb) to examine erythrocytes 

from Pb workers and controls. They found the principal Pb-binding protein peak to be 240 kDa 

(rather than the presumed hemoglobin peak reported by Barltrop and Smith (1972) and 

Raghavan and Gonick (1977), using Sephadex G-75 chromatography). This was shown to be 

ALAD by binding to specific ALAD antibodies. Two additional smaller Pb-binding peaks of 

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45 kDA and 10 kDa were also seen, but not identified. Bergdahl et al. (1997) attributed the 

discrepancies in the studies to the fact that Sephadex G-75 separates proteins in the range of 3 to 

80 kDa, making the separation of hemoglobin (molecular weight 64 kDa) from ALAD 

(molecular weight 240–280 kDa) very difficult. In addition, the earlier studies had utilized 

binding of 203Pb or 210Pb to identify the binding proteins, a technique which may have skewed 

the findings if ALAD were already saturated. ALAD binding capacity for Pb has been measured 

at 85 μg/dL in erythrocytes or 40 μg/dL in whole blood (Bergdahl et al., 1998), which would 

permit a greater degree of binding to the low molecular weight component when blood Pb 

exceeded 40 μg/dL. Bergdahl et al. (1998) have speculated that the low molecular weight 

component might be acyl-CoA-binding protein, identical to the kidney Pb-binding protein 

described by Smith et al. (1995b). Goering and Fowler (1987) had reported earlier that the 

presence of low molecular weight high affinity (Kd 10-8M) Pb-binding proteins in kidney and 

brain served as protection against ALAD inhibition in those organs, whereas the absence of the 

low molecular weight proteins in liver contributed to the greater sensitivity to ALAD inhibition 

in that organ. 

A summary of the findings on Pb-binding protein can be found in Table AX5-11.1. 

5.11.8 Summary 

• There appears to be a consensus that the enzyme, ALAD, a 280 kDa protein, is inducible 

and is the major Pb-binding protein within the erythrocyte. ALAD polymorphism 

influences the degree of Pb-binding as the ALAD-2 phenotype binds more Pb in a 

nontoxic fashion than ALAD-1. What is more confusing is the nature and importance of 

the low molecular weight erythrocytic Pb-binding protein. There is no doubt that it 

appears in Pb-exposed workers but not in controls and that its molecular weight is 

approximately 10 kDa. The in vitro addition of Pb to erythrocytes of controls results in 

progressively increasing Pb binding to a low molecular weight protein peak migrating in 

the same position as the low molecular weight protein from Pb workers. This confirms 

the fact that once the binding capacity of ALAD is saturated, Pb shifts to the low 

molecular weight protein. The nature of the low-molecular weight protein is also 

questionable, it has been variously identified as a 12 kDa protein with a high percentage of 

glycine plus histidine, aspartic acid, and leucine and as a 6.5 kDa molecule with a large 

percentage of cysteine and a greater UV absorbance at 254 than 280 nm. The latter 

findings suggest that the protein might be a metallothionein. 

• Metallothionein is a protein that is mildly inducible by Pb but to a much greater degree by 

zinc and cadmium. What is more significant is that Pb binds to pre-formed 

metallothionein, stimulated by zinc or cadmium, so that under these conditions a 

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Pb-thionein forms. Thus, concomitant Pb and cadmium exposure occurred in Pb workers 

that could account for the finding of a metallothionein-like protein in those workers. 

• Extensive studies of cytoplasmic Pb-binding proteins in non-Pb-treated rats, human, and 

monkeys have been reported. The Pb-binding protein in rat kidney has been identified as 

a cleavage product of α-2 microglobulin. The low molecular weight Pb-binding proteins 

in human kidney have been identified as thymosin $4 (molecular weight 5 kDa) and acylCoA binding protein (molecular weight 9 kDa). In human brain the Pb-binding proteins 

were thymosin β4 and an unidentified protein of 23 kDa. Antibodies to α-2 microglobulin 

and metallothionein did not cross-react with monkey kidney or brain Pb-binding proteins, 

suggesting species differences. Whether the low molecular weight human kidney and 

brain Pb-binding proteins are similar or identical to the low molecular weight Pb-binding 

proteins in erythrocytes is at present unknown. Perhaps some clarification would be 

provided were subsequent investigators to contrast normal with Pb-exposed rats and to 

measure the resting and inducible Pb-binding protein levels in kidney, brain, and 

erythrocyte. 

• The possible role of metallothionein as a renal Pb-binding protein assumes greater 

importance because of the work showing that metallothionein-null mice failed to respond 

to Pb exposure by developing intranuclear Pb inclusion bodies or greatly increased Pb 

content of the kidneys. 

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6. EPIDEMIOLOGIC STUDIES OF HUMAN HEALTH 

EFFECTS ASSOCIATED WITH LEAD EXPOSURE 

6.1 INTRODUCTION 

This chapter assesses information regarding the biological effects of lead exposure, 

with emphasis on (1) qualitative characterization of lead-induced effects and (2) delineation of 

concentration-response relationships for key health effects of most concern. Epidemiologic 

studies linking lead exposure to health effects were assessed in the 1986 Air Quality Criteria for 

Lead (U.S. Environmental Protection Agency, 1986a), an associated addendum (U.S. 

Environmental Protection Agency, 1986b), and a 1990 Supplement (U.S. Environmental 

Protection Agency, 1990). Many earlier studies reported lead effects on child development 

(psychometric intelligence), blood pressure and related cardiovascular endpoints, heme 

biosynthesis, kidney, and reproduction and development. Numerous more recent epidemiologic 

studies discussed in this chapter have further evaluated these relationships to lead exposure, 

thereby providing an expanded basis for assessment of health effects associated with exposure to 

lead at concentrations currently encountered by the general U.S. population. 

Special emphasis is placed here on discussion of the effects of lead exposure in children. 

Children are particularly at risk due to sources of exposure, mode of entry, rate of absorption and 

retention, and partitioning of lead in soft and hard tissues. The greater sensitivity of children to 

lead toxicity, their inability to recognize symptoms, and their dependence on parents and 

healthcare professionals make them an especially vulnerable population requiring special 

consideration in developing criteria and standards for lead. 

As discussed elsewhere in this document (Chapter 5), extensive experimental evidence 

links lead exposure with health effects in laboratory animals. Thus, many of the reported 

epidemiologic associations of lead health effects have considerable biological credibility. 

Accordingly, the new epidemiologic studies of lead assessed here are best considered in 

combination with information from the other chapters on lead exposure and on toxicological 

effects of lead in animals. The epidemiologic studies constitute important information on 

associations between health effects and exposures of human populations to “real world” lead 

concentrations and also help to identify susceptible subgroups and associated risk factors. 

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6.1.1 Approach to Identifying Lead Epidemiologic Studies 

Numerous lead epidemiologic papers have been published since completion of the 1986 

Lead AQCD/Addendum, and 1990 Supplement. A systematic approach has been employed to 

identify relevant new epidemiologic studies for consideration in this chapter. In general, an 

ongoing literature search has been used in conjunction with other strategies to identify lead 

epidemiologic literature pertinent to developing criteria for the National Ambient Air Quality 

Standards (NAAQS) for lead. A publication base was established using Medline, Pascal, 

BIOSIS, and Embase, and a set of search terms aimed at identifying pertinent literature. 

While the above search regime accessed much of the pertinent literature, additional 

approaches augmented such traditional search methods. For example, a Federal Register Notice 

was issued requesting information and published papers from the public at large. Also, non-EPA 

chapter authors, expert in this field, identified literature on their own, and EPA staff also 

identified publications as part of their assessment and interpretation of the literature. Lastly, 

additional potentially relevant publications are expected to be identified and included as a result 

of external review of this draft document by the public and CASAC. The principal criteria used 

for selecting literature for the present assessment is to focus mainly on those identified studies 

that evaluate relationships between health outcome and lead exposure at concentrations in the 

range of those currently encountered in the United States. New studies published or accepted for 

publication through June 2005, as identified using the approaches above, have been included in 

this draft lead air quality criteria document (Lead AQCD), and additional efforts are being made 

to identify and assess more recent studies. 

6.1.2 Approach to Assessing Epidemiologic Evidence 

Epidemiologic studies have evaluated lead effects on a wide range of health endpoints that 

include, but are not limited to: neurotoxic effects (e.g., psychometric intelligence, behavioral 

disturbances, and neurodevelopmental deficits), renal effects, cardiovascular effects, 

reproductive and developmental effects, genotoxic and carcinogenic effects, and immune effects. 

The epidemiologic strategies most commonly used in lead health studies are: (1) cross-sectional 

studies that examine the exposure and health outcome at a single point in time; and 

(2) prospective longitudinal cohort studies that follow a group of individuals over time. 

Both of these are types of observational rather than experimental studies. 

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An overall approach useful for assessing epidemiologic evidence was stated in the 2004 

PM AQCD (U.S. Environmental Protection Agency, 2004), as summarized here. That is, the 

critical assessment of epidemiologic evidence presented in this chapter is conceptually based 

upon consideration of salient aspects of the evidence of associations so as to reach fundamental 

judgments as to the likely causal significance of the observed associations (see Hill, 1965). The 

general evaluation of the strength of the epidemiologic evidence reflects consideration not only 

of the magnitude and precision of reported lead effect estimates and their statistical significance, 

but also of the robustness of the effects associations. Statistical significance corresponds to the 

allowable rate of error (Type I error) in the decision framework constructed from assuming that a 

simple null hypothesis of no association is true. It is a conditional probability; for statistical 

significance, typically there is a less than 0.05 chance of rejecting the null hypothesis given that 

it is true. Robustness of the associations is defined as stability in the effect estimates after 

considering a number of factors, including alternative models and model specifications, potential 

confounding by copollutants, as well as issues related to the consequences of measurement error. 

Consideration of the consistency of the effects associations, as discussed in the following 

sections, involves looking across the results obtained by various investigators in different 

locations and times. Relevant factors are known to exhibit much variation across studies, e.g., 

(1) presence and levels of other toxicants or pollutants of concern and (2) relevant demographic 

factors related to sensitive subpopulations. Thus, consideration of consistency is appropriately 

understood as an evaluation of the similarity or general concordance of results, rather than an 

expectation of finding quantitative results within a very narrow range. 

Looking beyond the epidemiologic evidence, evaluation of the biological plausibility of 

the lead-health effects associations observed in epidemiologic studies reflects consideration of 

both exposure-related factors and dosimetric/toxicologic evidence relevant to identification of 

potential biological mechanisms underlying the various health outcomes. These broader aspects 

of the assessment are only touched upon in this chapter but will be more fully integrated in 

discussions presented in Chapter 7 (Integrative Synthesis). 

In assessing the relative scientific quality of epidemiologic studies reviewed here and to 

assist in interpreting their findings, the following considerations were taken into account: 

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1 (1) To what extent are the biological markers used of adequate quality and sufficiently 

2 representative to serve as credible exposure indicators, well-reflecting geographic 

3 or temporal differences in study population exposures? 

4 (2) Were the study populations well defined and adequately selected so as to allow 

5 for meaningful comparisons between study groups or meaningful temporal 

6 analyses of health effects results?

7 (3) Were the health endpoint measurements meaningful and reliable, including clear 

8 definition of diagnostic criteria utilized and consistency in obtaining dependent 

9 variable measurements? 

10 (4) Were the statistical analyses used appropriate, as well as being properly performed 

11 and interpreted? 

12 (5) Were likely important covariates (e.g., potential confounders or effect 

13 modifiers) adequately controlled for or taken into account in the study design 

14 and statistical analyses? 

15 (6) Were the reported findings internally consistent, biologically plausible, and 

16 coherent in terms of consistency with other known facts? 

17 These guidelines provide benchmarks for judging the relative quality of various studies 

18 and in assessing the body of epidemiologic evidence. Detailed critical analysis of all 

19 epidemiologic studies on lead health effects, especially in relation to all of the above questions, 

20 is beyond the scope of this document. 

21 

22 6.1.3 Considerations in the Interpretation of Epidemiologic Studies of 

23 Lead Health Effects 

24 Prior to assessing results from recent lead epidemiologic studies, issues and questions 

25 arising from study designs and analysis methods used in the evaluation of lead health effects are 

26 briefly discussed. Study design can restrict the health effect parameters that can be estimated. 

27 Separate considerations need to be made for acute versus chronic effect studies, as well as 

28 individual versus aggregate-level analyses. Issues include measurement error, the functional 

29 form of relationships (especially at low exposure levels) and the potential for confounding. 

30 Aspects of these issues are briefly noted below, then are considered as various studies are 

31 reviewed in the following sections on specific health effect endpoints. Finally, they are further 

32 examined as part of the interpretive assessment(Section 6.9) at the end of this chapter. 

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Measurement error is an important factor to consider, both for measurement of the health 

effect outcome and the representativeness of the biomarkers of exposure (principally blood and 

bone lead) used in most key epidemiologic studies. For health outcome measures, the reliability 

and validity of the measurement need to be assessed. In addition, the appropriateness of the 

outcome measure for studying the hypothesis of interest needs to be determined. The critical 

issues of outcome measurement and classification are, to some extent, endpoint-specific, and will 

thusly be discussed further in the individual sections. 

Exposure misclassification can result in a notable reduction of statistical power in studies, 

especially in those that focus on the lower end of the exposure range. Limitations of blood lead 

as an exposure index include the use of a single blood lead concentration to represent lead body 

burden. Also of concern is the most relevant blood sample collection time point for to use in 

evaluating possible associations with health outcomes (e.g., at 2 years of age when peak lead 

exposure is expected versus concurrent blood lead samples). Another consideration is that 

similar blood lead concentrations in two individuals do not necessarily reflect similar body 

burdens. An added complication is that the relationship between lead intake and blood lead 

concentration appears to be curvilinear. Bone lead determinations are typically considered a 

measure of longer-term lead exposure; but, the X-ray fluorescence (XRF) method typically used 

to assess lead levels in bone also has limitations, including the relatively high minimum 

detection limit. The type of bone measured to determine lead exposure is another important 

aspect. 

The relationship between a measurement of a health outcome endpoint and an estimate of 

lead exposure based on a biomarker is an important concept. Modeling this relationship provides 

a numerical slope that quantifies the relationship between lead exposure and health outcome. 

These models must address differences in the relationship at different concentration ranges of 

exposure and present the functional form that best describes such data. Various models, both 

linear and nonlinear, have been considered to examine lead exposure-health effect relationships. 

This is especially important at low lead exposures. For example, a curvilinear relationship has 

been reported for neurodevelopmental and cardiovascular outcomes at low lead exposure levels. 

Depending on the subjects being examined for lead exposure effects, various other factors 

can lead to confounding of the relationship being considered. Potential confounding factors 

largely depend on the health outcome of interest and the study population. Some potential 

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confounding factors in children, for whom the major health concerns include neurological and 

developmental deficiencies, include: socioeconomic status (SES); nutritional status; quality of 

home environment (e.g., HOME score); parental education; parental IQ; and birth weight, as a 

few examples. For adults, factors that may confound the association between lead and 

cardiovascular health outcomes include: age; diet; alcohol use; smoking; and potential for 

copollutant exposures, such as cadmium. Control for potential confounding factors can be 

attempted at the study design phase and/or during statistical analysis. 

6.1.4 Approach to Presenting Lead Epidemiologic Evidence 

In the main body of this chapter, each section starts by concisely highlighting important 

points derived from the 1986 Lead AQCD/Addendum, and the 1990 Supplement. Particular 

emphasis is focused on studies and analyses that provide pertinent information for the critical 

assessment of health risks from lead exposure. Not all studies are accorded equal weight in the 

overall interpretive assessment of evidence regarding lead-associated health effects. Among 

well-conducted studies with adequate control for confounding, increasing scientific weight is 

accorded in proportion to the precision of their effect estimates. To ensure a thorough appraisal 

of the evidence, more detailed information on key features (including study design, analysis, lead 

biomarkers of exposure, and health outcome results) of important new studies are summarized in 

tables in the Annex for this Chapter 6 (Annex AX6). 

Emphasis is placed on main body text discussion below of (1) new studies employing 

standardized methodological analyses for evaluating lead effects across several cities and 

providing overall effect estimates based on combined analyses of information pooled across 

multiple cities; (2) studies conducted in the U.S. or Canada; and (3) meta-analyses of individual 

studies conducted in various cities. Multicity studies are of particular interest and value due to 

their evaluation of a wider range of lead exposures and large numbers of observations, thus 

generally providing more precise effect estimates than most smaller scale studies of single cities. 

Furthermore, multicity studies have the potential to provide especially valuable evidence 

regarding relative homogeneity and/or heterogeneity of lead health effects relationships across 

geographic locations. The potential impacts of the underlying health status of populations and 

cultural differences in the case of intelligence testing (one of the major health outcomes in 

children) also need to be accounted for in the assessment; thus, U.S. studies are emphasized over 

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non-U.S. studies. In accordance with the emphasis placed on the lead epidemiologic studies in 

this chapter, Chapter 6 Annex tables are organized by region, with multicity studies in each 

region presented first. 

In the ensuing sections, epidemiological studies of biological markers of lead exposure are 

discussed first, in Section 6.2. The neurotoxic effects of lead are next discussed in Section 6.3 

for children and adults, followed by discussion of the renal and cardiovascular effects of lead in 

Sections 6.4 and 6.5. Section 6.6 then discusses reproductive and developmental effects of lead, 

and Section 6.7 discusses genotoxic and carcinogenic effects of lead. Section 6.8 discusses the 

effects of lead on the immune system. The effects of lead on other organ systems (including the 

hematopoietic, endocrine, hepatic, gastrointestinal, and respiratory systems) are assessed in 

Section 6.9. Effects of lead on bone and teeth, as well as on ocular health are also discussed in 

Section 6.9. Finally, Section 6.10 provides an interpretative assessment of the overall 

epidemiologic evidence for lead health effects. 

6.2 BIOLOGICAL MARKERS OF LEAD BODY BURDEN 

AND EXPOSURE 

6.2.1 Lead in Blood 

6.2.1.1 Summary of Key Findings from the 1986 Lead AQCD 

The extensive use of blood lead concentration as a dose metric reflects mainly the greater 

feasibility of incorporating blood lead measurements into clinical or epidemiologic studies, 

compared to other potential dose indicators, such as lead in kidney, plasma, urine, or bone 

(Flegal and Smith, 1995; Graziano, 1994; Skerfving, 1988). However, blood lead measurements 

have several limitations as measures of lead body burden and exposure that relate to the kinetics 

of blood lead in relation to exposure and body burden. These limitations were noted in Section 

13.3.2 of the 1986 Lead AQCD, which discusses attributes and limitations of blood lead 

concentration as an indicator of internal exposure. Relevant developments since the 1986 Lead 

AQCD was completed include numerous studies of determinants of lead levels in bone (see 

Section 6.2.2), which provide further support for the importance of this relatively slow kinetic 

compartment in assessing the blood lead concentration as an index of lead exposure. The 

enhanced understanding of lead biokinetics has also been consolidated into exposure-biokinetics 

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models (see Chapter 4), which not only serve to illustrate exposure-blood-body burden 

relationships, but also provide a means for making predictions about these relationships that can 

be tested experimentally or in epidemiologic studies. The basic concepts laid out in the 1986 

Lead AQCD, that the concentration of lead in blood is largely determined by the relatively recent 

exposure history of the individual and that it reflects the level of lead in a relatively mobile and 

small compartment, remain valid. Especially in children, who experience a more rapid turnover 

of bone mineral, an endogenous source of lead, blood lead concentrations closely parallel 

changes in total body burden. 

6.2.1.2 Analytical Methods for Measuring Lead in Blood 

Analytical methods for measuring lead in blood include flame atomic absorption 

spectrometry (AAS), graphite furnace atomic absorption spectrometry (GFAAS), anode stripping 

voltammetry (ASV), inductively coupled plasma-atomic emission spectroscopy (ICP-AES), and 

inductively coupled plasma-mass spectrometry (ICP-MS). GFAAS and ASV are generally 

considered to be the methods of choice (Flegal and Smith, 1995). Background correction, such 

as Zeeman background correction that minimizes the impact of the absorbance of molecular 

species, must be applied. Limits of detection for lead using AAS are on the order of 5-10 μg/dL 

for flame AAS measurements, approximately 0.1 μg/dL for flameless AAS measurements, and 

0.005 μg/dL for GFAAS (Flegal and Smith, 1995; National Institute for Occupational Safety and 

Health, 1994). A summary of standard methods that have been reported for blood lead analysis 

are provided in Annex Table AX6-2.1. Sample preparation usually consists of wet ashing in 

heated strong acid (National Institute for Occupational Safety and Health, 1977a,b,c,d,e); 

however, preparation methods not requiring wet ashing have also been reported (Aguilera de 

Benzo et al., 1989; Delves and Campbell, 1988; Manton and Cook, 1984; National Institute for 

Occupational Safety and Health, 1977f; Que Hee et al., 1985; Zhang et al., 1997). The presence 

of phosphate, ethylenediaminetetraacetic acid (EDTA), or oxalate can sequester lead and cause 

low readings in flame AAS (National Institute for Occupational Safety and Health, 1984). 

A comparison of IDMS, ASV, and GFAAS showed that all three of these methods can be used to 

quantify lead levels in blood (Que Hee et al., 1985). 

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6.2.1.3 Levels of Lead in Blood 

Blood lead concentrations in the U.S. general population have been monitored in the 

National Health and Nutrition Examination Survey (NHANES) conducted by the Centers for 

Disease Control and Prevention. Data from the most recent survey (NHANES IV, Centers for 

Disease Control, 2005) are shown in Tables 6-2.1 and 6-2.2. For survey years 2001-2002, the 

geometric mean blood lead concentration for ages >1 year (n = 8,945) was 1.45 μg/dL (95% CI: 

1.39, 1.52); with the geometric mean in males (n = 4,339) being 1.78 μg/dL (95% CI: 1.71, 

1.86) and in females (n = 4,606) being 1.19 μg/dL (95% CI: 1.14, 1.25). Blood lead 

concentrations in the U.S. general population have decreased over the past three decades as 

regulations regarding lead paint, leaded fuels, and lead-containing plumbing materials have 

decreased exposure. Changes over time in children are shown in Figure 6-2.1. 

Yassin et al. (2004) analyzed occupational category strata from NHANES III (1988–1994; 

Table 6-2.3). The geometric mean for all adults (n = 11,126) included in the analysis was 

2.42 μg/dL (GSD 6.93), with the highest means estimated for vehicle mechanics (n = 169; 

GM 4.80 μg/dL [GSD 3.88]) and construction workers (n = 122; GM 4.44 μg/dL [GSD 7.84]). 

See Annex Table AX6-2.2 for a summary of selected measurements of blood lead levels in 

humans. 

6.2.1.4 Blood Lead as a Biomarker of Lead Body Burden 

A simple conceptual representation of the lead body burden is that it is comprised of a fast 

turnover pool, comprised mainly of soft tissue, and a slow pool, comprised mainly of skeletal 

tissues (Rabinowitz et al., 1976; see Chapter 4 for detailed discussion of this and other more 

complex models of lead biokinetics). The rapid pool has an elimination half-life of ~28 days and 

comprises <1% of the lead body burden. The slow pool has an elimination half-life of several 

decades and comprises >90% of the total lead body burden. Blood, which comprises ~1% of 

body burden, exchanges with both the slow and fast pools, and exhibits multiphasic elimination 

kinetics. The dominant phase, exhibited shortly after a change in exposure occurs, has a half-life 

of ~20–30 days. A slower phase becomes evident with longer observation periods following a 

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Survey Period 1999–2000 2001–2002 1999–2000 2001–2002 1999–2000 2001–2002 1999–20N 723 898 909 1,044 2,135 2,231 4,20Blood Lead 2.23 1.70 1.51 1.25 1.10 0.94 1.75 (μg/dL)a (1.96, 2.53) (1.55, 1.87) (1.36, 1.66) (1.14, 1.36) (1.04, 1.17) (0.90, 0.99) (1.68, 1aBlood lead concentrations presented are geometric means (95% CI). Table 6-2.2. Blood Lead Concentrations in U.S. by Gender, NHANES IV (1999–2002) Gender Males Females Survey Period 1999–2000 2001–2002 1999–2000 n 3,913 4,339 4,057 Blood Lead 2.01 1.78 1.37 (μg/dL)a (1.93, 2.09) (1.71, 1.86) (1.32, 1.43) aBlood lead concentrations presented are geometric means (95% CI). 

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Figure 6-2.1. Blood lead concentrations in U.S. children, 1-5 years of age. Shown are 

geometric means and 95% confidence intervals as reported from the 

NHANES II (1976–1980) and NHANES III Phase 1 (1988–1991; 

Pirkle et al., 1994); NHANES III Phase 2 (1991–1994; Pirkle et al., 1998); 

and NHANES IV (1999-2000, 2001-2002; Centers for Disease Control, 2005). 

1 decrease in exposure. The half-life of this slow phase has been estimated to be ~3 to 30 years 

2 and appears to correlate with finger bone lead levels. This characterization is supported by 

3 measurements of lead contents of cadaver tissues (Barry, 1975; Schroeder and Tipton, 1968), 

4 lead isotope kinetics in adults (Chamberlain et al., 1978; Rabinowitz et al., 1976; Griffin et al., 

5 1975), and measurements of blood and bone lead levels in retired lead workers (Schütz et al., 

6 1987; Christoffersson et al., 1986). 

7 As a consequence of a relatively large fraction of the body burden having a relatively slow 

8 turnover compared to blood, a constant lead uptake (or constant intake and fractional absorption) 

9 gives rise to a quasi-steady state blood lead concentration, while the body burden continues to 

10 increase, largely as a consequence of retention of lead in bone (Figure 6-2.2). As a result, the 

11 contribution of blood lead to body burden decreases over time. An abrupt change in lead uptake 

12 gives rise to a relatively rapid change in blood lead, to a new quasi-steady state, achieved in 

13 ~75-100 days (i.e., 3-4 times the blood elimination half-life). In the hypothetical simulation 

14 shown in Figure 6-2.2, body burden has approximately doubled (from 5 to 10 mg) as a result of a 

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December 2005 6-12 DRAFT-DO NOT QUOTE OR CITE Table 6-2.3. Blood Lead Concentrations by Occupation, NHANES III (1988-1994) Blood Lead (μg/d

Occupation n GM GSD Vehicle mechanics 169 4.80 3.88 Food service workers 700 2.00 2.69 Management, professional, technical, and sales workers 4,768 2.13 4.05 Personal service workers 1,130 2.48 4.52 Agricultural workers 498 2.76 4.02 Production workers: machine operators, material movers, etc. 1,876 2.88 4.24 Laborers other than in construction 137 3.47 3.36 Transportation workers 530 3.49 5.19 Mechanics other than vehicle mechanics 227 3.50 4.91 Construction trades people 470 3.66 4.64 Construction laborers 122 4.44 7.84 Health service workers 499 1.76 2.24 All workers 11,126 2.42 6.93 Data from Yassin et al. (2004). 

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Figure 6-2.2. Simulation of relationship between blood lead concentration and body 

burden in adults. A constant baseline intake gives rise to a quasi-steady 

state blood lead concentration, while the body burden continues to increase, 

largely as a consequence of retention of lead in bone (upper panel). An 

abrupt change in lead uptake gives rise to a relatively rapid change in blood 

lead, to a new quasi-steady state, and a relatively small change in body 

burden. The long-term average blood lead concentration more closely 

tracks the pattern of change in body burden (lower panel). Simulation 

based on lead biokinetics model of Leggett (1993) . 

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5-year period of increased lead uptake; however, the blood lead concentration prior to and 1 year 

following cessation of the increased uptake has not changed (~2 μg/dL). Therefore, a single 

blood lead concentration measurement, or a series of measurements taken over a short-time span, 

can be expected to be a relatively poor index of lead body burden. On the other hand, an average 

of individual blood lead concentrations measured over a longer period of time (long-term 

average blood lead concentrations) can be expected to be a better index of body burden. In the 

hypothetical simulation shown in Figure 6-2.2, both the long-term average blood lead 

concentration and the body burden have approximately doubled. 

The disparity in the kinetics of blood lead and body burden has important implications for 

the interpretation of blood lead concentration measurements in epidemiology studies. Crosssectional studies, by design, sample blood lead concentration at one time or over relatively 

narrow windows of time. In these samples, the blood lead concentration may or may not reflect 

well the body burden; it is more likely to do so if the measured value is a reflection of the longterm average blood lead concentration. However, in cross-sectional samples, this cannot be 

ascertained. Longitudinal sampling provides a means for estimating average blood lead 

concentrations over time, and such estimates are more likely to be more strongly influenced by 

differences in body burden, than by differences in short-term variability in exposure. The degree 

to which repeated sampling will reflect the actual long-term time-weighted average blood lead 

concentration will depend on the sampling frequency in relation to variability in exposure. High 

frequency variability in exposures can produce episodic (or periodic) oscillations in blood lead 

concentration and body burden that may not be captured with low sampling frequencies. 

The same basic concepts described above regarding lead biokinetics of adults also apply to 

children. The empirical basis for the understanding of the biokinetics of lead in children is much 

weaker than that for adults. However, based on the understanding of bone mineral kinetics and 

its importance as a mechanism for uptake and loss of lead from bone (Leggett, 1993; O’Flaherty, 

1991, 1993, 1995), the slow pool, described above for adults, is thought to be much more labile 

in children, reflecting a more rapid turnover of bone mineral in children. As a result, changes in 

blood lead concentration in children are thought to more closely parallel changes in total body 

burden (Figure 6-2.3). Nevertheless, in children, as in adults, the long-term time-weighted 

average blood lead concentration is more likely to provide a better reflection of lead body burden 

than a single sample. 

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402(c) Economic Analysis Chapter 5 415
Figure 6-2.3. Simulation of relationship between blood lead concentration and body 

burden in children. Blood lead concentration is thought to parallel body 

burden more closely in children than in adults, due to more rapid turnover 

of bone and bone-lead stores in children (upper panel). Nevertheless, the 

long-term average blood lead concentration more closely tracks the pattern 

of change in body burden (lower panel). Simulation based on Leggett (1993) 

lead biokinetics model. 

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402(c) Economic Analysis Chapter 5 416
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6.2.1.5 Blood Lead as a Biomarker of Lead Exposure 

Characterizing quantitative relationships between external lead exposures and blood lead 

concentrations has become central to concentration-response analyses for human populations 

exposed to lead. The 1986 Lead AQCD summarized the empirical basis for this as it stood at the 

time. A summary of empirically-derived regression slope factors relating lead exposures and 

blood lead is provided in Abadin and Wheeler (1993). More recent meta-analyses, based on 

structure equation modeling, provide further support for quantitative relationships between lead 

exposures and blood lead concentrations in children (e.g., U.S. Environmental Protection 

Agency, 2001; Lanphear et al., 1998; Succop et al., 1998). 

As noted above, the elimination half-life of lead in blood is ~25 to 30 days (Chamberlain 

et al., 1978; Rabinowitz et al., 1976; Griffin et al., 1975); therefore, the blood lead concentration 

mainly reflects the exposure history for the previous few months. However, a single blood lead 

measurement cannot distinguish between a history of long-term low level lead exposure or a 

history that includes higher acute exposures. This is illustrated in Figure 6-2.4. Two 

hypothetical children are simulated. Child A has a relatively constant lead intake from birth; 

whereas Child B has the same long-term lead intake as Child A, with a 1-year elevated intake 

which begins at age 24 months (Figure 6-2.4, upper panel). The absorption fraction is assumed 

to be the same for both children. Blood lead samples 1 and 5, or 2 and 4, will yield similar blood 

lead concentrations (~3 or 10 μg/dL, respectively), yet the exposure contexts for these samples 

are very different. Two samples (e.g., 1 and 2, or 4 and 5), at a minimum, are needed to 

ascertain if the blood lead concentration is changing over time. The rate of change can provide 

information about the magnitude of change in exposure, but not necessarily about the time 

history of the change (Figure 6-2.4, lower panel). Here again, time-integrated measurements of 

lead concentration may provide a means for accounting for some of these factors and, thereby, 

provide a better measure of long-term exposure. The same concepts apply to estimation of longterm exposure based on blood lead measurements in adults (Gerhardsson et al., 1992, 1995a; 

Roels et al., 1995). 

An additional complication is that the relationship between lead intake and blood lead 

concentration is curvilinear; that is, the increment in blood lead concentration per unit of lead 

intake decreases with increasing blood lead concentration, both in children (Lacey et al., 1985; 

Ryu et al., 1983; Sherlock and Quinn, 1986) and in adults (Kehoe, 1987; Laxen et al., 1987; 

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402(c) Economic Analysis Chapter 5 417
Figure 6-2.4. Simulation of temporal relationships between lead exposure and blood lead 

concentration in children. Child A and Child B have a relatively constant 

basal lead intake (μg/day/kg body weight) from birth; Child B experiences 

1-year elevated intake which begins at age 24 months (upper panel). Blood 

lead samples 1 and 5, or 2 and 4, will yield similar blood lead concentrations 

(~3 or 10 μg/dL, respectively), yet the exposure scenarios for these samples 

are very different. As shown in the example of Child C and Child D, two 

samples can provide information about the magnitude of change in exposure, 

but not necessarily the temporal history of the change (lower panel). 

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Pocock et al., 1983; Sherlock et al., 1982, 1984). The nonlinearity is evident even at blood lead 

concentrations below 25 μg/dL (Figure 6-2.5). The nonlinearity in the lead intake-blood lead 

concentration relationship is derived, at least in part, from a capacity limitation in the 

accumulation of lead in erythrocytes (Bergdahl et al., 1997, 1998, 1999; Manton et al., 2001; 

Smith et al., 2002). A capacity-limited process may also reside at the level of intestinal 

absorption; however, the dose at which absorption becomes appreciably limited in humans is not 

known. Lead intake-blood lead relationships also vary (a) with age, as a result of agedependency of gastrointestinal absorption of lead, and (b) with diet and nutritional status 

(Mushak, 1991). 

The blood lead concentration is also influenced by lead in bone. Evidence for the 

exchange of bone lead and soft tissue lead stores comes from analyses of stable lead isotope 

signatures of lead in bone and blood. As noted earlier, bone lead likely contributes to the slow 

phase of elimination of lead from blood that has been observed in retired lead workers 

(Christoffersson et al., 1986; Schütz et al., 1987). Bone lead stores may contribute 40-70% of 

the lead in blood (Smith et al., 1996). This contribution increases during pregnancy, when 

mobilization of bone lead increases, apparently as the bone is resorbed to produce the fetal 

skeleton (Gulson et al., 2003). The mobilization of bone lead during pregnancy may contribute, 

along with other mechanisms (e.g., increased absorption), to the increase in lead concentration 

that has been observed during the later stages of pregnancy (Gulson et al., 1997; Lagerkvist 

et al., 1996; Schuhmacher et al., 1996). In addition to pregnancy, other states of increased bone 

resorption appear to result in release of bone lead to blood; these include lactation, osteoporosis, 

and menopause (Gulson et al., 2003). These observations are consistent with epidemiologic 

studies that have shown increases in blood lead concentration after menopause and in association 

with decreasing bone density in postmenopausal women (Hernandez-Avila et al., 2000; Nash 

et al., 2004; Symanski and Hertz-Picciotto, 1995). The relationship between blood and bone lead 

is discussed further in Section 6.2.2 on bone lead as a biomarker of lead exposure. 

6.2.1.6 Summary of Blood Lead as a Biomarker of Lead Body Burden and Exposure 

The blood lead concentration measured in an individual will be determined by the recent 

exposure history of the individual, as well as the long-term exposure history that gives rise to 

accumulated bone lead stores. The contribution of the latter to blood lead may change with the 

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402(c) Economic Analysis Chapter 5 419
Figure 6-2.5. Simulation of relationships between lead intake and blood lead 

concentration in adults and children. The relationship between lead intake 

and blood lead concentration is curvilinear in adults and children. 

Predictions are for a 2-year-old child and 30-year-old adult, for a constant 

lead intake (μg/kg/day). Predictions are based on Leggett (1993, upper 

panel) and O’Flaherty (1993, 1995, lower panel). 

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duration and intensity of the exposure, age, and various physiological variables (e.g., nutritional 

status, pregnancy, menopause). Longitudinal measurements of blood lead can be expected to 

provide a more reliable measure of exposure history of an individual (and will more closely 

parallel body burden) compared to a single measurement; however, the degree to which this will 

apply will depend on the sampling frequency with respect to the temporal pattern of exposure. 

In general, higher blood lead concentrations can be interpreted as indicating higher 

exposures (or lead uptakes); however, they do not necessarily predict appreciably higher body 

burdens. Similar blood lead concentrations in two individuals (or populations) do not necessarily 

translate to similar body burdens or similar exposure histories. 

6.2.2 Lead in Bone 

6.2.2.1 Summary of Key Findings from the 1986 Lead AQCD 

In the 1986 Lead AQCD, the discussion on the distribution of lead in bone was fairly 

limited and mostly based on postmortem studies. The distribution between the two major 

compartments of cortical and trabecular bone were addressed especially based on the pioneering 

isotopic work of Rabinowitz et al. (1977). Estimates of the amount of lead in bone were also 

provided. There was limited discussion of the half-life of lead in bone as being on the order of 

several decades. 

One of the major conclusions of the 1986 Lead AQCD regarding bone lead was that the 

traditional view that the skeletal system was a total sink for body lead was now giving way to the 

notion that there were at least several bone compartments for lead, with different mobility 

profiles. The possibility of bone lead serving as a source of long-term internal exposure was also 

considered. 

Since 1986, the main focus of lead in bone studies has been on occupationally-exposed 

subjects, because of concern, until more recent times, about the ability to measure lower levels of 

lead in bone from environmentally-exposed subjects. Furthermore most of the focus has been on 

adult males, with very few studies on females and children. The newly available studies of lead 

in bone are discussed in the following sections. 

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6.2.2.2 Methodology of Bone Lead Analysis 

6.2.2.2.1 Analytical Methods for Measuring Lead in Bone 

Bone is comprised of two main types (cortical and trabecular) that have distinct rates of 

turnover and lead release, resulting in potential differences in implications with respect to 

toxicity aspects (further discussed in Section 6.2.2.3). The most commonly measured bones are 

the tibia, calcaneus, patella, and finger bone. For cortical bone, the midpoint of the tibia is 

measured. For trabecular bone, both the patella and calcaneus are measured. Recent studies 

favor measurement of the patella, because it has more bone mass and may afford better 

measurement precision than the calcaneus. The advantages and disadvantages of patella and 

calcaneus sites have not been thoroughly investigated. Bone lead measurements in cadavers, 

environmentally-exposed subjects, and occupationally-exposed subjects are presented in Annex 

Tables AX6-2.3, AX6-2.4, and AX6-2.5, respectively. 

Bone analysis methods for in vivo measurements have included AAS, ASV, ICP-AES, 

ICP-MS, laser ablation inductively coupled plasma mass spectrometry (LAA ICP-MS), thermal 

ionization mass spectrometry (TIMS), synchrotron radiation induced X-ray emission (SRIXE), 

particle induced X-ray emission (PIXE), and X-ray fluorescence (XRF). Since the 1986 Lead 

AQCD, there have been many new papers published on bone lead using XRF. The upsurge in 

popularity of the XRF method has paralleled a decline in the use of the other methods. 

In the past, two main approaches for XRF measurements have been used to measure lead 

concentrations in bone, the K-shell and L-shell methods. The K-shell method is now the most 

widely used, as there have been no further developments in L-shell devices since the early 1990s. 

The K-shell methods using 57Cd and 109Cd have been described in detail by Somervaille et al. 

(1989). Briefly, the K-shell XRF method uses 88.034 keV gamma rays from 109Cd to fluoresce 

the K-shell X-rays of lead. 

Since 1986, several investigators have reported refinements to hardware and software to 

improve the precision and accuracy of XRF measurements and there have been a number of 

investigations into the precision, accuracy and variability in XRF measurements (e.g., Aro et al., 

2000; Todd et al., 2000, 2001, 2002). Todd et al. (2000) provided a detailed discussion of 

factors that influence the variability and measurement uncertainty, including repositioning, 

sample measurement duration, overlying tissue, operator expertise, detector resolution, and 

changes to measurement process over time. Some of these aspects were also discussed by 

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Hu et al. (1995). From their cadaver and in vivo measurements, Todd et al. (2000) concluded 

that the uncertainty in an individual measurement was an underestimate of the standard deviation 

of replicate measurements, suggesting a methodological deficiency probably shared by most 

current 109Cd-based K-shell XRF lead measurement systems. In examining the reproducibility of 

the bone lead measurements over a 41⁄2 month period, Todd et al. found the average difference 

between the XRF results from short term and longer term measurements was 1.2 μg/g, indicating 

only a small amount of variability in the XRF results over a sustained period of time. 

6.2.2.2.2 Statistical Methods for Analyzing Bone Lead Concentrations in 

Epidemiologic Studies 

In the literature, XRF bone data has typically been reported in two ways: one involving a 

methodological approach to assessing the minimum detection limit and the other termed an 

epidemiologic approach by Rosen and Pounds (1998). In the methodological approach, a 

minimum detection limit is defined using various methods, including two or three times the 

square root of the background counts; one, two, or three times the SD of the background; and 

two times the observed median error. This approach relies upon the minimum detection limit to 

define a quantitative estimate that is of sufficient precision to be included in the statistical 

analysis. The following are examples of methodological minimum detection limits for bone lead 

analyses. Bellinger et al. (1994) observed minimum detection limits, equivalent to the SD, of 

5.4 μg/g for tibia and 9.2 μg/g for patella. Using twice the median observed error, Gerhardsson 

et al. (1993) observed minimum detection limits of 9.8 μg/g for tibia and 19.1 μg/g for 

calcaneus. For finger bone lead measurements, Christoffersson et al. (1986) observed a 

minimum detectable limit of 20 μg/g, which was equivalent to three times the square root of the 

background counts. 

With the epidemiologic approach, to determine the minimum detection limit of an 

instrument all values are used (including negative values), which results in extremely low 

detection limits. Rosen and Pounds (1998) noted that this approach yields population bone lead 

averages that they considered artificially low and inconsistent with observations from many other 

earlier studies. However, not including values that are negative or below the detection limit, or 

assigning these values a fixed number for the statistical analysis is also of concern. To examine 

and compare the two methods used to analyze data at low levels of bone lead concentration, 

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Kim et al. (1995) performed serial measurements on phantoms containing spiked amounts of 

lead. The results demonstrated that the use of methodological minimum detection limits to 

recode low-level observations reduced the efficiency of the analysis and the ability to distinguish 

between the phantoms. Using the epidemiologic approach of retaining all point estimates of 

measured bone lead concentrations provided less bias and greater efficiency in comparing the 

mean or median levels of bone lead of different populations. 

6.2.2.3 Bone Lead as a Biomarker of Lead Body Burden 

6.2.2.3.1 Uptake of Lead in Bone 

The dominant compartment for lead in the body is in bones. In human adults, more than 

90% of the total body burden of lead is found in the bones, whereas bone lead accounts for ~70% 

of the body burden in children (Barry, 1975). Bone is comprised of two main types, cortical and 

trabecular. The tibia consists of more than 95% cortical bone, the calcaneus and patella 

comprise more than 95% trabecular bone, and finger bone is a mixed cortical and trabecular bone 

although the second phalanx is dominantly cortical. The cortical and trabecular bones have 

distinct rates of turnover and lead release, as well as potentially different associated toxicity 

implications (Hu et al., 1998). For example, adult tibia has a turnover rate of about 2% per year 

whereas trabecular bone has a turnover rate of more than 8% per year (Rabinowitz, 1991). The 

proportion of cortical to trabecular bone in the human body varies by age, but on average is 

about 80 to 20 (International Commission on Radiological Protection, 1973). Although not so 

important for certain types of measurements, the periosteum is of limited dimension and may 

reflect a bone compartment of more rapid deposition and turnover of lead than the other two 

types (Skerfving et al., 1993), which would also likely have implications for toxicity, especially 

for chelation therapy. 

Much of the understanding of bone structure and metal deposition comes from studies of 

radioactive elements (e.g., International Commission on Radiological Protection, 1996). Durbin 

(1992, page 823) suggests that there is “an initial deposition of lead on anatomical bone surfaces 

with some skewing to the well nourished trabecular surfaces in red marrow, intense deposits at 

bone growth sites, and later on, a nearly diffuse labeling throughout the bone volume. For 

constant intake of lead during growth, it is expected that lead will be nearly uniformly distributed 

in the mineralized bone. Single or irregular intakes during growth are expected to result in 

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residual buried lines and hotspots superimposed on a relatively uniform diffuse concentration in 

bone mineral volume. . . For example, periosteal and subperiosteal lead deposits in the long 

bones, including those of the hands and feet, are likely to be greater than at many other sites, 

since bone growth continues at the periosteal surface while the endosteal surface is resorbed.” 

The importance of bone marrow was also stressed by Salmon et al. (1999), with a key 

factor affecting lead uptake into bone being the fraction of bone surface in trabecular and cortical 

bone adjacent to active bone marrow. The fraction of total marrow that is red and active 

decreases from 100% at birth to about 32% in adulthood (Cristy, 1981). Early lead uptake is 

greater in trabecular bone due to its larger surface area and higher metabolic rate. Of the total 

bone surface against red marrow, 76% is trabecular and 24% is cortical endosteal (Salmon et al., 

1999). Bone marrow has much lower lead concentrations than bone matrix (Skerfving 

et al., 1983). 

6.2.2.3.2 Half-Life of Lead in Bone 

Estimates of the half-life of lead in trabecular bone are partly dependent on the tissue 

analyzed and the “purity” of the trabecular component (e.g., patella, calcaneus, and phalanx). 

Earlier estimates of the half-life of lead in trabecular bone ranged from 12 to 19 years (Bergdahl 

et al., 1998; Gerhardsson et al., 1993). For cortical bone, estimates for the half-life of lead 

were on the order of 13 to 27 years (Bergdahl et al., 1998; Gerhardsson et al., 1993; 

Rabinowitz, 1991). 

With respect to half-lives in bone, recent K-shell XRF bone studies have indicated that 

earlier concepts of a constant rate of removal of lead from bone throughout adulthood assumed 

in models of human metabolism (Leggett, 1993; O’Flaherty, 1993) may be incorrect. In a study 

of active and retired smelter workers, Brito et al. (2001) suggested that people less than 40 years 

old had a shorter half-life for the release of lead from the tibia than those older than 40 years, 

4.9 years (95% CI: 3.6, 7.8) compared to 13.8 years (95% CI: 9.7, 23.8), respectively. Also, 

they suggested that less intensely exposed subjects with a lifetime averaged blood lead of 

#25 μg/dL had a shorter half-life in the tibia (6.2 years [95% CI: 4.7, 9.0]) than those with a 

lifetime averaged blood lead >25 μg/dL (14.7 years [95% CI: 9.7, 29.9]). 

Even by the end of the sixth decade, ~35 to 40% of skeletal mass consists of 

unremodelled first generation bone acquired during childhood and adolescence (International 

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Commission on Radiological Protection, 1973). This statement contrasts with that of O’Flaherty 

(1993) who suggested that because of the relatively short half-life of lead in the bones of children 

that much of the lead incorporated during active growth would not persist into adulthood. In a 

comparison of lead in tooth dentine and the tibia from young adults who were followed up after a 

period of 13 years, Kim et al. (1996) suggested that “pockets” of lead acquired in childhood may 

persist into adults. Likewise, McNeill et al. (2000) compared tibia lead levels and cumulative 

blood lead indices in a population of 19 to 29 year olds who had been highly exposed to lead in 

childhood from the Bunker Hill, Idaho smelter. They concluded that lead from exposure in early 

childhood had persisted in the bone matrix until adulthood. 

6.2.2.3.3 Changes in Bone Lead Concentrations with Age 

Conventional and XRF analyses of bone have shown significant increases in bone lead 

with age (Hu et al., 1990, 1996; Kosnett et al., 1994; Morgan et al., 1990). Kosnett et al. (1994) 

observed no significant change in bone lead concentrations up to age 20 years, but found an 

increasing trend with the same slope for men and women between the ages of 20 to 55 years and 

an increase to a faster rate in men older than 55 years. Kosnett et al. reanalyzed earlier cadaver 

cortical bone data of Drasch et al. (1987) and found that male bone lead values increased 

significantly after age 40 years, whereas female values slightly declined. A similar analysis of 

the post-mortem data of Barry (1975) showed an upward inflection for all males after age 

35 years. Kosnett et al. (1994) found no significant slope to the relationship between age and 

bone lead for the 10 to 20 year old subjects, in contrast to Barry (1975) and Drasch et al. (1987). 

Annual increments of lead to bone vary although no attempt has been made to determine 

whether the differences are significant. For example, the annual increment of 0.46 μg/g bone 

mineral/year found by Gordon et al. (1993) was slightly lower than that found by Somervaille 

et al. (1989), but the difference was not significant. After age 20 years, Kosnett et al. (1994) 

found the annual increment to be 0.38 μg/g bone mineral/year. Hu et al. (1990) reported a value 

of 0.31 μg/g bone mineral/year for subjects ranging in age from 20 to 58 years. 

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6.2.2.4 Distribution of Lead from Bone into Blood and Plasma 

6.2.2.4.1 Contribution of Bone Lead to Blood Lead 

Although the skeleton was recognized as a potentially significant contributor to blood lead 

in the 1986 Lead AQCD, there have been several investigations using both bone lead XRF and 

stable lead isotope methods which have helped quantify the contribution. The earlier estimation 

of skeletal contribution to blood lead was 70% by Manton (1985) and ~65% ranging up to 100% 

by Schütz et al. (1987). The more recent isotope studies confirmed these estimates. Using 

female immigrants to Australia and their children, Gulson et al. (1995, 1997, 1999a) found a 

mean value of 50% (range 16-73%) deriving from the skeleton. Smith et al. (1996) found a 

range of 40–70% in five patients who underwent total hip or knee joint replacement. Gwiazda 

et al. (2005) observed a range of 40-65% in two children and >90% in one child. Studies 

examining the bone lead contribution to blood lead are presented in Annex Table AX6-2.6. 

The contribution of skeletal lead to blood lead was further examined in females from 

varying environments. In middle-aged to elderly subjects (46-74 years), an increase of 19 μg/g 

of lead in tibia bone mineral was associated with an increase in blood lead of 1.7 μg/dL, which 

corresponds to a 0.09 μg/dL increase in blood lead per 1 μg/g bone mineral (Korrick et al., 

2002). A study of 108 former workers at the Bunker Hill smelter in northern Idaho and 

99 referents from the Spokane, WA area examined the endogenous bone lead release rate of 

postmenopausal and premenopausal women (Popovic et al., 2005). The results indicated that the 

endogenous release rate in postmenopausal women (0.13 μg/dL per μg/g bone) was greater than 

the rate found in premenopausal women (0.07 μg/dL per μg/g bone). In a Mexico City study, the 

endogenous bone lead release rate in postmenopausal women also was observed to be double 

that in premenopausal women (Garrido-Latorre et al., 2003). A change of 10 μg/g bone mineral 

was associated with an increase in blood lead of 1.4 μg/dL in postmenopausal subjects, 

compared to an increase of 0.8 μg/dL in premenopausal women. Lactation was also found to 

affect the endogenous bone lead release rate. After adjusting for patella lead concentration, an 

increase in blood lead levels of 12.7% (95% CI: 6.2, 19.6) was observed for women who 

practiced partial lactation and an increase of 18.6% (95% CI: 7.1, 31.4) for women who 

practiced exclusive lactation compared to those who stopped lactation (Téllez-Rojo et al., 2002). 

The mean cortical leads to current blood lead ratios for occupationally-exposed subjects 

are shown in Figure 6-2.6. Box plots were calculated using data from the following studies: 

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402(c) Economic Analysis Chapter 5 427
Figure 6-2.6. Cortical lead to blood leads ratios for occupationally-exposed subjects 

(both active and retired) and referents. Data compiled from several studies. 

See text for more details. 

1 Bergdahl et al., 1998; Brito et al., 2002; Christoffersson et al., 1984; Erfurth et al., 2001; Erkkil@

2 et al., 1992; Fleming et al., 1998; Gerhardsson et al., 1993; Hänninen et al., 1998; Juarez-Perez 

3 et al., 2004; Popovic et al., 2005; Roels et al., 1995; Schwartz et al., 2000a, 2000b; Somervaille 

4 et al., 1988, 1989; Todd et al., 2001. The mean cortical lead to current blood lead ratio is about 

5 1.2 (range 0.4-2.6) for active employees (n = 17). For retired employees (n = 7), the mean is 3.2 

6 (range 2.0-5.3), while for environmentally-exposed referent subjects from these industries (n = 7) 

7 the mean ratio is about 1.3 (range 1-2.2). The differences in the cortical lead to blood lead ratio 

8 between active and retired employees and retired employees and referents are significant 

9 (p < 0.01) but not between active employees and referents. Several investigators have pointed 

10 out the weak association between bone lead and blood lead in active employees in comparison 

11 with the stronger association with retired employees (e.g., Erkkilä et al., 1992; Fleming et al., 

12 1997; Gerhardsson et al., 1993). This is likely because circulatory lead of active employees 

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reflects mainly ongoing exposure whereas that in retired employees is more dependent on lead 

released from the skeleton. 

The mean tibia lead to current blood lead ratios for environmentally-exposed subjects is 

shown in Figure 6-2.7. The box plot for pregnancy-related subjects was calculated using data 

from the following studies: Brown et al., 2000; Chuang et al., 2001; Ettinger et al., 2004; Gomaa 

et al., 2002; Gonzalez-Cossio et al., 1997; Hernandez-Avila et al., 1996, 1998, 2002, 2003; 

Hu et al., 1996; Moline et al., 2000; Rothenberg et al., 2000; Sanin et al., 2001; Téllez-Rojo 

et al., 2002, 2004. The box plot for middle-aged and elderly subjects included the following 

studies: Berkowitz et al., 2004; Cheng et al., 1998a; Garrido-Lattore et al., 2003; Hu et al., 1996, 

2001; Korrick et al., 2002; Kosnett et al., 1994; Oliveira et al., 2002; Schafer et al., 2005; Tsaih 

et al., 2004; Webber et al., 1995. The box plot for the younger subjects (age range 1-30 years) 

included Farias et al., 1998; Kim et al., 1996; Rosen et al., 1989; Stokes et al., 1998. The mean 

tibia lead to blood lead ratio for pregnancy-related subjects (n = 21) is 1.5 (range 1.0-4.2) and is 

statistically significantly different (p < 0.001) from the mean ratio of 3.4 (range 1.6-5.4) for 

middle-aged to elderly subjects (n = 27). Similar relationships are observed for the patella lead 

to blood lead ratios for pregnancy-related subjects and middle-aged to elderly subjects. 

In several other studies of environmentally-exposed subjects, there is a stronger 

relationship between patella lead and blood lead than tibia lead and blood lead (e.g., HernandezAvila et al., 1996; Hu et al., 1996, 1998). Hu et al. (1998) suggest that these relationships 

indicate that trabecular bone is the predominant bone type providing lead back into circulation 

under steady-state and pathologic conditions. 

6.2.2.4.2 Partitioning of Bone Lead into Plasma 

Although most of the lead in whole blood is associated with erythrocytes (~99%), it has 

been suggested that the small fraction of lead in plasma (<0.3%) may be the more biologically 

labile and toxicologically active fraction of the circulating lead. Several authors have proposed 

that lead released from the skeleton was preferentially partitioned into serum compared with red 

cells (Cake et al., 1996; Hernandez-Avila et al., 1998; Tsaih et al., 1999) with one explanation 

being that the lead from endogenous sources was in a different form to that from exogenous 

sources. However, this concept has been withdrawn by its main proponents. In contrast to using 

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402(c) Economic Analysis Chapter 5 429
Figure 6-2.7. Tibia leads to blood lead ratios for environmentally-exposed pregnancyrelated subjects, middle-aged to elderly subjects, and younger subjects. 

Data compiled from several studies. See text for more details. 

1 urine as a proxy for serum and measuring lead isotopes, Gulson et al. (2000) concluded that there 

2 was no evidence for preferential partitioning of lead into serum compared with whole blood. 

3 

4 6.2.2.5 Mobilization of Lead From Bone 

5 Although earlier investigators such as Brown and Tompsett (1945), Ahlgren et al. (1976) 

6 and Christoffersson et al. (1984) suggested that the skeleton was a potential endogenous source 

7 of lead poisoning, the opposing concept of the skeleton as a “safe” repository for lead persisted 

8 until the mid-1980s and early 1990s. Potential mobilization of lead from the skeleton could 

9 occur at times of physiological stress associated with enhanced bone remodeling such as during 

10 pregnancy and lactation (Hertz-Picciotto et al., 2000; Manton, 1985; Silbergeld, 1991), 

11 menopause or in the elderly (Silbergeld, 1991; Silbergeld et al., 1988), extended bed rest 

12 (Markowitz and Weinberger, 1990), hyperparathyroidism (Kessler et al., 1999), and 

13 weightlessness. The lead deposited in the bone of adults can serve to maintain blood lead levels 

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long after exposure has ended (Fleming et al., 1997; Gulson et al., 1995; Inskip et al., 1996; 

Kehoe, 1987; Manton, 1985; Nilsson et al., 1991; O’Flaherty et al., 1982; Schütz et al., 1987; 

Smith et al., 1996). 

In the 1986 Lead AQCD, there was a comprehensive summary of chelation therapies and 

the recognition that there was limited release of lead from bones. The potential role of bone lead 

as an endogenous source of lead in blood, resulting in elevated levels for former lead employees, 

was mentioned although data to support this hypothesis were limited. 

6.2.2.5.1 Mobilization of Lead from Bone during Pregnancy and Lactation 

Bone lead studies of pregnant and lactating subjects are summarized in Annex Table 

AX6-2.7. Most of the bone XRF studies on pregnancy and lactation have focused on subjects 

from Mexico City and Latin subjects from Los Angeles, California. Relationships and/or health 

outcomes from these investigations include: patella bone as a significant contributor to blood 

lead (Brown et al., 2000; Hernandez-Avila et al., 1996); a positive association between plasma 

lead and bone lead in the highest bone lead group of pregnant women (Téllez-Rojo et al., 2004); 

a positive association of tibia and calcaneus lead with prenatal lead concentration, and calcaneus 

lead with postnatal lead (Rothenberg et al., 2000); a positive association of tibia lead and 

seasonal variations in blood lead (Rothenberg et al., 2001); maternal tibia and patella lead as 

significant predictors of fetal exposure determined using cord blood (Chuang et al., 2001); 

a positive association of calcaneus lead and increased systolic and diastolic blood pressure in the 

third trimester (Rothenberg et al., 2002); an inverse relationship between maternal tibia and 

patella lead, and birth weight (Gonzalez-Cossio et al., 1997; Sanin et al., 2001); an inverse 

association between tibia lead and birth length, and patella lead and head circumference 

(Hernandez-Avila et al., 2002); an inverse association of maternal patella bone and Mental 

Development Index (Gomaa et al., 2002); increased bone resorption during lactation (TéllezRojo et al., 2002); increased lead in breast milk with an increase in patella and tibia lead 

(Ettinger et al., 2004). 

Lead isotope studies on immigrant women to Australia (Gulson et al., 1997, 1998a) 

confirmed the earlier work of Manton (1985) of increased blood lead during pregnancy. Gulson 

et al. reported that, during pregnancy, blood lead concentrations in the first immigrant cohort 

(n = 15) increased by an average of about 20% compared to non-pregnant migrant controls 

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(n = 7). The percentage change in blood lead concentration was significantly greater during the 

postpregnancy period than during the second and third trimesters (p < 0.001). Skeletal 

contribution to blood lead, based on the isotopic composition for the immigrant subjects, 

increased in an approximately linear manner during pregnancy. The mean increases for each 

individual during pregnancy varied from 26% to 99%. Skeletal lead contribution to blood lead 

was significantly greater during the postpregnancy period than during the second and third 

trimesters. The contribution of skeletal lead to blood lead during the postpregnancy period 

remained essentially constant at the increased level of lead mobilization. In a follow-up study 

using a different immigrant cohort of 12 women with calcium supplementation at the 

recommended level of approximately 1,000 mg/day (National Institutes of Health, 1994), Gulson 

et al. (2004) found increased mobilization of lead occurred in the third trimester rather than in 

the second trimester as observed with first cohort. In addition, the extra flux released from bone 

during late pregnancy and postpartum varied from 50 to 380 μg (geometric mean 145 μg) 

compared with 330 μg in the previous cohort. 

In an extended monitoring of 7 subjects for up to 22 months postpartum, Gulson et al. 

(1999a) found that blood lead concentrations in some of the subjects decreased to about half the 

earlier levels almost immediately after cessation of breastfeeding. However, in 4 of the 7 cases 

there was a rebound in blood lead concentrations that exceeded the earlier levels in 3 cases. The 

authors interpreted these results to indicate that there is ongoing increased mobilization of lead 

from the maternal skeleton for much longer than predicted, probably associated with remodeling 

processes. Also using lead isotopes, Manton et al. (2003) observed that blood lead 

concentrations decreased in early pregnancy and rose during late pregnancy. They attributed 

these results to changes in bone resorption with decoupling of trabecular and cortical bone sites. 

6.2.2.5.2 Transplacental Transfer of Lead and Transfer through Breast Milk 

Transplacental transfer of lead in humans has been suggested in a number of studies based 

on cord blood to maternal blood lead ratios ranging from about 0.6 to 1.0 at the time of delivery. 

Maternal-to-fetal transfer of lead appears to be related partly to the mobilization of lead from the 

maternal skeleton. Evidence for transfer of maternal bone lead to the fetus has been provided 

from stable lead isotope studies in cynomolgus monkeys (Macaca fascicularis). Approximately 

7 to 39% of the maternal lead burden that is transferred to the fetus appears to derive from the 

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maternal skeleton (Franklin et al., 1997; O’Flaherty et al., 1998). Further evidence for maternalto-fetal transfer of lead in humans can be gained from stable lead isotope measurements. For 

example, a 0.99 correlation in lead isotopic ratios for maternal and cord blood (Manton, 1985; 

Gulson et al., 1998b) and the similarity of isotopic ratios in maternal blood and in blood and 

urine of newly-born infants provide strong evidence for placental transfer of lead to the fetus 

(Gulson et al., 1999b). 

Breast milk can also be a pathway of maternal excretion of lead. However, given the very 

low lead concentrations and analytical difficulties arising from high fat contents in breast milk, 

their analyses require careful attention. Selected studies appear to show a linear relationship 

between breast milk and maternal whole blood with the percentage of lead in breast milk 

compared with whole blood of <3% in subjects for blood lead concentrations ranging from 2 to 

34 μg/dL. Blood lead concentrations in breastfed newborn infants decreased in spite of the 

maternal blood lead concentrations having risen or remained elevated postpartum compared to 

lower levels during prepregnancy or in the first trimester (Gulson et al., 1999b). Similar trends 

were noted by Manton et al. (2000). However, in a Mexico City study, an association between 

patella lead and blood lead concentrations was higher for women with partial lactation than for 

those who stopped lactation, and it was increased among women who breastfed exclusively 

(Téllez-Rojo et al., 2002). In another Mexico City study, Ettinger et al. (2004) concluded that an 

interquartile increase in patella lead was associated with a 14% increase in breast milk lead, 

whereas for tibial lead the increase was ~5%. 

In conclusion, there is evidence that maternal-to-fetal transfer of lead occurs, likely 

resulting from the mobilization of lead from the maternal skeleton during pregnancy. Breast-fed 

infants appear to be at greater risk only if the mother is exposed to high lead concentrations 

either from exogenous sources or endogenous sources such as the skeleton. 

6.2.2.5.3 Mobilization of Lead in Bone During Menopause and in the Elderly 

Increases in blood lead for postmenopausal women have been attributed to release of lead 

from the skeleton associated with increased bone remodeling during menopause. Many of the 

studies have been based on blood lead concentration. Bone lead studies of menopausal and 

middle-aged to elderly subjects are summarized in Annex Table AX6-2.8. 

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Overall, the various studies of bone and blood lead levels, as well as hormone 

replacement therapy, have provided conflicting outcomes. Hormone replacement therapy alone 

or combined with calcium supplementation prevents bone resorption and increases the bone 

mineral density in trabecular and cortical bones of women with or without metabolic bone 

disease. The effect of hormone replacement therapy may result in a decrease of lead 

mobilization from bone along with a reduction in blood lead concentration levels. Several 

studies have found that tibia bone lead levels were higher in women who used hormone 

replacement therapy (Popovic et al., 2005; Webber et al., 1995). In contrast, other investigators 

have found no association between bone lead and use of estrogens (Berkowitz et al., 2004; 

Korrick et al., 2002). In addition, some studies observed a decrease in blood lead concentrations 

associated with hormone replacement therapy (Garrido-Latorre et al., 2003), whereas others 

observed no association (Webber et al., 1995). 

The endogenous release rate of lead from bone in postmenopausal women was double the 

rate in premenopausal former smelter employees (Popovic et al., 2005) and environmentallyexposed women from Mexico (Garrido-Latorre et al., 2003). In middle-aged to elderly males 

from the Normative Aging Study, patella lead accounted for the dominant portion of variance in 

blood lead (Hu et al., 1996). 

6.2.2.5.4 Effect of Nutritional Status on Mobilization of Lead from Bone 

Most studies that investigated the effect of nutritional status on the mobilization of lead 

from the skeleton have examined the effects of calcium supplementation. Several studies have 

suggested that dietary calcium may have a protective role against lead by decreasing absorption 

of lead in the gastrointestinal tract and by decreasing the mobilization of lead from bone stores to 

blood, especially during periods of high metabolic activity of the bone such as pregnancy, 

lactation, and menopause. An inverse association between patella lead and low calcium intake in 

postpartum women has been found (Hernandez-Avila et al., 1996). In contrast, Rothenberg et al. 

(2000) observed that dietary calcium intake had no effect on calcaneus lead in women monitored 

during the third trimester and 1 to 2 months postpartum. Likewise, no effect from calcium 

supplementation on bone lead was found amongst lactating women from Mexico City (TéllezRojo et al., 2002), although in a follow-up study, Hernandez-Avila et al. (2003) reported a 16.4% 

decrease in blood lead concentration among women with the highest patella bone lead levels who 

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were taking supplements. Gulson et al. (2004) observed that calcium supplementation was found 

to delay increased mobilization of lead from bone during pregnancy and halved the flux of lead 

release from bone during late pregnancy and postpartum. In another study, women whose daily 

calcium intake was 850 mg per day showed lower amounts of bone resorption during late 

pregnancy and postpartum than those whose intake was 560 mg calcium per day (Manton et al., 

2003). Téllez-Rojo et al. (2004) observed that plasma lead levels were inversely related to 

dietary calcium intake. Results for whole blood lead were similar but less pronounced. 

Some researchers have noted concerns regarding potential lead toxicity resulting from 

calcium supplementation. However, Gulson et al. (2001) observed that lead in calcium or 

vitamin supplements did not appear to increase blood lead concentrations. No information was 

available on the effects of other nutritional supplements (e.g., iron or zinc) on lead body burden. 

6.2.2.6 Summary of Bone Lead as a Biomarker of Lead Body Burden and Exposure 

Bone accounts for more than 90% of the total body burden of lead in adults and 70% in 

children. In addition, the longer half-life of lead in bone, which largely depends on the bone type 

but is generally estimated in terms of years compared to days for blood lead, allows a more 

cumulative measure of lead dose. The more widespread use of in vivo XRF lead measurements 

in bone and indirect measurements of bone processes with stable lead isotopes since the 1986 

Lead AQCD have enhanced the use of bone lead as a biomarker of lead body burden. 

In addition to considering bone lead as an indicator of cumulative lead exposure, lead in 

the skeleton can also be regarded as a source of lead. Key studies have examined the 

contribution of bone lead to blood lead; the preferential partitioning of bone lead into plasma; 

mobilization of lead from bones during pregnancy, lactation, and menopause; and the role of 

nutritional supplementation in bone mobilization. 

6.2.3 Lead in Teeth 

6.2.3.1 Summary of Key Findings from the 1986 Lead AQCD 

The importance of dentine as a potential indicator of lead exposure was noted in the 1986 

Lead AQCD. There was more emphasis and optimism on using dentine to assess lead exposure 

in this document as the bone XRF method was in its infancy. The issue of deciduous tooth type 

was addressed but there was little information on permanent teeth. The portion of the tooth 

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analyzed (i.e., whole tooth or circumpulpal dentine) was also addressed. In the 1990 Addendum, 

the use of tooth lead as an exposure metric was described in a number of the longitudinal and 

cross-sectional studies. 

6.2.3.2 Analytical Methods for Measuring Lead in Teeth 

Analytical methods for tooth analysis vary from the most widely used AAS, to energydispersive XRF, laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), and 

high precision lead isotopes. 

As a standard analytical method has yet to be established for tooth lead analysis, some of 

the discrepancies in findings between studies could arise from several factors, including 

differences in tooth type, part of the tooth analyzed, and tooth location. Any real differences 

among populations are unlikely to be the result of physiological factors such as blood supply to 

teeth or mineralization rates. As enamel and dentine in different teeth calcify at overlapping but 

different times (Orban, 1953), they could retain varying amounts of lead. 

In a systematic evaluation of the magnitude of random errors associated with dentine lead 

measurements, Fergusson et al. (1989) measured lead concentrations in two samples of dentine 

from 996 New Zealand children. They estimated that 15 to 20% of the variance was 

unexplained. Tests of differences of means and variances showed no significant differences 

between the two samples. 

Lead measurements in deciduous teeth in individuals from urban and remote 

environments and from polluted environments are presented in Annex Tables AX6-2.9 and 

AX6 2.10, respectively. Based on the limited number of studies, it would appear that the range 

in whole deciduous tooth lead for environmentally exposed subjects is about 1–10 μg/g, but the 

most likely levels are <5 μg/g and probably even <2 μg/g. Studies of whole deciduous teeth 

from industrial environments, including those in urban settings, are also commonly much less 

than 10 μg/g. 

The utility of circumpulpal dentine (Shapiro et al., 1973) as the metric of lead exposure in 

deciduous teeth has not been enthusiastically received. This is likely due to the separation 

difficulties, as well as the limited amount of circumpulpal dentine that may be present when the 

teeth are resorbed, prior to exfoliation. 

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In another approach to gain more information about exposure during pregnancy and early 

childhood, the teeth may be sectioned into dominantly enamel or dominantly dentine. These 

samples can then be analyzed for lead isotopic ratios and lead concentrations (Gulson and 

Wilson, 1994). Even for children living in lead mining and smelting communities, levels of lead 

in the enamel are generally low (<5 μg/g) and are consistent with other studies of whole teeth. 

However, higher levels are observed in the dentine samples (e.g., 32 μg/g), which likely reflect 

the early childhood exposure. Permanent teeth tend to have up to three times the level of lead 

compared with deciduous teeth, but the number of studies is very limited. 

6.2.3.3 Tooth Lead as a Biomarker of Lead Body Burden 

Compared with the amount of lead in the skeleton, tooth lead is a minor contributor to the 

body burden of lead. Most of the tooth lead information is based on analyses of deciduous teeth. 

There is still controversy over the amounts of lead in different whole teeth but it appears that the 

highest concentrations are in central incisors, with decreasing amounts in lateral incisors, 

canines, first molars, and second molars. Teeth from the upper jaw tend to have higher lead 

concentrations than those from the lower jaw. 

As teeth accumulate lead, tooth lead levels are generally considered an estimate of 

cumulative lead exposure. Rabinowitz et al. (1993) found that tooth lead was a better measure of 

exposure than current blood lead levels; however, it was not a good measure of the child’s 

cumulative exposure from birth to exfoliation due to the mobilization of lead from dentine. 

Teeth are composed of several tissues formed over the years. Therefore, if a child’s lead 

exposure during the years of tooth formation varied widely, different amounts of lead would be 

deposited at different rates (Rabinowitz et al., 1993). This may allow investigators to elucidate 

the history of lead exposure in a child. 

Gulson and Wilson (1994) advocated the use of sections of enamel and dentine to obtain 

additional information compared with analysis of the whole tooth (e.g., Fosse et al., 1995; 

Tvinnereim et al., 1997). For example, deciduous teeth lead in the enamel provides information 

about in utero exposure whereas that in dentine from the same tooth provides information about 

postnatal exposure until the tooth exfoliates at about 6 to 7 years of age. 

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6.2.3.4 Relationship between Tooth Lead and Blood Lead 

As with bone lead-blood lead relationships, there is interest in understanding more about 

potential relationships between tooth lead and blood lead. The tooth lead-blood lead relationship 

is more complex than the bone lead-blood lead relationship because of differences in tooth type, 

location, and analytical method. 

Rabinowitz (1995) used studies which reported values for dentine, whole shed teeth, or 

crowns, but discarded those measuring circumpulpal dentine because of the higher values in this 

medium. The mean tooth lead levels varied from 2.8 to 12.7 μg/g and blood lead levels from 

6.5 to 17 μg/dL. In a plot of blood versus tooth lead, Rabinowitz found a good fit (R2

 = 0.97; 

p < 0.0001) with the relationship: 

Tooth Lead (μg/g) = $ H [Blood Lead (μg/dL)], where $ = 0.49 (SE 0.04). 

In an earlier Boston study, Rabinowitz et al. (1989) found that the association between 

tooth and blood lead increased with age, first achieving statistical significance at 18 months; 

by 57 months, the correlation coefficient was 0.56. A correlation of 0.47 was found between 

current blood lead and incisors amongst 302 German children (Ewers et al., 1982). 

6.2.3.5 Mobilization of Lead from Teeth 

Although mobilization of lead from bone appears well established, this is not the case for 

lead in teeth. Conventional wisdom has lead fixed once it enters the tooth. Although that may 

be the case for the bulk of enamel, it is not true for the surface of the enamel and dentine. 

In evaluating deciduous teeth data, Rabinowitz et al. (1993) suggested that their data were 

compatible with a model that allows lead to be slowly removed from dentine. Such a process 

may be associated with resorption of the root and dentine that precedes exfoliation, which allows 

reequilibration of dentine lead with blood lead. 

In children exposed to lead sources from mining, paint, or petrol in communities such as 

the Broken Hill lead mining community, Gulson and Wilson (1994) and Gulson (1996) showed 

that the source of lead from the incisal (enamel) sections was different from the source of lead in 

the cervical (dentine) sections of deciduous teeth, reflecting the change in lead from in utero 

exposure to early childhood. Based on changes in the isotopic composition of enamel and 

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dentine in deciduous teeth sections from the Broken Hill mining community children, Gulson 

(1996) estimated that lead is added to dentine at a rate of approximately 2-3% per year. 

Stable lead isotopes and lead concentrations were measured in the enamel and dentine of 

permanent (n = 37) and deciduous teeth (n = 14) from 47 European immigrants to Australia to 

determine whether lead exchange occurs in teeth and how it relates to lead exchange in bone 

(Gulson et al., 1997). The authors concluded that enamel exhibited no exchange of its Europeanorigin lead with lead from the Australian environment, whereas dentine lead exchanged with 

Australian lead to the extent of ~1 ± 0.3% per year. 

6.2.3.6 Summary of Tooth Lead as a Biomarker of Lead Body Burden and Exposure 

Tooth lead is a minor contributor to the total body burden of lead. Moderate-to-high 

correlations have been observed between tooth lead levels and blood lead levels. Differences in 

tooth type, part of the tooth analyzed, and tooth location may contribute to some of the 

discrepancies in findings between studies of tooth lead. As teeth are composed of several tissues 

formed over the years, if a child’s lead exposure during the years of tooth formation varied 

widely, different amounts of lead would be deposited at different rates. Deciduous teeth lead in 

the enamel provides information about in utero exposure, whereas that in dentine provides 

information about postnatal exposure until the tooth exfoliates. 

6.2.4 Lead in Urine 

6.2.4.1 Summary of Key Findings from the 1986 Lead AQCD 

The 1986 Lead AQCD provided an extensive discussion of the physiological basis for 

“chelatable” urinary lead. Also discussed was lead excretion provoked by EDTA, including the 

pools of lead in the body that might be mobilized in the EDTA provocation test, and the 

relationship between the outcome and blood lead concentration. The 1986 Lead AQCD noted 

observations that formed the basis for application of the EDTA provocation test for detecting 

elevated lead body burden. 

6.2.4.2 Analytical Methods for Measuring Lead in Urine 

Standard methods that have been reported for urine lead analysis are summarized in 

Annex Table AX6-2.1 and are, in general, the same as those analyses noted for determination of 

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402(c) Economic Analysis Chapter 5 439
1 lead in blood. Reported detection limits are approximately 50 μg/L for AAS, 5–10 μg/L for ICP2 AES, and 4 μg/L for ASV for urine lead analyses. Sample preparation usually consists of wet 

3 ashing; however, chelation and solvent extraction has also been reported (National Institute for 

4 Occupational Safety and Health, 1994, 1977a). 

5 

6 6.2.4.3 Levels of Lead in Urine 

7 A summary of selected measurements of urine lead levels in humans can be found in 

8 Annex Table AX6-2.11. Urine lead concentrations in the U.S. general population have been 

9 monitored in NHANES. Data from the most recent survey (NHANES IV, Centers for Disease 

10 Control, 2005) for subjects $6 years of age are shown in Table 6-2.4. The geometric mean for 

11 the entire sample (n = 2,689) was 0.64 μg/g creatinine (95% CI: 0.60, 0.68). The geometric 

12 means for males (n = 1,334) and females (n = 1,335) were 0.64 μg/g creatinine (95% CI: 0.61, 

13 0.67) and 0.64 μg/g creatinine (95% CI: 0.59, 0.69), respectively. These values correspond to 

14 approximately 1-1.3 μg lead/day for an adult, assuming a daily creatinine excretion rate of 

15 approximately 1.5 g/day in adult females, a body weight of 70 kg for males and 58 kg for 

16 females, and a lean body mass fraction of 0.88 for males and 0.85 for females (Forbes and 

17 Bruining, 1976; International Commission on Radiological Protection, 1981). 

18 

19 

Table 6-2.4. Urine Lead Concentrations in U.S. by Age, NHANES IV (1999–2002) 

Age 6–11 years 12–19 years $20 years 

Survey Period 

n 

Urine Lead 

(μg/g)a 

1999–2000 

340 

1.17 

(0.98, 1.41) 

2001–2002

368 

0.92 

(0.84, 1.00) 

 1999–2000

719 

0.50 

(0.46, 0.54) 

 2001–2002 

762 

0.40 

(0.38, 0.43) 

1999–2000 

1406 

0.72 

(0.68, 0.76) 

2001–2002 

1559 

0.66 

(0.62, 0.70) 

(μg/g)2 

a

Urine lead concentrations presented are geometric means (95% CI) of μg lead/g creatinine. 

20 Geometric mean urinary lead excretion rates of 7-10 μg/g creatinine (maximum 43) have 

21 been reported in groups of children living in areas impacted by lead smelting operations 

22 (Brockhaus et al., 1988). Daily urinary lead excretion can exceed 200 μg/day in association with 

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occupational exposures (Biagini et al., 1977; Cramer et al., 1974; Lilis et al., 1968; Lin et al., 

2001; Wedeen et al., 1975). 

6.2.4.4 Urine Lead as a Biomarker of Lead Body Burden 

Urine is a major route of excretion of absorbed lead (Chamberlain et al., 1978; Griffin 

et al., 1975; Kehoe, 1987; Rabinowitz et al., 1976). The kinetics of urinary excretion following a 

single dose of lead is similar to that of blood (Chamberlain et al., 1978), likely due to the fact 

that lead in urine derives largely from lead in blood plasma. Evidence for this is the observation 

that urinary lead excretion is strongly correlated with the rate of glomerular filtration of lead (i.e., 

glomerular filtration rate H plasma lead concentration; Araki et al., 1986). Estimates of urinary 

clearance of lead from serum (or plasma) range from 13-22 L/day, with a mean of 18 L/day 

(Araki et al., 1986; Chamberlain et al., 1978; Manton and Cook, 1984; Manton and Malloy, 

1983). Estimates of blood-to-urine clearance, on the other hand, range from 0.03-0.3 L/day with 

a mean of 0.12 L/day (Araki et al., 1990; Berger et al., 1990; Chamberlain et al., 1978; Gulson 

et al., 2000; Koster et al., 1989; Manton and Malloy, 1983; Rabinowitz et al., 1976, 1973; Ryu 

et al., 1983; see Diamond, 1992 for an analysis of these data), consistent with a plasma to blood 

concentration ratio of approximately 0.005–0.01 L/day (U.S. Environmental Protection Agency, 

2003). Based on the above, urinary excretion of lead can be expected to reflect the concentration 

of lead in plasma and variables that affect delivery of lead from plasma to urine (e.g., glomerular 

filtration and other transfer processes in the kidney). 

Plasma lead makes a small contribution (<1%) to the blood lead concentration and a 

negligible contribution to total lead body burden. Furthermore, the kinetics of elimination of 

lead from plasma is fast, relative to lead in bone, where most of the lead burden resides. 

Therefore, the basic concepts described for blood as a biomarker for body burden also apply to 

urine. A single urine lead measurement, or a series of measurements taken over short-time span, 

is likely a relatively poor index of lead body burden (Figure 6-2.8). On the other hand, long-term 

average measurements of urinary excretion can be expected to be a better index of body burden. 

In the hypothetical simulation shown in Figure 6-2.8, both the long-term average urinary lead 

excretion rate and the body burden have approximately doubled. 

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402(c) Economic Analysis Chapter 5 441
Figure 6-2.8. Simulation of relationship between urinary lead excretion and body burden 

in adults. An abrupt change in lead uptake gives rise to a relatively rapid 

change in urinary excretion of lead, to a new quasi-steady state, and a 

relatively small change in body burden (upper panel). The long-term 

average urinary lead excretion more closely tracks the pattern of change in 

body burden (lower panel). Simulation based on Leggett (1993) lead 

biokinetics model. 

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402(c) Economic Analysis Chapter 5 442
1 6.2.4.5 Urine Lead as a Biomarker of Lead Exposure 

2 Assuming first-order kinetics, a plasma-to-urine clearance (UClP) of 13-22 L/day 

3 corresponds to half-time for transfer of lead from plasma to urine of 0.1-0.16 day for a 70 kg 

4 adult who has a plasma volume (VP) of approximately 3 L: 

5 

t1/ 2 = 

In(2)⋅VP 6 IClP 

7 

8 This translates to a very rapid steady-state, much faster than observed for blood lead after 

9 a change in exposure level. The kinetics of change in urinary lead excretion in response to a 

10 change in exposure, therefore, will be determined by variables that affect the plasma lead level, 

11 including partitioning of lead into erythrocytes and exchanges with lead in soft tissues and 

12 mobile pools within bone (e.g., bone surface). Here again, the basic concepts that apply to blood 

13 lead as a biomarker of exposure also apply to urine lead. Urinary lead excretion reflects, mainly, 

14 the exposure history of the previous few months; thus, a single urinary lead measurement cannot 

15 distinguish between a long-term low level of exposure or a higher acute exposure. The 

16 relationship between urinary lead concentration and lead uptake is thought to be linear, unlike 

17 that for blood lead concentration, although there are no direct empirical tests of this assumption 

18 in humans. This assumption predicts a linear relationship between lead intake (at constant 

19 absorption fraction) and urinary lead excretion rate. Figure 6-2.9 presents a simulated 

20 relationship between lead intake and urinary lead excretion in adults and children using both the 

21 Leggett (1993) model and O’Flaherty (1993, 1995) model. The major difference between the 

22 Leggett model and the O’Flaherty model is in the assignment of the time dependence of bone 

23 lead residence. The Leggett model assumes a slow accumulation of a nonexchangable lead pool, 

24 whereas the O’Flaherty model assumes a gradual distancing of lead from bone surfaces by 

25 diffusion throughout the bone volume (O’Flaherty, 1998). 

26 It is important to emphasize that the above concepts apply to urinary lead excretion rate, 

27 not to urinary lead concentration. The concentration of lead in urine (UPb) is a function of the 

28 urinary lead excretion (UEPb) and the urine flow rate (UFR, L/day): 

29 

30 UEPb = UPb ⋅UFR 

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402(c) Economic Analysis Chapter 5 443
Figure 6-2.9. Simulation of relationship between lead intake and urinary lead excretion in 

adults and children. Predictions are for a 2-year-old child and 30-year-old 

adult, for a constant lead intake (μg/kg/day). The relationship is linear, for 

intake and plasma lead concentration (not shown). Predictions are based on 

Leggett (1993, upper panel) and O’Flaherty (1993, 1995, lower panel). 

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Urine flow rate can vary by a factor or more than 10, depending on the state of hydration 

and other factors that affect glomerular filtration rate and renal tubular reabsorption of the 

glomerular filtrate. All of these factors can be affected by lead exposure at levels that produce 

nephrotoxicity (i.e., decreased glomerular filtration rate, impaired renal tubular transport 

function; see Section 6.4 for discussion of effects of lead on the renal system). Therefore, urine 

lead concentration measurements provide little reliable information about exposure (or lead body 

burden), unless they can be adjusted to account for unmeasured variability in urine flow rate 

(Araki et al., 1990). 

A determination of urinary lead excretion rate requires measurement of two variables, 

urine lead concentration, and urine flow rate; the later requires collection of a timed urine 

sample, which is often problematic in epidemiologic studies. Collection of un-timed (“spot”) 

urine samples, a common alternative to timed samples, requires adjustment of the lead 

measurement in urine to account for variation in urine flow (Diamond, 1988). Several 

approaches to this adjustment have been explored, including adjusting the measured urine lead 

concentration by the urine creatinine concentration, urine osmolality, or specific gravity (Araki 

et al., 1990). 

The measurement of lead excreted in urine following an injection (intravenous or 

intramuscular) of the chelating agent calcium disodium EDTA (EDTA provocation) has been 

used to detect elevated body burden of lead in adults (Biagini et al., 1977; Lilis et al., 1968; 

Wedeen, 1992; Wedeen et al., 1975) and children (Chisolm et al., 1976; Markowitz and Rosen, 

1981). EDTA-provoked urinary lead excretion has been shown to correlate with tibia bone lead 

measurements (Wedeen, 1992). Given the difficulties associated with the parenteral 

administration of EDTA, XRF measurements of bone lead, offer a more feasible alternative to 

the EDTA provocation test for assessment of bone lead stores in epidemiologic studies. More 

recently, DMSA (DMSA-provocation) has been used as an orally-effective alternative to EDTA 

and has been applied to epidemiologic studies as dose metric for lead body burden (e.g., Lee 

et al., 2001; Schwartz et al., 2001a, 2000a, 2000b). 

6.2.4.6 Summary of Urine Lead as a Biomarker of Lead Body Burden and Exposure 

Similar to blood lead concentration measurements, urinary lead excretion measured in an 

individual at a single point in time will reflect the recent exposure history of the individual and 

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physiological variables that determine the plasma lead concentration time profile. Longitudinal 

measurements of urinary lead excretion can be expected to provide a more reliable measure of 

exposure history of an individual and will more closely parallel body burden than will single 

measurements; however, the degree to which this will apply will depend on the sampling 

frequency with respect to the exposure temporal pattern. 

Although, in general, higher urinary lead excretion can be interpreted as indicating higher 

exposures (or lead uptakes), it does not necessarily predict appreciably higher body burdens. 

Similar urinary lead excretion rates in two individuals (or populations) do not necessarily 

translate to similar body burdens or similar exposure histories. 

Measurement of the urinary lead excretion rate requires either a timed urine sample, or an 

approach to adjusting measured urinary lead concentrations for variability in urine flow rate, 

which by itself may be affected by lead exposure (i.e., lead-induced nephrotoxicity). Both 

approaches, timed urine samples or adjustment of concentration, introduce complications into the 

assessment and uncertainties into the interpretation of urinary lead measurements as biomarkers 

of lead body burden or exposure. The EDTA-provocation test provides a more reliable indicator 

of elevated body burden than do measurements of basal lead excretion; however, it is not feasible 

to apply this test for epidemiologic investigations. The DMSA-provocation test may provide a 

more feasible alternative. 

6.2.5 Lead in Hair 

6.2.5.1 Summary of Key Findings from the 1986 Lead AQCD 

The 1986 Lead AQCD did not discuss applications of hair lead measurements for 

assessing lead body burden or exposure. 

6.2.5.2 Analytical Methods for Measuring Lead in Hair 

Methods used for hair lead analysis are summarized in Annex Table AX6-2.1. Wilhelm 

et al. (1989) reported a detection limit of 0.16 μg/g for GFAAS; use of GFAAS for hair lead 

measurements has been reported elsewhere (Annesi-Maesano et al., 2003). Gerhardsson et al. 

(1995a) reported a detection limit of 0.5 μg/g for XRF of the hair shaft; but Campbell and 

Toribara (2001) found XRF to be unreliable for hair root lead determinations. Use of other 

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methods has been reported, including ICP (Tuthill, 1996), ET/AAS (Drasch et al., 1997), and 

AAS (Sharma and Reutergardh, 2000; Esteban et al., 1999). 

6.2.5.3 Levels of Lead in Hair 

A summary of selected measurements of hair lead levels in humans can be found in 

Annex Table AX6-2.12. Reported hair lead levels vary considerably. Esteban et al. (1999) 

reported a geometric mean levels of 5.4 ng/g (range 1-39) for a sample of 189 children (aged 

1.9 to 10.6 years) residing in Russian towns impacted by smelter and battery plant operations. 

By contrast, Tuthill (1996) reported much higher levels in a sample of Boston, MA children 

(aged 6.5 to 7.5 years, n = 277). Approximately 41% had levels that ranged from 1 to 1.9 μg/g. 

DiPietro et al. (1989) reported a geometric mean hair lead level of 2.42 μg/g (10–90th percentile 

range <1.0-10.8) in a general population sample of U.S. adults (aged 20 to 73 years, n = 270). 

In a post-mortem sample of the general population from Germany (aged 16 to 93 years, n = 150), 

the median hair lead level was 0.76 μg/g (range 0.026-20.6) (Drasch et al., 1997). Also, 

Gerhardsson et al. (1995a) reported median values for postmortem samples of 8.0 μg/g (range 

1.5-29,000) in active workers (n = 6), 2.6 μg/g (range 0.6-9.3) in retired workers (n = 23), and 

2.1 μg/g (range 0.3-96) in a reference group (n = 10). 

6.2.5.4 Hair Lead as a Biomarker of Lead Body Burden 

Lead is incorporated into human hair and hair roots (Bos et al., 1985; Rabinowitz et al., 

1976) and has been explored as a possibly noninvasive approach for estimating lead body burden 

(Gerhardsson et al., 1995a; Wilhelm et al., 1989, 2002). Hair lead measurements are subject to 

error from contamination of the surface with environmental lead and contaminants in artificial 

hair treatments (i.e., dyeing, bleaching, permanents) and are a relatively poor predictor of blood 

lead concentrations, particularly at low levels (<12 μg/dL) (Campbell and Toribara, 2001; 

Drasch et al., 1997; Esteban et al., 1999). Studies evaluating quantitative relationships between 

hair lead and lead body burden have not been reported. Nevertheless, hair lead levels have been 

used as a dose metric in some epidemiologic studies (e.g., Annesi-Maesano et al., 2003; Esteban 

et al., 1999; Gerhardsson et al., 1995a; Powell et al., 1995; Sharma and Reutergardh, 2000; 

Tuthill, 1996). 

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6.2.5.5 Hair Lead as a Biomarker of Lead Exposure 

Rabinowitz et al. (1976) measured hair lead levels in two adult males who received 

a stable lead isotope supplement to their dietary intake for 124–185 days. Approximately 1% of 

the daily lead intake was recovered in hair. Temporal relationships between exposure levels and 

kinetics and hair lead levels, and kinetics of deposition and retention of lead in hair have not 

been evaluated. Higher hair lead levels were observed in lead workers than in reference subjects 

with lower blood lead levels (Mortada et al., 2001). 

6.2.5.6 Summary of Hair Lead as a Biomarker of Lead Body Burden and Exposure 

Although hair lead measurements have been used in some epidemiologic studies, an 

empirical basis for interpreting hair lead measurements in terms of body burden or exposure has 

not been firmly established. Hair lead measurements are subject to error from contamination of 

the surface with environmental lead and contaminants in artificial hair treatments (i.e., dyeing, 

bleaching, permanents) and, as such, are relatively poor predictor of blood lead concentration, 

particularly at low levels (<12 μg/dL). 

6.3 NEUROTOXIC EFFECTS OF LEAD 

This section assesses epidemiologic evidence for neurotoxic effects of lead exposure in 

children and adults. First presented are studies of the neurotoxic effects of lead on children, with 

a focus on several prospective studies examining neurocognitive ability. Other topics include 

measures of academic achievement, cognitive abilities, disturbances in behavior, mood, and 

social conduct, measures of brain anatomical development and activity, gene-environmental 

interaction, and reversibility of neurodevelopmental deficits. Then, neurotoxic effects of 

environmental and occupational lead exposure of adults are discussed. 

6.3.1 Summary of Key Findings on Neurotoxic Effects of Lead in Children 

from 1986 Lead AQCD and Addendum, and 1990 Supplement 

The 1986 Lead AQCD stated that children were particularly susceptible to lead-induced 

neural damage. In particular, human infants and toddlers below that age of 3 years were 

considered to be at special risk due to their in-utero exposure, increased opportunity for exposure 

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because of normal mouthing behavior of lead-containing objects, and increased rates of lead 

absorption due to factors such as iron and calcium deficiencies. 

Effective blood lead levels for producing encephalopathy or death in children were noted 

in the 1986 Lead AQCD as starting at 80–100 μg/dL. Various types of neural dysfunction were 

stated as being evident at lower blood lead levels. Behavioral (e.g., reaction time, psychomotor 

performance) and electrophysiological (e.g., altered electrophysiological patterns, evoked 

potential measures, and peripheral nerve conduction velocities) effects were observed at blood 

levels as low as 15-30 μg/dL and possibly lower. A concentration-response relationship between 

blood lead levels and IQ also was observed; a 1-2 point difference in IQ was generally seen with 

blood lead levels in the 15-30 μg/dL range. However, a study by Schroeder and Hawk (1987) 

reported a highly significant linear relationship between a measure of IQ and blood lead levels 

over the range of 6 to 47 μg/dL in a cohort of all African American children of low SES, 

suggesting that IQ effects might be detected even at these low levels. 

The 1986 Addendum discussed the newly published results of several prospective cohort 

studies on the developmental effects of lead in children. These studies improved upon the 

previous studies with longitudinal study design that followed children from the prenatal stage, a 

larger number of subjects, and better analytic techniques to more accurately measure blood lead 

levels. The four prospective studies (conducted in Boston, MA; Cincinnati, OH; Cleveland, OH; 

and Port Pirie, Australia) reported significant associations between prenatal and postnatal blood 

lead levels and neurobehavioral deficits, after adjusting for various potential confounding factors 

such as maternal IQ and HOME (Home Observation for Measurement of Environment) scores 

(Bellinger et al., 1984; Dietrich et al., 1986; Ernhart et al., 1985, 1986; McMichael et al., 1986; 

Vimpani et al., 1985; Wolf et al., 1985). In these studies, the observed maternal and cord blood 

lead levels were fairly low, with mean levels of approximately 10 μg/dL. These results led the 

1986 Addendum to conclude that neurobehavioral deficits, including declines in Bayley Mental 

Development Index (MDI) scores and other assessments of neurobehavioral function, are 

associated with prenatal blood lead exposure levels on the order of 10 to 15 μg/dL and possibly 

even lower, as indexed by maternal or cord blood lead concentrations. 

The 1990 Supplement updated evidence from the above-mentioned longitudinal cohort 

studies and summarized results from other more recent prospective cohort studies conducted in 

Glasgow, Scotland; Kosovo, Yugoslavia; Mexico City; and Sydney, Australia. Results from 

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several other international cross-sectional studies also were discussed. The collective evidence 

from the various prospective cohort and cross-sectional studies reaffirmed the conclusions from 

the 1986 Addendum that neurobehavioral effects were related to blood lead levels of 10 to 

15 μg/dL and possibly lower. Further analyses of the Boston data indicated that deficits in MDI 

could be detected in relation to cord blood lead levels of 6-7 μg/dL in children within the lower 

strata for SES (Bellinger et al., 1988). In the Port Pirie study, the relationship between postnatal 

blood lead levels and MDI at two years of age provided little evidence of a threshold effect 

(Wigg et al., 1988). Restricting the analysis to children with blood lead levels below 25 μg/dL 

yielded an even stronger association between integrated postnatal blood lead and McCarthy 

General Cognitive Index (GCI) scores in the Port Pirie study (McMichael et al., 1988). 

Impaired neurobehavioral development was associated with blood lead measures in 

pregnant women, umbilical cords, and infants up to at least 2 years of age; thus, no distinction 

could be made as to whether this level of concern applied to only fetuses or infants or preschoolage children. The issue of the persistence of the neurobehavioral effects from low-level lead 

exposure also was considered. Although the Boston and Cincinnati studies provided limited 

evidence suggesting that the effects of prenatal lead exposure on neurobehavioral development 

were not permanent, the evidence available to support this conclusion was inadequate. 

6.3.2 Neurotoxic Effects of Lead in Children 

Several major developments have occurred in lead research on child neurodevelopment 

following the 1986 Lead AQCD/Addendum and the 1990 Supplement. First, there has been an 

attempt to broaden outcome assessments beyond neurocognitive deficits. The earlier emphasis 

on neurocognitive measures (e.g., MDI, GCI, IQ) in previous studies is understandable from the 

perspectives of the strong psychometric properties of most of these rigorously standardized 

measures as well as the immediate pubic health concerns. Examples of other outcomes used to 

assess neurodevelopment include the number of errors on tests of visual-motor integration, the 

time required to complete a task assessing manual dexterity, the number of errors and false 

alarms on a continuous performance test, and the efficiency of short term memory. Additional 

neurodevelopment outcomes include those which elucidate brain-behavior relationships or the 

potential real life consequences of early exposure to lead, such as academic and vocational 

failure and maladjustment to the daily demands of living in a complex society. Thus, 

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epidemiologic studies of lead neurotoxicity have been expanded to adopt measures of academic 

achievement, specific cognitive abilities, behavior and mood, sensory acuities, neuromotor 

function, and direct measures of brain anatomical development and activity. Another 

development has been the initiation of nutritional and pharmacological intervention studies to 

assess the impact of treatment on reducing blood lead levels and preventing or moderating the 

degree of harm to the central nervous systems of young children. Also, in addition to blood and 

tooth lead, bone lead has emerged as a reliable biomarker of lead exposure. The technology for 

the assessment of lead in cortical (tibial) and trabecular (patellar) bone using K-shell X-ray 

fluorescence (XRF) has advanced to the point where it could be applied as a reliable and valid 

index of cumulative lead dose in neuroepidemiologic studies (Aro et al., 1994). 

In recent years, more studies have investigated the impact of blood lead levels below 

10 μg/dL on the developing brain. Average blood lead levels in U.S. children ages one to five 

years decreased from 15 μg/dL to approximately 3 μg/dL between 1976-1980 and 1991-1994, 

allowing newer studies to examine the effects of low level lead on the neurodevelopment of 

children (Centers for Disease Control, 2000; Pirkle et al., 1998). 

At the time of the last previous criteria review, it was recognized that estimating a 

threshold for toxic effects of lead on the central nervous system entailed difficulties. 

As discussed in the 1990 Supplement, insults to the human brain may be irreversible, making it 

difficult to determine whether any measured insult is the result of current or past exposures. 

An observed effect concurrent with a measured blood lead concentration may be the result of 

exposure in the child’s earlier life in the womb or infancy. There is also the critical question of 

reversibility or the persistence of lead effects identified in infants and preschoolers into school 

age and later. A given effect observed at younger ages may not persist due to functional 

compensation or a return to a normal neuromaturational trajectory (Dietrich et al., 1990). 

Another problem is that it is sometimes difficult to distinguish between neurobehavioral effects 

due to lead and effects owing to the many social, economic, urban-ecological, nutritional, and 

other medical factors that are known to have important effects on neurobehavioral development. 

Equally important is the high probability that the concentration-response relationship and even 

the neurobehavioral lesion associated with childhood lead exposure may vary as a function of 

these cofactors (Bellinger, 1995). 

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In the following sections, prospective cohort studies and cross-sectional studies of 

neurocognitive ability published since the 1990 Supplement are presented first. Then, studies 

examining the effect of lead on a variety of neurodevelopmental outcomes, including academic 

achievement; specific cognitive abilities; disturbances in behavior, mood, and social conduct; 

sensory acuities; neuromotor function; and brain anatomical development and acuity, are 

discussed. This is followed by a presentation of issues involved in understanding lead 

neurotoxicity in children, including gene-environment interactions, reversibility of lead effects, 

times of vulnerability, and potential threshold levels for effects. 

6.3.2.1 Neurocognitive Ability 

6.3.2.1.1 Prospective Longitudinal Cohort Studies of Neurocognitive Ability 

Several prospective longitudinal cohort studies were initiated in the 1980s because it 

became widely recognized that the cross-sectional study design was inadequate to address a 

number of research issues (U.S. Environmental Protection Agency, 1986; World Health 

Organization, 1977). These longitudinal studies were characterized by serial measures of dose 

(blood lead levels) spanning (in most cases) the prenatal and postnatal periods of central nervous 

system development, thus helping to clarify the temporal association between exposure and 

insult. Also, developmental assessments that extended into the school-age period were planned 

to determine if early lead associated neurobehavioral impairments were permanent or reversible 

in the fullness of time. It was also determined that assessment of potential confounding factors 

should be comprehensive and include measures of perinatal health, nutrition, maternal 

consumption of other neurotoxicants during pregnancy, parental intelligence, and direct 

observations of parenting behavior. These studies were also characterized by very careful 

attention to biostatistical issues and strategies (Bellinger, 1995; Ernhart, 1995). 

At the time of the 1990 Supplement, studies were underway or planned in the U.S., 

Australia, Scotland, the former Yugoslavia, and Mexico. These cohorts differed in the source 

and degree of lead exposure and in other important aspects, notably ethnicity and SES. 

Nevertheless, the early results from several of these studies have been largely responsible for the 

emergence of the current perspective that blood lead concentrations as low as 10 μg/dL, or 

perhaps even lower, may pose a risk for neurodevelopmental toxicity (Davis and Svendsgaard, 

1987; U.S. Environmental Protection Agency, 1990). Most of the prospective studies underway 

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in 1990 continued to follow their subjects into the later preschool and school age years with ageappropriate measures of intelligence. Continued follow-up of these cohorts was important due to 

the following: (1) greater reliability and precision of measurements attained with assessments of 

older children; (2) high predictability of adult intellectual functioning from measures of IQ in the 

older child; and (3) examination of potential effects of lead on important abilities that cannot be 

easily tapped during infancy such as executive functions and higher order reasoning (McCall, 

1979). 

A unique aspect of this research was that most investigators agreed during the formative 

stages of their projects to develop somewhat similar assessment protocols (Bornschein and 

Rabinowitz, 1985). This has facilitated comparison of results across studies and allowed for 

sophisticated meta- and pooled-analyses of these data (e.g., Pocock et al., 1994; Schwartz, 1994; 

World Health Organization, 1995; Lanphear et al., 2005; Rothenberg and Rothenberg, 2005). 

In the following sections, further updates on the individual prospective cohort studies are 

presented in chronological order of study initiation. The prospective cohort studies reviewed are 

summarized in Annex Table AX6-3.1. Results of the meta- and pooled-analyses are presented 

later in this section. 

Boston Study 

In the 1986 Addendum, the most advanced investigation at that time was the Boston 

Prospective Study (Bellinger et al., 1984). The subjects were 216 middle-to upper-middle-class 

Boston children, 90% of whom had cord blood lead levels below 16 μg/dL (maximum 

25 μg/dL). Cord blood lead levels in the “high” group (mean 14.6 μg/dL) were associated with 

lower covariate-adjusted scores on the Mental Development Index (MDI) of the Bayley Scales of 

Infant Development at 6 months of age. It was concluded that although lower level lead 

exposure in utero may result in delays in early sensorimotor development, the Boston results 

did not allow estimation of the persistence of these effects nor the public health significance of 

the findings. The association between higher cord blood lead and lower MDI persisted to 

24 months; however no association was observed between postnatal blood lead levels and MDI 

(Bellinger et al., 1985, 1986). 

Particular attention was focused on the Boston study, which was among the more mature 

in terms of follow-up, in the 1990 Supplement (Bellinger et al., 1987; Bellinger et al., 1991). 

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With respect to the effects of cord blood lead concentrations on MDI assessed longitudinally 

from 6 to 24 months, the lead associated deficits were evident across the entire range of blood 

lead levels starting at 10 μg/dL, which reinforced the previous designation of 10-15 μg/dL as a 

blood level of concern for early neurodevelopmental deficits. At approximately 5 years of age, 

cord blood lead levels were not significantly associated with the McCarthy GCI, but blood lead 

level at 2 years of age (mean 6.8 μg/dL [SD 6.3]) was significantly associated with lower scores. 

Although cord blood lead concentrations were not independently associated with deficits in 

5-year neurocognitive status, the risk of obtaining lower GCI scores was greater among subjects 

with higher prenatal and postnatal blood lead concentrations. Boston investigators also 

examined the relationship between lead measured in shed deciduous teeth obtained from 

102 children in their cohort (mean 2.8 ppm [SD 1.7]) and GCI at 5 years of age. Prior to 

covariate-adjustment, there was a very strong and significant relationship amounting to a loss of 

more than 10 points in GCI for each log increment in dentine lead. However, in the 

multivariable analysis the tooth lead coefficient, although negative, was no longer statistically 

significant. Reduced sample size should be taken into consideration in interpreting this null 

finding. 

Since the 1990 Supplement, the Boston investigators reexamined 148 of their subjects at 

10 years of age with the Wechsler Intelligence Scale for Children-Revised (WISC-R) and other 

neurobehavioral assessments (Bellinger et al., 1992). They examined the association of WISC-R 

scores at 10 years of age with blood lead concentrations in the cord blood and at 6 months, 

12 months, 18 months, 24 months, 57 months, and 10 years. Only blood lead levels at 

24 months were significantly associated with full scale and verbal IQ and marginally associated 

with performance IQ, after adjusting for HOME score, maternal age, birth weight, and maternal 

IQ. The integrated average blood lead level in this cohort over the first 2 years was 7.0 μg/dL 

(range 4-14 μg/dL). An increase of 10 μg/dL in blood lead level at age 2 was associated with a 

decrement of 5.8 points (95% CI: 1.8, 9.9) in full scale IQ. These findings indicated that 

children’s performance was much more strongly associated with blood lead levels at age 2 than 

with blood lead levels at other ages. It is unclear whether this reflects a special vulnerability of 

the nervous system during this period or simply the fact that blood lead level tends to peak in the 

second year. 

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A reanalysis involving the total Boston cohort that employed nonparametric smoothing 

revealed that the inverse association persisted at blood lead levels below 5 μg/dL (Schwartz, 

1994). Bellinger and Needleman (2003) reanalyzed data on 48 children whose measured blood 

lead concentrations never exceeded 10 μg/dL. Reduction in full scale IQ at 10 years was 

significantly associated with blood lead levels at 2 years of age following covariate adjustment. 

A larger deficit of 15.6 points (95% CI not presented) per 10 μg/dL increase in blood lead levels 

was observed in this cohort, compared to the 5.8 point deficit observed in the entire cohort. 

These findings indicated that the inverse slope might be steeper at blood lead levels below 

10 μg/dL. 

Cincinnati Study 

Interim results on a partial sample of 185 subjects from a cohort of 305 were available 

from the Cincinnati prospective study in the 1986 Addendum and the 1990 Supplement (Dietrich 

et al., 1986, 1987a). The Cincinnati study investigators reported an inverse relationship between 

prenatal maternal blood lead levels (mean 8.3 μg/dL) and 6 month Bayley MDI. This effect was 

mediated, in part, through lead-associated reductions in birth weight and gestational maturity. 

A more complete analysis of the full Cincinnati cohort confirmed these interim findings 

(Dietrich et al., 1987b). 

Further updates of the Cincinnati study appeared after the 1990 Supplement. The 

Kaufman Assessment Battery for Children (KABC) was administered to approximately 

260 children at 4 and 5 years of age (Dietrich et al., 1991; 1992). The principal findings at 

4 years were that higher neonatal blood lead concentrations were associated with poorer 

performance on all KABC subscales. However, this relationship was confined to children from 

the poorer families. Following full covariate adjustment, few statistically significant 

relationships remained. At 5 years of age, postnatal blood lead levels were associated with 

performance on all subscales of the KABC; however, few statistically significant relationships 

remained after adjustment for covariates. Nevertheless, it is of interest that at both 4 and 5 years 

the KABC subscale that assessed visual-spatial skills was among those that remained the most 

highly associated with various indices of postnatal exposure following covariate adjustment. 

At the age of approximately 7 years, 253 children in the Cincinnati cohort were administered the 

WISC-R (Dietrich et al., 1993a). In this cohort, approximately 35% had at least one blood lead 

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concentration $25 μg/dL while 95% exceeded 10 μg/dL sometime during the first 5 years of life. 

Postnatal blood lead concentrations were inversely associated with full scale and performance 

IQ, after adjusting for HOME score, maternal IQ, birth weight, birth length, child gender, and 

cigarette consumption during pregnancy. Figure 6-3.1 presents the unadjusted and adjusted 

concentration-response relationship between lifetime average blood lead concentrations and 

performance IQ. Following covariate adjustment, a statistically significant relationship was 

observed between postnatal blood lead levels at 5 and 6 years of age and full scale IQ. Postnatal 

blood lead levels at nearly all ages (including the integrated average blood lead level) were 

inversely associated with performance IQ. Blood lead levels at 6 years of age were most 

strongly associated with performance IQ – a 5.2 point [95% CI: 2.3, 8.1] decline was observed 

for each 10 μg/dL increase in blood lead level. A 10 μg/dL increase in lifetime average blood 

lead concentration was associated with a 2.6 point (95% CI: 0.2, 5.0) decline in performance IQ. 

At 15-17 years of age, the Cincinnati subjects were administered a comprehensive 

neuropsychological battery (Ris et al., 2004). Variables derived from the Cincinnati 

neuropsychological battery were subjected to a principal components factor analysis that yielded 

five factors, including a learning/IQ factor that had high loadings for the Vocabulary and Block 

Design subtests from the WISC-III as well as the Reading, Spelling, and Arithmetic subscales of 

the Wide Range Achievement Test-Revised (WRAT-R). Prenatal, Average Childhood, and 

78 month blood lead levels were used in a series of multiple regression analyses. Following 

covariate-adjustment, there was a trend towards significance for higher blood lead concentrations 

in later childhood (e.g., 78 months) to be associated with lower learning/IQ factor scores, but this 

was largely observed in subjects from the lower end of the socioeconomic scale in the sample. 

This finding is consistent with previous reports that children in the lower social strata may be 

more vulnerable to general effects on cognitive development and learning (Bellinger, 2000; 

Winneke and Kraemer, 1984). 

Cleveland Study 

Early results of the Cleveland prospective study also were reviewed in the 1986 

Addendum and 1990 Supplement. By selection, about half of the mothers had histories of 

alcohol abuse as measured by the Michigan Alcoholism Screening Test. The other women were 

matched controls. The initial cohort included 389 infants with a mean cord blood lead level of 

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402(c) Economic Analysis Chapter 5 456
Figure 6-3.1. Unadjusted and adjusted relationships between average lifetime blood lead 

concentrations and Wechsler Scale performance IQ. Mean " SD lifetime 

average blood lead concentrations within each category were as follows: 

0-10 μg/dL, 7.7 " 1.4 μg/dL (n = 68); >10-15 μg/dL, 12.3 " 1.4 μg/dL 

(n = 89); >15-20 μg/dL, 17.1 " 1.2 μg/dL (n = 53); and >20 μg/dL, 

26.3 " 5.0 μg/dL (n = 41). 

Source: Dietrich et al. (1993a). 

1 5.84 μg/dL (maximum 14.7). In addition to size, minor morphological anomalies, and 1- and 

2 5-minute Apgar performances, infants were evaluated on the Brazelton Neonatal Behavioral 

3 Assessment Scale (NBAS) and part of the Graham-Rosenblith Behavioral Examination for 

4 Newborns (G-R). Of the 17 neonatal outcomes examined, the NBAS Abnormal Reflexes scale 

5 and neurological soft signs assessed by G-R were associated with cord blood lead levels in the 

6 range of 3 to 15 μg/dL following covariate adjustment (Ernhart et al., 1986). A follow-up study 

7 observed a significant effect of the neurological soft signs measure on Bayley MDI scores at 

8 12 months; however, prenatal lead exposure was not associated with MDI scores at 6-24 months 

9 or Stanford-Binet IQ (S-B IQ) scores at 36 months (Wolf et al., 1985). 

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In 285 children from the original cohort, maternal and cord blood lead levels, as well as 

postnatal blood lead levels at 6 months, 2 years, and 3 years were examined in relation to Bayley 

MDI, Psychomotor Index (PDI), and Kent Infant Development Scale (KID) at 6 months, MDI at 

1 year and 2 years, and S-B IQ at 3 years of age (Ernhart et al., 1987, 1988). After covariate 

adjustment, only maternal blood lead level at delivery (mean 6.5 μg/dL [maximum 11.8]) was 

inversely associated with MDI, PDI, and KID scores at 6 months. No other indices of prenatal or 

postnatal lead exposure were inversely associated with assessments of global intellectual 

functioning. Language development also was assessed in the Cleveland cohort at 1, 2, and 

3 years of age. Few significant associations remained after covariate adjustment (MorrowTlulak and Ernhart, 1987). 

At 4 years and 10 months, 242 children from the Cleveland cohort were administered the 

Wechsler Preschool and Primary Scale of Intelligence (WPPSI) test. Significant negative 

correlations were observed between full scale, verbal, and performance IQ, and prenatal (both 

maternal and cord) and postnatal (at 2 years and 3 years) blood lead levels (Ernhart and MorrowTlulak, 1987). However, these associations were no longer significant after adjustment for 

various covariates, including HOME score, maternal IQ, parent education, race, medical 

problems, maternal alcohol use in pregnancy, Michigan Alcoholism Screening Test score, 

maternal use of marijuana, and several categories of psychosocial trauma scale. The authors 

reported a large contribution of these covariates to the variance of the WPPSI scores; the smaller 

effects of lead may have been suppressed by these other social factors. In particular, the HOME 

score was found to most strongly contribute to the child’s IQ. In 164 children, shed deciduous 

incisor were collected between ages 5 and 7. Circumpulpal dentine lead levels were found to be 

significantly associated with full scale, verbal and performance IQ, assessed using the WPPSI 

test, at 4 years and 10 months, after adjustment for various covariates except for HOME score. 

After additional adjusting for HOME score, the lead effects on all three IQ measures diminished, 

but remained statistically significant for verbal IQ (p = 0.01) and marginally significant for full 

scale IQ (p = 0.06). An increase in dentine lead from the 10th percentile to the 90th percentile 

level (13.5 μg/g to 129.4 μg/g) was associated with a 6.0 point (95% CI: 1.4, 10.6) decrease in 

verbal IQ and a 4.5 point (95% CI: !0.2, 9.2) decrease in full scale IQ. The estimated lead 

effect increased as a function of the level of measurement error in the dentine lead variable. 

This finding of an adverse effect for dentine lead is not consistent with previous analyses of the 

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Cleveland study showing that blood lead levels are, generally, not associated with cognitive 

outcomes after covariate adjustment. 

Port Pirie, Australia Study 

Preliminary results from the Port Pirie, Australia study also were described in the 1986 

Addendum (Vimpani et al., 1985). Lower Bayley MDI scores at 2 years from 592 children were 

significantly associated with higher integrated postnatal blood lead levels (approximately 20% of 

the sample had blood lead levels >30 μg/dL at the time of assessment), but not with maternal 

prenatal, delivery, or cord blood lead levels. Results of this interim analysis were interpreted 

with caution since important covariates such as maternal IQ and HOME scores were not 

available for the entire cohort at the time of the analyses. 

The Port Pirie cohort study had reported results out to 4 years when the 1990 Supplement 

was released (McMichael et al., 1988). Following adjustment for covariates, lead concentrations 

at most postnatal sampling points as well as an integrated average for the 4-year postnatal period 

were significantly and inversely associated with scores on the McCarthy Scales of Children’s 

Abilities. The GCI scores declined by approximately 4.5 points (95% CI: 0.2, 8.8) for a 

doubling in blood lead levels. Similar deficits occurred in the perceptual-performance and 

memory scores. The integrated postnatal blood lead levels among the 537 children in this cohort 

were among the highest of the prospective studies (geometric mean 19 μg/dL). However, further 

analyses indicated that the effects observed did not depend on children with the more extreme 

levels of exposure. The concentration-response relationship between blood lead and GCI was 

stronger among children with blood lead levels below 25 μg/dL than it was overall. 

Of all of the prospective studies of lead and child development, the Port Pirie cohort study 

was probably among the best positioned to reliably detect effects of low level lead exposure into 

later childhood owing to its wide range of exposure, large sample size, and lack of extremes in 

terms of sample social advantage or disadvantage. The WISC-R was administered to 

494 children between 7 and 8 years of age (Baghurst et al., 1992). IQ scores were examined in 

relation to ln-transformed blood lead concentration. Following adjustment for covariates there 

was little association with pre- and perinatal lead exposure assessments. However, significant 

decrements in full scale and verbal IQ were found to be associated with postnatal blood lead 

levels. The estimated effect size was a loss of 3.3 points (95% CI: 0.2, 6.5) in full scale IQ and 

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4.0 points (95% CI: 0.7, 7.2) in verbal IQ in association with a doubling of the integrated 

postnatal blood lead concentration up to three years. In light of the Cincinnati findings, it is of 

interest that the Block Design subtest of the WISC-R (a measure of visual-spatial abilities), 

exhibited the strongest association with lead exposure. Port Pirie investigators also collected 

deciduous central upper incisors from 262 children in their cohort (McMichael et al., 1994). 

After covariate adjustment, a significant inverse association was observed between tooth lead 

concentration and WISC-R full scale IQ at 7 years of age. The adjusted estimated decline in full 

scale IQ across the tooth lead range from 3 to 22 μg/g (range for 90% of population) was 

5.1 points (90% CI: 0.2, 10.0). Once again, the Block Design subtest was among the most 

highly sensitive. 

Port Pirie children were assessed again at 11-13 years of age to examine the persistent 

relationship between exposure to environmental lead and intelligence (Tong et al., 1996). At that 

age, Port Pirie investigators were able to recall 375 children for IQ assessments. At 11-13 years 

of age, the geometric mean lifetime average blood lead concentration was 14.1 μg/dL. WISC-R 

scores were significantly and inversely associated with integrated lifetime average blood lead 

concentrations out to 11-13 years. Later blood lead concentrations after 3 years of age were 

more predictive of lower IQ. Mean full scale IQ declined by 3.0 points (95% CI: 0.1, 5.9) for a 

doubling of lifetime average blood lead concentrations. The authors could find no clear evidence 

of a threshold level in their data. 

Sydney, Australia Study 

Unlike Port Pirie, the reports on the Sydney cohort study were consistently negative with 

respect to the effects of exposure on neurodevelopment (Cooney et al., 1989a,b; McBride et al., 

1989). In the 298 mothers and infants sampled, geometric mean blood lead levels at delivery 

were 9.1 μg/dL and 8.1 μg/dL, respectively, with less than 2% in excess of 15 μg/dL. Mean 

postnatal blood lead levels peaked at 16.4 μg/dL when children reached 18 months and then 

declined to 10.1 μg/dL at 48 months. No significant, inverse relationships were reported 

between prenatal or postnatal blood lead concentrations and neurodevelopmental assessments 

conducted from 6 months through 4 years of age. The McCarthy Scales of Children’s Abilities 

was administered to 207 children at 4 years of age but no associations with blood lead levels 

were observed prior to or following covariate-adjustment. As in the case of the Cleveland study, 

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the authors noted that the HOME score was a strong contributor to the neurodevelopmental 

assessments at all ages. As stated in the 1990 Supplement, this raises the questions of whether 

lead exposure might have covaried with HOME scores. If so, adjusting for HOME scores would 

reduce the statistical power to examine the effect of postnatal blood lead levels on the 

neurocognitive measures. Also note that the interpretation of the Sydney findings has been 

complicated by concerns about possible contamination of capillary blood lead samples collected 

during the early phases of the investigation (Cooney et al., 1989b). 

The Sydney prospective study further assessed 175 subjects that remained in the study at 

7 years of age (Cooney et al., 1991). Geometric mean blood lead concentrations peaked at 

2 years of age (15.2 μg/dL). The geometric mean blood lead level at 7 years of age was 

7.7 μg/dL. The WISC-R and other neurobehavioral assessments were administered. The 

adjusted correlations between postnatal blood lead levels and WISC-R scores were consistently 

negative but nonsignificant at the p = 0.05 level. The r value (units = SD of IQ per SD of blood 

lead) for the correlation between full scale IQ and concurrent blood lead at age 7 years was 

!0.06 (95% CI: !0.20, 0.09). The correlation coefficient is not significantly different form 

Bellinger et al. (1992) for 57-month-old children, !0.07 (95% CI: !0.23, 0.08), or from 

Lanphear et al. (2005) for children aged 4.8 to 10 years, !0.20 (95% CI: !0.28, !0.12). 

All correlation coefficients are for full scale IQ and concurrent blood lead concentrations. 

Results from this follow-up study were consistent with their earlier reports of no 

association between blood lead levels <15 μg/dL and developmental deficits. However, the 

authors noted that their study was not designed to examine small deficits associated with blood 

lead levels at this magnitude. They reported that the size of their cohort did not provide 

sufficient power to detect effects less than 5%. Cooney et al. concluded that results from their 

study indicate that if developmental deficits do occur at blood lead levels below 25 μg/dL, the 

effect size is likely to be less than 5%. 

Mexico City Study 

Preliminary results of the Mexico City cohort prospective study were presented in the 

1990 Supplement (Rothenberg et al., 1989). Blood lead levels from 42 mother-infant pairs were 

measured at 36 weeks of pregnancy (mean 15.0 μg/dL) and delivery (mean 15.4 μg/dL), and 

in the cord blood (mean 13.8 μg/dL). The Brazelton NBAS was administered to infants at 

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48 hours, 15 days, and 30 days after birth. None of the lead measures were associated with the 

NBAS outcomes; however, several differential lead measures (i.e., maternal blood lead at 

36 weeks of pregnancy minus cord blood lead) were found to be associated with several outcome 

variables. Increases in the blood lead of the mother during the last month of pregnancy or a cord 

blood lead level higher than the mother’s blood lead level were associated with adverse changes 

in Regulation of States, Autonomic Regulation, and Gestation Age. 

Schnaas et al. (2000) further examined the effect of postnatal blood lead level on 

cognitive development in 112 children with complete data from the Mexico City study. Lead 

was measured in blood every 6 months from 6 to 54 months. Intellectual status was assessed 

with the McCarthy GCI. The purpose of the study was to estimate the magnitude of the effect of 

postnatal blood lead level on the GCI and describe how the effect varies with the time between 

blood lead measurements and the neurocognitive assessments. The geometric mean blood lead 

level between 24-36 months was 9.7 μg/dL (range 3.0-42.7). A number of significant 

interactions were observed between blood lead levels and age of assessment. The greatest effect 

was found at 48 months, with a decrease of 4.0 points (95% CI not presented) in adjusted GCI 

score being observed for a doubling of the 24-36 month blood lead level. The authors concluded 

that 4 to 5 years of age (when children are entering school) appears to be a critical period for the 

manifestation of earlier postnatal blood lead level effects. 

In a related study, Gomaa et al. (2002) examined prenatal and postnatal lead exposure 

effects on the neurodevelopment of 197 children aged 2 years residing in Mexico City. Lead 

was measured in the umbilical cord and maternal venous blood samples at delivery. Maternal 

body burden was measured by obtaining cortical (tibial) and trabecular (patellar) bone lead 

measurements using K-shell XRF within 4 weeks of delivery. At 2 years of age, the Bayley 

MDI and PDI were administered. The major objective of this study was to compare lead levels 

in umbilical cord blood and maternal bone as independent predictors of infant mental 

development. Mean blood lead concentrations in the cord blood, at 12 months of age, and at 

24 months at age were 6.7 μg/dL (SD 3.4), 7.2 μg/dL (SD 2.8), and 8.4 μg/dL (SD 4.6), 

respectively. Mean maternal patella and tibia bone lead levels were 17.8 μg/g (range <1-76.6) 

and 11.5 μg/g (range <1-85.9), respectively. Following covariate adjustment, postnatal blood 

lead concentrations were not significantly associated with MDI; however, lead levels in cord 

blood and trabecular bone were found to be significantly associated with lower scores on the 

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Bayley MDI. Maternal trabecular bone lead levels predicted poorer sensorimotor functioning in 

children 2 years of age independent of the cord blood lead level. The authors concluded that 

higher maternal trabecular bone lead concentrations constitute an independent risk factor for 

impaired mental development in infants at 2 years of age and that this is likely due to the 

mobilization of maternal bone lead stores over the course of gestation. 

Kosovo, Yugoslavia Study 

The neurodevelopment results of a large birth cohort study of 577 children in two towns 

in Kosovo, Yugoslavia were not available at the time of the 1990 Supplement. The study took 

place in Titova Mitrovica, near the site of a longstanding lead smelter, refinery, and battery plant, 

and in Pristina, a less exposed community 25 miles to the south. A unique characteristic of this 

cohort was the high prevalence of anemia secondary to iron deficiency (34% with hemoglobin 

concentrations <10.5 μg/dL at 2 years of age). The investigators began providing iron-fortified 

multivitamin supplements to the entire cohort when the children were between 18 to 38 months 

of age (Wasserman et al., 1994). 

Like Port Pirie, this was one of the more highly exposed cohorts. Blood lead levels were 

obtained during the second trimester, at delivery, from the umbilical cord and postnatally at 

6-month intervals to 90 months. At birth, geometric mean cord blood lead levels were nearly 

21 μg/dL in the smelter area (Wasserman et al., 1992). At age 2 years, geometric mean blood 

lead concentrations were 35.5 μg/dL and 8.4 μg/dL among infants from Titova Mitrovica and 

Pristina, respectively. 

Neurocognitive measures of mental abilities were administered at 2, 4, 7, and 10-13 years 

of age. The relationships between these neurocognitive outcomes and log-transformed blood 

lead levels were assessed. A doubling of blood lead levels at 2 years of age was associated with 

a covariate-adjusted decline of 1.6 points (95% CI: 0.2, 3.0) in Bayley MDI. Statistically 

nonsignificant decrements in MDI were associated with blood lead levels measured at all other 

time points. Iron deficiency anemia also was an independent predictor of lower MDI 

(Wasserman et al., 1992). When examined at 4 years of age, the geometric mean blood lead 

concentration of children from the smelter area was 39.9 μg/dL, while the geometric mean for 

children in the “unexposed” area was 9.6 μg/dL (Wasserman et al., 1994). Children were 

administered the McCarthy Scales of Children’s Abilities. Higher prenatal and cord blood lead 

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concentrations were associated with lower GCI scores. Following covariate-adjustment, children 

of mothers with prenatal blood lead levels greater than 20 μg/dL scored a full standard deviation 

below children in the lowest exposure group (<5 μg/dL prenatal blood lead). A statistically 

significant association also was observed between nearly every blood lead measurement 

(at 6-month intervals since birth) and GCI. At 4 years of age, a doubling of blood lead levels 

was associated with a reduction of 2.8 points (95% CI: 1.4, 4.3) on the GCI. The PerceptualPerformance subscale of the McCarthy was found to be most sensitive to lead exposure. 

When 301 children were examined at 7 years of age with the WISC-III, significant 

associations were observed between postnatal blood lead concentrations and IQ, with 

consistently stronger associations between performance IQ and later blood lead measures 

(Factor-Litvak, 1999). The adjusted intellectual loss associated with a doubling in lifetime 

average blood lead was 2.7 points (95% CI: 1.7, 3.7) in full scale IQ, 2.8 points (95% CI: 1.7, 

4.0) in performance IQ, and 2.1 points (95% CI: 1.1, 3.2) in verbal IQ. By 7 years, measures of 

iron status were no longer significantly associated with IQ. 

At age 10-12 years, 290 subjects with complete data on exposure and covariate factors 

were assessed again with the WISC-III (Wasserman et al., 2003). However, in addition to wellcharacterized exposure histories based on serial blood lead assessments, tibial bone lead was 

measured using 109Cd based K-shell XRF (Todd et al., 2001) on a representative subsample of 

167 subjects from both communities. Blood lead and bone lead measures were highly correlated 

in Titova Mitrovica, but not in Pristina. Following covariate-adjustment, average lifetime 

blood lead level was significantly and negatively related to all components of WISC-III IQ. 

A doubling of average blood lead concentration was associated with a decrease in full scale, 

performance, and verbal IQ of 1.6 points (95% CI: 0.4, 2.8), 1.5 points (95% CI: 0.3, 2.8), and 

1.5 points (95% CI: 0.3, 2.6), respectively. The relationships between bone lead and IQ scores 

were stronger than those for blood lead, at least in the more highly exposed smelter community. 

For each doubling of tibial bone lead concentrations, full scale, performance, and verbal IQ 

decreased by an estimated 5.5, 6.2, and 4.1 points, respectively. The authors also reported that 

significant associations between tibial lead concentrations and IQ scores persisted despite 

inclusion of blood lead into the model. The inference drawn from these findings was that 

associations between bone lead and IQ outcomes may be stronger than those between blood lead 

measures and IQ. 

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Shanghai, China Study 

A prospective study of low-level prenatal and postnatal exposure was initiated in 1993 by 

Shen et al. (1998) in Shanghia, China. Pregnant women were recruited from a maternal and 

child health care facility in the community. Lead levels were determined on 348 cord blood 

samples. The geometric mean cord blood lead level was 9.2 μg/dL (range 1.6-17.5); 40.8% of 

the infants had cord blood lead levels $10 μg/dL. Infants were further selected for study on the 

basis of their cord blood lead concentrations – the low lead group (n = 64) had levels <30th 

percentile while the high lead group (n = 69) had levels >70th percentile. Mean cord blood lead 

concentrations in the high lead group and low lead group were 13.4 μg/dL (SD 2.0) and 

5.3 μg/dL (SD 1.4), respectively. At 3, 6, and 12 months, infants were administered the Chinese 

version of the Bayley Scales of Infant Development. Capillary blood samples were collected at 

each visit to ascertain levels of postnatal exposure. Mean blood lead at 1 year of age was 

14.9 μg/dL (SD 8.7) in the high lead group and 14.4 μg/dL (SD 7.7) in the low lead group. 

Postnatal blood lead levels were not significantly different in the high and low lead groups. 

At all three ages, the Bayley MDI, but not PDI, was associated with cord blood lead 

groupings following adjustment for covariates, which included a wide range of perinatal, 

demographic, social, and environmental factors. Postnatal blood lead concentrations were not 

associated to any Bayley measures. Differences in mean MDI between cord blood lead groups 

were 3.4 points at 3 months (p = 0.02), 6.3 points at 6 months (p = 0.03), and 5.2 points at 

12 months (p = 0.03). The early results of this prospective study are generally in accord with 

similar investigations in Boston, Cincinnati, and Cleveland. The authors concluded that the 

adverse effects of prenatal lead exposure on early neurobehavioral development are readily 

discernible and stable over the first year of life. 

Rochester Study 

The Rochester prospective study, initiated in 1994, examined the relationship between 

blood lead levels and IQ at 3 and 5 years of age in 172, predominantly African-American, lower 

SES children (Canfield et al., 2003a). Participants were enrolled when children were 5 to 

7 months of age in what was originally a study of lead dust control methods (Lanphear et al., 

1999). Blood lead concentrations were assessed at 6-month intervals until 2 years and annually 

thereafter. No data were available on prenatal exposure. The measure of IQ was the abbreviated 

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Stanford-Binet Intelligence Scale-4th Edition (SBIS-4). Potential confounders assessed included 

gender, birth weight, iron status, HOME scores, maternal IQ, SES, and tobacco use during 

pregnancy. 

Blood lead concentrations in the Rochester cohort were quite low for an urban population 

as this study was conducted after public health measures to reduce blood lead levels in children 

were already having a dramatic impact in the U.S. population. Blood lead levels peaked at 

2 years of age (mean 9.7 μg/dL). The mean lifetime average blood lead concentration was 

7.7 μg/dL at the age of 3 years and 7.4 μg/dL at the age of 5 years. At 5 years of age, 56% of the 

children had a peak blood lead concentration below 10 μg/dL. Following adjustment for 

covariates, there were significant inverse associations with full scale IQ at both 3 and 5 years of 

age for all blood lead variables, including lifetime average up to age of behavioral assessment. 

The effect of lead on IQ was estimated in all children using lifetime average, peak, 

concurrent, and average in infancy (6-24 months) blood lead levels. Lead effects on IQ for the 

subgroup of children whose peak lead concentration never exceeded 10 μg/dL also was 

estimated. Table 6-3.1 shows the covariate-adjusted changes in IQ for each 1 μg/dL increase in 

blood lead concentration for all children and children with peak blood lead concentrations below 

10 μg/dL. In all cases, the effect estimates were larger in the subsample of children with peak 

blood lead concentrations below 10 μg/dL. For example, the overall estimate including all 

children indicated that an increase in the lifetime average blood lead concentration of 1 μg/dL 

was associated with a decrease of 0.46 points (95% CI: 0.15, 0.76) in IQ. In comparison, a 

1 μg/dL increase in lifetime average lead concentration was associated with a decline of 

1.37 points (95% CI: 0.17, 2.56) in children with peak blood lead concentrations below 

10 μg/dL. In an accompanying editorial of the Canfield et al. (2003a) study, Rogan and Ware 

(2003) noted that the steepness in the concentration-response relationship below 10 μg/dL might 

have been influenced by 10 children with blood lead concentrations at or below 5 μg/dL and IQs 

above 115. However, they added that it was unlikely that the associations reported by Canfield 

et al. were solely due to these values. Regression diagnostics performed by Canfield et al. 

identified only one potential outlier (a child who had a low IQ and low lead concentration); 

however, this value was retained in all analyses as it did not pass the discordancy test. 

In the Rochester study, the relationship between children’s IQ score and their blood lead 

level was found to be nonlinear. A semiparametric analysis indicated a decline of IQ of 

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At 3 Years of Age At 5 Years of Age 

Type of Blood Lead Measurement n $ (95% CI) p $ (95% CI) p 

Β (95% 

All Children Lifetime average 172 !0.35 0.05 !0.57 0.003 !0.46 

(!0.69, 0.00) (!0.93, !0.20) (!0.76, !

Peak 172 !0.19 0.06 !0.26 0.02 !0.23 

(!0.39, 0.01) (!0.47, !0.05) (!0.40, !

Concurrent 171 !0.31 0.04 !0.61 <0.001 !0.46 

(!0.60, !0.01) (!0.99, !0.24) (!0.74, !

Average in infancy 172 !0.32 0.10 !0.53 0.01 !0.43 (6-24 mo) (!0.71, 0.07) (!0.93, !0.13) (!0.77, !

Children with Peak Blood Lead Concentrations below 10 μg/dLb 

Lifetime average 101 !1.22 0.07 !1.52 0.04 !1.37 

(!2.53, 0.09) (!2.94, !0.09) (!2.56, !

Peak 101 !1.36 0.002 !1.44 0.01 !1.40 

(!2.46, !0.27) (!2.55, ! 0.33) (!2.37, !

Concurrent 101 !1.36 0.009 !1.79 0.004 !1.58 

(!2.37, !0.35) (!3.00, !0.60) (!2.50, !

Average in infancy 105 !0.58 0.32 !0.92 0.12 !0.75 (6-24 mo) (!1.75, 0.59) (!2.09, 0.25) (!1.78, 0

a Estimates were adjusted for maternal IQ, race, level of education, use of tobacco during pregnancy, household income, HOME score

weight, and iron status. 

b A total of 71 children were found to have a peak blood lead concentration below 10 μg/dL at both ages; an additional 15 children ha

below 10 μg/dL at 3 years of age but at 5 years of age had a higher concentration or were not tested, and another 15 children had a p10 μg/dL at 5 years but were not tested at 3 years. The total number of children in the analysis of the average concentration in infan

children the peak blood lead concentration occurred after the age of 24 months. 

Source: Canfield et al. (2003a). 

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7.4 points for a lifetime average blood lead concentration of up to 10 μg/dL, while for levels 

between 10 to 30 μg/dL a more gradual decrease of approximately 2.5 points IQ was estimated. 

The authors concluded that the most important aspect of their findings was that effects below 

10 μg/dL that have been observed in previous cross-sectional studies (e.g., Chiodo et al., 2004; 

Fulton et al., 1987; Lanphear et al., 2000; see Section 6.3.2.1.2) have been confirmed in this 

rigorous prospective longitudinal investigation. 

Pooled-Analyses of Prospective Longitudinal Cohort Studies 

Investigators have collectively analyzed the results of multiple independent studies using 

the methods of meta- and pooled data analyses. A powerful approach involves pooling the raw 

data from several high quality studies to examine concentration-response relationships in a large 

sample of children with diverse sociodemographic backgrounds and levels of exposure. The 

studies reviewed here are summarized in Annex Table AX6-3.2. 

Lanphear et al. (2005) reported on a pooled analysis of seven prospective studies that 

were initiated prior to 1995. The analysis involved 1,333 children with complete data on 

confounding factors that were essential in the multivariable analyses. The participating sites 

included Boston, MA; Cincinnati, OH; Cleveland, OH; Rochester, NY; Mexico City; Port Pirie, 

Australia; and Kosovo, Yugoslavia. A prospective cohort study conducted in Sydney, Australia 

was not included because the authors were unable to contact the investigators (Cooney et al., 

1989b, 1991). The sample size of 175 for children at age 7 years in the Sydney cohort and the 

wide confidence intervals of the effect estimates, as implied by the lack of significant 

associations, indicate that the nonavailability of this study is unlikely to influence the results of 

the pooled analysis by Lanphear et al. 

The primary outcome measure was full scale IQ measured at school age (mean age at IQ 

testing was 6.9 years). All children were assessed with an age-appropriate version of the 

Wechsler scales. Four measures of lead exposure were examined: concurrent blood lead (blood 

lead level closest in time to the IQ test), maximum blood lead level (peak blood lead measured at 

any time prior to the IQ test), average lifetime blood lead (mean blood lead from 6 months to the 

concurrent blood lead test), and early childhood blood lead (defined as the mean blood lead from 

6 to 24 months). A pooled analysis of the relationship between cord blood lead levels and IQ 

also was conducted in the subsample for which cord blood lead tests were available. 

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Multivariate regression models were developed adjusting for site as well as ten common 

covariates assessing factors likely to be confounders of the relationship between lead and 

cognitive development, including HOME scores, birth weight, maternal education and IQ, and 

prenatal substance abuse. A thorough statistical analytic strategy was employed to determine the 

linearity or nonlinearity of the relationship between blood lead levels and full-scale IQ. 

Regression diagnostics also were performed to ascertain whether lead coefficients were affected 

by collinearity or influential observations. The fit of all four measures of postnatal blood lead 

levels was compared using the magnitude of the model R2

. The blood lead measure with the 

largest R2 (adjusted for the same covariates) was nominated a priori as the preferred blood lead 

index relating lead exposure to IQ in subsequent inspections of the relationships. Results were 

evaluated by applying a random-effects model (with sites random) rather than a fixed-effects 

model. The authors also examined the impact of any one site on the overall model by calculating 

the blood lead coefficient in seven identical models, each omitting one of the seven prospective 

cohort studies. Similar models were fitted for verbal and performance IQ as well. 

The median lifetime average blood lead concentration was 12.4 μg/dL (5th-95th 

percentile 4.1-34.8) with about 18% of the children having peak blood lead levels below 

10 μg/dL. The 5th to 95th percentile concurrent blood lead levels ranged from 0.8 to 4.7 μg/dL 

in the individual studies. The mean IQ of all children was 93.2 (SD 19.2) but this varied greatly 

between studies. All four measures of postnatal exposure were highly correlated. However, the 

concurrent blood lead level exhibited the strongest relationship with IQ, as assessed by R2

. 

Nevertheless, the results of the regression analyses for all blood lead measures were very similar. 

Multivariable analysis resulted in a six-term model including log of concurrent blood lead, study 

site, maternal IQ, HOME Inventory, birth weight, and maternal education. As illustrated in 

Figures 6-3.2 and 6-3.3, the shape of the log-linear model and the spline function indicated that 

the steepest declines in IQ were at blood lead concentrations below 10 μg/dL. The log-linear 

model estimated a decrement of 1.9 points (95% CI: 1.2, 2.6) in full scale IQ for a doubling of 

concurrent blood lead. Due to the log-linear relationship, the slope of the lead effect on IQ was 

greater in the lower ranges of exposure. The IQ point decrements associated with an increase in 

blood lead from <1 to 10 μg/dL compared to 10 to 20 μg/dL were 6.2 (95% CI: 3.8, 8.6) versus 

1.9 (95% CI: 1.2, 2.6). 

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Figure 6-3.2. Log-linear model (95% CI shaded) for concurrent blood lead concentration 

adjusted for HOME score, maternal education, maternal IQ, and birth 

weight. The mean IQ (95% CI) for the intervals <5, 5-10, 10-15, 15-20, 

and >20 μg/dL are shown. 

Source: Lanphear et al. (2005). 

Figure 6-3.3. Log-linear model for concurrent blood lead concentration along with linear 

models for concurrent blood lead levels among children with peak blood 

lead levels above and below 10 μg/dL. 

Source: Lanphear et al. (2005). 

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Rothenberg and Rothenberg (2005) reanalyzed the Lanphear et al. (2005) pooled study to 

examine the form of the concentration-response function for the lead exposure effect on child IQ. 

This further analysis also focused on concurrent blood lead levels. Rothenberg and Rothenberg 

reported that a log-linear relationship between blood lead and IQ was a significantly better fit 

within the ranges of the blood lead levels than was a linear-linear relationship (p = 0.009), with 

little evidence of residual confounding from included model variables. However, a segmented 

linear model also offers an appropriate alternative since limited data is available at lower levels. 

The log-linear model in Lanphear et al. estimated a decline of 6.2 points in full scale IQ 

for an increase in concurrent blood lead levels from <1 to 10 μg/dL. This effect estimate was 

comparable to the 7.4 point decrement in IQ for an increase in lifetime mean blood lead levels up 

to 10 μg/dL observed in the Rochester study (Canfield et al., 2003a), as well as other studies 

reviewed above. 

6.3.2.1.2 Cross-sectional Studies of Neurocognitive Ability 

Among the cross-sectional studies reviewed in the 1986 Lead AQCD and the 1990 

Supplement, the most thorough and methodologically rigorous were those of Needleman et al. 

(1979) and Fulton et al. (1987). Needleman et al. (1979) measured lead in the dentin of 

deciduous teeth in elementary school children from two Boston area communities. After 

statistical adjustment for a number of potential confounding factors, children in the higher tooth 

lead group performed significantly less well on full scale and verbal IQ. Differences in full scale 

IQ between the high and low tooth lead groups was on the order of 4.5 points. 

The general population study by Fulton et al. (1987) studied 501 children aged 6-9 years 

in Edinburgh, Scotland who were at risk for lead exposure owing to a plumbosolvent water 

supply and a large number of houses with lead plumbing. Blood lead levels averaged 11.5 μg/dL 

(range 3-34). Following covariate adjustment, there were statistically significant relationships 

between concurrent blood lead levels and total scores on the British Ability Scale and the 

Quantitative and Reading subscales. Data showed a clear concentration-response relationship 

with no evidence of a threshold. 

Recent cross-sectional studies of neurocognitive ability are summarized in Annex 

Table AX6-3.3. Key studies are further discussed in this section. Lanphear et al. (2000) 

examined the relationship between blood lead concentrations and cognitive deficits in a 

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nationally representative sample of 4,853 children aged 6 to 16 years children who participated 

in the third National Health and Nutrition Examination Survey (NHANES III). The purpose of 

the study was to examine the relationship between low blood lead concentrations (especially 

those below 10 μg/dL) and two subtests of the WISC-R, Block Design (a measure of visualspatial skills) and Digit Span (a measure of short-term and working memory). Academic 

achievement tests also were administered but are discussed in a later section. A number of 

potential confounders were assessed and included in multivariable analyses including gender, 

racial/ethnic background, child’s serum ferritin level, serum cotinine level, region of country, 

marital status and education level of primary caregiver, and a poverty index ratio (the ratio of 

total family income, as reported by the adult informant, to the federal poverty level for the year 

of the interview). Other potential confounders such as in utero and postnatal exposure to tobacco 

smoke, birth weight, and admission to the neonatal intensive care unit were only available for 

children between 6 and 11 years of age. Therefore, the authors conducted a secondary analysis 

of the data on these children to verify that inclusion of these potentially important variables did 

not alter the findings of the main analysis using the larger sample. 

The geometric mean blood lead concentration for children in the study sample was 

1.9 μg/dL (SE 0.1). Only 2.1% of the NHANES III sample in this analysis had blood lead 

concentrations greater or equal to 10 μg/dL. In multivariate analyses, a significant covariateadjusted relationship was found between blood lead level and scores on both WISC-R subtest for 

all children as well as among those children with blood lead levels <10 μg/dL. Blood lead 

concentration also was significantly associated with Block Design when the multivariate analysis 

was restricted to children with blood lead levels <7.5 μg/dL. For a 1 μg/dL increase in blood 

lead level, Block Design scores declined by 0.10 points (SE 0.04) for all children, 0.13 points 

(SE 0.06) for children with blood lead levels <10 μg/dL, and 0.11 points (SE 0.06) for children 

with blood lead levels <7.5 μg/dL. The authors concluded that deficits in intellectual functioning 

were associated with blood lead levels <10 μg/dL. While a large number of potential 

confounding factors were controlled in these analyses, interpretation of results must be tempered 

by the fact that no data on maternal IQ or direct observations of caretaking quality in the home 

were available. Furthermore, it is not clear whether the cognitive deficits observed were due to 

lead exposure that occurred during early childhood or a function of concurrent exposure. 

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Chiodo et al. (2004) studied the relationship between blood lead concentrations and IQ, 

assessed using WISC-III, in a sample of 237 African-American inner-city children from Detroit, 

MI at 7.5 years of age. This cohort was derived from a larger study of the effects of prenatal 

alcohol exposure on child development. However, approximately 83% of children for whom 

blood lead levels were obtained had either low or no gestational exposure to alcohol. Blood lead 

levels were low with a mean of 5.4 μg/dL (SD 3.3, range 1-25). Following covariate adjustment, 

there was a statistically significant association between blood lead concentrations and full scale, 

verbal and performance IQ, with the strongest relationship observed for performance IQ. 

Significant effects of lead on full scale and performance IQ were still evident at blood lead 

concentrations below 7.5 μg/dL. Nonparametric smoothing analyses confirmed that these effects 

were linear in nature. 

Walkowiak et al. (1998) conducted a cross-sectional study examining the relationships of 

low-level lead and mercury exposure, and various measures of neurocognitive and neuromotor 

functioning in 384 children aged 6 years in three German cities. Lead was measured in blood at 

the time of testing and mercury burden was estimated from urine samples. As their measure of 

IQ, they administered two subtests of the German WISC, Vocabulary and Block Design. These 

subtests were treated separately as well as a summed index, which served as a surrogate for full 

scale IQ. Blood lead concentrations were low (geometric mean 4.3 μg/dL [95th percentile 8.9]). 

Following covariate-adjustment, Vocabulary and the combined index, but not Block Design, 

exhibited negative associations with blood lead of statistical or borderline statistical significance; 

no associations were observed for mercury. The authors concluded that these findings roughly 

correspond with those of other studies that find effects of lead exposure on measures of 

intelligence at blood lead concentrations below 10 μg/dL. However, they also caution that some 

important covariates and potential confounding variables were not measured, including parental 

IQ and home environment (e.g., HOME score). 

Rabinowitz et al. (1991) studied the relationship between lead measured in shed 

deciduous teeth (central incisors) and psychometric intelligence in 443 children in grades 1 to 3 

in Taiwan. Two of the primary schools included in the study were in proximity to primary lead 

smelters. The Ravens Colored Progressive Matrices (RCPM), a test of nonverbal reasoning that 

is widely used in studies of non-western populations because of its more culturally neutral 

properties, was administered. Studies on a subsample of 60 children residing near the lead 

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smelters revealed mean blood lead level of 13.0 μg/dL (SD 4.4). Scores on the RCPM were 

negatively correlated with tooth lead concentrations. In multivariate analyses, parental education 

was a particularly important predictor of RCPM scores, but tooth lead concentrations still 

significantly predicted lower scores on the RCPM in families occupying the lowest social strata 

and among female subjects. 

Kordas et al. (2004) examined the relationship between lead exposure and various indices 

of psychometric intelligence in a cohort of 602 first grade children attending public schools in 

Torreon, a highly industrialized city in northern Mexico. This study investigated whether leadassociated deficits in intellectual attainment might be explained by correlated nutritional factors 

such as iron status, anemia, and growth. The mean blood lead concentration was 11.5 μg/dL 

(SD 6.1). Approximately half of the children had blood lead concentrations below 10 μg/dL and 

only 20% of the subjects had blood lead levels in excess of 15 μg/dL. Subjects were 

administered Spanish or Mexican versions of the Peabody Picture Vocabulary Test-Revised 

(PPVT-R), the Cognitive Abilities Test (CAT), and subtests of the WISC-R (Coding, Digit Span, 

and Arithmetic subtests). Letter and Number Sequencing tests (adapted from the Trail Making 

Test, Trails A) also were administered. Following adjustment for sociodemographic variables, 

anemia, iron status, and growth, higher blood lead levels were significantly associated with 

poorer performance on the PPVT, WISC-R Coding, and Number and Letter Sequencing. The 

authors concluded that lead’s association with iron deficiency anemia or growth retardation 

could not explain the relationship between lead and cognitive performance. The authors 

acknowledged that a major limitation of their study is the lack of earlier measures of lead 

exposure and nutritional status, and information on potentially confounding variables such as 

parental intelligence and quality of caretaking in the home. 

Bellinger et al. (2005) reported on a study of the relationship between blood lead levels 

and IQ in 55 children aged 4 to 14 years in Chennai, India. This is the first published study that 

has investigated neurodevelopmental morbidities associated with undue lead exposure in Indian 

children. Children were recruited from a rural primary school on the outskirts of the city. The 

mean blood lead concentration was 11.1 μg/dL (SD 5.6, range 2.5-38.3). The Binet-Kamath 

Intelligence test along with other measures of neurobehavior were administered. The covariateadjusted blood lead coefficient was negative but nonsignificant, perhaps due to the small sample 

size and highly variable performance of subjects with the lowest blood lead concentrations. 

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For example, the mean IQ of children in the highest blood lead quartile was 95.6 with a SD of 

13.3 compared to 102.0 with a larger SD of 22.5 for children in the lowest blood lead quartile. 

The cross-sectional studies examining the effect of lead on neurocognitive abilities varied 

widely in study location, population, age of testing, and outcomes measured. Collectively, they 

generally concluded that blood or tooth lead levels were significantly associated with declines in 

intelligence and other neurocognitive outcomes. In addition, these associations were consistently 

observed in studies with mean blood lead levels <10 μg/dL. 

6.3.2.1.3 Meta-Analyses of Studies of Neurocognitive Abilities 

The meta-analyses of studies investigating the association between lead and 

neurocognitive abilities included results from both prospective cohort studies and cross-sectional 

studies. The studies reviewed here are summarized in Annex Table AX6-3.2. Needleman and 

Gatsonis (1990) conducted a meta-analysis of 12 studies that used multiple regression techniques 

to assess the relationship between lead levels in tissues (blood or teeth) while adjusting for 

potentially confounding variables. Studies were weighted based on sample sizes, which ranged 

from 75 to 724 children. The authors divided studies into two groups according to the type of 

tissue analyzed for lead (blood or teeth). Joint p-values and average effect sizes as measured by 

partial correlation coefficients were calculated using two different methods by Fisher and by 

Mosteller and Bush (Rosenthal, 1984). The joint p-values for the blood lead studies were 

<0.0001 for both methods while joint p-values of <0.0006 and <0.004 were obtained for tooth 

lead studies. The partial correlations ranged from !0.27 to !0.0003. Sensitivity analyses 

revealed that no single study was responsible for the significance of the final findings. The 

authors concluded that the hypothesis that lead lowers children’s IQ at relatively low dose was 

strongly supported by their quantitative analysis. 

Another meta-analysis conducted by Schwartz (1994) took a different approach. Only 

studies relating blood lead to IQ were chosen for quantitative review since the concentration of 

lead in the bloodstream is the only index of exposure that has been used as the basis for public 

health policy. Three longitudinal and four cross-sectional studies relating blood lead to IQ were 

examined. Furthermore, while the work of Needleman and Gatsonis (1990) essentially involved 

combining partial correlations, the measure of effect used in the Schwartz analysis was the 

predicted change in full scale IQ as blood lead increased from 10 to 20 μg/dL. For the 

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prospective longitudinal studies, blood lead levels at 2 years of age or average blood lead levels 

up to 3 years of age were selected for the analysis. This approach by Schwartz may be related to 

the belief at the time of the analysis that blood lead levels during the first 3 years of life were the 

most critical in determining the severity of neurodevelopmental toxicity. The exclusion of blood 

lead levels from other time points may be of issue as it appears that later blood lead levels may 

be more predictive of mental deficits (Baghurst et al., 1992; Canfield et al., 2003a; Chen et al., 

2005; Dietrich et al., 1993a; Factor-Litvak et al., 1993). Studies were weighted by the inverse of 

the variances using a random-effects modeling procedure. The estimated decrease in IQ for an 

increase in blood lead from 10 to 20 μg/dL was 2.6 points (95% CI: 1.8, 3.4). Sensitivity 

analyses indicated that the results were not determined by any individual study. Effect estimates 

were similar for longitudinal and cross-sectional studies. In another analysis, studies with mean 

blood lead concentrations below 15 μg/dL and above 15 μg/dL had estimated effect sizes of 

!3.23 points (95% CI: !5.70, !0.76) and !2.32 points (95% CI: !3.10, !1.54), respectively. 

When the study with the lowest mean blood lead level was examined in greater detail using 

nonparametric smoothing, no evidence of a threshold was observed down to a blood lead level 

of 1 μg/dL. 

Pocock et al. (1994) conducted a review of the epidemiologic evidence for lead effects on 

IQ that included a meta-analysis. For the meta-analysis, the fixed-effect method described by 

Thompson and Pocock (1992) was used. Five prospective and 14 cross-sectional studies (with 

both tooth and blood lead measures) were included. For consistency, only blood lead levels at or 

around 2 years of age were considered for the prospective studies. Their overall conclusion was 

that a doubling of blood lead levels from 10 to 20 μg/dL, or tooth lead from 5 to 10 μg/g was 

associated with an average estimated deficit in IQ of around 1 to 2 points. 

Other earlier meta-analyses of lead-IQ studies have been published but are not reviewed 

here, because later work greatly extended these efforts and included more studies, rendering 

these analyses outdated (Needleman and Bellinger, 1988; Schwartz, 1985; Thacker et al., 1992). 

The meta-analyses of studies investigating the effect of lead on neurocognitive ability 

consistently observed significant associations between blood or tooth lead levels and decrements 

in IQ. The analysis by Schwartz (1994) observed no evidence of a threshold at blood lead levels 

below 10 μg/dL. 

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6.3.2.2 Measures of Academic Achievement 

There are relatively little data on the relationship between lead exposure and objective 

measures of academic achievement. A few earlier studies reported an inverse relationship 

between lead exposure and reading skills (Fergusson et al., 1988a; Fulton et al., 1987; Yule et al., 

1981). Since the 1990 Supplement, more studies have focused on the practical consequences of 

childhood lead exposure by including measures of academic performance in their batteries. 

Studies reviewed in this section are summarized in Annex Table AX6-3.4. 

Lanphear et al. (2000) examined the relationship between blood lead levels and a 

standardized measure of academic achievement in 4,853 children aged 6 to 16 years. The source 

of data for this study was the third National Health and Nutrition Examination Survey (NHANES 

III). This cohort was previously described in Section 6.3.2.1.2. Subjects were administered the 

Arithmetic and Reading subtests of the Wide Range Achievement Test-Revised (WRAT-R). 

The WRAT-R Arithmetic subtest includes oral and written problems ranging in level from 

simple addition to calculus, while the Reading subtest assesses letter recognition and word 

reading skills. The geometric mean blood lead concentration was 1.9 μg/dL. Only 2.1% of the 

subjects had blood lead levels equal to or greater than 10 μg/dL. Multiple linear regression 

revealed a 0.70 point (95% CI: 0.37, 1.03) decrement in arithmetic scores and a 0.99 point 

(95% CI: 0.62, 1.36) decrement in Reading scores for each 1 μg/dL increase in blood lead 

concentration (p < 0.001). In the next phase of the analysis, the adjusted relationship between 

performance on WRAT subtests and blood lead concentration for children with blood lead 

concentrations <10 μg/dL, <7.5 μg/dL, <5 μg/dL, or <2.5 μg/dL were carried out. Statistically 

significant inverse relationships between blood lead levels and performance for both Reading 

and Arithmetic subtests were found for children with blood lead concentrations below 5 μg/dL. 

Secondary analysis limited to younger children with data on all covariates did not alter findings 

from the main analysis. The authors concluded that results of these analyses suggest that deficits 

in academic skills are associated with blood lead concentrations lower than 5 μg/dL. However, 

although the relationship of blood lead concentration and achievement was adjusted for 

numerous potential confounders, the study lacked information on at least two covariates that 

have been shown to be important in other lead studies (HOME scores and parental IQ). Failure 

to adjust for these variables may have underestimated or overestimated the deficits in academic 

skills related to lead. Furthermore, as with all cross-sectional studies utilizing blood lead as the 

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index of dose, it is not clear whether the deficits in academic skills were due to lead exposure 

that occurred sometime during early childhood or due to concurrent exposure. Nevertheless, 

concurrent blood lead levels likely reflect both ongoing exposure and preexisting body burden. 

Needleman et al. (1990) reexamined the Chelsea and Somerville, MA cohort of first and 

second graders recruited in the 1970s (Needleman et al., 1979). One hundred and thirty-two of 

the original 270 children were recalled. Neurobehavioral deficits in relationship to the 

concentration of lead in shed deciduous teeth had persisted into late adolescence. Subjects with 

dentin lead levels >20 ppm were at higher risk of dropping out of high school (adjusted odds 

ratio of 7.4, [95% CI: 1.4, 40.7]) and of having a reading disability (adjusted odds ratio of 5.8 

[95% CI: 1.7, 19.7]). Higher dentin lead levels also were significantly associated with lower 

class standing, increased absenteeism, and lower vocabulary and grammatical reasoning scores 

on the Neurobehavioral Evaluation System (NES). The authors concluded that undue exposure 

to lead had enduring and important effects on objective parameters of success in real life. 

Bellinger et al. (1992) administered a battery of neuropsychological tests to 148 children 

in the Boston Lead Study cohort at age 10 years. The authors administered the short-form of the 

Kaufman Test of Educational Achievement (KTEA) in addition to IQ studies. The KTEA 

assesses reading, math, and spelling skills. The primary outcome was the Battery Composite 

Score. As previously indicated, exposures in this cohort were low with a peak mean blood lead 

at 18 months of only 7.8 μg/dL (SD 5.7). The cohort had a high SES that consisted of white 

intact families with college-educated parents. Average KTEA scores in this cohort were 

approximately one standard deviation above the population mean. Nevertheless, postnatal blood 

lead levels measured at virtually all ages were significantly associated with lower KTEA Battery 

Composite Scores. However, after covariate-adjustment, including full scale IQ in the model, 

only blood lead levels at 24 months of age were significantly predictive of lower academic 

achievement. Over the range of approximately 0 to 25 μg/dL, Battery Composite scores 

declined by approximately 8.9 points (95% CI: 4.2, 13.6) for each 10 μg/dL increase in 

24-month blood lead. The specific subscales of the KTEA that were most significantly 

associated with lead were Spelling and Math. Within the Math subscale, lead appeared to be 

more strongly associated with performance on the advanced quantitative Concepts/Applications 

items than on computation. The associations between these early measures of low level 

exposure to lead and achievement were significant even after adjustment for IQ, suggesting that 

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lead-sensitive neuropsychological processing and learning factors not reflected in indices of 

global intelligence may contribute to reduced performance on academic tasks. 

Leviton et al. (1993) reported on the relationship between pre- and postnatal lead 

exposure and academic problems in approximately 2,000 children born in one Boston hospital 

between 1979 and 1980 using the Boston Teacher Questionnaire (BTQ). A teacher provided an 

assessment of each child’s academic functioning when the child reached the age of 8 years. 

Mean umbilical cord blood lead was 6.8 μg/dL and mean tooth (dentin) lead concentration was 

2.8 μg/g. There was limited information on covariate factors. However, following adjustment 

for potential confounding variables, elevated dentin lead concentrations were associated with 

statistically significant reading and spelling difficulties as assessed by the BTQ among girls. The 

authors concluded that their findings supported the case for lead-associated learning problems at 

levels prevalent in the general population. However, they added that the inability to assess childrearing quality in this questionnaire study conducted by mail limits the inferences that came be 

drawn from the findings. 

Fergusson et al. (1993) examined the relationship between dentin lead levels in shed 

deciduous teeth at 6-8 years and measures of academic attainment and classroom performance in 

a birth cohort of over 1,200 New Zealand children enrolled in the Christchurch Health and 

Development Study when they reached 12-13 years of age. This study was an extension of 

earlier work in these children indicating a relationship between low lead levels and deficits in 

academic skills around the age of 8 years (Fergusson et al., 1988a). Average dentine lead levels 

in the cohort were 6.2 μg/g (SD 6.2). Measures of academic performance included word 

recognition from the Burt Reading Test, reading comprehension from the Progressive 

Achievement Test, a general measure of scholastic skills based on children’s scores on the Test 

of Scholastic Abilities, and teacher ratings of classroom performance in the areas of reading, 

written expression, and mathematics. Following adjustment for a wide range of covariates 

(including residence in potentially lead-hazardous housing), dentin lead levels were significantly 

associated with virtually every formal index of academic skills and teacher ratings of classroom 

performance. Statistical treatment of the data included a multivariate analysis of all 12 

regression equations simultaneously using LISREL modeling methods. This conservative 

analysis clearly showed that the probability of observing these results under the null hypotheses 

that lead was unrelated to all covariate-adjusted test outcomes was extremely small. In an 

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adjunct analysis, Fergusson and Horwood (1993) examined the effects of low-level lead 

exposure on the growth of word recognition in this cohort from 8 to 12 years of age. The 

New Zealand data were analyzed using growth curve modeling methods. After adjustment for 

potential confounding variables, children with dentin lead levels equal to or greater than 8 μg/g 

displayed significantly slower growth in word recognition abilities with no evidence of catch up. 

The authors concluded that these results were consistent with their earlier analyses and suggest 

that early exposure to very low levels of lead result in small but detectable and enduring deficits 

in children’s cognitive abilities. 

Academic achievement in relationship to lead was reexamined in the New Zealand cohort 

when subjects reached 18 years of age (Fergusson et al., 1997). The sample at 18 years consisted 

of 881 subjects, or approximately 70% of the original cohort. Measures of educational 

achievement included the Burt Reading Test, number of years of secondary education, mean 

number of School Certificate passes (based on results of national examinations), and leaving 

school without formal qualifications (analogous to failure to graduate from high school in the 

U.S.). As in previous analyses, a wide range of potentially confounding sociohereditary factors 

were measured and controlled for in multivariable analyses, which included both linear and 

logistic regressions. Prior to and following covariate adjustment there were statistically 

significant concentration-response relationships between dentin lead concentrations and lower 

reading test scores, having a reading level of less than 12 years, failing to complete 3 years of 

high school, leaving school without qualifications, and mean number of School Certificates 

subjects passed. The authors conclude that their results are consistent with the view that there is 

a relationship between early exposure to low levels of lead and later educational outcomes. The 

late results of the New Zealand studies confirm the findings of Needleman et al. (1990) in a 

cohort with lower levels of exposure to environmental lead. 

Rabinowitz et al. (1992) examined the relationship between tooth lead concentrations and 

scores on BTQ clusters in 493 Taiwanese children in grades one through three. Mean lead levels 

in incisors were 4.6 μg/g (SD 3.5). Factors associated with lead and the BTQ included 13 

variables measuring perinatal, familial, and economic parameters. Prior to adjustment for 

covariates, girls in this sample with higher exposures to lead evinced a borderline significant 

trend for reading difficulties while boys displayed significantly increased difficulties with respect 

to activity levels and task attentiveness. In multiple logistic regression models, the tooth lead 

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terms failed to achieve statistical significance. The authors concluded that lead levels found in 

the teeth of children in their Taiwanese sample were not associated with learning problems or 

syndromes as assessed by the BTQ. 

Wang et al. (2002) examined the relationship between blood lead levels and class ranking 

in 934 third graders living in an urban industrial area of Taiwan. The outcome variables were 

grades for Chinese (reading and writing), Mathematics, History and Society, and Natural 

Science. To avoid the impact of teacher’s bias in grading criteria, the authors converted the 

children’s grades into class rankings. A limited number of potentially confounding factors were 

measured, including maternal education and father’s SES. Mean blood lead level was 5.5 μg/dL 

(SD 1.89). In multiple regression analyses adjusting for gender, maternal education, and father’s 

SES, blood lead was significantly associated with lower class ranking in all academic subjects. 

The major shortcoming of this cross-sectional study is the lack of control for potentially 

important confounding factors such as parental intelligence. However, the strength and 

consistency of the reported relationships suggest that relatively low levels of lead may play a role 

in lowering academic performance. 

The results of these studies strongly suggest that lead exposure plays a role in the 

academic performance of children. The effects of lead on academic achievement appear to 

include children with blood lead levels that do not exceed 10 μg/dL. 

6.3.2.3 Measures of Specific Cognitive Abilities 

Outcomes of specific cognitive abilities, in particular, the domains of Attention and 

Executive Functions, Language, Memory and Learning, and Visuospatial Processing have 

been examined in some detail in recent studies. These studies are summarized in Annex 

Table AX6-3.5. 

In the aggregate, studies suggest that lead exposure impairs a child’s ability to regulate 

attention and engage several related higher order cognitive processes that have come to be 

termed “executive functions.” Executive functions refer to strategic planning, control of 

impulses, organized search, flexibility of thought and action, and self-monitoring of one’s own 

behavior—activities that help the subject maintain an appropriate mental set in order to achieve 

an immediate or future goal (Spreen et al., 1995). In some earlier studies, increased lead 

exposure was found to be associated with a higher frequency of negative ratings by teachers 

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and/or parents on behaviors such as inattentiveness, impulsivity, distractibility, and 

impersistence in assigned tasks, as well as slow psychomotor responses and more errors on 

simple, serial, and choice reaction time tasks (e.g., Hatzakis et al., 1989; Hunter et al., 1985; 

Needleman et al., 1979; Raab et al., 1990; Winneke et al., 1990). The concept that lead may 

impact executive functions in particular is biologically plausible. The prefrontal cortex is highly 

innervated by projections of neurons from the midbrain and has the highest concentration of 

dopamine of all cortical areas. Dopamine plays a key role in cognitive abilities mediated by the 

prefrontal cortex. It has been known for some time that the dopamine system is particularly 

sensitive to lead based upon data from studies of rodents and nonhuman primates (Cory-Slechta, 

1995). 

Bellinger et al. (1994) examined a portion of the original Chelsea and Somerville cohorts 

at 19-20 years of age. The principal neurobehavioral outcomes in the investigation were scores 

on a battery of attentional measures assembled by Mirsky (1987). Higher tooth lead 

concentrations were significantly associated with poorer scores on the Focus-Execute and Shift 

factors of the battery leading the authors to conclude that early lead exposure may be associated 

with poorer performance on executive/regulatory functions, which are thought to depend on the 

frontal or prefrontal regions of the brain. 

Stiles and Bellinger (1993) administered a neuropsychological battery of tests to 10-yearolds in the Boston Lead Study cohort. A large number of assessments were made and, as the 

authors acknowledge, the number of significant associations was about equal to those that would 

be expected by chance. However, as in previous studies, tasks that assess attentional behaviors 

and executive functions tended to be among those for which lead was a significant predictor of 

performance. For example, higher blood lead concentrations at 2 years were significantly 

associated with lower scores on the Freedom from Distractibility factor of the Wechsler scales 

and an increase in the percentage of preservative errors on the Wisconsin Card Sorting Test and 

the California Verbal Learning Test. 

Canfield et al. (2003b) conducted a comprehensive examination of the relationship 

between low-level lead exposure, executive functioning, and learning in children from the 

Rochester Lead Study cohort at 48 and 54 months of age. The authors used the Shape School 

Task (Espy, 1997), which requires only knowing simple shape and primary color names. 

However, embedded in the tasks are protocols requiring inhibition, attention switching, and a 

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combination of inhibition and switching mental sets. Following covariate-adjustment, blood lead 

level at 48 months was negatively associated with children’s focused attention while performing 

the tasks, efficiency at naming colors, and inhibition of automatic responding. Children with 

higher blood lead concentrations also completed fewer phases of the task and knew fewer color 

and shape names. 

Canfield et al. (2004) also administered portions of the Cambridge Neuropsychological 

Testing Automated Battery (CANTAB) to 174 children in the Rochester cohort at approximately 

66 months. Children were tested with the Working Memory and Planning CANTAB assessment 

protocols to assess mnemonic and executive functions. Blood lead levels ranged from 

0-20 μg/dL in this cohort. Following covariate adjustment, children with higher blood lead 

levels showed impaired performance on tests of spatial working memory, spatial memory span, 

cognitive and cognitive flexibility, and planning as indexed by tests of intradimensional and 

extradimensional shifts and an analog of the Tower of London task. 

Ris et al. (2004) administered an extensive neuropsychological battery to 16-17 year old 

subjects from the Cincinnati Lead Study cohort. In addition to executive functions as assessed 

by the Wisconsin Card Sorting Test and the Rey-Osterrieth Complex Figure, other domains 

examined included attention, memory, achievement, verbal abilities, visuoconstructional skills, 

and fine-motor coordination. A factor analysis of scores selected a priori revealed five factors 

that included Attention. A strong “executive functions” factor did not emerge. Following 

covariate-adjustment, the strongest associations between lead exposure and performance were 

observed for factor scores derived from the Attention component, which included high loadings 

on variables from the Conners Continuous Performance Test. However, this relationship was 

restricted to males as indicated by a strong lead by gender interaction. This obtained gender 

interaction suggests that neuromechanisms sub-serving attention were affected by lead in this 

cohort for boys but not girls. This is not surprising given the heightened vulnerability of males 

for a wide range of developmental perturbations. A substantial gender difference in the 

incidence of Attention Deficit/Hyperactivity Disorder (ADHD) is well established, and one could 

speculate that early exposure to lead exacerbates a latent potential for such problems. 

Visual-spatial skills have also been also been explored in some depth by a few studies. 

When investigations of lead-exposed children have used global IQ measures and conducted 

subscale analyses, it has been observed that Performance IQ or subtests contributing to the 

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performance IQ (i.e., Block Design) are frequently among the most strongly associated with 

biological indices of exposure (Baghurst et al., 1992; Chiodo et al., 2004; Dietrich et al., 1993a; 

McMichael et al., 1988; Wasserman et al., 1994). Dietrich et al. (1991, 1992) have also 

observed that integrated measures of lead exposure over a child’s lifetime are most consistently 

associated with simultaneous processing abilities, cognitive functions closely associated with 

visual-spatial integration skills and right cerebral functioning (Kaufman and Kaufman, 1983). 

In addition, studies employing specific measures of visual-motor integration skills such as the 

Developmental Test of Visual Motor Integration (VMI), the Bender Visual-Motor Gestalt Test 

and other have found them to be among the most consistently associated with early exposure to 

lead (Baghurst et al., 1995; Dietrich et al., 1993b; Wasserman et al., 2000a; Winneke et al., 

1990). In a follow-up of subjects in the Cincinnati Lead Study cohort at 16 years, Ris et al. 

(2004) observed a significant association between prenatal maternal blood lead levels and 

deficits in visual-spatial and constructional skills as indexed by Visual-Constructional factor 

scores. Variables with high loadings on this factor included scores on the WISC-III Block 

Design subtests and selected variables from the Rey Osterrieth Complex Figure. 

However, it is still unclear whether the domains of attention/executive functions or visualmotor integration per se are specifically sensitive to lead. This is because there is rarely a oneto-one correspondence between performance on a focused neuropsychological test and an 

underlying neuropsychological process. Thus, for example, a low score on the Berry VMI may 

reflect singular or multiple neurobehavioral deficits, including difficulties with graphomotor 

control, visual perception, behavioral monitoring (impulsivity), or planning (executive 

functions). 

6.3.2.4 Disturbances in Behavior, Mood, and Social Conduct 

The effects of lead on behavior and mood of children has been an area of recent research. 

Studies conducted prior to 1990 clearly pointed to behavioral problems as potential sequelae of 

lower level lead toxicity in children. Several early case control studies linked lead to 

hyperactivity (David et al., 1972, 1976, 1979). Low levels of lead in blood and/or teeth have 

been associated with teacher ratings of hyperactive behavior, aggression, and attention problems 

(e.g., Fergusson et al., 1988b; Hatzakis et al., 1985; Silva et al., 1988; Thomson et al., 1989; 

Yule et al., 1984). In the seminal study by Needleman et al. (1979), children with higher 

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concentrations of lead in dentin were more likely to be rated unfavorably by teachers on the 

dimensions of hyperactivity, impulsivity, and frustration tolerance. New studies reviewed in this 

section are summarized in Annex Table AX6-3.6. 

While there is no compelling evidence that lead is directly related to ADHD, elevated 

blood or tooth lead levels have been linked to behavioral features of ADHD, including 

distractibility, poor organization, lacking persistence in completing tasks, and daydreaming 

(Bellinger and Rappaport, 2002). Bellinger et al. (1994) studied the relationship between early 

exposure to lead and problem behaviors in the classroom in a cohort of 1,782 children born at 

one hospital in Boston. Lead levels in umbilical cord blood were low (mean 6.8 μg/dL [SD 3.1]) 

as were tooth lead levels (mean 3.4 μg/g [SD 2.4]). Teachers filled out the Achenbach Child 

Behavior Profile (ACBP) which yields both broad and narrow band scales indexing externalizing 

and internalizing problems. Cord blood lead levels were not associated with the prevalence or 

nature of behavioral problems reported by teachers. However, tooth lead level was significantly 

associated with ACBP Total Problem Behavior Scores (TPBS). TPBS scores increased by 

approximately 2 points for each log unit increase in tooth lead. Statistically significant tooth 

lead-associated increases in both externalizing and internalizing scores also were noted. Each 

log unit increase in tooth lead was associated with a 1.5 point increase in scores for these 

broadband scales assessing under- and overcontrol of behavior. Only weak associations were 

noted between tooth lead concentrations and the tendency to score in the clinically significant 

range on these scales. As the authors noted, it was somewhat surprising that lead exposure was 

not more strongly related to externalizing behavior problems than with internalizing behavior 

problems. This contradicted several earlier investigations, including one by Sciarillo et al. 

(1992) described below. It may be that more attention has been accorded under controlled 

behaviors, because they are more readily visible and disruptive in settings such as the classroom. 

Therefore, internalizing problems may be part of the full spectrum of behaviors in which lead’s 

developmental neurotoxicity is expressed in children. The authors also cautioned that residual 

confounding could not be ruled out, because of the lack of covariate information on parental 

psychopathology or direct observations of the family environment—a problem not unique to this 

particular study. Nevertheless, these data are in accord with other studies that social and 

emotional dysfunction may be another expression of increased lead exposure during the early 

postnatal period. 

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Sciarillo et al. (1992) examined the relationship between early exposure to lead and child 

behavior in a cohort of 150 subjects in Baltimore, MD. Children were separated into high 

exposure (two consecutive blood lead concentrations greater than or equal to 15 μg/dL) and low 

exposure groups. Blood lead also was treated as a continuous variable in regression analyses. 

Mothers of 2-5 year old children were administered the Achenbach Child Behavior Checklist 

(CBCL) and given the Center for Epidemiologic Studies Depression scale (CESD) as a control 

measure. Mean blood lead concentrations were 28.6 μg/dL (SD 9.3) and 11.3 μg/dL (SD 4.3) in 

the high and low exposure groups, respectively. When compared to the lower exposed group, 

children with higher blood lead levels had a significantly higher mean TBPS, and internalizing 

and externalizing scores. Using regression procedures to control for maternal symptoms on the 

CESD, blood lead concentrations were still significantly associated with an increase in the 

TBPS. Children in the high exposure group were also nearly 3 times more likely to have a TBPS 

in the CBCL’s clinical range. A significantly higher percentage of these children scored in the 

clinical range for CBCL subscales measuring aggressive and destructive behavioral tendencies. 

Fergusson et al. (1993) examined the relationship between tooth lead levels and 

inattention/restlessness in the large national New Zealand study of over 1,000 children at 12 and 

13 years of age. Mothers and teachers were asked to respond to a series of items derived from 

the Rutter and Conners parental and teacher questionnaires. The selected items related to the 

degree to which the child was restless, inattentive, easily distracted, and lacking in concentration. 

At each age, an index of the subject’s propensity to inattentive and restless behavior was 

obtained by summing the total reports of attention deficit behaviors made by both teacher and 

parent respondents. Following adjustment for a wide range of sociodemographic and other 

covariate factors, a statistically significant, concentration-response relationship was observed 

between tooth lead concentrations (range 1-12+ μg/g) and the inattention/restlessness variable. 

The authors concluded that their results were consistent with the view that early mildly elevated 

lead levels were associated with small but long term deficits in attentional behaviors. 

Two prospective studies have also examined measures of early exposure to lead and 

behavioral problems as assessed by the Achenbach system. Wasserman et al. (1998) studied the 

relationship between lead exposure and behavior in the Yugoslavian prospective study. The 

study survey 379 children at 3 years of age with the parent report form of the Achenbach CBCL. 

Following covariate adjustment, concurrent blood lead levels were significantly associated with 

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scores on the Destructive Behaviors CBCL subscale, although the variance accounted for by lead 

was small compared to sociodemographic factors. As blood lead increased from 10 to 20 μg/dL, 

CBCL subscale scores increased by approximately 0.5 points. The authors concluded that while 

statistically significant, the contribution of lead to social behavioral problems in this cohort was 

small compared to the effects of correlated social factors. Burns et al. (1999) examined the 

relationship between lead exposure and children’s emotional and behavioral problems at ages 

11-13 years in the Port Pirie, Australia cohort study. After adjusting for a number of 

confounding variables, including HOME scores, maternal psychopathology and the child’s IQ, 

regression models showed that for an increase in average lifetime blood lead concentrations from 

10 to 30 μg/dL, the externalizing behavior problem score increased by 3.5 points (95% CI: 1.6, 

5.4) in boys, but only by 1.8 points (95% CI: –0.1, 11.1) in girls. In contrast, internalizing 

behavior problems were predicted to increase by 2.1 points (95% CI: 0.0, 4.2) in girls, but by 

only 0.8 points (95% CI: –0.9, 2.4) in boys. 

Recently, the question of lead’s role in delinquent and criminal behavior has been 

addressed in several investigations. Previous studies linking attention deficits, aggressive and 

disruptive behaviors, and poor self-regulation with lead have raised the prospect that early 

exposure may result in an increased likelihood of engaging in antisocial behaviors in later life. 

Denno (1990) surveyed 987 Philadelphia African American youths enrolled in the 

Collaborative Perinatal Project. Data were available from birth through 22 years of age. The 

analysis initially considered over 100 predictors of violent and chronic delinquent behavior. 

Repeat offenders presented consistent features such as low maternal education, prolonged maleprovider unemployment, frequent moves, and higher lead intoxication (although Denno does not 

indicate the level of lead intoxication in her report). In male subjects, a history of lead poisoning 

was among the most significant predictors of delinquency and adult criminality. 

Needleman et al. (1996) examined the relationship between lead exposure and several 

measures of behavioral disturbance and delinquent behavior in subjects from the Pittsburgh 

Youth Study. The Pittsburgh Youth Study is a prospective study of the developmental course of 

delinquency (Loeber et al., 1991). The population consisted of 850 boys who were prescreened 

with an instrument that measured serious and potentially indictable behaviors extracted from the 

teachers’ and parents’ CBCL. Subjects who scored above the 30th percentile on the risk score 

and an approximately equal number of subjects randomly selected from the remainder of the 

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distribution formed the sample (n = 503). Body burden of lead was measured in the tibia by 

K-shell XRF. Measures of antisocial behavior were administered at 7 and 11 years of age and 

included the Self Reported Antisocial Behavior scale (SRA), the Self Report of Delinquent 

Behavior (SRD), and the parents’ and teachers’ versions of the CBCL. Outcome data were 

adjusted for a number of covariates including mother’s IQ, SES, childhood medical problems, 

and quality of child rearing. Parents of subjects with higher lead levels in bone reported 

significantly more somatic complaints, more delinquent and aggressive behavior, and higher 

internalizing and externalizing scores. Teachers reported significant increases in scores on 

somatic complaints, anxious/depressed, social problems, attention problems, delinquent 

behavior, aggressive behavior, and internalizing and externalizing problems in the higher lead 

subjects. At 11 years, subjects SRD scores also were significantly related to bone lead levels. 

More of the high lead subjects had CBCL scores in the clinical range for the CBCL subscales 

assessing attention problems, aggression, and delinquency. Odds ratios for these outcomes 

ranged from 1.5 (95% CI: 0.45, 4.9) for parental reports of aggression to 19.5 (95% CI: 8.9, 

41.6) for attention problems. The authors concluded that lead exposure was associated with an 

increased risk for antisocial and delinquent behavior. 

Dietrich et al. (2001) reported on the relationship between early exposure to lead and 

juvenile delinquency in 195 subjects from the Cincinnati Lead Study. Subjects were between 

16 and 17 years of age when examined. As previously described, this is an inner-city cohort of 

urban children exposed to relatively high levels of lead by virtue of their residence in older, 

deteriorated housing units. Relationships between prenatal (maternal) and postnatal exposure to 

lead (through serial blood lead determinations), and antisocial and delinquent behaviors (selfand parental reports) were examined. Parents were administered a questionnaire developed 

specifically for the study while CLS subjects were given the SRD. A wide range of candidate 

covariates and confounders were examined, but the only ones predicting antisocial or delinquent 

behavior were birth weight, HOME scores, SES, and parental IQ. In multiple linear regression 

analyses, prenatal exposure was significantly associated with a covariate-adjusted increase in the 

frequency of parent-reported delinquent and antisocial acts, while prenatal and postnatal 

exposure to lead was significantly associated with a covariate-adjusted increase in frequency of 

self-reported delinquent and antisocial behaviors, including marijuana use. To clarify the 

concentration-response relationships, blood lead indices were transformed to categorical 

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variables and least-square means were calculated from an analysis of covariance procedure. 

Subjects in the highest prenatal blood lead category (>10 μg/dL) engaged in 2.3 more delinquent 

acts over the preceding 12 months than subjects in the lowest category (#5 μg/dL). Using 

average childhood blood lead levels, subjects in the medium (16-20 μg/dL) and highest 

(>20 μg/dL) category engaged in approximately 1.5 more delinquent acts compared to the lowest 

category (#10 μg/dL). Subjects in the highest 78-month blood lead category (>15 μg/dL) 

engaged in 4.5 more delinquent acts than subjects in the lowest category (#5 μg/dL). The 

authors concluded that lead might play a measurable role in the epigenesis of behavioral 

problems in inner-city children independent of other social and biomedical cofactors assessed in 

the study. 

Needleman et al. (2002) conducted a case-control study where they examined the levels of 

lead in bone of 194 adjudicated delinquents and 146 non-delinquent community controls. 

Subjects were recruited from high schools in the city of Pittsburgh and environs of Allegheny 

County, PA. Since many delinquents are not arrested or adjudicated, care was taken to ensure 

that unidentified delinquents did not populate the control group. Potential control subjects were 

excluded from the analyses if they were found to have a Juvenile Court record or an SRD score 

above the 90th percentile. Tibial bone lead was measured by K-shell XRF. Covariates included 

race, parental education and occupation, presence of two parental figures in the home, number of 

children in the home, and neighborhood crime rate. Logistic regression analyses were 

undertaken to model the association between delinquent status and bone lead concentration. 

Cases had significantly higher average concentrations of lead in tibia than controls (11.0 μg/g 

[SD 32.7] versus 1.5 μg/g [SD 32.1]). Stratified analyses revealed this was true for both white 

and African American subjects. Following adjustment for covariates, adjudicated delinquents 

were four times more likely to have bone lead concentration greater than 25 μg/g than controls 

(odds ratio of 4.0 [95% CI: 1.4, 11.1]). The effect of lead on delinquency was found to be 

substantial in this study. Bone lead level was the second strongest factor in the logistic 

regression models, exceeded only by race. In models stratified by race, bone lead was exceeded 

as a risk factor only by single parent status. The authors concluded that elevated body lead 

burdens were associated with elevated risk for adjudicated delinquency. 

The extension of lead effects into delinquent and criminal behavior is significant for both 

the individual and society as a whole. The particular biological mechanisms that may underlie 

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lead’s effects on aggression, impulsivity, and poor self-regulation are not clearly understood. 

However, lead impacts a large number of sites and processes in the brain that are involved in 

impulse control (Lidsky and Schneider, 2003). Needleman et al. (2002) proposed another 

pathway. In addition to lead’s direct impact on brain development and neuronal function, lead 

exposure may increase risk of delinquency through a separate, indirect route: impaired cognitive 

abilities and academic performance. In other words, students who have difficulties in school and 

fail to achieve academic goals are more likely to become lawbreakers. 

6.3.2.5 Sensory Acuities 

In comparison to cognitive outcomes, there has been relatively less interest in the effects 

of lead on sensory functions. However, there are clear indications that lead exposure during the 

developmental period has an impact on complex aspects of visual and auditory acuities. Much of 

this work has been carried out in animal models (Otto and Fox, 1993). Epidemiologic studies 

have typically assessed hearing thresholds and features of auditory processing in lead-exposed 

children. Studies reviewed in this section are summarized in Annex Table AX6-3.7. 

Schwartz and Otto (1987) observed significant lead-associated elevations in pure-tone 

hearing thresholds at various frequencies within the range of human speech among over 4,500 

4-19 year old subjects in NHANES II. In a later study, this finding was replicated in a sample of 

over 3,000 6-19 year old subjects in the Hispanic Health and Nutrition Examination Survey 

(HHANES) (Schwartz and Otto, 1991). An increase in blood lead from 6 to 18 μg/dL was 

associated with a 2 db loss in hearing at all frequencies, and an additional 15% of children had 

hearing thresholds that were below the standard at 2,000 Hz. These relationships continued at 

blood lead levels less than 10 μg/dL. 

Dietrich et al. (1992) assessed the relationship between scores on a test of central auditory 

processing (SCAN) and prenatal/postnatal blood lead concentrations in 215 children 5 years of 

age drawn from the Cincinnati Lead Study. Higher prenatal, neonatal, and postnatal (up to 

concurrent) blood lead concentrations were associated with more incorrect identification of 

common monosyllabic words presented under conditions of filtering (muffling). Other variables 

associated with impaired central auditory processing included the results of pure-tone 

audiometry testing, social class, HOME scores, birth weight, gestational age, a measure of 

obstetrical complications, and consumption of alcohol during pregnancy. Following adjustment 

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for these covariates, neonatal and postnatal blood lead levels remained significantly associated 

with impaired performance on the Filtered Word subtest, more prominently in the right ear. 

In the right ear, the Filtered Word subtest score decreased by 0.7 points (p < 0.05; 95% CI not 

presented) for a 10 μg/dL increase in lifetime average blood lead levels. 

Osman et al. (1999) examined the relationship between concurrent blood lead levels and 

hearing loss in 155 children 4-14 years of age living in an industrial region of Poland. Blood 

lead levels ranged from 1.9 to 28 μg/dL (median 7.2 μg/dL). Hearing thresholds increased 

significantly with higher blood lead levels at all frequencies (500-8,000 Hz). This relationship 

remained statistically significant when restricted to children with blood lead levels below 

10 μg/dL. 

A limited number of epidemiologic studies provide supportive evidence of a relationship 

between lead exposure and auditory processing. Lead-related deficits in hearing and auditory 

processing may be one plausible mechanism by which an increased lead burden might impede a 

child’s learning (Bellinger, 1995). 

6.3.2.6 Neuromotor Function 

Relatively few studies have focused on neuromotor deficits as an outcome of early lead 

exposure. However, those that have examined motor functions in lead-exposed children often 

report positive findings. Studies reviewed in this section are summarized in Annex Table 

AX6-3.8. 

In an early study, unsteadiness, clumsiness, and fine-motor dysfunctions were noted in a 

group of mildly symptomatic lead-poisoned children in Boston, with such effects persisting long 

after medical treatment (Pueschel et al., 1972). A study of moderately exposed children living in 

the vicinity of a longstanding lead smelter in Greece found that children with blood lead levels of 

35-60 μg/dL had significantly lower scores on both the Gross and Fine Motor Composite scores 

from the Oseretsky scales when compared to controls (Benetou-Marantidou et al., 1988). 

Only two modern prospective studies of lead have assessed motor development in a 

comprehensive manner. Dietrich et al. (1993b) investigated the association between lead 

exposure and motor developmental status in 245 children 6 years of age in the Cincinnati Lead 

Study cohort. Following covariate adjustment, they found that postnatal lead exposure was 

significantly associated with poorer scores on measures of bilateral coordination, visual-motor 

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control, upper-limb speed and dexterity, and the fine motor composite from the BruininksOseretsky scales. Neonatal, but not prenatal, blood lead concentrations also were significantly 

associated with poorer scores on upper-limb speed and dexterity and the fine motor composite. 

The strongest and most consistent relationships were observed with concurrent blood lead levels 

(mean 10.1 μg/dL [SD 5.6]). A 10 μg/dL increase in concurrent blood lead levels was associated 

with a 4.6 point (95% CI: 2.1, 7.1) decline in the fine motor composite score. In the same 

Cincinnati cohort, postnatal lead exposure was associated with greater postural instability as 

assessed by a microprocessor-based strain gauge platform system (Bhattacharya et al., 1995). 

When assessed at 16 years of age, 78-month postnatal blood lead levels were significantly 

associated with poorer fine-motor skills as indexed by covariate-adjusted factor scores derived 

from a factor analysis of a comprehensive neuropsychological battery (Ris et al., 2004). The 

variables loading highly on the fine-motor component came from the grooved pegboard and 

finger tapping tasks. 

Some results of the Cincinnati Lead Study were replicated by Wasserman et al. (2000a) 

in the Yugoslavian Prospective Study. The authors adapted the Bruininks-Oseretsky Test of 

Motor Proficiency for use in their population residing in two towns in the province of Kosovo. 

The measure of exposure was the log of the lifetime average blood lead concentration through 

54 months of age. Following covariate-adjustment, average childhood blood lead concentrations 

were associated with poorer fine motor and visual motor function, but were found to be unrelated 

to gross motor function. 

A recent study by Despres et al. (2005) of multiple exposures including lead, mercury, 

and polychlorinated biphenyls found that only blood lead concentrations measured at the time of 

assessment were associated with neuromotor functions in 110 preschool Inuit children residing in 

Canada. The mean blood lead level was 5.0 μg/dL (range 0.8-27.1). Blood lead levels were 

significantly associated with increased reaction time, sway oscillations, alternating arm 

movements, and action tremor. Ten percent of the children had blood lead levels greater than 

101 μg/dL. After eliminating these children from the analyses, results remained significant for 

reaction time, sway oscillations, and alternating arm movements. These findings indicated that 

neuromotor effects of lead occurred at blood lead concentrations below 10 μg/dL. 

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6.3.2.7 Brain Anatomical Development and Activity 

Electrophysiological evaluations have been conducted on lead-exposed children in 

attempts to obtain a more direct measure of the toxicant’s impact on the nervous system. Much 

of this work was conducted by Otto and colleagues during the 1980s (e.g., Otto et al., 1985). 

Studies reviewed in this section are summarized in Annex Table AX6-3.9. These studies have 

demonstrated effects of lead on neurosensory functioning (auditory and visual evoked potentials) 

within a broad range of exposures (Otto and Fox, 1993). 

Rothenberg et al. (1994) reported that higher maternal blood lead levels at 20 weeks of 

pregnancy were associated with increased I-V and III-V interpeak intervals in the brainstem 

auditory evoked response recorded in 1-month-old infants. Mean maternal blood lead level at 

20 weeks in this subsample from the Mexico City Prospective Study was only 7.7 μg/dL with a 

range of 1-30.5 μg/dL. Rothenberg et al. (2000) repeated these measurements with a larger 

group of 5-7 year old children (n = 133). In contrast to their previous findings, prenatal blood 

lead levels at 20 weeks were associated with decreased interpeak intervals. However, after 

fitting a nonlinear model to their data, they observed that I-V and III-V interpeak intervals 

decreased as blood lead rose from 1 to 8 μg/dL and increased as blood lead rose from 8 to 

30 μg/dL. The biphasic effect was only observed with maternal blood leads at 20 weeks of 

pregnancy. Increasing postnatal blood lead at 12 and 48 months was related to decreased 

conduction intervals for I-V and III-V interpeak intervals across the entire blood lead range. 

The methods of Magnetic Resonance Imaging (MRI) and Magnetic Resonance 

Spectroscopy (MRS) have recently been applied in studies of lead-exposed children. Trope et al. 

(1998) were the first to apply MRI and MRS in an evaluation of a lead-exposed subject. The 

subject was a 10 year old boy who had a history of elevated blood lead levels as a toddler (e.g., 

51 μg/dL at 38 months). The subject was compared to his 9-year-old unexposed cousin. The 

investigation was particularly focused on N-acetylaspartate, a metabolite shown to decrease in 

processes that involve neuronal and axonal loss. Both children presented with normal volumetric 

MRI, MRS revealed a significant alteration in brain metabolites, with a reduction in Nacetylaspartate:creatine ratio for both gray an white matter compared to the subject’s cousin. 

Trope et al. (2001) performed identical MRI and MRS studies on a sample of 16 subjects with a 

history of elevated blood lead levels before five years of age (23 to 65 μg/dL). Average age at 

time of evaluation was 8 years. These subjects were compared to age-matched controls 

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composed of siblings or cousins. Control subjects had blood lead levels that never exceeded 

10 μg/dL. Although all of the participants had normal MRI examinations, the lead-exposed 

subjects exhibited a significant reduction in N-acetylaspartate:creatine and phosphocreatine 

ratios in frontal gray matter compared to controls. 

Meng et al. (2005) performed MRI and MRS studies on children with blood lead 

concentrations $27 μg/dL (n = 6) and age- and gender-matched controls with blood lead 

concentrations <10 μg/dL (n = 6). The average age at time of evaluation was approximately 

11 years. Subjects came from the Anhui province in China. Lead-exposed children had an 

average blood concentration of 37.7 μg/dL (SD 5.7) while controls averaged 5.4 μg/dL (SD 1.5). 

MRS was used to measure N-acetylaspartate, choline-containing compounds, and total creatine 

in the frontal lobes and hippocampus in cases and controls. All children presented with normal 

MRI with no evidence of structural abnormalities. However, peak values of N-acetylaspartate, 

choline, and creatine in all four brain regions were reduced in lead-exposed children relative to 

controls. The authors concluded that the reduced brain N-acetylaspartate levels they observed in 

cases may be related to decreased neuronal density or neuronal loss. Furthermore, reduced 

choline signal may indicate decreased cell membrane turnover or myelin alterations that can lead 

to central nervous system hypertrophy, while lower creatine may indicate reduced neuronal cell 

viability. 

Using functional MRI (fMRI), Cecil et al. (2005) examined the influence of childhood 

lead exposure on language function in a subsample of 48 young adults from the Cincinnati Lead 

Study. At age 20-23 years, subjects performed an integrated verb generation/finger tapping 

paradigm. Higher childhood average blood lead levels were significantly associated with 

reduced activation in Broca’s area, a recognized region of speech production in the left 

hemisphere. This association remained statistically significant after adjustment for the subject’s 

latest IQ assessment. Higher childhood blood lead levels also were associated with increased 

activation in the right temporal lobe, the homologue of Wernicke’s area (an area associated with 

speech production) in the left hemisphere. The results of this study suggest elevated childhood 

lead exposure strongly influences neural substrates of semantic language function on normal 

language areas with concomitant recruitment of contra-lateral regions resulting in a striking, 

dose-dependent atypical organization of language function. 

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6.3.2.8 Gene-Environment Interactions in the Expression of Lead-Associated 

Neurodevelopmental Deficits 

The discussion of gene-environment interactions with respect to lead exposure 

encompasses differential susceptibilities with respect to race, gender, and genetic polymorphisms 

associated with lead metabolism, and neurotransmitter metabolism and function. While the 

differential effects of lead on neurodevelopment have been studied to some extent with respect to 

race and gender, very little work has been accomplished with respect to specific genetic 

polymorphisms. 

In the U.S., African-American children are at increased risk for having an elevated blood 

lead level compared with white children. For example, in the last two NHANES surveys, 

African-American children were found to have significantly higher blood lead levels than whites, 

even after adjusting for urban residential status and family income (Brody et al., 1994; Mahaffey 

et al., 1982). However, reliable differences with respect to lead’s effects on neurodevelopmental 

morbidity as a function of race have not been reported with consistency. 

Most surveys find that boys have higher blood lead levels than girls. The data are less 

clear with respect to gender-related differences in lead-associated neurodevelopmental 

morbidities. At various assessments from birth to adolescence, a greater male vulnerability has 

been noted in the Cincinnati Lead Study (e.g., Dietrich et al., 1987b; Ris et al., 2004). Data from 

a cross-sectional study in England showed that the lead-IQ deficit association was more 

pronounced in boys at 6 years of age (Pocock et al., 1987). However, in a study of 764 children 

in Taiwan, it was found that the relationship between lead exposure and IQ scores was 

substantially stronger in girls (Rabinowitz et al., 1991). In the Port Pirie cohort study, lead 

effects on cognition were significantly stronger in girls at ages 2, 4, 7, and 11-13 years 

(Baghurst et al., 1992; McMichael et al., 1992; Tong et al., 2000). 

At least two genetic polymorphisms have been identified that can influence the 

absorption, retention and toxicokinetics of lead in humans (Onalaja and Claudio, 2000). The 

ALAD gene has been the most studied but, as yet, the consequences of the different alleles for 

susceptibility to the neurodevelopmental consequences of lead exposure are unclear. Individuals 

with the ALAD12 or ALAD22 polymorphism tend to have higher blood lead levels than those 

with ALAD11. ALAD2 could increase vulnerability by raising blood lead levels or decrease it 

by maintaining lead in a sequestered state in the bloodstream. Only one pediatric study has 

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examined this directly. Bellinger et al. (1994) found that subjects with the ALAD2 

polymorphism tended to have lower dentin levels than those with ALAD1. This is consistent 

with the concept that increased affinity of the ALAD2 polymorphism inhibits entry of lead from 

the blood stream into other tissues. After adjustment for exposure level, Bellinger et al. found 

that adolescents with the ALAD2 polymorphism performed better in the areas of attention and 

executive functioning assessed in their study when compared to subjects with the ALAD1 

polymorphism. However, as there were only 5 subjects with the ALAD2 form, meaningful 

statistical comparisons could not be made. 

The other gene that has been studied is the vitamin D receptor or VDR gene. This gene is 

involved in calcium absorption through the gut. Research on lead workers has shown that 

variant VDR alleles modify lead concentrations in bone, and the rate of resorption and excretion 

of lead over time (Schwartz et al., 2000c). Haynes et al. (2003) examined the relationship 

between the VDR Fok1 polymorphism and blood lead concentrations in 275 children enrolled in 

the Rochester Longitudinal Study. It was hypothesized that children homozygous for the 

F allele—a marker for increased calcium absorption—would have higher blood lead 

concentrations than heterozygotes and children homozygous for the f allele, after adjusting for 

environmental sources of lead (floor dust lead). A statistically significant interaction was found 

between floor dust lead loading and VDR-Fok1 genotypes on blood lead concentration, with the 

FF genotypes having the highest adjusted mean blood lead concentrations at 2 years of age. 

Consistent with other reports, Haynes et al. (2003) also found that African American children 

were significantly more likely to have the VDR-FF than were non-African American children. 

The ability of African American children to have increased calcium absorption may partially 

explain the higher blood lead concentrations observed in African American children. 

Unfortunately, there have been no studies to indicate which, if any, of the VDR polymorphisms 

are associated with increased vulnerability to the neurodevelopmental toxicity of lead. 

6.3.2.9 Reversibility of Lead-related Neurodevelopmental Deficits Associated 

with Prenatal and Postnatal Exposure 

The apparent persistence of the neurodevelopmental effects of lead observed into later 

childhood and adolescence has resulted in a widely held view that the damage to the central 

nervous system and resulting deficits in neurobehavior are irreversible. The ramifications of the 

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effects of lead on neurodevelopment depend not only on the extent of the initially observable 

effects in early childhood, but also on their enduring consequences for cognition, attainment, and 

behavior over the lifetime of the individual. Studies reviewed in this section are summarized in 

Annex Table AX6-3.10. 

Since 1990, several studies attempted to eliminate or at least reduce lead-associated 

neurodevelopmental damage through nutritional and/or pharmacological interventions. 

Optimism that such interventions might be effective was raised by a New York study published 

in the early 1990s (Ruff et al., 1993). In an observational study, children 13 to 87 months old 

with blood lead levels between 25 and 55 μg/dL were given chelation with EDTA and 

therapeutic iron when clinically indicated. The children were then followed for 6 months. Those 

whose blood lead levels fell the most had improved cognitive test scores, independent of whether 

they had been given iron or chelation therapy. Prior to this publication, the National Institute for 

Environmental Health Sciences (NIEHS) was already in the process of planning a multicenter 

clinical trial to determine if a recently licensed oral chelating drug (dimercaptosuccinic acid or 

“succimer”) might diminish the neurodevelopmental impact of lead in children with blood lead 

levels between 20 and 44 μg/dL (Rogan et al., 1998). 

The Treatment of Lead-Exposed Children (TLC) study was originally designed to test the 

hypothesis that children with moderate blood lead levels who were given succimer would have 

better scores than children given placebo on a wide range of tests measuring cognition, 

neuropsychological functions, and behavior at 36 months of follow-up (Rogan et al., 2001). 

TLC enrolled 780 children from four clinical sites into a randomized, placebo-controlled, 

double-blind trial of up to three 26-day courses of treatment with succimer. Most children 

lived in deteriorating inner-city housing. Seventy-seven percent of the subjects were African 

American. Succimer was effective in lowering the blood lead levels of subjects on active drug 

during the first 6 months of the trial. However, after 1 year, differences in the blood lead levels 

of succimer and placebo groups had virtually disappeared. All data analyses were conducted on 

an intent-to-treat basis. At 36 months of follow-up, the mean IQ score on the WPPSI-R of 

children given active drug was 1 point lower than that of children administered placebo, and 

children given succimer evinced more behavioral problems as rated by the primary caregiver on 

the Conners Parent Rating Scale. Children given succimer scored marginally better on the 

Developmental Neuropsychological Assessment (NEPSY), a battery of tests designed to measure 

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neuropsychological deficits that can interfere with learning. However, all of these differences 

were statistically nonsignificant. 

Although results for the first wave of follow-up for TLC were consistently negative for 

drug effects on cognition and behavior, they were not necessarily conclusive. Lead may affect 

higher-level neurocognitive processes that are inaccessible, difficult to assess, or absent in the 

preschool age child. In older children, scores on psychometric measures are more precise and 

reliable, a wider and more differentiated range of abilities can be examined, and early academic 

performance and social functioning outside the home environment can be evaluated. Therefore, 

TLC followed the cohort into the first years of elementary education to determine whether these 

later emerging neurodevelopmental functions were spared the effects of lead in treated children 

compared to placebo controls (Dietrich et al., 2004). While remaining within the limits of 

hypothesis driven inference, a comprehensive battery of tests were administered to TLC subjects 

at 7 and 7.5 years of age. These included assessments of cognition, learning, memory, global 

intellectual attainment, attention/executive functions, psychiatric status, behavioral and academic 

conduct, neurological functioning, and motor speed. However, treatment with succimer resulted 

in no benefit in cognitive, behavioral, neurological, and neuromotor endpoints. Indeed, children 

treated with succimer fared worse than children in the placebo group in several areas, including 

linear growth, hospitalized and outpatient injury events in the first 3 years of follow-up, and 

neuropsychological deficits as assessed by the Attention and Executive Functions core domain 

score from the NEPSY. The authors concluded that these latest follow-up data confirmed their 

previous finding that the TLC regimen of chelation therapy is not associated with 

neurodevelopmental benefits in children with blood lead levels between 20 and 44 μg/dL. 

Furthermore, these results emphasize the importance of taking environmental measures to 

prevent exposure to lead in light of the apparent irreversibility of lead-associated 

neurodevelopmental deficits. 

In addition to pharmacological interventions, a few studies have attempted to remediate or 

prevent lead-associated neurodevelopmental deficits through nutritional supplementation. 

Recent studies attempting to reduce lead absorption through mineral hypersupplementation have 

been disappointing (Sargent et al., 1999). However, to date there has been only one controlled 

clinical trial involving lead-exposed children where central nervous system outcomes have been 

the focus of study. Kordas et al. (2005) and Rico et al. (2005) conducted a double-blind 

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nutritional supplementation trial among 602 first grade children in the city of Torreon in northern 

Mexico. The city is located near a metal foundry that has been a source of lead contamination in 

the community. The average blood lead concentration at baseline was 11.5 μg/dL (SD 6.1). 

About half of the children had blood lead concentrations in excess of 10 μg/dL. Subjects 

received 30 mg ferrous fumarate, 30 mg zinc oxide, both, or placebo daily for 6 months. In their 

first report, the principal outcome assessment taken at baseline and at follow-up was the parent 

and teacher forms of the Conners Rating Scales. There were no consistently significant 

treatment effects and the authors concluded that this regimen of supplementation did not result in 

improvements in ratings of behavior in lead-exposed children over 6 months. In addition to 

behavior, the authors assessed cognitive functioning with 11 tests of memory, attention, visualspatial abilities, and learning. There were no consistent or lasting differences in cognitive 

performance among treatment groups confirming the earlier conclusion that nutritional 

supplementation alone is not effective in eliminating or reducing the impact of early lead 

exposure on functional neurodevelopment. 

Children’s blood lead levels generally decline after they peak at somewhere around 

2 years of age. However, the degree of decline is a function of a number of factors including 

previously acquired body burden and sources of continuing exposure. Some observational 

studies have examined the extent to which the rate of decline in blood lead levels is associated 

with improvements in neurocognitive status. Tong et al. (1998) assessed the reversibility of the 

cognitive effects of lead in early childhood in the Port Pirie, Australia cohort study. A total of 

375 children were followed to the age of 11-13 years. Average blood lead concentrations 

decreased from 21.2 μg/dL at 2 years to 7.9 μg/dL at 11-13 years. However, scores on 

standardized measures of intellectual attainment administered at 2, 4, 7, and 11-13 years of age 

in children whose blood lead levels declined the most were not significantly improved over those 

obtained by children with a more shallow decline in body burden. 

Liu et al. (2002) made use of the TLC succimer trial data set (Rogan et al., 2001) to 

examine the question of reversibility. As reviewed above, intent-to-treat analyses revealed no 

benefits of chelation on neurodevelopmental indices beyond 6 months of treatment. Thus, the 

scores on the cognitive tests from the two treatment groups could be analyzed either within the 

treatment groups or as a whole. Data from 741 children were available for analyses. Mean 

blood lead levels in TLC subjects were 26.2 μg/dL at baseline, 20.2 μg/dL at the 6-month 

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follow-up, and 12.2 μg/dL at the 36-month follow-up. Mean declines in blood lead levels were 

6.0 μg/dL from baseline to 6-month follow-up, 14.1 μg/dL from baseline to 36-month follow-up, 

and 8.0 μg/dL from 6- to 36-month follow-ups. Blood lead levels declined more quickly in the 

first 6 months in the succimer group than in the placebo group, but the mean blood lead levels 

were very similar at baseline and at the 36-month follow-up. Prior to examining changes in 

blood lead levels in relationship to changes in cognitive test scores, it was verified that baseline 

and later blood lead levels were indeed significantly associated with deficits on measures 

administered at specific points in the study after adjustment for sociohereditary factors surveyed 

in the study including maternal IQ. Unlike in the New York study by Ruff et al. (1993), Liu 

et al. (2002) found no overall effect of changing blood lead level on changes in cognitive test 

score from baseline to 6 months. However, during the follow-up from baseline to 36 months and 

from 6 to 36 months, falling blood lead levels were significantly associated with increased 

cognitive test scores, but only because of an association in the placebo group. Cognitive test 

scores increased by 2 points overall and 4 points in the placebo group when blood lead levels 

declined by 10 μg/dL from baseline to 36 months. There is a possibility that the succimer drug 

regimen blunted the beneficial effect. Due to the inconsistency in the results, the data do not 

provide strong supportive evidence that lead-induced cognitive impairments are reversible. 

Therefore, primary prevention and preventing additional increases in blood lead levels among 

children whose blood lead levels are high remain the only effective means of dealing with 

lead toxicity. 

6.3.2.10 Periods of Enhanced Developmental Susceptibility to Central Nervous 

System Effects of Environmental Lead 

It has been difficult to identify discrete periods of development when the fetus or child is 

particularly susceptible to lead’s effects on neurodevelopment. When the prospective studies of 

lead and child development were underway, it was hoped that this methodological approach 

would be revealing. However, these studies observed that age strongly predicted the period of 

peak exposure (around 18-27 months when there is maximum hand-to-mouth activity), making it 

difficult to distinguish whether greater neurotoxic effects resulted from increased exposure or 

enhanced susceptibility at a particular age. Furthermore, children with the highest blood lead 

levels tended to maintain their rank order relative to their lower exposed peers throughout these 

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402(c) Economic Analysis Chapter 5 500
1 studies (e.g., Dietrich et al., 1993a; McMichael et al., 1988), limiting the degree to which 

2 investigators could identify any particular period of development as critical. 

3 From the perspective of human neurodevelopmental biology, one could argue that the first 

4 3 years of life should represent a particularly vulnerable period. Maximal ingestion of lead 

5 coincides with the same period of time when major events are occurring in the development of 

6 the central nervous system including some neurogenesis, rapid dendritic and axonal outgrowth, 

7 synaptogenesis, synaptic pruning, and programmed apoptosis (see Figure 6-3.4). 

8 

9 

Figure 6-3.4. Golgi-stained section of human cerebral cortex taken from equivalent 

areas of the anterior portion of the middle frontal gyrus at different ages. 

Although the packing density of cortical neurons does not appear to change, 

there is a tremendous increase in the complexity of dendritic arborizations 

with increasing age with maximal density occurring between two and three 

years of age. 

Source: Nolte (1993). 

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This belief that the first 3 years represents a critical window of vulnerability is evident in 

the lead literature (Chen et al., 2005). Two major meta-analyses of the relationships between 

childhood lead exposure and IQ focused primarily on the strength of the association between IQ 

at school age and blood lead concentrations at 2 years of age or average blood lead levels up to 

3 years of age (Pocock et al, 1994; Schwartz, 1994). Neither meta-analysis considered the 

importance of concurrent blood lead associations in older children. The focus on these particular 

age groups implied that the interpretation most consistent with the overall results was that peak 

blood lead concentration, achieved somewhere between 1 and 3 years of age, was most likely 

responsible for the cognitive effects observed years later. These meta-analyses were highly 

influenced by findings from the Boston prospective study where blood lead concentrations at 

2 years of age have been exclusively and consistently associated with lower IQ and academic 

achievement (Bellinger et al., 1992). 

This particular interpretation of the lead literature has also influenced screening programs 

(which focus on 1 and 2 year olds), clinical trials that recruit children during the first 3 years of 

life, and current interpretation of the cross-sectional literature. For example, the report by 

Lanphear et al. (2000) that school-age children enrolled in the NHANES III survey displayed a 

significant inverse relationship between concurrent blood lead concentrations and measures of 

IQ and academic achievement at blood lead concentrations below 10 μg/dL was interpreted by 

some to reflect the effects of the children’s higher blood lead concentrations when they were 

between 1-3 years of age. 

However, it is not clear that only the period of peak blood lead concentration matters in 

terms of the risks for neurodevelopmental morbidity. Other prospective studies of children with 

both high and low lead exposures found concurrent or lifetime average blood lead levels to be 

more strongly associated with school age IQ and other measures of neurodevelopment (Canfield 

et al., 2003a; Dietrich et al., 1993a,b; Tong et al., 1996; Wasserman et al., 2000b). One study 

has recently attempted to address this question directly. Chen et al. (2005) sought to clarify the 

strength of the association between IQ and blood lead at various time points, to examine whether 

the cross-sectional associations observed in school age children 84-90 months of age represented 

residual effects from 2 years of age or “new” effects emerging among these children, and how 

the change in blood lead over time is related to IQ at later ages. Chen et al. (2005) used data on 

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780 children from the previously described TLC multicenter clinical trial (Dietrich et al., 2004; 

Rogan et al., 2001) to examine these relationships. Homogeneity between the two treatment 

groups was verified. There were no statistical differences between succimer and placebo groups 

in either blood lead concentrations or cognitive scores at the time points under consideration. 

At baseline, children were given the Bayley Scales of Infant Development. The children’s full 

scale IQ at the 36-month follow-up was measured with the WPPSI-R. At the 60 month followup, IQ was assessed with the WISC-III. All neurodevelopmental outcomes were adjusted for 

clinical center, race, gender, language, parent’s education, parent’s employment, single parent 

family, age at blood lead concentration, and caregiver’s IQ. 

Figure 6-3.5 displays the mean IQ at current and subsequent ages by quartiles of blood 

lead measured at 2, 5, and 7 years of age. The concurrent blood lead concentration always had 

the strongest association with IQ. As the children aged, the relationship grew stronger. The 

peak blood lead concentration from baseline to 7 years of age was not associated with IQ at 

7 years of age. Furthermore, in models including both prior and concurrent blood lead 

concentrations, concurrent blood lead was always more predictive of IQ. Adjustment for prior 

IQ did not fundamentally change the strength of the association with concurrent blood lead 

concentration. Chen et al. (2005) found a stronger relationship between IQ at 7 years of age and 

blood lead concentration at 7 years compared with blood lead at 2 years of age. A similar 

relationship was observed between IQ and blood lead at 5 years of age. The strength of the 

cross-sectional associations increase over time, despite lower blood lead concentrations in older 

children. These data support the idea that lead exposure continues to be toxic to children as they 

reach school age, and does not lend support to the interpretation that all of the damage is done by 

the time the child reaches 2 to 3 years of age. These findings also imply that cross-sectional 

associations observed in children, such as the study recently conducted by Lanphear et al. (2000) 

using data from NHANES III should not be dismissed. Chen et al. (2005) concluded that if 

concurrent blood lead remains important until school age for optimum cognitive development, 

and if 6 and 7 year olds are as or more sensitive to lead effects as 2 year olds, then the difficulties 

in preventing lead exposure are magnified but the potential benefits of prevention are greater. 

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Figure 6-3.5. Full scale IQ test scores by previous or concurrent blood lead concentration. 

Each data point shows the mean IQ test scores of children measured at 

baseline or at two follow-ups, grouped by quartiles of blood lead 

concentration. The abscissa of each point is the middle value of each 

blood lead concentration category. 

Source: Chen et al. (2005). 

1 6.3.2.11 Effect of Environmental Lead Exposure on Neurodevelopment at the 

2 Lower Concentration Range 

3 Over the last three decades, epidemiologic studies of lead and child development have 

4 demonstrated inverse associations between blood lead concentrations and children’s IQ and other 

5 outcomes at successively lower levels. The 1986 Addendum and 1990 Supplement concluded 

6 that neurobehavioral effects were related to blood lead levels of 10 to 15 μg/dL and possibly 

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lower. In response to these data, agencies such as the U.S. Centers for Disease Control and 

Prevention and the World Health Organization have repeatedly lowered the definition of an 

elevated blood lead concentration, which now stands at 10 μg/dL (CDC, 1991; WHO, 1995). 

At the time when these policies were put in place, there were too few studies of children with 

blood lead levels consistently below 10 μg/dL on which to base an opinion as to effects at lower 

levels of exposure. Since the removal of lead from gasoline, the median blood lead 

concentration has dropped dramatically in U.S. children, permitting more studies of this nature to 

be done in recent years. Furthermore, the use of meta- and pooled analytic strategies has 

permitted investigators to get a clearer picture of effects below 10 μg/dL. 

The Rochester Prospective Study (n = 172) by Canfield et al. (2003a) is illustrative. This 

study extended the relationship between blood lead concentrations and deficits in IQ to levels 

well below 10 μg/dL. Over half of the children in this study did not have a recorded blood lead 

concentration above 10 μg/dL. Nonlinear semiparametric smoothing revealed a covariateadjusted decline of more than 7 points up to 10 μg/dL of childhood average blood lead and a 

further decline of 2 points associated with an increase from 10 to 20 μg/dL. In response to the 

Rochester findings, Bellinger and Needleman (2003) reanalyzed data from the Boston 

Prospective Study focusing on children whose blood lead levels never exceeded 10 μg/dL 

(n = 48). In their analyses, 10 year IQ was inversely related to blood lead levels at 24 months 

following adjustment for covariates. Nonparametric smoothing analyses indicated that the 

inverse association persisted at blood lead levels below 5 μg/dL. 

Perhaps the most compelling evidence for effects below 10 μg/dL comes from an 

international pooled analysis of seven prospective cohort studies (n = 1,333) by Lanphear et al. 

(2005) described earlier. Although exposures in some cohorts were high, by pooling data from 

these studies a substantial number (n = 244) of children with blood lead levels that never 

exceeded 10 μg/dL could be included in the analyses. For the entire pooled data set, the 

observed decline of 6.2 points in IQ for an increase in blood lead levels from 1-10 μg/dL 

was comparable to the decrements for an increase in lifetime mean blood lead levels from 

<1-10 μg/dL observed in the Rochester Longitudinal Study (Canfield et al., 2003a). The pooled 

analysis of Lanphear et al. also demonstrated that deficits in IQ extended to blood lead levels 

<7.5 μg/dL. Therefore, recent evidence is suggestive of effects of lead on neurocognitive 

deficits at blood lead levels below 10 μg/dL, and possibly below 7.5 μg/dL, in children. 

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6.3.2.12 Selection and Validity of Neuropsychological Outcomes in Children 

A fair amount of material has been written about methodologies for neurobehavioral 

evaluation in studies of environmental chemicals and child development (Bellinger, 2002, 2003; 

Dietrich et al., 2005). Much of the discussion has centered on the ability of neurobehavioral tests 

to detect damage to the central nervous system as a result of in utero or early postnatal 

exposures. In other words, the sensitivity of these tests to toxicity has been in question. The 

sensitivity of a neuropsychological or any other diagnostic test is defined as the proportion with 

the abnormality that the test classifies as abnormal (true positives). In the selection of 

neurodevelopmental measures in studies of lead or any other toxicant, it is clearly advantageous 

to include tests that have the best prognostic value. This is particularly important in the current 

context, because the neurobehavioral endpoints reviewed in this document are being 

incorporated into an assessment of risk (Bellinger, 2002). In addition, it is important to select 

instruments that tap into neurodevelopmental domains that have shown to be sensitive to 

particular environmental toxicants. As evident in this review, a large number of 

neuropsychological instruments, tapping a wide range of domains have proven to be sensitive to 

lower level lead exposure. Certain domains such as attention, executive functions, visual-spatial 

skills, fine-motor abilities, academic achievement (reading in particular), and externalizing 

behaviors appear to be affected by lead with some degree of consistency. However, the 

identification of behavioral phenotypes for lead has been a largely elusive goal. There are a 

number of plausible reasons for this. The sample’s SES; level, pattern and timing of exposures; 

nutritional intake; general health; educational opportunities; and the particular instruments that 

were employed in a given study probably play an important role in between-study differences 

(Bellinger, 1995; Schantz, 1996). This may be one reason why the broad net provided by global, 

multiple domain assessments of cognition such as IQ have proven to be the most consistently 

sensitive across studies of various design and sample characteristics. These measures combine 

subscales that are representative of a broad number of underlying cognitive functions; thus, they 

are likely to pick up exposure-related deficits across cohorts that differ in their functional 

expressions of toxicity (Dietrich et al., 2005). 

The validity of neuropsychological tests as indices of neurodevelopment in lead studies 

also is of concern. In psychometrics, there are various types of validity. But the validity lead 

researchers are usually most concerned about is “construct validity.” If a measure has construct 

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validity it measures what it purports to measure. Most lead researchers utilize assessments with 

proven construct validity. This means that the instruments utilized by the investigator have 

proven that they possess concurrent and predictive “criterion” validity (i.e., it relates to other 

manifestations of the construct the instrument is supposed to be measuring and predicts an 

individual’s performance in the future in specific abilities). It also means that the instrument 

possesses good “convergent validity.” This means that the test returns similar results to other 

tests that purport to measure the same or related constructs. Finally, the instrument should 

demonstrate “discriminant validity.” That is, the instrument is not measuring a construct that it 

is not supposed to measure, it discriminates. 

Bellinger (2003) states that the general literature attests to robust observations between IQ 

and important measures of life success, such as grades in school, years of education, job success, 

social status, and income (Neisser et al., 1996; Salkever, 1995). Testing is difficult depending on 

examined age, especially for infants who are in a period of rapid developmental change. Also, 

the way an infant’s cognitive function can be probed is restricted. The lack of continuity 

between their response modalities and ones that can be exploited as a child gets older is also a 

factor. Still neurobehavioral tests scores in infancy do possess strong concurrent validity. 

There many potential sources of invalidity which researchers take steps to avoid. These 

include unreliability (an instrument that, all other things being equal, yields scores that are 

unrepeatable and inconsistent) and bias (e.g., due to factors such as culture, gender). Most 

modern standardized measures of development and cognitive attainment have taken steps to 

reduce these sources of invalidity and must meet certain minimum requirements such as those 

formulated by the American Educational Research Association, American Psychological 

Association, and the National Council on Measurement in Education (American Educational 

Research Association et al., 1999). One reason that global measures of IQ have been used so 

widely is because of their outstanding psychometric properties. The Wechsler series has 

excellent reliability and validity (Groth-Marnat, 2003). For example, the average internal 

consistency for the Wechsler children’s scales across all age groups is 0.96. Test-retest 

reliability is similarly very high. The underlying factor structure of these scales has also been 

strongly confirmed. The validity of so-called experimental measures of learning and cognition is 

sometimes less certain. 

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All measurement procedures have the potential for error, so the goal of the researcher is to 

minimize it. In elementary psychometric theory, any observed test score is made of the “true” 

score plus measurement error. It is assumed that measurement errors are essentially random (the 

child’s true score may not be reflected in the observed score because of errors of administration, 

inconsistency of administration across examiners, the child’s health, or aspects of the testing 

environment that are not conducive to performance). This does not mean that lead researchers 

cannot take pains to reduce these sources of error. In fact, most modern lead researchers do 

minimize measurement error through attention to training, establishing inter-examiner reliability, 

attention to child factors, site factors, and vigilant monitoring of examiner performance 

throughout the course of a study (Dietrich et al., 2005). 

6.3.2.13 Confounding, Causal Inference, and Effect Modification of the Neurotoxic 

Effect of Lead in Children 

The major challenge to observational studies of lead’s impact on parameters of child 

development has been the assessment and control for confounding factors. By definition, a 

confounder is associated with both the exposure and the outcome, thus has the potential to 

influence the association between the exposure and the outcome. Confounding by various 

factors can be controlled for in the design phase of the study or in the analytical phase. In the 

realm of lead research, there are a wide range of potential confounders, the foremost of which is 

SES. Socioeconomic status is measured rather crudely in most studies with such indices as the 

Hollingshead Four-Factor Index of Social Position that incorporates education and income of 

both parents. However, even these so-called blunt measures often account for a great deal of the 

variance in neurodevelopmental outcomes. Given the crude nature of these measures, to control 

for confounding by SES as well as rearing environment of the child, many recent lead studies 

have incorporated more direct assessments such as the HOME scale, parental intelligence, 

parental attitude assessments, and measures of parental substance abuse and psychopathology. 

Given the relatively high correlation between indices of lead exposure and social environmental 

factors, the consistency among studies in finding effects following adjustment for these 

confounding factors is remarkable. It is important to consider the enormous experimental animal 

evidence not compromised by the possibility of confounding in examining lead effects on health 

(Bellinger, 2004; Davis et al., 1990; U.S. Environmental Protection Agency, 1986a, 1990). 

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Another problem in the analyses of data on lead and child development is the lack of 

critical consideration of which potential confounder in a particular model “owns” the variance in 

neurodevelopmental performance. Thus, for example, in the case of social class it is assumed 

that if an effect of lead is reduced to nonsignificance following adjustment for some measure of 

socioeconomic standing, the assumption is that all of the variance belongs to the confounder. 

However, in some instances this could be seen as an excessively conservative interpretation and 

raises the specter of Type II error. Social class could be seen as either a confounder or a proxy 

for exposure. Lower social class in urban children is closely linked to residence in older housing 

in poor condition that, in turn, is associated with higher levels of environmental lead (Clark et al., 

1985). If studies adjust for social class in the usual manner, the effects of the toxicant will be 

underestimated (Bellinger, 2004). One extreme example of overcontrol of this nature can be 

found in the New Zealand studies where investigators regularly “controlled” for residence in 

older “weatherboard” housing (e.g., Fergusson et al., 1988a,b). However, it is worth noting that 

even in the models including this variable lead remained a significant predictor of intellectual 

and academic under-attainment in the Christchurch Health Study. 

Most of the important confounding factors in lead studies have been identified and efforts 

have been made to control them in studies conducted since the 1990 Supplement. Invocation of 

the poorly measured confounder as an explanation for positive findings is not substantiated in the 

database as a whole when evaluating the impact of lead on the health of U.S. children 

(Needleman, 1995). Of course, it is often the case that following adjustment for factors such as 

social class, parental neurocognitive function, and child rearing environment using covariates 

such as parental education, income, and occupation, parental IQ, and HOME scores, the lead 

coefficients are substantially reduced in size and statistical significance (Dietrich et al., 1991). 

This has sometimes led investigators to be quite cautious in interpreting their study as positive 

(Wasserman et al., 1997). This is a reasonable way of appraising any single study, and such 

extreme caution would certainly be warranted if forced to rely on a single study to confirm the 

lead effects hypothesis. Fortunately, a large database of high quality studies on which to base 

inferences regarding the relationship between lead exposure and neurodevelopment exists. 

In addition, lead has been extensively studied in animal models at doses that closely approximate 

the human situation. Experimental animal studies are not compromised by the possibility of 

confounding by such factors as social class and correlated environmental factors. The enormous 

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experimental animal literature that proves that lead at low levels causes neurobehavioral deficits 

and provides insights into mechanisms is to be considered when drawing causal inferences 

(Bellinger, 2004; Davis et al., 1990; U.S. Environmental Protection Agency, 1986a, 1990). 

In addition to being a confounder, social class and related variables have been shown to 

be effect modifiers in many studies of lead and child development (Bellinger, 2000; Tong et al., 

2000). Effect modification occurs when the magnitude of an association between an exposure 

(lead) and an outcome (neurobehavior) varies across strata of some other factor (Last, 2001). 

The disadvantages that accompany poor education and underemployment have been found to 

exacerbate the effects of lead when carefully examined (Bellinger et al., 1989). Indeed, 

evaluating potential effect modifiers should be considered an important part of an overall data 

analytic plan. 

6.3.3 Summary of the Epidemiologic Evidence for the Neurotoxic Effects 

of Lead in Children 

Effects of lead on neurobehavior have been detected with remarkable consistency across 

numerous studies of various designs, populations studied, and developmental assessment 

protocols. The negative impact of lead on IQ and other neurobehavioral outcomes persist in 

most recent studies following adjustment for numerous confounding factors including social 

class, quality of caregiving, and parental intelligence. 

Three meta-analyses and one international pooled analysis of seven prospective studies 

have confirmed that exposure to lead at low dose has an effect on the intellectual attainment of 

preschool and school age children. Recent analyses examining the association of lead with 

intellectual attainment and academic performance in children with low lead exposures have 

observed effects at blood lead concentrations below 10 μg/dL. The pooled analysis by Lanphear 

et al. (2005) observed a decline of 6.2 points (95% CI: 3.8, 8.6) in full scale IQ for an increase in 

concurrent blood lead levels from 1 to 10 μg/dL. 

The effects of lead on behavior and mood of children has been an area of recent research. 

These studies have demonstrated that the impact of lead may extend into increased risk for 

antisocial and delinquent behavior. This may be a consequence of attentional problems and 

academic underachievement among children who have suffered higher exposures to lead during 

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their formative years. Several studies that have used methods of MRI and MRS to assess direct 

measures of brain damage also are suggesting evidence of harm due to lead exposure. 

Attempts to eliminate or limit lead-associated neurodevelopmental morbidities with 

pharmacological or nutritional intervention strategies have been shown to be ineffective, further 

emphasizing the importance of taking environmental measures to reduce and possibly prevent 

exposure to lead in children. 

6.3.4 Summary of Key Findings on the Neurotoxic Effects of Lead in Adults 

from the 1986 Lead AQCD 

Lead intoxication in adults occurred primarily in occupational settings with historically 

high exposure levels. In more recent times, occupational lead exposure has been reduced to 

much lower levels and is often associated with no symptoms. The symptom constellation 

associated with high levels of lead exposure include impaired memory and attention span, 

irritability, headache, muscular tremors, and hallucinations (Cantarow and Trumper, 1944) that 

may progress to signs of frank encephalopathy (Smith et al., 1938). Symptoms of lead 

intoxication begin with blood lead >40 μg/dL (Baker et al., 1979) accompanied by poorer 

performance on cognitive and visuomotor tasks, reaction time, verbal learning, and reasoning 

ability that reflect involvement of both the central nervous system and the peripheral nervous 

system (Arnvig et al., 1980; Campara et al., 1984; Grandjean et al., 1978; Haenninen et al., 1978, 

1979; Hogstedt et al., 1983; Mantere et al., 1982; Valciukas et al., 1978; Zimmermann-Tansella 

et al., 1983). Impaired occulomotor function, measured by saccade accuracy and velocity, 

depended upon the age group of the lead-exposed worker (Baloh et al., 1979; Glickman et al., 

1984; Spivey et al., 1980). 

With regard to peripheral nerve function as measured by nerve conduction studies, the 

28 studies reviewed by the U.S. EPA in the 1986 Lead AQCD found no consistent single nerve 

involved but, overall, the exposed group had slower conduction velocity at blood lead 

concentrations as low as 30 μg/dL. 

Studies reviewed in 1986 found that amyotrophic lateral sclerosis (ALS) was 

inconsistently associated with elevated lead levels in the nervous system. Chelation for 1 year 

did not did not alter elevated lead levels in the tissue of patients with motor neuron disease. 

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6.3.5 Neurotoxic Effects of Lead in Adults 

6.3.5.1 Overview of Cognitive and Psychomotor Tests Associated with Adult 

Lead Exposure 

Examination of lead effects on neurobehavioral performance in adults differs from that in 

children, since the neurobehavioral tests in adults focus on loss of abilities previously present 

rather than the lack of attainment of those abilities. Also, there is contribution of cognitive 

reserve acquired by years of education, self-education, on-the-job training, avocational, and 

non-avocational activities that increases the ability to compensate for the effects of lead exposure 

on learning new information. Medical conditions requiring medications, head trauma, and other 

neuropsychiatric conditions that impact nervous system performance have increased in 

prevalence in the adult population. These factors may increase the impact of lead exposure or be 

mistaken for the effects of lead and, therefore, must be handled in the analysis. 

As alterations in mood may be associated with lead exposure, many neurobehavioral 

batteries use self-administered questionnaires to screen for mood. The Center for Epidemiologic 

Studies Depression Scale (CES-D) screens for depression. The Profile of Mood State (POMS) 

screens for six subscales, namely anger, confusion, depression, fatigue, anxiety/tension, and 

vigor. The six mood scales of the POMS were originally validated in a clinical psychiatric 

population; thus, the factor structure needed to be validated in an occupational population. 

Factor analysis of the POMS in lead smelter workers found only two relevant factors: 

(1) “general distress,” composed of the subscales anger, confusion, depression, fatigue, and 

tension; and (2) “psychological adjustment,” which contained vigor (Lindgren et al, 1999). 

This brings into question the use of the six scales as separate outcome variables in the study of 

lead exposure. 

Neurobehavioral tests commonly used to demonstrate the effects of lead are listed below 

(for a more complete description, see Lezak, 1995). Mini-Mental-State Examination (MMSE), 

a screening tool for cognitive impairment, is a compilation of many cognitive domains including 

orientation to time and place, registration, and recall of three words, attention, language, and 

visual construction with a total possible score of 30 (Folstein et al, 1975). MMSE is sensitive to 

age and education. In 194 healthy subjects aged 40 to 89 years with 7-21 years of education, 

only 1% of the subjects obtained an MMSE score of 24/30 and none below (Bleecker et al., 

1988). MMSE errors are sensitive to age effects including delayed recall, spelling “WORLD” 

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backwards and repetition of “no ifs, ands, or buts.” With lead exposure, examination of errors is 

important to compare with age-related changes and to determine the biological plausibility of the 

effects of exposure especially when performing repeated measures of the test. 

Neurobehavioral batteries should always include a benchmark test such as Vocabulary or 

a reading test such as the Wide Range Achievement Testing for Reading (WRAT) or the North 

American Reading Test (NART) that are considered to be resistant to neurotoxic exposure. 

Results from these tests should be adjusted for in the analysis. In blue-collar workers, this may 

be a better measure of educational achievement than years of education (Bleecker et al., 2002). 

Neuropsychological batteries screening for the effects of lead usually include the 

following domains (Lezak, 1995): attention/concentration (Digit Span); conceptual and 

executive functioning (Stroop, Trails B); visuoperceptive/visuoconstructive (Block Design); 

visuomotoric (Reaction Time, Pegboard Test, Digit Symbol Substitution, Trails A); verbal 

memory (Rey Auditory Verbal Learning Test, Logical Memory, Paired Associated Learning); 

and nonverbal memory (Rey-Osterreith Complex Figure, Benton Visual Retention). When 

analyzing the association of lead exposure and test performance, adjusting for potential 

confounders is critical. Potential confounders are namely age, education (preferably a measure 

of verbal intelligence), depressive symptoms, alcohol use, and smoking. In some cases, age 

(Bleecker et al., 1997a) and education (Bleecker et al., 2002) may serve as effect modifiers. 

The association of lead and poorer neurobehavioral outcome has been found to be present only in 

older workers or those with less education. 

6.3.5.2 Neurobehavioral Effects Associated with Environmental Lead Exposure 

Exposure to chronic low levels of environmental lead and its association with effects on 

the nervous system were examined in several populations originally followed to study conditions 

associated with aging: the VA Normative Aging Study (NAS) (Payton et al., 1998; Weiskopf 

et al., 2004; Wright et al., 2003); the Study of Osteoporotic Fractures (Muldoon et al., 1996); and 

the Kungsholmen Project on aging and dementia (Nordberg et al., 2000). Studies reviewed in 

this section are summarized in Annex Table AX6-3.11. 

The VA Normative Aging Study (NAS) is a multidisciplinary longitudinal investigation 

of the aging process established in 1963 and conducted at the VA Outpatient Clinic in Boston, 

MA. The NAS cohort cannot be considered to be exclusively representing the general 

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population, as bone lead measurements are higher than expected for only environmental 

exposure and, thus, suggest the possibility of other sources such as past occupational exposure, 

diet, and drinking water (Elmarsafawy et al., 2002, Vijayalakshmi et al., 1999). 

The relationship of bone lead and blood lead to psychiatric symptoms in NAS (Rhodes 

et al., 2003) found mood symptoms for anxiety and depression potentially associated with bone 

lead levels. Education also was inversely related to bone lead; however, high school graduates 

had significantly higher general stress that may be related to SES and not lead exposure. 

Neuropsychological testing in NAS found response speed sensitive to low levels of lead 

but it was not a consistent finding in all tests measuring the same domain upon examination of 

141 healthy men with a mean age of 67 years, education 14 years. The mean blood lead level 

was 6 μg/dL, patella bone lead was 32 μg/g bone mineral, and tibia bone lead was 23 μg/g bone 

mineral (Payton et al., 1998). Vocabulary, a measure of verbal intelligence and predictor of 

neurobehavioral performance, was used as an outcome variable instead of being adjusted for as a 

potential confounder. Education was negatively correlated with bone lead and blood lead, 

suggesting other factors bedsides lead exposure may have contributed to neuropsychological 

performance. The handling of multiple comparisons was not addressed. 

Another analysis of the NAS (Wright et al., 2003) examined 736 men, mean age 68 years 

with education level of 54% high school or less. The mean blood lead was 5 μg/dL, and mean 

patellar and tibia lead levels were 30 and 22 μg/g bone mineral, respectively. The subjects had a 

mean MMSE score of 27. Relation of MMSE scores <24 (n = 41) and blood lead by logistic 

regression estimated an odds ratio of 1.21 (95% CI: 1.07, 1.36). For patella lead and tibia lead, 

odds ratios of 1.21 (95% CI: 1.00, 1.03) and 1.02 (95% CI: 1.00, 1.04), respectively, were 

observed. Risk of MMSE <24 (6% of the present population versus 1% of previously described 

healthy aging study) when comparing the lowest and highest quartiles was 2.1 (95% CI: 1.1, 

4.1) for patella lead, 2.2 (95% CI: 1.1, 3.8) for tibia lead, and 3.4 (95% CI: 1.6, 7.2) for blood 

lead. Interaction of age with patella lead and blood lead in predicting MMSE found steeper 

decreases in MMSE scores relative to age in the higher quartiles of patella lead and blood lead. 

Types of errors on the MMSE were not included. It was not addressed how medical conditions 

and medications that occurred over the duration of the study and could potentially affect 

cognitive performance were handled. If the community dwelling population in NAS 

(Wright et al., 2003) had older individuals with chronic medical conditions and less education 

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(213 subjects had an education less than high school) living in areas with higher past lead 

pollution, the confounding may be impossible to sort out. 

Weisskopf et al. (2004) expanded the MMSE study in NAS by examining 466 men, mean 

age 70 years who had completed the MMSE twice with an interval of approximately 3.5 years. 

Mean blood lead was 4 μg/dL, and mean patella and tibia bone lead were 23 and 19 μg/g bone 

mineral, respectively. Baseline mean MMSE score was 27 and mean change in MMSE score 

over 3.5 years was 0.3 points. Even though MMSE change was significantly associated with 

bone lead, a change in MMSE score by a fraction of a point does not constitute a meaningful 

change of cognitive performance. To address the biological plausibility of change in the MMSE 

over 3.5 years, errors by functional domain need to be identified to rule out the possibility of 

random change with repeat performance. 

Muldoon et al. (1996) studied participants in the Study of Osteoporotic Fractures for an 

association of nonoccupational lead exposure and cognitive function. The Study of Osteoporotic 

Fractures began in 1986 and included women over age 65 years living in four different 

communities – Baltimore, MD; Portland, OR; Minneapolis, MN; and the Monongahela Valley 

outside of Pittsburgh, PA. A sample of 325 women from rural sites with a mean age of 71 years 

(mean blood lead 4.5 μg/dL) and 205 women from urban sites with a mean age of 69 years 

(mean blood lead 5.4 μg/dL) were examined. The urban group was more educated and had 

higher use of cigarettes and alcohol. Performance examined by blood lead groups adjusting for 

age, education, smoking, and alcohol use found no significant differences in the urban group. 

However, in the rural group, individuals with blood lead >7 μg/dL had significantly poorer 

performance when compared to those with blood lead <4 μg/dL for Trails B, Digit Symbol, and 

Reaction Time. Response time across blood lead groups increased for the rural group and 

decreased or remained the same for the urban group. Mean MMSE for the whole population was 

25, with poorer performance in the rural groupCthus, suggesting an increased prevalence of 

clinical cognitive disorders of another etiology. Even though the neuropsychological battery was 

simple, 9 participants were unable to perform some of the tests including 3 on the MMSE. 

Such severe impairments were not found with higher occupational exposures, which raises the 

question as to whether other factors not measured accounted for these differences attributed to 

blood lead. 

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In the Kungsholmen Project on aging and dementia in Stockholm, Sweden, no 

relationship was found between blood lead and MMSE (Nordberg et al., 2000). The study 

population included 762 participants with a mean age of 88 years. The mean blood lead in this 

group was 3.7 μg/dL and the mean MMSE was 25. In contrast to the other populations 

examined, this study cohort was more homogenous, comprised entirely of elderly Swedes. 

Their likelihood of prior exposure to elevated lead levels was low. 

Overall, these studies of environmental lead exposure in adults are difficult to interpret, as 

many competing risk factors for neurobehavioral performance in the elderly were not considered. 

Also, bone lead levels were higher than expected from environmental exposure suggesting 

unrecognized previous occupational exposure. The association of bone lead with 

neurobehavioral performance was unusual, in as much as it was not demonstrated in studies of 

occupational exposure (reviewed below). At this time, these studies do not demonstrate that the 

aging nervous system is at increased risk for poorer neurobehavioral performance related to 

environmental lead exposure as reported in children. 

6.3.5.3 Neurological Symptoms Associated with Occupational Lead Exposure 

Studies reviewed in this section are summarized in Annex Table AX6-3.12. Several 

occupational studies found blood lead levels of 29-43 μg/dL associated with POMS subscales 

(H@nninen et al., 1998; Maizlish et al., 1995; Niu et al., 2000). However, other studies with 

blood lead levels of 27-38 μg/dL found no relationship with POMS (Chia et al., 1997; Lucchini 

et al., 2000; Osterberg et al., 1997; Stollery et al., 1989). A screen for depression, CES-D, was 

administered to 803 lead-exposed Korean workers. CES-D was significant associated with tibia 

lead (mean 37 μg/g bone mineral), but not with blood lead (mean 32 μg/dL), after adjusting for 

covariates (Schwartz et al., 2001a). 

Dimercaptosuccinic acid (DMSA)-chelatable lead reflects the mobilizable fraction of lead 

in the soft tissue. Korean lead-exposed workers (n = 95) with DMSA-chelatable lead (mean 

289 μg) above the median of 261 μg were 6.2 times more likely to have tingling or numbness in 

their extremities, 3.3 times more likely to experience muscle pain, and 3.2 times more likely to 

feel irritable (Lee et al., 2000). The workers with higher chelatable lead were 7.8 times more 

likely to experience neuromuscular symptoms compared to workers with lower chelatable lead. 

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aminolevulinic acid (ALAD) in urine (mean 3 mg/L) predicted inability to sleep; however, blood 

lead (mean 45 μg/dL) was not significantly associated with any symptoms. 

In some studies, difficulty concentrating, irritability, fatigue, muscle pain, and joint pain 

were more likely in workers with a mean blood lead of 43 μg/dL (Maizlish et al., 1995) and 

27 μg/dL (Lucchini et al., 2000), whereas other studies with mean blood lead >30 μg/dL found 

no association with symptoms (Chia et al., 1997; Osterberg et al., 1997). Lucchini et al. (2000) 

provided an estimated threshold of blood lead 12 μg/dL for significant increase of neurological 

symptoms. 

In summary, even though one study suggested a threshold for neurological symptoms at a 

blood lead of 12 μg/dL (Lucchini et al., 2000), other studies with blood lead >30 μg/dL found no 

association with lead-related symptoms. The study by Lee et al. (2000) observed that higher 

levels of DMSA-chelatable lead was associated with irritability, tingling or numbness in their 

extremities, muscle pain, and neuromuscular symptoms. 

6.3.5.4 Neurobehavioral Effects Associated with Occupational Lead Exposure 

Studies reviewed in this section are summarized in Annex Table AX6-3.13. Discriminate 

analysis of neurobehavioral performance found the group of tests that best differentiates leadexposed workers (mean blood lead 49 μg/dL) from nonexposed workers were Simple Reaction 

Time (SRT), Digit Symbol (WAIS), and Trail Making Test (Part A) (Boey et al., 1988). Using a 

similar battery with 44 lead-exposed workers, mean blood lead 29 μg/dL, performance was 

significantly associated with blood lead for SRT, digit symbol and pursuit aiming (Niu et al., 

2000). 

Seventy workers grouped by blood lead (<20, 21-40, and 41-80 μg/dL) were examined on 

three occasions each separated by 4 months. Performance on reaction time was stable except in 

the high lead group where decision time was slowed more than movement time along with 

concentration difficulties that remained consistently across testing sessions. Memory testing did 

not improve with repetition in the high lead group (Stollery et al., 1991). Decision gaps as 

opposed to movement gaps were selectively affected by lead exposure in this population 

(Stollery, 1996). 

A review of occupational lead exposure in 1995 (Balbus-Kornfeld et al., 1995) concluded 

that the association of cumulative lead exposure or body burden of lead and neurobehavioral 

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performance in adults was inadequately covered in the literature. Studies have addressed these 

deficiencies with the use of a working lifetime integrated blood index and bone lead 

concentrations. Even though exposure assessment has improved, there is variability based upon 

differences in past exposure versus present exposure, duration of exposure, frequency of 

monitoring for blood lead, lead exposure from other occupational sources and nonoccupational 

activities. Measurement of bone lead addresses some of these problems but the relationship of 

bone lead concentration and lead levels in the brain or peripheral nervous system is inconsistent. 

Subsequent studies used measures of cumulative lead exposure, namely lifetime 

integrated blood index, weighted average blood lead, and bone lead. More consistent 

associations occurred with the lifetime integrated blood index and weighted average blood lead 

for visuomotor/visuoperceptive tasks of Pegboard, Pursuit Aiming, Digit Symbol, Trails, and 

Block Design (Bleecker et al., 1997a; Chia et al., 1997; H@nninen et al., 1998; Lindgren et al., 

1996; Schwartz et al., 2005) while others found no association with these lead exposure 

measures (Lucchini et al., 2000; Osterberg et al.,1997; Schwartz et al., 2001a). Age served as an 

effect modifier for the association of the lifetime integrated blood index with pegboard (Bleecker 

et al., 1997a). 

One difficulty with cumulative lead dose is the inability to separate the effect of past high 

exposure from a lower proximate exposure. To address this issue, workers with similar past high 

exposure were grouped by those with proximate exposure above blood lead of 40 μg/dL and 

those with proximate exposure below blood lead of 40 μg/dL and were compared on 

performance of verbal memory (Lindgren et al., 2003). Use of regression analyses found pattern 

group contributed significantly to the explanation of variance in verbal memory after adjusting 

for current blood lead and lifetime integrated blood index measures. The relationship between 

past high exposure and verbal memory no longer existed in the group that maintained proximate 

blood lead below 40 μg/dL, suggesting the possibility of reversibility of the effects of lead in 

adults. 

The first study to report the effects of cumulative lead exposure on the nervous system 

examined 467 Canadian lead smelter workers, with a mean of 18 years of employment (Lindgren 

et al., 1996). Their mean blood lead level was 28 μg/dL, the weighted average blood lead level 

was 40 μg/dL, and the lifetime integrated blood index was 765 μg·year/dL. Fourteen 

neuropsychological variables were examined by MANCOVA using exposure groups of high, 

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medium, and low. The analysis was adjusted for age, education, years employed, CES-D, and 

alcohol use. Exposure groups categorized using lifetime integrated blood index differed 

significantly on digit symbol, logical memory, Purdue dominant hand, and Trails A and B. 

No concentration-response relationship between blood lead and neuropsychological performance 

was found. From this smelter population, 256 workers currently employed had a median MMSE 

score of 29 (range 19-30). A concentration-response relationship between lifetime integrated 

blood index and MMSE was found only in the 78 workers with a WRAT-R reading grade level 

less than 6. The absence of a concentration-response relationship in workers with higher reading 

grade levels and the same lifetime integrated blood index dose was attributed to increased 

cognitive reserve (Bleecker et al., 2002). An in-depth examination of verbal learning and 

memory in this same population found no association with blood lead. However, increasing 

lifetime integrated blood index or weighted average blood lead was associated with poorer 

storage and retrieval of previously learned material. Alterations in the ability to organize 

materials in long-term memory interfered with retrieval efficiency (Bleecker et al., 2005a). 

The one test sensitive to blood lead in this smelter population was simple reaction time that had a 

curvilinear relationship with slowing beginning at a blood lead of approximately 30 μg/dL 

(Bleecker et al., 1997b). 

Fifty-four lead battery workers were stratified by those whose blood lead never exceeded 

50 μg/dL (n = 26) and those who had higher exposure in the past (n = 28) to examine the 

neuropsychological effects of current low level blood lead versus those of higher blood lead in 

the past (H@nninen et al., 1998). Partial correlations controlling for age, sex, and education in 

the low group found block design, digit symbol, digit span, similarities, Santa Ana 1, and 

memory for design associated with recent measures of exposure and embedded figures with 

maximum blood lead (mean maximum blood lead 40 μg/dL). Embedded figures, digit symbol, 

block design, and associative learning were associated with the lifetime integrated blood index 

(mean 823 μg·year/dL) and maximum blood lead (mean 69 μg/dL) in the high blood lead group. 

There was essentially no association with bone lead in either group. A concentration-response 

relationship existed for digit symbol, embedded figures, and memory for design. Overall past 

high exposure with blood lead levels >50 μg/dL had the greatest effect on tests requiring the 

encoding of complex visually presented stimuli. The authors concluded that the effect of lead on 

brain function was better reflected by history of blood lead than content of lead in bone. 

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However, some studies that included measures of cumulative lead and current lead 

exposures found the strongest association with current blood lead. Schwartz et al. (2001a) 

examined the associations of blood lead, DMSA-chelatable lead, and tibia lead with 

neurobehavioral tests in 803 Korean lead-exposed workers from a variety of industries and 

135 controls. In lead-exposed workers, the mean blood lead level was 32 μg/dL, DMSAchelatable lead level was 186 μg, and bone lead levels was 37 μg/g bone mineral, compared to 

controls with a mean blood lead level of 5 μg/dL and bone lead level of 6 μg/g bone mineral. 

Compared to controls, lead-exposed workers performed significantly worse on SRT, Digit Span, 

Benton Visual Retention, Colored Progressive Matrices, Digit Symbol, and Purdue Pegboard 

after controlling for age, gender, and education. The association of DMSA-chelatable lead with 

test performance became nonsignificant after the addition of blood lead in the model. Bone lead 

was not associated with neurobehavioral performance. Blood lead was the best predictor 

for significant decrements in neurobehavioral performance on Trails B, Purdue Pegboard 

(4 measures) and Pursuit Aiming (2 measures). The effect of a 5 μg/dL increase in blood lead 

was equivalent to an increase of 1.05 years in age. Use of LOWESS functions suggested a 

threshold at blood lead 18 μg/dL after which there is a decline of performance in Purdue 

Pegboard (assembly) and Trails B. 

From the above cohort of Korean lead workers, 212 consecutively enrolled workers were 

examined for protein kinase C (PKC) activity and the relations between blood lead and 

neurobehavioral performance (Hwang et al., 2002). Blood lead range from 5 to 69 μg/dL was 

associated significantly with decrements in Trails B, SRT, and Purdue Pegboard (3 measures). 

PKC activity, as measured by back-phosphorylation of erythrocyte membrane proteins, was not 

associated with neurobehavioral test scores. Addition of the interaction term of blood lead with 

PKC activity dichotomized at the median found significant effect modification with the 

association of higher blood lead and poorer neurobehavioral performance occurring only among 

workers with lower PKC activity that corresponds to higher in vivo PKC activity. The authors 

suggested that PKC activity might identify a subpopulation at increased risk of neurobehavioral 

effects of lead. 

Occupational lead exposure and longitudinal decline in neurobehavioral performance was 

examined in 576 current and former Korean lead workers who completed testing at three visits at 

approximately yearly intervals (Schwartz et al., 2005). At baseline, the mean blood lead was 

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31 μg/dL and the mean tibia lead was 38 μg/g bone mineral. Blood lead from baseline correlated 

with those from visit 2 and 3 and baseline tibial lead correlated with that measured at visit 2. 

Cross-sectional associations of blood lead or short-term change occurred with Trails A and B, 

Digit Symbol, Purdue Pegboard (4 measures), and Pursuit Aiming after adjusting for potential 

confounders. However, longitudinal blood lead was only associated with poorer performance on 

Purdue Pegboard (4 measures). Historical tibial bone lead was associated with digit symbol and 

Purdue Pegboard (dominant hand). Magnitude of lead associations was expressed as the number 

of years of increased age at baseline that was equivalent to an increase of lead from the 25th to 

75th percentile. The effect of cross-sectional blood lead at baseline was equivalent to 3.8 years 

of age, 0.9 years of age for historical tibial lead, and 4.8 years of age for longitudinal blood lead. 

In summary, performances on visuomotor and verbal memory tasks are consistently 

associated with occupational lead exposure. In several studies, cumulative blood lead index was 

found to be a strong predictor of neurobehavioral performance. Lead concentrations in bone 

were a weaker predictor of lead effects on brain function. 

6.3.5.5 Neurophysiological Function and Occupational Lead Exposure 

A meta-analysis including 32 nerve conduction studies with occupational lead exposure 

found blood lead to be a weak predictor of peripheral nerve impairment (Davis and Svendsgaard, 

1990). Nerve conduction velocities were reduced in lead-exposed subjects, with the greatest 

sensitivity observed in the median motor nerve. Decreasing effect sizes were observed with 

increasing duration of exposure. Meta-analyses of neurobehavioral effects in adults are 

presented in Annex Table AX6-3.14. 

Studies reviewed in this section are summarized in Annex Table AX6-3.15. Nerve 

conduction studies of workers in a lead battery factory (Kovala et al., 1997) found sensory 

amplitudes of the median and sural nerves had a negative correlation with long-term exposure 

(lifetime integrated blood index and duration of exposure). Chia et al. (1996b) also found the 

strongest concentration-response relationship between median sensory conduction velocity and 

lifetime integrated blood index. He et al. (1988) found sensory conduction abnormalities related 

to blood lead levels. 

Yokoyama et al. (1998) measured the distribution of conduction velocities in large 

myelinated fibers of the sensory median nerve twice at a year interval in 17 gunmetal workers. 

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In workers with a 1-year change in chelatable-lead (mobilized lead) greater than 440 μg/24 h, 

conduction velocities of faster fibers were decreased significantly. Measure of body burden 

(readily mobilized lead from soft tissue) was a stronger predictor of peripheral nerve impairment 

than blood lead. 

A group of studies examined vibration threshold in the extremities (Chuang et al., 2000; 

Kovala et al., 1997; Schwartz et al., 2001a, 2005). In 60 workers exposed to lead, Kovala et al. 

(1997) found vibration threshold at the ankle related to the lifetime integrated blood index and 

duration of exposure while the finger vibration threshold was associated with current blood lead 

exposure. Overall historical blood lead measures were more closely associated with peripheral 

nerve function than bone lead in this population. By contrast, Schwartz et al. (2001a) also 

examined vibration thresholds and bone lead in 803 Korean workers and 135 controls and found 

that tibia lead (mean 37 μg/g bone mineral) but not blood lead (mean 32 μg/dL) was significantly 

associated with poorer vibration threshold in the dominant great toe but not the finger. In a 

follow-up study of 576 lead workers who completed three visits at yearly intervals, vibration 

threshold in the toe was associated with current blood lead (mean 31 μg/dL), longitudinal blood 

lead, and tibia lead (38 μg/g) after adjusting for covariates (Schwartz et al., 2005). Chuang et al. 

(2000) reported on vibration perception in the foot in 206 lead battery workers. There was a 

significant association with blood lead (mean 28 μg/dL) and weighted average blood lead (mean 

32 μg/dL) with vibration perception in the foot after adjustment for covariates including the use 

of vibrating hand tools. A hockey stick regression analysis of foot vibration threshold versus 

mean blood lead concentration for the past 5 years found an inflection point around 30 μg/dL 

with a positive linear relation above this point, suggesting a potential threshold. 

Bleecker et al. (2005b) examined peripheral nerve function in 80 smelter workers using 

Current Perception Threshold (CPT), a neuro-selective test that measures integrity of the large 

and small myelinated nerve fibers and unmyelinated nerve fibers. CPT was not associated with 

blood lead (mean 26 μg/dL) or bone lead (mean 40 μg/g bone mineral). CPT for large 

myelinated nerve fibers had a curvilinear relationship with weighted average blood lead (mean 

42 μg/dL), with a threshold observed at 28 μg/dL. Results from further regression analyses 

suggested that even with cumulative lead exposure, intensity is more important than duration of 

exposure to lead with regard to the peripheral nervous system. At the highest criterion blood 

lead level, both large and small myelinated nerve fibers were impaired. The presence of 

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activated motor units, equated to ergonomic stressors by job title, enhanced the effect of lead on 

the peripheral nervous system. 

In summary, occupational lead exposure studies consistently found peripheral sensory 

nerve impairment as opposed to the classic motor neuropathy described historically with high 

lead exposure. A possible threshold for this effect on the sensory nerves was observed at a blood 

lead of 28 μg/dL. 

6.3.5.6 Evoked Potentials and Occupational Lead Exposure 

Visual evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs) 

measure speed of conduction in the visual and auditory pathway. BAEPs have discrete 

waveforms with wave I arising from the auditory nerve; its latency reflects peripheral 

transmission time. Wave III is predominantly generated from the caudal pons and wave V from 

the inferior colliculus. The use of interpeak latencies removes abnormalities in the auditory 

nerve latency from changes in brainstem transmission in the auditory pathway. Studies reviewed 

in this section are summarized in Annex Table AX6-3.16. 

Abbate et al. (1995) performed VEPs on 300 lead-exposed men (aged 30 to 40 years) in 

good health with no other neurotoxic exposure. Range of blood lead levels was 17 to 60 μg/dL. 

Individuals were stratified into 4 groups with mean blood lead levels of 23 μg/dL (n = 39), 

30 μg/dL (n = 113), 47 μg/dL (n = 89), and 56 μg/dL (n = 59). P100 latency measured for VEPs 

were significantly prolonged across the blood lead groups. Linear regression found the 

association of blood lead and P100 were significant in each group, but the relationship was not 

proportional. Prolonged VEP began at a blood lead levels of 17-20 μg/dL. With age limited to 

one decade, contribution from age was not a concern. Even though there was no comparison 

group, careful screening ruled out other medical and eye conditions, and other potential 

exposures. 

BAEPs recorded in 49 lead-exposed workers and age and sex matched controls (Discalzi 

et al., 1992) had mean blood lead levels of 55 μg/dL and a mean weighted average blood lead 

level of 54 μg/dL. Interpeak latencies, I-V, I-III, and III-V were all prolonged in the 

lead-exposed workers. In those workers with weighted average blood lead >50 μg/dL, I-V 

latency was longer. Discalzi et al. (1993) reported identical results in a subsequent publication 

of 22 battery storage workers with a mean blood lead of 47 μg/dL and a mean weighted average 

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blood lead of 48 μg/dL. Holstein et al. (1986) examined 20 adults accidentally exposed to lead 

through food until 1 year prior to the study. On the day of examination, the mean blood lead 

level was 31 μg/dL, while the mean weighted average blood lead was 43 μg/dL. Latencies I, III, 

and I-III interpeak intervals were longer in the exposed group with a concentration-response 

relationship observed for the weighted average blood lead and I-III interpeak interval. 

BAEPs were performed in 359 currently-employed smelter workers with a mean of 

17 years of employment. The mean blood lead levels was 28 μg/dL (SD 8.4), mean workinglifetime weighted average blood lead was μg/dL 39 (SD 11.9), and working-lifetime integrated 

blood lead index was 719 μg·year/dL (SD 421.0) (Bleecker et al., 2003). After adjusting for the 

contribution of age, blood lead and weighted average blood lead were significantly associated 

with Wave I, while lifetime integrated blood index was significantly associated with Wave III 

and I-III interpeak interval. Four groups similar in age were created with increasing 

abnormalities based upon clinical cut-off scores for wave I latency and I-V interpeak interval. 

Blood lead, weighted average blood lead, and lifetime integrated blood index were all 

significantly higher in the group with prolonged Wave I and I-V interpeak interval compared to 

the group with normal BAEPs. 

In summary, one detailed study found blood lead associated with prolonged VEPs with a 

threshold effect at 17-20 μg/dL. The four studies examining BAEPs and lead exposure 

consistently found prolonged interpeak latencies in the brainstem auditory pathway more 

strongly associated with cumulative or average blood lead exposure. 

6.3.5.7 Postural Stability, Autonomic Testing, and Electroencephalogram (EEG) 

and Occupational Lead Exposure 

Postural sway measures balance or steadiness on a force platform. It is a complex task 

that requires the integration of visual, vestibular, and peripheral sensory inputs, as well as motor 

output. No standard protocol is used across studies. Studies reviewed in this section are 

summarized in Annex Table AX6-3.17. 

Postural sway was evaluated in 49 chemical workers exposed to lead stearate, with a mean 

blood lead of 18 μg/dL, a mean weighted average blood lead of 24 μg/dL and a mean cumulative 

blood lead of 391 μg·year/dL (Yokoyama et al., 1997). Twenty-three controls were also 

examined. After adjustment for covariates, a concentration-response relationship was observed 

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for blood lead and sway in the anterior-posterior direction and for weighted average blood lead 

with right to left sway. The authors concluded that change in the vestibulocerebellum was 

affected by blood lead while the anterior cerebellar lobe was affected by average lead exposure. 

Chia et al. (1994) measured postural sway parameters in 60 lead storage battery workers 

(mean blood lead 36 μg/dL) and 60 controls (mean blood lead 6 μg/dL). Computerized postural 

sway measurements showed that lead workers had poorer postural stability that increased with 

eyes closed but no concentration-response association was observed with blood lead. A second 

publication examined cumulative blood lead over 10 years and found that lifetime integrated 

blood index for the 2 years prior to testing was associated with all postural sway parameters with 

eyes closed (Chia et al., 1996c). 

Postural control measured in 63 lead battery workers (mean past blood lead 38 μg/dL) 

indicated significantly increased mean body oscillations with eyes closed and head tilted forward 

(Ratzon et al., 2000). Total lead exposure was significantly associated with increased body 

oscillations with head tilted forward after adjusting for education, coffee consumption, hours of 

sleep, and estimate of health. In order to maintain balance, lead-exposed workers required 

increased oscillations when visual and vestibular inputs were altered. 

The effects of lead on the cardiac autonomic nervous system, expressed as the decrease of 

R-R interval variation on an electrocardiogram, was examined in 172 male lead-exposed workers 

(mean blood lead 36 μg/dL) (Teruya et al., 1991). A significant blood lead concentration-related 

decrease of R-R interval variation during deep breathing was present in 132 workers with stable 

blood lead over the past year. An approximate threshold effect was found at blood lead 

$20 μg/dL. Similar findings were reported by Niu et al. (2000) in 44 lead exposed workers who 

had a mean blood lead of 29 μg/dL. 

One hundred twenty-eight workers in the ceramic painting industry (mean blood lead 

13 μg/dL) were monitored for measures of sympathetic nerve function by variations in R-R 

interval on electrocardiography and changes in finger blood flow with postural changes using 

Doppler flowmetry (Ishida et al., 1996). No significant association was found between blood 

lead levels and the results of the neurophysiological tests, except for change in finger blood flow. 

Increased blood lead was associated with decreased changes in finger blood flow. 

Sixty workers in a lead battery factory examined with quantitative electroencephalographs 

found alpha and beta frequencies were more abundant in workers with higher long term lead 

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exposure (Kovala et al., 1997). Biomarkers of long-term lead exposure included tibia bone lead 

(mean 26 μg/g), calcaneal bone lead (mean 88 μg/g), lifetime integrated blood index (mean 

546 μg·year/dL), and weighted average blood lead (mean 32 μg/dL). The finding of slow alpha 

activity positively correlated with lead exposure may reflect increased episodes of 

“microdrowsiness” in workers with higher lead exposure. In the study by Niu et al. (2000), 

quantitative electroencephalographs in 44 lead-exposed workers (mean blood lead 29 μg/dL) 

indicated significantly increased beta activity and diminished amplitudes abnormalities in 81% 

of exposed workers. 

In summary, postural sway is associated with lead exposure at blood lead levels 

<40 μg/dL, and is believed to be caused by the effect of lead on the cerebellum. A standard 

protocol was not employed across the studies. Parasympathetic and sympathetic integrity is 

compromised in lead-exposed workers beginning at blood lead >20 μg/dL. Quantitative 

electroencephalographs found increased beta activity associated with lead exposure. 

6.3.5.8 Other Neurological Outcomes Associated with Lead in Adults 

Studies reviewed in this section are summarized in Annex Table AX6-3.18. The 1986 

Lead AQCD concluded that the evidence for an association of lead and ALS or motor neuron 

disease was inconsistent. The subsequent publications remain mixed but more studies are 

reporting an association. Using 109 cases of ALS and 256 controls matched for age, gender, and 

region of residence, Kamel et al. (2002) examined the relation of lead and ALS using blood lead 

and bone lead levels. Ranges of exposure were <1 to 14 μg/dL for blood lead, !4 to 107 μg/g 

for patella lead, and !7 to 61 μg/g for tibia lead. History of occupational lead exposure 

increased the risk of ALS (adjusted odds ratio of 1.9 [95% CI: 1.1, 3.3]). Elevations in both 

blood lead and patella and tibia bone lead were found in ALS cases, though the precision of these 

measurements was questioned. In summary, this study found lead exposure from historical 

questionnaire data and biological markers to be associated with ALS. The same data was used to 

determine the associations of ALS with polymorphism in ALAD and VDR and the influence of 

genotype in the previously discussed associations of ALS with lead (Kamel et al., 2003). The 

ALAD2 allele was associated with a 2-fold increased risk of ALS after adjustment for age, 

gender, region, education, and physical activity. Additionally adjusting for blood lead 

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strengthened the association of ALAD2 and ALS risk. This was not found for bone lead or 

occupational history of lead exposure. VDR was not associated with lead or ALS risk. 

A study from the Mayo Clinic examined risk factors for sporadic ALS in 45 male ALS 

patient-patient control pairs (Armon et al., 1991). When lifetime exposure to lead exceeded 

200 hours, the relative risk for ALS was 5.5 (95% CI: 1.44, 21.0). Overall, men with ALS had 

worked more at blue-collar jobs with significantly more time welding or soldering than controls 

(p < 0.01). The association between lead exposure and development of ALS was supported as 

these authors had the same findings in a previous pilot study of another patient population 

(Roelofs-Iverson et al., 1984). 

Another study of risk factors for ALS in 103 patients found increased odds ratio for 

manual occupation (2.6 [95% CI: 1.1, 6.3]) and occupational exposure to lead (5.7 [95% CI: 

1.6, 30]) (Chancellor et al., 1993). A Swedish study of 92 cases of motor neuron disease 

(includes ALS, progressive bulbar palsy, and progressive muscular atrophy) found a MantelHaenszel odds ratio for welding equal to 3.7 (95% CI: 1.1, 13.0) (Gunnarsson et al., 1992). 

Guidetti et al. (1996) performed a retrospective incidence, prevalence, and mortality 

survey in northern Italy. The area studied had documented lead pollution for years. Based upon 

79 cases, incidence and prevalence rates of ALS were comparable to the surrounding area. 

A subsequent publication by this group found that mean blood lead levels in cases of sporadic 

ALS and controls were not significantly different (mean blood lead of 13 μg/dL versus 

11 μg/dL) (Vinceti et al., 1997). Blood lead was associated with disability due to ALS but 

no support was found for involvement of lead in the etiology of sporadic ALS. 

Louis et al. (2003) examined the relationship between blood lead and essential tremor 

(ET) in 100 cases with ET (mean blood lead 3 μg/dL) and 143 controls (mean blood lead 

2 μg/dL). Ten cases and 7 controls had bone lead levels measured that were significantly 

correlated with blood lead suggesting that higher blood lead may have occurred in the past. 

Logistic regression adjusting for age and current cigarette smoking found an association between 

blood lead and ET. An odds ratio of 1.19 (95% CI: 1.03, 1.37) was estimated. Blood lead was 

higher in the 39 ET cases with no family history. Both current and lifetime prevalence of 

occupational lead exposure was the same in ET cases and controls. In a second publication 

(Louis et al., 2005), 63 ET cases (mean blood lead 4 μg/dL) and 101 controls (mean blood lead 

3 μg/dL) who were similar in age, education, gender, and ethnicity were examined for interaction 

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of blood lead and ALAD gene polymorphisms and increased odds of ET. Of the 63 ET cases, 

18 (29%) had an ALAD2 allele compared to 17 (17%) of the 101 controls (odds ratio of 

1.98 [95% CI: 0.93, 4.21]). When log blood lead was examined by presence of ALAD2 allele in 

ET, log blood lead was highest in ET cases with the ALAD2 allele, intermediate in ET cases 

without an ALAD2 allele, and lowest in controls (test for trend, $ = 0.10; p = 0.001). When the 

ALAD2 allele was present, blood lead was significantly associated with odds of ET (80.29 

[95% CI: 3.08, 2,096.36]). This increased odds of ET with an ALAD2 allele was 30 times 

greater than in individuals with only an ALAD1 alleles. In the highest log blood lead tertile, 

ALAD2 allele was present in 22% of ET cases and 5% of controls. It was proposed that 

increased blood lead along with the ALAD2 allele could affect the cerebellum and, thereby, 

increase the risk of tremor. 

Graves et al. (1991) performed a meta-analysis on 11 case-control studies of Alzheimer’s 

disease for occupational exposure to solvents and lead. Four studies had data for lead exposure 

with a pooled analysis of relative risks for occupational lead of 0.71 (95% CI: 0.36, 1.41). The 

exposure frequencies were 16 of 261 (6%) for the cases and 28 of 337 (8%) for the controls. 

These nonsignificant results were further confirmed by measuring lead concentration in the brain 

of cases with diffuse neurofibrillary tangles with calcification (DNTC), Alzheimer’s disease, and 

non-demented controls. The lead concentration was significantly higher in DNTC compared to 

Alzheimer’s disease and non-demented controls (Haraguchi et al., 2001). 

In summary, more studies are reporting an association with past exposure to lead, usually 

in the occupational setting, and the motor neuron disease ALS. There appears to be a 2-fold 

increased risk for ALS when the ALAD2 allele is present. The odds of ET in individuals with 

the ALAD2 allele were 30 times greater compared to those with only ALAD1 alleles. 

6.3.5.9 Occupational Exposure to Organolead and Inorganic Lead 

Compared to inorganic lead, organolead exposure has a greater impact on the brain and, 

therefore, is discussed separately. Direct comparison of trimethyl lead (a metabolite of 

organolead), tetraethyl lead, and inorganic lead on the in vitro assembly of microtubules from the 

mammalian brain found no effects with inorganic lead but trimethyl lead produced dramatic 

impairment of neurotubular structures and functions (Roderer and Doenges, 1983). Another 

study examining organic and inorganic lead found differential effects on neurite growth in 

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neurons in culture, suggesting that the mechanism of action for organic and inorganic lead was 

not the same (Audesirk et al., 1989). Studies reviewed in this section are summarized in Annex 

Table AX6-3.19. 

Two hundred and twenty-two current employees that manufactured tetraethyl lead had 

cumulative lead exposure associated with poorer performance in many cognitive domains but 

most often in manual dexterity and verbal memory/learning (Schwartz et al., 1993). Simple 

visual reaction time and blood lead had a curvilinear relation with an increase in simple visual 

reaction time occurring above a blood lead of 30 μg/dL (Balbus et al., 1997, 1998). 

In former organolead workers (n = 543), peak tibial lead was a stronger predictor of 

poorer cognitive function than current tibial lead (Stewart et al., 1999). Examination of the 

peripheral nervous system in this population found no strong association between lead 

biomarkers and measures of sensory and motor function (Tassler et al., 2001). Five hundred and 

thirty-five of these former organolead workers were re-examined over a 4-year period (Schwartz 

et al., 2000d, 2001b). Peak tibia lead predicted decline in tests of verbal memory and learning, 

visual memory, executive ability, and manual dexterity. Effect size for an increase of 15.7 μg/g 

bone mineral of peak tibia lead was equivalent to 5 more years of age at baseline. This 

relationship of neurobehavioral tests with bone lead levels was influenced by the apolipoprotein 

E (ApoE) genotype (Stewart et al., 2002). The slope of the relation between tibia lead and 

neurobehavioral outcome was more negative in those individuals with at least one ε4 allele than 

individuals without this allele. It is suggested that the presence of one Apo-ε-4 allele increases 

the risk of persistent central nervous system effects of lead. 

Overall when these neurobehavioral outcomes related to organolead exposure are 

compared to the literature reviewed with inorganic lead exposure, the absence of effects on the 

peripheral nerves and the global nature of central nervous system impairment suggests the 

impact on the brain is greater with organolead exposure. 

6.3.6 Summary of the Epidemiologic Evidence for the Neurotoxic Effects 

of Lead in Adults 

There is no consistent evidence that environmental lead exposure is associated with 

impaired cognitive performance in the elderly if competing risk factors are considered. In adults, 

the effect of lead on the nervous system may not be detected through neurobehavioral testing due 

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to cognitive reserve, the ability to compensate for brain impairment. Cognitive reserve is related 

to pre-morbid cognitive abilities, education, and occupational attainment, and is able to modify 

the clinical expression of central nervous system insult from lead exposure. Therefore, when 

chronic lead exposure is the same in two groups of individuals that differ by educational 

achievement levels, the concentration-response relationship will only be seen in the group with 

low educational achievement, as cognitive reserve allows the high educational achievement 

group to compensate for the central nervous system expression of the effects due to lead. 

Chronic occupational lead exposure affects the sensory nerve fibers in the extremities 

with a possible threshold at a weighted average blood lead level of 28 μg/dL. Intensity of lead 

exposure appears to be more critical than duration of exposure for this outcome. Slowing in the 

brainstem auditory pathway in the caudal pons was consistently associated with chronic 

occupational lead exposure. 

Past occupational exposure to lead increased the risk of developing ALS and motor 

neuron disease in 4 studies. This risk was increased 2-fold by the presence of the ALAD2 allele. 

Essential tremor in two well-done studies was associated with low blood lead levels (mean 

3 μg/dL). The odds of developing ET with the ALAD2 allele increased 30-fold compared to 

those individuals with only an ALAD1 allele. 

Numerous studies of occupational lead exposure also found chronic and current blood 

lead associated with visuomotor and memory impairment with a threshold effect at blood lead 

18 μg/dL. As with ET, postural sway abnormalities associated with blood lead <40 μg/dL is 

believed to result from the effects of lead on different parts of the cerebellum. 

6.4 RENAL EFFECTS OF LEAD 

6.4.1 Summary of Key Findings on the Renal Effects of Lead from the 

1986 Lead AQCD 

Chronic lead nephropathy is a disease characterized by tubulointerstitial nephritis, which 

can ultimately result in small, fibrotic kidneys. It occurs in individuals who sustain chronic highlevel lead exposure. In these individuals, lead exposure is the primary cause of renal failure. 

The pathophysiologic characteristics of lead nephropathy and the populations at increased risk 

for this diagnosis were the foci of the human research portion of Section 12.5, entitled “Effects 

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of Lead on the Kidney,” in the 1986 Lead AQCD. The 1986 document clearly identified several 

high-risk groups for this diagnosis, including children in the Queensland, Australia lead 

poisoning epidemic, moonshine alcohol drinkers, and lead workers in poorly controlled settings. 

The section concluded that data in the latter group indicated an increased risk for lead 

nephropathy associated with blood lead levels ranging from 40 to >100 μg/dL, with adverse 

renal effects possibly occurring at levels as low as 30 μg/dL. 

The 1986 Lead AQCD noted that research at that time was not sufficient to address some 

of the most critical questions relating to the impact of lead exposure on the kidney. The last 

paragraph of the renal section begins with “Among the questions remaining to be answered more 

definitively about the effects of lead on the kidneys is the lowest blood lead level at which renal 

effects occurs.” The last sentence reads “Conversely, the most difficult question of all may well 

be to determine the contribution of low levels of lead exposure to renal disease of non-lead 

etiologies.” Advances in the research conducted since that document was written allow a much 

more informed discussion of exactly those critical issues. As discussed below, recent research 

indicates that lead nephropathy is merely the tip of the iceberg in terms of the contribution that 

lead makes to renal dysfunction overall. Research increasingly indicates that lead, at much lower 

doses than those causing lead nephropathy, acts as a cofactor with other more established renal 

risks to increase the risk for renal dysfunction and the rate of subsequent decline. The 

populations at risk for renal dysfunction (diabetics and hypertensives) are increasing worldwide, 

particularly in countries where obesity is epidemic. Lead exposure is declining in many 

industrialized countries, although less so among high-risk minority populations. The extent of 

the public health impact of lead on the kidney depends on the balance of these two factors. 

6.4.2 Renal Outcome Definitions 

The renal literature can be confusing since several of the clinical renal measures are 

inversely related. Therefore, the pertinent outcomes are briefly reviewed below. The glomerular 

filtration rate (GFR) is considered to be the best measure of renal function. GFR is assessed by 

urinary clearance of exogenous (e.g., 125I-iothalamate) or endogenous (e.g., blood urea nitrogen 

[BUN] and serum creatinine) compounds. Creatinine is used most commonly. Therefore, 

increases in BUN or serum creatinine or decreases in renal clearance of creatinine or other 

markers are all consistent with decreased renal function. Serum creatinine and its reciprocal 

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have been the most frequently used measures of renal function in the lead-kidney literature. 

However, creatinine is not an ideal GFR marker, because it is influenced by factors such as 

muscle mass, diet, gender, age, and tubular secretion. Measurement or calculation of creatinine 

clearance takes some of these variables into account. Measured creatinine clearance utilizes 

timed urine collections, traditionally over a 24-h period, making compliance difficult. Therefore, 

equations to estimate creatinine clearance have gained popularity. The Cockcroft-Gault equation 

(Cockcroft and Gault, 1976) has been used most commonly. Recently, several equations to 

estimate actual GFR were studied in the Modification of Diet in Renal Disease (MDRD) Study 

(Levey et al., 1999). The abbreviated MDRD equation (GFR in mL/min/1.73m2

 = 186 H

creatinine!1.154 

H age!0.203 H (0.742 if female) H (1.212 if African American); Stevens and Levey 

[2005a]) estimates GFR more accurately than the Cockcroft-Gault equation in patients with renal 

insufficiency (Levey et al., 2003). Despite their promise, however, the MDRD equations are 

relatively new and their use in the literature on the renal effects of lead exposure has been limited 

to date. 

Cystatin C is another recent addition to the tools used to assess GFR (Stevens and Levey, 

2005b). This is a 13,000 Dalton, non-glycosylated basic protein, which is generated by all 

nucleated cells and filtered, reabsorbed, and catabolized, but not secreted, in the kidney. 

Very little appears in the urine. The majority of studies done to date indicate that serum cystatin 

C is a better marker for GFR than serum creatinine (Stevens and Levey, 2005b). 

Most of the renal outcome measures discussed above were developed for use in the 

clinical setting. Unfortunately, they are insensitive for early renal damage, as evidenced by the 

fact that serum creatinine remains normal after kidney donation. Therefore, in the last two 

decades, the utility of renal early biological effect (EBE) markers as indicators of preclinical 

renal damage has been of interest. These can be categorized as markers of function (i.e., low 

molecular weight proteins that should be reabsorbed in the proximal tubules such as β2-

microglobulin and retinol-binding protein [RBP]); biochemical alteration (i.e., urinary 

eicosanoids such as prostaglandin E2, prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, and 

thromboxane B2); and cytotoxicity (e.g., N-acetyl-β-D-glucosaminidase [NAG]) (Cardenas et al., 

1993). Elevated levels may indicate an increased risk for subsequent renal dysfunction. 

However, with the exception of microalbuminuria in diabetes and β2-microglobulin in cadmium 

exposure, most are research tools only and their prognostic value remains controversial. 

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European and Asian nephrotoxicant researchers have utilized them more frequently than have 

renal researchers in the United States. Prospective studies of most of these markers in 

nephrotoxicant-exposed populations are quite limited to date. 

6.4.3 Lead Exposure Measure Definitions 

Although these definitions are reviewed in detail elsewhere in this Lead AQCD, a brief 

discussion is included here due to the number of key studies in this section that measured bone or 

chelatable lead dose. Inorganic lead is a cumulative toxicant that is stored in bone. Blood lead is 

a relatively short-term measure (half-life of 30 days [Hu et al., 1998]) that reflects exposure from 

current exogenous sources and the release of lead from internal lead stores. Bone is a source of 

lead as well as a repository (Hu et al., 1998). As such, bone lead measures provide information 

on the potential for ongoing internal exposure as well as cumulative exposure. Lead in 

trabecular bone (commonly measured in the patella or calcaneus) is more bioavailable than lead 

in cortical bone (measured in the mid-tibia) and has a shorter half-life (Gerhardsson, et al., 1993; 

Hu et al., 1998). An additional lead measure, chelatable lead, is thought to represent a 

bioavailable pool of lead from blood, soft tissue, and bone. Either calcium disodium 

ethylenediaminetetraacetic acid (EDTA) or dimercaptosuccinic acid (DMSA; succimer) may be 

used for this purpose although DMSA is newer and, thus, has been used less frequently to date. 

6.4.4 Lead Nephrotoxicity in Adults 

6.4.4.1 General Population Studies 

Over the past two decades, several studies have examined the effect of lead exposure on 

renal function in environmentally exposed general populations. This is a new category of leadrenal research with no high quality examples (by current standards) having been available for 

review in the 1986 Lead AQCD. The studies discussed below provide critical evidence that the 

adverse effects of lead on the kidney occur at much lower doses than previously appreciated. 

General population studies of the renal effects of lead are further summarized in Annex 

Table AX6-4.1. 

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6.4.4.1.1 Cadmibel Study 

In the first large environmental study that adjusted for multiple renal risk factors, Staessen 

et al. (1992) evaluated 965 men and 1,016 women in the Belgian Cadmibel study. Lead dose 

was indexed by blood lead and zinc protoporphyrin. Renal outcome measures included serum 

creatinine and $2-microglobulin and 24-h measured and calculated (Cockcroft and Gault, 1976) 

creatinine clearances. Mean blood lead was 11.4 μg/dL (range 2.3-72.5) and 7.5 μg/dL (range 

1.7-60.3) in men and women, respectively. After adjustment, log transformed blood lead and 

zinc protoporphyrin, in separate models, were negatively associated with measured creatinine 

clearance (effect estimates are presented in Table 6-4.1). A 10-fold increase in blood lead was 

associated with a decrease in creatinine clearance of 10 and 13 mL/min in men and women, 

respectively. Both lead measures were also negatively associated with estimated creatinine 

clearance. This landmark study raised concern that the lead dose threshold for adverse renal 

effects in the general population was much lower than previously appreciated based on 

occupational data. 

6.4.4.1.2 Normative Aging Study 

Four studies assessing the renal impact of lead exposure in the Normative Aging Study 

have been published to date. Participants in this study were originally recruited in the 1960s in 

the Greater Boston area. Inclusion criteria included male gender, age between 21 and 80 years, 

and absence of chronic medical conditions. Payton et al. (1994) analyzed data from a periodic 

follow-up evaluation performed between 1988 and 1991 in 744 participants. Lead dose was 

assessed with blood lead; renal outcome measures included serum creatinine and 24-h measured 

and calculated (Cockcroft and Gault, 1976) creatinine clearances. Mean blood lead 

concentration and measured creatinine clearance were 8.1 μg/dL (SD 3.9) and 88.2 mL/min 

(SD 22.0), respectively. After adjustment, ln blood lead was negatively associated with ln 

measured creatinine clearance (effect estimates are presented in Table 6-4.1). Borderline 

statistically significant associations (p < 0.1) between blood lead and serum creatinine and 

estimated creatinine clearance were also observed. 

Kim et al. (1996) studied 459 men whose blood lead levels from past periodic 

examinations, conducted every 3-5 years during 1979-1994, were measured from stored samples. 

Participants were randomly selected to be representative of the entire Normative Aging Study 

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Reference Study location Study population Mean exposure and Analysis methods Sample size outcome measures Covariates adjusted for in analysis Major significant findings Muntner et al. (2003) Blood lead Multiple logistic regression NHANES III, 4.21 μg/dL (hypertensives) 1988-1994 3.3 μg/dL Age, race, gender, diabetes, systolic blood n = 15,211 (normotensives) pressure, smoking status, history of 4,813 hypertensives cardiovascular disease, body mass index, Renal outcomes = elevated alcohol consumption, household income, serum creatinine, chronic marital status, and health insurance kidney disease (GFR <60 mL/min/1.73 m2) Payton et al. (1994) Blood lead Boston, MA 8.1 μg/dL Normative Aging Study, 1988-1941 Measured creatinine n = 744 clearance Multiple linear regression Age, body mass index, analgesic and diuretic use, alcohol consumption, smoking status, systolic/ diastolic blood pressure 88.2 mL/min Kim et al. (1996) Blood lead at baseline Cross-sectional and longitudinal analyses Boston, MA 9.9 μg/dL Random-effects modeling Normative Aging Study, 1979-1994 Serum creatinine at n = 459 baseline Baseline age, time since initial visit and between visits, body mass index, smoking 1.2 mg/dL status, alcohol ingestion, education level, hypertension (defined as blood pressure 

$160 or 95 mm Hg or antihypertensive medication use), and baseline serum creatinine 

Higher odds ratios of both increasechronic kidney disease by quartile ohypertensives but not normotensiveOdds ratios for elevated serum creaBlood lead (range, μg/dL) % Quartile 1 (0.7–2.4) 7.Quartile 2 (2.5–3.8) 12Quartile 3 (3.9–5.9) 12Quartile 4 (6.0–56.0) 16

p < 0.001 for chi-squared test for trTwofold higher blood lead associat(95% CI: 1.20, 1.71) 

Log blood lead negatively associatecreatinine clearance !0.04 (95% CI: !0.079, !0.001) 

10 μg/dL higher blood lead associalower creatinine clearance 

In cross-sectional analyses of assoctransformed blood lead and concurrlargest $ was in the 141 participant#10 μg/dL: 0.06 (95% CI: 0.023, 0.097) Positive association between log trachange in serum creatinine over subin participants whose peak blood le0.027 (95% CI: 0.0, 0.054) 

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Reference Study location Study population Mean exposure and Analysis methods Sample size outcome measures Covariates adjusted for in analysis Major significant findings Wu et al. (2003) Blood lead Boston, MA 6.2 μg/dL Normative Aging Study, 1991-1995 Patella lead n = 709 32.1 μg/g bone Multiple linear regression Age, body mass index, hypertension, smoking status, alcohol ingestion, analgesic medication use Calculated creatinine clearance 71.3 mL/min Tsaih et al. (2004) Blood lead at baseline Longitudinal analysis, mean of 6 years Boston, MA 6.5 μg/dL between evaluations Normative Aging Study 1991-~2001 Tibia lead at baseline Age, body mass index, diabetes, hypertension, n = 448 21.5 μg/g bone mineral smoking status, alcohol consumption, analgesic use, baseline serum creatinine and its square Serum Creatinine at Baseline 1.3 mg/dL Staessen et al. (1992) 11.4 μg/dL (males) Blood lead Multiple linear regression Belgium Cadmibel Study 7.5 μg/dL (females) Age, age squared, body mass index, log transformed gamma-glutamyl transpeptidase, n = 1,981; 965 males Measured creatinine and diuretic use clearance 99 mL/min (males) 80 mL/min (females) Significant association between pat

clearance β = !0.069 (SE not provided) Lead dose not associated with chanSignificant interaction of blood and predicting annual change in serum For natural ln baseline blood lead β 

0.121) compared to β = 0.006 (95% 

non-diabetics 

For natural ln baseline tibia lead β = 

0.135) compared to β = 0.005 (95% 

non-diabetics 

Log transformed blood lead negativmeasured creatinine clearance !9.5 (95% CI: !18.1, !0.9) males 

!12.6 (95% CI: !20.3, !5.0) fema

Tenfold increase in blood lead assocreatinine clearance of 10 and 13 mrespectively 

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population in terms of age and follow-up. Renal status was assessed with serum creatinine. 

Data from 4-5 evaluations were available for the majority of participants. Relations were 

evaluated cross-sectionally (associations between blood lead and concurrent serum creatinine) 

as well as longitudinally (associations between blood lead and change in serum creatinine over 

the subsequent follow-up period). Mean age, blood lead level, and serum creatinine, at baseline, 

were 56.9 years (SD 8.3), 9.9 μg/dL (SD 6.1), and 1.2 mg/dL (SD 0.2), respectively. With 

random-effects modeling, a significant positive association between ln-transformed blood lead 

and concurrent serum creatinine was observed. This association was stronger when models were 

confined to participants with lower peak blood lead levels, i.e., the $ coefficient was largest in 

the 141 participants whose highest blood lead level was #10 μg/dL. In longitudinal analysis, 

ln-transformed blood lead was associated (p = 0.05) with change in serum creatinine over the 

subsequent follow-up period in the 428 participants whose highest blood lead level was 

#25 μg/dL. Similar to the cross-sectional analysis, the $ coefficient in the participants whose 

highest blood lead level was #10 μg/dL was larger; however, in the longitudinal analysis, the 

standard error also increased such that the p-value was not significant. 

Cortical and trabecular bone lead measurements were obtained in evaluations performed 

between 1991 and 1995 in 709 participants in the Normative Aging Study (Wu et al., 2003). 

Lead dose was assessed with blood, tibia, and patella lead concentrations. Renal outcome 

measures included serum creatinine and estimated creatinine clearance. Mean blood, tibia and 

patella lead levels were 6.2 μg/dL (SD 4.1), 22.0 μg/g bone mineral (SD 13.4), and 32.1 μg/g 

bone mineral (SD 19.5), respectively. After adjustment, analyses in the 670 participants from 

whom these data were available, revealed a significant inverse association between patella lead 

and creatinine clearance. A borderline significant (p = 0.08) inverse association between tibia 

lead and creatinine clearance was also observed. None of the lead measures were significantly 

associated with serum creatinine. 

Tsaih et al. (2004) reported associations between baseline lead dose and change in serum 

creatinine in 448 men. Lead dose was assessed with blood, tibia, and patella lead. Serum 

creatinine was measured at baseline and at follow-up, an average of 6 years later. Six percent 

and 26% of subjects had diabetes and hypertension, at baseline, respectively. Mean blood lead 

levels and serum creatinine decreased significantly over the follow-up period in the group. Lead 

dose was not associated with change in creatinine in all participants. However, the authors found 

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a significant interaction between lead dose (blood and tibia lead) and diabetes on change in 

serum creatinine. Interaction was also observed between tibia lead and hypertension, although it 

is possible that many of the 26 diabetics were also included in the hypertensive group and were 

influential there as well. 

6.4.4.1.3 NHANES III 

Muntner et al. (2003) analyzed associations between blood lead and renal outcomes in 

15,211 adult subjects enrolled in the NHANES III study, conducted from 1988 through 1994. 

Dichotomous renal outcome measures analyzed included elevated serum creatinine and chronic 

kidney disease (GFR < 60mL/min/1.73 m2

). Due to interaction between blood lead and 

hypertension, the population was stratified. Mean blood lead was 4.21 μg/dL in the 4,813 

hypertensives and 3.30 μg/dL in normotensives. The prevalence of elevated serum creatinine in 

hypertensives and nonhypertensives was 11.5% and 1.8%, respectively; prevalence of chronic 

kidney disease was similar. The odds ratios for both renal outcomes increased by quartile of 

blood lead among the hypertensive subjects but not among those without hypertension. Among 

those with hypertension, after adjustment for age, race and gender, the odds ratios for elevated 

creatinine in quartiles 2, 3, and 4 compared to the lowest quartile of blood lead, were 1.56 

(95% CI: 1.04, 2.35), 1.68 (95% CI: 1.24, 2.26), and 2.07 (95% CI: 1.26, 3.40), respectively. 

As shown in Table 6-4.1, the odds ratios were the same following additional adjustment. The 

authors noted that the “associations were strong, dose-dependent and consistent before and after 

comprehensive adjustment.” They also noted that in nonhypertensives, higher blood lead was 

associated with a higher prevalence of chronic kidney disease in diabetics. This study is notable 

for the sample size, for the reported associations being observed at the lowest mean blood lead 

level in any environmental study to date, for the comprehensive adjustment for other renal risk 

factors, and for the study population being representative of the U.S. population. 

6.4.4.1.4 Summary of Lead Nephrotoxicity in the General Population 

Studies of environmentally exposed general populations constitute one of the two most 

important types of research on the adverse renal effects of lead during the past two decades. 

Study designs are generally strong; some have the added strength of analyzing longitudinal data. 

Populations are large, assessment of lead dose is comprehensive, including the use of bone lead 

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as a measure of cumulative lead body burden in some studies, and statistical approaches are 

advanced, utilizing a range of exposure and outcome measures, while adjusting for numerous 

renal risk factors. Given these strengths, the fact that these studies have reached consistent 

conclusions provides strong evidence indicating that lead is a contributor to renal dysfunction in 

susceptible populations at much lower levels that those identified in the 1986 Lead AQCD. 

Chronic kidney disease has been observed at the lowest lead dose levels studied (category II 

from 2.5 to 3.8 μg/dL in Muntner et al. [2003]). An association between cumulative lead dose 

(mean tibia lead of 21.5 μg/g bone mineral) and longitudinal decline in renal function has been 

observed as well, although data on any threshold for this effect were not reported (Tsiah et al., 

2004). Susceptible populations include those with other risk factors for renal disease, including 

hypertension and diabetes. Populations who are also at increased risk for obesity, diabetes, and 

hypertension represent groups potentially most impacted by lead exposure. 

6.4.4.2 Occupational Studies 

The vast majority of studies in the lead-renal literature were conducted in the occupational 

setting. This was especially true prior to the 1986 Lead AQCD but is still currently the case. 

Occupational studies of the renal effects of lead are presented in Annex Table AX6-4.2. Recent 

studies in the general population, discussed above, and in the patient population, discussed in the 

next section, provide consistent evidence supporting a role for lead in renal dysfunction at lower 

lead concentrations of interest. However, one phenomenon that has been observed more 

frequently in occupational rather than environmental studies of lead exposure and kidney 

function deserves specific comment. 

Several studies have reported statistically significant negative associations between higher 

lead dose and worse renal function, specifically positive associations between higher lead dose 

and lower BUN, serum creatinine and/or higher creatinine clearance. Roels et al. (1994) 

observed higher mean creatinine clearance in 76 lead workers compared to 68 controls from the 

same smelter who were not occupationally exposed to lead (mean of 121.3 versus 

115.5 mL/min/1.73 m2

 in workers and controls, respectively [p < 0.05]). More importantly, in 

the combined group, tibia lead was positively correlated with measured creatinine clearance. 

However, no other significant associations between lead dose and the renal outcomes (which also 

included serum creatinine, urea nitrogen, and β2-microglobulin, along with urinary NAG, RBP 

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and β2-microglobulin as well as other early biological effect markers) were observed. Lead 

workers had evidence of high past exposure and controls also had high blood lead levels by 

current standards (mean blood and tibia lead levels were 43.0 and 14.1 μg/dL and 66 and 21 μg/g 

bone mineral, in workers and controls, respectively). 

Weaver et al. (2003a) performed a cross-sectional analysis of first evaluation data from a 

longitudinal study of 803 lead workers in South Korea, including 94 former lead workers. Lead 

exposure was assessed with job duration; blood, tibia, and DMSA-chelatable lead; and three 

hematologic measures as surrogates for lead dose. Clinical renal function was assessed with 

blood urea nitrogen (BUN), serum creatinine, measured creatinine clearance, and calculated 

creatinine clearance (Cockcroft and Gault, 1976). Urinary NAG and RBP were also measured. 

Mean job duration, and blood, tibia, and DMSA-chelatable lead levels were 8.2 years (SD 6.5), 

32.0 μg/dL (SD 15.0), 37.2 μg/g bone mineral (SD 40.4), and 767.8 μg/g creatinine (SD 862.1), 

respectively. Higher lead measures were associated with worse renal function in nine of the 

42 associations, however, an additional five were in the opposite direction (higher lead measures 

associated with lower serum creatinine and higher creatinine clearances). These opposite 

direction (inverse) associations were observed only for the clinical outcomes whereas the 

associations between higher lead dose and worse renal function were predominantly with the 

EBE markers. In three of 16 models (analyses) assessing effect modification by age on 

associations between lead job duration and the three lead dose biomarkers with the four clinical 

renal outcomes, positive associations between higher lead measures and worse renal function in 

participants in the oldest age tertile were significantly different from associations in those in the 

youngest age tertile, which were in the opposite (inverse) direction; this pattern was observed at 

borderline significance (p < 0.1) in three other models. However, this pattern was not observed 

in the EBE marker models. Similar inverse associations were observed in this population in the 

third evaluation, performed a mean of 2.2 years after collection of the data discussed above, 

but only with DMSA-chelatable lead and not patella, blood, or tibia lead (Weaver et al., 2005b). 

Hsiao et al. (2001) also reported positive associations between higher blood lead and lower 

concurrent serum creatinine in an analysis of 8 years of annual medical surveillance data in 

30 lead battery workers (this study is of note since it is one of the few longitudinal, occupational 

studies to date; additional findings are described in Annex Table AX6-4.2). 

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These inverse associations, evidenced by higher lead measures and lower BUN and serum 

creatinine and/or higher creatinine clearance, may represent lead-induced hyperfiltration, 

a phenomenon initially observed in patients with diabetes but also implicated in other settings, 

including hypertension and obesity (Nenov et al., 2000). In this process, initial supranormal 

renal function is paradoxically associated with increased risk for subsequent renal dysfunction. 

Hu (1991) has also reported increased mean creatinine clearance in 22 adults who were lead 

poisoned as children compared to matched controls. Longitudinal data for lead-exposed rodents 

(discussed in Section 5.7) are critical in relating this process to lead. However, in that work, 

despite similar initial hyperfiltration, subsequent renal dysfunction was much more severe in the 

high-dose lead-exposed rodents compared to the low-dose animals. This suggests that 

hyperfiltration may be one, but not the only, mechanism for the adverse renal effects of lead. 

Whether hyperfiltration contributes to pathology in humans is unclear; longitudinal studies are 

needed. 

Regardless, the issue for this document is that significant findings could be obscured if 

opposite direction associations are present in different segments of the study population and 

interaction models to address this are not performed. This is a valid concern, since the factors 

involved in these inverse associations in lead exposed populations are not well defined at 

present. Work by Weaver and colleagues have used age as the effect modifier; however, other 

factors, such as lead job duration, may be more important modifiers. 

Figure 6-4.1 provides an example of the different associations observed depending on 

whether effect modification is examined. In the work of Weaver et al. (2003a), in several 

models, no associations were observed when the entire population was studied; however, when 

interaction models using age as the effect modifier were evaluated, significant associations in 

opposite directions were observed. 

6.4.4.3 Patient Population Studies 

Studies in various patient populations have also contributed to the body of knowledge 

concerning adverse renal impacts of lead exposure. Such studies of renal effects of lead in 

patient populations are presented in Annex Table AX6-4.3. Populations studied include those 

with chronic renal insufficiency (CRI), end-stage renal disease (ESRD), gout, and hypertension. 

Patients were selected for study due to the fact that these diseases are thought to be increased by 

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402(c) Economic Analysis Chapter 5 541
Figure 6-4.1. Effect on renal function evaluation using age as the effect modifier. 

Source: Weaver et al. (2003a). 

1 high-level lead exposure, particularly when two or more coexist in the same patient. Early work 

2 in this area was discussed in the 1986 Lead AQCD, but some research is discussed again below 

3 in order to allow conclusions to be drawn on the data to date. Early research focused on patients 

4 with potential lead nephropathy; and lead body burdens of interest, assessed with EDTA 

5 chelation, were above 600 to 650 μg/72 h. More recent work has involved patients with CRI but 

6 not ESRD and lead body burdens below that range. Of note, the terminology for degree of renal 

7 dysfunction was more variable in the older literature. Therefore, for clarity in the discussion 

8 below, patients with impaired renal function who are not on dialysis are noted to have CRI, 

9 rather than using terms such as “failure” that were used in some of the original reports. 

10 Two issues have been a recurring concern in this work, particularly in work with patients 

11 on dialysis. The first concern is whether lead body burden is higher in all patients with renal 

12 insufficiency or failure due to decreased lead excretion (reverse causality). The second concern 

13 is whether EDTA-chelatable lead levels when measured over a 72-h period in patients with CRI 

14 can be equated to those in participants with normal renal function measured over 24 h. It is 

15 possible that, due to decreased excretion of EDTA in renal insufficiency, more lead per dose is 

16 ultimately chelated. These concerns have been addressed in various ways as noted in the 

17 research discussed below. Lastly, this work also illustrates the limitations of blood lead levels 

18 which often do not reflect the differences in lead body burden noted between populations. 

19 

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6.4.4.3.1 Lead Body Burden in Chronic Renal Disease 

Batuman et al. (1983) studied 27 hypertensives with CRI (defined as serum creatinine 

>1.5 mg/dL) and 21 without associated renal impairment. Blood lead levels were similar in the 

two groups. However, mean EDTA-chelatable lead levels were significantly higher in 

hypertensives with CRI than those without (860 and 340 μg/72 h, respectively). Further, 

chelatable lead levels in patients with CRI from causes not thought to be related to lead 

nephropathy and who had no history of lead exposure were similar to patients with hypertension 

but no CRI. This provides some evidence against reverse causality. 

Sanchez-Fructuoso et al. (1996) performed a similar study in a much larger number of 

patients in Spain, none of whom had a known history of lead exposure. These authors reported 

that EDTA-chelatable lead levels >600 μg/72 h were present in none of 30 controls, 16 (15.4%) 

of 104 patients with essential (primary) hypertension and normal renal function, 74 (56.1%) of 

132 patients with CRI of unknown etiology along with hypertension (64 of the 132 also had 

gout), but none of the 30 patients with CRI of known (non-lead related) etiology. Mean blood 

and EDTA-chelatable lead levels in the patients with CRI of known cause were not statistically 

different from controls with normal renal function. These researchers also reported significant 

correlations between bone lead levels (assessed by biopsy) and EDTA-chelatable lead level in 

12 patients whose chelatable lead levels were >600 μg/72 h, which provides support for the 

validity of chelatable lead levels in CRI. 

In contrast, Osterloh et al. (1989) reported no significant difference in EDTA-chelatable 

lead levels between 40 male subjects with hypertensive nephropathy (hypertension preceded 

renal insufficiency; serum creatinine 1.8-4 mg/dL) and 24 controls with renal dysfunction from 

other causes. Lead dose and serum creatinine were not correlated. Chelatable lead levels in this 

population were much lower than those reported by Wedeen et al. (1983) and Sanchez-Fructuoso 

et al. (1996). The authors noted that only 17% of their study participants had a history of 

possible lead exposure based on questionnaire. In contrast, Batuman et al. (1983) found that 

89% of patients with hypertension and CRI had a possible history of lead exposure. The 

inconsistent results in these studies may reflect differences in the patients studied. Batuman 

et al. (1983) studied Veterans Administration patients, Sanchez-Fructuoso et al. (1996) studied 

patients from a low-medium income area in Madrid, Spain, and Osterloh et al. (1989) recruited 

patients from the database of a large health maintenance organization in California. 

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Van de Vyver et al. (1988) reported lead data from bone biopsies in 153 dialysis patients, 

11 cadavers without known excessive lead exposure, 13 patients with renal insufficiency, gout, 

and/or hypertension and 22 lead workers. Bone lead levels in 5% of the dialysis population were 

in the range observed in lead workers, suggesting lead as a primary cause of their renal failure. 

Levels in the 10 patients with analgesic nephropathy were the lowest (all <7 μg/g). However, 

Winterberg et al. (1991) subsequently noted that the bone lead levels in patients with analgesic 

nephropathy and cadaver controls in Van de Vyver et al. (1988) were much higher than in 

control groups of other researchers. They reiterated the concern that lead did accumulate due to 

decreased renal excretion. In a longitudinal study, Price et al. (1992) reported similar half-lives 

of lead in bone in eight renal patients compared with age-matched controls who had XRF finger 

bone lead conducted twice 5 years apart. The small number and inclusion of outliers without 

formal statistical analysis limits conclusions that can be drawn from these data. The longitudinal 

studies of Lin and colleagues, discussed below, provide more definitive data in this regard. 

6.4.4.3.2 Impact of Lead Body Burden on Decline in Renal Function in Patients with CRI 

Lin and colleagues have addressed the issue of low-level lead as a cofactor with other 

renal risk factors in susceptible populations, including those with CRI and/or gout. They have 

approached this work in two ways: prospective follow-up of populations with CRI to determine 

if renal function decline is greater in those with higher lead body burdens and through 

randomized trials to determine if chelation therapy changes the rate of renal function decline. 

Importantly, their work is in an EDTA-chelatable lead range well below that considered 

abnormal as described in Section 6.4.4.3.1. 

In their most recent publication, Yu et al. (2004) followed 121 patients over a 4-year 

period. Eligibility required well-controlled CRI. Importantly, serum creatinine between 1.5 and 

3.9 mg/dL and EDTA-chelatable lead <600 μg/72 h were required at baseline. Patients with 

potentially unstable renal disease were excluded (i.e., due to systemic diseases such as diabetes). 

Sixty-three patients had “high-normal” EDTA-chelatable lead levels ($80 but <600 μg/72 h); 

58 had “low-normal” EDTA-chelatable lead levels (<80 μg lead/72 h). The groups were similar 

in most other baseline risk factors. Borderline statistically significant (p < 0.1) differences 

included mean older age in the high chelatable lead group and certain renal diagnoses. Fifteen 

patients in the “high-normal” chelatable lead group reached the primary endpoint (doubling of 

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serum creatinine over the 4-year study period or need for hemodialysis) compared to only two in 

the “low-normal” group (p = 0.001). 

In a Cox multivariate regression analysis, chelatable lead was significantly associated 

with overall risk for the primary endpoint (hazard ratio for each 1 μg chelatable lead was 1.01 

[95% CI: 1.00, 1.01; p = 0.002]). In this model, the only other variable reaching at least 

borderline significance (p < 0.1) was baseline serum creatinine. The associations between 

baseline chelatable lead or blood lead level and change in GFR (estimated by an MDRD 

equation [Levey et al., 1999]) were modeled separately using GEE. Based on these models, a 

10 μg higher chelatable lead level or a 1 μg/dL higher blood lead level reduced the GFR by 1.3 

and 4.0 mL/min, respectively, during the 4-year study period. Similar to the primary outcome 

analysis, of the many traditional renal risk factors adjusted for in these models, only diagnosis of 

chronic interstitial nephritis was significantly associated, in this case with an increase in GFR. 

Of note, chronic interstitial nephritis was also a more frequent diagnosis in the group with the 

low-normal chelatable lead levels (p = 0.09). 

6.4.4.3.3 Therapeutic EDTA Chelation in Patients 

Chelation in lead exposure is controversial due to the potential for it to be used in lieu of 

exposure reduction. Chelation in lead nephropathy, in particular, is controversial, because cases 

of acute tubular necrosis were reported following early clinical use of EDTA that involved large 

doses in the treatment of hypercalcemia and lead poisoning. Adverse renal effects have not been 

observed in subsequent work using much lower doses (Sanchez-Fructuoso et al., 1996; Wedeen 

et al., 1983). 

Work prior to the 1986 Lead AQCD suggested that chelation might be beneficial in lead 

nephropathy (Morgan, 1975; Wedeen et al., 1979). This issue has been addressed more 

recently by Lin and colleagues in patients with much lower lead doses. Lin et al. (1999) studied 

43 patients with serum creatinine and EDTA-chelatable lead levels between 1.5-4 mg/dL and 

150 and 600 μg/72 h, respectively. Patients were followed for 12 months to determine their 

baseline rate of renal function decline. A group of 32 was then randomized; and 16 underwent a 

2-month treatment period consisting of weekly chelation with 1 g EDTA; whereas the other 

16 continued their regular care. Traditional renal risk factors, such as blood pressure control, 

were similar in the two groups. Prior to therapeutic chelation, the rate of progression of renal 

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insufficiency was not statistically different. However, actual improvement in renal function was 

noted in the treated group during chelation and subsequent renal function decline was slower in 

this group. The mean difference in the change in the reciprocal of serum creatinine post therapy 

was 0.000042 L/μmol per month (95% CI: 0.00001, 0.00007). 

In subsequent work, Lin et al. (2003) published results of a randomized chelation trial in a 

larger group. This work included a 2-year prospective study of renal function decline prior to 

chelation in 202 patients with CRI and EDTA-chelatable lead <600 μg/72 h. Results of the Cox 

proportional-hazards model were similar to those reported in Yu et al. (2004). Associations 

between baseline EDTA-chelatable lead level and change in GFR were modeled using GEE. 

After adjustment, an increase of 10 μg in EDTA-chelatable lead was associated with a GFR 

decrease of 0.03 mL/min/1.73 m2 of body-surface area during the observation period (p < 0.001). 

Of note, this effect, although statistically significant, is 40-fold lower than that reported in Yu 

et al. (2004) over a follow-up period that is only 2-fold shorter. At 24 months, 64 patients whose 

EDTA-chelatable lead levels were 80-600 μg/72 h were randomized; half to a 3-month treatment 

period consisting of weekly chelation with 1 g EDTA until their excreted lead levels fell below 

60 μg/72 h and half to placebo infusion over 5 weeks. Renal risk factors were similar in the two 

groups. Mean blood lead levels were 6.1 μg/dL and 5.9 μg/dL in treated and control groups, 

respectively. In the subsequent 24 months, chelation in 19 (59%) participants was repeated due 

to increases in serum creatinine in association with rebound increases in EDTA-chelatable lead 

levels. Each received one additional chelation series (mean = 4.1 g EDTA) a mean of 13.7 

months after the first chelation period. At the end of the study period, mean estimated GFR 

increased by 2.1 mL/min/1.73 m2

 of body-surface area in the chelated group compared to a 

decline of 6.0 mL/min/1.73 m2

 of body-surface area in the controls (p < 0.01) (see Figure 6-4.2). 

The 95% CI for the difference between the chelated and control groups was !11.0 to !5.1 

mL/min/1.73 m2

 of body-surface area. 

Lin and colleagues have also reported chelation results in patients with gout. Historically, 

gout was known to be a risk from high-level lead exposure such as in the Queensland, Australia 

epidemic and in moonshine alcohol drinkers (U.S. Environmental Protection Agency, 1986a). 

Higher EDTA-chelatable lead levels in patients with both gout and CRI compared to those with 

CRI or gout alone have also been reported in several studies at lower levels of exposure 

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402(c) Economic Analysis Chapter 5 546
Figure 6-4.2. Estimated mean ("2 SE) glomerular filtration rate according to time in 

the chelation group (n = 31) and the control group (n = 30) during the 

observation and intervention periods. The patients in the chelation group 

received chelation therapy from month 24 to month 51. The asterisks 

indicate p < 0.05 by Student’s t-test. 

Source: Lin et al. (2003). 

1 (Batuman et al.,1981; Sanchez-Fructuoso et al., 1996; Lin et al., 2001). Lin and colleagues have 

2 pursued this finding in chelation studies of patients with CRI with and without gout (2001) and 

3 in otherwise healthy patients with and without gout (2002). Both studies reported significant 

4 associations between EDTA-chelatable lead and uric acid measures before chelation and 

5 improvement in urate clearance and other uric acid measures after chelation (see Annex Table 

6 AX6-4.3 for data). In contrast, Miranda-Carus et al. (1997) did not find correlations between 

7 EDTA-chelatable lead body burdens above or below 600 μg/120 h and uric acid measures. Uric 

8 acid parameters were unchanged following chelation, although only six participants were studied 

9 and all had EDTA-chelatable lead above 600 μg/120 h. Therefore, lack of power as well as 

10 different lead body burdens may be explanatory factors for differences between this work and the 

11 Lin studies. 

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The key studies in patients followed prospectively with and without chelation constitute 

the other major advance in research on the adverse renal effects of lead over the past two 

decades. This work suggests that lead is nephrotoxic in susceptible populations at lower levels 

than currently appreciated. Blood lead levels (mean = 4.2 μg/dL [range 1.0–13.4]) and body lead 

burdens (mean = 99.1 μg/72 h [range 2.5–530]) were associated with decline in GFR over a 

4-year follow-up period (Yu et al., 2004). Chelation was beneficial in a body lead burden range 

from 80 or 150 to 600 μg/72 h, depending on study (Lin et al., 2003; 1999). The published data 

do not allow a determination of whether a threshold exists. It is also possible that chelation has a 

direct beneficial effect on kidney function, regardless of lead exposure, since DMSA has been 

reported to prevent renal damage in a non-lead exposed rat model of nephrosclerosis (Gonick 

et al., 1996). If so, the benefits of chelation do not appear to occur via reversal of structural 

damage (Khalil-Manesh et al., 1992b); improved hemodynamics from reduction of reactive 

oxidant species may be a mechanism (Gonick et al., 1996). 

Strengths of the work of Lin and colleagues include prospective study design, lead dose 

assessment including bioavailable body burden, statistical analysis that includes GEE for 

longitudinal data, and adjustment for more renal risk factors than any of the other key studies 

discussed in Section 6.4. Limitations include that fact that, to date, this type of research has been 

conducted in relatively small number of participants and in only one center. As noted above, the 

two reported lead body burden $ coefficients in GEE models of decline in renal function vary 

widely. Therefore, small study sizes and differences in renal diagnoses between groups may be 

overly influential in the results. However, if confirmed in large populations, the potential public 

health benefit could be substantial. Therapeutic options would be available for high-risk 

patients, who, despite dramatic reductions in lead exposure in developed countries, are still 

adversely affected by lead. Lin et al. (2003) noted that, based on their data, chelation could 

delay the need for hemodialysis by 3 years. Therefore, this unique line of research is deserving 

of further study. Prospective studies consistent with the results of Yu et al. (2004) will likely be 

needed to justify randomized, controlled chelation trials. 

6.4.4.4 Mortality Studies 

As summarized in Steenland et al. (1992), mortality studies have consistently shown 

excess mortality from chronic kidney disease in lead workers. This increased risk has been most 

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apparent in workers exposed in earlier time periods, becoming nonsignificant in later calendar 

time periods in a number of studies. Steenland et al. (1992) reported similar results in a study of 

1990 former lead smelter workers. This cohort was made up of predominantly white men who 

had worked in a lead-exposed department for at least 1 year between 1940 and 1965. Mean (SD) 

blood lead, measured in 1976 in 173 members of this cohort, was 56.3 μg/dL (12.9). There were 

8 deaths from chronic kidney disease. Compared to the U.S. white male population, the 

standardized mortality ratio was 1.26 (95% CI: 0.54, 2.49). The standardized mortality ratio 

increased with duration of exposure from 0.79 in workers exposed 1-5 years to 2.79 in workers 

exposed >20 years, although the standardized mortality ratios did not reach significance (CI not 

reported). Lead exposure in U.S. industries has declined over the years, and this has been 

hypothesized as an explanation for the reduction in mortality from renal disease observed in this 

type of study. However, that fact that improved treatments for chronic renal disease have led to 

a decrease in mortality from end-stage renal disease (U.S. Renal Data System, 2004) may also be 

a factor. The mortality studies by Steenland et al. (1992) and others are further described in 

Annex Table AX6-4.4. 

6.4.5 Lead Nephrotoxicity in Children 

6.4.5.1 Studies in Adults Following Childhood Lead Poisoning 

Henderson clearly established an increased risk for lead nephropathy in adult survivors of 

untreated childhood lead poisoning (Henderson, 1955). Lead nephropathy was responsible for 

substantial mortality in the Queensland, Australia population. However, as noted in the 1986 

Lead AQCD, other studies of adults who survived childhood lead poisoning have not reported 

this degree of renal pathology. Studies published since 1986 have not observed the degree of 

renal pathology noted in the Queensland work either but have revealed some interesting findings. 

These studies, along with other studies of renal effects of lead in children, are presented in 

Annex Table AX6-4.5. Pertinent results are discussed below. 

A study of comparing 21 adults, who had experienced childhood lead poisoning between 

1930 and 1942, to age, sex, race, and neighborhood-matched controls found no significant 

differences in blood lead level, serum creatinine, or BUN (Hu, 1991). Mean measured creatinine 

clearance was unexpectedly higher in the previously lead-poisoned group compared to controls 

(112.8 versus 88.8 mL/min/1.73 m2

 [p < 0.01]). Mean in the lead-exposed group was also higher 

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than the predicted value of 94.2 mL/min/1.73 m2 from the nomogram of Rowe et al. (1976). 

One survivor, who was identified but not included in the study, had been diagnosed with chronic 

interstitial nephritis on renal biopsy. Her blood lead was 30 μg/dL and her presentation was thus 

consistent with actual lead nephropathy. Strengths of this study included clear criteria for lead 

poisoning and assessment of clinical renal function that included both measured and estimated 

creatinine clearances. However, the study was limited by small size and the fact that the number 

enrolled was a very small subset of the initially identified cohort of 192. At least 43 (22.4%) of 

the 192 were confirmed to be deceased. That group had evidence of higher initial lead exposure, 

which raises concern regarding survivor bias in the study group. More importantly, the higher 

mean creatinine clearance in the lead exposed group provides further evidence for lead-related 

hyperfiltration. Again, as discussed in the occupational study section, this may hamper attempts 

to detect associations between lead dose and adverse renal effects. 

Another study compared 62 participants who were diagnosed and chelated between 1966 

and 1972 for initial blood lead levels >100 μg/dL to 19 age-matched siblings whose initial blood 

lead levels were <40 μg/dL (Moel and Sachs, 1992). Mean initial blood lead level was 

150.3 μg/dL (SD 77.1) in the 62 survivors of lead poisoning; levels in the siblings could not be 

precisely quantified since values <40 μg/dL were not reported as exact values. Mean age at 

diagnosis was 2.2 years; age at follow-up was 22.2 years. Blood lead and renal function were 

serially monitored in the population. In 1983, mean blood lead in the poisoned group was 

statistically higher than in siblings (means of 14.5 and 11.6 μg/dL, respectively) but, by 1989, 

both groups had a mean lead of 7.4 μg/dL. Renal outcomes included serum creatinine, uric acid, 

and β2-microglobulin, fractional excretion of β2-microglobulin, urinary protein:creatinine ratio, 

and tubular reabsorption of phosphate. No statistically significant differences between 

previously lead-poisoned children and their siblings were observed. The prevalence of abnormal 

values between the two groups was not different. Initial blood lead level was not associated with 

serum creatinine, after adjustment for age, gender, and body mass index. However, since blood 

lead levels were not quantified in the siblings, their values were entered as 40 μg/dL in the 

continuous blood lead model. Lead was also entered as a dichotomous variable (poisoned versus 

siblings). Given the data available, the analysis was limited. No cumulative measure of lead 

was analyzed nor was the serially obtained data analyzed with longitudinal modeling. Four of 

62 participants did experience an increase in serum creatinine such that their levels were 

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$1.4 mg/dL by the end of the study period. These subjects may reflect lead-related renal 

toxicity, especially given the young age of the participants. However, it can be concluded that, 

despite lead exposures that are now considered extremely high, the degree of renal pathology 

was clearly not to the extent seen in Australia. The fact that these children were chelated when 

lead poisoning was diagnosed but the Queensland children were not may be an important 

distinction. Additional follow-up with longitudinal analysis would be of value in these children 

in order to evaluate their renal function as they develop other renal risk factors. 

6.4.5.2 Lead Body Burden in Children with Chronic Renal Disease 

Scharer et al. (1991) reported higher lead content in deciduous teeth in 22 German 

children, age 5-14 years, with varying degrees of renal insufficiency compared to a control group 

of 20 siblings or neighbors and a group of 16 children without known lead exposure. Mean 

dental lead content was 2.8, 1.7, and 1.4 μg/g, in the three groups, respectively. Lead levels in 

teeth were significantly higher in both the patient and sibling/neighbor control groups compared 

to the unexposed control group. Mean blood lead in the renal patients was only 2.9 μg/dL 

(range 1.1-10.1 μg/dL). Lead in teeth was not correlated with duration of renal impairment. 

However, reflective of the ongoing controversy at the time this article was published regarding 

whether decreased renal excretion causes increased lead storage, the authors attributed elevated 

lead levels to both exposure and accumulation from decreased renal excretion. 

6.4.5.3 General Population Studies in Children 

In the first study of the renal effects of lower level environmental lead exposure in 

children (as opposed to lead-poisoned children), Bernard et al. (1995) carried out a crosssectional study of 195 children in the Czech Republic. One hundred forty-four children (63 boys 

and 81 girls) lived in 2 areas close to a lead smelter (designated as exposed groups one and two). 

A control group of 51 children lived in a rural area. Blood lead levels and urinary renal early 

biologic effect markers (RBP, $2-microglobulin, NAG, albumin, and Clara cell protein) were 

obtained. Age ranged from 12 to15 years. In girls, mean blood lead concentrations in controls 

and exposure groups one and two were 8.4, 9.4, and 12.9 μg/dL, respectively. Corresponding 

values in boys were 8.7, 10.9, and 14.9 μg/dL, respectively. These levels were significantly 

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higher in both exposed groups compared to the control group. In contrast, blood cadmium levels 

were similar among all groups. After adjustment for age, sex, blood cadmium, and zinc 

protoporphyrin, log transformed blood lead was associated with log transformed RBP (β = 0.302, 

p = 0.005). 

Verbeck et al. (1996) studied 151 Romanian children residing at various distances from a 

lead smelter. Associations between blood lead levels and renal outcome measures (urinary RBP, 

NAG, α1-microglobulin, albumin, and alanine aminopeptidase) were analyzed. Mean age was 

4.6 years (range of 3-6 years); gender was evenly divided. Mean blood lead was 34.2 μg/dL 

(SD 22.4), which is much higher than in Bernard et al. (1995). After adjustment for age and 

gender, a 10 μg/dL increase in blood lead was associated with a 13.5% (90% CI: 10.2, 17) 

increase in NAG excretion. No threshold was observed. Blood cadmium levels measured in a 

subset of the population were all <2 μg/L; however, this variable was not entered into the 

regression model. 

Another study included 200 French children who resided close to smelters along with 

200 age and gender matched controls recruited from areas believed to be unpolluted by heavy 

metals (De Burbure et al., 2003). Blood lead and cadmium were measured. Renal outcomes 

included urinary total protein, albumin, transferrin, $2-microglobulin, RBP, brush border 

antigens, and NAG. Age ranged from 8.5 to 12.3 years. Geometric mean blood leads ranged 

from 2.7 μg/dL (SD 0.2) in female controls to 4.2 μg/dL (SD 0.2) in exposed males. The highest 

geometric mean blood cadmium was 0.52 μg/L. After adjustments for covariates, blood lead 

was not associated with any renal outcomes; however, blood cadmium was positively associated 

with NAG. This association was present in both control and exposed areas. Notably, the blood 

lead levels in this study were much lower than in the two studies discussed above. 

Staessen et al. (2001) studied 200 17-year-old Belgian children. The two exposed groups 

were recruited from industrialized suburbs, whereas, the control group was recruited from a rural 

area. Mean blood lead levels were 1.5, 1.8, and 2.7 μg/dL in controls, and exposed groups one 

and two, respectively. The renal outcome measures analyzed were urinary $2-microglobulin and 

serum cystatin-C. Although blood lead levels were low, after adjustment for sex and smoking 

status, blood lead was associated with both $2-microglobulin and cystatin-C. Interestingly, blood 

cadmium was not associated with either outcome. 

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The current lack of sensitive markers of early renal damage that have been shown to 

predict subsequent renal function decline in longitudinal studies of lead exposed populations is 

problematic for research in this field. This is particularly true when studying children who do 

not have many of the other renal risk factors, such as hypertension and diabetes that older adults 

do. Coratelli et al. (1988) reported a decline in urinary NAG in association with a 1 month 

period of decreased occupational exposure in 20 adult lead battery factory workers followed 

over a 1 year period. Clinical renal function measures were not studied however. Sarasua et al. 

(2003) studied 526 adults and children, a mean of 4.5 years after an initial evaluation of renal 

function including measurement of urinary albumin, NAG, RBP, and alanine aminopeptidase. 

These participants were drawn from three populations exposed to volatile organic compounds 

and explosives via groundwater and controls. Follow-up was performed to determine if the EBE 

markers remained elevated and whether the presence of elevated EBE markers at baseline was 

associated with abnormalities in serum creatinine, serum cystatin C, 24-h creatinine clearance, 

and urine osmolality at follow-up. Among children who had elevated EBE markers at baseline, 

renal EBE markers remained elevated in 38%. However, none remained elevated in the 32 who 

had completed adolescence by the time of the follow-up. The authors noted the potential for 

puberty related biomarker changes. Further, abnormalities in the clinical measures were rare at 

follow-up. In contrast, elevated EBE markers at baseline in adults with chronic medical 

conditions of risk to the kidney, such as diabetes and to a lesser extent heart disease and 

hypertension, had persistent elevation of EBE markers and evidence of worse renal function at 

follow-up. Limitations of this study include limited data analysis, some loss to follow-up, and 

limited information on whether the original exposures for which these populations were studied 

may have influenced these results. The authors stated that no significant differences in renal 

outcomes between participants from exposed and control communities at follow-up were 

observed and noted that kidney function was not worse in exposed communities in the initial 

evaluations, which appeared to refer to the biomarkers as well. However, this report does not 

indicate whether exposure changed between the initial biomarker collection and the follow-up 

(i.e., decreased substantially or stopped altogether). Still the study illustrates the need for further 

prospective research to validate EBE markers in nephrotoxicant-exposed populations. 

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6.4.6 Mechanisms for Lead Nephrotoxicity 

Individuals who have been heavily exposed to lead are at increased risk for both gout and 

renal disease (Shadick et al. 2000; Batuman 1993). Lead is thought to increase serum uric acid 

(urate) by decreasing its renal excretion (Emmerson, 1965; Ball and Sorensen, 1969; Emmerson 

and Ravenscroft, 1975). As discussed above, research in the last decade indicates that lead is 

nephrotoxic at lower levels than previously recognized. The same is true for uric acid (Johnson 

et al., 2003). Therefore, it is possible that one mechanism for lead-related nephrotoxicity, even 

at current lower levels of lead exposure, is via increasing serum uric acid. 

In order to address this question, Weaver et al. (2005a) analyzed data from 803 current 

and former lead workers to determine whether lead dose was associated with uric acid and 

whether previously reported associations between lead dose and renal outcomes (Weaver et al., 

2003) were altered after adjustment for uric acid. Outcomes included uric acid, blood urea 

nitrogen, serum creatinine, measured and calculated creatinine clearances, and urinary NAG and 

RBP. Mean uric acid, tibia lead, and blood lead levels were 4.8 mg/dL (SD 1.2), 37.2 μg/g bone 

mineral (SD 40.4), and 32.0 μg/dL (SD 15.0), respectively. None of the lead measures (tibia, 

blood, and DMSA-chelatable lead) were associated with uric acid, after adjustment for age, 

gender, body mass index, and alcohol use. However, when effect modification by age on these 

relations was examined, both blood and tibia lead were significantly associated in participants in 

the oldest age tertile (β = 0.0111 [95% CI: 0.003, 0.019] and β = 0.0036 [95% CI: 0.0001, 

0.007]) for blood and tibia lead, respectively). These models were further adjusted for blood 

pressure and renal function. Hypertension and renal dysfunction are known to increase uric acid. 

However, they are also risks associated with lead exposure. Therefore, adjustment for these 

variables in models of associations between lead dose and uric acid likely results in overcontrol. 

On the other hand, since non-lead-related factors contribute to both renal dysfunction and 

elevated blood pressure, lack of adjustment likely results in residual confounding. Therefore, as 

expected, associations between lead dose and uric acid decreased after adjustment for systolic 

blood pressure and serum creatinine, although blood lead remained borderline significantly 

associated (β = 0.0071 [95% CI: !0.001, 0.015]). However, when the population was restricted 

to the oldest tertile of workers with serum creatinine greater than the median (0.86 mg/dL), likely 

the highest risk segment of the population, blood lead remained significantly associated with uric 

acid even after adjustment for systolic blood pressure and serum creatinine (β = 0.0156). 

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Next, in models of renal function in all workers, uric acid was significantly associated with all 

renal outcomes except NAG. Finally, in the oldest tertile of workers, after adjustment for uric 

acid, associations between lead dose and NAG were unchanged, but fewer of the previously 

significant (p # 0.05) associations noted between lead dose and the clinical renal outcomes in 

Weaver et al. (2003a) remained significant. 

Data from the Normative Aging Study indicate that lead dose, at levels lower than those 

known to increase the risk for gout or in the study of Weaver et al. (2005a), is associated with 

increased uric acid (Shadick et al., 2000). Mean blood, patella, and tibia lead levels were 

5.9 μg/dL, 30.2 μg/g bone mineral, and 20.8 μg/g bone mineral, respectively, in 777 participants. 

A significant association between patella lead and uric acid (β = 0.007 [[95% CI: 0.001, 0.013]; 

p = 0.02) was found, after adjustment for age, BMI, diastolic blood pressure, alcohol ingestion, 

and serum creatinine. Borderline significant associations between tibia (p = 0.06) and blood lead 

(p = 0.1) and uric acid were also observed. Notably these associations were significant even 

after adjustment for blood pressure and renal function, providing further evidence that low-level 

lead increases uric acid. 

These data suggest that older workers comprise a susceptible population for increased uric 

acid due to occupational lead exposure. Uric acid may be one mechanism for lead-related 

nephrotoxicity. However, this is not the only mechanism, since in Weaver et al. (2005a), the 

association between blood lead and serum creatinine remained significant even after adjustment 

for uric acid. These mechanistic relations have more than just theoretical importance. Clinically 

relevant therapies may be possible since, as noted above, EDTA chelation has been reported to 

improve both renal function and urate clearance in patients with renal insufficiency and gout, 

even when EDTA-chelatable lead body burdens were low (Lin et al., 2001). 

6.4.7 Susceptible Populations for Lead Nephrotoxicity 

6.4.7.1 Chronic Medical Diseases 

The general population studies by Tsaih et al. (2004) and Muntner et al. (2003) (discussed 

in section 6.4.4.1 General Population Studies above) indicate that patient populations with 

diabetes and hypertension are at increased risk for adverse renal effects of lead. The work of 

Lin and colleagues (several articles discussed in section 6.4.4.3 Patient Population Studies 

above) indicates that patients with CRI and gout are also at increased risk. In these settings, lead 

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appears to acts as a cofactor with other renal risk factors to cause early onset of renal 

insufficiency and/or a steeper rate of renal function decline. It is likely that the presence of 

larger high risk populations within general populations is an important factor in the lower lead 

dose thresholds noted for the adverse effects of lead on the kidney in environmental compared to 

occupational research. 

6.4.7.2 Age 

The work of Weaver and colleagues (discussed in Section 6.4.4.2.3 Korean Lead Workers 

above) suggests that older age is a risk factor. This is consistent with research in general 

populations (Lindeman et al., 1985) and is biologically plausible, since most renal risk factors 

increase with age. Gonick and Behari (2002) have summarized the data regarding the potential 

contribution of lead exposure to essential hypertension; similar issues may be involved with the 

renal dysfunction observed in aging. 

6.4.7.3 Genetic Polymorphisms 

6.4.7.3.1 δ-Aminolevulinic Acid Dehydratase (ALAD) 

Research in the last two decades suggests that several genetic polymorphisms affect lead 

toxicokinetics (i.e., modify the relation between lead exposure and dose). Of those that are 

potentially relevant to the kidney, data on the gene that encodes for δ-aminolevulinic acid 

dehydratase (ALAD) are the most important in this regard. The ALAD enzyme is a principal 

lead binding protein; the isozymes in those with the ALAD2 allele are more electronegative and 

bind a greater proportion of blood lead than does the protein in individuals with the ALAD11 

genotype (Bergdahl et al., 1997). Research to date indicates that individuals with the ALAD2 

allele generally have higher blood lead levels than those with the ALAD11 genotype, although 

this may not be the case at lower levels of lead exposure (i.e., mean blood lead levels <10 μg/dL) 

(Kelada et al., 2001). Participants with the ALAD2 allele have been found to have lower bone 

lead levels in some studies (Hu et al., 2001; Kamel et al., 2003); other toxicokinetic differences 

have also been reported (Fleming et al., 1998; Hu et al., 2001; Schwartz et al., 1997; Smith et al., 

1995). Overall, these data suggest that tighter binding of lead by the isozymes of the ALAD2 

allele decreases lead sequestration in bone. 

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In contrast, data to determine whether the ALAD polymorphism impacts the renal toxicity 

of lead are still quite limited. The only environmentally exposed population in which this has 

been addressed is the Normative Aging Study. Wu et al. (2003) (discussed in detail in section 

6.4.4.1.2 above) analyzed data to determine whether the ALAD genetic polymorphism modified 

associations between lead dose and uric acid, serum creatinine, and estimated creatinine 

clearance, 114 (16%) of the study group were either homozygous or heterozygous for the variant 

ALAD2 allele. None of the three outcomes were significantly different by genotype. However, 

effect modification by genotype on the association between tibia lead and serum creatinine was 

observed; the $ coefficient (and slope) was greater in the group with the variant allele (β = 0.002 

[SE not provided]; p = 0.03). Effect modification of borderline significance (p < 0.1) on 

relations between of patella and tibia lead with uric acid was observed; this was significant in 

participants whose patella lead levels were above 15 μg/g bone mineral (β = 0.016 [SE not 

provided]; p = 0.04). Similar to the serum creatinine model, patella lead was associated with 

higher uric acid in those with the variant allele. Genotype did not modify lead associations in 

models of estimated creatinine clearance. 

The impact of the ALAD polymorphism on renal outcomes has been studied in four 

occupationally-exposed populations to date. The two that assessed both associations and effect 

modification by genotype are discussed here. Weaver et al. (2003b) analyzed data from 798 lead 

workers. Lead and renal function measures, as well as mean lead levels, were described in 

Weaver et al. (2003a) in Section 6.4.4.2 above. A total of 79 (9.9%) participants were 

heterozygous for the ALAD2 allele (none was homozygous). After adjustment, participants with 

the ALAD2 allele had lower mean serum creatinine and higher calculated creatinine clearance. 

Effect modification by ALAD on associations between blood lead and/or DMSA-chelatable lead 

and three of six renal outcomes was observed. Among those with the ALAD12 genotype, higher 

lead measures were associated with lower BUN and serum creatinine and higher calculated 

creatinine clearance. Among older workers (age $ median of 40.6 years), ALAD genotype 

modified associations between lead dose and uric acid levels. Higher lead dose was significantly 

associated with higher uric acid in workers with the ALAD11 genotype; associations were in the 

opposite direction in participants with the variant ALAD12 genotype (Weaver et al., 2005c). 

Ye and colleagues (2003) assessed effect modification by ALAD on associations between 

blood lead with urinary NAG and albumin in a study of 216 lead workers. Geometric mean 

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blood lead was 37.8 μg/dL in 14 workers with the ALAD12 genotype and 32.4 μg/dL in workers 

with the ALAD11 genotype. After adjustment for age, NAG was borderline statistically higher 

in those with the variant allele whose blood lead levels were $40 μg/dL. In all lead workers, 

after adjustment for age, gender, smoking, and alcohol ingestion, a statistically significant 

positive association between blood lead and creatinine adjusted NAG was observed in the 

workers with the ALAD12 genotype but not in lead workers with the ALAD11 genotype (the 

groups were analyzed separately rather than in an interaction model). 

Thus, two of the three studies reported steeper slopes for one or more associations 

between lead dose and adverse renal function in participants with the ALAD2 allele compared to 

those with the ALAD11 genotype which suggests that the variant ALAD gene confers additional 

risk for adverse renal outcomes in lead exposed populations. If the associations of Weaver et al., 

(2003b) represent lead-induced hyperfiltration their results could be consistent with increased 

risk from the variant allele as well. Ultimately, analysis of longitudinal data in the Korean lead 

worker population will be required to understand these complex relations. 

6.4.7.3.2 BsmI Polymorphism of the Vitamin D Receptor (VDR) Gene 

In contrast to ALAD, relatively few data on the BsmI polymorphism of the gene that 

encodes for the vitamin D receptor (VDR) are available in lead exposed populations. 

Polymorphisms of the VDR gene are of interest in these populations due to the role of vitamin D 

and its receptor in regulating both intestinal calcium absorption and bone mineralization. These 

pathways impact lead absorption from the gastrointestinal tract and may impact lead storage 

and/or release from bone (Onalaja and Claudio, 2000). Analysis of data from the first evaluation 

of the Korean lead worker cohort found that participants with the B allele had significantly 

higher blood, DMSA-chelatable, and tibia lead levels than those with the bb genotype (Schwartz 

et al., 2000a); significantly higher patella lead in workers with the B allele was reported in data 

from the third evaluation (Theppeang et al., 2004). A study of 216 lead workers similarly 

reported higher blood lead levels in workers with the B allele (n = 20), after adjustment for age, 

gender, smoking, alcohol ingestion, and calcium ingestion, education, ALAD genotype, and 

ambient lead exposure (Ye et al., 2003). In a study of 504 former organolead manufacturing 

workers, with an average of almost two decades since last occupational exposure, VDR genotype 

was not associated with tibia lead concentrations (Schwartz et al., 2000c). However, the slope 

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of the positive association between age and tibia lead concentration was steeper in participants 

with the B allele compared to those with the bb genotype and tibia lead declined with years since 

last exposure in participants with the bb genotype, but increased in those with the B allele. 

In contrast, Chuang and colleagues (2004) found no difference in current or cumulative blood 

lead by BsmI polymorphism in 544 lead workers. 

Work in two of the populations described above has also provided information on the 

impact of the BsmI VDR polymorphism. Of the 798 participants in Weaver et al. (2003b), 

89 (11.2%) had genotype Bb or BB. No significant differences were seen in renal outcomes by 

VDR genotype nor was consistent effect modification observed. However, those authors 

assessed effect modification by this polymorphism on associations between patella lead and renal 

outcomes in current and former Korean lead workers in data from the third evaluation where 

patella lead was measured. Results were compared to those with three other lead biomarkers. 

The same six renal outcomes as in Weaver et al. (2003a) were measured. Mean blood, patella, 

tibia, and DMSA-chelatable lead were 30.9 μg/dL (SD 16.7), 75.1 μg lead/g bone mineral 

(SD 101.1), 33.6 μg lead/g bone mineral (SD 43.4), and 0.63 μg lead/mg creatinine (SD 0.75), 

respectively, in 647 lead workers (Weaver et al. [2005b]). Little evidence of effect modification 

by genotype on associations between patella lead and renal outcomes was observed. However, 

the VDR polymorphism did modify associations between the other lead biomarkers and serum 

creatinine and calculated creatinine clearance. Higher lead dose was associated with worse renal 

function in participants with the variant B allele. Models in two groups, dichotomized by 

median age, showed this effect was present in the younger half of the population. The authors 

were able to exclude different participant subsets as an explanation for the difference in VDR 

findings between the two evaluations. Longitudinal changes in renal function between 

evaluations may account for these findings and are currently being evaluated in longitudinal 

data analysis. 

Ye and colleagues (2003) reported higher systolic blood pressure, after adjustment for 

age, in those with the variant allele whose blood lead levels were $40 μg/dL. In all lead 

workers, after adjustment for age, gender, smoking, and body mass index, a statistically 

significant positive association between blood lead and systolic blood pressure was observed in 

the 20 lead workers with the variant B allele, but not in lead workers with the bb genotype. 

Again, the fact that the genotype groups were analyzed separately, rather than in an interaction 

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model, decreased the study’s power to detect a difference. This could be an explanatory factor 

for the lack of effect modification by VDR genotype on associations between blood lead and 

urinary albumin and NAG observed. 

In conclusion, an increasing body of literature indicates that both of these polymorphisms 

affect lead toxicokinetics. However, data to determine if these polymorphisms impact renal 

function are still quite limited. Existing data are suggestive of an increased renal risk in lead 

exposed populations with the variant alleles of both polymorphisms. 

6.4.8 Confounding of the Renal Effects of Lead by Other Potential 

Risk Factors 

Studies selected for discussion in Section 6.4 above have generally controlled for at least 

the most basic risk factors known to affect renal function such as age, gender, and body mass 

index (or weight and height separately). Some have controlled for many other potentially 

important risk factors. In addition, exposure to other nephrotoxicants must be considered. 

Notably, although these are listed under confounders, some may be effect modifiers as well. 

6.4.8.1 Cadmium 

Similar to lead, cadmium is an ubiquitous nephrotoxicant that accumulates in the body. 

Environmental exposure in the United States occurs primarily through food and smoking 

(Agency for Toxic Substances and Disease Registry, 1993). Cadmium in food is a result of soil 

pollution from a variety of human activities such as phosphate fertilizer use, industrial releases 

from smelting, and fuel combustion. An analysis of NHANES III data, collected in a 

representative sample of the U.S. population from 1988-1994, indicates that mean urinary 

cadmium is 0.48 μg/g creatinine and 97.7% of the population has a level #2 μg/g creatinine 

(Paschal et al., 2000). Also similar to lead, cadmium causes proximal tubule pathology and is a 

risk factor for CRI. 

The existing data indicate that cadmium, at exposure levels common in the U.S., 

confounds associations between lead exposure and at least one renal outcome, NAG. Roels et al. 

(1994) reported higher mean NAG in their lead-exposed group; however, NAG was correlated 

with urinary cadmium but not blood or tibia lead, despite the fact that mean urinary cadmium 

was only 1.04 and 0.53 μg/g creatinine in workers and controls, respectively. Cardenas et al. 

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(1993) reported a similar finding. Bernard et al. (1995) found an association between urinary 

cadmium and the NAG-B isoenzyme (released with breakdown of proximal tubular cells) in 

49 cadmium workers and 20 age-matched controls. In multiple linear regression, urinary 

cadmium, but not lead, was associated with NAG-B, after adjustment for age. The association 

was significant even in the 44 participants with levels <2 μg/g creatinine. However, NAG-A 

(released by exocytosis) was correlated with urinary lead (the only lead measure), but not 

cadmium. Roels et al. (1995) reviewed data pertinent to the potential for cadmium confounding 

of associations between lead and NAG. In more recent work, Weaver et al. (2003a) measured 

urinary cadmium in a subset of 191 of the 803 workers in their study (mean urinary cadmium 

was 1.1 μg/g creatinine). Higher urinary cadmium levels were associated with higher NAG. 

Of the lead measures obtained, only tibia lead was significantly associated with NAG in the 

cadmium subset. When urinary cadmium and tibia lead were entered as covariates in the same 

model, both remained associated with NAG (p < 0.05). However, in comparing the effects, 

a 0.5 μg/g creatinine increase in cadmium had the same effect on NAG as a 66.9 μg/g bone 

mineral increase in tibia lead. When compared by ranges of exposure in this population, 

environmental level cadmium dose had a larger impact on NAG than did occupational lead dose. 

Cadmium exposure may confound relations between lead exposure and other renal 

outcomes as well, although the data are too limited to draw firm conclusions. Positive 

associations between urinary cadmium, which is thought to be the best measure of cumulative 

cadmium exposure in the absence of cadmium-related renal damage, and low molecular weight 

(LMW) proteinuria are well established in the occupational setting. LMW proteinuria, most 

commonly assessed by β2-microglobulin, is generally progressive at levels >1,500 μg/g 

creatinine in workers with substantial body burdens (one or more historical urinary cadmium 

>20 μg/g creatinine) but may also be progressive at lower levels (Roels et al., 1997; Bernard, 

2004). More importantly, clinical renal function also declines as evidenced by decreasing GFR 

in cadmium exposed workers followed longitudinally after removal from exposure due to LMW 

proteinuria (Roels et al., 1989; 1997). 

In contrast to the clear evidence that cadmium is a renal toxicant at occupational levels of 

exposure, the renal risk from lower level cadmium exposure remains uncertain. Most studies of 

environmental cadmium exposure are cross-sectional and have assessed EBE markers, rather 

than clinical renal outcomes (Alfven et al., 2002; Jarup et al., 2000; Noonan et al., 2002; Olsson 

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et al., 2002). The Cadmibel study, a general population study of exposed residents from both 

cadmium polluted and unpolluted areas (discussed in Section 6.4.4.1.1 above), found correlations 

between urinary cadmium and several urinary EBE markers (NAG, RBP, $2-microglobulin, 

calcium, and amino acids) (Buchet et al., 1990). In those models, after adjustment for urinary 

cadmium and other covariates, blood lead was significant in models of β2-microglobulin and 

amino acids but not NAG. However, in this same population, blood lead was inversely 

associated with creatinine clearance, whereas urinary and blood cadmium were not (Staessen 

et al., 1992). A 5 year follow-up was conducted to determine the significance of the EBE 

abnormalities (Hotz et al., 1999). In this study, models of renal function (two dichotomized 

outcomes: a 20% decline in creatinine clearance and a 20% increase in albumin excretion) in 

relation to quartiles of urinary cadmium and the EBE markers at baseline were analyzed by 

likelihood ratios. Baseline variables did not predict adverse renal outcomes. However, 25% of 

the original population was lost to follow-up; available data indicated that their baseline renal 

function was worse than those who participated in the follow-up study. This may have biased 

the study towards the null. 

Two recent publications suggest that low-level cadmium exposure is associated with 

adverse clinical renal outcomes. Elevated urine cadmium levels were associated with prevalent 

microalbuminuria and decreased calculated creatinine clearance after adjustment for age, sex, 

race, smoking, and use of diuretics in an analysis of 16,094 participants in the NHANES III 

study (Young et al., 2004). Hellstrom et al. (2001) reported increased rates of renal dialysis 

and transplantation in residents of cadmium-polluted areas in Sweden. Compared to the 

“no-exposure group” (domicile >10 km from a battery plant), age-standardized rate ratios were 

1.4 (95% CI: 0.8, 2.0) in the low-exposure group (domicile 2 to 10 km) and 1.9 (95% CI: 1.3, 

2.5) in the moderate-exposure group (domicile <2 km). Exposure categorization was based on 

environmental monitoring in the study areas. Cadmium dose was not directly measured although 

occupationally exposed participants were considered in a separate group. Neither of these 

studies assessed lead exposure as a covariate, which would be important given the Cadmibel 

results (Staessen et al., 1992). 

In conclusion, cadmium clearly confounds associations between lead dose and 

NAG. Given the similarities in both nephrotoxicants, cadmium may confound and/or modify 

associations between lead and other renal outcomes. However, data on the 

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concentration-response relation between environmental cadmium and the kidney are too limited 

to assess the potential for this at present. Future studies assessing both lead and cadmium are 

needed. 

6.4.9 Summary of the Epidemiologic Evidence for the Renal Effects of Lead 

In the last two decades, the quality of research on the renal impact of lead exposure has 

advanced dramatically. As a result, a much more accurate assessment of the adverse renal 

impact of lead exposure can now be made. Studies of environmentally-exposed general 

populations are one of the most important advances in this regard. The landmark Cadmibel 

study (Staessen et al., 1992) was the first to raise concern that the lead dose threshold for adverse 

renal effects in the general population was much lower than previously appreciated based on 

occupational data. Research in the Normative Aging Study population reached similar 

conclusions and suggested that both cumulative and circulating lead are associated with 

longitudinal decline in renal function. Diabetics were a particularly susceptible risk group in this 

regard. The NHANES III data analysis (Muntner et al., 2003) are notable for a sample size that 

is, by far, the largest of the environmental studies, comprehensive adjustment for other renal risk 

factors and the fact that population is representative of the U.S. population. Thus, the fact that 

renal dysfunction was observed in hypertensives at a mean blood lead of only 4.2 μg/dL and in 

the 1st quartile compared to the reference group (blood lead range from 2.5 to 3.8 μg/dL), 

provides strong evidence that the kidney is a target organ for adverse effects from lead at current 

U.S. environmental exposure levels. 

Studies involving the longitudinal assessment of renal function decline in susceptible 

patient populations in relation to baseline chelatable lead body burden and therapeutic chelation 

constitute the other major advance in lead-renal research in the last two decades. Chelation was 

beneficial in an EDTA-chelatable lead level range from 80 or 150 to 600 μg/72 h, depending on 

the study (Lin et al., 1999, 2003). These studies suggested that lead body burden, at much lower 

levels than previously recognized, contributes to renal dysfunction in populations with CRI from 

a range of causes. This work also suggests that renal function in patients with CRI stabilizes 

and, in some cases, improves after therapeutic EDTA chelation of lead levels well below the 

level currently thought to require chelation. 

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A finding of note from the occupational studies is the observation of inverse associations 

(higher lead dose with lower BUN, serum creatinine, and/or higher creatinine clearance) in 

several studies. This may indicate lead-related hyperfiltration and have mechanistic 

implications. Regardless, significant associations could be obscured if opposite direction 

associations are present in different segments of the study population and interaction models to 

address this are not performed. This is a valid concern, since the settings in which these inverse 

associations are most likely are not well defined. 

The renal impact in children from lead exposure at current environmental levels is 

difficult to assess, since the studies have involved measurement of EBE markers and their 

prognostic value is uncertain. Susceptible populations due to chronic medical diseases have 

clearly been established; risk from genetic polymorphisms may be important, but further study is 

required. Studies of potential mechanisms for the adverse renal effects of lead in humans, such 

as via uric acid have more than just theoretical importance, since EDTA chelation has been 

reported to improve both renal function and urate clearance in patients with renal insufficiency 

and gout (Lin et al., 2001). With an improved understanding of mechanisms, clinically relevant 

therapies may be possible. 

6.5 CARDIOVASCULAR EFFECTS OF LEAD 

6.5.1 Summary of Key Findings of the Cardiovascular Effects of Lead from 

the 1985 Lead AQCD and Addendum, and 1990 Supplement 

The greater part of the evidence reviewed up to 1990 included analyses of the largest 

datasets available at the time, the National Health and Nutrition Evaluation Survey II (NHANES 

II), studying the U.S. population between 1976 and 1980, and the British Regional Heart Study 

(BRHS), studying men aged 40-59 years from 24 British towns. Analyses of the Welsh Heart 

Programme, a regional Welsh study, and the Caerphilly Collaborative Heart Disease Study, a 

cohort study of men aged 45-59 years living in one town in Wales, as well as smaller population 

and occupational exposure studies in the U.S., Canada, and Europe provided supporting 

evidence. These studies set enduring design and analysis standards by example for evaluating 

cardiovascular effects associated with blood lead levels in samples from diverse populations. 

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In general, the reviewed studies used multiple linear regression modeling of blood 

pressure and multiple logistic regression modeling of hypertension, cardiovascular mortality, and 

other cardiovascular disease, allowing adjustment of the blood lead effect on outcome by other 

factors known or suspected to be related to the exposure and outcome under study. The most 

commonly considered potential confounding factors were age, body mass index (BMI), alcohol 

use, and cigarette smoking. 

These studies were almost exclusively cross-sectional studies, measuring cardiovascular 

outcome, blood lead, and control variables once, though one Canadian occupational study and 

one Danish birth-year cohort study used a longitudinal design. Studies sometimes presented 

analyses stratified by sex or age, by both sex and age, or by “race.” Other analyses only reported 

results for one particular stratum. Separate analyses of datasets partitioned by stratified variables 

always reduce sample size available for statistical models, and, thereby, may reduce power to 

detect real effects. 

Evaluated as a whole, the blood pressure studies supported a small but significant 

association between increasing blood lead concentrations and increasing blood pressure in study 

groups. The effect was more consistent across studies in middle-aged men than in other groups, 

ranging from a 1.5 to 3.0 mm Hg increase in systolic blood pressure for each doubling of blood 

lead from the mean blood lead level, and from a 1.0 to 2.0 mm Hg increase in diastolic blood 

pressure for each blood lead doubling, across a wide range of blood lead concentration down to 

7 μg/dL. Most studies using multiple regression analyses stratified by sex were unable to find 

significant associations between blood pressure and blood lead in females, though one reanalysis 

of the NHANES II dataset did report a statistically significant relationship between diastolic 

blood pressure and lead in women aged 20 to 74 years. In studies reporting the use of different 

blood lead-blood pressure concentration-response relationships, log blood lead terms had lower 

probability values than linear blood lead terms, suggesting that increases in blood pressure with 

incremental fixed incremental increases in blood lead might be greater at lower blood lead 

concentrations than at higher concentrations. 

Three studies of groups with occupational exposure reported mixed results. One study 

found significant excess mortality due to cardiovascular disease during the period 1946-1965 in a 

case-control study in the United Kingdom, but not 1966-1985. A study of U.S. battery and lead 

production workers from 1947-1980 found significant excess mortality due to “other 

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hypertensive disease” (codes 444-447 in the ICD 1955 classification system), but not due to 

hypertensive diseases outside those classifications. No excess mortality due to hypertension was 

found in a study of U.S. smelter workers between 1940 and 1965. 

The BRHS study failed to reveal significant associations between blood lead and ischemic 

heart disease and stroke. However, electrocardiogram abnormalities associated with left 

ventricular hypertrophy were found related to blood lead in a subset of the NHANES II data, 

confirming an earlier study finding significant associations between ischemic changes and blood 

lead in lead workers. 

Noninvasive measurement of bone lead concentration using XRF techniques was still 

maturing during the literature review period covered by the 1986 AQCD document and later 

addendum and supplement. No studies were reported using bone lead as a marker for lead 

exposure. 

6.5.2 Effects of Lead on Blood Pressure and Hypertension 

6.5.2.1 Introduction 

Blood lead concentration remained the most widely used exposure index in blood 

pressure/hypertension epidemiologic studies from 1990 to present. Obtaining the sample is 

relatively noninvasive and quick, measurement techniques are well standardized and inexpensive 

with access to external quality assurance programs worldwide, and existing regulation and 

medical decision-making are based on blood lead levels. If exogenous lead exposure were the 

only determinant for blood lead concentration, it could be fair to state that a single blood lead 

measurement represented exposure to lead during the 30-90 day period preceding the 

measurement. However, blood lead concentration represents a combination of recent exposure 

to external sources and the influence of internal sources, principally bone lead. As detailed in 

Section 6.2, bone is a long-term storage depot for much of the lead absorbed by the body from 

external sources, and by weight can represent over 95% of the total body burden of lead in 

middle-aged persons, especially if external exposures are currently low. Bone lead has residence 

times of years to decades. Bones constantly absorb lead from and release lead to the circulatory 

system. Consequently, blood lead concentration is not only determined by current and recent 

past external exposure but is also influenced by existing bone lead concentration to a degree 

determined by current external exposure, accumulated past exposure stored in bones, and the 

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physiological state of the bones due to aging, disease, pregnancy, and lactation, among others. 

Studies using only blood lead concentration, as an exposure index cannot determine the relative 

contributions of current exogenous exposure and endogenous exposure to blood lead. Thus, they 

are unable to assess what part of measured blood lead effect on the circulatory system is due to 

possibly higher long duration past exposure and what part is due to the possibly immediate toxic 

effects of currently circulating lead. They are, instead, assessing a combined effect of past and 

present exposure in a proportion that will differ among subjects according to their past and 

present exposure, health history, and age. 

Elevated blood pressure can be evaluated as a continuous measure (mm Hg) or as a 

dichotomized measure (hypertension). The definition of hypertension involves a categorical 

cut point of mm Hg above which one is hypertensive and below normotensive. Kannel 

(2000a,b) notes that this number has dropped over time for systolic/diastolic pressure and further 

notes a continuous graded influence of blood pressure even within what is regarded as the 

normotensive range. Some concern for an arbitrary definition as the cut point and one that has 

changed over time is a consideration. However defined, even if greater than the cut point at that 

time used clinically, the separation into these two groups offers a different perspective than 

blood pressure per se. Hypertension has a different clinical relevance than blood pressure 

changes themselves. The disease condition as an outcome and a change in mm Hg in relation to 

exposure both offer the opportunity for insight into the clinical relevance of the relationships. 

Biomarkers like bone lead and blood lead also add input into the acute/chronic nature. 

The recently developed in vivo technique of XRF measurement of bone lead 

concentration has been used in a handful of studies to better assess the role of past exposure to 

lead on blood pressure and hypertension in essentially cross-sectional studies. Bone lead 

concentration provides a record of cumulative past exposure due to the long residence times of 

lead in bones, though the specific temporal pattern of past exposure cannot be readily determined 

from the measurement. Primarily cortical bones such as tibia have residence times measured in 

decades, whereas primarily trabecular bones such as calcaneus and patella have residence times 

measured in years to decades, reflecting different metabolic rates of the two bone types. As there 

is continual interchange of lead in bone and lead in blood, studies combining the measurement 

and modeling of both bone lead and blood lead have the best chance of dissecting out the roles of 

past and present lead exposure on blood pressure and hypertension. 

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The growing field of toxicogenetics now includes lead exposure epidemiology. The 

several studies combining subject evaluation of polymorphisms of genes thought to play a role in 

either the origin of cardiovascular disease, the toxicokinetics of lead or both are also reviewed. 

All epidemiologic studies of the cardiovascular effects of lead reviewed in this section as well as 

other additional studies are further summarized in Annex Table 6-5.1. 

6.5.2.2 Blood Pressure and Hypertension Studies Using Blood Lead as Exposure Index 

6.5.2.2.1 NHANES Studies 

NHANES contributed the largest datasets analyzed in this review. As the surveys are also 

representative of the U.S. population, their results may be more readily applied to the general 

U.S. population than smaller cohort or occupational studies. The several papers using this 

dataset sometimes come to different conclusions, depending on the statistical techniques used in 

analysis, including logarithmic or linear specification of the lead variable, stratification of 

analyses according to sex or ethnic groups or use of interaction terms to define these groups, use 

of survey-design corrected models, choice of covariates in the models, and different age ranges 

analyzed. 

NHANES II (1976-1980) 

In one NHANES II-based study, males and females (number unreported but less than 

9,000 combined) aged 20 to 74 years were studied with separate stepwise multiple regression 

models adjusted for sampling design (Schwartz, 1991). Mean blood lead levels were not 

reported. Covariates common to both male and female models were age and age2

, BMI, race, 

family history, cholesterol, zinc, tricep fold, and natural log lead. Models for men also included 

height and cigarette smoking. Natural log blood lead was significantly associated with diastolic 

blood pressure (systolic not reported) in males, with a 2.03 mm Hg diastolic (95% CI: 0.67, 

3.39) increase for every doubling of blood lead, and for females a 1.14 mm Hg increase (95% CI: 

0.13, 2.08). Interactions between blood lead and sex and between blood lead and race in a 

combined model were insignificant (not shown). The conclusion from these interaction terms is 

that the association between blood lead and diastolic blood pressure was not significantly 

different between men and women or between races. There was no mention of consideration of 

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model diagnostics, and the stepwise modeling may incorrectly include or exclude potentially 

confounding variables. 

The other NHANES II-based study focused on black-white differences in blood pressure 

related to blood lead (Sorel et al., 1991). There were 473 blacks and 3,627 whites in the study, 

each nearly evenly divided by sex, aged 18 to 74 years. As is usual in U.S.-based studies, 

race/ethnicity was based on self-report. Survey design-adjusted multiple regression models were 

stratified on sex and included age, BMI, and linear blood lead as covariates. The effect of race 

and poverty index was assessed by including their terms in models with and without blood lead 

and determining change in race or poverty coefficients by comparing confidence intervals. Each 

1 μg/dL increase in linear blood lead significantly predicted increased systolic blood pressure for 

both males (2.23 mm Hg [95% CI: 0.69, 3.61]), but not females (0.98 mm Hg [95% CI: !9.78, 

3.06]) for each doubling of blood lead. The differences in black and white (race variable) blood 

pressure coefficients did not significantly change when lead was in or out of the model, either for 

subjects below the poverty index or above the poverty index. Race does not appear to 

significantly modify the relationship between blood lead and systolic blood pressure. The paper 

reported no model diagnostics. There were reporting inconsistencies in the female-stratified 

models, in which the coefficients and 95% CI did not correspond. 

NHANES III (1988-1994) 

A study using the NHANES III dataset from all adults 20 years of age and up examined 

the effect of natural log blood lead on systolic and diastolic blood pressure (Den Hond et al., 

2002). Multiple regression analyses for each blood pressure measurement were stratified by sex 

and race, yielding four models for each blood pressure measurement. The mean blood levels 

were 3.6 μg/dL in white males (n = 4,685), 2.1 μg/dL in white females (n = 5,138), 4.2 μg/dL in 

black males (n = 1,761), and 2.3 μg/dL in black females (n = 2, 197). One group of covariates 

(age, age-squared, BMI, hematocrit, smoking, alcohol consumption, and an indicator variable for 

use of antihypertensive medications) were first entered as a block regardless of significance in 

each model, then another group of variables (coffee consumption, dietary calcium, dietary 

sodium/potassium ratio, total serum protein, total serum calcium, diabetes, and poverty index) 

was entered stepwise in the model without lead and the variable retained only if it was 

statistically significant (p < 0.05). Then log-transformed blood lead was forced into each model. 

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The model building procedure resulted in eight distinct models, each with their own unique mix 

of covariates. No model diagnostics were reported, nor was adjustment of results by survey 

sample weights and design. Only blacks had significant lead-systolic blood pressure 

associations; each doubling in blood lead was associated with a 0.90 mm Hg (95% CI: 0.04, 1.8) 

and 1.20 mm Hg (95% CI: 0.4, 2.0) increase in males and females respectively. The association 

of lead-diastolic blood pressure was also significant for black females (0.50 mm Hg [95% CI: 

0.01, 1.1]). Interestingly, increasing blood lead was associated with significantly decreased 

diastolic blood pressure in white males (!0.6 mm Hg [95% CI: !0.9, !0.3]). The authors did 

not comment on their finding that the significant total serum calcium covariate in these two 

groups had opposite signs too (white male serum calcium $ = 6.50 mm Hg/mmol/L, black 

female serum calcium $ = !5.58 mm Hg/mmol/L). Though the authors offered no formal test of 

the difference between the two serum calcium coefficients, since both were significantly 

different than the null hypothesis coefficient of 0 and different in sign, it could be concluded that 

those coefficients were significantly different between the two groups. As the authors do not 

present the serum calcium coefficients before forcing lead into the models, it is not certain that 

blood lead in the model was associated with the significant sign difference of the calcium 

coefficients or if the calcium coefficients had opposite signs between the two groups without 

lead in the model. As each model had a different set of covariates, the presence or absence of 

one of the other covariates could have produced the same results. Nevertheless, this pattern of 

results may indicate significant confounding between serum calcium and blood lead associations 

with blood pressure. Though the study suggested differences between blacks and whites in 

response to lead, no statistical tests were performed of differences in lead coefficients based on 

race. In addition, the black-white effect differences associated with blood lead may be due to 

possible confounding in some or all of the models. 

Limiting the study sample from NHANES III to women aged 40 to 59 years, another 

group of researchers addressed the relationship between blood lead and both blood pressure 

(n = 1,786) and hypertension (n = 2,165) (Nash et al., 2003). Blood pressure models excluded 

women who reported being under treatment for hypertension. Separate blood pressure multiple 

regression models were presented for diastolic and systolic blood pressure, each with and 

without stratification for dichotomous premenopausal/postmenopausal status. One block of 

covariates was entered without regard to statistical significance (age, race/ethnicity, BMI, and 

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serum creatinine). Another block of covariates (education, poverty income ratio, alcohol use, 

and cigarette smoking status) was entered second but only retained if variables were significantly 

associated with blood pressure. Finally, linear blood lead was forced in last. Logistic regression 

models for hypertension used the same covariate entry scheme with and without stratification on 

the menopause variable, but using a blood lead quartile exposure variable. Despite the stated 

procedure for covariate selection, all models used the same set of covariates: linear (or quartile) 

lead, age, race/ethnicity, alcohol use, cigarette smoking status, BMI, and serum creatinine. 

All models were adjusted for survey weights and design. Linear lead was significantly 

associated with systolic blood pressure only in the entire study sample; each 1 μg/dL increase in 

blood lead was associated with a 0.32 mm Hg (95% CI: 0.01, 0.63) increase in blood pressure. 

No associations were observed in the menopause-stratified analyses. Linear lead also was 

significantly associated with diastolic blood pressure in the entire study sample (0.25 mm Hg 

[95% CI: 0.07, 0.43]). Odd ratios of diastolic hypertension (>90 mm Hg) in logistic regression 

models was significantly related to blood lead with an odds ratio of 4.26 (95% CI: 1.36, 12.99) 

comparing the 1st quartile blood lead group (0.5-1.6 μg/dL) to the 4th quartile blood lead group 

(4.0-31.1 μg/dL) in all women not taking antihypertensive medications. Further stratification 

produced occasional significant odds ratios for either diastolic or systolic hypertension. There 

were some differences in table and text reporting of results and an inconsistency between the SE 

and the p-values. 

Another study using the NHANES III database was notable for its formal testing of race 

and sex differences in lead effect by interactions terms (Vupputuri et al., 2003). The study used 

5,360 white men (mean blood lead 4.4 μg/dL), 2,104 black men (mean blood lead 5.4 μg/dL), 

5,188 white women (mean blood lead 3.0 μg/dL), and 2,300 black women (mean blood lead 

3.4 μg/dL). Multiple linear and logistic regression models of blood pressure and hypertension 

(systolic $140 mm Hg, diastolic $90 mm Hg, and/or taking antihypertensive medication), 

respectively, were adjusted for age, high school education, BMI, alcohol, leisure-time physical 

activity, and dietary intake of sodium, potassium, and total energy. The models used linear lead, 

except for one set of hypertension models with a cut point for “high” lead exposure at $5 μg/dL. 

Subjects taking antihypertensive medication (n = 2,496) were not included in linear regression 

models of blood pressure. Neither age nor blood lead range were reported, nor was the technique 

of selecting and entering covariates in multiple regression models. Only coefficients for linear 

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lead effect for each model were reported. Significant interactions in multivariate models were 

found between lead and race and between lead and sex, though these analyses were not shown. 

Only black men and women had significant linear lead-blood pressure effects in adjusted systolic 

(0.25 mm Hg [95% CI: 0.06, 0.44] for black men and 0.47 mm Hg [95% CI: 0.14, 0.80] for 

black women with each 1 μg/dL increase in blood lead) and diastolic blood pressure 

(0.19 mm Hg [95% CI: 0.02, 0.36] for black men and 0.32 mm Hg [95% CI: 0.11, 0.54] for 

black women). Linear blood lead association with hypertension was significant only in women. 

The odds ratios were 1.09 (95% CI: 1.04, 1.13) for white women and 1.10 (95% CI: 1.06, 1.16) 

for black women for each 1 μg/dL increase in blood lead. The authors presented insufficient 

detail to evaluate this pattern of results. The use of diagnostic testing was not mentioned. 

European Population Studies 

The Health Survey for England 1995 examined a representative sample of the English 

population living in private households and provided up to 2,563 men and 2,763 women with a 

mean age of 47.6 years in a study of blood lead-blood pressure relationships (Bost et al., 1999). 

Precise blood lead range was not given but was at least from less than 1.5 μg/dL to greater than 

8.5 μg/dL. The study used stepwise multiple regressions modeling of diastolic and systolic 

blood pressure stratified by sex, with and without adjustment for alcohol, and with and without 

subjects on antihypertensive medications. Candidate covariates, selected from a larger pool, 

included age, alcohol use (heavy drinkers versus all other drinkers and nondrinkers), SES 

(manual classes versus non-manual classes), location of residence in country (northern resident 

versus non-northern resident), smoking, and common log blood lead. As nonsignificant 

variables did not remain in the models, each model contained a unique mix of covariates. 

A doubling in blood lead in men was associated with an increase in diastolic blood pressure of 

1.07 mm Hg (95% CI: 0.37, 1.78) when alcohol consumption was not in the model and 

0.88 mm Hg (95% CI: 0.13, 1.63) when alcohol consumption was in the model. Women had a 

significant response to lead only for diastolic blood pressure in the model without adjustment for 

alcohol and with subjects using antihypertensive medication. There were no significant effects 

of lead on systolic blood pressure in any model. The authors provided no statistical justification 

for stratified modeling nor did they test for significant differences in lead coefficients as a result 

of the stratification. 

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U.S. Cohort Studies 

The Boston-based Normative Aging Study, part of a longitudinal study of male veterans, 

examined the effects of blood lead on blood pressure in 798 men, aged 45-93 years old, with 

blood lead between 0.5 and 35.0 μg/dL (Proctor et al., 1996). Using multiple regression 

modeling with forced entry of natural log lead and other covariates (age, age2

, BMI, dietary 

calcium, exercise, smoking, alcohol, heart rate, and hematocrit), the authors found a significant 

increase of only diastolic blood pressure (0.83 mm Hg [95% CI: 0.08, 1.52]) for each doubling 

of blood lead. Though the relationship between blood lead and systolic blood pressure was 

positive, it was not significant. Nearly half the blood lead measures were derived from frozen 

red blood cells collected previously (up to several years earlier) and corrected for hematocrit 

determined at the time blood pressure was measured. Possible errors in correction of these 

samples and the non-contemporaneous nature of the resulting blood lead concentrations may 

have compromised the results. 

Cheng et al. (2001), using the same Normative Aging Study data and stepwise multiple 

regression, found a near-zero association between systolic blood pressure and linear blood lead 

(!0.03 mm Hg for each μg/dL increase in blood lead) in 519 men aged 48 to 93. The subjects 

selected for this analysis were all free of hypertension (systolic>160 mm Hg or diastolic>95 

mm Hg). Differences in subject selection procedures and modeling techniques may have 

accounted in the different results between Cheng et al. and Proctor et al. They also reported on 

incidence of hypertension developing between 1991 and 1997 using Cox proportional hazards 

models. Controlling for age, age2

, BMI, and family history of hypertension, linear blood lead 

was not significantly associated with risk of developing hypertension (systolic >140 mm Hg or 

diastolic >90 mm Hg) in normotensives at the start of the period (rate ratio of 0.98 [95% CI: 

0.91, 1.06]) for each 1 μg/dL increase in blood lead. 

Gerr et al. (2002) similarly reported near-zero linear blood lead effects on blood pressure 

on a combined group of 19-29 year old males and females (n = 502), half of whom had lived 

around active lead smelters as children, using forced entry of all covariates. Among the 

covariates forced into the model was tibia lead concentration, expected to be significantly 

correlated with blood lead. This may have reduced or confounded the effects of blood lead. 

Korrick et al. (1999) examined linear and natural log blood lead effect on hypertension, 

defined as self-reported or physician diagnosis of hypertension or systolic or diastolic 

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$140/90 mm Hg, in 284 middle-aged women from the Nurse Health Study based in Boston. 

The association of hypertension and blood lead was nonsignificant. 

Rothenberg et al. (1999) tested a group of 1,527 women, aged 15 to 42 years, in their third 

trimester of pregnancy, with blood lead ranging from 0.5 to 40.4 μg/dL. They stratified testing 

into immigrant (n = 1,188) and nonimmigrant (n = 439) groups. They used forced entry of all 

covariates in multiple regression models, including natural log lead, age, BMI, coffee, iron 

supplement, and job stress, and found lead-related significant increases in systolic (1.18 mm Hg 

[95% CI: 0.45, 1.91] for each doubling of blood lead) and diastolic (1.02 mm Hg [95% CI: 

0.37, 1.34]) blood pressure only in immigrants. The small size of the nonimmigrant group may 

have reduced power to detect significant effects. In a follow-up of 668 women returning for 

postpartum testing (Rothenberg, et al., 2002), using multiple regression models with forced entry 

of natural log blood lead, tibia and calcaneus lead, age, BMI, parity, smoking, immigrant status, 

and education, the authors found a significant decreases in systolic (!1.05 mm Hg [95% CI: 

!1.96, !0.14]) and diastolic (!1.16 mm Hg [95% CI: !1.98, !0.35]) blood pressure associated 

with doubling in blood lead in the postpartum women. This subgroup of women had no 

significant blood lead effects in the third trimester. Although the covariate pattern was different 

from the larger prenatal study (Rothenberg et al., 1999), thorough testing of possible 

confounding, especially with the bone lead measures, revealed no significant change in blood 

lead effects. This study finding is similar to that reported by Den Hond et al. (2002) for 

white males. No significant effect of blood lead on prenatal or postpartum hypertension 

($140/90 mm Hg) was found. 

Morris et al. (1990) recruited a group of 105 women and 145 men, aged 18-80 years, from 

a clinic specializing in non-drug hypertension treatment. Blood lead ranged from 5-40.5 μg/dL. 

Multiple regression was performed with forced entry of natural log lead, age, BMI, dietary 

calcium, “other nutrients,” serum ionized calcium, and erythrocyte protoporphyrin. Only men 

were found to have lead-related significant increases in systolic (3.17 mm Hg [95% CI: !2.13, 

8.48] for each doubling of blood lead) and diastolic (1.32 mm Hg [95% CI: !2.12, 4.75]) blood 

pressure. Small study size limits conclusions based on nonsignificant findings in women. 

Dietary calcium is associated with reduced blood lead in many studies and could be considered a 

confounder with blood lead. Erythrocyte protoporphyrin is a biomarker of lead exposure and 

correlates with blood lead over at least part of the blood range in study subjects. There was the 

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inclusion of at least two collinear variables, a high proportion of covariates to subjects, and 

possible subject selection bias. 

European Cohort Studies 

The Glostrup Population Study (Copenhagen) studied 1,009 men and women (all born in 

1936) longitudinally from 1976 to 1987 (Møller and Kristensen, 1992). Blood lead ranged from 

2 to 62 μg/dL, depending on the year and sex stratum studied, with mean concentration dropping 

by ∼40% over the study period. They used multiple regression with forced entry of natural log 

lead, BMI, tobacco use, and physical activity. Strongest associations between a doubling of 

blood lead and blood pressure were found early in the study period. In 1976, a doubling of blood 

lead was associated with 3.42 mm Hg (95% CI: 1.25, 5.58) increase in systolic blood pressure 

and 2.95 mm Hg (95% CI: 1.08, 4.83) increase in diastolic blood pressure in women. For men 

in 1981, a doubling of blood lead was associated with an increase of 1.89 mm Hg (95% CI: 

0.00, 3.78) in systolic blood pressure and 1.14 mm Hg (95% CI: !0.37, 2.65) in diastolic blood 

pressure. No formal longitudinal analyses were performed, only analyses stratified by year and 

sex and analyses relating change in lead and other covariates to change in blood pressure from 

one study period to the next. As the relative risk of mortality was associated with increasing 

blood lead over the study period (see below), the general reduction in lead-associated blood 

pressure increase over the study period may have been masked by lead-associated mortality. 

The Europe New Risk Factor Project in Rome collected data from 1,319 males aged 

55-75 years with blood lead between 4.0 and 44.2 μg/dL (Menditto et al., 1994). They reported 

significantly increased systolic (4.71 mm Hg [95% CI: 2.81, 6.61]) and diastolic (1.25 mm Hg 

[95% CI: 0.33, 2.16]) blood pressure associated with a doubling of blood lead. 

The Cadmibel studies from Belgium specifically selected part of their study group from 

those living near nonferrous smelters. Staessen et al. (1993) reported on 827 men and 

821 women, aged 20 to 88 years, with blood lead ranging from 2.7 to 84.9 μg/dL for men and 

1.3 to 42.4 μg/dL for women. They forced natural log blood lead into stepwise multiple 

regression models stratified by sex. Covariates available for selection were age, age2

, BMI, 

pulse rate, log gamma-glutamlytranspeptidase, serum total calcium, log serum creatinine, urinary 

potassium, smoking, alcohol, contraceptive use, and menopause. Near-zero nonsignificant 

relationships were found between blood lead and blood pressure for systolic blood pressure for 

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women and diastolic blood pressure for men and women. They reported a significant decrease in 

men’s systolic blood pressure with increasing blood lead (!1.1 mm Hg for a doubling of blood 

lead), similar to the relationship found by Den Hond et al. (2002) for white men and by 

Rothenberg et al. (2002) for postpartum women. Stepwise regression results in different 

covariate patterns for each stratum and capitalizes on chance significance due to repeated testing. 

A follow-up of the Cadmibel study, the PheeCad study, evaluated 359 men and 

369 women, aged 20 to 82 years (Staessen et al., 1996). Fifty-nine percent of the men had 

occupational exposure. They were measured two times, at baseline and at follow-up about 

5 years later. Women’s mean blood lead at baseline and follow-up was 6.6 μg/dL (range 

3.3-24.50 and 4.8 μg/dL (range 1.7-11.8). Men’s mean blood lead at baseline and follow-up was 

11.4 μg/dL (range 5.6-28.8) and 7.7 μg/dL (range 3.7-20.1). Multiple regression models were 

stratified on sex and in women on menopausal status. Time-integrated blood pressure 

measurements were used. Each doubling of blood log lead was significantly associated with a 

5.19 mm Hg (95% CI: 1.05, 9.34) increase in diastolic blood pressure in 187 pre- and 

perimenopausal women. None of the other strata showed significant blood lead-related effects. 

Using 24-h ambulatory blood pressure readings during the follow-up showed significant 

associations between natural log blood lead and diastolic blood pressure in the group of all 

345 women (2.42 mm Hg [95% CI: 0.00, 4.84]). There were no significant lead effects on 

systolic blood pressure in women or all blood pressure in men. Change in blood pressure and 

change in covariates between baseline and follow-up were used to assess the effect of change of 

blood lead in longitudinal analyses, similar to Møller and Kristensen (1992) above. 

No significant effects of change in blood lead on change in blood pressure were found. Due to 

stratification and resulting small groups, there may have been reduced power to detect significant 

effects of lead. 

U.S. Occupational Studies 

Glenn et al. (2003) was one of the few studies to use a prospective design and was the 

only study using statistical techniques designed for repeated measures. They studied 496 male 

workers from New Jersey with former organolead exposure. Using generalized estimating 

equations with baseline linear blood lead, age, BMI, antihypertensive medication, smoking, 

education, measurement technician, and number of years to follow-up measurement of blood 

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402(c) Economic Analysis Chapter 5 576
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pressure (range 10 months-3.5 years), they found that every 1 μg/dL increase in baseline blood 

lead was associated with 1.13 mm Hg/year (95% CI: 0.25, 2.02) increase in blood pressure over 

the observation period. 

Schwartz et al. (2000b) reported significant blood lead associations with 543 male former 

organolead workers. Stepwise backward multiple regression showed an increase of 2.3 mm Hg 

in systolic blood pressure for each doubling in blood lead. The association with diastolic blood 

pressure was not significant. 

Sharp et al. (1990) studied 132 black bus drivers (blood lead range 3.1-20.9 μg/dL) and 

117 nonblack bus drivers (blood lead range 2.0-14.7 μg/dL) in San Francisco, aged 30 to 

60 years. They used natural log blood lead in multiple regression models and found for each 

doubling of blood lead an increase of 5.22 mm Hg (95% CI: 0.60, 9.84) in systolic blood 

pressure among blacks, 3.27 mm Hg (95% CI: 0.10, 6.44) in diastolic blood pressure among 

blacks, and !3.96 mm Hg (95% CI: !8.32, 0.42) in systolic blood pressure among nonblacks. 

Sokas et al. (1997) reported a possible race interaction (p = 0.09) on systolic blood 

pressure with linear blood lead in 264 construction workers aged 18-79 years. Each 1 μg/dL 

increase in blood lead increased systolic blood pressure in blacks by 0.86 mm Hg more than in 

whites. Neither the black or white lead coefficients were significant. 

European Occupational Studies 

Maheswaran et al. (1993) reported on 809 male factory workers with blood lead between 

less than 21 to more than 50 μg/dL from Birmingham, England. Unfortunately, the inclusion of 

factors that were related to blood lead, including additional direct measure of lead exposure in 

addition to linear blood lead, years working in factory, and inclusion of zinc protoporphyrin, may 

have biased the blood lead effect and resulted in nonsignificant lead effects on blood pressure. 

Telišman et al. (2004) also reported nonsignificant effects of natural log blood lead on 

blood pressure in 115 male industrial workers with blood lead between 9.9 and 69.9 μg/dL, but 

included erythrocyte protoporphyrin in models, a variable correlated with blood lead over much 

of the observed blood lead range. Coefficients were not given, as lead did not enter into stepwise 

regression models. 

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Asian Occupational Studies 

Male and female factory workers (n = 798) from Chonan, Korea (blood lead between 

17.8 and 64.8 μg/dL) were studied principally for the effects of genotype of ALAD and vitamin 

D receptor on cardiovascular response to lead (Lee et al., 2001). These aspects are covered more 

thoroughly below. As part of their work, the authors developed multiple regression models 

examining the effect of linear blood lead on blood pressure with forced entry of age and age2

, 

BMI, sex, antihypertensive medication, lifetime alcohol, and ALAD and vitamin D genotypes. 

A marginally significant effect of blood lead on systolic blood pressure (diastolic blood pressure 

not modeled) was noted, with a 10 μg/dL increase in blood lead associated with a 0.7 mm Hg 

(95% CI: !0.04, 1.4) increase in blood pressure. 

Nomiyama et al. (2002) used a combined group of 193 female crystal glass workers and 

nonexposed controls, aged 16 to 58 years, with blood lead between 3.8 and 99.4 μg/dL. The 

authors used a stepwise multiple regression with a novel technique to reduce collinearity among 

covariates. From a large group of covariates, they selected covariates eligible to enter the 

regression from a factor analysis. Although the stepwise entry of these variables resulted in 

different models for systolic and diastolic blood pressure, both models included linear blood 

lead, age, urine protein, and plasma triglycerides. The diastolic model additionally included 

family hypertension and low density lipoprotein. Each 10 μg/dL increase in blood lead was 

significantly associated with a 1.26 mm Hg (95% CI: 0.58, 1.94) increase in systolic blood 

pressure and a 1.05 mm Hg (95% CI: 0.52, 1.57) in diastolic blood pressure. In alternative 

models with ordered categories of blood lead, systolic blood pressure was 7.5 mm Hg (95% CI: 

3.0, 12.0) and diastolic blood pressure was 6.3 mm Hg (95% CI: 3.4, 9.1) higher in workers with 

blood lead $60 μg/dL than in controls with <11.4 μg/dL. Models did not control for BMI. 

Wu et al. (1996) examined the effect of ordered blood lead category on blood pressure of 

112 male (aged 18-67 years) and 110 female (aged 18-71 years) lead battery factory workers in 

multiple regression models. Blood lead ranged from 8.3 to 95.4 μg/dL. Nonsignificant blood 

lead effects were found possibly due to the inclusion of two additional lead exposure 

measurements, ambient air lead and work history, likely leading to substantial collinearity with 

blood lead. 

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402(c) Economic Analysis Chapter 5 578
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Meta-Analysis of Blood Lead-Blood Pressure Studies 

The most recent meta-analysis of the blood lead-blood pressure literature analyzed 

31 studies from a large pool of studies published up to 2001 (Nawrot et al., 2002). Two other 

meta-analyses were also published during this reporting period (Schwartz, 1995; Staessen et al., 

1994), covering many of the earlier papers cited in Nawrot et al. (2002), and derived similar 

coefficients for the lead effect, so they will not be reviewed here. The meta-analysis authors 

selected studies with 50 or more subjects, with subjects 10 years of age and up, with blood 

pressure and blood lead measurement techniques presented in sufficient detail to estimate effect 

sizes, and with preference given to papers with models adjusting for age, BMI, and “additional 

factors of proven importance.” Where possible, studies with stratified analyses based on sex and 

race were entered in the meta-analysis as separate subgroups. Studies were weighted by the 

number of subjects to arrive at estimates and CIs for lead effect on diastolic and systolic blood 

pressure. Nearly half the studies reported lead effects from linear lead terms, the remainder from 

log-transformed lead. To include both types of studies in the analyses, the authors reported 

effect sizes based on doubling the mean blood lead concentration. For models using logarithmic 

blood lead, this doubling has the same effect anywhere in the range of blood lead in the study. 

For models using linear blood lead, the doubling effect was referenced from the mean blood lead 

reported. Figures 6-5.1 and 6-5.2 depict the effect estimates for systolic and diastolic blood 

pressure, respectively, included in the meta-analysis from Nawrot et al. (2002). Ninety-five 

percent CIs overlapped for males and females and for blacks and whites, indicating no 

significant differences in lead effect by gender or race. In the group of studies as a whole, the 

combined meta-analysis coefficients for each doubling of blood lead were highly significant for 

both systolic (1.0 mm Hg [95% CI: 0.5, 1.4]) and diastolic (0.6 mm Hg [95% CI: 0.4, 0.8]) 

blood pressure. The meta-analysis supports the statistical association between increased blood 

lead and increased blood pressure over a wide range of populations in many studies. Two major 

systematic reviews of the lead-blood pressure literature were published during this review period 

(Hertz-Picciotto and Croft, 1993; Research Triangle Institute, 1999). The findings here, 

especially noting the significant effects from the meta-analysis (Nawrot et al., 2002), continue to 

support the significant association between blood lead and blood pressure/hypertension in 

diverse segments of the general population. 

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402(c) Economic Analysis Chapter 5 579
Figure 6-5.1. Change in the systolic pressure (effect estimate in mm Hg) associated with 

a doubling of the blood lead concentration. Studies arranged vertically by 

increasing study size. 

Study key: C = Caerphilly Study, HP = Welsh Heart Program, P = PheeCad Study, W = whites, 

B = blacks, NI = nonimmigrants, I = immigrants, FW = foundry workers, CS = civil 

servants. 

Source: Nawrot et al. (2002). 

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402(c) Economic Analysis Chapter 5 580
Figure 6-5.2. Change in the diastolic pressure (effect estimate in mm Hg) associated with 

a doubling of the blood lead concentration. Studies arranged vertically by 

increasing study size. 

Study key: C = Caerphilly Study, HP = Welsh Heart Program, P = PheeCad Study, W = whites, 

B = blacks, NI = nonimmigrants, I = immigrants, FW = foundry workers, CS = civil 

servants. 

Source: Nawrot et al. (2002). 

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402(c) Economic Analysis Chapter 5 581
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Quantitative estimates for the effect of doubling the mean blood lead concentration on 

systolic and diastolic blood pressure from the various studies discussed here are summarized in 

Tables 6-5.1 and 6-5.2. Results from these individual studies also generally appear to agree with 

the results of the meta-analysis by Nawrot et al. that increased blood lead levels are significantly 

associated with increased systolic and diastolic blood pressure. Figures 6-5.1 and 6-5.2 

graphically depict the results of many of the studies discussed. The effect estimates in the 

figures also reflect the effect of doubling blood lead on blood pressure. Most of the effects are 

based on concurrent blood lead. Effects for the entire study population are presented unless only 

effects in subsamples are reported. Other selection criteria used in a few instances 

were subjective. 

A Bayesian meta-analysis was performed to examine the use of log-linear and linear 

blood lead in blood pressure regression models (Figure 6-5.3). A significant blood lead effect on 

systolic pressure was observed using both log-linear and linear blood lead. Heterogeneity also 

was significant for both log-linear lead (p = 0.0002) and linear lead (p = 0.05). The source of 

heterogeneity could be due to several factors, including different methods of statistical analysis, 

different study protocols, and subject selection differences. The log-linear and linear lead effects 

were 0.62 mm Hg (95% CI: 0.12, 1.11) and 0.98 mm Hg (95% CI: 0.51, 1.45), respectively, for 

systolic blood pressure. The difference between the effect estimates from using log-linear or 

linear lead was nonsignificant. This meta-analysis suggests there are significant differences 

between the studies, but overall there is a combined effect of blood lead on systolic blood 

pressure. The fact that several individual studies did not detect a significant effect may be due to 

small study size or other factors affecting effect measurement precision. 

6.5.2.3 Blood Pressure and Hypertension Studies Using Bone Lead as Exposure Index 

Korrick et al. (1999) used a case-control design to study the relationship between 

hypertension and three measures of lead exposure (blood lead, tibia [cortical bone] lead, and 

patella [trabecular bone] lead in women. The final study sample consisted of 89 hypertension 

cases and 195 controls, excluding those with history of hypertension, cardiovascular disease, 

renal disease, diabetes, or malignancy, use of antihypertensive medications, BMI $29, and 

incomplete data, aged from 47 to 74 years. Cases were selected through a randomization 

procedure that produced approximately equal numbers of cases for each of three blood pressure 

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402(c) Economic Analysis Chapter 5 582
December 2005 6-182 DRAFT-DO NOT QUOTE OR CITE Table 6-5.1. Systolic and Diastolic Blood Pressure and Blood Lead Modeled with Linear 

(Coefficients Represent Effect of Doubling Blood Lead Calculated from Mean Blood Lead or Mid

Blood Lead Systolic Blood Pressure 

Study Population, Meana, Geom. Meanb, or (mm Hg) 

Reference, Study Location, Sample Size (n), Age Medianc (SD)d or (IQR)e Model Type and Model Unique Lead-Associated Coefficient UPeriod [years] [range] μg/dL Variables Considered Diagnostic Covariates Variables (95% CI) [SE] CoPOPULATION OR COMMUNITY STUDIES Cheng et al. (2001) Boston, U.S. Normative Aging Males (519) [mean age = 66.4] 5.9a (3.9)d [range not given] Multiple linear regression forced entry of linear lead, age, age2, BMI, family hypertension, smoking, Not stated Not applicable Alcohol, smoking, age, dietary calcium 

!0.2 

(!2.0, 1.6) 

[0.92] 

N

Study alcohol, dietary calcium. 1991-1997 

Hu et al. (1996) — — Almost completely — — — — 

overlapping with Cheng et al. (2001). 

Gerr et al. (2002) Eastern Washington, Western Idaho, 

Females and 

Males 

(502) 

[19-29] 

2.2a 

(1.9)d 

[<1->7] 

Linear multiple regression with forced entry of linear blood lead, tibia lead, age, BMI, sex, education, birth 

Not stated Not 

applicable 

Age, tibia lead, 

smoking, alcohol, 

hemoglobin 

0.0 

(!1.1, 1.1) 

[0.57]

 

ap

U.S. control pills, smoking, 1994 height, hemoglobin, serum 

albumin, childhood residence, income, alcohol. 

Nash et al. (2003) U.S.-NHANES 

Females 

(1,786) 

2.9a 

(not stated)d 

Multiple linear regression (survey weighted), 

Not stated Not 

applicable 

Alcohol, 

smoking, age 

0.9 

(0.0, 1.8) 

ap

III [40-59] [0.5-31.1] excluding treated [0.46] 1988-1994 hypertensives, with forced 

entry of linear lead, age, BMI, race/ethnicity, serum creatinine. Education, poverty, alcohol, smoking among variables for stepwise entry. 

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December 2005 6-183 DRAFT-DO NOT QUOTE OR CITE Table 6-5.1 (cont’d). Systolic and Diastolic Blood Pressure and Blood Lead Modeled with Li

(Coefficients Represent Effect of Doubling Blood Lead Calculated from Mean Blood Lead or Mid

Reference, Study Location, Period Study Population, Sample Size (n), Age [years] Blood Lead Meana, Geom. Meanb, or Medianc (SD)d or (IQR)e [range] μg/dL Model Type and Variables Considered Model Diagnostic Unique Covariates Systolic Blood Pressure (mm Hg) Lead-Associated Variables Coefficient (95% CI) [SE] 

U

Co

POPULATION OR COMMUNITY STUDIES (cont’d) Vupputuri et al. (2003) Black female (2,300) 3.4a (3.3)d Multiple linear regression (not survey corrected) with Not stated Not applicable Age, alcohol 1.6 (0.5, 2.7) 

ap

NHANES III, [$18-?] [not stated] forced entry of all variables: [0.82] U.S. Black male (2,104) 

[$18-?] 

5.4a 

(3.3)d 

[not stated] 

linear lead, age, BMI, education, alcohol, physical activity, dietary Na, K, and calories. 

1.3 

(0.3, 2.4) 

[0.54] 

White female 3.0a 0.3 

(5,188) (3.3)d (!0.4, 1.1) 

[$18-?] [not stated] [0.38] 

White male 4.4a 0.4 

(5,360) (3.3)d (!1.0, 1.8) 

([$18-?] [not stated] [0.72] 

Sorel et al. Female 13.2a Multiple linear regression Not stated Not Age Errors in (1991) (2,056) (not stated) (survey corrected) with applicable original article apNHANES II, [18-74] [not stated] forced entry of linear lead, U.S. 1976-1980 Male 20.1a age, BMI. 1.7 

(2,044) (not stated) (!0.6, 3.8) 

[18-74] [not stated] [0.56] 

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December 2005 6-184 DRAFT-DO NOT QUOTE OR CITE Table 6-5.1 (cont’d). Systolic and Diastolic Blood Pressure and Blood Lead Modeled with L

(Coefficients Represent Effect of Doubling Blood Lead Calculated from Mean Blood Lead or Mid

Reference, Study Location, Period Study Population, Sample Size (n), Age [years] Blood Lead Meana, Geom. Meanb, or Medianc (SD)d or (IQR)e [range] μg/dL Model Type and Variables Considered Model Diagnostic Systolic Blood Pressure (mm Hg) Unique Covariates Lead-Associated Variables Coefficient (95% CI) [SE] 

U

Co

POPULATION OR COMMUNITY STUDIES (cont’d) Hense et al. Female Not stated Multiple linear regression Not stated Not Age, smoking, 0.4 

(1994) (no alcohol) (not stated) with forced entry of linear applicable hematocrit (!2.6, 3.4) apAugsberg, (701) [<3->8] lead, age, BMI, hematocrit, [1.53] Denmark [28-67] residence, smoking in 1987-1988 Female (<40 g/day) (877) Not stated (not stated) [<3->10] women. In men, analyses were stratified by place of residence. 0.7 

(!1.5, 2.9) 

[1.12] 

[28-67] 

Female Not stated 11.0 

($40 g/day) (not stated) (3.8, 18.3) 

(83) [<3->14] [3.64] 

[28-67] 

Male, urban Not stated No blood lead values shown; — 

(118) (not stated) thus, there are no 

[28-67] [not stated] coefficients calculated and 

shown 

Male, rural Not stated Multiple linear regression Not stated Not Age, smoking, 2.8 

(no alcohol) (not stated) with forced entry of applicable hematocrit (!2.4, 8.0) ap

(147) [<5->11] linear lead, age, BMI, [2.63] 

[28-67] hematocrit, residence, 

Male, rural 

(<40 g/day) 

(463) 

Not stated 

(not stated) 

[<6->12] 

smoking in women. In men, analyses were stratified by place of residence. 

5.8 

(1.9, 9.8) 

[2.01] 

[28-67] 

Male, rural Not stated 5.0 

($40 g/day) (not stated) (0.6, 10.9) 

(356) [<7->15] [2.87] 

[28-67] 

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December 2005 6-185 DRAFT-DO NOT QUOTE OR CITE Table 6-5.1 (cont’d). Systolic and Diastolic Blood Pressure and Blood Lead Modeled with L

(Coefficients Represent Effect of Doubling Blood Lead Calculated from Mean Blood Lead or Mid

Reference, Study Location, Period Study Population, Sample Size (n), Age [years] Blood Lead Meana, Geom. Meanb, or Medianc (SD)d or (IQR)e [range] μg/dL Model Type and Variables Considered Model Diagnostic Unique Covariates Systolic Blood Pressure (mm Hg) Lead-Associated Variables Coefficient (95% CI) [SE] 

U

Co

OCCUPATIONAL STUDIES Glenn et al. Males, former — Only measured change in — — — — (2003) organolead blood pressure over a period New Jersey, workers ranging from 10 months to U.S. 5 years. Design not 1994-1998 commensurate with other studies in this table. See Glenn (2001), below. Glenn et al. (2001) Males, former organolead 5.2a (3.1)d Subset of Schwartz (2000), see below. — — — — New Jersey, workers [not stated] U.S. (213) 1996-1997 [mean age = 58.0] Schwartz et al. (2000b) Males, former organolead 4.6a (2.6)d Multiple backward elimination stepwise linear Not stated Age, BMI, smoking, Age, smoking 2.3 (0.2, 4.4) A

s

New Jersey, workers [1-20] regression models. Pool of antihyperte [1.15] anU.S. (543) available covariates not nsive 1996-1997 [41.7-73.3] specified. medications me

Sokas et al. Male, 8.0a Multiple linear regression, Not stated Linear lead, Age, hematocrit, Not given here, Li(1997) construction (not given) presumably with forced BMI, age, erythrocyte as coefficient BMaryland workers [2-30] entry (not stated). hematocrit, protoporphyrin was altered by heU.S. (264) Covariates available for erythrocyte presence of er1989-1990 [18-79] entry not stated. Insufficient protoporph race-lead pr

information given for yrin, race, interaction yrseparate black and white race by lead racblood pressure effects on interaction inblood pressure. 

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December 2005 6-186 DRAFT-DO NOT QUOTE OR CITE Table 6-5.1 (cont’d). Systolic and Diastolic Blood Pressure and Blood Lead Modeled with L

(Coefficients Represent Effect of Doubling Blood Lead Calculated from Mean Blood Lead or Mid

Blood Lead Systolic Blood Pressure 

Study Population, Meana, Geom. Meanb, or (mm Hg) 

Reference, Study Location, Sample Size (n), Age Medianc (SD)d or (IQR)e Model Type and Model Unique Lead-Associated Coefficient UPeriod [years] [range] μg/dL Variables Considered Diagnostic Covariates Variables (95% CI) [SE] CoOCCUPATIONAL STUDIES (cont’d) Maheswaran et al. (1993) Birmingham Europe Male factory workers (809) [mean age 31.5b (5.5)d [<21->50] Multiple linear regression, forced entry of age, BMI, alcohol, zinc protoporphyrin, years working, smoking, Not stated Not applicable Age, alcohol, zinc protoporphyrin, years working, 2.2 

(!0.9, 5.4) 

[1.60]

 

ap

Dates not given 43.3] linear lead. smoking 

Lee et al. (2001) Chonan, Korea 1997-1999 

Male and 

female leadusing factory 

32.0a 

(15.0)d 

[4-86] 

Multiple linear regression with forced entry of age, age2, sex, BMI, 

Not stated Not 

applicable 

Age, alcohol 2.2 

(!0.1, 5.5) 

[1.18] 

N

workers antihypertensive medication, 

(798) lifetime alcohol, ALAD and 

[17.8-64.8] vitamin D receptor 

genotypes. 

Lustberg et al. Overlapping — Used deciles as lead — — — — (2004) study with Lee variable. Chonan, Korea (2001), above 1997-1999 

Nomiyama et al. (2002) 

Female crystal 

toy makers and 

37.6a 

(9.2)d 

Multiple linear regression with forward stepwise 

Not stated Linear lead, 

age, urine 

Age 4.7 

(2.0, 7.4 ) 

 Li

a

Beijing, China nonexposed [3.8-99.4] addition of variables protein, [1.35] pDates not given sewing workers (p < 0.2). Candidate plasma 

(193) variables were selected from triglyceride trig

[16-58] a very large group and 

narrowed down to ten by hyfactor analysis. The ten available for entry were low not stated. lip

Wu et al. (1996) — — Ordered categories of lead — — — — Central Taiwan used. Coefficients cannot Data collection be calculated. dates not given 

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December 2005 6-187 DRAFT-DO NOT QUOTE OR CITE Table 6-5.2. Systolic and Diastolic Blood Pressure and Blood Lead Modeled with Logarith

(Coefficients Represent Effect of Doubling Blood Lead) Blood Lead Systolic Blood Pressure 

Reference, Study Population, Meana, Geom. Meanb, or (mm Hg) Study Location, Sample Size (n), Age Medianc (SD)d or (IQR)e Model Type and Model Unique Lead- Associated Coefficient (95% CI) Unique Period [years] [range] μg/dL Variables Considered Diagnostic Covariates Variables [SE] CovariatPOPULATION OR COMMUNITY STUDIES Den Hond Black males 4.2c (2.7, 6.5)e Multiple linear Not stated Serum total Alcohol, 0.9 Coffee, die

et al. (2002) (1,761) [<1.2->20.0] regression (no protein smoking, age (0.04, 1.8) Na, diabeNHANES III U.S. 1988-1994 

[$20] adjustment for survey 

design): forced entry of log lead, age, age2 , 

[0.43] serum to

protein

Black 

females 

(2,197) 

[$20] 

2.3c (1.4, 3.9)e 

[<0.8->9.0] 

BMI, hematocrit, smoking, alcohol, antihypertensive drugs. Forward stepwise entry (p < 0.05) among 

Dietary Na/Ca, 

serum total 

protein 

Alcohol, 

smoking, age 

1.2 

(0.4, 2.0) 

[0.42]

 Dietary Na

serum to

protein, se

total calci

White males 

(4,685) 

[$20] 

3.6c 

(2.3, 5.3)e 

[<1.2->15.0] 

coffee, dietary calcium, dietary Na/Ca, serum total protein, serum total calcium, diabetes. 

Dietary 

calcium, dietary 

Na/Ca, serum 

total protein, 

serum total 

Alcohol, 

smoking, age, 

dietary 

calcium 

0.3 

(!0.2, 0.7) 

[0.23]

 Dietary Na

serum to

protein, se

total calci

diabete

calcium 

White 2.1c Serum total Alcohol, 0.1 Dietary calc

females 

(5,138) 

[$20] 

(1.3, 3.4)e 

[<0.8->8.0] 

protein, diabetes smoking, age (!0.4, 0.5) 

[0.32]

serum to

protein, dia

Morris et al. (1990) 

Females 

(106) 

6.9a 

(3.6)d 

Linear multiple regression with 

Not stated Age, dietary 

calcium, BMI 

Age, dietary 

calcium 

Not stated Age, diet

calcium

Oregon, U.S. [18-80] [?-39] stepwise entry among hemoglob1984-1989 

Males 

(145) 

[18-80] 

8.0a 

(4.4)d 

[5-40.5] 

ln lead, age, BMI, dietary calcium, “other nutrients,” serum Ca2+ , 

erythrocyte protoporphyrin. 

Age, ionized 

calcium 

Age 3.2 

(Not given)

 Age, 

hemoglob

smokin

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December 2005 6-188 DRAFT-DO NOT QUOTE OR CITE Table 6-5.2 (cont’d). Systolic and Diastolic Blood Pressure and Blood Lead Modeled with Loga

(Coefficients Represent Effect of Doubling Blood Lead) Blood Lead Systolic Blood Pressure 

Reference, Study Population, Meana, Geom. Meanb, or (mm Hg) Study Location, Sample Size (n), Age Medianc (SD)d or (IQR)e Model Type and Model Unique Lead- Associated Coefficient (95% CI) UnPeriod [years] [range] μg/dL Variables Considered Diagnostic Covariates Variables [SE] CovPOPULATION OR COMMUNITY STUDIES (cont’d) Proctor et al. Males 6.5a Multiple linear regression with Not stated Not Alcohol, 0.6 N(1996) Normative Aging Study (798) [45-93] (4.0)d [0.5-35.0] forced entry of all variables: ln lead, age, age2, BMI, dietary calcium, exercise, applicable smoking, dietary calcium, age 

(!0.8, 1.9) 

[0.69]

app

Boston, U.S. smoking, alcohol, heart rate, 1991-1993 hematocrit. 

Rothenberg Pregnant 2.3b Multiple linear regression with Residual analyses, Not Age 1.2 Net al. (1999) women, (1.3)d forced entry of all variables: outliers, applicable (0.5, 1.9) appLos Angeles, immigrant [0.5-40.4] ln lead, age, BMI, coffee, iron heteroscedasticity [0.37] U.S. (1,188) supplement, job stress. 1995-1998 [>14-<44] 

Pregnant 

women, 

1.9b 

(+1.3, !0.8)d 

Age 0.3 

(!1.1, 1.6) 

nonimmigrants 

(439) 

[not stated] [0.67] 

[>14-<44] 

Rothenberg et al. (2002) 

Females third 

trimester 

1.9b 

(+3.6, !1.0)d 

Multiple linear regression with forced entry of all variables: 

Residual analyses, outliers, 

Not applicable 

Alcohol, smoking, age 

0.0 (!0.9, 0.8) 

N

app

Los Angeles, (637) [not stated] ln lead, age, BMI, education, heteroscedasticity [0.43] U.S. [15-43] immigrant status, smoking, 1995-2001 

Females 

postpartum 

(637) 

[15-43] 

2.3b 

(+4.2, !1.2)d 

[0.4-23.7) 

alcohol, parity. Hypertensive subjects $140/90 mm Hg (third trimester or postpartum) were excluded. 

!1.0 (!2.0, !0.1) 

[0.46]

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December 2005 6-189 DRAFT-DO NOT QUOTE OR CITE Table 6-5.2 (cont’d). Systolic and Diastolic Blood Pressure and Blood Lead Modeled with Loga

(Coefficients Represent Effect of Doubling Blood Lead) Blood Lead Systolic Blood Pressure 

Study Population, Meana, Geom. Meanb, or (mm Hg) 

Reference, Study Location, Sample Size (n), Age Medianc (SD)d or (IQR)e Model Type and Model Unique Lead- Associated Coefficient (95% CI) UniquPeriod [years] [range] μg/dL Variables Considered Diagnostic Covariates Variables [SE] CovariaPOPULATION OR COMMUNITY STUDIES (cont’d) Schwartz Females Not stated Multiple linear Not stated No results No results No results Race, zinc, 

(1991) (<5,000) regression with forced presented presented presented hypertenNHANES II U.S. [20-74] entry of ln lead, age, age2, and BMI. Stepwise tricep f

cholest

1976-1980 Males (<5,000) [20-74] entry (p < 0.05) among race, cigarettes/day, tricep skinfold, family hypertension, exercise, ln serum Zn, dietary K and Na, serum Race, zinc, 

hyperten

tricep fo

cholesterol, 

cigaret

cholesterol, height, and ln dietary vitamin C. Bost et al. Females 2.6b Multiple linear stepwise Not stated Age, BMI, Age No results Age, BMI, 

(1999) (2,763) (not stated) regression (forward or residency presented Health Survey [16-not [<1.5->8.5] backward not stated), (nonsignificant) for England given] with possible entry of 1995 Females (2,563) [16-not given] 3.7b (not stated) [<1.5->8.5] age, log BMI, log lead, alcohol, social class, place of residence, and smoking. Age, BMI, alcohol, social class Age, alcohol No results presented (nonsignificant) Age, BMI, 

Menditto et al. Males 11.3a Multiple linear Not stated BMI, heart rate, Smoking 3.9 BMI, hear(1994) (1,319) (not stated) regression with forward serum lipids, age, no other age, smoRome, Europe [55-75] [4.0-44.2] stepwise entry among ln glucose, measures given lipids, triglyNew Risk Factor lead, age, BMI, heart smoking, Project rate, lipids, triglycerides, skinfold, 1989-1990 glucose, smoking, triglycerides, alcohol, skinfold. skinfold 

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December 2005 6-190 DRAFT-DO NOT QUOTE OR CITE Table 6-5.2 (cont’d). Systolic and Diastolic Blood Pressure and Blood Lead Modeled with Log

(Coefficients Represent Effect of Doubling Blood Lead) Blood Lead Systolic Blood Pressure 

Study Population, Meana, Geom. Meanb, or (mm Hg) 

Reference, Study Location, Sample Size (n), Age Medianc (SD)d or (IQR)e Model Type and Unique Lead- Associated Coefficient (95% CI) Period [years] [range] μg/dL Variables Considered Model Diagnostic Covariates Variables [SE] OCCUPATIONAL STUDIES Sharp et al. (1990) Male bus drivers, 6.5b (+2.7, !1.9)d Linear multiple regression analysis of unspecified type. Used influence diagnostics to identify Not applicable Age, smoking 5.2 (0.6, 9.8) 

a

San Francisco, U.S. black (132) [3.1-20.9] All models presented here adjusted for ln lead, age, age2 , two influential subjects. Analyses [2.3] 1986 [30.4-60.7] BMI, caffeine, smoking. stratified by race Also examined effect of showed maximum stratified caffeine modeling 10% change in lead (not shown here as group sizes coefficients without Male bus drivers, nonblack (117) [30.6-58.9] 6.2b (+2.7, !1.8)d [2.0-14.7) were less than 100), and effect of successive addition of covariates on lead coefficient, and including alcohol use (not shown). influential subjects. Data shown here includes all subjects. 

!3.9 

(!8.3, 0.4) 

[2.3]

Telišman et al. Male 36.7b Linear multiple regression Not stated None given (2004) industrial (not given) with forward stepwise entry Zagreb, Croatia workers [9.9-69.9] among ln or linear lead, years 2000-? (115) of exposure, age, smoking, 

[20-43] alcohol, BMI, ALAD, 

erythrocyte protoporphyrin, blood Cd, serum Zn, serum Cu. Neither form of lead variable was reported as significant, but coefficients not shown. Even though forward stepwise was used and insignificant lead variables were not shown, other nonsignificant variables were shown in models. 

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Figure 6-5.3. Effect of doubling mean blood lead on estimate of blood pressure change 

with 95% CIs. Studies arranged vertically by increasing study size. 

Where multiple models from the same study were presented, such as 

repeated measures over time or adding a confounding variable, only the 

effect estimate from the first model is shown. When the same study was 

multiply published with subsamples, only the effect estimate from largest 

study is shown. 

Study key: B = blacks, W = whites, M = males, F = females, IMM = immigrants, 

non-IMM = nonimmigrants. 

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categories, hypertensive ($140 mm Hg or 90 mm Hg), high normal ($121/75 mm Hg up to 

hypertension limit), and low normal (<121/75 mm Hg). As many as four controls were matched 

to cases by 5 year age grouping. Though they did not match cases and controls on other 

potential confounding variables, they included these variables in their models. The dependent 

variable was constructed by placing blood pressure measurements into the three groups. The 

mean blood lead level was 3.1 μg/dL; the mean tibia and patella lead levels were 13.3 μg/g and 

17.3 μg/g, respectively. An ordered logistic regression with proportional odds assumptions was 

used to asses linear blood lead, patella and tibia bone lead effects on odds of hypertension, 

controlling for age, BMI, dietary calcium, alcohol use, dietary sodium, smoking, and family 

hypertension. They presented results from four models with the same covariates determined 

a priori, but with each lead variable tested separately. Only patella lead concentration 

significantly (p = 0.03) predicted increased odds for hypertension, but the effect was small. 

Each 10 μg/g increase in patella lead was associated with an odds ratio of 1.28 (95% CI: 1.03, 

1.60). Separate analyses testing interactions of alcohol use, age, and menopausal status showed 

no significant interaction with patella lead, though the small sample size had little power to 

detect significant interaction effects. Model diagnostics were given for justifying the use of 

proportional odds ordinal regression but none were given justifying use of a linear blood lead 

term in the models. 

Rothenberg et al. (2002) investigated associations between both hypertension and blood 

pressure with blood lead, tibia lead, and calcaneus lead in 668 women, aged 15-44 years, in the 

third trimester of pregnancy and during a 3-month postpartum period using a cohort design and 

multiple logistic and multiple linear regression modeling. Subject exclusion criteria were blood 

lead > than 5 geometric SDs from the geometric mean, documented renal disease, cardiovascular 

disease, diabetes, use of stimulant drugs, and extreme postnatal obesity (BMI >40). Geometric 

mean prenatal and postnatal blood lead levels were 1.9 μg/dL and 2.3 μg/dL, respectively. Mean 

tibia and calcaneus lead levels were 8.0 μg/g and 10.7 μg/g, respectively. Variables in all 

models were selected a priori and retained in the models regardless of significance level. Control 

variables were education, smoking status, immigrant status, parity, age, and BMI in all models. 

Prenatal models also controlled for postpartum hypertension in lieu of family history of 

hypertension. None of the subjects used antihypertensive medications during the study. 

All three lead variables were simultaneously tested in all models. Third trimester blood lead 

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ranged from 0.4 to 30.0 μg/dL, postpartum blood lead ranged from 0.2 to 25.4 μg/dL. Calcaneus 

lead ranged from !30.6 to 49.9 μg/g and tibia lead ranged from !33.7 to 42.5 μg/g. Only 

calcaneus lead was significantly associated with an increase in hypertension (either $140 mm Hg 

systolic or $90 mm Hg diastolic) during pregnancy, with an odds ratio of 1.86 (95% CI: 1.04, 

3.32) for each 10 μg/g increase of calcaneus lead. No association between calcaneus lead and 

hypotension was found postpartum. The authors found the same pattern of trabecular lead 

concentration association with blood pressure during but not after pregnancy in normotensive 

women. A 10 μg/g increase in calcaneus lead was associated with ~0.75 mm Hg (95% CI: 0.04, 

1.46) increase in systolic and ~0.58 mm Hg (95% CI: 0.01, 1.16) increase in diastolic blood 

pressure in the third trimester. Only blood lead, tested simultaneously with tibia and calcaneus 

lead, was significantly associated with postpartum maternal blood pressure, but the relationship 

was negative, higher blood lead associated with lower postpartum blood pressure. For a 

doubling in blood lead, the systolic blood pressure increased !1.05 mm Hg (95% CI: !1.96, 

!0.14) and diastolic increased !1.16 mm Hg (95% CI: !1.98, !0.30). Though the authors 

thoroughly explored lead interaction with all other covariates in the models, they were unable to 

discover an effect modifier among them to explain the relationship. Postpartum physiological 

changes were discussed in relation to this last result. Thorough diagnostic testing was performed 

for all models. Only linear age terms were used in the models without exploration of age2

 terms. 

The authors did not use the repeated measures nature of the design in their analyses, instead they 

analyzed third trimester pregnancy data and postpartum data separately. They did not 

statistically test differences in coefficients from the same variables in the two parts of the study. 

Two studies examined a subset of subjects participating in the Normative Aging Study. 

Hu et al. (1996) used a cross-sectional design of 590 men with median age in the mid-60s (range 

48-92 years). Blood lead ranged from 1 to 28 μg/dL, tibia lead from <1 to 96 μg/g, and patella 

lead from 1 to 142 μg/g. Logistic regression models were initially constructed by adding age, 

race, BMI, family history of hypertension, smoking, alcohol use, and dietary sodium and 

calcium. Testing linear blood lead, tibia lead, and patella lead one by one against hypertension 

status (systolic >160 mm Hg, diastolic >96 mm Hg, or taking antihypertensive medication), they 

found no significant relationships with any of the lead variables, each entered separately. Only 

when they used backward elimination of nonsignificant variables did they find a significant odds 

ratio of 1.50 (95% CI: 1.09, 2.10) for each doubling of tibia lead from the mean (20.8 μg/g) for 

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hypertension. Later, Cheng et al. (2001) followed up the same group, constructing a multiple 

linear regression model for systolic blood pressure (diastolic blood pressure was not mentioned 

in model descriptions) in subjects not hypertensive at baseline measurement. They used a fixed 

set of control variables, including age and age terms, BMI, family history of hypertension, and 

alcohol and calcium intake, selected by univariate and bivariate testing of a larger set. After 

entering linear blood lead, tibia, and patella bone lead separately into the models, they reported a 

significant association only with tibia lead (1.60 mm Hg [95% CI: 0.00, 4.44] increase in 

systolic blood pressure for each doubling of tibia lead from the mean). Several years later (not 

specified in methods but no more than 6 years), the group of subjects that was originally not 

classified as having definite hypertension was retested for presence of definite hypertension 

($160/95 mm Hg). Each lead measure was separately entered into a Cox’s proportional hazards 

model of incident definite hypertension. Only patella lead showed a significant increase in the 

rate ratio in subjects with no history of definite hypertension, 1.14 (95% CI: 1.02, 1.28) for each 

10 μg/g increase in patella lead. Similar results were obtained when the borderline hypertensive 

group (>140/90 mm Hg) was combined with the definite hypertension group in patella lead. 

A rate ratio of 1.23 [95% CI: 1.03, 1.48]) was estimated. Use of linear lead terms may have 

affected the ability of the studies to detect significant blood lead effects. 

A pair of studies using the same group of male workers (age range 42-74 years) 

previously exposed to organic and inorganic lead at an industrial plant in the U.S. investigated 

the role of blood lead and bone lead on blood pressure. Blood lead ranged between 1 and 

20 μg/dL and tibia lead ranged from !1.6 to 52 μg/g. The study by Schwartz et al. (2000b) 

controlled for age, BMI, current smoking, and current use of antihypertensive medication in 

backward elimination linear multiple regression models for blood lead, tibia lead, and DMSAchelatable lead, forcing each lead term into separate models. Only blood lead was a significant 

predictor of blood pressure. In multiple logistic regression models, only blood lead in workers 

<58 years of age was significant in predicting hypertension (>160/96 mm Hg). Although this 

study used linear blood lead in one model, it used another model with both linear and squaredblood lead. Both lead terms were significant in the respective models. In a follow-up study 

(Glenn et al., 2003) with most of the same subjects of the first study, subsequent measurements 

of blood pressure occurred at intervals of 4-12 months for 10.2 months to 3.5 years. The study 

was notable not only for its prospective nature but in the use of statistical models adjusting for 

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repeated measurements. Models were constructed by adding to a base model containing age at 

start of study, race, BMI, and indicator variables for technician. Lead variables were always 

forced in the models, but it is not clear if they were each tested separately. Other potential 

confounder variables were added stepwise to the model if they met a probability criterion. Both 

increasing linear blood lead and tibia lead were significantly associated with increasing systolic 

blood pressure times the number of years of follow-up blood measurement, but not with change 

in diastolic blood pressure. Each 10 μg/g increase in tibia lead was associated with a 

0.78 mm Hg, year (95% CI: 0.24, 1.31) increase in systolic blood pressure for workers followed 

for the longest time. No model diagnostics were reported. 

Gerr et al. (2002) tested the effect of blood lead and tibia lead only in young adults (age 

19-29 years), both males and females, on blood pressure. Half the subjects had grown up around 

an active lead smelter. Multiple linear regression models always used age, sex, height, BMI, 

current smoking status, frequency of alcohol consumption, current use of birth-control 

medication, hemoglobin level, serum albumin, and income, regardless of significance levels. 

Both blood lead (as a linear term) and bone lead (a four category ordinal variable from <1 μg/g 

to >10 μg/g) were tested together. Tibia lead concentration in the highest group was associated 

with a significant increase in both systolic (4.26 mm Hg) and diastolic (2.80 mm Hg) blood 

pressure when compared to the lowest tibia lead group. No model diagnostics were presented. 

6.5.3 Other Cardiovascular Outcomes 

6.5.3.1 Ischemic Heart Disease 

A community-based case-referent study taken from the Stockholm Heart Epidemiology 

Program compared survivors of first-time myocardial infarction with matched referents based on 

sex, age, year of study enrollment, and hospital catchment area (Gustavsson et al., 2001). The 

authors assessed lead exposure by a three category ordinal scale based on lead levels in airborne 

dust. In the comparison of unexposed to >0-0.03 mg/m3

 (mean 0.01 mg/3) and unexposed to 

>0.04 mg/m3

 (mean 0.10 mg/m3), the relative risk was 0.88 (95% CI: 0.69, 1.12) and 1.03 

(95% CI: 0.64, 1.65), respectively. 

In a reanalysis of the NHANES II dataset, the influence of linear blood lead in the 

diagnosis of left ventricular hypertrophy (LVH) based on examination of electrocardiograms and 

body habitus data in less than 9,900 subjects (exact number not given) of age 25-74 years was 

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tested in a survey-adjusted stepwise logistic regression model (Schwartz, 1991). The final model 

adjusted LVH by age, race, and sex. The odds ratio for LVH was 1.33 (95% CI: 1.20, 1.47) for 

each 10 μg/dL increase in blood lead over an unreported blood lead range. The author reported 

no significant interactions between blood lead and race or between blood lead and sex, though 

the article noted that the number of cases of LVH was small. The linear lead effect had greater 

significance than the natural log lead effect, the reverse of the relationship between the two lead 

specifications usually seen when blood pressure is the outcome variable. 

In another study of electrocardiograms in 775 men (mean age 68 years, range 48-93) from 

the Normative Aging Study, patella and tibia lead concentrations were significantly associated 

with increased heart rate-corrected QT and QRS intervals in men under 65 years but not over 

65 years in multiple regression stepwise analysis (Cheng et al., 1998b). Only tibia lead 

concentration was significantly associated with an increased odds ratio of intraventricular 

conduction deficit (2.23 [95% CI: 1.28, 3.90]) for every 10 μg/g increase in tibia lead), but only 

in men under 65 years. In contrast, both tibia and patella lead concentration was significantly 

associated with atrioventricular conduction deficit (odds ratio of 1.22 [95% CI: 1.02, 1.47] and 

1.14 [95% CI: 1.00, 1.29] for each 10 μg/g increase in tibia and patella lead, respectively), but 

only for men greater than or equal to 65 years. None of the lead measurements were 

significantly associated with arrhythmia. Linear blood lead terms were not significantly 

associated with any of the above outcomes. Though the authors reported examining both 

saturated models (models with all considered control and confounding variables, significant or 

not) and stepwise models, only stepwise models were presented or discussed with each lead term 

forced into separate models. Thus, each model had an individual mix of control/confounding 

variables, though age was common to all models. Despite using age as a control/confounding 

variable in all models, the article offered no statistical justification for the age-stratified analysis. 

A group of male and female battery factory workers (n = 108) working for at least 

10 years and who were hired from 1960 to 1983 had blood lead levels from 1970 to 1994 ranging 

from 5 to 93 μg/dL (Tepper et al., 2001). Using a fixed covariate multiple logistic regression 

model, including age, BMI, sex, and family history of hypertension, the authors found a 

nonsignificant odds ratios for risk of hypertension (>165/96 mm Hg or self-reported use of 

hypertension medications) comparing the first tertile (138-504 μg/dL@year) cumulative blood 

lead index with the third tertile (747-1447 μg/dL@year) index. Echocardiogram left ventricular 

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mass was not significantly related to cumulative blood lead index or time-weighted average 

blood lead. 

The discrepancy in blood lead results between the two electrocardiogram studies by 

Schwartz (1991) and Cheng et al. (1998b) could well be explained by population differences. 

Though both used large datasets, the age range of the NHANES II subject pool was between 

25 and 74 years and used both men and women, whereas the age range for the Normative 

Aging study was 48 to 93 years and used only men. Furthermore, the Cheng et al. study had 

775 subjects whereas the Schwartz had a much larger, though unspecified number. The Tepper 

et al. (2001) study had the least number of subjects (n = 108), which may have resulted in not 

detecting significant effects on a different measure of LVH. Nonetheless, the two 

electrocardiogram studies each reported a significant lead effect, and the study with bone lead 

(Cheng et al., 1998b) is particularly interesting, not only for its older sample but because the 

bone lead exposure measure reflected accumulated past exposure, which blood lead only partly 

reflects. The two studies are in agreement that lead exposure, either past or present, is 

significantly associated with ischemic heart disease. 

6.5.3.2 Stroke 

No published articles relating lead specifically to stroke were uncovered, though some 

ICD diagnostic codes (the cerebrovascular codes) reported in other parts of this section included 

stroke. 

6.5.3.3 Cardiovascular/Circulatory Mortality 

A recent follow-up of the NHANES II cohort provided mortality data used to associate 

past blood lead concentration with increased circulatory mortality in the U.S. population 

(Lustberg and Silbergeld, 2002). Blood lead concentration as measured during 1976-1980 was 

divided into three categories (<10 μg/dL, 10-19 μg/dL, and 20-29 μg/dL) after eliminating 

109 subjects with blood lead $30 μg/dL, leaving 4,190 subjects 30-74 years of age in the 

mortality sample followed to the end of 1992. During the follow-up period, 929 subjects died of 

all causes. ICD-9 codes 390-459 (circulatory) accounted for 424 deaths. Proportional hazards 

models using a priori selected potential confounding variables (age, sex, race, education, income, 

smoking, BMI, exercise, and location) were used to calculate risk ratios of cardiovascular 

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mortality for the two higher lead categories compared against a <10 μg/dL reference. The 

20-29 μg/dL category showed a significant relative risk of 1.39 (95% CI: 1.01, 1.91) for 

cardiovascular mortality. 

Another longitudinal study combined fatal and nonfatal coronary heart disease (ICD-8 

codes 410-414) and cardiovascular disease (ICD-8 codes 410-414 and 430-435) categories from 

a Danish 1936 birth cohort (N = 1052) followed from 1976-1990 (Møller and Kristensen, 1992). 

During the study period, 54 cases of cardiovascular disease with 19 deaths were reported. 

Log-transformed blood lead was used in a Cox proportional hazards model, controlling for a 

priori selected variables of tobacco use, cholesterol, physical activity, sex, systolic blood 

pressure, and alcohol. Two other models were also examined, those leaving out alcohol or both 

alcohol and systolic blood pressure. None of the adjusted models showed significant risk hazard 

for combined fatal and nonfatal cardiovascular disease, though blood lead was significantly 

associated with outcome in all models except the one containing both alcohol and systolic blood 

pressure for “total mortality” risk hazard, which presumably counted noncardiovascular 

mortality as well (not detailed in article). This article is notable for its detailed discussion of 

using confounding variables, such as hemoglobin and alcohol use, in multivariate models of 

lead-cardiovascular associations. Small sample size and low death rate may have contributed to 

the nonsignificant results. 

An occupational study, using 1,990 male workers who worked at least 1 day between 

1940 and 1965 in an active lead smelter in the U.S. (mean length of employment at smelter 

13.8 years; mean estimated length of lead exposure 9.9 years), failed to show an association with 

lead and standardized mortality ratios compared to the U.S. population reference group up to 

1988 (Steenland et al., 1992). Neither mortality from ischemic heart disease (ICD-9 410-414), 

hypertension with heart disease (ICD-9 402 and 404), hypertension with no heart disease (ICD-9 

401, 403, and 405), nor cerebrovascular disease (ICD-9 430-438) were significantly higher in the 

study group than in the U.S. population when examined in their totality or stratified by “high 

lead exposure” (>0.2 mg/m3

 lead in air, surveyed in 1975) or “duration of exposure.” Imprecise 

estimation of lead exposure may have contributed to the nonsignificant results. 

A study of 664 male workers in a Swedish lead smelter from 1942-1987 examined 

standardized mortality ratios for cardiovascular disease compared to the county population 

mortality figures from 1969-1989 (Gerhardsson et al., 1995a). Blood lead measurements were 

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available from the workers since 1969 (mean 62.1 μg/dL) and dropped steadily from that date to 

1985 (mean 33.1 μg/dL). The consecutive blood lead measurements in the subjects allowed 

construction of a cumulative blood lead index. Standardized mortality ratios were significantly 

elevated in the group for all cardiovascular diseases (ICD-8 390-458) and for ischemic heart 

disease (ICD-8 410-414), 1.46 (95% CI: 1.05, 2.02) and 1.72 (95% CI: 1.20, 2.42), 

respectively. However, there were no indications of a concentration-response relationship when 

analyses were stratified by cumulative blood lead index, peak blood lead, or other exposure 

indices. 

In a study of 1,261 male newspaper linotype operators working in 1961 and followed until 

1984, 38% had died from all causes (Michaels et al., 1991). Compared to the New York City 

population reference group, there was a marginally significant increased standardized mortality 

ratio in the printers of 1.35 (95% CI: 0.98, 1.82) for cerebrovascular disease (ICD-8 430-438), 

which became highly significant in those with 30 or more years exposure (1.68 [95% CI: 1.18, 

2.31]; 37 of the total 43 deaths due to cerebrovascular disease). Atherosclerotic heart disease 

(ICD-8 410-414) mortality in printers was significantly below that expected from the general 

population, with a standardized mortality ratio of 0.63 (95% CI: 0.59, 0.73). 

Two studies were longitudinal in nature, following the same cohort for a period from 

12 to 16 years (Lustberg and Silbergeld, 2002; Møller and Kristensen, 1992). They both used 

large community cohorts (NHANES II and a Danish birth cohort, respectively) and they both 

used multivariate proportional hazards models with blood lead as the principal predictor. Both 

studies found a significant increase in risk ratio with increased blood lead. 

Another study examined occupationally-exposed subjects and used population reference 

groups to assess differences in mortality. Steenland et al. (1992) showed no significant increased 

mortality from ischemic heart disease (ICD-9 410-414), hypertension with heart disease (ICD-9 

402 and 404), hypertension with no heart disease (ICD-9 401, 403, and 405), nor cerebrovascular 

disease (ICD-9 430-438) in the study group than in the U.S. population, even in the high lead 

exposure group. 

6.5.3.4 Other Cardiovascular Effects 

Peripheral arterial disease (PAD), flow-limiting atherosclerosis in lower limb muscular 

arteries, was studied using Phase 1 (1999-2000) of the NHANES IV, the most recent NHANES 

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dataset (Navas-Acien et al., 2004). PAD was categorized as a ratio of brachial artery (arm) 

systolic blood pressure to posterior tibial artery (ankle) systolic blood pressure < 0.90. One 

hundred thirty-nine subjects were classified as having PAD; there were 1,986 subjects without 

the disease. Blood lead was classified by quartile, with the 1st quartile containing subjects with 

blood lead <1.4 μg/dL and the 4th quartile containing subjects with blood lead >2.9 μg/dL. 

Age range was 40 to >70 years. Three sets of covariates were tested in separate models. The 

first set, common to all models, included age, sex, race, and education. The second set included 

the first set and added BMI, alcohol intake, hypertension, diabetes, hypercholesterolemia, and 

glomerular filtration rate. The third set added self-reported smoking status and serum cotinine. 

Compared to first quartile blood lead, 4th quartile blood lead subjects had significant odds ratios 

for PAD of 3.78 (95% CI: 1.08, 13.19) and 4.07 (95% CI: 1.21, 13.73) for the first two models. 

The odds ratio of 2.88 (0.87, 9.47) for the third model was not statistically significant. However, 

the increasing odds ratio trend from 1st through 4th quartile was significant for all 3 models 

(p $ 0.02). 

6.5.4 Potential Confounding of the Cardiovascular Effects of Lead 

6.5.4.1 Confounding by Copollutants 

High on the list of other metals that might be associated with cardiovascular disease is 

cadmium, through its known effects on kidney function. If blood lead and blood cadmium 

strongly covary in a sample by sharing a common source (e.g., when the study sample is drawn 

from a population living near a nonferrous smelter emitting both metals), including simultaneous 

blood lead and cadmium measurements in the same model would likely show a significant 

reduction in both coefficients when compared to either metal alone. If, however, blood cadmium 

and lead do not covary in the sample, their coefficients in the model together would be much the 

same as when tested separately. In a study of PAD (Navas-Acien et al., 2004) discussed in 

Section 6.5.3.4, investigators not only tested both lead and cadmium in separate models but also 

tested them simultaneously. The correlation coefficient between natural log lead and natural log 

cadmium was 0.32 (p < 0.001), highly significant, though leaving 90% of the variance between 

them unexplained. In addition, they tested possible interactions between lead and cadmium, and 

between the two metals and sex, race-ethnicity, smoking status, renal function, and C-reactive 

protein. Although none of the interactions were significant, when blood lead and blood cadmium 

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were in the same model together they both had significant trends of increasing odds ratios with 

increasing quartile of each metal, but the nonsignificant point estimate of the odds ratio for blood 

lead comparing 1st and 4th lead quartile tested alone dropped further when tested with cadmium 

(odds ratio of 2.88 versus 2.52). Cadmium between 1st and 4th quartile, on the other hand, 

showed a similar drop from cadmium tested alone to cadmium tested with lead (odds ratio of 

2.82 versus 2.42), but both point estimates remained significant. Thus, though point estimates of 

both lead and cadmium were approximately the same whether tested alone or together, the larger 

variance associated with the lead coefficients rendered them nonsignificant. Part of the 

difference in variance between the two metals could be explained by noting that the reference 

group (lowest quartile) for lead contained a little over half the number of subjects (n = 472; 18 

cases, 454 noncases) than the reference group for cadmium (n = 856; 27 cases, 829 noncases). 

The odds ratios for PAD with smoking status dropped from 4.13 (95% CI: 1.87, 9.12) to 3.38 

(95% CI: 1.56, 7.35) when lead was added to the model, but both odds ratios remained highly 

significant and the difference was not statistically tested. The failure to find a significant 

interaction between the two metals and between smoking status and both metals suggests that 

none of the odds ratio changes discussed above were significant. The same pattern of results was 

found when using cotinine blood levels instead of self-reported smoking habit. Adding cadmium 

alone or cadmium and lead together resulted in nonsignificant odds ratios for both indices of 

smoking. 

The Belgian Cadmibel studies also were ideally situated to test possible interactions 

between blood lead and cadmium, but the technique of stepwise addition of variables to the 

multiple regression models of blood pressure did not allow retention of both metal variables 

together in the same model (Staessen et al., 1996). From the lack of both cadmium and lead in 

any one model, it can be inferred that, if both variables had been forced into the model together, 

they both would have had nonsignificant coefficients. 

6.5.4.2 Confounding by Smoking Status 

Most studies reviewed in this section have controlled for tobacco use, where it often 

appears related to lower blood pressure. The majority of reviewed studies including smoking as 

a covariate never present the coefficients of smoking or related covariates. Only the NavasDecember 2005 6-201 DRAFT-DO NOT QUOTE OR CITE 

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Acien et al. (2004) study discussed in the previous section systematically addressed the issues 

related to possible confounding or effect modification with tobacco use. 

6.5.4.3 Confounding by Alcohol Consumption 

Possible confounding by alcohol use, generally associated with increased blood pressure, 

was thoroughly discussed in the 1990 Supplement (Grandjean et al., 1989). Alcohol, especially 

in Europe, contained substantial lead during much of the 20th century. This can be seen in the 

MONICA Augsberg, Germany cohort study (Hense et al., 1994). The study group was stratified 

by sex and then, only in men, by rural-urban location. Within each strata, the blood lead range 

differed by alcohol use. In women, for example, the 10th and 90th percentile values of blood 

lead were approximately (as estimated from graphs) 3.5 and 8.5 μg/dL for self-reported 

abstainers, 4.5 and 10.5 μg/dL in those drinking from 1 to 39 g/day, and 6.0 to 14.0 μg/dL in 

those drinking 40 plus g/day. Despite the finding that only women in the highest alcohol-use 

group had a significant lead effect, it cannot be determined if the increase in lead coefficient is 

significant because the three coefficients associated with use of alcohol strata were not tested for 

differences among themselves; they were only tested for their significance from the null 

hypothesis of 0. Another study was based on subjects from the New Risk Factors Survey from 

the area around Rome, intended to determine confounding effects of a number of social and 

biochemical variables on the blood lead-blood pressure relationship (Menditto et al., 1994). 

Alcohol consumption, as well as BMI, heart rate, non-HDL cholesterol, and HDL cholesterol, 

triglycerides, cigarettes smoked/day, and skinfold thickness were all examined. A doubling of 

blood lead was associated with an increase of 4.71 mm Hg in systolic and 1.25 mm Hg in 

diastolic blood pressure. Alcohol as a true confounding variable is likely limited to studies in 

areas where alcohol contributes significantly to blood lead. In a study of 249 bus drivers in San 

Francisco, CA, natural log lead coefficients against blood pressure changed less than 10% when 

alcohol use was included as a covariate (Sharp et al., 1990). Blood lead according to alcohol use 

was not reported. Another study based on a U.S. population found a significant increase in blood 

lead of a mixed group of males and females according to alcohol use, ranging from mean blood 

lead of 7.3 μg/dL in nonusers to 9.2 μg/dL in those reporting more than 2 ounces/day over 3 days 

(Morris et al., 1990), with no report of significant effects of alcohol on blood pressure. 

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6.5.4.4 Confounding by Dietary Calcium Intake 

The main thrust of the previously reported Morris et al. (1990) study was to examine the 

effects of dietary calcium on the effect of lead on blood pressure in 78 males and 64 females 

between 18 and 80 years, many of whom were hypertensive (undisclosed number), though those 

using medications for hypertension discontinued their use 1 month before testing started. 

Subjects were excluded if they had “secondary hypertension.” The investigators measured 

serum calcium and assessed dietary calcium intake, among other variables. There were no 

changes in blood lead or blood pressure noted as a result of dietary calcium supplementation. 

Proctor et al. (1996), using the Normative Aging Study, examined possible modification 

of the effect of natural log blood lead (blood lead range 0.5-35 μg/dL) on blood pressure in 

798 men aged 45-93 years by dietary calcium intake assessed by food questionnaire. The study 

used multiple regression models with a fixed set of covariates, including age and age2

, BMI, 

adjusted dietary calcium, exercise, smoking, alcohol use, sitting heart rate, and hematocrit. 

Increased blood lead was significantly associated with diastolic blood pressure and systolic blood 

pressure. Only systolic blood pressure significantly decreased with increased dietary calcium 

(0.004 mm Hg decrease for every 1 mg/day increase of dietary calcium). The authors formed 

dichotomized calcium intake (cut point at 800 mg/day) and blood lead (cut point at 15 μg/dL) 

variables to test the interaction between blood lead and calcium on blood pressure. They did not 

find a significant interaction. 

A study of a subset of the Cadmibel Study with 827 males and 821 females, age 20 to 

88 years, selected from areas known to represent a wide range of cadmium exposure, specifically 

studied total serum calcium interactions with blood lead on blood pressure (Staessen et al., 

1993). Stepwise regression models, selecting from log blood lead, age and age2

, BMI, pulse rate, 

log serum gamma-glutamyltranspeptidase, serum calcium, log serum creatinine, urinary 

potassium, smoking, alcohol intake, contraceptive pill use (females only), and a menopause 

indicator variable (females only), were stratified by sex for systolic and diastolic blood pressure. 

The stepwise procedure resulted in models each with a different mix of covariates. Increased 

serum calcium was significantly associated with increased systolic blood pressure in both males 

and females. Every increase of one log unit of blood lead was associated with nonsignificant 

changes in blood pressure in women but with a significant decrease in systolic blood pressure in 

men (systolic log blood lead $ = !5.2). A separate set of models were constructed with an 

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interaction term between serum calcium and log blood lead (details not shown). In women only, 

both main effects of lead and calcium and the interaction effect were significant (no coefficients 

presented). At the 25th percentile of serum calcium (2.31 μmol/L), a doubling of blood lead was 

associated with a 1.0 mm Hg increase in systolic blood pressure. At the 75th percentile of serum 

calcium (2.42 μmol/L) a doubling of blood lead was associated with a 1.5 mm Hg increase in 

systolic blood pressure. Furthermore, serum calcium may itself be confounded with age in 

women, as women showed a sharp rise in serum calcium in their sixth decade of life, coincident 

with menopause, whereas the trend for serum calcium in men was steadily downward for each 

subsequent decade of age. The authors did not test an interaction term including calcium and age 

or calcium and menopausal status. Thus, the significant interaction effect between calcium and 

lead on blood pressure may be a result of differences due to menopause. 

6.5.4.5 Summary of Potential Confounding of the Lead Effect on Cardiovascular Health 

The effects of cadmium exposure, smoking, alcohol use, dietary and serum calcium levels 

have all been formally tested in a few studies, without significant effects as confounders of the 

lead effect. Failure to find a significant confounding effect with lead, however, does not argue to 

maintain these variables uncritically in models of blood pressure. If alcohol contains lead, 

increased alcohol use will lead to increased blood lead. In this case, both variables in the model 

will be collinear and this tends to distort estimated coefficients and standard errors of their effect 

on cardiovascular outcome. Tobacco use may influence lead levels much more in occupational 

studies than in community exposure studies, especially if smoking in the factory is allowed. 

Frequent hand to mouth behavior will increase lead exposure and, consequently, raise blood lead 

concentrations. Serum calcium may statistically modify the lead effect differentially by gender 

due to menopause in women. Menopause also affects lead turnover. If serum calcium, blood 

lead, and blood pressure are all statistically related, serum calcium should not be used in blood 

lead-blood pressure/hypertension studies. 

6.5.5 Gene-Lead Interactions 

Study authors characterized sodium-potassium adenosine triphosphatase α2 (ATP1A2) 

polymorphism in 220 workers formerly exposed to a mix of organic and inorganic lead in the 

U.S., noted above in other references (Glenn et al., 2001). The ATP1A2 (3N) one kilobase probe 

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produced two homozygous (4.3/4.3 and 10.5/10.5) and one heterozygous (4.3/10.5) genotypes 

and two homozygous (8.0/8.0 and 3.3/3.3) and one heterozygous (8.0/3.3) genotypes for the 

2.5 kilobase ATP1A2 (5N) probe. Of the 209 subjects with data on both polymorphisms, 43.5% 

were doubly homozygous for 8.0/8.0 and 4.3/4.3, 34.4% were homozygous for 8.0/8.0 and 

heterozygous for 4.3/10.5, 11.5% were heterozygous for 8.0/3.3 and homozygous for 4.3/4.3, 

5.3%. Also, 5.3% were doubly homozygous for 8.0/8.0-10.5/10.5, and 4.8% were doubly 

heterozygous for the two genotypes. Although only 13 African American workers participated, 

prevalence of the 10.5 kilobase allele in the ATP1A2 (3N) genotype was statistically higher for 

them than for other races. Prevalence of hypertension ($160/96 mm Hg or use of hypertension 

medication) was significantly higher in those with the 10.5/10.5 genotype than in others. 

Controlling for age, BMI, lifetime number of alcoholic drinks, the 10.5/10.5 genotype was 

associated with an odds ratio of 7.7 (95% CI: 1.9, 31.4) for hypertension when compared to the 

4.3/4.3 homozygous genotype, but there were no effects of either blood lead, tibia lead, or their 

interaction with ATP1A2 (3N) genotype. A multiple linear regression model for linear blood lead 

and systolic blood pressure, controlling for age, use of hypertensive medication, current 

smoking, quartiles of lifetime alcohol consumption, and season, showed a significant main effect 

for 10.5/10.5 homozygous contrasted against combined 4.3/4.3 and 4.3/10.5 groups, associated 

with a 25.5 mm Hg reduction in blood pressure, primarily due to limited blood lead range of the 

homozygous group (maximum blood lead of the 10.5/10.5 group 9 μg/dL; maximum blood lead 

of the contrast group = 20 μg/dL). But the interaction between linear blood lead and the 

10.5/10.5 condition resulted in a significant increase of the blood lead effect on blood pressure 

by 5.6 mm Hg for every 1 μg/dL blood lead compared to the blood lead effect in the other 

genotypes. The authors stated, but did not show analysis or coefficients, that the ATP1A3 (3N) 

polymorphism also significantly interacted with tibia lead and systolic blood pressure. There 

were no significant relationships using the ATP1A2 (5N) gene. Thus, the ATP1A2 (3N) 

polymorphism appears to directly influence both prevalence of hypertension and the effect of 

lead on blood pressure, though the small group (n = 9 with all measures) with the important 

10.5/10.5 homozygous pattern would argue for enlarging this important study. 

Another research group focused on polymorphisms of two genes suspected to be involved 

in lead toxicokinetics, the vitamin D receptor (VDR) and delta-aminolevulinic acid dehydratase 

(ALAD) (Lee et al., 2001). Polymorphism of both genes is well studied and prevalence appears 

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associated with race or ethnic background. Nearly 800 Korean workers aged 18-65 years 

(79.4% males) from lead-using businesses were classified according to ALAD polymorphism 

(1-1 [homozygous] versus 1-2 [heterozygous]) and VDR polymorphism (bb [predominant 

homozygous] versus Bb plus BB [infrequent polymorphisms]). The homozygous 1-1 ALAD 

polymorphism was found in 90.1% of the group and the homozygous bb polymorphism was 

found in 88.8% of the group. When compared to a smaller group of non-lead-exposed workers, 

blood lead concentration (mean exposed 32.0 μg/dL [range 4-86] mean nonexposed 5.3 μg/dL 

[range 2-10] and tibia lead concentration mean exposed 37.2 μg/g [range !7-338]; and mean 

nonexposed 5.8 μg/dL [range !11-27]) were much higher. The study used stepwise multiple 

regression models, selecting covariates remaining significant in the models from among a large 

set of potential control and confounding variables. They also allowed potential confounders to 

remain in the models if “there were substantive changes in the coefficients of predictor 

variables” with their addition. Systolic models controlled for age and age2

, sex, BMI, 

antihypertensive medication use, and cumulative lifetime alcohol use. Depending on the 

presence or absence of linear blood lead, tibia lead, and DMSA chelatable lead in the models, 

and the gene-age interactions tested, blood urea was added to the model. Diastolic models 

controlled for age, sex, BMI, cumulative alcohol consumption, and linear blood lead. 

Hypertension (systolic >160 mm Hg or diastolic >96 mm Hg) logistic multiple regression 

models controlled for age, sex, BMI, tibia lead, and current alcohol use. Among the exposed 

workers bb VDR genotypes had significantly lower DMSA-chelatable blood lead and lower 

diastolic and systolic blood pressure than the combined Bb and BB genotypes. The only 

significant interaction reported between predictor variables and gene polymorphism on blood 

pressure was with the VDR polymorphism bb allele, who had a less pronounced increase in 

systolic blood pressure with age than subjects with the B allele. There were only marginally 

significant associations of systolic blood pressure with tibia lead and linear blood lead. There 

were no significant associations in models of diastolic blood pressure with linear blood lead, 

DMSA-chelatable blood lead, or tibia lead. Tibia lead was significantly associated with 

hypertension (odds ratio of 1.05 [95% CI: 1.00, 1.12] for each 10 μg/dL increase in tibia lead). 

Workers with VDR B allele had significantly higher prevalence of hypertension (odds ratio = 2.1 

[95% CI: 1.0, 4.4]) than workers with the bb genotype, but no other lead variable or interaction 

with VDR status was reported significant. Though VDR status was significantly related to blood 

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pressure and prevalence of hypertension, there were no significant effects of ALAD 

polymorphism on blood pressure or hypertension or of VDR interactions with any lead exposure 

variable. 

Lustberg et al. (2004) studied these same Korean lead workers (n = 793) to examine the 

relationships between the G894–T894 polymorphism in the gene regulating endothelial nitric oxide 

synthase (eNOS) and blood lead effects on blood pressure and hypertension. Nitric oxide 

metabolism has been suggested both as a mechanism for altered blood pressure and for 

moderating the effects of lead on blood pressure, though there is experimental support for and 

against both hypotheses. After classifying subjects as homogenous for the GG type (85%), 

heterogeneous for both types (TG) (14%), or homogenous for TT (1%), the TG and TT types 

were combined into a single group (TG/TT). Diastolic and systolic multiple regression models 

were constructed with a fixed set of covariates, including smoking, alcohol consumption, age, 

sex, BMI, and education. Logistic regression models used blood pressure criteria of either 

$140 mm Hg diastolic blood pressure, $90 mm Hg systolic blood pressure, or self-report of 

using antihypertensive medications. There was no effect of genotype on diastolic or systolic 

blood pressure or on hypertension prevalence in multiple regression models, nor any significant 

interaction of lead exposure indices with gene status. 

6.5.6 Summary of the Epidemiologic Evidence for the Cardiovascular 

Effects of Lead 

The combined blood lead studies using blood pressure/hypertension as an outcome 

continue to support the conclusions of the 1990 Supplement that there is a positive association 

between blood lead and increased blood pressure. The occasional finding of significant negative 

associations of blood lead with blood pressure (e.g., the Cadmibel study, one NHANES III study, 

the postpartum phase of the Los Angeles pregnancy study) have not been adequately explained 

and require further confirmation and study. The reported meta-analysis succinctly characterizes 

the blood pressure findings with blood lead: 1.0 mm Hg systolic pressure increase with each 

doubling of blood lead; 0.6 mm Hg diastolic pressure increase with each doubling of blood lead. 

Although females often show lower lead coefficients than males, and blacks higher lead 

coefficients than whites, where these differences have been formally tested, they are usually not 

statistically significant. The tendencies may well arise in the differential lead exposure in these 

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strata, lower in women than in men, higher in blacks than in whites. The same sex and race 

differential is found with blood pressure. 

The most promising developments in this field since the 1990 Supplement have been the 

use of bone lead as a long-term cumulative lead exposure index and the introduction of genetic 

analysis into the studies as potential lead effect modifiers. With one exception, all studies using 

bone lead have found a consistently positive and significant effect on blood pressure and/or 

hypertension. The ability to estimate past exposure in cross-sectional studies is a significant 

advance. The results of the bone lead studies to date highlight the important role of accumulated 

lead exposure in the development of cardiovascular problems. 

Though the study of genetic polymorphisms is still in its infancy in this field, it too holds 

great promise in accounting for individual variability in development of cardiovascular disease 

and individual response to lead exposure. 

6.6 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS OF LEAD 

6.6.1 Summary of Key Findings of the Reproductive and Developmental 

Effects of Lead from the 1986 Lead AQCD 

Lead has been implicated as a risk factor for reproductive outcomes for over a century 

Rom, 1976; Oliver, 1911). As early as 1860, increased rates of stillbirths and spontaneous 

abortions were found in women with occupational exposure to lead (usually in the ceramics 

industry) and in women with husbands employed in the lead industry, compared to unexposed 

women (Rom, 1976). Other early investigations found increased rates of physically and 

mentally “retarded” offspring among these same groups. In 1910, these findings resulted in the 

first lead-related occupational regulation; the British Committee on Occupational Health 

recommended that women not be employed in the lead industry (Oliver, 1911). These 

observations, however, were based on exposure levels far above those considered acceptable 

today, and current research now focuses on substantially lower exposure levels. 

The 1986 Lead AQCD provided evidence that lead, at high exposure levels, exerted 

significant adverse health effects on male reproductive functions. Several studies observed 

aberrations in both sperm count and morphology in men occupationally exposed to relatively 

high levels of lead (blood lead levels of 40-50 μg/dL). However, the effects of lead on female 

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reproductive function and fetal growth were suggestive but equivocal, perhaps due to the small 

sample sizes and inadequate controlling for potential confounding factors. 

This section provides a critical review of the literature regarding the associations between 

exposure to environmental lead and reproductive outcomes. First, the evidence for the placental 

transfer of lead is reviewed; this is key to providing a basis and mechanism for fetal exposure. 

Second, the association between exposure and each outcome is reviewed. Outcomes of interest 

are reproductive function (fertility), spontaneous abortion, fetal growth, preterm delivery, and 

congenital anomalies. Each section below begins with a summary of the literature up to 1986, 

the year of the last EPA Air Quality Criteria Document. Then, key studies are reviewed and 

each section ends with a conclusion based on the evidence provided. The conclusion is based on 

the generally accepted “Causal Criteria” for bodies of epidemiologic literature (Hill, 1965; 

Susser, 1991). 

6.6.2 Placental Transfer of Lead 

In 1968, Barltrop (1968) demonstrated that lead crosses the placenta beginning as early as 

gestational week 12. He found that the rate of transfer subsequently increased to term. Lead 

accumulations were found in the bones, livers, blood, hearts, kidneys, and brains of stillborn and 

spontaneously aborted fetuses. These observations were replicated by numerous investigators; 

for example, Casey and Robinson (1978) found lead accumulations in the livers, kidneys, and 

brains of stillborn fetuses. Lead accumulations were also found in the livers, brains and kidneys 

of first trimester abort fetuses (Chaube et al., 1972), suggesting placental transfer earlier than 

12 weeks of gestation. Newer findings, published since 1986, are reviewed below (also see 

Section 6.2.2.5.2). 

Placental transfer of lead is confirmed by correlations of maternal blood lead 

concentrations, umbilical cord blood lead, and placental lead concentrations in a variety of 

settings. Umbilical cord blood reflects fetal blood. Early studies, prior to 1986, found 

correlation coefficients between maternal and umbilical cord blood lead ranging from 0.5 to 0.8, 

all of which were highly statistically significant. More recent studies also find significant 

correlations between maternal and fetal blood lead. For example, a prospective study in Kosovo, 

Yugoslavia recruited 1,502 women at mid-pregnancy in two towns — one with high exposure 

due to the presence of a lead smelter, refinery, and battery plant, and one with relatively low 

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exposure. The correlation between maternal blood lead (either at delivery or at mid-pregnancy) 

and cord blood lead ranged from 0.8 to 0.9 (Graziano et al., 1990). Among women with 

substantially lower levels of exposure (e.g., blood lead 1.9 μg/dL) the correlation between 

maternal and cord blood lead was 0.79 (Harville et al., 2005). 

Chuang et al. (2001) propose that while maternal and cord whole blood lead are highly 

related, fetal exposure may be even more influenced by maternal plasma lead. Using data from a 

cohort of 615 women in Mexico City recruited in 1994-1995, these investigators used structural 

equation modeling to estimate the associations between whole blood lead, bone lead (cortical and 

trabecular), and the latent variable, plasma lead and cord blood lead. They found the strongest 

associations between whole blood lead and cord blood lead, even after accounting for plasma 

lead. The greatest contributors to plasma lead were bone lead and airborne lead. However, with 

declining exogenous lead exposure, these investigators note that the measurement of plasma and 

bone lead may become increasingly important in assessing fetal exposure. 

These data provide little doubt of fetal exposure to lead via placental transport. Further, it 

appears that lead crosses the placenta throughout pregnancy, leading to continual exposure of the 

fetus. Indeed, there is evidence to suggest that maternal blood leads during the later half of 

gestation increase (Gulson et al., 2004; Hertz-Picciotto et al., 2000; Rothenberg et al., 1994; 

Sowers et al., 2002). The magnitude of the increase ranges from 14-40%, possibly due to the 

different starting blood leads in each study (Bellinger, 2005). The increase in blood lead in the 

later half of pregnancy may result from physiologic changes in maternal homeostasis during 

pregnancy and, in particular, to mobilization of lead stores from other body organs (Bellinger, 

2005). Indirect evidence for such mobilization comes from the increased rate of bone turnover 

during the later half of gestation, prompted by the increased fetal need for calcium (Moline et al., 

2000). Thus, both the epidemiological evidence and the biological plausibility of the 

associations support the role of maternal-fetal transfer of lead. 

Additionally, in populations with greater lead burdens, the fetus may be at even greater 

increased risk for exposure and possible adverse effects of exposure. Among the variables 

associated with lead exposure in pregnant (and nonpregnant) women are: smoking and alcohol 

consumption (Graziano et al., 1990; Rhainds and Levallois, 1997), pica (Rothenberg et al., 

1999), use of ethnic remedies and cosmetics (Al-Ashban et al., 2004; Centers for Disease 

Control and Prevention, 1993), and food preparation in inappropriately lead-glazed pottery 

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(Azcona-Cruz et al., 2000; Rothenberg et al., 2000). There is some evidence that low calcium 

intake is also associated with higher blood lead (Gulson et al., 2004; Hernandez-Avila et al., 

2003; Hertz-Picciotto et al., 2000). Finally, the location where the mother resides (or resided as 

a child) may increase blood lead (Graziano et al., 1990). Blood leads are elevated among U.S. 

immigrants, especially those who migrated from countries where lead is still used as a gasoline 

additive (Centers for Disease Control and Prevention, 2000); indeed, blood leads are inversely 

associated with the number of years since migration (Centers for Disease Control and 

Prevention, 2000; Klitzman et al., 2002; Rothenberg et al., 1999). 

In conclusion, the epidemiologic evidence indicates that lead freely crosses the placenta, 

resulting in continued fetal exposure throughout pregnancy. Indeed, the evidence is strong that 

exposure increases during the later half of pregnancy. Exposure to the fetus is more pronounced 

in high-risk populations, especially those who migrated from countries still using lead as a 

gasoline additive. 

6.6.3 Effects of Lead on Reproductive Function 

6.6.3.1 Effects on Male Reproductive Function 

Male reproductive function is measured using the reproductive history of the male (i.e., 

number of pregnancies fathered), time to pregnancy and direct measures of semen quality 

(usually sperm count, motility and morphology). Most studies relating lead exposure to male 

reproductive function are based on data collected in the occupational setting linked to population 

birth registries and on studies directly collecting questionnaire exposure and outcome data. 

6.6.3.1.1 Sperm Count, Motility and Morphology 

Recent publications which purport a decline in sperm concentration, motility, and 

morphology seek the explanation in the rising use of man-made chemical endocrine disruptors 

(Auger et al., 1995; Fisch et al., 1997; Farrow, 1994; Gyllenborg et al., 1999; Kavlock et al., 

1996; Keiding et al., 1994; Kieding and Skakkebaek, 1996; Lerchl, 1995; Olsen et al., 1995; 

Sherins, 1995). Several studies from the 1970s and early 1980s suggest aberrations in both 

sperm count and morphology in men exposed to relatively high levels of lead. In the earliest 

study, Lancranjan et al. (1975) found decreased sperm counts and an increased prevalence of 

morphologically abnormal sperm among workers heavily exposed to lead (mean blood lead 

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74.5 μg/dL) as well as those moderately exposed (mean blood lead 52.8 μg/dL). These findings 

have been corroborated by results of studies in the U.S. (Cullen et al., 1984) and Italy (Assennato 

et al., 1986) which describe similar effects in workers with blood leads above 60 μg/dL. 

More recently, corroborating data was described in a comprehensive review by Apostoli 

et al. (1998). In studies of men with blood leads above 40 μg/dL, decreases in sperm count and 

concentration, motility and morphologic aberrations were found. Chowdhury et al. (1986) found 

a significant decrease in sperm count and motility and an increase in the number of sperm with 

abnormal morphology in 10 men with occupational lead exposure; the average blood lead in the 

exposed group was 42.5 μg/dL compared to 14.8 μg/dL in the unexposed. Similar results were 

found in a group of 30 lead-exposed factory workers compared to controls (Lerda, 1992). In a 

large study of male lead smelter workers, Alexander et al. (1996a) found a decreasing trend of 

sperm concentrations with increasing lead exposure. In this cohort, 152 workers provided blood 

specimens and 119 also provided semen samples. Geometric mean sperm concentrations were 

79.1, 56.5, 62.7, and 44.4 million cells/mL for blood leads of <15, 15-24, 25-39, and $40 μg/dL, 

respectively. Long-term body lead burden was estimated from current blood lead concentrations 

and historical blood lead monitoring data. Using this measure of long-term lead body burden, a 

similar trend was found for sperm concentration, total sperm count, and total motile sperm count. 

No associations were found for sperm morphology or serum concentrations of reproductive 

hormones. A study of traffic police in Peru, where leaded gasoline is still in use, found decreases 

in sperm morphology, concentration, motility and viability among men with blood lead 

$40 μg/dL compared to men with blood lead <40 μg/dL. 

Using data from an international study of 503 men employed in the lead industry, 

Bonde et al. (2002) considered the lowest adverse effect level associated with perturbed semen 

parameters. Median sperm concentration was reduced by 49% in men with blood lead 

>50 μg/dL; regression analysis indicated a threshold value of 44 μg/dL. These investigators 

conclude that adverse effects on sperm quality were unlikely at blood leads <45 μg/dL. 

In a population of couples undergoing either artificial insemination or in vitro fertilization, 

Benoff et al. (2003a,b) found higher concentrations of lead in seminal fluid in the male partner 

among couples who did not conceive, compared to those who did conceive. While not directly 

measuring the adverse effects of lead on sperm per se, these data suggest a possible mechanism 

for the transfer of lead from paternal exposure to the fetal environment. Hernandez-Ochoa et al. 

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(2005) also provide evidence that lead concentrations in seminal fluid may be a better indicator 

of exposure than blood lead. Mean blood lead in this sample was lower than in most other 

studies, 9.3 μg/dL. Decreases in sperm concentration, motility, morphology, and viability were 

correlated with seminal fluid lead or lead in spermatozoa, but not with blood lead. 

Overall, the available evidence suggests a small association between exposure to lead, 

usually in the workplace, and perturbed semen quality. It appears that sperm count and 

morphology (% normal forms) may be decreased at exposures >45 μg/dL. Future research 

should focus on studies of men exposed to lower levels of lead, as exposures in the very high 

range are associated primarily with occupational exposure. These studies should also account for 

variables known to be associated with semen quality and which may also be associated with 

exposure, e.g., social class, other environmental exposures such as heat and vibration, and 

lifestyle variables such as cigarette smoking and alcohol use. 

6.6.3.1.2 Time to Pregnancy 

Time to pregnancy represents a sensitive measure of fecundity. Time to pregnancy is 

important because it measures the end effect of perturbed reproductive function. While it is 

important and necessary to understand the associations between prenatal exposures and 

endocrine abnormalities and semen characteristics, they represent possible antecedents to the 

occurrence of pregnancy. Previous reports demonstrate good validity and reliability for reports 

of time to pregnancy in both males and females and when time to recall has been both long and 

short (Weinberg et al., 1993, 1994). 

One advantage to the use of this parameter, as compared to just an infertility measure, is 

that it does not require categorization of men into fertile and infertile groups. Among couples 

that succeed in establishing pregnancy, there is considerable variability in the time between 

discontinuation of contraception and conception (Weinberg et al., 1994). With the possible 

exception of cigarette smoking and age, very little is known regarding this intercouple 

variability. Delays in time to pregnancy may be indicative of a range of reproductive 

abnormalities of both partners, including impaired gametogenesis, hormonal disruptions, and 

very early unrecognized pregnancy loss. Time to pregnancy has the menstrual cycle as its 

natural unit and is thus measured in integer units of menstrual cycles. 

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Usually, time to the most recent pregnancy is taken as the outcome (Baird et al., 1986). 

The measure of exposure in these studies usually is the fecundity density ratio, which is similar 

to an incidence density ratio. Fecundity density ratios can be interpreted as the risk of pregnancy 

among the exposed during an interval, compared to the risk of pregnancy among the unexposed 

during the same interval. In such studies, the intervals of interest are menstrual cycles. 

Fecundity density ratios less than one indicate reduced fecundity (i.e., longer time to pregnancy) 

among the exposed compared to the unexposed, while those greater than one indicate enhanced 

fecundity (i.e., shorter time to pregnancy) in the exposed. Usually fecundity density ratios are 

calculated using discrete time Cox proportional hazards regression models. 

Several recent studies evaluate time to pregnancy when the male partner is occupationally 

exposed to lead. The Asclepios Project, a large European collaborative cross-sectional study, 

evaluated time to pregnancy in 1,108 men of whom 638 were exposed to lead (Joffe et al., 2003). 

The reference group consisted of lead workers for whom exposure did not coincide with time of 

pregnancy. The investigators only included pregnancies which resulted in live births. Fecundity 

density ratios were 1.12 (95% CI: 0.84, 1.49), 0.96 (95% CI: 0.77, 1.19), 0.88 (95% CI: 0.70, 

1.10) and 0.93 (95% CI: 0.76, 1.15) for blood leads <20, 20-29, 30-39, and $40 μg/dL, 

respectively. These results indicate that no association was found between blood lead and 

delayed time to pregnancy. Similar results were found when duration of exposure or cumulative 

exposure was used as the exposure metric. 

A separate report was published in the Italian group of men included in the Asclepios 

project (Apostoli et al., 2000). Blood lead at the time closest to conception was used as the 

measure of exposure. Lead-exposed men (n = 251) who had experienced at least one completed 

pregnancy were compared to nonexposed men (n = 45). Contrary to what was expected, time to 

pregnancy was significantly shorter among couples in which the male partner was exposed to 

lead compared to those in which the male partner was not exposed. In secondary analyses, time 

to pregnancy was longer among men with the highest blood lead (i.e., $40 μg/dL). Limiting the 

analysis solely to exposed men, time to pregnancy was longer among men with higher blood 

leads. 

Among 502 couples identified by Sallmen (2000) from the Finnish Institute of 

Occupational Health in which the male partner was exposed to lead, time to pregnancy was 

reduced among those with blood leads >10 μg/dL compared to those with blood leads 

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#10 μg/dL. However, when blood lead was stratified, no concentration-response relationship 

was found. Fecundity density ratios were 0.92 (95% CI: 0.73, 1.16), 0.89 (95% CI: 0.66, 1.20), 

0.58 (95% CI: 0.33, 0.96) and 0.83 (95% CI: 0.50, 1.32) for exposures of 10-20, 21-30, 31-40, 

and $40 μg/dL, respectively. In this study, blood leads close to the time of conception were 

available on 62% of men, while in 38% it was estimated using blood leads obtained at other 

points or based on job descriptions. 

Among 280 pregnancies in 133 couples in which the male partner was employed in a 

battery plant, 127 were conceived during exposure while the remainder conceived prior to 

exposure (Shiau et al., 2004). Time to pregnancy increased with increasing blood lead, 

especially when blood leads were $30 μg/dL. Fecundity density ratios were 0.50 (95% CI: 

0.34, 0.74) and 0.38 (95% CI: 0.26, 0.56) for blood leads 30-39 and >39 μg/dL, respectively. 

In 41 couples, one pregnancy occurred prior to exposure and one during exposure – time to 

pregnancy during exposure was significantly longer. Of note, this is the only study to estimate 

decreases in time to pregnancy when blood lead was below 40 μg/dL; time to pregnancy 

increased by 0.15 months for each 1 μg/dL increase in blood lead between 10 and 40 μg/dL. 

6.6.3.1.3 Reproductive History 

Population-based birth registries in the Scandanavian countries provide data on medically 

diagnosed pregnancies. These registries provide a basis for linking occupational data on lead 

exposure obtained by place and duration of employment or by direct measures of blood lead 

relative to the timing of marriage or conception. Using a roster of men employed in three battery 

plants in Denmark, Bonde and Kolstad (1997) matched all births to the 1,349 employees when 

they were age 20-49 years. A control group of 9,656 men who were not employed in a lead 

industry was chosen. No associations were found between employment or, among those 

employed in the lead industry, duration of employment in the lead industry and birth rate. 

A similar study in Finland (Sallmen, 2000) examined the association between conception 

and blood lead among men monitored for occupational exposure at the Finnish Institute of 

Occupational Health (n = 2,111). Men were categorized as probably exposed and possibly 

exposed based on their measured blood lead in relation to the time of marriage. A nonexposed 

group of 681 men with blood lead #10 μg/dL was similarly evaluated. Among men in the 

probable exposure group, the risk of failing to achieve a pregnancy increased with increased 

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blood lead in a monotonic concentration-response fashion. Compared to the nonexposed, the 

risk ranged from 1.3 to 1.9 for blood leads 10-20 μg/dL and >50 μg/dL, respectively. 

Lin et al. (1996) linked records from the Heavy Metal Registry in New York State to birth 

certificates from the New York State Office of Vital Statistics for the period 1981 to 1992. 

Exposure was defined as having at least one blood lead measurement above 25 μg/dL and 

identified 4,256 men. A reference group of 5,148 men was frequency matched for age and 

residence. The exposed group had fewer births than expected, and was especially pronounced 

among men employed in the lead industry for over 5 years. 

Among 365 men occupationally exposed to metals, Gennart et al. (1992) identified 

74 exposed continuously for more than 1 year and with at least one blood lead measurement 

>20 μg/dL. Compared to a reference group with no occupational exposure, the probability of at 

least one live birth was significantly reduced. Fertility decreased with increasing duration of 

exposure but no concentration-response relationship with blood lead was found (possibly due to 

the small sample size of exposed men). 

A study of men exposed to lead in a French battery plant (Coste et al., 1991) reported no 

effect on fertility. However, this study did not adequately control for potentially confounding 

variables, particularly those related to the women. Further, nonexposed workers were defined as 

those with no blood leads recorded which likely resulted in exposure misclassification. 

One potential mechanism to explain the associations between lead exposure and male 

reproductive outcomes may be through an effect of lead on circulating pituitary and testicular 

hormones. Several studies have evaluated this hypothesis in groups of workers (Braunstein 

et al., 1978; Cullen et al., 1984; Erfurth et al., 2001; Ng et al., 1991; Rodamilans et al., 1988). 

In general these studies find perturbations in concentrations of follicle stimulating hormone, 

luteinizing hormone, and testosterone. Although many of these studies were limited by small 

sample sizes, lack of control groups, and admixtures of exposure, taken together, they provide 

evidence for this possible mechanism. 

6.6.3.2 Genotoxicity and Chromosomal Aberrations 

The potential genotoxicity and ability to induce chromosomal aberrations speak to the 

mechanisms by which lead is a potential reproductive toxin. Two possible mechanisms by 

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which lead may affect reproduction are through affinity with proteins and ability to mimic the 

actions of calcium (Silbergeld et al., 2000). 

Data from occupational studies regarding the effects of lead on chromosomes are 

contradictory; however, the bulk of evidence suggests that there may indeed be a genotoxic 

effect. Early studies in occupational groups find associations between lead exposure and 

increased frequency of sister chromatid exchanges (Grandjean et al., 1983; Huang et al., 1988; 

Leal-Garza et al., 1986; Maki-Paakkanen et al., 1981). Similar results were found in a group of 

environmentally-exposed children with blood leads ranging from 30 to 63 μg/dL (Dalpra et al., 

1983). Increased frequencies of chromosomal aberrations, particularly chromatid aberrations, 

were found in battery plant workers and were correlated with increased blood lead (Huang et al., 

1988). A more marked increase was found when blood leads were above 50 μg/dL. Other 

occupational studies find similar associations (Al-Hakkak et al., 1986; Forni et al., 1976, 1980; 

Nordenson et al., 1978; Schwanitz et al., 1970). Other studies find no evidence of chromosomal 

aberrations when blood leads ranged from 38 to 120 μg/dL (Bauchinger et al., 1977; MakiPaakkanen et al., 1981; O’Riordan and Evans, 1974; Schmid et al., 1972; Schwanitz et al., 1975). 

More recently, two studies in battery plant workers (mean blood lead 40.1 μg/dL) and controls 

(mean blood lead 9.8 μg/dL) found an increase in high-frequency cells and sister chromatid 

exchanges among the workers, indicating the cytogenetic toxicity of lead (Duydu et al., 2001, 

2005). An increase in sister chromatid exchanges, although not statistically significant, was also 

found in individuals exposed to lead and/or alcohol and tobacco (Rajah and Ahuja, 1995, 1996). 

In the Lithuanian populations exposed to either environmental or occupational lead, a higher 

incidence of sister chromotid exchanges and chromosomal aberrations was found (Lazutka et al., 

1999), although these populations were also exposed to other potentially genotoxic substances. 

Recent data also indicates that lead may inhibit DNA repair responses among lead-exposed 

workers (Karakaya et al., 2005). 

Occupational exposure to lead, particularly when blood leads were high (i.e., over 

40 μg/dL) was associated with increased mitotic activity in peripheral lymphocytes and with an 

increased rate of abnormal mitosis (Forni et al., 1976; Minozzo et al., 2004; Sarto et al., 1978; 

Schwanitz et al., 1970). 

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6.6.3.2.1 Issues Concerning Studies of Male Fecundity Related to Lead Exposure 

In examining studies of fecundity and fertility, several issues relating to interpretation and 

bias must be addressed. Infertility usually is defined as 12 months of continuous unprotected 

intercourse without pregnancy. Fecundity represents both a characteristic of the individuals and 

a characteristic of a couple, meaning that both partners must be biologically able to procreate. 

Thus, one possible explanation for observations of reduced fecundity related to occupational lead 

exposure in the male partner is the exposure he “takes home” via transport of dust on clothing 

and shoes, ultimately resulting in an effect related to the female partner. Other possible 

interpretations need to account for measurement error, especially related to the outcomes of 

reproductive history and time to pregnancy, bias in the selection of subjects for study, and the 

control for potentially confounding variables. 

Both reproductive history and time to pregnancy are subject to errors of recall and rely on 

the veracity of the subject. Several studies have evaluated recall and veracity of the male partner 

using the female partner as the “gold standard.” In general, these find good reliability between 

the male and female (Weinberg et al., 1993, 1994). Nevertheless, it is possible, at least for 

studies using men as the sole informant, that the number of pregnancies a man has fathered is 

underreported. If reporting is nondifferential with regard to lead exposure, then associations will 

generally be biased towards the null value; however, since characteristics such as social 

circumstances, ethnicity, and age may affect both exposure and reporting, it is difficult to 

evaluate the role of bias. 

It was not clear from many of the studies that men with medical conditions which affect 

fecundity/fertility were excluded. Further, several prescription and over-the-counter medications 

also affect fecundity as does a history of surgery in the genital area (e.g., varicocele). To the 

extent that these conditions are related to the absence of employment in lead-industries, then the 

results may be subject to a type of “healthy worker” effect. Because it is unclear whether many 

of these studies asked about these conditions, this cannot be ruled out as a possible source 

of bias. 

In retrospective studies it is often useful to use the outcome of the most recent pregnancy 

in the primary analysis. The reason for this is to reduce any possible recall bias. This type of 

bias may also be an issue in studies which use occupational registry data, i.e., men may have 

fathered an additional pregnancy after employment in the industry ceased. 

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Variables considered potential confounders in studies of fertility and fecundity include 

sociodemographic characteristics (e.g., age, ethnicity, education, occupation); prenatal and recent 

lifestyle variables such as cigarette smoking, alcohol use, and medication use; exposures through 

occupation and hobby, and recent medication use. Also important in these studies is control for 

factors which may affect the partner’s fertility, e.g., cigarette smoking. Many of the studies 

reviewed did not carefully measure or adjust for confounding variables. 

The issues presented above potentially limit the interpretation of results from studies 

examining the association of lead exposure with male fecundity and fertility. Nevertheless, most 

studies find small associations between lead exposure at high levels (i.e., $45 μg/dL) and slightly 

reduced male fecundity or fertility. 

6.6.3.3 Effects on Female Reproductive Function 

Few data directly address the effects of lead exposure on fecundity in the female. 

A recent retrospective study of time to pregnancy among wives of lead workers provides limited 

support that lead exposure is associated with increased time to pregnancy. Fecundity density 

ratios were 0.92 (95% CI: 0.72, 0.16), 0.89 (95% CI: 0.66, 1.20), 0.58 (95% CI: 0.33, 0.96), 

and 0.83 (95% CI: 0.50, 1.32) for blood leads in the male partners of 10-20, 21-30, 31-38 and 

$39 μg/dL compared to <10 μg/dL, respectively. Note however, that exposure here is measured 

in the male partners and not the females. 

Time to pregnancy was evaluated in 121 women biologically monitored for lead exposure 

at the Finnish Institute of Occupational Health between 1973 and 1983 (Sallmen et al., 1995). 

Fecundity did not differ with level of exposure (defined as <10 μg/dL, 10-19 μg/dL and 

$20 μg/dL), but among women with blood leads between 29 and 50 μg/dL, there was a 

suggestion of reduced fecundity (longer time to pregnancy). However, only a small number of 

subjects (n = 8) were exposed in this range. 

In the limited number of studies, there is little evidence regarding the associations 

between lead exposure and fertility in the female to draw any conclusions at this time. 

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6.6.4 Spontaneous Abortion 

6.6.4.1 Spontaneous Abortion and Maternal Exposure to Lead 

Historical observations suggest increased rates of spontaneous abortion among leadexposed women, particularly those employed in cottage industries (Rom, 1976). Two early 

studies in a smelter town in Sweden (Nordstrom et al., 1978a, 1979) suggest elevated rates of 

spontaneous abortion among female employees at the smelter and among female residents living 

in close proximity to the smelter. Neither of these studies used biological markers of lead 

exposure. Moreover, the Swedish smelter study included other exposures such as arsenic, zinc, 

and cadmium; thus the conclusions for these analyses should be tempered. 

In contrast, a prospective study in and around a smelter town in Port Pirie, Australia 

(McMichael et al., 1986) did not find an association between blood lead concentration and 

spontaneous abortion. However, it was likely that complete ascertainment of spontaneous 

abortions was not obtained (Rowland and Wilcox, 1987) since most women were recruited for 

this study after the first trimester of pregnancy. A retrospective cohort study in two towns in the 

former Yugoslavia (Murphy et al., 1990) showed no associations between lead exposure and 

spontaneous abortion in the first reported pregnancy. One of these towns was a smelter town 

with relatively high lead exposure (at recruitment during mid-pregnancy, the mean blood lead 

concentration was 17.1 μg/dL, while in the control town the mean blood lead was 5.1 μg/dL). 

A similar study in Poland (Laudanski et al., 1991) evaluated the association between leadexposed and nonexposed areas for their reproductive histories. Among women in the exposed 

areas, 11% reported having at least one prior spontaneous abortion, compared to 19.5% of 

women in the unexposed areas. 

Two studies in Finland (Lindbohm et al., 1991; Taskinen, 1988) used hospital registry 

data to ascertain women with either spontaneous abortions or livebirths. Either maternal job 

histories (Taskinen, 1988) or both maternal and paternal job histories were obtained from a 

registry of occupational blood lead measurements. Neither study found evidence of an 

association between maternal exposure and spontaneous abortion. In the Lindbohm et al. (1991) 

study, maternal exposure was extrapolated from the occupation of the father. 

In Bulgaria, pregnant women residing in or near lead smelting areas or petrochemical 

plants were prospectively followed for pregnancy outcomes (Tabacova and Balabaeva, 1993). 

The investigators compared blood leads in those women with spontaneous abortions and those 

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without. Blood lead concentrations in cases were significantly higher than in controls (mean 

blood lead 7.1 μg/dL versus 5.2 μg/dL, respectively). However, this study did not fully describe 

the selection of women nor the definition for cases. 

Women employed by the U.S. Forest Service and exposed to lead-based paint (to mark 

trees for clearing) were studied using self-reported questionnaires (Driscoll, 1998). Adjustment 

was made for potential confounders and generalized estimating equations were used to adjust for 

multiple pregnancies per woman. Significant associations were found for three types of paint 

containing lead pigment (odds ratios of 4.3 [95% CI: 2.0, 9.3], 2.0 [95% CI: 1.2, 3.3] and 

1.8 [95% CI: 1.2, 2.6]). While these findings are intriguing, the response rate was only 59% 

(with no evaluation of selection bias) and the paint also contained solvents thought to be 

associated with spontaneous abortions. 

Borja-Aburto et al. (1999) examined the association between blood lead concentrations 

and spontaneous abortions in a nested case-control study using incidence density methods and 

matching for age, calendar time of study entry, public versus private clinic, and gestational age at 

study entry. They ascertained 668 women during the first trimester of pregnancy in Mexico 

City. After contacting women biweekly to update pregnancy status, they found 35 cases (6.4%) 

of spontaneous abortion among women not lost to follow up. An odds ratio of 1.8 (95% CI: 1.1, 

3.1) per 5 μg/dL increase in blood lead was observed after adjustment for spermicide use, active 

and passive smoking, use of alcohol and coffee, maternal age, education, income, physical 

activity, hair dye use, use of video display terminals, and medical conditions. Mean blood lead 

in cases (12.0 μg/dL, range 3.1-29 μg/dL) was slightly higher than in controls (10.1 μg/dL, range 

1.3-26 μg/dL). Further, after categorizing blood lead into 5 μg/dL intervals, a concentrationresponse relationship was evident. 

More recently, a small study of 57 female workers in a battery plant in China and 

62 controls found that 6 spontaneous abortions occurred in the exposed group, compared to none 

in the controls (Tang and Zu, 2003). A long-term follow-up of survivors of acute plumbism 

(Hu, 1991) found increased risk of spontaneous abortions or stillbirths (odds ratio of 1.6 

[95% CI: 0.6, 4.0]). Although the study was based on small numbers, the data suggest a 

persistent association between childhood exposure and outcomes later in life. 

A review of eight studies (Borja-Aburto et al., 1999; Driscoll, 1998; Laudanski et al., 

1991; Lindbohm et al., 1991; McMichael et al., 1986; Murphy et al., 1990; Tabacova and 

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Balabaeva, 1993; Taskinen, 1988) evaluating maternal exposure to lead (blood lead >30 μg/dL) 

and spontaneous abortion concluded that there was little evidence that lead exposure at these 

relatively high levels was associated with an increased risk in spontaneous abortions (HertzPicciotto, 2000). However, Hertz-Picciotto also concluded that methodological difficulties in 

most of these studies (i.e., small sample sizes, inadequate ascertainment of outcome, and possible 

residual confounding) limited the confidence in these data. Further, she noted that exposure in 

many of these studies was either measured in an ecologic fashion or biological measures were 

available, but they were not ascertained during a biologically meaningful period. 

Collectively, there is little evidence to support an association between lead exposure in the 

female and spontaneous abortion. The only well-designed study which finds an association is 

that of Borja-Aburto et al. (1999); however, these results need to be confirmed in other 

populations. Studies of spontaneous abortion need be done carefully to avoid possible bias due 

to recall, use of pregnancies other than the first, and confounding. Retrospective studies, for 

example, should take full pregnancy histories, including probing for spontaneous abortions 

versus induced abortions versus stillbirths. In some cultures, for example, induced abortions are 

frowned upon and women may report spontaneous abortions instead. Additionally, some women 

may confuse a stillbirth with spontaneous abortion, especially if she is unable to adequately date 

her pregnancy using date of last menstrual period. Although the use of the most recent 

pregnancy may curtail problems of recall, other concerns dictate that the first pregnancy be used 

in studies of spontaneous abortion because the risk of subsequent spontaneous abortion depends 

on the history of spontaneous abortion. Finally, while few variables are known confounders of 

this relationship, the following should be controlled: maternal age, education and other 

socioeconomic indicators, cigarette smoking, and alcohol use. Several studies of spontaneous 

abortion did not properly adjust for these potentially confounding variables. 

One final concern regards the type of spontaneous abortion. Very early spontaneous 

abortions, i.e., before a clinical pregnancy is diagnosed, may be missed; assuming, however, that 

both exposed and unexposed women have the same rates of early spontaneous abortions, this 

would bias the association towards the null. Indeed, this may be true, as many very early 

spontaneous abortions may be chromosomally abnormal and probably not attributable to lead 

exposure. 

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6.6.4.2 Spontaneous Abortion and Paternal Exposure to Lead 

Three studies evaluated paternal exposure to lead and spontaneous abortion. Lindbohm 

et al. (1991), using national databases to identify pregnancy outcomes among 99,186 births in 

Finland, found no association between paternal employment in jobs with lead exposure and 

spontaneous abortion (odds ratio of 0.9 [95% CI: 0.9, 1.0]). In a follow up case-control study 

(Lindbohm et al., 1991b), they ascertained paternal exposure status during the period of 

spermatogenesis in 213 cases of spontaneous abortion and 500 controls. Exposure was 

ascertained using blood lead concentrations measured during spermatogenesis for 6% of men; 

for the remaining 94%, exposure was estimated using a regression model where the independent 

variables were blood leads measured either prior to or after the period of spermatogenesis. 

Blood lead (either measured or estimated) was not associated with spontaneous abortion. 

When analysis was restricted to men with measured blood lead, blood lead concentrations 

>30 μg/dL were associated with an increased odds of spontaneous abortion (odds ratio of 

3.8 [95% CI: 1.2, 2.0]); however, this result was only based on 12 cases and 6 controls. 

The third study (Alexander et al., 1996b) found no association between men employed in 

a lead smelter and spontaneous abortion. For men with “moderate” exposure jobs the estimated 

odds ratio was 0.8 (95% CI: 0.5, 1.5) and for those with “high” exposure jobs, the estimated 

odds ratio was 1.4 (95% CI: 0.7, 2.5). Further when blood lead 1 year prior to the pregnancy 

was used as the exposure measure, no increased odds of spontaneous abortion was found. These 

results, however, are based on a low participation rate in eligible workers (37%) and should be 

interpreted with caution. Overall, the available studies provide little evidence for an association 

between lead exposure in the male and spontaneous abortions. 

6.6.5 Fetal Growth 

The results of epidemiologic studies regarding the association between lead exposure and 

birth weight are inconsistent. Cross-sectional studies (Clark, 1977; Gershanik et al., 1974; 

Moore et al., 1982; Rajegowda et al., 1972) did not find significant correlations between blood 

lead and birth weight, nor did a study using placental lead as the exposure variable (Wibberley 

et al., 1977). A case-control study (Bogden et al., 1978) comparing 25 low birth weight babies 

(1,500-2,500 grams) to 25 controls (>2,500 grams) matched on maternal age, race and social 

class found a small, nonsignificant difference in maternal and cord blood leads. Mean maternal 

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blood lead concentrations were 16.2 " 4.5 μg/dL and 15.3 " 5.2 μg/dL and mean cord blood 

leads were 13.8 " 4.4 μg/dL and 13.1 " 4.3 μg/dL in cases and controls, respectively. A further 

study (Huel et al., 1981) found no differences in maternal and fetal hair lead concentrations 

between infants born small-for-gestational-age compared to those of normal birth weight. 

In 1984, Needleman et al. (1984) reported on a cross-sectional study of 5,183 births of at 

least 20 weeks gestation in Boston, MA. No associations were found between the proportion of 

births under 2,500 grams and cord blood lead. Exposure levels in this study were relatively low 

for the time; cord blood leads ranged from <1 to 35 μg/dL. A reanalysis of these data found no 

relationship between cord blood lead and birth weight when birth weight was considered as a 

continuous variable (Bellinger, et al., 1991). However, when birth weight was categorized as 

low birth weight (<2,500 grams), small for gestational age (<10th percentile for gestational age), 

or intrauterine growth retarded (>2 standard deviations below the mean for gestational age), 

relative risks of 1.6 (95% CI: 1.0, 2.6), 1.2 (95% CI: 0.8, 1.6) and 1.9 (95% CI: 1.0, 3.4), 

respectively, were found for each 10 μg/dL increase in cord blood lead levels. Increased relative 

risks also were found for cord blood lead levels $15 μg/dL, compared to cord blood lead 

<15 μg/dL; however, only 83 of the 5,183 women had exposures in the high range, resulting in 

imprecise estimates. These data suggest that lead-related modest reductions in birth weight are 

perhaps plausible when birth weight is expressed as a function of gestational age. 

The prospective study of lead exposure in and around Port Pirie, Australia (McMichael 

et al., 1986) followed 749 pregnancies of at least 20 weeks duration. Mean maternal blood leads 

at mid-pregnancy were 10.1 μg/dL and 7.0 μg/dL for women residing in Port Pirie and the 

surrounding communities, respectively. After excluding 9 sets of twins and 10 cases for which 

the maternal last menstrual period could not be ascertained, no relationship was found between 

either cord blood lead or maternal blood lead measured at mid-pregnancy or at delivery and birth 

weight in a multivariate regression model controlling for known determinants of birth weight. 

A prospective study in two towns in Kosovo, Yugoslavia evaluated relationships between 

birth weight (adjusted for gestational age using last menstrual period) and (a) maternal blood 

lead at mid-pregnancy and delivery and (b) cord blood lead (Factor-Litvak et al., 1991). The 

towns were vastly different in exposure patterns, as one was the site of a lead smelter, refinery 

and battery plant (n = 401, mean mid-pregnancy blood lead 19.0 μg/dL) and one was relatively 

unexposed (n = 506, mean mid-pregnancy blood lead 5.6 μg/dL). No associations were found 

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between any of the biomarkers of lead and birth weight in either crude analyses or analyses 

adjusted for potentially confounding variables. 

While the aforementioned studies generally found no association between environmental 

lead exposure and birth weight, three other studies have shown large reductions in birth weight 

related to lead exposure. These studies, however, have questionable study designs. Nordstrom 

et al. (1978b, 1979) in a series of ecologic analyses known as the Swedish Smelter Study, found 

significant reductions in birth weight between the offspring of women either working at or living 

in close proximity to the smelter. The 125 gram deficit in birth weight among the offspring of 

women living closest to the smelter was confined to those with parity three or more, an 

observation which does not appear to be biologically plausible. Moreover, the ecological nature 

of the study did not allow for individual measurements of blood lead or for control of potentially 

confounding variables. Hence, while suggestive, these data do not provide strong evidence for a 

causal association between lead exposure and birth weight. 

In a cross-sectional study of 100 “normal” singleton births, a negative correlation was 

found between placental lead concentration and birth weight (Ward et al., 1987). Mean placental 

lead concentration in 21 infants weighing less than 3,000 grams was 2.35 " 0.9 μg/g compared to 

1.12 " 0.4 μg/g in 10 infants weighting more than 4,000 grams. This study has several 

limitations. First, no statistical adjustment was made for multiple comparisons (many exposures 

were studied). Second, potentially confounding variables were not controlled. Third, only 31 of 

the 100 infants, representing the extremes of the birth weight distribution, were studied. Hence, 

this study also does not provide strong evidence for an association. 

In Cincinnati, OH, the association between lead exposure and birth weight was examined 

in offspring of a cohort of young (mean maternal age = 22.7 years), inner city women, 

85% African American, 86% on public assistance, with a mean IQ of 75 (Dietrich et al., 1987a). 

The mean gestational period of the neonates, as determined by physical examination, was 

39.5 weeks. A decrement in birth weight of 172 grams was associated with an increase in blood 

lead from 10 to 30 μg/dL. Lead exposure in this group was relatively low with a mean blood 

lead of 8.0 " 3.7 μg/dL. In a sample of women from this cohort, the interaction between blood 

lead and maternal age was significantly associated with birth weight; the effect varied from a 

decrease of 64 grams for 18 year old mothers to 660 grams for 30 year old mothers, as blood lead 

rose from 10 to 30 μg/dL (Bornschein et al., 1989). Although the Cincinnati study is highly 

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suggestive of an effect (especially an effect which varies by maternal age) three factors should be 

considered in the interpretation of their findings. First, length of gestation was estimated by 

examining the neurological and physical maturity of the neonate (Ballard et al., 1979); other 

investigators find assessment of gestational age using this scale overestimates gestational age in 

preterm infants (Constantine et al., 1987; Kramer et al., 1988; Shukla et al., 1987; Spinnato et al., 

1984). Second, it is possible that the association between lead and birth weight differs by 

maternal characteristics such as race, ethnicity, and SES; however, no study has provided a 

population sufficiently heterogeneous to examine this possible source of difference. Finally, it is 

possible that confounding by unmeasured maternal lifestyle characteristics may account for the 

reported association. 

A hospital-based study of cord blood lead and pregnancy outcomes in Quebec, Canada, 

between June 1993 and January 1995 found a slight increase in cord blood lead levels among 

infants with birth weight <2,500 grams (Rhainds et al., 1999). For those infants with birth 

weight <2,500 grams, the geometric mean blood lead was 1.8 μg/dL (95% CI: 1.6, 2.9) 

compared to 1.6 μg/dL (95% CI: 1.5, 1.7), 1.6 μg/dL (95% CI: 1.5, 1.7), and 1.5 μg/dL 

(95% CI: 1.5, 1.6) among those with birth weights 2,500-2,990, 3,000-3,499, and $3,500 grams, 

respectively. Although suggestive, the study did not control for potentially confounding 

variables. The investigators also measured cord blood levels of mercury and organochlorine 

compounds, and observed that mean levels of these toxicants were higher as well in infants who 

weighed <2,500 g. 

More recently Irgens et al. (1998) using data from the Norwegian birth registry found that 

women occupationally exposed to lead (none/low compared to moderate/high) were more likely 

to deliver a low birth weight infant (odds ratio of 1.3 [95% CI: 1.1, 1.6]). No association was 

found for paternal occupational lead exposure. Parental occupational exposure to lead was not 

associated with low birth weight in the Baltimore-Washington Infant Study database (Min et al., 

1996), although subgroup analysis suggested that high paternal exposure may be associated with 

small-for-gestational-age infants (odds ratio of 2.9 [95% CI: 0.9, 9.2]). Similar findings were 

reported by Lin et al. (1998) who compared offspring of lead-exposed workers with those of bus 

drivers. No associations were reported between lead exposure and low birth weight except 

among the group of men with blood lead levels >25 μg/dL for over 5 years (relative risk of 3.4 

[95% CI: 1.4, 8.4]). 

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Using bone lead as the metric of exposure, Gonzalez-Cossio et al. (1997) found 

associations with tibia bone lead (but not with patella bone lead or umbilical cord blood lead) 

and reduced birth weight. Bone lead was measured one month after delivery. Infants with tibia 

bone lead in the highest quartile ($15.15 μg lead / g bone mineral) were, on average, 156 g 

lighter than those in the lowest quartile (#4.50 μg lead / g bone mineral). Further analyses of 

these data (Hernandez-Avila et al., 2002) found an association between infants in the highest 

quintile of tibia bone lead and shorter birth length (odds ratio of 1.8 [95% CI: 1.1, 3.2]). 

Two studies have considered the relationship between lead exposure and head 

circumference (Hernandez-Avila et al., 2002). Among 233 women in Mexico City, high 

maternal patella bone lead was associated with increased risk of a low head circumference score 

at delivery (1.02 per μg lead / g bone mineral [95% CI: 1.01, 1.04]). Similar findings were 

reported by Rothenberg et al. (1999) who found a reduction in six-month head circumference of 

1.9 cm (95% CI: 0.9, 3.0) as maternal blood lead rose from 1 to 35 μg/dL. This study, however 

was plagued by multiple comparisons as head circumference was measured nine times and 

prenatal blood lead six times – only one statistically significant result was found. 

Potential confounders need to be adjusted for to properly assess the relationship between 

lead exposure and fetal growth. Factors consistently associated with fetal growth include gender, 

ethnic origin, maternal body build (i.e., pre-pregnancy weight, height), parity, SES, gestational 

weight gain and nutritional intake during pregnancy, maternal illness, and cigarette smoking 

(Kramer, 1987). Factors with less established associations include alcohol consumption (Kline 

et al., 1987; Kramer, 1987) and street drug use (Kline et al., 1987; Kramer, 1987; Zuckerman 

et al., 1989). To the extent that these factors are associated with blood lead as well as with fetal 

growth, they must be accounted for in the analysis. 

Studies to date are inconsistent regarding the association between lead exposure and birth 

weight. Several large prospective studies find no association (Factor-Litvak et al., 1991; 

McMichael et al., 1990), while at least one (Bornschein et al., 1989) did find an association in 

specific subgroups of women. However, there is limited evidence (Bellinger et al., 1991) for an 

association between lead exposure and low birth weight (i.e., <2,500 g), small for gestational age 

(i.e., <10th percentile for gestational age), and intrauterine growth retardation (i.e., >2 standard 

deviations below the mean for gestational age). These prospective studies were all wellconducted, adequately measured exposure and outcome, and controlled for potential confounding 

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variables. They did, however, take place in very different populations, suggesting that the 

association between lead and fetal growth may depend on the population being studied. The 

Yugoslavia study (Factor-Litvak et al., 1991) took place in two towns in Kosovo, Yugoslavia, 

which were divergent on exposure and somewhat comparable on other variables. The Port Pirie 

study took place in a middle class area of Australia (McMichael et al., 1986). The Boston study 

(Bellinger et al., 1991) took place in a range of social strata in Boston; the exposure in the 

highest social group was attributable to renovation of older housing stock. Finally, in the 

Cincinnati study (Bornschein et al., 1989), the study sample was comprised of lower social class 

African Americans; the mean IQ of the mothers was 75. It is possible that in this latter study, 

there was some unmeasured variable which accounts for the observed interaction. Thus, the 

evidence suggests at most a small effect of lead exposure on birth weight and possibly a small 

association between lead exposure and several dichotomized measures of fetal growth. 

6.6.6 Preterm Delivery 

Early evidence regarding an association between environmental lead exposure and 

preterm delivery was inconsistent. In 1976, Fahim et al. found a preterm delivery rate of 13% in 

254 pregnant women living near a lead mining community in Missouri, compared to 3% in 

249 women living in a control location. These investigators also found higher concentrations of 

lead in amniotic membrane, but not higher placental or cord lead in preterm compared to term 

deliveries, regardless of the women’s residential locale. This observation prompted other studies 

of lead and preterm delivery. 

Of the cross-sectional studies, the three which show no association employed cord blood 

lead as the exposure measure and restricted gestational age (Angell and Lavery, 1982; Bellinger 

et al., 1991; Needleman et al., 1984; Rajegowda et al., 1972). In contrast, three other studies 

used different exposure markers (placental lead, maternal and cord blood lead, and maternal and 

fetal hair lead) and found statistically significant associations (Huel et al., 1981; Moore et al., 

1982; Ward et al., 1987). Other studies evaluated pregnancy outcomes in relation to maternal 

delivery blood lead (McMichael et al., 1986; Rahman and Hakeem, 2003). 

Of the prospective studies, the Cincinnati study (Bornschein et al., 1989) found no 

association between both maternal blood lead at mid-pregnancy or maternal blood lead during 

the neonatal period (10 days post delivery) and preterm delivery. However, gestational age was 

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estimated by examining the neurological and physical maturity of the neonates (which tends to 

overestimate gestational age) and not actual dates. In Port Pirie, Australia (McMichael et al., 

1986), a concentration-response relationship between maternal delivery blood lead and preterm 

delivery was reported. Odds ratios ranged from 2.1 to 4.4 in women with blood leads of 

7.7-10.6 μg/dL and >13.5 μg/dL, respectively, compared to those with blood lead <7.7 μg/dL. 

Savitz et al. (1990) used data from the National Natality Survey and found an odds ratio of 

2.3 (95% CI: 0.7, 7.0) between maternal occupational exposure to lead and preterm delivery; 

however, the estimated odds ratio was based on only 7 cases. In the Yugoslavia study (FactorLitvak et al., 1991) no associations were found between cord blood lead or blood lead measured 

at mid pregnancy or delivery and either preterm delivery (defined as delivery <37 completed 

weeks) or gestational age. A registry study in Norway (Irgens et al., 1998) which linked births 

between 1970 and 1993 to census-based occupation records found a slightly increased odds of 

preterm delivery among moderate/high lead-exposed women, compared to those with no or low 

exposure (odds ratio of 1.13 [95% CI: 0.98, 1.29]). Paternal exposure was not found to increase 

the risk of preterm birth. 

An ecologic study in Canada (Philion et al., 1997) examined 30 years of birth records, 

corresponding to 9,329 births in a smelter city and a control city. Outcome variables were 

intrauterine growth retardation defined as small for gestational age. The odds ratio for 

intrauterine growth retardation in the smelter city compared to the control city was 0.83. 

Further analysis, stratifying time into 5-year intervals also revealed no associations. 

A case control study in Mexico City (Torres-Sanchez et al., 1999) evaluated 161 preterm 

births and 459 full term births. Cord blood lead was significantly higher in the preterm group 

(9.8 " 2.0 μg/dL) compared to the full term group (8.4 " 2.2 μg/dL) only among primiparous 

women. 

Using data from the Baltimore-Washington Infant Study database, Min et al. (1996) 

found a small association between paternal occupational exposure in the high range and preterm 

delivery with appropriate weight for gestational age (odds ratio of 2.1 [95% CI: 0.7, 6.5]) and 

preterm delivery with small for gestational age (odds ratio of 2.4 [95% CI: 1.9, 3.1]). Similar 

findings were reported by Lin et al. (1998). Comparing the offspring of lead exposed workers 

with those of bus drivers, they found an elevated relative risk for preterm delivery (3.0 [95% CI: 

1.6, 6.8]) only among men with blood leads >25 μg/dL for over 5 years. 

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In contrast to fetal growth, few factors are consistently related to preterm delivery; thus in 

both developed and developing countries the majority of preterm deliveries remain unexplained 

(Kramer 1987; van den Berg and Oechsli, 1984). Factors which are inconsistently associated 

with preterm delivery include maternal age, SES, pre-pregnant weight, prior history of preterm 

delivery or spontaneous abortion, and cigarette smoking (Kline et al., 1987; Kramer, 1987). 

Thus, these factors must be evaluated as potentially confounding factors in studies of lead 

exposure and preterm delivery. 

For preterm delivery, or reduced length of gestation, the evidence for an association with 

lead exposure is contradictory. Several of the prospective studies find no evidence of an 

association (Bornschein et al., 1989; Factor-Litvak et al., 1991) while one finds a concentrationresponse relationship (McMichael et al., 1986). Further, two well-done registry studies (Irgens 

et al., 1998; Savitz et al., 1990) find some evidence of an association, albeit the number of 

exposed cases was small. It seems unlikely that the association between lead exposure and 

preterm delivery is large, but, more research is clearly necessary. 

6.6.7 Congenital Abnormalities 

Needleman et al. (1984) found an association between cord blood lead and minor 

congenital anomalies among 4,354 infants born in a single hospital in Boston, MA. All data 

were obtained from hospital records, not from direct examination of the infants. The most 

common anomalies were hemangiomas, lymphangiomas, minor skin problems (tags and 

papillae), and undescended testicles. Blood lead levels were not found to be associated with 

individual anomalies. 

More recently, a number of studies have considered parental lead related to occupational 

exposure and risk of congenital anomalies in the offspring. In Finland, Sallmen et al. (1992) 

evaluated the associations between congenital malformations and paternal exposure during the 

time of spermatogenesis. The overall estimated unadjusted odds ratio for men with blood lead 

levels >20 μg/dL was 2.4 (95% CI: 0.9, 6.5). Due to small sample sizes, the investigators could 

only adjust for one potentially confounding factor at a time; this resulted in odds ratios ranging 

from 1.9 to 3.2. Of note is the lack of consistency of malformations among the five men with the 

highest blood lead. The malformation observed included congenital heart disease, oral cleft, club 

foot, polydactyly, and anomalies of the adrenal gland. The breadth of these anomalies suggests 

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either that lead affects physical development throughout gestation or that this association 

represents a chance finding. Among 2,021 pregnancies, Alexander et al. (1996b) found slightly 

elevated odds ratios for congenital defects among men in the lead smelting industry with 

moderate exposure (odds ratio of 1.9 [95% CI: 0.6, 6.3]) and high exposure (odds ratio of 

2.7 [95% CI: 0.7, 9.6]). These estimates are based on 30 birth defects and 12 stillbirths. 

No analyses were presented which considered individual birth defects. In Norway, neither 

maternal (odds ratio of 1.25 [95% CI: 0.8, 1.9]) nor paternal (odds ratio of 0.94 [95% CI: 

0.8, 1.1]) occupational lead exposure was associated with serious birth defects (Irgens et al., 

1998). Similar results were reported by Kristensen et al. (1993) between paternal lead exposure 

and birth defects, with the exception of a fourfold increase in the risk of cleft lip among male 

offspring. 

The risk of parental lead exposure and neural tube defects was evaluated in a case-control 

study of 88,449 births (363 neural tube defects) over a 25-year period in Fylde, England (Bound 

et al., 1997). Women living in areas in which the water lead concentration was >10 μg/L were 

more likely to deliver a child with a neural tube defect. The association was consistent for 

anencephaly (n = 169) and spina bifida/cranium bifidum (n = 195), even after adjusting for social 

class. These authors posit that the association could be a direct effect of lead on neural tube 

closure or an indirect effect, the latter meaning a reduction in uptake of zinc (due to lead 

exposure) leading to a reduction in folate uptake. Irgens et al. (1998) partially confirmed these 

effects on neural tube defects in mothers occupationally-exposed to lead (relative risk of 2.87 

[95% CI: 1.05, 6.38]), but not for paternal lead exposure. 

The association between total anomalous pulmonary venous return and parental lead 

exposure during pregnancy (self reported, obtained from industrial hygiene measures, or from a 

job exposure matrix) was examined in the Baltimore-Washington Infant Study (Jackson et al., 

2004). In this case-control study, maternal periconceptional (i.e., 3 months prior to conception 

through the first trimester) exposure to lead resulted in an estimated odds ratio of 1.57 (95% CI: 

0.64, 3.47). For lead-exposed men, the estimated odds ratio was 1.83 (95% CI: 1.00, 3.42). 

Findings from this study support a possible association between paternal lead exposure and total 

anomalous pulmonary venous return. 

Taken together, the evidence suggests few associations between periconceptional or 

prenatal exposure to lead and congenital anomalies. There is a suggestion of small associations 

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with high levels of exposure, but many of those studies relied on occupational histories rather 

than on actual measures of blood lead levels. 

6.6.8 Summary of the Epidemiologic Evidence for the Reproductive and 

Developmental Effects of Lead 

There is little doubt that maternal to fetal transmission of lead results from placental 

transport. This transport occurs throughout pregnancy and may increase in the later stages. 

Further, there may be populations with increased fetal susceptibility, including populations with 

high rates of smoking and alcohol use, those using ethnic remedies and cosmetics, and those who 

use lead glazed pottery. Low levels of calcium intake may also increase fetal exposure. 

The available evidence suggests small associations between exposure to lead and male 

reproductive outcomes. These include perturbed semen quality and increased time to pregnancy. 

These associations appear at blood lead levels greater the 45 μg/dL, as most studies only 

considered exposure in the occupational setting. More research is needed regarding possible 

male reproductive effects at exposure levels in the lower (and currently more relevant) range. 

There are no adequate data to evaluate associations between lead exposure and female fertility. 

With one exception, there is no evidence to suggest an association between either 

maternal or paternal lead exposure and increased risk of spontaneous abortions. One study in 

Mexico where the mean maternal blood leads were in the moderate range (i.e. 10-12 μg/dL) 

suggests an association. 

To date, the evidence suggests at most a small association between lead exposure and 

birth weight and possibly small associations between lead exposure and several dichotomized 

measures of fetal growth. The reviewed studies occurred in very different populations, and the 

small associations may reflect some unmeasured or unknown confounding variable. It is 

unlikely that further epidemiologic research will fully resolve this question. However, several 

factors, such as maternal SES, maternal education, smoking prevention and reduced use of 

alcohol, related to lead exposure are associated with increases in birth weight (and decreases in 

blood lead) and are candidates for intervention. 

Similarly, the evidence suggests at most a small association between lead exposure and 

preterm delivery or reduced length of gestation. The available data also suggest limited 

associations between either periconceptional or prenatal lead exposure and congenital anomalies. 

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There is a suggestion of small associations with high levels of exposure, but many of those 

studies relied on occupational histories rather than on actual measures of blood lead. 

Overall, since the 1986 Lead AQCD, a substantial body of work has evaluated the 

associations between lead exposure and reproductive outcomes. It is now clear that lead clearly 

crosses the placenta during all trimesters and maternal exposure results in fetal exposure. 

For many other outcomes, the observed associations are relatively small, especially at the levels 

of exposure that are currently of interest. Nevertheless, there may be populations that are highly 

susceptible to lead-related reproductive effects, especially if they have additional risk factors for 

these outcomes. 

6.7 GENOTOXIC AND CARCINOGENIC EFFECTS OF LEAD 

6.7.1 Summary of Key Findings from the 1986 Lead AQCD 

The 1986 EPA Lead AQCD reviewed five epidemiologic studies of occupationally 

exposed workers (Cooper and Gaffey, 1975; Davies, 1984; Selevan et al., 1985; Sheffet et al., 

1982; McMichael and Johnson, 1982). These workers were exposed to inorganic lead 

compounds such as lead oxides and lead sulfides. The EPA noted that Cooper and Gaffey 

reported a significant increase in lung and gastrointestinal cancer among battery and smelter 

workers in the U.S. (standardized mortality ratios of 1.50 and 1.48 respectively among smelter 

workers, and 1.32 and 1.23 among battery workers). The EPA further noted that much of this 

exposure was by inhalation and ingestion of lead oxides, which are relatively insoluble, adding 

some plausibility to the occurrence of cancer at these two sites. Sheffet et al. (1982) provided 

some corroborating evidence for gastrointestinal cancer by finding a nonsignificant excess of 

stomach cancer among U.S. lead chromate pigment workers. However, Davies (1984) did not 

find any cancer excess among lead chromate pigment workers in the U.K. The EPA noted that 

Selevan (1984) found a significant excess of kidney cancer among U.S. lead smelter workers 

based on 6 cases. This finding was judged striking because it mimicked the findings of kidney 

cancer in animals. The EPA judged that the McMichael and Johnson (1982) study of lead 

poisoned workers was not particularly informative because the non-poisoned workers may have 

had substantial lead exposure and no details were given on how lead poisoning was determined. 

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In summary the EPA felt the evidence was insufficient, stating that “little can now be reliably 

concluded from available epidemiologic studies.” 

The studies by Cooper and Gaffey (1975) and Selevan (1984), which are both important 

because they are large occupational cohorts with documented high exposure, have been updated 

and are further reviewed below. A cohort study of U.K. battery workers (Malcolm and Barnett, 

1982) is also reviewed below. 

EPA in 1986 also presented data on human cytogenetic studies, reproducing data from 

an earlier 1980 International Agency for Research on Cancer (IARC) monograph for metals and 

metallic compounds (IARC, 1980). For lead, 10 chromosomal aberration studies were judged to 

be “positive” and 6 such studies were judged to be “negative.” On the whole the EPA 

considered that “under certain conditions lead compounds are capable of inducing chromosomal 

aberrations in vivo and in tissue cultures.” The EPA also reviewed more limited data from two 

human studies of sister chromatid exchange (Dalpra et al., 1983; Grandjean et al., 1983), one of 

which was positive and one negative. 

6.7.2 Summary of Key Findings by the International Agency for Research 

on Cancer and the National Toxicology Program 

IARC reviewed inorganic and organic lead compounds in its monograph number 87 in 

February of 2004 (IARC, 2005), and IARC concluded that inorganic lead compounds were 

probable human carcinogens (Group IIA). This classification is one step down from a 

classification as a “definite” human carcinogen (Group I). The IARC classification of inorganic 

lead compounds as probable human carcinogens was based on limited evidence in humans and 

sufficient evidence in animals. Also, IARC noted that there was insufficient information 

regarding organic lead compounds (e.g., tetraethyl lead) to make any judgment. 

Regarding the human studies, IARC based its evaluation largely on six occupational 

cohort studies of highly-exposed workers, which were felt to be particularly informative (battery 

workers in U.S. and U.K., smelter workers in Italy, Sweden, and the U.S.). The IARC 

assessment focused on four cancer sites, lung, stomach, kidney, and brain. IARC noted that lung 

showed a significant elevation in one study (Lundstrom et al., 1997) and nonsignificant 

elevations in a number of others. However, the significant elevation of lung cancer in 

Lundstrom et al. appeared to be inextricably associated with arsenic in addition to lead exposure 

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(Englyst et al., 2001). IARC concluded that the strongest epidemiologic evidence for lead 

carcinogenicity was for stomach cancer, noting that four cohort studies showed a consistent 

30-50% excess of stomach cancer vs. external referent populations. IARC noted that 

confounding by ethnicity, diet, Helicobacter pylori infections, or SES may have played a role in 

the stomach cancer excesses. Finally, IARC noted that while one cohort study showed a 2-fold 

excess of renal cancer (Steenland et al., 1992), the other studies showed no excess. Similarly, 

there were no consistent excesses of brain cancer, although one study did find a significant 

positive dose-response between glioma and blood leads, based on small numbers (Anttila et al., 

1996). 

The National Toxicology Program (NTP) in 2003 evaluated the carcinogenicity of lead 

and lead compounds. A summary of its evaluation can be found in NTPs Report on Carcinogens 

(www.ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s101lead.pdf), and the detailed evaluation is 

also available (NTP, 2004). NTP, like IARC, concluded that “lead and lead compounds are 

reasonably anticipated to be human carcinogens based on limited evidence from studies in 

humans and sufficient evidence from studies in experimental animals.” The NTP considered that 

“the strongest epidemiologic evidence was for lung and stomach cancer, which are consistently 

but weakly associated with occupational and industries entailing lead exposure and with indices 

of individual lead exposure, including job history and biological monitoring of occupationally 

exposed and general populations. However, most studies of lead exposure and cancer reviewed 

had limitations, including poor exposure assessment and failure to control for confounders (other 

factors that could increase the risk of cancer, including lifestyle factors and concurrent 

occupational exposure to other carcinogens), and did not demonstrate relationships between the 

amount of exposure (concentration or duration, for example) and the magnitude of cancer risk.” 

NTP, like IARC, also relied heavily on occupational cohort studies in its evaluation of the 

epidemiologic evidence. NTP (2003) noted that “the mechanisms by which lead causes cancer 

are not understood. Lead compounds do not appear to cause genetic damage directly, but may 

do so through several indirect mechanisms, including inhibition of DNA synthesis and repair, 

oxidative damage, and interaction with DNA-binding proteins and tumor-suppressor proteins.” 

Both the IARC and NTP evaluations of human evidence relied primarily on occupational 

studies of highly exposed workers, in which limited evidence of stomach and to some extent lung 

carcinogenicity was found. There are seven such studies with relatively large populations 

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(Anttila et al., 1995; Carta et al., 2005; Fanning, 1988; Gerhardsson et al., 1995a; Lundstrom 

et al., 1997; Steenland et al., 1992; Wong and Harris, 2000). A further study (Ades and 

Kazantzis, 1988) also addresses lead exposure in a large occupational cohort, although it is 

compromised by the strong correlation between arsenic and lead exposure in the cohort. 

It should be noted that the blood lead levels among these workers were generally three to five 

times higher than the blood lead levels in the two studies of the general U.S. population (Jemal 

et al., 2002; Lustberg and Silbergeld, 2002; both based on NHANES II) with environmental 

exposures. For example, mean blood levels in two studies of U.S. lead smelter workers averaged 

56 μg/dL in Steenland et al. (1990) in 1976 and 80 μg/dL in Cooper et al. (1985) during the 

period 1947-1972. In contrast, blood levels in the U.S. population enrolled in NHANES II in 

late 1976-1980 averaged 14 μg/dL. General population blood lead levels have decreased 

markedly since the 1970s in many industrial countries with the banning of leaded gasoline. For 

example, in the U.S. in the early 1990s general population levels averaged 3 μg/dL according to 

NHANES III (www.atsdr.cdc.gov/toxprofiles/, see lead toxicological profile, page 409). 

Regarding the occupational studies, while exposure is well documented, exposure-response data 

are generally not available, making impossible any quantitative inference about likely cancer 

effects in low exposure groups based on these studies. The high exposure occupational cohorts 

are the most informative for deciding whether lead is likely to cause cancer, simply because high 

doses are more likely to show detectable effects than low doses, if effects exist. If lead does 

cause cancer, and assuming there is no threshold below which exposure does not cause cancer 

(which is generally true for human carcinogens), current low level exposures to the general 

public may result in some level of cancers related to lead exposure due to the potential exposure 

of a large number of people. 

6.7.3 Meta-Analyses of Lead and Cancer 

There have been two published meta-analyses of the carcinogenicity of lead and lead 

compounds. The major findings of these studies are summarized in Table 6-7.1. Steenland and 

Boffeta (2000) relied on eight occupational cohort studies of highly-exposed workers (seven 

cohort studies, one nested case-control), all of which had documentation of exposure levels. 

Meta-analyses were conducted for lung, stomach, kidney, and brain cancer. The combined lung 

cancer relative risk relative risk was 1.30 (95% CI: 1.15, 1.46), based on 675 lung cancer deaths. 

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402(c) Economic Analysis Chapter 5 637
Table 6-7.1. Results of Meta-Analyses Addressing the Association Between 

Lead Exposure and Cancer 

Risk Estimate (95% CI) for indicated outcome 

[Number of studies utilized in estimate] 

Meta-Analysis Lung Cancer Stomach Cancer Renal Cancer 

Fu and Boffetta 1.24 (1.16, 1.33) 1.33 (1.18, 1.49) 1.19 (0.96, 1.48) 

(1995) [n = 15] [n = 10] [n = 5] 

Fu and Boffetta 1.42 (1.05, 1.92) 1.50 (1.23, 1.83) 1.26 (0.70, 2.26) 

(1995) [battery/smelter only] [battery/smelter only] [battery/smelter only] 

Steenland and 1.30 (1.15, 1.46) 1.34 (1.14, 1.57) 1.01 (0.72, 1.42)

Boffetta (2000) [n = 8 – cohort only] [n = 8 – cohort only] [n = 7 – cohort only] 

1 However, the authors noted that the lung cancer findings were not consistent across studies, and 

2 were influenced highly by one study (Lundstrom et al., 1997) in which confounding by arsenic 

3 was likely. Exclusion of this study dropped the combined lung cancer relative risk to 1.14 

4 (95% CI: 1.04, 1.73). The strongest positive evidence was for stomach cancer (relative risk 1.34 

5 [95% CI: 1.14, 1.57], 181 observed deaths). There was little positive evidence for renal cancer 

6 (relative risk 1.01 [95% CI: 0.72, 1.42], 40 deaths), or brain cancer (relative risk 1.06 [95% CI: 

7 0.81, 1.40]). All meta-analyses used fixed effects models, given that no evidence of 

8 heterogeneity was found across studies (there was significant heterogeneity for lung cancer 

9 when the Lundstrom et al. study was included, but not when it was excluded). 

10 Fu and Boffetta (1995) conducted an earlier meta-analysis in which they reviewed 

11 16 cohort and 7 case-control studies. Different numbers of studies were used for meta-analyses 

12 of different outcomes, dependent on whether that outcome was reported separately, among other 

13 factors. These authors focused their analysis on the occupational studies. Twelve of these 

14 studies were used in a meta-analysis of lung cancer, resulting in a combined relative risk of 1.29 

15 (95% CI: 1.10, 1.50) (random effects model). There was significant heterogeneity of lung 

16 cancer results across studies. Meta-analyses using fixed effects (no significant heterogeneity 

17 between studies) resulted in relative risks of 1.33 (95% CI: 1.18, 1.49) for stomach cancer 

18 (10 studies), of 1.19 (95% CI: 0.96, 1.48) for kidney cancer (5 studies), and 1.41 (95% CI: 1.16, 

19 1.71) for bladder cancer (5 studies). No meta-analysis was conducted for brain cancer. Separate 

20 analyses for stomach, lung, and kidney cancer were also conducted for those studies with the 

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highest occupational exposure to lead (3 to 5 studies of battery and smelter workers), which 

resulted in slightly higher relative risks. The authors concluded that “the findings from the 

workers with heavy exposure to lead provided some evidence to support the hypothesis of an 

association between stomach and lung cancer and exposure to lead. The main limitation of the 

present analysis is that the excess risks do not take account of potential confounders, because 

little information was available for other occupational exposures, smoking, and dietary habits. 

The excess risk of stomach cancer may also be explained, at least in part, by nonoccupational 

factors. For bladder and kidney cancers, the excess risks are only suggestive of a true effect 

because of possible publication bias. 

6.7.4 Genotoxicity of Lead 

The NTP reviewed in some detail the genotoxicity studies over the period 1970-2002. 

These studies are cross-sectional studies, mostly of occupationally exposed workers compared to 

a control population. Usually blood lead levels are available to document exposure. Outcomes 

consisted of chromosomal aberrations (CA), sister chromatid exchange (SCE), micronuclei 

formation (MN), and studies of DNA damage (often via the comet assay) and/or measures of the 

mitotic activity. Of these outcomes, only CAs have been shown to have a positive relationship to 

subsequent cancer (Hagmar et al., 2004, Rossner et al., 2005). SCEs are generally considered a 

marker of exposure to environmental agents which have some effect on DNA, but are not 

thought to necessarily predict cancer risk. MN and DNA damage are thought to indicate 

genotoxicity with unknown effect on cancer risk. These outcomes are somewhat informative 

regarding the possible human carcinogenicity of lead but are clearly secondary to direct 

information on cancer risk from epidemiologic studies. 

The most recent studies of the genotoxicity of lead are summarized in Annex Table 

AX6-7.1. Of eleven studies of chromosomal aberrations (CA), six were judged to show a 

positive relationship between CA and lead, four were judged negative, and one was neither 

clearly positive or negative. In general, these studies were done in the 1970s and 1980s; only 

one dates from the 1990s. There were nine studies of sister chromatid exchange. Of these, four 

were judged positive, three negative, and two could not be judged clearly one way or the other. 

It is notable that the positive studies were generally the most recent. There were four MN 

studies, all of which were judged positive. Finally, there were nine studies of DNA damage 

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402(c) Economic Analysis Chapter 5 639
1 and/or mitotic activity. These varied in the specific outcome, although many used a comet assay 

2 to measured oxidative damage to DNA. Eight of these nine studies were judged positive in the 

3 sense that increased DNA damage or mitotic activity was related to lead exposure, while one was 

4 judged negative. 

5 Since the NTP review, there have been three additional cytogenetic studies which are 

6 informative regarding lead (Palus et al., 2003, Minozzo et al., 2004, and Fracasso et al., 2002), 

7 as well as one mutation study (Van Larebeke et al., 2004). All four of these studies (two of DNA 

8 damage one of MN, and one of a specific mutation frequency) were positive in significantly 

9 linking lead exposure to the outcome. The results of these studies as well as those reviewed by 

10 the NTP are summarized in Table 6-7.2. 

11 

12 

Table 6-7.2. Results of Epidemiologic Studies on the Genotoxicity of Lead Exposurea 

Results 

Studied Outcome Positive Mixed Negative 

Chromosomal Aberrations

 (CA) 6 1 4 

Sister Chromatid Exchange 

 (SCE) 4 2 3 

Micronucleus Formation 

 (MN) 5 0 0 

DNA Damage/Mitosis 10 0 1 

Gene Mutation 1 0 0 

a Results summarize the overall findings of epidemiologic studies addressing the potential genotoxic effects of 

lead exposure. Some studies addressed multiple aspects of genotoxicity; for these studies, their results for each 

of the listed categories of genotoxic outcomes are presented separately. 

13 While the overall the evidence from cytogenetic studies is mixed, more recent studies 

14 which were focused on DNA damage or mitotic activity have tended to be largely positive. 

15 However, it is not known whether these outcomes predict subsequent cancer risk. 

16 

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6.7.5 Review of Specific Studies on the Carcinogenicity of Lead Since the 

1986 Lead AQCD 

6.7.5.1 Introduction 

The epidemiologic studies of lead exposure and cancer are listed in Table 6-7.3. The most 

relevant studies focus on exposure through occupational sources, wherein the most intense 

exposure to lead can be expected to occur. This exposure predominantly involves inorganic lead 

species. Relevant studies are discussed below, beginning with the most key studies of the 

general population will then be presented followed by a brief summary of other relevant studies 

examining the occupational studies. 

6.7.5.2 Key Studies of Occupational Populations in the U.S. 

There are seven key occupational studies based on highly exposed worker populations; 

these are all cohort studies with adequate numbers to address lung and/or stomach cancer. 

There are two cohorts based in the U.S. and five based outside it. Studies reviewed in this 

section are summarized in Annex Table AX6-7.2. 

Steenland et al. (1992) followed up 1,990 male U.S. lead smelter workers, employed from 

1940 to 1965, through 1988. Standardized mortality ratios indicated an excess of lung, stomach, 

kidney, and bladder cancer, but these excesses did not reach statistical significance. Focusing on 

a subgroup of workers classified as highly lead exposed based on air-monitoring records yielded 

a statistically significant excess for kidney cancer (standardized mortality ratio of 2.39 [95% CI: 

1.03, 4.71]), although it did not appear to increase with increasing duration of exposure. 

Estimates for the other cancers (standardized mortality ratio of 1.11 [95% CI: 0.82, 1.47] for 

lung; 1.28 [95% CI: 0.61, 2.34] for stomach; 1.33 [95% CI: 0.48, 2.90] for bladder) showed 

little change with restriction to the high-exposure group. While neither arsenic nor cadmium 

exposure could be controlled for, 1975 NIOSH monitoring data indicated less intense exposure 

to airborne cadmium or arsenic than to lead. Lead averaged 3.1 mg/m3

 and arsenic 14 μg/m3, 

compared to current OSHA standards of 0.05 mg/m3 for lead and 10 μg/m3 for arsenic. It is 

notable that a 1996 review of studies (Steenland et al., 1996) on arsenic-exposed workers 

concluded that significantly elevated rates of lung cancer were concentrated in studies where 

average exposures greatly exceeded OSHA standards (e.g., hundreds of μg/m3

). No data on 

workers’ smoking status were available. 

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402(c) Economic Analysis Chapter 5 641
Table 6-7.3. Epidemiologic Studies of Lead Exposure and Cancer in Specific 

Populations, by Geographic Region and Study Designa

 Epidemiologic Study Design 

Specific Study Population Cohort Nested Case-control Case-control 

United States 

Battery and lead production Cooper and Gaffey (1975), Cooper Cooper et al. (1989), 

workers et al. (1985), Wong and Harris Wong and Harris (2000) 

(2000) (same publication as 

cohort study) 

Copper workers (Utah) Rencher et al. (1977) 

Lead and zinc pigment plant Sheffet et al. (1982) 

workers 

Lead smelter workers (Idaho) Selevan et al. (1985), Steenland et 

al. (1992) 

Sample of deaths due to cancer Mallin et al. (1989) 

vs. noncancer deaths (Illinois) 

Brain cancer Cocco et al. (1998a) 

Central nervous system cancer Cocco et al. (1998b) 

Stomach cancer Cocco et al. (1999) 

NHANES II cohort mortality Jemal et al. (2002), Lustberg and 

follow-up, general U.S. Silbergeld (2002) 

population 

Canada 

Population-based cases Risch et al. (1988) 

Specific cancers versus all Siemiatycki et al. (1991) 

cancers 

Europe 

Glass workers (Finland) Sankila et al. (1990) 

Registry-derived liver cancer Kauppinen et al. (1992) 

cases vs. stomach cancer or 

myocardial infarctions (Finland) 

Workers via Cancer Registry Anttila et al. (1995) Anttila et al. (1996) 

(Finland) 

Renal-cell cancer vs. population Pesch et al. (2000) 

controls (Germany) 

Laryngeal cancer among Kandiloris et al. (1997) 

persons with no history of lead 

exposure (Greece) 

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402(c) Economic Analysis Chapter 5 642
Table 6-7.3 (cont’d). Epidemiologic Studies of Lead Exposure and Cancer in Specific 

Populations, by Geographic Region and Study Designa

 Epidemiologic Study Design 

Specific Study Population Cohort Nested Case-control Case-control 

Europe (cont’d) 

Glass workers (Italy) Cordioli et al. (1987) 

Lead and zinc miners: females Cocco et al. (1994b) 

only (Sardinia) 

Lead and zinc miners: male only Cocco et al. (1994a), Carta et al. 

(Sardinia) (1994); Carta et al. (2003) 

Lead and zinc smelter workers Cocco et al. (1996) 

(Sardinia) 

Lead and zinc smelter workers Cocco et al. (1997) 

(Sardinia, but different from 

Cocco et al. 1996) 

Glass workers (Sweden) Wingren and Englander (1990) Wingren and Axelson 

(1985, 1987, 1993) 

Copper and lead smelter workers Gerhardsson et al. (1995a) 

(Sweden) 

Copper and lead smelter workers 

(Sweden) (Lundström: full 

cohort; Englyst: sub-cohort) 

Gerhardsson et al. (1986), 

Lundström et al. (1997), Englyst 

et al. (2001) 

Lead-acid battery workers (U.K.) Dingwall-Fordyce and Lane Fanning (1988) 

(1963), Malcolm and Barnett 

(1982) 

Chromate (including lead- Davies (1984a, 1984b) 

chromate) workers (U.K.) 

Zinc, cadmium, and lead smelter Ades and Kazantzis (1988) Ades and Kazantzis 

workers (U.K.) (1988) (same publication 

as cohort study) 

Asia 

Gliomas vs. noncancer patients Hu et al. (1998) 

(China) 

Meningiomas vs. noncancer Hu et al. (1999) 

patients (China) 

Gall bladder cancer vs. gallstone Shukla et al. (1998) 

patients (India) 

Prostate cancer cases versus Siddiqui et al. (2002) 

benign prostate hyperplasia cases 

and normal controls (India) 

a Within regions, study populations are listed in chronological order based on the earliest published study on that specific 

worker population. Publications considered to be key studies are italicized. 

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Wong and Harris (2002) extended follow-up on the battery and smelter worker cohort 

previously reported on by Cooper et al., 1985 through 1995, an additional 15 years. With the 

additional follow-up, standardized mortality ratios for lung, tracheal, or bronchial cancer 

decreased to 1.14 (95% CI: 0.99, 1.30) for battery workers but showed little change for smelter 

workers at 1.22 (95% CI: 1.00, 1.47). A significantly elevated standardized mortality ratio for 

stomach cancer (1.53 [95% CI: 1.12, 2.05]) persisted among battery workers, with a lesser 

elevation among smelter workers (1.33 [95% CI: 0.75, 2.20]). Among other cancers, only 

thyroid cancer among all workers combined showed a significantly elevated standardized 

mortality ratio (3.08 [95% CI: 1.33, 6.07]). Cancer mortality did not increase with earlier year 

of hire for lung, stomach, or thyroid cancer. Lung and stomach cancer mortality peaked among 

workers with 10 to 19 years of factory employment and declined with longer employment 

duration. Thyroid cancer mortality occurred exclusively among workers with 20 or more years 

of exposure. As with earlier analyses based on this cohort, concomitant exposures to other 

compounds could not be controlled for, but as these were likely to be most intense among lead 

production workers, whose standardized mortality ratios were similar to or lower than those for 

battery workers, any bias resulting from such exposure probably was toward the null. No data 

were available to assess the possible role of smoking, diet, or other potential nonoccupational 

risk factors in the results. 

A nested case-control analysis was also conducted to further explore stomach cancer 

mortality within workers employed at the Philadelphia lead battery plant in the cohort (Wong 

and Harris, 2000). Among 30 workers who died of stomach cancer and 120 age-matched 

controls, job title histories were used to estimate duration of employment and cumulative 

exposure based on job-specific intensities of exposure. Duration of employment and estimated 

degree of lead exposure showed no elevation among workers who died of stomach cancer, nor 

did mortality increase across increasing tertiles of lead exposure. Little information appeared to 

be available on potential confounders. The authors suggested that in light of historically higher 

stomach cancer rates in Ireland and Italy and the observation of a higher proportion of Irish and 

Italian immigrants among lung cancer cases in the case-control study, differences in ethnicity 

may have contributed to the elevated standardized mortality ratios seen in the cohort as a whole. 

The recent IARC Working Group (IARC, 2005) concluded that, based on the ethnic composition 

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of the control population (23% Irish or Italian), confounding by race could account for only part 

of the observed association, however. 

The extended follow-up and nested case-control analyses on the original Cooper et al. 

(1985) cohort thus continued to provide evidence for some increase in lung and stomach cancer 

among these lead workers, but no consistent evidence of increasing cancer risk with increasing 

exposure within the lead worker cohort itself, especially for stomach cancer. 

Fanning (1998) studied deaths due to specific cancer types among U.K. battery and other 

factory workers. High to moderate lead exposure resulted in odds ratios for lung and digestive 

cancer of 0.93 and 1.13, respectively, with the latter elevation due mainly to stomach cancer 

(odds ratio of 1.34). No odds ratios reached nominal statistical significance, and no associations 

were noted for other cancer types. The excess of digestive cancer deaths was restricted to the 

1926 to 1965 period, during which lead exposures would have been most intense. Odd ratios for 

other cancers did not vary by period. Because each cancer case group was compared with a 

control group consisting of subjects who died from all other causes, including other cancers, 

odds ratios would have been biased downward if some of these other deaths also were leadrelated. However, most deaths were due to nonmalignant respiratory or circulatory diseases 

other than hypertension, mitigating the potential impact of such a bias. 

Anttila et al. (1995) linked 20,700 Finnish workers whose blood lead was monitored 

during 1973 to 1983 by the Finnish Institute of Occupational Health to the Finnish Cancer 

Registry. Exposure was subdivided according to highest peak blood level measured: low (0 to 

0.9 μmol/L [0 to 18.6 μg/dL]), moderate (1.0 to 1.9 μmol/L [20.7 to 39.4 μg/dL]), and high 

(2.0 to 7.8 μmol/L [41.4 to 161.6 μg/dL]). The total cohort showed no elevation in total or sitespecific cancer mortality, based on an standardized mortality ratio analysis. Among male 

workers with moderate exposure, incidence of total respiratory cancer and lung cancer both were 

elevated (standardized incidence ratio of 1.4 [95% CI: 1.0, 1.9 for both]). Risks of total 

digestive, stomach, bladder, and nervous-system cancer also were modestly elevated. However, 

risks did not increase in the high-exposure group. Risks of mortality for all cancer for both men 

and women (relative risk 1.4 of [95% CI: 1.1, 1.8]) and lung or tracheal cancer (relative risk of 

2.0 [95% CI: 1.2, 3.2]) were even stronger when a person-year analysis was applied to compare 

workers with moderate lead exposure to those with low exposure. Again, risks did not increase 

in the highest exposure group. This exposure group was smaller than the others, however, which 

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limited the power of analyses specific for high exposure workers. Thus, for example, the 

numbers of lung or tracheal cancer deaths among men in the low-, moderate-, and high-exposure 

groups were 25, 34, and 11, respectively, for the person-year-based analyses. 

It should be noted that for cancer, cumulative exposure, particularly during the earlier part 

of the follow-up period, might be more relevant than peak exposure, although the two were 

reported to be highly correlated (Anttila et al., 1995). Case-referent substudies of lung cancer 

used different exposure criteria (Anttila et al., 1995). Odds ratios increased most consistently 

with increasing cumulative exposure to lead. Among histologic subtypes, significantly elevated 

risk for squamous-cell cancer of the lung (odds ratio of 4.1 [95% CI: 1.1, 15]) for the highest 

blood lead group persisted after adjustment for smoking, although with additional adjustment for 

engine exhaust and solvent exposure, the risk declined (odds ratio of 3.4 [95% CI: 0.9, 13]). 

Results for female workers are not considered, as too few cancers (3 total) occurred to permit 

meaningful conclusions. Although the follow-up period was relatively short, the lung cancer 

association was analyzed in much greater detail than in most studies, and smoking was adjusted 

for, while the association between lead exposure and lung cancer weakened with control for 

engine exhaust and solvent exposure, the odds ratio remained well above 1. The highest odds 

ratio of all was observed for estimated risk of lung cancer among workers with peak blood lead 

levels of at least 0.8 μmol/L [$16.6 μg/dL] who were exposed to engine exhaust (odds ratio of 

14.9 [95% CI: 1.3, 178]; 11 cases). If engine exhaust was acting as an effect modifier, directly 

controlling for it might not have been appropriate. The exhaust could have served as a source of 

organic lead, as well. 

Gerhardsson et al. (1995a) followed up 664 male Swedish secondary lead smelter 

workers, tracing their cancer morbidity from 1969 to 1989. Compared to the population of the 

surrounding county, the workers’ standardized incidence ratio for all cancers was 1.27 (95% CI: 

0.91, 1.74), based on 40 tumors. Standardized incidence ratios for cancers at all specific sites 

except the brain were elevated, notably those for the respiratory system (1.32 [95% CI: 0.49, 

2.88]), stomach (1.88 [95% CI: 0.39, 5.50]), and colon (1.46 [95% CI: 0.30, 4.28]). Because of 

the small numbers of tumors (only 6, 3, and 3, respectively, even for the aforementioned sites), 

the reliability of estimates for most sites is limited. Restricting analyses to workers in the highest 

quartile of lead exposure based on routine blood lead monitoring data yielded a higher 

standardized incidence ratio for total gastrointestinal cancer (2.43 [95% CI: 1.11, 4.62]; 

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9 tumors), but not respiratory cancer. Availability of blood lead measurements is an advantage 

of this study, along with a lead-exposed worker population unlikely to have much exposure to 

arsenic, chromium, or cadmium. However, the cases were too few for detailed exposureresponse analyses by cancer type. Lack of data on smoking further restricts interpretation of the 

results. 

Lundström et al. (1997) followed 3,979 Swedish smelter workers from 1928 to 1987. 

Workers were further subdivided into those with high cumulative blood lead scores (mean times 

years exposed >10 μmol/L), and those exposed to “lead only” (excluding those from departments 

thought to have significant exposures to other potential carcinogens, such as arsenic, or little 

exposure to lead). The lung cancer standardized mortality ratio was 2.8 (95% CI: 2.0, 3.8) for 

the total cohort, 2.8 (95% CI: 1.8, 4.5) for the high-exposure subgroup, and reportedly similar 

for the subgroup exposed to lead only. With adjustment for a 15-year latency period, lung cancer 

standardized incidence ratios likewise differed little between the total cohort and high-exposure 

subgroup; however, among workers with exposure to lead only, the standardized incidence ratio 

rose from 3.1 (95% CI: 1.7, 5.2; 14 cases) for all workers to 5.1 (95% CI: 2.0, 10.5; 7 cases) for 

those with the highest exposure. With a 15-year latency period, elevated standardized incidence 

ratios also were observed for cancer of the brain and nervous system (1.6 [95% CI: 0.4, 4.2]) 

and renal pelvis, ureter, or bladder (1.8 [95% CI: 0.8, 3.4]) among the high-exposure subgroup. 

Non-respiratory cancers were too infrequent (5 total) in the high-exposure lead-only subgroup 

for meaningful analysis. This study’s size, extensive follow-up, and ability to integrate bloodbased and job-based exposure indices give it unusual power. The apparent increase in cancer 

risk with higher cumulative lead exposure that appeared when workers thought to be potentially 

exposed to other metals, such as arsenic and nickel, were excluded also appeared to strengthen 

the evidence for a specific link between lead and respiratory cancer. A subsequent study by 

Englyst et al. (2001), however, cast doubt on the efficacy of the “lead only” grouping. 

Englyst et al. (2001) conducted additional analyses on one element of the Lundström et al. 

(1997) cohort. A total of 1,093 workers from the smelter’s lead department was followed up 

through 1997. Significantly elevated lung cancer standardized incidence ratios were observed 

in all subcohorts, including the subcohort who had never worked in arsenic-exposed areas 

(3.6 [95% CI: 1.2, 8.3]; 5 cases). This subcohort is the same as the “lead-only” subgroup 

evaluated by Lundström et al. (1997). A review of detailed job histories obtained for all workers 

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with lung cancer, however, indicated that 13 of the 15 had “considerable” exposure to arsenic as 

well as lead, including all but 1 in the “lead only” subcohort. 

Carta et al. (2003) followed up the mortality of 918 Sardinian lead smelter workers from 

1972 through 2001. Smelter workers as a whole displayed an overall cancer mortality no higher 

than expected based on regional rates (standardized mortality ratio of 1.01). Cancer-specific 

standardized mortality ratios were, however, nonsignificantly elevated for cancers of the lung 

(1.21) and stomach (1.22) as well as for lymphoma and leukemia (1.82). Use of blood and 

ambient lead monitoring data available by department and task to categorize estimated exposure 

yielded a statistically significant upward trend with increasing lead exposure for lung cancer; no 

significant trend was seen for the other cancers, although in light of the small number of gastric 

cancer and lymphoma/leukemia deaths (4 and 6, respectively) interpretation of dose-response is 

problematic for these outcomes. 

6.7.5.3 Key Studies of the General Population 

There are two key general population cohort studies in which lead exposure is assessed 

via blood lead levels (see Annex Table AX6-7.3 for additional details). Jemal et al. (2002) 

conducted the first biomarker-based general population cohort study of lead exposure and 

cancer. The study employed the subsample of 3,592 white U.S. participants in NHANES II 

(1976 to 1980) who had undergone blood lead level determinations at time of entry. Deaths 

among this population were enumerated through 1992 by linkage to the National Death Index 

(NDI) and Social Security Administration Death Master File. Median blood lead levels in this 

population were 12 μg/dL. Adjusted for age, smoking, drinking, region, year, and gender, risk of 

mortality from any cancer rose across quartiles of blood lead level, but this trend was not 

statistically significant. The trend across quartiles was not consistent in gender-specific analyses, 

although relative risks were elevated for the highest quartile of blood lead level in both men and 

women (relative risk 2.0 for men and 1.6 for women). The relative risk for lung cancer based on 

comparison of subjects with blood lead levels above or below the median was 1.5 in the 

combined population, with higher risk observed among women (2.5 [95% CI: 0.7, 8.4]) than 

men. The highest relative risks were observed for cancer of the esophagus (3.7 [95% CI: 0.2, 

89]), pancreas (3.6 [95% CI: 0.6, 19.8]), and stomach (2.4 [95% CI: 0.3, 19.1]); no elevations 

were noted for cancers of other sites. 

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The lack of statistically significant results reflects the small number of deaths during 

follow-up, which limited the study’s power; of the nine major sites examined, the number of 

deaths ranged between 5 and 16 for all sites except the lung. Detailed exposure-response 

analyses were restricted to all cancers combined, although potential effects could have been 

strongly target-organ specific. In addition, the use of quartile cut points based on the distribution 

of lead concentrations estimated for the total U.S. population resulted in relatively small numbers 

in the referent group (lowest exposure quartile) for males and in the high-exposure quartile for 

females. Use of a biomarker provided an objective measure of lead exposure. Nevertheless, 

reliance on a single blood lead measurement produces less reliable estimates than would be 

obtained through multiple measurements and precludes addressing temporal changes in lead 

exposure over the follow-up period. Lack of control for exposure to occupational carcinogens 

other than lead and potential residual confounding by duration and intensity of tobacco smoking 

also could have biased the results, especially for men. Lustberg and Silbergeld (2002) carried 

out another biomarker-based general population study based on the same NHANES II mortality 

cohort used by Jemal et al. (2002). This study did not exclude nonwhites, however (thus gaining 

524 subjects) and employed more extensive adjustment for potential confounding factors than 

the Jemal et al. (2002) analyses (i.e., education, body mass index, and exercise were included in 

the regression models, although alcohol intake was not). In addition, persons with blood lead 

levels of 30 μg/dL or higher were excluded in order to restrict comparisons to levels below the 

OSHA standard for lead exposure. Persons with levels below 10 μg/dL served as the referent 

group. Survival analyses adjusted for potential confounders found a relative risk for cancer 

mortality of 1.5 (95% CI: 0.9, 2.5) for those with blood lead levels of 10 to 19 μg/dL, compared 

with those with levels below 10 μg/dL, rising to 1.7 (95% CI: 1.0, 2.8) for those with levels of 

20 to 29 μg/dL. Separate analyses of lung-cancer and non-lung-cancer deaths yielded estimates 

of increased risk for moderate- or high-exposure groups, compared with the referent population, 

both for lung cancer and non-lung cancer. However, none of the estimates reached the P < 0.05 

level of statistical significance, and the results for non-lung cancers showed no evidence of an 

exposure-response relationship. 

As with Jemal et al. (2002), the use of a biomarker for exposure and the prospective 

design of the study are strengths. Its attempts to control for potential confounders were more 

extensive, and its choice of cut points for the referent category yielded more males in the referent 

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group, although that group still included less than 20% of the study population. However, it is 

notable that blood lead levels rose significantly with smoking level. The models included terms 

for former smoking, current light smoking, and current heavy smoking (>1 pack per day). 

Nevertheless, some degree of residual confounding due to smoking might have remained, which 

could have contributed to the estimated risk of lung cancer for the highest exposure category 

(relative risk of 2.2 [95% CI: 0.8, 6.1]). Such residual confounding would have had less effect 

on the results for non-lung cancer. As noted regarding the other NHANES-based study, 

however, mortality due to cancers of other sites was too uncommon to allow for reliable sitespecific comparisons. In the Lustberg and Silbergeld analysis, all cause and cardiovascular 

mortality increased monotonically with blood lead level, which might indicate residual 

confounding from SES or smoking affecting both heart disease and cancer. 

6.7.5.4 Other Lead Studies 

There are a variety of other epidemiologic studies of lead exposure, which are less 

important than the key studies above but which offer some information. Studies reviewed in this 

section are summarized in Annex Table AX6-7.4. Rencher et al. (1977) compared Utah copper 

smelter workers’ mortality with that of miners for the same company. Workers in lead-exposed 

operations had a higher proportional mortality due to respiratory cancer in general and lung 

cancer specifically than did other workers, with or without control for smoking status. Among 

lead-exposed workers, those who developed lung cancer had significantly higher estimated lead 

exposure than the rest. Workers with lung cancer also had significantly higher estimated 

exposure to arsenic and sulfur dioxide, however, and these exposures were not adjusted for. 

Ades and Kazantzis (1988) conducted a cohort study of lung cancer mortality among 

4,393 U.K. zinc, lead, and cadmium smelter workers. Smelter workers had a lung cancer 

standardized mortality ratio of 1.25 (95% CI: 1.07, 1.44) compared with national rates, based on 

182 lung cancer deaths Potential effects of lead could not be adjusted for arsenic exposure or 

other exposures due to inadequate numbers. Cancer-specific standardized mortality ratios were 

calculated for production and maintenance workers from an Italian lead and zinc smelter 

followed from 1950 to 1992 by Cocco et al. (1997). Deaths from lung,, stomach, and all cancer 

were not elevated over regional rates. Cocco et al. (1996) followed 1,060 Sardinian lead and 

zinc smelter workers whose glucose-6-phosphate dehydrogenase (G6PD) phenotype had been 

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measured from 1973 through 1991. Despite the thought that G6PD-deficient workers might be 

more vulnerable to the depletion of red blood cell glutathione associated with lead toxicity, 

mortality from cancer and from all causes was slightly lower among G6PD-deficient workers 

than among G6PD-normal workers. Follow-up was subsequently extended through 2001 by 

Carta et al. (2003). 

Three European studies followed up cohorts of glass workers. Cordioli et al. (1987) 

studied 468 Italian glass workers. Workers producing low-quality glass containers were 

classified as being exposed to lead. A small elevation in mortality from all cancer (standardized 

mortality ratio of 1.3 [95% CI: 0.8, 1.8]) among glass workers was driven by significant 

excesses in lung cancer (2.1 [95% CI: 1.1, 3.6]) and laryngeal cancer (4.5 [95% CI: 1.2, 11.4]). 

The small number of deaths among exposed workers (28 total, 13 lung, and 4 laryngeal cancer) 

limited the study’s statistical power. Sankila et al. (1990) compared the incidence of cancer in 

1,803 male and 1,946 female Finnish glass workers with that of the national population. 

Glassblowers were considered to be a lead-exposed subgroup. Modest elevations in lung cancer 

risk were observed among glass workers for both men (standardized incidence ratio of 1.3 [95% 

CI: 1.0, 1.7]) and women (1.1 [95% CI: 0.5, 2.3]). However, the increased risk of lung cancer 

was not specific to glassblowers. In the final study, Wingren and Englander (1990) compared 

mortality in Swedish glass workers from work areas with airborne lead levels ranging from 

<0.001 up to 0.110 mg of lead/m3

, noting a significant elevation for pharyngeal cancer 

(standardized mortality ratio of 9.9 [95% CI: 1.2, 36.1]) and nonsignificant elevations for lung 

and colon cancer compared to national rates. 

Wingren and Axelson (1985, 1987, 1993) conducted a case-control analysis comparing 

stomach, colon, and lung cancer mortality among Swedish glass workers with that of the 

surrounding regional populations. A small early study of three parishes (Wingren and Axelson, 

1985) was expanded to include 11 parishes, thus encompassing most of the Swedish glass-work 

industry (Wingren and Axelson 1987). Mortality from cancer of the lung (odds ratio of 1.7 [90% 

CI: 1.1, 2.5]), stomach (1.5 [90% CI: 1.1, 2.0]), and colon (1.6 [90% CI: 1.0, 2.5]) all were 

elevated among glass workers as a whole (Wingren and Axelson, 1987). Among specific classes 

of glass workers, glassblowers had the highest odds ratios (2.3, 2.6, and 3.1 for lung, stomach, 

and colon cancer, respectively). When the data were analyzed according to level of estimated 

metal exposure, no consistent dose-response trend with lead was found for lung cancer, and the 

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association with stomach cancer was weaker for lead than for arsenic, copper, and other metals. 

In general in this study it was difficult to separate the independent cancer effects of different 

metals. 

Sardinian lead and zinc miners were studied in a set of three papers published in 1994. 

Carta et al. (1994) studied a small group of workers and Cocco et al. (1994a,b) expanded 

coverage to follow 1,741 male and 526 female workers from two mines. Number of cancer 

deaths were small. This study was limited because exposure characterization focused only on 

silica and radon daughters; no lead exposure specific analyses were performed. 

Davies (1984b) followed up 57 pigment factory workers who had been diagnosed with 

nonfatal lead poisoning, finding a small excess of lung cancer deaths (relative risk of 1.45), but 

with only 4 deaths in the lead-poisoned group this result did not reach statistical significance. 

Mallin et al. (1989) used death certificates for Illinois males to compare deaths from seven 

specific cancers with a control group of 3,198 randomly selected deaths from other causes. 

Based on occupations from death certificates, the odds ratio for cancer of the brain (3.0, 

p < 0.05) was significantly elevated in white male glass workers (as well as physicians and 

communications workers). No significant association was observed for other cancer sites, 

including lung and stomach. This isolated association is not consistent with the results for 

Swedish glass workers summarized above. The National Cancer Institute, NIOSH, and the 

National Center for Health Statistics have assembled a database that integrates industry, 

occupation, and cause of death information from death certificates in 24 states. This resource 

provides a very large sample size for case-control analyses of occupational exposures, but results 

are limited by a lack of detailed work history and no control over confounders. Cocco et al. 

(1998a) matched all 27,060 brain cancer deaths occurring among persons aged 35 or older during 

1984 to 1992 with four gender-, race-, age-, and region-matched deaths from nonmalignant 

causes. A job-exposure matrix was used to assign subjects to low, medium, or high probability 

and intensity of exposure. Risk of brain cancer mortality increased consistently with rising 

intensity of lead exposure among African American men but not among the other three racegender groups. Cooco et al. (1998b) broadened the study to CNS cancer deaths, and computed 

odds ratios for specific industries and occupations rather than particular substances. Statistically 

significant associations were found with some industries and some race/sex groups, but little 

inference can be made about lead carcinogenicity from these data. 

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In the third 24-state death-certificate study, 41,957 stomach cancer deaths were matched 

with 83,914 deaths due to nonmalignant causes (Cocco et al., 1999). A job-exposure matrix was 

used to assign subjects to low, medium, or high probability and intensity of exposure to lead and 

11 other chemicals. Elevated odds ratios occurred among white women (1.53 [95% CI: 1.10, 

2.12]), African-American men (1.15 [95% CI: 1.01, 1.32]), and African-American women 

(1.76 [95% CI: 0.74, 4.16]) with high probability of lead exposure. Odds ratio in the moderateprobability group were elevated only for African-American women (1.37 [95% CI: 0.58, 3.21]), 

and not elevated for any exposure group among white males. Risk showed no consistent 

increase with intensity of exposure in any group. The absence of any association with lead 

exposure among the largest race-gender group, white males, is notable, as is the general absence 

of association with intensity of exposure. More consistent elevations of odds ratios for stomachcancer mortality were observed for inorganic dust and nitrosamines than for lead. 

Anttila et al. (1996) presented a nested case-control analysis of 26 Finnish male workers 

with central nervous system (CNS) cancer and 200 controls, using the same Finnish occupational 

cohort as in Anttila et al. (1995). For CNS cancer incidence, odds ratios rose with increasing 

peak lifetime blood lead level; however, the trend was not statistically significant. Odds ratios 

for glioma mortality rose consistently and significantly with increasing peak and mean blood 

lead level, as well as duration of and estimated cumulative lead exposure. A strength of this 

study is the availability of blood lead measurements. Limitations include the small number of 

cases (10 gliomas among workers with complete exposure information), short follow-up time 

(maximum of 15 years), potential selection bias due to low response rates (60% for cases, 56% 

for controls), and possible coexposures such as solvents or other metals. 

Risch et al. (1988) compared 826 Canadian men with histologically confirmed bladder 

cancer with 792 Canadian population controls. Reported occupational exposure to lead yielded a 

significantly elevated smoking-adjusted odds ratio (2.0 [95% CI: 1.2, 3.5]) and a significant 

trend with duration of exposure. Of 17 other exposures examined, only one (tar and asphalt) was 

significantly associated with bladder cancer. These analyses relied on self-reported exposure, 

with the potential for inaccurate recall. Siemiatycki et al. (1991) conducted a case-control study 

in Canada using 3,730 cases of various histologically confirmed cancers. Occupational exposure 

to 293 substances, including lead, was estimated from interview data. Elevated odds ratios were 

noted for cancer of the lung (1.1 [90% CI: 0.9, 1.4]), stomach (1.2 [90% CI: 1.0, 1.6]), bladder 

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(1.3 [90% CI: 1.0, 1.6]), and kidney (1.2 [90% CI: 1.0, 1.6]). Strengths of this study are 

adjustment for smoking and other potential risk factors and reliance on interview-obtained 

exposure data, further evaluated by experts. Limitations include potential confounding by the 

other 292 occupational exposures and low quantitative detail regarding lead exposure. 

Kauppinen et al. (1992) conducted a nested case-control study in Finland, matching 344 

primary liver cancer deaths by age and gender to 476 stomach cancer deaths and 385 myocardial 

infarct deaths. No association was found between lead and liver cancer, which was not an a 

priori site of interest. Use of a control group with stomach cancer, which some other studies 

have linked to lead exposure, may have biased results toward a negative association. 

In a Chinese hospital-based case-control study, Hu et al. (1998) compared 218 patients 

with histologically confirmed primary gliomas with 436 patients with non-neurological, 

nonmalignant disease, matched by age, gender, and residence. An odds ratio could not be 

calculated for occupational exposure to lead because no glioma patients reported such exposure. 

In a parallel study, Hu et al. (1999) compared 183 patients with histologically confirmed 

primary meningiomas with patients with non-neurological, nonmalignant disease, matched by 

age, gender, and residence. Reported occupational exposure to lead was associated with risk of 

meningioma in both men (odds ratio of 7.20 [95% CI: 1.00, 51.72]) and women (5.69 [95% CI: 

1.39, 23.39]). Some elevation of odds ratios occurred in most of the 14 occupational exposures 

examined, including exposure to cadmium. Malczyk et al. (1999) measured urinary lead 

concentrations in 24 Polish bladder cancer cases. Ten out of the 24 cases had urinary lead levels 

above 90 μg/L, thus exceeding the upper limit of the range estimated as normal for a healthy 

person (10-90 μg/L). Results are limited by the lack of any measurements done on persons 

without bladder cancer from the same area. 

Pesch et al. (2000) compared occupational exposure to potential carcinogens among 

935 Germans newly diagnosed with renal-cell cancer and 4,298 controls selected from regional 

population registries and matched by age, gender, and area of residence. Lifetime job histories 

and information on smoking habits and other potential risk factors were collected by interview. 

Cumulative exposure to lead, as well as cadmium, solder fumes, welding fumes, and metals in 

general, was estimated based on previously published job exposure matrices and grouped into 

four ascending categories; separate estimates of lead exposure were calculated based on Britishand German-developed matrices. After adjustment for age and smoking, odds ratios for renal 

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cancer were elevated in men (1.5 [95% CI: 1.0, 2.3]) and women (2.6 [95% CI: 1.2, 5.5]) with 

the highest lead exposure, compared with the low-exposure groups based on the British matrix. 

When exposure was based on the German matrix, the odds ratio was less elevated among men 

(1.3 [95% CI: 0.9, 2.0]); no results for women were reported. Strengths of the study are its size 

and population base. The primary limitation is uncertainty regarding the specificity of the results 

for lead. Significant associations also were noted for exposure to cadmium, solder fumes, and 

organic solvents among men, for example, but no analyses attempting to account for other 

exposures were reported. It is thus unclear how much of the observed risk associated with lead 

exposure may be secondary to exposure to cadmium or other agents. 

Siddiqui et al. (2002) compared blood lead levels in Indian men with prostate cancer or 

benign prostatic hyperplasia to levels seen in normal controls of similar SES. Lead levels were 

significantly higher in both prostate cancer and benign prostatic hyperplasia cases than in 

controls, while zinc levels were lower. 

Kandiloris et al. (1997) found similar blood lead levels but lower aminolevulinic acid 

dehydratase (ALAD) activity in 26 laryngeal carcinoma cases compared to 53 controls from the 

same hospital. Shukla et al. (1998) found significantly higher mean bile lead in 38 newly 

diagnosed, histologically confirmed gall bladder cancer cases compared to 58 patients with 

gallstones diagnosed at the same Indian hospital surgical unit (58.38 ± 1.76 mg/L versus 

3.99 ± 0.43 mg/L). Cancer cases also showed elevated cadmium and chromium levels. 

6.7.6 Confounding of Occupational Lead Studies Due to Other Occupational 

Exposures: Arsenic, Cadmium 

A number of studies of lead workers come from smelters, where exposures to other metals 

are common. Of particular concern are other lung carcinogens, especially arsenic (workers 

exposed to high levels of arsenic historically have had a lung cancer relative risk of 3-4, see 

Steenland et al. 1996), but also cadmium. Glass workers are also of limited use for inference 

about lead effects, as they are also typically exposed to arsenic, cadmium, chromium, and nickel, 

all of which are lung carcinogens (e.g., see Wingren and Axelson, 1993). 

In some smelters, measurements have been taken which indicate clearly that exposures to 

these other carcinogens was minimal and the main suspect is lead (e.g., Steenland et al., 1992). 

In others, however, one is unable to disentangle the effects of arsenic and lead (Ades and 

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Kazantis, 1988, Lundstrom et al., 1997). As a result, these studies cannot yield strong evidence 

regarding the possible relation between lung cancer and lead specifically. The study by 

Lundstrom et al., 1997 is particularly important in this regard, because it had a high relative risk 

of 2.8 (95% CI: 2.0, 3.8), and had an important effect in raising the overall result when included 

in meta-analyses (e.g., Steenland and Boffetta [2000], where exclusion of the Lundstrom et al. 

study lowered the estimated combined lung cancer relative risk from 1.30 to 1.14). A subsequent 

publication by Englyst et al. (2001) indicated that the smelter workers studied by Lundstrom 

et al. (1997) were likely to have had significant exposure to arsenic, and the authors concluded 

that it was impossible to separate the effects of lead and arsenic. 

6.7.7 Confounding of Lead Studies: Smoking and Other Factors 

The most informative studies of lead carcinogenicity are those comparing highly exposed 

workers to general populations. In these comparisons one must consider typical differences 

between worker populations and the general populations, in particular differences due to 

smoking and diet. Smoking can be a major confounder for lung cancer, while diet or SES can 

be a confounder, albeit weaker, for stomach cancer. 

Regarding smoking, it has been shown both theoretically and empirically that 

confounding due to smoking differences between workers and the general population will 

typically account for an observed relative risk of approximately 1.1 to 1.2, with a possible 

maximum of about 1.4 (Axelson and Steenland, 1988; Siemiatycki et al., 1988). Furthermore, 

most occupational cohort studies are retrospective and have little information on smoking, 

making it impossible to control directly for potential confounding by this strong risk factor. 

As noted above, the lung cancer relative risk in the meta-analysis of Steenland and Boffetta 

(2000), after excluding the Lundstrom et al. study, was 1.14 (95% CI: 1.04, 1.73), based on 

seven occupational cohort studies, six of which used a non-worker external referent population, 

and none of which controlled for smoking as a confounder. This relatively small excess relative 

risk could plausibly be due to confounding by smoking. Unfortunately the occupational cohort 

studies were usually not followed by nested-case control studies of lung cancer which could have 

controlled for smoking, and furthermore they usually did not involve internal exposure-response 

analyses, wherein confounding by smoking is usually minimal. An exception was the lung 

cancer case-control study conducted by Anttila et al. (1995) within a large cohort of Finnish 

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workers with known blood lead levels. In this case-control study smoking-adjusted lung cancer 

odds ratios were increased among workers with higher estimated cumulative blood lead or higher 

peak blood lead exposure compared to workers with the lowest exposure, and the authors noted 

that smoking actually appeared to be a “weak negative confounder” for the high peak blood lead 

group. Also, in one large population-based case-control study with extensive information on 

other cancer risk factors, there remained an elevated odds ratio for lung cancer with substantial 

lead exposure after controlling for smoking (Siemiatycki et al., 1991). Hence there is some 

evidence that confounding by smoking does not explain the modest excess lung cancer risk seen 

in many studies. 

Diet high in salt or smoked meats, Helicobacter pylori infection, and SES are possible 

confounders for stomach cancer. Those of highest SES compared to those of lower SES have 

been shown to have a relative risk of about 3 (Tomatis, 1990). None of the occupational cohort 

studies, in which again stomach cancer in workers was compared to the general population, 

controlled for these potential confounders. However, these potential confounding factors are 

much less powerful risk factors in respect to stomach cancer than smoking is with respect to lung 

cancer, and hence are unlikely to account for relative risks higher than perhaps 1.1 or at most 1.2. 

Given that the occupational cohort studies had a combined relative risk of 1.34 (95% CI: 1.14, 

1.57) in the meta-analysis of Steenland et al. (2002) and 1.33 (95% CI: 1.18, 1.49) in that of Fu 

and Boffetta (1995), it seems unlikely that confounding by these factors can fully account for the 

excess stomach cancer risk observed in the occupational studies. 

6.7.8 Summary of Epidemiologic Evidence for the Genotoxic and 

Carcinogenic Effects of Lead 

The availability of studies of cancer in lead-exposed populations was relatively limited at 

the time of the 1986 Lead AQCD. The number and range of studies has notably expanded since 

that time, including extended follow-ups of major extant cohorts, new cohort and case-control 

studies, and analyses addressing not only cancer but genotoxicty. These new human data greatly 

expand our knowledge of possible lead carcinogenicity. Animals studies are primarily based on 

dermal exposure to lead acetate. While the animal studies clearly show a carcinogenic effect, 

they are of less relevance here because human exposures are usually to inhaled lead oxides. 

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Studies of genotoxicity consistently link lead exposed populations with DNA damage and 

micronuclei formation, although less consistently with the more established indicator of cancer 

risk, chromosomal aberrations. Epidemiologic studies, particularly those of the high exposed 

occupational cohorts, are the most informative for determining whether lead causes cancer, 

because in general we assume that any cancer effect will be strongest and most easily detected 

when exposure is highest. There are only two general population cohort studies at ambient 

levels, and these are of the same population (NHANES II in the late 1970s). These general 

population studies at lower exposure levels show internal dose-response trends but suffer at 

times from small numbers for site-specific analyses or lack of site-specific analyses altogether 

and, also, from possible residual confounding by SES and smoking. 

The strongest evidence in the key occupational studies linking lead exposure to actual 

human cancers is that for cancers of the lung and those of the stomach. Of seven large 

occupational cohort studies available (Ades and Kazantzis, 1988; Anttila et al., 1995; Carta et al., 

2005; Gerhardsson et al., 1995; Lundstrom et al., 1997; Steenland et al., 1992; Wong and Harris, 

2000), for example, all showed results consistent with an increase in lung cancer risk among 

lead-exposed workers, and in four of these studies the association was statistically significant. 

Further, where workers could be categorized as to their level of lead exposure, the greatest 

magnitude of association for lung cancer was usually seen for the highest exposure category. 

However, the modest elevation of lung cancer risk seen in most relevant studies is in the range of 

possible confounding due to smoking or other occupational exposures, particularly arsenic, 

which precludes the evidence from these studies being seen as conclusive. In particular, the one 

occupational study with the highest lung cancer risk (Lundstrom et al.) has been subsequently 

shown to be highly confounded by arsenic, and without this study, the combined evidence for a 

lung cancer elevation across studies is considerably reduced (e.g., the estimated relative risk falls 

from 1.30 to 1.14). A moderate elevation of stomach cancer is also found in most studies of 

occupationally exposed populations with applicable data on this outcome. As with lung cancer, 

it is possible that other risk factors such as intake of smoked meats or H. pylori infection could 

have contributed to the observed associations, but the observed elevation (meta-analysis of 1.33 

or 1.34) coupled with the known effect of diet makes it unlikely that the elevation in stomach 

cancer is entirely due to confounding by diet . Data for other sites such as kidney, brain, and 

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bladder show some indications of an excess, but the results across studies are not consistent and 

are based on small numbers. 

The epidemiologic data reviewed above from key high lead exposure occupational studies 

suggest a relationship between lead exposure and cancers of the lung and the stomach. These are 

supported by two meta-analyses. This is limited by potential confounders such as other 

occupational exposures (arsenic, cadmium), smoking, and dietary habits. General population 

cohort studies in which low lead exposure was assessed via blood levels and adjusted for 

confounders showed trends for a relationship, but were limited by relatively small numbers for 

site-specific analysis. A cancer assessment on lead has not been conducted using the U.S. EPA 

Guidelines for Cancinogen Risk Assessment (U.S. Environmental Protection Agency, 2005). 

However, the most recent IARC (2005) review concluded that inorganic lead compounds were 

probable human carcinogens (Group IIA), based on limited evidence in humans and sufficient 

evidence in animals. This classification is one step down from a classification as “definite” 

human carcinogen (Group I). 

6.8 EFFECTS OF LEAD ON THE IMMUNE SYSTEM 

6.8.1 Summary of Key Findings of the Effects of Lead on the Immune 

System from the 1986 Lead AQCD 

The 1986 Lead AQCD concluded that studies conducted in laboratory animal models 

provided evidence for immunosuppressive effects of lead; however, evidence for such effects in 

humans was lacking. Since then, the epidemiological study of immunological effects of lead has 

progressed considerably. The currently available epidemiologic and clinical observations are 

consistent with the greater body of evidence derived from studies in experimental animals 

indicating that lead can suppress cellular and humor immunity and decrease host resistance to 

infection agents and tumor cells (see Section 5.9). Findings from the epidemiologic studies 

suggest that lead exposure (as reflected in blood lead concentration) may be associated with 

effects on cellular and humoral immunity. These effects include changes in serum 

immunoglobulin levels (e.g., elevated serum IgE); perturbation of peripheral lymphocyte 

phenotype profiles, including decreases in peripheral blood T-cell abundance and changes in 

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T-cell:B-cell abundance ratios; suppression of lymphocyte activation; and suppression of 

neutrophil chemotaxis and phagocytosis. 

Available studies of associations between lead exposure and immunological outcomes are 

summarized in Annex Tables AX6-8.1 and AX6-8.2. In general, while the studies provide 

support for associations between lead exposure and immunological outcomes, the studies have 

numerous limitations that complicate the assessment of the strength of the associations and 

causation. Furthermore, the health consequences of outcomes that have been associated with 

lead exposure are uncertain. All studies have been cross-sectional in design and most included 

relatively small cohorts. The studies implemented varying degrees of quantitative analysis of 

potential covariables and confounders. In most studies, a detailed analysis of covariables and 

confounding was lacking, and many of the reports offered no analysis of covariables or 

confounding. Covariables that were considered (but not consistently) in multivariate analyses or 

controlled by stratification included age, sex, race, smoking habits, alcohol consumption, and 

illness and/or medications that might affect the immune system. Studies that offer the strongest 

designs are discussed in greater detail below. 

6.8.2 Host Resistance 

Associations between lead exposure and host resistance have not been rigorously 

examined in humans. Two analyses of illness surveys in children (Rabinowitz et al., 1990) and 

lead workers (Ewers et al., 1982) have been reported, which suggest a possible association 

between increasing blood lead concentrations (>10 μg/dL) and illness incidence or prevalence. 

Both studies relied on personal surveys for assessment of illness and neither study considered 

covariates or confounders in the analyses. 

6.8.3 Humoral Immunity 

Studies of biomarkers of humoral immunity in children have consistently found 

significant associations between increasing blood lead concentration and serum immunoglobulin 

levels, with increasing serum IgE in association with increasing blood lead concentration 

(Table 6-8.1; Karmaus et al., 2005; Lutz et al., 1999; Sun et al., 2003). These effects were 

evident at blood lead concentrations <10 μg/dL. Increasing serum IgE levels also have been 

observed with increasing blood lead concentration (blood lead $30 μg/dL) in association with 

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402(c) Economic Analysis Chapter 5 660
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and Serum Immunoglobulin Levels Blood Lead (μg/dL) Study Subjects 

na Mean (SD) Range IgA I

Children Annesi-Maesano et al. (2003) neonates 374 67 (48)b NR NR 

Karmaus et al. (2005) children, 7–10 yr 331 3 1–5e o 

Lutz et al. (1999) children, 9 mo–6 yr 270 NR 1–45 NR Sarasua et al. (2000) children, 6–35 mo 372 7 ~2–16d + N

Sun et al. (2003) children, 3–6 yr 73 NR ~3–40 NR Adults Heo et al. (2004) batter manufacture workers 606 ~22 (~10)e NR o 

Pinkerton et al. (1998) smelter workers 229 39f <2–55 o N

Sarasua et al. (2000) general population 433 4.3 ~1–10d o N

-, decrease; +, increase; o, no effect; NR, not reported, Ig, serum immunoglobulin level 

a total number of subjects (including reference group)b infants cord blood (maternal blood lead mean was 96 μg/dL (SD 58) c in association with increasing neonatal hair lead d 5–95th percentile range e mean of age-group means and SDs f median 

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occupational exposures to lead (Heo et al., 2004). Outcomes for other immunoglobulin indices 

in adults have been less consistent (Pinkerton et al., 1998; Sarasua et al., 2000). 

Possible associations between lead exposure and biomarkers of humoral immunity in 

children have been examined in several cross-sectional studies (Annesi-Maesano et al., 2003; 

Karmaus et al., 2005; Lutz et al., 1999; Reigart and Graher, 1976; Sarasua et al., 2000; Sun et al., 

2003; Wagnerova et al., 1986). Four studies warrant particular attention because they examined 

a relatively low range of blood lead concentrations and applied multivariate analyses to the data 

in attempts to control for possible covariables (Karmaus et al., 2005; Lutz et al., 1999; Sarasua 

et al., 2000; Sun et al., 2003). Three studies found significant associations between increasing 

blood lead concentration and serum IgE levels (Karmaus et al., 2005; Lutz et al., 1999; Sun 

et al., 2003). The reported percent increase in serum IgE levels measured in these studies ranged 

from approximately 50 to 400% The Lutz et al. (1999) study measured serum IgE and IgG 

(against Rubella) in 270 children (age range 9 months to 2 years; blood lead range 1-45 μg/dL). 

The observed blood lead-age-IgE relationship is shown in Figure 6-8.1. The highest IgE levels 

(mean 211 IU/mL, SD 441, n = 17) were observed in children who had blood lead concentrations 

in the range 15–19 μg/dL; by comparison, mean IgE levels were blood lead concentrations in the 

range of 15–19 μg/dL; by comparison, mean IgE levels were 52 IU/mL (SD 166) for subjects 

who had blood lead concentrations <10 μg/dL (n = 174). The Karmaus et al. (2005) study 

measured serum IgA, IgE, IgG, and IgM levels in 331 children (age range 7-10 years). Blood 

lead concentrations were lower in this study than in the Lutz et al. (1999) study (1–5 μg/dL). 

A multivariate linear regression analysis revealed a significant association between blood lead 

(p < 0.05) and serum IgE, however, the change in serum IgE level was not monotonic with 

increasing blood lead concentration (Figure 6-8.2). The highest IgE levels (adjusted mean 

59 IU/L) were observed in the children who had blood lead concentrations ranging from 2.8–3.4 

μg/dL (n = 86) and >3.4 μg/dL (n = 82). Sun et al. (2003) measured serum IgE, IgG, and IgM 

levels in children, ages 3–6 years (blood lead concentration range 2.6–44 μg/dL, n = 73). 

A nonparametric comparison of immunoglobulin levels between low (<10 μg/dL) and high 

($10 μg/dL) blood lead strata revealed significantly higher IgE levels (Figure 6-8.3) and 

significantly lower IgG and IgM levels in the high blood lead stratum. 

The study by Annesi-Maesano et al. (2003) provides further suggestive evidence for 

an association between lead exposure and increasing IgE levels. The study included 374 

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402(c) Economic Analysis Chapter 5 662
Figure 6-8.1. Relationship between blood lead concentration (PbB), age, and serum IgE 

level in children. Spearmen partial correlation between blood lead and 

serum IgE is 0.22 p = 0.0004, n = 221). 

Source: Lutz et al. (1999). 

1 mother-infant pairs who had relatively high mean blood lead levels (maternal mean 96 μg/dL, 

2 SD 58; infant cord 67 μg/dL, SD 48). Serum IgE level was significantly associated with 

3 increasing infant hair lead (p < 0.001), but not with cord blood lead or placental lead level. The 

4 association between IgE and hair lead levels was evident in a subset of mother-infant pairs, in 

5 which mothers were classified as nonallergenic, and was unrelated to maternal smoking (i.e., 

6 urinary cotinine). 

7 The ATSDR Multisite Lead and Cadmium Exposure Study (ATSDR, 1995) is one of the 

8 largest studies to assess humoral immune status in association with lead exposures; however, it 

9 did not include an assessment of IgE. The study included a cross-sectional analysis of serum 

10 IgA, IgG, and IgM levels in 1,561 subjects (age range 6 months to 75 years) who resided in areas 

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402(c) Economic Analysis Chapter 5 663
Figure 6-8.2. Relationship between blood lead concentration and serum IgE level in 

children. Mean serum IgE levels (standard deviations not reported) are 

adjusted for age, number of infections in the previous 12 months, exposure 

to passive smoke in the previous 12 months, and serum lipids (sum of 

cholesterol and triglycerides). Means of serum IgE levels in blood lead 

categories were significantly different (F-test p = 0.03). 

Source: Karmaus et al. (2005). 

1 impacted by lead mining and/or smelting operations and in 480 demographically-matched 

2 controls (Sarasua et al., 2000). A multivariate linear regression analysis of immunoglobulin 

3 levels and blood lead concentration (exposed and control groups combined) revealed 

4 associations between increasing blood lead and increasing serum IgA, IgG, and IgM levels 

5 in subjects 6–35 months of age (blood lead 5th–95th percentile range 1.7–16 μg/dL, 

6 Figure 6-8.4). 

7 Possible associations between lead exposure and biomarkers of humoral immunity also 

8 have been examined in several cross-sectional studies of lead workers (Alomran and Shleamoon, 

9 1988; Anetor and Adeniyi, 1998; Ayatollahi, 2002; Coscia et al., 1987; Ewers et al., 1982; Heo 

10 et al., 2004; Kimber et al., 1986; Pinkerton et al., 1998; Ündeger et al., 1996). Outcomes from 

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402(c) Economic Analysis Chapter 5 664
Figure 6-8.3. Relationship between blood lead concentration (lead) and serum IgE level in 

lead children. Mean serum IgE levels in female children whose blood lead 

concentrations were in the range 10–40 μg/dL (20.4 IU/L; n = 16) were 

significantly higher than for children whose blood lead concentrations 

<10 μg/dL (13.1 IU/L; n = 17). 

Source: Sun et al. (2003). 

1 these studies, with respect to humoral immune parameters, measured as serum and/or salivary 

2 immunoglobulin levels, are mixed. Some studies finding positive associations with blood lead 

3 (Heo et al., 2004), negative associations (Anetor and Adeniyi, 1998; Ewers et al., 1982; 

4 Pinkerton et al., 1998), or no (or mixed) effects (Alomran and Shleamoon, 1988; Kimber et al., 

5 1986; Queiroz et al., 1994b; Sarasua et al., 2000; Ündeger et al., 1996). 

6 Based on study design considerations (e.g., cohort criteria, size, treatments of covariates), 

7 three studies warrant particular attention (Heo et al., 2004; Pinkerton et al., 1998; Sarasua et al., 

8 2000). Of these, only Heo et al. (2004) assessed serum IgE levels consistent with outcomes 

9 reported in children, increasing blood lead concentration was significantly associated with 

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402(c) Economic Analysis Chapter 5 665
Figure 6-8.4. Relationship between blood lead concentration and serum immunoglobulin 

(Ig) levels in children. Shown are relative changes in serum Ig levels, 

adjusted for age, sex, and exposure location. P-values reflect comparison 

to <5 μg/dL blood lead category mean (<5 mg/dL, n = 165; 5-9.9 μg/dL, 

n = 136; 10–14.9 μg/dL, n = 47; $15 μg/dL, n = 24). 

Source: Sarasua et al. (2000). 

1 increasing serum IgE levels (Figure 6-8.5). The study measured serum IgE, IL-4 and IFN( in 

2 606 battery manufacture workers. Serum IgE levels were significantly higher in the blood lead 

3 stratum ($30 μg/dL) compared to lower strata (<10 or 10–29 μg/dL) for the age strata 30–39 

4 years, $40 years, and for all ages combined. 

5 Although the Pinkerton et al. (1998) study did not assess IgE outcomes, it offers the 

6 strongest study design of the three for assessment of other immunoglobulin classes. Although it 

7 is a relatively small cross-sectional study, it considered immune illnesses and immune 

8 suppressant drugs in the construction of the cohorts and examined a relatively large number of 

9 potential covariates in the data analysis. Serum immunoglobulin levels were measured in male 

10 smelter (n = 145) workers and hardware workers (n = 84). Excluded (by blind evaluation) from 

11 the study cohorts were individuals who had “serious” illnesses of the immune system, who were 

12 

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402(c) Economic Analysis Chapter 5 666
Figure 6-8.5. Relationship between blood lead concentration and serum IgE level in 

lead workers. Mean serum IgE levels in high blood lead category were 

significantly higher for all ages (shown), and within age categories 

$40 years and 30-39 years, but not within age category <30 years. 

Source: Heo et al. (2004). 

1 taking immune suppressant drugs, or who had chemical exposures (other than to lead) that might 

2 affect immune function. Median blood lead concentrations were 39 μg/dL (range 15–55) in the 

3 lead workers and <2 μg/dL (range <2–12) in the reference group. Covariate-adjusted (logistic 

4 regression) geometric mean serum IgA, IgG, and IgM, and salivary IgA levels in the lead 

5 workers were not significantly different from the reference group; however, the adjusted 

6 regression coefficient for serum IgG and time-integrated (but not current) blood lead 

7 concentration was negative and significant. 

8 The Sarasua et al. (2000) study, described above for its assessment of children, also 

9 included a cross-sectional analysis of serum IgA, IgG, and IgM levels in adults (age 16–75 years, 

10 n = 433; blood lead 5th–9th percentile range 1–10 μg/dL) and found no significant associations 

11 between blood lead and serum immunoglobulin levels (serum IgE outcomes were not assessed). 

12 Also germane to the evidence for effects of lead on humoral immunity in humans are the 

13 results of a clinical study in which serum immunoglobulin levels were repeatedly measured in a 

14 lead smelter worker who underwent CaEDTA therapy three times per week for a period of 

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10 weeks (Sata et al., 1998). Serum IgA, IgG, and IgM were significantly higher when assessed 

24 h after each CaEDTA treatment compared to assessments made prior to treatment. 

Furthermore, serum IgG levels were significantly negatively correlated with blood lead 

concentration during the treatment period. Before-treatment and after-treatment blood lead 

concentration means were 45.1 (SD 16.0) and 31.0 (SD 9.8), respectively. 

6.8.4 Cell-mediated Immunity 

Studies of biomarkers of cellular immunity in children have found significant associations 

between increasing blood lead concentration and decreases in T-cell abundance, with 

corresponding increases in B-cell abundance (Karmaus et al., 2005; Sarasua et al., 2000; Zhao 

et al., 2004). These effects have been observed in children whose blood lead concentrations 

were below 10 μg/dL (Karmaus et al., 2005; Sarasua et al., 2000), although not all studies (e.g., 

Lutz et al., 1999) have found such associations at higher blood lead concentrations (e.g., 10–45 

μg/dL). Studies of occupational lead exposures have also found associations between increasing 

blood lead concentration and changes in T-cell abundance (Fischbein et al., 1993; Pinkerton 

et al., 1998; Sata et al., 1997). Effects were observed in association with blood lead 

concentrations below 25 μg/dL (Fischbein et al., 1993) and in populations whose blood lead 

concentrations ranged from approximately 7 to 55 μg/dL (Pinkerton et al., 1998; Sata et al., 

1997). Outcomes from these studies are qualitatively summarized in Table 6-8.2 and are 

discussed in greater detail below. 

Several cross-sectional studies have examined possible associations between lead 

exposure and biomarkers of cellular immunity in children (Karmaus et al., 2005; Lutz et al., 

1999; Sarasua et al., 2000; Zhao et al., 2004). Three studies (Karmaus et al., 2005; Sarasua 

et al., 2000; Zhao et al., 2004) found significant associations between increasing lead exposure 

and decreases in T-cell abundance (Table 6-8.2). The largest study (Sarasua et al., 2000) 

examined abundance of total lymphocytes, T-cells (CD3+

), B-cells (CD20+), NK cells, and CD4+ 

and CD8+

 T-cell phenotypes in infants, children, and adolescents. Associations between 

increasing blood lead concentration and increasing B-cell abundance (% and number), and 

decreasing T-cell abundance (%) were found for children 6–35 months of age (n = 312), after 

adjustment for age, sex, and study site (of four mining/smelting sites). Comparison of adjusted 

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402(c) Economic Analysis Chapter 5 668
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and Serum Lymphocyte Abundances Blood Lead (μg/dL) Study Subjects 

na Mean (SD) Range 

Tb TH 

c TC 

d THC e 

Children Karmaus et al. (2005) children, 7–10 yr 331 3 1–5i ! o ! NR 

Lutz et al. (1999) children, 9 mo–6 yr 270 NR 1–45 o NR NR NR 

Sarasua et al. (2000) children, 6–35 mo 372 7 ~2–16i ! o o NR 

Zhao et al. (2004) children, 3–6 yr 73 NR ~3–40 o ! + ! Adults 

Fischbein et al. 1993) firearms instructors 87 31 (4)j NR ! ! o NR 

Pinkerton et al. (1998) smelter workers 229 39k <2–55 o o o o 

Sarasua et al. (2000) general population 433 4.3 ~1–10i o o o o 

Sata et al. (1997) lead stearate workers 99 19 7–50 o o + NR 

!, decrease; +, increase; o, no effect; NR, not reported; SD, standard deviation. 

a total number of subjects (including reference group)b T-cells (CD3+) c T-helper cells (CD4+

)

d Cytotoxic T-cells (CD8+) e CD4+CD8+ 

f T-memory cells (CD45RO+, CD45RA+) 

g Natural killer cells (e.g., CD16+, CD56+

)

h B-cells (e.g., CD19+, CD20+

)

i 5–95th percentile range j high exposure group k median 

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means for outcomes across blood lead strata revealed that the differences were significant for the 

$15 μg/dL stratum only, compared to the <5 μg/dL stratum. The Karmaus et al. (2005) study 

examined children in the age range 7–10 years (n = 331) who had blood lead concentrations 

<5 μg/dL. In addition to age and sex, regression models relating outcomes to blood lead 

concentration included exposure to environmental tobacco smoke and infections in the previous 

year as covariates. Similar to the Sarasua et al. (2000) study, Karmaus et al. (2005) found 

significant associations between blood lead concentration and decreased T-cell abundance 

(CD3+

, CD3+CD8+) and increased B-cell (CD19+) abundance (for the blood lead quartile 

2.2-2.8 μg/dL; Figure 6-8.6). Zhao et al. (2004) examined lymphocyte phenotype abundance in 

children in the age range 3–6 years (n = 73) and found significantly lower % abundance of T-cell 

phenotypes CD3+

CD4+, CD4+CD8+ and significantly higher abundance of D3+CD8+ cells in 

children whose blood lead concentrations were $10 μg/dL compared to <10 μg/dL. Lutz et al. 

(1999) found no significant associations between blood lead concentration and age-adjusted 

T-cell (CD3+

) or B-cell (CD19+) abundance or abundance of various other lymphocyte 

phenotypes (i.e., CD2+

, CD25+, CD28+, CD71+) in children whose blood lead concentrations 

were 10–14, 15–19, or 20–45 μg/dL compared to <10 μg/dL. 

A larger set of studies have evaluated potential associations between lead exposure and 

biomarkers of cellular immunity in adults (Basaran and Ündeger, 2000; Cohen et al., 1989; 

Coscia et al., 1987; Fischbein et al., 1993; Kuo et al., 2001; Mishra et al., 2003; Pinkerton et al., 

1998; Sarasua et al., 2000; Sata et al., 1998, 1997; Yücesoy et al., 1997b; Ündeger et al., 1996). 

Four studies warrant particular attention because they implemented relatively stronger study 

designs (i.e., cohort criteria, size, treatment of covariates): Fischbein et al., 1993; Pinkerton 

et al., 1998; Sarasua et al., 2000; and Sata et al., 1998). With one exception (Sarasua et al., 

2000), all were studies of relatively small occupational cohorts. The Sarasua et al. (2000) study 

included a cross-sectional analysis of abundance of total lymphocytes, B-cells, NK cells, and 

CD4+

 and CD8+ T-cell phenotypes in individuals (n = 433), age 16–75 years. Associations were 

not found between blood lead concentration and either B-cell or T-cell abundance, after 

adjustment for age, sex, and study site (of four mining/smelting sites). The study did detect 

significant associations among these variables in infants and children (see above discussion of 

cellular immunity outcomes in children). However, all three occupational studies found 

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402(c) Economic Analysis Chapter 5 670
Figure 6-8.6. Relationship between blood lead concentration and T- and B-cell 

abundances in children. Shown are relative changes in covariate-adjusted 

absolute cell numbers (cells/μL) compared to the lowest blood lead group; 

adjusted for age, number of infections in the previous 12 months, exposure 

to passive smoke in the previous 12 months, and serum lipids (sum of 

cholesterol and triglycerides). Abundances for T-cells, cytotoxic T-cells, 

and B-cells in the 2.2-2.8 μg/dL group were significantly different (p # 0.05) 

from the <2.2 μg/dL group. Receptor phenotypes assayed were: T-cells, 

CD3+; T-helper cells, CD3+CD4+; cytotoxic T-cells, CD3+CD8+; memory 

T-helper cells, CD4+CD45RO+; natural killer cells, CD16+CD56+; B-cells, 

CD3+CD5+CD19+. 

Source: Karmaus et al. (2005). 

1 significant associations between increasing blood lead concentration and changes in abundanceof 

2 circulating T-cells with either no effect or an increasing B-cell abundance (Fischbein et al., 1993; 

3 Pinkerton et al., 1998; Sata et al., 1997). The strengths of the Pinkerton et al. (1998) study have 

4 been described previously with respect to outcome measures for humoral immunity. The study 

5 included male smelter workers (n = 145, mean blood lead 39 μg/dL; range 15–55) and hardware 

6 workers (n = 84, mean <2 μg/dL, range <2–12). Covariate-adjusted significant outcomes were 

7 an increase in B-cell (CD19+) abundance (% and number) and increases in CD4+CD45RA+ cell 

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abundance (%, number) in association with increasing blood lead concentration. Covariateadjusted mean levels of monocytes (%), and T-cells (% D4+

CD8+, CD8+CD56+) were lower in 

lead workers compared to the reference group. 

The Fischbein et al. (1993) study examined a small group of firearms instructors (n = 51) 

and age-matched reference subjects (n = 36). Fifteen of the instructors had blood lead 

concentration $25 μg/dL (mean 31.4, SD 4.3), the mean of the remaining 21 subjects was 

4.6 μg/dL (SD 4.6). Mean blood lead concentration of the reference group was reported as 

<10 μg/dL. Increasing blood lead concentration was significantly associated with decreasing 

covariate-adjusted T-cell (CD4+

) abundance (Figure 6-8.7). Covariate-adjusted T-cell (CD3+ % 

and number, CD4+

 % and number, CD4+CD8+ number) abundance was significantly lower 

and B-cell (CD20+ cells % and number) abundance was higher in the instructors than in the 

reference group. 

The Sata et al. (1998) study included male lead stearate manufacture workers (n = 71) 

and a nonexposed reference group (n = 28). Mean blood lead concentration was 19 μg/dL (range 

7-50) in the lead workers (blood lead concentration for the reference group was not reported). 

Categorical covariate-adjusted lead exposure classification (exposed, not exposed) was 

significantly associated with lower T-cell (CD3+

CD45RO+) number. Lead workers, relative to 

the reference group, had significantly lower covariate-adjusted mean CD3+

CD45RO+ number 

and higher CD8+

 cells (%). 

The above observations of decreasing T-cell abundance in association with lead exposure, 

as assessed from blood lead concentrations, is supported by results of several smaller crosssectional studies, including Basaran and Ündeger (2000), Coscia et al. (1987), and Ündeger et al. 

(1996), as well as a clinical study in which T-cell and NK cell abundance was found to increase 

after CaEDTA chelation therapy of a lead smelter worker (Sata et al., 1997). Lower serum levels 

of the cytokines that function in the regulation of cellular immune responses, including IL-1$

and IFN-γ, in lead workers compared to nonexposed subjects have also been observed (Yücesoy 

et al., 1997a). 

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402(c) Economic Analysis Chapter 5 672
Figure 6-8.7. Relationship between lead exposure and T- and B-cell abundances in 

firearms instructors. Shown are relative changes in absolute cell numbers 

compared to the reference group. Comparisons of exposed relative to the 

reference group are shown as: * for p < 0.05; ** for p < 0.01; and *** for 

p < 0.002. Receptor phenotypes assayed were: T-cells, CD3+; T-helper cells, 

CD4+; cytotoxic T-cells, CD8+; natural killer cells, CD16+; B-cells, CD20+. 

The CD4+/CD8+ ratio (not shown) was significantly lower in both the low 

exposure (1.38 [SD 0.5], p < 0.002) and higher exposure group (0.95 

[SD 0.5], p < 0.002), compared to the reference group (1.95 [SD 0.66]). 

Source: Fischbein et al. (1993). 

1 6.8.5 Lymphocyte Function 

2 Limited evidence from occupational studies suggests that lead may suppress lymphocyte 

3 activation in humans. All available studies are of adults. Several studies have examined 

4 associations between lead exposure in adults and lymphocyte activation, assessed as a 

5 proliferative response to mitogens and/or antigens (Alomran and Shleamoon, 1988; Cohen et al., 

6 1989; Fischbein et al., 1993; Kimber et al., 1986; Mishra et al., 2003; Pinkerton et al., 1998; 

7 Queiroz et al., 1994b). Results of these have been mixed. Three studies found no significant 

8 associations between blood lead concentrations in lead workers and lymphocyte proliferative 

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response to activating agents (; Kimber et al., 1986; Pinkerton et al., 1998; Queiroz et al., 

1994b). Four studies found decreasing proliferative response with increasing blood lead 

concentration (Alomran and Shleamoon, 1988; Cohen et al., 1989; Fischbein et al., 1993; Mishra 

et al., 2003). The Alomran and Shleamoon (1988), Cohen et al. (1989), Mishra et al. (2003), and 

Queiroz et al. (1994b) studies, which found significant lead associations, included subjects who 

had relatively high blood lead levels (>60 μg/dL) compared to the Kimber et al. (1986) and 

Pinkerton et al. (1998) studies. The inclusion of subjects with higher lead concentrations may 

have contributed to the differences in outcomes. 

As noted in the previous section, the Fischbein et al. (1993) and Pinkerton et al. (1998) 

studies are particularly noteworthy because of the strengths of the cohort selection and the data 

analyses which attempted to account for potential confounders. Also, these are the only reported 

studies that examined antigen-specific lymphocyte activation in humans. Mean blood lead 

concentrations in the two studies were similar 31 μg/dL (SD 4) in the Fischbein et al. (1993) 

study and 39 μg/dL (range 15–55) in the Pinkerton et al. (1998) study. Both studies found no 

significant associations between lead exposures (i.e., blood lead concentration) and antigenspecific lymphocyte proliferation, assessed in the Pinkerton et al. (1998) study with tetanus 

toxoid as the antigen and in the Fischbein et al. (1993) study with staphylococcus aureus as the 

antigen. However, the Fischbein et al. (1993) study also measured mitogen-induced lymphocyte 

proliferation (induced with PHA or PWM) and found a significantly lower proliferative response 

to the mitogens in association with lead exposure. This study also found a significant association 

between increasing blood lead concentration and decreasing proliferative response in mixed 

lymphocyte cultures (i.e., proliferative response of lymphocytes from exposed subjects when 

incubated with inactivated lymphocytes from a reference subject). 

Inorganic lead has been shown by in vitro studies to perturb several aspects of lymphocyte 

function when introduced into primary isolates of human blood monocytes. Activated 

lymphocytes show altered lysosomal enzyme secretion and altered expression and secretion of 

cytokines (Bairati et al., 1997; Guo et al., 1996a; Hemdan et al., 2005). Lymphocytes activated 

with Salmonella enteritidis or to monoclonal antibodies of CD3, CD28 and CD40, and exposed 

to inorganic lead had suppressed expression of T-helper cell type TH-1 cytokines, interferon 

(IFN-(), interleukin (IL-1$), and tumor necrosis factor (TNF-"), whereas activation by CD 

antibodies increased secretion of TH-2 cytokines, IL-5, IL-6, and IL-10 (Hemdan et al. 2005). 

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Inorganic lead also activates transcription factor NK-6$ in CD4+

 cells (Pyatt et al., 1996), an 

important regulator of T-cell activation, and increases expression of MHC class II surface 

antigens (HLA-DR), an important surface antigen in the CD4+

 response to exogenous antigens 

(Guo et al., 1996b). Lead increases antibody production in cultured human B-cells (McCabe and 

Lawrence, 1991). These observations suggest that they may perturb cellular immune function 

through a variety of mechanisms. 

6.8.6 Phagocyte (Macrophage and Neutrophil) Function 

Studies of lymphocyte and phagocyte (i.e., macrophage, neutrophil) function have found 

associations between blood lead concentrations and suppressed activation of macrophages in 

children whose blood lead concentrations ranged from 4 to 50 μg/dL (Pineda-Zavaleta et al., 

2004). In addition, studies have observed suppressed PMNL chemotaxis in association with 

occupational exposures that resulted in blood lead concentrations of 12–90 μg/dL (Bergeret 

et al., 1990; Queiroz et al., 1994a, 1993). 

Pineda-Zavaleta et al. (2004) examined mitogen (PHA)- and cytokine (INF()-induced 

activation of blood monocytes collected from 65 children (age range 6–11 years) who resided 

near an active lead smelter. Mean blood lead concentrations of subjects at three schools were: 

7.0 μg/dL (range 3–25 μg/dL; 8,100 meters from smelter complex), 21 μg/dL (range 

11-49 μg/dL; 1,750 meters from smelter), and 30 (range 10–48 μg/dL; 650 meters from smelter). 

Endpoints measured were nitric oxide and superoxide anion production, a response generally 

attributed to activated macrophages. Increasing blood lead concentration was significantly 

associated with decreasing PHA-induced nitric oxide production and increasing INF(-induced 

superoxide anion production. The mitogen, PHA, activates macrophages indirectly through 

activation of lymphocytes, whereas INF(, a cytokine released from CD44 (TH1) cells, directly 

activates macrophages. Thus, one interpretation of this outcome is that lead suppressed T-cell 

mediated macrophage activation and stimulated cytokine-induced macrophage activation. 

Possible associations between occupational lead exposure and PMNL chemotaxis and 

phagocytic activity have been explored in several small cross-sectional studies. Consistent 

findings are significantly reduced chemotactic response and phagocytic activity (i.e., respiratory 

burst, luminal uptake) in lead workers compared to reference groups. The largest study is that of 

Queiroz et al. (1994a, 1993) which evaluated PMNL function in several (possibly overlapping) 

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cohorts of lead battery manufacture workers (n = 60). Blood lead concentrations in the study 

groups ranged from 12 to 90 μg/dL. PMNL chemotaxis and lytic activity were significantly 

lower in the lead workers compared to the reference group. Bergeret et al. (1990) assessed 

PMNL chemotaxis and phagocytosis in a group of battery smelting workers (n = 34) and in a 

group of reference subjects (n = 34) matched to the lead worker group by age, sex, ethnic origin, 

smoking and alcohol consumption habits, and intake of antibiotics and NSAIDs. Mean blood 

lead concentrations were 71 μg/dL (SD 18) in the lead workers and 9 μg/dL (SD 4) in the 

reference group. Significantly lower PMNL chemotactic response to FMLP and phagocytic 

response in opsonized zymosan were significantly lower in the lead workers than in the reference 

group. Lead introduced into primary cultures of human PMNLs suppressed chemotaxis and 

phagocytosis (Governa et al., 1987). 

6.8.7 Summary of the Epidemiologic Evidence for the Effects of Lead 

on the Immune System 

Several studies have examined possible associations between lead exposures and 

biomarkers of immune function. Findings from the epidemiologic studies suggest that lead 

exposure (as reflected in blood lead concentration) may be associated with effects on cellular and 

humoral immunity. These effects include changes in serum immunoglobulin levels; perturbation 

of peripheral lymphocyte phenotype profiles, including decreases in peripheral blood T-cell 

abundance and changes in T-cell:B-cell abundance ratios; suppression of lymphocyte activation; 

and suppression of neutrophil chemotaxis and phagocytosis. 

Studies of biomarkers of humoral immunity in children have consistently found 

significant associations between increasing blood lead concentration and serum Ig levels with 

increasing serum IgE in association with increasing blood lead concentration (Karmaus et al., 

2005; Lutz et al., 1999; Sun et al., 2003). These effects were evident at blood lead 

concentrations below 10 μg/dL. Findings of studies of adults have been mixed with significant 

associations between blood lead (>30 μg/dL) and serum immunoglobulin levels (Heo et al., 

2004; Pinkerton et al., 1998) and no association in a study group in which blood lead 

concentrations were <10 μg/dL (Sarasua et al., 2000). 

Studies of biomarkers of cellular immunity in children have found significant associations 

between increasing blood lead concentration and decreases in T-cell abundance, with 

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corresponding increases in B-cell abundance (Karmaus et al., 2005; Sarasua et al., 2000; Zhao 

et al., 2004). These effects have been observed in children whose blood lead concentrations 

were below 10 μg/dL (Karmaus et al., 2005; Sarasua et al., 2000), although not all studies have 

found such associations at higher blood lead concentrations (e.g., 10–45 μg/dL; Lutz et al., 

1999). Studies of occupational lead exposures have also found associations between increasing 

blood lead concentration and decreasing T-cell abundance (Pinkerton et al., 1998; Sata et al., 

1997; Fischbein et al., 1993). Effects were observed in association with blood lead 

concentrations below 25 μg/dL (Fischbein et al., 1993) and in populations whose blood lead 

concentrations ranged from approximately 7 to 55 μg/dL (Pinkerton et al., 1998; Sata et al., 

1997). 

Studies of lymphocyte and phagocyte (i.e., macrophage, neutrophil) function have found 

associations between blood lead concentrations and suppressed activation of macrophages in 

children whose blood lead concentrations ranged from 4 to 50 μg/dL (Pineda-Zavaleta et al., 

2004); suppressed PMNL chemotaxis in association with occupational exposures that resulted in 

blood lead concentrations of 12 to 90 μg/dL (Bergeret et al., 1990; Queiroz et al., 1994a, 1993), 

and suppressed mitogen-induced activation of peripheral lymphocytes in adults in association 

with occupational exposures that resulted in blood lead concentrations that ranged from 15 to 

55 μg/dL (Fischbein et al., 1993). 

6.9 EFFECTS OF LEAD ON OTHER ORGAN SYSTEMS 

6.9.1 Biochemical Effects of Lead 

6.9.1.1 Summary of Key Findings of the Biochemical Effects of Lead from the 

1986 Lead AQCD 

The 1986 Lead AQCD provided an extensive discussion of the effects of lead on heme 

biosynthesis and on quantitative relationships between exposure and effects in humans. Lead 

interferes with heme synthesis by inhibiting the enzymes δ-aminolevulinic acid dehydratase 

(ALAD) and ferrochelatase. As a consequence, heme biosynthesis decreases, relieving the ratelimiting enzyme of the heme synthesis pathway, δ-aminolevulinic synthetase (ALAS), from 

negative feedback inhibition by heme (Figure 6-9.1). The outcomes of decreased activity of 

ALAD and ferrochelatase, and increased activity of ALAS are increased urinary excretion of 

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402(c) Economic Analysis Chapter 5 677
Figure 6-9.1. Effects of lead on heme biosynthesis. 

Source: Derived from EPA (1986). 

1 coproporphyrin (CP) and δ-aminolevulinic acid (ALA), increased level of ALA in blood plasma, 

2 and increased erythrocyte protoporphyrin (EP) levels. 

3 Associations between lead exposure and blood ALAD activity and EP levels, and urinary 

4 ALA and CP excretion have been studied extensively in adults and children, and quantitative 

5 relationships between exposure and effect are well understood. Much of this information was 

6 available prior to completion of the 1986 Lead AQCD and is summarized in that criteria 

7 document (e.g., Alessio et al., 1976; Hernberg et al., 1970; Lilis et al., 1978; Piomelli et al., 

8 1982; Roels et al., 1979; Selander and Cramer, 1970; Valentine et al., 1982). Numerous studies 

9 published since the 1986 AQCD provide additional support for the lead concentration-response 

10 relationships in humans described in the 1986 AQCD. The most pertinent studies are 

11 summarized in Annex Tables AX6-9.1 and AX6-9.2. The studies that provide the strongest basis 

12 for empirically-derived expressions relating blood lead concentration, blood ALAD activity, 

13 urinary ALA, and EP are listed in Table 6-9.1 and are discussed below. 

14 

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402(c) Economic Analysis Chapter 5 678
December 2005 6-278 DRAFT-DO NOT QUOTE OR CITE Table 6-9.1. Blood Lead–Response Relationships for Heme Synthesis Biomarkers in Adults and 

Blood Lead P

Study n Age (μg/dL) Regression Equation (r) DoALAD Activity Decrease Roels and Lauwerys (1987) 143 10–13 yr 5–41 log[ALAD]= 1.864–0.015[blood lead] (r = 0.87) Alessio et al. (1976, 1977) 169 Adult (m) 15–150 log[ALAD]=3.73–0.031[blood lead] (r = 0.87) Hernberg et al. (1970) 158 Adult (m, f) 5–95 log[ALAD]=2.274–0.018[blood lead] (r = 0.90) Morita et al. (1997) 58 Adult (m) 2–82 log[ALAD]=1.8535–0.00971[blood lead] (r = 0.76) Urinary ALA Increase Roels and Lauwerys (1987) 37 10–13 yr 20–41 log[ALAU]=0.94+0.11[blood lead] (r = 0.54) Alessio et al. (1976, 1977) 316 Adult (m) 10–150 log[ALAU]=1.25+0.014[blood lead] (r = 0.62) Gennart et al. (1992) 183 Adult (m, f) 4–75 log[ALAU]=0.37+0.008[blood lead] (r = 0.64) Oishi et al. (1996) 418 Adult (m, f) 10–99 log[ALAU]= -0.387+0.022[blood lead] (r = 0.71) Selander and Cramer (1970) 150 Adult (m, f) 6–90 log[ALAU]= -1.0985+0.157[blood lead] (r = 0.74) Roels and Lauwerys (1987) 39 Adult (m) 10–60 log[ALAU]=0.37+0.006[blood lead] (r = 0.41) Roels and Lauwerys (1987) 36 Adult (f) 7–53 log[ALAU]=0.15+0.015[blood lead] (r = 0.72) 

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Blood Lead P

Study n Age (μg/dL) Regression Equation (r) DoEP Increase Piomelli et al. (1982) 2,002 2–12 2–98 log[EP]=1.099+0.016[blood lead] (r = 0.509) Roels and Lauwerys (1987) 51 10–13 15–41 log[EP]=1.321+0.025[blood lead] (r = 0.73) Soldin et al. (2003) 4,908 0–17 <1–103 EP = -0.0015[PbB]3+0.1854[blood lead]2– 

2.7554[PbB]+30.911 (r = 0.999) Alessio et al. (1976, 1977) 95 Adult (m) 10–90 log[EP]=0.94+0.0117[blood lead] 

Alessio et al. (1976, 1977) 93 Adult (f) 10–70 log[EP]=1.60+0.0143[blood lead] Gennart et al. (1992) 183 Adult (m) 4–75 log[EP]=0.06+0.019[blood lead] (r = 0.87) Roels and Lauwerys (1987) 39 Adult (m) 10–60 log[EP]=1.41+0.014[blood lead] (r = 0.74) Roels and Lauwerys (1987) 36 Adult (f) 7–53 log[EP]=1.23+0.027[blood lead] (r = 0.81) Wildt et al. (1987) 851 Adult (m) 10–80 log[EP]=1.21+0.0148[blood lead] (r = 0.72) Wildt et al. (1987) 139 Adult (f) 10–80 log[EP]=1.48+0.0113[blood lead] (r = 0.56) ALA, *-aminolevulinic acid; ALAD, *-aminolevulinic acid dehydratase; ALAU, urinary δ-aminolevulinic acid; EP, erythrocyte proto

PbB, blood lead concentration 

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Since completion of the 1986 Lead AQCD, a literature has developed on the effects of 

lead on serum and blood lipids, including cholesterol levels and indications of oxidative stress, in 

the form of lipid peroxides, depletion of erythrocyte reduced glutathione (GSH), and production 

of reactive oxygen species (ROS). These studies also are summarized in Annex Tables AX6-9.1 

and AX6-9.2, and key findings are discussed below. 

6.9.1.2 Heme Biosynthesis 

6.9.1.2.1 ALAD Inhibition 

Numerous studies published since completion of the 1986 AQCD have explored 

associations between lead exposure and inhibition of ALAD activity, as assessed from 

measurements of blood ALAD activity (Gurer-Orhan et al., 2004; Kim et al., 2002; Lee et al., 

2000; Makino et al., 1997; Roels and Lauwerys, 1987; Schuhmacher et al., 1997), or urinary 

ALA excretion (Gennart et al., 1992; Oishi et al., 1996; Schuhmacher et al., 1997; Wildt et al., 

1987; Soldin et al., 2003). Quantitative estimates derived from the larger, more recent studies 

are presented in Table 6-9.1. Blood lead concentration is inversely correlated with the log of 

blood ALAD activity and log of urinary ALA and quantitative estimates of the change in blood 

ALAD activity per unit change in blood lead concentration are consistent across studies. 

Halving of blood ALAD activity occurs with an increase in blood lead concentration of 

approximately 20 μg/dL in both children (Roels and Lauwerys, 1987) and adults (Morita et al., 

1997). These estimates are consistent with earlier studies of adults (e.g., Hernberg et al., 1970) 

and children (e.g., Alessio et al., 1976, 1977), discussed in the 1986 AQCD. Greater variability 

is apparent in estimates of the change in urinary ALA per unit change in blood lead 

concentration (Table 6-9.1). This may be related, in part, to gender-heterogeneity in the 

relationship. Roels and Lauwerys (1987) estimated that urinary ALA doubles in association with 

a 20 μg/dL increase in blood lead concentration in females and 50 μg/dL in males. In a much 

larger study (Oishi et al., 1996), an analysis that combined data from males (n = 253) and 

females (n = 165) found that a doubling of urinary ALA occurred in association with a 14 μg/dL 

increase blood lead concentration. Urinary ALA excretion increases as a linear function of 

plasma ALA concentration (Oishi et al., 1996); thus, the gender heterogeneity for the blood leadurinary ALA relationship may derive from a gender difference in the effect of lead on plasma 

ALA concentration or from differences in renal plasma clearance of ALA. 

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6.9.1.2.2 ALAD Polymorphism 

ALAD is a polymorphic enzyme with two alleles (ALAD1 and ALAD2) and three 

genotypes: ALAD1,1, ALAD1,2, and ALAD2,2 (Battistuzzi et al., 1981). The corresponding 

phenotypes appear to have nearly identical catalytic properties (Battistuzzi et al., 1981). The 

predominant genotype is ALAD1,1 which has a prevalence of approximately 90% (Astrin et al., 

1987; Battistuzzi et al., 1981; Hsieh et al., 2000; Shen et al., 2001). A higher percentage of 

erythrocyte lead was bound to ALAD in carriers of the ALAD2 allele (84%) compared to 

carriers of the ALAD1 allele (81%); however, no differences were evident in the distribution of 

lead between erythrocytes and plasma (Bergdahl et al., 1997), and there is no evidence that the 

ALAD genotype confers different sensitivity to inhibition of heme biosynthesis (Hsieh et al., 

2000; Perez-Brava et al., 2004; Schwartz et al., 1997; Suzen et al., 2003). 

6.9.1.2.3 Ferrochelatase Inhibition 

Lead inhibition of ferrochelatase results in an accumulation of protoporphyrin IX in 

erythrocytes (EP, also referred to as zinc protoporphyrin, or ZPP, or iron protoporphyrin, FEP, 

depending on the method used to make the measurement). Numerous studies have examined 

relationships between blood lead concentration and EP levels in adults and children. 

Quantitative estimates based on the most pertinent studies are presented in Table 6-9.1. Results 

across these studies are similar. In both children and adults (males and females), a doubling of 

EP levels occurs in association with an increase in blood lead concentration of approximately 

20 μg/dL (Piomelli et al., 1982; Soldin et al., 2003; Wildt et al., 1987). A pronounced gender 

difference in the relationship between EP and blood lead concentration was observed by Roels 

and Lauwerys (1987) which was not observed in the much larger study of Wildt et al. (1987). 

Inhibition of ferrochelatase also gives rise to an increase in urinary coproporphyrin, with a 

similar relationship to blood lead concentration; a doubling of urinary EP occurs in association 

with an increase in urinary coproporphyrin of approximately 20 μg/dL (Alessio et al., 1976). 

6.9.1.3 Effects on Blood Lipids 

Associations between occupational exposure to lead and changes in blood lipid 

composition have been observed. These include increased levels of lipid peroxides in blood 

and/or serum (Ito et al., 1985; Jiun and Hsien, 1994; Sugawara et al., 1991) and increased serum 

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levels of total and HDL cholesterol (Kristal-Boneh et al., 1999). Increased levels of glucose-6-

phosphate dehydrogenase (G6PD) in erythrocytes have also been observed in lead workers 

(Cocco et al., 1995; Gurer-Orhan et al., 2004). 

Kristal-Boneh et al. (1999) measured serum total, HDL, and LDL cholesterol, and 

triglycerides in a group of male battery manufacture workers. Covariate-adjusted serum totalcholesterol and HDL cholesterol levels were 6% and 12% higher, respectively, in lead workers 

(n = 56, mean blood lead 42 μg/dL, SD 15) compared to reference group (mean blood lead: 

2.7 μg/dL). Increasing blood lead concentration was significantly associated with increasing 

covariate-adjusted total cholesterol and HDL cholesterol. A similar outcome was found in a 

larger study (Ito et al., 1985) of male steel workers (n = 712, blood lead range 5–62 μg/dL). 

When stratified by age, total and HDL cholesterol levels in serum were 3.6% and 7.5% higher, 

respectively, in lead workers in the age range 40 to 49 years, compared to corresponding strata of 

the office workers (n = 155). Although a smaller study, the Kristal-Boneh et al. (1999) study 

considered a larger set of potential covariables (e.g., dietary fat, cholesterol, and calcium intakes, 

sport activities, alcohol consumption, cigarette smoking). 

Oxidative changes in blood lipids (e.g., increased levels of lipid peroxides and 

malondialdehyde levels) as well as decreased levels of erythrocyte superoxide dismutase (SOD), 

catalase, G6PD, and GSH peroxidase, indicative of increased oxidative stress, have been 

observed in lead workers, in comparison to reference groups (Ito et al., 1985; Jiun and Hsien, 

1994; Solliway et al., 1996; Sugawara et al., 1991). However, none of these studies have 

developed concentration-response relationships that take into account potential confounders. 

The largest study is that of (Ito et al., 1985), described above. When stratified by age, serum 

HDL cholesterol and serum lipoperoxide levels were 16% higher in the lead workers in the age 

range 40 to 49 years, compared to corresponding strata of the reference group. Serum 

lipoperoxide levels also appeared to increase as blood lead increased above 30 μg/dL, while 

erythrocyte SOD appeared to decrease with increasing blood lead concentration (a statistical 

evaluation was not reported). 

Evidence for increased oxidative stress (increased reactive oxygen species) in 

lymphocytes of lead workers has also been reported (Fracasso et al., 2002). Peripheral 

lymphocytes collected from battery manufacture workers (n = 37, mean blood lead: 40 μg/dL) 

exhibited increased DNA strand breaks, higher production of ROS and lower GSH levels 

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compared to a reference group of office workers (n = 29, mean blood lead 4 μg/dL). The 

covariate-adjusted odds ratios (exposed versus not exposed) were 1.069 (95% CI: 1.020, 1.120) 

for increased DNA strand breaks and 0.634 (95% CI: 0.488, 0.824) for lower GSH levels. 

6.9.2 Effects of Lead on the Hematopoietic System 

6.9.2.1 Summary of Key Findings of the Effects of Lead on the Hematopoietic System 

from the 1986 Lead AQCD 

The 1986 Lead AQCD concluded that lead decreases heme production and shortens 

erythrocyte survival; both effects contributing to lead-induced anemia in children and adults, 

which becomes evident in children at blood lead concentrations $40 μg/dL and, in adults, 

$50 μg/dL. The 1986 Lead AQCD also concluded that effects of lead on blood hemoglobin 

level extend below 50 μg/dL, with effects detected in lead workers at blood lead concentrations 

<25 μg/dL (Baker et al., 1979; Grandjean, 1979). More recent epidemiologic studies, 

summarized below, provide additional information on concentration-response relationships for 

hematopoietic effects of lead. The studies support the conclusion that clinical anemia can occur 

in children in association with blood lead concentrations >40 μg/dL (Schwartz et al., 1990). The 

newer studies suggest that perturbation of erythropoiesis, indicated by changes in serum 

erythropoietin, occurs in association with blood lead concentrations <40 μg/dL and in the 

absence of detectable changes in blood hemoglobin levels or hematocrit. Details regarding the 

design of these studies and outcomes are presented in Annex Tables AX6-9.3 and AX6-9.4. 

Outcomes of the most pertinent studies are discussed below. 

6.9.2.2 Blood Hemoglobin Levels 

Several studies reported since the completion of the 1986 Lead AQCD have explored 

associations between lead exposure and blood hemoglobin levels in children and adults. 

Consistent findings have been a lack of discernable depression of blood hemoglobin levels in 

study populations whose mean blood lead concentrations were #40 μg/dL (Table 6-9.2). Of note 

is the findings relating patella bone lead to both blood hemoglobin levels and hematocrit. 

The Kosovo prospective study of pregnancy outcomes is one of the largest epidemiologic 

evaluations of associations between lead exposure and blood hemoglobin levels in infants and 

children (Graziano et al., 2004; Factor-Litvak et al., 1999, 1998). The study included pregnant 

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402(c) Economic Analysis Chapter 5 684
December 2005 6-284 DRAFT-DO NOT QUOTE OR CITE Table 6-9.2. Summary of Results of Selected Studies of Associations Between Lead Exposu

Blood Hemoglobin Levels Blood Lead (μg/dL) Blood Study Subjects 

na Mean (SD) Range Hemoglobin Comme

Children Graziano et al. (2004) ages: 4.5–12 yr 311 6–9, 31–39b 3–70 o + erythr

Liebelt et al. (1999) ages: 1–6 yr 86 18c 2–84 o ! erythr

Adults Graziano et al. (1990) pregnant women 1,502 5, 17d 2–43 o ! erythrHu et al. (1994) male carpenters 119 8 2–25 o ! in ass

bone lea

Makino et al. (1997) male VCS workers 1,573 13 1–39 + (+) 1 g/

lead 

Solliway et al. (1996) male battery workers 100 10 23–63 o ! RBC 

Gennart et al. (1992) battery workers 183 51 (8) 40–70 ! ! hemat

Horiguchi et al. (1991) male lead refinery workers 40 54 (16) NR ! ! hemat

Poulos et al. (1986) male lead workers 160 18–27 (5)e NR ! ! hemat

-, decrease; +, increase; Hgb, hemoblogin; NR, not reported; PCV, packed cell volume SD, standard deviation; VCS, vinyl chloride stabilizer a total number of subjects (including reference group) b range of means of low and higher exposure groups c median d mean of low- and high-exposure groups e range of group means (standard deviation estimated for up range based on reported standard error). 

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women (n = 1502) and their children (n = 311) who resided in one of two regions of Kosovo, 

Yugoslavia; one was heavily impacted by lead industries (high-lead area), the other had 

relatively little lead contamination (low-lead area). Mean blood lead concentrations of children 

(measured at birth and at intervals to 12 years of age) ranged from 30 to 40 μg/dL in the highlead area and 6 to 9 μg/dL in the low-lead area. Mean blood hemoglobin levels in the low-lead 

and high-lead children, measured at 4.5, 6.5, 9.5, and 12 years of age, were not significantly 

different. These findings are consistent with those from a smaller cross-sectional study (n = 89; 

blood lead range 2 to 84 μg/dL, 84% <35 μg/dL) that also found no association between blood 

lead concentration and blood hemoglobin levels (Liebelt et al., 1999). Results from these two 

studies suggest that, in the absence of iron deficiency, lead exposures that result in blood lead 

concentrations <40 μg/dL do not produce detectable changes in blood hemoglobin levels 

in children. 

Associations between lead exposure and blood hemoglobin levels in adults have been 

examined in numerous epidemiological studies (Froom et al., 1999; Gennart et al., 1992; 

Horiguchi et al., 1991; Hu et al., 1994; Makino et al., 1997; Poulos et al., 1986; Romeo et al., 

1996; Solliway et al., 1996). The Graziano et al. (1990) and Makino et al. (1997) studies warrant 

particular attention because of the design (longitudinal), relatively large size (>1000 subjects), 

and relatively low blood lead levels of the subjects (<40 μg/dL). Both studies support the 

general conclusion that blood hemoglobin levels are not depressed in association with blood lead 

concentrations <40 g/dL. In the Kosovo prospective study, no discernable effect of lead on 

maternal blood hemoglobin levels was evident from a comparison of the high-lead exposure 

group (mean blood lead 17 μg/dL, range 7–43 μg/dL) with the low lead exposure group (mean 

blood lead 5.1 μg/dL, range 2–11 μg/dL). Makino et al. (1997) found a positive association 

between increasing blood lead concentration and increasing blood hemoglobin levels in a 

longitudinal survey of adult males (n = 1,573) who worked in pigment or vinyl chloride 

stabilizer manufacture (mean blood lead 13 μg/dL, range 1–39 μg/dL). A simple linear 

regression model predicted a 1 g/dL increase in blood hemoglobin per 10 μg/dL increase in 

blood lead concentration (typical level 10–20 g/dL). 

Two other cross-sectional studies are also notable, because of design considerations 

and/or blood lead concentration ranges of the subjects. Solliway et al. (1996) observed no 

differences in mean blood hemoglobin levels in a comparison of adult male battery manufacture 

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workers (n = 34, mean blood lead 41 μg/dL, range 23–63 μg/dL) and a matched reference group 

(n = 56, mean blood lead 7 μg/dL, range 1–13 μg/dL). Hu et al. (1994) conducted a crosssectional assessment of adult male carpentry workers (n = 119) whose blood lead concentrations 

were #25 μg/dL. Blood hemoglobin was not significantly associated with blood lead 

concentration. Of note, however, was the finding that increasing patella bone lead was 

significantly associated with decreasing blood hemoglobin levels. Covariate-adjusted blood 

hemoglobin levels were predicted to decrease by 1.1 g/dL per 37 μg/g increase (mean of first and 

fourth quartiles) in patella bone lead. 

Studies of lead workers whose blood lead levels were higher than in the studies noted 

above have, in general, found lower blood hemoglobin levels in association with increasing 

blood lead concentrations; these include Gennart et al. (1992) with a blood lead range of 40–70 

μg/dL, Horiguchi et al. (1991) with a mean blood lead level of 54 μg/dL (SD 16), and Poulos 

et al. (1986) with mean blood lead range of 21–27 μg/dL. In the latter study (Poulos et al., 

1986), blood hemoglobin levels decreased by 0.6–0.9 g/dL per 10 μg/dL increase in blood lead 

(simple linear regression) in adult males. Analyses or adjustments for potential covariables were 

not reported for these studies. 

6.9.2.3 Erythrocyte Volume and Number 

Schwartz et al. (1990) conducted a concentration-response analysis of data collected at the 

Bunker Hill smelter site in Idaho in 1974, shortly after the failure of the smelter bag house 

resulted in extensive contamination of the surrounding area with uncontrolled smelter emissions. 

This analysis is unique in that it collected hematocrit measurements in children (n = 579, age 

range 1–5 years) who had relatively high blood lead levels (range 11–164 μg/dL, approximately 

40% exceeded 40 μg/dL). A logistic model relating blood lead concentration and age to 

hematocrit predicted a 10% decrease in hematocrit (from 39.5 to 35.5%) in association with 

blood lead concentrations of 85, 115, and 145 μg/dL at ages 1, 3, and 5 years, respectively 

(Figure 6-9.2). A 10% probability of anemia (hematocrit <35%) was predicted in association 

with a blood lead concentration of approximately 20 μg/dL at age 1 year, 50 μg/dL at age 

3 years, and 75 μg/dL at age 5 years (Figure 6-9.2). 

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402(c) Economic Analysis Chapter 5 687
Figure 6-9.2. Relationship between blood lead and hematocrit in children. The top panel 

shows central tendency predictions based on a logistic regression model 

relating hematocrit and blood lead concentration, adjusted for age. The 

regression coefficients relating hematocrit and blood lead were ($ = 0.0133 

[SE 0.0041], p = 0.0005). The bottom panel shows corresponding 

concentration-response (hematocrit <35%) relationships. 

Source: Schwartz et al. (1990) 

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Numerous studies of associations between lead exposure and erythrocyte volume (e.g., 

hematocrit) or number have been reported in adults (Gennart et al., 1992; Horiguchi et al., 1991; 

Hsiao et al., 2001; Hu et al., 1994; Makino et al., 1997; Osterode et al., 1999; Poulos et al., 1986; 

Solliway et al., 1996). The Hu et al. (1994) and Makino et al. (1997) studies examined groups of 

workers that had blood lead concentrations that were relatively low, compared to other studies, 

and found either no association or weak association between blood lead concentration and 

hematocrit and/or erythrocyte number. The Hu et al. (1994) cross-sectional study of carpentry 

workers (n = 119, blood lead concentration range 2–25 μg/dL) found no association between 

blood lead concentration and hematocrit; however, increasing patella bone lead was associated 

with a significant decrease in hematocrit. Covariate-adjusted blood hematocrit was predicted to 

decrease by 0.03% (95% CI: 0.01, 0.05) per 37 μg/g increase (mean of first and fourth quartiles) 

in patella bone lead. The Makino et al. (1997) longitudinal study of pigment and vinyl chloride 

stabilizer manufacture workers (n = 1,573; blood lead concentration range 1–39 μg/dL) found a 

positive association between blood lead concentration and hematocrit, and erythrocyte count. 

A simple linear regression model predicted an increase in hematocrit of 0.6 (typically 43) and an 

increase in erythrocyte count of 0.07 H 106

/mm3 (typically 4–7 H 106/mm3) per 10 μg/dL increase 

in blood lead concentration. 

Studies that included subjects who had higher blood lead concentrations (i.e., >40 μg/dL) 

have, in general, found negative associations between blood lead concentration and hematocrit 

Gennart et al., 1992; Horiguchi et al., 1991; Poulos et al., 1986; Solliway et al., 1996), with two 

exceptions, Hsiao et al. (2001) and Osterode et al. (1999). Hsiao et al. (2001) conducted an 

11-year retrospective longitudinal analysis of blood lead concentration, hematocrit, and 

erythrocyte count in a group of battery manufacture workers (n = 30; mean blood lead 

concentration 30–60 μg/dL). A repeated measures regression analysis (generalized estimation 

equation) yielded a significant association between increasing blood lead concentration and 

increasing hematocrit and erythrocyte count. Osterode et al. (1999) measured erythrocyte 

number and packed cell volume in a group of lead workers (n = 20) and an age-matched 

reference group (n = 20). Mean blood lead concentration was 45.5 μg/dL (range 16–91 μg/dL) 

in the lead workers and 4.1 μg/dL (range 3-14 μg/dL) in the reference group. Mean erythrocyte 

number and packed cell volume in the lead workers and reference group were not different. 

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6.9.2.4 Erythropoiesis 

Several studies have found associations between lead exposure and serum erythropoietin 

levels in children (Graziano et al., 2004; Liebelt et al., 1999) and adults (Graziano et al., 2001; 

Osterode et al., 1999; Romeo et al. 1996). A qualitative summary of outcomes from these 

studies are provided in (Table 6-9.3). 

Two studies have examined possible association between lead exposure and serum 

erythropoietin levels in children. In the Kosovo prospective study (Factor-Litvak et al., 1999, 

1998; Graziano et al., 2004) a significant association was evident between increasing blood lead 

concentration (3–70 μg/dL) and increasing serum erythropoietin levels after adjustment for age 

and blood hemoglobin levels (Figure 6-9.3). The association weakened with age; it was 

significant at ages 4.5 and 6.5 years, but not at ages 9.5 or 12 years. A multivariate linear 

regression model predicted a 36% increase in serum erythropoietin per 10 μg/dL increase 

(3-13 μg/dL, hemoglobin 13 g/dL) in blood lead at age 4.5 years, and an 18% increase per 

10 μg/dL at age 6.5 years. These outcomes suggest that erythropoiesis is stimulated in children 

in association with increasing blood lead concentrations below 40 μg/dL and in the absence of 

depressed blood hemoglobin levels. 

A smaller cross-sectional study examined serum erythropoietin levels in a group of 

children (n = 89), 1 to 6 years of age (Liebelt et al., 1999). The blood lead concentration range in 

the study group (2–84 μg/dL) was similar to that in the Graziano et al. (2004) study and, 

consistent with this study, Liebelt et al. (1999) found no association between blood lead 

concentration and serum hemoglobin levels. However, in contrast to the Graziano et al. (2004) 

study, blood hemoglobin-adjusted serum erythropoietin levels decreased in association with an 

increase in blood lead concentration (0.3 mIU/mL decrease per 10 μg/dL increase blood lead). 

The Liebelt et al. (1999) study did not include age as a covariate in the regression model, which 

was shown in the Kosovo prospective study to be a significant covariable in blood lead-serum 

erythropoietin relationship (Graziano et al., 2004); this may have contributed to the different 

outcome in the two studies. Liebelt et al. (1999) studied a convenience sample from a 

lead/primary care clinic (rather than a prospectively selected cohort) that specifically excluded 

children who had symptoms of severe iron deficiency, or were taking iron supplements or other 

bone marrow suppressing drugs. Iron status of the children in the Graziano et al. (2004) study 

was not reported. However, serum ferritin levels in the mothers, at mid-pregnancy, was not 

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Blood Lead (μg/dL) Serum Study Subjects 

na Mean (SD) Range Erythropoietin 

Children Graziano et al. (2004) Liebelt et al. (1999) 

Adults 

Graziano et al. (1990) 

Osterode et al. (1999) 

Romeo et al. (1996) 

ages: 4.5–12 yr 

ages: 1–6 yr 

pregnant women 

male lead workers 

male lead workers 

311 

86 

48 

40 

141 

6–9, 31–39b 

18c 

NR 

45 

30, 65b,d 

3–70 2–84 2–40 

16–91 30–92 

+ adjusted 

! adjusted ! stratified 

! adjusted 

! no associ

!, decrease; +, increase; Hgb, hemoblogin; NR, not reported; PCV, packed cell volume SD, standard deviation. 

a total number of subjects (including reference group)b range of means of low and higher exposure groups c median d reference group mean was 10 μg/dL (range 3–20) 

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Figure 6-9.3. Relationship between blood lead and serum erythropoietin in children. 

Shown are central tendency predictions based a generalized estimating 

equation (for repeated measures) relating serum erythropoietin and 

cumulative lifetime average blood lead concentration, adjusted for age and 

blood hemoglobin levels (13 g/dL). The regression coefficients relating 

erythropoietin and blood lead were significant for ages 4.5 ($ = 0.21 [95% 

CI: 0.13, 0.30], p < 0.0001) and 6.5 years ($ = 0.12 [95% CI: 0.03, 0.20], 

p < 0.001). 

Source: Graziano et al. (2004). 

1 indicative of iron deficiency (Graziano et al., 1990). Although the direction of the outcome 

2 measure was different in the two studies, both studies (Graziano et al., 2004; Liebelt et al., 1999) 

3 found evidence for an effect of lead exposure on serum erythropoietin levels in the absence of 

4 significant lead-associated changes in blood hemoglobin levels. 

5 Three studies have found associations between lead exposure and changes in 

6 erythropoiesis biomarkers in adults. As part of the Kosovo prospective study, serum 

7 erythropoietin was measured at mid-pregnancy and at term in a subset of women enrolled in the 

8 study (Graziano et al., 1991). The high- and low-lead cohorts were constructed from the six 

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highest and lowest mid-pregnancy blood lead concentrations, within each of four blood 

hemoglobin strata, ranging from 9.0 to 12.9 g/dL. Mean blood lead concentrations in the strata 

ranged from 17 to 39 μg/dL in the high-lead group and 2.4 to 3.6 μg/dL in the low lead group. 

Serum erythropoietin levels significantly decreased in association with increasing blood lead 

concentration, independently of an effect of blood hemoglobin (Figure 6-9.4). Romeo et al. 

(1996) also found an association between increasing blood lead concentration and decreasing 

serum erythropoietin, in the absence of discernable changes in blood hemoglobin levels, in a 

comparison of groups male lead workers (n = 28, blood lead range 30–92 μg/dL) and a similaraged reference group (n = 113, mean blood lead 10 μg/dL, range 3–20). Osterode et al. (1999) 

examined several measures of erythropoiesis in a group of lead workers (n = 20, mean age 

46 years) and in an age-matched reference group (n = 20). Mean blood lead concentration was 

45.5 μg/dL (range 16–91) in the lead workers and 4.1 μg/dL (range 3–14) in the reference group. 

Mean blood hemoglobin levels in the lead worker and reference groups were not different. Lead 

workers with had blood lead concentrations $60 μg/dL had significantly lower circulating 

erythrocyte progenitor cells than the reference group. Also, erythrocyte progenitor cell number 

was significantly negatively correlated with blood lead concentration and urine lead 

concentration. Serum erythropoietin levels increased exponentially with decreasing packed 

blood cell volume in the reference group, but not in the lead workers (i.e., serum erythropoietin 

level was not significantly correlated with packed cell volume in the lead workers). Thus, unlike 

the reference group (blood lead concentration #14 μg/dL), lead workers appeared to have a 

suppressed erythropoietin response to declining blood cell volume. 

Collectively, the results of the above studies suggest that lead exposure depresses serum 

erythropoietin levels, in the absence of significant depression in blood hemoglobin levels. Leadinduced nephrotoxicity may contribute to a suppression of erythropoietin levels in lead-exposed 

individuals. Although this cannot be entirely ruled out in these studies, both the Romeo et al. 

(1996) and Osterode et al. (1999) studies excluded people who had a history of hematological or 

kidney disease. Nevertheless, renal nephrotoxicity, including proximal tubular nephropathy, 

could have been a confounder in these studies which included subjects whose blood lead 

concentrations were >40 μg/dL. 

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402(c) Economic Analysis Chapter 5 693
Figure 6-9.4. Association between blood lead concentration and serum erythropoietin in 

pregnant women. Shown are combined data for mid-pregnancy and 

delivery. Each bar represents the mean ("SD) of 12 subjects. ANOVA of 

the data at mid-pregnancy and at delivery showed blood lead effects 

(p = 0.049, p = 0.055, respectively) and blood hemoglobin effects (p = 0.0001. 

p = 0.009, respectively), with no significant interaction between the two 

variables. 

Source: Graziano et al. (2001). 

1 6.9.2.5 Other Effects on Erythrocyte Metabolism and Physiology 

2 6.9.2.5.1 Erythrocyte Nucleotide Metabolism 

3 Lead inhibits erythrocyte pyrymidine-5Nnucleotidase (P5N) and adenine dinucleotide 

4 synthetase (NADS). Associations between increasing blood lead concentration and decreasing 

5 blood P5N and NADS activity have been observed in studies of lead workers (Kim et al. 2002; 

6 Mohammed-Brahim et al., 1985; Morita et al., 1997). Mean blood lead concentrations in these 

7 study groups were $35 μg/dL and ranged up to 80 μg/dL. 

8 

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6.9.2.5.2 Erythrocyte Deformability 

Horiguchi et al. (1991) compared the deformability of erythrocytes collected from adult 

male secondary lead refinery workers (n = 17, age range 24–58 years) with a reference group of 

male subjects (n = 13, age range 22–44 years). Erythrocyte deformability was assessed as 

microfilterability of erythrocytes under a negative (!10 cm H2O) pressure head. Erythrocytes 

from the lead workers showed significantly lower deformability compared to the reference 

group. The mean blood lead concentration in the lead workers was 53.5 μg/dL (SD 16.1). 

6.9.2.5.3 Erythrocyte Membrane Transport 

Hajem et al. (1990) measured erythrocyte membrane activities of Na+

-K+-ATAase, Na+-

K+

-co-transport, Na+-Li+-antiport, and passive Na+ and K+ permeability in erythrocytes collected 

from adult males (n = 122, geometric mean blood lead: 16 μg/dL, range 8.0–33.0) and hair lead 

was 5.3 μg/g (95% CI: 4.44, 6.23, range 0.9–60). Na+

-K+-co-transport activity was negatively 

correlated with blood lead concentration but not with hair lead (geometric mean 5.3 μg/g, range 

0.9–60), and Na+

-K+-ATPase activity was negatively correlated with hair lead, but not with 

blood lead. 

6.9.3 Effects of Lead on the Endocrine System 

6.9.3.1 Summary of Key Findings of the Effects of Lead on the Endocrine System from 

the 1986 Lead AQCD 

The 1986 Lead AQCD concluded that various endocrine processes may be affected by 

lead at relatively high exposure levels. These included effects on thyroid hormone levels (e.g., 

Refowitz, 1984; Robins et al., 1983), effects on male sex hormone levels (e.g., Braunstein et al., 

1978), and impairment of the production of 1,25-dihydroxy vitamin D (1,25-OH-D) (e.g., Rosen 

et al., 1980). Effects on these endocrine systems were concluded to be apparent only at blood 

lead concentrations exceeding 30–40 μg/dL. The 1986 Lead AQCD concluded that studies from 

which the effects of lead on reproductive hormones in females could be assessed were lacking. 

More recent epidemiologic studies have examined possible associations between lead 

exposure (as reflected by blood and/or bone lead levels) and various biomarkers of endocrine 

function, including the thyroid, male reproductive, and calcitropic endocrine systems. These 

studies have examined endocrine outcomes at lower blood lead ranges and in the absence of 

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overt clinical lead toxicity, and have more rigorously attempted to control for confounding 

factors. Evidence for lead effects on these systems, in association with blood lead concentrations 

below 30–40 μg/dL, remains absent. The strongest study designs have yielded no associations, 

or weak associations, between lead exposure and thyroid hormone status (Erfurth et al., 2001; 

Schumacher et al., 1998; Tuppurainen et al., 1988; Zheng et al., 2001). Similarly, studies of the 

male reproductive system that attempted to control for confounding effects of age, have yielded 

mixed outcomes (Alexander et al., 1998, 1996; Erfurth et al., 2001; Gustafson et al., 1989; 

McGregor and Mason, 1990; Ng et al., 1991). Results of a more recent epidemiologic study of 

the calcitropic endocrine system in children suggest that associations between serum vitamin D 

status and blood lead may not be present in calcium-replete children who have average lifetime 

blood lead concentrations below 25 μg/dL (Koo et al., 1991). In adults, exposures to lead that 

result in blood lead concentrations >40–60 μg/dL may increase, rather than decrease, circulating 

levels of 1,25-OH-D and PTH (Kristal-Boneh et al., 1999; Mason et al., 1990), possibly as a 

compensatory response to increased urinary calcium losses, secondary to impaired kidney 

function. Details regarding the design of these studies and outcomes are presented in Annex 

Tables AX6-9.5 and AX6-9.6. Outcomes of the most pertinent studies are summarized below. 

6.9.3.2 Thyroid Endocrine Function 

Several studies have examined possible associations between lead exposure and thyroid 

hormone status. Most of these have been studies of occupational exposures. The results of these 

studies have been mixed; some studies have found significant associations with lead exposure 

(e.g., blood lead concentration), but most studies have found none or relatively weak 

associations. In studies that have controlled for the effects of age, outcomes also have been 

mixed, with the strongest study designs finding none or weak associations between lead 

biomarkers and thyroid hormone status (Erfurth et al., 2001; Schumacher et al., 1998; 

Tuppurainen et al., 1988; Zheng et al., 2001). The strength of the association and, possibly, the 

direction of the effect (i.e., increase or decrease in hormone levels) may change with exposure 

duration or level (Robins et al., 1983; Tuppurainen et al., 1988). The overall picture that 

emerges is that those studies that have included subjects having blood lead concentrations 

exceeding 100 μg/dL have found depression of serum T3 and/or T4 levels, without a detectable 

increase in serum TSH. However, studies in which the blood lead distribution was dominated by 

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levels well below 100 μg/dL, have found either no effects or subclinical increases in serum T3, 

T4, with no change in TSH levels. Outcomes from the most pertinent studies are summarized 

qualitatively in Table 6-9.4 and are described in greater detail below. 

Siegel et al. (1989) measured serum total thyroxine (TT4) and free thyroxine (FT4) in 

children ages 11 months to 7 years (n = 68) who were outpatients at a clinical care facility. 

Mean blood lead concentration in the study group was 25 μg/dL (range 2–77). In a simple 

(univariate) linear regression analysis, hormone levels were not significantly associated with 

blood lead concentration. 

Zheng et al. (2001) measured concentrations of TT4 and transthyretin (TTR) in serum and 

cerebral spinal fluid (CSF) of adult hospital patients (n = 82) admitted for evaluation of CSF 

clinical chemistry (e.g., for head wounds, tumors, neurological symptoms). Mean blood lead 

concentration was 14.9 μg/dL (SD 8.3). Age-adjusted serum TT4 and TTR, and CSF TT4 were 

not significantly associated with blood lead concentration; however, increasing CSF lead 

concentration was associated with decreasing CSF TTR levels (r = −0.30, p = 0.023). 

Possible associations between lead exposure and thyroid hormone status have been 

examined in several studies of lead workers (Dursun and Tutus, 1999; Erfurth et al., 2001; 

Gennart et al., 1992; Gustafson et al., 1989; Horiguchi et al., 1987; Lopez et al., 2000; Refowitz, 

1984; Robins et al., 1983; Schumacher et al., 1998; Singh et al., 2000; Tuppurainen et al., 1988). 

Of these, six warrant particular attention because the design and/or analysis attempted to control 

for effects of age (Erfurth et al., 2001; Dursun and Tutus, 1999; Gustafson et al., 1989; 

Schumacher et al., 1998; Tuppurainen et al., 1988; Robins et al., 1983). Outcomes of these 

studies are summarized in Table 6-9.4. The largest studies were Erfurth et al. (2001), 

Schumacher et al. (1998), and Tuppurainen et al. (1988). 

Erfurth et al. (2001) was a cross-sectional study of secondary smelter workers (n = 62) 

and a reference group of metal (not lead) workers (n = 26). Excluded from the study were 

individuals with ongoing thyroid disease or who were taking thyroid hormone supplements or 

other drugs that would interfere with thyroid hormone levels (e.g., beta-blockers). Median blood 

lead concentration in the lead workers was 31 μg/dL (range 8–93 μg/dL). Age-adjusted basal 

serum levels of FT3, FT4, and TSH were not associated with blood, urine, or finger bone lead 

levels. Thyroid releasing hormone (TRH)-induced TSH secretion (area under serum TSH 

concentration-time curve) was measured in an age-matched subset of the study group (9 lead 

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Thyroid Hormone Levels Blood Lead (μg/dL) Study Subjects 

na Mean (SD) Range T3 

Children Siegel et al. (1989) children, 11 mo–7 yrs 68 25 2–77 NR Adults Dursun and Tutus (1999) metal powder manufacture workers 57 17.1 (9.0) 1–36 + Erfurth et al. (2001) secondary smelter workers 88 31.1c 4–93 o 

Gustafson et al. (1989) secondary smelter workers 42 39.4 (2.1) NR o Robins et al. (1983) brass foundry workers 47 NR 16–127 NR Schumacher et al. (1998) primary smelter workers 151 24.1 15>40% o Tuppurainen et al. (1988) battery manufacture workers 176 55.9 (23.8) 5–134 ! 

Zheng et al. (2001) general population 82 14.9 (8.3) NR NR !, decrease; +, increase; o, no effect; NR, not reported; T3, triiodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone 

a Total number of subjects (including reference group)b basal/thyroid releasing hormone-stimulated c median 

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workers and 11 reference subjects) and was not significantly different in the two groups. The 

Schumacher et al. (1998) study measured serum FT4, TT4, and TSH levels in a group of male 

workers (n = 151) at the Trail British Columbia smelter complex. Excluded from the study were 

individuals who had ongoing clinical thyroid disease. Mean blood lead concentration in the 

study group was 24 μg/dL (15% >40 μg/dL). Covariate-adjusted (age, alcohol consumption) 

hormone levels were not significantly associated with current blood lead concentration or 

10-year average blood lead concentrations. Prevalence of abnormal hormone values was also 

unrelated to blood lead concentration. 

Tuppurainen et al. (1988) measured serum total triiodothyronine (TT3), FT4, TT4, 

and TSH levels in a group of male battery manufacture workers (n = 176). Mean blood lead 

concentration was 56 μg/dL (range 14–134 μg/dL). Although, hormone levels were not 

significantly associated with blood lead concentrations, increasing exposure (i.e., employment) 

duration was significantly associated with decreasing FT4 (r2

 = 0.071, p = 0.001) and TT4 (r2 = 

0.059, p = 0.021) levels. The r2

 was not improved by including age or blood lead as covariables. 

Strength of the association was greater when the analysis was restricted to workers who had an 

exposure duration >7.6 years (FT4: r2

 = 0.33, p < 0.002; TT4: r2 = 0.21, p < 0.001). Consistent 

with the results of the Tuppurainen et al. (1988) study, Robins et al. (1983) found a significant 

association between increasing blood lead concentration and decreasing FT4 (r2

 = 0.085, 

p = 0.048) in a group of brass foundry workers (n = 47). The blood lead range in the subjects 

was 16–127 μg/dL. When stratified by race (black, white) the association was significant in the 

black stratum (r2

 = 0.21, p = 0.03), but not in the white stratum (r2 = 0.05, p = 0.27). The 

strength of association was not changed by including age in the regression model. Both the 

Robins et al. (1983) and Tuppurainen et al. (1988) included subjects with blood lead 

concentrations >100 μg/dL. 

Blood lead concentrations were lower in the Dursun and Tutus (1999) and Gustafson et al. 

(1989) studies than in the above studies, and both studies found significant associations between 

lead exposure and increasing serum TT4 levels. Dursun and Tutus (1999) measured serum FT3, 

TT3, FT4, TT4, and TSH in a group of metal powder manufacture workers (n = 27) and a 

reference group (n = 30). Mean blood lead concentration in the workers was 17 μg/dL (range 9– 

36 μg/dL). A linear regression model that included age, blood lead concentration, and exposure 

duration, indicated a significant association between increasing exposure duration and increasing 

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serum TT4 levels (r2 = 0.3, p = 0.03). The Gustafson et al. (1989) study examined a group of 

male secondary smelter workers (n = 21) and reference subjects, individually matched to the lead 

workers by age, sex, and work shift. Mean blood lead concentration in the workers was 

39 μg/dL (SD 2). Serum TT4 levels were significantly higher (p < 0.02) in the lead workers 

compared to the reference group. The difference strengthened when the analysis was restricted 

to the age range <40 years (p = 0.01). 

6.9.3.3 Reproductive Endocrine Function 

6.9.3.3.1 Male Reproductive Endocrine Function 

Low testosterone (TES) levels, blunted sex hormone secretion in response to 

gonadotropin releasing hormone (GNRH), and defects in spermatogenesis have been observed in 

humans exhibiting clinical neurological symptoms of lead poisoning (Braunstein et al., 1978; 

Cullen et al., 1984). However, the effects of lower exposure levels on reproductive endocrine 

status are less clear. Possible associations between lead exposure and changes in male 

reproductive hormone levels have been examined in studies of lead workers. Of these, five 

studies attempted to control for effects of age, an important determinant of testosterone levels 

(Alexander et al., 1998; Erfurth et al., 2001; Gustafson et al., 1989; McGregor and Mason, 1990; 

Ng et al., 1991). The outcomes from these studies are qualitatively summarized in Table 6-9.5. 

Blood lead ranges in the latter studies were similar (4–90 μg/dL), yet outcomes were mixed, with 

no change (Erfurth et al., 2001; Gustafson et al., 1989; McGregor and Mason, 1990) or 

subclinical decrease (Alexander et al., 1998, 1996; Ng et al., 1991) in serum testosterone (TES) 

in association with lead exposure. Mixed effects were observed for the effect of lead exposure 

on serum follicle stimulating hormone (FSH) and luteinizing hormone (LH), increases 

(McGregor and Mason, 1990; Ng et al., 1991), decreases (Gustafson et al., 1989), and with no 

change (Alexander et al., 1998, 1996; Erfurth et al., 2001) in hormone levels observed. The 

inconsistency in the direction of effects on TES and the two androgen regulating pituitary 

hormones, FSH and LH, is particularly noteworthy. In the absence of an abnormality in the 

hypothalamic-pituitary regulation of testosterone levels, an association between declining serum 

TES (or free TES) and increasing FSH and LH levels would be expected. Erfurth et al. (2001) 

observed a suppressed FSH response to GNRH in a group of lead workers compared to an 

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Male Sex Hormone Levels in Adults Blood Lead (μg/dL) 

na Study Subjects Mean (SD) Range FSH L

Alexander et al. (1998, 1996) primary smelter workers 152 NR 5–58 o Erfurth et al. (2001) secondary smelter workers Gustafson et al. (1989) secondary smelter workers McGregor and Mason (1990) lead workers Ng et al. (1991) battery manufacture workers 

88 31.1c 4–93 o/-d,e o

42 39.4 (2.1) NR – 

176 NR 17–77 + 

171 35 (13) 10–72 + 

!, decrease; +, increase; o, no effect; NR, not reported, FSH, follicle stimulating hormone, LH, luteinizing hormone; PRL, prolactin; Ta total number of subjects (including reference group)b in association with increasing semen lead levels, not with blood lead c median d basal/gonadotropin releasing hormone-stimulated e effect was evident in comparison between groups, but not in multivariate regression that adjusted for age 

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age-matched reference group; however, the magnitude of the response was not significantly 

associated with lead exposure indices in a multivariate regression analysis that accounted for age. 

Alexander et al. (1998, 1996) examined serum FSH, LH, and TES in males (n = 152) who 

worked at the Trail British Columbia smelter complex. Covariate-adjusted hormone levels and 

prevalence of clinically abnormal values were unrelated (p $ 0.05) to blood lead concentration 

(range 5–58 μg/dL); however, increasing semen lead concentration (range 0.3-17 μg/dL) was 

significantly associated with decreasing semen testosterone levels (p = 0.004). Erfurth et al. 

(2001) measured serum TES, sex hormone binging globulin (SHBG), and GNRH-stimulated 

changes in serum FS, LH, and PRL in male secondary smelter workers (n = 62) and in 

a reference group (n = 26). Mean blood lead in the lead workers was 31 μg/dL (range 

8-93 μg/dL). Age-adjusted basal hormone levels were unrelated to blood, plasma, or urine lead 

concentrations. In an age-matched subset of the cohorts (n = 9 lead workers, n = 11 reference), 

median GNRH-stimulated serum FSH was significantly lower in lead workers than in the 

reference group; however, GNRH-stimulated LH, FSH, and PRL were not significantly 

associated with any of the lead measures in a multivariate regression analysis. Gustafson et al. 

(1989) measured serum FSH, LH, and TES (total and free) in a group of male secondary smelter 

workers (n = 21) and in a group of reference subjects individually matched to the lead workers 

by age, sex, and work shift. Mean blood lead concentrations were 39 μg/dL (SD 2) in the lead 

workers and 5.0 μg/dL (SD 0.2) in the reference group. Serum FSH levels were significantly 

lower (p = 0.009) in lead workers compared to reference group. When the analysis was 

restricted to the age range <40 years, lead workers had significantly lower FSH and LH 

compared to the reference group. McGregor and Mason (1990) measured serum FSH, LH, TES, 

and SHBG in a group of male lead workers (n = 90) and in a reference group (n = 86). Blood 

lead range in the lead workers was 17–77 μg/dL; blood lead concentrations in the reference 

subjects were <12 μg/dL. Prevalences of abnormal hormone levels in the lead workers and 

reference group were not different; however, age-adjusted serum FSH was significantly higher in 

lead workers compared to reference group and increasing FSH levels were significantly 

associated with increasing blood lead concentrations. Increasing serum LH was significantly 

associated with increasing exposure duration but not with blood lead concentration or age. 

Serum TES or SHBG levels were unrelated to blood lead concentration or exposure duration. 

Ng et al. (1991) measured serum FSH, LH, PRL, and TES in a group of male battery 

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manufacture workers (n = 122) and a reference group (n = 49). Mean blood lead concentrations 

were 35 μg/dL (range 10–77 μg/dL) in the lead workers and 8 μg/dL (range 3-15 μg/dL) in the 

reference group. When cohorts were stratified by age, serum FSH and LH levels were 

significantly higher in lead workers <40 years of age compared to corresponding age stratum of 

the reference group; serum TES was significantly lower in lead workers $40 years of age, 

compared to the same age stratum in the reference group. Covariate-adjusted (age, tobacco 

smoking) serum TES levels were significantly lower in lead workers in the 10-year exposure 

duration stratum, compared to the reference group. Covariate-adjusted serum FSH and LH were 

significantly higher in lead workers in the <10-year exposure duration stratum, compared to the 

reference group. 

6.9.3.3.2 Female Reproductive Endocrine Function 

Although delays in sexual maturation in humans have been associated with blood lead 

concentrations (Selevan et al., 2003; Wu et al., 2003), and lead has been shown to alter levels of 

female sex hormones and the menstrual cycle in nonhuman primates (Foster, 1992; Franks et al., 

1989; Laughlin et al., 1987), epidemiologic studies of interactions between lead exposure and 

reproductive endocrinology in females have not been reported. Lead introduced into cultures of 

human ovarian granulosa cells suppresses progesterone production (Paksy et al., 2001) and 

suppresses expression of aromatase and estrogen receptor $ (Taupeau et al., 2003). 

6.9.3.4 Pituitary and Adrenal Endocrine Function 

Several studies of possible associations between lead exposure and levels of pituitary 

hormones that regulate production and secretion of thyroid hormones (see Section 6.9.3.2) and 

reproductive hormones (see Section 6.9.3.3) have been reported. In addition to the above 

studies, Gustafson et al. (1989) found that serum cortisol levels were lower in a group of male 

secondary smelter workers (n = 21) compared to a reference group individually matched to the 

lead workers by age, sex, and work shift. Mean blood lead concentration were 39 μg/dL (SD 2) 

in the workers and 5.0 μg/dL (SD 0.2) in the reference group. Campbell et al. (1985) measured 

various biomarkers of status of the renin-angiotensin-aldosterone system in male welders (n = 5) 

and reference subjects (n = 8). Mean blood lead concentration was 35 μg/dL (range 8-62 μg/dL). 

Significant positive correlations were observed between blood lead concentration and plasma 

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aldosterone (r = 0.53, p < 0.002), which may have been, at least in part, secondary to a lead 

effect on plasma renin activity (r = −0.76, p < 0.001) and angiotensin I levels (r = 0.68, 

p < 0.002). Saenger et al. (1984) found lower urinary levels of 6-$-OH-cortisol, but not cortisol, 

in children who had elevated urinary lead in an EDTA provocation test (>500 μg/24 h), 

compared to children who did not have elevated urinary lead levels, or whose blood lead 

concentrations were <30 μg/dL. The change in urinary excretion of 6-$-OH-cortisol in the 

absence of a change in cortisol levels may reflect an effect of lead on liver cytochrome P450 

activity, rather than an effect on the adrenal gland (see Section 6.9.4). 

6.9.3.5 Calcitropic Endocrine Function 

Children exposed to relatively high level of lead >30 μg/dL may exhibit depressed levels 

of circulating 1,25-OH-D (Mahaffey et al., 1982; Rosen et al., 1980). These effects were not 

detected in a study of calcium-replete children with average lifetime blood lead levels below 25 

μg/dL (Koo et al., 1991). In adults, lead exposures that result in blood lead concentrations 

 >40–60 μg/dL may increase, rather than decrease, circulating levels of 1,25-OH-D and PTH. 

These studies also are summarized in Annex Tables AX6-9.5 and AX6-9.6. Outcomes from the 

more pertinent studies are qualitatively summarized in Table 6-9.6 and are discussed in greater 

detail below. 

Epidemiologic studies of possible associations between lead exposure and vitamin D 

status in children have yielded mixed results. Mahaffey et al. (1982) and Rosen et al. (1980) 

observed lower 1,25-OH-D in association with increasing blood lead concentration. Koo et al. 

(1991) found no association between 1,25-OH-D and blood lead concentration. The Koo et al. 

(1991) study was a longitudinal analysis of a subset of a prospective study of pregnancy 

outcomes. Serum calcium magnesium, phosphorus, PTH, CAL, 25-OH-D, 1,25-OH-D, and 

bone mineral content were measured in children (n = 105) at ages 21, 27, and 33 months. Mean 

lifetime average blood lead concentrations (based on quarterly assessments) was 9.7 μg/dL 

(range 4.8–23.6 μg/dL). The range of highest values observed was 6–63 μg/dL. A structural 

equation model was developed that initially considered age, sex, race, sampling season, and 

dietary intake of calcium, phosphorus, and vitamin D as covariables; the final model retained 

age, sex, race, and sampling season. Decreasing blood lead (ln-transformed) was significantly 

associated with covariate-adjusted decreasing serum phosphorus. No other covariate-adjusted 

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and Calcitropic Hormones Study Subjects 

na 

Blood Lead (μg/dL

Mean (SD) 

) 

Range PTH C

Children Koo et al. (1991) ages: 21, 27, 33 mo 105 9.7 5–24 o Mahaffey et al. (1982) ages: 1–16 yr 177 NR 12–120 o Rosen et al. (1980) ages: 1–5 yr 45 18, 47, 74b 10–120 + 

Adults Chalkley et al. (1998) smelter workersc 19 47 21–76 NR N

Kristal-Boneh et al. (1998) battery manufacture workers 140 43 1–77 + N

Mason et al. (1990) lead workers 138 NR 15–95 o N!, decrease; +, increase; o, no effect; NR, not reported, PTH, parathyroid hormone; CAL, calcitonin; 1,25D, 1,25-dihydroxyvitamin Dhydroxyvitamin D 

a total number of subjects (including reference group)

b group means: low, moderate, high c cadmium, lead, zinc smelter workers, effect on 1,24D in association with high blood cadmium and lead and high urinary cadmium 

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outcomes were significantly associated with blood lead. The distribution of dietary calcium 

intakes was 4% for #600 mg/day, 55% for 600–1200 mg/day, and 41% for >1200 mg/day. 

Intakes of phosphorous were similar, suggesting that the subjects were nutritionally replete with 

respect to these two nutrients. 

The different outcomes in Koo et al. (1991) compared to the Mahaffey et al. (1982) and 

Rosen et al. (1980) studies may reflect, in part, the lower blood lead range in the subjects in Koo 

et al. (1991) (range of lifetime average 5–24 μg/dL, range of observed highest values 6–63 

μg/dL) compared to the Mahaffey et al. (1982) and Rosen et al. (1980) studies (10–120 μg/dL). 

Subjects in the Koo et al. (1991) study also had higher calcium intakes (4% with #600 mg/day, 

43% with >1200 mg/day) than in the Rosen et al. (1980) study (mean 580 mg/day [SE 15] in 

high blood lead group). Calcium intake (and/or related nutritional factors) may also have been 

an uncontrolled confounder in the Rosen et al. (1980) study, as higher blood lead concentration 

appeared to be associated with lower calcium intakes (Sorrell et al., 1977). Mahaffey et al. 

(1982) did not report calcium intakes. Thus, the effect of lead exposure on vitamin D status may 

be more pronounced at higher blood lead concentrations (i.e., >60 μg/dL) and in combination 

with lower intakes of calcium (or other nutritional limitations). 

Studies of lead workers have found evidence for higher serum levels of 1,25-OH-D and 

PTH in association with increasing blood lead concentration (Chalkley et al., 1998; KristalBoneh et al., 1998; Mason et al., 1990). The Chalkey et al. (1998) study was a small study 

(n = 19) of subjects exposed to both cadmium and lead, and effects of lead and cadmium on 

1,25-OH-D could not be isolated. The Kristal-Boneh et al. (1998) and Mason et al. (1990) 

studies included larger samples of subjects whose exposure was primarily, but not exclusively, 

to lead. Attempts were made to control for effects of age and, in the Kristal-Boneh et al. (1998) 

study, other potential covariables. Kristal-Boneh et al. (1998) measured serum calcium, 

magnesium, phosphorus, PTH, 25-OH-D, and 1,25-OH-D in a group of male battery 

manufacture workers (n = 56) and a reference group (n = 90). Mean blood lead concentrations 

were 43 μg/dL (SD 14, range 1-77 μg/dL) in the lead worker group and 4.5 μg/dL (SD 2.6, range 

1.4–19 μg/dL) in the reference group. Serum 1,25-OH-D and PTH, but not 25-OH-D, were 

significantly higher in lead workers compared to the reference group. Increasing blood lead 

concentration (ln-transformed) was significantly associated with covariate-adjusted increasing 

serum PTH and 1,25-OH-D levels. No effects on serum calcium were apparent. Occupational 

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lead exposure was also significantly associated with increasing PTH and 1,25-OH-D level. 

Covariates retained in the multivariate model were age, alcohol consumption, smoking; calcium 

intake, magnesium intake, and calorie intake. Mason et al. (1990) measured serum calcium, 

phosphate, PTH, and 1,25-OH-D in male lead workers (n = 63) and in a reference group (n = 75) 

and found significantly higher prevalence of elevated 1,25-OH-D (defined as >2 SD higher than 

reference mean) in lead workers (13%) compared to the reference group (1.3%). Serum levels of 

1,25-OH-D were also significantly higher in lead workers compared to the reference group. 

After stratification of the lead workers into exposure categories (high exposure: blood lead $40 

μg/dL and bone lead $40 μg/g; low exposure: blood lead #40 μg/dL and bone lead  #40 μg/g), 

serum 1,25-OH-D levels were significantly higher in the high lead group. Serum calcium levels 

were not different in the two groups. Increasing blood lead was significantly associated with 

increasing 1,25-OH-D levels (r2

 = 0.206; with age and bone lead included, r2 = 0.218). After 

excluding 12 subjects whose blood lead concentrations >60 μg/dL, the regression coefficient was 

no longer significant (r2

 = 0.162, p = 0.26). 

6.9.4 Effects of Lead on the Hepatic System 

6.9.4.1 Summary of Key Findings of the Effects of Lead on the Hepatic System 

from the 1986 Lead AQCD 

The 1986 Lead AQCD noted that effects of lead on liver function in humans had not been 

extensively studied. Possible association between lead exposures (blood lead concentrations 

>70 μg/dL) and nonspecific liver injury (i.e., increases in liver enzymes in serum) were noted 

based on studies of workers (e.g., Cooper et al., 1973; Hammond et al., 1980). Also noted was 

evidence for possible association of suppression of hepatic cytochrome P450 activity with high 

blood lead concentrations (>70 μg/dL) (Meredith et al., 1977). 

Few studies of hepatic effects of lead on humans have been reported since the 1986 Lead 

AQCD. Studies of hepatic enzyme levels in serum suggest that liver injury may be present in 

lead workers; however, associations specifically with lead exposures are not evident (Al-Neamy 

et al., 2001; Hsiao et al., 2001). Studies of urinary metabolites of cytochrome P450 phenotypes 

CYP2A6 and CYP3A4 suggest possible associations between lead exposure and suppression of 

hepatic enzyme activity. The effect on CYP2A6 activity was observed in children with high lead 

burdens (i.e., blood lead concentration >40 μg/dL, EDTA-provoked urinary lead >500 μg/dL). 

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The effect on CYP3A4 was observed in association with blood lead ranges of approximately 

30-112 μg/dL (based on reported serum lead concentrations). These studies are summarized in 

Annex Table AX6-9.7 and the most pertinent findings are discussed below. 

6.9.4.2 Non-specific Hepatic Injury 

Possible association between occupational lead exposure and liver injury has been 

assessed from measurements of serum enzymes (Al-Neamy et al., 2001; Hsiao et al., 2001). 

Al-Neamy et al. (2001) found significantly higher serum activity of alkaline phosphatase (AP) 

and lactate dehydrogenase (LDH), both within clinically normal ranges, in a group (n = 100) of 

male lead workers (e.g., gas pump attendants, garage workers, printing workers, construction 

workers), compared to an age-matched reference group (n = 100). Serum levels of alanine 

aminotransferase (ALT), aspartate aminotransferase (AST), and (-glutamyl transferase ((-GT) 

were not different in the two groups. The mean lead concentrations were 78 μg/dL (SD 43) 

in the lead workers and 20 μg/dL (SD 12) in the reference group. Hsiao et al. (2001) found no 

association between blood lead concentration and ALT activity, in a longitudinal study of a 

group of battery manufactory workers (n = 30). Mean blood lead concentrations ranged from 

60 μg/dL (approximate range 25–100 μg/dL) at the start of the study (1989) and 30 μg/dL 

(approximate range 10–60 μg/dL) in the final year of the study (1999). 

6.9.4.3 Hepatic Cytochrome P-450 Function 

Urinary excretion of 6-$-hydroxycortisol (6-$-OH-cortisol) derives primarily from 

oxidation of cortisol through the hepatic cytochrome P450 phenotype CYP3A4. A lower urinary 

6-$-OH-cortisol:cortisol ratio is indicative of possible suppression of hepatic CYP3A4 activity. 

Saenger et al. (1984) found significantly lower (~45% lower) urinary excretion of 6-$-OHcortisol and lower urinary 6-$-OH-cortisol:cortisol ratio in 2–9 year-old children (n = 26) who 

qualified for chelation (EDTA-provoked urinary lead >500 μg/24 h) than in children who did not 

qualify, and significantly lower than in an age-matched reference group. Urinary 6-$-OHcortisol:cortisol ratio was significantly correlated with blood lead (r = −0.514, p < 0.001), urinary 

lead, and EDTA-provoked urinary lead (r = −0.593, p < 0.001). Mean blood lead concentrations 

were 46 μg/dL (range 33–60 μg/dL), prior to chelation, and 42 μg/dL (range 32-60 μg/dL) in the 

children who did not qualify for chelation. 

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Satarug et al. (2004) measured urinary excretion of 7-hydroxy-coumarin (7-OHcoumarin) following a single oral dose of coumarin to assess effects of cadmium and lead 

exposure on cytochrome P450 phenotype CYP2A6. The rationale for this approach is that 

7-hydroxylation of coumarin occurs solely through the CYP2A6 pathway. Coumarin-induced 

urinary 7-OH-coumarin was measured in a group (n = 118) selected from the general population 

in Bangkok, Thailand. All subjects were nonsmokers. The study found a significant association 

between increasing urinary lead and decreasing covariate-adjusted urinary 7-OH-coumarin in 

males, but not in females. Covariates retained included age and zinc excretion. A significant 

association, in opposite direction, was found between urinary cadmium and urinary 7-OHcoumarin. Mean urinary lead levels (blood lead concentrations were not reported) were 1.3 μg/g 

creatinine (range 0.1–1.2 μg/dL) in males, and 2.4 μg/g creatinine (range 0.6–6.8 μg/dL) in 

females. Mean serum lead concentrations were 4 μg/L (range 1–28 μg/dL) in males and 3 μg/dL 

(range 1–12 μg/dL) in females. The range 1–28 μg/L serum would correspond to a blood lead 

concentration range of approximately 30–112 μg/dL (U.S. Environmental Protection Agency, 

2003). These results are consistent with observations of depressed excretion of metabolites of 

the CYP2A6 substrate, phenazone, in association with overt clinical lead toxicity in lead workers 

(Fischbein et al., 1977; Meredith et al., 1977). 

6.9.5 Effects of Lead on the Gastrointestinal System 

6.9.5.1 Summary of Key Findings of the Effects of Lead on the Gastrointestinal 

System from the 1986 Lead AQCD 

The 1986 Lead AQCD described gastrointestinal colic (abdominal pain, constipation, 

intestinal paralysis) as a consistent early symptom of lead poisoning in humans and noted that 

such symptoms may be present in association with blood lead concentrations in the range of 

30-80 μg/dL. The 1986 Lead AQCD concluded that information was insufficient to establish 

clear concentration (i.e., blood concentration)-response relationships in the general population in 

association with environmental exposure. Subsequent to the 1986 AQCD several studies of 

prevalence of symptoms of gastrointestinal colic in lead workers have been reported that provide 

evidence for symptoms in association with blood lead concentrations >50–80 μg/dL (Awad el 

Karim et al., 1986; Holness and Nethercott, 1988; Lee et al., 2000; Matte et al., 1989). 

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Summaries of these studies are presented in Annex Table AX6-9.8. Similar types of studies of 

children have not been reported. 

6.9.5.2 Gastrointestinal Colic 

Lee et al. (2000) collected data on symptoms (self-reported questionnaire) in male lead 

workers (n = 95) who worked in secondary smelters, PVC-stabilizer manufacture facilities, or 

battery manufacture facilities. A logistic regression model was applied to the prevalence data for 

gastrointestinal symptoms (loss of appetite, constipation or diarrhea, abdominal pain). The 

covariate-adjusted odds ratio for symptoms, in association with blood lead concentration 

($versus <the group median, 45.7 μg/dL), was not significant (1.8, [95% CI: 0.7, 4.5]). The 

corresponding odds ratio for DMSA-provoked urinary lead ($versus <260.5 μg/4 h, the group 

median) was also not significant (1.1, [95% CI: 0.4, 2.5]). However, the odds ratio for 

neuromuscular symptoms in association with DMSA-provoked urinary lead was significant 

(7.8, [95% CI: 2.8, 24.5]), suggesting that neuromuscular symptoms may occur in association 

with exposures that are insufficient to result in detectable gastrointestinal symptoms. Covariates 

retained in the final regression models were age, tobacco smoking, and alcohol consumption. 

Three other studies have attempted to quantify associations between lead exposure and 

gastrointestinal symptoms in lead workers (Awad el Karim et al., 1986; Holness and Nethercott, 

1988; Matte et al., 1989). Holness and Nethercott (1988) found a significantly (p < 0.05) higher 

prevalence of symptoms in a group of demolition workers (n = 119) in association with a blood 

lead concentration range 50–70 μg/dL (n = 87), 37% for abdominal cramps and 42% for 

constipation, or >70 μg/dL (n = 19) 77% for abdominal cramps and 62% for constipation 

compared to a group of workers in which the blood lead concentration range was <50 μg/dL 

(n = 13), prevalences of 8% and 6%. Awad el Karim et al. (1986) found higher prevalence of 

gastrointestinal symptoms, for abdominal colic and constipation, respectively, in male battery 

manufacture workers, 41.3% for abdominal colic and 41.4% for constipation, compared to a 

reference group of workers, n = 40 prevalences of 7.5% and 10% for abdominal colic and 

constipation, respectively. The blood lead ranges were 55–81 μg/dL in the lead workers and 

7-33 μg/dL in the reference group. Matte et al. (1989) did not find a significant difference in 

prevalence of gastrointestinal symptoms (decreased appetite, nausea, abdominal pain) among a 

group of battery manufacture and repair workers (n = 63) when stratified by blood lead 

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concentration (60 μg/dL, $60 μg/dL). The prevalence ratio (high/low blood lead strata) for 

abdominal pain was 1.5 (95% CI: 0.5, 4.6). 

In a small study of environmentally-exposed adults, Bercovitz and Laufer (1991) found 

that the lead level in the dentine of patients with gastrointestinal ulcers (n = 11), even long after 

recovery, were significantly higher (mean lead 75.02 μg/g [SE 8.15]) than that in healthy 

subjects (mean lead 25.62 μg/g [SE 10.15]). Ten of the 11 peptic ulcer patients had a higher lead 

level than the healthy subjects. In these 10 patients, increased severity of the ulcer and longevity 

of suffering was associated with increased tooth lead levels. The authors suggested that 

increased absorption of lead was associated with damage to the epithelial mucosal cells of the 

gastrointestinal tract. 

6.9.6 Effects of Lead on the Respiratory System 

6.9.6.1 Summary of Key Findings of the Effects of Lead on the Respiratory System 

from the 1986 Lead AQCD 

The 1986 Lead AQCD did not discuss effects of lead on the respiratory tract on humans. 

Only one study since the 1986 document has examined the association between lead and 

respiratory health outcomes. 

6.9.6.2 Pulmonary Function 

Bagci et al. (2004) conducted pulmonary function tests on a group of male battery 

manufacture workers (n = 22), automobile exhaust repair workers (n = 40), and a group of 

hospital workers (n = 24). Mean blood lead concentrations were 37 μg/dL (SD 8) in the battery 

manufacture group, 27 μg/dL (SD 9) in the exhaust repair group, and 15 μg/dL (SD 3) in the 

hospital workers. Lead workers and the reference group had similar tobacco smoking 

prevalences (51–56%). Battery manufacture workers had significantly lower forced expiratory 

volume in one second (FEV1), FEV1:vital capacity (VC) ratio, FEV1/forced vital capacity (FVC) 

ratio, forced expiration flow (FEF), and maximum voluntary ventilation (MVV) compared to 

the hospital workers. Blood lead concentration was significantly negatively correlated with 

FEV1/FVC (r = −0.31, p = 0.006) and FEF (r = −0.30, p = 0.009) after adjusting for age, 

cigarette smoking, and exposure duration. Results from this study are further summarized in 

Annex Table AX6-9.9. 

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6.9.7 Effects of Lead on Bone and Teeth 

6.9.7.1 Summary of Key Findings of the Effects of Lead on Bone and Teeth from 

the 1986 Lead AQCD 

The 1986 Lead AQCD did not discuss the effects of lead on bone and teeth. Since 

completion of the 1986 AQCD, an additional development in lead epidemiology has been studies 

that have explored possible associations between lead exposure and risk of dental caries 

(Campbell et al., 2000; Dye et al., 2002; Gemmel et al., 2002; Moss et al., 1999). In addition, 

a limited number of studies also examined the toxic effect of lead on bone. These studies are 

summarized in Annex Table AX6-9.10. 

6.9.7.2 Bone Toxicity 

The number of papers dealing with direct toxicity of lead on bone is limited. Most papers 

are reviews (Hu et al., 1991; Puzas, 2000; Puzas et al., 1992; Rabinowitz, 1991; Silbergeld, 

1991; Silbergeld et al., 1993; Vig and Hu, 2000) or based on cellular studies (e.g., Pounds 

et al., 1991) or animals. 

Various authors have suggested that lead is a potential risk factor for osteoporosis because 

of the pivotal role of the skeleton in lead toxicokinetics (Goyer et al., 1994). Bone cells 

accumulate lead actively and earlier ideas suggested that lead was incorporated into the mineral 

matrix of the bone (Wittmers et al., 1988). However, in an in vivo iliac bone biopsy using laser 

microbeam mass analysis on a lead-intoxicated adult female following chelation therapy, Flood 

et al. (1988) found the extracellular lead was concentrated in the superficial 3 to 6 μm of the 

osteoid zone of bony trabeculae. As lead was absent from the deeper parts of the mineralized 

matrix, the authors suggested that lead binds more strongly to the organic matrix than to bone 

mineral. 

There is increasing evidence from cell culture experiments, animal studies, and from 

measurements in humans that lead may exert detrimental effects on bone mineral metabolism. 

In humans this evidence comes from several studies. Following on from the earlier observations 

of Rosen et al. (1980) that 1,25 (OH)2 vitamin D levels are reduced in lead poisoned children, 

Markowitz et al. (1988) found that osteocalcin levels were inversely related to lead body burden 

in moderately lead poisoned children. During chelation treatment for lead, the osteocalcin levels 

were shown to increase. 

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An inverse relationship between blood lead and stature and chest circumference has been 

observed in children from the NHANES II study (Schwartz et al., 1986). There are several 

explanations for the inverse correlation between blood lead and growth in children. First, blood 

lead level may be a composite factor for genetic, ethnic, nutritional, environmental, and 

sociocultural factors. Second, nutritional deficits that retard growth also enhance lead 

absorption. Finally, there may be a direct effect of low level lead on growth in children. This 

condition was explained by Dowd et al. (1994) as resulting from the inhibition by Pb2+ of 

binding of osteocalcin to hydroxyapatite. Effects similar to those described by Schwartz et al. 

(1986) were reported by Angle and Kuntzelman (1989), Lauwers et al. (1986), and Shukla et al. 

(1989). 

Puzas et al. (1992) suggested lead could upset the very sensitive interactive metabolic 

activity of osteoblasts and chondrocytes and thereby affect bone growth. In a later review, Puzas 

(2000) enlarged upon his earlier paper and described in more detail the potential mechanism of 

lead on growth plate cartilage metabolism and effects of lead on osteoclasts and osteoblasts, 

especially associated with osteoporosis. 

Observational studies by Spencer et al. (1992, 1994) suggested a link between 

occupational exposure to lead and Paget’s disease in both males and females but the authors 

declined to advocate a causal effect. Later Spencer et al. (1995) found that 92% of a group of 

48 patients with Paget’s disease were exposed to lead either from occupational or environmental 

sources. Adachi et al. (1998) explored a possible association between lead and bone disease 

from XRF analyses of cortical and trabecular bone lead content in 117 patients who attended a 

metabolic bone disease clinic (n = 92) or were undergoing dialysis for renal failure (n = 25). 

In patients suffering from Paget's disease, cortical bone lead content was higher than it was in 

controls, patients with osteoporosis, and patients on dialysis. Trabecular bone lead content was 

lowest in patients with Paget's disease or osteitis fibrosa. However, the authors could not 

distinguish between two alternatives, the first being that increased bone turnover due to Paget's 

disease releases lead from trabecular bone that is then available for deposition into cortical bone, 

or secondly, that an increased lead content in cortical bone may cause increased turnover with 

release of lead from trabecular bone. 

In another facet of the Normative Aging Study, Shadick et al. (2000) investigated a 

possible association between long-term lead accumulation and hyperuricemia and gouty arthritis 

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in 777 male subjects. They found a positive association between patella bone lead and uric acid 

levels (p = 0.022) but no association between bone or blood lead and gout in this 

environmentally-exposed group. 

6.9.7.3 Dental Health 

Caries is considered an infectious disease arising from a multifactorial process involving 

particular flora, dietary exposures, and a susceptible host (Schafer and Adair, 2000). Increased 

caries risk has been detected in association with increasing blood lead concentrations in 

populations whose mean blood lead concentrations are approximately 2–3 μg/dL (Dye et al., 

2002; Gemmel et al., 2002; Moss et al., 1999). 

Several studies have examined relationships between lead exposure and the occurrence of 

dental caries in children and adults. The two largest studies were analyses of data collected in 

the NHANES III; both found significant associations between increasing caries prevalence and 

increasing blood lead concentrations in children and adolescent (Moss et al., 1999) and the adult 

(Dye et al., 2002) populations, whose geometric mean blood lead concentration was ∼2.5 μg/dL. 

In the Moss et al. (1999) study, the odds ratios for caries in association with a 5 μg/dL increase 

in blood lead concentration (i.e., from <2 μg/dL) was 1.8 (95% CI: 1.3, 2.5). Outcomes of two 

smaller studies were mixed, with one study finding no significant association between blood lead 

and caries prevalence (Campbell et al., 2000) and one study finding significant associations 

(Gemmel et al., 2002); the latter, in children whose mean blood lead concentration was 2.9 

μg/dL (maximum 13 μg/dL). 

The Moss et al. (1999) NHANES III analysis included the results of coronal caries 

examinations on 24,901 subjects, stratified by age: 2–5 years (n = 3,547), 6–11 years (n = 2,894), 

and $12 years (n = 18,460). Specific outcomes assessed varied by age group: for children 2–11 

years who had at least one deciduous tooth, the number of deciduous teeth displaying decayed or 

filled surfaces (DFS); for subjects $6 years and who had at least one permanent tooth, the 

number of permanent teeth displaying decayed or filled surfaces; and for subjects $12 years, the 

sum of decayed, missing, and filled surfaces on permanent teeth (DMFS). In a multivariate 

linear regression model, increasing blood lead concentration (log-transformed) was significantly 

associated with covariate-adjusted increases in dfs in the 2–5 year age group ($ = 1.78 [SE 0.59], 

p = 0.004) and in the 6–11 year age group ($ = 1.42 [SE 0.51], p = 0.007). Log-transformed 

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blood lead also was associated with increases in DFS in the 6-11 years age group ($ = 0.48 

[SE 0.22], p = 0.03) and in the $12 years age group ($ = 2.50 [SE 0.69], p<0.001), and increases 

in DMFS in the $12 years age group ($ = 5.48 [SE 1.44], p = 0.01). The odds ratios (compared 

to 1st tertile, #1.66 μg/dL) for the binomial outcome, 0 or $1 DMFS, were 1.36 (95% CI: 1.01, 

2.83) for the blood lead concentration range 1.66-3.52 μg/dL, and 1.66 (95% CI: 1.12, 2.48) for 

the range >3.52 μg/dL. Corresponding population risks attributable to blood lead concentration 

were 9.6% and 13.5% in the blood lead strata, respectively. An increase in blood lead of 

5 μg/dL was associated with an odds ratio of 1.8 (95% CI: 1.3, 2.5). Covariates included in 

the models were age, gender, race/ethnicity, poverty income ratio, exposure to cigarette smoke, 

geographic region, educational level of head of household, carbohydrate and calcium intakes, 

and frequency of dental visits. 

Gemmel et al. (2002) conducted a cross-sectional study of associations between blood 

lead concentration and dental caries in children, 6-10 years of age (n = 543), who resided either 

in an urban (n = 290) or rural (n = 253) setting. Mean blood lead concentrations were 2.9 μg/dL 

(SD 2.0, maximum 13 μg/dL) in the urban group and 1.7 μg/dL (SD 1.0, maximum 7 μg/dL) in 

the rural group. Increasing blood lead concentration (ln-transformed) was significantly 

associated with covariate-adjusted number of caries (dfs + DFS) (ln-transformed) in the urban 

group ($ = 0.22 [SE 0.08], p = 0.005), but not in the rural group ($ = –0.15 [SE 0.09], p = 0.09). 

When dfs counts were stratified by permanent or deciduous teeth, the blood lead association in 

the urban group was significant for deciduous teeth ($ = 0.28 [SE 0.09], p = 0.002), but not for 

permanent teeth ($ = 0.02 [SE 0.07], p = 0.8). Covariates retained in the linear regression model 

were age, sex, ethnicity, family income, education of female guardian, maternal smoking, 

frequency of tooth brushing, firmness of toothbrush bristles, and frequency of chewing gum. 

Campbell et al. (2000) was a retrospective cohort study in which dfs were assessed in 

children 7-12 years of age (n = 248) from Rochester, NY. Mean blood lead concentration, 

measured at ages 18 and 37 months of age, was 10.7 μg/dL (range 18.0-36.8 μg/dL). The 

covariate-adjusted odds ratios for caries associated with a blood lead concentration >10 μg/dL 

compared to #10 μg/dL were 0.95 μg/dL (95% CI: 0.43, 2.09) for permanent teeth and 

1.77 μg/dL (95% CI: 0.97, 3.24) for deciduous teeth. Covariates retained in the logistic model 

were age, grade in school, number of tooth surfaces at risk. Other covariates examined in the 

models, all of which had no significant effect on the outcome, were gender, race/ethnicity, SES, 

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parental education, residence in community supplied with fluoridated drinking water, and 

various dental hygiene variables. This study did not demonstrate that lead exposure >10 μg/dL 

as a toddler was a strong predictor of caries among school-age children, but the authors noted 

that this might be due to limited statistical power. 

Dye et al. (2002) analyzed data collected in NHANES III on indices of periodontal bone 

loss. The analysis was confined to subjects 20-69 years of age (n = 10,033). The geometric 

mean blood lead concentration of the study group was 2.5 μg/dL (SE 0.08), with 2.4% of the 

group having blood lead levels >10 μg/dL. Increasing log-transformed blood lead was 

significantly associated with increasing prevalence of covariate-adjusted dental furcation 

($ = 0.13 [SE 0.05], p = 0.005). Dental furcation is indicative of severe periodontal disease. 

Covariates retained in the linear regression model were age, sex, race/ethnicity, education, 

smoking, and age of home. Smoking status was a significant interaction term when included in 

the model ($ = 0.10 [SE 0.05], p=0.034). When stratified by smoking status, the association 

between dental furcation and blood lead concentration was significant for current smokers 

($ = 0.21 [SE 0.07], p = 0.004) and former smokers ($ = 0.17 [SE 0.07], p=0.015), but not for 

nonsmokers ($ = –0.02 [SE 0.07], p = 0.747). 

Some studies examined the relationship between tooth lead concentrations and dental 

caries. In their compilation of metal concentrations in 1,200 deciduous teeth from a Norwegian 

population, Tvinnereim et al. (2000) found that carious teeth had higher lead concentrations than 

noncarious teeth. Gil et al. (1994) measured lead concentrations from 220 whole deciduous and 

permanent teeth from Coruna, Spain. The geometric mean lead level was 10.36 μg/g of tooth. 

There was a significant increase in teeth lead levels with advancing age. Permanent teeth 

showed higher mean lead values (13.09 μg/g [SEM 1.07]) than deciduous teeth (3.96 μg/g 

[SEM 1.07]). The authors reported a possible relationship between increased lead content and 

periodontal pathology but did not observe any relationship between caries and lead 

concentrations. 

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6.9.8 Effects of Lead on Ocular Health 

6.9.8.1 Summary of Key Findings of the Effects of Lead on Ocular Health from the 

1986 Lead AQCD 

The 1986 Lead AQCD did not address effects of lead on ocular health in humans. 

Various disturbances of the visual system have been observed in association with overt clinical 

lead poisoning, including retinal stippling and edema, cataracts, ocular muscle paralysis, and 

impaired vision (see Otto and Fox, 1993 for review). Two longitudinal studies completed since 

1986 provide evidence for possible associations between lead exposure and visual evoked retinal 

responses in children of mothers whose blood lead concentrations in mid-pregnancy were in the 

range of 10–32 μg/dL (Rothenberg et al., 2002), and evidence for a possible association between 

lead exposure and risk of cataracts in middle-aged males whose tibia bone lead levels were in 

the range 31–126 μg/g (Schaumberg et al., 2004). These studies are summarized in Annex 

Table AX6-9.11. 

6.9.8.2 Ocular Effects 

In the Mexico City prospective lead study, Rothenberg et al. (2002) measured 

flash-evoked electroretinograms (ERG) in a subset of the study group (n = 45) at ages 7–10 

years. As part of the prospective study, blood lead concentrations had been measured during 

pregnancy and in the children, at birth and every 6 months, thereafter. Increasing maternal blood 

lead, measured at 12 weeks of gestation, was significantly associated with increasing ERG awave and b-wave amplitude, with significant increases in a-wave in the second maternal blood 

lead tertile (range 6.0–10.0 μg/dL), and a-wave and b-wave in the third maternal blood lead 

tertile (range 10.5–32.5 μg/dL), compared to the first blood lead tertile (range 2.0–5.5 μg/dL). 

No other blood lead measurements were significantly associated with any ERG outcomes. 

As part of the longitudinal Normative Aging Study, Schaumberg et al. (2004) analyzed 

prevalence of cataracts in adult males (n = 642), mean age 69 years (range 60–93). Subjects 

were stratified by blood lead, patella bone lead, or tibia bone lead quintiles for a logistic 

regression analysis of the odds ratios for cataracts (first quintile as reference). Covariate 

adjusted odds ratio for cataracts in the fifth tibia bone lead quintile was significant (3.19 [95% 

CI: 1.48, .90]). Odds ratios for cataracts were not significantly associated with patella bone lead 

(1.88 [95% CI: 0.88, 4.02]) or blood lead (0.89 [95% CI: 0.46, 1.72]). The first and fifth 

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quintile lead levels were 0–11 μg/g and 31–126 μg/g for tibia bone; 1–16 μg/g and 43–165 μg/g 

for patella bone; and 1.0–3.0 μg/g and 8–35 μg/g for blood. Covariates retained in the 

regression model were age, smoking, history of diabetes; and daily intake of vitamin C, vitamin 

E, and carotenoids. 

Cavalleri et al. (1982) measured visual fields of male workers in a polyvinyl pipe 

manufacturing facility (n = 35) who were exposed to lead stearate. Workers in a reference group 

(n = 350) were individually matched for age, smoking, and alcohol consumption. Visual 

sensitivity was significantly lower in lead workers compared to the reference group; however, 

visual sensitivity index was not significantly associated with blood or urine lead. Prevalence of 

scotoma in the mesopic field was 28.5% in the lead workers and 0% in the reference group. 

Mean blood lead levels were 46 μg/dL (range 21–82 μg/dL) in the lead workers and 30 μg/dL 

(range 21-42 μg/dL) in the reference group. 

6.9.9 Summary of the Epidemiologic Evidence for the Effects of Lead 

on Other Organ Systems 

Biochemical Effects of Lead 

Evidence for disruption of heme synthesis derives from numerous studies in which lead 

exposure has been associated with decreased activities of enzymes in the heme synthesis 

pathway (i.e., ALAS, ferrochelatase) and increased levels of substrates for heme synthesis (i.e., 

ALA, coproporphyrin, erythrocyte protoporphrin) in both children and adults. Quantitative 

relationships between blood lead concentration and the above biomarkers of impaired heme 

synthesis are highly consistent across studies (e.g., Alessio et al., 1977, 1976; Gennart et al., 

1992; Hernberg et al., 1970; Morita et al., 1997; Oishi et al., 1996; Piomelli et al., 1982; Roels 

and Lauwerys, 1987; Selander and Cramer, 1970; Soldin et al., 2003; Wildt et al., 1987). 

Increases in blood lead concentration of approximately 20–30 μg/dL are sufficient to halve 

erythrocyte ALAD activity and sufficiently inhibit ferrochelatase to double erythrocyte 

protoporphyrin levels. 

Associations between occupational exposure to lead and changes in blood lipid 

composition have been observed. These include increased levels of lipid peroxides in blood 

and/or serum (Jiun and Hsien, 1994; Sugawara et al., 1991; Ito et al., 1985) and increased serum 

levels of total and HDL cholesterol (Kristal-Boneh et al., 1999). Effects on serum cholesterol 

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levels were evident in association with a mean blood lead concentration of 42 μg/dL (KristalBoneh et al., 1999) or a range of 5–62 μg/dL (approximated mean 14 μg/dL) (Ito et al., 1985). 

Oxidative changes in blood lipids (e.g., increased levels of lipid peroxides and malondialdehyde 

levels) as well as decreased levels of erythrocyte superoxide dismutase, catalase, G6PD, and 

GSH peroxidase; and increased lymphocyte reactive oxygen species and depleted GSH levels, 

indicative of increased oxidative stress, have been observed in lead workers in association with 

blood lead concentrations >30 μg/dL (Fracasso et al., 2002; Ito et al., 1985; Jiun and Hsien, 

1994; Solliway et al., 1996; Sugawara et al., 1991). 

Disruption of Hemoglobin Synthesis and Declines in Erythrocyte Numbers 

Exposures that result in blood lead concentrations below 40 μg/dL appear to be tolerated 

without a decline in blood hemoglobin levels or hematocrit. However, perturbation of 

erythropoiesis, indicated by changes in serum erythropoietin and progenitor cells, occurs in 

association with blood lead concentrations below 40 μg/dL and in the absence of detectable 

changes in blood hemoglobin levels or hematocrit in children (Graziano et al., 2004; Liebelt 

et al., 1999) and adults (Graziano et al., 1990; Osterode et al., 1999; Romeo et al., 1996). Risk of 

clinical anemia in children becomes appreciable at much higher blood lead concentrations; a 

10% decrease in hematocrit has been estimated to occur in association with blood lead 

concentrations $85 μg/dL; a 10% probability of anemia (hematocrit <35%) was estimated to be 

associated with a blood lead concentration of approximately 20 μg/dL at age 1 year, 50 μg/dL at 

age 3 years, and 75 μg/dL at age 5 years. (Schwartz et al., 1990). In adults, with blood lead 

levels below 25 μg/dL, increasing patella bone lead, but not blood lead, was associated with a 

significant decrease in hematocrit. 

Effects on the Endocrine System 

Several studies have examined possible associations between lead exposures in children 

and adults and various biomarkers of endocrine function, including the thyroid, male 

reproductive, and calcitropic endocrine systems. The strongest study designs have yielded no 

associations, or weak associations, between lead exposure and thyroid hormone status (Erfurth 

et al., 2001; Schumacher et al., 1998; Tuppurainen et al., 1988; Zheng et al., 2001). Studies of 

occupational exposures which included subjects having blood lead concentrations exceeding 

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100 μg/dL have found depression of serum T3 and/or T4 levels, without a detectable increase in 

serum TSH; however, studies in which the blood lead distribution was dominated by levels well 

below 100 μg/dL, have found either no effects or subclinical increases in serum T3, T4, with no 

change in TSH levels. 

Studies of the male reproductive system that attempted to control for confounding effects 

of age have yielded mixed outcomes (Alexander et al., 1998, 1996; Erfurth et al., 2001; 

Gustafson et al., 1989; McGregor and Mason, 1990; Ng et al., 1991). Blood lead ranges in these 

studies were similar (4–90 g/dL), yet outcomes were mixed, with no change (Erfurth et al., 2001; 

Gustafson et al., 1989; McGregor and Mason, 1990), or subclinical decrease (Alexander et al., 

1998, 1996; Ng et al., 1991) in serum testosterone (TES) in association with lead exposure. 

There are also mixed effects on serum follicle stimulating hormone (FSH) and luteinizing 

hormone (LH) with increases (McGregor and Mason, 1990; Ng et al., 1991), decreases 

(Gustafson et al., 1989), and with no change (Alexander et al., 1998, 1996; Erfurth et al., 2001) 

in hormone levels observed. The inconsistency in the direction of effects on TES and the two 

androgen-regulating pituitary hormones, FSH and LH, is particularly noteworthy, in the absence 

of evidence for effects of lead exposure on GNRH-induced FSH (Erfurth et al. 2001). 

Children exposed to relatively a high level of lead >30 μg/dL may exhibit depressed 

levels of circulating 1,25-OH-D (Mahaffey et al., 1982; Rosen et al., 1980). However, 

associations between serum vitamin D status and blood lead may not be present in calciumreplete children who have average lifetime blood lead concentrations below 25 μg/dL (Koo 

et al., 1991). In adults, exposures to lead that result in blood lead concentrations >40–60 μg/dL 

may increase, rather than decrease, circulating levels of 1,25-OH-D and PTH (Kristal-Boneh 

et al., 1999; Mason et al., 1990). 

Effects on the Hepatic System 

Few studies of hepatic effects of lead on humans have been reported since the 1986 Lead 

AQCD. Studies of hepatic enzyme levels in serum suggest that liver injury may be present in 

lead workers; however, associations specifically with lead exposures are not evident (Al-Neamy 

et al., 2001; Hsiao et al., 2001). Studies of urinary metabolites of cytochrome P450 phenotypes 

CYP2A6 and CYP3A4 suggest possible associations between lead exposure and suppression of 

hepatic enzyme activity. The effect on CYP2A6 activity was observed in children with high lead 

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burdens (i.e., blood lead concentration >40 μg/dL, EDTA-provoked urinary lead >500 μg/dL). 

The effect on CYP3A4 was observed in association with blood lead ranges of approximately 

30-112 μg/dL (based on reported serum lead concentrations). 

Effects on the Gastrointestinal System 

Several studies of prevalence of symptoms of gastrointestinal colic in lead workers 

provide evidence for symptoms in association with blood lead concentrations >50–80 μg/dL 

(Awad el Karim et al., 1986; Holness and Nethercott, 1988; Lee et al., 2000; Matte et al., 1989). 

Similar types of studies of children have not been reported. 

Effect on Bone and Teeth 

There is limited, but suggestive evidence of an association between lead exposure and 

bone toxicity. However, in most studies, it is difficult to assess the direct contribution of lead on 

bone diseases or reduced growth. Several studies that have explored possible associations 

between lead exposure and risk of dental caries (Campbell et al., 2000; Dye et al., 2002; Gemmel 

et al., 2002; Moss et al., 1999). Increased caries risk has been detected in association with 

increasing blood lead concentrations in populations whose mean blood lead concentrations are 

approximately 2-3 μg/dL (Dye et al., 2002; Gemmel et al., 2002; Moss et al., 1999). 

Ocular Health 

Various disturbances of the visual system have been observed in association with overt 

clinical lead poisoning, including retinal stippling and edema, cataracts, ocular muscle paralysis, 

and impaired vision (Otto and Fox, 1993). Two longitudinal studies completed since the 1986 

Lead AQCD provide evidence for possible associations (a) between lead exposure and visual 

evoked retinal responses in children of mothers whose blood lead concentrations in midpregnancy was 10.5–32.5 μg/dL (Rothenberg et al., 2002) and (b) between lead exposure and 

risk of cataracts in middle-aged males whose tibia bone lead levels were 31-126 μg/g 

(Schaumberg et al., 2004). 

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6.10 INTERPRETIVE ASSESSMENT OF THE EVIDENCE IN 

EPIDEMIOLOGIC STUDIES OF LEAD HEALTH EFFECTS 

6.10.1 Introduction 

A remarkable expansion has occurred since the 1990 Lead Supplement in the extent of the 

database available for drawing inferences about the various expressions of lead toxicity. 

Moreover, the nature of the evidence available has changed as well. Many of the studies 

conducted prior to 1990 focused on the issue of whether an observed observation was likely to be 

real or the result of chance, selection bias, residual confounding, or some other methodological 

error. The validity of any association still needs to be assured. The studies since 1990 mainly 

focus on characteristics of the pertinent concentration-response relationships, including the 

functional forms of the relationships, the slopes of the relationships, the natural histories of 

adverse effects, and the effect modifying influences of various co-exposures and host 

characteristics. 

6.10.2 Exposure and Outcome Assessment in Lead Epidemiologic Studies 

6.10.2.1 Assessment of Lead Exposure and Body Burdens Using Biomarkers 

For any health endpoint of interest, the most useful biomarker of exposure is one that 

provides information about the lead dose at the critical target organ and, moreover, reflects the 

exposure averaging time that is appropriate to the underlying pathogenetic processes (e.g., 

cumulative over lifetime, cumulative over a circumscribed age range, concurrent, etc.). In recent 

studies of lead and health, the exposure biomarkers most frequently used are blood lead and bone 

lead. For outcomes other than those relating to hematopoeisis and bone health, these biomarkers 

provide information about lead dose that is some distance from the target organ. For example, 

given that the central nervous system is considered the critical target organ for childhood lead 

toxicity, it would be most helpful to be able to measure, in vivo, the concentration of lead at the 

cellular site(s) of action in the brain. Because such measurements are not currently feasible, 

however, investigators must rely on measurements of lead in the more readily accessible but 

peripheral tissues. The relationship between brain lead and lead in each of these surrogate 

tissues is still poorly understood, although the pharmacokinetics clearly differs among these 

compartments. In both rodents and nonhuman primates, brain lead level falls much more slowly 

than blood lead level following chelation with succimer and, in the rodent, in nonchelated 

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animals after cessation of exposure. These observations suggest that using blood lead as an 

index of lead in the brain will result in exposure misclassification, although the magnitude of this 

bias in any specific setting will be difficult to characterize. The most likely direction, however, 

would be underestimation of the amount of lead in the brain, at least under scenarios involving 

chronic exposure. 

As an exposure biomarker, blood lead level has other limitations. Only about 5% of an 

individual’s total body lead burden resides in blood. Furthermore, blood consists of several subcompartments. More than 90% of lead in whole blood is bound to red cell proteins such as 

hemoglobin, with the balance in plasma. From a toxicological perspective, this unbound fraction 

is likely to be the most important sub-compartment of blood lead because of the ease with which 

it diffuses into soft tissues. The concentration of lead in plasma is much lower than in whole 

blood, however. For example, in a group of pregnant women with blood lead levels below 

10 μg/dL, plasma lead levels were less than 0.3% of the whole blood lead level. The greater 

relative abundance of lead in whole blood makes its measurement much easier (and more 

affordable) than the measurement of lead in plasma. The use of whole blood lead as a surrogate 

for plasma lead could be justified if the ratio of whole blood lead to plasma lead were well 

characterized, but this is not so. At least some studies suggest that it varies several-fold among 

individuals with the same blood lead level. Moreover, the ability of red cells to bind lead is 

limited, so the ratio of blood lead to plasma lead would be expected to be nonlinear. Thus, 

interpreting whole blood lead level as a proxy for plasma lead level, which, itself, is a proxy for 

brain lead level, will result in some exposure misclassification. 

Another limitation in the use of blood lead as the exposure biomarker is that its residence 

time in blood is closely linked to red cell lifetime, with a half-time on the order of 30 days. 

Thus, a high blood lead level does not necessarily indicate a high body lead burden. Similarly, 

individuals who have the same blood lead level will not necessarily have similar body burdens or 

exposure histories. The rate at which blood lead level changes with time/age depends on 

exposure history due to re-equilibration of lead stored in the various body pools. In nonchelated 

children, the time for blood lead to decline to a value less than 10 μg/dL was linearly related to 

baseline blood lead level. A single blood lead measurement might therefore provide limited 

information about an individual’s lead exposure history, a difficulty frequently cited with respect 

to the interpretation of cross-sectional studies of pediatric lead toxicity, in which children’s blood 

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lead level is often measured only once, and sometimes only well after the period when levels 

typically peak (18-30 months). If it is exposures to lead in the early postnatal years that are most 

detrimental to children’s development, categorizing a child’s exposure status based on the blood 

lead level that is contemporaneous with the measurement of neurodevelopment at school-age 

could result in exposure misclassification. Unless intra-individual stability of serial blood lead 

levels is very high within a study cohort, misclassification would probably be non-differential, 

more likely resulting in an underestimate rather than an overestimate of the effect of lead on 

child neurodevelopment (Jurek et al., 2005). This concern must be qualified, however, by recent 

data from some longitudinal studies indicating that concurrent blood lead level, even at ages well 

beyond 18 to 30 months, is sometimes the strongest predictor of late outcomes (Dietrich et al., 

1993a,b; Canfield et al., 2003a; Tong et al., 1996; Wasserman et al., 2000b). Age-related 

changes in vulnerability, and the reasons why it might differ across studies, remain uncertain. 

It might be that among children with chronically elevated exposure, but not in children with 

relatively low lifetime exposure, blood lead level measured at school-age is a reasonably good 

marker of cumulative exposure. That concurrent blood lead level is, under some circumstances, 

a stronger predictor of school-age outcomes than is blood lead level in the early postnatal years 

does not necessarily imply greater vulnerability of the brain to ongoing than to past exposure. 

The development of X-ray-fluorescence (XRF) methods for measuring lead in 

mineralized tissues offers another approach for characterization and reconstruction of exposure 

history. Such tissues are long-term lead storage sites, with a half-life measured in decades and 

contain approximately 90% of the total body lead burden in adults and 70% in children. Thus, 

bone lead is an index with a long exposure averaging time. XRF methods have proven useful in 

studying individuals with occupational lead exposure, those living in highly polluted 

environments, and those for whom community lead exposures are or, in the past, were relatively 

high (e.g., Korrick et al., 1999; Schwartz et al., 2000a,b,c,d). In a relatively highly exposed 

cohort of pregnant women in Mexico City, higher bone lead levels at one month postpartum 

were associated with reduced birth weight, less infant weight gain, smaller head circumference 

and birth length, and slower infant development (Gomaa et al., 2002; Gonzalez-Cossio et al., 

1997; Hernandez-Avila et al., 2002; Sanin et al., 2001). Among children living near a large lead 

smelter in Yugoslavia, IQ at age 10-12 years was more strongly associated, inversely, with tibia 

lead level than with blood lead level (Wasserman et al., 2003). 

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Current XRF methods for measuring bone lead levels have limitations, however. 

Temporal features of exposure history cannot readily be discerned. Some progress has been 

made toward this goal by examining the spatial distribution of lead in teeth in relation to the 

relative abundance of stable lead isotopes, but the specialized technologies needed to carry out 

these analyses are unlikely ever to be widely available, and the unpredictability of tooth 

exfoliation makes this tissue difficult to collect unless the study design involves contact with 

(and the cooperation of) participants at the appropriate ages. Current XRF methods might not be 

sufficiently sensitive for studies of the health effects of low-dose community exposures. The 

bone lead levels of a large percentage of subjects might be below the detection limit, e.g., 80% in 

a case-control study of bone lead levels and juvenile delinquency in which the minimum 

detection limit was 21.5 μg/g bone mineral (Needleman et al., 2002). Even among individuals 

known to have histories of substantial lead exposures, such as adolescents and young adults who 

grew up near the Bunker Hill smelter in Idaho (McNeill et al., 2000), bone lead levels tend to be 

low. Lead appears to be deposited at sites of most active calcification. In children, this is 

trabecular bone, in which the rate of fractional resorption in early childhood is high. Depending 

on the amount of the child’s ongoing exposure, lead deposited in bone might not remain there for 

decades, making bone lead level an imprecise index of lifetime lead exposure. This concern also 

exists in the use of tooth lead to represent cumulative lead exposure in children. Rabinowitz 

et al. (1993) observed that a child’s tooth lead level was more strongly related to blood lead level 

around the time of tooth exfoliation than to an integrated index of blood lead level prior to 

exfoliation. Finally, it is difficult to compare the performance of different laboratories using 

XRF methods to measure bone lead because of the absence of standard reference materials. 

Nevertheless, efforts continue to modify the instrumentation or measurement protocols to reduce 

the detection limit. 

A major research need is the development and validation of biomarkers of critical dose 

that, compared to blood lead or bone lead, are fewer toxicokinetic steps removed from the sites 

of lead’s actions in the brain. One promising front in the effort to deduce the contents of the 

“black box” separating external dose and clinical disease is the measurement of processes and 

products that potentially mediate the association between them. For example, magnetic 

resonance spectroscopy (MRS) has been used in small case series to measure the ratio of 

N-acetylaspartate (NAA) to creatine, which are a marker of neuronal and axonal damage and 

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thus, an early biological effect rather than a biomarker of exposure. In children, higher lead 

exposures are associated with lower NAA to creatine ratios in the frontal gray matter and, to a 

lesser extent, in frontal white matter (Trope et al., 1998, 2001). Similarly, an adult who had 

higher bone and blood lead levels than did his monozygotic twin had both greater 

neuropsychological deficits and lower NAA to creatine ratios in the hippocampus, frontal lobe, 

and midbrain (Weisskopf et al., 2004). While much remains uncertain about the interpretation of 

MRS, the use of this and other biochemical imaging methods, in combination with more 

conventional structural and functional imaging methods, might bring us closer to understanding 

the mechanisms of lead neurotoxicity. With the number of toxicokinetic steps separating lead 

levels at the critical target organs from the usual exposure biomarkers, the progress made in 

characterizing the concentration-response relationships is remarkable. 

6.10.2.2 Assessment of Health Outcomes 

Outcome measurement and outcome classification have generally received less attention 

from investigators than have exposure measurement and misclassification. The specific 

problems are, to some extent, endpoint domain-specific. With regard to neurodevelopmental 

toxicities, critical issues are whether the assessment instruments used are psychometrically sound 

and appropriate for the study cohort, the data generated will support adequate tests of the study 

hypotheses, and whether the instruments have been administered and scored consistently and 

correctly. With regard to the cardiovascular toxicities of increased blood pressure/prevalence of 

hypertension, the critical issue is whether the blood pressure value recorded for a participant is 

an accurate estimate. Multiple measurements of blood pressure are frequently made in a study 

but investigators usually have not taken advantage of the collected information to quantify the 

amount of error in the measurements. This information can be used to improve the reliability of 

the measurements, which would be expected to improve the precision of the associations 

estimated. Similarly, aggregating scores to estimate latent variables representing, for instance, 

“language skills” or “visual-spatial skills” is an approach that might take advantage of the 

overlapping information provided by the multiple tests included in neurobehavioral test batteries, 

producing more reliable endpoint variables. This approach, however, has not been widely 

applied in lead studies. 

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6.10.3 Concentration-Response Relationship of Lead Health Effects 

Recent studies have not altered the consensus that the developing nervous system is the 

organ system that is most sensitive to lead toxicity in children and adults. Neurobehavioral 

deficits appear to occur at lower levels of exposure than do other adverse health effects, although 

adverse effects in other organ systems have been observed in some susceptible populations at 

similarly low levels (e.g., adverse renal outcomes in individuals with hypertension or chronic 

renal insufficiency). Effects have been reported at blood lead levels as low as 1 to 2 μg/dL in the 

case of neurobehavioral toxicity. Accumulating data appear to validate well the statement made 

in the 1996 AQCD and Addendum, and 1990 Supplement that adverse effects occur at blood 

lead levels of 10 to 15 μg/dL or “possibly lower.” In a recent study of 6 to 16 year old children 

in the NHANES III survey, concentration-related deficits in reading and arithmetic scores were 

found even when analyses were restricted to children with concurrent blood lead levels below 

5 μg/dL (Lanphear et al., 2000). 

Canfield et al. (2003a) applied semi-parametric models with penalized splines to their 

data, essentially allowing the data to reveal the functional form that best described them. These 

analyses showed that the IQ decline per μg/dL increase in blood lead was greater below 

10 μg/dL than it was above 10 μg/dL. The estimated slope of the IQ decline per μg/dL was 

greatest among children for whom the maximum blood lead level measured over the course of 

the study never exceeded 10 μg/dL. A similarly steeper slope at lower than at higher blood lead 

levels was found in a re-analysis of the Boston prospective study (Bellinger and Needleman, 

2003). 

Identifying the functional form that best fits a particular set of data and that presumably 

serves as the best description of the pertinent underlying concentration-response relationship is 

clearly important. The linear model (Figure 6-10.1) is, as the name implies, linear over the entire 

range of the exposure data. For certain tests, the assumption is made that the residuals (observed 

– predicted response) are normally distributed with constant variance, but violations of this 

assumption (heteroscedasticity) have no real effect on the estimation and minimal effect on the 

tests of significance (see Annex Section AX6.10). If heteroscedasticity is present but all other 

conditions are met, regression still yields unbiased estimators, but the standard errors can be 

larger than when remedial efforts such as using weighted regression are employed. The use of 

regression requires no assumption concerning the distribution of the independent variable 

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402(c) Economic Analysis Chapter 5 727
Figure 6-10.1. Comparison of a linear and log-linear model to describe the relationship 

between exposure and response. 

1 (lead exposure marker). However, when the form of the heteroscedasticity is an increase in 

2 variance with level of blood lead and when the data are lognormally distributed or otherwise 

3 skewed, there are possibly a large number of influential data points at high blood lead where the 

4 data is least reliable. In this case, a log transformation of blood leads may result in more precise 

5 estimation of the slope parameter. The presence of heteroscedasticity and other departures from 

6 assumptions forming the basis for regression analysis can be detected by using diagnostic tests or 

7 graphics. These are rarely used in epidemiologic studies of lead health effects. 

8 The log-linear model (see Figure 6-10.1) is written as: 

9 Response = α + $ Ln(lead exposure marker), 

10 where Ln is the natural logarithmic function. The log-linear model is concave upwards 

11 (assuming that the estimated coefficient is negative). It approaches a linear function for very 

12 high exposure values, but approaches infinity at very low exposure values. In other words, it is 

13 assumed that the adverse effect of lead is greater at lower than at higher blood lead levels. 

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Blood lead levels have been shown repeatedly to follow a lognormal distribution (Azar et al., 

1975; Billick et al., 1979; Hasselblad and Nelson, 1975; Yankel et al., 1977; Hasselblad et al., 

1980; U.S. Environmental Protection Agency, 1986), but this fact is not an argument for 

choosing the log-linear model. The choice of either log-linear or linear may be based on the 

Akaike’s Information Criteria (Akaike, 1973), J-test (Davidson and MacKinnon, 1981), or other 

statistical tests if the choice is to be based on the best fitting model. Rothenberg and Rothenberg 

(2005) compared the linear lead model with the log-linear lead model for the pooled data from 

Lanphear et al. (2005) using the J-test. The J-test showed that the log lead specification was still 

significant (p = 0.009) in a model that also included the linear lead specification, indicating that 

the log lead specification described the data significantly better than did the linear lead 

specification. Other models have been used, such as nonparametric models, spline functions, 

and polynomial models, but the vast majority of the analyses have used either a linear model or a 

log-linear model. 

Nonlinear concentration-response relationships are not uncommon in toxicology, although 

many of these are claimed to be examples of hormesis, with the lowest doses of a toxicant being 

associated with a beneficial effect rather than a greater adverse effect. A biological mechanism 

for a steeper slope at lower than at higher blood lead levels has not been identified. Perhaps the 

predominant mechanism at very low blood lead levels is rapidly saturated, and that a different, 

less rapidly saturated process becomes predominant at blood lead levels greater than 10 μg/dL. 

This ad hoc explanation is more descriptive than explanatory, however, and the specific 

processes that would produce this result have not yet been identified. Nevertheless, relationships 

of this apparent form have been observed in several data sets, indicating the need to determine 

whether such a relationship is real or a statistical artifact. 

An important caveat regarding efforts to specify the functional form of the concentrationresponse relationship is that the accuracy that can be achieved is constrained by the extent to 

which the biomarker of lead concentration does, in fact, reflect the concentration at the critical 

target organ, the brain. The greater the misclassification, the more uncertain will be the 

biological relevance of the best statistical description of the concentration-response relationship. 

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6.10.4 Interindividual Variability in Susceptibility to Lead Toxicity 

Although increased lead exposure has been linked to adverse health effects in many 

different organ systems, scatterplots reveal tremendous variability of observed points about the 

best fit lines representing the concentration-response relationships. In other words, individuals 

for whom the lead biomarker measured has the same value can have markedly different values 

on the health indicator measured. Even for neurobehavioral deficits in children, the correlation 

between biomarker level and test score rarely exceeds !0.2, indicating that the explained 

variance in the test score generally does not exceed 5%. A major challenge is therefore to 

decompose this variability, to distinguish components of it that reflect error from components 

that reflect biological processes that determine an individual’s response to lead. 

Deviation of the observed points from the fitted point can have many sources. Exposure 

misclassification is one source. The lead biomarker measured might not adequately capture the 

lead dose delivered to the target organ and at the time that is most appropriate biologically. 

In general, the error would be expected to be non-differential, i.e., it would not introduce a 

systematic bias in estimation of the concentration-response relationship. On average, such 

misclassification would be expected to result both in an attenuation of the slope of the 

concentration-response relationship and an increase in the scatter of the observations. As focus 

shifts to the risks associated with lower and lower levels of lead exposure, the importance of 

errors introduced by poor dosimetry will assume greater importance insofar as the effects at such 

levels will presumably be more subtle and increasingly difficult to detect amid the noise 

contributed by exposure misclassification. Outcome misclassification is another source of error 

that is likely to contribute to apparent interindividual variability in response. This results if the 

indicator of the critical health effect that is measured is fallible, i.e., an imperfect measure of the 

target function. Such misclassification would generally be expected to be non-differential, 

introducing random noise rather than a systematic bias. 

Another likely source of scatter in observed points is true interindividual variability in 

response to a given lead dose. That is, the magnitude of individual response to lead might 

depend on other characteristics of that individual. Three major categories of such effect 

modifying factors that might influence susceptibility to lead toxicity are genetic polymorphisms, 

nutritional status, and social environmental factors. Adequate data are not available to provide a 

quantitative estimate of the amount of interindividual variability in susceptibility to lead. 

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6.10.4.1 Influence of Genetic Polymorphisms on Risk 

Genetic polymorphisms that are presumed to influence lead toxicokinetics and/or 

toxicodynamics have been identified, mostly in studies of adults who were occupationally 

exposed to lead. Compared to workers with the wild type allele of amino levulinic acid 

dehydratase, workers with the variant allele had a higher mean blood lead level, greater leadassociated renal dysfunction, and an increased risk of amyotrophic lateral sclerosis (Kamel et al., 

2003). Lead workers with the ATP1A2(3N) polymorphism appear to be at increased risk of leadassociated effects on blood pressure (Glenn et al., 2001). The slope of the association between 

floor dust lead and blood lead is steeper among children with the less common variant of the 

vitamin D receptor (Fox 1 or B) than among children with the wild-type allele (Haynes et al., 

2003). In adults, these same alleles are associated with higher blood lead levels and increased 

blood pressure (Schwartz et al., 2000c; Lee et al., 2001). Greater lead-associated reductions in 

renal function have been observed in adults with a variant allele of nitric acid synthetase, 

although cardiovascular outcomes, such as blood pressure and hypertension do not appear to 

depend on eNOS (endogenous nitric oxide synthase) allele (Weaver et al., 2003). Adults with 

variants of the hemochromatosis gene (C282Y and/or H63D) have higher patella lead levels 

(Wright et al., 2004). Only one polymorphism has been shown to modify lead neurotoxicity. 

Lead workers with the apolipoprotein E4 allele showed greater lead-associated decreases in 

neurobehavioral function than did workers with the E1, E2, or E3 alleles (Stewart et al., 2002). 

This work is in its early stages, and while it promises to shed light on bases of susceptibility to 

lead toxicity, firm conclusions cannot yet be drawn. 

6.10.4.2 Influence of Nutritional Status on Risk 

Only limited epidemiologic data are available on the role of nutritional status in 

modifying an individual’s risk of lead toxicity. Adjusting for severity of environmental lead 

contamination, iron-deficient children appear to have higher blood lead levels than iron-replete 

children (Bradman et al., 2001). One interpretation of these data is that children experiencing the 

same external lead dose can experience different internal doses. In another study of iron status, a 

decline in blood lead level was associated with improved cognitive performance in ironsufficient but not in iron-deficient children (Ruff et al., 1996). Among the possible explanations 

for this finding is that iron deficiency contributes to pharmacodynamic variability, increasing the 

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toxicity of a given lead dose. Some evidence suggests that the intellectual deficit associated with 

an elevated blood lead level is greater among undernourished children than well-nourished 

children (Gardner et al., 1998). 

Several studies have suggested that dietary calcium may have a protective role by 

decreasing absorption of lead in the gastrointestinal tract and decreasing the mobilization of lead 

from bone stores to blood, especially during periods of high metabolic activity of the bone such 

as pregnancy and lactation. Lower calcium intake during pregnancy, especially the second half, 

appears to increase the mobilization of lead from bone compartments (Hernandez-Avila et al., 

1996). However, in other studies, calcium supplementation had no effect on bone lead levels 

pregnant and lactating women (Rothenberg et al., 2000; Téllez-Rojo et al., 2002). 

6.10.4.3 Influence of Health Status on Risk 

The influence of an individual’s health status on susceptibility to lead toxicity has been 

demonstrated most clearly for renal outcomes. Individuals with diabetes, hypertension, and 

chronic renal insufficiency are at increased risk of lead-associated declines in renal function and 

adverse effects have been demonstrated at blood lead levels below 5 μg/dL (Lin et al., 2001, 

2003; Muntner et al., 2003; Tsaih et al., 2004). As discussed in an earlier section, children with 

nutritional deficiencies also appear to be more vulnerable to lead-associated neurobehavioral 

deficits. 

6.10.4.4 Influence of Co-Exposures on Risk 

Epidemiologic studies do not provide an adequate basis for determining whether cigarette 

smoking and/or alcohol affect the nature or severity of the health effects associated with lead 

exposure. Both factors have often been included in models of both child and adult health 

outcomes in order to adjust for potential confounding. In addition, both have been evaluated as 

pertinent pathways of adult exposure. However, their possible roles as effect modifiers have not 

been well studied. 

Although most individuals are not exposed to lead in isolation but to lead in combination 

with other toxicants including cadmium, arsenic, mercury, and polychlorinated biphenyls, 

epidemiologic studies generally have focused solely on lead. Other toxicant exposures have 

sometimes been measured but are usually treated as potential confounders in the statistical 

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analyses, with their status as potential modifiers of lead toxicity left unexplored (Bellinger, 

2000). As a result, epidemiologic studies do not provide an adequate basis for determining 

whether co-exposure to other toxicants affects the nature or severity of the health effects 

associated with lead exposure. 

6.10.4.5 Influence of Timing of Exposure on Risk 

6.10.4.5.1 Children 

Studies do not provide a definitive answer to the question of whether lead-associated 

neurodevelopmental deficits are the result of exposure during a circumscribed critical period or 

of cumulative exposure. Although support can be cited for the conclusion that it is exposure 

within the first few postnatal years that is most important in determining long-term outcomes 

(Bellinger et al., 1992), other studies suggest that concurrent blood lead level is as predictive, 

and perhaps more predictive, of long-term outcomes than are early blood lead levels (Canfield 

et al., 2003a; Dietrich et al., 1993a,b; Tong et al., 1996; Wasserman et al., 2000b). Because of 

the complex kinetics of lead, an accumulative toxicant, it is extremely difficult to draw strong 

conclusions from these observational studies about windows of heightened vulnerability in 

children. The high degree of intraindividual “tracking” of blood lead levels over time, especially 

among children in environments providing substantial, chronic exposure opportunities (e.g., 

residence near a smelter or in older urban dwellings in poor repair), poses formidable obstacles 

to identifying the time interval during which exposure to lead caused the health effects measured 

in a study. It could be that damage occurred during a circumscribed period when the critical 

substrate was undergoing rapid development, but that the high correlation between serial blood 

lead levels impeded identification of the special significance of exposure at that time. Under 

such circumstances, an index of cumulative blood lead level or concurrent blood lead level, 

which might be a good marker of overall body burden under conditions of relatively steady-state 

exposure, might bear the strongest association with the adverse effect. 

6.10.4.5.2 Aging Population 

Increases in blood lead for postmenopausal women have been attributed to release of lead 

from the skeleton associated with increased bone remodeling during menopause in both 

occupationally- and environmentally-exposed women (Garrido-Latorre et al., 2003; Popovic 

et al., 2005). In middle-aged to elderly males from the Normative Aging Study, patella lead 

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accounted for the dominant portion of variance in blood lead (Hu et al., 1996). These findings 

provide evidence that the skeleton may serve as a potential endogenous source of lead in the 

aging population. 

Considerable evidence also suggests that indicators of cumulative or long-term lead 

exposure are associated with adverse effects in several organ systems, including the central 

nervous, renal, and cardiovascular systems. Among occupationally-exposed men, higher tibia 

lead levels have been associated with increased cognitive decline over repeated assessments 

(Schwartz et al., 2005). With regard to the renal system, increased lead exposure may accelerate 

the effects of normal aging, producing a steeper age-related decline in function. Weaver et al. 

(2003) observed that higher lead exposure and dose were associated with worse renal function in 

older workers, but with lower blood urea nitrogen and serum creatinine in young workers. 

6.10.4.5.3 Pregnancy 

Potential mobilization of lead from the skeleton also occurs during pregnancy and 

lactation due to increased bone remodeling (Hertz-Picciotto et al., 2000; Manton, 1985; 

Silbergeld, 1991). In women who have been exposed to lead in childhood and have accumulated 

large stores in their bones, there may be significant mobilization of lead from bone to blood 

during late pregnancy and lactation. The greatest probability of lead toxicity for the mothers will 

be in postpartum while they are lactating; the infants will be particularly vulnerable during the 

prenatal period, especially in the last weeks of pregnancy (Manton et al., 2003). 

A variety of adverse reproductive outcomes have been associated with higher paternal or 

maternal lead exposures, including reduced fertility, spontaneous abortion, gestational 

hypertension, congenital malformations, fetal growth deficits, and neurobehavioral deficits in 

offspring. The levels of exposure at which different adverse outcomes occur vary. Increased 

risks of spontaneous abortion, neurobehavioral deficits in offspring and, in some studies, 

gestational hypertension, have been reported at pregnancy blood lead levels below 10 μg/dL 

(Bellinger, 2005). 

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6.10.5 Reversibility of Lead Health Effects 

6.10.5.1 Natural History of Effects 

The absence of a clear operational definition of “reversibility” is a major impediment to 

drawing inferences about the natural history of any adverse effect associated with an 

accumulative neurotoxicant such as lead. Rather than indicating irreversibility, a performance 

deficit that remains detectable after external exposure has ended could reflect ongoing toxicity 

due to lead remaining at the critical target organ or lead deposited at the organ post-exposure as 

the result of redistribution of lead among body pools. As noted earlier, brain lead levels can 

remain elevated long after blood lead levels fall. A rigorous test of reversibility would require 

that every lead atom has been cleared from the body. This being unattainable, investigators must 

exploit opportunities that permit only weaker tests of hypotheses about reversibility. These 

include assessing the persistence of deficits previously associated with lead biomarkers and 

evaluating performance changes associated with natural experiments, i.e., events such as 

chelation or a change in external exposure that would be expected to perturb the equilibrium of 

lead among different body pools. 

The likelihood of reversibility, as defined above, appears to be related, at least for the 

adverse effects observed in certain organ systems, to both the age-at-exposure and the age-atassessment. In occupationally-exposed adults, the central and peripheral nervous system 

correlates of higher lead burdens appear to attenuate if exposure is reduced. 

The prospective studies of childhood lead exposure, involving serial measurements of 

lead biomarkers and health outcomes, provide the best opportunities available to assess the 

natural history of adversities associated with low-level lead exposures. In some prospective 

studies, associations observed in infancy between biomarkers of prenatal exposure and 

neurodevelopment attenuated by the time children reached preschool age. It can be difficult to 

determine, however, whether this reflects actual disappearance of the effect or an increased 

difficulty in detecting it due to the emergence of associations between neurodevelopment and 

lead biomarkers measured postnatally. It is notable, however, that in some prospective studies of 

children, associations between biomarkers of prenatal lead exposure and various outcomes in 

middle adolescence have been reported, suggesting that the persistence of the associations might 

be endpoint-specific. For example, among children in Kosovo, Yugoslavia, IQ scores at the age 

of 8 years were inversely associated with a composite index of prenatal lead exposure (average 

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of mothers’ blood lead levels at midpregnancy and at delivery) (Wasserman et al., 2000). This 

association was independent of changes in postnatal blood lead levels. Among 15 to 17 year old 

inner-city children in Cincinnati, OH, maternal blood lead levels in the 1st trimester (ranging 

from 1 to ~30 μg/dL) were inversely related to attention and visuoconstruction (Ris et al., 2004) 

and positively related to the frequency of self-reported delinquent behaviors (Dietrich et al., 

2001). 

The results of the prospective studies are more consistent in showing that higher postnatal 

lead biomarkers are associated with neurocognitive deficits that persist, in some studies, into 

early adulthood when the concurrent lead exposures are generally much lower. Ongoing external 

exposure does not appear to be necessary to maintain the deficits, although, as noted previously, 

it is not possible to exclude entirely a role for ongoing endogenous exposures of the target organs 

resulting from the redistribution, over time, of lead stores among different compartments. These 

data are consistent with those from experimental nonhuman primate studies, in which the 

temporal characteristics of exposure are manipulated as opposed to merely observed as in the 

human studies. 

In most epidemiologic studies, the potential for true longitudinal analysis of the data has 

not been fully exploited, with the data evaluated in what is effectively a series of cross-sectional 

analyses. 

6.10.5.2 Medical Interventions 

Data from the Treatment of Lead Poisoned Children (TLC) study, a randomized 

controlled trial of the late outcomes of children treated for lead poisoning, support the hypothesis 

that the deficits associated with exposures of such magnitude are persistent and, possibly, 

permanent (Dietrich et al., 2004; Rogan et al., 2001). At 36-months post-treatment and at age 7 

years, no significant differences in cognition or behavior were noted between the succimer and 

placebo groups. Current blood lead levels were significantly associated with cognitive 

performance at baseline, 36-months post-treatment, and at 7 years of age, and the regression 

coefficients were similar in magnitude to those estimated in observational studies (i.e., ~3 point 

IQ decline per 10 μg/dL increase in blood lead), providing a linkage between the results of the 

observational studies and those of this experimental study. However, within-child analyses 

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indicated that changes in developmental test scores over time were not consistently associated 

with changes over time in blood lead level. 

6.10.6 Confounding of Lead Health Effects 

6.10.6.1 Adjustment for Confounding in Epidemiologic Studies of Lead 

The possibility that the adverse health effects associated with increased lead exposure in 

epidemiologic studies are, in fact, due to risk factors with which increased lead exposure is 

associated remains the most important impediment to drawing causal inferences. Various 

approaches have been taken to reduce the uncertainty this creates. Some investigators have 

specified the sampling frame or the eligibility criteria so as to increase the homogeneity of the 

study participants on factors known to be strong risk factors for the outcome of interest, thereby 

reducing the correlation between them and lead, and their potential to confound any association 

observed between increased lead exposure and poor outcome. Reducing confounding by means 

of design decisions has the disadvantage that an investigator cannot determine whether the 

impact of lead on the outcome varies depending on the factor whose range of potential values has 

been restricted. More frequently, however, investigators have relied on statistical procedures, 

applied post data collection, to identify and control for potential confounding. Unlike sample 

restriction, this approach preserves the opportunity to explore possible modification of the lead 

effect by cofactors. 

Adjustment for confounding has been performed primarily using multiple regression 

analyses and data stratification. For multiple regression modeling, stepwise regression has been 

frequently used for covariate selection. Stepwise regression has many faults and is often less 

acceptable then the use of a few well-chosen covariates. However, the stepwise regression 

methodology may be considered less bias as it selects from a class of variables that represent a 

wide scientific viewpoint rather than the narrower one of the investigator. One problem with 

stepwise regression pointed out by Bellinger (2004) is that the usual adjustment strategy assumes 

that all the variance in the response shared by the exposure and the confounder belongs to the 

confounder. In some settings, this is likely to be excessively conservative, because confounders 

can, to some extent, also be proxies for exposure. This is further discussed in the next section. 

Splitting the data set into smaller data sets (partitioning or stratification) and analyzing 

those data sets separately was used in some of the studies examining the relationship between 

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blood pressure and lead. This practice also has some advantages and disadvantages. 

An advanced statistical method could be used to determine how the partitioning should be done 

(Young and Hawkins, 1998), which could reveal relationships that would not be possible to 

detect using the usual regression techniques. A disadvantage of partitioning a small data set is 

that the smaller sample size may lack the power to detect otherwise detectable associations and 

to yield reliable estimates. 

The segmented line model consists of joined straight line segments where the joined 

points are chosen to best fit the data (Quandt, 1958). The log-linear and the quadratic models 

have shown in several cases to better fit the biomarker-response relationship than the linear 

model. However, these models are not considered practicable for extrapolation outside the range 

of the biomarker variable. The segmented line model is suggested as a more reasonable model 

for extrapolation into the low-concentration sparse-data region. 

6.10.6.2 Confounding Adjustment on Lead Health Effect Estimates 

The ability of the investigator to determine how much of the apparent association between 

a lead biomarker and an outcome reflects residual confounding by a cofactor depends on the 

characteristics of the joint distribution of lead and the cofactor. Co-factors for lead health effects 

include maternal IQ, maternal smoking, alcohol use, birth weight, and many others depending on 

the health outcome of interest. Some of these cofactors are truly independent predictors and can 

be adjusted for using multiple regression analyses. Under some circumstances, however, lead 

and the cofactor may be so highly related that one cannot be confident that their associations 

with the outcome have been disentangled by the statistical methods applied. Moreover, the true 

causal relationships among lead, the cofactors, and the outcome might not be sufficiently well 

understood that the outcome variance shared by lead and the cofactors can be characterized 

appropriately in the analyses. 

In studies of lead and neurodevelopment, the magnitude of the lead coefficient, reflecting 

the decline in test score per unit increase in the lead biomarker, is substantially reduced, often by 

half or more, by adjusting for markers of the social environment. During the 1980s, adjustment 

for parental IQ and quality of the home environment (e.g., HOME scores) became almost 

mandatory if the findings of a study of lead and children's cognitive outcomes were to be 

considered credible. While both factors surely strongly influence child outcomes in ways that 

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are independent of lead, a case can also be made that lead might contribute to the associations. 

A parent’s IQ presumably reflects the parent's early lead exposure and, assuming that the 

physical environments in which a parent and child grow up are not completely unrelated to one 

another, provide similar lead exposure opportunities. Adjusting for parent IQ in evaluating the 

association between a child's lead exposure and his or her IQ, therefore, will result in an 

underestimate of the contribution of the child's lead exposure to his or her IQ. Similarly, if early 

lead exposure alters child behavior, the transactional model of child development would generate 

the prediction that the changes will elicit different behaviors from parents, altering the 

characteristics of the child rearing environment. For instance, increased lead exposure might 

result in an infant being more irritable, less soothable, and the parent less nurturing. In so far as 

measurement of the quality of the rearing environment in studies occurs after the children have 

experienced some lead exposure, the hypothesis that lead is responsible for shaping some aspects 

of that environment cannot be entirely dismissed, and control for HOME scores might be 

excessively conservative. For example, in the pooled analysis by Lanphear et al. (2005) that 

included seven prospective studies, the crude coefficient for concurrent lead and childhood IQ 

score was −4.66 (95% CI: −5.72, −3.60), but the coefficient adjusted for study site, HOME 

score, birth weight, maternal IQ, and maternal education was −2.70 (95% CI: −3.74, −1.66). 

Other aspects of model building in assessing the association of lead with health outcomes 

also warrant comment. In many studies of lead and cognitive outcomes in children, investigators 

have adjusted for factors such as birth weight or length of gestation that might, themselves, 

reflect adverse effects of lead, i.e., mediating factors that lie between lead and condition on the 

causal pathway. The coefficient estimated for lead in a model that contained such factors would 

be smaller in magnitude than it would be if terms for such mediating factors had not been 

included. 

Recognizing imperfections in the ability to measure such factors well, a concern is 

expressed that the lead coefficient could be reduced further, perhaps all the way to the null, 

if better, more comprehensive methods of measurement were applied. On the other hand, the 

methods used to adjust for such factors may be excessively conservative insofar as they attribute 

to a factor all of the outcome variance that it shares with lead, despite the likelihood that the true 

relationships among lead, social factors, and outcome are unlikely to be as simple as this model 

assumes. Some factors might, in part, be markers of lead exposure opportunities. For example, 

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both lead biomarker levels and lower cognitive function in children are associated with lower 

social class standing. Social class is a complex construct that conveys information about a 

multitude of factors that might influence children's health, including the amount of lead in 

environmental media. Thus, some of the association between lower social class and poorer 

health might reflect the effect of higher lead exposure. If so, routine adjustment of health 

outcome for social class in assessing the association between increased lead exposure and poorer 

health in children will fail to distinguish these lead-related and non-lead-related components of 

the association between social class and health, and, in fact, will assume that all of it is non-leadassociated. It is nearly impossible to actually determine if the problem of overadjustment exists 

in a particular data set. There are several statistical methods which attempt to address this 

problem. These include using partial F tests, ridge regression, path analysis, and structural 

equations. None of these methods are completely satisfactory. 

6.10.7 Inferences of Causality 

Even with more sophisticated and nuanced models, however, any conclusions about the 

causal forces generating the results of any observational epidemiologic study are necessarily 

uncertain. In the absence of random assignment to exposure group, residual confounding will 

always be a possible explanation of an observed association. As in other areas of epidemiology, 

a weight-of-evidence approach remains the best option available as a basis for drawing of causal 

inferences. If the association between a lead biomarker and a health outcome of interest is 

observed in settings that vary widely in terms of the characteristics of the social environment 

including sociodemographic and cultural characteristics, characteristics of the study participants, 

including nutritional status, genetic factors, and lifestyle factors, the likelihood that the 

association is attributable, in its entirety, to residual confounding is reduced. For instance, the 

pooled analyses of data contributed by many of the international prospective studies provide a 

compelling demonstration that the association between blood lead level and child IQ is 

remarkably robust across disparate socio-cultural settings (Lanphear et al., 2005). Even such 

consistency in the effect estimate across diverse settings is only indirect and weak evidence of 

causality, however. In general, epidemiologic studies rarely provide data that enhance our 

understanding of the “black box” between biomarkers of lead burden and indicators of health 

status. Epidemiologic data identify associations between exposure biomarkers and health 

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indicators, but are not highly informative regarding possible mechanisms of lead toxicity that 

underlie the associations. A critical stage in applying the overall weight-of-evidence approach is 

the examination of the epidemiologic data in the context of data from experimental animal 

behavioral and mechanistic studies. Although such data have their own limitations, they are not 

subject to many of the most important potential biases that can becloud the interpretation of the 

epidemiologic data. 

6.10.8 Effects on the Individual Versus Effects on the Population 

The critical distinction between population and individual risk, an issue pertinent to many 

questions in chronic disease epidemiology, has frequently been blurred in discussions of the 

public health implications of lead-associated decrements in health. With respect to 

neurodevelopment, while it may be true that a two- or three-point decline in IQ may not be 

consequential for an individual, the same level of decline observed in a population mean is of 

great importance. Similarly, although an increase of a few mm Hg in blood pressure may 

generally not be of concern for an individual’s well-being, a very modest increase in the 

population mean is associated with substantial increases in the percentages of individuals with 

values that are sufficiently extreme that they exceed the criteria used to diagnose illness (Rose 

and Day, 1990). In other words, the mean value conveys substantial information about the 

percentage of individuals with clinically relevant, extreme values of the indicator. Moreover, 

interventions that shift the population mean by an amount that is without clinical consequence 

for an individual have been shown to produce substantial changes in the percentage of 

individuals with indicator values that are clinically significant (Bellinger, 2004). The following 

subsections will discuss quantitatively lead-related effects of a population level change in IQ and 

blood pressure. 

6.10.8.1 Effects of Lead on Intelligence 

The outcome most often examined to investigate neurotoxic effects of lead is IQ. 

Although the definition of “intelligence” is quite abstract, IQ remains a useful outcome measure 

as it is correlated with important measures of life success, such as academic achievement, 

earnings, and social status (Bellinger, 2003; Weiss, 2000). Several studies reported quantitative 

relationships between full scale IQ and current blood lead levels for children aged 5 to 11 years 

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402(c) Economic Analysis Chapter 5 741
1 old, and these are summarized in Table 6-10.1. The estimated relationships as reported by the 

2 authors are used. 

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Table 6-10.1. Summary of Studies with Quantitative Relationships for 

IQ and Blood Lead 

Estimated Slope Estimated Slope 

(IQ points/μg/dL) – (IQ points/μg/dL) – 

Blood Lead 10th to Blood Lead Under 

 Reference Study Location n 90th Percentile 10 μg/dL 

Bellinger et al. (1992) Boston, Massachusetts 116 !0.5 NA 

Canfield et al. (2003a) Rochester, New York 182 !0.7 !0.8 

Dietrich et al. (1993a) Cincinnati, Ohio 221 !0.3 !0.3 

Ernhart et al. (1989) Cleveland, Ohio 160 !0.1 NA 

Wasserman et al. (1997) Kosovo, Yugoslavia 231 !0.2 NA 

Baghurst et al. (1992) Port Pirie, South Australia 324 !0.2 !0.4 

Silva et al. (1988) Dunedin, New Zealand 579 !0.3 !0.3 

Lanphear et al. (2005) International Pooled Analysis 1,333 !0.5 !0.2 

5 The curves over a range of blood lead levels from the 10th percentile to the 90th 

6 percentile are shown in Figure 6-10.2. The curves are restricted to that range because log-linear 

7 curves become very steep at the lower end of the blood lead levels, and this may be an artifact of 

8 the model chosen. The percentiles are estimated using various methods and are only 

9 approximate values. Studies which estimated a linear relationship are shown as reported, and 

10 similarly for the log-linear relationships. Note that these are not forest plots of slopes or hazard 

11 ratios – they are the actual estimated relationships. 

12 The analysis by Lanphear et al. included the studies of Baghurst et al. (1992), Bellinger 

13 et al. (1992), Canfield et al. (2003a), Dietrich et al. (1993a), Ernhart et al. (1989) and Wasserman 

14 et al. (1997). The pooled analysis also included the Mexico City study of Schnaas et al. (2000). 

15 The results from Schnaas et al. are not included in Table 6-10.1 or Figure 6-10.2 because the 

16 

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402(c) Economic Analysis Chapter 5 742
Figure 6-10.2. Concentration-response relationships of IQ to blood lead for the individual 

studies and the pooled analysis by Lanphear et al. (2005). 

1 authors did not provide regression coefficients in their paper, thus concentration-response 

2 relationship were not estimable. The study by Silva et al. (1988) is not included in the pooled 

3 analysis of Lanphear et al., but is included in this section as its results are comparable 

4 and informative. 

5 Several conclusions can be drawn from these graphs. First, note that the overall IQ levels 

6 are quite different. This results from different populations and from different applications of the 

7 IQ tests. Second, all studies showed a decreasing IQ score as the blood lead level increased. 

8 It is the slope of the studies that is relevant, not the actual IQ scores. Third, for studies with 

9 lower blood lead levels, the slopes appear to be steeper. This is the reason that many authors 

10 choose to use the log-linear model. However, for those studies where the blood leads were 

11 generally high, the log-linear and linear models are almost identical. Thus it is not surprising 

12 that some authors chose a linear model instead of a log-linear model. The curves in Figure 

13 6-10.2 do not show evidence of a no-effect threshold because the slopes increase as the blood 

14 lead levels become smaller. The observed mean adjusted IQ levels (for blood lead <5, 5 to 10, 

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402(c) Economic Analysis Chapter 5 743
1 10 to 15, 15 to 20, and >20 μg/dL) reported by Lanphear et al. (2005) also show no evidence of a 

2 threshold, as seen in Figure 6-10.3. 

3 

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Figure 6-10.3. Mean blood lead levels adjusted for HOME Score, maternal education, 

maternal IQ, and birth weight from the pooled analysis of seven studies by 

Lanphear et al. (2005). Mean adjusted IQ levels at blood lead levels of <5, 

5 to 10, 10 to 15, 15 to 20, and >20 μg/dL are shown. 

5 Weiss (1990) predicted, on purely statistical grounds, that a downward shift of five points 

6 in mean IQ, if the amount of dispersion in the distribution remained the same, should be 

7 accompanied by a doubling of the numbers of individuals with scores two or more standard 

8 deviations below the mean and a reduction by half of the number of individuals with scores two 

9 or more standard deviations above the mean. With respect to lead, the general accuracy of this 

10 prediction has been empirically demonstrated in two different datasets by Needleman et al. 

11 (1982) and Bellinger (2004). The example below provides further evidence of the change in 

12 percentages of individuals with IQ <70 or <50 points after restricting the analysis to those with 

13 blood lead levels less than 10 μg/dL. 

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The average slope was estimated for those studies with a significant portion of the 

subjects with blood lead levels less than 10 μg/dL. These average slopes are given in Table 

6-10.1. In addition, the results of Lanphear et al. (2005) were considered. The average slope 

at blood lead levels less than 10 μg/dL from that pooled analysis was !0.5 IQ points per μg/dL. 

Based on the individual studies and the pooled analysis it appears that the average slope 

is between !0.3 and !0.5 points per μg/dL, with the exception of the large negative slope of 

!0.8 points per 10 μg/dL from the study by Canfield et al. (2003a). The value of !0.4 points per 

μg/dL will be used in calculations of the implications of the slope at blood lead levels less than 

10 μg/dL. 

A nonexposed population was assumed to have a standard mean IQ of 100 and standard 

deviation of 15 at a blood lead exposure of 0 μg/dL. The fraction of the population that would 

have an IQ <70 or <50 as a function of blood lead level was then calculated. The results are 

shown in Figure 6-10.4. Note that the fraction with an IQ level below 70, a level often requiring 

community support to live (World Health Organization, 1992) increases from a little over 

2 percent for no lead exposure to about 4 percent with a blood lead level of 10 μg/dL. 

In addition, the fraction with an IQ level below 50, a level often requiring continuous support to 

live (World Health Organization, 1992) increases from a little over 4 per 100,000 for no lead 

exposure to about 11 per 100,000 with a blood lead level of 10 μg/dL. 

A shift in the mean value of a health indicator has substantial importance for both 

extremes of the distribution. In the case of lead, a downward shift in the mean IQ value is 

associated not only with a substantial increase in the percentage of individuals achieving very 

low scores, it is associated as well with a substantial decrease in the percentage achieving very 

high scores. Based on the study by Bellinger et al. (1987) examining intelligence test scores of 

lead-exposed children, Weiss (1988) discussed the shift of the population distribution of IQ from 

a mean of 100 and a standard deviation of 15 to a mean of 95, a 5% reduction. When the mean 

IQ level is 100, 2.3% of the individuals in a given population would score above 130. However, 

with the population distribution shift and the resulting mean decline in IQ, only 0.99% of the 

individuals would score above 130. Weiss states that the implication of such as loss transcends 

the current circumscribed definitions of risk. 

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402(c) Economic Analysis Chapter 5 745
Figure 6-10.4. Effect of blood lead on fraction of population with IQ level <70 or 

<50 points. 

1 6.10.8.2 Cardiovascular Effects of Lead 

2 In studies investigating the cardiovascular effects of lead, blood pressure has been 

3 examined most frequently. Results from the Framingham Heart Study show that higher levels of 

4 blood pressure, even within the nonhypertensive range, impose increased rates of cardiovascular 

5 disease (Kannel, 2000a,b). A continuous graded increase in cardiovascular risk is observed as 

6 blood pressure increases, with no evidence of a threshold value. Most events arise not in the 

7 most severe cases, but mainly in those with high normal blood pressure (i.e., mild hypertension). 

8 This view is further supported by the Seventh Report of the Joint National Committee on 

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Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (Chobanian et al., 

2003). Kannel (2000b) states that reducing even moderate elevation in blood pressure is likely to 

be beneficial. 

Kannel (2000a) states that systolic blood pressure exerts a strong, influence on 

cardiovascular events, as it is the prime causal function of hypertension and its adverse 

cardiovascular sequelae. Cardiovascular events include coronary disease, stroke, peripheral 

artery disease, and cardiac failure. Risk ratios are larger for cardiac failure and stroke, but 

coronary disease (i.e., myocardial infarction, angina pectonis, sudden death) is the most common 

and most lethal sequela of hypertension (Kannel, 1996). Kannel (2000a) notes that the 

Framingham Heart Study has recognized that elevated blood pressure tends to occur alongside 

other major risk factors of cardiovascular disease such as glucose intolerance, dyslipidemia, 

abdominal obesity, and left ventricular hypertrophy, among others. If a cluster of multiple risk 

factors is present, the hazard is formidable for coronary disease and stroke. 

No critical level of blood pressure is evident. The risk appears to be simply proportional 

from the lowest to the highest level recorded. In the Multiple Risk Factor Intervention Trial 

(MRFIT), Neaton et al. (1995) confirmed a continuing and graded influence of systolic blood 

pressure on cardiovascular disease mortality extending down into the range of <140 mm Hg. 

The Prospective Studies Collaboration (2002) meta-analysis of 61 prospective studies relates 

blood pressure to vascular mortality without indication of a threshold down to 115/75 mm Hg. 

The absence of a demonstrable safe or critical level of blood pressure suggests using the range of 

blood pressure rather than discrete categories such as hypertension. 

Many studies have suggested a relationship between blood lead and systolic blood 

pressure. In particular, the meta-analysis of Nawrot et al. (2002) indicated that a doubling of the 

blood lead corresponded to a 1 mm Hg increase in systolic blood pressure. Although this 

magnitude of increase is not clinically meaningful for an individual, a population shift of 

1 mm Hg is important. 

The Framingham Heart Study results (Kannel, 2000a) were used to estimate a typical 

population distribution of systolic blood pressure values (Figure 6-10.5). The distribution of 

systolic blood pressure values was approximated well by a lognormal distribution for both 

women and men (p $ 0.4). The relationship between systolic blood pressure and the risk of 

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402(c) Economic Analysis Chapter 5 747
Figure 6-10.5. Distribution of systolic blood pressure in women and men aged 35 to 

64 years from the Framingham Heart Study (Kannel, 2000a). 

1 cardiovascular events was also given by Kannel (2000a). The relationships are shown in 

2 Figure 6-10.6. 

3 To estimate population risk, it was assumed that the effect of blood lead on blood pressure 

4 was to shift the entire distribution by the amount given by Nawrot et al. (2002). For each shift in 

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402(c) Economic Analysis Chapter 5 748
Figure 6-10.6. Relationship of cardiovascular events (coronary disease, stroke, 

peripheral artery disease, cardiac failure) to systolic blood pressure in 

women and men aged 35 to 64 years from the Framingham Heart Study 

(Kannel, 2000a). 

1 the distribution, the entire distribution was integrated out over the risk given in Figure 6-10.6. 

2 The result estimated was expected number of cardiovascular events per 1,000 person years, and 

3 this was plotted for blood lead levels ranging from 5 to 15 μg/dL for both women and men. The 

4 results are shown in Figure 6-10.7. Although the effects are modest, they translate into a large 

5 number of events for a moderate population size. For example, a decrease in blood lead from 

6 10 to 5 μg/dL results in an annual decrease of 27 events per 100,000 women and 39 events per 

7 100,000 men. 

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402(c) Economic Analysis Chapter 5 749
Figure 6-10.7. Effect of blood lead on expected annual risk of cardiovascular events per 

1,000 person years. 

1 6.10.9 Summary of Key Findings and Conclusions Derived from Lead 

2 Epidemiology Studies 

3 The remarkable progress that has been made since the mid-1980s in understanding the 

4 effects of lead on health can be gauged by noting the changes that have occurred over time in 

5 the questions investigators have addressed. In the 1980s, the question of interest was often, 

6 “Does low-level lead exposure affect health?” The questions asked in recent studies have more 

7 often focused on details of the associations, including the shapes of concentration-response 

8 relationships, especially at levels well within the range of general population exposures, 

9 biological and socio-environmental factors that either increase or decrease an individual’s risk, 

10 the prognoses associated with lead-associated effects, the efficacy of interventions to reduce 

11 adverse effects, and so on. In fact, “low-level,” a term long-used to describe exposures that are 

12 not sufficiently high to produce clinical signs and symptoms, is increasingly being recognized as 

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a descriptor that has little biological meaning and is interpretable only in a specific historical 

context. What was considered “low” in the 1980s is an order of magnitude higher than the 

current mean level in the U.S. population, and the current mean remains perhaps as much as two 

orders of magnitude above “natural” background levels in humans. The current CDC screening 

guideline for children of 10 μg/dL is not a “bright line” separating toxicity from safety, but 

merely a risk management tool. There is no level of lead exposure that can be clearly identified, 

with confidence, as “safe.” Recent studies of lead neurotoxicity in infants have observed adverse 

effects at blood lead levels of only 1 or 2 μg/dL and adverse renal outcomes have been reported 

at blood lead levels below 5 μg/dL. Public health interventions have resulted in declines, over 

the last 25 years, of more than 90% in the mean blood lead level within all age and gender 

subgroups of the U.S. population, substantially decreasing the numbers of individuals at risk of 

lead toxicities. 

The following are a listing of key health outcomes discussed earlier in the epidemiology 

chapter: 

•	 Neurotoxic effects of lead in children. The effects of lead on neurobehavior in children 

have been observed with remarkable consistency across numerous studies of various 

designs, populations, and developmental assessment protocols. The negative impact of 

lead on neurocognitive ability and other neurobehavioral outcomes persist in most recent 

studies even after adjustment for numerous confounding factors including social class, 

quality of caregiving, and parental intelligence. An international pooled analysis of seven 

prospective cohort studies offers evidence that exposure to lead has an effect on the 

intellectual attainment of preschool and school age children even at blood lead levels 

below 10 μg/dL. 

Epidemiologic studies have demonstrated that lead also may be associated with 

increased risk for antisocial and delinquent behavior, which may be a consequence of 

attention problems and academic underachievement among children who have suffered 

higher exposures to lead during their formative years. Direct measures of brain damage 

using Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) 

also are suggesting evidence of harm due to lead exposure. Pharmacological or nutritional 

intervention strategies generally have not shown to eliminate or reduce lead-associated 

neurodevelopmental morbidities. 

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•	 Neurotoxic effects of lead in adults. Environmental lead exposure has not been found to 

be associated with impaired cognitive performance in the elderly if competing risk factors 

are considered. In adults, the effect of lead on the nervous system may not be detected 

through neurobehavioral testing due to cognitive reserve, the ability to compensate for 

brain impairment. 

Numerous studies of occupational lead exposure observed associations of blood 

lead with peripheral sensory nerve impairment, visuomotor and memory impairment, and 

postural sway abnormalities. Past occupational exposure to lead also was associated with 

increased risk of developing Amyotrophic Lateral Sclerosis (ALS), motor neuron disease, 

and essential tremor. The odds of developing ALS and essential tremor were significantly 

increased in individuals with the ALAD2 allele. These neurobehavioral impairments in 

occupationally-exposed individuals were typically associated with higher blood lead levels 

(approximately 30-40 μg/dL); however, essential tremor was found to be associated with 

much lower blood lead levels (mean 3 μg/dL). 

•	 Renal effects of lead. In the general population, both cumulative and circulating lead was 

found to be associated with longitudinal decline in renal functions. In the large NHANES 

III study, renal dysfunction was observed in hypertensives at a mean blood lead of only 

4.2 μg/dL. These results provide strong evidence that the kidney is a target organ for 

adverse effects from lead in adults at current U.S. environmental exposure levels. The 

renal impact in children environmental lead exposure is difficult to assess since the most 

studies have measured early biological effect markers and their prognostic value is 

uncertain. 

Studies involving the longitudinal assessment of renal function decline in 

susceptible patient populations observed that low levels of blood lead (<5 μg/dL) and 

chelatable lead levels were associated with decline in glomerular filtration rate over a 

4 year follow-up period in patients with chronic renal insufficiency. Renal function in 

these patients was found to stabilize and, in some cases, improve after therapeutic 

chelation. 

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•	 Cardiovascular effects of lead. Epidemiologic studies support the relationship between 

increased lead exposure and increased adverse cardiovascular outcome, including 

increased blood pressure and increased incidence of hypertension. A recent meta-analysis 

reported that a doubling of blood lead level was associated with a 1.0 mm Hg increase in 

systolic blood pressure and a 0.6 mm Hg increase in diastolic pressure. Studies also have 

found that cumulative past lead exposure (e.g., bone lead) may be as important, if not 

more, than present exposure in assessing cardiovascular effects. The evidence for an 

association of lead with cardiovascular morbidity and mortality is limited but supportive. 

•	 Reproductive and developmental effects of lead. The epidemiologic evidence suggests 

small associations between exposure to lead and male reproductive outcomes, including 

perturbed semen quality and increased time to pregnancy. These associations appear at 

blood lead levels greater the 45 μg/dL, as most studies only considered exposure in the 

occupational setting. There are no adequate data to evaluate associations between lead 

exposure and female fertility. For many other outcomes, the observed associations are 

fairly small, especially at the levels of exposure that are currently of interest. However, 

there may be populations that are highly susceptible to lead-related reproductive effects, 

especially if they have additional risk factors for these outcomes. 

•	 Genotoxic and carcinogenic effects of lead. Studies of genotoxicity consistently find 

associations of lead exposure with DNA damage and micronuclei formation; however, the 

associations with the more established indicator of cancer risk, chromosomal aberrations, 

are inconsistent. Epidemiologic studies of highly-exposed occupational populations 

suggest a relationship between lead and cancers of the lung and the stomach; however the 

evidence is limited by the presence of various potential confounders, including 

coexposures (e.g., arsenic, cadmium), smoking, and dietary habits. The 2004 IARC 

review concluded that lead was a probable carcinogen based on limited evidence in 

humans and sufficient evidence in animals. 

•	 Effects of lead on the immune system. Several studies have examined possible 

associations between lead exposures and biomarkers of immune function. Findings from 

recent epidemiologic studies suggest that lead exposure may be associated with effects on 

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cellular and humoral immunity. These effects include changes in serum immunoglobulin 

levels; perturbation of peripheral lymphocyte phenotype profiles, including decreases in 

peripheral blood T-cell abundance and changes in T-cell to B-cell abundance ratios; 

suppression of lymphocyte activation; and suppression of neutrophil chemotaxis and 

phagocytosis. Studies of biomarkers of humoral immunity in children have consistently 

found significant associations between increasing blood lead concentrations and serum 

IgE levels at blood lead levels below 10 μg/dL. 

•	 Effects of lead on the hematopoietic system. Lead exposure has been associated with 

disruption of heme synthesis in both children and adults. Increases in blood lead 

concentration of approximately 20–30 μg/dL are sufficient to halve erythrocyte ALAD 

activity and sufficiently inhibit ferrochelatase to double erythrocyte protoporphyrin levels. 

Perturbation of erythropoiesis, indicated by changes in serum erythropoietin and 

progenitor cells, occurs in the absence of detectable changes in blood hemoglobin levels or 

hematocrit in children and adults at blood lead levels below 40 μg/dL. Risk of clinical 

anemia in children becomes appreciable at much higher blood lead concentrations. 

•	 Effects of lead on the hepatic and gastrointestinal system. Studies of hepatic enzyme 

levels in serum suggest that liver injury may be present in lead workers; however, 

associations specifically with lead exposures are not evident. Studies of urinary 

metabolites of cytochrome P450 phenotypes CYP2A6 and CYP3A4 suggest possible 

associations between lead exposure and suppression of hepatic enzyme activity in adults 

and children. Several studies observed an association between occupational lead exposure 

and prevalence of symptoms of gastrointestinal colic. These hepatic and gastrointestinal 

effects are largely observed only at blood lead concentrations (>40 μg/dL). 

•	 Effects of lead on the endocrine system. Most studies have yielded no associations, or 

weak associations, of lead exposure with thyroid hormone status and male reproductive 

endocrine status in highly-exposed occupational populations. Children exposed to 

relatively high levels of lead (blood lead >30 μg/dL) exhibit depressed levels of circulating 

1,25-dihydroxy vitamin D (1,25-OH-D). However, associations between serum vitamin D 

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status and blood lead were not evident in a study of calcium-replete children who had 

average lifetime blood lead concentrations below 25 μg/dL. 

•	 Effects of lead on bone and teeth. The epidemiologic evidence is limited, but suggestive 

of an association between lead exposure and bone toxicity. Studies have found an 

association between occupational exposure to lead and Paget’s disease. However, it is 

difficult to assess whether increased lead results from bone diseases or the bone disease is 

a result of increase lead exposure. Increased risk of dental caries has been associated with 

lead exposure in children and adults. Lead effects on caries were observed in populations 

whose mean blood lead levels were less than 10 μg/dL. 

•	 Effects of lead on ocular health. Recent longitudinal studies provide evidence for 

possible associations between lead exposure and adverse ocular health outcomes in low- to 

moderately-exposed populations. In children whose mothers had blood lead levels of 

10.5–32.5 μg/dL in mid-pregnancy, an association was observed between lead exposure 

and visual evoked retinal responses. Middle-aged males whose tibia bone lead levels were 

31–126 μg/g had increased risk of cataracts. 

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20 Bauchinger, M.; Dresp, J.; Schmid, E.; Englert, N.; Krause, Chr. (1977) Chromosome analyses of children after 

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29 Epidemiology 6: 101-103. 

30 Bellinger, D. C. (1995) Interpreting the literature on lead and child development: the neglected role of the 

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32 Bellinger, D. C. (2000) Effect modification in epidemiologic studies of low-level neurotoxicant exposures and 

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34 Bellinger, D. (2002) Perspectives on incorporating human neurobehavioral end points in risk assessments. Risk 

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49 Bellinger, D.; Leviton, A.; Waternaux, C.; Allred, E. (1985) Methodological issues in modelling the relationship 

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5 Bellinger, D.; Leviton, A.; Waternaux, C. (1989) Lead, IQ and social class. Int. J. Epidemiol. 18: 180-185. 

6 Bellinger, D.; Leviton, A.; Waternaux, C.; Needleman, H.; Rabinowitz, M. (1989) Low-level lead exposure, social 

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8 Bellinger, D.; Leviton, A.; Sloman, J. (1990) Antecedents and correlates of improved cognitive performance in 

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10 Bellinger, D.; Leviton, A.; Rabinowitz, M.; Allred, E.; Needleman, H.; Schoenbaum, S. (1991) Weight gain and 

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12 Bellinger, D.; Sloman, J.; Leviton, A.; Rabinowitz, M.; Needleman, H. L.; Waternaux, C. (1991) Low-level lead 

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14 Bellinger, D. C.; Stiles, K. M.; Needleman, H. L. (1992) Low-level lead exposure, intelligence and academic 

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16 Bellinger, D.; Hu, H.; Titlebaum, L.; Needleman, H. L. (1994) Attentional correlates of dentin and bone lead levels 

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18 Bellinger, D.; Leviton, A.; Allred, E.; Rabinowitz, M. (1994) Pre- and postnatal lead exposure and behavior 

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28 Benoff, S.; Centola, G. M. (2003b) Increased seminal plasma lead levels adversely affect the fertility potential of 

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U.S. EPA 2005 Air Quality Criteria Document (AQCD) for Lead

Available at http://cfpub2.epa.gov/ncea/cfm/recordisplay.cfm?deid=141779

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Yucesoy, B.; Turhan, A.; Ure, M.; Imir, T.; Karakaya, A. (1997b) Simultaneous effects of lead and cadmium on NK 

cell activity and some phenotypic parameters. Immunopharmacol. Immunotoxicol. 19: 339-348. 

Zentner, L. E. A.; Rondo, P. H. C. (2004) Lead contamination among pregnant Brazilian women living near a lead 

smelter. Int. J. Gynecol. Obstet. 87: 147-148. 

Zhang, Z.-W.; Shimbo, S.; Ochi, N.; Eguchi, M.; Watanabe, T.; Moon, C.-S.; Ikeda, M. (1997) Determination of 

lead and cadmium in food and blood inductively coupled plasma mass spectrometry: a comparison with 

graphite furnace atomic adsorption spectrometry. Sci. Total Environ. 205: 179-187. 

Zhao, Z. Y.; Li, R.; Sun, L.; Li, Z. Y.; Yang, R. L. (2004) Effect of lead exposure on the immune function of 

lymphocytes and erythrocytes. in preschool children. J. Zhejiang Univ. Sci. 5(8): 1001-1004. 

Zheng, W.; Lu, Y. M.; Lu, G. Y.; Zhao, Q.; Cheung, 0.; Blaner, W. S. (2001) Transthyretin, thyroxine, and retinolbinding protein in human cerebrospinal fluid: effect of lead exposure. Toxicol. Sci. 61(1): 107-114. 

Zimmermann-Tansella, C.; Campara, P.; Andrea, F. D.; Savontto, C.; Tansella, m. (1983) Psychological and 

physical complaints of subjects with low exposure to lead. Hum. Toxicol. 2: 615-623. 

Zuckerman, B.; Amaro, H.; Cabral, H. (1989) Validity of self-reporting of marijuana and cocaine use among 

pregnant adolescents. J. Pediatr. ( St. Louis) 115: 812-815. 

December 2005 6-408 DRAFT-DO NOT QUOTE OR CITE 

U.S. EPA 2005 Air Quality Criteria Document (AQCD) for Lead

Available at http://cfpub2.epa.gov/ncea/cfm/recordisplay.cfm?deid=141779

402(c) Economic Analysis Chapter 5 809
402(c) Economic Analysis Chapter 5 810 

5A.2 Ecological Effects 

When lead is released in an uncontrolled manner into the environment, whether indoors or 

outdoors, it ultimately becomes a part of the larger environment in which humans, animals and 

plants live. In the case of renovation work, the immediate concern is primarily with releases 

occurring outdoors due to exterior RRP events that do not follow the work practices specified in 

the proposed regulations. Interior releases, however, can eventually be washed, swept, or disposed 

of into outdoor environments. When lead-paint dust and debris are disposed of responsibly, the 

impact may be minimal. However, in the absence of the proposed regulations, it is anticipated that 

lead will ultimately enter the environment and thereby provide a source of exposure to aquatic or 

terrestrial receptors. 

Lead can affect biota in various ways. Plants are exposed to lead both through their foliage 

(through atmospheric deposits) and their roots. The extent to which plants uptake lead from the 

soil depends on various factors, including “cation exchange capacity, soil composition (e.g., 

organic matter component, calcium content)... [and] is favored at lower pH values and in soils with 

low organic carbon content” (U.S. EPA 2005b). In plants, exposure to lead can result in decreased 

photosynthesis, transpiration, water absorption and growth (U.S. EPA 1986, 2005b). Soil 

microorganisms (decomposers) appear to be more sensitive to lead than higher plants (U.S. EPA 

1986). 

Avian and mammalian species are exposed to lead primarily through food. Exposure may take 

place through direct ingestion of soil or through the ingestion of lead-contaminated plants or prey. 

Effects of lead on avian and mammalian species include increased mortality, adverse effects on 

growth and reproduction, as well as developmental and behavioral changes. Effects on soil 

invertebrates include decreased growth and reproduction as well as increased mortality (U.S. EPA 

1986). 

One benchmark indicator of the toxicity of lead to plants and animals is the Ecological Soil 

Screening Levels (Eco-SSLs) developed by the U.S. EPA’s Office of Emergency and Remedial 

Response. These contaminant concentration levels are intended for use in identifying contaminants 

of potential concern (COPCs) during the screening stage of an ecological risk assessment. EcoSSLs are derived separately for plants, soil invertebrates, birds and mammals and represent 

conservative estimates of contaminant concentrations that may pose a risk to each group of species 

(U.S. EPA 2005b). Table 5A-1 presents current Eco-SSLs for lead (as of March 2005). 

Table 5A-1: Eco-SSLs for Lead (mg/kg dry weight in soil) 

Wildlife Plants Invertebrates Avian Mammal 

120 1,700 11 56 

Source: U.S. EPA 2005b 

In addition to terrestrial species, lead is also highly toxic to aquatic life. The Agency has 

established both acute and chronic fresh and saltwater criteria for lead. Because the effects 

threshold increases with water hardness, these criteria vary depending upon the hardness of the 

water for a given area. The higher the hardness, the higher the criterion. (U.S. EPA 1985). 
402(c) Economic Analysis Chapter 5 811 

The impacts of lead on domestic animals have been well-documented. Lead-based paint is the 

most commonly reported source of lead exposure for household cats and dogs. According to Jill E. 

Madison, “Renovations of older houses involving sanding or scraping lead-based paint is believed 

to be the major origin of the lead-based paint in [paint ingestion] instances” (Madison 2005). Lead 

poisoning symptoms in dogs include GI abnormalities, such as anorexia or colic, and behavioral 

changes, including anxiety, salivation, blindness and muscular spasms (Merck & Co. 2003). Lead 

poisoning in dogs may also cause seizures (Thomas 2005). Cats are less likely to be exposed to 

lead because they are less likely to chew on lead-containing surfaces. Because of their grooming 

habits, however, they may ingest lead particles. Food avoidance is one of the major symptoms of 

lead poisoning in cats (Madison 2005). Similarly to dogs and cats, birds may also be exposed to 

lead through lead-based paint. According to Merck & Co., “in avian species, anorexia, ataxia, loss 

of condition, wing and leg weakness and anemia are the most notable signs” (Merck & Co. 2003). 

Although specific economic benefits to ecological components have not been quantified in this rule, it is 

reasonable to assume that proposed rule is likely to reduce the amount of lead released from renovation 

activities, thereby reducing the lead body burdens to plants and animals. 
402(c) Economic Analysis Chapter 5 812 

Appendix 5B: Adult Health Benefits Calculations 

5B.1 Health Benefits to Men 

Lead exposure has also been shown to adversely affect adults. The epidemiological data on the effects of 

lead in adults are discussed in Appendix 5A. The health effects in adults that are quantified and included 

in the benefits analysis are all related to the effects of lead on blood pressure.18 The estimated 

relationships between these health effects and lead exposure differ between men and women. The 

quantified health effects include increased incidence of hypertension, initial coronary heart disease 

(CHD), strokes (initial cerebrovascular accidents and atherothrombotic brain infarctions) and increased 

mortality. This section describes the methods for quantifying health effects for men; the next section 

describes the health effects for women. Note that the dose-response functions noted below rely on older 

published data; not all of these data are included in the review in Appendix 5A. EPA intends to perform 

an expanded risk assessment for this rulemaking and plans on examining the more recent data discussed 

in Appendix 5A on the blood-lead-blood pressure relationship, as well as more recent data on the 

relationship of blood pressure to the risk of cardiovascular disease, as part of that effort. The 

uncertainties in the quantification of adult effects compared to children’s IQ effects is discussed in 

Section 5.5.5.

5B.1.1 Changes in Hypertension 

Quantifying the relationship between blood-lead levels and hypertension 

Increased blood-lead (PbB) has been linked to increased blood pressure (BP) in adult males, especially 

men aged 40-59 years (Pirkle 1985). Further studies have demonstrated a dose-response relationship for 

hypertension (defined as diastolic blood pressure above 90 mm Hg for this model) in males aged 20-74 

years (Schwartz 1988). This relationship is: 

2.744 0.793*(ln ) 2.744 0.793*(ln ) 1 2 1

1

1

1 Pr( ) PbB PbB

e e

Hyp − − + − +∆ = (1)

where: 

)Pr(HYP) = the change in the probability of hypertension; 

 PbB1 = PbB level in the control scenario; and 

 PbB2 = PbB level in the no-control scenario. 

Quantifying the relationship between blood-lead and blood pressure 

Because PbB has been identified as a risk factor in a number of cardiovascular effects (Shurtleff 1974, 

McGee and Gordon 1976, PPRG 1978), it is useful to quantify the effect of changes in PbB levels on 

changes in blood pressure for reasons other than predicting the probability of hypertension. Based on 

results of a meta-analysis of several studies, Schwartz (1992a,b) estimated a relationship between a 

change in blood pressure associated with a decrease in PbB from 10 μg/dL to 5 μg/dL. The coefficient 

 

18 Citing laboratory studies with rodents, U.S. EPA (1990) also presents evidence of the genotoxicity and/or 

carcinogenicity of lead compounds. While such animal toxicological evidence suggests that human cancer effects 

are possible, dose-response relationships are not currently available. 
402(c) Economic Analysis Chapter 5 813 

reported by Schwartz (1992 a,b) leads to the following function relating blood pressure to blood-lead for 

men: 

1.4 ln( )

2

1

PbB

PbB

∆DBPmen = × (2)

where: 

aDBPmen = the change in men's diastolic blood pressure expected from change in PbB; 

 PbB1 = PbB level in the control scenario (in :g/dL); and 

 PbB2 = PbB level in the no-control scenario (in :g/dL). 

This PbB to blood pressure relationship is used to estimate the incidence of initial coronary heart disease, 

strokes (atherothrombotic brain infarctions and initial cerebrovascular accidents) and premature mortality 

in men.

5B.1.2 Changes In Coronary Heart Disease 

Quantifying the relationship between blood pressure and coronary heart disease 

Estimated blood pressure changes can be used to predict the increased probability of the initial occurrence 

of CHD and stroke (EPA 1987). Increased blood pressure would also increase the probability of 

reoccurrence of CHD and stroke, but these quantified relationships are not available. First-time CHD 

events in men can be predicted using an equation with different coefficients for each of three age groups. 

For men between 40 and 59 years old, information from a 1978 study by the Pooling Project Research 

Group (PPRG) was used. PPRG (1978) presents a multivariate model (controlling for smoking and 

serum cholesterol) that relates the probability of CHD to blood pressure. The model used data from five

different epidemiological studies. From this study, the equation for the change in 10-year probability of 

the occurrence of a CHD event is:

40 59 4.996 0.030365*( ) 4.996 0.030365*( ) 1 2 1

1

1

1 Pr( ) DBP DBP

e e

CHD − − − + − +∆ = (3) 

where: 

aPr(CHD40-59) = change in 10-year probability of occurrence of a CHD event for men between 

 40-59 years old; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

 DBP2 = mean diastolic blood pressure in the no-control scenario. 

The relationship between BP and first-time CHD in older men was determined from information 

presented in Shurtleff (1974, Table 1-2). This study also uses data from the Framingham Study (McGee 

and Gordon 1976) to estimate univariate relationships between blood pressure and a variety of health 

effects by sex and for each of the following age ranges: 45-54, 55-64 and 65-74 years. Single composite 

analyses for ages 45-74 were also performed for each sex. For every equation, t-statistics on the variable 

blood pressure are significant at the 99th percent confidence interval. For men aged 60 to 64 years old, 

the first-time CHD event can be predicted from the following equation: 
402(c) Economic Analysis Chapter 5 814 

60 64 5.19676 0.02351*( ) 5.19676 0.02351*( ) 1 2 1

1

1

1 Pr( ) DBP DBP

e e

CHD − − − + − +∆ = (4) 

where: 

aPr(CHD60-64) = change in 2 year probability of occurrence of a CHD event for men between 60- 

 64 years old; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

 DBP2 = mean diastolic blood pressure in the no-control scenario. 

For men aged 65 to 74 years old, the following equation uses data from Shurtleff (1974, Table 1-2) to 

predict the probability of a first-time CHD event: 

65 74 4.90723 0.02031*( ) 4.90723 0.02031*( ) 1 2 1

1

1

1 Pr( ) DBP DBP

e e

CHD − − − + − +∆ = (5) 

where: 

aPr(CHD65-74) = change in 2 year probability of occurrence of a CHD event for men between 65- 

 74 years old; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

 DBP2 = mean diastolic blood pressure in the no-control scenario.

The probability changes calculated using the functions above are used to estimate the number of CHD 

events avoided in a given year. The resulting CHD incidence estimates include both fatal and non-fatal 

events. However, because mortality benefits are independently estimated in this analysis, it is important 

to capture only the non-fatal CHD events. Shurtleff (1974) reported that two-thirds of all CHD events 

were non-fatal. This factor was therefore applied to the estimate of avoided CHD events for each age 

category.

5B.1.3 Changes in Initial Cerebrovascular Accidents and Initial Atherothrombotic Brain 

Infarctions 

Quantifying the relationship between blood pressure and first-time stroke 

Two types of health events are categorized as strokes: initial cerebrovascular accidents (CA) and initial 

atherothrombotic brain infarctions (BI). The risk has been quantified for the male population between 45 

and 74 years old (Shurtleff 1974, Tables 8-2 and 9-2). For initial cerebrovascular accidents, the logistic 

equation is:

∆ Pr(CAmen ) = 8.58889 0.04066*( ) 1 1

1

DBP

e − + 8.58889 0.04066*( ) 2 1

1

DBP

e − + − (6) 

where: 

aPr(CAmen) = change in 2 year probability of cerebrovascular accidents in men; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

 DBP2 = mean diastolic blood pressure in the no-control scenario. 
402(c) Economic Analysis Chapter 5 815 

For initial atherothrombotic brain infarctions, the logistic equation is: 

9.9516 0.04840*( ) 9.9516 0.04840*( ) 1 2 1

1

1

1 Pr( ) men DBP DBP

e e

BI − − + − +∆ = (7) 

where: 

aPr(BImen) = change in 2 year probability of brain infarctions in men; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

 DBP2 = mean diastolic blood pressure in the no-control scenario.

Similar to CHD events, this analysis estimates only non-fatal strokes (to avoid double-counting with 

premature mortality). Shurtleff (1974) reported that 70 percent of strokes were non-fatal. This factor was 

applied to the estimates of both CA and BI.

5B.1.4 Changes in Premature Mortality 

Quantifying the relationship between blood pressure and premature mortality 

Information also exists to predict the increased probability of premature death from all causes as a 

function of increased blood pressure. U.S. EPA (1987) used population mean values for serum 

cholesterol and smoking to reduce results from a 12-year follow-up of men aged 40-54 years old in the 

Framingham Study (McGee and Gordon 1976) to an equation in one explanatory variable:

40 54 5.3158 0.03516*( ) 5.3158 0.03516*( ) 1 2 1

1

1

1 Pr( ) DBP DBP

e e

MORT − − − + − +∆ = (8) 

where: 

aPr(MORT40-54) = the change in 12 year probability of death for men 40-54 years old; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

 DBP2 = mean diastolic blood pressure in the no-control scenario.

Information from Shurtleff (1974, Table 12-2) can be used to estimate the probability of premature death 

in men older than 54 years old. This study has a 2-year follow-up period, so a 2-year probability is 

estimated. For men aged 55 to 64 years old, mortality can be predicted by the following equation: 

55 64 4.89528 0.01866*( ) 4.89528 0.01866*( ) 1 2 1

1

1

1 Pr( ) DBP DBP

e e

MORT − − − + − +∆ = (9) 

where: 

aPr(MORT55-64) = the change in 2 year probability of death in men 55-64 years old; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

 DBP2 = mean diastolic blood pressure in the no-control scenario.

For men aged 65 to 74 years old, premature mortality can be predicted by the following equation:

65 74 3.05723 0.00547*( ) 3.05723 0.00547*( ) 1 2 1

1

1

1 Pr( ) DBP DBP

e e

MORT − − − + − +∆ = (10) 

where: 
402(c) Economic Analysis Chapter 5 816 

aPr(MORT65-74)= the change in 2 year probability of death in men 65-74 years old; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

 DBP2 = mean diastolic blood pressure in the no-control scenario.

5B.2 Health Benefits to Women 

5B.2.1 Blood Lead-Blood Pressure Relationship 

Analysis of data from the second National Health and Nutrition Examination Survey19 (NHANES II) by 

Schwartz (1991) indicates a significant association between blood pressure and blood-lead in women. The 

effect of lead exposure on the blood pressure of women, relative to the effect on men, is examined in a 

review of ten published studies (Schwartz 1992). All of the reviewed studies included data for men, and 

some included data for women. The results of this study suggest that the effect on blood pressure for 

women of this decrease was less than the effect of the same change observed in men. However, a recent 

study by Nash et al. (2003) examined the relationship between blood lead and changes in blood pressure 

and hypertension in peri- and post- menopausal women ages 40-59. The study found small but 

statistically significant changes in both systolic and diastolic blood pressure when comparing the highest 

and lowest exposure quartiles. Women in the highest exposure quartile also had a higher risk of diastolic 

(>90 mm Hg) hypertension. The overall mean blood lead among these women was 2.9 mg/dL but the 

lowest quartile mean was 1.0 while the highest quartile mean was 6.3 mg/dL. The difference in mean 

systolic and diastolic blood pressure between these two groups was 1.7 and 1.4 mm Hg, respectively. 

While the grouping of exposures into quartiles makes the use of the data for dose-response somewhat 

difficult, the difference between mean blood lead in the lowest quartile and highest quartiles was about 

5.3 mg/dL while the difference in mean diastolic blood pressure between these two quartiles was 1.4 mm 

Hg. This compares to an estimated change of 1 mm Hg diastolic blood pressure for a change from 10 

mg/dL to 5 mg/dL blood lead, reported for men in Schwartz 1992b (p. 227). While the figures are not 

directly comparable, it suggests that the effect in women 40-59 may be similar to the effect in men. The 

Nash study also found that the adjusted odds ratios for diastolic hypertension (using the lowest quartile as 

the reference group) showed a strong dose-response relationship (that is, the odds ratio increase for each 

quartile of blood lead level). 

 Appendix 5A discusses the data on the relationship between blood lead and blood pressure effects in 

women. The Appendix concludes that “although females often show lower lead coefficients than males, 

... where these differences have been formally tested, they are usually not statistically significant. The 

tendencies may well arise in the differential lead exposure ...lower in women than in men .... The same 

sex ... differential is found with blood pressure.” 

Based on this information, the same equations were used to calculate the change in blood pressure in 

women as in men.

(1.4) ln( )

2

1

PbB

PbB ∆DBPwomen = × (11)

 

19 The Second National Health and Nutrition Examination Survey (NHANES II) was conducted by the U.S. 

Department of Health and Human Services from 1976 to 1980 and provides researchers with a comprehensive set of 

nutritional, demographic and health data for the U.S. population (NHANES 2005). 
402(c) Economic Analysis Chapter 5 817 

where: 

aDBPwomen = the change in women's diastolic blood pressure expected from a change in PbB; 

 PbB1 = PbB level in the control scenario; and 

 PbB2 = PbB level in the no-control scenario.

Although women are at risk of having lead-induced hypertension, there is not a dose-response function 

for hypertension in women available at this time. Thus, the hypertension dose response for men was used 

to make an estimate of hypertension cases among women. 

5B.2.2 Changes in Coronary Heart Disease 

Quantifying the relationship between blood pressure and coronary heart disease 

Increased blood pressure in women results in the same effects as for men (the occurrence of CHD, two 

types of stroke and premature death). However, the general relationships between blood pressure and 

these health effects are not identical to the dose-response functions estimated for men. All relationships 

presented here have been estimated for women aged 45 to 74 years old using information from Shurtleff 

(1974). First-time CHD events in women can be estimated from the following equation (Shurtleff 1974, 

Table 1-2): 

6.9401 0.03072*( ) 6.9401 0.03072*( ) 1 2 1

1

1

1 Pr( ) women DBP DBP

e e

CHD − − + − +∆ = (12) 

where: 

aPr(CHDwomen) = change in 2 year probability of occurrence of CHD event for women 45-74 

 years of age; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

 DBP2 = mean diastolic blood pressure in the no-control scenario. 

Again, non-fatal CHD events were estimated by assuming that two-thirds of the estimated events were not 

fatal (Shurtleff 1974). 

5B.2.3 Changes in Atherothrombotic Brain Infarctions and Initial Cerebrovascular Accidents 

Quantifying the relationship between blood pressure and first-time stroke 

For initial atherothrombotic brain infarctions in women, the logistic equation is (Shurtleff 1974, Table 9-

2): 

10.6716 0.0544*( ) 10.6716 0.0544*( ) 1 2 1

1

1

1 Pr( ) women DBP DBP

e e

BI − − + − +∆ = (13) 

where: 

aPr(BIwomen) = change in 2 year probability of brain infarction in women 45-74 years of age; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

 DBP2 = mean diastolic blood pressure in the no-control scenario. 

The relationship between blood pressure and initial cerebrovascular accidents can be predicted by the 

following logistic equation (Shurtleff 1974, Table 8-2): 
402(c) Economic Analysis Chapter 5 818 

9.07737 0.04287*( ) 9.07737 0.04287*( ) 1 2 1

1

1

1 Pr( ) women DBP DBP

e e

CA − − + − +∆ = (14) 

where: 

aPr(CAwomen) = change in 2 year probability of cerebrovascular accident in women 45-74 years 

 of age; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

DBP2 = mean diastolic blood pressure in the no-control scenario. 

The predicted incidences of avoided atherothrombotic brain infarctions and cerebrovascular accidents 

were multiplied by 70 percent to estimate only non-fatal strokes (Shurtleff 1974). 

5B.2.4 Changes in Premature Mortality 

Quantifying the relationship between blood pressure and premature mortality 

The risk of premature mortality in women can be estimated by the following equation (Shurtleff, 1974, 

Table 12-2): 

5.40374 0.01511*( ) 5.40374 0.01511*( ) 1 2 1

1

1

1 Pr( ) women DBP DBP

e e

MORT − − + − +∆ = (15) 

where: 

aPr(MORTwomen) = the change in 2 year probability of death for women 45-74 years of age; 

 DBP1 = mean diastolic blood pressure in the control scenario; and 

 DBP2 = mean diastolic blood pressure in the no-control scenario.
402(c) Economic Analysis Chapter 5 819 

Appendix 5C: Identifying and Characterizing Lead Loadings for 

Interior Renovation, Repair and Painting Tasks 

5C.1 Renovation, Repair, and Painting Tasks, Work Components, and Estimated Time 

Requirements 

Dust loading levels for RRP tasks can be estimated using the 1997 EPA Lead Exposure Associated with 

Renovation and Remodeling Activities: Environmental Field Sampling Study (EFSS). (U.S. EPA 

1997a). The 1997 study measured lead levels in dust and air, primarily in the rooms where the renovation 

work was performed. The levels measured in the work area were extrapolated to adjacent rooms for this 

analysis because the lead dust levels in adjacent rooms provide an estimate for the average lead dust level 

in a home. In the 1997 study, lead loadings were quantified for specific work components (e.g., drilling, 

sawing, HVAC work) rather than for a task as defined by the POMS and AHS (e.g., replacing a sink). 

Consequently, it was necessary to match the work components described in the 1997 study to the 

renovation and remodeling tasks described in the POMS and AHS. 

Table 5C-1 lists the work components for which lead loading data were provided in the renovation and 

remodeling study. The exhibit provides a brief description of the activity summarized from the 

renovation study (1997). The components are followed in parentheses by the units of measure (e.g., 

carpet one home, replace 3 windows, carry out one hour of work) used to evaluate lead loadings in the 

EPA study. These units are either time or activities. 

There were differences in the conditions under which different work components were carried out. 

Carpet removal and window replacement were each self-contained observational phases of the study, 

where only the types and locations of the samples were specified in the sampling design. Housing style, 

lead levels and other factors varied. The remainder of the work components was carried out in the 

“controlled, experimentally-designed (CED) phase,” with observations and measurements made for one 

hour of work in controlled environments. The type and conduct of the renovation activity, as well as the 

type and location of samples, were controlled (U.S. EPA 1997a, pg 8-45) in the CED phase. 
402(c) Economic Analysis Chapter 5 820 

Table 5C-1: Work Components Listed in the 1997 EPA Renovation Study with Lead Loading Dataa 

Activity Description 

A 

Carpet removal 

(1 house or 

apartment) 

Removal of 2 to 5 rooms of carpeting from 8 units (1 apartment, 1 duplex and 6 

single-family homes) of various sizes (pgs. 8-6 and 8-7). The quantity of carpet 

removed ranged from 246 to 732 ft2

 per unit and was not related to the size of the unit. 

The geometric mean (pg A-5) was used in this analysis. 

B Windows 

(3 units) 

Removal and replacement of 3 windows each in 4 structures. Windows were selected 

to represent all approaches to window replacement, all types of windows and the 

various lead levels that could be encountered in this type of work (pg 8-22). The 

geometric mean (pg. A-23) was used in this analysis. 

C 

Paint 

removal/sanding 

(time) 

In each unit, paint was removed in one area. Paint was removed in half of the area by 

hand scraping and sanding and the other half by power sanding. No vacuum 

attachments or dust reduction methods were used (pg 8-48). 

D Demolition 

(time) 

In each unit, three large structure removal activities were carried out involving the 

demolition of one or more walls, usually a single plaster wall. Removal involved 

removing the surface of the wall, and NOT the underlying structure, so that an 

exposed wall structure was available for installation of new drywall (pg 8-46). 

E HVAC 

(time) 

One HVAC repair/replacement activity was carried out in each unit, involving 

removal of several sections of the HVAC ductwork (pg 8-46). 

F Door modification 

(time) 

This work involved trimming wood from the edge of an existing door, sanding it 

smooth and drilling a hole for installation of a doorknob, characterized as a small 

surface disruption. The work involved primarily sawing and sanding (pgs 8-46-47). 

G Power drilling 

(time) A lattice of holes was drilled into either plaster walls or wood doors or walls (pg 8-47) 

H Sawing 

(time) 

A series of 15 parallel cuts, 5 feet in length, were made into either plaster walls or 

wood baseboards using either a rough or fine blade (pg 8-47). 

I Component removal 

(time) 

The following were removed in one unit: lead-painted wood trim, baseboards, doors, 

and door-jambs (pg 8-47). 

a. Page numbers where data are located in the 1997 renovation document are listed in parenthesis. 

This analysis estimated the number of work hours, or the number of alternative units (such as windows 

replaced) required for each component of each renovation, repair, and painting task expected to generate 

lead dust detailed in the POMS and AHS. The activities typically required in each RRP task were 

analyzed using a normative approach due to the wide variability in homes, materials and the way that 

work is carried out. This approach used assumptions about what a professional would reasonably do in 

the process of carrying out a specific task in an average home (average homes are defined in Chapter 4). 

For example, replacing plumbing fixtures in a home is likely to require a small amount of two activities - 

sawing and drilling into wood or plaster. The number of fixtures replaced is not specified in the AHS. 

The work was estimated to require an hour or less of each work component. Although the full work of 

replacing plumbing fixtures is likely to require more time than this, the work involves many other 

activities that do not cause lead disruption. For example, the estimated time to complete tasks did not 

include the actual plumbing activities that would not generate lead paint dust, such as sawing new copper 

pipe. 

The process of estimating time and work components for RRP tasks involves uncertainty. The AHS 

remodeling statistics report the types of renovation activities but not the extent of work. This analysis 

uses reasonable assumptions regarding task size. For example, EPA assumed that one-half of the 

windows in an average size house would be replaced when the survey respondent said windows were 
402(c) Economic Analysis Chapter 5 821 

replaced. As noted above, when plumbing fixtures were replaced in a home, it was assumed that two 

major fixtures were replaced (e.g., a toilet and sink), and EPA estimated that one hour each was spent on 

drilling and sawing. Time units were measured in hours with the smallest unit of time for any task being 

one hour. For example, tasks figured to involve drilling were estimated to generate at least one hour 

worth of lead (18 μg/ft2

; see Table 5C-3) in the room adjacent to the workroom. 

An argument could be made that of the work components included in the analysis, power drilling and 

sawing may not occur continuously for the duration of an hour. However, in calculating the amount of 

lead generated by a unit of either component, it was assumed that the work occurs uninterrupted for an 

entire hour. This could have resulted in an over estimate of the number of households with increased lead 

levels due to RRP. Households that conducted only one renovation or repair task comprised of power 

drilling were not included in the analysis since the expected lead generation was below the EPA floor lead 

dust hazard level of 40 μg/ft2

. Conversely, households that conducted renovation or repair tasks 

comprised of power drilling and sawing or just sawing were included in the analysis as the expected lead 

generation was above the EPA floor lead dust hazard level. 

Some tasks posed more difficult estimation problems. For example, carpet replacement, which is a very 

common renovation activity, can be carried out in one or most rooms in a house. Carpet replacement was 

measured in the renovation study on a per-home basis, in homes ranging from a single apartment to a 

multi-story house. The number of rooms of carpet replaced and the square footage did not appear to be 

correlated to home size. The lack of correlation is not unexpected due to the very small sample size in the 

study (8 homes) and because the number of rooms needing carpet removal varies within a home and does 

not include the entire house. 

In the analysis, EPA assumed that the amount of carpet replaced in the study is representative of carpet 

reported in the 2003 AHS. This was based on a review of home types and sizes. Although carpet 

replacement in the renovation study cannot be specifically matched to its national occurrence and scope, 

the renovation study probably provides a reasonable approximation of the types of units, amount replaced, 

and resulting lead loadings from replacement, based on the information available for review. In addition, 

the amount of lead released during carpet replacement is quite high, so that if less carpet were replaced, 

the lead contamination threshold of 40 μg/ft2

 would still likely be exceeded. 

Variability in the amount of work required for a particular task is an uncertainty for most tasks. The 

variability may be due to the type of materials involved, their age, their condition, etc, as well as the 

scope of work (e.g., number or size of units). For example, replacing a free-standing bathroom sink may 

involve minimal carpentry and focus solely on plumbing, while replacing a sink in a vanity may involve 

removing the cabinet, re-cutting the counter area, etc. The wood may have many coats of paint or none, 

and the materials may have other variations that alter the work component time required and the amount 

of lead paint released. Estimates of the work components carried out and the number of units of work 

(e.g., hours) required was made considering a pre-1978 housing stock, but work on individual homes will 

vary. 
402(c) Economic Analysis Chapter 5 822 

5C.2 Work Component Lead Loading Levels 

The renovation study (U.S. EPA 1997a) provides both airborne (workers’ breathing zone) and floor lead 

loading measurements for each component, following a specific increment of work (e.g., 102 minutes of 

sanding) or a particular activity (e.g., replacing 3 windows). EPA chose to use floor lead loadings as the 

relevant contamination measure in this analysis because they could be matched to the selected 

benchmarks. Floor lead loading measurements ranged mostly from 1 to 6 feet away from the actual work 

site in most study evaluations. The 6-foot location was used for estimating loadings in this analysis. The 

relationship between lead loadings and distance from the worksite declines steeply over the first few feet 

and then tapers off more gradually. The goal in using these loadings is to estimate contamination levels 

throughout the work area. Consequently, the most distant measurement is more appropriate for 

estimating lead loadings in other locations. The workroom lead loadings at 6 feet were subsequently 

scaled to adjacent room lead loadings for this analysis. 

All floor measurements used in this analysis were taken one hour post-activity. These were available for 

all activities, unlike some of the longer post-activity measurements, and so provide consistency in 

deposition time. However, the use of these data will likely underestimate lead loadings because airborne 

lead can continue to settle for many hours after work is completed. This was illustrated in the 1997 

renovation study, where some measurements were taken both one and two hours post-activity. The study 

found that deposition continued to occur through the second hour, although at a lower rate (pg A-31 in 

U.S. EPA 1997a shows lead loadings for the carpet removal work component for one and two hours postactivity). This observation indicates that floor loadings at one hour post-activity are a low estimate of 

potential lead loadings. 

Table 5C-2 lists the contaminant levels measured in the 1997 renovation study for each renovation, repair, 

and painting task. For activities quantified on the basis of work duration, the contaminant levels are 

presented first as they were reported in the 1997 renovation report. This is followed by the levels 

standardized to one hour of work. The standardized value was calculated by proportionally scaling the 

contaminant levels to one hour of work. For example, it was assumed that if 150 μg/ft2

 resulted from 1.5 

hours of work, then 100 μg/ft2

 would result from 1.0 hour of work. 

The 1997 EPA study reports a distribution of contamination levels for each task at the 6-foot distance 

(U.S. EPA 1997a). For purposes of this analysis, the 50th percentile values were chosen as most 

representative of the “average” levels that may occur as a result of the work. They are listed under 

“measured levels” in Table 5C-2. Maximum or upper 95th percentile airborne lead contaminant values 

were not used in this analysis directly; however, they are included in the exhibit as an indication of the 

potential range of exposures that may occur as a result of RRP activities. 

As shown in Table 5C-2, measurements of contamination resulting from two different types of materials 

(i.e., wood and plaster) were made for some work components and yielded different lead releases and lead 

loadings. Because the proportion of work to be carried out in a typical task on each type of material 

cannot be estimated, EPA calculated an average lead loading level for the two media. For paint removal, 

drilling, sawing and clean-up, one half hour of work on each type of media was assumed to occur and 

contamination from the two half hours were added to yield an average hourly lead loading. For example, 

floor lead loadings for drilling wood and plaster were 3.61 μg/ft2

 and 0.1025 μg/ft2 per minute, 

respectively. When these are each multiplied by 30 minutes and added together, the resulting average (18 
402(c) Economic Analysis Chapter 5 823 

μg/ft2) represents one half-hour of work on each media. This value was used in the analysis as a 

representative of the floor lead loading generated by one hour of drilling. 

Lead concentration in household paint varies considerably. The 1997 renovation analysis does not 

include a quantitative evaluation of the percent of lead in paint, the thickness of the paint or the number of 

layers of paint that was present in the structural materials. Data are also not available on those 

characteristics for the national housing stock. Because EPA designed its 1997 study to capture the 

spectrum of housing types and ages, the study housing units are likely to have similar lead concentrations 

to those throughout the country. However, the lack of information is a source of uncertainty in the 

analysis. 

5C.3 Estimated Contamination Levels Throughout the House

The 1997 renovation study included measurements of lead concentrations in air and dust floor loadings in 

work areas, as shown in Table 5C-2. The measured levels in the work area are not a good measure of 

residents’ exposure for two reasons: 

• Clean-up always takes place in the work area after task completion, so that residents are not 

exposed to pre-clean-up levels (i.e., the primary measurement in the U.S. EPA 1997a study). 

Although some data on post-clean-up levels exist, they are limited. Contractors usually broomclean or vacuum (frequently using a shop vac) the work area and remove debris. 

• Lead dispersion is airborne and the heaviest particles settle within a short distance from the 

worksite. This causes adjacent rooms to have a lower lead loading than that found in the work 

area, and these adjacent rooms are a better measure of lead loadings occurring throughout the 

house. 

Lacking direct lead loading measurements in rooms adjacent to where most RRP activities occurred, EPA 

estimated these loadings. The estimates are based on the observed relationships between the workroom 

and adjacent room contamination for window replacement. Adjacent room levels were available only for 

airborne samples, not for floor samples. It is reasonable to use airborne levels because the lead that settles 

to the floor results from airborne particles moving through the home. The airborne lead levels in adjacent 

rooms contribute directly to the floor levels in those rooms. Of the two work components for which 

adjacent room data are available, window replacement and carpet removal, window replacement is most 

similar to other work components. It involves working with wood, plaster, and other structural materials, 

as do the other components. Carpet removal is a unique activity and carpeting is also a unique material 

known to be a “sink” for lead. 
402(c) Economic Analysis Chapter 5 824 

Table 5C-2: Renovation, Repair, and Painting Work Components and Related Floor Lead Loadings and Air 

Concentrations (Based on data from U.S. EPA, 1996. All measurements are in the work room 

unless noted as “adjacent.”) 

Floor Lead Loading 

(μg/ft2

) a Air Concentrations (μg/m3

) 

Renovation Task 

Time 

(minutes 

or units) 

Average 

lead 

loading 

measured

Average 

lead 

loading 

per unit 

or hour 

Average 

personal 

concentration 

measured 

Average 

concentration 

for one unit 

or hour 

(See Column 

2) 

Maximumb

measured 

Maximum 

concentration 

for one unit 

or hour 

Work 

room 

N/A because floor 

replaced 8.4 8.4 221.3 221.3 Carpet 

Adjacent 

room 

Rooms 

needing recarpeting 

(see text) 130.4 130c

 0.3 0.3 13.4 13.4 

Work 

room 

3 windows 878.4 878d

 7.5 7.5 44.3 44.3 

Window 

Adjacent 

room 

not 

available 

not 

available 1.2 not available 4.2 not available 

Hand 63 254 242 1,410 1,343 

Paint Power 39 571 879 3,170 4,877 

Removal 

via 

sanding 

Both 

methods 

(1/2 hour 

each) 

102 15,500e

 9,118 413 561 2,290 3,110 

Demolition 61 1,530 1,505 108 107 403 396 

HVAC 48 414 518 50 63 66.6 83 

Door 68 6,700 5,912 590 521 4,480 3,953 

Wood 36 130 217 15 25 16.3 27 

Plaster 40 4.1 6 7 11 127 191 

Drilling Both 

methods 

(1/2 hour 

each) 

112 

Wood 41 7,900 11,561 546 799 1,020 1,493 

Plaster 19 480 1,516 110 347 681 2,151 

Sawing Both 

methods 

(1/2 hour 

each) 

6,539 

Component 

Removal 160 1,464 549 344 129 370 139 

a. Measurements taken one hour after work was completed. No maximums were available for floor lead loadings 

other than window and carpet removal (see text). 

b. All but carpet and window data are 95th percentiles. See U.S. EPA 1997a for a description of the maximum 

levels estimated for carpet and window replacement. 

c. Maximum was reported as 6135 :g/ft2

 for the floor in the adjacent room. 

d. Maximum was reported as 54.515 :g/ft2

 for the floor in the adjacent room. 

e. A single value was reported for 102 minutes (hand and power sanding not measured separately). 
402(c) Economic Analysis Chapter 5 825 

The airborne window replacement lead concentrations shown in Table 5C-2 for the same room (7.5 

μg/m3

) and the adjacent room (1.2 μg/m3) were used to obtain a ratio that is expected to be characteristic 

of the “workroom-adjacent room” floor lead loadings relationship for other work components. This ratio 

between the workroom and the adjacent room was calculated as: 

1.2 μg/m3 / 7.5 μg/m3

 = 0.16 (a dimensionless value) 

EPA multiplied this ratio (0.16) times the workroom floor lead loadings for each activity shown in Table 

5C-2 to estimate the floor lead loadings in an adjacent room for one unit of work. For example, one hour 

of demolition results in 1,505 μg/ft2

 in the workroom. This is multiplied by 0.16 to obtain an estimate of 

the floor lead loadings in the adjacent rooms of 241 μg/ft2

. Table 5C-3 contains the estimated floor lead 

loadings in adjacent rooms for all the work components after applying the 0.16 scaling factor to each task 

shown in Table 5C-2. 

Table 5C-3: Work Components, Unit/Time of Measurement, Measured and Estimated Floor Lead Loadings 

and a Comparison to the Proposed EPA Floor Standard (40 μg/ft2) 

Work Componenta I.D. Codeb

Measured Level 

in Work Room 

(μg/ft2

)

c

Estimated Levels in 

Adjacent Rooms 

(μg/ft2

)

d

One Unit Exceeds 

Proposed EPA Standard 

Carpet removal A Not available 130e

 Yes 

Window replacement B 878 141 Yes 

Paint removal C 9118 1459 Yes 

Demolition D 1505 241 Yes 

HVAC E 518 83 Yes 

Door removal F 5912 946 Yes 

Drilling G 112 18 No 

Sawing H 6539 1046 Yes 

Component removal I 549 88 Yes 

a. See definitions in Table 5C-1. 

b. Identification codes that were used to assign specific work components to each task are listed in Table 5C-4 and 

Table 5C- 5. 

c. Measurements in the work room are taken from 

d. A multiplier of 0.16 was used to estimate floor lead loading in adjacent rooms. See text for discussion. 

e. The value for carpet replacement is an actual measurement, as opposed to an estimated value. 

Adjacent room loadings are assumed to be reasonably representative of lead loadings throughout the 

house. However, lead loadings will vary in a home and also vary over time. In the absence of clean-up, 

the lead loadings in rooms nearest the workroom will initially be the highest. The levels will decline as 

activities and physical processes cause lead to be moved to other rooms. Consequently, although the 

loading estimates in this analysis are relevant for an extended period after the RRP work, the specific 

dynamics of the very long-term loadings are not known. Actual levels in homes depend on a variety of 

factors including home size, airflow, resident behavior, the paint’s lead concentration and thickness, and 

other factors. In a very large house, there would likely be some rooms with lower lead loadings than 

those near the workroom. In the absence of specialized clean-up, however, the lead would eventually be 

distributed to all rooms in the house. Based on available data, it was not possible to determine the 
402(c) Economic Analysis Chapter 5 826 

distribution of lead loadings in the various rooms of a home over the long term. The most relevant rooms 

are those where residents (especially children) spend most of their time. 

5C.4 Renovation, Repair, and Painting Tasks and Lead Loading Estimates 

This analysis uses the 1995 Property Owners and Managers Survey (POMS) (U.S. Census 1995) and the 

1997 and 2003 American Housing Survey (AHS) (U.S. Census 1997 and 2003) to characterize the 

different RRP tasks that households perform and the lead loadings that result from performing these tasks. 

The AHS and the POMS provide data on the type of housing unit (e.g., single-family homes, apartment 

buildings, the age of the structure) and other critical features of the housing stock (e.g., number of rooms, 

type of interior RRP). The AHS also describes the residents of homes in which these tasks take place, 

including whether there are children under the age of 6, the size of families and other demographic 

features. 

In 1997, the AHS provided detailed survey information on renovation and repair tasks performed in 

homes from a panel of residents living in over 50,000 housing units. In 2003, the AHS continued to 

cover renovation and repair activities, but reported the data in less detail, combining the 1997 AHS tasks 

into a smaller number of tasks. As a result, EPA uses the 2003 AHS for characterizing some RRP tasks 

and 1997 AHS data to characterize RRP tasks where the level of detail in the 2003 survey is not 

sufficient. The survey results are extrapolated to the national population using weighting factors that 

adjusted the survey housing stock to match the national housing stock.20 From the three data sources 

mentioned above, those tasks likely to generate some lead dust in homes built prior to 1978 were 

identified. Because it is not known which respondents to the AHS live in structures that actually have 

lead paint, data from the 2000 HUD National Survey of Lead and Allergens in Housing was used to 

estimate the number of RRP events occurring in homes that contain lead-based paint and to estimate the 

number of homes with a pre-existing lead hazard. 

To determine the estimated exposure to lead dust resulting from an RRP event, EPA estimated the total 

floor lead loadings for the RRP tasks where painted surfaces are likely to be disturbed. Table 5C-4 shows 

the RRP tasks that are reported in the 2003 AHS (owner-occupied RRP) and the 1995 POMS (rental unit 

RRP), the work components associated with each task, and the estimated household dust loadings 

(outside work area) resulting from the work components. Since some tasks are too general to assign work 

components to, 1997 AHS data are used to estimate the work components and resulting household lead 

loadings for these tasks. In these cases, Table 5C-4 lists the 1997 tasks and Table 5C- 5 shows the work 

components and lead loadings associated with these tasks. An average weighted by the relative 

frequencies observed in the 1997 AHS data is used to estimate the lead loading associated with the more 

general task used in the analysis. For example, the lead loading associated with 2003 AHS task 45, 

Added/Replaced Doors Or Windows In Home (1,991 μg/ft2

) is estimated as the weighted average of 5,492 

(loading for 1997 AHS Task 45) and 1,599 (loading for 1997 AHS Task 46); 1997 tasks 45 and 46 are 

weighted based on the relative frequency of their occurrence in the 1997 AHS. 

Using the task definitions in the AHS, EPA estimated the amount of time each component would 

typically be employed for each task. While the actual amount of each component used may vary widely 

within a task, data are not available to provide a distribution of values. Further data collection would be 

necessary to improve this effort. The number of units of each work component was multiplied by the 

 

20 For this analysis, sample weights developed by the Harvard University Joint Center for Housing were used to 

develop national estimates. 
402(c) Economic Analysis Chapter 5 827 

expected household dust loading resulting from one unit of each activity. The totals for each component 

were summed to get an overall estimate of the floor loading outside the work area for each task. For 

example, replacing plumbing fixtures in a home (task #47 listed in Table 5C-4) was estimated to require 

one hour each of drilling and sawing. Drilling results in 18 μg/ft2

 and sawing 1,046 μg/ft2 (from Table 

5C-3) with a summed estimate of 1,064 μg/ft2

. All tasks shown exceed EPA’s proposed standard of 40 

μg/ft2

 of lead on floors. 
402(c) Economic Analysis Chapter 5 828 

Table 5C-4: RRP Tasks and Their Associated Lead Loadings 

2003 AHS Task 

Description 

(Owner-Occupied Units) 

2003 AHS Task 

ID

POMS Task Description 

(Rental Units) 

1997 AHS Task ID or 

2003 Work Componentsa

Resulting Lead 

Loading 

Outside Work 

Areab 

(μg/ft2) 

1997 Task 16 

1997 Task 17 

1997 Task 18 

1997 Task 19 

1997 Task 21 

Remodeled Bathroom 71 Renovation Of Bathroom 

1997 Task 25 

5,701 

1997 Task 26 

1997 Task 27 

1997 Task 29 

1997 Task 30 

1997 Task 32 

1997 Task 33 

Remodeled Kitchen 72 Replacement Of Kitchen 

1997 Task 34 

10,874 

Added Room, Or Room Created 

Through Structural Changes 

8, 9, 10, 26, 35, 

36 N.A. 4D, 2G, 2H, 4I, F, 4C 10,226 

Added/Replaced Internal Water 1997 Task 40 

Pipes In Home 40 Upgrading Plumbing System 1997 Task 41 

288 

Added/Replaced Electrical Wiring 1997 Task 42 

To Home 42 Unit Rewired 

1997 Task 43 

746 

Added/Replaced Doors Or Windows 1997 Task 45 

In Home 45 N.A. 

1997 Task 46 1,991 

Added/Replaced Plumbing Fixtures 

In Home 47 N.A. G, H 1,064 

1997 Task 55 Installed Paneling Or Ceiling Tiles 55 N.A. 

1997 Task 56 3,433 

Added/Replaced Central Air 

Conditioning 57 2G, 2H, 8E 2,792 

Added/Replaced Built-In Heating 

Equipment 58 

Upgrading Heating System; 

Heating/AC Unit Repaired; 

Add Or Upgrade AC.c G, H, 2I 1,240 

Other Major Improvements Or 

Repairs Inside Home 64 Other Major Repairs Or 

Capital Improvement 2G, 2H, 2C, 2I 5,222 

Added/Replaced Security System In 

Home 74 Addition of Security System G, C 1,477 

Interior Painting N.A. Interior Painting 4C 5,836 

a. See Table 5C-5 for the work component key, 1997 task descriptions, and lead loadings associated with the 1997 

tasks. 

b. Loadings shown are the estimated loadings for the room adjacent to the work area. Loading estimated based on 

1997 tasks are calculated as the weighted average loading according to the 1997 AHS. 

c. The loading associated with rental units reporting any of these tasks is estimated as the weighted average loading 

observed for owner-occupants reporting task 57 and/or task 58 (a loading of 3,226). Note that these tasks are 

frequently performed together. 

Source: EPA Calculations 
402(c) Economic Analysis Chapter 5 829 

Table 5C- 5: Work Components Assigned to each Interior Renovation Task and Expected Lead Loadings 

AHS 

Task 

ID 

Task Name 

Work Components (listed in 

Key) and number of units of 

each component (see text). 

Estimated 

Household Levels 

(μg/ft2

) 

16 Moved Walls In Bathroom 2D, 2I, G, H, F, 4C 8,504 

17 Added/Replaced Cabinets In Bathroom G, H, I, C 2,611 

18 Added/Replaced Flooring In Bathroom I 88 

19 Added/Replaced Counter Tops In Bathroom G, H, I, C 2,611 

21 Added/Replaced Tub/Shower In Bathroom G, C 1,477 

25 Painted/Papered/Wall Tiles Bathroom 2C 2,918 

26 Moved Walls In Kitchen 4D, 2G, 2H, 4I, F, 4C 10,226 

27 Added/Replaced Cabinets In Kitchen 2G, 2H, 2I, 2C 5,222 

29 Added/Replaced Counter Tops In Kitchen 2G, 2H, 2I, C 3,763 

30 Added/Replaced Other Built-In Appliances In 

Kitchen G, H, I 1,152 

32 Added/Replaced Lighting Fixtures In Kitchen G, C 1,477 

33 Added/Replaced Other Electrical Items In Kitchen G, H, I 1,152 

34 Painted/Papered/Wall Tiles Kitchen 4C 5,836 

40 Added Internal Water Pipes To Home 2G, 2H 2,128 

41 Replaced Internal Water Pipes In Home 3G 54 

42 Added Electrical Wiring To Home G, C 1,477 

43 Completely Rewired The Electrical Wiring In 

Home 4G, I 160 

45 Added Doors/Windows To Home 2H, 2D, 2C 5,492 

46 Replaced Door/Windows To Home B, C 1,599 

55 Installed New Paneling/Ceiling Tiles G, C 1,477 

56 Replaced Existing Paneling/Ceiling Tiles 8I, 2C, G, H 4,686 

Key: 

A = carpet removal (See text) B = replace windows (3 windows)

C = paint removal (1 hour) D = interior demolitions (1 hour) 

E = HVAC (1 hour) F = door removal (1 hour) 

G = drilling (1 hour) H = sawing (1 hour) 

I = remove trim (1 hour) 

5C.5 Interior Painting 

5C.5.1 Number of Homes Painted 

This analysis identified the number of homes performing an interior painting event using the 1997 AHS. 

This is described in more detail in Chapter 4 of this document. 

5C.6 Background Lead Loadings in Homes 

Background lead levels existing in homes prior to RRP work have not been added to the loading levels 

resulting from RRP events in this analysis, although they may have an impact on one task: carpet 
402(c) Economic Analysis Chapter 5 830 

removal.21 The lead loadings reported in the renovation study (U.S. EPA 1997a) include only postactivity levels on floors for most tasks and involved a sampling method that started with a clean, smooth 

floor surface at the outset of the task (window and carpet replacement did not take this approach and 

include pre-existing levels). In actual practice any RRP event will add to the background level. 

 

21 The high lead levels generated by carpet replacement are assumed to be due to the presence of accumulated lead 

(Yiin 2002). The levels reported in EPA’s renovation study reflect carpet removal from a home with lead-based 

paint.
402(c) Economic Analysis Chapter 5 831 

Appendix 5D: Distributions of Inputs and Results 

As described in section 5.5, the estimation of benefits uses a Monte Carlo approach to reflect the 

uncertainties inherent in the available data. Several of the inputs used in the analysis are described as 

distributions, and the results are expressed as a distribution of estimates. This appendix supplements 

section 5.5 by providing additional details on the various distributions. 

5D.1 Custom Distributions for Input Parameters 

Four of the input parameters are in the form of custom distributions. These are: Soil Lead 

Concentrations, Frequency of Household Cleaning, Percent of House Represented by Work Room Area, 

and Initial Interior Lead Levels. 

The distribution of soil lead concentrations due to exterior painting events is shown in Table 5D-1. There 

are five paint-removal techniques. Within a housing type, the likelihood of occurrence for each of the 

five techniques is assumed to be the same. But the number of exterior paint removal events varies across 

housing types based on the number of housing units of each type. Thus the percentage of exterior paint 

removal events by technique varies across housing types. Also, the lead concentration for a particular 

paint removal approach varies across housing types because the relationship of the perimeter area to the 

rest of the yard area also varies across housing types.22. 

 

22 For each housing type, the analysis assumes that one-quarter of the exterior paint removal events 

encompass the entire exterior, one-quarter encompass only one side of the home and the other one-half 

encompass some thing in between. 
402(c) Economic Analysis Chapter 5 832 

Table 5D-1: Custom Distribution Values for Input Parameter: Soil Lead 

Concentration Outdoors without Rule 

Whole House Event 

Soil Conc. (μg/g) 

Probability of 

Occurrence /Percent 

of Households 

Single Family Owner 

Exterior paint – alkaline 577 0.031 

Exterior paint - heat gun 1,166 0.031 

Exterior paint - paint shaver 575 0.031 

Exterior paint - safe stripper 1,023 0.031 

Exterior paint – wet scrape 983 0.031 

Single Family Renter 

Exterior paint – alkaline 565 0.085 

Exterior paint - heat gun 1070 0.085 

Exterior paint - paint shaver 563 0.085 

Exterior paint - safe stripper 947 0.085 

Exterior paint – wet scrape 913 0.085 

Multi-Family Unit 

Exterior paint – alkaline 559 0.085 

Exterior paint - heat gun 1028 0.085 

Exterior paint - paint shaver 558 0.085 

Exterior paint - safe stripper 914 0.085 

Exterior paint – wet scrape 883 0.085 

Source: See Section 5.2.3 for development of the lead concentrations. See Section 

4.2.5 for development of probabilities. 

The second custom distribution is represents the frequency of household cleaning. In estimating benefits, 

households are assumed to clean their house immediately following the contractor cleaning at the end of 

the RRP project. After that cleaning, the household is assumed to clean the house on a regular basis, with 

the frequency drawn from the distribution shown in Table 5D- 2. 

Table 5D- 2: Custom Distribution Values for Input Parameter: 

Frequency of Household Cleaning per Year 

Frequency of 

Cleaning Per Year 

Probability of 

Occurrence 

Greater than Weekly 104 40% 

Weekly 52 45% 

Less than Weekly 26 15% 

Source: Simcox, 1995 

The house-wide average interior lead loadings are calculated using the lead loadings in the workroom and 

in the adjacent room, weighted by the percent of house the workroom and the adjacent room represent. 

These percentages are shown in Table 5D-3 (and as Table 5-8 in this report). These values are not used 

by them selves, but are combined with the lead loading likelihood values, as shown in Table 5D-4 below. 
402(c) Economic Analysis Chapter 5 833 

Table 5D-3: Work Area Size by Event Type (Percent of 

Housing Unit) 

Event Type 

Work Area 

Size 

Kitchen 6% 

Bathroom 3% 

Addition 5% 

Non-Room-Specific 30% 

Interior Painting 16% 

Average Household Work Area 24% 

Source: Calculated from the American Housing Survey, 

see Chapter 4 for details. 

Each combination of RRP events yields a specific lead loading in the workroom. A “combination of RRP 

events” refers to the event or events performed in a single housing unit in one year. This may be a single 

event (e.g., renovating a kitchen), or it may be a several events involving multiple rooms (e.g., a kitchen 

and a bathroom). In addition, RRP events where the type of activity is reported but not the location with 

in the home. Examples are: added or replaced doors or windows, internal water pipes or electrical wiring, 

other major improvements or repairs. These events are referred to as Non-Room Specific events. 

Associated with each of the workroom lead loadings is an adjacent room lead loading, equal to 16 percent 

of the workroom lead load. 

Each combination of RRP events has a particular probability of occurring, based on the American 

Housing Survey data and likelihood of lead. Because the category called Non-Room Specific RRP events 

contains so many different RRP activities (See Table 4-2) and each combination of activities has its own 

estimated lead loading, the most commonly reported Percent of Home that is Work Area is 29.9 percent. 

The final column in Table 5D-4 presents the probability that the particular RRP event and associated lead 

loadings will occur. The most commonly occurring single RRP event is interior painting. Combinations 

shown with a 0.0% probability on the table have a positive but very small likelihood (less than 0.05%) of 

occurring. 
402(c) Economic Analysis Chapter 5 834 

Table 5D-4: Custom Distribution Values for Input Parameters: Initial Lead Dust Level 

in Work Area After Indoor Work, and Percentage of Area of the Home 

That is a Work Area 

Work Area Loading 

(μg/ft2

) 

Adjacent Room Loading 

(μg/ft2) 

Percent of Home 

that is Work Area

Probability of 

Occurrence1 

36475 5836 16.0% 23.2% 

12443.75 1991 29.9% 8.4% 

32637.5 5222 29.9% 6.9% 

67962.5 10874 5.6% 5.5% 

103593.75 16575 8.9% 4.0% 

20162.5 3226 29.9% 3.2% 

6650 1064 29.9% 3.0% 

110243.75 17639 29.9% 2.3% 

69112.5 11058 29.9% 2.2% 

35631.25 5701 3.3% 1.8% 

104437.5 16710 21.6% 1.7% 

100600 16096 29.9% 1.4% 

42281.25 6765 29.9% 1.3% 

4662.5 746 29.9% 1.3% 

68268.75 10923 29.9% 1.1% 

43125 6900 29.9% 1.1% 

136231.25 21797 29.9% 1.1% 

56637.5 9062 29.9% 1.1% 

74612.5 11938 29.9% 1.1% 

140068.75 22411 24.9% 1.1% 

72106.25 11537 19.3% 1.0% 

48918.75 7827 29.9% 1.0% 

9231.25 1477 29.9% 0.8% 

114906.25 18385 29.9% 0.7% 

48075 7692 29.9% 0.7% 

80406.25 12865 29.9% 0.7% 

19093.75 3055 29.9% 0.6% 

88125 14100 29.9% 0.6% 

146718.75 23475 29.9% 0.5% 

39287.5 6286 29.9% 0.5% 

116037.5 18566 29.9% 0.5% 

17106.25 2737 29.9% 0.5% 

142881.25 22861 29.9% 0.4% 

55793.75 8927 29.9% 0.4% 

41137.5 6582 29.9% 0.4% 

40293.75 6447 29.9% 0.4% 

108256.25 17321 29.9% 0.4% 

151381.25 24221 29.9% 0.4% 

74918.75 11987 29.9% 0.4% 

32606.25 5217 29.9% 0.4% 

137075 21932 29.9% 0.3% 
402(c) Economic Analysis Chapter 5 835 

Table 5D-4: Custom Distribution Values for Input Parameters: Initial Lead Dust Level 

in Work Area After Indoor Work, and Percentage of Area of the Home 

That is a Work Area 

Work Area Loading 

(μg/ft2

) 

Adjacent Room Loading 

(μg/ft2) 

Percent of Home 

that is Work Area

Probability of 

Occurrence1 

172706.25 27633 29.9% 0.3% 

52800 8448 29.9% 0.3% 

78756.25 12601 29.9% 0.3% 

46943.75 7511 29.9% 0.3% 

130406.25 20865 29.9% 0.3% 

111087.5 17774 29.9% 0.3% 

21675 3468 29.9% 0.3% 

104743.75 16759 29.9% 0.3% 

123756.25 19801 29.9% 0.3% 

147543.75 23607 29.9% 0.3% 

26812.5 4290 29.9% 0.2% 

41868.75 6699 29.9% 0.2% 

140893.75 22543 29.9% 0.2% 

62443.75 9991 29.9% 0.2% 

54725 8756 29.9% 0.2% 

122687.5 19630 29.9% 0.2% 

37300 5968 29.9% 0.2% 

75762.5 12122 29.9% 0.2% 

1800 288 29.9% 0.2% 

63912.5 10226 5.2% 0.2% 

144731.25 23157 29.9% 0.2% 

77193.75 12351 29.9% 0.2% 

92268.75 14763 29.9% 0.2% 

76768.75 12283 29.9% 0.2% 

21456.25 3433 29.9% 0.2% 

119475 19116 29.9% 0.2% 

184018.75 29443 29.9% 0.2% 

79581.25 12733 29.9% 0.2% 

84550 13528 29.9% 0.2% 

11312.5 1810 29.9% 0.2% 

177368.75 28379 29.9% 0.2% 

152512.5 24402 29.9% 0.1% 

116881.25 18701 29.9% 0.1% 

33900 5424 29.9% 0.1% 

107250 17160 29.9% 0.1% 

179356.25 28697 29.9% 0.1% 

89275 14284 29.9% 0.1% 

88431.25 14149 29.9% 0.1% 

83418.75 13347 29.9% 0.1% 

111393.75 17823 29.9% 0.1% 

127350 20376 29.9% 0.1% 

63287.5 10126 29.9% 0.1% 
402(c) Economic Analysis Chapter 5 836 

Table 5D-4: Custom Distribution Values for Input Parameters: Initial Lead Dust Level 

in Work Area After Indoor Work, and Percentage of Area of the Home 

That is a Work Area 

Work Area Loading 

(μg/ft2

) 

Adjacent Room Loading 

(μg/ft2) 

Percent of Home 

that is Work Area

Probability of 

Occurrence1 

59387.5 9502 29.9% 0.1% 

73775 11804 29.9% 0.1% 

94775 15164 29.9% 0.1% 

38562.5 6170 29.9% 0.1% 

52737.5 8438 29.9% 0.1% 

124600 19936 29.9% 0.1% 

79275 12684 29.9% 0.1% 

120700 19312 29.9% 0.1% 

44862.5 7178 29.9% 0.1% 

120762.5 19322 29.9% 0.1% 

156393.75 25023 29.9% 0.1% 

68237.5 10918 29.9% 0.1% 

72931.25 11669 29.9% 0.1% 

80425 12868 29.9% 0.1% 

135068.75 21611 29.9% 0.1% 

72625 11620 29.9% 0.1% 

45706.25 7313 29.9% 0.1% 

23756.25 3801 29.9% 0.1% 

47787.5 7646 29.9% 0.1% 

43950 7032 29.9% 0.1% 

109831.25 17573 29.9% 0.1% 

145462.5 23274 29.9% 0.1% 

87056.25 13929 29.9% 0.1% 

55568.75 8891 29.9% 0.1% 

109406.25 17505 29.9% 0.1% 

163825 26212 29.9% 0.1% 

69081.25 11053 29.9% 0.1% 

25556.25 4089 29.9% 0.1% 

25200 4032 29.9% 0.1% 

116056.25 18569 29.9% 0.1% 

78343.75 12535 29.9% 0.1% 

157175 25148 29.9% 0.1% 

160231.25 25637 29.9% 0.1% 

111912.5 17906 29.9% 0.1% 

24825 3972 29.9% 0.1% 

98918.75 15827 29.9% 0.1% 

171543.75 27447 29.9% 0.1% 

61300 9808 29.9% 0.1% 

91200 14592 29.9% 0.1% 

45081.25 7213 29.9% 0.1% 

159162.5 25466 29.9% 0.1% 

163043.75 26087 29.9% 0.1% 
402(c) Economic Analysis Chapter 5 837 

Table 5D-4: Custom Distribution Values for Input Parameters: Initial Lead Dust Level 

in Work Area After Indoor Work, and Percentage of Area of the Home 

That is a Work Area 

Work Area Loading 

(μg/ft2

) 

Adjacent Room Loading 

(μg/ft2) 

Percent of Home 

that is Work Area

Probability of 

Occurrence1 

113668.75 18187 29.9% 0.1% 

109100 17456 29.9% 0.1% 

174837.5 27974 29.9% 0.1% 

143725 22996 29.9% 0.0% 

110925 17748 29.9% 0.0% 

105262.5 16842 29.9% 0.0% 

53581.25 8573 29.9% 0.0% 

157237.5 25158 29.9% 0.0% 

39256.25 6281 29.9% 0.0% 

100568.75 16091 29.9% 0.0% 

17450 2792 29.9% 0.0% 

152112.5 24338 29.9% 0.0% 

124906.25 19985 29.9% 0.0% 

112825 18052 29.9% 0.0% 

6462.5 1034 29.9% 0.0% 

166881.25 26701 29.9% 0.0% 

91718.75 14675 29.9% 0.0% 

59450 9512 29.9% 0.0% 

131918.75 21107 29.9% 0.0% 

30687.5 4910 29.9% 0.0% 

95862.5 15338 29.9% 0.0% 

85587.5 13694 29.9% 0.0% 

136200 21792 29.9% 0.0% 

50368.75 8059 29.9% 0.0% 

161056.25 25769 29.9% 0.0% 

83843.75 13415 29.9% 0.0% 

192868.75 30859 29.9% 0.0% 

102475 16396 29.9% 0.0% 

14243.75 2279 29.9% 0.0% 

89212.5 14274 29.9% 0.0% 

125268.75 20043 29.9% 0.0% 

210468.75 33675 29.9% 0.0% 

13893.75 2223 29.9% 0.0% 

278431.25 44549 29.9% 0.0% 

15881.25 2541 29.9% 0.0% 

160593.75 25695 29.9% 0.0% 

156775 25084 29.9% 0.0% 

60231.25 9637 29.9% 0.0% 

167706.25 26833 29.9% 0.0% 

181937.5 29110 29.9% 0.0% 

293600 46976 29.9% 0.0% 

58150 9304 29.9% 0.0% 
402(c) Economic Analysis Chapter 5 838 

Table 5D-4: Custom Distribution Values for Input Parameters: Initial Lead Dust Level 

in Work Area After Indoor Work, and Percentage of Area of the Home 

That is a Work Area 

Work Area Loading 

(μg/ft2

) 

Adjacent Room Loading 

(μg/ft2) 

Percent of Home 

that is Work Area

Probability of 

Occurrence1 

221343.75 35415 29.9% 0.0% 

99543.75 15927 8.5% 0.0% 

409031.25 65445 29.9% 0.0% 

114493.75 18319 29.9% 0.0% 

149300 23888 29.9% 0.0% 

61187.5 9790 29.9% 0.0% 

111987.5 17918 29.9% 0.0% 

68575 10972 29.9% 0.0% 

139637.5 22342 29.9% 0.0% 

76412.5 12226 29.9% 0.0% 

29393.75 4703 29.9% 0.0% 

106193.75 16991 29.9% 0.0% 

104712.5 16754 29.9% 0.0% 

148387.5 23742 29.9% 0.0% 

7750 1240 29.9% 0.0% 

26118.75 4179 29.9% 0.0% 

123531.25 19765 29.9% 0.0% 

37643.75 6023 29.9% 0.0% 

115750 18520 29.9% 0.0% 

89637.5 14342 29.9% 0.0% 

186600 29856 29.9% 0.0% 

48518.75 7763 29.9% 0.0% 

13112.5 2098 29.9% 0.0% 

197531.25 31605 29.9% 0.0% 

178887.5 28622 29.9% 0.0% 

238681.25 38189 29.9% 0.0% 

45212.5 7234 29.9% 0.0% 

67950 10872 29.9% 0.0% 

51512.5 8242 29.9% 0.0% 

95081.25 15213 29.9% 0.0% 

137043.75 21927 29.9% 0.0% 

95925 15348 29.9% 0.0% 

100950 16152 29.9% 0.0% 

131250 21000 29.9% 0.0% 

28325 4532 29.9% 0.0% 

84993.75 13599 29.9% 0.0% 

193250 30920 29.9% 0.0% 

199518.75 31923 29.9% 0.0% 

204181.25 32669 29.9% 0.0% 

96287.5 15406 29.9% 0.0% 

85068.75 13611 29.9% 0.0% 

142850 22856 29.9% 0.0% 
402(c) Economic Analysis Chapter 5 839 

Table 5D-4: Custom Distribution Values for Input Parameters: Initial Lead Dust Level 

in Work Area After Indoor Work, and Percentage of Area of the Home 

That is a Work Area 

Work Area Loading 

(μg/ft2

) 

Adjacent Room Loading 

(μg/ft2) 

Percent of Home 

that is Work Area

Probability of 

Occurrence1 

57306.25 9169 29.9% 0.0% 

31475 5036 29.9% 0.0% 

93093.75 14895 29.9% 0.0% 

140862.5 22538 29.9% 0.0% 

238750 38200 29.9% 0.0% 

127825 20452 10.4% 0.0% 

128418.75 20547 29.9% 0.0% 

66537.5 10646 29.9% 0.0% 

89418.75 14307 29.9% 0.0% 

172675 27628 29.9% 0.0% 

117487.5 18798 29.9% 0.0% 

147512.5 23602 29.9% 0.0% 

32768.75 5243 29.9% 0.0% 

200275 32044 29.9% 0.0% 

67106.25 10737 29.9% 0.0% 

129568.75 20731 29.9% 0.0% 

77500 12400 29.9% 0.0% 

28106.25 4497 29.9% 0.0% 

325712.5 52114 29.9% 0.0% 

72900 11664 29.9% 0.0% 

146306.25 23409 29.9% 0.0% 

300512.5 48082 29.9% 0.0% 

117743.75 18839 29.9% 0.0% 

74887.5 11982 29.9% 0.0% 

23256.25 3721 29.9% 0.0% 

20893.75 3343 29.9% 0.0% 

70531.25 11285 29.9% 0.0% 

91875 14700 29.9% 0.0% 

138162.5 22106 29.9% 0.0% 

20543.75 3287 29.9% 0.0% 

52356.25 8377 29.9% 0.0% 

339131.25 54261 29.9% 0.0% 

177337.5 28374 29.9% 0.0% 

144143.75 23063 29.9% 0.0% 

113975 18236 29.9% 0.0% 

164643.75 26343 29.9% 0.0% 

155950 24952 29.9% 0.0% 

192287.5 30766 29.9% 0.0% 

366575 58652 29.9% 0.0% 

133500 21360 29.9% 0.0% 

42093.75 6735 29.9% 0.0% 

105606.25 16897 29.9% 0.0% 
402(c) Economic Analysis Chapter 5 840 

Table 5D-4: Custom Distribution Values for Input Parameters: Initial Lead Dust Level 

in Work Area After Indoor Work, and Percentage of Area of the Home 

That is a Work Area 

Work Area Loading 

(μg/ft2

) 

Adjacent Room Loading 

(μg/ft2) 

Percent of Home 

that is Work Area

Probability of 

Occurrence1 

191262.5 30602 29.9% 0.0% 

48743.75 7799 29.9% 0.0% 

74425 11908 29.9% 0.0% 

209856.25 33577 29.9% 0.0% 

153962.5 24634 29.9% 0.0% 

183987.5 29438 29.9% 0.0% 

136581.25 21853 29.9% 0.0% 

94731.25 15157 29.9% 0.0% 

75731.25 12117 29.9% 0.0% 

161743.75 25879 29.9% 0.0% 

69531.25 11125 29.9% 0.0% 

94300 15088 29.9% 0.0% 

109375 17500 29.9% 0.0% 

31850 5096 29.9% 0.0% 

97356.25 15577 29.9% 0.0% 

93937.5 15030 29.9% 0.0% 

58887.5 9422 29.9% 0.0% 

179325 28692 29.9% 0.0% 

100587.5 16094 29.9% 0.0% 

34056.25 5449 29.9% 0.0% 

103581.25 16573 29.9% 0.0% 

62031.25 9925 29.9% 0.0% 

186625 29860 29.9% 0.0% 

141737.5 22678 29.9% 0.0% 

164893.75 26383 29.9% 0.0% 

128193.75 20511 29.9% 0.0% 

62662.5 10026 29.9% 0.0% 

37268.75 5963 29.9% 0.0% 

188587.5 30174 29.9% 0.0% 

146556.25 23449 29.9% 0.0% 

57462.5 9194 29.9% 0.0% 

338293.75 54127 29.9% 0.0% 

172425 27588 29.9% 0.0% 

132312.5 21170 29.9% 0.0% 

208056.25 33289 29.9% 0.0% 

172275 27564 29.9% 0.0% 

165625 26500 29.9% 0.0% 

269981.25 43197 29.9% 0.0% 

225637.5 36102 29.9% 0.0% 

53312.5 8530 29.9% 0.0% 

132987.5 21278 29.9% 0.0% 

64800 10368 29.9% 0.0% 
402(c) Economic Analysis Chapter 5 841 

Table 5D-4: Custom Distribution Values for Input Parameters: Initial Lead Dust Level 

in Work Area After Indoor Work, and Percentage of Area of the Home 

That is a Work Area 

Work Area Loading 

(μg/ft2

) 

Adjacent Room Loading 

(μg/ft2) 

Percent of Home 

that is Work Area

Probability of 

Occurrence1 

43918.75 7027 29.9% 0.0% 

173056.25 27689 29.9% 0.0% 

62537.5 10006 29.9% 0.0% 

41837.5 6694 29.9% 0.0% 

24100 3856 29.9% 0.0% 

37337.5 5974 29.9% 0.0% 

57837.5 9254 29.9% 0.0% 

15693.75 2511 29.9% 0.0% 

63737.5 10198 29.9% 0.0% 

327862.5 52458 29.9% 0.0% 

127675 20428 29.9% 0.0% 

104006.25 16641 29.9% 0.0% 

302662.5 48426 29.9% 0.0% 

99437.5 15910 29.9% 0.0% 

38906.25 6225 29.9% 0.0% 

64112.5 10258 29.9% 0.0% 

127412.5 20386 29.9% 0.0% 

127650 20424 29.9% 0.0% 

11031.25 1765 29.9% 0.0% 

121275 19404 29.9% 0.0% 

263950 42232 29.9% 0.0% 

18906.25 3025 29.9% 0.0% 

29862.5 4778 29.9% 0.0% 

123681.25 19789 29.9% 0.0% 

26337.5 4214 29.9% 0.0% 

98481.25 15757 29.9% 0.0% 

41081.25 6573 29.9% 0.0% 

108325 17332 29.9% 0.0% 

126112.5 20178 29.9% 0.0% 

119693.75 19151 29.9% 0.0% 

73743.75 11799 29.9% 0.0% 

70562.5 11290 29.9% 0.0% 

169462.5 27114 29.9% 0.0% 

80393.75 12863 29.9% 0.0% 

93162.5 14906 29.9% 0.0% 

135912.5 21746 29.9% 0.0% 

43006.25 6881 29.9% 0.0% 

19250 3080 29.9% 0.0% 

93781.25 15005 29.9% 0.0% 

8450 1352 29.9% 0.0% 

70762.5 11322 29.9% 0.0% 

34568.75 5531 29.9% 0.0% 
402(c) Economic Analysis Chapter 5 842 

Table 5D-4: Custom Distribution Values for Input Parameters: Initial Lead Dust Level 

in Work Area After Indoor Work, and Percentage of Area of the Home 

That is a Work Area 

Work Area Loading 

(μg/ft2

) 

Adjacent Room Loading 

(μg/ft2) 

Percent of Home 

that is Work Area

Probability of 

Occurrence1 

71675 11468 29.9% 0.0% 

200037.5 32006 29.9% 0.0% 

89112.5 14258 29.9% 0.0% 

73143.75 11703 29.9% 0.0% 

118675 18988 29.9% 0.0% 

46656.25 7465 29.9% 0.0% 

59768.75 9563 29.9% 0.0% 

42306.25 6769 29.9% 0.0% 

145100 23216 29.9% 0.0% 

132075 21132 29.9% 0.0% 

56012.5 8962 29.9% 0.0% 

68681.25 10989 29.9% 0.0% 

70412.5 11266 29.9% 0.0% 

256200 40992 29.9% 0.0% 

137650 22024 29.9% 0.0% 

121543.75 19447 29.9% 0.0% 

60456.25 9673 29.9% 0.0% 

20193.75 3231 29.9% 0.0% 

168393.75 26943 29.9% 0.0% 

9550 1528 29.9% 0.0% 

69762.5 11162 29.9% 0.0% 

88012.5 14082 29.9% 0.0% 

97662.5 15626 29.9% 0.0% 

34437.5 5510 29.9% 0.0% 

29906.25 4785 29.9% 0.0% 

152081.25 24333 29.9% 0.0% 

145431.25 23269 29.9% 0.0% 

55887.5 8942 29.9% 0.0% 

202100 32336 29.9% 0.0% 

110225 17636 29.9% 0.0% 

72518.75 11603 29.9% 0.0% 

48487.5 7758 29.9% 0.0% 

92787.5 14846 29.9% 0.0% 

96931.25 15509 29.9% 0.0% 

46875 7500 29.9% 0.0% 

134137.5 21462 29.9% 0.0% 

125425 20068 29.9% 0.0% 

168550 26968 29.9% 0.0% 

176937.5 28310 29.9% 0.0% 

107218.75 17155 29.9% 0.0% 

176112.5 28178 29.9% 0.0% 

99743.75 15959 29.9% 0.0% 
402(c) Economic Analysis Chapter 5 843 

Table 5D-4: Custom Distribution Values for Input Parameters: Initial Lead Dust Level 

in Work Area After Indoor Work, and Percentage of Area of the Home 

That is a Work Area 

Work Area Loading 

(μg/ft2

) 

Adjacent Room Loading 

(μg/ft2) 

Percent of Home 

that is Work Area

Probability of 

Occurrence1 

60487.5 9678 29.9% 0.0% 

127731.25 20437 29.9% 0.0% 

102531.25 16405 29.9% 0.0% 

33306.25 5329 29.9% 0.0% 

174125 27860 29.9% 0.0% 

82362.5 13178 29.9% 0.0% 

29893.75 4783 29.9% 0.0% 

133831.25 21413 29.9% 0.0% 

123850 19816 29.9% 0.0% 

14400 2304 29.9% 0.0% 

35350 5656 29.9% 0.0% 

125931.25 20149 29.9% 0.0% 

246431.25 39429 29.9% 0.0% 

121043.75 19367 29.9% 0.0% 

98650 15784 29.9% 0.0% 

100731.25 16117 29.9% 0.0% 

105156.25 16825 29.9% 0.0% 

45775 7324 29.9% 0.0% 

65868.75 10539 29.9% 0.0% 

38343.75 6135 29.9% 0.0% 

131556.25 21049 29.9% 0.0% 

54093.75 8655 29.9% 0.0% 

12412.5 1986 29.9% 0.0% 

136218.75 21795 29.9% 0.0% 

129262.5 20682 29.9% 0.0% 

287431.25 45989 29.9% 0.0% 

36043.75 5767 29.9% 0.0% 

161900 25904 29.9% 0.0% 

24856.25 3977 29.9% 0.0% 

208750 33400 29.9% 0.0% 

213412.5 34146 29.9% 0.0% 

85412.5 13666 29.9% 0.0% 

92062.5 14730 29.9% 0.0% 

81362.5 13018 29.9% 0.0% 

128375 20540 29.9% 0.0% 

151893.75 24303 29.9% 0.0% 

99625 15940 29.9% 0.0% 

51318.75 8211 29.9% 0.0% 

77468.75 12395 29.9% 0.0% 

111881.25 17901 29.9% 0.0% 

81187.5 12990 29.9% 0.0% 

35856.25 5737 29.9% 0.0% 
402(c) Economic Analysis Chapter 5 844 

Table 5D-4: Custom Distribution Values for Input Parameters: Initial Lead Dust Level 

in Work Area After Indoor Work, and Percentage of Area of the Home 

That is a Work Area 

Work Area Loading 

(μg/ft2

) 

Adjacent Room Loading 

(μg/ft2) 

Percent of Home 

that is Work Area

Probability of 

Occurrence1 

49843.75 7975 29.9% 0.0% 

217606.25 34817 29.9% 0.0% 

51350 8216 29.9% 0.0% 

28643.75 4583 29.9% 0.0% 

79550 12728 29.9% 0.0% 

181906.25 29105 29.9% 0.0% 

105231.25 16837 29.9% 0.0% 

66637.5 10662 29.9% 0.0% 

113943.75 18231 29.9% 0.0% 

148356.25 23737 29.9% 0.0% 

156743.75 25079 29.9% 0.0% 

29425 4708 29.9% 0.0% 

246500 39440 29.9% 0.0% 

84962.5 13594 29.9% 0.0% 

208025 33284 29.9% 0.0% 

233387.5 37342 29.9% 0.0% 

29206.25 4673 29.9% 0.0% 

111362.5 17818 29.9% 0.0% 

116025 18564 29.9% 0.0% 

141706.25 22673 29.9% 0.0% 

188556.25 30169 29.9% 0.0% 

193218.75 30915 29.9% 0.0% 

16981.25 2717 29.9% 0.0% 

22112.5 3538 29.9% 0.0% 

43381.25 6941 29.9% 0.0% 

42187.5 6750 29.9% 0.0% 

45050 7208 29.9% 0.0% 

20862.5 3338 29.9% 0.0% 

1.Probabilities shown as 0.0% have a positive but very small values. 

Source: See Appendix 5C for development of lead loadings. See Chapter 4 for development 

of probabilities 
402(c) Economic Analysis Chapter 5 845 

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http://www.atsdr.cdc.gov/toxprofiles/tp13.html 

Apostoli, P., et al. 2004. Lead and cardiopathy. Medicina del Lavoro, 95(2): 124-132. 

Bagchi, D. and H.G. Preuss. 2005. Effects of acute and chronic oval exposure of lead on blood pressure 

and bone mineral density in rats. Journal of Inorganic Biochemistry, 99(5): 1155-1164. 

Baghurst, P. A., et al. 1992. Environmental exposure to lead and children’s intelligence at the age of 

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§402(c) Economic Analysis Chapter 6 1 

6. Comparison of Benefits to Costs 

This chapter evaluates the various regulatory options under consideration in terms of their net benefits 

(i.e. benefits minus costs). Because there is a range of estimated IQ points gained for each option, net 

benefits are presented as a range of the estimates for each option. It is important to remember that these 

estimates only partially account for the benefits of the rule; some important groups of benefits are 

excluded from monetization. 

Four regulatory options are analyzed in this report – three allow for flexibility in applying the specific 

work practices and one is prescriptive. The options also differ in terms of the age of housing covered in 

the first year. By the second year they all cover the same housing stock. The regulatory options cover the 

following housing units: 

Table 6- 1: Definitions of Regulatory Options 

First Year – Phase 1 Second Year – Phase 2 

Option A 

All renter-occupied target housing units built 

before 1978, and owner-occupied target 

housing units built before 1978 where a 

child under the age of six resides. Flexible 

application of work practices 

All renter-occupied target housing built 

before 1978, and owner-occupied target 

housing units built before 1978 where a 

child under the age of six resides. 

Flexible application of work practices 

Option B 

All renter-occupied target housing units built 

before 1960, and owner-occupied target 

housing units built before 1960 where a 

child under the age of six resides, plus all 

target housing units built before 1978 where 

a child with an increased blood-lead level 

resides.a

 Flexible application of work 

practices 

Same as Option A. 

Option C 

All renter-occupied target housing units built 

before 1950, and owner-occupied target 

housing units built before 1950 where a 

child under the age of six resides, plus all 

target housing units built before 1978 where 

a child with an increased blood-lead level 

resides.a

 Flexible application of work 

practices 

Same as Option A. 

Option D 

The prescriptive option. Covers the same 

housing units as Option B – but requires 

specific work practices. 

The prescriptive option. Covers the 

same housing units as Option B – but 

requires specific work practices. a

 Where increased is defined as greater than or equal to 10 μg/dL or a State or local government level 

of concern, if lower. 

The proposed rule is Option B. 

The costs for these four options are estimated in Chapter 4 and summarized in Table 6-2. In terms of first 

year costs, the regulatory options display a wide range, from $924 million down to $393 million. The 

range is much narrower in terms of annualized costs, from $588 million down to $488 million when 

calculated with a three percent discount rate and from $629 million down to $518 million when calculated 

with a seven percent discount rate. First year costs are much higher, in part because the lead-based paint 

test kits used in the first year to determine if lead is present are assumed to have a much higher false 
§402(c) Economic Analysis Chapter 6 2 

positive rate, as compared to the improved tests anticipated to be available after the first year. Work 

practice costs are higher in the first year because the less accurate lead-based paint test kits result in more 

cases where a false positive test results in the unnecessary use of the rule’swork practices. The regulatory 

options that phase in housing units (Options B, C and D) have higher training and certification costs than 

Option A in the second year because some of the initial training and certification costs are incurred in the 

second year under these options (when the regulated universe is expanded). 

Table 6-2: Comparison of Options – Cost per Individual Protecteda 

Annual Cost 

(millions 2005$) 

Annual Number of At-Risk 

Individuals Protectedb

(millions)

Annual Cost per At-Risk 

Individual Protected 

Year 1 Year 2 Annual

-ized Year 1 Year 2 Annual 

Average Year 1 Year 2 Annual

-ized 

3 Percent Discount Rate 

Option A $924 $495 $505 5.31 5.29 4.81 $174 $94 $105 

Option B $531 $552 $492 4.53 5.29 4.79 $117 $104 $103 

Option C $393 $572 $488 3.66 5.29 4.78 $107 $108 $102 

Option D $645 $649 $588 4.53 5.29 4.79 $142 $123 $123 

7 Percent Discount Rate 

Option A $924 $476 $551 5.31 5.29 4.81 $174 $90 $115 

Option B $531 $532 $526 4.53 5.29 4.79 $117 $101 $110 

Option C $393 $551 $518 3.66 5.29 4.78 $107 $104 $108 

Option D $645 $625 $629 4.53 5.29 4.79 $142 $118 $131 a Assuming 75% compliance with the regulations. Number of individuals protected reflects occupants of 

housing with LBP where LSWP are used as a result of the rule, and not just individuals for whom benefits are 

monetized (i.e., children under the age of 6, and adults over the age of 40). 

b

At-risk individuals are individuals living in housing units where RRP takes place, there is lead-based paint and 

the contractor does not already use the work practices prescribed in the regulation. The number protected may 

be higher under Scenario 1. 

One measure of the impact of each option of the rule is the number of individuals protected by the 

regulation above and beyond those protected in the baseline conditions without the rule. Protected 

individuals (children, teenagers and adults) are those living in housing units where the following three 

conditions are met: Renovation, Repair and Painting (RRP) events take place, lead-based paint is both 

present and disturbed, and the occupant would not otherwise be protected to the level of the rule under the 

baseline work practices. The measures of costs and benefits estimated in this analysis address the 

incremental improvement in protection above these baseline conditions. 

In the right-most set of columns in Table 6-2, the options are compared in terms of cost-per-individual 

protected. Option C is the most cost-effective in Year 1, but Option A is the most cost-effective in Year 2 

because of the investment in training and certification that occurred in Year 1 under Option A. Using the 

50-year annualized costs, the three flexible options (A, B and C) have approximately the same cost per atrisk individual protected and they all are more cost-effective than Option D, in which work practices are 

prescribed.1

 

1 Because annualized annual costs are slightly higher when calculated using a 7 percent discount rate than with a 3 

percent discount rate, annualized costs per individual protected are also slightly higher with a 7 percent discount 

rate. See Section 4.7.3 for more discussion of annualized costs under alternative discount rates. 
§402(c) Economic Analysis Chapter 6 3 

Another way to compare the efficiency of the options is to examine their net benefits. Based on the 

subset of benefits that have been monetized, Table 6-3 and Table 6- 4 display net benefit calculations for 

the first year of the rule and the annualized value of the rule, respectively. Benefits are shown separately 

for Scenarios 1 and 2 (Tables a and b). As described in detail in Section 5.5.3, the two scenarios differ as 

to how much contractor and household cleaning already occurs in the baseline; in addition, adult benefits 

are not estimated under Scenario 2. There are additional uncertainties in the quantification of adult 

effects, which are addressed in Section 5.5.5. Scenario 2 produces a lower estimate of benefits because it 

assumes a higher level of baseline cleaning than Scenario 1 and quantifies only children’s IQ benefits. 

Benefits in the form of IQ points gained are presented for each scenario and regulatory option. Adult 

health benefits for each regulatory option are also included in Scenario 1. There is a range of estimates 

for each option because each of the six alternative sets of blood-lead modeling assumptions for children’s 

IQ produces a separate estimate. The range is composed of the lowest and the highest IQ point estimate 

for the option. 

Under Scenario 1 (Table 6-3a), all of the net benefit estimates are positive. Under Scenario 2 (Table 6-

3b) the first year costs are the same as under Scenario 1; however, the benefits and net benefit estimates 

are smaller. All of the net benefit estimates remain positive, except for the lowest estimate for Option A.2

 

There is no clearly preferred option based on first year net benefits because, under either scenario, the 

ranges of net benefit estimates overlap substantially. Under Scenario 1, Option A presents both the 

highest minimum and the highest maximum value. Under Scenario 2, Option B presents the highest 

minimum value for net benefits, while Option A presents the highest value overall for net benefits. 

 

2 As discussed in Chapter 5, the lowest value in the range of Children’s IQ benefits is likely to underestimate the IQ 

benefits. For each option, this estimate assumes that the only children who benefit from the reduced exposure are 

children ages 1-2 years; other children under the age of 6 years are not included in this low estimate. 
§402(c) Economic Analysis Chapter 6 4 

Table 6-3a: Comparison of Options – Scenario 1 -- First Year Net Benefits 

First 

Year 

Costa 

(millions 

2005$)

Children’s IQ 

Benefits – First 

Yearb 

(millions 

2005$) 

Adult 

Health 

Benefits – 

First Year b

(millions 

2005$) 

Sum of 

Children’s IQ 

and Adult 

Benefits 

(millions 2005$)

Net Benefitsc -- 

Children’s IQ 

and Adult 

Health 

(millions 

2005$)

Option A $924 $990 -$5,583 $2,367 $3,357 -$7,950 $2,433 - $7,026 

Option B $531 $849 - $4,945 $2,057 $2,906 - $7,002 $2,375 - $6,471 

Option C $393 $668 - $3,810 $1,676 $2,344 - $5,486 $1,951 - $5,093 

Option D $645 $849 - $4,945 $2,057 $2,906 -$7,002 $2,261 - $6,357 

a Developed in Chapter 4. 

b Developed in Chapter 5 – range for children’s IQ benefits reflects alternative models for blood 

lead, exposure estimates and population of children. 

c Difference between sum of benefits and costs. 

Table 6-3b: Comparison of Options – Scenario 2a -- First Year Net 

Benefits 

First Year 

Costb 

(millions 

2005$)

Children’s IQ 

Benefits – First 

Yearc 

(millions 2005$) 

Net Benefitsd

 – 

Children’s IQ Only 

(millions 2005$)

Option A $924 $810 - $4,555 ($114) - $3,631 

Option B $531 $695 - $3,901 $164 - $3,370 

Option C $393 $545 - $3,105 $152 - $2,712 

Option D $645 $695 - $3,901 $50 - $3,256 

a While recognizing that adults will benefit from the rule, Scenario 2 does 

not try to quantify adult benefits. 

b Developed in Chapter 4. 

c Developed in Chapter 5 – range reflects alternative models for blood lead, 

exposure estimates and population of children. d Difference between sum of benefits and costs.

When comparing options on the basis of annualized net benefits (Table 6- 4a and Table 6- 4b), very little 

difference appears among Options A, B and C. This is not surprising, since the primary differences in the 

options occur in the first year the rule takes effect. After that year, all options address the same universe 

of pre-1978 housing. And after the second year, the population of firms and renovators being trained and 

re-trained levels off to approximately the same number each year. Thus, over a 50-year period, there is 

little difference among the three flexible options. Scenario 2 produces a lower estimate of benefits from 

the rule because it assumes a higher level of baseline cleaning than Scenario 1; in addition, adult benefits 

are not estimated under Scenario 2. There are additional uncertainties in the quantification of adult 

effects, which are addressed in Section 5.5.5. Both benefits and costs have slightly higher annualized 

estimates when a 7 percent discount rate is used, as compared to a 3 percent discount rate. Under both 

scenarios, net benefits are also slightly higher under the 7 percent discount rate. Regardless of which 

scenario or discount rate is used, however, there is little difference among Options B, C and D. The only 

substantial difference among the options is between the flexible options (A, B and C) and the prescribed 
§402(c) Economic Analysis Chapter 6 5 

option (D). The lack of flexibility appears as a roughly $100 million reduction in net benefits as 

compared to the other options. 

Table 6- 4a: Comparison of Options – Scenario 1 -- Annualized Costs and Net Benefits 

Annualized 

Cost 

(millions 

2005$)a 

Children’s IQ 

Benefits – 

Annualized 

(millions 

2005$)b 

Adult Health 

Benefits – 

Annualized 

(millions 

2005$) b

Sum of Children’s 

IQ and Adult 

Benefits -- 

Annualized 

(millions 2005$)

Net Benefits – 

Children’s IQ 

and Adult Health 

-- Annualized c

(millions 2005$)

Annualized using 3 Percent Discount Rate 

Option A $505 $947 - $5,336 $2,262 $3,209 - $7,599 $2,704 - $7,093 

Option B $492 $941 - $5,311 $2,250 $3,191 - $7,562 $2,699 - $7,069 

Option C $488 $934 - $5,267 $2,235 $3,170 - $7,503 $2,682 - $7,015 

Option D $588 $941 - $5,311 $2,250 $3,191 - $7,562 $2,603 - $6,973 

Annualized using 7 Percent Discount Rate

Option A $551 $1,008 - $5,680 $2,408 $3,415 - $8,087 $2,865 - $7,537 

Option B $526 $997 - $5,633 $2,385 $3,383 - $8,019 $2,857 - $7,493 

Option C $518 $984 - $5,551 $2,358 $3,342 - $7,909 $2,824 - $7,391 

Option D $629 $997 - $5,633 $2,385 $3,383 - $8,019 $2,754 - $7,390 a Developed in Chapter 4 

b Developed in Chapter 5 – range for children’s IQ benefits reflects alternative models for blood lead, 

exposure estimates and population of children c Difference between sum of benefits and costs 

Table 6-4b: Comparison of Options – Scenario 2a – Annualized Costs and Net 

Benefits 

Annualized 

Costb 

(millions 2005$)

Children’s IQ Benefits 

– Annualizedc 

(millions 2005$) 

Net Benefitsd

 – 

Children’s IQ Only 

(millions 2005$)

Annualized using 3 Percent Discount Rate 

Option A $505 $774 - $4,354 $269 - $3,849 

Option B $492 $770 - $4,329 $277 - $3,837 

Option C $488 $764 - $4,298 $276 - $3,810 

Option D $588 $770 - $4,329 $181 - $3,741 

Annualized using 7 Percent Discount Rate 

Option A $551 $824 - $4,635 $273 - $4,084 

Option B $526 $816 - $4,587 $290 - $4,061 

Option C $518 $805 - $4,530 $287 - $4,012 

Option D $629 $816 - $4,587 $187 - $3,958 

a While recognizing that adults will benefit from the rule, Scenario 2 does not try to 

quantify adult benefits. 

b Developed in Chapter 4 

c Developed in Chapter 5 – range reflects alternative models for blood lead, 

exposure estimates and population of children d Difference between sum of benefits and costs 
§402(c) Economic Analysis Chapter 7 1 

7. Sensitivity Analysis 

To address some of the uncertainties in this analysis, this section considers the impacts of several 

alternative assumptions on the cost estimates presented in Chapter 4. Where the changes in assumptions 

also affect benefits, these benefit impacts are described. Fourteen alternative estimates are presented in 

this sensitivity analysis. They include: 

Alternative Estimate 1: An estimate with an alternative assumption about the baseline level of 

required work practices; it is assumed that Renovation, Repair, and Painting (RRP) events in 

states and cities with similar RRP regulations do not incur work practice costs. 

Alternative Estimate 2: An estimate with the alternative assumption that 100 percent of regulated 

RRP events are in compliance with the rule instead of 75 percent. 

Alternative Estimate 3: An estimate with the alternative assumption that 60 percent of regulated RRP 

events are in compliance with the rule instead of 75 percent. 

Alternative Estimate 4: An estimate with the alternative assumption that 30 percent of regulated RRP 

events are in compliance with the rule instead of 75 percent. 

Alternative Estimate 5: An estimate with the alternative assumption that the false positive rate for the 

test kit is 47 percent, instead of 63 percent, in the first year. 

Alternative Estimate 6: An estimate with the alternative assumption that the false positive rate for the 

test kit is 78 percent, instead of 63 percent, in the first year. 

Alternative Estimate 7: An estimate with the alternative assumption that the false negative rate for 

the test kit is five percent, instead of zero. 

Alternative Estimate 8: An estimate with the alternative assumption that using the test kit to check 

for the presence of lead-based paint (LBP) costs $20 per-event instead of $10. 

Alternative Estimate 9: An estimate with the alternative assumption that the test kit is not available 

until the third year the rule is in effect, instead of the second year. 

Alternative Estimate 10: An estimate with the alternative assumption that the improved test kit is not 

available until the sixth year the regulation is effective. 

Alternative Estimate 11: An estimate with the alternative assumption that the expansion of the 

regulatory universe and the availability of the improved test kit is delayed until the sixth year the 

regulation is effective. 

Alternative Estimate 12: An estimate with the alternative assumption that the improved test kit has a 

false positive rate of 15 percent rather than 10 percent. 

Alternative Estimate 13: An estimate with an alternative assumption about the number of firms and 

individuals seeking training and certification. 

Alternative Estimate 14: An estimate that considers the costs and benefits of an alternative regulatory 

option where cleaning verification is not required. 

7.1 Alternative Estimate 1: Adjusted for State and Local RRP Regulations 

In this section of the sensitivity analysis, EPA assumes that the baseline work practices utilized in certain 

states and cities are approximately the same as those that will be required under the RRP rule because of 

existing state and local RRP regulations. Thus, the compliance costs incurred in these states will include 

cleaning verification, training, and certification costs but not work practice compliance costs. Since only 

two states and one city currently require renovation contractors to seek lead-safe work practice training, 

the baseline level of training is minimal and therefore not considered in this analysis. Thus, there is no 

training cost adjustment in this section of the sensitivity analysis. 
§402(c) Economic Analysis Chapter 7 2 

7.1.1 Overlap between State and Local Regulations and the Renovation, Repair and Painting Rule 

Section 3.2.3 of Chapter 3 identified eight states and six cities that have promulgated rules that address 

Renovation, Repair, and Painting projects in older housing. These regulations vary from prohibitions 

against the use of certain work practices when disturbing LBP to specific site preparation and clean-up 

requirements. 

The regulations promulgated in five of the identified states and four of the identified cities are similar 

(although not identical) to the work practice standards established by the RRP Rule, making it likely that 

regulated events in these states will not incur most of the work practice compliance costs associated with 

the new rule.1

 In Massachusetts, for example, workers performing RRP jobs in any pre-1978 housing unit 

are already required to remove all movable objects from the work area, to cover non-movable objects 

with plastic sheeting, and to shut down and seal off all HVAC ducts exposed to the work area. All 

surfaces contaminated with lead debris or dust must be cleaned using a HEPA vacuum, wet wiping, or 

another acceptable method. If Massachusetts contractors already comply with these regulations, they will 

not incur additional costs from corresponding work practice requirements in the RRP Rule. They will, 

however, still incur the costs of cleaning verification, which is not required by Massachusetts regulations. 

Other states where regulated projects are likely to be in compliance with the RRP rule work practice 

standards (not including cleaning verification) are New Jersey, Vermont, Rhode Island and California.2

 

Cities with similar regulations include Chicago (Illinois), New York City (New York), Kansas City 

(Missouri), and Cleveland (Ohio). In New Jersey, Vermont, Rhode Island, New York City, and 

Cleveland, local rules dictate the use of specific work practices when performing regulated projects. In 

California, as well as in Chicago and Kansas City, regulations prohibit the creation of uncontained lead 

dust and debris, implicitly requiring the use of containment during renovation work. 

State and city regulations differ in terms of the regulated housing stock. Some apply to all pre-1978 

housing, while others apply only to pre-1978 or pre-1960 rental units. Table 7-1 describes the housing 

stock covered by each state and city rule. 

 

1

 The three remaining states promulgated regulations that prohibit certain work practices but do not require any site 

preparation or containment. These regulations do not overlap with the proposed RRP Rule and are thus not 

accounted for in this analysis. Projects conducted in these states are likely to incur the full work practice costs 

associated with the rule. In addition, voluntary programs are not accounted for in this analysis because of lack of 

data on the level of participation. 

2

 San Francisco exterior events are exempted under the California regulations. 
§402(c) Economic Analysis Chapter 7 3 

7.1.2 Adjustment of the Work Practice Compliance Costs 

For this sensitivity analysis, EPA assumes that events subject to city and state regulations incur the cost of 

the cleaning verification but will not incur any other work practice costs since they are assumed to already 

be using lead-safe renovation techniques.3

 EPA also assumes that the number of renovation events 

subject to state and city regulations is proportional to the regulated housing stock located in these 

states/cities. Thus, to account for the increased level of baseline work practices assumed under this 

sensitivity analysis alternative, the work practice compliance costs are reduced by the percentage of the 

U.S. housing stock (by age and occupancy) that is subject to more comprehensive state and local 

renovation rules.4

 Because some regulations apply only to exterior or only to interior events and others 

apply only to rental units, EPA calculates separate percentages for interior, exterior, owner-occupied, and 

renter-occupied RRP. These percentages are presented in Table 7-2. 

 

3

 Because the majority of city and state regulatory requirements are not identical to the work practices established by 

the Renovation, Repair and Painting Rule, this assumption may underestimate the total cost of the RRP Rule under 

Alternative Estimate 1. At the same time, the assumption that cleaning verification costs will be incurred for all 

events may slightly overestimate the cost of the rule since New Jersey and New York City regulations require postrenovation dust testing. Furthermore, it is possible that the presence of local regulations encourages contractors to 

take additional precautions, even though these are not explicitly required by the law. 

4 This is in addition to the percentage of events assumed to employ baseline work practices. The data collected on 

baseline work practices were collected in 1999, before most of these state and local regulations were in place.

Table 7-1: Description of Housing Stock Subject to State and City Renovation Regulations 

State/City Interior Projectsa Exterior Projects 

California All pre-1978 housing All pre-1978 housing 

Massachusetts All pre-1978 housing All pre-1978 housing 

New Jersey All pre-1978 multi-family housing, 

except owner-occupied units 

All pre-1978 multi-family housing, except 

owner-occupied units 

Vermont All pre-1978 rental housing All pre-1978 rental housing 

Rhode Islandb None All buildings and structures 

New York City, NY All pre-1978 multi-family rental 

housing with 3 or more units. 

Owner-occupied units exempt. 

None 

Chicago, IL Pre-1978 buildings frequented by 

children six years old and younger 

Pre-1978 buildings frequented by children 

six years old and younger 

Kansas City, MO Pre-1978 buildings Pre-1978 buildings 

Cleveland, OH Pre-1978 target housing Pre-1978 target housing a Each state/city may provide for slightly different small construction job exceptions. This analysis 

assumes that the definition of a small job under each regulation is the same as the definition used in 

Section 4.5.5 of Chapter 4. b The Rhode Island Department of Health regulations, which cover interior events, are not included in this 

analysis because they apply to a very small number of renovation projects (some EBL cases only). See 

Chapter 3 for further discussion. 
§402(c) Economic Analysis Chapter 7 4 

7.1.3 Comparison of the Costs 

Table 7-3 presents the 50-year annualized cost estimates for Alternative Estimate 1. The percentages 

reported in Table 7-2 are used to reduce the work practice costs to reflect the baseline utilization of 

required work practices in certain states and cities. Note that cleaning verification, training, and 

certification costs are the same as the Primary Estimates. Thus, under this alternative, 50-year annualized 

costs are about 14 to 16 percent lower than the Primary Estimates presented in Chapter 4 of this analysis. 

7.1.4 Comparison of the Benefits 

In this analysis, the benefits of the RRP Rule are correlated with the numbers of children and adults 

protected from lead exposure, which in turn are a function of the number of events involving LSWP as a 

result of the regulation. Since it is assumed that a larger share of the population is protected in the 

baseline under Alternative Estimate 1, the increment of benefits associated with the new rule is smaller. 

If state and local regulations were as protective of human health as the proposed RRP Rule, estimated 

benefits would decline by the percentages presented in Table 7-2. In other words, since state and city 

rules already protect the health of people living in locally regulated housing, the benefits of this protection 

could not be attributed to the RRP Rule. 

However, work practice standards alone are unlikely to be as protective of human health as a combination 

of containment, cleaning verification, training, and certification requirements. Contractors required to use 

Table 7-2: Percent of Nation-wide Housing Stock Subject to State and City Renovation 

Regulations 

 Type of Event and Unit Affected Pre-1978b Pre-1960 Pre-1950 

Interior Events, All Unitsa 19.12% 21.35% 21.79% 

Interior Events, Owner-Occupied Units Only 13.58% 14.20% 13.51% 

Interior Events, Renter-Occupied Units Onlya 28.77% 34.61% 35.74% 

Exterior Events, All Unitsa 17.63% 18.31% 18.05% 

Exterior Events, Owner-Occupied Units Only 14.01% 14.72% 14.09% 

Exterior Events, Renter-Occupied Units Onlya 23.94% 24.95% 24.73% a New York City data includes all pre-1960 renter-occupied multi-family structures with two 

units or more. b

 The pre-1978 housing stock is approximated using pre-1980 housing stock data. 

Source: U.S. Census Bureau 2000c. 

Table 7-3: Alternative Estimate 1: 50-Year Annualized Cost Estimates and Percent Change: 

Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 1: 

Adjusted for State 

and Local RRP 

Regulations 

$432 $421 $417 $494 $471 $449 $442 $528 

Percent Change -14.5% -14.5% -14.5% -16.0% -14.5% -14.6% -14.5% -16.1% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations 
§402(c) Economic Analysis Chapter 7 5 

containment, for example, may not do so effectively unless they have been trained in how to properly lay 

down, affix, and dispose of plastic sheeting. 

7.2 Alternative Estimate 2: 100% Compliance Assumption 

Alternative Estimate 2 employs the alternative assumption that 100 percent of regulated RRP events are 

in compliance with the rule rather than 75 percent as in the Primary Estimate. 

 

7.2.1 Comparison of the Costs 

For the Primary Estimate it is assumed that 75 percent of events are in compliance based on compliance 

rates observed for the Occupational Safety and Health Administration’s (OSHA) regulations (Gilkeya et 

al 2003 and Weil 1999). The alternative assumption that 100 percent of events will be in compliance is 

considered here. Although going from 75 percent to 100 percent compliance is a 33 percent increase in 

the compliance rate, the costs increase by over 50 percent (see Table 7-4). The percentage increase in 

costs is greater than the increase in the compliance rate because some compliance costs are incurred in the 

baseline under both alternatives.5

 That is, it is assumed that renovators who are using a work practice 

activity in the baseline that will be required by the rule will continue to use that practice and will comply 

with the rule under either estimate. The training and certification costs are 33 percent higher under 

Alternative Estimate 2 compared to the Primary Estimate; this reflects the 33 percent increase in the 

compliance rate. 

 

7.2.2 Comparison of the Benefits 

Scenario 1 and Scenario 2 have different assumptions about the level of protection provided by baseline 

work practices; more protection is assumed in the baseline under Scenario 2. See Section 5.5.3 for a more 

detailed discussion of the two scenarios. 

 

5

 Specifically, in the baseline it is assumed that renovators are spending about 35 cents of every dollar of work 

practice costs needed to attain 100 percent compliance under the flexible options (A, B, and C). For the postregulation Primary Estimate it is assumed that renovators spend 75 cents of every dollar of work practice costs that 

would be needed to attain 100 percent compliance. Therefore, there is a 63 percent increase in costs [(100-35)/(75-

35) – 1 = 63%] under Alternative Estimate 2. Since training and certification costs increase 33 percent under this 

alternative, total costs rise by about 57 percent overall under the flexible options. 

Table 7-4: Alternative Estimate 2: 50-Year Annualized Cost Estimates and Percent Change: 

Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 2: 100% 

Compliance Assumption $795 $774 $766 $940 $866 $827 $813 $1,004 

Percent change 57.2% 57.2% 57.1% 59.7% 57.3% 57.1% 57.1% 59.7% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 6 

Scenario 1 

Under Scenario 1 the level of protection provided by baseline work practices is assumed to be 

computationally equivalent to assuming that 20 out of every 100 individuals who reside where RRP is 

performed and LBP is present have adequate protection from baseline work practices to avoid harmful 

lead exposures (See Section 5.5.3 for further explanation). Under Alternative 2, all 100 of these 

individuals have adequate protection (compared to 75 of the 100 under the Primary Estimate). Thus, 

under Alternative Estimate 2 benefits are higher than for the Primary Estimate. 

The assumptions underlying Alternative Estimate 2 imply that benefits are higher than for the Primary 

Estimate. If it is assumed that non-compliance is independent of household LBP likelihoods, the type of 

RRP activities performed, and occupant composition (e.g., number, age and sex of occupants), then 

estimated benefits would be 45 percent higher under this alternative.6,7 That is, if the independence 

assumption holds, the monetized benefits presented in Chapter 5 would be precisely 45 percent higher for 

all options and all years under this alternative. 

Scenario 2 

Under Scenario 2 it is assumed that 20 out of every 100 individuals who reside where RRP is performed 

and LBP is present have adequate protection from baseline work practices to avoid harmful lead 

exposures (See Section 5.5.3 for further explanation). In addition, it is assumed that some households: (1) 

receive additional contractor cleaning (15 out of every 100 individuals who reside where RRP is 

performed and LBP is present), (2) receive additional household cleaning (15 out of every 100 individuals 

who reside where RRP is performed and LBP is present), and (3) additional contractor cleaning of the 

room adjacent to the work area (10 out of every 100 individuals who reside where RRP is performed and 

LBP is present). It is assumed that this additional contractor cleaning occurs in the subset of housing 

units that are in compliance with the rule. 

Under Alternative Estimate 2 and Scenario 2, the benefits are 48 percent higher compared with the 

Primary Estimate. For Alternative Estimate 2, the benefits increase more under Scenario 2 compared to 

Scenario 1 because the baseline level of protection is greater under Scenario 2. This is because the 

benefits for the Primary Estimate are smaller under Scenario 2 compared to Scenario 1. In other words, if 

compliance increases to 100% the post-rule level of protection increases by the same amount under 

Scenarios 1 and 2, but this is a larger percentage of those incrementally benefiting under Scenario 2, 

because there are fewer of these individuals compared to Scenario 1. 

 

6

 Similarly to the costs, the same level of protection from baseline work practices is assumed under both alternatives; 

therefore, the percentage increase in benefits is larger than the percentage increase in compliance. However, the 

assumed baseline level of protection (20 percent) is lower relative to the baseline work practice costs incurred (35 

percent). 

7

 The 45 percent is estimated as follows: Under Scenario 1 in the baseline, the level of protection provided by 

baseline work practices is assumed to be computationally equivalent to assuming that 20 out of every 100 

individuals who reside where RRP is performed and LBP is present have adequate protection from baseline work 

practices to avoid harmful lead exposures. Under the Primary Estimate, 75 out of 100 individuals have adequate 

protection (an increase of 55). Under Alternative Estimate 2, all 100 individuals are assumed to avoid exposure; an 

increase of 80 from the baseline level. This represents a 45 percent increase in individuals avoiding exposure (80/55 

– 1) = 45%. 
§402(c) Economic Analysis Chapter 7 7 

These estimates are calculated under the assumption that non-compliance is independent of household 

LBP likelihoods, the type of RRP performed, and occupant composition (e.g., number, age and sex of 

occupants). 

7.3 Alternative Estimate 3: 60% Compliance Assumption 

Alternative Estimate 3 employs the alternative assumption that 60 percent of regulated RRP events are in 

compliance with the rule rather than 75 percent as in the Primary Estimate. 

7.3.1 Comparison of the Costs 

For the Primary Estimate it is assumed that 75 percent of events are in compliance based on compliance 

rates observed for the Occupational Safety and Health Administration’s (OSHA) regulations (Gilkeya et 

al 2003 and Weil 1999). The alternative assumption that only 60 percent of events will be in compliance 

is considered here. Although going from 75 percent to 60 percent compliance is a 20 percent decline in 

the compliance rate, the costs decrease by over 30 percent (see Table 7-5). The percentage decrease in 

costs is larger than the decrease in the compliance rate because some compliance costs are incurred in the 

baseline under both alternatives.8

 That is, it is assumed that renovators who are using a work practice 

activity in the baseline that will be required by the rule will continue that practice and will comply with 

the rule under either estimate. The training and certification costs are 20 percent lower under Alternative 

Estimate 3 compared to the Primary Estimate; this reflects a 20 percent decrease in the compliance rate. 

7.3.2 Comparison of the Benefits 

Scenario 1 and Scenario 2 have different assumptions about the level of protection provided by baseline 

work practices; more protection is assumed in the baseline under Scenario 2. See Section 5.5.3 for a more 

detailed discussion of the two scenarios. 

 

8

 Specifically, in the baseline it is assumed that renovators are spending about 35 cents of every dollar of work 

practice costs needed to attain 100 percent compliance under the flexible options (A, B, and C). For the postregulation Primary Estimate it is assumed that renovators spend 75 cents of every dollar of work practice costs that 

would be needed to attain 100 percent compliance. For Alternative Estimate 3 it is assumed that renovators spend 

60 cents for every dollar of work practice costs that would be needed to attain 100 percent compliance. Therefore, 

there is a 38 percent decrease in costs [(60-35)/(75-35) – 1 = -38%] under Alternative Estimate 3. Since training and 

certification costs remain unchanged under this alternative, total costs decline by 30 percent overall. 

Table 7-5: Alternative Estimate 3: 50-Year Annualized Cost Estimates and Percent Change: 

Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 3: 60% 

Compliance 

Assumption 

$342 $334 $331 $382 $373 $357 $351 $408 

Percent Change -32.3% -32.2% -32.2% -35.1% -32.3% -32.2% -32.2% -35.1% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 8 

Scenario 1 

Under Scenario 1 the level of protection provided by baseline work practices is assumed to be 

computationally equivalent to assuming that 20 out of every 100 individuals who reside where RRP is 

performed and LBP is present have adequate protection from baseline work practices to avoid harmful 

lead exposures (See Section 5.5.3 for further explanation). Under Alternative 3, 60 of these 100 

individuals have adequate protection (compared to 75 of the 100 under the Primary Estimate). Thus, 

under Alternative Estimate 3 benefits are lower than for the Primary Estimate. 

If it is assumed that non-compliance is independent of household LBP likelihoods, the type of RRP 

activities performed, and occupant composition (e.g., number, age and sex of occupants), then estimated 

benefits would be 27 percent lower under this alternative.9,10 That is, if the independence assumption 

holds, the monetized benefits presented in Chapter 5 would be precisely 27 percent lower for all options 

and all years under this alternative. 

Scenario 2 

Under Scenario 2 it is assumed that 20 out of every 100 individuals who reside where RRP is performed 

and LBP is present have adequate protection from baseline work practices to avoid harmful lead 

exposures (See Section 5.5.3 for further explanation). In addition, it is assumed that some households: (1) 

receive additional contractor cleaning (15 out of every 100 individuals who reside where RRP is 

performed and LBP is present), (2) receive additional household cleaning (15 out of every 100 individuals 

who reside where RRP is performed and LBP is present), and (3) additional contractor cleaning of the 

room adjacent to the work area (10 out of every 100 individuals who reside where RRP is performed and 

LBP is present). It is assumed that this additional contractor cleaning occurs in the subset of housing 

units that are in compliance with the rule. 

Under Alternative Estimate 3 and Scenario 2, the benefits are 29 percent lower compared with the 

Primary Estimate. For Alternative Estimate 3, the benefits decline more under Scenario 2 compared to 

Scenario 1 because the baseline level of protection is greater under Scenario 2. In other words, the postrule level of protection declines by the same amount under Scenarios 1 and 2, but this is a larger 

percentage of those incrementally benefiting under Scenario 2, because there are fewer of these 

individuals under Scenario 2. 

These estimates are calculated under the assumption that non-compliance is independent of household 

LBP likelihoods, the type of RRP performed, and occupant composition (e.g., number, age and sex of 

occupants). 

7.4 Alternative Estimate 4: 30% Compliance Assumption 

Alternative Estimate 4 employs the alternative assumption that 30 percent of regulated RRP events are in 

compliance with the rule rather than 75 percent as in the Primary Estimate. 

 

9

 Similarly to the costs, the same level of protection from baseline work practices is assumed under both alternatives; 

therefore, the percentage decrease in benefits is larger than the percentage decrease in compliance. However, the 

assumed baseline level of protection is lower relative to the baseline work practice costs incurred. 

10 The 27 percent is calculated using the same steps described in footnote 7. 
§402(c) Economic Analysis Chapter 7 9 

7.4.1 Comparison of the Costs 

For the Primary Estimate it is assumed that 75 percent of events are in compliance based on compliance 

rates observed for the Occupational Safety and Health Administration’s (OSHA) regulations (Gilkeya et 

al 2003 and Weil 1999). The alternative assumption that only 30 percent of events will be in compliance 

is considered here. Although going from 75 percent to 30 percent compliance is a 60 percent decline in 

the compliance rate, the costs decrease by about 80 percent (see Table 7-5); this decline is driven by an 

85% reduction in work practice costs. The percentage decrease in costs is larger than the decrease in the 

compliance rate because some compliance costs are incurred in the baseline under both alternatives. The 

training and certification costs are 60 percent lower under Alternative Estimate 4 compared to the Primary 

Estimate; this reflects a 60 percent decrease in the compliance rate. 

7.4.2 Comparison of the Benefits 

Scenario 1 

Under Scenario 1 the level of protection provided by baseline work practices is assumed to be 

computationally equivalent to assuming that 20 out of every 100 individuals who reside where RRP is 

performed and LBP is present have adequate protection from baseline work practices to avoid harmful 

lead exposures (See Section 5.5.3 for further explanation). Under Alternative 4, 30 of these 100 

individuals have adequate protection (compared to 75 of the 100 under the Primary Estimate). Thus, 

under Alternative Estimate 4 benefits are lower than for the Primary Estimate. 

If it is assumed that non-compliance is independent of household LBP likelihoods, the type of RRP 

performed, and occupant composition (e.g., number, age and sex of occupants), then estimated benefits 

would be 82 percent lower under this alternative.11,12 That is, if the independence assumption holds, the 

monetized benefits presented in Chapter 5 would be precisely 82 percent lower for all options and all 

years under this alternative. 

 

11 Similarly to the costs, the same level of protection from baseline work practices is assumed under both 

alternatives; therefore, the percentage decrease in benefits is larger than the percentage decrease in compliance. 

However, the assumed baseline level of protection is lower relative to the baseline work practice costs incurred. 12 The 82 percent is calculated using the same steps described in footnote 7. 

Table 7-6: Alternative Estimate 4: 50-Year Annualized Cost Estimates and Percent Change: 

Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary 

Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 4: 

30% 

Compliance 

Assumption 

$99 $97 $96 $101 $108 $104 $102 $108 

Percent Change -80.4% -80.3% -80.3% -82.9% -80.5% -80.3% -80.2% -82.9% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 10 

Scenario 2

Under Scenario 2 it is assumed that 20 out of every 100 individuals who reside where RRP is performed 

and LBP is present have adequate protection from baseline work practices to avoid harmful lead 

exposures (See Section 5.5.3 for further explanation). In addition, it is assumed that some households: (1) 

receive additional contractor cleaning (15 out of every 100 individuals who reside where RRP is 

performed and LBP is present), (2) receive additional household cleaning (15 out of every 100 individuals 

who reside where RRP is performed and LBP is present), and (3) additional contractor cleaning of the 

room adjacent to the work area (10 out of every 100 individuals who reside where RRP is performed and 

LBP is present). It is assumed that this additional contractor cleaning occurs in the subset of housing 

units that are in compliance with the rule. 

Under Alternative Estimate 4 and Scenario 2, the benefits are 85 percent lower compared with the 

Primary Estimate. For Alternative Estimate 4, the benefits decline more under Scenario 2 compared to 

Scenario 1 because the baseline level of protection is greater under Scenario 2. In other words, the postrule level of protection declines by the same amount under Scenarios 1 and 2, but this is a larger 

percentage of those incrementally benefiting under Scenario 2, because there are fewer are these 

individuals under Scenario 2. 

These estimates are calculated under the assumption that non-compliance is independent of household 

LBP likelihoods, the type of RRP performed, and occupant composition (e.g., number, age and sex of 

occupants). 

7.5 Alternative Estimate 5: Test Kits with 47% Rate of False Positives 

Test Kits that are currently available have false positive rates that range from 47 percent to 78 percent. 

The Primary Estimate assumes a false positive rate of 63 percent, the midpoint of the range, for the first 

year that the rule’s requirements are effective. Alternative Estimate 5 employs an alternative assumption 

that the false positive rate for the Test Kit is 47 percent, instead of 63 percent, in the first year. 

7.5.1 Comparison of the Costs 

Since this alternative estimate only impacts the work practice standard costs during the first year of 

regulation, the impact on the 50-year annualized costs is less than 1 percent. In the first year, however, 

the costs are about 5 to 9 percent lower, since a more accurate Test Kit results in fewer cases where a 

false positive test results in the use of unnecessary and more expensive LSWP. 

Table 7-7: Alternative Estimate 5: 50-Year Annualized Cost Estimates and Percent Change: 

Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 5: Test Kit 

with 47% Rate of False 

Positives 

$502 $491 $487 $587 $544 $524 $516 $626 

Percent Change -0.7% -0.3% -0.2% -0.3% -1.1% -0.5% -0.3% -0.5% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 11 

7.5.2 Comparison of the Benefits 

There is no impact on the benefits estimate under this alternative, because it is assumed that the test kit 

always identifies LBP when present. That is, the false negative rate is assumed to be zero for both 

estimates. 

7.6 Alternative Estimate 6: Test Kits with 78% Rate of False Positives 

Test kits that are currently available have false positive rates that range from 47 percent to 78 percent. 

The Primary Estimate assumes a false positive rate of 63 percent, the midpoint of the range, for the first 

year that the rule’s requirements are effective. Alternative Estimate 6 employs an alternative assumption 

that the false positive rate for the test kit is 78 percent, instead of 63 percent, in the first year. 

7.6.1 Comparison of the Costs 

Since this alternative estimate only impacts the work practice standard costs during the first year of 

regulation, the impact on the 50-year annualized costs is one percent or less. In the first year, however, 

the costs are about 5 to 9 percent higher, since a less accurate test kit results in more cases where a false 

positive test results in the use of unnecessary and more expensive LSWP. 

7.6.2 Comparison of the Benefits 

There is no impact on the benefits estimate under this alternative, because it is assumed that the test kit 

always identifies LBP when present. That is, the false negative rate is assumed to be zero for both 

estimates. 

7.7 Alternative Estimate 7: Test Kits with 5% Rate of False Negatives 

For the Primary Estimate in this analysis, it is assumed that there are never false negative test kit results; 

i.e., the test is always positive for LBP if it is present. Alternative Estimate 7 assumes that the new test 

kits will have a false negative rate of 5 percent. 

Table 7-8: Alternative Estimate 6: 50-Year Annualized Cost Estimates and Percent Change: 

Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 6: Test Kit 

with 78% Rate of False 

Positives 

$508 $493 $488 $590 $556 $528 $519 $632 

Percent Change 0.6% 0.2% 0.2% 0.3% 1.1% 0.4% 0.3% 0.5% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 12 

7.7.1 Comparison of the Costs 

The higher false negative rate assumed under Alternative Estimate 7 will lower costs because LSWP will 

not be used during some events where there is LBP. Table 7-9 shows the Alternative Estimate 7 50-year 

annualized costs; they decline by about 2.5 percent. 

7.7.2 Comparison of the Benefits 

Benefits are lower under this alternative, since some individuals will perform RRP activities where there 

is LBP, but will not use LSWP because a test kit found no LBP. If false negative results are independent 

of other factors that might affect the relative benefits of using LSWP, then benefits would be five percent 

lower for this alternative compared to the Primary Estimate (reflecting the five percent decline in LSWP 

use when LBP is present—the decline is 5 percent under both Scenario 1 and Scenario 2). 

7.8 Alternative Estimate 8: Test Kits Cost $20 per Event 

For the Primary Estimate, using a test kit is estimated to cost $10 per event. Lead test kits currently can 

be purchased in bulk at a cost of approximately $0.50 per test; it is assumed that about four tests will 

require about 15 minutes of a Certified Renovator’s time, yielding a total cost for materials and time of 

$10 per event. There are several reasons why a test kit might be more expensive, for example (1) if they 

are not purchased in bulk, (2) if certified renovators decide to conduct more extensive testing than 

assumed, or (3) if the improved test kits are more expensive than those currently on the market. Thus, 

Alternative Estimate 8 assumes a testing cost of $20 per event, or an increase of $10 per-event over the 

Primary Estimate. 

7.8.1 Comparison of the Costs 

The 50-year annualized cost estimates are presented in Table 7-10. Under Alternative Estimate 8 costs 

increase by approximately 20 percent. 

Table 7-9: Alternative Estimate 7: 50-Year Annualized Cost Estimates and Percent Change: 

Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 7: Test Kit 

with 5% Rate of False 

Negatives 

$493 $480 $475 $572 $537 $513 $504 $611 

Percent Change -2.5% -2.6% -2.6% -2.8% -2.5% -2.5% -2.6% -2.8% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 13 

7.8.2 Comparison of the Benefits 

There is no impact on the benefits estimate under this alternative, because it is assumed that the test kit 

always identifies LBP when present. That is, the false negative rate is assumed to be zero for both 

estimates. 

7.9 Alternative Estimate 9: One Year Delay in Development of Improved Test Kits 

In the Primary Estimate it is assumed that the more accurate test kit is available in the second year after 

the rule is in effect. Alternative Estimate 9 considers the alternative assumption that the improved test kit 

is not available until the third year the rule is in effect. 

7.9.1 Comparison of the Costs 

The 50-year annualized costs are two to almost four percent higher under the assumptions of Alternative 

Estimate 9 compared to the Primary Estimate (see Table 7-11). Since Alternative Estimate 9 considers a 

one-year delay in the availability of the new test kit, the only cost component that differs between this 

alternative and the Primary Estimate is the work practice costs in the second year the rule is in effect; they 

are about 70 percent higher under this alternative. 

7.9.2 Comparison of the Benefits 

There is no impact on the benefits estimate under this alternative, because both the current and improved 

test kits always identify LBP when present. That is, the false negative rates are zero for both test kits. 

Table 7-10: Alternative Estimate 8: 50-Year Annualized Cost Estimates and Percent 

Change: Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 8: $20 Test 

Kit $608 $593 $588 $689 $660 $632 $622 $735 

Percent Change 20.3% 20.4% 20.5% 17.1% 19.8% 20.1% 20.2% 16.8% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 

Table 7-11: Alternative Estimate 9: 50-Year Annualized Cost Estimates and Percent 

Change: Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 9: 1-Year 

Delay in Development 

of Improved Test Kit 

$516 $503 $498 $603 $570 $545 $537 $654 

Percent Change 2.1% 2.2% 2.2% 2.4% 3.5% 3.7% 3.7% 4.1% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 14 

7.10 Alternative Estimate 10: Improved Test Kit Delayed Four Years 

In the Primary Estimate it is assumed that the more accurate test kit is available in the second year after 

the rule is in effect. Alternative Estimate 10 considers the alternative where the improved test kit is not 

available until the sixth year the regulation is effective. Under the Primary Estimate it is assumed that the 

improved test kit is available in the second year. 

7.10.1 Comparison of the Costs 

For all options, the 50-year annualized costs are higher under Alternative 10 compared to the Primary 

Estimate because the delay in the availability of the improved test kit results in higher work practice costs 

in years two through five (see Table 7-12). Delaying the availability of the improved test kit is costly, 

because a test with a higher false positive rate will result in more instances where LSWP will be used 

even though no LBP is disturbed. In other words, the improved test kit will result in fewer cases where 

costly LSWP are used needlessly. Note that the rank of the options, in terms of the costs, does not change 

under these alternatives. 

7.10.2 Comparison of the Benefits 

There is no impact on the benefits estimate under this alternative, because the delay in the availability of 

the improved test kit does not impact any events with potential benefits. 

7.11 Alternative Estimate 11: Improved Test Kit and Regulatory Universe Expansion 

Delayed Four Years 

In the Primary Estimate it is assumed that the more accurate test kit is available in the second year after 

the rule is in effect. Alternative Estimate 11 considers the alternative where the expansion of the 

regulatory universe and the availability of the improved test kit are both delayed until the sixth year the 

regulation is effective. Under the Primary Estimate it is assumed that both the improved test kit and the 

regulatory expansion occurs in the second year. 

7.11.1 Comparison of the Costs 

Table 7-13 shows that the 50-year annualized costs are lower under Alternative 11 compared to the 

Table 7-12: Alternative Estimate 10: 50-Year Annualized Cost Estimates and Percent Change: 

Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 10: 

Improved Test 

Kit Delayed 4 

Years. 

$546 $533 $529 $643 $620 $596 $587 $721 

Percent Change 8.1% 8.3% 8.4% 9.2% 12.6% 13.2% 13.4% 14.6% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 15 

Primary Estimate for Options B, C, and D; this implies that the cost savings from delaying the regulation 

of units built between 1960 and 1978 (Options B and D) and 1950 and 1978 (Option C), are greater than 

the increase in costs associated with the delayed availability of the improved test kit. Since Option A 

does not phase-in the regulation of any units, costs are higher under Alternative 11 compared to the 

Primary Estimate. Delaying the availability of the improved test kit is costly, because a test with a higher 

false positive rate will result in more instances where LSWP will be used even though no LBP is 

disturbed. In other words, the improved test kit will result in fewer cases where costly LSWP are used 

needlessly. 

7.11.2 Comparison of the Benefits 

Chapter 5 presents the estimated monetized benefits of the RRP rule. The differences in benefits under 

each option stems solely from their different regulated universes. In the first year, benefits are highest 

under Option A (the largest regulated universe) and lowest under Option D (the smallest regulated 

universe); benefits under Options B and D are the same. In the second year, the options all have the same 

Primary Estimate benefits (they have the same regulated universe). Since the Primary Estimate and 

Alternative 11 assume the same regulated universe under Option A, the benefits are the same for the 

Primary Estimate and Alternative 11. However, the benefits of Alternative 11 are lower for Options B, C, 

and D: they are approximately equal to the first-year benefits of the Primary Estimates in years one 

through five, and approximately equal to the second year benefits of the Primary Estimate beginning in 

year six.13 In other words, the jump in benefits from the expansion of the regulated universe is realized in 

year six rather than year two. 

7.12 Alternative Estimate 12: Improved Test Kits Have 15% Rate of False Positives 

Alternative Estimate 12 considers the alternative assumption that the improved test kit has a false positive 

rate of 15 percent rather than the 10 percent rate that is assumed for the Primary Estimate. 

7.12.1 Comparison of the Costs 

The 50-year annualized costs are 4.6 to 5.6 percent higher under the assumptions of Alternative Estimate 

12 compared to the Primary Estimate (see Table 7-14). If the improved test kit has a higher false positive 

 

13 The pre-78 housing stock (and therefore the number of individuals affected and the benefits), declines by 0.41% 

each year. 

Table 7-13: Alternative Estimate 11: 50-Year Annualized Cost Estimates and Percent Change: 

Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 11: 

Improved Test Kit 

and Regulatory 

Universe 

Expansion 

Delayed 4 Years. 

$546 $485 $464 $583 $620 $514 $476 $620 

Percent Change 8.1% -1.4% -4.9% -0.9% 12.6% -2.4% -8.0% -1.5% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 16 

rate, then LSWP will be used more frequently when LBP is not present. Therefore, under this alternative 

assumption the work practice costs are higher than under the Primary Estimate each year after the first 

year—when the improved test kits are assumed to become available. 

7.12.2 Comparison of the Benefits 

There is no impact on the benefits estimate under this alternative, because it is assumed that the test kits 

always identify LBP when present. That is, the false negative rates are zero under both alternatives. 

7.13 Alternative Estimate 13: More Firms and Individuals Seek Certification 

Alternative Estimate 13 assumes a different number of firms and individuals seek training and 

certification. Under the Primary Estimate, it is assumed that the number of firms and individuals seeking 

training and certification will be a function of the housing stock that is regulated. That is, it is assumed 

that some firms will specialize in RRP in regulated housing and other firms will not work in those units. 

For Alternative Estimate 13 it is assumed that specialization in regulated units does not occur, so all firms 

and individuals that perform Residential Remodeling will seek training and certification. For the Primary 

Estimate of the number of firms and individuals that will seek training and certification, the number of 

firms and individuals that specialize in Residential Remodeling is adjusted downward to reflect the fact 

that only a fraction of Residential Remodeling occurs in regulated housing; this adjustment is omitted 

under Alternative Estimate 13. 

It is worth clarifying that both estimates adjust the number of firms and individuals in the industries 

affected by the RRP rule to account for their relative revenues from Residential Remodeling; e.g., if only 

25 percent of an industry’s revenue is from Residential Remodeling, it is assumed only 25 percent of the 

firms and individuals in that industry seek training and certification. In addition, for both estimates there 

is no adjustment for the relative amount of RRP work that disturbs more than two square feet of a painted 

surface. For example, a substantial number of Residential Remodelers specialize in roofing, where they 

would be unlikely to be subject to any of the RRP rule’s requirements.14 Thus, for the Primary Estimate, 

a substantial amount of specialization is assumed, but not total specialization. 

 

14 Due to data limitations, the percentage of all Residential Remodeling that is regulated was not estimated. 

Table 7-14: Alternative Estimate 12: 50-Year Annualized Cost Estimates and Percent 

Change: Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 12: 

Improved Test Kit with 

15% Rate of False 

Positives 

$530 $517 $512 $621 $576 $552 $543 $663 

Percent Change 4.9% 5.0% 5.1% 5.6% 4.6% 4.9% 4.9% 5.4% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 17 

7.13.1 Comparison of the Costs 

Table 7-15 presents the estimated costs for an alternative with no specialization in regulated RRP. That 

is, the estimated number of firms are not adjusted by the proportion of housing units that are regulated. 

The number of Certified Renovators is assumed to increase proportionally to the increase in the number 

of firms. For Alternative Estimate 13, the training and certification costs are nearly two and a half times 

the Primary Estimate’s costs. This results in a 19 to 26 percent increase in the 50-year annualized cost of 

the rule. 

7.13.2 Comparison of the Benefits 

It is assumed that the regulated RRP work would be spread across more firms and individuals under this 

alternative, but this is not expected to impact benefits. 

7.14 Alternative Estimate 14: No Cleaning Verification Required 

Alternate Estimate 14 considers the potential costs and benefits if cleaning verification were not required 

by the proposed rule. Under this Alternative Estimate, a certified renovator would only need to perform a 

standard visual inspection after a renovation to determine whether visible dust, debris, or residue was still 

present in the work area, and would not have to use a disposable cleaning cloth as required under the 

proposed rule. 

 

The Primary Estimate assumes that compliance with the work practice requirements in the rule 

(containment, cleaning, and cleaning verification) reduces lead levels in floor dust to 40 μg/ft2

. If this 

level is not reached upon the first verification, it is assumed that additional rounds of cleaning and 

verification will reduce lead levels to 40 μg/ft2

. The Primary Estimate uses a value of 40 μg/ft2 to 

represent the distribution of lead levels from 0 to 40 μg/ft2

 that is assumed to result from compliance with 

the rule. Little information is available about the number of events that would fail to achieve the 40 μg/ft2

or the distribution of lead levels for RRP events that fail to achieve the 40 μg/ft2

 level in the absence of 

cleaning verification. In the absence of data describing the distribution of dust lead levels following the 

initial cleanup, Alternate Estimate 14 assumes that, without cleaning verification, 30% of events would 

exceed the lead dust level of 40 ug/ft2

, and increases the average dust lead levels for those events in 

increments of 40 μg/ft2

 (80, 120, 160 ug/ft2). 

Table 7-15: Alternative Estimate 13: 50-Year Annualized Cost Estimates and Percent 

Change: Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 13: 

Alternative Assuming 

more Firms and 

Individuals Seek 

Certification 

$602 $603 $599 $700 $660 $661 $654 $764 

Percent Change 19.2% 22.6% 22.9% 18.9% 19.9% 25.7% 26.4% 21.5% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 18 

7.14.1 Comparison of the Costs 

The 50-year annual costs are 7.6 to 8.6 percent lower under the assumptions of Alternative Estimate 14 

compared to the Primary Estimate (see Table 7-16). In other words, the costs of cleaning verification 

account for about 8 percent of the total incremental increase in work practice costs due to the rule. It is 

worth noting that they represent a smaller percentage of the costs of using all required LSWP (i.e., when 

baseline work practice costs are not accounted for). This is because it is assumed that the baseline level 

of cleaning verification is zero. 

7.14.2 Comparison of the Benefits 

Under Alternative Estimate 14, for both Scenarios 1 and 2, the annualized benefits do not decline as much 

as the annualized costs. While costs decline between $54 million and $37 million dollars (See Table 7-

16), the benefits decline by as much as $20 million and as little as $0.1 million, depending on the option, 

scenario, assumed discount rate, and the blood-lead model specification for children’s IQ (See Table 7-

17). 

It should be noted that Alternative Estimate 14 is based on assumptions and therefore must not be 

interpreted as conclusive evidence that the benefits of cleaning verification are not worth the additional 

cost. Although Alternative Estimate 14 considered scenarios where 30 percent of renovations had 

average dust lead levels of 80, 120, and 160 μg/ft2, there is considerable uncertainty about the number of 

renovations that have dust lead levels above or below 40 μg/ft2, as well as the concentration of lead dust 

in the absence of clearance verification. 

Table 7-16: Alternative Estimate 14: 50-Year Annualized Cost Estimates and Percent Change: 

Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 14: 

Alternative 

regulatory option 

with no cleaning 

verification

$467 $455 $451 $538 $508 $486 $478 $575 

Change $38 $37 $37 $50 $43 $40 $40 $54 

Percent Change -7.7% -7.6% -7.6% -8.6% -7.7% -7.6% -7.6% -8.6% 

See Table 7-18 for Option Descriptions. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 19 

7.15 Summary of Alternatives 

Table 7-18 presents a summary of the 50-year annualized alternative cost estimates. The cost estimates 

are lower under Alternative Estimate 1 because work practice costs are assumed to be incurred in the 

baseline in states with existing RRP regulations. For Alternatives 2, 3, and 4, the table shows that costs 

are increasing with increases in the assumed compliance rate. Costs increase with the higher test kit cost 

(Alternative 8). Costs decrease with decreases in the false positive rate for the existing test kits 

(Alternative 5) and increase with increases in the false positive rate (Alternative 6), although costs are not 

very sensitive to changes in this rate. Costs move in the opposite direction of the rate of false negatives, 

decreasing as the false negative rate increases (Alternative 7). In Alternative 12, the cost increases with 

the increase in false positive rate for the improved test kit. The estimates for Alternatives 9, and 10 show 

that costs will be higher if the improved test kit development is delayed, but will be lower overall (for 

Options B, C and D) if a four-year delay in development of an improved test kit is accompanied by a 

four-year delay in regulatory expansion (Alternative 11). Alternative Estimate 13 shows that costs are 

higher if there is less specialization in RRP by firms choosing to work in regulated units such that more 

firms are seeking certification. Alternative 14 shows that removing cleaning verification reduces costs by 

about 8 percent, and the benefits are reduced by about 1.8 percent or less. 

Table 7-19 and Table 7-20 present the 50-year annualized benefits of the alternative estimates compared 

to the primary estimates and Table 7-21 and Table 7-22 present the same kind of information for net 

benefits. The range of estimates in all these tables reflects the different blood-lead model specifications. 

Table 7-17: Range of Estimated Differences in Benefits Between 

Alternative Estimate 14 and the Primary Estimate 

(50-Year Annualized Benefits, millions $2005) 

Estimated 

Benefit Change A B C D 

3 Percent Discount Rate 

Scenario 1 

80 μg/ft2 -$0.1 to -$8 -$0.1 to -$8 -$0.1 to -$8 -$0.1 to -$8

120 μg/ft2 -$0.1 to -$8 -$0.1 to -$8 -$0.1 to -$8 -$0.1 to -$8

160 μg/ft2 -$0.6 to -$12 -$0.5 to -$11 -$0.5 to -$11 -$0.5 to -$11 

Scenario 2 

80 μg/ft2 -$0.1 to -$7 -$0.1 to -$6 -$0.1 to -$6 -$0.1 to -$6

120 μg/ft2 -$0.3 to -$12 -$0.3 to -$12 -$0.3 to -$12 -$0.3 to -$12

160 μg/ft2 -$1.7 to -$19 -$1.7 to -$19 -$1.6 to -$19 -$1.7 to -$19

7 Percent Discount Rate

Scenario 1 

80 μg/ft2 -$0.1 to -$8 -$0.1 to -$8 -$0.1 to -$8 -$0.1 to -$8

120 μg/ft2 -$0.3 to -$8 -$0.2 to -$8 -$0.2 to -$8 -$0.2 to -$8

160 μg/ft2 -$1.0 to -$12 -$0.9 to -$12 -$0.9 to -$12 -$0.9 to -$12 

Scenario 2 

80 μg/ft2 -$0.1 to -$7 -$0.1 to -$7 -$0.1 to -$7 -$0.1 to -$7

120 μg/ft2 -$0.3 to -$13 -$0.3 to -$13 -$0.3 to -$13 -$0.3 to -$13

160 μg/ft2 -$1.8 to -$20 -$1.7 to -$20 -$1.7 to -$20 -$1.7 to -$20

See Table 7-18 for Option Descriptions. The range of estimates reflects the different bloodlead model specifications. 80, 120, and 160 μg/ft2 refer to the average post-renovation dust 

lead levels assumed to occur in 30 percent of renovations in the absence of clearance 

verification. 

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 20 

Not all alternatives are presented in these tables. Only those where the benefits estimate differs from the 

primary benefits estimate are presented.15 

Alternative Estimates 2, 3, 4 consider alternative rates of compliance and indicate that net benefits are 

increasing with the assumed compliance rate. For Alternative Estimate 7, the net benefits are lower 

compared to the Primary Estimate because under this alternative more individuals will perform RRP 

activities where there is LBP, but will not use LSWP because a test kit did not indicate the presence of 

LBP. Under Alternative Estimate 11, the net benefits are slightly lower compared to the Primary 

Estimate. Under Alternative Estimate 14 the net benefits are slightly higher compared to the Primary 

Estimate. 

 

15 For Alternative Estimate 1, an alternative benefits estimate was not estimated because of data limitations. 

Benefits were not affected under all the other alternatives. 
§402(c) Economic Analysis Chapter 7 21 

 

Table 7-18: Alternative 50-Year Annualized Cost Estimates for Sensitivity Analysis: 

Estimated with Discount Rates of 3 and 7 Percent (millions $2005) 

Discount Rate 3 Percent 7 Percent 

Option A B C D A B C D 

Primary Estimate $505 $492 $488 $588 $551 $526 $518 $629 

Alternative 1: Adjusted for 

State and Local RRP 

Regulations 

$432 $421 $417 $494 $471 $449 $442 $528 

Alternative 2: 100% 

Compliance Assumption $795 $774 $766 $940 $866 $827 $813 $1,004 

Alternative 3: 60% 

Compliance Assumption $342 $334 $331 $382 $373 $357 $351 $408 

Alternative 4: 30% 

Compliance Assumption $99 $97 $96 $101 $108 $104 $102 $108 

Alternative 5: Test Kit with 

47% Rate of False Positives $502 $491 $487 $587 $544 $524 $516 $626 

Alternative 6: Test Kit with 

78% Rate of False Positives $508 $493 $488 $590 $556 $528 $519 $632 

Alternative 7: Test Kit with 

5% Rate of False Negatives $493 $480 $475 $572 $537 $513 $504 $611 

Alternative 8: $20 Test Kit $608 $593 $588 $689 $660 $632 $622 $735 

Alternative 9: One-Year Delay 

in Development of Improved 

Test Kit 

$516 $503 $498 $603 $570 $545 $537 $654 

Alternative 10: Improved Test 

Kit Delayed 4 Years $546 $533 $529 $643 $620 $596 $587 $721 

Alternative 11: Improved Test 

Kit and Regulatory Universe 

Expansion Delayed 4 Years 

$546 $485 $464 $583 $620 $514 $476 $620 

Alternative 12: Improved Test 

Kit with 15% Rate of False 

Positives 

$530 $517 $512 $621 $576 $552 $543 $663 

Alternative 13: Alternative 

Assuming More Firms and 

Individuals Seek Certification 

$602 $603 $599 $700 $660 $661 $654 $764 

Alternative 14: No Cleaning 

Verification Required $467 $455 $451 $538 $508 $486 $478 $575 

Option Descriptions: Option A: All pre-1978 renter-occupied target housing units and all pre-1978 owneroccupied target housing units where children under the age of six reside are subject to the rule; WPS 

requirements are flexible. Option B: All pre-1960 renter-occupied target housing units and all pre-1960 owneroccupied target housing units where children under the age of six reside are subject to the rule in the first year it 

is in effect (Phase 1); in the second year (Phase 2), all pre-1978 renter-occupied target housing units and all pre1978 owner-occupied target housing units where children under the age of six reside are subject to the rule; WPS 

requirements are flexible. Option C: All pre-1950 renter-occupied target housing units and all pre-1950 owneroccupied target housing units where children under the age of six reside are subject to the rule in the first year it 

is in effect (Phase 1); in the second year (Phase 2), all pre-1978 renter-occupied target housing units and all pre1978 owner-occupied target housing units where children under the age of six reside are subject to the rule; WPS 

requirements are flexible. Option D: All pre-1960 renter-occupied target housing units and all pre-1960 owneroccupied target housing units where children under the age of six reside are subject to the rule in the first year it 

is in effect (Phase 1); in the second year (Phase 2), all pre-1978 renter-occupied target housing units and all pre1978 owner-occupied target housing units where children under the age of six reside are subject to the rule; WPS 

requirements are prescriptive.

Source: EPA Calculations. 
§402(c) Economic Analysis Chapter 7 22 

Table 7-19: 50-Year Annualized Benefits of Alternatives and the Primary Estimatea, b

(3 Percent Discount Rate, millions 2005$) 

 Scenario 1 

Option A B C D 

Primary Estimate 3,209 to 7,599 3,191 to 7,562 3,170 to 7,503 3,191 to 7,562 

Alternative 2: 100% 

Compliance Assumption 4,653 to 11,018 4,628 to 10,964 4,596 to 10,879 4,628 to 10,964 

Alternative 3: 60% 

Compliance Assumption 2,343 to 5,547 2,330 to 5,520 2,314 to 5,477 2,330 to 5,520 

Alternative 4: 30% 

Compliance Assumption 578 to 1,368 574 to 1,361 571 to 1,350 574 to 1,361 

Alternative 7: Test Kit with 

5% Rate of False Negatives 3,049 to 7,219 3,032 to 7,184 3,011 to 7,128 3,032 to 7,184 

Alternative 11: Improved Test 

Kit and Regulatory Universe 

Expansion Delayed 4 Years 

3,209 to 7,599 3,096 to 7,108 2,979 to 6,752 3,096 to 7,108 

Alternative 14: Alternative 

regulatory option with no 

cleaning verification 

3,209 to 7,587 3,191 to 7,550 3,170 to 7491 3,191 to 7,550 

Scenario 2

Primary Estimate 774 to 4,354 770 to 4,329 764 to 4,298 770 to 4,329 

Alternative 2: 100% 

Compliance Assumption 1,146 to 6445 1,139 to 6407 1,131 to 6361 1,139 to 6407 

Alternative 3: 60% 

Compliance Assumption 550 to 3,092 547 to 3,074 542 to 3,052 547 to 3,074 

Alternative 4: 30% 

Compliance Assumption 116 to 653 115 to 649 115 to 645 115 to 649 

Alternative 7: Test Kit with 

5% Rate of False Negatives 736 to 4,137 731 to 4,113 726 to 4,083 731 to 4,113 

Alternative 11: Improved Test 

Kit and Regulatory Universe 

Expansion Delayed 4 Years 

774 to 4,354 747 to 4,069 718 to 3,868 747 to 4,069 

Alternative 14: Alternative 

regulatory option with no 

cleaning verification 

774 to 4,336 770 to 4,310 764 to 4,279 770 to 4,310 

a

Presents only the alternatives where the alternative estimate differs from the primary benefits estimate. For 

Alternative Estimate 1, an alternative benefits estimate was not estimated because of data limitations. Benefits 

were not affected under all the other alternatives. b

The range of estimates reflects the different blood-lead model specifications.

Source: EPA Calculations 
§402(c) Economic Analysis Chapter 7 23 

 

Table 7-20: 50-Year Annualized Benefits of Alternatives and the Primary Estimatea, b

(7 Percent Discount Rate, millions 2005$) 

 Scenario 1 

Option A B C D 

Primary Estimate 3,415 to 8,087 3,383 to 8,019 3,342 to 7,909 3,383 to 8,019 

Alternative 2: 100% 

Compliance Assumption 4,952 to 11727 4,905 to 11,627 4,846 to 11,468 4,905 to 11,627 

Alternative 3: 60% 

Compliance Assumption 2,493 to 5904 2,469 to 5,854 2,440 to 5,774 2,469 to 5,854 

Alternative 4: 30% 

Compliance Assumption 615 to 1,456 609 to 1,443 602 to 1,424 609 to 1,443 

Alternative 7: Test Kit with 

5% Rate of False Negatives 3,245 to 7,683 3,214 to 7,618 3,175 to 7,513 3,214 to 7,618 

Alternative 11: Improved Test 

Kit and Regulatory Universe 

Expansion Delayed 4 Years 

3,415 to 8,087 3,281 to 7,538 3,142 to 7,118 3,281 to 7,538 

Alternative 14: Alternative 

regulatory option with no 

cleaning verification 

3,415 to 8,075 3,383 to 8,007 3,342 to 7,897 3,383 to 8,007 

Scenario 2

Primary Estimate 824 to 4,635 816 to 4,587 805 to 4,530 816 to 4,587 

Alternative 2: 100% 

Compliance Assumption 1,220 to 6,859 1,207 to 6,789 1,191 to 6,704 1,207 to 6,789 

Alternative 3: 60% 

Compliance Assumption 585 to 3,291 579 to 3,257 571 to 3,216 579 to 3,257 

Alternative 4: 30% 

Compliance Assumption 124 to 695 122 to 688 121 to 679 122 to 688 

Alternative 7: Test Kit with 

5% Rate of False Negatives 783 to 4,403 775 to 4,358 765 to 4,303 775 to 4,358 

Alternative 11: Improved Test 

Kit and Regulatory Universe 

Expansion Delayed 4 Years 

824 to 4,635 791 to 4,312 757 to 4,077 791 to 4,312 

Alternative 14: Alternative 

regulatory option with no 

cleaning verification 

824 to 4,614 816 to 4,567 805 to 4,510 816 to 4,567 

a

 Presents only the alternatives where the alternative estimate differs from the primary benefits estimate. For 

Alternative Estimate 1, an alternative benefits estimate was not estimated because of data limitations. Benefits 

were not affected under all the other alternatives. b

The range of estimates reflects the different blood-lead model specifications.

Source: EPA Calculations 
§402(c) Economic Analysis Chapter 7 24 

Table 7-21: 50-Year Annualized Net Benefits of Alternatives and the Primary Estimatea, b

(3 Percent Discount Rate, millions 2005$) 

 Scenario 1 

Option A B C D 

Primary Estimate 2,704 to 7,093 2,699 to 7,069 2,682 to 7,015 2,603 to 6,973 

Alternative 2: 100% 

Compliance Assumption 3,858 to 10,223 3,854 to 10,191 3,830 to 10,113 3,688 to 10,025 

Alternative 3: 60% 

Compliance Assumption 2,000 to 5,205 1,996 to 5,186 1,983 to 5,146 1,948 to 5,138 

Alternative 4: 30% 

Compliance Assumption 479 to 1,269 478 to 1,264 474 to 1,254 474 to 1,260 

Alternative 7: Test Kit with 

5% Rate of False Negatives 2,556 to 6,726 2,552 to 6,704 2,536 to 6,653 2,460 to 6,612 

Alternative 11: Improved Test 

Kit and Regulatory Universe 

Expansion Delayed 4 Years 

2,663 to 7,052 2,611 to 6,623 2,516 to 6,289 2,512 to 6,525 

Alternative 14: Alternative 

regulatory option with no 

cleaning verification 

2,742 to 7,121 2,737 to 7,096 2,719 to 7,041 2,653 to 7,012 

Scenario 2

Primary Estimate 269 to 3,849 277 to 3,837 276 to 3,810 181 to 3,741 

Alternative 2: 100% 

Compliance Assumption 351 to 5,650 366 to 5,633 364 to 5,595 199 to 5,467 

Alternative 3: 60% 

Compliance Assumption 208 to 2,750 213 to 2,740 212 to 2,721 164 to 2,692 

Alternative 4: 30% 

Compliance Assumption 17 to 554 19 to 552 18 to 548 15 to 549 

Alternative 7: Test Kit with 

5% Rate of False Negatives 243 to 3,644 252 to 3,633 251 to 3,608 159 to 3,541 

Alternative 11: Improved Test 

Kit and Regulatory Universe 

Expansion Delayed 4 Years 

228 to 3,808 261 to 3,584 254 to 3,405 163 to 3,486 

Alternative 14: Alternative 

regulatory option with no 

cleaning verification 

308 to 3,869 315 to 3,855 313 to 3,829 231 to 3,772 

a

Presents only the alternatives where the alternative estimate differs from the primary benefits estimate. For 

Alternative Estimate 1, an alternative benefits estimate was not estimated because of data limitations. Benefits 

were not affected under all the other alternatives. b

The range of estimates reflects the different blood-lead model specifications.

Source: EPA Calculations 
§402(c) Economic Analysis Chapter 7 25 

Table 7-22: 50-Year Annualized Net Benefits of Alternatives and the Primary Estimatea, b

(7 Percent Discount Rate, millions 2005$) 

 Scenario 1 

Option A B C D 

Primary Estimate 2,865 to 7,537 2,857 to 7,493 2,824 to 7,391 2,754 to 7,390 

Alternative 2: 100% 

Compliance Assumption 4,086 to 10,861 4,078 to 10,800 4,033 to 10,655 3,901 to 10,623 

Alternative 3: 60% 

Compliance Assumption 2,121 to 5,531 2,113 to 5,497 2,089 to 5,423 2,061 to 5,445 

Alternative 4: 30% 

Compliance Assumption 507 to 1,348 505 to 1,340 499 to 1,321 501 to 1,336 

Alternative 7: Test Kit with 

5% Rate of False Negatives 2,708 to 7,146 2,701 to 7,105 2,671 to 7,009 2,602 to 7,006 

Alternative 11: Improved Test 

Kit and Regulatory Universe 

Expansion Delayed 4 Years 

2,795 to 7,467 2,768 to 7,024 2,665 to 6,642 2,661 to 6,918 

Alternative 14: Alternative 

regulatory option with no 

cleaning verification 

2,907 to 7,567 2,897 to 7,521 2,864 to 7,419 2,807 to 7,432 

Scenario 2

Primary Estimate 273 to 4,084 290 to 4,061 287 to 4,012 187 to 3,958 

Alternative 2: 100% 

Compliance Assumption 354 to 5,993 380 to 5,962 378 to 5,891 203 to 5,785 

Alternative 3: 60% 

Compliance Assumption 212 to 2,918 223 to 2,900 221 to 2,865 171 to 2,849 

Alternative 4: 30% 

Compliance Assumption 16 to 588 19 to 584 18 to 577 15 to 580 

Alternative 7: Test Kit with 

5% Rate of False Negatives 246 to 3,866 262 to 3,845 260 to 3,799 163 to 3,746 

Alternative 11: Improved Test 

Kit and Regulatory Universe 

Expansion Delayed 4 Years 

204 to 4,014 278 to 3,798 280 to 3,600 171 to 3,692 

Alternative 14: Alternative 

regulatory option with no 

cleaning verification 

316 to 4,106 330 to 4,081 327 to 4,032 240 to 3,992 

a

 Presents only the alternatives where the alternative estimate differs from the primary benefits estimate. For 

Alternative Estimate 1, an alternative benefits estimate was not estimated because of data limitations. Benefits 

were not affected under all the other alternatives. b

The range of estimates reflects the different blood-lead model specifications.

Source: EPA Calculations 
§402(c) Economic Analysis Chapter 7 26 

References 

Gilkeya, David; Jacob Hautaluomaa, Taslim Ahmeda, Thomas Keefea, Robert Herrona, Philip Bigelowb. 

2003. Construction Work Practices and Conditions Improved After 2-Years’ Participation in the 

HomeSafe Pilot Program. American Industrial Hygiene Association Journal, May/June 2003. 

Weil, David. 1999. Assessing OSHA Performance: Evidence from the Construction Industry. Boston 

University, October 1999. 

U.S. Census Bureau. 2000c. "H34. Year Structure Built [10] - Universe: Housing Units." American Fact 

Finder. Available at: http://factfinder.census.gov/ (Downloaded 10/26/2005) 
402(c) Chapter 8 1 

8. Estimated Impacts of §402(c) 

In addition to the cost and benefit analyses presented in Chapters 4 to 6, several other types of impacts are 

important to consider in evaluating a regulation. This chapter presents analyses that report the impact of 

the Renovation, Repair and Painting (RRP) Rule on the paperwork burden, the financial condition of 

small entities, whether the regulation has a disproportionate effect on low-income and or minority 

persons, and the environmental health risk or safety risk to children due to the regulation. It also responds 

to the Unfunded Mandates Reform Act (UMRA) and the National Technology Transfer and 

Advancement Act (NTAA), as well as to Executive Orders 13132 (Federalism), 13175 (Tribal 

Implications), 13211 (Energy Effects), and 12898 (Environmental Justice). 

8.1 Paperwork Reduction Act 

The Paperwork Reduction Act of 1995 (PRA) (superseding the PRA of 1980) is implemented by the 

Office of Management and Budget (OMB) and requires that agencies submit a supporting statement to 

OMB for any information collection that solicits the same data from more than nine parties. The PRA 

seeks to ensure that Federal agencies balance their need to collect information with the paperwork burden 

imposed on the public by the collection. 

The definition of “information collection” includes activities required by regulations, such as permit 

development, monitoring, recordkeeping, and reporting. The term “burden” refers to the “time, effort, or 

financial resources” the public expends to provide information to or for a Federal agency, or to otherwise 

fulfill statutory or regulatory requirements. PRA paperwork burden is measured in terms of annual time 

and financial resources the public devotes to meet one-time and recurring information requests (44 U.S.C. 

3502(2); 5 C.F.R. 1320.3(b)). 

Information collection activities may include: 

• reviewing rule requirements; 

• using technology to collect, process, and disclose information; 

• adjusting existing practices to comply with requirements; 

• searching data sources; 

• completing and reviewing the response; and 

• transmitting or disclosing information. 

Agencies must provide information to OMB on the parties affected, the annual reporting burden, and the 

annualized cost of responding to the information collection. 

8.1.1 RRP Firm Paperwork Burden 

RRP Firms are estimated to spend approximately half an hour to fill out and mail the Application for 

Renovator Certification when they are applying for initial certification or re-certification (which occurs 

every three years). It is estimated that firms will spend an average of three hours to familiarize 

themselves with the RRP rule’s requirements when becoming certified. In addition, firms will spend an 

average of 5 minutes per RRP event keeping records that demonstrate compliance with the Renovation, 

Repair and Painting Rule training and work practice requirements. As there are a little over 60 events per 

firm annually, this translates to approximately 5 burden hours per firm on average. This adds up to an 

average burden in the first year of 8.7 hours per firm. At a loaded wage rate of $31.64, the paperwork 
402(c) Chapter 8 2 

cost in the first year will average $276 per firm (See Table 8-1). Additional costs are minor; these costs 

include an application printout, one photocopy for personal records, an envelope, and a stamp. The total 

first year information collection cost is estimated to average $276 per firm. Every three years firms must 

complete the certification form to apply for re-certification, as well as keep records that demonstrate 

compliance with the RRP Rule. The total time required during a re-certification year is 5.7 hours, at a 

cost of $181 per firm. In years where firms do not need to apply for certification or re-certification, firms 

will only incur the five-hour recordkeeping burden at a cost of $165. 

Table 8-1: Costs to RRP Firms Associated with Information Collection 

First Year/Initial 

Certification Year Re- Certification Year Other Years 

Activity 

Burden 

Hours Cost 

Burden 

Hours Cost 

Burden 

Hours Cost 

Certification forma 0.5 $15.82 0.5 $15.82 $0 

Rule familiarization a 3 $94.93 $0 $0 

Recordkeeping a 5.2 $164.85 5.2 $164.85 5.2 $164.85 

2 photocopiesb $0.16 $0.16 $0 

1 envelopec $0.02 $0.02 $0 

1 stamp $0.37 $0.37 $0 

Total* 8.7 $276 5.7 $181 5.2 $165 

*Rounded to nearest dollar. 

Sources: a

Wages: Bureau of Labor Statistics (SOC 47-1011). Wages were inflated from 2004$ to 2005$ using the BLS 

Employment Cost Index for the Construction Industry.; b The average price of a photo copy is eight cents; cThe average 

cost of a business envelope is two cents.

8.1.2 Training Provider Paperwork Burden 

EPA has also estimated the information collection burden imposed on Training Providers. Similarly to 

certified firms, accredited Training Providers incur an accreditation and re-accreditation paperwork 

burden. To comply with the RRP rule, Training Providers must gain accreditation and keep records on 

both the courses they provide and the students they train. In addition, they must notify EPA before 

offering each course (to facilitate EPA’s enforcement activities) and after each course (so EPA has a 

record of the individuals who have completed the course). 

Burden Associated with Obtaining and Maintaining Accreditation 

It is assumed that Training Providers will spend an average of four hours of professional time and two 

hours of clerical time completing the accreditation statement.1

 It is assumed that accredited Training 

Providers will spend an average of eight hours familiarizing themselves with the rule. An average of one 

additional hour of clerical time will be spent on annual recordkeeping. This results in an average burden 

of 15 hours in the first year. Using a loaded wage rate of $38.76 for professional time and $23.54 for 

clerical time, the average accreditation cost to Training Providers is $536. Additional costs considered 

include one printout of the accreditation statement, one copy of course records, an envelope, and a stamp. 

Training Providers applying for re-accreditation will incur an average of four hours of professional time 

and two hours of clerical time, as well as one hour of recordkeeping time. This is an average of seven 

hours of burden at a cost of $226. In other years, the Training Providers will only incur the average of 

one hour of recordkeeping time at a cost of $24. 

 

1

 Time assumptions are based on information provided in the EPA’s (2005) Supporting Statement for OMB Review 

under The Paperwork Reduction Act: TSCA Sections 402/404 Training, Certification, Accreditation and Standards 

for Lead-Based Paint Activities. (EPA ICR No. 1715.06, OMB Control No:2070-0155).
402(c) Chapter 8 3 

Burden Associated with Notification Requirements 

It is assumed that the pre-notification for each class requires an average of 0.15 hours and that each postnotification requires an average of 1.54 hours. The post notifications are more time consuming because 

the Training Provider must send records pertaining to each student who attended the course. 

Approximately 12 percent of courses will also require a re-notification, which is also estimated to take 

0.15 hours. This adds up to an average of 1.7 clerical hours per course. The number of courses offered 

per year depends on the number of individuals who need to be trained. It is assumed that Training 

Providers offer 40 courses in the first year, or a total of 70 hours. It is assumed that each notification 

requires one photocopy, one envelope, and one stamp; thus approximately two of each are required percourse. The average cost of notifications in the first year is approximately $1,700 per Training Provider. 

There will be approximately 30 courses offered per Training Provider in the second year of the rule at an 

average cost of a little under $1,300. In year three of the rule there will be 15 courses offered per training 

provider with a total cost of about $630 on average. 

Total Training Provider Burden 

As shown in Table 8-2, training providers who are accredited in the first year the rule is in effect will 

incur an average cost of $2,224 for paperwork costs in year one ($536 in accreditation costs and $1,688 in 

notification costs). Total costs for subsequent years of the rule depend on whether or not the Training 

Provider undergoes accreditation or re-accreditation in that year. 
402(c) Chapter 8 4 

Table 8-2: Costs to Training Providers Associated with Information Collection 

Accreditation Costs 

First Year/Initial 

Accreditation Year 

Re- Accreditation 

Year Other Years 

Accreditation/Re-Accreditation Activities 

Burden 

Hours 

Cost Burden 

Hours 

Cost Burden 

Hours 

Cost 

 Accreditation statement a 4 $155.04 4 $155.04 $0 

 Rule familiarization a 8 $310.08 $0 $0 

 Clerical time statement a 2 $47.08 2 $47.08 $0 

 Recordkeeping a 1 $23.54 1 $23.54 1 $23.54 

 2 photocopiesb $0.16 $0.16 $0 

 1 envelopec $0.02 $0.02 $0 

 1 stampd $0.37 $0.37 $0 

 Total* 15 $536 7 $226 1 $24 

Notification Costs 

 Year 1 of the RRP 

Rule (40 Courses) 

Year 2 of the RRP 

Rule (30 Courses)

Year 3 of the RRP 

Rule (15 Courses)

Notification Activities Burden 

Hours 

Cost Burden 

Hours 

Cost Burden 

Hours 

Cost 

 Clerical time burden a 70 $1,647.80 53 $1,247.62 26 $612.04 

 Photocopiesb $6.80 $5.10 $2.55 

 Envelopesc $1.70 $1.28 $0.64 

 Stampsd $31.45 $23.59 $11.80 

 Total* 70 $1,688 53 $1,278 35 $627 

*Rounded to nearest dollar. 

Sources: a

Wages: Bureau of Labor Statistics (SOC 47-1011); b The average price of a photo copy at Copy Cop, Kinkos, Staples, 

and Office Max is eight cents; c

The average cost of a business envelope at Staples, Office Max, and Office Depot dU.S. Postal 

Service

8.2 Unfunded Mandates Reform Act (UMRA) 

Title II of the Unfunded Mandates Reform Act of 1995, Pub. L. 104-4, establishes requirements for 

Federal agencies to assess the effects of their regulatory actions on State, local, and Tribal governments, 

and the private sector. Under section 202 of the UMRA, EPA generally must prepare a written statement, 

including a cost-benefit analysis, for proposed and final rules with “Federal mandates” that might result in 

expenditures by State, local, and Tribal governments, in the aggregate, or by the private sector, of $100 

million or more in any one year. 

Before promulgating a regulation for which a written statement is needed, section 205 of the UMRA 

generally requires EPA to identify and consider a reasonable number of regulatory alternatives and adopt 

the least costly, most cost-effective, or least burdensome alternative that achieves the objectives of the 

rule. The provisions of section 205 do not apply when they are inconsistent with applicable law. 

Moreover, section 205 allows EPA to adopt an alternative other than the least costly, most cost-effective, 

or least burdensome alternative if the Administrator publishes with the rule an explanation of why that 

alternative was not adopted. Before EPA establishes any regulatory requirements that might significantly 

or uniquely affect small governments, including Tribal governments, it must have developed under 

section 203 of the UMRA a small government agency plan. The plan must provide for notifying 

potentially affected small governments, enabling officials of affected small governments to have 

meaningful and timely input in the development of EPA regulatory proposals with significant 
402(c) Chapter 8 5 

intergovernmental mandates, and informing, educating, and advising small governments on compliance 

with regulatory requirements. 

This section identifies the government entities that may be affected by the proposed rules. It also assesses 

the impact on the various regulatory options under consideration. 

8.2.1 Affected Government Entities 

The Renovation, Repair, and Painting (RRP) Rule will affect activities in publicly owned housing. While 

most of what is commonly referred to as public housing is owned by state or local governments and 

provided for the benefit of low-income and/or elderly households, other public entities (such as public 

colleges and universities) may provide regulated housing. As with the private sector, the RRP regulations 

will increase the cost of operating this housing by requiring that staff be trained and appropriate work 

practices be undertaken, including cleaning verification. 

Public housing that receives funding from the U.S. Department of Housing and Urban Development 

already must comply with HUD regulations regarding lead paint and so are unlikely to incur additional 

costs due to this rule. These housing units and their RRP events have been excluded from the cost and 

benefit estimates presented in Chapters 4, 5 and 6 of this report. Four states (Massachusetts, New York, 

Hawaii, and Connecticut) and one local government (New York City) have been identified as operating 

public housing that does not receive HUD funds. RRP activities in these units are likely to be covered by 

this rule. 

Massachusetts has approximately 50,000 state-funded public housing units operated through 235 local 

housing authorities (Stainton 2001). 

New York is home to the country’s first state-subsidized public housing program. New York has 

constructed 143 housing developments that are owned by 42 municipal housing authorities since the 

program began in 1939. Due to the increased burden on the State’s Public Housing Modernization 

Program (PHMP), New York has federalized some of their units. Units that have been federalized must 

adhere to federal rules and regulations, including existing lead standards (DHCRb 2005). Housing that 

has been updated through PHM has undergone lead testing. 

The New York City Housing Authority (NYCHA) is the largest public housing authority in North 

America, housing 175,116 families in 345 developments. Of these, 12,158 units are state-funded and 

7,971 of these units are city-funded. 

The Housing and Community Development Corporation of Hawaii (HCDCH) manages 6,200 units in 81 

developments of federal and state public housing, which support 14,000 residents. State-funded public 

housing makes up 14 percent (868 units) of HCDCH’s housing stock. Both private and public employees 

manage these units and operating costs are completely funded by rental income (HCDCH 2002). 

The state of Connecticut does not officially sponsor public housing. Local housing authorities run 

Connecticut public housing. These housing authorities receive municipal tax-breaks and municipalities 

receive Payments in Lieu of Taxes (PILOT) from the state. 

While these state and local programs make up only a relatively small percentage of all public housing, 

they are locally important. At the same time, it is important to note that in Massachusetts state 

regulations already require the use of certain work practices when performing renovations in pre-1978 
402(c) Chapter 8 6 

housing. New York City also has an extensive regulatory program that applies to multi-unit dwellings 

where children under the age of seven reside. In both cases, these requirements may partially reduce the 

incremental burden of complying with the RRP Rule. See Chapter 3 of this Economic Analysis for more 

information on these programs. 

In 2000, there were over 14 million students enrolled in colleges and universities in the United States and 

over 3 million students enrolled in graduate or professional schools. Of these students, over 11 million 

attend public colleges and nearly 2 million attend public graduate schools (U.S. Census Bureau 2000d). 

According to the US Census, over 2 million students reside in dormitories—group quarters that are not 

affected by the RRP rule (U.S. Census Bureau 2000e). The remaining students must either reside offcampus in private housing, or in college-owned apartments and individual units. Individual, collegeowned housing units include but are not limited to, undergraduate suites and apartments, married student 

housing, graduate student apartments, and faculty housing. These types of units are not differentiated 

from the general housing stock in the Census; therefore it is difficult to determine how many of these 

units exist or the age of these units. 

8.2.2 Expenditures by State, Local, and Tribal Governments 

Information is not available on the number of renovation events in target housing with lead-based paint 

owned by State, local, and Tribal governments not already covered by HUD regulations. However, it is 

possible to calculate how many events would be needed to exceed the $100 million UMRA threshold. 

Under the preferred option there will be 5.8 million regulated RRP events as a result of the rule in the first 

year (Phase 1), at a cost of $531 million. In the second year (Phase 2), there will be 10.7 million 

regulated events at a cost of $552 million (discounted at 3 percent)2

. This is equivalent to an average cost 

of about $92 per event in the first year and $52 per event in the second year.3

 In order to generate $100 

million in costs, there would have to be over 1.0 million events in the first year, and over 1.9 million such 

events in the second year. It seems unlikely that there would be this many events in the public housing 

that does not receive HUD grants, or in other government owned housing that is covered by the rule. 

Therefore, the rule is not expected to result in the expenditure by State, local, and Tribal governments, in 

the aggregate, of $100 million or more. However, given the cost results presented in Chapter 4, the rule is 

expected to result in an expenditure by the private sector of $100 million or more in any one year. 

8.3 Regulatory Flexibility Act 

The Regulatory Flexibility Act (RFA) of 1980, amended by the Small Business Regulatory Enforcement 

Fairness Act (SBREFA) of 1996, requires regulators to assess the effects of regulations on small entities 

including businesses, nonprofit agencies, and governments. In some instances, agencies are also required 

to examine regulatory alternatives that may reduce adverse economic effects on significantly impacted 

small entities. The RFA requires agencies to prepare an initial and final regulatory flexibility analysis for 

each rule unless the Agency certifies that the rule will not have a significant economic impact on a 

substantial number of small entities. The RFA, however, does not specifically define “a significant 

economic impact on a substantial number” of small entities. Sections 603 and 604 of the RFA require 

 

2 Using a 7 percent discount rate, the total cost of the 5.8 million events in the second year is estimated to be $532 

million, or about $50 per event. At a per-event cost of $50, there would have to be over 2 million regulated events 

in the second year to yield $100 million in costs.

3 Note that these average costs include some events where the only costs incurred are those of a lead-based paint test 

kit. Note also that these costs differ from the costs used in the Regulatory Flexibility Analysis because they 

represent first and second year, rather than annualized, costs of the rule. 
402(c) Chapter 8 7 

that regulatory flexibility analyses identify the types, and estimate the numbers, of small entities to which 

the proposed rule will apply; and describe the rule requirements to which small entities will be subject 

and any regulatory alternatives, including exemptions and deferral, which would lessen the rule’s burden 

on small entities. 

This analysis looks at the impacts of the Renovation, Repair and Painting Rule on small businesses in the 

affected construction and residential real estate industry sectors, as well as on small governments and 

non-profit organizations. The rule requires that all establishments that perform renovation work in 

regulated housing get certified by EPA, ensure that their employees are trained as either renovators or 

workers, and use lead-safe work practices whenever disturbing more than the exempt amount of leadbased paint. As such, construction and real estate establishments, as well as government agencies and 

non-profits that renovate or repair properties subject to the rule, will incur the costs of training, 

certification, and lead-safe work practice use. 

The impacts on Training Providers are not analyzed because the rule will result in an increased demand 

for their services and thus the impacts are positive. Although the rule may also result in additional costs 

for Training Providers (i.e. costs of developing and becoming accredited for a new course, keeping 

records, and submitting notifications), Training Providers are expected to recoup these costs via tuition 

fees. These tuition fees are accounted for in the training costs of renovation and real estate firms. 

8.3.1 Definitions of Small Entity 

The Regulatory Flexibility Act defines a small government as a government of a city, county, town, 

school district or special district with a population of less than 50,000. A small non-profit organization is 

defined as any not-for-profit enterprise which is independently owned and operated and is not dominant 

in its field. The RFA relies on the definition of a “small business” found in the Small Business Act, 

which authorizes the Small Business Administration (SBA) to develop definitions for “small business.” 

For this analysis, EPA uses SBA’s definition of a small business for each industry. 

For many industry sectors, the SBA definition of a small business is based on revenues, with the revenue 

standards varying by industry. In establishing revenue standards, SBA considers a number of economic 

and market characteristics that may allow a firm to exercise dominance in an industry. These standards 

represent the maximum revenue that a for-profit enterprise may have, and still qualify as a small business. 

The following eleven NAICS codes are the general and specialty contractors this rule will impact, and 

their respective SBA threshold. These are followed with the two NAICS codes for residential real estate 

industries that are also likely to be affected by the rule. 
402(c) Chapter 8 8 

Table 8-3: SBA Revenue Thresholds for Small Business by NAICS Code

NAICS Industry Description 

SBA Revenue 

Threshold 

(Millions $) 

General and Specialty Contractor Industries 

236118 Residential remodelers $28.5 

238170 Siding contractors $12 

238350 Finish carpentry contractors $12 

238290 Other building equipment contractors $12 

238390 Other building finishing contractors $12 

238340 Tile and terrazzo contractors $12 

238220 Plumbing and HVAC contractors $12 

238150 Glass and glazing contractors $12 

238320 Painting and wall covering contractors $12 

238210 Electrical contractors $12 

238310 Drywall and insulation contractors $12 

Residential Property Owners and Managers 

531311 Residential Property Managers $1.5 

531110 Lessors of Residential Buildings and Dwellings $6.0 

Source: U.S. Small Business Administration 2004. 

In this analysis, impacts of the RRP rule on small businesses are considered first, followed by impacts on 

small governments and non-profit organizations. 

8.3.2 Impacts on Small Businesses - General Methodology Overview 

This analysis measures the potential impacts of the Renovation, Repair and Painting (RRP) Rule on small 

businesses in terms of annual compliance costs as a percentage of annual revenues, or the cost impact 

ratio. This approach is based on the premise that the cost impact percentage is an appropriate measure of 

an entity’s ability to afford the costs attributable to a regulatory change. For purposes of determining 

small entity impacts, comparing annual compliance costs to annual revenues provides a reasonable 

indication of the magnitude of the regulatory burden relative to a commonly available and objective 

measure of a company’s business volume. Where regulatory costs represent a very small fraction of a 

typical establishment’s revenue, the impacts of a regulation are likely to be minimal. 

General Assumptions and Approach 

Two groups of regulated businesses are considered in this analysis: small construction establishments and 

small residential real estate businesses. The goal of this analysis is to evaluate the impacts of the RRP 

Rule on small businesses in a typical year. Several assumptions are made throughout this analysis so as 

to develop a more realistic portrayal of the long-term effects of the rule on small businesses. First, 

annualized costs of the rule are used to measure the impacts of the regulation. Second, the analysis 

recognizes that both construction and residential real estate establishments will pass some of their 

compliance costs to their customers, either through higher prices charged for renovation, or through 

increases in rent. A cost pass-through scenario is developed based on data on the elasticities of supply 

and demand for housing and incorporated into the analysis. 

Establishment, rather than firm-level data is used throughout the analysis. Census information was 

available primarily at the establishment level, making a firm-level analysis unfeasible. Because 
402(c) Chapter 8 9 

establishments, and not firms, are analyzed, an assumption is made that none of the small establishments 

are subsidiaries of larger firms. This assumption leads to an overestimate of the number of small 

independent establishments affected by the rule. Furthermore, since firm-level revenues of multiestablishment businesses are higher than establishment revenues, the use of establishment data may result 

in a higher cost-impact ratio than is actually the case. 

The cost-impact ratios estimated for the residential real estate industries (NAICS 531110 and NAICS 

531311) in this small business analysis are based on employment and revenue data for employer 

establishments only. As discussed in Chapter 4, there are no Census data on the amount of renovation 

and repair work performed by residential property managers and lessors on their own properties. EPA 

thus assumed that all establishments with employees that manage or lease housing units subject to the 

regulation would seek certification and train their employees as renovators or workers, as appropriate. 

Since it is likely that only some of these establishments will get certified and those that do obtain 

certification will train only some of their employees, this approach leads to an overestimate of the number 

of establishments certified and the number of people trained. 

While it is likely that both employer establishments and self-employed managers/lessors perform some 

regulated RRP work, self-employed managers/lessors (who have no staff and thus lower manpower) are 

much more likely to hire an outside firm to perform renovation work on their properties than employer 

establishments. Because the approach used to estimate the number of certified employers in these 

industries already results in an overestimate of the number of establishments and people certified and 

trained, and because self-employed managers/lessors are less likely to perform regulated renovation work 

themselves, EPA did not include non-employer establishments in these sectors in its estimates of training 

and certification costs. In reality, residential property manager and lessor establishments with employees 

will train only some of their staff and some non-employers in these industries will seek training and 

certification. 

Costs Incurred by Small Establishments 

Establishments that perform RRP work in regulated housing will incur the costs of training, certification 

and using lead-safe work practices during projects that involve lead-based paint. In order to distribute the 

total costs of the rule between small and large establishments, EPA assumed that the compliance cost 

incurred by each establishment is a function of the number of regulated renovation events that the 

establishment performs in a typical year. EPA thus calculated an average compliance cost per event by 

dividing the total annualized cost of the rule by the estimated annual number of renovation events taking 

place in regulated housing (See Section 8.3.5 for further discussion). This per-event cost includes the 

costs of complying with work practice, training and certification requirements. The use of annualized 

costs provides a more accurate representation of the long-term (typical year) impacts of the rule. 

Cost-Impact Ratio Estimation for the Construction and Residential Real Estate Industries 

The following seven steps describe the general approach used to calculate the cost-impact ratios for the 

construction and residential real estate industry sectors. To estimate the impacts of the costs of the rule 

on small entities in the affected industries, the following calculations were performed for each sector: 

1. Certified establishments were classified as either small or large businesses, depending on their 

revenues. Self-employed contractors were combined with small employer establishments to form 

one small business category. 

2. Census data were used to characterize a “typical” small establishment (including revenues and 

number of employees) in each of the affected industry sectors. 
402(c) Chapter 8 10 

3. The average number of regulated events performed by an establishment each year was estimated 

by multiplying the ratio of regulated events to trained personnel by the establishment employment 

size. 

4. An average per-event compliance cost was calculated using the annualized 50-year cost of the 

rule under each option and the average number of renovation events performed in regulated 

housing in a typical year. 

5. The change in per-event price and quantity of regulated events, as well as the resulting change in 

contractor revenues were estimated using available data on the elasticities of supply and demand 

for housing. 

6. Establishment compliance costs were calculated by multiplying the post-rule number of events 

performed by the establishment by the average annualized compliance cost per event under each 

option. 

7. Cost-impact ratios were calculated for a typical small establishment in each industry sector by 

dividing the compliance costs incurred by the establishment (Step 6) by the establishment’s postrule RRP revenues (Step 5). 

The following sections present a detailed discussion of the steps taken to estimate the various parameters 

(number of establishments and employees, events per establishment, establishment revenues, etc.) used to 

obtain the cost-impact ratios for small construction and residential real estate establishments. 

8.3.3 Number of Small Establishments and Individuals Affected Under Each Option 

Number of Small Businesses Affected – First Year 

The data used in this analysis were drawn primarily from the 2002 U.S. Economic Census. As discussed 

in Chapter 2, Census data were used to estimate the number of non-employer establishments (selfemployed contractors) in the affected construction industries (see Table 2-5 in Chapter 2). The 2002 

Census also provides data on the number, revenue and employment of establishments with payroll by 

revenue bracket for each of the eleven construction industry sectors affected by the rule. In Chapter 2, 

these data were used to classify construction establishments into two main size classes – establishments 

with annual revenues of less than $10 million, and establishments with annual revenues of $10 million or 

more. The percent of establishments, employees, net value of construction and total value of business 

contributed by establishments in each revenue bracket can be found in Table 2-8 of Chapter 2. 

Because 2002 revenue bracket data for Lessors of Residential Buildings and Dwellings and Residential 

Property Managers are not yet available, 1997-year data were used to estimate the percent of 

establishments in these sectors that were small businesses. These percentages, as well as the percent of 

industry revenues and employment contributed by small and large establishments, are presented in Table 

2-12 (Chapter 2). 

The Small Business Administration revenue thresholds for establishments in the construction sectors are 

currently set at $28.5 million for Residential Remodelers and at $12 million for the ten specialty 

contractor industries. However, in applying the U.S. Economic Census data to the SBA definition of 

small business, it is not possible to estimate the exact number of construction establishments that have 

revenues below the SBA threshold because the U.S. Economic Census groups all establishments with 

revenues of $10 million or more into one revenue bracket. Applying the U.S. Economic Census data 

therefore requires either under or overestimating the number of small businesses affected by the rule. On 

the one hand, using data for the entire industry would overestimate the number of small businesses 

affected by the rule. It would also underestimate the rule’s impact on small businesses because the 

impacts would be calculated using the revenues of large businesses in addition to small businesses. On 
402(c) Chapter 8 11 

the other hand, applying the closest, albeit lower, revenue bracket would underestimate the number of 

small businesses affected by the rule while at the same time overestimating the impacts. For example, 

because the $10 million cut-off is below the SBA threshold for the Residential Remodeler industry, using 

the U.S. Economic Census data may lead to an underestimate of the number of small businesses in this 

sector, although likely a small underestimate.4

 At the same time, using these data may lead to a slight 

overestimate of the impacts of the rule, as the average revenues of small businesses will appear smaller 

when larger establishments (those with revenues of $10 to $28.5 million) are left out. Section 8.3.2 

already discussed assumptions that may result in an overestimation of the number of affected small 

businesses. Moreover, using data on all small businesses regardless of size would defeat the purpose of 

estimating impacts on small business. EPA has concluded that a substantial number of small businesses 

will be affected by the rule. Consequently, EPA has chosen to be more conservative in estimating the 

cost impacts of the rule on small businesses by using the $10 million threshold for construction industry 

sectors. 

As with the Residential Remodelers and the ten specialty contractor industries discussed above, it is not 

possible to estimate the exact number of small Residential Property Manager establishments or Lessor of 

Residential Buildings and Dwellings establishments, because Census-defined revenue brackets group 

establishments with revenues of $1 million to $5 million and $5 million to $10 million, respectively. For 

the same reasons set forth above (i.e., EPA has already concluded that a substantial number of small 

businesses in these industries will be affected by the rule and the Agency had the choice to either 

overestimate or underestimate the impacts), it has chosen to overestimate the impacts. Thus, EPA has 

applied the U.S. Economic Census data for establishments with revenues of less than $1 million to 

Residential Property Managers , and the U.S. Census Economic data for establishments with revenues of 

less than $5 million to Lessor of Residential Buildings.5

In order to estimate the number of certified small establishments with paid employees, EPA assumed that 

the number of certified small employers is proportional to the total number of small employer 

establishments in the industry. The total number of certified establishments in each industry (calculated 

in Chapter 4) was multiplied by the percentage of establishments in that industry that have revenues 

below the revenue thresholds described above. For the 11 construction industry sectors, the resulting 

number of small employer establishments was added to the total number of certified self-employed 

contractors to obtain the total number of small certified establishments. The resulting first-year estimates 

(by industry and option) are presented in Table 8-4. 

 

4 Because 99.7 percent of Residential Remodeler establishments earn less than $10 million per year, any 

underestimate of the number of establishments is likely to be minimal.

5 Approximately 85 percent of Residential Property Manager establishments earn less than $1 million per year, and 

about 99 percent of Lessor of Residential Buildings and Dwellings establishments earn less than $5 million per year. 
402(c) Chapter 8 12 

Number of Small Establishments Affected - Long Term 

Table 8-5 shows the total first, second, third and 50-year average numbers of small businesses affected by 

the regulations under each option. Under all four options, all firms performing RRP projects in pre-1978 

renter-occupied target housing units and pre-1978 owner-occupied target housing units where a child 

under the age of six resides will be subject to the regulations from the second year onward. As such, 

starting with the second year, the total number of small businesses affected by the rule will be the same 

under all options. The number of affected businesses is expected to decrease proportionally to the 

number of regulated events, which in turn decline at an annual rate of 0.41 percent (see Section 4.2.6 of 

Chapter 4 for discussion). 

Table 8-4: Number of Certified Small Establishments by Option (First Year) 

NAICS Description Option Aa,b Options B &Da,b Option Ca,b

236118 Residential remodelers 44,165 23,307 16,044 

238170 Siding contractors 3,213 1,696 1,167 

238350 Finish carpentry contractors 31,361 16,551 11,394 

238290 Other building equipment contractors 1,457 769 530 

238390 Other building finishing contractors 1,995 1,053 725 

238340 Tile and terrazzo contractors 4,480 2,364 1,628 

238220 Plumbing and HVAC contractors 15,072 7,955 5,476 

238150 Glass and glazing contractors 1,329 701 484 

238320 Painting and wall covering contractors 17,407 9,188 6,323 

238210 Electrical contractors 10,716 5,655 3,893 

238310 Drywall and insulation contractors 7,329 3,868 2,663 

Total, Small Construction Establishments 138,524 73,105 50,327 

531311 Residential Property Managers 6,335 3,343 2,301 

531110 Lessors of Residential Real Estate 17,372 9,169 6,312 

Total, All Industries 162,232 85,617 58,939 

a. EPA applied U.S. Economic Census data regarding: entities with less than $10 million in revenues to 

establishments in the 11 construction sectors; entities with less than $1 million in revenues to Residential 

Property Manager establishments; and entities with less than $5 million in revenues to Lessors of Residential 

Real Estate. 

b. Option Descriptions: Option A: All pre-1978 renter-occupied target housing units and all pre-1978 owneroccupied target housing units where children under the age of six reside are subject to the rule; WPS 

requirements are flexible. Option B: All pre-1960 renter-occupied target housing units and all pre-1960 owneroccupied target housing units where children under the age of six reside are subject to the rule in the first year it 

is in effect (Phase 1); in the second year (Phase 2), all pre-1978 renter-occupied target housing units and all pre1978 owner-occupied target housing units where children under the age of six reside are subject to the rule; WPS 

requirements are flexible. Option C: All pre-1950 renter-occupied target housing units and all pre-1950 owneroccupied target housing units where children under the age of six reside are subject to the rule in the first year it 

is in effect (Phase 1); in the second year (Phase 2), all pre-1978 renter-occupied target housing units and all pre1978 owner-occupied target housing units where children under the age of six reside are subject to the rule; WPS 

requirements are flexible. Option D: All pre-1960 renter-occupied target housing units and all pre-1960 owneroccupied target housing units where children under the age of six reside are subject to the rule in the first year it 

is in effect (Phase 1); in the second year (Phase 2), all pre-1978 renter-occupied target housing units and all pre1978 owner-occupied target housing units where children under the age of six reside are subject to the rule; WPS 

requirements are prescriptive. Note that in the first year, Options B, C and D also apply to any pre-1978 housing 

where a child with an increased blood-lead level resides. 

Source: U.S. Census Bureau 2000a; U.S. Census Bureau 2004b; U.S. Census Bureau 2005 b-f,i; U.S. Small 

Business Administration 2005. 
402(c) Chapter 8 13 

Table 8-5: Total Number of Small Establishments Affected, by Option 

 Option Aa

 Options B &Da Option Ca

Year 1 162,232 85,617 58,939 

Year 2 161,567 161,567 161,567 

Year 3 160,904 160,904 160,904 

50-year Average 146,955 145,423 144,889 

 a. See Table 8-4, Footnote 2 for option definitions. 

Source: EPA calculations 

8.3.4 Average Small Establishment Revenues, Employment Size and Number of Renovation Events 

Performed 

As discussed in Chapter 4, the total number of people trained and the number of establishments certified 

are assumed to change from option to option and over time in proportion to the regulated housing stock 

and the number of regulated events. Since both the number of establishments and the number of people 

trained are changing proportionally, however, the average establishment employment size, revenues, and 

number of events performed each year are, for the purposes of this analysis, assumed to stay constant 

across options and over time. 

Revenues 

Cost-impact ratio analysis compares the cost of a regulation to a firm’s (in this case, establishment’s) total 

revenues, not just to its revenues from the regulated activity. As such, for construction establishments, 

the costs of the rule were compared to the total value of business done, rather than just to the total value 

of construction work. For real estate establishments, total revenues were used. Because no data are 

available specifically for establishments expected to seek certification under the regulations, EPA 

assumed that average revenues of these businesses do not differ significantly from industry averages. 

EPA calculated the revenues of a small certified construction business as a weighted average of small 

employer and non-employer revenues. The 2002 U.S. Economic Census presents data on the number of 

and total value of business done by construction establishments with total annual revenues of $0 to $10 

million and $10 million or more. To estimate the average revenues of small employers in each of the 

affected construction sectors, the total value of business done by establishments in the $0 to $10 million 

bracket was divided by the total number of establishments in that bracket. Since Census presents revenue 

figures in year 2002 dollars, the resulting average revenues were inflated to 2005 dollars using the 

Consumer Price Index. 6 In Chapter 2, EPA estimated the number of non-employers in each of the 

affected construction sectors as well as the revenues of these establishments (Table 2-5, Chapter 2). Perestablishment revenues were estimated for the cost impact ratio analysis by dividing non-employer 

revenues (inflated to 2005 dollars) by the number of non-employer establishments in each industry. 

Average revenues of certified small establishments are presented in Table 8-6.7

 Because the 2002 U.S. 

Economic Census does not yet provide data by revenue bracket for Residential Property Manager and the 

Lessor of Residential Buildings and Dwellings sectors, EPA used data from the 1997 Economic Census to 

estimate the percent of establishments in each industry that qualify for small business status. EPA used 

1997 Census data to calculate the percent of industry revenues contributed by these establishments (See 

Table 2-12, Chapter 2). These percentages were then applied to the 2002 numbers of establishments and 

 

6 All items, US city average, Series Id: CUUR0000SA0. Used annual data for 2002 and half-year data for 2005. 

7 There may be some slight variation in average small establishment revenues from option to option due to rounding. 

From the second year onward, however, the number of regulated events and trained personnel will be the same as 

under Option A. Thus, Option A data was used in this analysis.
402(c) Chapter 8 14 

industry revenue figures to estimate the number and revenues of small and large employers in each 

industry. Average small and large employer revenues (calculated by dividing the revenues of 

establishments in each industry and revenue bracket by the corresponding number of establishments) 

were inflated to 2005 dollars using the Consumer Price Index.8

 The resulting estimates are presented in 

Table 8-6. 

Table 8-6: Average Revenues of Small Businesses Affected by the RRP Rule 

NAICS Industry Description 

Small Business 

Revenues 

(2005$) 

236118 Residential remodelers $182,932 

238170 Siding contractors $201,569 

238350 Finish carpentry contractors $100,713 

238290 Other building equipment contractors $585,771 

238390 Other building finishing contractors $231,442 

238340 Tile and terrazzo contractors $130,097 

238220 Plumbing and HVAC contractors $432,677 

238150 Glass and glazing contractors $336,896 

238320 Painting and wall covering contractors $86,839 

238210 Electrical contractors $351,694 

238310 Drywall and insulation contractors $240,488 

Total Average, Construction Establishments $217,546 

531311 Residential Property Managers $342,477 

531110 Lessors of Residential Real Estate $821,350 

Total2 Average, All Industries $289,530 

Weighted average of employer and non-employer revenues. 

Source: EPA Calculations; U.S. Census Bureau 2005c,f,i; U.S. Small Business 

Administration 2005; U.S. Census Bureau 2004b; U.S. Census Bureau 2000a. 

Employment Size of Small Construction Establishments 

In order to estimate the employment size of an average small establishment in each affected industry, 

EPA used U.S. Economic Census data to determine the portion of each industry’s employees that work 

for small businesses. This percentage was applied to the estimated number of trained employees in each 

sector to calculate the number of trained renovators and workers employed by small certified 

establishments and, for the eleven construction industry sectors, combined with the number of certified 

self-employed contractors to calculate an average small business employment size. 

Table 8-7 presents the percent of the workforce employed by small establishments,9

 the total number of 

trained personnel in each industry (under Option A), and the estimated average numbers of trained 

professionals working for small certified establishments. While numbers in this table are based on the 

Option A scenario, as discussed at the beginning of this section, the average employment size of 

establishments in each industry is the same under each option. 

 

8 All items, US city average. Series Id: CUUR0000SA0.

9

 See Sections 2.2.4 and 2.5.2 of Chapter 2 for discussion of these percentages.
402(c) Chapter 8 15 

Table 8-7: Number of Trained Employees per Small Certified Establishment (Option A) 

NAICS Description % Workforce 

employed by 

Small 

Employersa,b

Trained 

Employees, Small 

Estab. c

Average Small 

Estab. Employment 

Size d

236118 Residential remodelers 95 62,479 1.4 

238170 Siding contractors 90 6,169 1.9 

238350 Finish carpentry contractors 86 42,284 1.3 

238290 Other building equipment contractors 60 6,060 4.2 

238390 Other building finishing contractors 81 4,268 2.1 

238340 Tile and terrazzo contractors 91 7,005 1.6 

238220 Plumbing and HVAC contractors 70 46,962 3.1 

238150 Glass and glazing contractors 82 3,025 2.3 

238320 Painting and wall covering contractors 92 26,687 1.5 

238210 Electrical contractors 68 33,737 3.1 

238310 Drywall and insulation contractors 64 16,202 2.2 

Average, Small Construction Establishments 254,880 1.8 

531311 Residential Property Managers 40 33,192 5.2 

531110 Lessors of Residential Real Estate 86 71,285 4.1 

Average, All Industries 359,357 2.2 

a. EPA applied U.S. Economic Census data regarding: entities with less than $10 million in revenues to 

establishments in the 11 construction sectors; entities with less than $1 million in revenues to Residential 

Property Manager establishments; and entities with less than $5 million in revenues to Lessors of Residential 

Real Estate. 

b. Percentages shown for presentation purposes only. Calculations used unrounded ratio of small establishment 

data to industry data. 

c. Total number of trained employees working for small construction establishments is the sum of trained 

personnel working for small employers and the total number of certified self-employed contractors. 

d. For construction industry sectors calculated by dividing the total number of trained employees of small 

establishments by the sum of certified small employer establishments and certified self-employed contractors. 

Source: U.S. Census Bureau 2000a; U.S. Census Bureau 2004b; U.S. Census Bureau 2005 b-f,i; U.S. Small 

Business Administration 2005. 

Average Number of Events Performed by Small Construction Establishments 

As discussed in Section 8.3.2, in this analysis the costs of the rule are attributed to establishments on a 

per-event basis. In order to estimate the total number of events performed by establishments in each of 

the affected industries, and in order to distribute these events between small and large establishments, 

EPA assumed that the number of events performed by each establishment is proportional to the number of 

people the establishment employs. Furthermore, EPA assumed that the number of events performed by 

each trained employee will be the same across all industries, including Residential Property Managers and 

Lessors of Residential Buildings and Dwellings. If property managers and lessors perform fewer events 

than estimated here, the impacts on these establishments will be slightly smaller, and the impacts on 

construction firms will be larger. 

The number of events per small establishment in a particular industry was calculated as follows: 

EPA estimated the average number of events per certified renovator or worker by calculating the ratio of 

the total number of regulated RRP events to the total number of trained personnel. Because the number 

Number of Events = (Events/Employee) X (Estab (Events/Employee) X (Establishment Employment Size) lishment Employment Size)
402(c) Chapter 8 16 

of people trained, as estimated in Chapter 4, was assumed to be proportional to the regulated housing 

stock and the number of regulated events, the number of RRP events per employee does not change over 

time and is approximately the same across options.10

To estimate the average number of events performed by a small establishment in a given industry, the 

establishment’s average employment size (Table 8-7) was multiplied by the average number of events per 

person (23). Table 8-8 presents the average estimated number of events per small establishment. 

Table 8-8: Number of Events performed by Small Establishments 

NAICS Description Annual Number 

of Events per 

Employee 

Average Small 

Establishment 

Employment Size 

Annual Number of 

Events per Small 

Establishment a

236118 Residential remodelers 23.0 1.4 33 

238170 Siding contractors 23.0 1.9 44 

238350 Finish carpentry contractors 23.0 1.3 31 

238290 Other building equipment contractors 23.0 4.2 96 

238390 Other building finishing contractors 23.0 2.1 49 

238340 Tile and terrazzo contractors 23.0 1.6 36 

238220 Plumbing and HVAC contractors 23.0 3.1 72 

238150 Glass and glazing contractors 23.0 2.3 52 

238320 

Painting and wall covering 

contractors 23.0 1.5 35 

238210 Electrical contractors 23.0 3.1 72 

238310 Drywall and insulation contractors 23.0 2.2 51 

Average, Small Construction Establishments 23.0 1.8 42 

531311 Residential Property Managers 23.0 5.2 121 

531110 Lessors of Residential Real Estate 23.0 4.1 94 

Average, All Industries 23.0 2.2 51 

a. Number of events per establishment rounded to the nearest event. 

Source: EPA Calculations. 

 

10 While there are slight differences in the estimates of the number of events per person under each of the four 

options in the first year, from the second year onward the number of regulated events and trained personnel under 

each option will be the same as under Option A. Option A data is used in this analysis. 
402(c) Chapter 8 17 

8.3.5 Estimating the Costs of the RRP Rule Incurred by Small Establishments 

Average Per-Event Cost of Compliance 

In Section 4.7.3 of Chapter 4, EPA estimated the 50-year annualized costs of the RRP Rule under each of 

the four regulatory options considered. Using costs discounted at a 3 percent rate, the total per-event cost 

was estimated as the total annualized cost of the rule under each option divided by the average annual 

number of regulated events.11 The number of events taking place in a “typical” year over the 50-year 

period covered by the annualized costs was calculated assuming that the number of events will decrease 

annually in proportion to the demolition of the pre-1980 housing stock, or at a rate of 0.41 percent per 

year. Table 8-9 presents the total number of events taking place in the first year and the second year the 

rule is in effect, as well as the average number of regulated events taking place in a “typical” year. The 

table also presents the total annualized cost of the rule under each of the options and the estimated 

average annualized compliance cost per event. Note that total annualized and per-event costs are 

significantly higher under Option D, which includes prescriptive work practice requirements. Because 

the per-event cost is derived from the total annualized cost of compliance, it includes the cost of training, 

certification and lead-safe work practices. This average cost includes some RRP events where the only 

cost incurred is that of the lead-based paint (LBP) test kit, where the test showed no lead. 

Table 8-9: Total Number of Regulated Events, Total Annualized Costs and Average 

Compliance Cost per Event 

 Option Aa

 Options B a Option Ca Option Da

Year 1 Events 10,727,895 5,818,980 4,298,336 5,818,980 

Year 2 Events 10,683,911 10,683,911 10,683,911 10,683,911 

50-year Average Events 9,717,689 9,619,510 9,589,097 9,619,510 

Annualized Cost (millions $) $505 $492 $488 $588 

Per-Event Cost ($) $52.00 $51.17 $50.86 $61.17 

 a. See Table 8-4, Footnote b for option definitions.

Source: EPA Calculations 

Firms’ Ability to Pass Costs of Compliance on to their Customers 

As demonstrated in Table 8-9, small establishments are estimated to incur an average annualized 

compliance cost of about $51 to $61 per regulated renovation event. The requirements of the RRP Rule 

thus effectively raise the cost of performing renovation work in housing subject to the rule by $51 to $61. 

Contractors faced with this cost increase have two options – they can either choose to absorb this cost, 

decreasing their per-event profits, or they can try to pass at least a portion of the cost on to their 

customers, increasing the price of renovation work. 

 

11 Costs annualized using a 3 percent discount rate are used because the analysis assumes that establishments will 

pass some of the costs of compliance onto their customers. As such, compliance costs are expected to offset 

consumption rather than investment. 
402(c) Chapter 8 18 

A firm’s ability to pass on costs depends largely on the elasticities of supply and demand for renovation 

services. The role of supply and demand elasticities in determining the impacts of a rule are discussed in 

detail in Appendixes 3A and 3B of this economic analysis. In general, given a fixed supply curve, the 

more inelastic the demand for renovation services, the greater the portion of the costs that suppliers can 

pass on to their customers. Given a fixed demand curve, higher supply elasticity allows for greater cost 

pass-through. 

In order to estimate the impacts of the regulations on small businesses assuming that these establishments 

will be able to pass some of the costs on to their customers, EPA reviewed a variety of literature on the 

supply and demand elasticities of housing, construction and renovation. Based on this literature, EPA 

selected values for the elasticities of supply and demand to be used in this small business impact analysis. 

The vast majority of available literature focused on the supply/demand elasticities for new housing 

construction, rather than renovation and repair work. In addition, more information was available on the 

demand for housing than on supply. 

The elasticity of demand for housing services is generally considered to be in the range of –0.5 to –1.0 

(Mayo 1981; Malpezzi and Maclennan 2001) or –0.75 to –1.2 (Ellwood and Polinski 1979), with a 

preferred estimate of slightly less than 1.0 in absolute value. While intuitively the demand for housing 

might appear less elastic than the demand for renovation12, one paper estimated a renovation demand 

elasticity of –0.28 and stated that renovation demand is “very inelastic” (Gyourko and Saiz, 2003). 

Because the elasticity of demand estimates are fairly consistent across the literature surveyed, EPA used 

the median of the –0.28 to –1.2 range, or –0.74, as an estimate of the elasticity of demand for lead-safe 

renovation services. As such, the demand is considered slightly inelastic in this analysis. Since at least 

some of the renovation jobs covered by the rule are necessary maintenance and repair projects rather than 

discretionary alteration and remodeling jobs, assuming a somewhat inelastic demand for renovation is 

reasonable. 

Based on the literature surveyed, the supply of housing services, unlike the demand for these services, is 

believed to be highly elastic, especially in the long run. Estimates of housing supply elasticities generally 

range from 1.0 to 13 (DiPasquale and Wheaton 1994, Topel and Rosen 1988; Blackley 1999; Malpezzi 

and Maclennan 2001), with one study identifying a much higher elasticity of supply for physical 

structures (ES = 38, Gyourko and Saiz 2004). No elasticity numbers specific to the supply of renovation 

services could be found. Given the range of data presented in the literature, EPA estimated a supply 

elasticity of 6 for renovation services. This estimate is likely to be conservative, and as such, to lead to an 

overestimate of the impacts of the regulation on small construction establishments. 

 

12 While housing is a basic necessity, many renovation projects are discretionary. In addition to being able to 

choose whether to do a renovation project at all, consumers can choose between doing the work themselves or hiring 

an outside contractor. In the case of regulated renovation work, they can also choose between hiring a firm that is in 

compliance and a firm that is not. 
402(c) Chapter 8 19 

D

S2

S1

Q2 Q1

P1

P2

Quantity

Price

D

S2

S1

Q2 Q1

P1

P2

Quantity

Price

Changes in Price and Quantity; Post-Rule Revenues 

The costs of training, certification and lead-safe work practices required by the RRP Rule increase the 

cost of performing renovation work by about $51 to $61 per event. As demonstrated in Figure 8.1, an 

increase in the cost of supplying a service causes the supply curve, S1 to shift upward to S2. As a result 

of this shift, the equilibrium price of the service increases from P1 to P2, and the equilibrium quantity of 

services demanded decreases from Q1 to Q2. These changes in price and quantity, in turn, result in a 

change in supplier revenues. Whereas prior to the cost increase, the supplier earned the equivalent of 

Q1*P1 from his services, after the cost increase, he earns the equivalent of Q2*P2. 

Figure 8.1: Shifts in supply and market equilibrium 

resulting from increases in supply costs 

The resulting changes in the price and quantity of services (in this case, regulated renovation projects), as 

well as in the revenues of suppliers providing these services (in this case, contractors and residential real 

estate establishments) can be calculated as follows: 

∆P = (ES*C)/(ES-ED) 

∆Q = [ES*ED*(C/P1)*Q1]/[ES-ED] 

∆R = (P1+∆P)*(Q1+∆Q) – (P1*Q1) 

Where: 

• ∆P= Change in price 

• ∆Q= Change in quantity 

• ∆R = Change in revenues from regulated renovation events 

• ES = Price elasticity of supply (ES = 6) 

• ED = Price elasticity of demand (ED = -0.74) 

• C = Per unit cost increase (Cost of compliance, varies from option to option) 

• P1 = Initial equilibrium price ($1,900) 

• Q1 = Initial equilibrium quantity 

Note: This model assumes that the changes in quantity and price will be small enough that the 

elasticities will remain unchanged (Model based on HUD 1994). 

These calculations were performed for small establishments in each of the construction sectors, under 

each of the regulatory options considered. In each case, Q1 was equal to the average number of events 

per small establishment (Table 8-9) and P1 was equal to $1,900, the median cost per task subject to the 
402(c) Chapter 8 20 

regulation.13 The resulting estimates of the changes in price and quantity of regulated renovation services 

demanded (and supplied), and the resulting changes in contractor revenues are presented in Table 8-10 to 

Table 8-13 (for Options A through D). Note that with relatively inelastic demand and elastic supply, the 

average revenues of small construction establishments increase slightly under the rule. 

As demonstrated in these tables, the number of events performed by each establishment decreases 

slightly with the increase in price. This reduction in the quantity of events performed represents a 

decrease in the number of events that are in compliance with the regulations, rather than a decrease in the 

cumulative number of renovations performed. Throughout this analysis, EPA has assumed that about 75 

percent of all regulated renovation events will be performed in compliance with the RRP Rule 

requirements. The decrease in the number of events performed by certified establishments contributes to 

the 25 percent of regulated events that are likely to be conducted by untrained personnel using noncompliant work practices. 

 Table 8-10: Estimated changes in the price and number of renovation events, and resulting changes in small establishment 

revenues: Option A (Per-Event Cost Increase = $52.00)

 NAICS Industry Description 

Q1 (Initial 

Number of 

Events per 

Estab.) 

Per-Event 

Price Increase 

(Cost passed 

on to 

consumers) 

Decrease 

in 

Quantity

New Number 

of Regulated 

Events per 

Estab. 

Change in 

Revenues 

New Small 

Establishment 

Revenues 

236118 Residential remodelers 33 $46.29 -0.59 32.41 +$370 $183,302 

238170 Siding contractors 44 $46.29 -0.79 43.21 +$493 $202,062 

238350 Finish carpentry contractors 31 $46.29 -0.56 30.44 +$347 $101,060 

238290 Other building equipment contractors 96 $46.29 -1.73 94.27 +$1,075 $586,846 

238390 Other building finishing contractors 49 $46.29 -0.88 48.12 +$549 $231,991 

238340 Tile and terrazzo contractors 36 $46.29 -0.65 35.35 +$403 $130,500 

238220 Plumbing and HVAC contractors 72 $46.29 -1.30 70.70 +$806 $433,483 

238150 Glass and glazing contractors 52 $46.29 -0.94 51.06 +$582 $337,478 

238320 Painting and wall covering contractors 35 $46.29 -0.63 34.37 +$392 $87,231 

238210 Electrical contractors 72 $46.29 -1.30 70.70 +$806 $352,500 

238310 Drywall and insulation contractors 51 $46.29 -0.92 50.08 +$571 $241,059 

Average, Small Construction Establishments 42 $46.29 -0.76 41.24 +$470 $218,016 

531311 Residential Property Managers 121 $46.29 -2.18 118.82 +$1,355 $343,832 

531110 Lessors of Residential Real Estate 94 $46.29 -1.69 92.31 +$1,053 $822,403 

Average, All Industries 51 $46.29 -0.92 50.08 +$571 $290,101 

Source: EPA Calculations 

 

13 The $1,900 median cost per task is estimated using the 2003 American Housing Survey. Only spending reported 

for the tasks that are assumed to potentially disturb surfaces with LBP are included in the estimates (see Chapter 4). 

However, some spending on out-of-scope tasks may be included and some spending on in-scope tasks may be 

excluded, because the costs of multiple RRP tasks are sometimes reported under a single task of the respondents 

choosing.
402(c) Chapter 8 21 

Table 8-12: Estimated changes in the price and number of renovation events, and resulting changes in small establishment 

revenues: Option C (Per-Event Cost Increase = $50.86)

 NAICS Industry Description 

Q1 (Initial 

Number of 

Events per 

Estab.) 

Per-Event 

Price Increase 

(Cost passed 

on to 

consumers) 

Decrease 

in 

Quantity

New Number 

of Regulated 

Events per 

Estab. 

Change in 

Revenues 

New Small 

Establishment 

Revenues 

236118 Residential remodelers 33 $45.27 -0.58 32.42 +$362 $183,294 

238170 Siding contractors 44 $45.27 -0.78 43.22 +$483 $202,052 

238350 Finish carpentry contractors 31 $45.27 -0.55 30.45 +$340 $101,053 

238290 Other building equipment contractors 96 $45.27 -1.69 94.31 +$1,053 $586,824 

238390 Other building finishing contractors 49 $45.27 -0.86 48.14 +$538 $231,980 

238340 Tile and terrazzo contractors 36 $45.27 -0.63 35.37 +$395 $130,492 

238220 Plumbing and HVAC contractors 72 $45.27 -1.27 70.73 +$790 $433,467 

238150 Glass and glazing contractors 52 $45.27 -0.92 51.08 +$571 $337,467 

238320 Painting and wall covering contractors 35 $45.27 -0.62 34.38 +$384 $87,223 

238210 Electrical contractors 72 $45.27 -1.27 70.73 +$790 $352,484 

238310 Drywall and insulation contractors 51 $45.27 -0.90 50.10 +$560 $241,048 

Average, Small Construction Establishments 42 $45.27 -0.74 41.26 +$461 $218,007 

531311 Residential Property Managers 121 $45.27 -2.13 118.87 +$1,328 $343,805 

531110 Lessors of Residential Real Estate 94 $45.27 -1.66 92.34 +$1,031 $822,381 

Average, All Industries 51 $45.27 -0.90 50.10 +$560 $290,090 

Source: EPA Calculations 

Table 8-11: Estimated changes in the price and number of renovation events, and resulting changes in small establishment 

revenues: Option B (Per-Event Cost Increase = $51.17)

 NAICS Industry Description 

Q1 (Initial 

Number of 

Events per 

Estab.) 

Per-Event 

Price Increase 

(Cost passed 

on to 

consumers) 

Decrease 

in 

Quantity

New Number 

of Regulated 

Events per 

Estab. 

Change in 

Revenues 

New Small 

Establishment 

Revenues 

236118 Residential remodelers 33 $45.55 -0.59 32.41 +$364 $183,296 

238170 Siding contractors 44 $45.55 -0.78 43.22 +$486 $202,055 

238350 Finish carpentry contractors 31 $45.55 -0.55 30.45 +$342 $101,055 

238290 Other building equipment contractors 96 $45.55 -1.70 94.30 +$1,059 $586,830 

238390 Other building finishing contractors 49 $45.55 -0.87 48.13 +$541 $231,983 

238340 Tile and terrazzo contractors 36 $45.55 -0.64 35.36 +$397 $130,494 

238220 Plumbing and HVAC contractors 72 $45.55 -1.28 70.72 +$795 $433,472 

238150 Glass and glazing contractors 52 $45.55 -0.92 51.08 +$574 $337,470 

238320 Painting and wall covering contractors 35 $45.55 -0.62 34.38 +$386 $87,225 

238210 Electrical contractors 72 $45.55 -1.28 70.72 +$795 $352,489 

238310 Drywall and insulation contractors 51 $45.55 -0.90 50.10 +$563 $241,051 

Average, Small Construction Establishments 42 $45.55 -0.75 41.25 +$464 $218,010 

531311 Residential Property Managers 121 $45.55 -2.15 118.85 +$1,335 $343,812 

531110 Lessors of Residential Real Estate 94 $45.55 -1.67 92.33 +$1,037 $822,387 

Average, All Industries 51 $45.55 -0.90 50.10 +$563 $290,093 

Source: EPA Calculations 
402(c) Chapter 8 22 

Table 8-13: Estimated changes in the price and number of renovation events, and resulting changes in small establishment 

revenues: Option D (Per-Event Cost Increase = $61.17)

 NAICS Industry Description 

Q1 (Initial 

Number of 

Events per 

Estab.) 

Per-Event 

Price Increase 

(Cost passed 

on to 

consumers) 

Decrease 

in 

Quantity

New Number 

of Regulated 

Events per 

Estab. 

Change in 

Revenues 

New Small 

Establishment 

Revenues 

236118 Residential remodelers 33 $54.46 -0.70 32.30 +$429 $183,361 

238170 Siding contractors 44 $54.46 -0.93 43.07 +$572 $202,141 

238350 Finish carpentry contractors 31 $54.46 -0.66 30.34 +$403 $101,116 

238290 Other building equipment contractors 96 $54.46 -2.04 93.96 +$1,248 $587,019 

238390 Other building finishing contractors 49 $54.46 -1.04 47.96 +$637 $232,079 

238340 Tile and terrazzo contractors 36 $54.46 -0.76 35.24 +$468 $130,565 

238220 Plumbing and HVAC contractors 72 $54.46 -1.53 70.47 +$936 $433,613 

238150 Glass and glazing contractors 52 $54.46 -1.10 50.90 +$676 $337,572 

238320 Painting and wall covering contractors 35 $54.46 -0.74 34.26 +$455 $87,294 

238210 Electrical contractors 72 $54.46 -1.53 70.47 +$936 $352,630 

238310 Drywall and insulation contractors 51 $54.46 -1.08 49.92 +$663 $241,151 

Average, Small Construction Establishments 42 $54.46 -0.89 41.11 +$546 $218,092 

531311 Residential Property Managers 121 $54.46 -2.57 118.43 +$1,573 $344,050 

531110 Lessors of Residential Real Estate 94 $54.46 -1.99 92.01 +$1,222 $822,572 

Average, All Industries 51 $54.46 -1.08 49.92 +$663 $290,193 

Source: EPA Calculations 

Small Establishment Compliance Costs and Calculations of Cost-Impact Ratios 

As discussed earlier in this analysis, contractors are expected to pass some of the costs of the rule onto 

their customers, increasing their revenues. The impacts of the rule are measured by a cost-impact ratio 

that compares the total annualized compliance costs per establishment (calculated as the per-event cost of 

compliance multiplied by the new, lower number of events per establishment) to the new revenues that 

account for the higher price charged to consumers and the decrease in the number of renovation events. 

The results are presented in Table 8-14 through Table 8-17. As demonstrated in these tables, under these 

elasticity assumptions, the cost of the rule incurred by small businesses is expected to amount to between 

0.6 and 2.0 percent of their revenues under Options A through C (0.9 percent on average) and between 0.7 

and 2.4 percent of their revenues under the prescriptive Option D (1.1 percent on average). 
402(c) Chapter 8 23 

Table 8-14: Estimated Direct Costs Incurred by Contractors under the RRP Rule and Resulting Cost-Impact Ratios by 

Industry (Option A) 

NAICS Industry Description 

Per-Event 

Compliance 

Cost 

Post-Rule 

Number of 

Regulated 

Events 

Direct Cost 

of Rule 

Incurred by 

Contractor 

Post-Rule 

Contractor 

Revenues 

CostImpact 

Ratio 

236118 Residential remodelers $52.00 32.41 $1,685 $183,302 0.9% 

238170 Siding contractors $52.00 43.21 $2,247 $202,062 1.1% 

238350 Finish carpentry contractors $52.00 30.44 $1,583 $101,060 1.6% 

238290 Other building equipment contractors $52.00 94.27 $4,902 $586,846 0.8% 

238390 Other building finishing contractors $52.00 48.12 $2,502 $231,991 1.1% 

238340 Tile and terrazzo contractors $52.00 35.35 $1,838 $130,500 1.4% 

238220 Plumbing and HVAC contractors $52.00 70.70 $3,676 $433,483 0.8% 

238150 Glass and glazing contractors $52.00 51.06 $2,655 $337,478 0.8% 

238320 Painting and wall covering contractors $52.00 34.37 $1,787 $87,231 2.0% 

238210 Electrical contractors $52.00 70.70 $3,676 $352,500 1.0% 

238310 Drywall and insulation contractors $52.00 50.08 $2,604 $241,059 1.1% 

Average, Small Construction Establishments $52.00 41.24 $2,145 $218,016 1.0% 

531311 Residential Property Managers $52.00 118.82 $6,178 $343,832 1.8% 

531110 Lessors of Residential Real Estate $52.00 92.31 $4,800 $822,403 0.6% 

Average, All Industries $52.00 50.08 $2,604 $290,101 0.9% 

Source: EPA Calculations 

Table 8-15: Estimated Direct Costs Incurred by Contractors under the RRP Rule and Resulting Cost-Impact Ratios by 

Industry (Option B) 

NAICS Industry Description 

Per-Event 

Compliance 

Cost 

Post-Rule 

Number of 

Regulated 

Events 

Direct Cost 

of Rule 

Incurred by 

Contractor 

Post-Rule 

Contractor 

Revenues 

CostImpact 

Ratio 

236118 Residential remodelers $51.17 32.41 $1,659 $183,296 0.9% 

238170 Siding contractors $51.17 43.22 $2,212 $202,055 1.1% 

238350 Finish carpentry contractors $51.17 30.45 $1,558 $101,055 1.5% 

238290 Other building equipment contractors $51.17 94.30 $4,825 $586,830 0.8% 

238390 Other building finishing contractors $51.17 48.13 $2,463 $231,983 1.1% 

238340 Tile and terrazzo contractors $51.17 35.36 $1,810 $130,494 1.4% 

238220 Plumbing and HVAC contractors $51.17 70.72 $3,619 $433,472 0.8% 

238150 Glass and glazing contractors $51.17 51.08 $2,614 $337,470 0.8% 

238320 Painting and wall covering contractors $51.17 34.38 $1,759 $87,225 2.0% 

238210 Electrical contractors $51.17 70.72 $3,619 $352,489 1.0% 

238310 Drywall and insulation contractors $51.17 50.10 $2,563 $241,051 1.1% 

Average, Small Construction Establishments $51.17 41.25 $2,111 $218,010 1.0% 

531311 Residential Property Managers $51.17 118.85 $6,082 $343,812 1.8% 

531110 Lessors of Residential Real Estate $51.17 92.33 $4,725 $822,387 0.6% 

Average, All Industries $51.17 50.10 $2,563 $290,093 0.9% 

Source: EPA Calculations 
402(c) Chapter 8 24 

Table 8-16: Estimated Direct Costs Incurred by Contractors under the RRP Rule and Resulting Cost-Impact Ratios by 

Industry (Option C) 

NAICS Industry Description 

Per-Event 

Compliance 

Cost 

Post-Rule 

Number of 

Regulated 

Events 

Direct Cost 

of Rule 

Incurred by 

Contractor 

Post-Rule 

Contractor 

Revenues 

CostImpact 

Ratio 

236118 Residential remodelers $50.86 32.42 $1,649 $183,294 0.9% 

238170 Siding contractors $50.86 43.22 $2,198 $202,052 1.1% 

238350 Finish carpentry contractors $50.86 30.45 $1,549 $101,053 1.5% 

238290 Other building equipment contractors $50.86 94.31 $4,796 $586,824 0.8% 

238390 Other building finishing contractors $50.86 48.14 $2,448 $231,980 1.1% 

238340 Tile and terrazzo contractors $50.86 35.37 $1,799 $130,492 1.4% 

238220 Plumbing and HVAC contractors $50.86 70.73 $3,597 $433,467 0.8% 

238150 Glass and glazing contractors $50.86 51.08 $2,598 $337,467 0.8% 

238320 Painting and wall covering contractors $50.86 34.38 $1,749 $87,223 2.0% 

238210 Electrical contractors $50.86 70.73 $3,597 $352,484 1.0% 

238310 Drywall and insulation contractors $50.86 50.10 $2,548 $241,048 1.1% 

Average, Small Construction Establishments $50.86 41.26 $2,098 $218,007 1.0% 

531311 Residential Property Managers $50.86 118.87 $6,045 $343,805 1.8% 

531110 Lessors of Residential Real Estate $50.86 92.34 $4,696 $822,381 0.6% 

Average, All Industries $50.86 50.10 $2,548 $290,090 0.9% 

Source: EPA Calculations 

Table 8-17: Estimated Direct Costs Incurred by Contractors under the RRP Rule and Resulting Cost-Impact Ratios by 

Industry (Option D) 

NAICS Industry Description 

Per-Event 

Compliance 

Cost 

Post-Rule 

Number of 

Regulated 

Events 

Direct Cost 

of Rule 

Incurred by 

Contractor 

Post-Rule 

Contractor 

Revenues 

CostImpact 

Ratio 

236118 Residential remodelers $61.17 32.30 $1,976 $183,361 1.1% 

238170 Siding contractors $61.17 43.07 $2,635 $202,141 1.3% 

238350 Finish carpentry contractors $61.17 30.34 $1,856 $101,116 1.8% 

238290 Other building equipment contractors $61.17 93.96 $5,748 $587,019 1.0% 

238390 Other building finishing contractors $61.17 47.96 $2,934 $232,079 1.3% 

238340 Tile and terrazzo contractors $61.17 35.24 $2,156 $130,565 1.7% 

238220 Plumbing and HVAC contractors $61.17 70.47 $4,311 $433,613 1.0% 

238150 Glass and glazing contractors $61.17 50.90 $3,114 $337,572 0.9% 

238320 Painting and wall covering contractors $61.17 34.26 $2,096 $87,294 2.4% 

238210 Electrical contractors $61.17 70.47 $4,311 $352,630 1.2% 

238310 Drywall and insulation contractors $61.17 49.92 $3,054 $241,151 1.3% 

Average, Small Construction Establishments $61.17 41.11 $2,515 $218,092 1.2% 

531311 Residential Property Managers $61.17 118.43 $7,245 $344,050 2.1% 

531110 Lessors of Residential Real Estate $61.17 92.01 $5,628 $822,572 0.7% 

Average, All Industries $61.17 49.92 $3,054 $290,193 1.1% 

Source: EPA Calculations 
402(c) Chapter 8 25 

8.3.6 Impacts on Small Governments 

Similarly to privately-owned businesses, public agencies and authorities that conduct renovation work on 

regulated properties will incur the costs of certification, training and work practice compliance under the 

RRP Rule. Specifically, the rule could potentially affect housing authorities and other governmental 

bodies such as educational institutions operated by small governments that use an in-house crew to 

perform renovation work on their properties that qualify as target housing. 

As noted earlier, public housing authorities that receive funding from the U.S. Department of Housing 

and Urban Development must comply with HUD regulations regarding lead paint, and so are unlikely to 

incur additional costs due to this rule. None of the housing authorities identified in section 8.2.1 as 

operating public housing that does not receive HUD funding qualifies as a small government under the 

Regulatory Flexibility Act. Nor were any colleges or universities operated by small governments 

identified. To the extent that there are any small governments that conduct renovation work on regulated 

properties, the cost of the rule to them is likely to be low. As shown in Table 8-9, under Option B, the 

cost of the rule is estimated to be $51 per event when averaged across all regulated events. The cost per 

event for small governments would be similar. 

8.3.7 Impacts on Small Non-profit Organizations 

The Renovation, Repair and Painting Rule also may affect several types of small non-profit organizations 

that offer housing. These organizations may serve a number of populations, including elderly, recovering 

alcoholics or drug addicts, low-income families, or political refugees. There are also private colleges and 

universities operated by non-profits that provide apartment-style housing for graduate students and 

married students. Non-profit organizations that provide housing and use an on-site crew for renovation 

work in buildings subject to the regulations will incur certification, training and work practice costs. 

The number of non-profits that conduct renovation work on regulated housing units is not known, nor is 

the number of RRP events they conduct that would require lead safe work practices as a result of the rule. 

The cost for small non-profit organizations is likely to be low. As shown in Table 8-9, under Option B, 

the cost of the rule is estimated to be $51 per event when averaged across all regulated events. The cost 

per event for small non-profit organizations would be similar. Some small non-profit organizations (such 

as colleges and universities) may be able to pass some of the costs on to their customers. 

8.3.8 Conclusions 

The RRP Rule is expected to affect, on average, approximately 145,000 small contractors and real estate 

establishments per year under the preferred option. After accounting for the ability of firms to pass some 

of the costs through to their customers, impacts on small businesses are expected to range from 0.6 to 2.0 

percent of revenues under the preferred option. The number of small governments and small non-profits 

affected was not calculated, but the cost per event is expected to be similar to that for businesses. 
402(c) Chapter 8 26 

8.4 Executive Order 13132 - Federalism 

Under Executive Order 13132, entitled Federalism (64 FR 43255, August 10, 1999), EPA must determine 

whether this proposed rule has “federalism implications,” (i.e. whether it has substantial direct effects on 

the states, on the relationship between the national government and the states, or on the distribution of 

power and responsibilities among the various levels of government, as specified in Executive Order 

13132). 

As discussed in Chapter 4, states would be able to apply for, and receive authorization to administer these 

proposed requirements, but would be under no obligation to do so. In the absence of a state authorization, 

EPA will administer these requirements. While the cost analysis assumes that EPA will administer and 

enforce the program in all places, it also assumes that states would incur similar costs if they administer 

and enforce the regulation. 

As discussed in Section 8.2, much of the target housing owned by state governments receives funding 

from HUD, and must already comply with HUD regulations regarding lead paint. These state 

governments are unlikely to incur additional costs due to this rule. The small number of states with 

housing authorities that do not receive HUD funding may incur additional costs due to this rule, as are 

certain other types of entities such as state colleges and universities that operate apartment type housing 

for graduate students and married students. Given the low cost per event, this rule is not expected to have 

a significant impact on states. 

8.5 Executive Order 13175 - Tribal Implications 

Under Executive Order 13175, entitled Consultation and Coordination with Indian Tribal Governments

(59 FR 22951, November 6, 2000), EPA must determine that this proposed rule does not have tribal 

implications (i.e. whether it has substantial direct effects on tribal governments, on the relationship 

between the Federal government and the Indian tribes, or on the distribution of power and responsibilities 

between the Federal government and Indian tribes). Tribes would be able to apply for and receive 

authorization to administer these proposed requirements on Tribal lands, but Tribes would be under no 

obligation to do so. In the absence of a Tribal authorization, EPA will administer these requirements. 

The number of Tribal authorities that conduct renovation work on regulated properties is not known. But 

given the low cost per event, this rule is not expected to have a significant impact on Tribes. 

8.6 Protection of Children from Environmental Health Risk and Safety Risks 

Under Executive Order 13045, a regulation must be reviewed if the regulatory action is economically 

significant and concerns an environmental health risk or safety risk that may disproportionately affect 

children. Since children are particularly susceptible to the IQ loss and adverse health effects caused by 

exposure to lead dust, a significant objective of the RRP regulation is the protection of children’s health. 

All four of the regulatory options cover all children living in regulated homes where RRP events occur; 

the options differ in terms of the definition of regulated homes. Option C (units built before 1950) covers 

the fewest housing units (and thus the fewest children) in year one, while Option A (units built before 

1978) covers the largest number of housing units and thus children in year one. The options are identical 

in terms of number of children covered in year two and beyond. As shown in Table 8-18, Options B and 

D cover about 85% of potentially affected children in the first year, while Option C covers about 66%. 
402(c) Chapter 8 27 

Thus substantially more children are protected in the first year of the rule under option A than under any 

other Option. This difference disappears in year two. 

Table 8-18: Number of Children Under 6 Residing in Affected 

Housing by Option and Year of Rule – Units 

where RRP take place and LBP present a

First Year of the Rule 

Second Year and 

Each Subsequent 

Year of the Rule 

Option 

Number Percent of 

Option A Number Percent of 

Option A 

Option A 786,562 100% 783,337 100% 

Option B 668,010 85% 783,337 100%

Option C 519,941 66% 783,337 100%

Option D 668,010 85% 783,337 100%

a. These data have been adjusted downward to account for 

the baseline level of lead-safe work practice use. 

Source: EPA Estimates – see chapter 5

8.7 Executive Order 13211 - Energy Effects 

Under the Executive Order 13211, entitled Actions concerning Regulations that Significantly Affect 

Energy Supply, Distribution, or Use (66 FR 28355, May 22, 2001), EPA must identify actions that will 

have a significant adverse energy effect. Adverse effects are defined as: 

1. Reductions in crude oil supply in excess of 10,000 barrels per day; 

2. Reductions in fuel production in excess of 4,000 barrels per day; 

3. Reductions in coal production in excess of 5 million tons per year; 

4. Reductions in natural gas production in excess of 25 million mcf per year; 

5. Reductions in electricity production in excess of 1 billion kilowatt-hours per year or in excess of 

500 megawatts of installed capacity; 

6. Increases in energy use required by the regulatory action that exceed any of the thresholds above; 

7. Increases in the cost of energy production in excess of one percent; 

8. Increases in the cost of energy distribution in excess of one percent; or 

9. Other similarly adverse outcomes. 

The regulations under consideration will not significantly reduce energy production nor significantly 

increase energy costs. 

8.8 National Technology Transfer and Advancement Act 

Section 12(d) of the National Technology Transfer and Advancement Act of 1995 (“NTTAA”), Public 

Law No. 104-113, 12(d) (15 U.S.C. 272 note) directs EPA to use voluntary consensus standards in its 

regulatory activities unless to do so would be inconsistent with applicable law or otherwise impractical. 

Voluntary consensus standards are technical standards (e.g., materials specifications, test methods, 

sampling procedures, and business practices) that are developed or adopted by voluntary consensus 

standards bodies. The NTTAA directs EPA to provide Congress, through OMB, explanations when the 

Agency decides not to use available and applicable voluntary consensus standards. 
402(c) Chapter 8 28 

As detailed in Chapter 4, EPA is proposing to adopt a number of work practice requirements that could be 

considered technical standards for performing renovation projects in residences that contain lead-based 

paint. EPA is not proposing, however, to require traditional clearance examinations, including dust 

sampling, following renovation projects. Instead, it is proposing to require that a visual inspection for 

dust, debris, and residue be conducted after cleaning and before post-renovation cleaning verification is 

performed. 

8.9 Executive Order 12898 – Environmental Justice 

Under Executive Order 12898, when promulgating a regulation, EPA investigates whether there are 

disproportionately high and adverse human health or environmental effects on minority and low income 

populations. The proposed regulation requires that contractors, when undertaking renovation activities in 

regulated housing, reduce the risk of exposure to lead by employing the use of safe work practices. In 

addition, contractors are required to undertake cleaning verification at the end of each project. 

This environmental justice analysis looks at the distribution of renovation events and individuals 

protected across three race and two income groups. Although it would be preferable to perform a joint 

environmental justice analysis for the race and income groups, relevant data was not available to make 

these population inferences. Therefore, the analysis was performed separately for the race and income 

groups. 

Overall, the disadvantaged groups considered appear to have similar distributions of households and 

individuals affected under the various options. However, since these disadvantaged groups are more 

likely to reside in rental and older housing they are more likely to be affected under the options that 

emphasize regulating older and/or rental housing. In addition, individuals and children with food 

insecurity (i.e. those who do not have healthy diets or do not eat enough because of poverty) are more 

susceptible to ill health effects from lead dust. Thus, they stand to accrue greater benefits under all of the 

options considered. 

Following the work practice, cleaning, and cleaning verification steps in the rule will increase costs for 

renovation, repair and painting activities in housing covered by the rule. These additional costs may lead 

some lower income homeowners or some landlords of properties in lower income neighborhoods to avoid 

using certified renovators or recommended practices. The incremental costs of the rule’s work practices 

range from $23 to $528, depending on the size of the work area, not including the cost of the lead-based 

paint test kit. These costs are likely to be a small part of the total cost of the renovation, repair, and 

painting projects. EPA believes that these costs are unlikely to result in significant changes in consumer 

behavior. If however, the increased costs result in more projects being undertaken by uncertified firms or 

by do-it-yourselfers, the risks in these instances would be the same as in the baseline and would not 

constitute new risks resulting from the rule. EPA believes that the rule would result in new risks only if 

the increased costs caused individuals to delay work such as painting until lead-based paint began peeling 

and chipping, creating a lead hazard. This is expected to occur infrequently given the rule’s low cost per 

event. 

Low Income: 

For the purposes of this analysis, EPA defines low income individuals as individuals who reside below 

the level set by the federal government’s official poverty definition. Based on data from the 2000 

Decennial Census, 12.4% of individuals were living below the poverty level (U.S. Census Bureau 2000f). 
402(c) Chapter 8 29 

It is therefore relevant to determine if the potential costs and benefits resulting from the proposed RRP 

regulations will have a disproportionately greater effect on low income individuals. 

The data in Table 8-19 compares the relative numbers of householders below the poverty level who are 

owners and renters. As is evident from the data, low income individuals are much more likely to be 

renters than homeowners. For each definition of old housing listed (i.e. pre-198014, pre-1960, pre-1950), 

it is more than three times more likely that a renter of old housing will be a low income individual than it 

is for an owner. The number of low income householders living below poverty in rental housing is 

almost double the number who are living in owned housing. Further, out of all pre-2000 rental 

households, 17% of individuals reside below the poverty level and in pre-1980 rental housing units. 

Because of the disproportionately high number of low income individuals living in rental housing, it is 

reasonable to conclude that a rule affecting all pre-1978 rental housing will benefit a significant 

proportion of low income families in housing where lead-based paint is disturbed by RRP activities. 

Table 8-19: Number and Percentage of Householders Below Poverty by Year Housing Built by Tenure 

 Owner Occupied Housing Renter Occupied Housing 

Year 

Housing 

Built

Total Below Poverty 

Percentage Below 

Poverty Out of All 

Pre-2000 Owner 

Housing 

Total Below Poverty

Percentage Below 

Poverty Out of All 

Pre-2000 Rental 

Housing

Pre-2000 4,371,712 6.26% 8,086,254 22.67% 

Pre-1980 3,133,302 4.49% 6,059,817 16.99% 

Pre-1960 1,765,185 2.53% 3,100,214 8.69% 

Pre-1950 1,167,604 1.67% 2,093,142 5.87% 

Source: U.S. Census Bureau 2000g.

Race: 

The 2000 Census data shows that Black/African American individuals and Asian individuals tend to 

reside in rental housing more than White individuals. The data in Table 8-20 compares the percentages of 

owners and renters for three categories of race, “White Alone,” “Black/African American Alone,” and 

“Asian Alone.” Compared with 28.73% of White individuals who resided in rental housing in 2000, 

53.67% and 46.76% of Black/African American and Asian individuals, respectively, resided in rental 

housing. Also, in 2000, there were more Black/African American individuals who were renters than 

owners. Thus, an RRP regulation aimed at rental housing will serve to benefit these minority groups. 

Although no data were available for race by age of housing unit, this analysis uses pre-2000 housing to 

provide a general idea of these proportions. 

 

14 Note: For the purposes of this analysis, since Census data are not available for the category of all pre-1978 

housing, pre-1980 housing data is used to approximate pre-1978 housing.
402(c) Chapter 8 30 

Table 8-20: Number and Percentage of Householders by Race by Tenure in 2000

Race Total Percentage Owner Percentage Renter 

White Alone 83,715,168 71.27% 28.73% 

Black/African American Alone 11,977,309 46.33% 53.67% 

Asian Alone 3,117,356 53.24% 46.76% 

Source: U.S. Census Bureau 2000h. 

Conclusions 

The Renovation, Repair and Painting Rule seeks to protect both children and adults residing in rental 

target housing units or owner-occupied target housing units where a child under the age if six resides 

from exposure to lead during renovation work. As such, EPA concludes that the rule will not lead to 

disproportionately high and adverse human health or environmental effects on minority and low income 

populations. On the contrary, since a larger percentage of poor and minority households reside in rental 

housing, they may reap a greater share of the benefits. 
402(c) Chapter 8 31 

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