# A STATEMENT BY THE



# C ENTERS FOR 

# D ISEASE 

# C ONTROL AND 

# P REVENTION



# A UGUST 

# 2005

**U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES**

Centers for Disease Control and Prevention 

# Preventing

Lead Poisoning

in

Young

Children

# Preventing

Lead Poisoning

in

Young Children

A Statement by the Centers for Disease Control and Prevention

August 2005

Centers for Disease Control and Prevention

Julie L. Gerberding, MD, MPH, Director

National Center for Environmental Health

Tom Sinks, PhD, Acting Director

Division of Emergency and Environmental Health Services

Jim Rabb, Acting Director

Lead Poisoning Prevention Branch

Mary Jean Brown, ScD, RN, Chief



# U.S. Department of Health

and Human Services, Public Health Service

Suggested reference:

Centers for Disease Control and Prevention. Preventing Lead Poisoning in Young Children. Atlanta:

CDC; 2005.

# iii 

# Table of Contents

Advisory Committee on Childhood Lead Poisoning Prevention

Members, Ex-Offi cio and Liaison Representatives

...................................................... v

Preface

........................................................................................................................... ix

Introduction

.................................................................................................................... 1

Preventing Childhood Lead Poisoning in the United States

....................................... 1

CDC’s Blood Lead Level of Concern

.............................................................................. 2

Responding to Data on Adverse Health Effects at Blood Lead

Levels <10 μg/dL from a Public Health Perspective

.................................................... 3

Recommendations

.......................................................................................................... 5

Conclusion

...................................................................................................................... 8

References

...................................................................................................................... 8

Appendix: A Review of Evidence of Adverse Health Effects

Associated with Blood Lead Levels <10 μg/dL in Children

....................................... 11

Appendix Table of Contents

............................................................................ i

Summary

........................................................................................................ iii

Work Group Members

.................................................................................... vi

Abbreviations and Acronyms

....................................................................... vii

Background

..................................................................................................... 1

Review Methods

.............................................................................................. 4

Results

............................................................................................................. 8

Discussion

..................................................................................................... 13

Overall Conclusions

...................................................................................... 29

Research Needs

............................................................................................. 32

Appendix A: Literature Review and Classifi cation Update

....................... A-1

Appendix B: Critique of NHANES III Data by Stone, et al. (2003)

.......... B-1

References

.................................................................................................... R-1

# v 

# Advisory Committee on Childhood Lead Poisoning

Prevention Members, Ex-Offi cio

and Liaison Representatives

CHAIR

Carla Campbell, MD, MS

The Children’s Hospital of Philadelphia

Philadelphia, Pennsylvania

EXECUTIVE SECRETARY

Mary Jean Brown, ScD, RN

Chief, Lead Poisoning Prevention

Branch

National Center for Environmental

Health

Centers for Disease Control

and Prevention

Atlanta, Georgia

MEMBERS

William Banner, Jr. MD, PhD

The Children’s Hospital at Saint Francis

Tulsa, Oklahoma

Helen J. Binns, MD, MPH*

Children’s Memorial Hospital

Chicago, Illinois

Walter S. Handy, Jr., PhD

Cincinnati Health Department

Cincinnati, Ohio

Ing Kang Ho, PhD

University of Mississippi Medical

Center

Jackson, Mississippi

Jessica Leighton, PhD, MPH

New York City Department of Health

& Mental Hygiene

New York, New York Valarie Johnson

Urban Parent to Parent

Rochester, New York

Tracey Lynn, DVM, MPH†

Alaska Department of Health

and Social Services

Anchorage, Alaska

Sally Odle

SafeHomes, Inc.

Waterbury, Connecticut

George G. Rhoads, MD, MPH

University of Medicine and Dentistry

of New Jersey

Piscataway, New Jersey

Catherine M. Slota-Varma, MD

Pediatrician

Milwaukee, Wisconsin

Wayne R. Snodgrass, PhD, MD

University of Texas Medical Branch

Galveston, Texas

Kevin U. Stephens, Sr., MD, JD

New Orleans Department of Health

New Orleans, LA

Kimberly M. Thompson, ScD

Harvard School of Public Health

Boston, Massachusetts

*ACCLPP member until May 2004

†ACCLPP member until October 2004

# vi EX-OFFICIO

Centers for Disease Control

and Prevention

Robert J. Roscoe, MS

Centers for Medicare and

Medicaid Services

Jerry Zelinger, MD

National Institute for Occupational

Safety and Health Sciences

Walter Rogan, MD

U.S. Agency for International

Development

John Borrazzo, PhD

U.S. Consumer Product Safety

Commission

Lori Saltzman

U.S. Department of Housing and

Urban Development

David E. Jacobs, Ph.D., CIH

U.S. Environmental Protection Agency

Jacqueline E. Mosby, MPH

U.S. Food and Drug Administration

Michael P. Bolger, PhD

LIAISON REPRESENTATIVES

Alliance for Healthy Homes

Anne M. Guthrie, MPH

American Academy of

Nurse Practitioners

Jan Towers, PhD

American Academy of Pediatrics

J. Routt Reigart, II, MD (1997-2004) American Association of Poison

Control Centers

George C. Rodgers, Jr., MD, PhD

American Industrial Hygiene Association

Steve M. Hays, CIH, PE

American Public Health Association

Ben Gitterman, MD

Association of Public Health Laboratories

Henry Bradford, Jr., PhD

Council of State and Territorial

Epidemiologists

Ezatollah Keyvan-Larijani, MD, DrPH

National Center for Healthy Housing

Pat McLaine, RN, MPH

REVIEW OF EVIDENCE FOR

EFFECTS AT BLLS <10 μg / dL WORK

GROUP

Michael L. Weitzman, MD

Work Group Chair

Center for Child Health Research

University of Rochester

Tom Matte, MD, MPH

National Center for

Environmental Health

Centers for Disease Control

and Prevention

David Homa, PhD

National Center for

Environmental Health

Centers for Disease Control

and Prevention

Jessica Sanford, PhD

Battelle Memorial Institute

# vii Alan Pate

Battelle Memorial Institute

Joel Schwartz, Ph.D.

Department of Environmental Health

Harvard School of Public Health

David Bellinger, PhD,

Neuroepidemiology Unit Children’s

Hospital

Harvard Medical School

David A. Savitz, PhD

Department of Epidemiology

University of North Carolina School

of Public Health

Carla Campbell, MD, MS

Division of General Pediatrics

The Children’s Hospital of Philadelphia Patrick J. Parsons, PhD

Wadsworth Center for Laboratories

and Research

New York State Department of Health

Betsy Lozoff, MD

Center for Human Growth and

Development

University of Michigan

Kimberly Thompson, ScD

Department of Health Policy

and Management

Harvard School of Public Health

Birt Harvey, MD

Pediatrician

Palo Alto, California

# ix 

# Preface

This is the fi fth revision of Preventing Lead Poisoning in Young Children by

the Centers for Disease Control and Prevention (CDC). As with the previous

statements, the recommendations presented here are based on scientifi c evidence

and practical considerations. This revision accompanies a companion document,

A Review of Evidence of Adverse Health Effects Associated with Blood Lead Levels

<10 μg/dL in Children , developed by Advisory Committee on Lead Poisoning

Prevention which reviews the scientifi c evidence for adverse effects in children at

blood lead levels below 10 μg/dL.

The data demonstrating that no “safe” threshold for blood lead levels (BLLs)

in young children has been identifi ed highlights the importance of preventing

childhood exposures to lead. It confi rms the need for a systematic and society wide

effort to control or eliminate lead hazards in children’s environments before they

are exposed. This emphasis on primary prevention, although not entirely new , is

highlighted here and is clearly the foremost action supported by the data presented

in A Review of Evidence of Adverse Health Effects Associated with Blood Lead Levels

<10 μg/dL in Children.

Although there is evidence of adverse health effects in children with blood lead

levels below 10 μg/dL, CDC has not changed its level of concern, which remains

at levels > 10 μg/dL. We believe it critical to focus available resources where the

potential adverse effects remain the greatest. If no threshold level exists for adverse

health effects, setting a new BLL of concern somewhere below 10 μg/dL would

be based on an arbitrary decision. In addition, the feasibility and effectiveness

of individual interventions to further reduce BLLs below 10 μg/dL has not been

demonstrated.

CDC is conducting several activities to focus efforts on preventing lead exposures

to children. First, beginning in 2003, CDC required state and local health

departments receiving funding for lead poisoning prevention activities to develop

and implement strategic childhood lead poisoning elimination plans. Second, CDC

and its federal partners, the Department of Housing and Urban Development and

the Environmental Protection Agency, launched new initiatives to control leadbased paint hazards in the highest risk housing, addressing where successive cases

of lead poisoning have been identifi ed. Third, CDC and other federal agencies are

developing a systematic and coordinated response to identify and eliminate nonpaint sources of exposure (e.g., lead jewelry, food and traditional medicines, and

cosmetics).

CDC continues to monitor progress toward the Healthy People 2010 objective of

eliminating elevated BLLs in children at the national level through the National

Health and Nutritional Examination Survey and at the state and local levels

through the blood lead surveillance system. These complementary data provide

# x essential information for the rational distribution of resources to communities with

the highest risk for lead exposure.

I wish to thank both current and former members of the Advisory Committee on

Childhood Lead Poisoning Prevention and consultants who developed the documents in this statement and acknowledge their contribution to the health of the

nation’s children. The Committee considered a number of controversial issues,

examined the existing data and reviewed the report of the work group. This 2005

statement represents agreement of 12 of the 13 Advisory Committee members serving on the committee as of October 19-20, 2004.

Thomas Sinks, Ph.D.

Acting Director

National Center for Environmental Health/Agency for Toxic Substances

and Disease Registry

# 1 INTRODUCTION

The U.S. Department of Health and Human Services has established an ambitious

goal of eliminating elevated blood lead levels (BLLs) in children by 2010, a

qualitatively different goal from earlier goals that focused on reducing the BLL

considered toxic by various target amounts. 1 

# Recent research on lead’s health effects

at low levels, which suggests societal benefi ts from preventing even low level lead

exposure in childhood, underscores the importance of this public health goal.

This revised statement describes the public health implications of research fi ndings

regarding adverse health effects at low BLLs summarized in the accompanying

review, and focuses on the Centers for Disease Control and Prevention’s blood lead

“level of concern.” This statement aims to guide public health practice and policy

development and review necessary steps to ensure progress toward meeting the

2010 goal.

PREVENTING CHILDHOOD LEAD POISONING IN THE UNITED STATES

The reduction of BLLs in the United States during 1970-1999, primarily because of

implementation of federal and state regulations to control lead exposure, was one

of the most signifi cant public health successes of the last half of the 20th century. 2



# Nonetheless, some populations and geographic areas remain at disproportionately

high risk for lead exposure. 3-5 

# Specifi c strategies that target screening to high-risk

children are essential to identify children with BLLs > 10 μg/dL. Once identifi ed,

children with elevated BLLs should receive follow-up services as recommended in

Managing Elevated Blood Lead Levels Among Young Children

. 6



# However, preventing elevated BLLs is the preferred course of action. A compelling

body of evidence points to the limited effectiveness of waiting until children’ s BLLs are elevated before intervening with medical treatments, environmental

remediation, or parental education. 7-12 

# Data indicate that in many cases it takes

years to reduce children’s BLLs once levels are elevated whether the initial blood

lead elevation is very high or moderate. 13-15 

# The most common high-dose sources of

lead exposure for U. S. children are lead-based paint and lead-contaminated house

dust and soil. Recent studies have identifi ed methods to reduce common household

lead hazards safely. 16 

# Thus, a multitiered approach that includes secondary

prevention through case identifi cation and management of elevated BLLs is needed

to eliminate childhood lead poisoning. However, because no level of lead in a child’s

blood can be specifi ed as safe, primary prevention must serve as the foundation of

the effort.

# 2 CDC’S BLOOD LEAD LEVEL OF CONCERN

The adverse health effects associated with elevated BLLs have been widely studied

and documented. Previously, CDC responded to the accumulated evidence of

adverse effects associated with lead exposures by lowering the BLL of concern.

Between 1960 and 1990 the blood lead level for individual intervention in children

was lowered from 60 μg/dL to 25 μg/dL. In 1991 the CDC recommended lowering

the level for individual intervention to 15 μg/dL and implementing communitywide primary lead poisoning prevention activities in areas where many children

have BLLs > 10 μg/dL. 17 

# Some activities, such as taking an environmental history,

educating parents about lead, and conducting follow-up blood lead monitoring

were suggested for children with BLLs of > 10 μg/dL. 7 

# However, this level, which

was originally intended to trigger communitywide prevention activities, has been

misinterpreted frequently as a defi nitive toxicologic threshold.

As the accompanying review of recent studies indicates, additional evidence exits of

adverse health effects in children at BLLs <10 μg/dL. The available data are based

on a sample of fewer than 200 children whose BLLs were never above 10 μg/dL and

questions remain about the size of the effect.

At this time there are valid reasons not to lower the level of concern established in

1991 including the following:

• No effective clinical or public health interventions have been identifi ed that

reliably and consistently lower BLLs that already are <10 μg/dL. Nonetheless,

the sources of lead exposure and the population-based interventions that can

be expected to reduce lead exposure are similar in children with BLLs <10 μg/

dL and > 10 μg/dL, 18 

# so preventive lead hazard control measures need not be

deferred pending further research fi ndings or consensus.

• No one threshold for adverse effects has been demonstrated. Thus the process for

establishing a lower level of concern would be arbitrary and no particular BLL

cutoff can be defended on the basis of the existing data. In addition, establishing

a lower level of concern may provide a false sense of safety about the well being

of children whose BLLs are below the threshold.

• The adverse health effects associated with elevated BLLs are subtle. Individual

variation in response to exposure and other infl uences on developmental status,

make isolating the effect of lead or predicting the overall magnitude of potential

adverse health effects exceedingly diffi cult.

• Establishing a level of concern substantially <10 μg/dL probably would be

accompanied by a sharp increase in misclassifi cation of children as having an

elevated BLL. The uncertainty associated with laboratory testing is too great

to ensure that a single blood lead test reliably classifi es individual children at

# 3 levels <10 μg/dL. This misclassifi cation could confuse both parents and clinicians

and expenditure of resources on testing that does not aid decision making.

• Efforts to identify and provide services to children with BLLs <10 μg/dL may

defl ect needed resources from children with higher BLLs who are likely to

benefi t most from individualized interventions.

• Efforts to eliminate lead exposures through primary prevention have the

greatest potential for success. Reducing exposures will benefi t all children,

regardless of their current BLL.

RESPONDING TO DATA ON ADVERSE HEALTH EFFECTS AT BLOOD LEAD

LEVELS <10 μg/dL FROM A PUBLIC HEALTH PERSPECTIVE

Since 1991, CDC has emphasized the need to make primary prevention of lead

poisoning, through interventions that control or eliminate lead hazards before

children are exposed

, a high priority for health, housing, and environmental

agencies at the state, local, and federal levels. 18-20 

# Federal and state policies and

programs, largely as the result of Title X of the 1992 Housing and Community

Development Act (Public Law 102-550), increasingly have focused on the need

for primary prevention using strategies known to effectively reduce residential

lead hazards. 21 

# Research fi ndings also indicate that primary prevention would be

expected to benefi t all children at high risk because communities with the largest

percentages of children with BLLs > 20 μg/dL also have the largest percentage

of children with BLLs that are lower but still above the national average of

approximately 2 μg/dL. 18 

# These data underscore the importance of targeting efforts

to communities where risk for exposure is highest and provide a strong rationale

for primary prevention efforts. The strategies described below will effectively direct

efforts to achieve the Healthy People 2010 objective to eliminate lead poisoning in

young children and can be expected to reduce lead exposure for all children. 1



# Primary Prevention

CDC’s Advisory Committee on Childhood Lead Poisoning Prevention recently issued

updated recommendations calling for the nation to focus on primary prevention

of childhood lead poisoning. 22 

# Because the 2010 health objective of eliminating

childhood lead poisoning can be achieved only through primary prevention, 22 

# this

document provides important guidance to state and local agencies regarding the

implementation of primary prevention activities. Given that the most important

measure of a successful primary prevention strategy is elimination of lead exposure

sources for young children, we focus here on the two main exposure sources for

children in the United States: lead in housing and non-essential uses of lead in

other products.

# 4 Lead in Housing -Because lead-based paint is the most important source of lead

exposure for young children, the fi rst essential element of primary prevention is

implementation of strategies to control lead paint-contaminated house dust and

soil and poorly maintained lead paint in housing. 23-25 

# After 10 or more years of

widespread blood lead testing and data collection by CDC-supported state and local

agencies, the specifi c addresses of housing units at which children repeatedly have

been identifi ed with elevated BLLs are known to local offi cials. Two examples are:

• In Detroit, 657 addresses accounted for nearly 1,500 children with BLLs > 20

μg/dL during the last 10 years because the sources of lead were never controlled

completely when the initial case occurred. These housing units also probably

were the source of lead exposure for several thousand Detroit children with

BLLs > 10 μg/dL. 26



# • In Louisville, Kentucky, 35% of children identifi ed with elevated BLLs during

the last 5 years resided in 79 housing units; these units represent <0.3% of all

housing units in the community. 27



# These experiences are repeated in high-risk communities across the country . The

infrastructure needed to identify high-risk housing and to prevent and control

lead hazards in such housing is largely in place. Established fi rms certifi ed in

lead hazard evaluation and control now exist in most communities, as do other

skilled trades people trained in lead-safe work practices necessary during routine

maintenance and painting. Systematic identifi cation and reduction of residential

lead sources, particularly in old, poorly maintained housing where children with

elevated BLLs are known to have lived, combined with periodic monitoring of

housing conditions to detect new deterioration and resultant lead hazards will

prevent lead exposure to children in the future and break the cycle of repeated cases

of elevated BLLs.

Other steps critical to success in controlling lead hazards in housing and preventing

lead exposure in the future are 1) enforcement of lead safety and housing code

requirements to ensure good property maintenance; 2) widespread adoption of leadsafe work practices to control, contain, and clean up lead dust during painting and

remodeling projects; and 3) periodic monitoring of housing conditions to detect new

deterioration and resultant lead hazard.

Nonessential Uses of Lead -Because areas of the United States report that as

many as 35% of children identifi ed with elevated BLLs have been exposed to items

decorated or made with lead, in some cases resulting in life-threatening BLLs, 28



# the second crucial element of a primary prevention strategy is identifi cation and

restriction or elimination of nonessential uses of lead, particularly in both imported

and domestically manufactured toys, eating and drinking utensils, cosmetics, and

traditional medicines. This effort requires identifying communities where cultural

practices and traditional medicines may put children at risk and incorporating

# 5 lead poisoning prevention activities into health and community services that

reach families at high risk for lead exposure from nonpaint sources. 7 

# The 2010

health objective cannot be achieved without a more systematic approach that, at

a minimum, allows identifi cation of lead-contaminated items and prohibits their

sale before children are exposed. Ultimately, all nonessential uses of lead should be

eliminated.

RECOMMENDATIONS

Changes in the Focus of CDC-Funded Programs

To achieve these goals, CDC is focusing on eliminating childhood lead poisoning by

preferentially funding programs to provide lead-related services for communities

and populations with large numbers of children at high risk for lead exposure. The

cooperative agreements with 42 state and local health departments funded for 2003-

2006 emphasize the importance of primary prevention and require funded state

and local programs to work aggressively to develop and implement the necessary

partnerships, programs and activities. CDC requires its state and local partners

to undertake a strategic planning process, which includes gathering input from

housing professionals, pediatric health-care providers, advocacy groups, parents of

children with elevated BLLs, and others interested in preventing lead poisoning

in children. These strategic plans, developed by local partners to respond to local

conditions, drive primary prevention activities for the 3-year grant cycle.

Progress toward eliminating childhood lead poisoning can be measured only by

ongoing surveillance of BLLs in childhood populations where the risk for exposure

is high, as well as continued monitoring of population-based BLLs through the

National Health and Nutrition Examination Survey. 29 

# CDC’s role in supporting

state and local efforts and providing technical assistance to improve data

management and reporting is essential to these activities.

Recommendations to Federal, State, and Local Government Agencies

Achieving the Healthy People 2010 objective to eliminate childhood lead poisoning

requires collaboration by many different federal, state and local agencies. Many

of the roles and responsibilities for federal partners in the elimination effort are

detailed in the report of the President’s Task Force on Environmental Health

Risks and Safety Risks in Children. 29 

# However, all levels of government share

responsibility for primary prevention of childhood lead poisoning. Government

agencies have the ability, through legislative and enforcement actions to spearhead

prevention efforts and articulate clear public health goals and strategic priorities at

the federal, state, and local government levels.

Federal agencies should:

1. Support and disseminate information about, and adequately fund, programs and

interventions that will lead to full implementation of primary prevention.

# 6 2. Expand fi nancial resources for permanent measures to control or eliminate

residential lead hazards.

3. Monitor and enforce regulations controlling lead content of various

environmental media, including air, water, and soil.

4. Identify populations in which the risk for exposure to nonpaint sources of lead is

high, and develop strategies to minimize the risk.

5. Develop and implement regulatory and voluntary strategies to control

nonessential uses of lead, particularly in items that are easily accessible to

young children, such as toys, jewelry, eating and drinking utensils, traditional

remedies, and cosmetics.

6. Evaluate the effectiveness of primary prevention activities in reducing lead

exposure and eliminating childhood lead poisoning, particularly in areas where

the risk for lead poisoning is substantially higher than for the general U. S.

childhood population.

7. Develop new mathematical models of lead exposure or modify existing models,

e.g., the Integrated Exposure Uptake and BioKinetic (IEUBK) Model for lead in

children, currently used to establish thresholds for lead exposure in consumer

products and areas with pervasive lead contamination. The exposure modeling

should predict the magnitude of the increase in BLLs in a child as a result of

exposure to a specifi c lead source rather than the probability of a BLLs > 10 μg/dL.

State and local agencies should:

1. Update or establish and enforce regulatory requirements for lead safe housing

that link lead safety to the housing and/or sanitary code.

2 Require that properties that have undergone lead paint abatement or

substantial renovation to lead painted surfaces meet the EPA dust clearance

testing prior to re-occupancy. Require dust testing in all cases where public

health agencies have ordered paint repair, particularly in the homes of children

already identifi ed with elevated BLLs.

3 Promote broad use of lead-safe work practices for routine painting and

maintenance projects in older homes, and make training in such practices widely

available at low or no cost to painters, remodelers, landlords, and maintenance

workers.

4. Establish formal agreements among health, social services, housing, and legal

agencies to increase the sharing of data, educational information, violations, and

success stories.

# 7 5. Provide information to caregivers about temporary measures that can reduce

lead exposure as described in Managing Elevated Blood Lead Levels Among

Young Children, 6 

# as well as information and referral for permanent abatement

services.

Recommendations to Health-Care Providers and Community-Based Health

and Social Service Agencies

CDC recommends that health care providers continue their traditional role of

providing anticipatory guidance as part of routine well-child care, assessing risk for

exposure to lead, conducting blood lead screening in children, and treating children

identifi ed with elevated BLLs. In addition health-care and social service providers

are urged to expand their roles. They should keep abreast of research data that

clarify the relationship between lead exposure and neurocognitive development

in children. They also can strongly advocate for children and foster lead exposure

prevention by helping facilitate implementation of the specifi c strategic plans to

eliminate childhood lead poisoning in their local and state communities. Health-care

and social service providers are highly effective child advocates, and their active

participation in the process provides the expertise and leadership needed to reach

this goal. Health-care and social service providers should:

1. Provide culturally appropriate education to all pregnant women and to families

with young children about the principal sources of lead and ways to reduce

exposure.

2. Target outreach, education, and screening programs to populations with the

greatest risk for lead exposure.

3. Become aware of, and actively support, lead poisoning elimination efforts in the

community.

4. Express concern to federal, state, and local policy and decision makers that

children live in a lead safe environment and actively support legislation and

regulatory initiatives. Advocate for lead-safe, affordable housing by supporting

appropriate legislation.

5. Become aware of and comply with lead screening policies issued by Medicaid or

state and local health departments.

6. Ensure training of staff members engaged in housing renovation or

rehabilitation in lead-safe work practices.

# 8 CONCLUSION

The Healthy People 2010 objective to eliminate BLLs >10 μg/dL in children is

within our grasp. Research to further characterize and isolate the harmful effects

of lead associated with various BLLs will help answer remaining questions

and further refi ne the public health response. However, the approach needed is

clear: identify and address existing lead hazards before children are exposed,

otherwise hundreds of thousands of children will be placed at risk needlessly

. The overall reduction of lead in the environment will benefi t all children.

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dust lead, interior house dust lead and childhood lead exposure in an urban environment. In:

Trace Substances in Environmental Health; Proceedings of the University of Missouri’s annual

Conference on Trace Substances in Environmental Health. St. Louis: University of Missouri;

1987;20:322–32.

24 

# Lanphear BP, Matte TD, Rogers J, Clickner RP, Dietz B, Bornschein RL, et al. The contribution of

lead-contaminated house dust and residential soil to children’s blood lead levels. A pooled analysis

of 12 epidemiologic studies. Environ Res 1998;79:51–68.

25 

# Manton WI, Angle CR, Stanek KL, Reese YR, Kuehnemann TJ. Acquisition and retention of lead

by young children. Environ Res 2000;82:60–80.

26 

# Wendland-Bowyer W. Worst Michigan Neighborhoods: Lead-poisoned blocks pinpointed. Detroit

Free Press 2003 July 29;1.

# 10 27 

# Meyer PA, Staley F, Staley P, Curtis J, Blanton C, Brown MJ. Improving strategies to prevent

childhood lead poisoning using local data. Int J Hyg Environ Health In Press 2005.

28 

# CDC. Brief report: Lead poisoning from ingestion of a toy necklace —Oregon, 2003. MMWR

2004;53:509–11.

29 

# President’s Task Force on Environmental Health Risks and Safety Risks to Children. Eliminating

childhood lead poisoning: A federal strategy targeting lead paint hazards. Washington, DC:

President’s Task Force on Environmental Health Risks and Safety Risks to Children; 2004.

# 11 

# APPENDIX

A REVIEW OF EVIDENCE OF ADVERSE HEALTH EFFECTS

ASSOCIATED WITH BLOOD LEAD LEVELS <10 μ 

# g/dL IN CHILDREN

Reported by

Work Group of the Advisory Committee on

Childhood Lead Poisoning Prevention

to

CENTERS FOR DISEASE CONTROL AND PREVENTION

National Center for Environmental Health

AUGUST 2005

# i 

# Appendix Table of Contents

Page

SUMMARY

.................................................................................................................... iii

WORK GROUP MEMBERS

......................................................................................... vi

ABBREVIATIONS AND ACRONYMS

........................................................................ vii

BACKGROUND

............................................................................................................. 1

REVIEW METHODS

..................................................................................................... 4

RESULTS

....................................................................................................................... 8

Studies Relating Postnatal Lead Exposure to IQ or

General Cognitive Index

.................................................................................... 8

Studies of Health Endpoints Other than IQ and CGI

....................................... 10

DISCUSSION

............................................................................................................... 13

Biologic Plausibility

............................................................................................. 14

Blood Lead Measurement

.................................................................................... 17

Blood Lead Age Trend, Tracking, and Inference Concerning

Blood Lead-Effect Relations in Children

......................................................... 18

Quality of Neurobehavioral Assessments

........................................................... 21

Potential Confounding Factors

........................................................................... 23

Causal Direction

.................................................................................................. 28

OVERALL CONCLUSIONS

........................................................................................ 29

RESEARCH NEEDS

................................................................................................... 32

APPENDIX A: LITERATURE REVIEW AND CLASSIFICATION UPDATE

......... A-1

APPENDIX B: CRITIQUE OF NHANES III DATA BY STONE, ET AL. (2003)

.... B-1

REFERENCES

............................................................................................................ R-1

# ii List of Figures

Figure 1. Expected variation in regression slopes given hypothetical “true”

threshold blood lead–IQ relation (A).

......................................................... 33

Figure 2. Cognitive Function Regression Coeffi cients for Blood Lead Age

< 2 years and Outcome Age > 4 years

........................................................... 35

Figure 3. Cognitive Function Regression Coeffi cients for Blood Lead Age

> 4 years and Outcome Age > 4 years

........................................................... 36

Figure 4. Age trend in blood lead levels

..................................................................... 37

Figure 5. Hypothetical observed blood lead–IQ association

...................................... 38

Figure 6. Hypothetical “true” blood lead–IQ relationship

......................................... 38

Figure 7. Hypothetical blood lead IQ slopes associated with residual

confounding (see text)

.................................................................................. 39

List of Tables

Table 1. Lowest blood lead level (BLL) considered elevated by CDC and

the US Public Health Service

...................................................................... 40

Table 2. Summary of studies estimating association of postnatal PbB

with cognitive function

................................................................................ 41

Table 3. Summary of studies estimating association of postnatal PbB

with performance scale IQ

.......................................................................... 58

Table 4. Summary of studies estimating association of postnatal PbB

with verbal scale IQ

..................................................................................... 65

Table 5. Studies of health endpoints other than IQ or GCI in relation

to BLLs <10 μg/dL

....................................................................................... 72

Table 6. Selected methodologic details from cohort studies

.................................... 77

# iii 

# EXECUTIVE SUMMARY

In March 2002, the Centers for Disease Control and Prevention (CDC) Advisory

Committee on Childhood Lead Poisoning Prevention (ACCLPP) established a work

group (WG) to review the available evidence of possible health effects of blood lead

levels (BLLs) of below 10 micrograms per deciliter (μg/dL), the level of concern

currently established by CDC. The WG was charged with designing and following

a rigorous protocol to review studies of the health effects of lead exposure at very

low BLLs. The workgroup intended to focus on studies of the effects of peak BLLs

at <10 μg/dL in children never known to have a BLL exceeding 10 μg/dL. However,

there are relatively few such studies and the workgroup decided to review the

larger number of studies that could indirectly support or refute the existence of

a threshold near 10 μg/dL. Although the workgroup members were the primary

authors of this report, the ACCLPP reviewed the document and it was revised based

on their comments. The majority of ACCLPP members accepted the fi ndings of the

report, with two members dissenting.

Methods

The following criteria were used for selecting relevant studies to review:

• BLLs were measured using graphite furnace atomic absorption spectrometry

(GFAAS) or anodic stripping voltammetry (ASV);

• the study was published in English;

• for studies in which IQ or General Cognitive Index (GCI) was a measured

outcome, an assessment of the association between BLLs in children and IQ

or GCI was included; and

• for studies in which IQ or GCI was not a measured outcome, an assessment of

the association between BLLs in children and a specifi ed health outcome was

included.

For each relevant study, a structured abstraction was performed that captured the

following:

• study location and sample size;

• age at which BLL and cognitive or health outcome was measured;

• the distribution of BLLs (mean or other measure of central tendency and

variance) and percentage of participants with BLL <10 μg/dL;

# iv • crude and adjusted regression coeffi cients relating BLLs to outcome;

• other measures of association (e.g., correlation coeffi cients); and

• model type and covariates included in adjusted models.

When reviewing the evidence, including indirect evidence from IQ studies, the

workgroup considered both alternate explanations for study fi ndings and potential

effect of residual confounding.

Conclusions

The main conclusions reached by the WG are summarized as follows.

1. Does available evidence support a negative association between

measured BLLs <10 μ g/dL and children’s health?

• The overall weight of available evidence supports an inverse (negative)

association between BLLs <10 μg/dL and the cognitive function of

children.

• A steeper slope in the dose-response curve was observed at lower

rather than higher BLLs.

• The available evidence has important limitations, including the small

number of directly relevant cohort studies and the inherent limitations

of cross-sectional studies (i.e., the lack of data regarding both BLLs

earlier in life and key covariates).

• For health endpoints other than cognitive function (i.e., other

neurologic functions, stature, sexual maturation, and dental caries),

consistent associations exist between BLLs <10 μg/dL and poorer

health indicators.

2. Are the observed associations likely to represent causal effects of

lead on health?

• Though not defi nitive, the available evidence supports the conclusion

that the observed associations between BLLs <10 μg/dL and cognitive

function are caused, at least in part, by lead toxicity.

• The strength and shape of the causal relationship are uncertain

because of limitations of the available evidence.

# v • The health effects of lead are uncertain in individual children who

have BLLs measured at a single point in time. Thus, scientifi c evidence

does not provide a basis for classifying individual children with BLLs

<10 μg/dL as “lead poisoned,” as the term is used in the clinical setting.

• The greatest source of uncertainty in evidence concerning the

relationship between BLLs <10 μg/dL and children’s cognitive function

is the potential for residual confounding, especially by socioeconomic

factors.

• The available data for health endpoints other than cognitive function,

taken mostly from cross-sectional studies, are limited; therefore, fi rm conclusions concerning causation can not be made.

Future Research Needs

The WG identifi ed the following research needs to address gaps in the existing

base of evidence and to allow for more defi nite conclusions about the strength and

shape of the causal relationship.

• Prospective observational studies designed to minimize the chance of residual

confounding.

• Randomized trials to test interventions designed to reduce BLLs <10 μg/dL

and assess the impact on children’s cognitive development.

• Animal and in vitro studies to identify mechanisms of lead toxicity at low

BLLs that could explain the observed steeper slope at lower compared with

higher BLLs.

# vi A Review of Evidence of Adverse Health Effects Associated

with Blood Lead Levels <10 μg/dL in Children

Reported by

A Work Group of the CDC Advisory Committee on Childhood Lead Poisoning

Prevention on Health Effects of Blood Lead Levels <10 μg/dL in Children

Work Group Members

Michael Weitzman, MD

Work Group Chair

Center for Child Health Research

University of Rochester Patrick J. Parsons, PhD

Wadsworth Center for

Laboratories and Research

New York State Department

of Health

Joel Schwartz, PhD

Department of Environmental Health

Harvard School of Public Health Betsy Lozoff, MD

Center for Human Growth

and Development

University of Michigan

David Bellinger, PhD Kimberly M. Thompson, ScD

Neuroepidemiology Unit

Children’s Hospital

Harvard Medical School Department of Health Policy

and Management

Harvard School of Public Health

David A. Savitz, PhD

Department of Epidemiology

University of North Carolina School

of Public Health Birt Harvey, MD

Pediatrician

Palo Alto, California

Carla Campbell, MD

Division of General Pediatrics

The Children’s Hospital of Philadelphia

This review was prepared for the work group by the following:

Thomas D. Matte, MD, MPH

David Homa, PhD

National Center for Environmental Health

Centers for Disease Control and Prevention

and

Jessica Sanford, PhD

Alan Pate

Battelle Memorial Institute

# vii 

# Abbreviations and Acronyms

AAS atomic absorption spectrometry

ACCLPP Advisory Committee on Childhood Lead Poisoning Prevention

ALAD amino levulinic acid dehydratase

ALAU urinary amino levulinic acid

ASV anodic stripping voltammetry

ATSDR Agency for Toxic Substances and Disease Registry

BLL blood lead level

EBLL elevated blood lead level

EP erythrocyte protoporphyrin

EPA Environmental Protection Agency

ETAAS electrothermal atomization techniques based on the graphite

furnace

ETS environmental tobacco smoke

FEP free erythrocyte protoporphyrin

GCI General Cognitive Index

# viii GFAAS graphite furnace atomic absorption spectrophotometry

HOME Home Observation for Measurement Environment

ICP-MS inductively coupled plasma mass spectrometry

ID-MS isotope dilution mass spectrometry

MCV mean corpuscular volume

MDI Mental Developmental Index of the Bayley Scales of Infant

Development for children

MeHg methylmercury

MSCA McCarthy Scales of Children’s Ability

NCCLS National Committee for Clinical Laboratory Standards

NCEH National Center for Environmental Health

NHANES National Health and Nutrition Examination Survey

NMDA N-methyl-D-aspartate

PbB Blood lead

PCAACN Practice Committee of the American Academy of Clinical

Neuropsychology

PKC protein kinase C, a calcium dependent enzyme

# ix QA/QC quality assurance/quality control

SES socioeconomic status

U-RBP urinary retinal binding protein

WG work group

WISC-R Wechsler Intelligence Scale for Children—Revised

WISC-III Wechsler Intelligence Scale for Children—Third Edition

WRAT Wide Ranging Achievement test arithmetic and reading scores

ZPP zinc protoporphyrin

# 1 

# Background

Charge to the Work Group

In March 2002, the Advisory Committee on Childhood Lead Poisoning

Prevention agreed to establish a work group (WG) to review evidence of possible

health effects of lead at blood lead levels less than 10 micrograms per deciliter

(μg/dL), currently the threshold for defi ning an elevated blood lead level according

to CDC guidelines (CDC 1991). The work group was charged as follows:

“In October 1991, the Centers for Disease Control and Prevention

issued Preventing Lead Poisoning in Young Children. This document

heralded a change in the defi nition of the level for intervention for

children with elevated blood lead levels (EBLLs) from a lead level of

25 μg/dL to 10 μg/dL. The report explained that this change was due

to new data that indicated signifi cant adverse effects of lead exposure

in children at levels once thought to be unassociated with adverse

effects. The 1991 document identifi ed a goal to reduce children’s blood

lead levels below 10 μg/dL. Interventions for individual children were

recommended at levels of 15 μg/dL and above.

Research fi ndings published and disseminated since October 1991

suggest that adverse effects from lead exposure and toxicity occur

at blood lead levels below 10 μg/dL. Some studies suggest that some

effects may be greater at blood lead levels (BLLs) below 10 μg/dL

than at higher BLLs. Such research fi ndings raise concerns about the

inability to control lead exposure with conventional methods and lend

credence to the importance of primary prevention measures to prevent

lead exposure to children.

The work group will be convened by the Advisory Committee on

Childhood Lead Poisoning Prevention to review the existing evidence

for adverse effects of lead exposure and toxicity on children at very low

blood lead levels and to focus on effects at levels of 10 μg/dL and below.

Rigorous criteria will be established for the literature review. The work

group will then create, in conjunction with the committee, a summary

of the evidence for publication.”

Scientifi c and Public Health Context for the WG Review

Prior reviews that compiled the extensive evidence from in vitro , animal,

and human studies established lead as a multi-organ toxicant, including studies

showing health effects at BLLs near 10 μg/dL (ATSDR 1999; WHO 1995; USEPA

1986). The published studies include a large body of literature establishing that

# 2 lead is a developmental toxicant and that harmful effects of lead on children’ s development can occur without clinical signs, symptoms, or abnormal routine

laboratory tests. In addition, a growing number of studies suggest that BLLs

prevalent in the general population are associated with adverse health effects

in adults and in the offspring of pregnant women. Finally, in more recent years,

bone-lead levels measured by x-ray fl uorescence have been used in epidemiologic

studies as a measure of cumulative lead exposure. Although these were not

considered in this review, a number of studies showing inverse relations of

bone-lead level to health in general population samples (e.g., Cheng et al. 2001) add

further evidence that cumulative lead exposure may be harmful to health at typical

background exposure levels for the population in the United States.

The observation that available epidemiologic evidence does not demonstrate a

threshold below which no effect of lead is possible is not new. A review prepared for

a 1986 workshop on lead exposure and child development stated, “There is little

evidence for a threshold or no-effect level below which the lead/IQ association is

not found. IQ defi cits have been reported in studies where the mean lead level is 13

μg/dL (Yule et al. 1981) and similar defi cits in the Danish study where the primary

measure was tooth lead, but BLLs are lower at around 7 μg/dL.” (Smith 1989) A

review, meta-regression, and reanalysis of existing data (Schwartz 1994) reached

essentially the same conclusion. Available data did not suggest a threshold below

which no association between BLLs and intelligence in young children was evident.

Recent studies (Canfi eld et al. 2003; Lanphear et al. 2000; Moss et al. 1999; Wu

et al. 2003) provided more direct evidence of an association between BLLs and

adverse health effects in the domains of cognitive function, neurologic function,

growth, dental caries, and onset of puberty at levels well below 10 μg/dL. Thus, a

reexamination of this issue is in order.

As evidence from experimental animal studies and human epidemiologic studies

has grown, CDC has lowered the BLL considered elevated for the purpose of

interpreting clinical test results of an individual child (Table 1). CDC guidelines also

have provided criteria for identifying children who have more severe manifestations

of lead toxicity and/or a higher risk of lead-related sequellae. For example, CDC’ s 1975 and 1978 guidelines defi ned clinical “lead poisoning” on the basis of BLLs,

symptoms, and/or levels of erythrocyte protoporphyrin (EP) or other indicators of

lead-related biochemical derangements. CDC’s 1985 guidelines used the terms “lead

toxicity” and “lead poisoning” interchangeably to refer to BLLs > 25 μg/dL with EP

> 35 μg/dL. However, the guidelines acknowledged that “lead poisoning” is generally

understood for clinical purposes to refer to episodic, acute, symptomatic illness

from lead toxicity. CDC’s 1985 guidance also cautioned that blood lead thresholds

established to guide follow-up and treatment for individual children “should not

be interpreted as implying that a safe level of blood lead has been established.” In

1991, CDC guidelines more directly acknowledged the diffi culty in assigning terms

to specifi c ranges of BLLs given the different settings in which BLLs are interpreted

and given that manifestations of lead toxicity occur along a continuum: “It is not

# 3 possible to select a single number to defi ne lead poisoning for the various purposes

of all of these groups [e.g. clinicians, public health offi cials, and policy makers]”

(CDC 1991). These guidelines also noted, “Some [epidemiologic] studies have

suggested harmful effects at even lower levels [than a BLL of 10 μg/dL].”

In addition to these changes in criteria used to evaluate blood lead test results

for individual children, recent analyses by the U.S. Department of Housing and

Urban Development (HUD 1999) and the U.S. Environmental Protection Agency

(USEPA 2000) to support the development of regulations governing lead exposure

have assumed that the relation of increasing blood lead to decrements in children’ s IQ extends to BLLs <10 μg/dL.

As BLLs considered elevated have fallen, measures to reduce or remove

lead from a number of sources, including gasoline, soldered food and beverage

containers, paint, drinking water, and industrial emissions have resulted in a

dramatic decline in BLLs in the United States since the mid-1970s (Pirkle et al.

1994). The Second National Health and Nutrition Examination Survey (NHANES

II) conducted from 1976 to 1980 demonstrated that, among U.S. children ages 6

months through 2 years, 84% of white children and more than 99% of black children

had BLLs > 10 μg/dL, and the median BLLs were 14 and 19 μg/dL, respectively

(Mahaffey et al. 1982). A decline in BLLs during the course of that survey was

noted, paralleling the falling consumption of leaded gasoline (Annest et al. 1983).

A continued decline in BLLs was evident in subsequent NHANES surveys (Pirkle

et al. 1994; NCEH 2003) and in clinical blood-lead test data compiled by state and

local health agencies (Hayes et al. 1994; CDC 2003). Nationally, it is estimated that

by 1999-2000, the prevalence of BLLs > 10 μg/dL among children 1 to 5 years of age

had fallen to 2.2% and the median level to 2.2 μg/dL (NCEH 2003).

Although these reductions in lead exposure represent great progress, scientifi c advances have shed light on harmful effects of lead at levels of exposure once

thought safe. In addition, industrial activity has widely dispersed lead in the

environment from naturally occurring deposits. As a result, even at the lower

exposure levels that prevail today, typical body burdens of lead are likely to be

much higher than those present in pre-industrial humans, which by one estimate

corresponded to a BLL of 0.016 μg/dL (Smith et al. 1992). Therefore, the potential

for additional subclinical adverse effects of lead from currently prevailing

exposures deserves careful study. Finally, although falling BLLs have benefi ted

all demographic groups (Pirkle et al. 1994), stark demographic and geographic

disparities continue to refl ect the historic pattern; the risk of elevated BLLs in

communities where poverty and older (i.e., that built before 1950) housing are

prevalent remains several fold higher than the national average (Lanphear et al.

1998).

# 4 

# Review Methods

Scope and Approach

Given the charge to the work group and the scientifi c and public health context,

the WG did not attempt a comprehensive review of all evidence relating lead

exposure to health. Instead, the WG set out to answer the following questions:

1. Does available evidence support negative associations between health

indicators and children’s blood lead levels measured <10 μg/dL?

2. Are the observed associations likely to represent a causal effect of lead on

health?

To address these questions, the WG established criteria (see Methods) for

published studies that would address the fi rst question. In addition, the work

group identifi ed issues relevant to making causal inference from any observed

associations. Identifying such issues is an essential step in interpreting evidence

relevant to the WG charge. Human studies to assess potential health effects of

environmental toxicants, such as lead, are usually observational in design (i.e., the

health status of participants is related to some measure of exposure, dose, or body

burden that varies on the basis of environmental factors and not experimental

manipulations by the investigator). For ethical reasons, the limited number of

human experimental studies that have evaluated causal relations between toxicant

exposures and health usually have involved attempts to reduce exposure or body

burden and assess the impact on health status. Such studies of lead-exposed

children are rare, and to date none have focused on children with BLLs <10 μg/dL.

Observational studies have inherent limitations—not specifi c to studies of lead

toxicity—with the potential to produce biased results. Biases from observational

studies can obscure true causal effects of toxicant exposures or produce associations

between toxicant exposures and health status when no causal relation is present.

Thus, statistical associations from individual observational studies or multiple

studies subject to similar biases cannot establish causal relationships; additional,

non-statistical criteria may be used to evaluate such evidence. Although causal

criteria have been stated in various ways, the Surgeon General’s Report on Smoking

and Health (U.S. Public Health Service 1964) provides a useful set of criteria. They

include:

• The consistency of the association . Is a similar association observed across

studies with varying methods and populations?

• The strength of the association. The strength of an association is the

extent to which the risk of a disease or a measure of health status varies in

# 5 relation to exposure and can be expressed, for example, as a relative risk or

regression coeffi cient. It is distinguished from the statistical signifi cance of an

association that refl ects both the strength of the association and the sample

size. An additional criterion, specifi city of the association, is closely related to

strength of the association and is considered less important in the context of

multifactorial health conditions.

• The temporal relationship of associated variables. Does the hypothesized

causal exposure occur before the health outcome associated with it?

• Coherence of the association. Is the observed association consistent with

other relevant facts including, for example, experimental animal studies and

the descriptive epidemiology of the health condition under study?

The application of these criteria does not provide a clear demarcation for

concluding defi nitive proof of causation versus inadequate evidence. Rather, the

more the available evidence meets these criteria, the greater the confi dence in

causal inference about an association. Consistent with these criteria, the WG

identifi ed several issues specifi cally relevant to inferring causality from associations

(or the lack of associations) of BLLs to health measures observed in studies of lowlevel lead exposure. These potential biases are not unique to studies of children

with BLLs < 10 μg/dL (e.g., Smith 1989). However, the larger number of human and

experimental animal studies (including primate studies) and the nature of observed

health effects associated with higher BLLs have conclusively demonstrated the

adverse health effects of lead. However, far fewer studies of possible health effects of

BLLs <10 μg/dL have been conducted, and the relative importance of some sources

of bias may be greater at these lower levels. Therefore, the work group considered

several issues in interpreting the fi ndings of available studies (see Discussion).

At the time of the WG’s review, a consortium of investigators from several longitudinal studies of lead exposure and cognitive function in children were conducting a reanalysis of data pooled from these studies. These studies included serial

measures of blood lead level, cognitive function, and a large number of potential

confounders, thus providing stronger evidence than is available from cross-sectional

studies. A focus of the pooled reanalysis involved studying the shape of the association between postnatal lead exposure at low levels and measured IQ (B. Lanphear

,personal communication, 2003). The WG reviewed published reports from individual cohort studies from which data were pooled, but the fi nal results of this pooled reanalysis were not available for inclusion in the WG report. [Note: Results of the pooled

renanlysis were published (Lanphear et al 2005) after the WG fi nished its review.]

Because of the nature of its charge, the WG did not develop policy

recommendations or address questions relevant to such recommendations. Such

policy decisions and questions will, if appropriate, be considered by the full ACCLPP

after reviewing the fi ndings of this report.

# 6 Criteria for Relevant Studies

The WG initially considered, then rejected, limiting its review to studies for

which published results provide direct comparisons between children with varying

BLLs <10 μg/dL. Such a review would include a relatively small number of studies.

Instead, the group decided that the larger number of studies that have included

IQ as an outcome could, collectively, indirectly support or refute the existence

a threshold near 10 μg/dL for the blood lead–IQ association. The rationale for

this approach is based on that used in a review and metaregression reported by

Schwartz (1994) and outlined in the following paragraphs.

Suppose that, hypothetically, a threshold exists near 10 μg/dL, above which

mean IQ decreases linearly with increasing blood lead, with a slope equal to x and

below which mean IQ is not associated with blood lead 1 

# (see Figure 1—Hypothesized

“true” relation A). In studies of children who have BLLs <10 μg/dL, estimated

slopes would be, in the absence of sampling error, equal to 0. For studies in which

all children have BLLs above the threshold, the estimated slope would be, again

ignoring sampling error, equal to x. For studies in which some children have blood

lead above and others below the threshold, estimated slopes will vary between 0 and

x as shown in Figure 1. Thus, if regression coeffi cients estimating the IQ–blood lead

slope are less negative (approaching 0) in populations with lower mean BLLs than

in populations with higher mean levels, a threshold near 10 would be suggested.

The absence of such a trend or an increase in slopes with decreasing mean blood

lead level of the population studied would provide evidence against such a threshold

and instead support “true” relations B and C, respectively. This ideal hypothetical

case presumes that effect sizes from the studies compared are based on models that

correctly specify the form of the BLL–IQ relation and that factors that might modify

the relation do not vary across studies.

Because of this approach, studies that assessed the association between blood

lead and measured IQ were included in this review, even if the published results

did not examine blood lead–IQ associations limited to BLLs <10 μg/dL (as was true

in most cases). An additional reason for considering studies that measured IQ was

the relationship of IQ to other outcomes of policy and public health importance

including educational success and earnings potential (Grosse et al. 2002). Because

the McCarthy Scales of Children’s Ability (MSCA) General Cognitive Index (GCI)

was used in a number of studies to measure cognitive function in preschool children

and because GCI and IQ scores have similar distributions, studies using GCI as an

outcome were also included in this review.

____________________

1 

# The concept of a threshold existing for the population makes little sense toxicologically since even if

individual thresholds exist, these are likely to vary. Nonetheless, the threshold concept plays a major

role in regulatory toxicology, and it only becomes clear in cases like lead that such constructs can be

highly problematic.

# 7 The following criteria were used to select relevant studies to review for this

report:

1. Blood lead levels were measured using graphite furnace atomic absorption

spectrophotometry (GFAAS) or anodic stripping voltametry.

2. The study was published in English.

In addition,

For studies in which IQ or GCI was a measured outcome, the

study analyses included an assessment of the association between

BLLs measured in children and IQ or GCI.

For studies in which IQ or GCI was not a measured outcome, the

study analyses included an assessment of the association between

BLLs <10 μg/dL measured in children and a health outcome. The

assessment could either be formal (e.g., non-linear modeling, linear

modeling restricted to populations with all or at least 95% of children

having BLLs <10 μg/dL, statistical comparison of two or more subgroups with BLLs <10 μg/dL) or informal (e.g., graphical display of

results permitting visual assessment of blood lead–outcome relation in

the range <10 μg/dL).

Literature Search

To identify potentially relevant articles, a comprehensive report published by the

Agency for Toxic Substances and Disease Registry (ATSDR 1999) was reviewed fi rst

to identify cited articles that related to low-level lead exposure in children. The list

of potentially relevant citations identifi ed in the ATSDR report was supplemented

by three computerized literature searches, using Dialog ®



# to search Medline, Toxfi le,

and other bibliographic databases. Search terms (see Appendix A) were chosen to

identify articles reporting on blood lead measurements and one or more domains

of health related to lead exposure including neurodevelopment, cognitive function,

intelligence, behavior, growth or stature, hearing, renal function, blood pressure,

heme synthesis, hematopoiesis, and Vitamin D metabolism. The fi rst search

spanned articles published from 1995 through 2002 and indexed as of September

2002, the month and year that the initial search was performed. The second search

was performed in April 2003 and spanned the period 2002 through the search date.

A third search, spanning the years 1990 through 1996, was performed when a

relevant article not cited in the ATSDR toxicological profi le was identifi ed by one of

the work group members. In addition, potentially relevant articles were identifi ed

by work group members and through citations in articles identifi ed previously.

# 8 Abstracts were reviewed initially. If they were ambiguous or if they suggested

the article was relevant, full articles were checked for relevance. Articles deemed

relevant were abstracted for this report. Appendix A summarizes the number of

possibly relevant references identifi ed, full articles checked for relevance, and

relevant articles abstracted and considered in the review.

Structured Abstracts

For each relevant study, a structured study abstraction was performed that

captured the following information: the study location, sample size, age at which

blood lead was measured, age at which the outcome was measured, available

information about the blood lead distribution (including mean or other measure

of central tendency, variance, and percent of participants with BLLs <10 μg/dL),

the crude and adjusted regression coeffi cients relating blood lead to outcome (if

available), the type of model fi t (linear, log linear, or other), and the covariates

included in the adjusted model. If regression coeffi cients were not available, other

measures of association reported (e.g., correlation coeffi cients) were noted. Because

some studies fi t multiple blood lead-outcome models (e.g., cohort studies with blood

lead and IQ measured at multiple ages), relevant information about each model

estimated was abstracted. For IQ studies, covariates measured and not included in

adjusted models were recorded when available.

Review of Cohort Study Methods

Among relevant published results were those from cohort studies specifi cally

designed and conducted to study the relation of BLLs to children’ s cognitive

function and other health outcomes. Because these studies had the strongest

and best-documented study designs for this review, methods used for blood lead

measurement and neuropsychological assessment were summarized for these

studies. This information was collected from published studies; in some cases, the

studies were supplemented by information provided through correspondence with

the investigators.



# Results

Studies Relating Postnatal Lead Exposure to IQ or General Cognitive

Index

Studies in which IQ or GCI were measured as an outcome and other criteria

were met included 23 published reports from 16 separate study populations. Results

from these studies are summarized in Table 2 (full scale IQ and GCI), Table 3

(performance IQ), and Table 4 (verbal IQ). Within each table, results are grouped

according to the age at blood-lead measurement and age at outcome measurement;

# 9 each grouping displays results sorted according to the measure of central tendency

of the blood-lead distribution. Because some studies used linear models (BLLs were

untransformed) and some used log-linear models (BLLs were log transformed),

estimated regression coeffi cients were, when possible, used to calculate the

estimated change in IQ or GCI corresponding to a blood lead increase from 5 to

15 μg/dL to allow for comparisons across studies. Covariates included in adjusted

models are grouped into several broad domains that were addressed in most of the

published studies.

Among studies that provided results for the size and direction of the associations

between BLLs and Full Scale IQ or GCI, regardless of statistical signifi cance, a majority revealed that both crude and adjusted associations were consistent

with an adverse effect—IQ decreases with increasing levels of blood lead. In most

cases, covariate adjustment attenuated, but did not eliminate, these estimated

associations. Findings for performance and verbal IQ were similar , with some

studies showing stronger associations of lead with performance IQ and others with

verbal IQ.

Notable exceptions to this pattern, however, were found. Results from the

Cleveland cohort (Ernhart et al. 1987, 1988, 1989) indicated a crude inverse

association between blood lead and IQ but no association with covariate adjustment.

In the Cincinnati and Boston cohort studies, BLLs measured at or below 12 months

of age showed no association or a slightly positive association with covariateadjusted IQ (Dietrich et al. 1993; Bellinger et al. 1992). Though published results

from a cohort study in Costa Rica (Wolf et al. 1994) did not provide the size and

direction of the estimated blood lead–IQ slope, unpublished results provided to

the WG did show covariate-adjusted IQ increasing with BLL (B. Lozoff, personal

communication 2003). The estimated BLL–IQ association in the Kosovo cohort was

strengthened substantially with covariate adjustment (Wasserman et al. 1997).

No trend toward attenuation of the association between blood lead and IQ (or

GCI) across studies with decreasing average BLLs is evident (Figures 2 and 3). In

one of these studies, analyses were presented that provide more direct information

concerning the association between BLL and cognitive function at BLLs <10 μg/dL.

The steepest estimates of blood lead–IQ slope from the Rochester (Canfi eld et al.

2003) studies were based on analyses restricted to children whose measured BLL

never exceeded 10 μg/dL. The estimated slope was substantially larger than those

estimated from the entire study population (9.2 versus 5.3 IQ point reduction

in covariate adjusted IQ for BLL increase from 5 to 15 μg/dL). Canfi eld and his

colleagues (2004) also reported a non-linear model supporting a steeper blood lead–

IQ slope at lower levels. Though published as a letter to the editor , rather than in a

peer-reviewed article (and therefore not included in the structured review), similar

fi ndings were reported for a reanalysis of the Boston cohort: a steeper BLL–IQ

slope in the population of children whose measured BLLs never exceeded 10 μg/dL,

compared with the entire study population (Bellinger et al. 2003).

# 10 Most of the published studies included at least one measure of socio-economic

status. All of the published results from cohort studies were adjusted for Home

Observation for Measurement Environment (HOME) score and birth weight; all

except the Costa Rica cohort were adjusted for a measure of maternal intelligence.

A reanalysis of the data from the Costa Rica cohort with adjustment for maternal

IQ was consistent with the original fi nding of a non-signifi cant positive blood

lead–IQ slope (B. Lozoff, personal communication, 2003). Prenatal exposure to

maternal smoking was adjusted in the majority of studies, whereas only in the Port

Pirie cohort was a measure of postnatal environmental tobacco smoke exposure

included. Iron defi ciency anemia was included as a covariate in results from the

Costa Rica study, which found no association of lead and IQ; the inverse blood

lead–IQ associations in the Rochester study (Canfi eld et al. 2003) and the Karachi

study (Rahman et al. 2002) were adjusted for serum transferrin saturation and

hemoglobin, respectively. In addition, in the Kosovo study (Wasserman et al.

1997), alternative models were fi t with adjustment for hemoglobin, resulting in no

appreciable change in the lead coeffi cient.

Not all studies reported regression coeffi cients that could be used to estimate the

change in IQ associated with a BLL change of 5 to 15 μg/dL, and the overall pattern

of results summarized above and in Figures 2 and 3 might have been altered had

regression coeffi cients been available from all studies. For example, a member

of the WG provided results of reanalysis of the data from the Costa Rica cohort,

which showed no evidence of an inverse relation of BLL to IQ with adjustment for

maternal IQ and other covariates used in the published result (W olff et al. 1994;

B. Lozoff, personal communication, 2003).

Studies of Health Endpoints Other than IQ and CGI

More stringent criteria were required for inclusion of studies in this review if they

assessed health endpoints other than general intelligence as measured by IQ or GCI.

These studies are summarized in Table 5 and are described in the following paragraphs.

Cognitive Function

Lanphear et al. (2000) analyzed data on BLLs on performance on standardized

tests of cognitive function of 4,853 children age 6 through 16 years who were

evaluated as part of the NHANES III survey, a multiphasic health interview

and examination survey of a stratifi ed probability sample of the U.S. population,

carried out from 1988 through 1994. In this population, with a geometric mean

BLL of 1.9 μg/dL and 98% of children having BLLs <10 μg/dL, signifi cant inverse

relations were found between BLLs and scores on the Wide Ranging Achievement

Test (WRAT) arithmetic and reading scores and on the WISC-R block design and

digit span subscales. The relationships were strengthened (the slopes became more

negative) as analyses were progressively restricted to children with lower BLLs.

Stone et al. (2003) reanalyzed the data used by Lanphear et al. (2000). While the

# 11 results they present are largely consistent with the fi ndings of Lanphear et al.,

they provided a critique of the validity of the NHANES III data for evaluating leadrelated impacts on neuropsychological development in children. Their critique did

not provide results that could be summarized in the structured abstract format used

in this report, so a discussion of the Stone et al. critique is found in Appendix B.

Other Neurobehavioral Measures and Visual Function

Three reports (Altman et al. 1998; Walkowiak et al. 1998; Winneke et al. 1994)

describe the relation of blood lead to several neurobehavioral measures and to

visual function assessed in 384 school children 5 to 7 years of age in three cities in

Eastern Germany. Blood lead levels were generally low, with a geometric mean of

4.25 μg/dL and 95% of children having BLLs <10 μg/dL. Walkowiak et al. (1998)

reported a signifi cant negative association between BLLs and WISC vocabulary

subscale scores. Continuous performance test false positive and false negative

responses increased with increasing BLLs. Other measures inversely related to

BLL included performance on a pattern comparison test, fi nger tapping speed

(Winneke et al. 1994), and visual evoked potential interpeak latency (Altman et

al. 1998). Mendelsohn and colleagues (1999) found a 6 point defi cit in the Mental

Developmental Index (MDI) of the Bayley Scales of Infant Development for children

aged 12 to 36 months with BLLs 10-24 μg/dL compared with children who had BLLs

<10 μg/dL. A scatterplot of covariate-adjusted MDI versus blood lead suggests the

association continues at BLLs <10 μg/dL.

Neurotransmitter Metabolite Levels

Among children ages 8 through 12 years with mean BLL of 3.95 μg/dL, a direct

relation of blood lead (PbB) to higher urinary homovanillic acid, a neurotransmitter

metabolite, was found for the subset of children with BLLs >5 μg/dL (Alvarez Leite

et al. 2002).

Growth

Two studies examined the relation of BLLs <10 μg/dL to somatic growth. Ballew

et al. (1999), using the NHANES III data, found that BLLs were inversely related to

height and to head circumference among children 1 to 7 years of age. A birth cohort

of children in Mexico had BLLs and head circumference assessed every 6 months

from 6 to 48 months of age, during which time the median BLL varied from 7 to

10 μg/dL (Rothenberg et al. 1999). Most postnatal blood lead measures were

inversely correlated with covariate adjusted head circumference, with the strongest

relation found between blood lead at age 12 months and head circumference at 36

months. Kafourou and colleagues (1997) reported a signifi cant negative association

between BLL and covariate-adjusted head circumference and height in a population

of children with a median BLL of 9.8 μg/dL, with a scatterplot suggesting the

relation extends to BLLs <10 μg/dL.

# 12 Sexual Maturation

Two studies, both based on analyses of the NHANES III data, found an

association between BLLs <10 μg/dL and later puberty in girls. Selevan et al. (2003)

found that BLLs of 3 μg/dL, compared with 1 μg/dL, were associated with signifi cant

delays in breast and pubic hair development in African American and Mexican

girls. The trend was similar, but not signifi cant, for non-Hispanic white girls. Age at

menarche was also delayed in relation to higher BLLs, but the association was only

signifi cant for African-American girls. Wu et al. (2003) reported similar fi ndings

for girls in the NHANES III population but did not stratify the analysis by racial/

ethnic group. Compared with BLLs 2.0 μg/dL and below, BLLs of 2.1–4.9 μg/dL were

associated with signifi cantly lower odds of attaining Tanner 2 stage pubic hair and

menarche; whereas no overall association with breast development was noted.

Dental Caries

In the NHANES III population, the odds of having dental caries, comparing

children ages 5–17 years in the middle tertile of the BLL distribution (range of

BLLs 1.7–4.1 μg/dL) with those in the lowest tertile, was signifi cantly elevated

(odds ratio=1.36, 95% confi dence interval 1.01–1.83) (Moss et al. 1999). Gemmel

et al. (2002) evaluated the association between BLLs and caries in 6–10 year old

children from urban communities in eastern Massachusetts (mean BLL=2.9 μg/dL)

and a rural community (mean BLL=1.7 μg/dL) in Maine. They found a signifi cant

direct relation of BLL to caries in the former, but not the latter population in which

a non-signifi cant decrease in caries’ frequency was observed with increasing blood

lead. In the urban population, the trend of increasing caries with PbB level was

evident comparing children with BLLs of 1, 2, and 3 μg/dL.

Blood pressure and renal function

Among 66-month-old children in Kosovo, a graph depicting adjusted mean

systolic and diastolic blood pressure versus BLL showed no consistent trend across

4 groups of children (approximately 28 per group) with BLLs spanning a range from

approximately 5 to 10 μg/dL (Factor Litvak et al. 1996). In a population of 12- to

15-year-old children living near a lead smelter and a control group, urinary retinal

binding protein (U-RBP) was found to be signifi cantly associated with BLL in a

stepwise regression. When urinary RBP excretion was examined by BLL tertiles,

signifi cantly lower U-RBP was seen in the group with BLL < 8.64 μg/dL compared

with BLLs 8.64–12.3 μg/dL.

Heme synthesis biomarkers

Roels et al. (1987) studied the relations of PbB to heme synthesis biomarkers

and reported no evident threshold for inhibition of aminolevulinic acid dehydratase

synthesis at PbB as low as 8–10 μg/dL, while the threshold for increasing erythrocyte

# 13 protoporphyrin levels was evident in the range of 15–20 μg/dL, consistent with other

studies, including two meeting criteria for inclusion in this report (Rabinowitz et al.

1986; Hammond et al. 1985).



# Discussion

Question 1: Does available evidence support an inverse association between

children’s blood lead levels <10 μg/dL and children’s health?

The weight of available evidence, both indirect and direct, clearly favors an

inverse association between these BLLs and cognitive function among children.

The indirect evidence comes from the great majority of studies that have examined

BLLs in relation to standardized measures of overall cognitive function; these

studies reveal an inverse relationship and no trend toward weaker associations

in populations with lower BLL distributions. More direct evidence of such an

association comes from a recent analysis of data from a cohort designed from the

start to study the relation of blood lead to child development (Canfi eld et al. 2003).

This study demonstrated that the inverse relation between BLL and cognitive

function exists and is stronger at BLLs <10 μg/dL compared with higher BLLs; it

also does not show a threshold within the range of routinely measured BLLs below

which no association was present. A recent letter to the editor described a reanalysis

of the Boston cohort data (Bellinger et al. 2003) with fi ndings consistent with

Canfi eld et al (2003). Several recent analyses of data from the NHANES III and

other populations also provide direct evidence of associations that imply adverse

impacts of lead on indicators of children’s neurocognitive development, stature,

head circumference, dental caries, and sexual maturation in girls, occurring at

measured BLLs <10 μg/dL. Though the number of studies providing direct evidence

of associations at BLLs <10 μg/dL is limited and most are cross-sectional, they

provide supporting evidence of an association in the context of the much larger

number of studies that relate slightly higher levels of lead in blood to impairments

of children’s health.

Question 2: Are the observed associations likely to be causal?

Though the weight of evidence favors an association between children’ s BLLs

<10 μg/dL and health and, indeed, suggests that such relationships become steeper

as BLLs decrease, the WG considered a number of concerns that must be addressed

in judging whether such associations are likely to be causal. The work group

concluded that collectively, these concerns and limitations of the available evidence

preclude defi nitive conclusions about causation and leave considerable uncertainty

concerning the magnitude and form of causal relations that may underlie these

associations. At the same time, available evidence does not refute the interpretation

that these associations are, at least in part, causal. These issues are discussed

individually in the following text, followed by overall conclusions.

# 14 Biologic Plausibility

Evidence from experimental animal and in vitro studies, which are not subject

to confounding infl uences of concern in human observational studies, can establish

causation and identify mechanisms that might be operative in humans assuming

a suitable animal model. Thus, evidence from experimental animal and in vitro

studies can help to assess potential dose–response relationships and thresholds

within the context of any uncertainty added due to interspecies extrapolation.

Therefore, an important consideration in judging whether associations between

BLLs <10 μg/dL and health outcomes are likely to represent causal relationships is

whether such relationships are biologically plausible on the basis of experimental

animal and in vitro studies. These studies can also help to assess potential dose–

response relationships and thresholds, but extrapolation from in vitro and animal

models to human health risk adds additional uncertainty.

Lead is the most extensively studied environmental neurotoxicant. Animal

and in vitro studies have provided abundant information concerning biochemical

and physiologic changes caused by lead. Along with clinical and epidemiologic

data, this evidence has clearly established that lead is toxic to the developing and

mature nervous system. These data have been extensively reviewed elsewhere

(USEPA 1986; ATSDR 1999; WHO 1995; Davis et al. 1990) and are not exhaustively

reviewed here. Rather, this discussion highlights evidence concerning potential

mechanisms of lead toxicity and data from animal studies that are relevant to the

biologic plausibility of the toxicity of lead, especially to the developing nervous

systems of children exposed at BLLs <10 μg/dL.

Although the precise mechanisms of action and their relative importance in

different manifestations of lead toxicity are not known defi nitively, in vitro studies

demonstrate that lead can interfere with fundamental biochemical processes. At the

most basic level, many of the proposed mechanisms of lead toxicity involve binding

to proteins and/or interference with calcium dependent processes (Goldstein 1993).

For some of the adverse health effects of lead (e.g., anemia), the lead-associated

biochemical changes that contribute to the effect in humans are well understood.

Lead interferes with heme synthesis in part by binding to sulfhydryl groups in the

enzyme amino levulinic acid dehydratase (ALAD) (ATSDR 1999), which is especially

sensitive to inhibition by lead (less than 0.5 micromoles per liter in vitro) (Kusell

et al. 1978; Dresner et al. 1982). This inhibition causes delta amino levulinic acid,

a potential neurotoxic agent, to accumulate. Lead also inhibits ferrochelatase, an

enzyme catalyzing the incorporation of iron into protoporphyrin to form heme. This

inhibition also may involve lead binding to protein sulfhydryl groups.

Although anemia and accumulation of protoporphyrin IX in erythrocytes are the

most obvious consequence of impaired heme synthesis, this pathway could play a

role in lead-related impairment of cellular function throughout the body (USEP A

# 15 1986). By interfering with heme synthesis and perhaps by inducing enzymes that

inactivate heme, lead can decrease the levels of heme in body tissues (Fowler et al.

1980). A reduction in the body heme pool may impair heme-dependent biochemical

processes, such as cellular respiration, energy production, and the function of the

cytochrome p-450 monooxygenase system involved in detoxifi cation of xenobiotics

and in transformation of endogenous compounds such as vitamin D precursors

(USEPA 1986).

For other more complex health effects of lead, such as impaired neurocognitive

development and behavioral change, a number of plausible mechanisms have

been demonstrated in animal and in vitro systems. Lead’s impact on one or

more biochemical systems needed for normal brain development and function

could account for the neurobehavioral effects observed at low levels of exposure.

Especially sensitive to lead in vitro is the activation of protein kinase C (PKC), a

calcium dependent enzyme. Lead binds more avidly to PKC than its physiologic

ligand, calcium, causing activation at picomolar concentrations in vitro. (Markovac

and Goldstein 1988). The interactions between lead exposure and PKC activity in

the brain are complex; chronic lead exposure may reduce activity of PKC associated

with cell membranes while increasing cytosolic PKC activity. Lead effects on PKC

activity have been proposed to mediate potential impacts of lead on cell growth and

differentiation, including that of neural cells (Deng and Poretz 2002), the bloodbrain barrier, and long-term potentiation (a process related to memory) (Hussain et

al. 2000). Lead also interferes with calcium-dependent control of neurotransmitter

release at presynaptic nerve terminals; it may thereby interfere with signaling

between neurons and possibly with development of neural networks. In both animal

and in vitro studies, lead has been demonstrated to interfere with neurotransmitter

systems, including interfering with dopamine binding and the inhibition of

N-methyl-D-aspartate (NMDA) receptor activity.

The large body of evidence from animal studies of lead exposure and

neurodevelopment supports a causal effect that is persistent following exposure

early in life and that generally parallels human studies in terms of the domains of

function that are impaired (WHO 1995). Concerning blood lead–effect relationships,

direct cross-species comparisons of BLLs cannot be made (Davis et al. 1990), and

most animal studies demonstrating lead-related developmental neurotoxicity

involved doses that produced BLLs well above 10 μg/dL. However, available studies

provide strong evidence of adverse effects in animals with BLLs near 10 μg/dL. It

should be noted that BLLs cited in animal studies generally involve mean levels

achieved in experimental groups with individual animals varying, sometimes

substantially, around that mean.

Non-human primates experimentally exposed to lead early in life demonstrate

dose related impairments in learning and behavior (Bushnell and Bowman 1979;

Rice 1985; Levin and Boman 1986). One study, involving monkeys dosed during

the fi rst 200 days of life with 100 μg/kg/day lead or 50 μg/kg/day lead resulting

# 16 in average peak BLLs of 25 and 15 μg/dL respectively, showed defi cits relative

to control monkeys (dose=0μg/kg/day lead; average peak BLL=3 μg/dL) at age 3

years on “discrimination reversal” tasks (the animals are taught to respond to a

cue and then the cue is changed and the ability to learn the new cue, with and

without irrelevant cues, is measured). At the time of testing, mean BLLs in the

exposed groups had fallen to 13 and 11 μg/dL, respectively. Both exposure groups

showed defi cits, but defi cits in the lower exposed group were evident only with

more complex tasks (e.g., including irrelevant cues) (Rice 1985). The same monkeys

showed persistent impairments at 9 to 10 years of age (Gilbert and Rice 1987).

Experimental studies in rats have demonstrated behavioral effects at mean BLLs

of 10–20 μg/dL (Cory-Slechta et al. 1985; Brockel and Cory-Slechta 1998).

There is uncertainty about the relationship of the tissue or cellular levels of lead

linked to physiologic changes in animal and in vitro studies to the corresponding

human blood lead level required to produce such levels at target sites. Although

most (90 to 99%) lead in whole blood is in red cells, plasma lead level likely better

refl ects lead transferred from bone stores and available for transfer to target

tissues (Cake et al. 1996). Because red cells have limited capacity to accumulate

lead, the relation of blood lead to plasma or serum lead is non-linear with serum

lead increasing more rapidly at higher BLLs (Leggett 1993). In subjects with a

mean BLL of 11.9 μg/dL, plasma lead levels ranged from 0.3 to 0.7% of whole BLLs

(Hernandez-Avila et al. 1998). The relation of plasma serum levels in intact animals

to tissue levels measured in in vitro models is probably more complex. It is also

uncertain whether in vitro studies demonstrating possible mechanisms for low-level

lead toxicity refl ect mechanisms operative in the intact animal. For example, Zhao

et al. (1998) found that lead interfered with PKC in choroid plexus endothelial cells

in a dose dependent fashion over the concentration range of 0.1-10 micromolar

. However, no effect on choroid plexus PKC activity was seen in an in vivo model.

Conclusions: The fundamental nature of biochemical and physiologic changes

linked to lead in in vitro and experimental animal studies illustrates potential

mechanisms for lead toxicity that might be operative in humans at very low

exposure levels. Experimental animal studies support the biologic plausibility of

adverse health effects of lead in children at BLLs near 10 μg/dL. However, defi nite

conclusions concerning the relationship of health status of children and BLLs <10

μg/dL cannot be drawn from these studies because of limitations of extrapolating

from in vitro systems to intact animals and from animals to humans and because

of the limited amount of data available from studies of animals dosed to produce a

range of BLLs less than 10 μg/dL. Data from primates, which can most readily be

extrapolated to humans, are especially limited.

On the other hand, given the uncertainty in extrapolating across species, the

fact that animal test systems cannot match the complexity of learning tasks faced

by young children, and the relatively small relative difference in BLLs shown to be

harmful in animals and those at issue in children, adverse health effects in children

at BLLs <10 μg/dL are biologically plausible.

# 17 Blood Lead Measurement

The precision and accuracy of blood-lead measurements performed in an

epidemiologic study impacts observed results. If BLLs are systematically over or

underestimated, biases in estimated blood lead response relationships and/or no

effect thresholds will result. All blood lead measurements involve some random

error, which, if a true association between blood lead and health exists, will tend to

bias estimates of the relation toward the null (i.e., no effect) value. The quality of

blood lead measurements varies between laboratories, between different analytical

technologies, and between different specimen collection techniques. In addition,

laboratory performance for blood lead has improved markedly over the last three

decades and continues to improve as new analytical technologies are developed.

Each of these factors becomes important in assessing the quality of blood-lead

measurements used in published studies. In this section, specimen collection and

laboratory factors that can affect blood-lead precision and accuracy are considered.

The widespread industrial use and dispersal of lead, particularly during the

last century, has ensured that it is a ubiquitous contaminant. Therefore, to prevent

false-positive results, stringent procedures are necessary to reduce environmental

contamination of blood collection devices and supplies. Consequently , venous blood

collected using evacuated tubes and needles certifi ed as “lead-free” is considered

the most appropriate specimen for blood lead measurements (NCCLS 2001).

However, collection of venous blood from pediatric subjects is sometimes diffi cult;

thus, capillary blood from a fi nger puncture is used widely for screening purposes.

Published studies have compared the quality of blood lead results for capillary and

venous specimens drawn simultaneously (Schlenker et al. 1994; Schonfeld et al.

1994; Parsons et al. 1997). With stringent precautions, particularly rigorous hand

washing, contamination errors can be held to <4% (Parsons et al. 1997). Therefore,

although venous blood is preferable for epidemiologic studies of environmental lead

exposure, use of capillary blood is acceptable if collected by staff specially trained

in the technique using devices certifi ed as “lead-free.” Data should be provided

showing an acceptably low rate of contamination errors and low mean bias in the

capillary BLLs as collected using the study protocol.

Currently, three analytical approaches to blood lead measurement are used:

atomic absorption spectrometry (AAS); anodic stripping voltammetry (ASV), and

inductively coupled plasma mass spectrometry (ICP-MS). A thorough discussion

of these analytical techniques is beyond the scope of this report; however , a comprehensive assessment has been published by the National Committee for

Clinical Laboratory Standards (NCCLS 2001). Briefl y, the older fl ame atomization

AAS methods, which include MIBK-extraction and Delves cup, are less precise,

with a detection limit near 5 μg/dL for Delves cup (Parsons and Slavin. 1993).

Thus, they are not well suited for examining relationships between BLLs <10 μg/

dL and health. The electrothermal atomization techniques based on the graphite

furnace (ETAAS) are more precise and more sensitive and, therefore, have better

# 18 detection limits, typically around 1.0 μg/dL. A direct comparison between ASV and

ETAAS techniques (Bannon et al. 2001) shows that the latter has better precision

and better accuracy. Nonetheless, when operated in experienced hands and with

a stringent quality assurance/quality control (QA/QC) program that includes

calibration standards traceable to the mole via isotope dilution mass spectrometry

(ID-MS), ASV can deliver blood-lead measurements with accuracy and precision

suffi cient to examine health effects at BLLs <10 μg/dL (Roda et al. 1988).

In order to assess the accuracy and precision of blood-lead measurements made

for research purposes, investigators should provide information on the laboratory’ s performance in measuring external quality control samples and on the between-run

standard deviation for routine quality control samples that span the relevant blood

lead range for a given study.

Conclusions: The key considerations relevant to judging the accuracy and

precision of blood lead measurements in published studies include the type and

quality of blood specimen collected, analytical methodology used by the laboratory

, and internal and external QA/QC procedures in place. For the purpose of studying

the relationship between BLLs <10 μg/dL and health endpoints venous samples are

preferred and capillary samples are acceptable with evidence of a rigorous protocol

to control contamination errors. Acceptable analytic methods include electrothermal

AAS, ASV, and ICP-MS. Information on laboratory performance (i.e., accuracy and

precision) from external and internal quality control data should be provided.

To be included in this review, studies were required to have employed suitable

measurement methods. In addition, venous samples were used for most postnatal

blood lead measurements in the relevant cohort studies (Table 6) and others cited

in this report. Given this and the blood lead quality control procedures reported

in the most informative studies, it is highly unlikely that systematic errors in

measurement in the relevant studies were suffi cient to bias the observed blood

lead distributions enough that associations observed <10 μg/dL were attributable

to BLLs above that threshold. Random variation in BLLs and random error in

BLL measurement would make it diffi cult to collect suffi cient data to identify a

threshold, if one were to exist.

Blood Lead Age Trend, Tracking, and Inference Concerning Blood Lead

— Effect Relations in Children

Age-related changes in children’s BLLs and within-child correlation of blood lead

measured at different ages may infl uence observed associations between BLL and

health at a given age. In addition, the biologic impact of lead in children is likely

determined not only to the BLL measured at any one time but, also, the ages at

which a given level occurs and the duration of exposure.

# 19 Under most exposure scenarios, children’s BLLs show a characteristic age trend.

A newborn’s BLL will largely refl ect the BLL of its mother. Because adult women

tend to have lower BLLs than young children, umbilical cord BLLs are generally

lower than BLLs during childhood. During the latter half of the fi rst year of life,

however, children’s BLLs begin to increase as the infant becomes more active,

mobile, and exposed to ambient lead. The onset of ambulation during this period is

likely to be important, as are play patterns that bring the child into contact with

environmental media such as lead-contaminated dust and soils. Other factors that

affect exposure include the increased hand-to-mouth activity of children, including

the practice of eating “in place,” i.e., in play areas. Physiologic factors, such as more

effi cient absorption of ingested lead in children compared with adults, and their

greater food and air intake on a body weight basis might also contribute to the early

postnatal rise in BLL.

The mean BLL within a study sample generally peaks during 18 to 36 months

of age, and slowly declines over the next few years. This blood lead profi le is seen

among economically disadvantaged urban minority children (Dietrich et al. 2001)

and among children living near lead smelters (Figure 4) (Tong et al. 1996). In

cohorts with extremely high exposures, the blood lead decline might be very gradual

(e.g., Wasserman et al. 1997). In the Cincinnati Study, the same general profi le

was evident in each of four strata defi ned by average lifetime BLL, suggesting that

it is, to some extent, independent of the overall level of exposure. This blood lead

profi le has not been observed in all study cohorts, however. In the Boston Study, for

example, mean BLL varied minimally, from 6.2 to 7.6 μg/dL, from birth through 5

years of age (Rabinowitz et al. 1984; Bellinger et al. 1991).

One implication of the typical profi le is that maximum level is often associated

with age, constituting an obstacle to an effort to identify age-specifi c vulnerability

to lead toxicity. Compounding this challenge is that, under many exposure scenarios

(particularly those involving higher exposures), intra-individual stability of BLL

tends to be substantial. That is, BLL tends to “track,” so that if, at time 1, child A

has a higher BLL than child B, child A is likely to have a higher BLL than child B

at time 2 as well. Thus, children’s rank ordering tends to be similar over time even

though, in absolute value, BLL rises and falls over the course of childhood. Again,

however, the degree of intra-individual stability varies from cohort to cohort. In

the Boston Study cohort, for instance, the extent was limited; this stability is likely

attributable to the generally low BLLs of the study population (Rabinowitz et al.

1984).

A BLL measured after 36 months of age will, on average, be lower than the BLL

that would have been measured if a child’s blood been sampled sometime during

the 18 to 36 month period. Suppose, however, that the critical period with regard to

producing an adverse health outcome is the 18 to 36 month period, and that, in a

study conducted post-36 months, an inverse association is noted between concurrent

BLL and a health endpoint. If the concurrent BLL is the only index of lead exposure

# 20 history available, basing a dose–effect assessment on it will, to the extent that the

natural history of BLLs in the study cohort follows the canonical form illustrated

above, result in an underestimate of the BLL responsible for any adverse health

effects noted at the time of or subsequent to blood sampling. In other words, one

will conclude that adverse health effects occur at lower BLLs than is the case. For

instance, assume that the inverse association shown in Figure 5 holds between IQ

and concurrent blood lead in a cross-sectional study of 6 year olds.

If, however, the BLL of each child was, on average, 5 μg/dL greater at age 2 than

at age 6, and age 2 is the time of greatest toxicologic signifi cance (i.e., it is age at

which lead exposure produced the IQ defi cit observed at age 6), then the dose–effect

relationship that underlies the association seen at age 6 would be more accurately

described as in Figure 6.

This dataset would thus not be informative with respect to the functional form of

the dose–effect relationship at levels below 10 μg/dL insofar as (hypothetically) all

children had a BLL greater than 10 μg/dL at age 2.

Other uncertainties apply to interpreting blood lead–health associations (or

lack of associations) observed at any point in time. First, the relation of age to

vulnerability to lead toxicity is not well understood. Is BLL during the age period

18 to 36 months more toxicologically critical than a measure of cumulative lifetime

exposure, such as the area under the curve or some other exposure index? Also, it is

possible that the critical age varies with dose, health endpoint, or sociodemographic

factors. Available studies do not provide consistent answers to these questions.

For example, in the Boston cohort, blood lead at age 24 months was most strongly

related to IQ at age 10 years (Bellinger et al. 1992), whereas in the Port Pirie

Cohort, the lifetime average BLL through age 5 years was most predictive of IQ at

age 11 to 13 years.

If 18 to 36 months is the critical age of exposure, theoretically , it is possible to

“adjust” an observed blood lead distribution measured at age 6 by some function

to refl ect the downward trend in BLL with age and estimate the blood lead

distribution at a different age, (e.g., age 2 years). However, a “one size fi ts all”

adjustment likely is not appropriate for all children. Moreover, the appropriate

adjustment is likely to be study-site-specifi c (i.e., depend on the key exposure

sources and pathways of a particular study cohort).

It would be possible to get a general sense of how accurately past peak exposure can

be estimated for children in cross-sectional studies by using data collected in prospective

studies in which blood lead was measured frequently during the period spanning birth to

school-age. Examining the distribution of the differences between BLLs measured at ages

18 to 36 months and at age 6 would suggest the amount of exposure misclassifi cation that

would result from applying a constant adjustment factor.

# 21 Conclusions: Because of age trends in blood lead and the tendency of BLLs

to “track” within individual children, inferences drawn from cross-sectional

associations between blood lead and health at a given age should be interpreted

cautiously because of the infl uence of likely higher BLLs occurring earlier in life. It

may be possible to apply data on age trends and within-subject correlation of blood

lead to estimate, from an observed blood lead–health association, the approximate

relation to BLLs at an earlier age. However, because age trends and the extent of

“tracking” of blood lead levels vary from one population to another , it is not possible

to estimate with confi dence the distribution of blood lead levels earlier in life for any

given population whose blood lead levels were only measured at one point in time. If

the only relevant studies available are based on cross-sectional data (e.g., data from

NHANES III), age trends and “tracking” of BLLs would represent a substantial

challenge to inferring a causal link between BLLs <10 μg/dL and adverse health

impacts. However, recently published results from two cohort studies (Canfi eld et

al. 2003; Bellinger et al. 2003) showed inverse associations between BLLs measured

early in life (6 to 24 months and 24 months, etc.) and IQ measured at older

ages among children whose measured BLLs did not exceed 10 μg/dL. Therefore,

associations observed in cross-sectional studies cited in this report likely do not

exclusively result from the impact of higher BLLs experienced earlier in life.

Quality of Neurobehavioral Assessments

As with blood lead (exposure) measurements, the accuracy, precision, and

consistency of neurobehavioral assessments can infl uence observed blood leadoutcome relations. In order to judge whether the data from a study should be

considered in characterizing the functional form of the dose–effect relationship at

BLLs <10 μg/dL, one would like to have access to the following information about

the conduct of the neurobehavioral assessments:

• Assurance that examiners were blinded to all aspects of children’s lead

exposure histories.

• The assessment setting. Assessments can be standardized when carried out

in a hospital, neighborhood health center, or community center, but may be

diffi cult to standardize in a participant’s home.

• Essentials of the process by which an examiner was trained, including the

criterion used to certify an examiner (e.g., percent agreement on an item-byitem basis with some gold standard, average difference in scores assigned

compared with gold standard, correlation with gold standard in terms of

scores assigned).

• The plan implemented for supervision of test administration over the

course of data collection (e.g., periodic observation of test sessions, live or by

videotape).

# 22 • The plan implemented for supervision of test scoring over the course of data

collection (e.g., double scoring of a sample of protocols).

• The number of neurobehavioral examiners used over the course of data

collection.

• If more than one assessor was used, whether the data analysis plan included

evaluation of an “assessor” effect (i.e., as a main effect and as a modifi er of

lead’s association with endpoints).

While some have argued that neurobehavioral examiners should have

professional qualifi cations (e.g., Kaufman 2001 cites the need for a clinician with

graduate-level training in psychometrics, neuropsychology, etc.), the Practice

Committee of the American Academy of Clinical Neuropsychology supports the

widespread practice of using non-doctoral level personnel, with appropriate training

and supervision by a doctoral-level psychologist, in the administration and scoring

of clinical neuropsychological evaluations (Brandt et al. 1999).

Assuming examiners are blinded regarding BLLs, most problems with quality

of neurobehavioral assessment would be expected to mask or underestimate true

associations rather than create spurious ones. It is possible, for example, that

use of non-professional examiners might introduce noise into the data, masking

an association between toxicant exposure and performance. In one study of

methylmercury (MeHg) exposure (Grandjean et al. 1997), MeHg was inversely

associated with children’s scores on the Similarities subtest of the WISC-III

among children tested by the supervising doctoral-level study examiner . Assuming

that blinding was preserved, use of non-professional examiners likely would not

introduce a positive bias in effect estimates.

Measurement quality problems causing bias of associations away from the null,

without loss of blinding, are theoretically possible. For example, if one examiner

consistently yields lower scores than another and that examiner, without knowledge

of BLLs, is assigned to assessments of a segment of the study population at higher

risk for lead exposure, a spurious inverse association could be created between lead

level and neuropsychological test scores.

Conclusions: The key considerations in judging the quality of neurobehavioral

assessments in the research setting are the blinding of examiners to leadexposure history, the training and supervision of examiners, and the setting

for examinations. If examiners are truly blinded, other data quality problems

generally will bias estimated relationships between blood lead and outcomes

toward the null. Therefore, given that examiners were blinded to BLLs in cohort

studies demonstrating associations (Table 6) and the NHANES III survey, errors in

measurement of neuropsychological function likely did not contribute to observed

associations with BLLs <10 μg/dL.

# 23 Potential Confounding Factors

Social Factors

Socioeconomic factors infl uence both lead exposure and many health outcomes,

including intellectual development, growth, and a number of chronic conditions,

creating the potential for social factors to confound associations between children’ s lead exposure and health in observational studies. Because cognitive function

as refl ected in measured intelligence is strongly associated with socioeconomic

status (SES) and because cognitive function in children is the most studied health

endpoint in studies of lead-exposed children, this discussion is focused on possible

SES confounding of associations between BLL and measured intelligence. The

potential for reported subtle effects of lead on IQ and related measures of intellect

to be attributable to confounding by socioeconomic factors warrants serious

consideration (Bellinger et al. 1989). Key relations required for confounding to

occur are almost certainly present—SES has been shown to be related to BLLs,

presumably because the neighborhoods and homes in which families of lower

income reside are associated with higher levels of lead in soil and residences.

Socioeconomic status also is clearly related to measures of intelligence, whether

through parental stimulation, nutrition, or resources available in the home. W ith an

inverse relationship between socioeconomic factors and lead levels (i.e., higher SES

predictive of lower lead levels) and a positive relationship between socioeconomic

factors and measures of intelligence (higher SES predictive of higher intelligence

test scores), failure to adjust for the confounding effect of socioeconomic factors will

result in confounding that overstates the harmful effect of lead on IQ because the

socioeconomic effect will be mixed with any true effect of lead exposure. In addition,

confounding by social factors may be a concern for some other lead-associated

health measures with social gradients such as height (Silventoinen 2003).

Data presented from most of the key studies included in this review strongly

suggest that substantial confounding by socioeconomic factors occurs. Even

with adjustment for crude measures (e.g., parental education and household

income ) (Lanphear et al. 2000), the apparent lead effect on cognitive function is

greatly reduced. Such a pattern in which adjustment for a crude proxy results

in a substantial decrement in the magnitude of association would suggest that

“residual confounding” may be present in the adjusted estimate of effect. If residual

confounding is indeed present, then tighter control for confounding with more

refi ned measures of the social environment may further attenuate or eliminate the

apparent effect (Savitz et al. 1989).

The following factors complicate this scenario:

1. Socioeconomic status is a very elusive construct to fully capture; it is far more

complex than is refl ected in parental education or income. Socioeconomic

status includes many aspects of economic means and associated lifestyle,

# 24 so that adjustment for operational measures, such as education or income,

will always be incomplete. Adjustment for an imperfect proxy measure of a

confounder results in residual confounding (Greenland et al. 1985; Savitz et

al. 1989).

2. Long-term lead exposure is imperfectly refl ected in a current blood lead

measure or to some extent, even from a series of blood lead measures (see

Blood Lead Tracking) (Bellinger et al. 1989). Whatever physiologic effect lead

might produce, available evidence suggests that the impact is chronic and

cumulative. Beyond what is refl ected in a blood-lead measure, SES may be

indicative of historical exposure; thus, the observed effect of socioeconomic

status would partly refl ect an effect of lead exposure above and beyond the

blood-lead measure.

The nature and magnitude of these associations is less clear when focusing on

BLLs <10 μg/dL. Measures of social advantage, including income and parental

education, are associated with BLLs <10 μg/dL (e.g., Lanphear et al. 2000).

However, the relative importance of different aspects of socioeconomic status

and the pathways by which they affect lead exposure are not entirely clear . The

association between lower income and deterioration of paint in older housing

contributes to variation in BLLs, even BLLs <10 μg/dL. The increase in geometric

mean blood lead associated with living in an older home is greater for children from

low-income families than for those from middle income families (Pirkle et al. 1998).

Nonetheless, with the elimination of lead in gasoline and the continued decline

in the proportion of homes with leaded paint (Jacobs et al. 2002), the relative

importance of lead exposure sources possibly is changing. It is also possible that

the association of social factors with lead exposure is different for populations with

BLLs <10 μg/dL than for those above that level.

Several strategies have been applied to address the role of socioeconomic factors

and isolate a non-specifi c effect of socioeconomic factors on IQ from an effect of

lead exposure. First, populations can be sought or even constructed in which blood

lead is not closely associated with SES as demonstrated most clearly in the Boston

cohort (Bellinger et al. 1987). In that population, all in a relatively low blood lead

range for that time and the great majority of relatively advantaged SES, there was

a weak positive gradient between socioeconomic status and lead. The Kosovo cohort

(Wasserman et al. 1997) also departed from the usual trend in that the more SES

advantaged of the two communities studied was the site of a lead smelter . As a

result, adjustment for social and other covariates actually strengthened the inverse

relation of blood lead to IQ in that population.

Second, improved measures of socioeconomic factors have been applied to better

control for non-specifi c effects. That is, by refi ning and decomposing the construct

of socioeconomic status, it is possible to adjust more fully for the confounding

dimensions such as nutrition, parental stimulation, attitudes towards achievement,

# 25 etc., and not adjust for the aspects that primarily serve as a proxy for lead exposure,

such as age of housing and neighborhood. One example among published research

of refi ning and decomposing the construct of socioeconomic status has been the use

of the HOME scales to adjust for stimulation provided by caregivers. Use of HOME

scales has in some cases further attenuated but not eliminated apparent lead–IQ

associations.

A third approach to examine the possibility of confounding of the blood lead–IQ

relation at low levels would be to conduct a formal statistical assessment of the

extent to which the strength of the observed association across studies varies in

relation to control for relevant confounders, using meta-regression, as was applied

by Schwartz (1994). This approach could be refi ned to assess possible residual

confounding. One challenge in performing such an analysis using published

summary data is the diffi culty in operationalizing measures of the tightness of SES

adjustment while controlling for other aspects of study design that might infl uence blood lead–IQ slopes. An alternative approach is discussed later in this report (see

Research Needs).

Conclusions: On the basis of available evidence the observed associations

between blood lead below 10 μg/dL and cognitive function likely do not entirely

result from confounding. This conclusion is supported by the following evidence:

• The studies showing the strongest relationship (Canfi eld et al. 2003;

Bellinger et al. 2003) at low levels employed the HOME scale for adjustment,

which is the best available measure for assessing the impact of the home

environment on child development.

• Two cohorts, Kosovo and Boston, in which strong associations were found

between blood lead and IQ, were characterized by a direct, rather than

inverse, correlation of blood lead with social advantage.

• Associations of children’s blood lead close to 10 μg/dL and intelligence have

been seen in diverse geographic and social settings.

• Animal data have demonstrated effects of lead at BLLs near 10 μg/dL.

On the other hand, the ability to detect confounding by omitted covariates by

comparisons across studies is limited because, for most covariates of potential

interest, the number of relevant studies in one group being compared is limited.

In other words, for a given covariate, either few studies included it (e.g., postnatal

ETS exposure) or few excluded it (e.g., SES). At this point, the case for residual

confounding by social environment is speculative, but available studies relating

blood lead to cognitive function in children cannot entirely exclude the possibility

that observed associations are at least partly infl uenced by it. Such a possibility

does increase uncertainty about the actual strength and shape of blood lead

relationships at BLLs less than 10 μg/dL.

# 26 Iron Status

Nutritional factors, such as iron and zinc intake, that might be correlated with

lead uptake and might infl uence children’s health, could confound associations

between BLLs and health from observational studies. The potential for iron

defi ciency to confound the association between blood lead and neurodevelopmental

status has been of most concern and is the focus of this discussion. The likelihood

of such bias is dependent upon the extent to which iron status was controlled in

a given study and the prevalence of iron defi ciency in a study population. Iron

defi ciency may impair neurodevelopment in a manner similar to low-level lead

exposure and the populations at increased risk for iron defi ciency and lead toxicity

may overlap (Lozoff et al. 1991; Wasserman et al. 1999). However, the association

between iron defi ciency and blood lead is not consistent across populations (CDC

2002). Therefore, the potential for iron to confound an association of blood lead with

neurodevelopmental status will vary across populations, depending on both the

prevalence of iron defi ciency and its association with blood lead level.

For research purposes adequate assessment of iron status entails determination

of hemoglobin or hematocrit and at least two other measures of iron status.

Generally accepted defi nitions of iron defi ciency and iron defi ciency anemia depend

on age- and sex-specifi c normal ranges. The iron status measures most commonly

used are mean corpuscular volume (MCV), free erythrocyte protoporphyrin (FEP)

or zinc protoporphyrin (ZPP), transferrin saturation, ferritin, and, more recently

, transferrin receptor. The standard for defi ning iron defi ciency is values indicating

iron defi ciency on at least two of these measures and/or response to iron therapy

with an increase in hemoglobin to at least 10 g/L. The utility of ferritin in young

infants is under debate, making it important that functional measures, such as

MCV or ZPP be obtained. There are limitations of each measure (e.g., ferritin goes

up with infection, MCV is down in hemoglobinopathies, etc.).

Although iron defi ciency with low hemoglobin has been associated with later

impairment of cognitive function (Grantham-McGregor et al. 2001), it is not certain

which measure(s) of iron status are most strongly related to neurodevelopmental

outcomes. In studies of children with higher BLLs, controlling for hemoglobin

is problematic because lead toxicity can reduce hemoglobin in the normal range

or cause frank anemia. This is less of a concern in studies of children with BLLs

<10 μg/dL, a range in which no meaningful impact on hemoglobin levels has been

observed.

Conclusions: Measurement of iron defi ciency has been absent or suboptimal in

most of the studies reviewed. Two studies in which iron status was controlled for

using transferrin saturation (Canfi eld et al. 2003) and serum ferritin (Lanphear

et al. 2000) found strong inverse relationships between blood lead and cognitive

function, whereas a third study that controlled for the presence of iron-defi ciency

anemia found the opposite (Wolf et al. 1994). Furthermore, iron-defi ciency anemia

# 27 is the measure of iron status most clearly linked to impaired cognitive function;

therefore, it seems unlikely that the prevalence of iron defi ciency anemia could be

high enough in the populations showing the strongest inverse relations of blood

lead to cognitive function (Canfi eld et al. 2003; Bellinger et al. 2003; Lanphear et

al. 2000) to entirely explain these associations. In the NHANES III data used by

Lanphear et al. (2000), the prevalence of iron defi ciency ranged from 1% to 9%,

depending on the age and sex group (CDC 2002). Finally, in Kosovo, following

treatment of iron-defi cient children with iron supplements, no association of earlier

hemoglobin levels with IQ at age 4 (Wassserman et al. 1994) or age 7 (Wasserman

et al. 1997) was found. Thus, iron defi ciency likely does not completely explain the

inverse associations between BLLs <10 μg/dL and cognitive function.

Tobacco

Blood lead levels in children have been associated with exposure to

environmental tobacco smoke (assessed by caregiver report or by urinary cotinine

levels) in both general population surveys (Stromberg et al. 2003; Mathee et al.

2002; Lanphear et al. 2000; Mannino et al. 2003) and in studies of children living

near lead smelters (Willers et al. 1988; Baghurst et al. 1992; Baghurst et al. 1999).

The explanation for this association is not entirely clear; possibilities include

enhancement of lead uptake by environmental tobacco smoke (ETS), exposure to

lead in ETS itself, and differences in cleaning practices or child supervision between

households with and without smokers.

Maternal smoking during pregnancy has been associated with behavioral

problems and impaired cognitive development in children; fetal hypoxia is one

possible contributing mechanism (Habek et al. 2000). Evidence for an effect of

prenatal or postnatal ETS exposure on neurodevelopment is less clear (Eskenazi

et al. 1999). As with studies of lead and neurodevelopment, social factors may

confound, at least in part, the association between maternal smoking and

neurodevelopment (Baghurst et al. 1992). A child’s prenatal exposure to maternal

smoking or pre- or postnatal exposure to ETS could, if these are causally related

to impaired neurodevelopment or other adverse health outcomes, confound the

observed associations of lead and health. In addition, if a relationship between

postnatal ETS and neurodevelopment is established, lead exposure could be a

mediating factor.

Conclusions: Of the studies reviewed, most did not assess prenatal or postnatal

ETS as a possible confounding factor. Those that assessed tobacco at all controlled

for maternal smoking during pregnancy. However, the two exceptions, Lanphear

et al. (2000) in which serum cotinine measurements were used to control for ETS

and a study based on the Port Pirie cohort (Tong et al. 1996; Baghurst et al. 1992)

which reported postnatal parental smoking, provide no evidence that confounding

by tobacco exposure accounts for the associations observed between blood lead and

adverse health effects. Limitations in available studies leave some uncertainty as

# 28 to what contribution, if any, ETS might make to observed associations between BLL

and health.

Causal Direction

Inference of causation from observational epidemiologic studies is sometimes

complicated by the possibility that the health outcome under study could be a

cause of the exposure or causally related to a third factor which itself is a cause of

the exposure under study. Two factors that infl uence blood lead levels—mouthing

behavior and calcium balance—are relevant to assessing causal direction in studies

of the health effects of lead at low levels.

Mouthing behavior

An important pathway of lead uptake by young children is ingestion of leadcontaminated dust (Charney et al. 1980; Bornschein et al. 1985), presumably

through mouthing of hands, surfaces, and objects on which the dust is deposited.

Although mouthing behavior is diffi cult to measure, children with more reported

mouthing behavior have higher BLLs in relation to environmental lead exposure

(Lanphear et al. 1998; Bellinger et al. 1986; Baghurst et al. 1999). Pica (purposeful

ingestion of non-food items) can be a consequence of impaired neurodevelopment

and can predispose one to lead ingestion (Cohen et al. 1976; McElvaine et al. 1992;

Shannon et al. 1996), but the relation of variation in “normal” age-appropriate

mouthing behavior to neurodevelopment is uncertain. However, in groups of

children, average measured or caregiver reported mouthing has been shown to

diminish with age (Juberg et al. 2001; Tulve et al. 2002). Nonetheless, it is unclear

whether, at the individual level, more frequent mouthing behavior is a marker

(independent of its effect on lead ingestion) for delayed neurodevelopment. If such

behavior is a marker, then an association between blood lead level and impaired

neurodevelopment would result, and failure to adjust for mouthing behavior

would result in an overestimate of the blood-lead effect. On the other hand, if

measured mouthing behavior is associated with cumulative lead exposure above

and beyond that refl ected in measured BLLs, then controlling for mouthing

behavior could amount to over control, underestimating the true effect of lead on

neurodevelopmental measures.

Conclusions: At this point, no direct evidence supports reverse causation by

mouthing behavior, and this hypothesis remains speculative. Arguing against this

possibility, Tong et al. (1996) reported that an early measure of neurocognitive

development, the Bailey MDI, was not predictive of later BLLs.

Calcium balance

Calcium balance changes in relation to growth during childhood and during

the rapid expansion of bone mass during puberty and the pubertal growth spurt

# 29 (Bronner et al. 1998; van Coeverden et al. 2002; Bailey et al. 2000); estradiol may

infl uence bone mineral deposition in pubertal girls (Cadogan et al. 1998). It is

possible that effect of skeletal growth and puberty on calcium balance could cause

lower BLLs (Thane et al. 2002), just as the opposite changes in calcium balance

during menopause appear to cause an increase in blood lead (Hernandez-A vila et

al. 2000; Garrido Latorre et al. 2003). It should be noted that the average age at

menarche among U.S. adolescents dropped by approximately 2.5 months between

the periods 1963-1970 and 1988-94 and that this trend was accounted for in part

by a rising prevalence of obesity (Anderson et al. 2003). Average BLLs were likely

falling substantially during this same period.

Conclusions: Because human studies linking blood lead at levels <10 μg/dL to

delayed puberty and smaller stature are, with one exception, cross-sectional and

evidence is limited on this topic, reverse causation via changes in calcium balance

cannot be ruled out as accounting for at least some of the observed associations.

While the parallel secular trends in decreasing age at menarche and decreasing

BLLs could be explained in part to a causal effect of lead delaying age at menarche,

it is also possible that other secular trends (e.g. increasing obesity rates) have

caused the trend toward earlier menarche.



# Overall Conclusions

Question 1: Does available evidence support an inverse association between

children’s blood lead levels <10 μg/dL and children’s health?

Because of the large number of studies that have assessed cognitive function as

an outcome, the review and conclusions by the WG primarily focus on this health

domain. The consensus of the WG is that the overall weight of available evidence

supports an inverse association between BLLs <10 μg/dL and the cognitive function

of children. The evidence for such an association is bolstered by the consistency

across both cross-sectional and longitudinal studies in varied settings with blood

lead distributions overlapping 10 μg/dL and by the lack of any trend towards a

weaker association in studies with lower population mean BLLs. More recent

studies and analyses best suited to examining this association (Canfi eld et al. 2003;

Bellinger et al. 2003) have added to, rather than refuted, evidence for such an

association noted in prior CDC guidance (1991).

In reaching this conclusion, the WG is mindful of limitations in the available

evidence base. Relatively few studies have directly examined the association

between BLLs <10 μg/dL and health status among children and many of those that

have are cross sectional studies in which data are unavailable on BLLs earlier in

life and key covariates. The WG concluded that fi ndings from numerous published

studies relating BLL to cognitive function, while not limited to children with BLLs

# 30 <10 μg/dL, collectively were not consistent with a threshold for the BLL-cognitive

function association at 10 μg/dL. This indirect evidence, however , is less persuasive

than cohort studies and analyses that directly assess the relationship between BLL

and health <10 μg/dL. These directly relevant studies analyzed data for children

whose measured BLLs did not exceed 10 μg/dL (to the investigator’s knowledge).

Likely included in these analyses were some children who, because of random

variation in BLL or age trends, did at some time have a BLL > 10 μg/dL that was

not measured. Such misclassifi cation could produce an apparent inverse association

between BLLs <10 μg/dL and health status even if a threshold existed at 10 μg/dL.

Such misclassifi cation, however, could not account for the observed BLL–IQ relation

in the Canfi eld (2003) study, in which a steeper slope was observed at BLLs <5 μg/dL

than at levels 5–10 μg/dL.

For health endpoints other than cognitive function, including other neurologic

functions, stature, sexual maturation, and dental caries, available data are more

limited and less replication of fi ndings exists across studies. Nonetheless, the

available data from these studies are consistent with associations between higher

BLLs and poorer health indicators for values <10 μg/dL .

Question 2: Are the observed associations likely to be causal?

The work group concluded that, while available evidence does not permit a

defi nitive causal interpretation of the observed associations between higher BLLs

and adverse health indicators for values <10μg/dL, the weight of available evidence

favors, and does not refute, the interpretation that these associations are, at least in

part, causal. The WG also concluded that the limitations of the available evidence,

including likely residual confounding by social environment, leave uncertainty

about the absolute strength and shape of the causal relation at the population level.

Even greater uncertainty attends the use of associations observed in the relevant

population studies for interpretation of BLLs measured in individual children at a

single point in time. Thus, the WG does not believe that the individual children can

be classifi ed as “lead poisoned,” as the term is used in the clinical setting, on the

basis of the associations observed in studies reviewed for this report. The basis of

the overall WG conclusions is discussed below and is followed by a summary of the

important limitations in the available evidence.

The WG explored other possible explanations (aside from causation) for these

associations and concluded that none are likely to fully explain the observed

data. The context of evidence from animal, in vitro, and human studies of adult

populations, also supports the consensus of the WG conclusion that the observed

associations most likely represent, at least in part, causal adverse impacts of lead

on children’s cognitive function at BLLs <10 μg/dL.

The greatest source of uncertainty in interpreting the relationship between BLLs

<10 μg/dL and cognitive function is the potential for residual confounding by social

# 31 factors. The conditions for residual confounding appear to be present: BLLs are

strongly infl uenced by SES, SES is clearly related to measured cognitive function,

and social factors that could infl uence BLL and cognitive function are diffi cult to

measure precisely. Other sources of potential bias are, individually, less concerning

than social confounding, but collectively they add to the overall uncertainty about

the absolute strength and shape of the relation of BLL to impaired cognitive

function. These include, random error in blood lead measurement and in a single

BLL as a measure of chronic exposure, possible infl uence of factors that have not

been fully addressed in published studies, including blood lead tracking and age

trend, which limits cross-sectional studies in particular, tobacco smoke exposure,

iron defi ciency, and mouthing behavior. Error in measuring lead exposure would

bias observed associations towards the null, while failure to adjust for the other

factors noted would most likely bias observed associations away from the null.

The recently reported trend of asymptotically increasing slopes of lead-associated

decrements in cognitive test scores at lower BLLs (Bellinger et al. 2003; Canfi eld

et al. 2003; Lanphear et al. 2000) would be expected if residual confounding were

operative as illustrated in Figure 7. The graph on the left depicts a comparison of

two groups of children who live in a high exposure setting. They differ , on average,

with respect to aspects of the home and social environment that are not captured

in measured covariates. This results in one group ingesting and absorbing twice

as much lead and having, after adjustment for measured covariates, a mean IQ 1

point lower than the children raised in a more favorable environment. Assuming a

roughly linear relation of lead intake to blood lead, the result is that one group has

a mean blood lead twice as high, corresponding to a 10 μg/dL difference in blood

lead and an estimated blood lead-IQ slope attributable to residual confounding

of 0.1 IQ points per μg/dL. The fi gure on the right depicts the same hypothetical

two populations living in a low exposure setting. The same imperfectly measured

differences in social environment contribute to the equivalent covariate-adjusted

difference in mean IQ, but in this case, although one group ingests twice as much

contaminated dust as before, lower levels of lead contamination result in the two

children having a blood lead difference of only 1 μg/dL in blood lead level. The

result is an estimated blood lead-IQ slope attributable to residual confounding of

1.0 IQ points per μg/dL. In addition, a convincing and directly relevant biologic

mechanism for such a dose response relation has yet to be demonstrated. Though

this hypothetical example cannot demonstrate that residual confounding underlies

the steep blood lead-IQ slopes observed at low levels, it does support the need for

caution in interpreting the absolute value of the estimated effect sizes.

The available data for these other health endpoints, taken mostly from crosssectional studies, are more limited and fi rm conclusions concerning causation

cannot be made at this time.

# 32 

# Research Needs

Resolving residual confounding through observational studies

It may be somewhat easier to identify study populations with BLLs <10 μg/dL

in which socioeconomic factors are not associated with exposure as compared to

populations with more widely varying blood lead levels within many low SES

children, but few high SES children, may have blood lead levels above 20 or 30 μg/dL.

Confi guring a cohort similar to the one in Boston or assembling one from the pieces

of others already studied could be helpful in isolating socioeconomic and lead effects

from one another. Another formal statistical approach that could be applied to

pooled data across multiple studies is the application of a hierarchical modeling

approach as proposed by Schwartz et al. (2003, in press).

Controlled intervention trials

While experimental designs can establish causation with greater confi dence

than observational studies, intentionally exposing some children to higher BLLs

in a randomized controlled design would be unethical. However, randomized

trials in which interventions are tested for their ability to reduce BLLs <10 μg/dL

or prevent their increase provide an opportunity to support or refute a causal

relationship between BLLs <10 μg/dL and adverse health outcomes. Studies testing

such interventions should measure covariates relevant to assessing health effects,

allowing a test of the causal hypothesis should they be successful at suffi ciently

reducing BLLs.

Animal and in vitro studies to explore mechanisms and dose-response

relations

While the overall evidence from animal or in vitro models supports the biologic

plausibility of adverse effects of lead at BLLs <10 μg/dL, the WG is unaware of

directly relevant animal or in vitro studies that demonstrate a steeper slope for

adverse effects of lead exposure at lower BLLs than observed at higher levels.

Demonstrating such a relationship in experimental studies and identifying possible

mechanisms would increase confi dence in a causal interpretation of the observed

blood lead-response relationship in studies such as Canfi eld et al. (2003).

# 33 Figure 1. Expected variation in regression slopes given hypothetical

“true” threshold blood lead - IQ relation (A).

Notes 

# : Figures 2 and 3



# Selected estimates of change in outcome (Full Scale IQ or McCarthy General

Cognitive Index (GCI) derived from regression coeffi cients and listed in Table 2 and

the corresponding mean BLLs of the study population are displayed in Figures 2

and 3. Figure 2 contains results from studies where the BLLs were measured at

ages < 2 years, and outcome measures were measured at ages > 4 years. Figure 3

contains the results when both the BLLs and outcome measures were measured

at ages > 4 years. Both the crude (open dot) and adjusted (solid dot) coeffi cients

are displayed in the fi gures when both are available. (The Kosovo and European

Multicenter Study papers did not provide the crude coeffi cient). Although multiple

models for a single study population may have been fi t to results from differing

ages within the defi ned age categories, only the regression coeffi cients for the

highest age at which blood lead was measured (per study population) are included

in the fi gures. (The highest outcome measure age was used as a tiebreaker when

necessary.) Also, when models for both a concurrent blood lead measure and a

lifetime average blood lead measure existed for the highest age at which blood lead

was measured (Port Pirie and Rochester), the concurrent results were included.

For the study that provided multiple models for the same highest-age blood lead

versus outcome measure (Lavrion, Greece), the results from the model that included

the most covariates were included. Any studies not providing both a regression

coeffi cient and blood lead mean were excluded. Three-letter abbreviations for each

study population, defi ned in the legends below, were used on the plots. Hypothetic al me an and range of observed

da ta from epidemiologic studie s



# Blood lead leve l IQ

-Hyp ot hesized thre sh ol d Hypothesized “true”

relati on s

B A

C

# 34 Legend for Figure 2

Abbreviation Study population Reference

number Blood lead and

outcome ages

Bos Boston, Massachusetts 7 24 months / 10 years

Cin Cincinnati, Ohio 13 15-24 months / 6.5 years

Kos Kosovo, Serbia 37 24 months / 4 years

Por Port Pirie, Australia 23 24 months / 4 years

Roc Rochester, New York 11 6-24 months / 5 years

Legend for Figure 3

Abbreviation Study

population Reference

number Blood lead and

outcome ages

Bos Boston, Massachusetts 7 10 years / 10 years

Cin Cincinnati, Ohio 13 51-60 months / 6.5 years

Eur European Multicenter

Study 39 6-11 years / 6-11 years

Kar Karachi, Pakistan 28 6-8 years / 6-8 years

Kos Kosovo, Serbia 37 48 months / 4 years

Lav Lavrion, Greece 20 primary school / primary

school

Por Port Pirie, Australia 35 11-13 years / 11-13 years

Roc Rochester, New York 11 5 years / 5 years

# 35 Figure 2. Cognitive Function Regression Coeffi cients for Blood Lead Age

< 2 years and Outcome Age > 4 years.**Estimated Outcome Measure for PbB 5 to 15 μg/dL**



# Mean Blood Lead (μg/dL)

# 36 Figure 3

. Cognitive Function Regression Coeffi cients for Blood Lead Age

> 4 years and Outcome Age > 4 years.**Estimated Outcome Measure for PbB 5 to 15 μg/dL**



# Mean Blood Lead (μg/dL)

# 37 Source: Tong et al. 1996. Figure 4. Age trend in blood lead levels (BLLs).**μg/dL**

# 38 Figure 5. Hypothetical observed association between blood lead and IQ.

Figure 6. Hypothetical “true” association between blood lead and IQ.



# Blood lead level (μg/dL) at age 2 **IQ**

10 15 20 **Blood lead level (μg/dL) at age 6 IQ** 

5 10 15

# 39 Figure 7. Hypothetical slopes of the relationship between blood lead

and IQ associated with residual confounding (see Overall

Conclusions)

.

**High exposure setting**

**Blood lead level (μg/dL)** 10 20 0

-1 

# Low exposure setting

**Blood lead level (μg/dL)**

1 2 0

-1**IQ difference IQ difference** 

# 40 **Table 1. Lowest blood lead level (BLL) considered elevated by CDC and the US**

**Public Health Service**

Year and Reference BLL

(μg/dL)

1971 (Surgeon General) 40

1975 (CDC) 30

1978 (CDC) 30

1985 (CDC) 25

1991 (CDC) 10

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# 72Age atmeasurementStudypopulation(ref., type, n)HealthoutcomeBLLOutcomeBLLdistributionCovariatesResults on BLL-outcomeassociation <10 μg/dLNHANES III(22, X, 4853)Cognitivefunctionand academicachievement6-16 years6-16 yearsGeometric mean(GM)=1.9 μg/dL,98% <10 μg/dLSex, race/ethnicity, poverty,region, parent/caregivereducation and maritalstatus, serum ferritin, serumcotinine.Signifi cant inverse relationships between BLLand WRAT arithmetic, WRAT reading, WISCR block design, WISC-R digit span. For allbut block design, regression slopes becamemore negative with restriction of analysesto children with BLL <10, < 7.5, < 5.0, and< 2.5 μg/dL.Leipzig,Gardelegen,Duisberg,Germany(36, X, 384)Attention,sensorimotorfunction, andcognitivefunction5-7 years5-7 yearsGM=4.25 μg/dL,95 % <9 μg/dLFor WISC vocabularyand block design: Studyarea, visual acuity andcontrast sensitivity,parental education, sex,breastfeeding, height,nationality.For NES2 patterncomparison, patternmemory, tapping, simplereaction time, andcontinuous performance test:study area, visual acuityand contrast sensitivity,age, parental education,sex, birthweight, smokingin pregnancy, number ofsiblings, height, computerfamiliarity.Signifi cant negative association betweenWISC vocabulary and CPT results.Associations strongest in Gardelegen,community with lowest mean BLL.Leipzig,Gardelegen,Duisberg,Germany(40, X, 367)Neurobehavioralandneurophysiologicfunction6 years6 yearsMedian=5 μg/dL,95 % <10 μg/dLFor NES2 tapping, benton(pattern memory), reactiontime, pattern comparison:age, sex, parentaleducation, study area.For Visual Evoked Potentials:age, gender, study area.Signifi cant negative association of logtransformed blood lead with tapping speedand with pattern comparison.No signifi cant association of log-transformedBLL with visual evoked potential peaklatencies.**Table 5. Studies of health endpoints other than IQ or GCI in relation to BLLs <10 μg/dL.**

# 73Age atmeasurementStudypopulation(ref., type, n)HealthoutcomeBLLOutcomeBLLdistributionCovariatesResults on BLL-outcomeassociation <10 μg/dLNew York(24, X, 68)Mentaldevelopment12-36months12-36monthsMean=10.3 μg/dLReceives public assistance,maternal education, HOME -Stim Q, child race, maternalIQ, anemia or low MCV,birth order, sex, ageSignifi cantly lower Bayley MDI for children>10 μg/dL vs <10; scatterplot of adjustedMDI vs. BLL suggests relation linear relationcontinues at BLL <10.Leipzig,Gardelegen,Duisberg,Germany(1, X, 746)NES1 – TappingTest and patternrecognition5 and 6years5 and 6yearsMedian=5 μg/dLand 95thpercentileof overall frequencydistribution for PbBwas <10 μg/dLMaternal education, child’ssex, child’s ageAuthors report that after adjustment forconfounders a signifi cant defi cit for tappingand pattern comparison in relation to BLL(p<0.05) was found, but no regressioncoeffi cient or dose-response analyses arepresented.Leipzig,Gardelegen,Duisberg,Germany(2, X, 384)Visual function5-7 years5-7 yearsGM=4.25 μg/dL,95% <9 μg/dLChild’s age, assessmentsite, birth weight, child’smedical history, headcircumference, child weight,quality of fi xationVisual evoked potential interpeak latencieswere signifi cantly prolonged in relation to BLLfor one of three visual stimuli tested and nonsignifi cantly prolonged for a second stimulus.No signifi cant association between BLL andcontrast sensitivity was seen.Study locationnot stated(3, X, 400)Neurotransmitterandneuroendocrinelevels8.5-12.3years8.5-12.3yearsMean=3.95 μg/dLNo signifi cant correlation overall betweenBLL and serum prolactin (Pro-S) or urinaryhomovanillic acid (HVA-U). Analysisperformed on only those children BLL >5μg/dL showed a weak but statistically directrelation to BLL.NHANES III(5, X, 4391)Stature and headcircumference1-7 years1-7 yearsEthnic group, iron status,dietary intake, medicalhistory, sociodemographicfactors, and householdcharacteristicsSignifi cant inverse association of BLL tostature and head circumference (estimateddecrease of 1.57 cm in stature and 0.52 cmin head circumference for each 10 μg/dLincrease in BLL).

# 74Age atmeasurementStudypopulation(ref., type, n)HealthoutcomeBLLOutcomeBLLdistributionCovariatesResults on BLL-outcomeassociation <10 μg/dLMexico City(30, L, 119-199)Headcircumferenceevery 6monthsfrom 6-48monthsevery 6monthsfrom 6-48monthsMedian postnatalvaried from 7-10 μg/dLBirth problems, child’srace, maternal headcircumference, headcircumference at birthNatural log of blood lead at 12, 18, and24 months signifi cantly related to headcircumference at 36 months; Natural log ofblood lead at 12 months signifi cantly relatedto head circumference at 42 months. Mostother partial correlations between postnatalblood were negative. Plot of covariateadjusted head circumference at 36 monthsvs. natural log of blood lead at 12 monthsshows inverse relation that appears tocontinue below 10 μg/dL.Lavrion, Elefsina,Loutraki Greece(21, X, 522)Somatic growth,including headcircumference,height, andchestcircumference6-9 years6-9 yearsMean=12.3 μg/dL,Median=9.8 μg/dLPaternal education,paternal occupation, child’ssex, child’s age, iron status,assessment site, father’sheight, mother’s heightSignifi cant negative association of BLLand head circumference and height withscatterplot suggesting relation continuesbelow 10 μg/dL. No signifi cant associationwith chest circumference.NHANES III(32, X, 2186)girls: 1964 withpubic hair stage,1986 with breastdevelopmentstage and 1796with age atmenarche.)(AfricanAmerican only)Pubertaldevelopment ingirls8-18 years8-18 yearsGMs: Non-Hispanicwhites:=1.4 μg/dL;African Americans:= 2.1; MexicanAmericans= 1.7μg/dL.BLLs >5 μg/dL: 2.7%,11.6% and 12.8%,respectivelyFamily income,ever smoked 100cigarettes, child’s age,iron status, child’s medicalhistory, height, BMI, agesquaredFor age at menarche: height,family income, ever smoked100 cigarettes, child’s age,iron status, child’s medicalhistory, height, MI, agesquaredBlood lead levels of 3 μg/dL (comparedwith BLLs of 1 μg/dL) were associated withsignifi cant delays in breast and pubic hairdevelopment in African American andMexican girls. The trend was similar, but notsignifi cant, for non-Hispanic white girls. Ageat menarche was also delayed in relationto higher BLLs, but the association was onlysignifi cant for African-American girls.

# 75Age atmeasurementStudypopulation(ref., type, n)HealthoutcomeBLLOutcomeBLLdistributionCovariatesResults on BLL-outcomeassociation <10 μg/dLNHANES III(42, X, Sample I:1706 ages 8-16years with pubichair and breastdevelopment info;Sample II: 1235girls aged 10-16had info onmenarche)(all races)Pubertaldevelopment ingirls8-16 years8-16 years98.5% <10; 54.3%0-2.0Poverty income ratio, familysize, metro residence,child’s age, child’s race,BMICompared with BLLs 2.0 μg/dL and below,BLLs of 2.1-4.9 were associated withsignifi cantly lower odds of attaining TannerStage 2 pubic hair (0R=0.48, 95% CI0.25-0.92) and menarche (OR=0.42,95% CI 0.18-0.97); no signifi cantassociation with breast development wasnoted.NHANES III(25, X, 24901)Dental caries2+ years2+ yearsGMs: Age 2-5years=2.9 μg/dL, Age6-11 years=2.1 μg/dL;Age 12+ years=2.5μg/dL;74-88% ofparticipants with BLL<5 μg/dL in each agegroupPoverty income ratio,maternal education,exposure to cigarette smoke,child’s sex, child’s age,child’s race, assessment site,child’s medical history, dayssince last dental visit, usualfrequency of dental visitsComparing children 5-17 years of age inmiddle tertile of BLL (range of BLLs: 1.7-4.1)to those in lowest tertile, odds ratio fordental caries was 1.36 (1.01-1.83)Boston &Cambridge, MAandFarmington, ME(18, X, 543)Dental caries6-10 years6-10 yearsMeans: Cambridge/Boston 2.9 μg/dL,Farmington 1.7 μg/dLAge, sex, family income,education of femaleguardian, ethnicity, maternalsmoking, tooth brushingfrequency, tooth brush bristlehardness, gum chewingIn Cambridge/Boston, number of carioussurfaces increased signifi cantly with log BLLin linear regression and in graph comparingchildren with BLL of 1, 2, and 3μg/dL. InFarmington, non-signifi cant decrease incarious surfaces with increasing BLLKosovo(17, L, 281)Blood pressure66 months66 monthsK. Mitrovica:mean=37.3 μg/dL(sd=12.0); Pristina:mean=8.7 μg/dL(sd=2.8)For systolic blood pressure:birth order, child’s sex,child’s race, height, BMIFor diastolic blood pressure:birth order, child’s raceFigures showing adjusted mean systolic anddiastolic blood pressure for 10 blood leadgroups with approximately equal numbers ineach ordered by blood lead shows noconsistent trend among the 4 blood leadgroups with BLL approximately 5-10 μg/dL.

# 76Age atmeasurementStudypopulation(ref., type, n)HealthoutcomeBLLOutcomeBLLdistributionCovariatesResults on BLL-outcomeassociation <10 μg/dLBelgium(29, X, 143)Heme synthesisbiomarkers10-13years10-13yearsMeans: Boys: <1 km:28.7 μg/dL (SD=8);2.5 km: 15.6 (2.9);urban: 10.6 (2.0);rural: 9.2 (2.3) Girls:<1 km: 20.7 (7.6);2.5 km: 9.8 (3.8);urban: 9 (2.0); rural:8.7 (17)Not specifi edDose-effect relationships are plotted for FEP,ALAD, and ALAU. No threshold evident forALAD inhibition. Authors state if it exists, itmust be below 8-10 μg/dL. A BLL 5 thresholdfor increasing FEP evident at 15-20 μg/dLPb.Boston(27, L, 249originallyrecruited; 201 at2 years)Heme synthesisbiomarkers6-24months6-24monthsMean=7 μg/dLNot specifi edNo relationship between incidence ofelevated erythrocyte protoporphyrin levelsand BLLs below 15 μg/dLCincinnati(19, L, 165)Heme synthesisbiomarkers6-30months6-30monthsNot presentedNone presented, cruderesults onlySignifi cant positive association reported forFEP and ZPP and log transformed BLL at allages. Threshold for relationship at BLLbetween 15 and 20 μg/dL.Pribam, CzechRepublic(9, X, 246)Renal function12-15years12-15yearsMean ranged from8.39 μg/dL in girlsin the control area to14.9 μg/dL in boys inpolluted area 2None presented, cruderesults onlyUrinary RBP was found to be signifi cantlyassociated with BLL in a stepwise regression.When urinary RBP excretion was examinedby BLL tertiles, signifi cantly lower U-RBP wasseen in the group with BLL <8.64 μg/dLcompared with BLL 8.64-12.3.

# 77**T a** **ble 6. S e** **lected m e** **thodologic details from cohort studies** **Qu al** **i t** **y A** **ssu ran** **c e** **C o** **mm ent** **s Study** **P opu** **l a** **t i** **o n** **B l** **o od-** **l e** **a d** **M e** **as u** **r em** **ent C** **ogn iti** **v e** **F u** **n ct** **i o** **n M** **e a** **s u** **r em** **ent**BostonSamples were measuredby capillaryandvenous and were analyzed by ASV andGFAAS.BloodMDI was administeredat6-monthintervals beginning at6months ofage,by examiners blindtotheinfants’(6,7,34)specimensfor6-,12-,18,and24-monthspecimenswerecollected incapillarytubesbytrainedleadlevels.(Bellinger,etal.,1985)ForWISC-R,most childrenweretestedinasinglesession,2wereseentechnicians.Blood samples wereassayed induplicateortriplicate.Theanalyticalsystem wasinasecond session to completetesting,and 7weretestedintheir homes byparentalrequest.Psychologistscalibratedwithaqueous standardsofknownleadconcentrations.Each batchofsamples waswere blind toall aspects ofchild'sdevelopmental andleadexposure histories.accompanied by a blood sample ofknown lead concentrationstoquantifyintralaboratoryreliability.Several standardizedbloodsampleswithlead concentrationsalsowereincludedaftertheybecameavailablein1982fromCDC.(Rabinowitz,etal.,1985)57-monthvenous bloodsamples wereobtained.Lead was measured induplicatebyGFAAS.An aliquot of a standardized bloodsampleprovidedbytheNationalBureau ofStandardswasincluded ineachbatchofsamples.(Bellinger, etal.,1991)CincinnatiSamples were measuredby venipuncture,heel stick, and fingerstickforinfants andwereanalyzed byForWISC-R,oneexperiencedpsychometrician performedalltheassessments.Children weretestedata(13)ASV.Bloodsamples were obtainedusing eithervenipunctureorheelstick.Approximately72%ofallpediatric clinic.Theexaminerwasblindtotheexposurelevelsofthechild.ForMDI,allassessmentstooksamples are venipuncture.Forheel stick,two capillarytubes werefilledforduplicatePbBplace ina prenataland childwelfare clinic.Psychometrictests were administered ataninner-cityhealth clinicdetermination.Ifvenipuncturewaspossible,pediatricvacutainertubes werefilled,one forPbBbythestudyleaderortrainedassistantwithwhominter-testerreliabilityhadbeenpreviouslyestablished.determinationanda secondfor serumironandtotalironbindingcapacity(TIBC)analyses.TheTesterswereblindtochildren'sblood-leadlevels.samplewas aliquotedand duplicateanalysesperformed accordingtoapredetermined protocol usingASV.Thelaboratoryparticipatesinboththe CDC andPAStateBlood Leadand ProtoporphyrinPrograms.A seriesofbench-topQCsamplesandblindQCsampleswere analyzedwitheachrun.(Bornscheinetal.,1985)ClevelandSamples were measuredby venousandwere analyzed by GFAAS.Bloodsampleswerecollected inWPPSI,MDI,andStanfordBinet IQtests wereconductedbywell-trainedexaminersblindtoall riskand(14,15, 16)heparinizedplasticsyringeswhichhadbeen determinedtobe freeoftracemetals.The concentrationbackgroundinformation.Hometestingwasusedtocontrolattrition,tominimizebiasinattrition,andtoof leadinwholeblood sampleswasdetermined byGFAAS.All sampleswere runinduplicate.ThefacilitateadministrationoftheHOMEInventory.Inter-observer agreementwaschecked through observationwithin-run(sameday) reproducibilitywasevaluatedfor asample ofadult wholeblood.Theobtainedandduplicate scoringbyasupervisorfor approximatelyoneoutofevery26examinations.Agreementwasvalueswere55.2ug/dl,1.34,and2.4%,respectively,for themean, SD, and coefficient of variation.maintainedat r=.99.Answer sheetswerecheckedforpossibleirregularitiesbythesupervisorwithinafewRegular assessmentofaccuracy and precision using CDCsamples ofbovinebloodwere conducteddays ofeachadministration.and foundtobewithinthecertified range.Twointer-laboratory reviewswereconductedfor furtherdeterminationof accuracy.Blood-leadlevelswerenot adjustedfor hematocrit.(Ernhart, etal., 1985)Costa RicaSamples were measuredby venousandwere analyzedbyGFAAS.VenipuncturesamplesweretakenSpanish versionsofBayley MDIand WPPSIwereused intheassessment.Asingletester,trainedby oneof(41)andredbloodcellswerepromptlyseparated andfrozenforfuture analysisinthe U.S.Thefrozenredtheprimaryinvestigatorsandthemostseniorresearch psychologistinthecountry, administeredthecellswereanalyzedusingGFAAS inalaboratorythatparticipatesinCDC'sMaternaland ChildHealthassessments.Thetesterwasblindtothe children'sironstatusand neverknew theblood-leadlevels(theseResources Development ProficiencyTesting ProgramforBloodLead.QualitycontrolwasmonitoredwereperformedintheU.S.).(Lozoff, personalcommunication)throughcertifiedcontrolsobtained fromtheNationalBureauofStandards.Redcellleadvalueswereconvertedtowholeblood-lead levelsusingtheformulaofRosenetal.(1974).KosovoSamples weremeasuredby venousandwereanalyzed by GFAAS.All bloodspecimens wereThree Yugoslavian psychologistsscoredtheWISC-RandtheMcCarthyGCIindependently.Allinterviewsand(37,38)refrigerated onsiteand transportedonweticetoColumbiaUniversitywhereallassays wereassessmentinstrumentsweretranslatedandadministeredinthe two dominantlanguagesoftheregion,Serboperformed.ThelaboratoryparticipatesinCDC'sPBBQCprogramandiscertified byOSHA.OvertheCroatianandAlbanian.Trainingand reliability visits occurred.Theaverageinterclasscorrelationfor96 testsstudyperiod,interclasscorrelationwithQCvalueswascomputed,withcorrelationcoefficientsof.95foroverstudyperiodwas calculated.PbB.Mexico CitySamples were measuredby venousandwere analyzed by ASV.Samples wereanalyzedatFourtrainedpsychologistsblindtochildren's leadlevels administeredtheMcCarthyGCI.Astherewereno(31)EnvironmentalSciencesAssociates(ESA)Laboratories,Inc., whichisaCDCreferencelabforthenormsfortheMcCarthyscaleintheMexican population,theU.S.normswereusedtocalculateGCI,withaBloodLead Proficiency TestingProgramand alsoparticipatesintheNewYorkStateDepartmentofSpanishtranslationof thetest.Interexaminer reliabilitywasassessedbycalculatingthecorrelationinGCIControlProgram.AllsampleswereanalyzedusingASV.Sampleswithmeanduplicatevalues<5scores assigned bytwo ofthepsychologists withthe scoresofathirdpsychologistwhomtheyobservedug/dlwerereanalyzedinduplicatebygraphitefurnaceAAS.Mean values oftheduplicateswereusedapplyingthetestinallpossiblecombinationswith10subjectsforeachcombination.Meanobserver-examinerasdata.(Rothenberg, et al.,1994)correlationwas.99.

# A-1 

# APPENDIX A :

LITERATURE REVIEW AND CLASSIFICATION UPDATE

# A-3 The literature review began with the Agency for Toxic Substances and Disease

Registry’s Toxicological Profi le for Lead (ATSDR Tox Profi le), published July 1999.

The Health Effects chapter was thoroughly read and all articles relating to low

blood lead levels in children were chosen, regardless of whether they demonstrated

signifi cant results. New literature searches were then performed by Battelle’s

Technical Information Center. The year 1995 was chosen as the cutoff date for the

new searches because the WG felt that, before this time, research rarely focused

on BLLs <10 μg/dL, and that most relevant articles before 1995 were cited in the

ATSDR Toxicological Profi le. Searches were performed on a variety of databases

using DIALOG and a set of keywords.

The following is an example of the DIALOG, including databases and keywords:

SYSTEM 

# : OS - DIALOG OneSearch

File 6 

# : NTIS 1964-2003/May W3 (c) 2003 NTIS, Intl Cpyrght All Rights Res

File 103 

# : Energy SciTec 1974-2003/May B1 (c) 2003 Contains copyrighted material

File 266 

# : FEDRIP 2003/Mar Comp & dist by NTIS, Intl Copyright All Rights Res

File 161 

# : Occ.Saf.& Hth. 1973-1998/Q3 (c) Format only 1998 The Dialog Cor p.

File 156 

# : ToxFile 1965-2003/May W2 (c) format only 2003 The Dialog Corporation

File 155 

# : MEDLINE(R) 1966-2003/May W2 (c) format only 2003 The Dialog Cor p.

File 162 

# : Global Health 1983-2003/Apr (c) 2003 CAB International

File 71 

# : ELSEVIER BIOBASE 1994-2003/May W3 (c) 2003 Elsevier Science B.V.

File 40 

# : Enviroline(R) 1975-2003/May

File 73 

# : EMBASE 1974-2003/May W1 (c) 2003 Elsevier Science B.V.

File 34 

# : SciSearch(R) Cited Ref Sci 1990-2003/May W2 (c) 2003 Inst for S ci Info

File 5 

# : Biosis Previews(R) 1969-2003/May W2 (c) 2003 BIOSIS

Set Items Description

S1 512735 NATAL? OR PRENATAL? OR PERINATAL? OR POSTNATAL?

S2 1244432 INFANT? ? OR INFANCY

S3 2607491 CHILD? ? OR CHILDREN? ?

S4 253558 LEAD/TI,DE,ID

S5 184354 PB

S6 68959 RN=7439-92-1

S7 5798237 BLOOD

S8 14048 (S1:S3) AND (S4:S6) AND S7

S9 2153692 GROWTH/TI,DE,ID

S10 31450 STATURE

S11 634981 NUTRITION

S12 169948 HEARING

S13 200409 (RENAL OR KIDNEY)(3N)FUNCTION?

S14 669012 BLOOD()PRESSURE

S15 13 HEMESYNTHESIS

S16 61334 HEMATOPOIESIS

S17 20269 (VITAMIN()D)(3N)METABOLI?

S18 1441 S8 AND (S9:S17)

S19 438 S18 AND PY=1990:1996

S20 422 S19/ENG OR (S19 AND LA=ENGLISH)

S21 353 S20/HUMAN

S22 190 RD (unique items)

S23 190 Sort S22/ALL/PY,D

# A-4 S24 19583 NEUROBEHAVIO?

S25 272980 NEUROLOGICAL?

S26 166224 NEUROLOGIC

S27 148942 NEUROTOXIC?

S28 15459 NEURODEVELOPMENT?

S29 7061 COGNITIVE()DEVELOPMENT

S30 2878983 BEHAVIOR? OR BEHAVIOUR?

S31 3 IMPULSITIVITY

S32 54987 HYPERACTIVITY

S33 10725 ADHD

S34 31451 IQ OR (INTELLIGENCE()QUOTIENT? ?)

S35 3350 WISC

Ref Items Index-term

E1 715223 *DC=A8.186. (Central nervous system)

E2 645734 DC=A8.186.211. (Brain)

E3 23250 DC=A8.186.211.132. (Brain stem)

S36 715223 DC=’A8.186.’:DC=’A8.186.211.132.’

S37 2936 (S8 AND (S24:S36)) NOT S18

S38 964 S37 AND PY=1990:1996

S39 941 S38/ENG OR (S38 AND LA=ENGLISH)

S40 808 S39/HUMAN

S41 415 RD (unique items)



# This literature search was fi rst run for the years 1995-2002. In spring, 2003, the

search was rerun for the years 2002-2003 to determine the relevance of recently

published articles. Also at this time, the search was rerun for the years 1990-1996

for relevant articles that were not cited in the ATSDR Toxicological Profi le. Titles

and abstracts from each literature search were reviewed, and relevant articles were

ordered for further review. Additional articles were identifi ed while reviewing the

selected articles and were added to the list of references, as were several articles

recommended by workgroup members.

The table below provides a summary of all the articles obtained from the various

sources. This table shows when the search was performed, the years covered in the

search, the number of articles found in the literature search, the number of articles

ordered after the titles and abstracts had been reviewed, and the number of articles

that were relevant for abstraction.

# A-5 Summary of Literature Review Results

Date of

Search Years

Covered Number

of Unique

References

Found Number of

reviewed for

relevance Number of Articles

Abstracted into the

Database

9/02 1995-2002 327 79 12

4/03 2002-2003 119 14 4 a



# 5/03 1990-1996 605 25 4

ATSDR

Tox Profi le Prior to

1996 - 107 24

Referrals b 

# various 10 12 6

Total: 235 50

Relevant articles cited in Tables 2- 5 42

a 

# A 5 th 

# article, Stone et al. 2003, was obtained from this search and is not abstracted into the database but

its relevance is discussed elsewhere in the report.

b 

# Referrals include articles that were recommended by workgroup members, as well as those articles cited as

references in studies identifi ed in the ATSDR Tox Profi le or literature searches.

# B-1 

# APPENDIX B

:



# DISCUSSION OF CRITIQUE OF

NHANES III DATA BY STONE ET AL. (2003)

# B-3 Stone et al. (2003) reanalyzed the data used by Lanphear et al. (2000). While

the results they present are largely consistent with the fi ndings of Lanphear et

al. (2000), they provided a critique of the validity of the NHANES III data for

evaluating lead-related impacts on neuropsychological development in children.

Because their critique cuts across on neuropyschological measurements performed

in the survey, the main points of their paper are summarized in this appendix, as

follows.

• Stone et al. note that the weighted mean values for the four measures used

by Lanphear et al. are below the predicted mean based on standardization

data for these tests collected in the early 1970s for the WISC-R) and early

1980s for the WRAT. Stone et al. argue that the mean values should be

higher than predicted by the standardization means because of secular

improvements in cognitive test scores. One possible reason cited for the

discrepancy is that NHANES tests were not administered by a psychologist.

It is unclear, however, if the population sample used in the standardization

data was equally representative of the U.S. population at that time or if

changes in the population composition since then would lead to an increase

or decrease in overall mean test performance. More importantly, it is unclear

how a bias in mean score, even if real, and the use of non-psychologists for

testing could produce associations between BLLs and test scores, given

that examiners could not have known the BLLs of participants. If nonpsychologists produced less precise test results than psychologists would

have, the expected impact on regression coeffi cients would be a bias toward

the null.

• The age-adjusted scores used in NHANES are correlated with age, and

they should not be. Stone et al. show that age is negatively correlated with

arithmetic, block design, and digit span and positively correlated with reading.

However, since BLLs decrease with age across the age range studied, the

negative correlations would tend to produce a trend towards higher scores with

increasing blood lead for those tests, the opposite of the fi ndings of Stone et al.

• Imputation of missing covariate values was performed for a substantial

proportion of observations in the analyses performed by Lanphear et al.

While imputation could increase covariate mismeasurement and residual

confounding, analyses presented by Stone et al. demonstrate essentially similar

fi ndings when analyses are restricted to observations with full rank data.

• Relevant covariates, including whether a child has repeated a grade,

whether interviews were in Spanish, and several other factors, were not

included in analyses. However, two problems are evident in alternative “two

stage” analysis provided by Stone et al. First, it uses predicted rather than

residual blood lead level as an independent variable in a model relating

blood lead to test scores. This amounts to testing the relation to test scores

of a linear combination of covariates, many included in the model with test

score as the outcome. In addition at least one variable – having to repeat

a grade – is included as a covariate, possibly result serious over control as

# B-4 discussed earlier. Lead associated cognitive and behavioral effects have, not

surprisingly, been associated with an increased risk of failure to complete

high school. Thus, controlling for failure to complete a grade could amount to

controlling for an effect of, rather than a confounder of the lead effect.

As a whole, the Stone et al. critique of the NHANES III data do not provide a

convincing argument that the fi ndings reported by Lanphear et al. (2000) result

from problems with the sample or testing methods. However, the WG did consider

the limitations of the Lanphear et al. study, including its cross-sectional design

and limited data on potential confounders. This study was weighed in the overall

context of other relevant studies, including the more persuasive cohort studies,

which are largely consistent with the associations Lanphear et al. report.

# R-1 

# REFERENCES

# R-3 Note: Table R-1, which follows this alphabetical listing of references,

identifi es the numbered references that are used in Tables 2 through 6

(which also are included in the alphabetical listing).

Agency for Toxic Substances and Disease Registry. Toxicological profi le for lead. Atlanta:

U.S. Department of Health and Human Services, 1999.

Al-Saleh, I., Nester, M., DeVol, E., Shinwari, N., Munchari, L., Al-Shahria, S. Relationships

between blood lead concentrations, intelligence, and academic achievement of Saudi

Arabian schoolgirls. Int J Hyg Environ Health. 2001;204: 165–174.

Altmann, L., Sveinsson, K., Kramer, U., Weishoff-Houben, M., Turfeld, M., Winneke, G.,

et al. Visual functions in 6-year old children in relation to lead and mercury levels.

Neurotoxicol Teratol. 1998;20:9–17.

Altmann, L., Sveinsson, K., Kramer, U., Winneke, G., Wiegand, H. Assessment of

neurophysiologic and neurobehavioral effects of environmental p ollutants in 5- and

6-year-old children. Environ Res. 1997;73:125–131.

Alvarez Leite, E.M., Leroyer, A., Nisse, C., Haguenoer, J.M., de Burbure, C.Y., Buchet, J.P.,

et al. Urinary homovanillic acid and serum prolactin levels in children with low

environmental exposure to lead. Biomarkers. 2002;7:49–57.

Anderson, S.E., Dallal, G.E., Must, A. Relative weight and race infl uence average age at

menarche: results from two nationally representative surveys of U.S. girls studied

25 years apart. Pediatrics. 2003;111:844–850.

Annest, J.L., Pirkle, J.L., Makuc, D., Neese, J.W., Bayse, D.D., Kovar, M.G. Chronological

trend in blood lead levels between 1976 and 1980. N Engl J Med. 1983;308:1373–1377.

Baghurst, P.A., McMichael, A.J., Wigg, N.R., Vimpani, G.V., Robertson, E.F., Roberts, R.J.,

et al. Environmental exposure to lead and children’s intelligence at the age of seven

years. The Port Pirie Cohort Study. N Engl J Med. 1992;327:1279–1284.

Baghurst, P.A., Tong, S.L., Sawyer, M.G., Burns, J.M., McMichael, A.J. Sociodemographic

and behavioural determinants of blood lead concentrations in ch ildren aged 11-13

years. The Port Pirie Cohort Study. Med J Aust. 1999;170:63–67.

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