TOXICOLOGICAL PROFILE FOR 

LEAD 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

Agency for Toxic Substances and Disease Registry
 

August 2007 
LEAD ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and does not imply endorsement by the 

Agency for Toxic Substances and Disease Registry. 
LEAD iii 

UPDATE STATEMENT 

A Toxicological Profile for Lead, Draft for Public Comment was released in September 2005. This 

edition supersedes any previously released draft or final profile. 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch 

1600 Clifton Road NE 

Mailstop F-32 

Atlanta, Georgia 30333 
LEAD iv 

This page is intentionally blank. 
v 

FOREWORD

This toxicological profile is prepared in accordance with guidelines developed by the Agency for 

Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary. 

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health 

effects information for the hazardous substance described therein. Each peer-reviewed profile identifies 

and reviews the key literature that describes a hazardous substance's toxicologic properties. Other 

pertinent literature is also presented, but is described in less detail than the key studies. The profile is not 

intended to be an exhaustive document; however, more comprehensive sources of specialty information 

are referenced. 

The focus of the profiles is on health and toxicologic information; therefore, each toxicological 

profile begins with a public health statement that describes, in nontechnical language, a substance's 

relevant toxicological properties. Following the public health statement is information concerning levels 

of significant human exposure and, where known, significant health effects. The adequacy of information 

to determine a substance's health effects is described in a health effects summary. Data needs that are of 

significance to protection of public health are identified by ATSDR and EPA. 

Each profile includes the following: 

(A) The examination, summary, and interpretation of available toxicologic information and 

epidemiologic evaluations on a hazardous substance to ascertain the levels of significant 

human exposure for the substance and the associated acute, subacute, and chronic health 

effects; 

(B) A determination of whether adequate information on the health effects of each substance is 

available or in the process of development to determine levels of exposure that present a 

significant risk to human health of acute, subacute, and chronic health effects; and 

(C) Where appropriate, identification of toxicologic testing needed to identify the types or levels 

of exposure that may present significant risk of adverse health effects in humans. 

The principal audiences for the toxicological profiles are health professionals at the Federal, State, 

and local levels; interested private sector organizations and groups; and members of the public. 

This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that 

has been peer-reviewed. Staff of the Centers for Disease Control and Prevention and other Federal 

scientists have also reviewed the profile. In addition, this profile has been peer-reviewed by a 

nongovernmental panel and is being made available for public review. Final responsibility for the 

contents and views expressed in this toxicological profile resides with ATSDR. 
vi 

The toxicological profiles are developed in response to the Superfund Amendments and 

Reauthorization Act (SARA) of 1986 (Public Law 99-499) which amended the Comprehensive 

Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This 

public law directed ATSDR to prepare toxicological profiles for hazardous substances most commonly 

found at facilities on the CERCLA National Priorities List and that pose the most significant potential 

threat to human health, as determined by ATSDR and the EPA. The availability of the revised priority 

list of 275 hazardous substances was announced in the Federal Register on December 7, 2005 (70 FR 

72840). For prior versions of the list of substances, see Federal Register notices dated April 17, 1987 

(52 FR 12866); October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17, 1990 (55 

FR 42067); October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); February 28, 1994 (59 

FR 9486); April 29, 1996 (61 FR 18744); November 17, 1997 (62 FR 61332); October 21, 1999 (64 FR 

56792); October 25, 2001 (66 FR 54014); and November 7, 2003 (68 FR 63098). Section 104(i)(3) of 

CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each 

substance on the list. 
LEAD vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children? 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)? 

Section 3.7 Children’s Susceptibility 

Section 6.6 Exposures of Children 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) Fax: (770) 488-4178 

1-888-232-6348 (TTY) 

E-mail: cdcinfo@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 
LEAD viii 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

Other Agencies and Organizations 

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, 

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226­

1998 • Phone: 800-35-NIOSH. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212. 

Referrals 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347­

4976 • FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk 

Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 
LEAD ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Henry Abadin, M.S.P.H. 

Annette Ashizawa, Ph.D. 

Yee-Wan Stevens, M.S. 

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA 

Fernando Llados, Ph.D. 

Gary Diamond, Ph.D. 

Gloria Sage, Ph.D. 

Mario Citra, Ph.D. 

Antonio Quinones, Ph.D. 

Stephen J. Bosch, B.S. 

Steven G. Swarts, Ph.D. 

Syracuse Research Corporation, North Syracuse, NY 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1. Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2.	 Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3. Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

4. Green Border Review. Green Border review assures the consistency with ATSDR policy. 
LEAD x 

This page is intentionally blank. 
LEAD xi 

PEER REVIEW 

A peer review panel was assembled for lead. The panel consisted of the following members: 

1. Philip Landrigan, M.D., Ethel H. Wise, Professor of Community and Preventive Medicine and 

Professor of Pediatrics, Director, Division of Environmental and Occupational Medicine, Mount 

Sinai School of Medicine, New York, New York; 

2. Deborah Cory-Slechta, Ph.D., Director, Environmental and Occupational Health Sciences 

Institute, Chair, Department of Environmental and Occupational Medicine, Robert Wood Johnson 

Medical University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey; and 

3. Howard Hu, M.D., M.P.H., Professor of Occupational and Environmental Medicine, Harvard 

School of Public Health, Boston, Massachusetts. 

These experts collectively have knowledge of lead's physical and chemical properties, toxicokinetics, key 

health end points, mechanisms of action, human and animal exposure, and quantification of risk to 

humans. All reviewers were selected in conformity with the conditions for peer review specified in 

Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as 

amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 
LEAD xii 

This page is intentionally blank. 
LEAD xiii 

CONTENTS 

DISCLAIMER ..............................................................................................................................................ii 

UPDATE STATEMENT .............................................................................................................................iii 

FOREWORD ................................................................................................................................................v 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS....................................................................vii 

CONTRIBUTORS.......................................................................................................................................ix 

PEER REVIEW ...........................................................................................................................................xi 

CONTENTS...............................................................................................................................................xiii 

LIST OF FIGURES ..................................................................................................................................xvii 

LIST OF TABLES.....................................................................................................................................xix 

1. PUBLIC HEALTH STATEMENT..........................................................................................................1 

1.1 WHAT IS LEAD? .......................................................................................................................1 

1.2 WHAT HAPPENS TO LEAD WHEN IT ENTERS THE ENVIRONMENT? ..........................2 

1.3 HOW MIGHT I BE EXPOSED TO LEAD? ..............................................................................4 

1.4 HOW CAN LEAD ENTER AND LEAVE MY BODY? ...........................................................7 

1.5 HOW CAN LEAD AFFECT MY HEALTH?............................................................................. 8 

1.6 HOW CAN LEAD AFFECT CHILDREN?................................................................................9 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO LEAD?..........................11 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED 

 TO LEAD? ................................................................................................................................14 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH?...............................................................................................14 

1.10 WHERE CAN I GET MORE INFORMATION? .....................................................................18 

2. RELEVANCE TO PUBLIC HEALTH .................................................................................................19 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO LEAD IN THE UNITED 

STATES ....................................................................................................................................19 

2.2 SUMMARY OF HEALTH EFFECTS......................................................................................21 

2.3 LEAD DOSE-RESPONSE RELATIONSHIPS........................................................................31 

3. HEALTH EFFECTS..............................................................................................................................35 

3.1 INTRODUCTION.....................................................................................................................35 

3.2 DISCUSSION OF HEALTH EFFECTS................................................................................... 36 

3.2.1 Death .....................................................................................................................................36 

3.2.2 Systemic Effects....................................................................................................................49 

3.2.3 Immunological and Lymphoreticular Effects........................................................................96 

3.2.4 Neurological Effects............................................................................................................101 

3.2.5 Reproductive Effects...........................................................................................................136 

3.2.6 Developmental Effects........................................................................................................142 

3.2.7 Genotoxic Effects................................................................................................................148 

3.2.8 Cancer .................................................................................................................................151 

3.3 TOXICOKINETICS................................................................................................................156 

3.3.1 Absorption...........................................................................................................................156 

3.3.1.1 Inhalation Exposure....................................................................................................156 

3.3.1.2 Oral Exposure.............................................................................................................158 

3.3.1.3 Dermal Exposure ........................................................................................................166 

3.3.2 Distribution .........................................................................................................................168 

3.3.3 Metabolism..........................................................................................................................173 

3.3.4 Excretion .............................................................................................................................174 
LEAD xiv 

3.3.4.1 Inhalation Exposure....................................................................................................174 

3.3.4.2 Oral Exposure.............................................................................................................175 

3.3.4.3 Dermal Exposure ........................................................................................................175 

3.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ...........175 

3.3.5.1 O'Flaherty Model........................................................................................................185 

3.3.5.2 IEUBK Model ............................................................................................................189 

3.3.5.3 Leggett Model ............................................................................................................194 

3.3.5.4 Model Comparisons....................................................................................................197 

3.3.5.5 Slope Factor Models...................................................................................................199 

3.4 MECHANISMS OF ACTION ................................................................................................ 202 

3.4.1 Pharmacokinetic Mechanisms............................................................................................. 202 

3.4.2 Mechanisms of Toxicity......................................................................................................208 

3.4.3 Animal-to-Human Extrapolations.......................................................................................220 

3.5 CHILDREN’S SUSCEPTIBILITY.........................................................................................220 

3.6 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................224 

3.6.1 Biomarkers Used to Identify or Quantify Exposure to Lead...............................................226 

3.6.2 Biomarkers Used to Characterize Effects Caused by Lead.................................................231 

3.7 INTERACTIONS WITH OTHER CHEMICALS .................................................................. 234 

3.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE............................................. 237 

3.9 METHODS FOR REDUCING TOXIC EFFECTS................................................................. 247 

3.9.1 Reducing Peak Absorption Following Exposure ................................................................247 

3.9.2 Reducing Body Burden .......................................................................................................248 

3.9.3 Interfering with the Mechanism of Action for Toxic Effects..............................................251 

3.10 ADEQUACY OF THE DATABASE......................................................................................253 

3.10.1 Existing Information on Health Effects of Lead.............................................................253 

3.10.2 Identification of Data Needs ...........................................................................................255 

3.10.3 Ongoing Studies..............................................................................................................270 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................277 

4.1 CHEMICAL IDENTITY.........................................................................................................277 

4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................277 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................289 

5.1 PRODUCTION .......................................................................................................................289 

5.2 IMPORT/EXPORT .................................................................................................................294 

5.3 USE..........................................................................................................................................294 

5.4 DISPOSAL..............................................................................................................................299 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................301 

6.1 OVERVIEW............................................................................................................................301 

6.2 RELEASES TO THE ENVIRONMENT................................................................................303 

6.2.1 Air .......................................................................................................................................309 

6.2.2 Water...................................................................................................................................313 

6.2.3 Soil ......................................................................................................................................315 

6.2.4 Paint ....................................................................................................................................316 

6.3 ENVIRONMENTAL FATE....................................................................................................317 

6.3.1 Transport and Partitioning...................................................................................................317 

6.3.2 Transformation and Degradation ........................................................................................322 

6.3.2.1 Air...............................................................................................................................322 

6.3.2.2 Water ..........................................................................................................................323 

6.3.2.3 Sediment and Soil.......................................................................................................324 
LEAD xv 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT...............................326 

6.4.1 Air .......................................................................................................................................327 

6.4.2 Water...................................................................................................................................329 

6.4.3 Sediment and Soil ...............................................................................................................331 

6.4.4 Paint ....................................................................................................................................335 

6.4.5 Other Sources......................................................................................................................336 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .....................................344 

6.6 EXPOSURES OF CHILDREN...............................................................................................363 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ...........................................374 

6.8 ADEQUACY OF THE DATABASE......................................................................................375 

6.8.1 Identification of Data Needs ...............................................................................................376 

6.8.2 Ongoing Studies ..................................................................................................................380 

7. ANALYTICAL METHODS ...............................................................................................................383 

7.1 BIOLOGICAL MATERIALS.................................................................................................383 

7.2 ENVIRONMENTAL SAMPLES............................................................................................ 390 

7.3 ADEQUACY OF THE DATABASE......................................................................................398 

7.3.1 Identification of Data Needs ...............................................................................................399 

7.3.2 Ongoing Studies ..................................................................................................................400 

8. REGULATIONS AND ADVISORIES ...............................................................................................403 

9. REFERENCES ....................................................................................................................................415 

10. GLOSSARY ......................................................................................................................................523 

APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1 

B. USER'S GUIDE ..................................................................................................................................B-1 

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS......................................................................C-1 

D. A FRAMEWORK TO GUIDE PUBLIC HEALTH ASSESSMENT DECISIONS AT LEAD 

SITES .................................................................................................................................................D-1 

E. INDEX................................................................................................................................................. E-1 
LEAD xvi
 

This page is intentionally blank. 
LEAD xvii 

LIST OF FIGURES 

3-1. Change in the Systolic Pressure Associated with a Doubling of the Blood Lead Concentration.......53 

3-2. Change in the Diastolic Pressure Associated with a Doubling of the Blood Lead Concentration .....54 

3-3. Indicators of Renal Functional Impairment Observed at Various Blood Lead Concentrations in 

Humans................................................................................................................................................81 

3-4. Relative Bioavailability (RBA) of Ingested Lead from Soil and Soil-like Test Materials as Assessed 

in an Immature Swine Model ............................................................................................................162 

3-5. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance .....................................................................................................177 

3-6. Lead Metabolism Model...................................................................................................................179 

3-7. Compartments and Pathways of Lead Exchange in the Marcus (1985b) Model..............................180 

3-8. Schematic Model for Lead Kinetics in Marcus (1985a) Bone Model..............................................181 

3-9. Compartmental Model for Lead in Plasma and Red Blood Cells in the Marcus (1985c) Model.....183 

3-10. Compartments and Pathways of Lead Exchange in the O’Flaherty Model....................................186 

3-11. Structure of the IEUBK Model for Lead in Children .....................................................................190 

3-12. Compartments and Pathways of Lead Exchange in the Leggett Model .........................................195 

3-13. Blood Lead Concentrations in Children Predicted by the O’Flaherty, IEUBK, and Leggett 

Models............................................................................................................................................198 

3-14. Blood Lead Concentrations in Adults Predicted by the O’Flaherty and Leggett Models ..............200 

3-15. Effects of Lead on Heme Biosynthesis...........................................................................................212 

3-16. Multiorgan Impact of Reduction of Heme Body Pool by Lead......................................................215 

3-17. Existing Information on Health Effects of Lead.............................................................................254 

6-1. Frequency of NPL Sites with Lead Contamination..........................................................................302 
LEAD xviii 

This page is intentionally blank. 
LEAD xix 

LIST OF TABLES 

2-1. Blood and Bone Lead Concentrations Corresponding to Adverse Health Effects.............................32 

3-1. Internal Lead Doses Associated with Health Effects from Selected Studies...................................... 37 

3-2. Characteristics of the Study Population in Meta-Analyses of Effects of Lead on Blood Pressure ....51 

3-3. Selected Studies of Lead-Induced Nephrotoxicity in Humans...........................................................78 

3-4. Summary of Dose-Response Relationships for Effects of Lead Exposure on Biomarkers of 

Glomerular Filtration Rate .................................................................................................................83 

3-5. Major Prospective Studies of Intellectual Development in Children ............................................... 126 

3-6. Genotoxicity of Lead In Vivo ...........................................................................................................149 

3-7. Genotoxicity of Lead In Vitro...........................................................................................................152 

3-8. Percent Relative Lead Mass of Mineral Phases Observed in Test Materials Assessed for Relative 

Bioavailability in Immature Swine ..................................................................................................163 

3-9. Ranking of Relative Bioavailability of Lead Mineral Phases in Soil ...............................................165 

3-10. Comparison of Slope Factors in Selected Slope Factor Models.....................................................201 

3-11. Effects of Nutritional Factors on Lead Uptake in Animals ............................................................238 

3-12. Ongoing Studies on Lead................................................................................................................271 

4-1. Chemical Identity of Lead and Compounds.....................................................................................278 

4-2. Physical and Chemical Properties of Lead and Compounds ............................................................283 

5-1. Facilities that Produce, Process, or Use Lead...................................................................................290 

5-2. Facilities that Produce, Process, or Use Lead Compounds...............................................................292 

5-3. Current U.S. Manufacturers of Lead Metal and Selected Lead Compounds....................................295 

5-4. U.S. Lead Production 1999–2003.....................................................................................................296 

5-5. Current and Former Uses of Selected Lead Compounds.................................................................. 298 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Lead ........................... 305 

6-2. Releases to the Environment from Facilities that Produce, Process, or Use Lead Compounds.......307 

6-3. Historic Levels of Lead Emissions to the Atmosphere in the United States....................................310 

6-4. National Lead Emission Estimates (in 103 Metric Tons/Year), 1979–1989....................................312 
LEAD xx 

6-5. Lead Levels in Various Food Categories..........................................................................................337 

6-6. Lead Levels in Canadian Foods 1986–1988.....................................................................................339 

6-7. Contribution of Various Food Categories to the Average Daily Intake (AVDI) of Lead in Adults 

(1980–1982) .....................................................................................................................................346 

6-8. Daily Average Intake of Lead (μg Lead/Day)..................................................................................348 

6-9. Dietary Exposure Estimates of U.S. Populations to Lead Based on the Dietary Exposure Potential 

Model (DEPM).................................................................................................................................350 

6-10. Lead Concentrations for Various Media From the NHEXAS Arizona Study................................351 

6-11. Total Lead Exposure of Subject Population From the NHEXAS Arizona Study ..........................352 

6-12. Geometric Mean Blood Lead Levels (μg/dL) and the 95th Percentile Confidence Interval, by
 

Race/Ethnicity, Sex, and Age.........................................................................................................355 

6-13. Geometric Mean and Selected Percentile Urine Concentrations (μg/L) of Lead in the U.S. 

Population From 1999 to 2002.......................................................................................................357 

6-14. Median, Range, and Weighted Geometric Mean Blood Lead Levels in U.S. Workers, Ages 18–
 

64 in 1988–1994.............................................................................................................................361 

6-15. Median, Range, and Weighted Geometric Mean Blood Lead Levels in U.S. Workers, Ages 18–
 

64 by Industrial Categories ............................................................................................................362 

6-16. Blood Levels of Lead in Children (1–5 Years) in 1976–2002........................................................367 

6-17. Ongoing Research Regarding the Environmental Fate and Exposure of Humans to Lead ............ 381 

7-1. Analytical Methods for Determining Lead in Biological Materials.................................................385 

7-2. Analytical Methods for Determining Lead in Environmental Samples............................................391 

7-3. Ongoing Research Regarding the Analytical Methods for Lead in Environmental and Biological 

Samples ............................................................................................................................................401 

8-1. Regulations and Guidelines Applicable to Lead and Lead Compounds...........................................404 
LEAD 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about lead and the effects of exposure to it. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in 

the nation. These sites are then placed on the National Priorities List (NPL) and are targeted for 

long-term federal clean-up activities. Lead has been found in at least 1,272 of the 1,684 current 

or former NPL sites. Although the total number of NPL sites evaluated for this substance is not 

known, the possibility exists that the number of sites at which lead is found may increase in the 

future as more sites are evaluated. This information is important because these sites may be 

sources of exposure and exposure to this substance may harm you. 

When a substance is released either from a large area, such as an industrial plant, or from a 

container, such as a drum or bottle, it enters the environment. Such a release does not always 

lead to exposure. You can be exposed to a substance only when you come in contact with it. 

You may be exposed by breathing, eating, or drinking the substance, or by skin contact. 

If you are exposed to lead, many factors will determine whether you will be harmed. These 

factors include the dose (how much), the duration (how long), and how you come in contact with 

it. You must also consider any other chemicals you are exposed to and your age, sex, diet, 

family traits, lifestyle, and state of health. 

1.1 WHAT IS LEAD? 

Lead is a heavy, low melting, bluish-gray metal that occurs naturally in the Earth's crust. 

However, it is rarely found naturally as a metal. It is usually found combined with two or more 

other elements to form lead compounds. 

Metallic lead is resistant to corrosion (i.e., not easily attacked by air or water). When exposed to 

air or water, thin films of lead compounds are formed that protect the metal from further attack. 

Lead is easily molded and shaped. Lead can be combined with other metals to form alloys. 

Lead and lead alloys are commonly found in pipes, storage batteries, weights, shot and 
LEAD 2 

1. PUBLIC HEALTH STATEMENT 

ammunition, cable covers, and sheets used to shield us from radiation. The largest use for lead is 

in storage batteries in cars and other vehicles. 

Lead compounds are used as a pigment in paints, dyes, and ceramic glazes and in caulk. The 

amount of lead used in these products has been reduced in recent years to minimize lead’s 

harmful effect on people and animals. Tetraethyl lead and tetramethyl lead were once used in 

the United States as gasoline additives to increase octane rating. However, their use was phased 

out in the United States in the 1980s, and lead was banned for use in gasoline for motor vehicles 

beginning January 1, 1996. Tetraethyl lead may still be used in gasoline for off-road vehicles 

and airplanes. It is also still used in a number of developing countries. Lead used in 

ammunition, which is the largest non-battery end-use, has remained fairly constant in recent 

years. However, even the use of lead in bullets and shot as well as in fishing sinkers is being 

reduced because of its harm to the environment. 

Most lead used by industry comes from mined ores ("primary") or from recycled scrap metal or 

batteries ("secondary"). Lead is mined in the United States, primarily in Alaska and Missouri. 

However, most lead today is “secondary” lead obtained from lead-acid batteries. It is reported 

that 97% of these batteries are recycled. 

For more information on the physical and chemical properties of lead, please see Chapter 4. For 

more on the production and use of lead, please see Chapter 5. 

1.2 WHAT HAPPENS TO LEAD WHEN IT ENTERS THE ENVIRONMENT? 

Lead occurs naturally in the environment. However, most of the high levels found throughout 

the environment come from human activities. Environmental levels of lead have increased more 

than 1,000-fold over the past three centuries as a result of human activity. The greatest increase 

occurred between the years 1950 and 2000, and reflected increasing worldwide use of leaded 

gasoline. Lead can enter the environment through releases from mining lead and other metals, 

and from factories that make or use lead, lead alloys, or lead compounds. Lead is released into 

the air during burning coal, oil, or waste. Before the use of leaded gasoline was banned, most of 
LEAD 3 

1. PUBLIC HEALTH STATEMENT 

the lead released into the U.S. environment came from vehicle exhaust. In 1979, cars released 

94.6 million kilograms (208.1 million pounds) of lead into the air in the United States. In 1989, 

when the use of lead was limited but not banned, cars released only 2.2 million kg (4.8 million 

pounds) to the air. Since EPA banned the use of leaded gasoline for highway transportation in 

1996, the amount of lead released into the air has decreased further. Before the 1950s, lead was 

used in pesticides applied to fruit orchards. Once lead gets into the atmosphere, it may travel 

long distances if the lead particles are very small. Lead is removed from the air by rain and by 

particles falling to land or into surface water. 

Sources of lead in dust and soil include lead that falls to the ground from the air, and weathering 

and chipping of lead-based paint from buildings, bridges, and other structures. Landfills may 

contain waste from lead ore mining, ammunition manufacturing, or other industrial activities 

such as battery production. Disposal of lead-containing products contribute to lead in municipal 

landfills. Past uses of lead such as its use in gasoline are a major contributor to lead in soil, and 

higher levels of lead in soil are found near roadways. Most of the lead in inner city soils comes 

from old houses with paint containing lead and previous automotive exhaust emitted when 

gasoline contained lead. 

Once lead falls onto soil, it sticks strongly to soil particles and remains in the upper layer of soil. 

That is why past uses of lead such as lead in gasoline, house paint, and pesticides are so 

important in the amount of lead found in soil. 

Small amounts of lead may enter rivers, lakes, and streams when soil particles are moved by 

rainwater. Small amounts of lead from lead pipe or solder may be released into water when the 

water is acidic or “soft”. Lead may remain stuck to soil particles or sediment in water for many 

years. Movement of lead from soil particles into groundwater is unlikely unless the rain falling 

on the soil is acidic or "soft". Movement of lead from soil will also depend on the type of lead 

compound and on the physical and chemical characteristics of the soil. 
LEAD 4 

1. PUBLIC HEALTH STATEMENT 

Sources of lead in surface water or sediment include deposits of lead-containing dust from the 

atmosphere, waste water from industries that handle lead (primarily iron and steel industries and 

lead producers), urban runoff, and mining piles. 

Some lead compounds are changed into other forms of lead by sunlight, air, and water. 

However, elemental lead cannot be broken down. 

The levels of lead may build up in plants and animals from areas where air, water, or soil are 

contaminated with lead. If animals eat contaminated plants or animals, most of the lead that they 

eat will pass through their bodies. Chapter 6 contains more information about what happens to 

lead in the environment. 

1.3 HOW MIGHT I BE EXPOSED TO LEAD? 

Lead is commonly found in soil especially near roadways, older houses, old orchards, mining 

areas, industrial sites, near power plants, incinerators, landfills, and hazardous waste sites. 

People living near hazardous waste sites may be exposed to lead and chemicals that contain lead 

by breathing air, drinking water, eating foods, or swallowing dust or dirt that contain lead. 

People may be exposed to lead by eating food or drinking water that contains lead. Drinking 

water in houses containing lead pipes may contain lead, especially if the water is acidic or “soft”. 

If one is not certain whether an older building contains lead pipes, it is best to let the water run a 

while before drinking it so that any lead formed in the pipes can be flushed out. People living in 

areas where there are old houses that have been painted with lead paint may be exposed to higher 

levels of lead in dust and soil. Similarly, people who live near busy highways or on old orchard 

land where lead arsenate pesticides were used in the past may be exposed to higher levels of 

lead. People may also be exposed to lead when they work in jobs where lead is used or have 

hobbies in which lead is used, such as making stained glass. 

Foods may contain small amounts of lead. However, since lead solder is no longer used in cans, 

very little lead is found in food. Leafy fresh vegetables grown in lead-containing soils may have 

lead-containing dust on them. Lead may also enter foods if they are put into improperly glazed 
LEAD 5 

1. PUBLIC HEALTH STATEMENT 

pottery or ceramic dishes and from leaded-crystal glassware. Illegal whiskey made using stills 

that contain lead-soldered parts (such as truck radiators) may also contain lead. Cigarette smoke 

may also contain small amounts of lead. The amount of lead found in canned foods decreased 

87% from 1980 to 1988 in the United States, which indicates that the chance of exposure to lead 

in canned food from lead-soldered containers has been greatly reduced. Lead-soldered cans are 

still used in some other nations. In the most recent studies, lead was not detectable in most foods 

and the average dietary intake of lead was about 1 microgram (a microgram is a millionth of a 

gram) per kilogram of body weight per day. Children may be exposed to lead by hand-to-mouth 

contact after exposure to lead-containing soil or dust. 

In general, very little lead is found in lakes, rivers, or groundwater used to supply the public with 

drinking water. More than 99% of all publicly supplied drinking water contains less than 

0.005 parts of lead per million parts of water (ppm). However, the amount of lead taken into 

your body through drinking water can be higher in communities with acidic water supplies. 

Acidic water makes it easier for the lead found in pipes, leaded solder, and brass faucets to be 

dissolved and to enter the water we drink. Public water treatment systems are now required to 

use control measures to make water less acidic. Plumbing that contains lead may be found in 

public drinking water systems, and in houses, apartment buildings, and public buildings that are 

more than 20 years old. However, as buildings age, mineral deposits form a coating on the 

inside of the water pipes that insulates the water from lead in the pipe or solder, thus reducing the 

amount of lead that can leach into the water. Since 1988, regulations require that drinking water 

coolers must not contain lead in parts that come into contact with drinking water. 

Breathing in, or swallowing airborne dust and dirt, is another way you can be exposed to lead. In 

1984, burning leaded gasoline was the single largest source of lead emissions. Very little lead in 

the air comes from gasoline now because EPA has banned its use in gasoline for motor vehicles. 

Other sources of lead in the air include releases to the air from industries involved in iron and 

steel production, lead-acid-battery manufacturing, and nonferrous (brass and bronze) foundries. 

Lead released into air may also come from burning of solid waste that contains lead, windblown 

dust, volcanoes, exhaust from workroom air, burning or weathering of lead-painted surfaces, 

fumes and exhaust from leaded gasoline, and cigarette smoke. 
LEAD 6 

1. PUBLIC HEALTH STATEMENT 

Skin contact with dust and dirt containing lead occurs every day. Recent data have shown that 

inexpensive cosmetic jewelry pieces sold to the general public may contain high levels of lead 

which may be transferred to the skin through routine handling. However, not much lead can get 

into your body through your skin. 

In the home, you or your children may be exposed to lead if you take some types of home 

remedy medicines that contain lead compounds. Lead compounds are in some non-Western 

cosmetics, such as surma and kohl. Some types of hair colorants, cosmetics, and dyes contain 

lead acetate. Read the labels on hair coloring products, use them with caution, and keep them 

away from children. 

People who are exposed at work are usually exposed by breathing in air that contains lead 

particles. Exposure to lead occurs in many jobs. People who work in lead smelting and refining 

industries, brass/bronze foundries, rubber products and plastics industries, soldering, steel 

welding and cutting operations, battery manufacturing plants, and lead compound manufacturing 

industries may be exposed to lead. Construction and demolition workers and people who work 

at municipal waste incinerators, pottery and ceramics industries, radiator repair shops, and other 

industries that use lead solder may also be exposed. Painters who sand or scrape old paint may 

be exposed to lead in dust. Between 0.5 and 1.5 million workers are exposed to lead in the 

workplace. In California alone, more than 200,000 workers are exposed to lead. Families of 

workers may be exposed to higher levels of lead when workers bring home lead dust on their 

work clothes. 

You may also be exposed to lead in the home if you work with stained glass as a hobby, make 

lead fishing weights or ammunition, or if you are involved in home renovation that involves the 

removal of old lead-based paint. For more information on the potential for exposure to lead, 

please refer to Chapter 6. 
LEAD 7 

1. PUBLIC HEALTH STATEMENT 

1.4 HOW CAN LEAD ENTER AND LEAVE MY BODY? 

Some of the lead that enters your body comes from breathing in dust or chemicals that contain 

lead. Once this lead gets into your lungs, it goes quickly to other parts of the body in your blood. 

Larger particles that are too large to get into your lungs can be coughed up and swallowed. You 

may also swallow lead by eating food and drinking liquids that contain it. Most of the lead that 

enters your body comes through swallowing, even though very little of the amount you swallow 

actually enters your blood and other parts of your body. The amount that gets into your body 

from your stomach partially depends on when you ate your last meal. It also depends on how old 

you are and how well the lead particles you ate dissolved in your stomach juices. Experiments 

using adult volunteers showed that, for adults who had just eaten, the amount of lead that got into 

the blood from the stomach was only about 6% of the total amount taken in. In adults who had 

not eaten for a day, about 60–80% of the lead from the stomach got into their blood. In general, 

if adults and children swallow the same amount of lead, a bigger proportion of the amount 

swallowed will enter the blood in children than in adults. Children absorb about 50% of ingested 

lead. 

Dust and soil that contain lead may get on your skin, but only a small portion of the lead will 

pass through your skin and enter your blood if it is not washed off. You can, however, 

accidentally swallow lead that is on your hands when you eat, drink, smoke, or apply cosmetics 

(for example, lip balm). More lead can pass through skin that has been damaged (for example, 

by scrapes, scratches, and wounds). The only kinds of lead compounds that easily penetrate the 

skin are the additives in leaded gasoline, which is no longer sold to the general public. 

Therefore, the general public is not likely to encounter lead that can enter through the skin. 

Shortly after lead gets into your body, it travels in the blood to the "soft tissues" and organs (such 

as the liver, kidneys, lungs, brain, spleen, muscles, and heart). After several weeks, most of the 

lead moves into your bones and teeth. In adults, about 94% of the total amount of lead in the 

body is contained in the bones and teeth. About 73% of the lead in children’s bodies is stored in 

their bones. Some of the lead can stay in your bones for decades; however, some lead can leave 
LEAD 8 

1. PUBLIC HEALTH STATEMENT 

your bones and reenter your blood and organs under certain circumstances (e.g., during 

pregnancy and periods of breast feeding, after a bone is broken, and during advancing age). 

Your body does not change lead into any other form. Once it is taken in and distributed to your 

organs, the lead that is not stored in your bones leaves your body in your urine or your feces. 

About 99% of the amount of lead taken into the body of an adult will leave in the waste within a 

couple of weeks, but only about 32% of the lead taken into the body of a child will leave in the 

waste. Under conditions of continued exposure, not all of the lead that enters the body will be 

eliminated, and this may result in accumulation of lead in body tissues, especially bone. For 

more information on how lead can enter and leave your body, please refer to Chapter 3. 

1.5 HOW CAN LEAD AFFECT MY HEALTH? 

Scientists use many tests to protect the public from harmful effects of toxic chemicals and to find 

ways for treating persons who have been harmed. 

One way to learn whether a chemical will harm people is to determine how the body absorbs, 

uses, and releases the chemical. For some chemicals, animal testing may be necessary. Animal 

testing may also help identify health effects such as cancer or birth defects. Without laboratory 

animals, scientists would lose a basic method for getting information needed to make wise 

decisions that protect public health. Scientists have the responsibility to treat research animals 

with care and compassion. Scientists must comply with strict animal care guidelines because 

laws today protect the welfare of research animals. 

The effects of lead are the same whether it enters the body through breathing or swallowing. The 

main target for lead toxicity is the nervous system, both in adults and children. Long-term 

exposure of adults to lead at work has resulted in decreased performance in some tests that 

measure functions of the nervous system. Lead exposure may also cause weakness in fingers, 

wrists, or ankles. Lead exposure also causes small increases in blood pressure, particularly in 

middle-aged and older people. Lead exposure may also cause anemia. At high levels of 

exposure, lead can severely damage the brain and kidneys in adults or children and ultimately 
LEAD 9 

1. PUBLIC HEALTH STATEMENT 

cause death. In pregnant women, high levels of exposure to lead may cause miscarriage. Highlevel exposure in men can damage the organs responsible for sperm production. 

We have no conclusive proof that lead causes cancer (is carcinogenic) in humans. Kidney 

tumors have developed in rats and mice that had been given large doses of some kind of lead 

compounds. The Department of Health and Human Services (DHHS) has determined that lead 

and lead compounds are reasonably anticipated to be human carcinogens based on limited 

evidence from studies in humans and sufficient evidence from animal studies, and the EPA has 

determined that lead is a probable human carcinogen. The International Agency for Research on 

Cancer (IARC) has determined that inorganic lead is probably carcinogenic to humans. IARC 

determined that organic lead compounds are not classifiable as to their carcinogenicity in 

humans based on inadequate evidence from studies in humans and in animals. See 

Chapters 2 and 3 for more information on the health effects of lead. 

1.6 HOW CAN LEAD AFFECT CHILDREN? 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 

Studies carried out by the Centers for Disease Control and Prevention (CDC) show that the 

levels of lead in the blood of U.S. children have been getting lower and lower. This result is 

because lead is banned from gasoline, residential paint, and solder used for food cans and water 

pipes. However, about 310,000 U.S. children between the ages of 1 and 5 years are believed to 

have blood lead levels equal or greater than 10 μg/dL, the level targeted for elimination among 

young children in the Unites States by 2010. 

Children are more vulnerable to lead poisoning than adults. Children are exposed to lead all 

through their lives. They can be exposed to lead in the womb if their mothers have lead in their 

bodies. Babies can swallow lead when they breast feed, or eat other foods, and drink water that 

contains lead. Babies and children can swallow and breathe lead in dirt, dust, or sand while they 

play on the floor or ground. These activities make it easier for children to be exposed to lead 
LEAD 10 

1. PUBLIC HEALTH STATEMENT 

than adults. The dirt or dust on their hands, toys, and other items may have lead particles in it. 

In some cases, children swallow nonfood items such as paint chips; these may contain very large 

amounts of lead, particularly in and around older houses that were painted with lead-based paint. 

The paint in these houses often chips off and mixes with dust and dirt. Some old paint contains 

as much as 50% lead. Also, compared with adults, a bigger proportion of the amount of lead 

swallowed will enter the blood in children. 

Children are more sensitive to the health effects of lead than adults. No safe blood lead level in 

children has been determined. Lead affects children in different ways depending on how much 

lead a child swallows. A child who swallows large amounts of lead may develop anemia, kidney 

damage, colic (severe “stomach ache”), muscle weakness, and brain damage, which ultimately 

can kill the child. In some cases, the amount of lead in the child’s body can be lowered by 

giving the child certain drugs that help eliminate lead from the body. If a child swallows smaller 

amounts of lead, such as dust containing lead from paint, much less severe but still important 

effects on blood, development, and behavior may occur. In this case, recovery is likely once the 

child is removed from the source of lead exposure, but there is no guarantee that the child will 

completely avoid all long-term consequences of lead exposure. At still lower levels of exposure, 

lead can affect a child’s mental and physical growth. Fetuses exposed to lead in the womb, 

because their mothers had a lot of lead in their bodies, may be born prematurely and have lower 

weights at birth. Exposure in the womb, in infancy, or in early childhood also may slow mental 

development and cause lower intelligence later in childhood. There is evidence that these effects 

may persist beyond childhood. 

Children with high blood lead levels do not have specific symptoms. However, health workers 

can find out whether a child may have been exposed to harmful levels of lead by taking a blood 

sample. They can also find out how much lead is in a child’s bones by taking a special type of 

x-ray of the finger, knee, or elbow. This type of test, however, is not routine. More information 

regarding children’s health and lead can be found in Section 3.5. 
LEAD 11 

1. PUBLIC HEALTH STATEMENT 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO LEAD? 

If your doctor finds that you have been exposed to substantial amounts of lead, ask whether your 

children might also have been exposed. Your doctor might need to ask your state health 

department to investigate. 

If your doctor finds that you have been exposed to substantial amounts of lead, ask whether your 

children might also have been exposed. Your doctor might need to ask your state health 

department to investigate. 

The most important way families can lower exposures to lead is to know about the sources of 

lead in their homes and avoid exposure to these sources. Some homes or day-care facilities may 

have more lead in them than others. Families who live in or visit these places may be exposed to 

higher amounts of lead. These include homes built before 1978 that may have been painted with 

paint that contains lead (lead-based paint). If you are buying a home that was built before 1978, 

you may want to know if it contains lead based paint. Federal government regulations require a 

person selling a home to tell the real estate agent or person buying the home of any known leadbased hazards on the property. Adding lead to paint is no longer allowed. If your house was 

built before 1978, it may have been painted with lead-based paint. This lead may still be on 

walls, floors, ceilings, and window sills, or on the outside walls of the house. The paint may 

have been scraped off by a previous owner, but paint chips and lead-containing dust may still be 

in the yard soil. Decaying, peeling, or flaking paint can introduce lead into household dust and 

the area where this is occurring should be repainted. If your paint is decaying or your child has 

symptoms of lead poisoning, you may want to have your house tested for lead. In some states, 

homeowners can have the paint in their homes tested for lead by their local health departments. 

The National Lead Information Center (1-800-532-3394) has a listing of approved risk assessors 

(people who have met certain criteria and are qualified to assess the potential risks of a site) and 

of approved testing laboratories (for soil, paint, and dust). 

Sanding surfaces painted with lead-based paint or using heat to peel the paint may cause 

exposure to high levels of lead. Many cases of lead poisoning have resulted from do-it-yourself 
LEAD 12 

1. PUBLIC HEALTH STATEMENT 

home renovations. Therefore, any renovations should be performed by a licensed contractor who 

will minimize exposure to household members. It is important for the area being renovated to be 

isolated from the rest of the house because of lead-containing dust. The federal government 

requires that contractors who test for or remove lead must be certified by the EPA or an EPAapproved state program. Ask to see certifications of potential contractors. Your state health 

department or environmental protection division should be able to identify certified contractors 

for you. The National Lead Abatement Council (P.O. Box 535; Olney, MD 20932; telephone 

301-924-5490) can also send you a list of certified contractors. 

Families can lower the possibility of children swallowing paint chips by discouraging their 

children from chewing or putting these painted surfaces in their mouths and making sure that 

they wash their hands often, especially before eating. Lead can be found in dirt and dust. Areas 

where levels of lead in dirt might be especially high are near old houses, highways, or old 

orchards. Some children have the habit of eating dirt (the term for this activity is pica). 

Discourage your children from eating dirt and other hand-to-mouth activity. 

Non-Western folk remedies used to treat diarrhea or other ailments may contain substantial 

amounts of lead. Examples of these include: Alarcon, Ghasard, Alkohl, Greta, Azarcon, Liga, 

Bali Goli, Pay-loo-ah, Coral, and Rueda. If you give your children these substances or if you are 

pregnant or nursing, you may expose your children to lead. It is wise to know the ingredients of 

any medicines that you or your children use. 

Older homes that have plumbing containing lead may have higher amounts of lead in drinking 

water. Inside plumbing installed before 1930 is most likely to contain high levels of lead. 

Copper pipes have replaced lead pipes in most residential plumbing. You cannot see, taste, or 

smell lead in water, and boiling your water will not get rid of lead. If you have a water-lead 

problem, EPA recommends that anytime water in a particular faucet has not been used for 

6 hours or longer, you should flush your cold water pipes by running water until it is cold 

(5 seconds–2 minutes). Because lead dissolves more easily in warm water than in cold water, 

you should only use cold water for drinking, cooking, and preparing baby formula. You can 

contact your local health department or water supplier to find out about testing your water for 
LEAD 13 

1. PUBLIC HEALTH STATEMENT 

lead. If your water tests indicate a significant presence of lead, consult your water supplier or 

local health department about possible remedies. 

You can bring lead home in the dust on your hands or clothes if lead is used in the place where 

you work. Lead dust is likely to be found in places where lead is mined or smelted, where car 

batteries are made or recycled, where electric cable sheathing is made, where fine crystal glass is 

made, or where certain types of ceramic pottery are made. Pets can also bring lead into the home 

in dust or dirt on their fur or feet if they spend time in places that have high levels of lead in the 

soil. 

Swallowing of lead in house dust or soil is a very important exposure pathway for children. This 

problem can be reduced in many ways. Regular hand and face washing to remove lead dusts and 

soil, especially before meals, can lower the possibility that lead on the skin is accidentally 

swallowed while eating. Families can lower exposures to lead by regularly cleaning the home of 

dust and tracked in soil. Door mats can help lower the amount of soil that is tracked into the 

home; removing your shoes before entering the home will also help. Planting grass and shrubs 

over bare soil areas in the yard can lower contact that children and pets may have with soil and 

the tracking of soil into the home. 

Families whose members are exposed to lead dusts at work can keep these dusts out of reach of 

children by showering and changing clothes before leaving work, and bagging their work clothes 

before they are brought into the home for cleaning. Proper ventilation and cleaning—during and 

after hobby activities, home or auto repair activities, and hair coloring with products that contain 

lead—will decrease the possibility of exposure. 

Lead-containing dust may be deposited on plant surfaces and lead may be taken up in certain 

edible plants from the soil by the roots; therefore, home gardening may also contribute to 

exposure if the produce is grown in soils that have high lead concentrations. Vegetables should 

be well washed before eating to remove surface deposits. Certain hobbies and home or car repair 

activities like radiator repair can add lead to the home as well. These include soldering glass or 

metal, making bullets or slugs, or glazing pottery. Some types of paints and pigments that are 
LEAD 14 

1. PUBLIC HEALTH STATEMENT 

used as facial make-up or hair coloring contain lead. Cosmetics that contain lead include surma 

and kohl, which are popular in certain Asian countries. Read the labels on hair coloring 

products, and keep hair dyes that contain lead acetate away from children. Do not allow children 

to touch hair that has been colored with lead-containing dyes or any surfaces that have come into 

contact with these dyes because lead compounds can rub off onto their hands and be transferred 

to their mouths. 

It is important that children have proper nutrition and eat a balanced diet of foods that supply 

adequate amounts of vitamins and minerals, especially calcium and iron. Good nutrition lowers 

the amount of swallowed lead that passes to the bloodstream and also may lower some of the 

toxic effects of lead. 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN 

EXPOSED TO LEAD? 

The amount of total lead in the blood can be measured to determine if exposure to lead has 

occurred. This test shows if you have been recently exposed to lead. Lead can be measured in 

teeth or bones by x-ray techniques, but these methods are not widely available. These tests show 

long-term exposures to lead. The primary screening method is measurement of blood lead. 

Exposure to lead also can be evaluated by measuring erythrocyte protoporphyrin (EP) in blood 

samples. EP is a part of red blood cells known to increase when the amount of lead in the blood 

is high. However, the EP level is not sensitive enough to identify children with elevated blood 

lead levels below about 25 micrograms per deciliter (μg/dL). These tests usually require special 

analytical equipment that is not available in a doctor’s office. However, your doctor can draw 

blood samples and send them to appropriate laboratories for analysis. For more information on 

tests to measure lead in the body, see Chapters 3 and 7. 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. 

Regulations can be enforced by law. The EPA, the Occupational Safety and Health 
LEAD 15 

1. PUBLIC HEALTH STATEMENT 

Administration (OSHA), and the Food and Drug Administration (FDA) are some federal 

agencies that develop regulations for toxic substances. Recommendations provide valuable 

guidelines to protect public health, but cannot be enforced by law. The Agency for Toxic 

Substances and Disease Registry (ATSDR) and the National Institute for Occupational Safety 

and Health (NIOSH) are two federal organizations that develop recommendations for toxic 

substances. 

Regulations and recommendations can be expressed as “not-to-exceed” levels, that is, levels of a 

toxic substance in air, water, soil, or food that do not exceed a critical value that is usually based 

on levels that affect animals; they are then adjusted to levels that will help protect humans. 

Sometimes these not-to-exceed levels differ among federal organizations because they used 

different exposure times (an 8-hour workday or a 24-hour day), different animal studies, or other 

factors. 

Recommendations and regulations are also updated periodically as more information becomes 

available. For the most current information, check with the federal agency or organization that 

provides it. Some regulations and recommendations for lead include the following: 

CDC recommends that states develop a plan to find children who may be exposed to lead and 

have their blood tested for lead. CDC recommends that the states test children: 

• at ages 1 and 2 years; 

• at ages 3–6 years if they have never been tested for lead; 

• if they receive services from public assistance programs for the poor such as 

Medicaid or the Supplemental Food Program for Women, Infants, and Children; 

• if they live in a building or frequently visit a house built before 1950; 

• if they visit a home (house or apartment) built before 1978 that has been recently 

remodeled; and/or 

• if they have a brother, sister, or playmate who has had lead poisoning. 
LEAD 16 

1. PUBLIC HEALTH STATEMENT 

CDC considers children to have an elevated level of lead if the amount of lead in the blood is at 

least 10 μg/dL. Many states or local programs provide intervention to individual children with 

blood lead levels equal to or greater than 10 μg/dL. Medical evaluation and environmental 

investigation and remediation should be done for all children with blood lead levels equal to or 

greater than 20 μg/dL. Medical treatment (i.e., chelation therapy) may be necessary in children if 

the lead concentration in blood is higher than 45 μg/dL. 

EPA requires that the concentration of lead in air that the public breathes be no higher than 

1.5 micrograms per cubic meter (μg/m3) averaged over 3 months. EPA regulations no longer 

allow lead in gasoline. The Clean Air Act Amendments (CAAA) of 1990 banned the sale of 

leaded gasoline as of December 31, 1995. 

Under the Lead Copper Rule (LCR), EPA requires testing of public water systems, and if more 

than 10% of the samples at residences contain lead levels over 0.015 milligrams per liter (mg/L), 

actions must be taken to lower these levels. Testing for lead in drinking water in schools is not 

required unless a school is regulated under a public water system. The 1988 Lead Contamination 

Control Act (LCCA) was created to help reduce lead in drinking water at schools and daycare 

centers. The LCCA created lead monitoring and reporting requirements for schools, as well as 

the replacement of fixtures that contain high levels of lead. However, the provisions in the 

LCCA are not enforceable by the federal government and individual states have the option to 

voluntarily comply with these provisions or create their own. 

To help protect small children, the Consumer Product Safety Commission (CPSC) requires that 

the concentration of lead in most paints available through normal consumer channels be not more 

than 0.06%. The Federal Hazardous Substance Act (FHSA) bans children’s products containing 

hazardous amounts of lead. 

The Department of Housing and Urban Development (HUD) develops recommendations and 

regulations to prevent exposure to lead. HUD requires that federally funded housing and 

renovations, Public and Indian housing be tested for lead-based paint hazards and that such 

hazards be fixed by covering the paint or removing it. When determining whether lead-based 
LEAD 17 

1. PUBLIC HEALTH STATEMENT 

paint applied to interior or exterior painted surfaces of dwellings should be removed, the 

standard used by EPA and HUD is that paint with a lead concentration equal to or greater than 

1.0 milligram per square centimeter (mg/cm2

) of surface area should be removed or otherwise 

treated. HUD is carrying out demonstration projects to determine the best ways of covering or 

removing lead-based paint in housing. 

EPA has developed standards for lead-paint hazards, lead in dust, and lead in soil. To educate 

parents, homeowners, and tenants about lead hazards, lead poisoning prevention in the home, 

and the lead abatement process, EPA has published several general information pamphlets. 

Copies of these pamphlets can be obtained from the National Lead Information Center or from 

various Internet sites, including http://www.epa.gov/opptintr/lead. 

OSHA regulations limit the concentration of lead in workroom air to 50 μg/m3

 for an 8-hour 

workday. If a worker has a blood lead level of 50 μg/dL or higher, then OSHA requires that the 

worker be removed from the workroom where lead exposure is occurring. 

FDA includes lead on its list of poisonous and deleterious substances. FDA considers foods 

packaged in cans containing lead solders to be unsafe. Tin-coated lead foil has been used as a 

covering applied over the cork and neck areas of wine bottles for decorative purposes and to 

prevent insect infestations. Because it can be reasonably expected that lead could become a 

component of the wine, the use of such foil is also a violation of the Federal Food, Drug, and 

Cosmetic Act. FDA has reviewed several direct human food ingredients (i.e., food dyes) and has 

determined them to be “generally recognized as safe” when used in accordance with current 

good manufacturing practices. Some of these ingredients contain allowable lead concentrations 

that range from 0.1 to 10 ppm. 

Please see Chapter 8 for more information on federal and state regulations and guidelines for 

lead. 
LEAD 18 

1. PUBLIC HEALTH STATEMENT 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These 

clinics specialize in recognizing, evaluating, and treating illnesses that result from exposure to 

hazardous substances. 

Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You 

may request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information 

and technical assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at 

cdcinfo@cdc.gov, or by writing to: 

Agency for Toxic Substances and Disease Registry 

 Division of Toxicology and Environmental Medicine 

1600 Clifton Road NE 

 Mailstop F-32 

 Atlanta, GA 30333 

 Fax: 1-770-488-4178 

Organizations for-profit may request copies of final Toxicological Profiles from the following: 

National Technical Information Service (NTIS) 

5285 Port Royal Road 

 Springfield, VA 22161 

 Phone: 1-800-553-6847 or 1-703-605-6000 

 Web site: http://www.ntis.gov/ 
LEAD 19 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO LEAD IN THE UNITED 

STATES 

Lead is a naturally occurring metal found in the Earth's crust at about 15–20 mg/kg. In comparison to the 

two most abundant metals in the Earth, aluminum and iron, lead is a relatively uncommon metal. Lead 

rarely occurs in its elemental state, but rather its +2 oxidation state in various ores throughout the earth. 

The most important lead containing ores are galena (PbS), anglesite (PbSO4), and cerussite (PbCO3). The 

world’s reserves of lead are estimated at 7.1x107

 tons, with over one third located in North America. 

Levels of lead in the environment (not contained in ore deposits) have increased over the past three 

centuries as a result of human activity. Human exposure to lead is common and results from the many 

uses of this metal due to its exceptional properties. The largest industrial use of lead today is for the 

production of lead batteries, largely used in the automobile industry. Other uses of lead include the 

production of lead alloys, use in soldering materials, shielding for x-ray machines, and in the manufacture 

of corrosion and acid resistant materials used in the building industry (see Chapter 5 for more details 

regarding lead usage). 

The greatest potential for human exposure to lead arises from its previous use as an additive in gasoline, 

which resulted in its widespread dispersal throughout the environment, and its use as a pigment in both 

interior and exterior paints. Although the use of lead as a gasoline additive has been gradually phased out 

and completely banned by 1995 in the United States and its use in paints was banned in 1978, human 

exposure to lead continues because unlike organic chemicals released to the environment, lead does not 

degrade to other substances. Leaded paint is still prevalent in many older homes in the United States, and 

peeling or flaking paint contributes to indoor and outdoor dust levels. Prior to World War II, lead-arsenic 

compounds were used as pesticides, especially in orchards. Because lead does not degrade and is strongly 

absorbed to soil, the lead released from past uses still remains in the soil. Since the ban on the use of 

leaded gasoline took effect, lead emissions to the atmosphere have decreased significantly. According to 

the EPA, atmospheric emissions of lead decreased 93% over the 21-year period of 1982–2002. The 

atmospheric concentration of lead varies greatly, with the highest levels observed near stationary sources 

such as lead smelters. Levels of lead in ambient air range from about 7.6x10-5 μg/m3

 in remote areas such 

as Antarctica to >10 μg/m3

 near point sources. The EPA national ambient air quality standard for lead is 

1.5 μg/m3

. 
LEAD 20 

2. RELEVANCE TO PUBLIC HEALTH 

The amount of lead contained in pipes and plumbing fittings have been strictly regulated since 1988; 

however, human exposure to lead from drinking water still occurs as a consequence of leaching of lead 

from corroding pipes and fixtures or lead containing solder. Based on several data sets, it is estimated 

that <1% of the public water systems in the United States have water entering the distribution system with 

lead levels above 5 μg/L. Copper pipes have replaced lead pipes in most residential plumbing. 

Section 1417 of the Safe Drinking Water Act, which took effect in August 1998, requires that all pipes, 

fixtures, and solder be lead-free. However, lead-free means that solders and flux may not contain 

>0.2% lead, while pipes, pipe fittings, and well pumps may not contain >8% lead. The EPA requires 

public water distribution systems to reduce the corrosivity of water if >10% of the water samples exceed 

15 μg/L of lead. 

Occupational exposure to lead occurs for workers in the lead smelting and refining industries, battery 

manufacturing plants, steel welding or cutting operations, construction, rubber products and plastics 

industries, printing industries, firing ranges, radiator repair shops, and other industries requiring flame 

soldering of lead solder. In these occupations, the major routes of lead exposure are inhalation and 

ingestion of lead-bearing dusts and fumes. In the smelting and refining of lead, mean concentrations of 

lead in air can reach 4,470 μg/m3

; in the manufacture of storage batteries, mean airborne concentrations of 

lead from 50 to 5,400 μg/m3

 have been recorded; and in the breathing zone of welders of structural steel, 

an average lead concentration of 1,200 μg/m3

 has been found. 

Certain populations may be exposed to lead from other sources. Several non-western folk medicines can 

contain substantial levels of lead. Lead glazing that is applied to some pottery and ceramic ware may 

leach lead into foods or liquids that are stored in them (see Section 6.4.5 for more information). The FDA 

regulates the amount of leachable lead from food containers (see Table 8-1). 

Blood lead levels (PbB) in the general population of the United States have been decreasing over the past 

3 decades as regulations regarding lead paint, leaded fuels, and lead-containing plumbing materials have 

reduced exposure. PbBs measured as a part of the National Health and Nutrition Examination Surveys 

(NHANES) indicated that from 1976 to 1991, the mean PbBs of the U.S. population aged from 1 to 

74 years dropped 78%, from 12.8 to 2.8 μg/dL. The prevalence of PbBs ≥10 μg/dL also decreased 

sharply from 77.8 to 4.3%. Data from NHANES III, phase II (1991–1994) showed that 4.4% of children 

aged 1–5 years had PbBs ≥10 μg/dL, and the geometric mean PbBs for children 1–5 years old was 

2.7 μg/dL. From the most recent sampling data conducted for 1999–2002, 1.6% of children aged 1– 

5 years had PbBs ≥10 μg/dL, with a geometric mean PbBs of 1.9 μg/dL (see Section 6.5 for greater 
LEAD 21 

2. RELEVANCE TO PUBLIC HEALTH 

detail). The Centers for Disease Control and Prevention (CDC) action level for children ≤7 years of age 

is 10 μg/dL. A tiered approach is recommended for managing lead-exposed children (see Section 3.9). 

Analysis of lead in whole blood is the most common and accurate method of assessing lead exposure. 

Erythrocyte protoporphyrin (EP) tests can also be used, but are not as sensitive at low blood lead levels 

(≤20 μg/dL); the screening test of choice is blood lead levels. X-ray fluorescence techniques (XRF) can 

be used for the determination of lead concentration in bones. Lead partitions to the bone over a lifetime 

of exposure; therefore, bone lead measurements are a good indicator of cumulative exposure, whereas 

measurements of lead in blood are more indicative of recent exposure. However, XRF is primarily used 

in the research area and is not widely available (see Sections 3.3 and 3.6.1 for greater detail). 

2.2 SUMMARY OF HEALTH EFFECTS 

An enormous amount of information is available on the health effects of lead on human health. In fact, 

the toxic effects of lead have been known for centuries, but the discovery in the past few decades that 

levels of exposure resulting in relatively low levels of lead in blood (e.g., <20 μg/dL) are associated with 

adverse effects in the developing organism is a matter of great concern. Most of the information gathered 

in modern times regarding lead toxicity comes from studies of workers from a variety of industries and 

from studies of adults and children in the general population. The most sensitive targets for lead toxicity 

are the developing nervous system, the hematological and cardiovascular systems, and the kidney. 

However, due to the multi-modes of action of lead in biological systems, lead could potentially affect any 

system or organs in the body. 

Studies of lead workers suggest that long-term exposure to lead may be associated with increased 

mortality due to cerebrovascular disease. The same was found in a study of adults from the general 

population who were hospitalized for lead poisoning during childhood. Population studies suggest that 

there is a significant association between bone-lead levels and elevated blood pressure. Blood lead levels 

(PbBs) also have been associated with small elevations in blood pressure. Between the two biomarkers, 

bone lead appears to be the better predictor. Lead also affects kidney functions; glomerular filtration rate 

appears to be the function affected at the lowest PbBs. Decreased glomerular filtration rate has been 

consistently observed in populations with mean PbB <20 μg/dL and two studies have reported effects at 

PbB <10 μg/dL. Lead may alter glomerular filtration rate by several mechanisms. 
LEAD 22 

2. RELEVANCE TO PUBLIC HEALTH 

Lead has long been known to alter the hematological system by inhibiting the activities of several 

enzymes involved in heme biosynthesis. Particularly sensitive to lead action is δ-aminolevulinic acid 

dehydratase (ALAD). Inhibition of ALAD activity occurs over a wide range of PbBs beginning at 

<10 μg/dL. The anemia induced by lead is primarily the result of both inhibition of heme synthesis and 

shortening of erythrocyte lifespan, but lead also can induce inappropriate production of the hormone 

erythropoietin leading to inadequate maturation of red cell progenitors, which can contribute to the 

anemia. 

A recent study in children 8–10 years of age suggested that lead accelerates skeletal maturation, which 

might predispose to osteoporosis in later life. Lead also has been associated with increased occurrence of 

dental caries in children and periodontal bone loss, which is consistent with delayed mineralization in 

teeth observed in studies in animals. Current mean PbBs in these cohorts were <5 μg/dL; however, the 

cross-sectional nature of the studies precluded assessment of the exposure history. 

Changes in circulating levels of thyroid hormones, particularly serum thyroxine (T4) and thyroid 

stimulating hormone (TSH), generally occurred in workers having mean PbB ≥40–60 μg/dL. Altered 

serum levels of reproductive hormones, particularly follicle stimulating hormone (FSH), luteinizing 

hormone (LH), and testosterone have been observed at PbB ≥30–40 μg/dL. Lead also has been shown to 

decrease circulating levels of the active form of vitamin D, 1,25-dihydroxyvitamin D, in children with 

moderate to high PbB (30–60 μg/dL), but not in children with low to moderate PbB (average lifetime PbB 

between 4.9 and 23.6 μg/dL, geometric mean, 9.8 μg/dL). Normal levels of vitamin D are important for 

maintaining calcium homeostasis. 

Altered immune parameters have been described in lead workers with PbB in the range of 30–70 μg/dL. 

Reported effects included changes in some T-cell subpopulations, response to T-cell mitogens, and 

reduced chemotaxis of polymorphonuclear leukocytes. Several studies of children reported significant 

associations between PbB and increases in serum IgE levels. IgE is the primary mediator for type-I 

hypersensitivity and is involved in various allergic diseases such as asthma. These findings in children 

along with results from studies in rodents exposed in utero have led some to suggest that lead may be a 

risk factor for childhood asthma, although a recent relatively large study (4,634 children) found that PbB 

was less a predictor of asthma than was race. 

Exposure to high amounts of lead resulting in PbBs of 100–120 μg/dL in adults or 70–100 μg/dL in 

children produce encephalopathy, a general term that describes various diseases that affect brain function. 
LEAD 23 

2. RELEVANCE TO PUBLIC HEALTH 

Symptoms develop following prolonged exposure and include dullness, irritability, poor attention span, 

epigastric pain, constipation, vomiting, convulsions, coma, and death. Lead poisoning in children can 

leave residual cognitive deficits that can be still detected in adulthood. Neurobehavioral effects including 

malaise, forgetfulness, irritability, lethargy, headache, fatigue, impotence, decreased libido, dizziness, 

weakness, and paresthesia have been reported in lead workers with PbBs in the range of 40–80 μg/dL. 

Also, PbBs between 40 and 80 μg/dL have been associated with neuropsychological effects in lead 

workers. A recent study of lead workers reported that higher tibia lead was associated with increased 

prevalence and severity of white matter lesions, as assessed by brain MRI. Studies of older populations 

with current mean PbBs <10 μg/dL have reported associations between PbB and/or bone lead and poorer 

performance in neurobehavioral tests. Lead also has been shown to affect nerve conduction velocity and 

postural balance in workers with PbB in the range of 30–60 μg/dL. Alterations of somatosensory evoked 

potentials also have been reported in lead workers with mean PbBs in the range of 30–50 μg/dL. 

As previously mentioned, one of the major concerns regarding lead toxicity is the cognitive and neurobehavioral deficits that are observed in children exposed to lead. Prospective studies have provided the 

greatest amount of information. Analyses of these and other studies suggest that an IQ decline of 1– 

5 points is associated with an increase in PbB of 10 μg/dL. Of special interest and concern are the results 

of recent studies that have reported neurobehavioral deficits in children associated with PbBs <10 μg/dL 

and an apparent lack of threshold down to even the lowest PbBs recorded in these studies. Lead also has 

caused neurobehavioral alterations in developing animals, and at PbBs similar to those reported in 

children. Studies in animals, particularly in monkeys, have provided key information for the 

interpretation of a cognitive basis for IQ changes. Studies of children also have shown associations 

between PbB and growth, delayed sexual maturation in girls, and decreased erythropoietin production. 

Some studies of humans occupationally or environmentally exposed to lead have observed associations 

between PbB and abortion and preterm delivery in women and alterations in sperm and decreased fertility 

in men. On the other hand, there are several studies that found no significant association between lead 

exposure and these end points. At least for the effects in males, the threshold PbB appears to be in the 

range of 30–40 μg/dL. Studies have shown that lead can affect the association of protamines with DNA 

in sperm cells from exposed males. Lead does so by competing or reducing zinc in protamine P2 in vivo, 

which would leave sperm chromatin and DNA open to damage from other exposures. 

In vitro mutagenicity studies in microorganisms have yielded mostly negative results for lead, but lead is 

a clastogenic agent, as shown by the induction of chromosomal aberrations, micronuclei and by sister 
LEAD 24 

2. RELEVANCE TO PUBLIC HEALTH 

chromatid exchanges in peripheral blood cells from lead workers. Studies of cancer in lead workers have 

been inconclusive. A meta-analysis of eight major occupational studies on cancer mortality or incidence 

in workers with high lead exposure concluded that there is some limited evidence of increased risk of 

lung cancer and stomach cancer, although there might have been confounding with arsenic exposure in 

the study with highest relative risk of lung cancer. The results also showed a weak evidence for an 

association with kidney cancer and gliomas. In the only study of the general population available, there 

was suggestive evidence for an increase risk of cancer mortality in women, but not men, with a threshold 

PbB of 24 μg/dL. This study used data from the Second National Health and Nutrition Survey 

(NHANES II) Mortality Study. Lead has produced primarily renal tumors in rodents by a mechanism not 

yet elucidated. Some nongenotoxic mechanisms that have been proposed for lead-induced cancer include 

inhibition of DNA synthesis and repair, alterations in cell-to-cell communication, and oxidative damage. 

The Department of Health and Human Services (DHHS) has determined that lead and lead compounds 

are reasonably anticipated to be human carcinogens based on limited evidence from studies in humans 

and sufficient evidence from animal studies. The EPA has determined that lead is a probable human 

carcinogen based on sufficient evidence from studies in animals and inadequate evidence in humans. The 

International Agency for Research on Cancer (IARC) has determined that inorganic lead is probably 

carcinogenic to humans based on sufficient evidence from studies in animals and limited evidence of 

carcinogenicity from studies in humans. IARC also determined that organic lead compounds are not 

classifiable as to their carcinogenicity in humans based on inadequate evidence from studies in humans 

and animals. 

A discussion of the most sensitive end points for lead toxicity, neurodevelopmental, cardiovascular/renal, 

and hematological, is presented below. The reader is referred to Chapter 3, Health Effects, for 

information on additional effects. 

Neurodevelopmental Effects. Lead can impair cognitive function in children and adults, but 

children are more vulnerable than adults. The increased vulnerability is due in part to the relative 

importance of exposure pathways (i.e., dust-to-hand-mouth) and differences in toxicokinetics (i.e., 

absorption of ingested lead). Although the inhalation and oral routes are the main routes of exposure for 

both adults and children, children are more likely to have contact with contaminated surfaces due to 

playing on the ground and to hand-to-mouth activities. Furthermore, children absorb a larger fraction of 

ingested lead than adults. However, perhaps more important is the fact that the developing nervous 

system is especially susceptible to lead toxicity. During brain development, lead interferes with the 
LEAD 25 

2. RELEVANCE TO PUBLIC HEALTH 

trimming and pruning of synapses, migration of neurons, and neuron/glia interactions. Alterations of any 

of these processes may result in failure to establish appropriate connections between structures and 

eventually in permanently altered functions. Because different brain areas mature at different times, the 

final outcome of the exposure to lead during development (i.e., in utero vs. pediatric exposure) will vary 

depending on the time of exposure. This has been demonstrated in studies in animals. The time of 

exposure-specific response appears to have contributed to the failure to identify a “behavioral signature” 

of lead exposure in children. Other factors that may affect individual vulnerability are certain genetic 

polymorphisms, such as that for the vitamin D receptor, the lead-binding enzyme ALAD, or the APOE 

genotype. One important additional factor shown to influence the toxicity of lead is the characteristics of 

the child’s rearing environment, a modifying factor. It has been argued that effect modification is a 

property of a true association and should be distinguished from confounding. Effect modification can 

explain inconsistencies in findings, and if it exists, failure to address it will lead to an error in inference. 

For example, if social class is an effect modifier of the association between PbB and IQ, and differs 

between two cohorts, the strength of the association based on these two studies will necessarily be 

different. 

Despite the many factors that can potentially work against finding agreement among studies, the 

preponderance of the evidence indicates that lead exposure is associated with decrements in cognitive 

function. Meta-analyses conducted on cross-sectional studies or a combination of cross-sectional and 

prospective studies suggest that an IQ decline of 1–5 points is associated with an increase in PbB of 

10 μg/dL. Most importantly, no threshold for the effects of lead on IQ has been identified. This has been 

confirmed by a series of recent studies in children that found significant inverse associations between 

cognitive function and PbBs <10 μg/dL. Moreover, these and other studies have shown that the slope of 

the lead effects on cognitive variables is steeper (the effect is greater) at lower than at higher PbBs (supralinear dose-response relationship). However, there is not complete agreement on the interpretation of the 

lack of linearity in the dose-response relationship among the scientific community. Some have argued, 

based on a theoretical statistical analysis, that the supra-linear slope is a required outcome of correlations 

between data distributions where one is log-normally distributed and the other is normally distributed. 

Perhaps the strongest evidence for nonlinearity is provided by an international pooled analysis of seven 

prospective studies (details in Section 3.2.4). After testing several models, these investigators determined 

that the shape of the dose-response was nonlinear insofar as the quadratic and cubic terms for concurrent 

PbB were statistically significant (p<0.001, p=0.003, respectively). Additional support for the steeper 

slope at low PbB was provided by plotting the individual effects estimates for each of the seven cohorts, 

adjusted for the same covariates. The plot showed that the studies with the lowest mean PbBs had a 
LEAD 26 

2. RELEVANCE TO PUBLIC HEALTH 

steeper slope compared with studies with higher PbBs. Yet further evidence for nonlinearity was 

presented when the data were divided at two cut-points a priori (maximal PbB above and below 10 μg/dL 

and above and below 7.5 μg/dL). The investigators then fit separate linear models to the data in each of 

those ranges and compared the PbB coefficients for the concurrent PbB index. The stratified analyses 

showed that the effects estimate for children with maximal PbB <7.5 μg/dL was significantly greater 

(p=0.015) than those with a maximal PbB ≥7.5 μg/dL. Similar results were seen at the cut-off point of 

10 μg/dL. A reanalysis of the pooled studies found that a log-linear relationship between PbB and IQ was 

a better fit within the ranges of PbBs in the studies than was a linear relationship (p<0.009). Collectively, 

the results of the pooled analysis and of additional studies provide suggestive evidence of lead effects on 

cognitive functions in children at PbBs <10 μg/dL and, possibly as low as 5 μg/dL. It should be stressed, 

however, that the effects of lead on IQ and other neurobehavioral scores are very small compared with the 

effects of other factors such as parents’ IQ, but is also important to stress that lead exposure, unlike most 

of those other factors, is highly preventable. 

The other aspect that has been questioned regarding the nonlinear shape of the dose-response relationship 

is the apparent lack of a biological mechanism that could produce this result, and this clearly represents a 

data need. To explain the nonlinear shape of the dose-response, it was proposed that “the initial damage 

caused by lead may reflect the disruption of different biological mechanisms than the more severe effects 

of high exposures that result in encephalopathy or frank mental disability. This might explain why, 

within the range of exposures not producing overt clinical effects, an increase in PbB beyond a certain 

level might cause little additional impairment in children’s cognitive function.” 

While measurements of IQ are convenient in that they allow comparison across populations of different 

demographic and cultural characteristics, and help define the extent of the public health issue, they only 

partially advance our understanding of the problem of lead-induced behavioral toxicity. It is important to 

elucidate the underlying basis of the deficits in IQ as well as the behavioral mechanisms that account for 

them. It was noted that “the answers are critical not only to further define neurobiological mechanisms 

associated with learning deficits, but also to determine behavioral or neurochemical therapeutic 

approaches to alleviate them.” Studies in animals have provided answers to some of these questions. 

Studies in animals have great utility because the possibility of confounding is reduced with the controlled 

experimental design and genetic factors. In addition, they address specific domains of cognitive function 

and allow determination of critical periods of exposure. Results of behavioral tests performed primarily 

in rats and monkeys exposed to lead have suggested that the impaired performance is the result, at least in 

part, of a combination of distractibility, inability to inhibit inappropriate responding, and perseveration in 
LEAD 27 

2. RELEVANCE TO PUBLIC HEALTH 

behaviors that are no longer appropriate. Evaluation of children exposed to lead with different subscales 

of IQ tests in conjunction with assessments of behavior on teacher’s rating scales on young school-age 

children suggest that increased distractibility, impulsivity, short attention span, and inability to follow 

simple and complex sequences of directions are associated with increased lead body burden. The 

similarity between neurobehavioral effects in lead-exposed children and in animals, and the fact that the 

deficits are observed at similar PbBs should stimulate continued research to elucidate the biochemical and 

morphological substrates that underlie specific behaviors. 

Although the decrement of IQ points in children associated with lead exposure is generally small, lead 

neurotoxicity may have major implications for public health when exposure is considered in terms of 

large populations and its preventable nature. One study quantified the economic benefits from projected 

improvements in worker productivity resulting from the reduction in children’s exposure to lead in the 

United States since 1976. Based on data from NHANES (a study designed to provide national estimates 

of the health and nutritional status of the U.S. civilian noninstitutionalized population aged 2 months and 

older) and meta-analyses, it was estimated that mean PbBs declined 15.1 μg/dL between 1976 and 

1999 and that IQ scores increased between 0.185 and 0.323 points for each 1 μg/dL blood lead 

concentration. It was further estimated that each IQ point raises worker’s productivity by 1.76–2.38%, 

and that the economic benefit for each year’s cohort of 3.8 million 2-year-old children ranges from 

$110 to $319 billion. In another study, using an environmentally attributable fraction model, it was 

estimated that the present value of economic losses in the United States attributable to lead exposure in 

amounts to $43.4 billion per year in each annual birth cohort. More recently, one study estimated that 

mild mental retardation and cardiovascular outcomes resulting from exposure to lead amounts to almost 

1% of the global burden of disease, with the highest burden in developing regions. 

A related and important issue is whether lead-lowering interventions, such as with chelators, are 

paralleled by improvement in health outcomes reportedly altered by lead. In one study, improvement in 

cognitive functions was related to decreases in blood lead but not to chelation treatment. In a multi-center 

study of 780 children, chelation therapy lowered blood lead by a mean of 4.5 μg/dL during the 6 months 

after initiation of treatment, but it did not improve scores on tests of cognition, behavior, or neuropsychological function in children with PbB below 45 μg/dL. Re-analysis of these data showed that 

improvement in test scores was associated with greater falls in PbB only in the placebo group. A further 

evaluation of this cohort showed that chelation therapy lowered blood lead, but produced no benefits in 

cognitive, behavioral, or neuromotor end points. The conclusion of this series of studies reached by the 

investigators was that chelation therapy is not indicated in children with moderate blood lead levels. 
LEAD 28 

2. RELEVANCE TO PUBLIC HEALTH 

Thus, it appears that lead abatement must remain the primary approach in the public health management 

of lead poisoning. 

Cardiovascular/Renal Effects. Although lead has been shown to produce various cardiovascular 

and renal effects in animals, end points of greatest concern for humans at low exposures and low PbB are 

elevations in systemic blood pressure and decrements in glomerular filtration rate. These effects may be 

mechanistically related and, furthermore, can be confounders and covariables in epidemiological studies. 

Decrements in glomerular filtration rate may contribute to elevations in blood pressure, and elevated 

blood pressure may predispose people to glomerular disease. 

Effects on Blood Pressure. Numerous covariables and confounders affect studies of associations 

between PbB and blood pressure, including, age, body mass, race, smoking, alcohol consumption, 

ongoing or family history of cardiovascular/renal disease, and various dietary factors. Varying 

approaches and breadth of inclusion of these may account for some of the disparity of results that have 

been reported. Including confounders in a regression model will attenuate the apparent association 

between lead exposure and the measured health outcome. Measurement error may also be an important 

factor. Blood pressure estimates based on multiple measurements or, preferably, 24-hour ambulatory 

measurements, are more reproducible than single measurements. Few studies have employed such 

techniques and, when used, have not found significant associations between PbB and blood pressure. 

An additional limitation of blood lead studies, in general, is that PbB may not provide the ideal biomarker 

for long-term exposure to target tissues that contribute a hypertensive effect of lead. Bone lead appears to 

be a better predictor of lead-induced elevations in blood pressure than PbB. In a recent prospective 

analysis of the Normative Aging Study, higher tibial lead levels, but not PbBs, were associated with 

higher systolic blood pressure and abnormalities in electrocardiographic conduction. 

Chronic lead exposure increases blood pressure in rats through diverse mechanisms that include 

alterations in neurohumoral control of peripheral vascular resistance, heart rate, and cardiac output (see 

Section 3.4.2). Studies conducted in animal models provide strong evidence for the plausibility of lead 

elevating blood pressure in humans. Meta-analyses of the epidemiological findings have found a 

persistent trend in the data that supports a relatively weak, but significant association. Quantitatively, this 

association amounts to an increase in systolic blood pressure of approximately 1 mmHg with each 

doubling of PbB. The results of more recent epidemiology studies indicate that the lead contribution to 

elevated blood pressure is more pronounced in middle age than at younger ages. A longitudinal study of 
LEAD 29 

2. RELEVANCE TO PUBLIC HEALTH 

males, mean age 67 years, found positive associations between systolic blood pressure and bone lead 

concentrations, and increased risk of hypertension in association with increased bone lead concentration. 

Based on this study, an increase in patella bone lead from the midpoint of the lowest quintile (12.0 μg/g) 

to the highest quintile (53.0 μg/g) was associated with a 1.71-fold increase in hypertension risk (rate-ratio, 

95%; confidence interval [CI], 1.08–2.71). A case-control study of women, ages >55 years, found 

increased risk of hypertension in association with increased bone lead concentration. In this study, an 

increase in patella bone lead from 6 to 31 μg/g was associated with a 1.86-fold (odds ratio [OR], 95%; CI, 

1.09–3.19) increase in risk of hypertension. A large-scale cross-sectional analysis of the NHANES III 

data on males and females, age 40–59 years, found increasing risk for hypertension in association with 

increasing PbB, with higher risks in postmenopausal women than in premenopausal women. Risks of 

diastolic hypertension for pre- and postmenopausal women, combined, who were in the highest blood 

lead quartile (mean, 6.4 μg/dL; range, 3.0–31.1) was predicted to be 3.4-fold higher (OR, 95%; CI, 1.3– 

8.7) than that of women in the lowest quartile (mean, 1 μg/dL; range, 0.5–1.6); corresponding risks for 

postmenopausal women were 8.1 times greater (OR, 95%; CI, 2.6–24.7) (highest vs. lowest quartile). 

The results of two analyses of the NHANES III data on adult subjects provides evidence for an 

association between increasing PbB and increasing blood pressure that is more pronounced in blacks than 

whites. Lead exposures during infancy and childhood (reflected in PbB) have been associated with 

increased blood pressure and altered responses to acute pressor stresses in childhood. Lead poisoning in 

childhood has also been associated with hypertension during adulthood in the absence of clinically 

significant renal disease and discernable elevations in PbB. 

Effects in Renal Glomerular Filtration. Classic lead nephrotoxicity is characterized by proximal tubular 

nephropathy, glomerular sclerosis, and interstitial fibrosis and related functional deficits, including 

enzymuria, low- and high-molecular weight proteinuria, impaired transport of organic anions and glucose, 

and depressed glomerular filtration rate. In humans, the overall dose-effect pattern suggests an increasing 

severity of nephrotoxicity associated with increasing PbB, with effects on glomerular filtration evident at 

PbBs below 10 μg/dL, enzymuria and proteinuria becoming evident above 30 μg/dL, and severe deficits 

in function and pathological changes occurring in association with PbB exceeding 50 μg/dL. Thus, the 

renal effects of greatest concern, at low exposures (i.e., low PbB), are on glomerular filtration. 

The results of epidemiological studies of general populations have shown a significant effect of age on the 

relationship between glomerular filtration rate (assessed from creatinine clearance of serum creatinine 

concentration) and PbB (see Section 3.2.2. Renal Effects). Furthermore, as noted previously, 

hypertension can be both a confounder in studies of associations between lead exposure and creatinine 
LEAD 30 

2. RELEVANCE TO PUBLIC HEALTH 

clearance as well as a covariable with lead exposure. Another important complication in the assessment 

of associations between lead exposure and adverse effects on glomerular filtration is the potential 

confounding effect of decrements in glomerular filtration rate and increased lead body burden. Lead 

exposure has also been associated with increases in glomerular filtration rate. This may represent a 

benign outcome or a potentially adverse hyperfiltration, which may contribute to subsequent adverse renal 

effects. Increases in glomerular filtration rate have been observed in the early phases of development of 

chronic renal injury in rats. When age and other covariables that might contribute to glomerular disease 

are factored into the dose-response analysis, decreased glomerular filtration rate has been consistently 

observed in populations that have average PbBs <20 μg/dL, with some studies finding effects at PbBs 

<10 μg/dL (see Section 3.2.2, Table 3-4). Two studies provide evidence for an effect at lead 

concentrations below 10 μg/dL. A longitudinal study found a significant relationship between increasing 

serum creatinine concentration and increasing PbB below 10 μg/dL. A cross-sectional analysis of data 

from the NHANES III found increased risk of chronic renal disease (defined as severely depressed 

glomerular filtration rate) in association with PbB <6 μg/dL. The confounding and covariable effects of 

hypertension are also relevant to the interpretation of the regression coefficients reported in these studies. 

Given the evidence for an association between lead exposure and hypertension, and that decrements in 

glomerular filtration rate can be a contributor to hypertension, it is possible that the reported 

hypertension-adjusted regression coefficients may underestimate the actual slope of the PbB relationship 

with serum concentration of creatinine or creatinine clearance. 

Hematological Effects. The adverse hematological effects of lead are mainly the result of its 

perturbation of the heme biosynthesis pathway. The activity of ALAD, an enzyme occurring early in the 

heme synthesis pathway, is negatively correlated with PbBs between 5 and 95 μg/dL. Although 

inhibition of ALAD occurs at very low exposure levels, there is some controversy as to the toxicological 

significance of a depression in ALAD activity in the absence of a detectable effect on hemoglobin levels. 

Nevertheless, because the impairment of heme synthesis has a far-ranging impact not limited to the 

hemopoietic system, there is concern that developing organisms might be particularly susceptible. 

A potential consequence of the inhibition of heme synthesis is a decreased formation of mixed function 

oxidases in the liver resulting in impaired metabolism of endogenous compounds, as well as impaired 

detoxification of xenobiotics. Mitochondrial cytochrome oxidase is another heme-requiring protein that 

could be affected by heme synthesis inhibition. In addition, tryptophan pyrrolase, a hepatic hemerequiring enzyme system, is inhibited via the reduction in the free hepatic heme pool. This could 

ultimately lead to increased levels of the neurotransmitter serotonin in the brain and increased aberrant 
LEAD 31 

2. RELEVANCE TO PUBLIC HEALTH 

neurotransmission in serotonergic pathways. Inhibition of heme synthesis also results in increased levels 

of δ-aminolevulinic acid (ALA), which has a structure similar to that of the inhibitory neurotransmitter 

gamma-aminobutyric acid (GABA), and therefore, interferes with GABA neurotransmission. Finally, a 

prospective study of children with moderate PbB (25–40 μg/dL) and hemoglobin levels within normal 

limits found that serum erythropoietin (EPO) was positively associated with PbB at ages 4.5 and 

6.5 years, but the magnitude of the association gradually declined from 4.5 to 12 years. EPO is a 

glycoprotein hormone produced in the kidney that regulates both steady-state and accelerated erythrocyte 

production. This suggested that in nonanemic children with moderate PbB, hyperproduction of EPO is 

necessary to maintain normal hemoglobin concentrations. The decline in slope with age suggested that 

the compensatory mechanism gradually begins to fail due to direct lead-induced inhibition of EPO 

production or indirectly through toxic effects of lead on the kidney. Inhibition of EPO production may 

contribute to lead-induced anemia. Anemia occurs at PbBs of ≥20 μg/dL. 

2.3 LEAD DOSE-RESPONSE RELATIONSHIPS 

MRLs were not derived for lead because a clear threshold for some of the more sensitive effects in 

humans has not been identified. In addition, deriving an MRL would overlook the significant body of 

PbB literature. These data suggest that certain subtle neurobehavioral effects in children may occur at 

very low PbBs. In lieu of MRLs, ATSDR has developed a framework to guide decisions at lead sites. 

This approach utilizes site-specific exposure data to estimate internal doses as measured by PbBs (see 

Appendix D). 

Epidemiological studies and clinical observations provide evidence for a progression of adverse health 

effects of lead in humans that occur in association with PbBs ranging from <10 to >60 μg/dL (Table 2-1). 

At the low end of the blood lead concentration range, adverse effects include delays and/or impaired 

development of the nervous system, delayed sexual maturation, neurobehavioral effects, increased blood 

pressure, depressed renal glomerular filtration rate, and inhibition of pathways in heme synthesis. 

Although fewer studies have examined associations between health outcomes and bone lead 

concentrations, recent studies provide evidence for adverse effects occurring in association with bone lead 

concentrations in excess of 10 μg/g (e.g., cardiovascular/renal, neurobehavioral effects). 

The timing of exposure, in addition to the exposure intensity, appears to be an important variable in the 

exposure-response relationship for lead. Exposures that occur during pre- and postnatal development, 

which result in PbBs of 10 μg/dL or less, produce delays or impairments of neurological and sexual 
LEAD 32 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-1. Blood and Bone Lead Concentrations Corresponding to Adverse 

Health Effects 

Age Effect Blood leada (μg/dL) Bone leada (g/g) 

Children Depressed ALAD <5 ND 

Children Neurodevelopmental effects <10 ND 

Children Sexual maturation <10 ND 

Children Depressed vitamin D >15 ND 

Children Elevated EP >15 ND 

Children Depressed NCV >30 ND 

Children Depressed hemoglobin >40 ND 

Children Colic >60 ND 

Adults (elderly) Neurobehavioral effects >4 >30 

Adults Depressed ALAD <5 ND 

Adults Depressed GFR <10 >10 

Adults Elevated blood pressure <10 >10 

Adults Elevated EP (females) >20 ND 

Adults Enzymuria/proteinuria >30 ND 

Adults Peripheral neuropathy >40 ND 

Adults Neurobehavioral effects >40 ND 

Adults Altered thyroid hormone >40 ND 

Adults Reduced fertility >40 ND 

Adults Depressed hemoglobin >50 ND 

a

Concentration range associated with effect. 

ALAD = δ-aminolevulinic acid dehydratase; EP = erythrocyte protoporphyrin; GFR = glomerular filtration rate; 

NCV = nerve conduction velocity; ND = no data 
LEAD 33 

2. RELEVANCE TO PUBLIC HEALTH 

development. Cognitive deficits, hypertension, and depressed glomerular filtration rate have been 

observed in older adults (>60 years and/or postmenopause) in association with PbBs <10 μg/dL. This 

may reflect a higher vulnerability with age and/or the effects of cumulative life-time exposures that are 

less evident in younger populations that have lower time-integrated exposures. 

The epidemiological literature provides a basis for associating specific biomarkers (e.g., PbB, bone lead 

concentration) with adverse health effects. Prediction of health outcomes that might result from any 

given environmental exposure requires an understanding of the relationships between environmental 

exposure (level, frequency, duration), human physiology and behaviors that result in intake of lead (e.g., 

ingestion of dust, drinking water, inhalation), and lead biokinetics. Models that predict PbBs 

corresponding to specific exposure scenarios have been used in this context for the purpose of assessing 

lead health risks. Two general approaches have been explored: (1) integrated exposure-biokinetics 

models that simulate lead exposure, intake, absorption, tissue distribution, and excretion of lead in 

humans; and (2) slope factor models that predict PbB based on an empirically-derived linear parameter 

relating exposure level, or rate of lead absorption, to PbB. Descriptions of exposure-biokinetics and slope 

factor models that have been used or have potential use in assessing exposure-effect relationships in 

human populations are described in Section 3.3.5 and in Appendix D. 
LEAD 34 

2. RELEVANCE TO PUBLIC HEALTH 

This page is intentionally blank. 
LEAD 35 

3. HEALTH EFFECTS 

3.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of lead. It contains 

descriptions and evaluations of toxicological studies and epidemiological investigations and provides 

conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found in Appendix C at the end of 

this profile. 

This chapter will focus primarily on inorganic lead compounds (lead, its salts, and oxides/sulfides), the 

predominant forms of lead in the environment. The available data on organic (i.e., alkyl) lead compounds 

indicate that some of the toxic effects of alkyl lead are mediated through metabolism to inorganic lead 

and that during the combustion of gasoline containing alkyl lead, significant amounts of inorganic lead 

are released to contaminate the environment. In addition, the lead alkyl halides in automobile exhausts 

are quickly oxidized by sunlight and air, and do not appear to be present at hazardous waste sites in 

significant amounts. By far, most lead at hazardous waste sites is inorganic lead. The limited data 

available on alkyl lead compounds indicate that the toxicokinetic profiles and toxicological effects of 

these compounds are qualitatively and quantitatively different from those of inorganic lead (EPA 1985b). 

The database for lead is unusual in that it contains a great deal of data concerning dose-effect 

relationships in humans. These data come primarily from studies of occupationally exposed groups and 

the general population. For the general population, exposure to lead occurs primarily via the oral route, 

with some contribution from the inhalation route, whereas occupational exposure is primarily by 

inhalation with some contribution by the oral route. Because the toxic effects of lead are the same 

regardless of the route of entry into the body, the profile will not attempt to separate human dose data by 

routes of exposure. The dose data for humans are generally expressed in terms of absorbed dose and not 

in terms of external exposure levels, or milligrams per kilogram per day (mg/kg/day). The most common 

metric of absorbed dose for lead is the concentration of lead in the blood (PbB), although other indices, 

such as lead in bone, hair, or teeth also are available (further information regarding these indices can be 

found in Section 3.3.2 and Section 3.6.1). The concentration of lead in blood reflects mainly the exposure 

history of the previous few months and does not necessarily reflect the larger burden and much slower 

elimination kinetics of lead in bone. Lead in bone is considered a biomarker of cumulative or long-term 
LEAD 36 

3. HEALTH EFFECTS 

exposure to lead because lead accumulates in bone over the lifetime and most of the lead body burden 

resides in bone. For this reason, bone lead may be a better predictor than blood lead of some health 

effects. 

The database on effects of lead in animals is extensive and, in general, provides support for observations 

in human studies, with some consistency in types of effects and PbB-effect relationships. However, 

animal data on lead toxicity are generally considered less suitable as the basis for health effects 

assessments than are the human data. There is no absolutely equivalent animal model for the effects of 

lead on humans. In this profile, animal studies will be discussed only to the extent that they support the 

findings in humans. 

Due to the extent of the lead database, it is impossible to cite all, or even most, of the studies on a specific 

topic. ATSDR acknowledges that all studies that add a new piece of information are valuable, but the 

relative impact on the overall picture regarding lead toxicity varies among studies. Given that the goal of 

Chapter 3 is to provide an overall perspective on the toxicology of lead, some sections focus on studies 

that have provided major contributions to the understanding of lead toxicity over those that only add a 

small piece of information into a very big puzzle or that only reiterate findings previously published. 

Health outcomes associated with internal lead doses from selected studies are presented in Table 3-1. 

3.2 DISCUSSION OF HEALTH EFFECTS 

3.2.1 Death 

Mortality studies for workers exposed occupationally to lead as well as studies of the general population 

are available (see also Section 3.2.8, Cancer). Two cohorts of male lead workers, 4,519 battery plant 

workers and 2,300 lead production workers, all of whom had been employed for at least 1 year during the 

period 1946–1970, were studied for mortality from 1947 through 1980 (Cooper 1988; Cooper et al. 

1985). Overall mortality and standardized mortality ratios (SMRs) were determined. From 1947 through 

1972, mean PbBs were 63 μg/dL for 1,326 battery plant workers and 80 μg/dL for 537 lead production 

workers (PbB data were not available for many of the workers and most of the monitoring was done after 

1960). For both groups, the number of observed deaths from all causes combined was significantly 

greater (p<0.01) than expected, based on national mortality rates for white males. The increased 

mortality rates resulted in large part from malignant neoplasms; chronic renal disease, including 
Table 3-1. Internal Lead Doses Associated with Health Effects from Selected Stu

Population studied Exposure Biomarkers Effect Comments Cardiovascular a 519 males, 67 years old (mean) 

667 pregnant females, 15–44 years old 

496 adults, 56 years old (mean) 

294 females, 61 years old (mean) 

General population 

General population 

Occupational 

General population 

20.3 ppm (mean tibia Pb) Increased risk of 

hypertension; no significant association with PbB or patella lead 

10.7 ppm (mean calcaneus Pb) Hypertension; a 

10 ppm increase in calcaneus Pb was associated with a 0.70 mmHg increase in systolic blood pressure and 0.54 mmHg diastolic blood pressure 

4.6 μg/dL (mean PbB at Increase in systolic 

baseline) blood pressure 14.7 ppm (mean tibia Pb at associated with year 3 of study) PbB and tibia Pb 

17.3 ppm (mean patella Pb) Increased risk of 

hypertension; no significant association with tibia Pb or PbB 

Longitudinal study (Normative AStudy). Covariates: age and bmass index; race; family history hypertension; education; tobacsmoking and alcohol consumptand dietary intakes of sodium acalcium. Subjects were free frodefinite hypertension at baselin

Longitudinal study of pregnancyCo-variates: age and body maindex, parity, postpartum hypertension, tobacco smokingeducation. 

Longitudinal study. Covariatesand body mass index; diagnosidiabetes, arthritis, or thyroid disease; education; and blood pressure measurement interval

Case-control study (Nurses HeStudy). Covariates: age and bmass index, dietary sodium intaand family history of hypertensi
Table 3-1. Internal Lead Doses Associated with Health Effects from Selected Stu

Population studied Exposure Biomarkers Effect Comments 146 males, 67 years old (mean) 13,781 males and females, >20 years old 

543 females, 50 years old (mean) 

508 males and females, 19–24 years old 

General population General population 

General population 

General population 

24 ppm (mean tibia Pb) 2.1–4.2 μg/dL median PbB in white and black males and females 

6.4 μg/dL (mean PbB) 4.0– 31 μg/dL (range) 

>10 ppm (tibia Pb) 

Increased risk of hypertension; an increase in tibia Pb from 8 to 37 ppm associated with a 1.5 odds ratio for hypertension Bordeline association between PbB and systolic BP in black males and significant association in black females; no association in whites 

Increased risk of diastolic hypertension 

Increase in systolic 

and diastolic blood pressure 

Case-control study. Covariatesbody mass index and family hisof hypertension. NHANES III analysis. Covariatage and body mass index; hematocrit, total serum calciumprotein concentrations; tobacco smoking; alcohol and coffee consumption; dietary calcium, potassium, and sodium intakesdiabetes; and use of antihypertensive drugs. 

NHANES III analysis. Co-variarace, age, and body mass indetobacco smoking, and alcohol consumption. 

Cohort follow-up study of Bunkchildren. Covariates: gender, and body mass index; blood hemoglobin and serum albumin concentrations; education; tobasmoking and alcohol consumptcurrent use of birth control pillsincome; and current PbB. 
Table 3-1. Internal Lead Doses Associated with Health Effects from Selected Stu

Population studied Exposure Biomarkers Effect Comments 775 males, 68 years old (mean) 122 children, 9 years of age 

Gastrointestinal Children 

Hematological 159 adults 

579 children, 1– 5 years old 

143 children, 10– 13 years old 

General population General population 

General 

population 

General 

population and occupational 

Residence near lead ore smelter 

Residence near lead smelter 

22.2 ppm (mean tibia Pb) 1.98 μg/dL (mean PbB prenatal); 4.62 μg/dL (mean PbB at evaluation) 

60–100 μg/dL (PbB range) 

5–95 μg/dL (PbB range) 

PbB >20 μg/dL 

5–40 μg/dL (PbB range) 

Significant 

association with EKG changes and conduction defects. Less strong association with patella Pb; no association with PbB Higher prenatal PbB associated with higher resting systolic BP; higher childhood PbB associated with greater peripheral resistance response to stress 

Colic 

Decreased ALAD activity 

Anemia 

Decreased ALAD activity 

Cross-sectional study (NormatiAging Study). Covariates: agebody mass index, diastolic bloopressure, fasting blood glucose level, alcohol consumption, and serum HDL concentration. Covariates included in the modwere: maternal age, educationSES, HOME score, health and nutrition, substance use during pregnancy, and infant and childcharacteristics. 

Compilation of unpublished dat

Four groups of subjects were analyzed. One unexposed groand three worker groups. 

Anemia defined as hematocrit 

<35%. Iron status was not available. 

There was no obvious thresholALAD-PbB relationship. A threfor elevation of EP was evident between 15 and 20 μg/dL PbB. 
Table 3-1. Internal Lead Doses Associated with Health Effects from Selected Stu

Population studied Exposure Biomarkers Effect Comments Musculoskeletal 290 children, 6– 10 years old 

6,541 children 2– 11 years old 

10,033 males and females 20–69 years old 

Renal b 

744 males, 64 years old (mean) 

459 males, 57 years old (mean) 

General population 

General population 

General population 

General population 

General population 

2.9 μg/dL (mean PbB) 

2.9 μg/dL (geometric mean PbB for 2–5-year-olds); 2.1 μg/dL for 6–11-year-olds) 

2.5 μg/dL (geometric mean PbB) 

8 μg/dL (mean PbB) <4– 26 μg/dL (range) 

10 μg/dL (mean PbB) 0.2– 54 μg/dL (range) 

Increased caries in urban children 

Increasing PbB associated with increased number of dental caries in both groups 

Increasing PbB associated with periodontal bone loss 

Decrease in GFR; an increase in PbB of 10 μg/dL was associated with a decrease in creatinine clearance rate of 10.4 mL/minute 

Decrease in GFR; a 10-fold increase in PbB was associated with a significant increase in serum creatinine 

No increase in caries was seen 253 rural children (PbB, 1.7 μg/Covariates: sex, race, SES, maternal smoking, parental education, and dental hygiene variables. 

NHANES III analysis. Covariatincluded age, gender, race-ethnpoverty income ratio, exposure tobacco smoke, geographic regparental education, carbohydraand calcium intake, and dental visits. 

NHANES III analysis. Covariatincluded age, gender, race/ethneducation, SES, age of home, smoking, and periodontal disea

Cross-sectional study (NormatiAging Study). Covariates: age body mass index; systolic and diastolic blood pressure; alcohoconsumption and tobacco smokand analgesic or diuretic medications. 

Longitudinal study (Normative AStudy). Covariates: age and bomass index; hypertension; alcoconsumption and tobacco smokand education. 
Table 3-1. Internal Lead Doses Associated with Health Effects from Selected Stu

Population studied Exposure Biomarkers Effect Comments 707 males, 62 years old (mean) 4,813 males and females, >20 years old 

1,981 males and females, 48 years old (mean) 

803 males and females, 18–65 years old 

General population General population 

General population 

Occupational 

6.5 μg/dL (mean PbB) 21 ppm (mean tibia Pb) 4.2 μg/dL (mean PbB) 

11 μg/dL (mean PbB), 2– 72 μg/dL (range in men); 7.5 μg/dL (1.7–60 μg/dL range in women) 32 μg/dL (mean PbB) 

37 ppm (mean tibia lead) 

Decrease in GFR; PbB and tibia, but not patella Pb, predicted increases in serum creatinine in men with diabetes and hypertension Decrease in GFR in subjects with hypertension 

Decrease in GFR; a 10-fold increase in PbB associated with decrease of 10–13 mL/minute in creatinine clearance 

Increasing tibia lead associated with increased serum creatinine and uric acid; increasing PbB associated with increasing BUN 

Prospective study (Normative AStudy). Covariates: age and bomass index; diabetes and hypesion; alcohol consumption and tobacco smoking; and educatioNHANES III analysis. Covariatage, gender, and body mass insystolic blood pressure; cardiovascular disease and diabetes mellitus; alcohol consumption acigarette smoking; and househincome, marital status, and heainsurance. 

Cross-sectional study (CadmibStudy). Covariates: age and bomass index; urinary  glutamyltraferase activity; diabetes mellituand analgesic or diuretic therap

Cross-sectional study of Koreaworkers. Associations significaonly for >46-year-old workers. Covariates included age, gendebody mass index, current/formeexposed status, and hypertens
Table 3-1. Internal Lead Doses Associated with Health Effects from Selected Stu

Population studied Exposure Biomarkers Effect Comments Endocrinological 75 men 58 males, mean age 31.7 years 68 children, 11 months–7 years old 30 children, 1–5 years old 

Immunological 38 children, 3–6 years old 279 children, 9 months–6 years old 

Occupational 

Occupational General population General population General population 

General population 

50–98 μg/dL (PbB range) 

51.9 μg/dL (mean PbB) 

2–77 μg/dL (PbB range) 25 μg/dL (mean PbB) 33–120 μg/dL (PbB range) PbB >10 μg/dL 

1–45 μg/dL (PbB range) 

Decreased serum T3 and T4 

TSH significantly 

higher than in controls (mean PbB 9.5 μg/dL in controls) 

No effect on serum T4 or FT4 

Decreased serum Vitamin D levels Increased IgE and decreased IgG and IgM in females 

Increased serum IgE 

No significant correlation for FT

and TSH in this PbB range. TST3, FT4, and T4 increased in thrange 8–50 μg/dL. Cross-sectional study. The association between PbB and Twas independent of employmenlength. T3 was lower in a subgof 17 workers employed for 17.5 years than in those emplofor 2.4 years. Covariates: sex, race, SES, anhemoglobin; 56% of the childrehad PbB <24 μg/dL. 

15 children with mean PbB of 18 μg/dL served as a comparisgroup. 35 children with PbB <10 μg/dL served as controls. No such efwas seen in males or in the combined analysis of males anfemales. 

No other parameter of cellular ohumoral immunity showed a sigcant association with PbB. Covariates: age, race, sex, nutrition, and SES. 
Table 3-1. Internal Lead Doses Associated with Health Effects from Selected Stu

Population studied Exposure Biomarkers Effect Comments Neurological 172 children, 5 years old 

4,853 children, 6– 16 years old 

237 children, 7.5 years old 

780 children, 7 years old 

General population 

General population 

General population 

General population 

7.7 μg/dL (lifetime average PbB) 

1.9 μg/dL (geometric mean PbB) 

5.4 μg/dL (current mean PbB) 

8 μg/dL (mean PbB at age 7) 

7.4 IQ points decline with PbB increase 1– 10 μg/dL 

PbB <5 μg/dL associated with decrease in arithmetic and reading skills 

PbB associated with decrements in domains of attention, executive, function, visualmotor integration, social behavior, and motor skills 

Concurrent PbB 

always has the strongest association with IQ 

Children tested with Stanford-BIntelligence Scale. Covariates: birth-weight, iron status; mothe

IQ, education, race, smoking, income, and HOME score. 

NHANES III (1988–1994). Covariates: sex, race, iron statexposure to second-hand smokregion of the United States, mastatus, country, parental educapoverty index, and birth weightExposure history was unknown

Associations were present at Pas low as 3 μg/dL; 19 variables were controlled for in addition talcohol and drug use. 

Children had been treated for elevated PbB (20–44 μg/dL at 2 years of age and were followeuntil 7 years of age with serial Itests. 
Table 3-1. Internal Lead Doses Associated with Health Effects from Selected Stu

Population studied Exposure Biomarkers Effect Comments 146 children, 12 and General 6.1 μg/dL (mean maternal PbB One SD 

24 months old population during first trimester of (0.014 μg/dL) in 

pregnancy) first trimester 

plasma Pb associated with a reduction of 3.5 points in MDI score at 24 months of age 

294 children, 12 and General PbB <10 μg/dL 24-month PbB 24 months old population inversely 

associated with MDI and PDI scores at 24 months; 12-month PbB associated with PDI scores at 12 months 

736 older adults General 4.5 μg/dL (mean PbB) Impaired cognitive 

population 29.5 ppm (mean patella Pb) test performance 

Study of women in Mexico CityPotential confounders included child’s sex, PbB at 24 months, height for age and weight, and maternal age and IQ. 

MDI and PDI scores of the BSIwere evaluated at 12 and montConditions for inclusion includePbB <10 μg/dL, gestation age ≥37 weeks, and birth weight >2,000 g. 

Associations were found for boPbB and bone lead. Age, education, and alcohol intake wincluded in regression models. 
Table 3-1. Internal Lead Doses Associated with Health Effects from Selected Stu

Population studied Exposure Biomarkers Effect Comments Reproductive 74 adult men 

251 men 

98 men 121 women Developmental 329 infants, 1 month old 

Occupational 

Occupational 

Occupational 

General 

population General population 

46.3 μg/dL (mean PbB) 

10–40 μg/dL (PbB range) 

36.7 μg/dL (mean PbB) 

≥5.1 μg/dL (cord blood PbB) 5.6 μg/dL (mean infant PbB at 1 month) 15.3 ppm (maternal patella Pb) 

Decreased fertility 

Weak evidence of decreased fertility Significantly higher alterations in sperm density, motility, viability, and indicators of prostate function than in a reference group 

Increased pre-term 

births 

Infant PbB at 1 month and maternal patella bone inversely associated with weight gain 

Wife=s variables controlled for included parity, time since prevbirth, age, birth cohort, employmstatus, and education. Husban

variables included smoking, alcintake, education, and parametreflecting exposure intensity anduration. 

Only couples with one pregnanwere included in study. Associexisted only with younger mateage (<30 years). Cross-sectional study. Referengroup consisted of 51 men with mean PbB of 10.3 μg/dL. Expoand controls were comparable age, smoking status, and alcohconsumption. The effect was evident only amprimiparous, but not multiparouwomen. 

Infant age, sex, breast feeding practices, and infant health werincluded in regression models. Maternal variables: age, paritymaternal anthropometry, educaand hospital of recruitment. 
Table 3-1. Internal Lead Doses Associated with Health Effects from Selected Stu

Population studied Exposure Biomarkers Effect Comments 233 infants, General 7.0 μg/dL (mean cord blood Cord PbB Variables included in models w1 month old population Pb) associated with low maternal height, calf circumfere

14.1 ppm (maternal patella Pb) birth length; patella smoking, parity, reproductive 

lead associated history, age and education, hoswith low head cir­ of delivery, infant sex, and cumference gestational age. 

4,391 children, 1– General 1–72 μg/dL (PbB range) Decrease of Data from NHANES III. Models 7 years old population 1.57 cm in stature included: age, sex, ethnicity, a

and 0.52 cm in poverty-income ratio. Models ahead considered head of household circumference per cation, exposure to cigarette sm10 μg/dL increase nutrient intake, iron status, anein PbB history of anemia, previous test

for high PbB, and previous treament for lead poisoning. 

1,706 girls, General 1–22 μg/dL (PbB range) Delayed sexual Data from NHANES III. Covari8–16 years old population maturation race/ ethnicity, age, family size

residence in metropolitan area, poverty-income ratio, and body mass index. 

2,741 girls, 8– General 3 μg/dL (geometric mean PbB) Delayed sexual Data from NHANES III. Covari18 years old population maturation age, height, body mass index, 

history of tobacco smoking or anemia, dietary intake of iron, vitamin C, calcium, and family income. 

aSee also Table 3-2. bSee also Table 3-3. 

ALAD = δ-aminolevulinic acid dehydratase; BP = blood pressure; BUN = blood urea nitrogen; EKG = electrocardiogram; EP = erythrocyt

glomerular filtration rate; HDL = high density lipoprotein; Ig = immunoglobin; NHANES III = Third National Health and Nutrition ExaminatSES = socioeconomic status; TSH = thyroid stimulating hormone 
LEAD 47 

3. HEALTH EFFECTS 

hypertension and nephritis; and "ill-defined" causes. Three additional studies provided suggestive 

evidence of increased mortality due to cerebrovascular disease in lead workers (Fanning 1988; Malcolm 

and Barnett 1982; Michaels et al. 1991). Malcolm and Barnett (1982) studied causes of death between 

1921 and 1976 among lead acid battery plant workers and found a significant increase in deaths due to 

cerebrovascular disease among workers 65–69 years of age. In addition, a marginally significant increase 

in the incidence of deaths due to nephritis and nephrosis was observed in the lead workers during 1935– 

1958, but not at later periods, compared to workers with no lead exposure. Fanning (1988) compared the 

causes of death among 867 workers exposed to lead from 1926 to 1985 with 1,206 workers having low or 

no lead exposure and found a significant increase in deaths due to cerebrovascular disease among workers 

who died between 1946 and 1965 as compared to controls. No other cause produced an excess of deaths 

in lead workers. Environmental lead levels and biological monitoring for body lead burdens were not 

available for the entire period. The author suggested that the increased risk of death due to cerebrovascular disease was not present from 1965 to 1985 because of stricter occupational standards resulting in 

lower levels of exposure. Michaels et al. (1991) followed a cohort of 1,261 white male newspaper 

printers (typesetters) from January 1961 through December 1984. These workers had little or no 

occupational exposure to any other potentially toxic agents. It was assumed that lead exposure ceased in 

1976 when the transition to computerized typesetting occurred. SMRs were calculated for 92 cause-ofdeath categories using the mortality rates of New York City as the comparison population. The authors 

found that there were no significantly elevated nonmalignant or malignant causes of death in this cohort. 

In fact, the SMRs were generally less than unity, indicating that there were fewer deaths than expected, 

which the authors attributed to the "healthy worker effect." However, the SMR for cerebrovascular 

disease was significantly elevated in those members of the cohort employed for >30 years. Since there 

was no excess of arteriosclerotic heart disease, it appeared that lead exposure selectively increased 

cerebrovascular disease. 

Few studies of the general population have been conducted. McDonald and Potter (1996) studied the 

possible effects of lead exposure on mortality in a series of 454 children who were hospitalized for lead 

poisoning at Boston’s Children Hospital between 1923 and 1966 and who were traced through 1991. Of 

the 454 patients eligible for the study, 88% had a history of paint pica or known lead exposure; 90% had 

radiologic evidence of skeletal changes consistent with lead poisoning; and 97% had characteristic 

gastrointestinal, hematologic, and/or neurologic symptoms. The average PbB level in 23 children tested 

was 113 μg/dL; PbB tests were performed routinely at the hospital only after 1963. A total of 86 deaths 

were observed, 17 of these cases were attributed to lead poisoning. Although the distribution of causes of 

mortality generally agreed with expectations, there was a statistically significant excess of death from 
LEAD 48 

3. HEALTH EFFECTS 

cardiovascular disease (observed/expected [O/E], 2.1; 95% confidence interval [CI], 1.3–3.2). Three of 

four deaths from cerebrovascular accidents occurred in females, and 9 of 12 deaths from arteriosclerotic 

heart disease occurred in males. Two men died from pancreatic cancer (O/E, 10.2; 95% CI, 1.1–36.2) and 

two from non-Hodgkin’s lymphoma (O/E, 13.0; 95% CI, 1.5–46.9). 

Lustberg and Silbergeld (2002) used data from the Second National Health and Nutrition Examination 

Survey (NHANES II) to examine the association of lead exposure and mortality in the United States. A 

total of 4,292 blood lead measurements were available from participants aged 30–74 years who were 

followed up through December 31, 1992. After adjusting for potential confounders, individuals with PbB 

between 20 and 29 μg/dL had 46% increased all-cause mortality, 39% increased circulatory mortality, and 

68% increased cancer mortality compared with those with PbB <10 μg/dL. The results also showed that 

nonwhite subjects had significantly increased mortality at lower PbB than did white subjects, and that 

smoking was associated with higher cancer mortality in those with PbB of 20–29 μg/dL compared with 

those with PbB <20 μg/dL. Recently, Schober et al. (2006) used data from NHANES III (1988–1994) to 

determine relative risk of mortality from all causes, cancer, and cardiovascular disease in 

9,757 participants who were ≥40 years of age. After adjusting for covariates, relative to PbBs <5 μg/dL, 

the relative risks of mortality from all causes for those with PbB 5–9 and ≥10 μg/dL were 1.24 (95% CI, 

1.05–1.48) and 1.59 (95% CI, 1.28–1.98), respectively. Similar observations were reported for deaths due 

to cardiovascular disease and cancer, and tests for trend were statistically significant (p<0.01) for both 

causes of death. Of interest also is a study that describes trends in lead poisoning-related deaths in the 

United States between 1979 and 1998 (Kaufmann et al. 2003). Reviews of death certificates revealed that 

approximately 200 lead poisoning-related deaths occurred from 1979 to 1998. The majority were among 

males (74%), African Americans (67%), adults of age ≥45 years (76%), people living in the South region 

of the United States (70%), and residents in cities with populations <100,000 habitants (73%). Lead 

poisoning was the underlying cause of death in 47% of the deaths. The authors also found that alcohol 

(moonshine ingestion) was a significant contributing cause for 28% of adults. 

In summary, the information available suggests a potential association between lead exposure and 

cerebrovascular disease. There is no information from studies in animals that would support or refute the 

existence of a possible association between lead exposure and mortality due to cerebrovascular disease. 
LEAD 49 

3. HEALTH EFFECTS 

3.2.2 Systemic Effects 

Respiratory Effects. Very limited information was located regarding respiratory effects in humans 

associated with lead exposure. A study of 62 male lead workers in Turkey reported significant alterations 

in tests of pulmonary function among the workers compared to control subjects (Bagci et al. 2004). The 

cohort consisted of 22 battery workers, 40 exhaust workers, and 24 hospital workers with current PbB of 

37, 27, and 15 μg/dL, respectively. Workers and controls were matched for age, height, weight, and 

smoking habit. No association was found between PbB and duration of employment. No information 

was provided regarding exposure levels, medical histories of the workers or potential exposure to other 

chemicals. No relevant information was located from studies in animals. 

Cardiovascular Effects. Although lead has been shown to produce various cardiovascular effects in 

animals (Vaziri and Sica 2004), end points of greatest concern for humans at low exposures and low PbBs 

are elevations in systemic blood pressure and decrements in glomerular filtration rate. These effects may 

be mechanistically related and, furthermore, can be confounders and covariables in epidemiological 

studies. Decrements in glomerular filtration rate may contribute to elevations in blood pressure, and 

elevated blood pressure may predispose people to glomerular disease. Effects of lead on glomerular 

filtration are discussed in Section 3.2.2, Renal Effects. Other cardiovascular changes have been noted in 

association with increasing lead body burdens and/or lead exposures in humans that include changes in 

cardiac conduction and rhythm (Böckelmann et al. 2002; Cheng et al. 1998; Kirkby and Gyntelberg 1985; 

Kosmider and Petelenz 1962), which may be secondary to lead-induced impairment of peripheral nerve 

conduction (see Section 3.2.4, Neurological Effects). 

Effects on Blood Pressure. Numerous epidemiological studies have examined associations between lead 

exposure (as indicated by PbB or bone lead concentration) and blood pressure. Meta-analyses of the 

epidemiological findings have found a persistent trend in the data that supports a relatively weak, but 

significant association. Quantitatively, this association amounts to an increase in systolic blood pressure 

of approximately 1 mmHg with each doubling of PbB (Nawrot et al. 2002; Schwartz 1995; Staessen et al. 

1994). The results of more recent epidemiology studies indicate that the lead contribution to elevated 

blood pressure is more pronounced in middle age than at younger ages. Numerous covariables and 

confounders affect studies of associations between PbB and blood pressure, including age, body mass, 

race, smoking, alcohol consumption, ongoing or family history of cardiovascular/renal disease, and 

various dietary factors (e.g., dietary calcium). Including confounders in a regression model will attenuate 

the apparent association between lead exposure and the measured health outcome (e.g., Moller and 
LEAD 50 

3. HEALTH EFFECTS 

Kristensen 1992). For example, adjusting for alcohol consumption will decrease the apparent association 

between blood lead concentration and blood pressure, if alcohol consumption contributes to lead intake 

and, thereby, blood lead concentration (Bost et al. 1999; Hense et al. 1993; Hertz-Picciotto and Croft 

1993; Wolf et al. 1995). Conversely, failure to account for important effect modifiers (e.g., inherited 

disease) will result in overestimation of the apparent strength of the association. Varying approaches and 

breadth of inclusion of these may account for the disparity of results that have been reported. 

Measurement error may also be an important factor. Blood pressure estimates based on multiple 

measurements or, preferably, 24-hour ambulatory measurements, are more reproducible than single 

measurements (Staessen et al. 2000). Few studies have employed such techniques and, when used, have 

not found significant associations between PbB and blood pressure (Staessen et al. 1996b). 

An additional limitation of blood lead studies, in general, is that PbB may not provide the ideal biomarker 

for long-term exposure to target tissues that contribute a hypertensive effect of lead. Bone lead, a metric 

of cumulative or long-term exposure to lead, appears to be a better predictor of lead-induced elevations in 

blood pressure than PbB (Cheng et al. 2001; Gerr et al. 2002; Hu et al. 1996a; Korrick et al. 1999; 

Rothenberg et al. 2002a). In a recent prospective analysis of the Normative Aging Study, higher patellar 

lead levels, but not PbB, were associated with higher systolic blood pressure and abnormalities in 

electrocardiographic conduction (Cheng et al. 1998, 2001). 

Epidemiology studies, alone, cannot prove cause and effect relationships between lead exposure and 

blood pressure or cardiovascular disease. However, studies conducted in animal models support the 

plausibility of blood pressure effects of lead in humans. These studies have shown that long-term lead 

exposure can elevate blood pressure in nutritionally replete rats (Carmignani et al. 1988; Iannaccone et al. 

1981; Khalil-Manesh et al. 1993; Victery et al. 1982a, 1982b), and have identified potential mechanisms 

for the effect (Carmignani et al. 2000; Ding et al. 1998; Gonick et al. 1997; Purdy et al. 1997; Vaziri and 

Ding 2001; Vaziri et al. 1999a, 1999b, 2001). 

Meta-analyses. A recent meta-analysis of 31 studies published between 1980 and 2001, which included a 

total of 58,518 subjects (Nawrot et al. 2002), estimated the increase in systolic pressure per doubling of 

PbB to be 1 mmHg (95% CI, 0.5–1.5) and the increase in diastolic pressure to be 0.6 mmHg (95% CI, 

0.4–0.8) (Table 3-2; Figures 3-1 and 3-2). This outcome is similar to two other meta-analyses. A metaanalysis reported by Staessen et al. (1994) included 23 studies (published between 1984 and 1993; 

33,141 subjects) and found a 1 mmHg (95% CI, 0.4–1.6) increase in systolic blood pressure and 

0.6 mmHg (95% CI, 0.2–1.0) in diastolic pressure per doubling of PbB. Schwartz (1995) conducted a 
LEAD 51 

3. HEALTH EFFECTS 

Table 3-2. Characteristics of the Study Population in Meta-Analyses of Effects of 

Lead on Blood Pressure 

Reference No.a Pop.b 

Men 

(%)c HTd 

Age 

(years)e SBPf

 DBPf 

Lead 

(μg/dL)g 

1h Pocock et al. 1984; 

Shaper et al. 1981 

7,379 GP 100 Y 49 

(40–59) 

145 82 15.13 

(2.07–66.3)Ae 

2 Kromhout 1988; 

Kromhout et al. 1985 

152 GP 100 Y 67 

(57–76) 

154 92 18.23 

(10.77–27.97)Ac 

3 Moreau et al. 1982, 1988; 

Orssaud et al. 1985 

431 WC 100 Y 41 

(24–55) 

131 75 18.23 

(8.91–49.94)Ae 

4 Weiss et al. 1986, 1988 89 WC 100 Y 47 

(30–64) 

122 83 24.45 

(18.65–29.01)Mx 

5 de Kort and Zwennis 105 BC 100 N 40 136 83 29.22 

1988; de Kort et al. 1987 (25–80) (4.35–83.29)Ae 

6 Lockett and Arbuckle 116 BC 100 Y 32 119 80 37.5 

1987 (?–?) (14.92–95.52)Ae 

7 Parkinson et al. 1987 428 BC 100 Y 36 127 80 27.97 

(18–60) (6.01–49.52)Ac 

8 Rabinowitz et al. 1987 3,851 GP 0 Y 28 

(18–38) 

121 76 7.04 

(3.73–10.15)Ac 

9 Elwood et al. 1988a, 

1988bi 

1,136 GP 100 Y 56 

(49–65) 

146 87 12.64 

(6.01–26.11)Gc 

10 Elwood et al. 1988a, 

1988bj 

1,721 GP 50 Y 41 

(18–64) 

127 78 10.15 

(4.56–23.21)Gc 

11 Gartside 1988; Harlan 

1988; Harlan et al. 1985; 

6,289 GP 53 Y 30 

(10–74) 

127 80 13.47 

(2.07–95.93)Ge 

Pirkle et al. 1985; 

Ravnskov 1992k 

12 Neri et al. 1988l

 288 BC 100 ? ? ? ? 45.17 

(?–?) (6.01–65.06)Ae 

13 Neri et al. 1988m 2,193 GP ? Y 45 

(25–65) 

? ? 23.41 

(0–47.03)Me 

14 Grandjean et al. 1989, 

1991n 

1,050 GP 48 Y 40 

(40–40) 

? ? 11.6 

(3.94–60.09)Ae 

15 Reimer and Tittelbach 58 BC 100 ? 32 134 81 39.99 

1989 (?–?) (12.85–70.24)Ac 

16 Apostoli et al. 1990 525 GP 48 Y 45 

(21–60) 

132 84 13.05 

(2.07–28.18)Ae 

17 Morris et al. 1990 251 GP 58 Y ? ? ? 7.46 

(23–79) (4.97–38.95)Ae 

18 Sharp et al. 1988, 1989, 

1990 

249 WC 100 N 43 

(31–65) 

128 83 6.63 

(2.07–14.92)Pe 

19 Staessen et al. 1984o

 531 WC 75 Y 48 126 78 11.4 

(37–58) (4.14–35.22)Ge 

20 Møller and Kristensen 439 GP 100 Y 40 ? ? 13.68 

1992p (40–40) (4.97–60.09)Ae 
LEAD 52 

3. HEALTH EFFECTS 

Table 3-2. Characteristics of the Study Population in Meta-Analyses of Effects of 

Lead on Blood Pressure 

Reference No.a Pop.b 

Men 

(%)c HTd 

Age 

(years)e SBPf

 DBPf 

Lead 

(μg/dL)g 

21 Hense et al. 1993 3,364 GP 51 Y 48 

(28–67) 

129 80 7.87 

(1.24–37.09)Ae 

22 Maheswaran et al. 1993 809 BC 100 Y 43 129 84 31.7 

(20–65) (0–98.01)Ae 

23 Menditto et al. 1994 1,319 GP 100 Y 63 140 84 11.19 

(55–75) (6.22–24.66) 

24 Hu et al. 1996a; Proctor et 

al. 1996q 

798 GP 100 Y 66 

(43–93) 

134 80 5.59 

(0.41–35.02)Pe 

25 Staessen et al. 1996a, 

1996br 

728 GP 49.3 Y 46 

(20–82) 

130 77 9.12 

(1.66–72.52)Ge 

26 Sokas et al. 1997s

 186 BC 99 Y 43 130 85 7.46 

(18–79) (2.07–30.04)Pe 

27 Bost et al. 1999 5,326 GP 48 Y 48 

(16–?) 

135 75 63.82 

(?–?)G 

28 Chu et al. 1999 2,800 GP 53 Y 44 

(15–85) 

123 78 6.42 

(0.41–69)Ae 

29 Rothenberg et al. 1999a, 

1999b 

1,627 GP 0 Y 27 

(?–?) 

110 59 2.28 

(?–?)G 

30 Schwartz and Stewart 543 BC 100 Y 58 128 77 4.56 

2000 (41–73) (1.04–20.1)Ae 

31 Den Hond et al. 2001t

 13,781 GP 53.2 Y 48 

(20–90) 

125 73 3.11 

(0.62–55.94)Ge 

a

No.: Number of persons in whom relevant data were available. 

b

Pop.: Study population: BC = blue collar workers; GP = sample from general population; WC = white collar 

employees 

c

Men: Percentage of men 

d

HT: Indicates whether the sample included (Y = yes) or did not include (N = no) hypertensive patients. e

Age: Mean age or midpoint of age span (range or approximate range given between parentheses). f

SBP, DBP: Mean systolic and diastolic blood pressures 

g

Lead: Measure of central tendency: A = arithmetic mean; G = geometric mean; M = midpoint of range; 

P = P50 (median). The spread of blood lead is given between parentheses: c = P5–P05 interval; P10–P90 interval, or 

interval equal to 4 times the standard deviation; e = extremes; x = approximate limits of distribution. h

Number refers to reference in Figures 3-1 and 3-2. 

i

Caerphilly Study

j

Welsh Heart Program 

k

NHANES (National Health and Nutrition Examination Survey) 

l

foundry workers 

mCanadian Health Survey 

n

Glostrup Population Study, cross-sectional analysis (1976) 

o

London Civil Servants 

p

Glostrup Population Study, longitudinal analysis (1976–1987) 

q

Normative aging study 

r

PheeCad (Public Health and Environmental Exposure to Cadmium) Study 

s

Because of missing information, only the effect in whites is included. 

t

NHANES III Survey 

Source: Nawrot et al. 2002 
LEAD 53 

3. HEALTH EFFECTS 

Figure 3-1. Change in the Systolic Pressure Associated with a Doubling of the 

Blood Lead Concentration* 

(1) Pocock 84 ♂ 7379 

(2) Kromhout 85 ♂ 152 

(3) Orssaud 85 ♂ 431 

(4) Weiss 86 ♂ 89 

(5) de Kort 87 ♂ 105 

(6) Lockett 87 ♂ 116 

(7) Parkinson 87 ♂ 428 

(8) Rabinowitz 87 ♀ 3851 

(9) Elwood (C) 88 ♂ 1136 

(10) Elwood (HP) 88 ♂ 865 

(10) Elwood (HP) 88 ♀ 856 

(11) Gartside (W) 88 ♂ 2705 

(11) Gartside (B) 88 ♂ 350 

(11) Gartside (W) 88 ♀ 2827 

(11) Gartside (B) 88 ♀ 407 

(12) Neri (FW) 88 ♂ 288 

(13) Neri 88 ♂ ♀ 2193 

(14) Grandjean 89 ♂ 504 

(14) Grandjean 89 ♀ 546 

(15) Reimer 89 ♂ 58 

(16) Apostoli 90 ♂ 254 

(16) Apostoli 90 ♀ 271 

(17) Morris 90 ♂ 145 

(17) Morris 90 ♀ 106 

(18) Sharp (W) 90 ♂ 117 

(18) Sharp (B) 90 ♂ 132 

(19) Staessen 90 ♂ 398 

(19) Staessen 90 ♀ 133 

(20) Moller 92 ♂ 439 

(21) Hense 93 ♂ 1703 

(21) Hense 93 ♀ 1661 

(22) Maheswaran 93 ♂ 809 

(23) Menditto 94 ♂ 1319 

(24) Proctor 96 ♂ 798 

(25) Staessen (P) 96 ♀ 339 

(25) Staessen (P) 96 ♂ 345 

(26) Sokas (W) 97 ♂ 186 

(27) Bost 99 ♂ 2563 

(27) Bost 99 ♀ 2763 

(28) Chu 99 ♂ 1471 

(28) Chu 99 ♀ 1329 

(29) Rothenberg (N) 99 ♀ 439 

(29) Rothenberg (I) 99 ♀ 1188 

(30) Schwartz 00 ♂ 543 

(31) Den Hond (W) 01 ♂ 4685 

(31) Den Hond (B) 01 ♂ 1761 

(31) Den Hond (W) 01 ♀ 5138 

(31) Den Hond (B) 01 ♀ 2197 

ALL ♂ ♀ 58518 

-20 -10 0 10 20 30 

SBP 

*Data were digitized from Nawrot et al. 2002. Circles represent means (mmHg) of individual groups; squares 

represent combined groups; and open circles represent nonsignificant associations (plotted as zero). Bars represent 

95% confidence limits. See Table 3-2 for more details on study groups. 

B = blacks; C = Caerphilly Study; CS = civil servants; FW = foundry workers; HP = Welsh Heart Program; 

I = immigrants; NI = non-immigrants; P = Public Health and Environmental Exposure to Cadmium Study; W = whites 
LEAD 54 

3. HEALTH EFFECTS 

Figure 3-2. Change in the Diastolic Pressure Associated with a Doubling of the 

Blood Lead Concentration* 

(1) Pocock 84 ♂ 7379 

(2) Kromhout 85 ♂ 152 

(3) Orssaud 85 ♂ 431 

(4) Weiss 86 ♂ 89 

(5) de Kort 87 ♂ 105 

(6) Lockett 87 ♂ 116 

(7) Parkinson 87 ♂ 428 

(8) Rabinowitz 87 ♀ 3851 

(9) Elwood (C) 88 ♂ 1136 

(10) Elwood (HP) 88 ♂ 865 

(10) Elwood (HP) 88 ♀ 856 

(11) Gartside (W) 88 ♂ 2705 

(11) Gartside (B) 88 ♂ 350 

(11) Gartside (W) 88 ♀ 2827 

(11) Gartside (B) 88 ♀ 407 

(12) Neri (FW) 88 ♂ 288 

(13) Neri 88 ♂ ♀ 2193 

(14) Grandjean 89 ♂ 504 

(14) Grandjean 89 ♀ 546 

(15) Reimer 89 ♂ 58 

(16) Apostoli 90 ♂ 254 

(16) Apostoli 90 ♀ 271 

(17) Morris 90 ♂ 145 

(17) Morris 90 ♀ 106 

(18) Sharp (W) 90 ♂ 117 

(18) Sharp (B) 90 ♂ 132 

(19) Staessen 90 ♂ 398 

(19) Staessen 90 ♀ 133 

(20) Moller 92 ♂ 439 

(21) Hense 93 ♂ 1703 

(21) Hense 93 ♀ 1661 

(22) Maheswaran 93 ♂ 809 

(23) Menditto 94 ♂ 1319 

(24) Proctor 96 ♂ 798 

(25) Staessen (P) 96 ♀ 339 

(25) Staessen (P) 96 ♂ 345 

(26) Sokas (W) 97 ♂ 186 

(27) Bost 99 ♂ 2563 

(27) Bost 99 ♀ 2763 

(28) Chu 99 ♂ 1471 

(28) Chu 99 ♀ 1329 

(29) Rothenberg (N) 99 ♀ 439 

(29) Rothenberg (I) 99 ♀ 1188 

(30) Schwartz 00 ♂ 543 

(31) Den Hond (W) 01 ♂ 4685 

(31) Den Hond (B) 01 ♂ 1761 

(31) Den Hond (W) 01 ♀ 5138 

(31) Den Hond (B) 01 ♀ 2197 

ALL ♂ ♀ 58518 

-15 -10 -5 0 5 10 15 20 25 

DBP 

*Data were digitized from Nawrot et al. 2002. Circles represent means (mmHg) of individual groups; squares 

represent combined groups; and open circles represent nonsignificant associations (plotted as zero). Bars represent 

95% confidence limits. See Table 3-2 for more details on study groups. 

B = blacks; C = Caerphilly Study; CS = civil servants; FW = foundry workers; HP = Welsh Heart Program; 

I = immigrants; NI = non-immigrants; P = Public Health and Environmental Exposure to Cadmium Study; W = whites 
LEAD 55 

3. HEALTH EFFECTS 

meta-analysis that encompassed a similar time frame (15 studies published between 1985 and 1993) and 

found a 1.25 mmHg (95% CI, 0.87–1.63) increase in systolic blood pressure per doubling of PbB 

(diastolic not reported). The latter analysis included only those studies that reported a standard error on 

effect measurement (e.g., increase in blood pressure per doubling of PbB). Of the 15 studies included in 

the Schwartz (1995) analysis, 8 were also included in the Staessen et al. (1994) analysis. 

Longitudinal Studies—General Populations—Adults. The Normative Aging Study is a longitudinal 

study of health outcomes in males, initially enrolled in the Boston area of the United States between 

1963 and 1968. At enrollment, subjects ranged in age from 21 to 80 years (mean, 67 years) and had no 

history of heart disease, hypertension, cancer, peptic ulcer, gout, bronchitis, or sinusitus. Physical 

examinations, including seated blood pressure and medical history follow-ups, have been conducted at 

approximately 3–5-year intervals. Beginning in 1991, PbB and bone x-ray fluorescence (XRF) 

measurements (mid-tibia and patella) were included in the examinations. Data collected for a subset of 

the study population (840 subjects) observed between 1991 and 1997 were analyzed for associations 

between blood pressure and blood or bone lead concentrations (Cheng et al. 2001). Mean baseline PbB 

was 6.1 μg/dL (standard deviation [SD], 4.0) for the entire study group and 5.87 μg/dL (SD, 4.01) in the 

normotensive group (n=323). Mean bone lead concentrations in the normotensive subjects (n=337) were: 

tibia, 20.27 μg/g (SD, 11.55); patella, 28.95 (SD, 18.01). Based on a cross-sectional linear multivariate 

regression analysis of 519 subjects who had no hypertension at the time of first bone and blood lead 

measurement, covariate-adjusted systolic blood pressure was not significantly associated with PbB or 

patella lead concentration; however, increasing tibia lead concentration was associated with increasing 

systolic blood pressure. Follow-up examinations were completed on 474 subjects, allowing a longitudinal 

analysis of hypertension risk. Covariate-adjusted risk (risk ratio, RR; proportional hazards model) of 

hypertension (systolic >160 mm Hg or diastolic >95 mm Hg) was significantly associated with patella 

bone lead concentrations (RR, 1.29; 95% CI, 1.04–1.61), but not with PbB (RR, 1.00; 95% CI, 0.76–1.33) 

or tibia bone lead concentration (RR, 1.22; 95% CI, 0.95–1.57). Increases in patella lead concentration 

from 12.0 μg/g (mid-point of lowest quintile) to 53.0 μg/g (mid-point of highest quintile) were associated 

with a rate ratio of 1.71 (95% CI, 1.08–2.70). Covariates considered in the analyses included age and 

body mass index; race; family history of hypertension; education; tobacco smoking and alcohol 

consumption; and dietary intakes of sodium and calcium. A cross-sectional case-control analysis of the 

Normative Aging Study also found significant associations between bone lead concentration and risk of 

hypertension (see discussion of Hu et al. 1996a). The observation that risk of hypertension in middleaged males increased in association with increasing patella bone lead concentration, but not tibia bone 

lead or PbB, is consistent with a similar finding in middle-aged females, derived from the Nurses Health 
 

LEAD 56 

3. HEALTH EFFECTS 

Study (Korrick et al. 1999). Associations between PbB and hypertension risk in middle-aged women 

have been found in larger cross-sectional studies (Nash et al. 2003). These observations suggest that, in 

some populations, blood pressure increases may be more strongly associated with cumulative lead 

exposure (reflected in bone lead levels) than more contemporaneous exposures (reflected in blood lead 

concentrations). 

A random sample from the general population of Belgium (728 subjects, 49% male, age 20–82 years old) 

was studied during the period 1985 through 1989 (baseline; from Cadmibel study, Dolenc et al. 1993) and 

reexamined from 1991 through 1995 (follow-up) (Staessen et al. 1996b). Multiple seated blood pressure 

measurements were taken during the baseline and follow-up periods; multiple ambulatory measurements 

were taken during the follow-up period. The baseline PbB for the study group was 8.7 μg/dL (range, 1.7– 

72.5). Based on a linear multivariate regression analysis (with log-transformed blood lead 

concentrations), covariate-adjusted time-integrated systolic or diastolic blood pressure, or changes in 

systolic or diastolic blood pressure (follow-up compared to baseline) were not significantly associated 

with PbB or zinc photoporphyrin (ZPP) concentrations. The covariate adjusted risk for hypertension of 

doubling of the baseline PbB was not significantly >1. Covariates considered in the above analyses 

included gender, age, and body mass index; menopausal status; smoking and alcohol consumption; 

physical activity; occupational exposure to heavy metals; use of antihypertensive drugs, oral 

contraceptives, and hormonal replacement therapy; hematocrit or blood hemoglobin concentration; and 

urinary sodium, potassium, and γ-glutamyltransferase activity. 

A random sample of the general population of Denmark (451 males, 410 females, age 40 years) was 

studied in 1976 (baseline) and reexamined in 1981 (Grandjean et al. 1989). Baseline and follow-up 

observations included sitting blood pressure measurements, physical examination and health histories, 

and PbB measurements. The median baseline PbB was 13 μg/dL (90th percentile, 20) and 9 μg/dL 

(90th percentile, 13) in males and females, respectively. Covariate adjusted linear regression coefficients 

for relating systolic or diastolic blood pressure with PbB (log-transformed) were not statistically 

significant in males or females. Covariates considered in the analysis included height-adjusted weight 

index, exercise, smoking, alcohol intake, occupation, blood hemoglobin, serum cholesterol, and serum 

triglycerides. Similar conclusions were reported from a prospective study of this same population; 

adjustment for cardiovascular risk factors (i.e., body mass index, tobacco smoking, alcohol consumption, 

physical fitness) attenuated an apparent association between PbB and systolic and diastolic blood pressure 

(Moller and Kirstensen 1992). 
LEAD 57 

3. HEALTH EFFECTS 

Longitudinal Studies—General Population—Pregnancy. A longitudinal study examined associations 

between blood pressure and lead exposure during pregnancy and postpartum (Rothenberg et al. 2002b). 

The study included 667 subjects (age 15–44 years) registered at prenatal care clinics in Los Angeles 

during the period 1995–2001, and who had no history of renal or cardiovascular disease, postnatal obesity 

(body mass index >40), or use of stimulant drugs (e.g., cocaine, amphetamines). Measurements of sitting 

blood pressure and PbB were made during the third trimester and at 10 weeks postnatal. Tibia and 

calcaneus bone lead concentrations (XRF) were measured at the postnatal visit. Mean (geometric) PbBs 

were 1.9 μg/dL (+3.6/-1.0, geometric standard deviation [GSD]) during the third trimester and 2.3 μg/dL 

(+4.3/-1.2, GSD) postnatal. Mean (arithmetic) bone lead concentrations were 8.0 μg/g (11.4, SD) in tibia 

and 10.7 μg/g (11.9, SD) in calcaneus. Covariate-adjusted risk (odds ratio, OR) of hypertension 

(≥140 mmHg systolic or ≥90 mmHg diastolic) in the third trimester was significantly associated with 

increasing calcaneous bone lead concentration (OR, 1.86; 95% CI, 1.04–3.32). A 10 μg/g increase in 

calcaneous bone lead concentration was associated with a 0.77 mmHg (95% CI, 0.04–1.36) increase 

systolic blood pressure in the third trimester and a 0.54 mmHg (95% CI, 0.01–1.08) increase in diastolic 

blood pressure. Covariates included in the final model were age and body mass index, parity, postpartum 

hypertension, tobacco smoking, and education. 

Longitudinal Studies—General Population—Children. Possible associations between blood pressure 

and lead exposure in young children were studied as part of a prospective study of pregnancy outcomes 

(Factor-Litvak et al. 1996). The study group consisted of 281 children, age 5.5 years, from the Kosovo, 

Yugoslavia prospective study (see Section 3.2.4 for more details on this cohort). Approximately half of 

the children (n=137) lived in a town with heavy lead contamination (exposed group) and the other half 

(n=144) were from a relatively uncontaminated town (reference group). Mean PbBs were 37.3 μg/dL in 

the exposed group and 8.7 μg/dL in the reference group. Covariate-adjusted linear regression coefficients 

relating blood pressure and PbB at 5.5 years of age were not significantly >0: systolic, 0.054 (95% CI, 

-0.024–0.13); diastolic, -0.042 (95% CI, -0.01–0.090). Regression coefficients for the integrated average 

PbB (assessed every 6 months from birth) were similar in magnitude: systolic, 0.047 (95% CI, -0.037– 

0.13), diastolic, 0.041 (95% CI, -0.016–0.098). Covariates included in the analysis were gender, height 

and body mass index, birth order, and ethnicity. 

A prospective study designed to assess various environmental factors on development examined possible 

associations between PbB and blood pressure in a group of 122 children (66 females) at 9 years of age 

(Gump et al. 2005). The mean PbB at the time of evaluation was 4.62 μg/dL (SD±2.51). Outcomes 

measured included heart rate, diastolic and systolic blood pressure, stroke volume, cardiac output, and 
 

 

LEAD 58 

3. HEALTH EFFECTS 

total peripheral resistance; these were assessed at rest and following an acute pressor stress (arm 

immersion in ice water). General linear models were used to explore associations between PbB and 

outcomes. Increasing cord PbB was significantly associated with increasing covariate-adjusted resting 

systolic blood pressure (β, 12.16; Standard error [SE], 4.96; p= 0.016). Increasing childhood PbB was 

significantly associated with an increased total peripheral vascular resistance in response to the acute 

pressor stress (β, 0.88 dyn-s/cm5

 per μg/dL; 95% CI, 0.024–0.152; p=0.007). Covariates considered in 

the models included: maternal age, education, IQ, socioeconomic status (SES), HOME score, health, 

nutrition; substance use during pregnancy; infant birth characteristics (e.g., gestational age, birth weight, 

head circumference, Ballard score); and childhood characteristics (e.g., body mass index, SES). 

Longitudinal Studies—Occupational. A population of 496 current and former employees of an organic 

lead manufacturing facility (mean age, 55.8 years) located in the eastern United States, was studied during 

the period 1994–1996 with follow-up examinations at approximately 4–14-month intervals through 

1998 (Glenn et al. 2003). Multiple seated blood pressure measurements were taken at each examination. 

PbB was measured at the initial examination (baseline) and tibia bone XRF measurements were taken in 

1997. The mean PbB was 4.6 μg/dL and the mean tibia bone lead concentration was 14.7 μg/g. Based on 

a generalized estimating equation model, covariate-adjusted systolic blood pressure was significantly 

associated with baseline PbB or tibia bone lead concentration. A one standard deviation increase in PbB 

was associated with a 0.64 mmHg (95% CI, 0.14–1.14) increase in systolic blood pressure and a 

0.009 (95% CI, -0.24–0.43) increase in diastolic blood pressure. A one standard deviation increase in 

tibia bone lead concentration was associated with a 0.73 mmHg (95% CI, 0.23–1.23) increase in systolic 

blood pressure and a 0.07 mmHg (95% CI, -0.29–0.42) increase in diastolic blood pressure. Covariates 

considered in the analyses included race; age and body mass index; diagnosis of diabetes, arthritis, or 

thyroid disease; education; and blood pressure measurement interval. 

A population of 288 foundry workers was studied during the period 1979–1985, during which multiple 

blood pressure and PbB measurements were taken (Neri et al. 1988). Linear regression coefficients were 

estimated for the relationship between PbB and systolic or diastolic blood pressure, for each of 

288 subjects. The average covariate (age and body weight) adjusted regression coefficient (mmHg per 

μg/dL blood lead) was 0.210 (SE, 0.139, p=0.064) for systolic pressure and 0.298 (SE, 0.111, p<0.05) for 

diastolic pressure. 

A population of 70 Boston policemen was studied during the period 1969–1975, during which multiple 

seated blood pressure measurements were taken (years 2–5) and PbB measurements were taken in 
LEAD 59 

3. HEALTH EFFECTS 

year 2 (Weiss et al. 1986, 1988). Covariate adjusted linear regression coefficients (mmHg per μg/dL) 

were determined, with exposure represented as low (20–29 μg/dL) or high (≥30 μg/dL). After adjusting 

for covariates, high PbB was a significant predictor of subsequent elevation in systolic blood pressure of 

1.5–11 mmHg in the working policemen with normal blood pressure. Low PbB (20–29 μg/dL) was not a 

predictor of subsequent systolic blood pressure elevations. Diastolic pressure was unrelated to PbB. 

Covariates retained in the model were previous systolic blood pressure, body mass index, age, and 

cigarette smoking. 

Case-control Studies—General Population. A case-control study examined potential associations 

between blood pressure and blood and bone lead concentrations in a population of middle-aged women 

(mean age, 61 years; Korrick et al. 1999). Cases (n=89) and age-matched controls (n=195) were a subset 

of women who resided in the Boston area of the United States (recruited during the period 1993–1995) 

who were enrolled in the National Nurses Health Study (NHS). Cases were selected based on selfreported physician diagnosis of hypertension as part of the NHS. Potential controls were excluded from 

consideration if they had a history of hypertension or other cardiovascular disease, renal disease, diabetes, 

malignancies, obesity, or use of antihypertensive or hypoglycemic medication. Controls were stratified 

based on measured blood pressure: low normal (<115 mm Hg systolic and <75 mmHg diastolic), or high 

normal (>134 and <140 mmHg systolic or >85 and <90 mmHg diastolic). Multiple sitting blood pressure 

measurements, PbB, and tibia and patella bone lead concentration measurements were taken at the 

beginning of the study. Self-reported information on medical history was provided as part of the NHS 

every 2 years. The mean PbB (cases and controls combined) was 3 μg/dL (range, <1–14 μg/dL). Mean 

bone lead concentrations were: tibia, 13.3 μg/g and patella, 17.3 μg/g. Risk of hypertension was assessed 

using a logistic regression model. Covariate-adjusted risk of hypertension (defined as systolic pressure 

≥140 mm Hg or diastolic ≥90 mm Hg) was significantly associated with increasing patella lead 

concentration, but not with tibia bone concentration or PbB. An increase from the 10th to the 

90th percentile of patella bone lead concentration (from 6 to 31 μg/g) was associated with an increase in 

the odds of hypertension of 1.86 (95% CI, 1.09–3.19). Covariates considered in the regression models 

included: age and body mass index; dietary calcium and sodium intakes; alcohol consumption and 

tobacco smoking, and family history of hypertension. Of these, age and body mass index, dietary sodium 

intake, and family history of hypertension were included in the final model. The OR (odds of being a 

case/odds of being in control group) of hypertension with increasing patella lead concentration was 

1.03 (95% CI, 1.00–1.05). When stratified by age, the ORs were 1.04 (95% CI, 1.01–1.07) in the 

>55 years of age groups and 1.01 (95% CI, 0.97–1.04) in the age group ≤55 years. Stratification by 

menopausal status resulted in ORs of 1.04 (95% CI, 1.01–1.06) for the postmenopausal group and 
LEAD 60 

3. HEALTH EFFECTS 

0.98 (95% CI, 0.91–1.04) for the premenopausal group (78 of 89 of the cases, 93%, were postmenopausal). The observation that risk of hypertension in women increased in association with increasing 

patella bone lead concentration, but not tibia bone lead or PbB, is consistent with a similar finding in men, 

derived from the longitudinal Normative Aging Study (Cheng et al. 2001). Associations between PbB 

and hypertension risk in postmenopausal women also have been found in larger cross-sectional studies 

(Nash et al. 2003; see below). 

As part of the Normative Aging Study, a case-control study examined potential associations between 

blood pressure and blood and bone lead concentrations in a population of middle-aged males (mean age, 

66 years; Hu et al. 1996a). The Normative Aging Study is a longitudinal study of health outcomes in 

males, initially enrolled in the Boston area of the United States between 1963 and 1968. At enrollment, 

subjects ranged in age from 21 to 80 years (mean, 67 years) and had no history of heart disease, 

hypertension, cancer, peptic ulcer, gout, bronchitis, or sinusitus. Physical examinations, including seated 

blood pressure and medical history follow-ups, have been conducted at approximately 3–5-year intervals. 

Beginning in 1991, PbB and bone x-ray fluorescence (XRF) measurements (mid-tibia and patella) were 

included in the examinations. Cases (n=146) and age-matched controls (n=444) were a subset of the 

study group who resided in the Boston area of the United States (recruited during the period 1993–1995) 

who were observed between 1991 and 1994. Hypertension cases were taking daily medication for the 

management of hypertension and/or had a systolic blood pressure >160 mmHg or diastolic pressure 

≥96 mmHg. The mean PbBs in cases and controls were 6.9 μg/dL (4.3, SD) and 6.1 μg/dL (4.0, SD), 

respectively. Mean bone lead concentrations in cases and controls were: tibia, 23.7 μg/g (14.0, SD) and 

20.9 μg/g (11.4, SD), respectively; and patella, 35.1 μg/g (19.5, SD) and 31.1 μg/g (18.3, SD), 

respectively. Risk of hypertension (OR) was assessed using a logistic regression model. Covariateadjusted risk of hypertension was significantly associated with increasing tibia lead concentration, but not 

with patella bone concentration or PbB. An increase in tibia bone lead concentration from the mid-point 

of the lowest quintile (8 μg/g) to the mid-point of the highest quintile (37 μg/g) was associated with an 

OR of 1.5 (95% CI, 1.1–1.8). Covariates in the final regression model included body mass index and 

family history of hypertension. A longitudinal analysis of the Normative Aging Study also found 

significant associations between bone lead concentration and risk of hypertension (see discussion of 

Cheng et al. 2001). 

A case-control study examined the association between PbB and hypertension risk in middle-aged and 

menopausal women (Al-Saleh et al. 2005). Hypertension cases (n=100; age, 47–92 years) and controls 

(n=85; age, 45–82 years) were selected from the King Faisal Hospital Hypertension Clinic (Saudi Arabia) 
 

 

LEAD 61 

3. HEALTH EFFECTS 

during the period 2001–2002. Hypertension case inclusion criteria were: taking medication, or >160 mm 

Hg systolic pressure, or >95 mm Hg diastolic pressure. Control inclusion criteria were: average 

systolic/diastolic pressure <120/80 mm Hg, and no record of >130/85 mm Hg). Mean PbB of the case 

group was 4.8 μg/dL (range, 1.4–28) and of the control group was 4.6 μg/dL (range, 1.2–18). Covariate 

adjusted ORs in association with a median PbB ≥3.86 μg/dL was 5.27 (95% CI, 0.93–30; p=0.06). 

Cross-sectional Studies—General Population. Several analyses of possible associations between blood 

pressure and PbB have been conducted with data collected in the NHANES (II and III). The NHANES 

III collected data on blood pressure and PbB on approximately 20,000 U.S. residents during the period 

1988–1994. The results of two analyses of the NHANES III data on adult subjects provides evidence for 

an association between increasing PbB and increasing blood pressure that is more pronounced in blacks 

than whites (Den Hond et al. 2002; Vupputuri et al. 2003). Den Hond et al. (2002) analyzed data 

collected on 13,781 subjects of age 20 years or older who were white (4,685 males; 5,138 females) or 

black (1,761 males; 2,197 females). Median PbBs (μg/dL, inter-quartile range) were: white males, 

3.6 (2.3–5.3); white females, 2.1 (1.3–3.4); black males, 4.2 (2.7–6.5); and black females, 2.3 (1.4–3.9). 

Based on multivariate linear regression (with log-transformed blood lead concentration), the predicted 

covariate-adjusted increments in systolic blood pressure per doubling of PbB (95% CI) were: white 

males, 0.3 (95% CI, -0.2–0.7, p=0.29); white females, 0.1 (95% CI, -0.4–0.5, p=0.80); black males, 

0.9 (95% CI, 0.04–1.8, p=0.04); and black females, 1.2 (95% CI, 0.4–2.0, p=0.004). The predicted 

covariate-adjusted increments in diastolic blood pressure per doubling of PbB (95% CI) were: white 

males, -0.6 (95% CI, -0.9– -0.3, p=0.0003); white females, -0.2 (95% CI, -0.5– -0.1, p=0.13); black 

males, 0.3 (95% CI, -0.3–1.0, p=0.28); and black females, 0.5 (95% CI, 0.01–1.1, p=0.047). Covariates 

included in the regression models were: age and body mass index; hematocrit, total serum calcium, and 

protein concentrations; tobacco smoking; alcohol and coffee consumption; dietary calcium, potassium, 

and sodium intakes; diabetes; and use of antihypertensive drugs. Poverty index was not included as a 

covariate in the above predictions because its independent effect was not significant; however, when 

included in the regression model for black males, the effect size was not significant. 

Vupputuri et al. (2003) analyzed the NHANES III subset of 14,952 subjects of age 18 years or older who 

were white (5,360 males; 5,188 females) or black (2,104 males; 2,197 females). Mean PbBs (μg/dL, 

±SE) were: white males, 4.4±0.1; white females, 3.0±0.1; black males, 5.4±0.2; and black females, 

3.4±0.1. Based on multivariate linear regression, the predicted covariate-adjusted increments in systolic 

blood pressure per one standard deviation increase of PbB (95% CI) were: white males, 0.29 (95% CI, 

-0.24–0.83, p≥0.05); white females, 0.34 (95% CI, -0.49–1.17, p≥0.05); black males, 0.83 (95% CI, 0.19– 
 

LEAD 62 

3. HEALTH EFFECTS 

1.44, p<0.05); and black females, 1.55 (95% CI, 0.47–2.64, p<0.010). The predicted covariate-adjusted 

increments in diastolic blood pressure per one standard deviation increase in PbB (95% CI) were: white 

males, 0.01 (95% CI, -0.38–0.40, p≥0.05); white females, -0.04 (95% CI, -0.56–0.47, p≥0.05); black 

males, 0.64 (95% CI, -0.08–1.20, p<0.05); and black females, 1.07 (95% CI, 0.37–1.77, p<0.01). 

Covariates included in the regression models were: age and body mass index; alcohol consumption; 

dietary calorie, potassium, and sodium intakes; and physical activity. The analyses of Den Hond et al. 

(2002) and Vupputuri et al. (2003) suggest an association between blood pressure and PbB in blacks but 

not in whites; among blacks, the association was significant for women and or borderline significance for 

men. 

A more recent analysis of the NHANES III data focused on females between the ages of 40 and 59 years 

(Nash et al. 2003). The study group (n=2,165) had a mean age of 48.2 years and mean PbB of 2.9 μg/dL 

(range, 0.50–31.1). Based on multivariate linear regression, covariate-adjusted systolic and diastolic 

blood pressure was significantly associated with increasing PbB. Increasing PbB from the lowest (0.5– 

1.6 μg/dL) to highest (4.0–31.1 μg/dL) quartile was associated with a 1.7 mmHg increase in systolic 

pressure and a 1.4 mmHg increase in diastolic pressure. The study group was stratified by blood lead 

concentration (quartile), and into pre- and postmenopausal categories. Increased risk of diastolic (but not 

systolic) hypertension (systolic ≥140 mmHg diastolic ≥90 mmHg) was significantly associated with 

increased blood lead concentration. When stratified by menopausal status, the effect was more 

pronounced in the postmenopausal group. Covariates included in the models were race, age, and body 

mass index; tobacco smoking, and alcohol consumption. The Nursing Health Study (Korrick et al. 1999) 

found significant associations between hypertension risk and patella lead concentration in postmenopausal women, but not with PbB. However, the Nash et al. (2003) study included 850 postmenopausal 

subjects, compared to 78 in the Korrick et al. (1999) case-control study. 

The NHANES II collected data on PbB and blood pressure during the period 1976–1980. In general, 

PbBs were higher in the NHANES II sample than in NHANES III sample (Pirkle et al. 1998), providing a 

means to explore possible associations between blood pressure and higher PbB than is possible with the 

NHANES III data. While various analyses have yielded somewhat conflicting results (Gartside 1988; 

Harlan 1988; Harlan et al. 1985; Landis and Flegal 1988; Pirkle et al. 1985; Schwartz 1988), they support 

the general findings of the more recent longitudinal and case-control studies (including those of the 

NHANES III) that increasing PbB is associated with increasing blood pressure in middle-aged adults. 
LEAD 63 

3. HEALTH EFFECTS 

An analysis of the NHANES II data on white males (40–59 years of age, n=564) found a significant 

association between increasing systolic or diastolic blood pressure and increasing PbB, after accounting 

for significant covariates (Pirkle et al. 1985). Covariates considered in the analysis included 

87 nutritional and diet variables, cigarette smoking, alcohol consumption, socioeconomic status, and 

family history of hypertension. Those included in the final linear regression model for diastolic blood 

pressure were age and body mass index; blood hemoglobin concentration and serum albumin 

concentration; and dietary potassium and vitamin C intakes. Additional covariates included in the 

systolic blood pressure model were dietary riboflavin, oleic acid, and vitamin C. Blood lead statistics for 

the study group were not reported; however, the association appeared to have been evaluated over a range 

of 7–38 μg/dL. Lead was also a significant predictor of diastolic hypertension (≥90 mm Hg). Gartside 

(1988) stratified the NHANES II data into age and race categories and also found significant associations 

between systolic (but not diastolic) blood pressure and PbB in white males in age categories between 

36 and 55 years. In these age categories, doubling PbB was associated with an increase in systolic blood 

pressure of approximately 4 mmHg. The statistical model used was a forward linear regression; however, 

the covariates retained in the final models were not reported. Other analyses of the NHANES II data for 

men have addressed the issue of possible time-trend effects confounded by variations in sampling sites 

(Landis and Flegal 1988; Schwartz 1988). These analyses confirm that correlations between systolic or 

diastolic blood pressure and PbB in middle-aged white males remain significant when sampling site is 

included as a variable in multiple regression analyses. Accuracy of blood pressure data in the NHANES 

II has been challenged (e.g., digit preference by people recording the measurements, differing variability 

among survey sites). When these sources of variability are accounted for, the magnitude of the covariateadjusted PbB—blood pressure relationship decreases; however, it remains significant, and strongest, for 

white males in the 49–50-year-old group (Coate and Fowles 1989). 

Relationships between PbB and hypertension were evaluated in a survey of 7,731 males, aged 40– 

59 years, from 24 British towns in the British Regional Heart Study (BHRS) (Pocock et al. 1984, 1988). 

The PbB distributions in the study group were approximately: <12.4 μg/dL, 27%; 12.4–16.6 μg/dL, 45%; 

18.6–22.8 μg/dL, 19%; and >24.9 μg/dL, 8%. The most recent, multivariate analysis of the data from this 

survey (Pocock et al. 1988), found that covariate-adjusted systolic blood pressure increased by 

1.45 mmHg and diastolic blood pressure increased by 1.25 mmHg for every doubling in PbB. Covariates 

included in the regression model included age, body mass index, alcohol consumption, cigarette smoking, 

and socioeconomic factors. Covariate-adjusted risk of ischemic heart disease (OR) was not significantly 

associated with PbB. PbBs in cases (n=316) of ischemic heart disease were not statistically different, 
 

 

LEAD 64 

3. HEALTH EFFECTS 

when compared to those of the rest of the study group, after adjustment was made for age, number of 

years smoking cigarettes, and town of residence. 

A more recent survey conducted in Great Britain (Health Survey for England, HSE) collected data 

annually on blood pressure and PbB. An analysis of the HSE data collected in 1995 included 2,563 males 

(mean age, 47.5 years) and 2,394 females (mean age, 47.7) (Bost et al. 1999). Multiple seated blood 

pressure measurements were taken. Mean (geometric) PbBs were 3.7 μg/dL in males and 2.6 μg/dL in 

females. Based on multivariate linear regression (with log-transformed PbB), increasing covariateadjusted diastolic blood pressure was significantly associated with increasing PbB in males, but not in 

females. Covariates included in the above model were: age and body mass index, alcohol consumption 

and tobacco smoking, socioeconomic status, and region of residence; subjects who were on 

antihypertensive agents were excluded. 

A cross-sectional study of potential associations between blood and bone lead, and blood pressure in older 

adults was conducted as part of the longitudinal Baltimore Memory Study (Martin et al. 2006). The study 

group consisted of 964 adults (age, 50–70 years, 65% female) who were evaluated for blood pressure and 

PbB during the period 2001–2002, and tibia lead during the period 2002–2004. Mean PbB concentration 

in the study group was 3.5 μg/dL (SD±2.3) and tibia lead was 18.8 μg/g (SD±12.4). Increasing PbB (but 

not tibia lead) was significantly associated (linear regression model) with increasing covariate-adjusted 

systolic (β, 0.99 mm Hg per μg/dL; 95% CI, 0.47–1.51; p<0.01) and diastolic blood pressure (β, 0.51; 

95% CI, 0.24–0.79; p<0.01). Covariates included in the model included age, gender, body mass index, 

sodium and potassium intakes, SES, and race/ethnicity). Covariate-adjusted ORs for hypertension 

(>140 mm Hg systolic pressure or >90 mmHg diastolic pressure) were significantly associated with tibia 

lead (but not PbB) only when the multivariate logistic model excluded SES (OR, 1.21; 95% CI, 1.02– 

1.43; p=0.03) or SES and race/ethnicity (OR, 1.24; 95% CI, 1.05–1.47; p=0.01) from the model. When 

SES and race/ethnicity were included in the model, the odds ratios were not significant for tibia lead (OR, 

1.16; 95% CI, 0.98–1.77; p=0.09) or PbB (OR, 1.01; 95% CI, 0.86–1.19). 

The potential effects of childhood exposure to lead on bone lead—blood pressure relationships in 

adulthood have been examined in a cohort study (Gerr et al. 2002). The exposed cohort consisted of 

251 people (ages 19–24 years in 1994), who resided in any of five towns near the former Bunker Hill 

smelter in Silver Valley, Idaho and were between the ages of 9 months and 9 years during the period 

1974–1975, when uncontrolled emissions from the smelter resulted in contamination of the region and 

elevated PbB in local children. The reference cohort consisted of 257 Spokane, Washington residents in 
LEAD 65 

3. HEALTH EFFECTS 

the same age range as the exposed cohort. Individuals were excluded from participating in the study if 

they were black, pregnant, had a history of hypertension or chronic renal failure, or had a PbB exceeding 

15 μg/dL at the initial examination. Subjects were given a physical examination, which included medical 

history, multiple measurements of sitting blood pressure, PbB measurement, and XRF measurement of 

tibia bone lead concentration. Relationships between blood pressure and bone lead were assessed using 

the general linear model, in which bone lead was expressed categorically (μg/g): <1, 1–5, >5–10, and 

>10. Covariate-adjusted systolic and diastolic blood pressures were significantly higher in the highest 

bone lead category compared to the lowest category; the differences being 4.26 mmHg (p=0.014) systolic 

pressure and 2.80 mmHg (p=0.03) diastolic pressure. Covariates retained in the final models included 

gender, age and body mass index; blood hemoglobin and serum albumin concentrations; education; 

tobacco smoking and alcohol consumption; current use of birth control pills; income; and current PbB. 

While residence (exposed vs. reference) was not a significant variable in predicting blood pressure, 82% 

of subjects in the highest bone lead group were members of the exposed group (i.e., residents of the 

contaminated towns in 1974–1975). Mean PbB during the exposure period, 1974–1975, was also higher 

in the high bone lead group (65 μg/dL) compared to the lower bone lead groups (2–2.4 μg/dL). Similar 

findings were reported by Hu et al. (1991a) in a pilot study of subjects with well-documented lead 

poisoning in 1930–1942 in a Boston area. Exposed subjects (mean current age, 55 years; mean current 

PbB, 6 μg/dL) and controls were matched for age, race, and neighborhood. Comparison of 21 matched 

pairs showed that the risk of hypertension was significantly higher in subjects who had experienced 

plumbism (RR, 7.0; 95% CI, 1.2–42.3). Kidney function, evaluated by measurements of creatinine 

clearance rate was significantly higher in subjects with plumbism than in controls, but serum creatinine 

was not significantly different than in controls subjects. The results from these two studies (Gerr et al. 

2002; Hu 1991a) suggest the possibility that high childhood exposures to lead may contribute to higher 

blood pressure in adulthood. However, epidemiological studies of children have not found significant 

associations between increasing PbB and blood pressure (Factor-Litvak et al. 1996; Friedlander 1981; 

Rogan et al. 1978; Selbst et al. 1993). 

Studies in Animal Models. Early studies in experimental animals suggested that long-term lead exposure 

could elevate blood pressure in nutritionally replete rats (Carmignani et al. 1988; Iannaccone et al. 1981; 

Khalil-Manesh et al. 1993; Victery et al. 1982a, 1982b). These observations have been corroborated with 

more recent studies, as well as studies that have identified numerous potential mechanisms for the effect 

that are relevant to humans (Carmignani et al. 2000; Ding et al. 1998; Gonick et al. 1997; Purdy et al. 

1997; Vaziri and Ding 2001; Vaziri et al. 1999a, 1999b, 2001). 
LEAD 66 

3. HEALTH EFFECTS 

Other Cardiovascular Effects. Several studies have explored possible associations between lead 

exposure and cardiovascular disease mortality and morbidity. In a multivariate analysis of the data from 

the British Regional Heart Study (7,731 males, age 40–59 years; 8% of cohort had PbB >24.9 μg/dL), 

covariate-adjusted risk of ischemic heart disease (OR) was not significantly associated with PbB (Pocock 

et al. 1988). Cooper (1988) reported significantly elevated SMRs for “other hypertensive disease” (i.e., 

malignant hypertension, or essential benign hypertension, or hypertensive renal disease) among male 

battery plant workers (n= 4,519; mean PbB, 63 μg/dL) and lead production workers (n=2,300; mean PbB, 

80 μg/dL). The study did not explore associations between SMRs and biomarkers of lead exposure (e.g., 

PbB). SMRs for cardiovascular disease were not elevated among 1,987 male lead smelter workers who 

worked at the Bunker Hill smelter facility in northern Idaho (i.e., who were hired between 1950 and 

1965 and who worked at least 1 year) (Selevan et al. 1985, 1988). The study did not explore associations 

between SMRs and biomarkers of lead exposure (e.g., PbB). SMRs for ischemic heart disease were 

significantly elevated (SMR, 1.72; 95% CI, 1.16–1.79) among male smelter workers (n=644) who worked 

for at least 3 months during the period 1942–1987; however, the SMRs were across time-integrated PbB 

quartiles (Gerhardsson et al. 1995a). 

Data from a subset of the Normative Aging Study were analyzed to assess possible associations between 

electrocardiographic abnormalities and body lead burdens (Cheng et al. 1998). The Normative Aging 

Study is a longitudinal study of health outcomes in males, initially enrolled in the Boston area of the 

United States. Subjects enrolled in the study, between 1963 and 1968, ranged in age from 21 to 80 years 

(mean, 67; SD, 7), and had no history of heart disease or hypertension. Physical examinations, including 

electrocardiograms and medical history follow-ups, have been conducted at approximately 3–5-year 

intervals. Beginning in 1991, PbB and bone XRF measurements (midtibia and patella) were included in 

the examinations. Data collected for a subset of the study population (775 subjects) observed between 

1991 and 1995 and for whom complete data were acquired, were analyzed for associations between blood 

and bone lead concentrations and electrocardiographic abnormalities (e.g., heart rate, conduction defects, 

arrhythmia). The mean age of the subjects at the time of evaluation was 68 years (range, 48–93). Lead 

levels were: blood, 5.79 μg/dL (SD, 3.44); tibia bone, 22.19 μg/g (SD, 13.36); and patella bone, 

30.82 μg/g (SD, 19.19). The study group was stratified by age (<65 or ≥65 years) for multivariate 

regression (linear and logistic) analyses. Covariate-adjusted QT and QRS intervals were significantly 

associated with tibia bone lead in subjects <65 years of age. A 10 μg/g increase in tibia lead 

concentration was associated with a 5.01 millisecond increase in the QT interval and 4.83 millisecond 

increase in QRS interval. Covariates included in the analyses were age, body mass index, diastolic blood 

pressure, fasting blood glucose level, and alcohol consumption. Covariate-adjusted OR for 
 

LEAD 67 

3. HEALTH EFFECTS 

intraventricular conduction defect was significantly associated with increasing tibia bone lead in the 

<65 year-age group; ORs were not significant for the older age group. In the age group ≥65 years, the OR 

for atrioventricular conduction defect with increasing tibia bone lead concentration was 1.22 (95% CI, 

1.02–1.47; p=0.03), and for patella bone lead concentration, 1.16 (95% CI, 1.00–1.29; p<0.01); ORs were 

not significant for the younger age group. Covariates included in the models were age and serum HDL 

concentration. Risk of arrhythmia was not significantly associated with blood or bone lead 

concentrations. 

A study of 95 lead smelter workers and matched (age, occupational status, duration of employment) 

unexposed reference group found a significantly higher incidence of ischemic ECG changes (20%) in the 

lead workers than in the reference group (6%) (Kirkby and Gyntelberg 1985). Mean PbB was 53 μg/dL 

in the exposed group and 11 μg/dL in the reference group. 

A cross-sectional analysis of the NHANES (for the period 1999–2000) data found a significant 

association between PbB and risk of peripheral artery disease (Navas-Acien et al. 2004). The analysis 

included 2,125 subjects (1,055 females, 1,070 males) whose ages were ≥40 years. Geometric mean PbB 

was 2.1 μg/dL (25th–75th percentile range, 1.5–2.9). The increasing PbB was significantly associated with 

increasing covariate-adjusted OR for peripheral artery disease (ankle brachial index <0.9 in one or both 

legs). For the upper quartile PbB (>2.9 μg/dL), the ORs were 4.07 (95% CI, 1.21–13.73), without 

adjustment for smoking status and 2.52 (95% CI, 0.75–8.51) with adjustment for smoking. Other 

covariates included in the analysis were age, gender, race, education, body mass index, alcohol 

consumption, hypertension, diabetes, hypercholesterolemia, glomerular filtration, and C-reactive protein. 

As part of the Baltimore-Washington Infant Study, a case-control study examined possible associations 

between lead exposure and risk of total anomalous pulmonary venous return (TAPVR), a rare congenital 

malformation in which pulmonary veins deliver oxygenated blood to the right atria rather than the left 

atria (Jackson et al. 2004). Cases (n=54) were recruited during the period 1981–1989. Controls (n=522) 

consisted of a stratified random sample of live-born infants without birth defects (excluding twins, low 

birth weight infants, and infants whose race was other than black or white). Subjects were classified as 

having been exposed to lead (or not) during critical maternal (i.e., from 3 months prior to conception 

through third trimester) or paternal (i.e., within 6 months prior to conception) periods based on selfreporting of occupational or environmental exposures, reported in an administered questionnaire. 

Prevalence of maternal lead exposure was 17% among cases and 11% among controls; prevalence of 

paternal lead exposure was 61% among cases and 46% among controls. The OR for TAPVR in 
 

LEAD 68 

3. HEALTH EFFECTS 

association with any maternal lead exposure during the critical maternal period was 1.57 (95% CI, 0.64– 

3.47; p=0.27); the OR for any paternal lead exposure was 1.83 (95% CI, 1.00–3.42, p=0.045). 

Several small-scale studies have reported changes in peripheral hemodynamics in association with 

occupational exposures to lead. Effects observed in these studies may represent effects of lead on either 

the cardiovascular and/or autonomic nervous systems. A study conducted in Japan compared the results 

of finger plethysmographic assessments in 48 male workers in a lead refinery and 43 male controls who 

had no occupational lead exposure (Aiba et al. 1999). Ages of the exposed and reference groups were 

similar (mean±SD; 46±15 and 49±11 years, respectively). Mean PbB in the exposed group was 

43.2 μg/dL (25.2, SD), PbBs for the control group were not measured. Covariate-adjusted acceleration 

plethysmography parameters were significantly different in the exposure group compared to the reference 

group and were significantly associated with PbB. The prevalence of abnormal parameter values 

(<25th percentile value) was significantly higher in the exposure group and prevalence increased with 

increasing duration of employment or increasing PbB. A study of ceramic painters in Japan evaluated 

postural changes in finger blood flow in relation to PbB (Ishida et al. 1996). Subjects of the study were 

50 males (age, 55±12 years) and 78 females (age, 52±8 years) who were not currently receiving 

pharmacological treatment. Finger blood flow parameters evaluated were the percent change in finger 

blood flow in response to standing from a supine position, and the rate of decrease in blood flow in 

response to standing. The mean (geometric) PbB was 16.5 μg/dL (2.1, SD; range, 3.5–69.5 μg/dL) in 

males and 11.1 μg/dL (1.7, SD; range, 2.1–31.5 μg/dL) in females. Both percent change in blood flow 

and rate of decrease in blood flow significantly decreased with increasing PbB in both males and females. 

Covariate-adjusted postural change in finger blood flow was significantly associated with PbB. 

Covariates included in the regression model were age, body mass index total blood cholesterol 

concentration, skin temperature, alcohol consumption and tobacco smoking. 

Gastrointestinal Effects. Colic is a consistent early symptom of lead poisoning in occupationally 

exposed cases or in individuals acutely exposed to high levels of lead, such as occurs during the removal 

of lead-based paint. Colic is characterized by a combination of the following symptoms: abdominal pain, 

constipation, cramps, nausea, vomiting, anorexia, and weight loss. Although gastrointestinal symptoms 

typically occur at PbBs of 100–200 μg/dL, they have sometimes been noted in workers whose PbBs were 

between 40 and 60 μg/dL (Awad El Karim et al. 1986; Baker et al. 1979; Haenninen et al. 1979; Holness 

and Nethercott 1988; Kumar et al. 1987; Marino et al. 1989; Matte et al. 1989; Pagliuca et al. 1990; 

Pollock and Ibels 1986; Rosenman et al. 2003; Schneitzer et al. 1990). 
LEAD 69 

3. HEALTH EFFECTS 

Colic is also a symptom of lead poisoning in children. EPA (1986a) has identified a LOAEL of 

approximately 60–100 μg/dL for children. This value apparently is based on a National Academy of 

Sciences (NAS 1972) compilation of unpublished data from the patient groups originally discussed in 

Chisolm (1962, 1965) and Chisolm and Harrison (1956) in which other signs of acute lead poisoning, 

such as severe constipation, anorexia, and intermittent vomiting, occurred at ≥60 μg/dL. 

Hematological Effects. Lead has long been known to alter the hematological system. The anemia 

induced by lead is microcytic and hypochromic and results primarily from both inhibition of heme 

synthesis and shortening of the erythrocyte lifespan. Lead interferes with heme synthesis by altering the 

activities of δ-aminolevulinic acid dehydratase (ALAD) and ferrochelatase. As a consequence of these 

changes, heme biosynthesis is decreased and the activity of the rate-limiting enzyme of the pathway, 

δ-aminolevulinic synthetase (ALAS), which is feedback inhibited by heme, is subsequently increased. 

The end results of these changes in enzyme activities are increased urinary porphyrins, coproporphyrin, 

and δ-aminolevulinic acid (ALA); increased blood and plasma ALA; and increased erythrocyte 

protoporphyrin (EP). 

Studies of lead workers have shown that ALAD activity correlated inversely with PbB (Alessio et al. 

1976; Gurer-Orhan et al. 2004; Hernberg et al. 1970; Meredith et al. 1978; Schuhmacher et al. 1997; Tola 

et al. 1973; Wada et al. 1973), as has been seen in subjects with no occupational exposure (Secchi et al. 

1974). Erythrocyte ALAD and hepatic ALAD activities were correlated directly with each other and 

correlated inversely with PbBs in the range of 12–56 μg/dL (Secchi et al. 1974). 

General population studies indicate that the activity of ALAD is inhibited at very low PbB, with no 

threshold yet apparent. ALAD activity was inversely correlated with PbB over the entire range of 3– 

34 μg/dL in urban subjects never exposed occupationally (Hernberg and Nikkanen 1970). Other reports 

have confirmed the correlation and apparent lack of threshold in different age groups and exposure 

categories (children—Chisolm et al. 1985; Roels and Lauwerys 1987; adults—Roels et al. 1976). Studies 

of children in India and China also have reported significant decreases in ALAD activity associated with 

PbB ≥10 μg/dL (Ahamed et al. 2005; Jin et al. 2006). Inverse correlations between PbB and ALAD 

activity were found in mothers (at delivery) and their newborns (cord blood). PbB ranged from 

approximately 3 to 30 μg/dL (Lauwerys et al. 1978). In a study in male volunteers exposed to particulate 

lead in air at 0.003 or 0.01 mg lead/m3

 for 23 hours/day for 3–4 months mean PbB increased from 

20 μg/dL (pre-exposure) to 27 μg/dL at the 0.003 mg/m3

 exposure level and from 20 μg/dL (preexposure) to 37 μg/dL at the 0.01 mg/m3

 exposure level. ALAD decreased to approximately 80% of 
LEAD 70 

3. HEALTH EFFECTS 

preexposure values in the 0.003 mg/m3 group after 5 weeks of exposure and to approximately 53% of 

preexposure values in the 0.01 mg/m3

 group after 4 weeks of exposure (Griffin et al. 1975). Similar 

observations were made in a study of volunteers who ingested lead acetate at 0.02 mg lead/kg/day every 

day for 21 days (Stuik 1974). The decrease in erythrocyte ALAD could be noticed by day 3 of lead 

ingestion and reached a maximum by day 14. Mean PbB was approximately 15 μg/dL before exposure 

and increased to approximately 40 μg/dL during exposure. Cools et al. (1976) reported similar results in 

a study of 11 volunteers who ingested lead acetate that resulted in a mean PbB of 40 μg/dL; the mean preexposure PbB was 17.2 μg/dL. 

Inhibition of ALAD and stimulation of ALAS result in increased levels of ALA in blood or plasma and in 

urine. For example, in a case report of a 53-year-old man with an 11-year exposure to lead from 

removing old lead-based paint from a bridge, a PbB of 55 μg/dL was associated with elevated urinary 

ALA (Pollock and Ibels 1986). The results of the Meredith et al. (1978) study on lead workers and 

controls indicated an exponential relationship between PbB and blood ALA. Numerous studies reported 

direct correlations between PbB and log urinary ALA in workers. Some of these studies indicated that 

correlations can be seen at PbB of <40 μg/dL (Lauwerys et al. 1974; Selander and Cramer 1970; Solliway 

et al. 1996), although the slope may be different (less steep) than at PbBs >40 μg/dL. In a study of 

98 occupationally exposed subjects (mean PbB, 51 μg/dL) and 85 matched referents (mean PbB, 

20.9 μg/dL), it was found that log ZPP and log ALA in urine correlated well with PbB (Gennart et al. 

1992a). In the exposed group, the mean ZPP was 4 times higher than in the comparison group, whereas 

urinary ALA was increased 2-fold. 

Correlations between PbBs and urinary ALA similar to those observed in occupationally exposed adults 

have also been reported in nonoccupationally exposed adults (Roels and Lauwerys 1987) and children 

(unpublished data of J.J. Chisolm, Jr., reported by NAS 1972). Linear regression analyses conducted on 

data obtained from 39 men and 36 women revealed that increases in urinary ALA may occur at PbB 

>35 μg/dL in women and >45 μg/dL in men (Roels and Lauwerys 1987). A significant linear correlation 

between PbB and log ALA was obtained for data in children 1–5 years old with PbBs 25–75 μg/dL. The 

correlation was seen primarily at PbBs >40 μg/dL, but some correlation may persist at <40 μg/dL (NAS 

1972). 

A dose-related elevation of EP or ZPP in lead workers has been documented extensively (Herber 1980; 

Matte et al. 1989). Correlations between PbB and log EP or ZPP indicate an apparent threshold for EP 

elevation in male workers at 25–35 μg/dL (Grandjean and Lintrup 1978; Roels et al. 1975) for FEP and a 
LEAD 71 

3. HEALTH EFFECTS 

threshold of 30–40 μg/dL for EP (Roels and Lauwerys 1987; Roels et al. 1979). The threshold for EP 

elevation appears to be somewhat lower (20–30 μg/dL) in women than in men (Roels and Lauwerys 

1987; Roels et al. 1975, 1976, 1979; Stuik 1974), regardless of whether exposure is primarily by 

inhalation (occupational) or oral (nonoccupational). These studies were controlled for possible 

confounding factors such as iron deficiency or age, both of which increase erythrocyte ZPP. 

Many studies have reported the elevation of EP or ZPP as being exponentially correlated with PbBs in 

children. However, peak ZPP levels lag behind peak levels of PbB. The threshold for this effect in 

children is approximately 15 μg/dL (Hammond et al. 1985; Piomelli et al. 1982; Rabinowitz et al. 1986; 

Roels and Lauwerys 1987; Roels et al. 1976), and may be lower in the presence of iron deficiency 

(Mahaffey and Annest 1986; Marcus and Schwartz 1987). A study of 95 mother-infant pairs from 

Toronto showed a significant inverse correlation between maternal and umbilical cord lead levels and 

FEP (Koren et al. 1990). Most (99%) infants had cord PbBs below 7 μg/dL; in 11 cases, the levels were 

below the detection limit. The cord blood FEP levels were higher than the maternal levels. This may 

reflect immature heme synthesis and increased erythrocyte volume rather than lead poisoning, or perhaps 

an early effect of lead poisoning. 

The threshold PbB for a decrease in hemoglobin in occupationally exposed adults is estimated by EPA 

(1986a) to be 50 μg/dL, based on evaluations of the data of Baker et al. (1979), Grandjean (1979), Lilis et 

al. (1978), Tola et al. (1973), and Wada et al. (1973). For example, 5% of smelter workers with PbBs of 

40–59 μg/dL, 14% with levels of 60–79 μg/dL, and 36% with levels of >80 μg/dL had anemia. In a study 

of 98 workers from a lead acid battery factory with a mean PbB of 51 μg/dL, the mean hemoglobin 

concentration was not significantly different than in an unexposed group of 85 subjects (mean PbB, 

21 μg/dL). However, four exposed workers, but no controls, had hemoglobin levels below the level 

considered as the limit value for defining anemia (13 μg/dL) (Gennart et al. 1992a). Similar lack of 

correlation between PbB and hemoglobin was reported in a study of 94 Israeli lead workers with a mean 

PbB of 38.1 μg/dL (range, 6–113 μg/dL) (Froom et al. 1999). Solliway et al. (1996) also reported no 

significant differences in hemoglobin concentration between a group of 34 workers from a battery factory 

(mean PbB 40.7 μg/dL, range 23–66 μg/dL) and a group of 56 nonexposed persons (mean PbB 6.7 μg/dL, 

range 1–13 μg/dL). However, red blood cell count was significantly lower in exposed workers than in the 

controls. Lead-induced anemia is often accompanied by basophilic stippling of erythrocytes (Awad El 

Karim et al. 1986; Pagliuca et al. 1990). In a study of workers with a relatively low mean PbB of 

8.3 μg/dL (range, 2–25 μg/dL), it was found that PbB did not correlate with either hemoglobin or 

hematocrit; however, patellar lead significantly correlated with a decrease in hemoglobin and hematocrit 
LEAD 72 

3. HEALTH EFFECTS 

even after adjusting a number of confounders (Hu et al. 1994). The PbB threshold for decreased 

hemoglobin levels in children is judged to be approximately 40 μg/dL (EPA 1986a; WHO 1977), based 

on the data of Adebonojo (1974), Betts et al. (1973), Pueschel et al. (1972), and Rosen et al. (1974). In a 

pilot study of subjects who suffered lead poisoning in 1930–1942 in a Boston area, hemoglobin and 

hematocrit were significantly decreased compared to unexposed matched controls (Hu 1991a). The mean 

current age of the subjects was 55 years and the mean current PbB was 6 μg/dL. No difference was 

noticed in red blood cell size or shape between exposed and control subjects. Hu et al. (1991a) suggested 

that the effect observed may have represented a subclinical effect of accumulated bone lead stores on 

hematopoiesis. 

Other studies have shown that adverse effects on hematocrit may occur at even lower PbBs in children 

(Schwartz et al. 1990). Anemia was defined as a hematocrit of <35% and was not observed at PbB below 

20 μg/dL. Analyses revealed that there is a strong negative nonlinear dose-response relationship between 

PbBs and hematocrit. Between 20 and 100 μg/dL, the decrease in hematocrit was greater than 

proportional to the increase in PbB. The effect was strongest in the youngest children. The analysis also 

revealed that at PbBs of 25 μg/dL, there is a dose-related depression of hematocrit in young children. 

Similar results also have been reported by others (Kutbi et al. 1989). 

Lead also inhibits the enzyme pyrimidine-5’-nucleotidase within the erythrocyte, which results in an 

accumulation of pyrimidine nucleotides (cytidine and uridine phosphates) in the erythrocyte or 

reticulocyte and subsequent destruction of these cells. This has been reported in lead workers, with the 

greatest inhibition and marked accumulations of pyrimidine nucleotides apparent in workers with overt 

intoxication, including anemia (Paglia et al. 1975, 1977). PbBs in these workers ranged between 45 and 

110 μg/dL, and 7 of 9 were anemic. Pyrimidine-5'-nucleotidase activity was correlated inversely with 

PbB when corrected for an enhanced population of young cells due to hemolytic anemia in some of the 

workers (Buc and Kaplan 1978). Erythrocyte pyrimidine-5'-nucleotidase is inhibited in children at very 

low PbBs. A significant negative linear correlation between pyrimidine-5'-nucleotidase and PbB level 

was seen in 21 children with PbBs ranging from 7 to 80 μg/dL (Angle and McIntire 1978). Similar 

results were seen in another study with 42 children whose PbB ranged from <10 to 72 μg/dL (Angle et al. 

1982). Additional findings included a direct correlation between cytidine phosphate levels and PbBs 

(log-log). There was no indication of a threshold for these effects of lead in these two studies. 

In summary, of all the parameters examined, ALAD activity appears to be the most sensitive indicator of 

lead exposure. In studies of the general population, ALAD activity was inversely correlated with PbBs 
LEAD 73 

3. HEALTH EFFECTS 

over the entire range of 3–34 μg/dL. In contrast, the threshold PbB for increase in urinary ALA in adults 

is approximately 40 μg/dL; for increases in blood EP or ZPP, the threshold in adults is around 30 μg/dL, 

and the threshold for increased ZPP in children is about 15 μg/dL in children. Threshold PbBs for 

decreased hemoglobin levels in adults and children have been estimated at 50 and 40 μg/dL, respectively. 

Although the measurement of ALAD activity seems to be a very sensitive hematological marker of lead 

exposure, the inhibition of the enzyme is so extensive at PbBs ≥30 μg/dL that the assay cannot distinguish 

between moderate and severe exposure. 

Studies in animals, in general, support the findings in humans and indicate that the effects depend on the 

chemical form of lead, duration of exposure, and animal species. Of particular interest are the results of a 

study in a cohort of 52 monkeys administered lead acetate orally for up to 14 years (Rice 1996b). PbB 

was dose-related and ranged between 10 and 90 μg/dL. Decreased hematocrit and hemoglobin was 

observed in monkeys at 7 (PbB 25 μg/dL) and 11 years (PbB 90 μg/dL) of age; hemoglobin also was 

decreased at 6 years of age when PbB was 23 μg/dL. All changes that occurred were within normal 

ranges, which led Rice (1996b) to conclude that under the conditions of the study, there were no leadrelated hematological effects. 

Musculoskeletal Effects. Several case reports of individuals who experienced high exposures to 

lead either occupationally or through the consumption of illicit lead contaminated whiskey described the 

occurrence of a bluish-tinged line in the gums (Eskew et al. 1961; Pagliuca et al. 1990). The etiology of 

this "lead line" has not been elucidated. This effect has also been observed in workers exposed to high 

lead levels who had exposures via dust or fume. Individuals having high exposures to lead have also been 

reported to complain of muscle weakness, cramps, and joint pain (Holness and Nethercott 1988; Marino 

et al. 1989; Matte et al. 1989; Pagliuca et al. 1990). Rosenman et al. (2003) described musculoskeletal 

effects (frequent pain/soreness and/or muscle weakness) in lead workers with PbB ≥40 μg/dL. 

A study of the association between lead exposure and bone density in children was recently published 

(Campbell et al. 2004). The cohort consisted of 35 African American children 8–10 years of age from 

Monroe County, New York State. The cohort was divided into two groups, one (n=16) with mean 

cumulative PbB of 6.5 μg/dL (low-exposure group) and the other (n=19) with mean cumulative PbB of 

23.6 μg/dL (high-exposure group). The groups were similar by sex, age, body mass index, socioeconomic status, physical activity, or calcium intake. Contrary to what was expected, subjects with high 

cumulative exposure had a higher bone mineral density than subjects with low-lead cumulative exposure. 

Among 17 bony sites examined, four were significantly different (p<0.05). Campbell et al. (2004) 
LEAD 74 

3. HEALTH EFFECTS 

speculated that lead accelerates skeletal maturation by inhibiting proteins that decrease the rate of 

maturation of chondrocytes in endochondral bone formation. A lower peak bone mineral density 

achieved in young adulthood might predispose to osteoporosis in later life. 

A limited number of studies have explored the effects of oral lead exposure on bone growth and 

metabolism in animals (Escribano et al. 1997; Gonzalez-Riola et al. 1997; Gruber et al. 1997; Hamilton 

and O’Flaherty 1994, 1995; Ronis et al. 2001). These data, all from intermediate-duration studies in rats, 

indicate that oral lead exposure may impair normal bone growth and remodeling as indicated by 

decreased bone density and bone calcium content, decreased trabecular bone volume, increased bone 

resorption activity, and altered growth plate morphology. In general, rats appear to be less sensitive than 

humans to lead effects in bone. A recent study in mice reported that lead delays fracture healing at 

environmentally relevant doses and induces fibrous nonunions at higher doses by the progression of 

endochondral ossification (Carmouche et al. 2005). In studies in cultured osteoblast-like cells, lead 

disrupted the modulation of intracellular calcium by 1,25-dihydroxyvitamin D in a biphasic manner (Long 

and Rosen 1994). Another effect seen in this culture system was the inhibition by lead of 1,25-dihydroxyvitamin D3-stimulated synthesis of osteocalcin, a protein constituent of bone that may play a 

major role in normal mineralization of bone. Reduced plasma levels of osteocalcin have been reported in 

“moderately lead-poisoned” children (Pounds et al. 1991). Lead also inhibited secretion of osteonectin/ 

SPARC, a component of bone matrix, and decreased the levels of osteonectin/SPARC mRNA from 

osteoblast-like cells in culture (Sauk et al. 1992). Lead inclusion bodies are commonly found in the 

cytoplasm and nuclei of osteoclasts, but not other bone cells, following in vivo lead exposure (Pounds et 

al. 1991). 

The studies that have examined relationships between lead exposure, as reflected by PbB, and the 

occurrence of dental caries in children have, for the most part, found a positive association (Campbell et 

al. 2000a; Gemmel et al. 2002; Moss et al. 1999). Moss et al. (1999) conducted a cross-sectional analysis 

of measurements of PbB and dental caries in 24,901 people, including 6,541 children 2–11 years of age, 

recorded in the NHANES III (1988–1994). Mean (geometric) PbBs were 2.9 μg/dL in children 2–5 years 

of age and 2.1 μg/dL in children 6–11 years of age. Increasing PbB was significantly associated with 

increased number of dental caries in both age groups, after adjustment for covariates. An increase in PbB 

of 5 μg/dL was associated with an adjusted OR of 1.8 (95% CI, 1.3–2.5) for the age group 5–17 years. 

Covariates included in the models were age, gender, race/ethnicity, poverty income ratio, exposure to 

cigarette smoke, geographic region, educational level of head of household, carbohydrate and calcium 

intakes, and dental visits. A retrospective cohort study conducted in Rochester, New York compared the 
LEAD 75 

3. HEALTH EFFECTS 

risk of dental caries among 154 children 7–12 years of age associated with PbB less than or exceeding 

10 μg/dL, measured at ages 18 and 37 months of age (Campbell et al. 2000a). The OR (adjusted for age 

at examination, grade in school, and number of dental surfaces at risk) for caries on permanent teeth 

associated with a PbB exceeding 10 μg/dL was 0.95 (95% CI, 0.43–2.09; p=0.89) and for deciduous teeth, 

1.77 (95% CI, 0.97–3.24; p=0.07). Other covariates examined in the models, all of which had no 

significant effect on the outcome, were gender, race/ethnicity, SES, parental education and residence in 

community supplied with fluoridated drinking water, and various dental hygiene variables. Gemmel et al. 

(2002) conducted a cross-sectional study of associations between PbB and dental caries in 543 children, 

6–10 years of age, who resided either in an urban (n=290) or rural (n=253) setting. Increasing PbB was 

significantly associated with the number of caries in the urban cohort, but not in the rural cohort. The 

mean PbBs were 2.9 μg/dL (SD, 2.0) in the urban group and 1.7 μg/dL (SD, 1.0) in the rural group. 

Covariates examined in the models were gender, race/ethnicity, SES, maternal smoking, parental 

education, and various dental hygiene variables. 

Dye et al. (2002) conducted a cross-sectional analysis of measurements of blood lead concentration and 

indices of periodontal bone loss in 10,033 people, 20–69 years of age, recorded in the NHANES III 

(1988–1994). Mean (geometric) PbB was 2.5 μg/dL (SE, 0.08). Increasing blood lead concentration was 

significantly associated with periodontal bone loss, after adjustment for covariates. Covariates examined 

in the analysis included age, gender, race/ethnicity, education, SES, age of home, smoking, and dental 

furcation (an indicator of severe periodontal disease) as well as an interaction term for smoking and dental 

furcation. 

Studies in animals also have examined the effect of lead exposure on teeth. For example, young rats 

whose mothers were exposed to lead since young adults, during pregnancy, and lactation had a 

significantly higher mean caries score than a control group (Watson et al. 1997). The mean PbB achieved 

in the dams was 48 μg/dL and in the breast milk 500 μg/dL; PbB in the offspring was not determined. 

Lead also has been reported to delay mineralization in teeth, resulting in less hard enamel (Gerlach et al. 

2002) and eruption rate in hypofunctional teeth (Gerlach et al. 2000). 

Hepatic Effects. In children, exposure to lead has been shown to inhibit formation of the hemecontaining protein cytochrome P-450, as reflected in decreased activity of hepatic mixed-function 

oxygenases. Two children with clinical manifestations of acute lead poisoning did not metabolize the test 

drug antipyrine as rapidly as did controls (Alvares et al. 1975). Another study found a significant 

reduction in 6β-hydroxylation of cortisol in children who had positive urinary excretion of lead 
LEAD 76 

3. HEALTH EFFECTS 

(≥500 μg/24 hours) upon ethylenediamine tetraacetic acid (EDTA) provocative tests compared with an 

age-matched control group (Saenger et al. 1984). These biochemical transformations are mediated by 

hepatic mixed-function oxygenases. 

The association between lead exposure and serum lipid profile was examined in a study of Israeli workers 

(Kristal-Boneh et al. 1999). The mean PbB of the 87 workers was 42.3 μg/dL and that of 56 control 

subjects was 2.7 μg/dL. After adjusting for confounders including nutritional variables, the authors found 

statistically higher values for total cholesterol (212 vs. 200 mg/dL) and HDL cholesterol (47 vs. 

42 mg/dL) in the workers compared to controls; no significant differences were seen for LDL cholesterol 

and triglycerides. These findings are of dubious biological significance, particularly since the HDL/total 

cholesterol ratio was the same in the two groups. A study in rats administered lead acetate for 7 weeks 

that resulted in PbBs of 17 and 32 μg/dL reported a dose-related increase in triglycerides and decrease in 

HDL cholesterol (Skoczynska et al. 1993). The authors speculated that the increase in serum triglycerides 

could have been caused by lead-induced inhibition of lipoprotein lipase activity or decreased activity of 

hepatic lipase; no possible explanation was offered for the decrease in HDL cholesterol. 

A study of workers in the United Arab Emirates reported that a group of 100 workers with a mean PbB of 

78 μg/dL had significantly higher concentrations of amino acids in serum than 100 controls whose mean 

PbB was 20 μg/dL (Al-Neamy et al. 2001). Tests for liver function that included serum aspartate 

aminotransferase (AST) and alanine aminotransferase (ALT) activities found small (≤10%) but 

statistically significant increases in alkaline phosphatase and lactate dehydrogenase activities in the serum 

of the workers. A study in rats treated with lead acetate for 4 months found decreased AST and ALT 

activities in hepatic homogenates, but activities in serum were not monitored (Singh et al. 1994). 

Collectively, the information regarding effects of lead on the liver in humans and animals is scarce and 

does not allow for generalizations. 

Renal Effects. Lead nephrotoxicity is characterized by proximal tubular nephropathy, glomerular 

sclerosis and interstitial fibrosis (Diamond 2005; Goyer 1989; Loghman-Adham 1997). Functional 

deficits in humans that have been associated with excessive lead exposure include enzymuria, low- and 

high-molecular weight proteinuria, impaired transport of organic anions and glucose, and depressed 

glomerular filtration rate. A few studies have revealed histopathological features of renal injury in 

humans, including intranuclear inclusion bodies and cellular necrosis in the proximal tubule and 

interstitial fibrosis (Biagini et al. 1977; Cramer et al. 1974; Wedeen et al. 1975, 1979). 
LEAD 77 

3. HEALTH EFFECTS 

A large number of studies of lead nephropathy in humans have been published (Table 3-3). Most of these 

studies are of adults whose exposures were of occupational origin; however, a few environmental and/or 

mixed exposures are represented and a few studies of children are also included (Bernard et al. 1995; Fels 

et al. 1998; Verberk et al. 1996). In most of these studies, PbB was the biomarker for exposure, although 

more recent epidemiological studies have explored associations between toxicity and bone lead 

concentrations. These studies provide a basis for establishing blood lead, and in some cases, bone lead 

concentration ranges associated with specific nephrotoxicity outcome. The studies are sorted in 

Figure 3-3 by the central tendency blood lead concentration reported in each study; details about the 

subjects and exposures are provided in Table 3-3. End points of kidney status captured in this data set 

include various measures of glomerular and tubular dysfunction. Data on changes in glomerular filtration 

rate represent measurements of either creatinine clearance or serum creatinine concentration. 

Measurements of enzymuria represent, mainly, urinary N-acetyl-D-glucosaminidase (NAG), are also 

represented. Increased excretion of NAG has been found in lead-exposed workers in the absence of 

increased excretion of other proximal tubule enzymes (e.g., alanine aminopeptidase, alkaline phosphatase, 

glutamyltransferase) (Pergande et al. 1994). Data points indicating proteinuria refer to total urinary 

protein, urinary albumin, or urinary LMW protein (e.g., 2μG or RBP). Indices of impaired transport 

include clearance or transport maxima for organic anions (e.g., p-aminohippurate, urate) or glucose 

(Biagini et al. 1977; Hong et al. 1980; Wedeen et al. 1975). A few studies have provided histopathological confirmation of proximal tubular injury (Biagini et al. 1977; Wedeen et al. 1975, 1979). 

Figure 3-3 illustrates a few general trends regarding the relationship between PbB and qualitative aspects 

of the kidney response. A cluster of observations of decrements in glomerular filtration rate appear at the 

low end of the PbB range (<20 μg/dL); the significance of these studies is discussed in greater detail 

below. Outcomes for the various renal toxicity end points are mixed over the PbB range 20–50 μg/dL. 

Enzymuria or proteinuria were detected in most studies in which these end points were evaluated, 

whereas indications of depressed glomerular filtration rate were, with only one exception, not observed 

over this PbB range. At PbBs >50 μg/dL, functional deficits, including enzymuria, proteinuria, impaired 

transport, and depressed glomerular filtration rate, dominate the observations. The overall dose-effect 

pattern suggests an increasing severity of nephrotoxicity associated with increasing PbB, with effects on 

glomerular filtration evident at PbBs below 20 μg/dL, enzymuria and proteinuria becoming evident above 

30 μg/dL, and severe deficits in function and pathological changes occurring in association with PbBs 

exceeding 50 μg/dL. 
 

LEAD 78 

3. HEALTH EFFECTS 

Table 3-3. Selected Studies of Lead-Induced Nephrotoxicity in Humansa 

Exposure Blood lead 

No. Reference 

Exposure 

type 

Number of 

subjects 

Age 

(year) 

duration 

(year) 

concentration 

(μg/dL)b 

Biomarker 

evaluatedc 

1 Muntner at al. 2003 Unknown 4,831 >20 NA 5 SCr* 

(<1–56) 

2 Hu 1991b Environmental 22 55 NA 6 CCr*d 

(2–11) 

3 Lin et al. 2001 Unknown 55 57 NA 7 CCr* 

(1–16) 

4 Staessen et al. Environmental 1,981 48 NA 8 CCr*, SCr* 

1992 (~2–70) 

5 Payton et al. 1994 Environmental 744 64 NA 8 CCr* 

(4–26) 

6 Kim et al. 1996a Unknown 459 57 NA 10 SCr* 

(<1–54) 

7 Staessen et al. Environmental 531 48 NA 10 SCr* 

1990 (<4–35) 

8 Bernard et al. 1995 Environmental 154 13 NA 12 UNAG*, 

(3–35) URBP* 

9 Fels et al. 1998 Environmental 62 10 NA 13 SCr, UE, 

(SD=6) UP, ULMWP 

10 Sonmez et al. 2002 Occupational 13 32 0.14 25 SCr, UNAG* 

(SD=10) 

11 Chia et al. 1994 Occupational 128 28 3 30 UNAG* 

(4–66) 

12 Chia et al. 1995a, Occupational 137 28 >0.5 SCr, 

1995b 30 

(4–66) 

Sβ2μG*, 

UAlb, 

Uβ2μG, 

URBP 

13 Weaver et al. 

2003a, 2005 

Occupational 803 40 1–36 

32 

BUN*e 

, 

SCr*e

, CCr, 

(4–86) UNAG*e 

, 

URBP 

14 Mortada et al. 2001 Occupational 43 33 10 32 SCr, UNAG*, 

(SD=17) UAlb* 

15 Gerhardsson et al. 

1992 

Occupational 100 37–68 14–32 32 

(5–47) 

CCr, SCr, 

Uβ2μG*, 

UNAG* 

16 Verberk et al. 1996 Environmental 151 4.6 NA 34 UNAG* 

(<5–~110) 

17 Factor-Litvak et al. Environmental 394 6 6 35 UP* 

1999 (20–40) 

18 Omae et al. 1990 Occupational 165 18–57 0.1–26 37 

(9–60) 

CCr, CUA, 

Uβ2μG, 

Cβ2μG 
 

LEAD 79 

3. HEALTH EFFECTS 

Table 3-3. Selected Studies of Lead-Induced Nephrotoxicity in Humansa 

Exposure Blood lead 

Exposure Number of Age duration concentration Biomarker 

No. Reference type subjects (year) (year) (μg/dL)b evaluatedc 

19 Cardozo dos Occupational 166 33 4.5 37 SCr, UNAG*, 

Santos et al. 1994 (16–88)f UAlb, UP 

20 Wedeen et al. 1975 Occupational 4 36 5–8 40 GFR, RPF, 

(29–52) TMPAH, HP 

21 Hsiao et al. 2001 Occupational 30 38 13 40 SCrg 

(<10–98) 

22 Huang et al. 2002 Occupational 40 30 5 42 Uβ2μG, UP 

(24–63) 

23 Fels et al. 1994 Occupational 81 30 7 42 UP* 

(21–73) 

24 Pergande et al. Occupational 82 30 7 42 SCr, UP*, 

1994 (21–73) UE* 

25 Roels et al. 1994 Occupational 76 44 6–36 43 CCr*d

, 

(26–68) UNAG* 

26 Kumar and Occupational 22 32.5 NA CCr, 43 Krishnaswamy Uβ2μG*, (30–69) 1995 UNAG* 

27 Buchet et al. 1980 Occupational 25 45 13 44 CCr, SCr, 

(34–61) Uβ2μG, UP 

28 de Kort et al. 1987 Occupational 53 42 12 47 SCr, BUN 

(44–51) 

29 Verschoor et al. Occupational 155 30–51 <2–>10 47 UNAG*, 

1987 (34–66) URPB* 

30 Cardenas et al. Occupational 41 39 14 SCr, UP, 

1993 Uβ2μG, 48 UNAG*, (36–65) UTBX*, 

UPG* 

31 Wedeen et al. 1975 Occupational 1 40 5 GFR*, 

48 TMPAH*, 

HP* 

32 Gennart et al. 1992 Ocupational 98 38 8 SCr, UNAG, 51 Uβ2μG, (45–70) URBP 

33 Wedeen et al. 1979 Occupational 15 41 14 52 GFR*, HP* 

(20–98) 

34 Ehrlich et al. 1998 Occupational 382 41 12 54 SCr,* SUA* 

(23–110) 

35 Pinto de Almeida et Occupational 52 38 NA 64 SCr* 

al. 1987 (SD=16) 

36 Hong et al. 1980 Occupational 6 35 7 68 GFR*, TMG* 

(34–110) 

37 Wedeen et al. 1975 Occupational 3 28 3–5 GFR*, RPF*, 72 TMPAH*, (51–98) HP* 
 

LEAD 80 

3. HEALTH EFFECTS 

Table 3-3. Selected Studies of Lead-Induced Nephrotoxicity in Humansa 

Exposure Blood lead 

Exposure Number of Age duration concentration Biomarker 

No. Reference type subjects (year) (year) (μg/dL)b evaluatedc 

38 Baker et al. 1979 Occupational 160 29–62 4–31 77 GFR*, BUN* 

(16–280) 

39 Lilis et al. 1968 Occupational 102 32–61 >10 79 GFR*, SCr* 

(42–149) 

40 Lilis et al. 1980 Occupational 449 NA 12 80 SCr*, BUN* 

(<40>80) 

41 Cramer et al. 1974 Occupational 7 45 9 103 GFR*, HP* 

(71–109) 

42 Biagini et al. 1977 Occupational 11 44 12 103 GFR*, 

(60–200) CPAH*, HP* 

a

See Figure 3-3 for graphical representation of lead-induced renal effects. b

Blood lead concentrations are reported central tendencies with range or SD in parentheses. c

Asterisk indicates association with lead exposure. d

Significant increase in creatinine clearance. 

e

Significant in upper age tertile (>46 years). 

f

3rd and 97th percentile. 

g

Significant decrease in serum creatinine concentration. 

BUN = blood urea nitrogen, CCr = creatinine clearance; Cβ2μG = β2μG clearance, CPAH=p-aminohippurate (PAH) 

clearance; CUA = uric acid clearance; GFR = glomerular filtration rate; HP = histopathology; Sβ2μG = serum β2μG; 

SCr = serum creatinine; SD = standard deviation; SUA = serum uric acid; RPF= renal plasma flow; TMG = transport 

maximum for glucose; TMPAH = transport maximum for PAH; UAlb = urine albumin; Uβ2μG = urine β2μG; 

UE = urine enzymes; ULMWP = urine low molecular weight proteins; UNAG = urine N-acetyl-β-D-glucosaminidase; 

UP = urine protein; UPG = urine prostaglandins; URBP = urine retinol binding protein; UTBX = urine thromboxane 
0 45

LEAD 81 

3. HEALTH EFFECTS 

Figure 3-3. Indicators of Renal Functional Impairment Observed at Various Blood 

Lead Concentrations in Humans* 

120 

80 

40 

0 

-40 

-80 

-120 

5 10 15 20 25 30 35 40 

Study Number 

a 

b 

b 

Depressed GFR 

Enzymuria 

Proteinuria 

Impaired transport 

Degenerative changes 

c a 

Blood Pb (μg/dL) 

No Effect Level Effect Level 

*Refer to Table 3-3 for study details (indexed by study number) 

a = Increase in creatinine clearance; b = >46 years of age; c = Decrease in serum creatinine; GFR = glomerular 

filtration rate 

Source: Diamond 2005 
LEAD 82 

3. HEALTH EFFECTS 

Inconsistencies in the reported outcomes across studies may derive from several causes. Varying 

uncertainty also exists, across studies, in exposure history of subjects and in the biomarkers assessed. In 

addition, occupational studies are subject to a healthy worker bias (i.e., tendency for workers who 

experience adverse effects to remove themselves, or be removed, from exposure). 

Observations made in animal models provide evidence for the plausibility of effects of lead on renal 

glomerular and tubular function in humans. In rats, proximal tubular injury involves the convoluted and 

straight portions of the tubule (Aviv et al. 1980; Dieter et al. 1993; Khalil-Manesh et al. 1992a, 1992b; 

Vyskocil et al. 1989), with greater severity, at least initially, in the straight (S3) segment (Fowler et al. 

1980; Murakami et al. 1983). Typical histological features include, in the acute phase, the formation of 

intranuclear inclusion bodies in proximal tubule cells (see below for further discussion); abnormal 

morphology (e.g., swelling and budding) of proximal tubular mitochondria (Fowler et al. 1980; Goyer 

and Krall 1969); karyomegaly and cytomegaly; and cellular necrosis, at sufficiently high dosage. These 

changes appear to progress, in the chronic phase of toxicity and with sufficient dosage, to tubular atrophy 

and interstitial fibrosis (Goyer 1971; Khalil-Manesh et al. 1992a, 1992b). Glomerular sclerosis has also 

been reported (Khalil-Manesh et al. 1992a). Adenocarcinomas of the kidney have been observed in longterm studies in rodents in which animals also developed proximal tubular nephropathy (Azar et al. 1973; 

Goyer 1993; Koller et al. 1985; Moore and Meredith 1979; Van Esch and Kroes 1969). 

Effects on Glomerular Filtration Rate. In humans, reduced glomerular filtration rate (i.e., indicated by 

decreases in creatinine clearance or increases in serum creatinine concentration) has been observed in 

association with exposures resulting in average PbBs <20 μg/dL (Figure 3-3, Table 3-3). 

The results of epidemiological studies of general populations have shown a significant effect of age on the 

relationship between glomerular filtration rate (assessed from creatinine clearance of serum creatinine 

concentration) and PbB (Kim et al. 1996a; Muntner et al. 2003; Payton et al. 1994; Staessen et al. 1990, 

1992; Weaver et al. 2003a, 2005b). Furthermore, hypertension can be both a confounder in studies of 

associations between lead exposure and creatinine clearance (Perneger et al. 1993) and a covariable with 

lead exposure (Harlan et al. 1985; Muntner et al. 2003; Payton et al. 1994; Pirkle et al. 1985; Pocock et al. 

1984, 1988; Tsaih et al. 2004; Weiss et al. 1986). These factors may explain some of the variable 

outcomes of smaller studies in which the age and hypertension effects were not fully taken into account. 

When age and other covariables that might contribute to glomerular disease are factored into the doseresponse analysis, decreased glomerular filtration rate has been consistently observed in populations that 

have average PbB <20 μg/dL (Table 3-4). In the Kim et al. (1996a) and Muntner et al. (2003) studies, a 
LEAD 83 

3. HEALTH EFFECTS 

Table 3-4. Summary of Dose-Response Relationships for Effects of Lead 

Exposure on Biomarkers of Glomerular Filtration Rate 

Mean PbB Change in end point 

Number of (range) (per 10-fold increase 

Reference Exposure Subjects (μg/dL) End point in blood lead) 

Payton et al. 1994 Mixeda 744 M 8.1 (4–26) CCr 

(mL/minute) 

-10b 

Staessen et al. 1992 Environmental 

Kim et al. 1996a Mixeda 

1,016 F 

965 M 

459 M 

7.5 (1.7–65) 

9.9 (0.2–54) 

CCr 

(mL/minute) 

SCr (mg/dL) 

-10 Fc 

-13 M 

0.08d 

0.14e 

Staessen et al. 1990 Environmental 133 F 

398 M 

12 (6–35) SCr (mg/dL) 0.07 Mf 

a

U.S. Veterans Administration Normative Aging Study 

b

Partial regression coefficient, -0.040 ln mL/minute creatinine clearance per ln μmol/L blood lead concentration. c

Partial regression coefficient, -9.51 mL/minute creatinine clearance per log μmol/L blood lead concentration. d

Partial regression coefficient, 2.89 μmol/L serum creatinine per ln μmol/L blood lead concentration. e

In subjects with blood lead concentrations less than 10 μg/dL, the partial regression coefficient was 5.29 μmol/L 

serum creatinine per ln μmol/L blood lead concentration. f

Reported 0.6 increase in serum creatinine (μmol/L) per 25% increase in blood lead concentration (μmol/L, logtransformed) in males (two subjects with serum creatinine concentrations exceeding 180 μmol/L excluded; 

regression coefficient not reported for females). 

CCr = creatinine clearance; F = females; ln = natural logarithm; M = males; PbB = blood lead concentration; 

SCr = serum creatinine concentration 
LEAD 84 

3. HEALTH EFFECTS 

significant relationship between serum creatinine and PbB was evident in subjects who had PbB below 

10 μg/dL (serum creatinine increased 0.14 mg/dL per 10-fold increase in PbB). Assuming a glomerular 

filtration rate of approximately 90–100 mL/minute in the studies reported in Table 3-4, a change in 

creatinine clearance of 10–14 mL/minute would represent a 9–16% change in glomerular filtration rate 

per 10-fold increase in PbB. Estimating the change in glomerular filtration rate from the incremental 

changes in serum creatinine concentration reported in Table 3-4 is far less certain because decrements in 

glomerular filtration do not necessarily give rise to proportional increases in serum creatinine 

concentrations. A 50% decrement in glomerular filtration rate can occur without a measurable change in 

serum creatinine excretion (Brady et al. 2000). Nevertheless, the changes reported in Table 3-4 (0.07– 

0.14 mg/dL) would represent a 6–16% increase, assuming a mean serum creatinine concentration of 0.9– 

1.2 mg/dL. This suggests at least a similar, and possibly a substantially larger, decrement in glomerular 

filtration rate. The confounding and covariable effects of hypertension are also relevant to the interpretation of the regression coefficients reported in these studies. Given the evidence for an association 

between lead exposure and hypertension, and that decrements in glomerular filtration rate can be a 

contributor to hypertension, it is possible that the reported hypertension-adjusted regression coefficients 

may underestimate the actual slope of the blood lead concentration relationship with serum creatinine 

concentration or creatinine clearance. 

Another important complication in the assessment of associations between lead exposure and adverse 

effects on glomerular filtration is the potential confounding effect of decrements in glomerular filtration 

rate and increased lead body burden. Lead exposure has also been associated with increases in 

glomerular filtration rate (Hsiao et al. 2001; Hu 1991b; Roels et al. 1994). This may represent a benign 

outcome or a potentially adverse hyperfiltration, which may contribute to subsequent adverse renal 

effects. Increases in glomerular filtration rate have been observed in the early phases of development of 

chronic renal injury in rats (Khalil-Manesh et al. 1992a). 

The observations suggestive of a relationship between PbB and decrements in glomerular filtration rate 

derived from the studies presented in Table 3-3 are consistent with those of a smaller prospective clinical 

study in which progression of renal insufficiency was related to higher lead body burden among patients 

whose PbB was <15 μg/dL (Lin et al. 2001; Yu et al. 2004). Mean PbB in a high lead body burden group 

(EDTA provocation test yielded >600 μg excreted/72 hours) were 6.6 μg/dL (range, 1.0–15 μg/dL) 

compared to 3.9 μg/dL (1–7.9 μg/dL) in a low body burden group. 
LEAD 85 

3. HEALTH EFFECTS 

The above observations suggest that significant decrements in glomerular filtration rate may occur in 

association with PbB below 20 μg/dL and, possibly, below 10 μg/dL (Kim et al. 1996a; Muntner et al. 

2003). This range is used as the basis for estimates of lead intakes that would place individuals at risk for 

renal functional deficits. 

Longitudinal Studies—General Population. Three studies of glomerular function and lead exposure 

were conducted as part of the Normative Aging Study, a longitudinal study of health outcomes in 

2,280 males, initially enrolled in the Boston area of the United States between 1963 and 1968. At 

enrollment, subjects ranged in age from 21 to 80 years (mean, 67), and had no history of heart disease, 

hypertension, cancer, peptic ulcer, gout, bronchitis, or sinusitus. Physical examinations, including seated 

blood pressure and medical history follow-ups, were conducted at approximately 3–5-year intervals. 

Beginning in 1987, participants were requested to provide 24-hour urine samples for analysis, including 

urine creatinine; and beginning in 1991, blood and bone concentrations were included in the 

examinations. Data collected from a subset of the study population (744 subjects, observed between 

1988 and 1991) were analyzed for associations between serum creatinine, renal creatinine clearance, and 

blood lead concentrations (Payton et al. 1994). Mean age of the study group was 64.0 years (range, 43– 

90). Mean baseline PbB was 8.1 μg/dL (range, <4–26 μg/dL). Based on multi-variate linear regression 

(with log-transformed PbB), covariate-adjusted creatinine clearance was significantly associated with 

blood lead concentration (regression coefficient, -0.0403; SE, 0.0198; p=0.04). A 10-fold increase in PbB 

was associated with a decrease in creatinine clearance of 10.4 mL/minute. This would represent a 

decrease in creatinine clearance of approximately 11% from the group mean of 88 mL/minute. Covariates included in the regression model were age and body mass index; systolic and diastolic blood 

pressure; alcohol consumption and tobacco smoking; and analgesic or diuretic medications. 

In a subsequent longitudinal study, data collected from a random subset of the Normative Aging Study 

population (459 subjects, observed between 1991 and 1994) were analyzed for associations between 

serum creatinine and PbB (Kim et al. 1996a). Mean age of the study group was 56.9 years (range, 37.7– 

87.5). Mean PbB was 9.9 μg/dL (range, 0.2–54.1 μg/dL). Based on multivariate linear regression (with 

log-transformed PbB), covariate-adjusted serum creatinine concentration (mg/dL) was significantly 

associated with PbB. A 10-fold increase in PbB was associated with an increase of 0.08 mg/dL in covariate-adjusted serum creatinine (95% CI, 0.02–0.13). This would represent an increase of 

approximately 7% from the group mean of 1.2 mg/dL. When subjects were stratified by PbB, the 

association was significant for three blood lead categories: ≤40, ≤25, and ≤10 μg/dL. In subjects who 

had PbB ≤10 μg/dL, serum creatinine was predicted to increase 0.14 mg/dL per 10-fold increase in PbB 
LEAD 86 

3. HEALTH EFFECTS 

(approximately 11% increase from the unstratified group mean). Covariates included in the models were 

age and body mass index; hypertension; alcohol consumption and tobacco smoking; and education. 

A prospective study included 707 subjects from the Normative Aging Study who had serum creatinine, 

blood lead and bone lead measurements taken during the period 1991–1995 (baseline), and a subset of the 

latter group (n=448) for which follow-up serum creatinine measurements made 4–8 years later (Tsaih et 

al. 2004). Mean age of the study group was 66 years at the time of baseline evaluation and 72 years at 

follow-up. Mean PbB was 6.5 μg/dL at baseline and 4.5 at follow-up. Baseline bone lead concentrations 

were: tibia, 21.5 μg/g and patella, 32.4 μg/g and were essentially the same at follow-up. Associations 

between covariate-adjusted serum creatinine concentrations and lead measures were significant (p<0.05) 

in the study group only for blood lead and follow-up serum creatinine. Covariates included in the models 

were age and body mass index; diabetes and hypertension; alcohol consumption and tobacco smoking; 

and education. When stratified by diabetes and hypertension status, significant associations between 

serum creatinine concentration and lead measures (blood or bone lead) were found in the diabetic (n=26) 

and hypertensive groups (n=115), suggesting the possibility of interactions between lead exposure, 

glomerular function, diabetes, or hypertension. An increase in tibia bone lead concentration from the 

mid-point of the lowest to the highest quintile (9–34 μg/g) was associated with a significantly greater 

increment in serum creatinine concentration among diabetics (1.08 mg/dL per 10 years) compared to nondiabetics (0.062 mg/dL per 10 years). 

Cross-sectional Studies—General Population. The NHANES III collected data on serum creatinine 

concentrations and PbB on approximately 20,000 U.S. residents during the period 1988–1994. Muntner 

et al. (2003) analyzed data collected on 15,211 subjects of age 20 years or older. Subjects were stratified 

into normotensive (n=10,398) or hypertensive categories (n=4,813; ≥140 mmHg systolic pressure or 

≥90 mmHg diastolic pressure). Mean PbB was 3.30 μg/dL in the normotensive group and 4.21 μg/dL in 

the hypertensive group. Associations between PbB and risk of elevated serum creatinine concentrations 

or chronic renal disease (i.e., depressed glomerular filtration rate) were explored using multivariate 

regression. Elevated serum creatinine concentration was defined as ≥1.5 or ≥1.3 mg/dL in non-Hispanic 

Caucasian males and females, respectively; ≥1.6 mg/dL (males) or 1.4 mg/dL (females) for non-Hispanic 

African Americans; or ≥1.4 mg/dL (males) or ≥1.2 mg/dL (females) for Mexican Americans. Glomerular 

filtration rate was estimated from serum creatinine concentration using a predictive algorithm (Levey et 

al. 1999). Chronic renal disease was defined as glomerular filtration rate <60 mL/minute per 1.73 m2

 of 

body surface area. Covariate-adjusted ORs were estimated for PbB quartiles 2 (2.5–3.8 μg/dL), 3 (3.9– 

5.9 μg/dL), and 4 (6.0–56.0 μg/dL), relative to the 1st quartile (0.7–2.4 μg/dL). The ORs for elevated 
 

LEAD 87 

3. HEALTH EFFECTS 

serum creatinine concentration and chronic renal disease, but not in the normotensive group, exceeded 

unity in all quartiles of PbB and showed a significant upward trend with PbB. Covariate-adjusted ORs 

for chronic renal disease were: 2nd quartile, 1.44 (95% CI, 1.00–2.09); 3rd quartile, 1.85 (95% CI, 1.32– 

2.59); and 4th quartile, 2.60 (95% CI, 1.52–4.45). A 2-fold increase in PbB was associated with an OR of 

1.43 (95% CI, 1.20–1.72) for elevated serum creatinine concentration or 1.38 (95% CI, 1.15–1.66) of 

chronic renal disease. Covariates included in the models were age, gender and body mass index; systolic 

blood pressure; cardiovascular disease and diabetes mellitus; alcohol consumption and cigarette smoking; 

and household income, marital status, and health insurance. A stronger association between PbB and 

depressed glomerular filtration rate (i.e., creatinine clearance) also was found in people who have 

hypertension, compared to normotensive people, in the smaller prospective study (Tsaih et al. 2004). 

An analysis of relationships between PbB and renal creatinine clearance was conducted as part of the 

Belgian Cadmibel Study (Staessen et al. 1992). The Cadmibel Study was a cross-sectional study, 

originally intended to assess health outcomes from cadmium exposure. Subjects recruited during the 

period 1985–1989 resided for at least 8 years in one of four areas (two urban, two rural) in Belgium. One 

of the urban and rural areas had been impacted by emissions from heavy metal smelting and processing. 

PbB and creatinine clearance measurements were obtained for 965 males (mean age, 48 years) and 

1,016 females (mean age, 48 years). Mean PbB was 11.4 μg/dL (range, 2.3–72.5) in males and 7.4 μg/dL 

(range, 1.7–6.0) in females. Based on multivariate linear regression (with log-transformed PbB), covariate-adjusted creatinine clearance was significantly associated with PbB in males. A 10-fold increase 

in PbB was associated with a decrease in creatinine clearance of 13 mL/minute in males and 

30 mL/minute in females. This would represent a decrease in creatinine clearance of approximately 13% 

from the group mean of 99 mL/minute in males, or 38% from the group mean of 80 mL/minute in 

females. Covariates included in the regression model were age and body mass index; urinary γ-glutamyltransferase activity; and diuretic therapy. A logistic regression model was applied to the data to examine 

the relationship between risk of impaired renal function, defined as less than the 5th percentile value for 

creatinine clearance in subjects who were not taking analgesics or diuretics (<52 mL/minute in males or 

48 mL/minute in females). A 10-fold increase in PbB was associated with a covariate-adjusted risk for 

impaired renal function of 3.76 (95% CI, 1.37–10.4; p=0.01). Covariates included in the logistic model 

were age and body mass index; urinary γ-glutamyltransferase activity; diabetes mellitus; and analgesic or 

diuretic therapy. 

A cross-sectional study of civil servants in London examined relationships between PbB and serum 

creatinine concentration (Staessen et al. 1990). Participants included 398 males (mean age, 47.8 years) 
 

 

LEAD 88 

3. HEALTH EFFECTS 

and 133 females (mean age, 47.5 years). Mean PbB was 12.4 μg/dL in males and 10.2 μg/dL in females. 

Serum creatinine concentration was significantly (p=0.04, linear regression with log-transformed PbB) 

associated with PbB in males, but not in females. The association was no longer significant after 

excluding two subjects from the analysis who had serum creatinine concentrations exceeding 180 μmol/L 

(2 mg/dL). The predicted increase in serum creatinine concentration per 25% increase in PbB was 

0.6 μmol/L (95% CI, -0.2–1.36). Although several covariates were considered in the analysis of the 

blood lead concentration data, covariates included in the regression model for serum creatinine 

concentration were not reported. 

The Agency for Toxic Substances and Disease Registry (1995) conducted a cross-sectional analysis of 

possible associations between lead exposure and serum creatinine concentration or BUN among residents 

of four NPL sites (Granite City, Illinois; Galena, Kansas; Joplin, Mississippi; Palmerton, Pennsylvania). 

The study consisted of a target group of NPL site residents (n=1,645) and a comparison group (n=493) 

that had similar distributions of gender, age, SES, education, and housing age. Geometric mean blood 

lead concentrations were 4.26 μg/dL (SD±0.71) in the target group and 3.45 μg/dL (SD±0.74) in the 

comparison group. Multivariate regression analyses (linear and logistic) of subsets of the study group 

(e.g., age strata) did not reveal significant associations between PbB and either serum creatinine 

concentration or BUN. 

Cross-sectional Studies—Occupational Exposures. As part of a longitudinal study of health outcomes 

among Korean lead workers, cross-sectional studies of potential associations between biomarkers of lead 

exposure (PbB, tibia lead, DMSA evoked urinary lead) have been conducted (Weaver et al. 2003a, 2003b, 

2005a, 2005b). The cross-sectional study of the first of three longitudinal evaluations included 

803 current and former lead workers (age range, 18–65 years; 639 males) and 135 controls (age range, 

22–60 years; 124 males), enrolled in the study during the period 1997–1999 (Weaver et al. 2003a, 2005a). 

Mean PbB of the lead workers was 32 μg/dL (range, 4–86 μg/dL); mean tibia lead was 37 μg/g (range, 

-7–338 μg/dL). Significant associations were evident in the upper age tertile (>46 years), but not at 

younger ages, between increasing covariate-adjusted tibia lead and increasing serum creatinine (β, 

0.0008 mg/dL per μg/dL; p<0.01) and increasing serum uric acid concentration (β, 0.0036 mg/dL per 

μg/dL; p=0.04); and between increasing PbB and increasing BUN (β, 0.0615 mg/dL per μg/dL; p<0.01). 

Covariates included age, gender, body mass index, current/former exposure status, and hypertension. In a 

subsequent cross-sectional study of the third evaluation of this same study group (n=652), performed 

during the period 1999–2001, similar age-dependent outcomes were observed (Weaver et al. 2005b). 

Significant associations between increasing serum creatinine and increasing tibia lead (β, 0.000451; 
 

 

 

LEAD 89 

3. HEALTH EFFECTS 

p=0.04), patella lead (β, 0.000147; p=0.04), or PbB (β, 0.001266; p=0.02) were evident in the upper age 

tertile (46 years). 

Experimental studies in laboratory animals have shown that exposures to lead that result in blood lead 

concentrations exceeding 50 μg/dL can depress glomerular filtration rate and renal blood flow and 

produce glomerular sclerosis (Aviv et al. 1980; Khalil-Manesh et al. 1992a, 1992b). 

Endocrine Effects. Occupational studies provide evidence for an association between high exposures 

to lead and changes in thyroid, pituitary, and testicular hormones. There are a number of inconsistencies 

in the available findings that are related in part to small sample sizes, possible confounding effects by age, 

tobacco use, and other factors, responses that remained within reference limits, and differences in 

laboratory methods of hormonal evaluation. Changes in circulating levels of thyroid hormones, 

particularly serum thyroxine (T4) and thyroid stimulating hormone (TSH), generally occurred in workers 

having mean PbB ≥40–60 μg/dL. Altered serum levels of reproductive hormones, particularly follicle 

stimulating hormone (FSH), luteinizing hormone (LH), and testosterone, have been observed at PbB ≥30– 

40 μg/dL. Some data, mainly results of tests of hormonal stimulation tests, suggest that the changes in 

thyroid and testicular hormones are secondary to effects of lead on pituitary function. 

Decreases in serum T4 were found in studies of workers with very high PbB (Cullen et al. 1984; Robins et 

al. 1983). Serum T4 and estimated free thyroxine (EFT4) were reduced in three of seven men who had 

symptomatic occupational lead poisoning and a mean PbB of 87.4 μg/dL (range, 66–139 μg/dL) (Cullen 

et al. 1984). There were no effects on thyroid binding globulin (TBG), total triiodothyronine (T3), TSH, 

or TSH response to thyrotrophin releasing hormone (TRH) stimulation. A clinical study similarly found 

subnormal (low to borderline) serum T4 and EFT4 values in 7 of 12 (58%) foundry workers with a mean 

PbB of 65.8 μg/dL (Robins et al. 1983). However, in a cross-sectional study of 47 men from the same 

foundry with PbB <50 μg/dL and a mean employment duration of 5.8 years, only 12 (26%) had evidence 

of reduced T4 and EFT4 (Robins et al. 1983). Serum T3 and TSH levels (only measured in the clinical 

study) and thyroid binding capacity (TBC, only measured in the cross-sectional study) were normal, and 

regression analyses showed no clear correlation between T4 or EFT4 and PbB. The thyroid effects in 

these studies (i.e., reduced T4 with inappropriately low TSH or poor TRH response) are consistent with a 

primary pituitary or hypothalamic insufficiency. Evaluation of 176 Kenyan male car battery factory and 

secondary lead smelter workers (mean PbB, 56 μg/dL; mean lead exposure duration 7.6±5.1 years) 

showed that serum T4, FT4, T3, and TSH levels were similar in subgroups of 93 workers with PbB 

≤56 μg/dL and 83 workers with PbB ≥56 μg/dL (Tuppurainen et al. 1988). Regression analysis found no 
LEAD 90 

3. HEALTH EFFECTS 

significant correlations between PbB and any of the thyroid measures. However, there were weak but 

statistically significant negative correlations between duration of exposure and levels of T4 and FT4, and 

these associations were stronger in the ≥56 μg/dL subgroup. 

Several studies found alterations in serum thyroid hormone and TSH in the PbB range of 40–60 μg/dL 

(Gustafson et al. 1989; López et al. 2000; Singh et al. 2000a). Mean serum levels of T4 and FT4 were 

significantly higher in 75 male lead-battery factory workers with a mean PbB of 50.9 μg/dL (mean work 

duration 6.1 years) than in 62 unexposed referents (no workplace lead exposure) with a mean PbB of 

19.1 μg/dL (López et al. 2000). There were no group differences in serum T3 and TSH. Regression 

analyses showed significant positive correlations for serum T4, FT4, T3, and TSH vs. PbB in the range 8– 

50 μg/dL, and significant negative correlations for T4 and T3 vs. PbB in the range 50–98 μg/dL, indicating 

a drop in circulating hormones at PbBs around 50 μg/dL that is consistent with the results of the Cullen et 

al. (1984) and Robins et al. (1983) studies cited above. There were no significant associations between 

PbB or hormone levels vs. time in workplace or age, and all hormone values were within normal 

reference ranges. Gustafson et al. (1989) measured serum levels of T3, T4, and TSH in 25 male lead 

smelter workers (mean PbB, 39 μg/dL) and 25 matched controls without occupational lead exposure 

(mean PbB, 4 μg/dL). There were no overall group differences in the three thyroid measures, although 

serum TSH was significantly increased in the most heavily exposed individuals (mean PbB, >41 μg/dL). 

Analysis of a subgroup that reported no intake of selenium pills showed that serum T4 was significantly 

higher in the exposed workers. Additionally, serum T4 was significantly increased in a subgroup of 

14 workers under the age of 40 (mean PbB, 39 μg/dL). Serum T4, T3, and TSH were assessed in 58 male 

petrol pump workers or automobile mechanics who had a mean PbB of 51.9 μg/dL and mean lead 

exposure duration of 13 years (Singh et al. 2000a). Comparison with an unexposed control group of 

35 men (mean PbB, 9.5 μg/dL) showed no significant differences in T4 and T3 levels, although T3 was 

significantly lower in a subgroup of 17 workers with a longer mean exposure time (17.5 years) than in 

41 workers with shorter exposure (2.4 years). Serum TSH was significantly higher in the exposed 

workers compared to controls, as well as in a subgroup of 50 workers with higher mean PbB (55.4 μg/dL) 

than in 8 workers with a lower mean PbB (31.5 μg/dL), although all TSH values remained within the 

normal laboratory range. 

Workers with PbBs of approximately 20–30 μg/dL showed no clear indications of thyroid dysfunction 

(Dursun and Tutus 1999; Erfurth et al. 2001; Refowitz 1984; Schumacher et al. 1998). Serum T4, EFT4, 

and TSH were assessed in a cross-sectional study of 151 male lead smelter workers that examined doseresponse relationships across specifically defined levels of lead exposure (Schumacher et al. 1998). The 
LEAD 91 

3. HEALTH EFFECTS 

mean duration of employment in lead-exposed areas was 4.3 years, the mean current PbB was 24 μg/dL 

(15% exceeded 40 μg/dL), and the mean PbB for the preceding 10 years was 31 μg/dL (26% exceeded 

40 μg/dL). The thyroid hormones were evaluated in relation to four levels of current and 10-year 

cumulative lead exposure (<15, 14–24, 25–39, and ≥40 μg/dL). Mean levels of T4, EFT4, and TSH were 

similar in all exposure categories and within laboratory normal limits for both current and cumulative 

exposure. There was no evidence of an exposure response with increasing lead burden, and controlling 

for age and alcohol consumption did not significantly alter the findings. Erfurth et al. (2001) found that 

serum concentrations of FT4, FT3, and TSH were similar in groups of 62 secondary lead smelter workers 

(median PbB, 33.2 μg/dL, median exposure time, 8 years) and 26 matched referents with no known 

occupational exposure to lead (median PbB, 4.1 μg/dL). There were no significant associations between 

these hormones and PbB, plasma lead, and bone lead levels after adjustment for age. Additionally, there 

was no difference in TSH response to TRH stimulation in subgroups of 9 exposed workers (median PbB, 

35.2 μg/dL) and 11 referents (median PbB, 4.1 μg/dL). There were no adverse changes in thyroid 

hormones in workers with a mean PbB of 17.1 μg/dL who were exposed to lead for an average of 

16.70 years (range, 1–22 years) in a Turkish metal powder-producing factory (Dursun and Tutus 1999). 

Comparison with 30 subjects from the general population (mean PbB, 2.37 μg/dL) showed that serum 

levels of T4, FT4, and FT3, but not T3 or TSH, were statistically significantly increased in the workers. 

However, all five thyroid measures were within normal reference limits. Refowitz (1984) found no 

correlation between levels of T4 or EFT4 and PbB in 58 secondary copper smelter workers in which the 

preponderance of PbBs were below 40 μg/dL. 

No significant effects of lead on thyroid function have been found in children, but the number and/or 

quality of the available studies do not allow drawing firm conclusions. Thirty-six male and 32 female 

children ranging in age from 11 months to 7 years (median age of 25 months) took part in a study of the 

effects of lead exposure on thyroid function in inner city children (Siegel et al. 1989). PbB, T4, and 

T4 uptake were determined, and sex, race, socioeconomic status, and hemoglobin were also assessed for 

each child. The PbBs ranged from 2.0 to 77 μg/dL, with a mean of 25 μg/dL. Forty-four percent of the 

children had moderately elevated lead levels (>24 μg/dL). Linear regression analysis revealed that there 

was no association between PbB and either T4 or FT4. The results of this study are consistent with the 

findings of a small study of 12 children (2–5 years old) from the Omaha Lead and Poison Prevention 

Program with PbBs in the range of 41–72 μg/dL (Huseman et al. 1992). The authors found that basal 

TSH, T4, T3, and prolactin were within normal ranges. Also, TSH and prolactin responses to TRH, and 

cortisol responses to insulin were not altered by lead. However, Huseman et al. (1992) did find that the 

peak human growth hormone (HGH) response to an L-dopa and insulin test, although within normal 
LEAD 92 

3. HEALTH EFFECTS 

limits, was significantly lower in children with toxic levels of lead compared with the peak response in 

children with lower PbB (<30 μg/dL). Furthermore, the mean 24-hour HGH in children with high PbB 

was not only significantly lower than those of normal children, but was comparable with that of children 

with HGH neurosecretory dysfunction. High PbB was also associated with a lower mean insulin-like 

growth factor I. A study of male adolescents in Turkey reported that 42 subjects who worked at auto 

repair workshops and had a mean PbB of 7.3 μg/dL (SD±2.92 μg/dL) had a significantly lower (p<0.05) 

serum level of FT4 (1.12 ng/mL) compared to 55 control subjects (1.02 ng/mL) with a mean PbB of 

2.1 μg/dL (SD±1.24 μg/dL) (Dundar et al. 2006). There were no significant effects on serum FT3 or TSH 

levels or in thyroid volume. Based on the small difference in FT4 values between exposed and unexposed 

subjects, the lack of increase in TSH, and the fact that many other chemicals normally present at auto 

repair workshops could have influenced the results, the significance of these findings is unknown. 

Effects of occupational exposure to lead on pituitary gonadotrophins and testicular hormones were 

investigated in male workers (see also Section 3.2.5, Reproductive Effects). Changes in serum FSH, LH, 

and testosterone were found in several studies of highly exposed workers, but there are no clear patterns 

of response. The preponderance of evidence is consistent with an indirect effect(s) of lead on the 

hypothalamic-pituitary axis (i.e., a disruption of gonadotrophin secretions), although direct effects on 

testicular hormonal production are possible. Plasma concentrations of FSH, LH, testosterone, and 

prolactin were measured in a study of 122 male lead battery factory workers with a mean current PbB of 

35.2 μg/dL and mean exposure duration of 6 years (Ng et al. 1991). Levels of FSH and LH were 

significantly increased compared to a control group of 49 nonexposed workers (8.3 μg/dL), and 

concentrations of these hormones increased with increasing PbB in the range of 10–40 μg/dL. Age was 

not a confounding factor, although duration of exposure affected the results. Workers exposed for 

<10 years had significantly increased LH and FSH and normal testosterone and prolactin levels, whereas 

those exposed for ≥10 years had increased testosterone and normal LH, FSH, and prolactin. Rodamilans 

et al. (1988) assessed serum levels of LH, FSH, testosterone, and steroid binding globulin (SBG) in 

23 male lead smelter workers with PbB in the range of 60–80 μg/dL. Comparison with an unexposed 

group of 20 men (PbB 17 μg/dL) showed that serum LH was significantly increased in the workers and 

that the magnitude of the effect did not increase with duration of exposure. A significantly lower free 

testosterone index (testosterone/SBG ratio) in the workers exposed for 1–5 years and significant changes 

in serum testosterone (lower), SGB (higher), and free testosterone index (lower) in the workers exposed 

for >5 years indicated an exposure duration-related effect on serum testosterone. 
LEAD 93 

3. HEALTH EFFECTS 

Other studies of male workers have found different results. Erfurth et al. (2001) found no significant 

differences in basal serum levels of FSH, LH, prolactin, testosterone, sex hormone binding globulin, and 

cortisol in groups of 11 lead male workers (median PbB, 35.2 μg/dL) and 9 matched referents (median 

PbB, 4.1 μg/dL), although there was a tendency toward lower serum FSH concentrations in the exposed 

group. Additionally, measurements of serum FSH, LH, and prolactin after administration of gonadotrophin-releasing hormone (GRH) showed that the level of stimulated FSH was significantly lower in the 

workers. None of the basal or stimulated hormone levels correlated with lead exposure indices (blood 

lead, plasma lead, or bone lead) or age. Gustafson et al. (1989) found that plasma FSH, plasma LH, and 

serum cortisol levels were lower in male workers (mean PbB, 39 μg/dL) than in unexposed controls 

(mean PbB, 4 μg/dL); however, all hormone values were within normal reference limits. Serum FSH and 

LH values were similar in 98 male lead acid battery workers with a mean PbB of 51 of μg/dL and a group 

of 85 nonoccupationally exposed subjects (mean PbB, 20.9 μg/dL) (Gennart et al. 1992a), although the 

high PbB in the comparison group might have obscured detection of an effect. Cullen et al. (1984) found 

increased serum FSH and LH and borderline low serum testosterone levels in one of seven men with 

symptomatic occupational lead poisoning and a mean PbB of 87.4 μg/dL. Although serum testosterone 

concentration was normal in most of these patients, five had defects in spermatogenesis and six had 

subnormal glucocorticoid production. Serum testosterone levels were significantly lower in groups of 

male workers with lead poisoning (n=6, mean PbB, 38.7 μg/dL) and lead exposure (n=4, mean PbB, 

29.0 μg/dL) than in an unexposed control group (n=9, mean PbB 16.1 μg/dL), but testosterone-estradiolbinding globulin capacity and serum levels of estradiol, LH, FSH, and prolactin were normal (Braunstein 

et al. 1978). Both lead groups had appropriate responses for serum testosterone and FSH to stimulation 

by human chorionic gonadotrophin (HCG) and clomiphene, and serum FSH to stimulation by gonadotrophin releasing hormone (GRH) and clomiphene citrate. The lead exposed group also had a normal LH 

response to challenge by GRH and clomiphene citrate, although the LH response was suppressed in the 

lead poisoned group. Both lead groups had reduced estradiol response to stimulation by clomiphene 

citrate, although there was no effect following stimulation by HCG. Testicular biopsies performed on the 

two most heavily exposed men showed oligospermia and testicular lesions. Further information 

regarding effects of lead on sex hormone levels in humans and animals can be found in Section 3.2.5. 

Information is also available on the effects of lead exposure on serum erythropoietin (EPO) concentration. 

EPO is a glycoprotein hormone that regulates both steady-state and accelerated erythrocyte production. 

More than 90% of EPO is produced in the proximal renal tubules. Serum EPO was evaluated in a group 

of women from the Yugoslavia Prospective Study (see Section 3.2.4 for a detailed description of the 

Yugoslavia Prospective Study) in mid-pregnancy (n=5) and at time of delivery (n=48) (Graziano et al. 
LEAD 94 

3. HEALTH EFFECTS 

1991). Analysis of the variance showed that women with higher PbB had inappropriately low levels of 

EPO both at mid-pregnancy and at delivery. Graziano et al. (1991) speculated that lead may interfere 

with the mechanism of EPO biosynthesis, which appears to begin with increased calcium entry into the 

renal cells. In a study of lead workers, serum EPO levels from two groups of 28 exposed workers were 

significantly lower than in 113 control subjects (Romeo et al. 1996). Mean PbBs in the two exposed 

groups and in the controls were 38.3, 65.1, and 10.4 μg/dL, respectively. However, there was no 

correlation between PbB and EPO in any group. Hemoglobin levels were not affected by lead and were 

comparable among the three groups. In an additional study of male lead workers (n=20) with and without 

anemia, those with PbBs ≥60 μg/dL showed a significant reduction in erythroid progenitor cells and in 

granulocyte/macrophage progenitor cells (Osterode et al. 1999). However, EPO was in the normal range 

and did not increase in the presence of lead-induced anemia. Osterode et al. (1999) suggested that leadinduced kidney toxicity might be the reason why EPO was not adequately generated at higher PbB. 

Ocular Effects. Lead is known to affect visual evoked potentials in adults and children (see 

Section 3.2.4 and review by Otto and Fox [1993]), but less is known regarding effects of lead on other eye 

structures. Recently, Schaumberg et al. (2004) examined the relationship of cumulative lead exposure 

with the development of cataracts in a group of 642 participants in the Normative Aging Study. Lead 

exposure was assessed by measuring PbB (mean, 5 μg/dL; range, 0–35 μg/dL) and lead in the tibia (mean, 

20 ppm; range, 0–126 ppm) and patella (mean, 29 ppm; range, 0–165 ppm). The mean age of the subjects 

was 69 years (range, 60–93 years). A total of 122 cases of cataract were found. After controlling for age, 

tibia lead, but not patella lead, was a significant predictor of cataract. Also, PbB was not associated with 

increased risk of developing cataracts. Schaumberg et al. (2004) suggested that lead might be disrupting 

the lens redox status by inducing oxidative damage to lens epithelial cells. Changes consistent with lens 

opacity also were observed in Fisher 344 rats exposed to 2,000 ppm lead in the drinking water for 

5 weeks, which produced a mean PbB of approximately 30 μg/dL (Neal et al. 2005). Examination of 

two-dimensional protein spot patterns of the rats’ lenses showed significant alterations in the protein 

expression profile of both αA- and βA4-crystallins, alterations of which may decrease lens clarity through 

increased light scattering. The mechanism for this effect has not been elucidated. 

In their review on lead effects on visual function, Otto and Fox (1993) mention that earlier studies 

reported alterations of the electroretinogram (ERG) in lead workers. Rothenberg et al. (2002a) reported 

alterations in scotopic (rod-mediated) retinal function in a group of 45 children (7–10 years old) 

participants in the Mexico City Lead Study (Rothenberg et al. 2002a). These alterations, consisting of 

increased a- and b-waves, appeared to be a new form of rod dysfunction and were associated with 
LEAD 95 

3. HEALTH EFFECTS 

maternal blood lead levels measured during the first trimester of pregnancy; the threshold for the effect 

was 10.5 μg/dL. Alterations in rod function, evidenced by the appearance of central scotoma, also had 

been reported earlier in lead workers with moderate PbB (mean, 47 μg/dL) (Cavalleri et al. 1982). 

Changes in ERG components also have been reported in rats (Fox and Chu 1988; Fox and Farber 1988; 

Fox and Katz 1992; Fox and Rubinstein 1989) and monkeys exposed during development (Bushnell et al. 

1977; Kohler et al. 1997; Lilienthal et al. 1988, 1994). Tests conducted in monkeys >2 years after 

cessation of life exposure to lead revealed alterations in the ERG under scotopic conditions similar to 

those recorded during lead exposure, and at a time when PbB was below 10 μg/dL (Lilienthal et al. 1994). 

Since the alteration could be reproduced by treatment with dopamine antagonists, Lilienthal et al. (1994) 

suggested that the observed effects may be mediated by a permanent change of dopamine function. The 

series of studies from Fox and coworkers in the rat showed that low-level lead exposure during postnatal 

development has a detrimental effect on the rods of the retina, but not on cones. They also showed that 

developing and adult retinas exhibited qualitatively similar structural and functional alterations, but 

developing retinas were much more sensitive, and in both cases, alterations in retinal cGMP metabolism 

was the underlying mechanism leading to lead-induced ERG deficits and rod and bipolar cell death (Fox 

et al. 1997). Using a preparation of rat retina in vitro, Fox and coworkers demonstrated that rod mitochondria are the target site for calcium and lead and that these ions bind to the internal metal binding site 

of the mitochondrial permeability transition pore, which initiates a cascade of apoptosis in rods (He et al. 

2000). 

Other Systemic Effects. Lead interferes with the conversion of vitamin D to its hormonal form, 

1,25-dihydroxyvitamin D. This conversion takes place via hydroxylation to 25-hydroxyvitamin D in the 

liver followed by 1-hydroxylation in the mitochondria of the renal tubule by a complex cytochrome 

P-450 system (Mahaffey et al. 1982; Rosen and Chesney 1983). Evidence for this effect comes primarily 

from studies of children with high lead exposure. 

Lead-exposed children with PbBs of 33–120 μg/dL had marked reductions in serum levels of 1,25-dihydroxyvitamin D (Rosen et al. 1980). Even in the range of 33–55 μg/dL, highly significant depressions 

in circulating 1,25-dihydroxyvitamin D were found, but the most striking decreases occurred in children 

whose PbB was >62 μg/dL. In addition, children with PbB >62 μg/dL also had significant decreases in 

serum total calcium and ionized calcium and significant increases in serum parathyroid hormone. These 

conditions would tend to enhance production of 1,25-dihydroxyvitamin D; thus, the inhibition caused by 

lead may have been greater than was indicated by 1,25-dihydroxyvitamin D levels. Serum levels of 

1,25-dihydroxyvitamin D returned to normal within 2 days after chelation therapy. These results are 
LEAD 96 

3. HEALTH EFFECTS 

consistent with an effect of lead on renal biosynthesis of 1,25-dihydroxyvitamin D. A strong inverse 

correlation between 1,25-dihydroxyvitamin D levels and PbB was also found among children with PbB 

ranging from 12 to 120 μg/dL, with no change in the slope of the line at levels <30 μg/dL (Mahaffey et al. 

1982). 

Results obtained by Koo et al. (1991) indicate that low to moderate lead exposure (average lifetime PbB 

between 4.9 and 23.6 μg/dL, geometric mean, 9.8 μg/dL) of young children (n=105) with adequate 

nutritional status, particularly with respect to calcium, phosphorus, and vitamin D, had no effect on 

vitamin D metabolism, calcium and phosphorus homeostasis, or bone mineral content. The authors 

attributed the difference in results from those other studies to the fact that the children in their study had 

lower PbB (only 5 children had PbB >60 μg/dL and all 105 children had average lifetime PbB <45 μg/dL 

at the time of assessment) and had adequate dietary intakes of calcium, phosphorus, and vitamin D. They 

concluded that the effects of lead on vitamin D metabolism observed in previous studies may only be 

apparent in children with chronic nutritional deficiency and chronically elevated PbB. Similar 

conclusions were reached by IPCS (1995) after review of the epidemiological data. 

In general, data in animals support the findings in humans. For example, depression of plasma levels of 

1,25-dihydroxyvitamin D was observed in rats fed 0.82% lead in the diet as lead acetate for 7–14 days 

(Smith et al. 1981). High calcium diets protected against this effect. An additional finding was that lead 

blocked the intestinal calcium transport response to exogenous 1,25-dihydroxyvitamin D, but had no 

effect on bone response to the vitamin D hormone. Although the lead exposure and resulting PbB 

(≥174 μg/dL) were high in this study, the results provide support for the disturbances in vitamin D 

metabolism observed in children exposed to high levels of lead. 

3.2.3 Immunological and Lymphoreticular Effects 

Numerous studies have examined the effects of lead exposure on immunological parameters in lead 

workers and a smaller number of studies provide information on effects in members of the general 

population, including children. The results although mixed, give some indication that lead may have an 

effect on the cellular component of the immune system, while the humoral component is relatively 

unaffected. However, it should be noted that the clinical significance of these relationships is as yet 

unknown. 
LEAD 97 

3. HEALTH EFFECTS 

Workers exposed occupationally for 4–30 years, and whose PbB at the time of testing ranged from 25 to 

53 μg/dL (mean, 38.4 μg/dL), had serum concentrations of IgG, IgA, and IgM not significantly different 

from unexposed controls whose PbB at the time of testing ranged from 8 to 17 μg/dL (mean, 11.8 μg/dL) 

(Kimber et al. 1986). Alomran and Shleamoon (1988) also reported nonsignificant alterations in serum 

IgG and IgA levels in 39 workers exposed to lead oxides with a mean PbB of 64 μg/dL compared to 

19 unexposed subjects (PbB not provided). Another study found no alterations in serum IgA and IgM 

levels among 25 workers with a mean PbB of 74.8 μg/dL (range, 38–100 μg/dL) compared to 16.7 μg/dL 

(range, 11–30 μg/dL) among 25 controls; however, IgG was significantly reduced among the workers 

(Basaran and Ündeger 2000; Ündeger et al. 1996). A study of 145 lead-exposed male workers from a 

large secondary lead smelter in the United States with a median PbB of 39 μg/dL (range, 25–55 μg/dL) 

also found no significant differences in serum immunoglobulin levels between the workers and a group of 

84 unexposed workers with a mean PbB of <2 μg/dL (range, 2–12 μg/dL) (Pinkerton et al. 1998). Ewers 

et al. (1982) reported that lead workers with PbB of 21–90 μg/dL (median, 59 μg/dL) had more colds and 

influenza infections per year and had a significant suppression of serum IgM levels relative to a 

comparison group (median PbB, 11.7 μg/dL); neither serum IgA or IgG levels in workers were 

significantly different than in the comparison group. However, salivary IgA levels were significantly 

lower in the workers than in the control group. Secretory IgA is a major factor in the defense against 

respiratory and gastrointestinal infections (Koller 1985). A study of 606 Korean workers found that mean 

serum IgE levels were positively related to PbB in the range of <10–≥30 μg/dL (Heo et al. 2004). 

Alterations in response to T-cell mitogens also have been reported in lead workers. Mishra et al. (2003) 

studied three groups of workers (n=84) who had mean PbBs of 6.5, 17.8, and 128 μg/dL and found that 

lymphocyte proliferation to phytohemagglutinin (PHA) was inhibited relative to a control group; natural 

killer (NK) cell activity was unaffected. The lymphocytes from the workers studied by Alomran and 

Shleamoon (1988) (mean PbB, 64 μg/dL) also were significantly less responsive to stimulation by PHA 

and concanavalin A (con A) than those from the controls (PbB not provided), and the severity of the 

depression was related to the duration of exposure. Impaired response to T-cell mitogens was also 

reported among a group of 51 firearm instructors (Fischbein et al. 1993). Fifteen of the 51 firearm 

instructors had PbBs ≥25 μg/dL (mean 31.4 μg/dL), whereas the rest had a mean PbB of 14.6 μg/dL. In 

contrast, Kimber et al. (1986) reported that responses to PHA and NK cell activity were not altered in 

their study of workers whose mean PbB was 34.8 μg/dL, compared with an unexposed group with a mean 

PbB of 11.8 μg/dL. Pinkerton et al. (1998) found no alterations in lymphoproliferative responses to 

tetanus toxoid or in NK cell activity in workers with a median PbB of 39 μg/dL. It should be noted, 
LEAD 98 

3. HEALTH EFFECTS 

however, that firearm instructors are likely to be exposed to a number of metal haptens, such as nickel and 

antimony. 

Changes in T-cell subpopulations also have been reported. Ündeger et al. (1996) and Basaran and 

Ündeger (2000) described a significant decrease in the number of CD4+

 cells and C3 and C4 complement 

levels in workers with a mean PbB of 74.8 μg/dL. A significant decrease in percentage and number of 

CD3+

 and CD4+ cells also was observed in the study of firearm instructors, but other cell types including 

CD8+

, B-lymphocytes, or NK cells were not significantly altered relative to controls (Fischbein et al. 

1993). Pinkerton et al. (1998) found no significant differences in the percentages of CD3+

 cells, 

CD4+

 T cells, CD8+ T cells, B cells, or NK cells between exposed and unexposed workers, but reported 

that the percentage and number of CD4+

/CD45RA+ cells was positively associated with cumulative lead 

exposure. A study of 71 male workers engaged in the manufacturing of lead stearate who had a mean 

PbB of 19 μg/dL (range, 7–50 μg/dL) did not find significant differences in the number or percentages of 

CD4+

 or CD3+ cells between the lead-exposed workers and a control group (PbB not measured) of 

28 workers with no known occupational exposure to lead (Sata et al. 1998). However, the exposed 

workers had a significant reduction in the number of CD3+

CD45RO+ (memory T) cells and a significant 

increase in the percentage of CD8+

 cells compared to controls. Also, there was a significant correlation 

between the percentage of CD3+

CD45RA+ cells and PbBs in the exposed workers. At the time of the 

study, no subject had any signs or symptoms indicative of infection. 

A small study of 10 occupationally-exposed workers whose mean PbB was 33 μg/dL reported that 

chemotaxis of polymorphonuclear leukocytes (PMN), stimulated through a specific membrane receptor, 

was impaired, compared to a group of 10 unexposed subjects with a mean PbB of 12.6 μg/dL (Valentino 

et al. 1991). The investigators suggested that the reduction of chemotaxis might be partially due to a leadrelated modification of plasma membrane lipids, because PMN locomotion is influenced by fatty acids. 

The data available on the immunologic effects of lead exposure on children are sparse. In a comparison 

of 12 preschool children having a mean PbB of 45.3 μg/dL (range, 41–51 μg/dL) and elevated FEP with 

7 preschool children with a mean PbB of 22.6 μg/dL (range, 14–30 μg/dL), it was found that there were 

no differences between groups with respect to complement levels, immunoglobulin levels (IgM, IgG, 

IgA), or antitoxoid titers following booster immunization with tetanus toxoid (Reigart and Graher 1976). 

The small number of children and the relatively high PbB of the control group, as judged by current 

views, limit the conclusions that can be drawn from this report. Lutz et al. (1999) conducted a survey of 

the immune system’s function in a cohort of 279 children aged 9 months to 6 years, with PbB ranging 
LEAD 99 

3. HEALTH EFFECTS 

from 1 to 45 μg/dL. Exposure was due primarily to lead-based paint. Of the comprehensive number of 

parameters of cellular and humoral immunity evaluated, only the serum IgE levels showed a statistically 

significant relationship with PbB, as PbB increased so did IgE levels. Variables controlled for in this 

study included age, race, gender, nutrition, and socioeconomic level. The assessment of IgE levels in this 

and other studies is important because IgE is the primary mediator for type-I hypersensitivity and is 

involved in various allergic diseases such as asthma. Some investigators have suggested that lead may be 

a risk factor for childhood asthma (Dietert et al. 2002), although recently, Joseph et al. (2005) conducted a 

study of 4,634 children screened for lead from 1995 to 1998 and found that PbB was less a predictor of 

asthma than was race and did not affect the relationship of race to prevalent or incident asthma. IgE 

levels were not monitored in the study. 

A study of Chinese children (3–6 years old) also examined the association between PbB and serum IgG, 

IgM, and IgE levels (Sun et al. 2003). The cohort consisted of 38 children with PbB ≥10 μg/dL (highlead group) and 35 children with PbB <10 μg/dL (controls). No significant association between 

immunoglobulins and PbB was found for the entire group (n=73). However, when the cohort was divided 

by sex, IgG and IgM were significantly lower and IgE was significantly higher in high-dose females 

(n=16) than in control females (n=17); no such relationship was seen among males. A study of 

374 French mother-infant pairs reported a significant correlation (p<0.001) between infant hair level and 

cord blood IgE levels (Annesi-Maesano et al. 2003). In this cohort, mean PbB was relatively high, 

96 μg/dL (SD, 58 μg/dL) in the mothers and 67 μg/dL (SD, 48 μg/dL) in cord blood. No significant 

association was found between placental lead level or cord PbB and IgE levels. Further suggestive 

evidence for an association between IgE and lead burden is provided by a study of 331 German children 

(7–8 years of age) with a geometric mean PbB of 2.7 μg/dL, which found a significant association 

(p<0.05) between PbB and increased serum IgE levels (Karmaus et al. 2005). Analysis of stratified data 

showed that the highest IgE levels were observed in the children with PbB in the range between 2.8– 

3.4 and >3.4 μg/dL. No significant associations were seen between PbB and serum levels of IgA, IgG, or 

IgM (Karmaus et al. 2005). 

A small study of 70 Chinese children (3–6 years old) reported that 35 of them with a mean PbB of 

14.1 μg/dL (SD, 4.0 μg/dL) had a significantly lower (p<0.01) serum levels of CD4+ cells than 

35 children with a mean PbB of 6.4 μg/dL (SD, 1.3 μg/dL) (Li et al. 2005). There were no significant 

differences between the two groups regarding B, CD3+, CD8+, or NK cells. Sarasua et al. (2000) 

conducted a much bigger study of 2,041 children and adults who lived in areas with elevated soil levels of 

cadmium and lead (n=1,561) or in comparison communities (n=480) in the United States. Mean blood 
LEAD 100 

3. HEALTH EFFECTS 

lead levels were 7 μg/dL for participants aged 6–35 months; 6 μg/dL for participants aged 36–71 months; 

4 μg/dL for participants aged 6–15 years, and 4.3 μg/dL for participants aged 16–75 years. Parameters 

monitored included IgA, IgG, and IgM, and peripheral blood lymphocyte phenotypes (T cells B cells, NK 

cells, and CD4/CD8 subsets). The results of the multivariate analyses showed no significant differences 

in any of the immune marker distributions attributed to lead for subjects over 3 years of age. However, in 

children under 3 years, there were small but significant associations between increased PbB, particularly 

in those over 15 μg/dL, and increases in IgA, IgG, IgM, and circulating B-lymphocytes. 

Many studies have been published on the effects of lead on immune parameters in animals. Developing 

organisms appear to be more sensitive than adult animals and a number of studies have been designed to 

determine critical windows of vulnerability during development, including fetal development. Studies 

conducted in the late 1970s showed that prenatal and postnatal exposure of rats to lead leading to a PbB 

of approximately 29 μg/dL induced several alterations in the offspring tested at 35–45 days of age, 

including depression of antibody responses to sheep red blood cells, decreased serum IgG (but not IgA or 

IgM) levels, decreased lymphocyte responsiveness to mitogen stimulation, impaired DTH, and decreased 

thymus weights as compared with controls (Faith et al. 1979; Luster et al. 1978). In a later study, 

exposure of mice to lead through gestation and lactation resulted in reduced humoral immunity in the 

pups tested at 8 weeks of age (Talcott and Koller 1983). The DTH response was reduced but the 

difference with controls was not statistically significant. Blood lead levels were not available in this 

study. Miller et al. (1998) compared responses of the immune system between fetal and adult exposures. 

Exposure of pregnant rats to lead acetate in the drinking water during breeding and pregnancy resulted in 

PbBs of up to 112.0 μg/dL during pregnancy and lactation. Immune function was assessed in the 

offspring at 13 weeks of age and in the dams at 7–8 weeks postpartum. At these times, PbB was 

approximately 12 μg/dL in the dams and 0.68–2.63 μg/dL in offspring. Results from a comprehensive 

battery of tests showed no significant effects in lead-exposed dams. However, alterations were observed 

in the offspring and included decreased DTH response, altered cytokine production, and elevated serum 

IgE. Also, total leukocyte counts were significantly decreased, but analyses of subpopulation distribution 

revealed no significant treatment-related effects. These findings indicate that exposure in utero may 

result in alterations in immune parameters that persist beyond the exposure period when PbB had returned 

to the normal range. Similar results were reported in a study in mice in which immunotoxic changes were 

found at PbB <20 μg/dL (Snyder et al. 2000). Altered DTH responses were seen in adult mice at PbBs of 

87 μg/dL but not 49 μg/dL (McCabe et al. 1999) providing further evidence of increased sensitivity in 

developing animals compared to adults. More recent studies by Dietert and coworkers have shown that 

gestational exposure to lead resulting in PbB of approximately 38 μg/dL has a greater immunotoxic effect 
LEAD 101 

3. HEALTH EFFECTS 

in female offspring than in male offspring (Bunn et al. 2001a) and that the embryo is more sensitive if 

exposure occurs late in gestation (gestation day [Gd] 15–21) than earlier during gestation (Gd 3–9) (Bunn 

et al. 2001b). 

While many responses of the immune system observed in humans can be reproduced in experimental 

animals, recent observations from studies of perinatal exposure of animals suggest that caution should be 

exercised when extrapolating from animals to humans, since the immune functions depend on animal 

species, gender, and specially, developmental stage. 

3.2.4 Neurological Effects 

Neurological Effects in Adults. The most severe neurological effect of lead in adults is lead 

encephalopathy, which is a general term to describe various diseases that affect brain function. Early 

symptoms that may develop within weeks of initial exposure include dullness, irritability, poor attention 

span, headache, muscular tremor, loss of memory, and hallucinations. The condition may then worsen, 

sometimes abruptly, to delirium, convulsions, paralysis, coma, and death (Kumar et al. 1987). 

Histopathological findings in fatal cases of lead encephalopathy in adults are similar to those in children. 

Severe lead encephalopathy is generally not observed in adults except at extremely high PbBs (e.g., 

460 μg/dL [Kehoe 1961]). Other data (Smith et al. 1938) suggest that acute lead poisoning, including 

severe gastrointestinal symptoms and/or signs of encephalopathy, can occur in some adults at PbBs that 

range from approximately 50 to >300 μg/dL, but the data are somewhat ambiguous. 

Neurobehavioral Effects in Adults. Occupational exposure to lead has often been associated with 

signs of neurotoxicity. The literature contains numerous case reports and small cohort studies that 

describe a higher incidence of these symptoms, including malaise, forgetfulness, irritability, lethargy, 

headache, fatigue, impotence, decreased libido, dizziness, weakness, and paresthesia at PbBs that range 

from approximately 40 to 120 μg/dL following acute-, intermediate-, and chronic-duration occupational 

exposure (Awad El Karim et al. 1986; Baker et al. 1979, 1983; Campara et al. 1984; Haenninen et al. 

1979; Holness and Nethercott 1988; Lucchini et al. 2000; Marino et al. 1989; Matte et al. 1989; Pagliuca 

et al. 1990; Pasternak et al. 1989; Pollock and Ibels 1986; Rosenman et al. 2003; Schneitzer et al. 1990; 

Zimmerman-Tanselia et al. 1983). 
LEAD 102 

3. HEALTH EFFECTS 

In addition to the findings mentioned above, numerous studies have reported neuropsychological effects 

in lead workers. PbB in these studies ranged between 40 and 80 μg/dL. For instance, Parkinson et al. 

(1986) reported that lead workers exhibited greater levels of conflict in interpersonal relationships 

compared with unexposed workers. In another study, lead workers (45–60 μg/dL) performed much worse 

than workers with lower PbB on neurobehavioral tests, with general performance on cognitive and visualmotor coordination tasks and verbal reasoning ability most markedly impaired (Campara et al. 1984). 

Disturbances in oculomotor function (saccadic eye movements) in lead workers with mean PbB of 57– 

61 μg/dL were reported in a study by Baloh et al. (1979) and a follow-up by Spivey et al. (1980), and in a 

study by Glickman et al. (1984). Deficits in hand-eye coordination and reaction time were reported in 

190 lead-exposed workers (mean PbB, 60.5 μg/dL) (NIOSH 1974). Most of the workers had been 

exposed between 5 and 20 years. A similar study, however, reported no differences in arousal, reaction 

time, or grip strength between a reference group (mean PbB, 28 μg/dL) and workers who had been 

exposed to lead for 12±9.5 years (mean PbB, 61 μg/dL) (Milburn et al. 1976); however, the relatively 

high mean PbB in the referents may have obscured the results. Disturbances in reaction time, visual 

motor performance, hand dexterity, IQ test and cognitive performance, nervousness, mood, or coping 

ability were observed in lead workers with PbBs of 50–80 μg/dL (Arnvig et al. 1980; Haenninen et al. 

1978; Hogstedt et al. 1983; Mantere et al. 1982; Valciukas et al. 1978). Baker et al. (1983) reported 

impaired verbal concept formation, memory, and visual/motor performance among workers with PbB 

>40 μg/dL. Similar findings were reported in a cohort of 43 Venezuelan workers from a lead smelter who 

had a mean-employment duration of 4 years and a mean PbB of 42 μg/dL (Maizlish et al. 1995). The 

authors observed a significant association between altered mood states and current, peak, and timeweighted average (TWA) blood lead levels. Other parameters such as memory, perceptual speed, 

reaction time, and manual dexterity tended to be poorer with increasing exposure, but the magnitude of 

the effect was small. 

A study of 91 workers divided into three groups based on PbBs (<20, 21–40, and 41–80 μg/dL) noted that 

workers with high PbB concentrations showed evidence of impairment on tests of serial reaction time and 

category search, with only weak impairment on tasks measuring syntactic reasoning and delayed verbal 

free recall (Stollery et al. 1989, 1991). In general, the magnitude of the impairment correlated with PbB. 

The impairment of serial reaction time was the best predictor of PbB. The main deficit was a slowing of 

sensory motor reaction time, which was seen most clearly when the cognitive demands of the task were 

low. The response tended to be restricted to workers in the high PbB level group. A subsequent study of 

70 workers showed that lead impaired both the speed of making simple movements, as well as decisions, 

and suggested that decision slowing is due to central rather than peripheral factors (Stollery 1996). A 
LEAD 103 

3. HEALTH EFFECTS 

study of 427 Canadian lead workers whose mean current PbB was 27.5 μg/dL, and mean duration of 

employment was 17.7 years examined the correlation between short- and long-term measures of exposure 

to lead and performance on neuropsychological tests (Lindgren et al. 1996). Tasks that tested primarily 

visuomotor skills were significantly associated with a cumulative dose-estimate. Lindgren et al. (1996) 

indicated that the lack of an association between current blood lead or a TWA and neuropsychological 

performance was not necessarily inconsistent with other studies that found such an association since in 

their study the current mean PbBs were lower than in other studies. Current PbB as well as a TWA may 

have lacked the sensitivity to detect the decrement in performance. 

Ehle and McKee (1990) reviewed the methodology and conclusions of 14 published reports to determine 

if any consensus regarding neurobehavioral effects of low-level lead exposure in adults could be reached. 

A PbB of 60 μg/dL was set as the upper limit of exposure. The investigators concluded that “the 

methodologies in the studies reviewed were so varied and the cultures in which the studies were 

conducted so diverse that it is impossible to generalize across findings.” However, Ehle and McKee 

(1990) found some evidence that increased irritability and fatigue may lead to interpersonal problems. 

They also found suggestive evidence for subtle changes in the ability to process information quickly and 

for impaired ability to input and integrate novel information and to store this information in short-term 

memory. Balbus-Kornfeld et al. (1995) reviewed 21 studies for evidence that cumulative exposure to 

lead is associated with decreased performance in neurobehavioral tests in adults. Only three studies used 

a measure of cumulative exposure and two others used duration of exposure as a surrogate for cumulative 

exposure. The conclusion of the analysis was that “the current (at the time of the Balbus-Kornfeld study) 

scientific literature provides inadequate evidence to conclude whether or not cumulative exposure to or 

absorption of lead adversely affects performance in neurobehavioral tests in adults.” 

More recent studies of lead workers have reported significant associations between longitudinal 

decrements in cognitive function and past high PbB (Bleecker et al. 2005; Chen et al. 2005; Hänninen et 

al. 1998; Lindgren et al. 2003) and past high tibial lead (Schwartz et al. 2000b; Stewart et al. 1999). In 

the Lindgren et al. (2003) study, results of five neuropsychological measures showed that verbal memory 

was significantly better in a group with past high exposure followed by lower exposure than in a group 

with continuous high exposure, suggesting that reversibility of function may occur when PbB is 

maintained below 40 μg/dL. A small study of 27 Chinese lead workers also reported improvement in 

neurobehavioral performance over a period of 4 years during which the mean PbB was reduced from 

26 to 8 μg/dL (Chuang et al. 2005). From a battery of 10 neurobehavioral tests, finger tapping, pattern 

comparison reaction time, and memory (visual patterns) significantly improved during the study period. 
LEAD 104 

3. HEALTH EFFECTS 

Past high tibia lead (mean peak was 24 ppm), as a measure of cumulative lead dose, also was found 

significantly related to smaller total brain volume, frontal and total gray matter volume, and parietal white 

matter volume in 532 former organolead workers (Stewart et al. 2006). Of nine smaller regions of 

interest, higher tibia lead was associated with reduced volume of the cingulated gyrus and insula. 

Changes in brain morphology were assessed by brain MRI. Potential confounders assessed were age, 

systolic and diastolic blood pressure, smoking history, ApoE genotype, education, alcohol consumption, 

depression status, and race. Previous studies of this cohort had found tibia lead associated with a decline 

in cognitive function (Schwartz et al. 2000b; Stewart et al. 1999). 

Lucchini et al. (2000) reported that in a group of 66 workers with a mean current PbB of 27 μg/dL (range, 

6–61 μg/dL) and exposure of 11 years, current, but not cumulative, exposure was associated with 

impaired visual contrast sensitivity; results from neurobehavioral tests were unaffected. Barth et al. 

(2002) also found in a group of 47 workers a significant correlation between current exposure (mean PbB, 

31 μg/dL, range, 11–62 μg/dL) and cognitive deficits, particularly visuo-spatial abilities and executive 

functions related to the prefrontal cortex; however, no correlation was found between cumulative 

exposure measures and cognitive parameters. Recently, Schwartz et al. (2005) reported on a longitudinal 

study of the effects of lead on neurobehavioral test scores using both PbB and tibia lead as measures of 

dose. The cohort comprised 576 former and current lead workers who were evaluated from 1997 to 2001. 

At baseline (Schwartz et al. 2001), mean PbB was 32 μg/dL (SD±15 μg/dL) and mean tibia lead was 

37 ppm (SD±40 ppm). In the recent publication, the investigators developed regression models that 

separated recent from cumulative dose, acute from chronic effects, and cross-sectional from longitudinal 

relations. The results showed consistent associations of both PbB and tibia lead with current 

neurobehavioral test scores and also with declines in test scores over time; the associations with PbB were 

stronger than those with tibia lead. The stronger associations were mainly in executive abilities, manual 

dexterity, and peripheral vibration threshold; the magnitude across an interquartile range of exposure was 

equivalent to 1–5 years of aging. Schwartz et al. (2005) pointed out that: “the significant measurement 

error, especially for tibia lead and change measures, and the relatively short follow-up interval, could 

obscure the relations between lead dose and changes in test scores” and that this knowledge must be 

factored into their inferences about the likely health effects. 

Meyer-Baron and Seeber (2000) did a meta-analysis to determine the size of performance effects caused 

by exposure to inorganic lead that translated into PbBs <70 μg/dL. A total of 22 studies that met some 

minimum requirements were considered, and of these, 12 studies provided data to analyze the results of 

13 tests. The mean PbB in the lead workers ranged from 31 to 52 μg/dL and those of the controls ranged 
LEAD 105 

3. HEALTH EFFECTS 

from 6 to 20 μg/dL. Statistically significant effects were observed for the Block Design, Logical 

Memory, and Santa Ana (dominant hand) tests. The first two tests indicate impairments of central 

information processing, particularly for the functions visuo-spatial organization and short-term verbal 

memory; Santa Ana tests manual dexterity. Meyer-Baron and Seeber (2000) stated that the extent of 

decreased performance was comparable to changes of performance that can be expected during aging of 

up to 20 years. Goodman et al. (2002) conducted a meta-analysis of 22 studies that met inclusion criteria. 

The PbB among the study subjects ranged from 24 to 63 μg/dL for exposed and from 0 to 28 μg/dL for 

unexposed workers. Only 2 tests (Digit Symbol and D2) out of 22 neurobehavioral tests analyzed showed 

a significant effect between exposed and unexposed workers. Digit Symbol evaluated motor persistence, 

sustained attention, response-speed, and visuo-motor coordination, whereas D2 requires visual selectivity 

at a fast speed on a repetitive motor response task. The tests that were found altered in the Meyer-Baron 

and Seeber (2000) study were not significantly affected in the analysis of Goodman et al. (2002). The 

latter investigators concluded that the available data are inconclusive and unable to provide adequate 

information on the neurobehavioral effects of moderate PbB. 

In summary, in studies where adults were exposed occupationally to lead, a number of neurobehavioral 

parameters were reportedly affected. Although as Goodman et al. (2002) pointed out, the lack of true 

measures of pre-morbid state, observer bias, and publication bias affect the overall assessment, the 

preponderance of the evidence indicates that lead is associated with neurobehavioral impairment in adult 

workers at PbBs below 70 μg/dL. 

Krieg et al. (2005) used data from the NHANES III to assess the relationship between PbB in adults and 

performance on the three computerized neurobehavioral tests included in the survey: simple reaction 

time, symbol-digit substitution, and serial-digit learning. The age of the participants ranged from 20 to 

59 years old and a total of 4,937 completed all three tests. The study also evaluated 26 previously 

published cross-sectional occupational studies conducted in various countries that used the same 

neurobehavioral tests included in the survey. Potential confounders evaluated in the analysis included 

sex, age, education, family income, race/ethnicity, computer or video game familiarity, alcohol use, test 

language, and survey phase. In the NHANES III, the PbB of those taking the neurobehavioral tests 

ranged from 0.7 to 42 μg/dL and the geometric and arithmetic means were 2.5 and 3.3 μg/dL, 

respectively. The results showed no statistically significant relationships between PbB and 

neurobehavioral test performance after adjustment for confounders. In the occupational studies, the mean 

PbB in the controls was 11.4 μg/dL (range, 3.7–20.4 μg/dL), whereas the mean in the exposed groups was 

41.1 μg/dL (range, 24.0–72 μg/dL). The groups exposed to lead in the occupational studies consistently 
LEAD 106 

3. HEALTH EFFECTS 

performed worse than control groups on the simple reaction time and digit-symbol substitution tests. 

Some possible explanations for the lack of association between PbB and neurobehavioral scores in the 

survey mentioned by Krieg et al. (2005) include lack of toxicity of lead in adults at the levels investigated, 

a sample size or study design that did not allow enough precision to detect a relationship, or 

neurobehavioral tests that are not sensitive to the toxicity of lead at the levels investigated. 

The effects of lead exposure on neurobehavioral parameters in nonoccupational cohorts of older persons 

also have been evaluated. Muldoon et al. (1996) conducted a wide range of cognitive tests designed to 

assess memory, language, visuo-spatial ability, and general intellectual status, as well as sensorimotor 

function in a group of 530 female participants in the Study of Osteoporotic Fractures. The cohort 

consisted of 325 rural dwellers and 205 urban dwellers with geometric mean PbB of 4.5 μg/dL and 

5.4 μg/dL, respectively; the overall range was 1–21 μg/dL. The corresponding mean ages were 71.1 and 

69.4 years. For the group, the scores on the various tests were average, consistent with normal values 

reported for older women. PbB showed a significant inverse association with performance only among 

the rural dwellers. After adjusting for age, education, and tobacco and alcohol consumption, women with 

PbB ≥8 μg/dL performed significantly worse in tests of psychomotor speed, manual dexterity, sustained 

attention, and mental flexibility than women with PbB ≤3 μg/dL. Similar results were found for reaction 

time tests after further adjusting for history of diabetes and/or arthritis. A similar study was conducted in 

a cohort of 141 men participants in the Normative Aging Study (Payton et al. 1998). In this study, in 

addition to PbBs, lead in bone (tibia and patella) was also measured. The mean PbB among the 

participants was 5.5 μg/dL (range not provided), and the mean age was 66.8 years. Tibial and patellar 

bone lead showed a stronger correlation with each other than either of them with blood lead. After 

adjusting for age and education, the results showed that men with higher PbB recalled and defined fewer 

words, identified fewer line-drawn objects, and required more time to attain the same level of accuracy on 

a perceptual comparison test as men with the lowest level of PbB. In addition, men with higher blood and 

tibial lead copied spatial figures less accurately, and men with higher tibial lead had slower response for 

pattern memory. The results showed that PbB was the strongest predictor of performance on most tests. 

Also of interest was the finding that lead in the tibia, which changes at a slower rate, showed more 

significant relationships with cognitive test scores than patellar bone lead, which changes more rapidly. 

A more recent study of 526 participants of the Normative Aging Study with a mean age of 67.1 years and 

mean PbB of 6.3 μg/dL reported that patellar lead was significantly associated with psychiatric symptoms 

such as anxiety, depression, and phobic anxiety (Rhodes et al. 2003). In an additional study of Normative 

Aging Study participants (mean PbB, 4.5 μg/dL; mean patella Pb, 29.5 ppm), it was found that both bone 
LEAD 107 

3. HEALTH EFFECTS 

and blood lead were associated with poor test performance (Weisskopf et al. 2004; Wright et al. 2003c). 

According to the investigators, these findings are consistent with the theory that bone lead chronically 

remobilizes into blood, thus accelerating cognitive decline. In yet an additional study, Shih et al. (2006) 

reported that in a group of 985 of sociodemographically diverse urban-dwelling adults in the United 

States (mean age, 59.4 years) higher tibia lead levels were consistently associated with worse 

performance in tests of cognitive function after adjusting for confounders; no such association was found 

with PbB. Mean tibia lead was 18.7 ppm (SD±11.2 ppm) and mean PbB was 3.5 μg/dL (SD±2.2 μg/dL). 

An increase in one interquantil range of tibia lead was equivalent to 2.2–6.1 more years of age across the 

tests conducted, the average tibia lead effects was 36% of the age effect. Shih et al. (2006) suggested 

that, in the population studied, a proportion of what was termed normal age-related decrements in 

cognitive function may be attributable to neurotoxicants such as lead. 

Peripheral Physiological Effects in Adults. There are numerous studies available on peripheral 

nerve function that measured the conduction velocity of electrically stimulated nerves in the arm or leg of 

lead workers. Representative studies are summarized below. A prospective occupational study found 

decreased nerve conduction velocities (NCVs) in the median (motor and sensory) and ulnar (motor and 

sensory) nerves of newly employed high-exposure workers after 1 year of exposure and in the motor 

nerve conduction velocity of the median nerve of this group after 2 or 4 years of exposure (Seppalainen et 

al. 1983); PbBs ranged from 30 to 48 μg/dL. Although the severity of the effects on NCV appeared to 

lessen with continued exposure, several of the high-exposure workers in this study quit 1 or 2 years after 

starting. Thus, the apparent improvement in NCVs may have been due to a healthy worker effect. A 

similar healthy worker effect may have accounted for the negative results of Spivey et al. (1980) who 

tested ulnar (motor and slow fiber) and peroneal (motor) nerves in 55 workers exposed for 1 year or more 

and whose PbBs ranged from 60 to 80 μg/dL. The studies differed in design; one prospectively obtained 

exposure history, while the other did it retrospectively. The end points that were measured also differed; 

Spivey et al. (1980) did not test the median nerve, which was the most sensitive end point in the study by 

Seppalainen et al. (1983). Ishida et al. (1996) found no significant association between PbBs of 2.1– 

69.5 μg/dL and median nerve conduction velocity among a group of 58 male and 70 female ceramic 

painters. 

In cross-sectional occupational studies, significant decreases in NCVs were observed in fibular (motor) 

and sural (sensory) nerves as a function of PbB with duration of exposure showing no effect (Rosen and 

Chesney 1983). In another study, decreases in NCVs of ulnar (sensory, distal) and median (motor) nerves 

were seen primarily at PbBs >70 μg/dL (Triebig et al. 1984). Duration of exposure and number of lead­
LEAD 108 

3. HEALTH EFFECTS 

exposed workers in these two studies were 0.5–28 years and 15 workers (Rosen and Chesney 1983), and 

1–28 years and 133 workers (Triebig et al. 1984). Results of an earlier study by Araki et al. (1980) 

suggest that the decrease in NCV is probably due to lead since median (motor) NCVs in workers with a 

mean PbB of 48.3 μg/dL were improved significantly when PbB was lowered through CaNa2EDTA 

chelation therapy. A study by Muijser et al. (1987) presented evidence of improvement of motor NCV 

after cessation of exposure. After a 5-month exposure, the PbB was 82.5 μg/dL and decreased to 

29 μg/dL 15 months after the termination of exposure, at which time, NCVs were not different from a 

control group. 

The results of these studies indicate that NCV effects occur in adults at PbBs <70 μg/dL, and possibly as 

low as 30 μg/dL. Ehle (1986), in reviewing many of the studies of NCV effects, concluded that a mild 

slowing of certain motor and sensory NCVs may occur at PbBs <60 μg/dL, but that the majority of 

studies did not find correlations between PbB and NCV below 70 μg/dL and that slowing of NCV is 

neither a clinical nor a subclinical manifestation of lead neuropathy in humans. Other reviewers have 

pointed out that decreases in NCV are slight in peripheral neuropathies (such as that induced by lead) that 

involve axonal degeneration (Le Quesne 1987), and that although changes in conduction velocity usually 

indicate neurotoxicity, considerable nerve damage can occur without an effect on conduction velocity 

(Anderson 1987). EPA (1986a) noted that although many of the observed changes in NCV may fall 

within the range of normal variation, the effects represent departures from normal neurological 

functioning. NCV effects are seen consistently across studies and although the effects may not be 

clinically significant for an individual, they are significant when viewed on a population basis. This is 

further supported by the meta-analysis of 32 studies of effects of lead exposure on NCV (Davis and 

Svendsgaard 1990). 

More recent studies also have produced mixed results. Chia et al. (1996a) measured NCV in a group of 

72 male workers from a lead battery-manufacturing factory and 82 unexposed referents. Measurements 

of NCV in the median and ulnar nerves, as well as of PbB were performed every 6 months over a 3-year 

period. The geometric mean PbB for the exposed workers at the beginning of the study was 36.9 μg/dL 

compared to 10.5 μg/dL for the referents. Baseline measurements revealed significant slower NCV in 

workers, mostly in the median nerve. Serial measurements in the exposed workers over the 3-year period 

showed a peak in PbB in the third test which was followed by a decrease in median sensory conduction 

velocity and ulnar sensory nerve conduction velocity in the fourth test. Evaluation at the end of the study 

of 28 workers who completed the 3-year period showed significant associations between PbB and five out 
LEAD 109 

3. HEALTH EFFECTS 

of the eight parameters measured. The same was observed when only workers with PbB ≥40 μg/dL were 

included in the analysis, but no significant association was found among workers with PbB <40 μg/dL. 

Yeh et al. (1995) evaluated nerve conduction velocity and electromyographic (EMG) activity in a group 

of 31 workers from a battery recycling factory and 31 sex- and age-matched controls. The mean duration 

of exposure to lead was 30.4 months and the mean PbB was 63 μg/dL (range, 17–186 μg/dL); PbB was 

not measured in the control group. Eighty percent of the workers (n=25) had extensor weakness of the 

distal upper limbs and six of these workers had weakness in dorsiflexion of the foot; data for the control 

group were not provided. These 25 workers were classified as the lead neuropathy subgroup and the 

remaining 6 as the lead exposure subgroup. Studies of motor nerve conduction experiments showed a 

significantly increased distal latency in the median nerve from exposed workers relative to controls, but 

no such effect was seen in the ulnar, peroneal, and tibial nerves. Studies of sensory nerve conduction did 

not reveal any significant differences between exposed and control workers. Ninety-four percent of the 

exposed workers had abnormal EMG, but no mention was made regarding the control group. After 

controlling for age and sex, the authors found a significant positive association between an index of 

cumulative exposure to lead (ICL) and the distal motor latencies of tibial nerves and significant negative 

association between ICL and the NCVs of sural nerves. No correlation was found between current PbB 

or duration of exposure and neurophysiological data. Taken together, the data available suggest that in 

lead workers slowing of NCV starts at a mean PbB of 30–40 μg/dL. 

Other Physiological Effects in Adults. Studies also have shown that exposure to lead affects 

postural balance. For example, Chia et al. (1996b) evaluated the possible association between postural 

sway parameters and current PbB, cumulative PbB at different years of exposure, and an index of total 

cumulative exposure to lead in a group of 60 workers; 60 unexposed subjects served as a control group. 

The current mean PbB was 36 μg/dL (range, 6.4–64.5 μg/dL) among the workers and 6.3 μg/dL (range, 

3.1–10.9 μg/dL) among the referents. Exposed and referents differed significantly in postural sway 

parameters when the tests were conducted with the eyes closed, but not with the eyes open. Although the 

postural sway parameters were not significantly correlated with current PbB or with total cumulative lead 

exposure, a significant correlation existed with exposure during the 2 years prior to testing. The authors 

speculated that the lack of correlation between postural sway and cumulative lead exposure could be due 

to underestimation of cumulative exposure and/or to the effects of lead being reversible. A similar study 

of 49 male lead workers employed at a chemical factory producing lead stearate found that an increase in 

postural sway with the eyes open in the anterior-posterior direction observed in exposed workers was 

related to current PbB (mean, 18 μg/dL) (Yokoyama et al. 1997). Also, an increase in sway with the eyes 
LEAD 110 

3. HEALTH EFFECTS 

closed in the right-left direction was significantly related to the mean PbB in the past. According to 

Yokoyama et al. (1997), the change in the vestibulo-cerebellum seemed to reflect current lead absorption, 

whereas the change in the anterior cerebellar lobe reflected past lead absorption. Changes in postural 

balance observed in a group of 29 female lead workers with a mean PbB of 55.7 μg/dL in a more recent 

study from the same group of investigators led them to suggest that lead affects the anterior cerebellar 

lobe, and the vestibulo-cerebellar and spinocerebellar afferent systems (Yokoyama et al. 2002). Other 

studies also have reported decreased postural stability in lead workers (Dick et al. 1999; Iwata et al. 2005; 

Ratzon et al. 2000), but whether the alterations are associated with current measures of exposure or 

measures of cumulative exposure remains to be elucidated. 

The effect of lead exposure on somatosensory evoked potentials has been evaluated in numerous studies 

of lead workers. Comprehensive reviews on this topic are available (Araki et al. 2000; Otto and Fox 

1993). For example, delayed latencies of visual evoked potentials have been reported in several studies of 

lead workers with PbB of approximately 40 μg/dL (Abbate et al. 1995; Araki et al. 1987; Hirata and 

Kosaka 1993). In contrast, no significant association was found between exposure to lead and the 

latencies of visual and brainstem auditory evoked potentials in a group of 36 female glass workers with a 

mean PbB of 56 μg/dL and mean exposure duration of 7.8 years (Murata et al. 1995). Also, in a similar 

study of 29 female lead workers with a mean PbB of 55.7 μg/dL (range, 26–79 μg/dL) and a mean 

employment duration of 7.9 years in a glass factory, Yokoyama et al. (2002) reported no significant 

differences in the latencies of brain auditory evoked potentials (BAEP) between the workers and 

14 control workers (mean PbB, 6.1 μg/dL). Counter and Buchanan (2002) reported delayed wave 

latencies consistent with sensory-neural hearing impairment in adults with chronic exposure to lead 

through ceramic-glazing work and with mean PbB of 47 μg/dL, and suggested that this finding may be 

attributable to occupational noise exposure in combination with lead intoxication. Bleecker et al. (2003) 

found dose-dependent alterations in BAEP among lead workers with a mean PbB of 28 μg/dL and a 

mean-employment duration of 17 years. Analysis of the results led them to suggest that current lead 

exposure preferentially affected conduction in the distal auditory nerve while chronic lead exposure 

appeared to impair conduction in the auditory nerve and the auditory pathways in the lower brainstem. 

An additional parameter that has been studied in lead-exposed workers is the electrocardiographic R-R 

interval variability, a measure of peripheral autonomic function. R-R interval variability was significantly 

depressed in a group of 36 female glass workers compared to a group of 17 referents with no known 

occupational exposure to lead (Murata et al. 1995). The mean PbB was 55.6 μg/dL and the mean 

exposure duration was 7.8 years. However, Gennart et al. (1992a) found no association between exposure 
LEAD 111 

3. HEALTH EFFECTS 

and R-R interval variations in the electrocardiogram. The study group consisted of 98 workers from a 

lead acid battery factory (exposure group) and 85 people who had no occupation exposure to lead 

(reference group). The mean duration of occupational exposure was 10.6 years. Mean PbB at the time of 

the examination was 51 μg/dL (range, 40–75 mg/dL) in the exposure group, and 20.9 μg/dL (range, 4.4– 

39 mg/dL) in the reference group. More studies are needed to establish whether this parameter is truly 

affected by lead exposure, and if so, to evaluate the shape of the dose-response relationship. 

Neurological Effects in Children. High-level exposure to lead produces encephalopathy in 

children. The most extensive compilation of dose-response information on a pediatric population is the 

summarization by the National Academy of Sciences (1972) of unpublished data from the patient 

populations reported in Chisolm (1962, 1965) and Chisolm and Harrison (1956). This compilation relates 

the occurrence of acute encephalopathy and death in children in Baltimore, Maryland, associated with 

PbBs determined by the Baltimore City Health Department between 1930 and 1970. Other signs of acute 

lead poisoning and blood lead levels formerly regarded as asymptomatic were also summarized. An 

absence of signs or symptoms was observed in some children at PbB of 60–300 μg/dL (mean, 105 μg/dL). 

Acute lead poisoning symptoms other than signs of encephalopathy were observed at PbB of 

approximately 60–450 μg/dL (mean, 178 μg/dL). Signs of encephalopathy such as hyperirritability, 

ataxia, convulsions, stupor, and coma were associated with PbB of approximately 90–800 μg/dL (mean, 

330 μg/dL). The distribution of PbBs associated with death (mean, 327 μg/dL) was virtually the same as 

for levels associated with encephalopathy. 

Additional evidence from medical reports (Bradley and Baumgartner 1958; Bradley et al. 1956; Gant 

1938; Rummo et al. 1979; Smith et al. 1983) suggests that acute encephalopathy in the most susceptible 

children may be associated with PbBs in the range of 80–100 μg/dL. However, a study reported 19 cases 

of acute encephalopathy in infants of mean age 3.8 months and with mean PbB of 74.5 μg/dL (range, 

49.7–331 μg/dL) following use of traditional medicines containing lead (surma, Bint al Thahab) (Al 

Khayat et al. 1997a). Seven cases had PbB ≤70 μg/dL. In this report, lead level at 2 months 

postchelation was a significant predictor of abnormal results in the Denver Developmental Screening Test 

carried out for a mean period of 20 months. 

Histopathological findings in fatal cases of lead encephalopathy in children include cerebral edema, 

altered capillaries, and perivascular glial proliferation. Neuronal damage is variable and may be caused 

by anoxia (EPA 1986a). 
LEAD 112 

3. HEALTH EFFECTS 

Numerous studies clearly show that childhood lead poisoning with encephalopathy results in a greatly 

increased incidence of permanent neurological and cognitive impairments. Additional studies indicate 

that children with symptomatic lead poisoning without encephalopathy (PbB, >80–100 μg/dL) also have 

an increased incidence of lasting neurological and behavioral damage. 

Neurobehavioral Effects in Children. The literature on the neurobehavioral effects of lead in 

children is extensive. With the improvement in analytical methods to detect lead in the various biological 

media in recent years and in study design, the concentrations of lead, particularly in blood, associated 

with alterations in neurobehavioral outcomes keep decreasing. In fact, the results of some recent studies 

suggest that there may be no threshold for the effects of lead on intellectual function. Due to the 

enormous size of the database on neurobehavioral effects of lead in children, below are summaries of 

representative and/or major studies published on specific areas. For further information, the reader is 

referred to recent reviews on this topic (Bellinger 2004; Koller et al. 2004; Lidsky and Schneider 2003; 

Needleman 2004). 

Many studies conducted decades ago reported negative associations between intellectual function, usually 

measured as IQ on various intelligence scales, and increased PbB, although other exposure indices were 

sometimes used. For example, de la Burde and Choate (1972) reported a mean Stanford-Binet IQ 

decrement of 5 points, fine motor dysfunction, and altered behavioral profiles in 70 preschool children 

exhibiting pica for paint and plaster and elevated PbBs (mean, 58 μg/dL), when compared with results for 

matched control subjects not engaged in pica for paint and plaster. A follow-up study on these children 

(ages 1–3 years) at 7–8 years of age reported a mean Wechsler Intelligence Scale for Children (WISC) 

full-scale IQ decrement of 3 points and impairment in learning and behavior, despite decreases in PbB 

since the original study (de la Burde and Choate 1975). Rummo et al. (1979) observed hyperactivity and 

a decrement of approximately 16 IQ points on the McCarthy General Cognitive Index (GCI) among 

children who had previously had encephalopathy and whose average maximum PbB at the time of 

encephalopathy were 88 μg/dL (average PbB, 59–64 μg/dL). Asymptomatic children with long-term lead 

exposures and average maximum PbB of 68 μg/dL (average PbB level, 51–56 μg/dL versus 21 μg/dL in a 

control group) had an average decrement of 5 IQ points on the McCarthy GCI. Their scores on several 

McCarthy Subscales were generally lower than those for controls, but the difference was not statistically 

significant. Children with short-term exposure and average maximum PbB of 61 μg/dL (average PbB, 

46–50 μg/dL) did not differ from controls. PbB in the referent group averaged 21 μg/dL, which is high 

for so-called “controls.” Fulton et al. (1987) provided evidence of changes in intellectual function at 

lower PbB in a study of 501 children, 6–9 years old from Edinburgh, Scotland, exposed to lead primarily 
LEAD 113 

3. HEALTH EFFECTS 

via drinking water. The geometric mean PbB of the study population was 11.5 μg/dL, with a range of 

3.3–34 μg/dL and ten children had PbB >25 μg/dL. Multiple regression analyses revealed a significant 

relation between tests of cognitive ability and educational attainment (British Ability Scales [BAS]) and 

PbB after adjustment for confounding variables. The strongest relation was with the reading score. 

Stratification of the children into 10 groups of approximately 50 each based on PbB and plotting the 

group mean lead values against the group mean difference from the school mean score revealed a doseeffect relationship extending from the mean PbB of the highest lead groups (22.1 μg/dL) down through 

the mean PbB of the lowest-lead group (5.6 μg/dL), without an obvious threshold. It should be 

mentioned, however, that the size of the effect on the score was small compared with the effect of other 

factors. For the combined BAS score, only 0.9% of a total 45.5% variance explained by the covariates in 

the optimal regression model could be attributed to the effect of lead. 

Needleman et al. (1979) examined the relationship between intellectual function and lead in dentin in a 

group of 158 first- and second-grade children. In comparison with children having dentin lead levels 

<10 ppm, children having dentin lead levels >20 ppm had significantly lower full-scale WISC-Revised 

scores; IQ deficits of approximately 4 points; and significantly poorer scores on tests of auditory and 

verbal processing, on a test of attention performance, and on a teachers' behavioral rating. A 

concentration of lead in dentin of 20 ppm corresponds to a PbB of approximately 30 μg/dL (EPA 1986a). 

Further analysis of Needleman’s data showed that for children with elevated lead levels, the observed IQ 

was an average 3.94 points below the expected based on their mother’s IQ scores, whereas for children 

with low lead levels, it was 1.97 points greater than the expected IQ (Bellinger and Needleman 1983). 

This meant that the children in the elevated lead group had a lower mean IQ than those in the low lead 

group when maternal IQ was partialled out. When 132 children from the initial study were reexamined 

11 years later, impairment of neurobehavioral function was still related to the lead content of teeth shed at 

the ages of 6 and 7 years (Needleman et al. 1990). Higher lead levels in childhood were significantly 

associated with lower class standing in high school, increased absenteeism, lower grammatical-reasoning 

scores, lower vocabulary, poorer hand-eye coordination, longer reaction times, and slower finger tapping. 

However, no significant associations were found with the results of 10 other tests of neurobehavioral 

functioning. These later effects could stem from a poor academic start as opposed to effects of lead 

exposure; however, it could also be that the early lead exposure resulted in long-term consequences. 

Other studies of lead dentin and intellectual functions support Needleman’s findings in that deficits have 

not been found below lead dentin concentrations of approximately 10 ppm (Damm et al. 1993; Hansen et 

al. 1989; Pocock et al. 1987). The association between bone lead and intellectual function also has been 

studied. A study of 156 male adolescents, 11–14 years of age, in the Pittsburgh school system reported 
LEAD 114 

3. HEALTH EFFECTS 

that increasing bone lead levels (10–53 ppm) was significantly associated with poorer performance on 

complex language processing tasks (e.g., 4-syllable Nonword Repetition Task, subset 8 of Revised Token 

Task, responding to spoken commands) (Campbell et al. 2000b). Covariates considered in the analysis 

included child age, race, SES, and maternal IQ. 

Low Lead Level and Intellectual Function. Several studies have been published in recent years that 

support the view that there is no apparent threshold in the relationship between PbB and neurobehavioral 

functions. Most of these studies have been cross-sectional studies with the inherent limitation that such 

type of study of school-age children might reflect latent damage done by a higher PbB at an earlier age, 

which could only be reliably detected at school age. However, recent data from Chen et al. (2005) 

showed that the effect of concurrent PbB on IQ may be greater than currently believed. These 

investigators analyzed data from a clinical trial of 780 children who were treated for elevated PbB (20– 

44 μg/dL) at approximately 2 years of age and followed until 7 years of age with serial IQ tests and 

measurements of PbB. Mean PbB at 5 and 7 years of age was 12 and 8 μg/dL, respectively. The results 

showed that concurrent PbB always had the strongest association with IQ and, as the children aged, the 

relationship grew stronger. The peak PbB from baseline (approximately 2 years old) to 7 years of age 

was not associated with IQ at 7 years of age. Futhermore, in the model including both prior and 

concurrent PbB, concurrent PbB was always more predictive of later IQ scores. The results were 

interpreted as support for the idea that lead exposure continues to be toxic to children as they reach school 

age, and that not all of the damage is done by the time the child is 2 or 3 years old. 

Lanphear et al. (2000a) analyzed data on blood lead concentrations and various assessments of cognitive 

abilities conducted on 4,853 U.S. children, ages 6–16 years, as part of the NHANES III, 1988–1994. 

Four cognitive measures were tested: arithmetic skills, reading skills, nonverbal reasoning (block design), 

and short-term memory (digit span). Potential confounders that were assessed included gender, 

racial/ethnic background, child’s serum ferritin levels, serum cotinine level, region of the country, marital 

status and education level of primary caregiver, and poverty index ratio. Although no data were available 

on important potential confounding factors such as maternal IQ or direct observations of caretaking 

quality in the home, control for the poverty index ratio and education of the primary caregiver may have 

served as surrogate. The geometric mean PbB of the sample was 1.9 μg/dL and 2.1% exceeded 10 μg/dL. 

After adjustment for potential covariables, an inverse association between PbB and cognitive scores was 

evident, which was significant for all end points when PbBs of only <10 μg/dL were included in the 

analysis. When the PbB range was restricted to <7.5 μg/dL, the inverse relationship was significant for 
LEAD 115 

3. HEALTH EFFECTS 

arithmetic skills, reading skills, and nonverbal reasoning; when restricted to <5.0 μg/dL, the inverse 

relationship was significant for arithmetic skills and reading skills. 

Canfield et al. (2003) reported the results of evaluations of 172 children from the Rochester Longitudinal 

Study. Fifty-eight percent of the children had PbBs below 10 μg/dL. PbB was measured at ages 6, 12, 

24, 36, 48, and 60 months. IQ of children was assessed with the Stanford-Binet Intelligence Scale at the 

age of 3 and 5 years. The highest mean PbB was observed at age 2 years (9.7 μg/dL) and the lowest at 

the age of 6 months (3.4 μg/dL). The mean PbB at 5 years of age was 6.0 μg/dL. After adjustment for 

covariables, an increase in lifetime average PbB of 1 μg/dL was associated with a decrease in IQ of 

0.46 IQ points (95% CI=-0.76–0.15). Similar findings were obtained when the children were tested at 

3 and 5 years of age. When the analysis was limited to children whose highest observed PbB were 

<10 μg/dL, an increase in the lifetime average PbB of 1 μg/dL was associated with a decrease in IQ of 

1.37 IQ points (95% CI=-2.56–0.17). The results also showed a nonlinear relationship between IQ and 

PbB (i.e., an increase from 1 to 10 μg/dL was associated with a decline of 8.0 points in IQ, whereas, an 

increase from 10 to 30 μg/dL was associated with a decline of approximately 2.5 points). At the age of 

5.5 years, the children were given the Working Memory and Planning Battery of the Cambridge 

Neuropsychological Test Automated Battery to evaluate specific cognitive functions (Canfield et al. 

2004). The results showed that children with the greatest exposure performed more poorly on tests of 

spatial working memory, spatial memory span, intradimensional and extradimensional shifts, and an 

analog of the Tower of London task. 

Evidence for absence of a lower-bound threshold for postnatal lead exposure also was provided in a study 

of 237 African-American, inner-city children 7.5 years of age with a current mean PbB of 5.4 μg/dL 

(Chiodo et al. 2004). The children were assessed in areas of intelligence, reaction time, visual-motor 

integration, fine motor skills, attention (including executive function), off-task behaviors, and teacherreported withdrawn behaviors. A total of 21 variables were considered as potential confounders. 

Multiple regression analysis showed negative association with lead exposure in the areas of overall IQ, 

performance IQ, reaction time, visual-motor integration, fine motor skills, and attention including 

executive function, off-task behaviors, and teacher-reported withdrawn behavior. Regression analyses in 

which lead exposure was dichotomized at 10 μg/dL were no more likely to be significant than analyses 

dichotomizing exposure at 5 μg/dL. Chiodo et al. (2004) indicated that data on maternal and child 

nutritional status, including iron deficiency, were not available so that their possible influence on the 

association between lead neurobehavioral outcomes could not be controlled. 
LEAD 116 

3. HEALTH EFFECTS 

Kordas et al. (2006) studied the association between lead and cognitive function in 594 first-grade 

children exposed to lead from a metal foundry in Torreón, Mexico. Their ages ranged from 6.2 to 

8.5 years and their mean PbB was 11.4 μg/dL (SD±6.1 μg/dL). Fifty-one percent of the children had 

PbBs ≥10 μg/dL. Children were assessed on performance on 14 tests of global or specific cognitive 

function. Examiners were experienced testing children and were unaware the children’s PbB. The nature 

of the lead-cognition relation was described using both linear and spline (segmented) regression methods. 

Covariates included in the analyses were age, gender, SES, maternal formal education, parental 

involvement in schooling family structure, birth order, arsenic exposure, and hemoglobin concentration. 

Also, all models were adjusted for the tester administering cognitive tasks and the school each child 

attended. After adjusting for covariates, PbB was significantly associated (p<0.05) with poorer scores 

measuring math abilities, vocabulary, and visual short-term memory. Using segmented regressions, the 

investigators observed that the slope describing the associations of PbB with the math and vocabulary test 

scores below a cutoff of 12 and 10 μg/dL, respectively, were steeper than slopes above those cutoff 

points. Examination of segmented lead coefficients using a stratified analysis at various levels of 

covariates showed that the pattern of steeper estimates at low PbBs vs. higher PbBs was generally 

conserved. Furthermore, the data showed that the nonlinear relationship was most pronounced for 

children who already tended to be at risk for poorer performance (fewer family resources, lower maternal 

education, and lower parental involvement in school work). Although some important covariates such as 

HOME inventory and maternal IQ were not controlled for in the study, control for other family 

background characteristics may have served as surrogates. 

Using data from a prospective study conducted in Mexico City, Mexico, Téllez-Rojo et al. (2006) 

evaluated the relationship between PbB and neurodevelopment in 294 children at 12 and 24 months of 

age. Two cohorts comprised the sample: one recruited at the time of delivery and another recruited 

prenatally. To be included in the study, children needed to have a PbB <10 μg/dL at both 12 and 

24 months of age, a gestation age of 37 weeks or longer, and a birth weight >2,000 g. MDI and PDI 

scores of a Spanish version of the Bayley Scales of Infant Development II (BSID II) were the primary 

dependent variables. Non-lead variables that were related to BDID II scores at p<0.1 in bivariate analysis 

were included in multivariate models. Also included in the multivariate models were maternal age and IQ 

and children’s gender and birth weight. Adjusting for covariates, children’s PbBs at 24 months were 

significantly inversely associated (p<0.01) with both MDI and PDI scores at 24 months. PbB at 

12 months of age was not associated with concurrent MDI or PDI, or with MDI scores at 24 months of 

age, but was significantly associated (p<0.01) with PDI scores at 24 months. An increase of 

1 logarithmic unit in 24-month PbB was associated with a reduction of 4.7 points in MDI score at 
LEAD 117 

3. HEALTH EFFECTS 

24 months. For both the MDI and PDI scores at 24 months of age, the coefficients that were associated 

with PbB were significantly larger (p≤0.01) among children with PbBs <10 μg/dL than in children with 

PbBs >10 μg/dL. Moreover, for MDI scores, the slope of the association was steeper over the range up to 

5 μg/dL than between 5 and 10 μg/dL. 

Perhaps the strongest evidence for an association between low PbB and intellectual impairment in 

children as well as for a nonlinear dose-response is provided by a pooled analysis of 1,333 children who 

participated in seven international prospective cohort studies and were followed from birth or infancy 

until 5–10 years of age (Lanphear et al. 2005). The participant sites included Boston, Massachusetts; 

Cincinnati, Ohio; Cleveland, Ohio; Rochester, New York; Mexico City; Port Pirie, Australia; and 

Kosovo, Yugoslavia. The full-scale IQ score was the primary outcome measured. The median lifetime 

PbB was 12.4 μg/dL (5th–95th percentiles, 4.1–34.8 μg/dL), while the concurrent mean PbB was 9.7 μg/dL 

(5th–95th percentiles, 2.5–33.2 μg/dL); 244 children (18%) had PbBs that never exceeded 10 μg/dL. Four 

measures of blood lead were examined: concurrent PbB (PbB closest to the IQ test), maximum PbB 

(peak PbB measured at any time before IQ test), average lifetime PbB (mean PbB from 6 months to 

concurrent PbB tests), and early childhood PbB (mean PbB from 6 to 24 months). In the subsequent 

analyses, concurrent PbB and average lifetime PbB were generally stronger predictors of lead-associated 

intellectual deficits than the other two indices. Potential confounding effects of other factors associated 

with IQ scores were examined by multiple regression analysis and included HOME inventory, child’s sex, 

birth weight, birth order, maternal education, maternal IQ, maternal age, marital status, prenatal smoking 

status, and prenatal alcohol use. Using various models, including the linear model, cubic spline function, 

the log-linear model, and the piece-wise model, Lanphear et al. (2005) determined that the nonlinear 

model was a better fit for the data. Using a log-linear model, the investigators found a 6.9 IQ point 

decrement (95% CI, 4.2–9.4) for an increase in concurrent PbB from 2.4 to 30 μg/dL. However, the 

decrease in IQ points was greatest in the lowest ranges of PbB. The estimated IQ decrements associated 

with increases in PbB of 2.4–10, 10–20, and 20–30 μg/dL were 3.9 (95% CI, 2.4–5.3), 1.9 (95% CI, 1.2– 

2.6), and 1.1 (95% CI, 0.7–1.5), respectively. To further investigate whether the lead-associated 

decrement was greater at lower PbBs, the investigators divided the data at two cut-off points a priori, a 

maximal PbB of 7.5 and 10 μg/dL. They then fit separate linear models to the data in each of those 

ranges and compared the PbB coefficients for the concurrent PbB index. The coefficient for the 

103 children with maximal PbB <7.5 μg/dL was significantly greater than the coefficient for the 

1,230 children with maximal PbB ≥7.5 μg/dL (linear β=-2.94 [CI 95%, -5.16–-0.71]) vs. -0.16 (95% CI, 

-2.4–-0.08). The coefficient for the 244 children who had maximal PbB<10 μg/dL was not significantly 

greater than that for 1,089 children who had maximal PbB ≥10 μg/dL. Potential limitations 
LEAD 118 

3. HEALTH EFFECTS 

acknowledged by the authors included the fact that the HOME inventory and IQ tests had not been 

validated in all cultural or ethnic communities, lack of examination of other predictors of 

neurodevelopmental outcomes such as maternal depression, and the unique limitations of each individual 

study. 

A nonlinear relationship between first trimester of pregnancy blood lead and the MDI at 24 months was 

recently reported by Hu et al. (2006). In the study, the investigators measured lead in maternal plasma 

and whole blood lead during each trimester in 146 pregnant women in Mexico City. Measurements were 

also conducted in cord blood at delivery and when the infants were 12 and 24 months old. The primary 

outcome was the MDI scores at 24 months of age. The criteria for inclusion in the study were: child born 

with at least 37 weeks of gestational age; at least one valid measurement of plasma lead during any of the 

three visits made during pregnancy; complete information on maternal age and IQ; and child’s PbB at 

24 months, sex, weight, and height. Potential confounders included in the analyses were child’s sex, PbB 

at 24 months of age, height for age and weight, and maternal age and IQ. Mean maternal PbB during the 

first, second, third trimester, and delivery ranged from 6.1 μg/dL (SD±3.2 μg/dL) to 7.3 μg/dL 

(SD±4.3 μg/dL); plasma lead during pregnancy ranged between 0.014 and 0.016 μg/dL. Mean PbB in the 

cord, at 12 months, and 24 months were 6.2 μg/dL (SD±3.9 μg/dL), 5.2 μg/dL (SD±3.4 μg/dL), and 

4.8 μg/dL (SD±3.8 μg/dL), respectively. The results of the analyses showed that both maternal plasma 

and whole blood lead during the first trimester (but not in the second or third trimester) were significant 

predictors (p<0.05) of poorer MDI scores. Also, in models combining all three trimester measures and 

using standardized coefficients, the effect of first-trimester maternal plasma was substantially greater than 

the effects of second- and third-trimester plasma lead. A one standard deviation change in first-trimester 

plasma lead was associated with a reduction in MDI scores of 3.5 points (p=0.03). Inspection of the 

relationship between first-trimester plasma lead and MDI at 24 months showed that the slope was steeper 

at plasma lead levels corresponding to whole blood lead levels <10 μg/dL than at higher plasma lead 

concentrations, as observed also in the studies summarized above. As a possible explanation, Hu et al. 

(2006) speculated that lead might be affecting the process of neuronal differentiation, which is primarily a 

first-trimester event. Limitations of the study acknowledged by the investigators include the relatively 

small sample size, the lack of control for a measure of home conditions, and the fact that infant PbB at 

24 months did not significantly predict lower MDI score (as observed, for example, in Téllez-Rojo et al. 

[2006]). Another recent study that reported an association between prenatal lead exposure and 

intellectual function is that of Schnaas et al. (2006) who reported that IQ of 6–10-year-old children 

decreased significantly (p<0.0029; 95% CI, -6.45–-1.36) only with increasing natural-log third trimester 

PbB, but not with PbB at other times during pregnancy or postnatal PbB measurements. However, 
LEAD 119 

3. HEALTH EFFECTS 

because their observations began after the 12th week of pregnancy, the effects of the first trimester PbB 

could not be examined. As with other studies, the dose-response PbB-IQ function was log-linear, with a 

steeper slope at PbB <10 μg/dL. 

Other studies that have reported cognitive impairments associated with low lead exposure include AlSaleh et al. (2001), Bellinger and Needleman (2003), Carta et al. (2003), Emory et al. (2003), Gomaa et 

al. (2002), and Shen et al. (1998). Although individually all of these studies have limitations, 

collectively, they support the association between low blood lead and intellectual impairment in children. 

Major Prospective Studies. The Port Pirie, Australia, prospective study examined cohorts of infants born 

to mothers living in the vicinity of a large lead smelting operation in Port Pirie and infants from outside 

the Port Pirie area. The study population consisted initially of 723 singleton infants. The children were 

followed from birth to age 11–13 years old; at this later age, 375 children remained in the cohort. 

Maternal blood and cord lead levels were slightly, but significantly, higher in the Port Pirie cohort than in 

the cohort from outside Port Pirie (e.g., mean cord blood lead was 10 vs. 6 μg/dL). The main outcome 

measures were the Bayley Mental Developmental Index (MDI) at age 2 years, the McCarthy GCI at age 

4 years, and IQ from the Wechsler Intelligence Scale at ages 7 and 11–13 years (Baghurst et al. 1987, 

1992, 1995; McMichael et al. 1988, 1994; Tong et al. 1996). Covariates in the models included: child 

gender, birth weight, siblings, infant feeding style and duration of breast feeding; maternal IQ, age at 

child’s birth and marital status; parental tobacco use; SES, and HOME score. Analysis of the associations 

between blood lead concentrations (tertiles) in children of ages 2 or 11–13 years, and developmental 

status showed that the covariate-adjusted differences in development scores between the top and bottom 

tertiles were 4 points on the MDI at age 2; 4.8 points on the McCarthy GCI at age 4; and 4.9 and 4.5 IQ 

points at age 7 and 11–13 years, respectively. At age 7 years, both prenatal and postnatal PbB were 

inversely associated with visual motor performance (Baghurst et al. 1995). Analysis of the relationship 

between individual changes in PbB and individual changes in measures of cognitive development during 

the life of the cohort found that the mean PbB in the children decreased from 21.2 μg/dL at age 2 years to 

7.9 μg/dL at age 11–13 years; however, cognitive scores in children whose blood lead concentration 

declined the most were generally not improved relative to the scores of children whose PbB declined least 

(Tong et al. 1998). Changes in IQ and declines in PbB that occurred between the ages of 7 and 11– 

13 years suggested better cognition among children whose PbB declined most. The overall conclusion 

was that the cognitive deficits associated with exposure to lead in early childhood appeared to be only 

partially reversed by a subsequent decline in PbB. Throughout the various assessments, it was noted that 

children from disadvantaged backgrounds were more sensitive to the effects of lead than those of a higher 
LEAD 120 

3. HEALTH EFFECTS 

socioeconomic status, and that girls were more sensitive to the effects of lead than boys (Tong et al. 

2000). 

The Mexico City, Mexico, Prospective Study evaluated children born to mothers residing in Mexico City 

(Rothenberg et al. 1989, 1994a; Schnaas et al. 2000). The study recruited 502 pregnant women; 

436 ultimately were included in the study. An analysis of a subset of 112 children for whom complete 

data were available for evaluation of GCI (McCarthy scales) at 6-month intervals between ages 36 and 

60 months revealed significant associations between PbB and GCI, after adjusting for covariates. Mean 

PbBs were 10.1 μg/dL at 6–18 months, 9.7 μg/dL at 24–36 months, and 8.4 μg/dL at 42–54 months of 

age. Increasing PbBs at 24–36 months, but not 6–18 months or prenatal, were associated with significant 

declines in GCI at 48 months; increasing PbBs at 42–54 months were associated with decreased GCI at 

54 months. Covariates included in the models were child gender, 5-minute Apgar score, birth weight, and 

birth order; maternal education and IQ; and family SES. HOME scores were not included and were 

assumed to have been accounted for by maternal IQ because of the strong correlation between the latter 

and HOME score. The main finding of this series of studies was that postnatal, but not prenatal, PbBs 

were associated with intellectual function and that the strength of the association between mean PbB and 

GCI increases with age up to 4 years, after which, it becomes less strong and continues to decrease. 

The Yugoslavia Prospective Study evaluated children born to women from two towns in Kosovo, 

Yugoslavia; Kosovska Mitrovica (K. Mitrovica), the site of a lead smelter, refinery, and battery plant; and 

Pristina, a town 25 miles to the south of K. Mitrovica, which was considered not to have been impacted 

by industrial lead emissions (Factor-Litvak et al. 1991, 1999; Wasserman et al. 1992). A total of 

1,502 women were recruited at mid-pregnancy: 900 women from Pristina and 602 from K. Mitrovica. A 

sample of 392 infants was selected for follow-up based on umbilical cord lead, town of residence, and 

parental education. The infants from K. Mitrovica were assigned to one of three groups based on cord 

PbB: low (<15 μg/dL), middle (15–20 μg/dL), and high (>20 μg/dL). Outcomes examined in the followup included measures of intelligence at ages 2 (MDI of the Bayley Scales), 4 (McCarthy Scales of 

Children’s Abilities), and 7 years (Wechsler Intelligence Scale for Children-III), and behavior problems at 

age 3 (Child Behavior Checklist) and 12 years (Wechsler Intelligence Scale for Children-III). Covariates 

included in the models were child gender, birth weight, iron status (blood hemoglobin), siblings and 

ethnicity (language spoken in home); maternal age, education and Raven’s test score; and HOME score. 

The geometric mean PbB in children in K. Mitrovica increased from 22.4 μg/dL, at birth, to 39.9 μg/dL, 

at age 4; in children from Pristina, it increased from 5.4 to 9.6 μg/dL over this same age range 

(Wasserman et al. 1994). PbB was significantly associated with poorer intellectual function at ages 
LEAD 121 

3. HEALTH EFFECTS 

2 years (Wasserman et al. 1992), 4 years (Wasserman et al. 1994), and 7 years (Wasserman et al. 1997). 

An increase in PbB from 10 to 30 μg/dL was predicted to be associated with loss in intellectual function 

of 2.5 points at age 2 years, 4.5 points at age 4 years, and 4.3 points at age 7 years. In both towns 

combined, PbB measured concurrently with the Child Behavior Checklist was associated with small 

increases in behavioral problems, which the authors considered small compared with the effects of social 

factors (Wasserman et al. 1998). In a subsequent publication, Wasserman et al. (2000a) observed that 

while postnatal elevations that occurred before the age of 2 years and continued afterwards were 

associated with the largest decrements in IQ (50% increase in postnatal lead associated with 2.71 point IQ 

loss), elevations in PbB that occurred only after the age of 2 years were also associated with decrements. 

Thus, prenatal and postnatal exposures that occurred at any time during the first 7 years were 

independently associated with small decrements in later IQ scores (Wasserman et al. 2000a); 

identification of a particularly critical period of vulnerability during brain growth and maturation within 

this age range was not evident from this analysis. 

In addition, evaluation of 283 children at the age of 54 months showed that PbB was significantly 

associated with poorer fine motor and visual motor function, but was unrelated to gross motor 

coordination. An estimated 2.6 and 5.8% of the variance in fine motor composite and visual motor 

integration was due to PbB, respectively. At age 12, the assessment of the children included 

measurements of tibial bone in addition to current PbB (Wasserman et al. 2003). At this age, mean PbB 

in the exposed children was approximately 31 μg/dL and mean tibial bone lead was 39 ppm, both 

measures significantly higher than those of a comparison group. Both bone lead and PbB were associated 

with intelligence decrements, but the bone lead-IQ associations were stronger than those for PbB. For 

each doubling of tibial bone, Full Scale, Performance, and Verbal IQ decreased by an estimated 5.5, 6.2, 

and 4.1 points, respectively. Analyses conducted in a subsample stratified by quartiles showed that the 

greatest decrements in intelligence appeared to occur at relatively low lead exposure, from quartile 1 to 

quartile 2. These transitions corresponded to tibial lead up to 1.85 ppm, mean serial PbB up to 7 μg/dL, 

and current PbB up to 5.6 μg/dL. 

The Boston, Massachusetts, study examined the association between lead exposure and neurobehavioral 

parameters in 249 middle-class and upper-middle class Boston children (Bellinger et al. 1984, 1985a, 

1985b, 1986a, 1986b, 1987a, 1987b, 1989a, 1989b, 1991, 1992). Cord PbBs were determined at delivery 

and MDI and PDI scores were measured every 6 months thereafter. Infants born at <34 weeks of 

gestation were excluded from the study. Cord PbBs were <16 μg/dL for 90% of the subjects, with the 

highest value being 25 μg/dL. On the basis of cord PbBs, the children were divided into low-dose 
LEAD 122 

3. HEALTH EFFECTS 

(<3 μg/dL; mean, 1.8 μg/dL), medium-dose (6–7 μg/dL; mean, 6.5 μg/dL), and high-dose (≥10 μg/dL; 

mean, 14.6 μg/dL) exposure groups. Multivariate regression analysis revealed an inverse correlation 

between cord PbB and MDI scores at 6, 12, 18, and 24 months of age (Bellinger et al. 1985a, 1985b, 

1986a, 1986b, 1987a). The high-lead group had an average deficit of 4.8 points on the covariate-adjusted 

MDI score as compared with the low-lead group. MDI did not correlate with postnatal PbB lead levels. 

No correlations between PDI and cord or postnatal blood lead levels were seen. Subsequent studies of 

this cohort showed that the younger the infants, the more vulnerable they are to lead-induced 

developmental toxicity (Bellinger et al. 1989a, 1989b). Infants in lower socioeconomic groups showed 

deficits at lower levels of prenatal exposure (mean PbB, 6–7 μg/dL) than children in higher 

socioeconomic groups. The early postnatal PbBs (range, 10–25 μg/dL) were also associated with lower 

MDI scores, but only among children in lower socioeconomic groups. Evaluation of the children at 

approximately 5 years of age showed that deficits in GCI scores correlated significantly with PbB at 

24 months of age (mean 7 μg/dL), but not with prenatal PbB (Bellinger et al. 1991). These results suggest 

that prenatal PbB is a better predictor of cognitive development in infants than in 4–5-year-old children 

and that early developmental deficits associated with elevated PbB may not persist to 4–5 years of age, 

especially in socioeconomically advantaged families. Evaluation of 148 of the Boston cohort children at 

age 10 years showed that all postnatal blood lead levels were inversely associated with Full Scale IQ 

measured at age 10; however, only the associations involving PbB at ages 10 years, 57 months, and 

24 months were statistically significant (Bellinger et al. 1992). This was also seen for both Verbal and 

Performance IQ scores. After adjusting for confounding, only the coefficient associated with 24-month 

blood lead level remained significant. It was also shown that the association between 24-month PbB and 

Full Scale IQ at age 10 years was not due simply to the high correlation between GCI scores at age 

5 years and IQ. The decline in Full Scale IQ corresponded to 5.8 points per 10 μg/dL of increase in 

24-month PbB. PbB at 24 months was also significantly associated with Verbal IQ and five WISC-R 

subtest scores. Only PbBs at 24 months were significantly associated with adjusted K-TEA scores. For 

each 10 μg/dL of increase in 24-month PbB, the battery composite score declined 8.9 points. The results 

suggested that timing of exposure may be more important than magnitude alone and supported the 

hypothesis of an age-specific vulnerability. Reanalyses of data, from 48 children whose PbB never 

exceeded 10 μg/dL at birth or at any of the evaluations throughout the study, showed that an inverse 

association between IQ and PbB persisted at PbBs below 5 μg/dL and that the inverse slope was greater at 

lower PbBs than at higher PbBs (Bellinger and Needleman 2003). 

The Cincinnati, Ohio, study sample consisted of 305 mothers residing in predesignated lead-hazardous 

areas of the city (>80% black) (Dietrich et al. 1986, 1987a, 1987b). Maternal PbBs were measured at the 
LEAD 123 

3. HEALTH EFFECTS 

first prenatal visit; cord PbB was measured at delivery; infant PbB was measured at 10 days and at 

3 months of age; and neurobehavioral tests were performed at 3 and 6 months of age. Mean PbBs were as 

follows: prenatal (maternal), 8.0 μg/dL (range, 1–27 μg/dL); umbilical cord, 6.3 μg/dL (range, 1– 

28 μg/dL); 10-day-old and 3-month-old infants, 4.6 and 5.9 μg/dL (range, 1–22 μg/dL for each). Multiple 

regression analyses, with perinatal health factors such as birth weight and gestational age treated as 

confounders, showed inverse correlations between prenatal or cord PbB and performance on the MDI at 

3 months, and between prenatal or 10-day neonatal PbB and performance on the MDI at 6 months. No 

significant correlation of PbB with PDI was seen. Male infants and low socioeconomic status infants 

appeared to be more sensitive to the effect on the MDI. Multiple regression analyses for male or low 

socioeconomic status infants showed covariate-adjusted decrements of 0.84 or 0.73 MDI points per μg/dL 

of prenatal or 10-day neonatal PbB, respectively (i.e., an approximate 8-point deficit for a 10-μg/dL 

increase in PbB) (Dietrich et al. 1987a). Cognitive development of 258 children was assessed by the 

Kaufman Assessment Battery for Children (K-ABC) when the children were 4 years old (Dietrich et al. 

1991). Higher neonatal PbBs were associated with poorer performance in all K-ABC subscales; however, 

there was a significant interaction between neonatal PbB and socioeconomic status, which suggested that 

children from less advantaged environments express cognitive deficits at lower PbBs than do children 

from families of relatively higher socioeconomic status. Prenatal (maternal) PbBs were not related to 

4-year cognitive status. No statistically significant effects of postnatal PbB on any of the K-ABC 

subscales was found after covariate adjustment. Evaluation of 253 children at 6.5 years of age showed 

that when PbB regression coefficients were adjusted for HOME score, maternal IQ, birth weight, birth 

length, child sex, and cigarette consumption during pregnancy, postnatal PbB continued to be associated 

with lower Performance IQ (Dietrich et al. 1993a). Also, examination of the PbB concentration for the 

group from 3 to 60 months of age showed that PbB peaked at approximately 2 years of age and declined 

thereafter. It was also found that, of the various cofactors, maternal IQ was usually the strongest predictor 

of a child’s Full Scale IQ. Further analysis of the results suggested that average lifetime PbB 

concentrations in excess of 20 μg/dL were associated with deficits in Performance IQ on the order of 

about 7 points when compared with children with mean PbB concentrations ≤10 μg/dL. At 72 months of 

age, 245 children were evaluated for motor development status (Dietrich et al. 1993b). The authors 

hypothesized that measures of motor development may be less confounded with socio-hereditary 

cofactors in lower socioeconomic status populations than cognitive or other language-based indices. 

After adjusting for HOME scores, maternal IQ, social class, and child sex and race, both neonatal and 

postnatal PbB were associated with poorer performance on a measure of upper-limb speed and dexterity 

and a composite index of fine motor coordination. Prenatal (maternal) PbB was not related to motor 

proficiency. Further analysis of the results revealed that children having a mean lifetime PbB of ≥9 μg/dL 
LEAD 124 

3. HEALTH EFFECTS 

appeared to experience a deficit on both the Bilateral Coordination subtests and Fine Motor Composite 

relative to children in the lowest PbB quartile. Information collected at approximately 6.5, 11, and 

15 years of age showed that children with the highest PbB at age 15 years (mean, 2.8 μg/dL; range, 1– 

11.3 μg/dL) had lower verbal comprehension scores over time and greater decline in their rate of 

vocabulary development at age 15 than children with lower PbB (Coscia et al. 2003). The study also 

showed that socioeconomic status and maternal intelligence were statistically significantly associated 

with growth patterns in both tests scores, independent of the effects of lead. The most recent publication 

in this series provides the results of a neuropsychological evaluation of 195 adolescents age 15– 

17 years old from this cohort (Ris et al. 2004). The neuropsychological tests yielded five factors labeled 

Memory, Learning/IQ, Attention, Visual Construction, and Fine-Motor. The results showed a significant 

effect of PbB at 78 months on the Fine-Motor factor. The results also showed a stronger association 

between lead exposure and Attention and Visuoconstruction in males than in females. The study also 

confirmed that adolescents from disadvantaged homes had increased vulnerability toward the effects of 

lead. 

The Cleveland, Ohio, study evaluated neurodevelopmental effects in a sample of urban, disadvantaged, 

mother-infant pairs (33% black) (Ernhart et al. 1985, 1986, 1987). The mean PbBs at the time of delivery 

were 6.5 μg/dL (range, 2.7–11.8 μg/dL) for 185 maternal samples and 5.8 μg/dL (range, 2.6–14.7 μg/dL) 

for 162 cord samples. There were 132 mother-infant pairs with complete data. The infants were 

evaluated for anomalies using a systematic, detailed protocol and for neurobehavioral effects using the 

NBAS and part of the Graham-Rosenblith Behavioral Examination for Newborns (G-R), including a 

Neurological Soft Signs scale. Hierarchical regression analysis was performed. No evidence of an 

association between PbB and morphological anomalies was found. Using the complete set of data, 

abnormal reflexes and neurological soft signs scales were significantly related to cord PbB and the muscle 

tonicity scale was significantly related to maternal PbB. Using data from the mother-infant pairs, the only 

significant association that was found was between the Neurological Soft Signs score and cord PbB, 

which averaged 5.8 μg/dL and ranged up to only 14.7 μg/dL; no association with maternal PbBs was seen 

(Ernhart et al. 1985, 1986). A later analysis related PbBs obtained at delivery (maternal and cord blood) 

and at 6 months, 2 years, and 3 years of age to developmental tests (MDI, PDI, Kent Infant Development 

Scale [KID], and Stanford-Binet IQ) administered at 6 months, 1 year, 2 years, and 3 years of age, as 

appropriate (Ernhart et al. 1987). After controlling for covariates and confounding risk factors, the only 

significant associations of PbB with concurrent or later development were an inverse association between 

maternal (but not cord) PbB and MDI, PDI, and KID at 6 months, and a positive association between 

6-month PbB and 6-month KID. The investigators concluded that, taken as a whole, the results of the 
LEAD 125 

3. HEALTH EFFECTS 

21 analyses of correlation between PbB and developmental test scores were "reasonably consistent with 

what might be expected on the basis of sampling variability," that any association of PbB with measures 

of development was likely to be due to the dependence of both PbB and development on the caretaking 

environment, and that if low-level lead exposure has an effect on development, the effect is quite small. 

Ernhart et al. (1987) also analyzed for reverse causality (i.e., whether developmental deficit or 

psychomotor superiority in infants at 6 months of age contributes to increases in subsequent blood lead 

levels). No significant correlations were observed when covariates were controlled. Greene and Ernhart 

(1991) conducted further analyses of the 132 mother-infant pairs in the Cleveland Prospective Study 

searching for a potential relationship between prenatal lead exposure and neonatal size measures (weight, 

height, and head circumference) and gestational age. No such relationship was observed. 

Table 3-5 presents a summary of the major prospective studies. 

While the majority of the available studies of neurobehavioral effects of lead in children have observed 

associations between increasing lead burden and measures of cognitive development, a smaller number of 

studies failed to detect such effects. Harvey et al. (1988) found no significant correlation between PbB 

(mean 13 μg/dL) and measures of IQ in a study of 201 children 5.5 years of age in England. Similar 

results were reported by McBride et al. (1982), Smith et al. (1983), Lansdown et al. (1986), Ernhart and 

Greene (1990), Wolf et al. (1994), Minder et al. (1998), and Prpić-Majić et al. (2000). In the former five 

studies, the mean PbB was between 10 and 16 μg/dL, whereas in the Minder et al. (1998) and Prpić-Majić

et al. (2000) studies, the mean PbBs were 4.4 μg/dL (range, 0.8–16 μg/dL) and 7.1μg/dL (range, 2.4– 

14.2 μg/dL), respectively. Finding diverging results in the assessment of such complex parameters is not 

totally unexpected given the differences in methodology and the statistical issues involved (see 

Chapter 2 for further discussion). 

Meta-analyses. Needleman and Gatsonis (1990) did a meta-analysis of 12 studies, 7 of which used blood 

lead as a measure of exposure and 5 used tooth lead. Covariates examined by the studies were SES; 

parental factors (i.e., parent health score); parent IQ; parental rearing measures; perinatal factors (i.e., 

birth weight, length of hospital stay after birth); physical factors (i.e., age, weight, medical history), and 

gender. The t-value of the regression coefficient for lead was negative in all but one study, and ranged 

from -0.36 to 0.48 in the PbB group and from -3 to -0.03 in the tooth lead group. Their analysis also 

showed that no single study appeared to be responsible for the significance of the final finding. 

Somewhat unusual in this analysis is the fact that the evaluation is based on accumulated p values rather 

than accumulated effect sizes. Pocock et al. (1994) analyzed 5 prospective studies, 14 cross-sectional 
Table 3-5. Major Prospective Studies of Intellectual Development in Children 

Outcome 

Study cohort Lead biomarker measured Results and main conclusions Refe592 Infants born to women living near a smelter in Port Pirie, Australia, followed from birth to age 11–13. 112 Infants born to women in Mexico City, Mexico, followed at 6 months intervals between ages 6 and 60 months. 

577 Infants born to women living near a lead smelter, refinery, and battery plant in K. Mitrovica, Yugoslavia, followed from birth to age 12. 

216 Middle- and upperclass Boston, Massachusetts, children followed from birth to age 10. 

Mean cord PbB was 10 μg/dL; 21.2 μg/dL at age 2; 7.9 μg/dL at age 11–13 Mean PbB at 6–18 months was 10.1 μg/dL; 9.7 μg/dL at 24–63 months; 8.4 μg/dL at 42–54 months 

Mean PbB at birth was 22.4 μg/dL; 39.9 μg/dL at age 4; 31 μg/dL at age 12; mean tibia lead was 39 ppm at age 12 

90% of cord PbB was <16 μg/dL; mean PbB of 7 μg/dL at 24 months 

MDI, GCI, IQ GCI 

MDI, GCI, WISC, IQ 

MDI, PDI, GCI, WISC, IQ 

Four point difference in MDI score 

between top and bottom PbB tertiles at age 2; 4.8 point difference in GCI score at age 4; 4.5 IQ points difference at age 11–13. Deficits associated with lead were only partially reversed by decline in blood lead past infancy. 

Increasing PbB at 24–36 months 

associated with lowed GCI at 48 months; increasing PbB at 42– 54 months associated with lower GCI at 54 months. Postnatal, but not prenatal PbB associated with intellectual function. 

PbB was associated with poorer MDI at age 2, GCI at age 4, WISC at age 7. Tibia lead showed stronger association with IQ decrements than PbB at age 12. Both prenatal and postnatal PbB independently associated with small decrements in IQ. 

Inverse correlation between cord PbB and MDI scores at 6, 12, 18, and 24 months. No correlation between PDI scores and PbB. Lower GCI at age 5 correlated with PbB at age 2, but not prenatal PbB. Full scale IQ at age 10 associated with PbB at 24 months. Timing of exposure more important than magnitude alone. 

Bagh199519881996Roth1994

Fact199919922003 

Belli198519871991
Table 3-5. Major Prospective Studies of Intellectual Development in Children 

Outcome 

Study cohort Lead biomarker measured Results and main conclusions Refe305 Children born to women living in predesignated lead-hazardous areas of Cincinnati, Ohio, followed to age 15–17. 

Mean prenatal PbB was 8 μg/dL; cord PbB was 6.3 μg/dL; 5.9 μg/dL at 3 months; 2.8 μg/dL at age 15 years 

K-ABC, MDI, PDI 

Prenatal PbB inversely correlated with MDI at 3 and 6 months. Lower KABC scores at 4 years associated with higher neonatal PbB. Postnatal PbB associated with lower performance IQ at 6.5 years. Neonatal and postnatal PbB associated with altered motor 

Coscet al1991al. 2

development at age 6. 

389 Children born to urban disadvantaged women in Cleveland, Ohio followed from birth to 7 years old. 

Mean PbB in cord was 5.8 μg/dL; mean prenatal PbB was 6.5 μg/dL 

MDI, PDI, KID, NBAS, IQ 

Neurological soft signs associated with cord PbB. Only maternal PbB at delivery (6.5 μg/dL) associated with MDI, PDI, and KID scores at 6 months. Dentine lead at 5 years associated with decreased verbal and full scale IQ. 

Ernh1987Ernh

GCI = McCarthy General Cognitive Index; KABC = Kaufman Assessment Battery for Children; KID = Kent Infant Development Scale; MD

Index; NBAS = Brazelton Neonatal Behavioral Assessment Scale; PDI = Psychomotor Developmental Index; WISC = Weschler Intellige
LEAD 128 

3. HEALTH EFFECTS 

studies of blood lead, and 7 cross-sectional studies of tooth lead separately and together. Only studies 

published since 1979 were included in the analysis. Analyses of the prospective studies showed no 

association of cord blood lead or antenatal maternal blood lead with subsequent IQ. PbB at around age 

2 had a small and significant inverse association with IQ, which was greater than that for mean PbB over 

the preschool years; the estimated mean change was -1.85 IQ points for a change in PbB from 10 to 

20 μg/dL. For the cross-sectional studies of PbB, the combined estimate for mean change in IQ for a 

change in PbB from 10 to 20 μg/dL was -2.53 IQ points. For the cross-sectional studies of tooth lead, the 

mean change in IQ for a change in tooth lead from 5 to 10 μg/g was -1.03 IQ points. Comparison of the 

association with and without adjustment for covariates showed that, with few exceptions, adjusting 

reduced the association by <1.5 points. Analysis of the 26 studies simultaneously indicated that a 

doubling of PbB from 10 to 20 μg/dL or of tooth lead from 5 to 10 μg/g is associated with a mean deficit 

in Full Scale IQ of around 1–2 IQ points. A threshold below which there is negligible influence of lead 

could not be determined. 

An analysis carried out by Schwartz (1994) included a total of eight studies, three longitudinal and five 

cross-sectional, relating blood lead to Full Scale IQ in school age children. To evaluate potential 

confounding, the baseline meta-analysis was followed by sensitivity analyses in order to contrast results 

across studies that differ on key factors that are potential confounders. The analyses showed an estimated 

decrease of 2.57 IQ points for an increase in PbB from 10 to 20 μg/dL. Analyses that excluded individual 

studies showed that no single study appeared to dominate the results. For longitudinal studies, the loss 

was 2.96 IQ points and for cross-sectional studies, the loss was 2.69 IQ points. For studies in 

disadvantaged populations, the estimated IQ loss was 1.85 IQ points versus 2.89 IQ points in 

nondisadvantaged populations. Also of interest in Schwartz’s analysis was the fact that a trend towards a 

higher slope at lower blood lead levels was seen. Direct analysis of the Boston prospective study 

(Bellinger et al. 1992), which had the lowest mean PbB concentration (6.5 μg/dL) showed no evidence of 

a threshold for the effects of lead on IQ. 

The European Multicenter Study (Winneke et al. 1990) combined eight individual cross-sectional studies 

from eight European countries that shared a common protocol with inherent quality assurance elements. 

A total of 1,879 children, age 6–11 years, were studied. PbB concentration was used as a measure of 

exposure, and the range was 5–60 μg/dL. The overall statistical analysis was done using a uniform 

predetermined regression model with age, gender, occupational status of the father, and maternal 

education as confounders or covariates. The results of the analyses showed an inverse association 

between PbB and IQ of only borderline significance (p<0.1), and a decrease of 3 IQ points was estimated 
LEAD 129 

3. HEALTH EFFECTS 

for a PbB increase from 5 to 20 μg/dL. Much higher and significant associations were found for tests of 

visual-motor integration and in serial choice reaction performance. Yet, the outcome variance explained 

by lead never exceeded 0.8% of the total variance. No obvious threshold could be located on the doseeffect curves. 

A Task Group on Environmental Health Criteria for Inorganic Lead conducted separate meta-analyses on 

four prospective studies and four cross-sectional studies (IPCS 1995). The European Multicenter Study 

was one of the cross-sectional studies included in the analyses. The outcome measured was Full Scale IQ 

at age 6–10 years old, and the measure of exposure was PbB. In the analyses of prospective studies, when 

cumulative exposure rather than lead at a specific time was used as measure of exposure, the association 

between changes in PbB and changes in IQ did not reach statistical significance (p>0.05). However, 

weighing studies according to the inverse of their variance produced a weighed mean decrease in Full 

Scale IQ of 2 points for a 10 μg/dL increase in PbB. When PbB at specific times were considered, the 

inverse association varied from significant and very strong to less strong and of borderline significance, 

depending on the specific time chosen. Analyses of cross-sectional studies showed a significant inverse 

association between increase in PbB and decrease in IQ in only 2 out 10 studies; however, there was no 

evidence of statistical heterogeneity. The meta-analysis estimated that Full Scale IQ was reduced by 

2.15 IQ points for an increase on PbB from 10 to 20 μg/dL. IPCS (1995) also confirmed the positive 

association between lead measures and indicators of social disadvantage. When social and other 

confounding factors are controlled, the effect in most cases was to reduce the strength of the association 

between lead measures and IQ without, however, changing the direction. IPCS (1995) concluded that 

their analysis revealed a consistency between studies which pointed towards a “collectively significant” 

inverse association between PbB and full-scale IQ. IPCS (1995) also noted that below the 10–20 μg/dL 

PbB range, “uncertainties increased, concerning firstly the existence of an association and secondly 

estimates of the magnitude of any putative association.” 

Thacker et al. (1992) reviewed 35 reports from five prospective studies that examined the relationship 

between PbB and mental development in children. However, efforts to pool the data with meta-analytic 

techniques were unsuccessful because the methods used in the studies to analyze and report data were 

inconsistent. Specific issues mentioned by Thacker et al. (1992) included (a) IQ and PbB were not 

always measured at comparable times in different studies, (b) there were differences among studies in 

independent variable, data transformations, and statistical parameters reported, (c) results conflicted when 

measurement intervals were comparable, (d) patterns of regression and correlation coefficients were 

inconsistent, and (e) data were insufficient to interconvert the parameters reported. 
LEAD 130 

3. HEALTH EFFECTS 

Lead and Delinquent Behavior. The possible association between lead and antisocial behavior has been 

examined in several studies. In 1996, Needleman and coworkers published the results of a study of 

301 young males in the Pittsburgh School System. After adjustment for covariates, the investigators 

found that bone lead levels at 12 years of age were significantly related to parents and teacher’s Child 

Behavior Checklist ratings of aggression, attention, and delinquency. A later study from the same group 

of investigators reported the results of a case-control study of 194 youths aged 12–18, arrested and 

adjudicated as delinquent by the Juvenile Court of Allegheny County, Pennsylvania, and 146 nondelinquent controls from high schools in the city of Pittsburgh (Needleman et al. 2002). The association 

between delinquent status and bone lead concentrations was modeled using logistic regression. Also, 

separate regression analyses were conducted after stratification by race. Care was taken to insure that 

unidentified delinquents did not populate the control group. Bone lead was significantly higher in cases 

than in controls (11.0 vs. 1.5 ppm) and this also applied to both racial categories, white and African 

American. After adjusting for covariates and interactions, and removal of noninfluential covariates, 

adjudicated delinquents were 4 times more likely to have bone lead concentrations higher than 25 ppm 

than controls. Covariates included in the models were child race; parental education and occupation; 

absence of two parental figures in the home; number of children in the home; and neighborhood crime 

rate. Limitations of the study include the lack of blood lead data and definition of dose-effect 

relationships. Also, explicit information on SES factors was not provided and there were large 

differences in social confounders between cases and controls. 

Dietrich et al. (2001) examined the relationships between prenatal and postnatal exposure to lead and 

antisocial and delinquent behaviors in a cohort study of 195 urban, inner city adolescents recruited from 

the Cincinnati Prospective Lead Study between 1979 and 1985. At the time of the study, the subjects 

were between approximately 15 and 17 years of age; 92% were African-American and 53% were male. 

The mean prenatal (maternal) PbB concentration was 8.9 μg/dL. Blood was sampled shortly after birth 

and on a quarterly basis thereafter, until the children were 5 years old. From birth to 5 years of age, 35% 

of the cohort had PbBs in excess of 25 μg/dL, 79% >15 μg/dL, and 99% >10 μg/dL. As adolescents, the 

mean PbB was 2.8 μg/dL. After adjustment for covariables that were independently associated with 

delinquent behavior, prenatal blood lead concentration was significantly associated with an increase in the 

frequency of parent-reported delinquent and antisocial behaviors, while prenatal and postnatal blood lead 

concentrations (i.e., at 78 months or childhood average) were significantly associated with an increase in 

the frequency of self-reported delinquent and antisocial behaviors, including marijuana use. Limitations 

of the study are the inclusion of only four variables in the covariate analysis despite the fact that nine 
LEAD 131 

3. HEALTH EFFECTS 

were selected, only total scores were reported omitting the results for all delinquency variables, and 

maternal levels but not cord levels were used in the analysis. 

Two ecological investigations correlated leaded gasoline sales or ambient lead levels with crime rates. 

Stretesky and Lynch (2001) examined the relationship between air lead concentrations and the incidence 

of homicides across 3,111 counties in the Unites States. The estimated air lead concentrations across all 

counties ranged from 0 to 0.17 μg/m3

. After adjusting for sociologic confounding and nine measures of 

air pollution, they reported a 4-fold increase in homicide rate in those counties with the highest air lead 

levels compared to controls. Nevin (2000) found a statistical association between sales of leaded gasoline 

and violent crime rates in the United States after adjusting for unemployment and percent of population in 

the high-crime age group. As with most ecological investigations, the results are difficult to interpret 

because there are no measurements of individual exposure levels or controls of confounders. 

Many of the behavioral deficits observed in children exposed to lead have been reproduced in studies in 

animals, particularly monkeys, and at similar blood lead levels. Such studies have suggested that the 

impaired performance on a variety of tasks is the result, at least in part, of a combination of distractibility, 

inability to inhibit inappropriate responding, and perseveration in behavior that are no longer appropriate. 

Behavioral tests that have been proven useful in this area of research include discrimination reversal, 

spatial delayed alternation, delayed matching to sample, and intermittent schedules of reinforcement. 

Representative studies are summarized below. Additional information can be found in reviews about this 

topic and references therein (Cory-Slechta 1995, 1997, 2003; Rice 1993, 1996a). 

Rhesus monkeys treated orally from birth with doses of lead that produced PbBs ≥32 μg/dL for 5 months 

to 1 year showed impairment in a series of discrimination reversal tasks early in life and when they were 

tested at 33 months of age and at 49–55 months of age (Bushnell and Bowman 1979a, 1979b). The 

monkeys tested at 49–55 months of age had mean PbBs of 4, 5, and 6 μg/dL, for controls, low-dose, and 

high-dose monkeys, respectively. The corresponding mean PbBs during the year of treatment were 4, 32, 

and 65 μg/dL. Additional experiments were conducted in monkeys exposed to lower levels of lead that 

peaked at approximately 15 or 25 μg/dL, and then decreased to steady state PbBs of about 11 and 

13 μg/dL, respectively (Rice 1985). At 3 years of age, the monkeys were tested on a series of nonspatial 

discrimination reversal problems with irrelevant form cues, which provided the opportunity to study 

distractibility. The results showed that the treated monkeys attended to irrelevant cues in a systematic 

way. This suggested that the treated monkeys were being distracted by the irrelevant cues to a greater 

degree than the controls. Similar conclusions were reached when these same monkeys were tested again 
LEAD 132 

3. HEALTH EFFECTS 

at 9–10 years of age on a series of spatial discrimination reversal tasks without irrelevant cues. Studies in 

which the dosing periods varied in order to evaluate possible sensitive periods of exposure showed that 

spatial and nonspatial tasks were affected differentially depending on the developmental period of lead 

exposure (Rice 1990; Rice and Gilbert 1990a). These studies also suggested that while exposure 

beginning after infancy produces impairment, continuous exposure during and after infancy magnifies the 

effects. 

Spatial delayed alternation testing has provided evidence of perseverative behavior and inability to inhibit 

inappropriate responding. For example, Levin and Bowman (1986) dosed monkeys from birth to 1 year 

of age, a regimen that produced PbBs of approximately 80 μg/dL during most of the treatment period, 

although peak PbB reached near 300 μg/dL during the initial phase of treatment. Tests conducted when 

the monkeys were 5–6 years of age, when mean PbB was about 5μg/dL, indicated that the treated 

monkeys perseverated on an alternation strategy even when it was not rewarded. Inappropriate 

responding also was observed in monkeys that had much lower (11–13 μg/dL) steady state PbBs and were 

tested at 7–8 years of age (Rice and Karpinski 1988). Further studies to determine possible sensitive 

periods of exposure showed no significant difference in the degree of impairment on a spatial delayed 

alternation task among three groups of monkeys exposed at different times during development (Rice and 

Gilbert 1990b). One group of monkeys was dosed with lead from birth onward; another group was dosed 

from birth to 400 days of age, and a third group began to receive lead at 300 days of age; testing was 

conducted at that 6–7 years of age. Perseverative behavior has also been put in evidence in studies in 

monkeys using the delayed matching to sample paradigm (Rice 1984). 

Further evidence that lead induces behavior that can be characterized as failure to inhibit inappropriate 

responding has been obtained using intermittent schedules of reinforcement, particularly, the fixed 

interval (FI) schedule of reinforcement. For instance, monkeys with a steady-state PbB of approximately 

30 μg/dL tended to respond excessively or inappropriately (e.g., with more responses than controls during 

time-outs) when responses were not rewarded (Rice and Willes 1979). In addition, lead-treated monkeys 

with a steady-state PbB of 11 or 13 μg/dL were also slower to learn reinforcement schedule, which 

required a low rate of responding (Rice and Gilbert 1985). Similar observations were made in adult 

monkeys dosed with lead from birth, having a peak PbB of 115 μg/dL by 100 days of age and a steady 

state PbB of 33 μg/dL at 270 days of age (Rice 1992). Increases in response rate on FI performance have 

been seen in rats at comparable PbB to those in monkeys. For example, Cory-Slechta et al. (1985) 

reported that postweaning exposure of rats having PbBs of 15–20 μg/dL had a significantly higher rate of 

response and significantly shorter interval bar-press responses on a FI operant schedule of food 
LEAD 133 

3. HEALTH EFFECTS 

reinforcement than control rats. Similar results were obtained at higher exposure levels in a series of 

earlier studies (Cory-Slechta and Thompson 1979; Cory-Slechta et al. 1981, 1983). The same group of 

investigators also showed that rats exposed to lead after weaning and having a PbB of approximately 

11 μg/dL showed inappropriate responding in a Fixed-Ratio (FR) waiting-for-reward paradigm (Brockel 

and Cory-Slechta 1998). Treated rats increased the response rates and decreased the mean longest 

waiting time than control rats. 

Peripheral Neurological Effects in Children. Effects of lead on peripheral nerve function have 

been documented in children. Frank peripheral neuropathy has been observed in children at PbBs of 60– 

136 μg/dL (Erenberg et al. 1974). Of a total of 14 cases of childhood lead neuropathy reviewed by 

Erenberg et al. (1974), 5 also had sickle cell disease (4 were black), a finding that the authors suggested 

might indicate an increased susceptibility to lead neuropathy among children with sickle cell disease. 

Seto and Freeman (1964) reported signs of peripheral neuropathy in a child with a PbB of 30 μg/dL, but 

lead lines in the long bones suggested past exposures leading to peak PbB of ≥40–60 μg/dL and probably 

in excess of 60 μg/dL (EPA 1986a). NCV studies have indicated an inverse correlation between peroneal 

NCV and PbB over a PbB range of 13–97 μg/dL in children living near a smelter in Kellogg, Idaho 

(Landrigan et al. 1976). These data were reanalyzed to determine whether a threshold exists for this 

effect. Three different methods of analysis revealed evidence of a threshold for NCV at PbBs of 20– 

30 μg/dL (Schwartz et al. 1988). NCV in the sural and peroneal nerves from young adults exposed to 

lead during childhood (20 years prior to testing) while living near a lead smelter in the Silver Valley, 

Idaho, were not significantly different than in a control group. Current PbBs in the exposed and control 

groups were 2.9 and 1.6 μg/dL, respectively. Data from past blood lead surveillance indicated a mean 

childhood PbB of approximately 45 μg/dL. 

Other Neurological Effects in Children. Several studies of associations between lead exposure 

and hearing thresholds in children have been reported, with mixed results. A study of 49 children aged 6– 

12 years revealed an increase in latencies of waves III and V of the BAEP associated with PbB measured 

5 years prior to the tests (mean, 28 μg/dL) (Otto et al. 1985). The current mean PbB was 14 μg/dL (range, 

6–59 μg/dL). Assessment of a group of children from the Mexico City prospective study revealed 

significant associations between maternal PbB at 20 weeks of pregnancy (geometric mean, 7.7 μg/dL; 

range, 1–31 μg/dL) and brainstem auditory evoked responses in 9–39-day-old infants, 3-month-old 

infants, and children at 67 months of age (Rothenberg et al. 1994b, 2000). In the most recent assessment, 

I–V and III–V interpeak intervals decreased as PbB increased from 1 to 8 μg/dL and then increased as 

PbB rose from 8 to 31 μg/dL. Rothenberg et al. (2000) hypothesized that the negative linear term was 
LEAD 134 

3. HEALTH EFFECTS 

related to lead effect on brainstem auditory pathway length, and that the positive term was related to 

neurotoxic lead effect on synaptic transmission or conduction velocity. 

Robinson et al. (1985) and Schwartz and Otto (1987, 1991) provided suggestive evidence of a leadrelated decrease in hearing acuity in 75 asymptomatic black children, 3–7 years old, with a mean PbB of 

26.7 μg/dL (range, 6–59 μg/dL). Hearing thresholds at 2,000 Hertz increased linearly with maximum 

blood lead levels, indicating that lead adversely affects auditory function. These results were confirmed 

in an examination of a group of 3,545 subjects aged 6–19 years who participated in the Hispanic Health 

and Nutrition Survey (Schwartz and Otto 1991). An increase in PbB from 6 to 18 μg/dL was associated 

with a 2-dB loss in hearing at all frequencies, and an additional 15% of the children had hearing 

thresholds that were below the standard at 2,000 Hz. 

Osman et al. (1999) found a significant association between blood lead concentration (2–39 μg/dL) and 

hearing thresholds in a group of 155 children ages 4–14 years, after adjustment for covariates. The 

association remained significant when the analysis was confined to 107 children who had blood lead 

concentrations below 10 μg/dL. Osman et al. (1999) also reported increased latency of wave I of the 

BAEP in children with PbB above 10 μg/dL compared to children with PbB below 4.6 μg/dL. Covariates 

included in the regression models were child gender age, Apgar score, absence of ear and nasopharynx 

pathologies; history of ear diseases, frequent colds, mumps, gentamycin use, or exposure to 

environmental noise; and maternal smoking during pregnancy. Increased BAEP interpeak latencies was 

also described in a study of Chinese children with a mean PbB of 8.8 μg/dL (range, 3.2–38 μg/dL) after 

controlling for age and gender as confounding factors (Zou et al. 2003). 

In contrast with results of the studies mentioned above, Counter et al. (1997a) found no difference in 

hearing threshold between groups of children who had relatively low or higher exposures to lead (mainly 

from local ceramics glazing and automobile battery disposal). PbBs were 6 μg/dL (range, 4–12 μg/dL, 

n=14) and 53 μg/dL (10–110 μg/dL, n=62), respectively. In a separate study of the same cohort, Counter 

et al. (1997b) found normal wave latencies and neural transmission times, and no correlation between 

PbB and interpeak latencies in children with a median PbB of 40 μg/dL (range, 6.2–128.2 μg/dL). 

Furthermore, audiological tests showed normal cochlear function and no statistical relation between 

auditory thresholds and PbB concentration. Subsequent studies of these children showed no evidence that 

PbB affected the cochlea (Buchanan et al. 1999) or BAEP interpeak conduction (Counter 2002). It is 

worth noting that Counter and coworkers studied children in small villages in the Andes mountains who 

may not be very representative of the general population. 
LEAD 135 

3. HEALTH EFFECTS 

Studies in animals also have provided mixed results regarding exposure to lead and auditory function. 

Some monkeys dosed with lead from birth through 13 years of age had elevated thresholds for pure tones, 

particularly at higher frequencies (Rice 1997). These monkeys had a PbB of approximately 30 μg/dL 

until 10–11 years old and 50–70 μg/dL when they were tested at 13 years of age. Studies by Lasky et al. 

(1995) and Lilienthal and Winneke et al. (1996) in monkeys chronically exposed to lead and with 

moderate PbBs suggested that lead might be altering cochlear function. However, a more recent study by 

Lasky and coworkers showed that continuous exposure of monkeys beginning shortly after birth until 1– 

2 years old, resulting in PbB 35–40 μg/dL, had no significant effect on middle ear function, cochlear 

function, or auditory evoked potentials assessed at least 1 year after exposure to lead (Lasky et al. 2001c). 

A study of 384 6-year-old German children with a geometric mean PbB concentration of 4.3 μg/dL 

(range, 1.4–17.4 μg/dL) from three environmentally contaminated areas in East and West Germany found 

significant lead-related deficits for two out of three visual evoked potentials (VEP) interpeak latencies 

after adjusting for confounding effects (Altmann et al. 1998). No association was found between PbB 

concentrations and VEP amplitudes. These results confirmed previous findings from the same group of 

investigators (Winneke et al. 1994). Altmann et al. (1998) also measured visual contrast sensitivity and 

found no significant association between this parameter and lead. Alterations in scotopic (rod-mediated) 

retinal function were reported in a group of 45 children (7–10 years old) participants in the Mexico City 

Lead Study (Rothenberg et al. 2002a). The association was significant only with lead measures during 

the first trimester of pregnancy and not with other periods during pregnancy or throughout postnatal 

development. The threshold for the effect was 10.5 μg/dL. Results from studies in animals are in general 

agreement with the findings in humans. For example, studies in rats exposed to lead via the mother’s 

milk, which produced PbBs of approximately 19 μg/dL in the pups, reported reductions in retinal 

sensitivity attributed to selective alterations of the rods (Fox et al. 1991, 1997). Impairment of scotopic 

visual function was reported in monkeys treated with lead during the first year of life to produce mean 

PbBs of 55 or 85 μg/dL and tested 18 months later when PbBs had returned near controls levels 

(14 μg/dL) (Bushnell et al. 1977). Lilienthal et al. (1988) reported alterations in visual evoked potentials 

and in the ERG in monkeys exposed to lead during gestation and then for life, and tested at approximately 

7 years old; at this time, the PbBs in the two treated groups were approximately 40 and 60 μg/dL. 

Alterations of the ERG under scotopic conditions were still present when the monkeys were tested again 

more than 2 years after termination of exposure (Lilienthal et al. 1994). Rice (1998) reported that lifetime exposure of monkeys to lead producing steady-state PbBs between 25 and 35 μg/dL altered temporal 
LEAD 136 

3. HEALTH EFFECTS 

visual function, in six out of nine animals; however, there was no evidence of impairment of spatial visual 

function. 

Bhattacharya et al. (1993) examined the effect of lead exposure on postural balance in 109 children from 

the Cincinnati Lead Program Project. The mean age of the children was 5.8 years and the geometric 

mean PbB for the first 5 years of life was 11.9 μg/dL (range, 5.1–28.2 μg/dL). Balance was assessed in a 

system that provided a quantitative description of postural sway by measuring the movement pattern of 

the body’s center of gravity during testing. Sway area was significantly correlated with PbB in tests 

performed with the eyes closed, but not in a test performed with the eyes open. This led the authors to 

suggest that lead-induced sway impairment might be related to modifications of the functions of 

vestibular and proprioception systems, on which close-eye tests rely more. Sway length was significantly 

correlated with blood lead under all test conditions. 

3.2.5 Reproductive Effects 

A number of studies have examined the potential association between lead exposure and reproductive 

parameters in humans. The available evidence suggest that occupational and environmental exposure 

resulting in moderately high PbBs might result in abortion and pre-term delivery in women, and in 

alterations in sperm and decreased fertility in men. 

Effects in Females. Female workers at a lead smelter in Sweden had an increased frequency of 

spontaneous miscarriage when employed during pregnancy (294 pregnancies, 13.9% ended in spontaneous abortion) or when employed at the smelter prior to pregnancy and still living within 10 km of the 

smelter (176 pregnancies, 17% ended in spontaneous abortion) (Nordstrom et al. 1979). The abortion 

rates in these two groups of pregnant women were significantly higher than in women who were pregnant 

before they became employed at the smelter and in women who became pregnant after employment but 

lived >10 km from the smelter. Although no environmental or biological monitoring for lead was 

available, women who worked in more highly contaminated areas of the smelter were more likely to have 

aborted than were other women. A nested control-case study of a cohort of 668 pregnant women in 

Mexico City showed that the risk of spontaneous abortion (defined as loss of pregnancy by gestation 

week 20) increased with increasing PbB (Borja-Aburto et al. 1999). Notably, there was a 1.13-fold 

increase in the risk of spontaneous abortion per μg/dL increase in PbB. Mean PbBs in cases and controls 

were 12.0 and 10.1 μg/dL, respectively. 
LEAD 137 

3. HEALTH EFFECTS 

Negative associations also have been reported. For instance, no association was found between PbBs and 

spontaneous abortions in a cohort of women living in Port Pirie, a lead smelter community in South 

Australia and the surrounding rural area and neighboring towns (Baghurst et al. 1987). Mean, 

midpregnancy PbBs in women living in Port Pirie or outside of the town were 10.6 μg/dL (n=531) and 

7.6 μg/dL (n=171), respectively (Baghurst et al. 1987; McMichael et al. 1986). While no association was 

found between PbB and spontaneous abortions, 22 of 23 miscarriages and 10 of 11 stillbirths occurred 

among the Port Pirie residents, with only 1 miscarriage and 1 stillbirth occurring among residents outside 

Port Pirie. Maternal PbB was lower in the cases of stillbirth than in the cases of live birth, but fetal and 

placental levels in this and another study (Wibberley et al. 1977) were higher than in cases of normal 

birth. Davis and Svendsgaard (1987) suggested that these findings may be due to a transfer of lead from 

mother to fetus, which is toxic to the fetus. Alexander and Delves (1981) showed a reduction in maternal 

PbB during the progression of pregnancy and concluded that the reduction could not be explained by 

dilution of PbB in an increasing plasma volume. The authors suggested that lead was being transferred to 

placental or fetal tissues or eliminated from maternal blood via other pathways. The rates of spontaneous 

abortions were also compared in a prospective study of females living close to a lead smelter 

(midpregnancy mean PbB, 15.9 μg/dL; n=304) and females living 25 miles away (midpregnancy mean 

PbB, 5.2 μg/dL; n=335) (Murphy et al. 1990). Women were recruited at midpregnancy and their past 

reproductive history (first pregnancy; spontaneous abortion/fetal loss prior to 7th month; stillbirth/fetal 

loss from 7th month) was examined. The results indicated no difference between the two groups. The 

spontaneous abortion rates in women living close to the smelter or 25 miles away were 16.4 and 14.0%, 

respectively, but the differences were not statistically significant. 

In the study of Australian women mentioned above, the rate of preterm delivery (delivery before the 

37th week) was significantly higher in women living in the smelter town (566 pregnancies, 5.3% preterm 

deliveries; mean PbB, 11.2 μg/dL at the time of delivery) than in women not living in the town 

(174 pregnancies, 2.9% preterm deliveries; mean PbB, 7.5 μg/dL at the time of delivery) (McMichael et 

al. 1986). Similarly, Torres-Sánchez et al. (1999) observed that preterm births were almost 3 times more 

frequent in women with umbilical PbB ≥5.1 μg/dL than in women with PbB <5.1 μg/dL. In a study of 

121 women biologically monitored for exposure to lead at the Finnish Institute of Occupational Health 

from 1973 to 1983, there was no evidence of alterations in the time-to-pregnancy (TTP) or decreased 

fecundability (Sallmen et al. 1995). Women were categorized as having very low exposure (PbB, 

<10 μg/dL), low exposure (PbB, between 10 and 19 μg/dL), or moderate-to-high exposure (PbB, 

≥20 μg/dL). 
LEAD 138 

3. HEALTH EFFECTS 

Stillbirths have been reported in rats exposed to doses of lead that resulted in PbBs much higher than 

those reported in the studies in women mentioned above. Treatment of Sprague-Dawley rats with lead in 

the drinking water on gestation days 5–21 resulted in 19% incidence of stillbirth compared to 2% 

observed in a control group (Ronis et al. 1996). PbBs in the dams and offspring in this experiment were 

>200 μg/dL. In subsequent studies using a similar experimental protocol, the same group of investigators 

reported that treatment of rats with lead in the drinking water on gestation days 5–21 resulted in 28% 

incidence of stillbirth (Ronis et al. 1998b). The mean PbB level in the pups at birth in this exposure 

group was 197 μg/dL. In studies with female monkeys, exposure to lead in the drinking water for 

75 months resulted in reduced circulating concentration of progesterone, suggesting impaired luteal 

function; however, treatment with lead did not prevent ovulation; the PbB was approximately 70 μg/dL 

(Franks et al. 1989). The monkeys also exhibited longer and more variable menstrual cycles and shorter 

menstrual flow. Female Cynomolgus treated daily for up to 10 years with gelatin capsules containing 

lead acetate had significantly suppressed circulating levels of LH, FSH, and estradiol although 

progesterone concentrations were not significantly affected (Foster 1992). PbB in these monkeys was 

approximately 35 μg/dL. Also, a study in rats showed that exposure to lead can enhance some parameters 

of estrogen stimulation, inhibit other estrogenic responses, and some responses remain unaltered 

(Tchernitchin et al. 2003). In that study, female rats were administered lead acetate every 3 days from 

age 7 days and until they were 19 days old; the PbB in these rats was approximately 47 μg/dL. Lead 

enhanced the estrogen-induced eosinophilia and reduced the estrogen-induced edema deep in the 

endometrial stroma of treated rats. In addition, lead altered the proportion of eosinophils in the different 

histological layers in the uterus. A recent study with human granulosa cell in vitro showed that 

incubation with lead reduced aromatase activity as well as P-450 aromatase and estrogen receptor 

β protein levels (Taupeau et al. 2003). P-450 aromatase converts C19 androgens to C18 estrogenic 

steroids and is essential for follicular maturation, oogenesis, ovulation, and normal luteal functions in 

females. Moreover, mice that lack the ability to synthesize endogenous estrogen suffer folliculogenic 

disruption and fail to ovulate and are thus infertile. Mice that lack the estrogen receptor β also have a 

poor reproductive capacity attributed to folliculogenesis blockade (Taupeau et al. 2003). 

Effects in Males. A study of 2,111 Finnish workers occupationally exposed to inorganic lead showed a 

significant reduction in fertility relative to 681 unexposed men (Sállmen et al. 2000a). The risk ratio (RR) 

for infertility in exposed men appeared to increase with increasing PbB; thus, the RRs for the PbB 

categories 10–20, 21–30, 31–40, 41–50, and ≥51 μg/dL were 1.27, 1.35, 1.37, 1.50, and 1.90, 

respectively; however, there was no evidence of decreased fertility in couples who had achieved at least 

one pregnancy. Based on the latter finding, the authors suggested that lead exposure was not associated 
LEAD 139 

3. HEALTH EFFECTS 

with a delay in pregnancy. A significant reduction in fertility was observed in a group of 74 exposed 

workers (mean exposure period, 10.7 years; mean PbB, 46.3 μg/dL) relative to a control group of 

138 men (mean PbB, 10.4 μg/dL) (Gennart et al. 1992b). Duration of exposure was associated with 

decreased fertility. A study of 4,256 male workers with PbB >40 μg/dL (sampled before 1986) or 

≥25 μg/dL (sampled from 1981–1992) showed a reduction in the number of births relative to a control 

group of 5,148 subjects (Lin et al. 1996). Workers with the highest cumulative exposure to lead had the 

most marked reduction in fertility. A study of 163 Taiwanese male lead battery workers showed 

decreased fertility in men with PbB in the range of 30–39 and ≥40 μg/dL, but there was no significant 

reduction in fertility in men with PbB of ≤29 μg/dL (Shiau et al. 2004). There was no effect on fertility 

among men (n=229) employed in a French battery factory (Coste et al. 1991) or among Danish men 

(n=1,349) exposed to lead (mean PbB of a subset of 400 workers, 39.2 μg/dL) during the manufacture of 

batteries (Bonde and Kolstad 1997). There was weak evidence of increased time-to-pregnancy (TTP) in 

the wives of 251 occupationally-exposed men in Finland with PbB ranging from 10 to 40 μg/dL or higher 

(Sállmen et al. 2000b). The study included only couples who had at least one pregnancy and the 

association was limited to men whose wives were <30 years old. A study with similar exposure levels in 

251 Italian men did not find an association between lead exposure in men and delayed TTP in their wives 

(Apostoli et al. 2000). There was no association between occupational exposure to lead and low fertility 

in a multi-country (Belgium, Finland, Italy, and England) study of 638 men exposed occupationally to 

lead (Joffe et al. 2003). Mean PbB in exposed men ranged from 29.3 to 37.5 μg/dL, but most were below 

50 μg/dL. Although the evidence for reduced fertility is not conclusive, it appears that a threshold for 

fertility effects in men could be in the PbB range of 30–40 μg/dL. 

Studies have shown that sperm quality is affected by occupational exposure to lead. Although there is 

some variation in the results, most of the available studies suggest that reductions in sperm concentration, 

indications of adverse effects on sperm chromatin, and evidence of sperm abnormalities may occur in 

men with mean PbB > 40 μg/dL but not in men with lower PbBs. A study of 81 lead smelter workers 

showed an association between PbB and sperm concentration (Alexander et al. 1998a). In addition, 

although PbB concentrations were not related to serum testosterone, a reduction in serum testosterone 

with increasing semen lead concentration was observed. In a study of 150 male workers with long-term 

lead exposure, men with a mean PbB of 52.8 μg/dL showed asthenospermia, hypospermia, and 

teratospermia (Lancranjan et al. 1975). These effects were not evident in two groups of men with mean 

PbBs of 41 or 23 μg/dL. The effect of lead was thought to be directly on the testes because tests for 

changes in gonadotropin secretion were negative. Secretion of androgens by the testes was not affected. 

A cross-sectional study of 149 industrial workers in Zagreb, Croatia, found that 98 men who had 
LEAD 140 

3. HEALTH EFFECTS 

moderate occupational exposure to lead (mean PbB, 36.7 μg/dL) had significantly lower sperm density, 

and lower counts of total motile and viable sperm; lower percentage and count of progressively motile 

sperm; higher prevalence of morphologically abnormal sperm head; and lower level of indicators of 

prostate secretory function compared with 51 referents (mean PbB, 10.3 μg/dL) (Telisman et al. 2000). 

No significant differences were found for semen volume or percentages of motile, viable, and pathologic 

sperm. Workers also had significantly higher serum estradiol than the refernce group, but there were 

differences in serum FSH, LH, prolactin, and testosterone levels (Telisman et al. 2000). A study of 

workers in a Swedish battery factory showed decreased seminal plasma constituents, low semen volumes, 

and reduced functional maturity of sperm in men with mean PbB of approximately 45 μg/dL during the 

study period (Wildt et al. 1983). The unexposed (control) group of men had a mean PbB of about 

21 μg/dL. A study of men employed in a lead smelter showed that workers with current PbB of 

≥40 μg/dL had an increased risk of below normal sperm and total sperm count relative to those with PbBs 

<15 μg/dL (Alexander et al. 1996). A cross-sectional survey of 503 European workers showed a 49% 

reduction in the median sperm concentration in men with PbB ≥50 μg/dL, whereas there was no 

significant difference in sperm concentration between the reference group of men (mean PbB, ≤10 μg/dL) 

and men with mean PbB of 10–50 μg/dL (Bonde et al. 2002). Although there was no association between 

PbBs and abnormal sperm chromatin, there were indications of deterioration of the sperm chromatin in 

men with the highest lead concentrations in spermatozoa (Bonde et al. 2002). Changes in sperm 

chromatin also have been reported in monkeys exposed to lead for life and with a mean PbB of 56 μg/dL 

(Foster et al. 1996). In mammalian spermatozoa, DNA is tightly packaged with protamines in the 

nucleus. Since lead binds tightly to free thiols, it might compete or replace the zinc atoms that are 

normally bound with nuclear protamines. These changes could affect normal disulfide bond formation, 

alter DNA-protamine binding, or impair chromatin decondensation during fertilization (Quintanilla-Vega 

et al. 2000; Silbergeld et al. 2003). Sperm protamine plays an important role in the condensationdecondensation events that are critical to fertilization, and cases of male infertility have been associated 

with deficiencies in human protamine (Quintanilla-Vega et al. 2000). A recent study from the latter group 

supported their earlier hypothesis that lead affects sperm chromatin condensation (Hernández-Ochoa et al. 

2005). In a group of 68 urban men with a geometric mean PbB of 9.3 μg/dL (range, 1.9–24.4 μg/dL) 54% 

of semen samples showed values for sperm chromatin condensation outside the normal range. In 

addition, evaluation of semen quality parameters and sperm chromatin showed that sperm concentration, 

motility, morphology, and viability were negatively associated with lead in spermatozoa, whereas semen 

volume was negatively associated with lead seminal fluid. PbB did not associate with either semen 

quality parameters or nuclear chromatin decondensation, and PbB did not correlate with lead levels in any 

semen compartment (Hernández-Ochoa et al. 2005). Smaller studies (<40 men/study) of men exposed to 
LEAD 141 

3. HEALTH EFFECTS 

lead have also shown detrimental changes in sperm quality (Assennato et al. 1987; Chowdhury et al. 

1986; Lerda 1992). 

Direct toxic effects of lead on the testicle might mediate the adverse reproductive effects of lead in 

occupationally exposed men. A study of 122 workers (mean PbB, 35.1 μg/dL; mean exposure duration, 

6 years) employed in three lead battery factories in Singapore showed higher serum LH and FSH 

concentrations in the exposed workers than in 49 unexposed individuals (mean PbB, 8.3 μg/dL) (Ng et al. 

1991). However, there was no difference in testosterone levels between these two groups. Raised LH 

and FSH levels are an indication of Leydig and Sertoli cell failure (Ng et al. 1991). These results are in 

general agreement with those of earlier studies of lead workers with high PbBs (≥66 μg/dL). These 

findings indicate that lead can act directly on the testes to cause depression of sperm count and peritubular 

testicular fibrosis, reduced testosterone synthesis, and disruption of regulation of LH (Braunstein et al. 

1978; Cullen et al. 1984; Rodamilans et al. 1988). 

The question of whether lead poisoning as a child can have adverse reproductive effects later in life was 

examined in a group of 35 survivors of childhood plumbism who had been admitted to the Boston 

Children's Hospital for treatment from 1930 to 1944 (Hu 1991b). Plumbism was diagnosed in children 

who showed repeated ingestion of lead-containing material or x-ray or clinical evidence of lead 

poisoning. Although the rates of spontaneous abortions or stillbirths in this group of survivors appeared 

to be higher than in unexposed matched subjects, the differences were not statistically significant (RR, 

1.60; 95% CI, 0.6–4.0). 

Sperm parameters also have been examined in animals exposed to lead. Evaluation of 15–20-year-old 

Cynomolgus monkeys administered lead acetate for their lifetime and having a mean PbB of 56 μg/dL 

showed no significant alterations in parameters of semen quality such as sperm count, viability, motility, 

and morphology, or in circulating levels of testosterone (Foster et al. 1996). Adverse sperm effects have 

been observed in rats, but at relatively high PbBs (Barratt et al. 1989; Hsu et al. 1998a, 1998b). A 

significant reduction in the number of spermatozoa within the epididymis was observed in mice 

administered lead acetate in drinking water for 6 weeks, but PbBs were not provided (Wadi and Ahmad 

1999). In male rats exposed maternally to lead during gestation and lactation and administered lead for an 

additional 9 months after weaning, there were no significant effects on sperm count or sperm morphology 

(Fowler et al. 1980). The PbB in these animals ranged from 4.5 to 67 μg/dL. 
LEAD 142 

3. HEALTH EFFECTS 

Numerous studies in animals have reported testicular effects following exposure to lead. For example, 

Foster et al. (1998) evaluated changes in testis ultrastructure, semen characteristics, and hormone levels in 

monkeys exposed to lead from postnatal day 300 to 10 years of age (postinfancy), from postnatal day 0 to 

400 (infancy), or for their lifetime. PbBs in lifetime and postinfancy exposed monkeys were approximately 35 μg/dL compared to <1.0 μg/dL in controls and infancy exposed animals. Electron microscopic 

analysis revealed disruption of the general architecture of the seminiferous epithelium that involved 

Sertoli cells, basal lamina, and spermatids in the groups exposed for lifetime and during infancy, with 

equal severity. No such alterations were seen controls or in the postinfancy exposure group. The results 

showed that lead exposure in monkeys during infancy can induce testicular alterations that persist in later 

life when blood lead concentrations had decreased considerably. Circulating concentrations of FSH, LH, 

and testosterone were not altered by treatment with lead, and semen characteristics were not affected by 

treatment with lead. Other effects reported in recent studies in rats following oral dosing with lead 

include disorganization and disruption of spermatogenesis and reduction in the activities of the enzymes 

alkaline phosphatase and Na+

-K+-ATPase (Batra et al. 2001), and an increase in the percentage of 

seminiferous tubules showing apoptotic germ cells (Adhikari et al. 2001). No PbBs were reported in 

these two studies. Also, male rats administered lead acetate in water for 1 week (PbB, 12–28 μg/dL) 

showed a dose-related increase in gonadotropin-releasing hormone (GnRH) mRNA (Sokol et al. 2002). 

However, lead did not have an effect on the serum concentrations of hypothalamic gonadotropin-releasing 

hormone (GnRH) or LH, suggesting a compensatory mechanism in the hypothalamic-pituitary axis. In 

the only study of exposure by the inhalation route, CD-1 male mice exposed to 0.01 M lead acetate 

intermittently for 4 weeks showed a time-related increase in the fraction of damaged mitochondria in 

Sertoli cells, which according to the investigators could lead to a transformation process that may 

interfere with spermatogenesis (Bizarro et al. 2003). 

3.2.6 Developmental Effects 

This section summarizes studies of the effects of lead exposure on end points other than neurological in 

developing organisms exposed during the period from conception to maturity. Neurodevelopmental 

effects are summarized in Section 3.2.4. 

No reports were found indicating low levels of lead as a cause of major congenital anomalies. However, 

in a study of 5,183 consecutive deliveries of at least 20 weeks of gestation, cord blood lead was associated 

with the incidence of minor anomalies (hemangiomas and lymphangiomas, hydrocele, skin anomalies, 

undescended testicles), but not with multiple or major malformations (Needleman et al. 1984). In 
LEAD 143 

3. HEALTH EFFECTS 

addition, no particular type of malformation was associated with lead. According to the investigators, the 

results suggested that lead may interact with other teratogenic risk factors to enhance the probability of 

abnormal outcome. 

Anthropometric Indices. Since the report by Nye (1929) of runting in overtly lead-poisoned children, a 

number of epidemiological studies have reported an association between PbB and anthropometric 

dimensions. For example, a study of 1-month-old Mexican infants found that infant PbB (measured at 

birth in umbilical cord and at 1 month of age) was inversely associated with weight gain, with an 

estimated decline of 15.1 grams per μg/dL of blood lead (Sanín et al. 2001). The mean infant (at 

1 month) and maternal PbBs (1 month postpartum) were 5.6 and 9.7 μg/dL, respectively; mean umbilical 

cord lead was 6.8 μg/dL. They also found that children who were exclusively breastfed had significantly 

higher weight gains, but this gain decreased significantly with increasing levels of maternal patella lead. 

An additional study from the same groups of investigators reported that birth length of newborns 

decreased as maternal patella lead increased, and also that patella lead was significantly related to the risk 

of a low head circumference score (Hernandez-Avila et al. 2002). In the Mexico City Prospective Study, 

an increase in PbB at 12 months of age from 6 to 12.5 μg/dL was associated with a decrease in head 

circumference of 0.34 cm (Rothenberg et al. 1999c). Also, a study by Stanek et al. (1998) reported that in 

children aged 18–36 months, with a mean PbB of 6.4 μg/dL, PbB was inversely related with head 

circumference. 

In the Cincinnati Prospective Study, higher prenatal PbB was associated with reduced birth weight and 

reduced gestational age (Dietrich et al. 1987a). Analyses of the data indicated that for each natural log 

unit increase in PbB, the decrease in birth weight averaged 114 g, but ranged from 58 to 601 g depending 

on the age of the mother (Bornschein et al. 1989). The investigators reported that the threshold for this 

effect could be approximately 12–13 μg/dL PbB. In addition, a decrease in birth length of 2.5 cm per 

natural log unit of maternal PbB was seen, but only in white infants. In a later report, the prenatal PbB 

(mean, 8.2 μg/dL; range, 1–27 μg/dL) was related to lower birth weight (Dietrich et al. 1989). PbBs 

≥10 μg/dL also were significantly associated (p<0.05) with a decrease in total days of gestation and an 

increase risk of preterm and small-for-gestational-age birth in a sample of 262 mother-infant pairs from 

the general population in California (Jelliffe-Pawlowski et al. 2006). Lower mean birth weight and In a 

study of 705 women from Camden, New Jersey, with PbBs throughout pregnancy below 1.5 μg/dL, PbB 

showed no significant association with low birth weight, preterm delivery, Apgar scores, or small-forgestational age (Sowers et al. 2002a). In contrast, in a study of 148 Russian mothers and 114 Norwegian 

mothers with maternal and cord PbBs as low as 1.2 μg/dL, PbBs had a negative impact on birth weight 
LEAD 144 

3. HEALTH EFFECTS 

and child’s body mass index (BMI, weight in kg divided by the square of the height in meters) with or 

without adjusting for gestational age (Odland et al. 1999). In a study of 89 mother-infant pairs from 

Spain, higher placental lead levels were unrelated to smaller birth weight, head and abdominal 

circumference, or shorter length at birth (Falcón et al. 2003). 

Analyses of data for 2,695 children ≤7 years old from the NHANES II study indicated that PbB (range, 4– 

35 μg/dL) was a statistically significant predictor of children's height, weight, and chest circumference, 

after controlling for age, race, sex, and nutritional covariates (Schwartz et al. 1986). The mean PbB of the 

children at the average age of 59 months appeared to be associated with a reduction of approximately 

1.5% in the height that would be expected if the PbB had been zero. An analysis of data on PbB for 

4,391 U.S. children, ages 1–7 years, recorded in the NHANES III (1988–1994) showed that increasing 

PbB (1–72 μg/dL) was significantly associated with decreasing body stature (length or height) and head 

circumference, after adjusting for covariates (Ballew et al. 1999). An increase in PbB of 10 μg/dL was 

associated with a 1.57 cm decrease in stature and a 0.52 cm decrease in head circumference. A study of 

1,454 Mexican-American children aged 5–12 who were participants in the Hispanic Health and Nutrition 

Examination Survey (HHANES) conducted in 1982–1984 found that PbBs in the range of 2.8–40 μg/dL 

were related with decreased stature (Frisancho and Ryan 1991). The mean PbB in males and females was 

10.6 and 9.3 μg/dL, respectively. Eighty-two percent of the variance in height in males was accounted by 

hematocrit and PbB; in females, the same 82% was accounted by age, poverty index, and PbB. After 

adjusting for these covariates, children whose PbB was above the median for their age and sex (9– 

10 μg/dL range) were 1.2 cm shorter than children with PbBs below the median. Angle and Kuntzelman 

(1989) also reported reduced rates of height and weight from birth to 36 months in children with PbB of 

≥30 μg/dL. 

Evaluation of 260 infants from the Cincinnati Prospective Study revealed that postnatal growth rate 

(stature) from 3 to 15 months of age was inversely correlated with increases in PbB during the same 

period, but this effect was significant only for infants whose mothers had prenatal PbB >7.7 μg/dL 

(Shukla et al. 1989). Reevaluation of 235 infants during the second and third years of life revealed that 

mean PbB during the second and third years was negatively associated (p=0.002) with attained height at 

33 months of age (Shukla et al. 1991). However, this association was observed only among children who 

had mean PbBs greater than the cohort median (10.8 μg/dL) during the 3–15-month interval. It also 

appeared that the effect of lead exposure (both prenatal and during the 3–15-month interval) was transient 

as long as subsequent exposure was not excessive. 
LEAD 145 

3. HEALTH EFFECTS 

An absence of significant associations between lead exposure and anthropomorphic measures has also 

been reported. Evaluation of 359 mother-infant pairs from the Cleveland Prospective Study found no 

statistically significant effect of PbBs on growth from birth through age 4 years 10 months after 

controlling for a variety of possible confounding factors (Greene and Ernhart 1991). Also, a study of 

104 children who suffered lead poisoning (PbB up to 470 μg/dL) between the ages of 16 and 55 months 

and underwent chelation therapy showed normal height when they were evaluated at 8 and 18 years of 

age (Sachs and Moel 1989). At age 18, all patients had PbBs <27 μg/dL. A study by Kim et al. (1995) 

found that bone lead was not associated with physical growth in a cohort of children followed 

longitudinally for 13 years. The children were first assessed in 1975–1978 and then in 1989–1990. 

However, the study found that dentin lead was positively associated with BMI as of 1975–1978 and 

increased BMI between 1975–1978 and 1989–1990. Confounders controlled for included age, sex, 

baseline body size, and mother’s socioeconomic status. According to the investigators, the results 

suggested that chronic lead exposure during childhood may result in obesity that persists into adulthood. 

As previously mentioned under Musculoskeletal Effects, studies in animals, mostly rats, indicate that oral 

lead exposure may impair normal bone growth and remodeling as indicated by decreased bone density 

and bone calcium content, decreased trabecular bone volume, increased bone resorption activity, and 

altered growth plate morphology (Escribano et al. 1997; Gonzalez-Riola et al. 1997; Gruber et al. 1997; 

Hamilton and O’Flaherty 1994, 1995; Ronis et al. 2001). Ronis et al. (2001) showed that in rats, 

exposure to lead reduced somatic longitudinal bone growth and bone strength during the pubertal period. 

These effects could not be reversed by a growth hormone axis stimulator or by sex appropriate hormone, 

suggesting that the lead effects are not secondary to growth hormone axis disruption. It should be 

mentioned that the blood lead levels achieved in the pups were in the range of 67–192 μg/dL. 

Sexual Maturation. Two studies provide information on the effect of lead exposure on sexual maturation 

in girls. Selevan et al. (2003) performed an analysis of data on blood lead concentrations and various 

indices of sexual maturation in a group of 2,741 U.S. female children and adolescents, ages 8–18 years, 

recorded in the NHANES III (1988–1994). Increasing PbB was significantly associated with decreasing 

stature (height) and delayed sexual development (lower Tanner stage, a numerical categorization of 

female sexual maturity based on breast and pubic hair development), after adjusting for covariates. The 

geometric mean PbB among the three major race/ethnicity categories recorded in the NHANES III was 

1.4 μg/dL (95% CI, 1.2–1.5) in non-Hispanic whites, 2.1 μg/dL (95% CI, 1.9–2.3) in African Americans, 

and 1.7 μg/dL (95% CI, 1.6–1.9) in Mexican Americans. ORs for differences in breast and pubic hair 

development, and age at menarche were significant in comparisons made at PbBs of 1 and 3 μg/dL in the 
LEAD 146 

3. HEALTH EFFECTS 

African American group. Delays in sexual development, estimated for Tanner stages 2–5, ranged from 

4 to 6 months. ORs were significant for breast and pubic hair development, but not for age at menarche 

in the Mexican American group. Covariates included in the models were age, height, body mass index; 

history of tobacco smoking or anemia; dietary intakes of iron, vitamin C and calcium; and family income. 

Selevan et al. (2003) acknowledged that other factors associated with body lead burden and pubertal 

development that they did not assess may be responsible for the observed associations. In addition, they 

noted that reporting of past events, such as age at menarche and dietary history, could have been subject 

to errors in recall. Finally, potential confounders that were measured at the time of the study may have 

differed during periods critical for pubertal development or other unmeasured confounders may have 

affected the results. 

An additional study of the same cohort also found a significant and negative association between PbB and 

delayed sexual maturation (Wu et al. 2003a). The study included 1,706 girls 8–16 years old with PbB 

ranging from 0.7 to 21.7 μg/dL. PbBs were categorized in three levels: 0.7–2, 2.1–4.9, and 5.0– 

21.7 μg/dL. Covariates included in the models were race/ethnicity, age, family size, residence in a 

metropolitan area, poverty income ratio, and body mass index. Girls who had not reached menarche or 

stage 2 pubic hair had higher PbBs than did girls who had. Among girls in the three levels of PbB 

mentioned above, the unweighted percentages of 10-year-old girls who had attained Tanner stage 2 pubic 

hair were 60, 51, and 44%, respectively, and for 12-year-old girls who reported reaching menarche, the 

values were 68, 44, and 39%, respectively. These negative relationships remained significant in logistic 

regression even after adjustment for the covariates mentioned above. Interestingly, no significant 

association was found between PbB and breast development, in contrast to the findings of Selevan et al. 

(2003) who used the same database. Wu et al. (2003b) concluded that although they found a significant 

negative association between low PbB and some markers of sexual maturation, judicious interpretation of 

the results is needed given the cross-sectional study sample and limited attention to other nutritional or 

genetic factors that may impact the findings. 

Some studies have reported delays in sexual maturation in animals exposed to lead, although associated 

with PbBs much higher than those measured in girls in the Selevan et al. (2003) and Wu et al. (2003b) 

studies. For example, Grant et al. (1980) reported delayed vaginal opening in female rats exposed in 

utero and via lactation and then directly. PbBs in these female offspring ranged between 20 and 

40 μg/dL. Exposure of male and female Sprague-Dawley rats prepubertally (age 24–74 days) to lead 

acetate in the drinking water resulted in significant reduction in testis weight and in the weight of 

secondary sex organs in males and in delayed vaginal opening and disruption of estrus cycle in females 
LEAD 147 

3. HEALTH EFFECTS 

(Ronis et al. 1996). However, these effects were not observed in rats exposed postpubertally (day 60– 

74 in males, 60–85 in females). Mean PbBs in rats exposed prepubertally and postpubertally were 57 and 

31 μg/dL, respectively. In the same study, an additional group of rats was exposed during gestation and 

continuing through lactation and postpubertally. In this group, the effects were much more severe than in 

the rats exposed only pre- or postpubertally, and were consistent with the much higher PbB achieved in 

the offspring, approximately 316 μg/dL. In follow-up studies, it was found that prenatal lead exposure 

that continued until adulthood (85 days old) delayed sexual maturation in male and female pups in a doserelated manner (Ronis et al. 1998a, 1998b, 1998c). PbBs in the pups between the ages of 21 and 85 days 

were >100 μg/dL and reached up to 388 μg/dL. Effects at much lower PbBs were reported by Dearth et 

al. (2002), who treated Fisher 344 rats with lead by gavage from 30 days before mating until weaning the 

pups at 21 days of age. A cross-fostering design allowed the female pups to be exposed during gestation 

and lactation or during only one of those periods. PbB in the dams was about 38 μg/dL at breeding, 

peaked at about 46 μg/dL on lactation day 1, and decreased thereafter. Pups exposed during gestation and 

lactation had the highest PbB of 38.5 μg/dL on day 10; at this time, the PbBs in pups exposed during 

gestation only and lactation only were 13.7 and 27.6 μg/dL, respectively. By day 30, all three groups had 

PbBs ≤3 μg/dL. Vaginal opening as well as first diestrus was significantly delayed to similar extents in all 

treated groups. This delay was associated with decreased serum levels of insulin-like growth 

factor-1 (IGF-1), LH, and estradiol. Since liver IGF-1 mRNA was not affected, it appeared that lead 

altered translation and/or secretion of IGF-1, which in turn decreased LH-releasing hormone at the 

hypothalamic level. A subsequent study in both Sprague-Dawley and Fisher 344 rats (Dearth et al. 2004) 

showed that the latter strain is more sensitive to maternal lead exposure than Sprague-Dawley rats 

regarding puberty-related effects, which could, in part, explain the discrepancy with the effect levels 

reported by Ronis and coworkers. Results similar to those of Dearth et al. (2002) were reported in Swiss 

mice by Iavicoli et al. (2004). Female offspring of mice treated with various levels of lead in the diet 

during pregnancy, lactation, and then directly showed dose-related delay in sexual maturation. Blood 

lead levels of the dams were not determined; blood lead levels of the female offspring determined once at 

estrus (day 24–44) ranged from 0.7 to 13.2 μg/dL. Removing lead from the control diet (0.2 ppm Pb) 

reduced PbB in the offspring from 2–3 to 0.7 μg/dL and accelerated puberty from age 33–37 days to age 

21 days. 

Hematological Effects. The hypothesis that PbB might be associated with depressed erythropoietin 

(EPO) in children was examined in subjects from the Yugoslavia Prospective Study (Factor-Litvak et al. 

1998; Graziano et al. 2004) (see Section 3.2.4 for a detailed description of the Yugoslavia Prospective 

Study). EPO is a glycoprotein hormone that regulates both steady-state and accelerated erythrocyte 
LEAD 148 

3. HEALTH EFFECTS 

production. Nearly all of the EPO is produced in the proximal tubule of the kidney. PbB, EPO, and 

hemoglobin were measured at ages 4.5, 6.5, 9.5, and 12. In addition, tibial lead concentration was 

measured at age 12. Mean PbBs in the exposed children at the age of 4.5 and 9 years were 39 and 

28 μg/dL, respectively, and mean hemoglobin concentration throughout the study period was within 

normal limits. The results of the analyses, after adjusting for hemoglobin, showed that serum EPO was 

positively associated with PbB at ages 4.5 and 6.5 years, but the magnitude of the association gradually 

declined from 4.5 to 12 years. This suggested that in children with moderate PbB, hyperproduction of 

EPO is necessary to maintain normal hemoglobin concentrations. The decline in slope with age 

suggested that the compensatory mechanism gradually begins to fail due to lead-induced loss of renal 

endocrine function. No association was found between tibia lead and EPO. Different results were 

reported by Liebelt et al. (1999) in a pilot study of 86 children between 1 and 6 years of age with a 

median PbB of 18 μg/dL (range, 2–84 μg/dL) recruited from a university-based lead clinic and primary 

care clinic. The investigators in that study found an inverse relationship between PbB and serum EPO 

concentration. Confounding by age in the Liebelt et al. (1999) study may have contributed to the 

discrepancy in results. A study of 88 children (2–15 years old) living in a highly lead-contaminated area 

in the Equatorian Andes reported a significant inverse correlation between PbB and hemoglobin 

concentration (Counter et al. 2000). The mean PbB was 43.2 μg/dL and the range was 6.2–128.2 μg/dL. 

3.2.7 Genotoxic Effects 

The potential genotoxic effects of lead have been studied in lead workers and members of the general 

population, as well as in in vitro cultures of mammalian cells and microorganisms. Although not always 

consistent, the results suggest that lead is a clastogenic agent, as judged by the induction of chromosomal 

aberrations, micronuclei, and sister chromatid exchanges (SCE) in peripheral blood cells (Table 3-6). 

Nordenson et al. (1978) reported a significant increase in chromosomal aberrations in peripheral 

lymphocytes from a group of 26 lead workers with a mean PbB of approximately 65 μg/dL, and so did 

Schwanitz et al. (1970), Forni et al. (1976), Al-Hakkak et al. (1986), and Huang et al. (1988b) in workers 

with mean PbBs of 60–80 μg/dL (n=8), 40–50 μg/dL (n=11), 64 μg/dL (n=19), and 50 μg/dL (n=21), 

respectively. Schwanitz et al. (1975) reported a small, but not statistically significant increase in 

chromosomal aberrations in lead workers with a mean PbB of 38 μg/dL. Negative results were reported 

by Mäki-Paakkanen et al. (1981) among a group of 13 workers with a mean PbB of 49 μg/dL, by Bulsma 

and De France (1976) in 11 volunteers who ingested lead acetate for 49 days and had a PbB of 40 μg/dL, 

and by O’Riordan and Evans (1974) in 70 workers with PbBs ranging from <40 μg/dL to 120 μg/dL. A 
LEAD 149 

3. HEALTH EFFECTS 

Table 3-6. Genotoxicity of Lead In Vivo 

Species (test system) End point Results Reference 

Drosophila melanogaster Chromosome loss or – Ramel and Magnusson 1979 

nondisjunction 

Mouse bone marrow, rat Structural chromosomal ± Bruce and Heddle 1979; Deknudt and 

bone marrow, mouse aberrations or gaps, Gerber 1979 

leukocyte, monkey micronucleus formation; + Deknudt et al. 1977 

lymphocyte, rabbit unscheduled DNA + Jacquet and Tachon 1981 synthesis, sister – Jacquet et al. 1977 chromatid exchange 

– Muro and Goyer 1969 

+ Tachi et al. 1985 

– Willems et al. 1982 

+ Jagetia and Aruna 1998 

Lead workers, peripheral Micronuclei + Vaglenov et al. 2001 

lymphocytes + Vaglenov et al. 1998 

Lead workers, peripheral DNA damage + Danadevi et al. 2003 

lymphocytes + Fracasso et al. 2002 

Lead workers, peripheral Chromosomal aberration + Al-Hakkak et al. 1986 

lymphocytes + Forni et al. 1976 

– Mäki-Paakkanen et al. 1981 

+ Nordenson et al. 1978 

_ O'Riordan and Evans 1974 

+ Schwanitz et al. 1975 

+ Huang et al. 1988b 

Children, general Chromosomal aberration _ Bauchinger et al. 1977 

population 

Adults, general Chromosomal aberration _ Bulsma and De France 1976 

population 

Lead workers, peripheral Sister chromatid ± Grandjean et al. 1983 

lymphocytes exchange – Mäki-Paakkanen et al. 1981 

+ Huang et al. 1988b 

+ Duydu et al. 2001 

+ Wu et al. 2002 

Children, general Sister chromatid – Dalpra et al. 1983 

population exchange 

Adults, general Altered cell division + Bulsma and De France 1976 

population 

Lead workers, peripheral Altered cell division + Sarto et al. 1978 

lymphocytes + Schwanitz et al. 1970 

– = negative result; + = positive result; ± = inconclusive result; DNA = deoxyribonucleic acid 
LEAD 150 

3. HEALTH EFFECTS 

study of 30 children living in a town with a lead plant also found no evidence for lead-induced 

chromosomal aberrations; PbBs among the children ranged from 12 to 33 μg/dL (Bauchinger et al. 1977). 

Exposure concentrations were not reported in any of the studies mentioned above. 

A significant increase in sister chromatid exchanges was reported in 23 lead workers whose mean PbB 

was approximately 32 μg/dL (Wu et al. 2002). In this study, the TWA exposure concentration, measured 

for 11 lead workers, ranged from 0.19 to 10.32 mg/m3

. Similar results were obtained in a study of 

31 workers with a mean PbB of 36 μg/dL (Duydu et al. 2001). In the latter study, the urinary 

concentration of ALA exhibited a stronger correlation with SCE frequencies than PbB, which led the 

authors to suggest a possible ALA-mediated mechanism in the genotoxic effects of lead. An increase in 

SCE frequencies also was reported in workers with a PbB ≥80 μg/dL, but not less (Huang et al. 1988b). 

In contrast, in a group of 18 workers with a mean PbB of 49 μg/dL, there was no detectable increase in 

SCE frequency relative to controls (PbB <10μg/dL)(Mäki-Paakkanen et al. 1981); the concentration of 

lead in air ranged from 0.05 to 0.5 mg/m3

. Grandjean et al. (1983) observed that PbB and SCE rates 

decreased in lead workers after summer vacation. They also noticed that newly employed workers failed 

to show any increase in SCE rates during the first 4 months of employment despite increases in both ZPP 

and PbB, suggesting that genotoxic effects may occur after long exposure to lead. This could also suggest 

that current PbB is not a good biomarker of genotoxic effects. A study of 19 children living in a widely 

contaminated area reported no significant differences in SCE rates between the exposed children (PbB, 

30–60 μg/dL) and 12 controls (PbB, 10–21 μg/dL) (Dalpra et al. 1983). 

An increased incidence of micronuclei in peripheral lymphocytes was observed in a group of 22 lead 

workers whose mean PbB was 61 μg/dL relative to control groups with mean PbBs of 18 or 28 μg/dL 

(Vaglenov et al. 1998). The concentration of lead in the air ranged from 0.13 to 0.71 mg/m3

 (mean, 

0.45 mg/m3

). After the workers consumed a polyvitamin-rich diet for 4 months, the micronuclei 

frequency showed a significant reduction, which led the authors to suggest that oxidative damage might 

be involved in the genotoxicity of lead. However, since concurrent controls were not administered 

vitamins, and the exposed workers were not divided into vitamin-treated and untreated groups, the 

possibility that the reduction in micronuclei was unrelated to the treatment with vitamins could not be 

ruled out. In a subsequent study from the same investigators in which lead workers were stratified into 

four exposure levels, PbBs >25 μg/dL were associated with significant increases in micronuclei frequency 

(Vaglenov et al. 2001). 
LEAD 151 

3. HEALTH EFFECTS 

Lead exposure also has been shown to be associated with DNA damage. For example, battery plant 

workers (n=37) had significantly elevated levels of DNA breaks in lymphocytes compared to unexposed 

subjects (n=29) (Fracasso et al. 2002). Moreover, the authors found significant correlations between 

DNA breaks and increased production of reactive oxygen species (ROS) and decreased glutathione levels 

in the lymphocytes, pointing to oxidative stress as a possible cause for the specific responses. Similar 

results were reported in a study in which workers were exposed to an air lead concentration of 

0.004 mg/m3

 and had a mean PbB of 25 μg/dL (Danadevi et al. 2003). DNA damage also was observed 

in a mice model of lead inhalation (Valverde et al. 2002). A single 60-minute exposure to 6.8 μg/m3

 lead 

acetate induced DNA damage in the liver and lung, but subsequent inhalation induced DNA damage also 

in the nasal epithelium, whole blood, kidney, bone marrow, and brain; no DNA damage was seen in the 

testicles. In general, DNA damage in the lung, liver, and kidney was correlated with length of exposure 

and lead concentration in the tissue. 

For the most part, mutagenicity tests in microorganisms have yielded negative results (Table 3-7). 

3.2.8 Cancer 

Almost all of the information regarding lead exposure and cancer in humans is derived from studies of 

lead workers and involves exposure to inorganic lead. Several reviews on this topic have been published 

recently (Landrigan et al. 2000; Silbergeld 2003; Silbergeld et al. 2000; Steenland and Boffetta 2000). 

Malcolm and Barnett (1982) studied the causes of death of 754 subjects from a cohort of 1,898 retired 

lead acid battery workers during the period 1925–1976 in the United Kingdom. The only significant 

finding regarding cancer was a small but significant excess of malignant neoplasms of the digestive tract 

(observed/expected, 21/12.6) among men dying in service and who were classified as having the highest 

lead exposure; the excess was confined to the period 1963–1966, when lead levels were presumably 

higher than in later years. A subsequent study of workers from the same manufacturing facilities found 

no association between lead exposure and deaths from malignant neoplasms, either in general or for 

specific sites (Fanning 1988). Cooper et al. (1985) followed mortality rates among cohorts of 

4,519 battery-plant workers and 2,300 lead production workers during 34 years. An increased SMR was 

found for total malignancies in both groups of workers (statistically significant only in the battery 

workers) attributed to digestive and respiratory cancers. These small excesses of cancer deaths could not 

be correlated with onset or duration of exposure. In addition, no adjustments could be made for other 

concomitant industrial exposures or for smoking. Smoking could easily explain the small increase in 
LEAD 

3. HEALTH EFFECTS 

152 

Table 3-7. Genotoxicity of Lead In Vitro 

End point 

Species (test 

system) 

Resultsa 

With 

activation 

Without 

activation Reference 

Salmonella typhimurium 

(reverse mutation); Escherichia 

coli (forward mutation, DNA 

modification); Saccharomyces 

cerevisia (reverse mutation); 

Bacillus subtilis (rec assay) 

S. cerevisiae 

E. coli RNA polymerase or 

Avian myetoblastosis DNA 

polymerase 

Chinese hamster ovary cells; 

Syrian hamster embryo cells 

Chinese hamster fibroblasts 

Human melanoma cells 

Human lymphocytes 

Human lymphocytes 

Human lymphocytes 

Human melanoma cells 

Gene mutation or – – 

DNA modification 

Gene conversion – – 

or mitotic 

recombination 

RNA or DNA NA + 

synthesis 

Chromosomal NA + 

aberration, DNA 

repair, mitotic 

disturbance 

Micronuclei NA + 

Micronuclei NA + 

Structural NA + 

chromosomal – 

aberration 

– 

– 

DNA double- NA + 

strand breaks, 

DNA-protein 

cross-links 

Sister chromatid NA – 

exchange + 

Sister chromatid NA + 

exchange 

Bruce and Heddle 1979; 

Dunkel et al. 1984; 

Fukunaga et al. 1982; 

Kharab and Singh 1985; 

Nestmann et al. 1979; 

Nishioka 1975; Rosenkranz 

and Poirier 1979; Simmon 

1979b 

Fukunaga et al. 1982; 

Kharab and Singh 1985; 

Nestmann et al. 1979; 

Simmon 1979a 

Hoffman and Niyogi 1977; 

Sirover and Loeb 1976 

Ariza et al. 1998; 

Bauchinger and Schmid 

1972; Costa et al. 1982; 

Robison et al. 1984; Zelikoff 

et al. 1988 

Thier et al. 2003 

Poma et al. 2003 

Beek and Obe 1974 

Deknudt and Deminatti 1978 

Gasiorek and Bauchinger 

1981 

Schmid et al. 1972 

Woźniak and Blasiak 2003 

Beek and Obe 1975 

Niebuhr and Wulf 1984 

Poma et al. 2003 

C = negative result; + = positive result; DNA = deoxyribonucleic acid; NA = not applicable; RNA = ribonucleic acid 
LEAD 153 

3. HEALTH EFFECTS 

respiratory cancer in an industrial cohort that contained an excess of heavy smokers. Cocco et al. (1998b) 

found a 60% increased risk of cancer of the gastric cardia for subjects with high-level exposure to lead. 

However, cross-tabulation of gastric cardiac cancer risk by probability and levels of exposure to lead did 

not show consistent trends. No association was found between lead exposure and stomach cancer in a 

nested case-control study at a battery plant that had 30 stomach cancer deaths (Wong and Harris 2000); 

the 30 cases represented half of 60 stomach cancers in the total cohort of about 6,800 workers. No doseresponse was found using a variety of exposure indices. 

A study of 437 Swedish smelter workers with verified high lead exposure for at least 3 years from 1950 to 

1974 reported an increased SMR only for lung cancer, which did not achieve statistical significance when 

compared with national and county mortality rates specified for cause, sex, and calendar periods 

(Gerhardsson et al. 1986b). Environmental lead levels and PbBs were available for all workers since 

1950. Mean PbB for the workers was 58 μg/dL in 1950 and 34 μg/dL in 1974. A follow-up study of 

1,992 workers at this smelter found an increased SMR (1.5, 95% CI, 0.8–2.4) for all malignancies among 

a group with the highest exposure, and a considerably higher SMR (4.1, 95% CI, 1.5–9.0) for lung cancer 

(Lundstrom et al. 1997). However, since the workers may have been exposed to other carcinogens, 

including arsenic, the specific role of lead cannot be ascertained. A third study of 664 Swedish workers 

found an increase in deaths due to malignant neoplasms, but no dose-response pattern could be discerned, 

and the risk estimates did not increase when a latency period of 15 years was applied (Gerhardsson et al. 

1995a). The study also found an increased incidence of gastrointestinal malignancies among the workers 

exposed to lead, a tendency that was related to employment before 1970 and not to lead dose or to latency 

time. Data regarding dietary and smoking habits were not available. 

A study of 20,700 Finnish workers exposed to lead during 1973–1983 found a 1.4-fold increase in the 

overall cancer incidence and a 1.8-fold increase in the incidence of lung cancer among workers who had 

ever had a PbB ≥21 μg/dL (Anttila et al. 1995). The overall mortality for the whole cohort, however, was 

less than expected, and there was no clear excess mortality for specific causes of death. In a subsequent 

study of this same cohort, an excess risk of nervous system cancer, specifically gliomas, was found in 

workers with a PbB ≥29 μg/dL compared with those whose PbB had not exceeded 14.4 μg/dL (Anttila et 

al. 1996). However, the authors stated that no firm conclusions could be drawn because of the small 

number of cases, the rather short follow-up time, and the low response rate. Data from Cocco et al. 

(1998a) also suggested that exposure to lead may be associated with an increase in brain cancer risk. The 

authors analyzed 27,060 cases of brain cancer and 108,240 controls that died of nonmalignant diseases in 
LEAD 154 

3. HEALTH EFFECTS 

24 U.S. states in 1984–1992. The risk was observed mainly among men likely to have been heavily 

exposed to lead, which comprised 0.3–1.9% of the study population. 

Cocco et al. (1997) evaluated cause-specific mortality among workers of a lead-smelting plant in Italy. 

The cohort consisted of 1,388 men whose vital status was followed from January 1950, or 12 months after 

the date of hiring, whichever was later, through December 1992. Compared with the national mortality 

rates, stomach cancer and lung cancer were significantly decreased, while deaths from cancer of the liver 

and biliary tract, bladder cancer, and kidney cancer were increased nonsignificantly above expectation. 

Compared to regional mortality rates, bladder cancer, kidney cancer, and brain cancer were increased. 

Cocco et al. (1997) noted that as kidney cancer accounts for about 0.4% of the total deaths both at the 

national and regional level, the small size of the cohort may not have allowed detection of small increases 

over the very low background rate. Selevan et al. (1985) and a follow-up by Steenland et al. (1992) also 

reported an excess in kidney cancer among workers employed at a lead smelter in Kellogg, Idaho. 

Finally, in a study of cancer incidence in workers exposed to tetraethyl lead, a statistically significant 

association was found between exposure to this compound and rectal cancer (OR, 3.7; 90% CI, 1.3–10.2) 

(Fayerweather et al. 1997). The OR increased 4 times at the high-to-very high cumulative exposure level, 

demonstrating a dose-response relationship. When a latency period of 10 years was assumed, the 

association became even more pronounced. No increases in the incidence of cancer at other sites (i.e., 

brain, kidney, lung, spleen, and bone) were observed in the exposed workers. 

Fu and Boffetta (1995) conducted a meta-analysis of lead-worker studies focusing on overall cancer, 

stomach cancer, lung cancer, kidney cancer, and bladder cancer. They found a significant excess risk of 

overall cancer, stomach cancer, lung cancer, and bladder cancer. More recently, Steenland and Boffetta 

(2000) did a meta-analysis of eight major occupational studies on cancer mortality or incidence in 

workers with high lead exposure. The results provided some limited evidence of increased risk of lung 

cancer and stomach cancer, although there might have been confounding with arsenic exposure in the 

study with highest relative risk of lung cancer. The results also showed a weak evidence for an 

association with kidney cancer and gliomas. 

In the only available study of the general population, Jemal et al. (2002) examined the relationship of PbB 

and all cancer mortality using data from the NHANES II Mortality Study. The study consisted of 

203 deaths (117 men, 86 women) among 3,992 whites (1,702 men, 1,890 women) with an average of 

13.3 years of follow-up. Log-transformed PbB was either categorized into quartiles or treated as a 
LEAD 155 

3. HEALTH EFFECTS 

continuous variable in a cubic regression spline. After adjusting for confounding covariates, the analyses 

of the association of quartiles of PbB with all cancer mortality revealed that the risk of cancer mortality 

was not significantly associated with PbB among men and women combined and among separate analyses 

of men and women. In addition, none of the site-specific cancer relative risks were significant. Spline 

analyses found no dose-response for men and women combined or for men alone. However, for women, 

there appeared to be a threshold at about the 94th percentile of lead, corresponding to a PbB of 24 μg/dL. 

The authors noted that the results of the spline analysis in women need to be replicated before they can be 

considered believable and concluded that individuals with PbB in the range of the NHANES II (weighted 

median, 13 μg/dL) do not appear to have increased risk of cancer mortality. 

The available data on the carcinogenicity of lead following ingestion by laboratory animals indicate that 

lead is carcinogenic, and that the most common tumors that develop are renal tumors (Azar et al. 1973; 

Koller et al. 1985; Van Esch and Kroes 1969). Administration of lead compounds by the parenteral route 

produced similar results. Subcutaneous administration of lead phosphate to rats was associated with high 

incidence of renal tumors (Balo et al. 1965; Zollinger 1953). A study in mice provided suggestive 

evidence of carcinogenicity of lead following perinatal exposure (Waalkes et al. 1995). In that study, 

mice were exposed to one of three doses of lead acetate in the drinking water from gestation day 12 until 

4 weeks postpartum, such that offspring were exposed in utero and via lactation. Offspring were not 

exposed directly and were sacrificed at 112 weeks postpartum. Renal tubular cell adenomas occurred in 

high-dose male offspring at a rate of 20% (5/25), whereas renal tubular cell carcinomas occurred in lowdose males (1/25) and in mid-dose males (1/25); no carcinomas were seen in low- or mid-dose males. In 

exposed male offspring, the incidence of renal tubular cell atypical hyperplasia was increased in a doserelated manner. In female offspring, lesions occurred at a lower rate. 

The mechanism of lead-induced carcinogenicity in animals is not known, but some nongenotoxic 

mechanisms that have been proposed include inhibition of DNA synthesis and repair, alterations in cellto-cell communication, and oxidative damage (Silbergeld et al. 2000). Based on inadequate evidence in 

humans and sufficient evidence in animals, EPA has classified inorganic lead in Group B2, probable 

human carcinogen (IRIS 2005). The Department of Health and Human Services has determined that lead 

and lead compounds are reasonably anticipated to be human carcinogens (NTP 2005). The International 

Agency for Research on Cancer has determined that inorganic lead is probably carcinogenic to humans 

and that organic lead compounds are not classifiable as to their carcinogenicity to humans (IARC 2004). 
LEAD 156 

3. HEALTH EFFECTS 

3.3 TOXICOKINETICS 

Overview. Inorganic lead can be absorbed following inhalation, oral, and dermal exposure, but the latter 

route is much less efficient than the former two. Studies in animals have shown that organic lead is well 

absorbed through the skin. Inorganic lead in submicron size particles can be almost completely absorbed 

through the respiratory tract, whereas larger particles may be swallowed. The extent and rate of 

absorption of lead through the gastrointestinal tract depend on characteristics of the individual and on 

physicochemical characteristics of the medium ingested. Children can absorb 40–50% of an oral dose of 

water-soluble lead compared to 3–10% for adults. Gastrointestinal absorption of inorganic lead occurs 

primarily in the duodenum by saturable mechanisms. The distribution of lead in the body is routeindependent and, in adults, approximately 94% of the total body burden of lead is in the bones compared 

to approximately 73% in children. Lead in blood is primarily in red blood cells. Conditions such as 

pregnancy, lactation, menopause, and osteoporosis increase bone resorption and consequently also 

increase lead in blood. Lead can be transferred from the mother to the fetus and also from the mother to 

infants via maternal milk. Metabolism of inorganic lead consists of formation of complexes with a 

variety of protein and nonprotein ligands. Organic lead compounds are actively metabolized in the liver 

by oxidative dealkylation by P-450 enzymes. Lead is excreted primarily in urine and feces regardless of 

the route of exposure. Minor routes of excretion include sweat, saliva, hair, nails, and breast milk. The 

elimination half-lives for inorganic lead in blood and bone are approximately 30 days and 27 years, 

respectively. Several models of lead pharmacokinetics have been proposed to characterize such 

parameters as intercompartmental lead exchange rates, retention of lead in various tissues, and relative 

rates of distribution among the tissue groups. Some models are currently being used or are being 

considered for broad application in lead risk assessment. 

3.3.1 Absorption 

3.3.1.1 Inhalation Exposure 

Inorganic Lead. Inorganic lead in ambient air consists of aerosols of particulates that can be deposited in 

the respiratory tract when the aerosols are inhaled. Amounts and patterns of deposition of particulate 

aerosols in the respiratory tract are affected by the size of the inhaled particles, age-related factors that 

determine breathing patterns (e.g., nose breathing vs. mouth breathing), airway geometry, and air-stream 

velocity within the respiratory tract (James et al. 1994). Absorption of deposited lead is influenced by 

particle size and solubility as well as the pattern of regional deposition within the respiratory tract. Larger 

particles (>2.5 μm) that are deposited in the ciliated airways (nasopharyngeal and tracheobronchial 
LEAD 157 

3. HEALTH EFFECTS 

regions) can be transferred by mucociliary transport into the esophagus and swallowed. Smaller particles 

(<1 μm), which can be deposited in the alveolar region, can be absorbed after extracellular dissolution or 

ingestion by phagocytic cells (see Section 3.4.1 for further discussion). 

The respiratory tract deposition and clearance from the respiratory tract have been measured in adult 

humans (Chamberlain et al. 1978; Hursh and Mercer 1970; Hursh et al. 1969; Morrow et al. 1980; Wells 

et al. 1975). In these studies, exposures were to lead-bearing particles having mass median aerodynamic 

diameters (MMAD) below 1 μm and, therefore, deposition of the inhaled lead particles can be assumed to 

have been primarily in the bronchiolar and alveolar regions of the respiratory tract (James et al. 1994) 

where transport of deposited lead to the gastrointestinal tract is likely to have been only a minor 

component of particle clearance (Hursh et al. 1969). Approximately 25% of inhaled lead chloride or lead 

hydroxide (MMAD 0.26 and 0.24 μm, respectively) was deposited in the respiratory tract in adult subjects 

who inhaled an inorganic lead aerosol through a standard respiratory mouthpiece for 5 minutes (Morrow 

et al. 1980). Approximately 95% of deposited inorganic lead that is inhaled as submicron particles is 

absorbed (Hursh et al. 1969; Wells et al. 1975). Rates of clearance from the respiratory tract of inorganic 

lead inhaled as submicron particles of lead oxide, or lead nitrate, were described with half-times of 

0.8 hours (22%), 2.5 hours (34%), 9 hours (33%), and 44 hours (12%) (Chamberlain et al. 1978). These 

rates are thought to represent, primarily, absorption from the bronchiolar and alveolar regions of the 

respiratory tract. 

Rates and amounts of absorption of inhaled lead particles >2.5 μm will be determined, primarily, by rates 

of transport to and absorption from the gastrointestinal tract. Absorption of lead from the gastrointestinal 

tract varies with the chemical form ingested, age, meal status (e.g., fed vs. fasted), and a variety of 

nutritional factors (see Section 3.3.1.2 for further discussion). 

Organic Lead. Following a single exposure to vapors of radioactive (203Pb) tetraethyl lead 

(approximately 1 mg/m3

 breathed through a mouthpiece for 1–2 minutes) in four male subjects, 37% of 

inhaled 203Pb was initially deposited in the respiratory tract, of which approximately 20% was exhaled in 

the subsequent 48 hours (Heard et al. 1979). One hour after the exposure, approximately 50% of the 203Pb 

burden was associated with liver, 5% with kidney, and the remaining burden widely distributed 

throughout the body (determined by external gamma counting), suggesting near complete absorption of 

the lead that was not exhaled. In a similar experiment conducted with (203Pb) tetramethyl lead, 51% of 

the inhaled 203Pb dose was initially deposited in the respiratory tract, of which approximately 40% was 
LEAD 158 

3. HEALTH EFFECTS 

exhaled in 48 hours. The distribution of 203Pb 1 hour after the exposure was similar to that observed 

following exposure to tetraethyl lead. 

The relatively rapid and near complete absorption of tetraalkyl lead that is inhaled and deposited in the 

respiratory tract is also supported by studies conducted in animal models (Boudene et al. 1977; Morgan 

and Holmes 1978). 

3.3.1.2 Oral Exposure 

Inorganic Lead. The extent and rate of gastrointestinal absorption of ingested inorganic lead are 

influenced by physiological states of the exposed individual (e.g., age, fasting, nutritional calcium and 

iron status, pregnancy) and physicochemical characteristics of the medium ingested (e.g., particle size, 

mineralogy, solubility, and lead species). Lead absorption may also vary with the amount of lead 

ingested. 

Effect of Age. Gastrointestinal absorption of water-soluble lead appears to be higher in children than in 

adults. Estimates derived from dietary balance studies conducted in infants and children (ages 2 weeks to 

8 years) indicate that approximately 40–50% of ingested lead is absorbed (Alexander et al. 1974; Ziegler 

et al. 1978). In adults, estimates of absorption of ingested water-soluble lead compounds (e.g., lead 

chloride, lead nitrate, lead acetate) ranged from 3 to 10% in fed subjects (Heard and Chamberlain 1982; 

James et al. 1985; Rabinowitz et al. 1980; Watson et al. 1986). Data available on lead absorption between 

childhood and adulthood ages are very limited. While no absorption studies have been conducted on 

subjects in this age group, the kinetics of the change in stable isotope signatures of blood lead in mothers 

and their children as both come into equilibrium with a novel environmental lead isotope profile, suggest 

that children ages 6–11 years and their mothers may absorb a similar percentage of ingested lead (Gulson 

et al. 1997b). 

Studies in experimental animals provide additional evidence for an age-dependency of gastrointestinal 

absorption of lead. Absorption of lead, administered as lead acetate (6.37 mg lead /kg, oral gavage), was 

higher in juvenile Rhesus monkeys (38% of dose) compared to adult female monkeys (26% of the dose) 

(Pounds et al. 1978). Rat pups absorb approximately 40–50 times more lead via the diet than do adult rats 

(Aungst et al. 1981; Forbes and Reina 1972; Kostial et al. 1978). This age difference in absorption may 

be due, in part, to the shift from the neonatal to adult diet, and to postnatal physiological development of 

intestine (Weis and LaVelle 1991). 
LEAD 159 

3. HEALTH EFFECTS 

Effect of Fasting. The presence of food in the gastrointestinal tract decreases absorption of water-soluble 

lead (Blake and Mann 1983; Blake et al. 1983; Heard and Chamberlain 1982; James et al. 1985; 

Maddaloni et al. 1998; Rabinowitz et al. 1980). In adults, absorption of a tracer dose of lead acetate in 

water was approximately 63% when ingested by fasted subjects and 3% when ingested with a meal 

(James et al. 1985). Heard and Chamberlain (1982) reported nearly identical results. The arithmetic 

mean of reported estimates of absorption in fasted adults was 57% (calculated by ATSDR based on Blake 

et al. 1983; Heard and Chamberlain 1982; James et al. 1985; Rabinowitz et al. 1980). Reported fed/fasted 

ratios for absorption in adults range from 0.04 to 0.2 (Blake et al. 1983; Heard and Chamberlain 1983; 

James et al. 1985; Rabinowitz et al. 1980). Mineral content is one contributing factor to the lower 

absorption of lead when lead is ingested with a meal; in particular, the presence of calcium and phosphate 

in a meal will depress the absorption of ingested lead (Blake and Mann 1983; Blake et al. 1983; Heard 

and Chamberlain 1982). 

Effect of Nutrition. Lead absorption in children is affected by nutritional iron status. Children who are 

iron deficient have higher blood lead concentrations than similarly exposed children who are iron replete, 

which would suggest that iron deficiency may result in higher absorption of lead or, possibly, other 

changes in lead biokinetics that would contribute to lower PbB (Mahaffey and Annest 1986; Marcus and 

Schwartz 1987). Evidence for the effect for iron deficiency on lead absorption has been provided from 

animal studies. In rats, iron deficiency increases the gastrointestinal absorption of lead, possibly by 

enhancing binding of lead to iron binding proteins in the intestine (Bannon et al. 2003; Barton et al. 

1978b; Morrison and Quaterman 1987) (see Section 3.4.1 for further discussion). 

Dietary calcium intake appears to affect lead absorption. An inverse relationship has been observed 

between dietary calcium intake and blood lead concentration in children, suggesting that children who are 

calcium-deficient may absorb more lead than calcium-replete children (Mahaffey et al. 1986; Ziegler et 

al. 1978). An effect of calcium on lead absorption is also evident in adults. In experimental studies of 

adults, absorption of a single dose of lead (100–300 μg lead chloride) was lower when the lead was 

ingested together with calcium carbonate (0.2–1 g calcium carbonate) than when the lead was ingested 

without additional calcium (Blake and Mann 1983; Heard and Chamberlain 1982). A similar effect of 

calcium occurs in rats (Barton et al. 1978a). In other experimental animal models, absorption of lead 

from the gastrointestinal tract has been shown to be enhanced by dietary calcium depletion or 

administration of vitamin D (Mykkänen and Wasserman 1981, 1982) (see Section 3.4.1 for further 

discussion). 
LEAD 160 

3. HEALTH EFFECTS 

Effect of Pregnancy. Absorption of lead may increase during pregnancy. Although there is no direct 

evidence for this in humans, an increase in lead absorption may contribute, along with other mechanisms 

(e.g., increased mobilization of bone lead), to the increase in PbB that has been observed during the later 

half of pregnancy (Gulson et al. 1997b, 1998b, 2004; Lagerkvist et al. 1996; Rothenberg et al. 1994b; 

Schuhmacher et al. 1996). 

Effect of Dose. Lead absorption in humans may be a capacity limited process, in which case, the 

percentage of ingested lead that is absorbed may decrease with increasing rate of lead intake. Studies, to 

date, do not provide a firm basis for discerning if the gastrointestinal absorption of lead is limited by dose. 

Numerous observations of nonlinear relationships between blood lead concentration and lead intake in 

humans provide support for the existence of a saturable absorption mechanism or some other capacity 

limited process in the distribution of lead in humans (Pocock et al. 1983; Sherlock and Quinn 1986; 

Sherlock et al. 1984) (see Section 3.4.1 for discussion of saturable uptake of lead in red blood cells). 

However, in immature swine that received oral doses of lead in soil, lead dose-blood lead relationships 

were curvilinear, whereas dose-tissue lead relationships for bone, kidney, and liver were linear. The same 

pattern (nonlinearity for blood lead concentration and linearity for tissues) was observed in swine 

administered lead acetate intravenously (Casteel et al. 1997). These results suggest that the nonlinearity 

in the lead dose-blood lead concentration relationship may derive from an effect of lead dose on some 

aspect of the biokinetics of lead other than absorption. In fasted rats, absorption was estimated at 42 and 

2% following single oral administration of 1 and 100 mg lead/kg, respectively, as lead acetate, suggesting 

a limitation on absorption imposed by dose (Aungst et al. 1981). Evidence for capacity-limited processes 

at the level of the intestinal epithelium is compelling, which would suggest that the intake-uptake 

relationship for lead is likely to be nonlinear (see Section 3.4.1 for further discussion); however, the dose 

at which absorption becomes appreciably limited in humans is not known. 

Effect of Particle Size. Particle size influences the degree of gastrointestinal absorption (Ruby et al. 

1999). In rats, an inverse relationship was found between absorption and particle size of lead in diets 

containing metallic lead particles that were ≤250 μm in diameter (Barltrop and Meek 1979). Tissue lead 

concentration was a 2.3-fold higher when rats ingested an acute dose (37.5 mg Pb/kg) of lead particles 

that were <38 μm in diameter, than when rats ingested particles having diameters in the range of 150– 

250 μm (Barltrop and Meek 1979). Dissolution kinetics experiments with lead-bearing mine waste soil 

suggest that surface area effects control dissolution rates for particles sizes of <90 μm diameter; however, 

dissolution of 90–250 μm particle size fractions appeared to be controlled more by surface morphology 
LEAD 161 

3. HEALTH EFFECTS 

(Davis et al. 1994). Similarly, Healy et al. (1982) found that the solubility of lead sulfide in gastric acid 

in vitro was much greater for particles that were 30 μm in diameter than for particles that were 100 μm in 

diameter. 

Absorption from Soil. Absorption of lead in soil is less than that of dissolved lead, but is similarly 

depressed by meals. Adult subjects who ingested soil (particle size <250 μm) collected from the Bunker 

Hill NPL site absorbed 26% of the resulting 250 μg/70 kg body weight lead dose when the soil was 

ingested in the fasted state, and 2.5% when the same soil lead dose was ingested with a meal (Maddaloni 

et al. 1998). The value reported for fasted subjects (26%) was approximately half that reported for 

soluble lead ingested by fasting adults, approximately 60% (Blake et al. 1983; Heard and Chamberlain 

1983; James et al. 1985; Rabinowitz et al. 1980). Measurements of the absorption of soil lead in infants 

or children have not been reported. 

Additional evidence for a lower absorption of soil lead compared to dissolved lead is provided from 

studies in laboratory animal models. In immature swine that received oral doses of soil-like materials 

from various mine waste sites (75 or 225 μg Pb/kg body weight), relative bioavailability of soil-borne 

lead ranged from 6 to 100%, compared to that of a similar dose of highly water-soluble lead acetate 

(Casteel et al. 1997; EPA 2004b; Figure 3-4). Electron microprobe analyses of lead-bearing grains in the 

various test materials revealed that the grains ranged from as small as 1–2 μm up to a maximum of 

250 μm (the sieve size used in preparation of the samples), and that the lead was present in a wide range 

of different mineral associations (phases), including various oxides, sulfides, sulfates, and phosphates 

(Table 3-8). These variations in size and mineral content of the lead-bearing grains are the suspected 

cause of variations in the rate and extent of gastrointestinal absorption of lead from different samples of 

soil. Based on these very limited data, the relative bioavailability of lead mineral phases were rankordered (Table 3-9). 

Studies conducted in rats provide additional evidence for a lower absorption of soil-borne lead compared 

to water-soluble lead. Fed rats were administered lead in soil from mine waste over a 30-day period, and 

relative bioavailability compared to that of lead acetate was estimated from measurements of PbB 

(Freeman et al. 1992). For one test soil, relative bioavailability estimates for samples having lead 

concentrations of 1.62 and 4.05 ppm were 18.1 and 12.1% in males and 25.7 and 13.8% in females for 

average lead dosages of 1.13 and 3.23 mg Pb/kg/day in males, and 1.82 and 4.28 mg Pb/kg/day in females 

(1.62 and 4.05 ppm Pb), respectively. For a second test soil, relative bioavailability estimates for samples 

having lead concentrations of 78.2 and 19.5 ppm were 19.6 and 21.5% in males and 26.8 and 22.1% in 
3. HEALTH EFFECTS 

0.0

0.2

0.4

0.6

0.8

1.0

1.2

0 5 10 15 20

Test Material

RBA

Galena

Paint

Figure 3-4. Relative Bioavailability (RBA) of Ingested Lead from Soil and Soil-like 

Test Materials as Assessed in an Immature Swine Model* 

RBA 

1.2 

1.0 

0.8 

0.6 

0.4 

0.2 

0.0 

0 5 10 15 20 

Test Material 

Galena 

Paint 

Test Material 

1 California Gulch Fe/Mn PbOe/Mn PbO 

2 Jasper Co Low Lead Yard 

3 Jasper Co High Lead Mill 

4 Aspen Residential 

5 Aspen Berm 

6 California Gulch Phase 1 Residential Soil 

7 N IST Paint 

8 Jasper Co High Lead Smelter 

9 Palmerton Location 2 

10 Murray Smelter Soil 

11 Palmerton Locaton Location 4 

12 Murray Smelter Slag 

13 Bingham Creek Residential 

14 Bingham Creek Channel 

15 Califonria Gulch AV Slag 

16 Midvale Slag 

17 Butte Soil 

18 California Gulch Oregon Gulch Tailings 

19 Galena-enrichena-enriched Soil 

LEAD 162 

*RBA is the bioavailability (BA) of the lead in the test material compared to that of lead acetate relative to lead acetate 

(BAtest/BAacetate). See Table 3-8 for mineral composition of test materials. 

Source: EPA 2004c 
LEAD 163 

3. HEALTH EFFECTS 

Table 3-8. Percent Relative Lead Mass of Mineral Phases Observed in Test 

Materials Assessed for Relative Bioavailability in Immature Swinea
 

1 2 

Test material 

Cal. Gulch Fe/Mn PbO Jasper County low lead yard 

3 4 Jasper County high lead mill 

Aspen residential 

5 6 Aspen Berm 

Cal. Gulch Phase I residential soil 

7 8 NIST paint

Jasper County high lead smelter 

9 

Palmerton location 2 

10 Murray smelter soil 11 12 Palmerton location 4 Murray smelter slag 13 Bingham Creek residential 14 Bingham Creek channel soil 15 16 Cal. Gulch AV slag Midvale slag 17 18 Butte soil Cal. Gulch Oregon Gulch tailings 19 Galena-enriched soil 

Mineral 

phase 

Anglesite 0.5 2 1 7 10 1 1 6 4 1.0 28 2 36 

As(M)O 0.003 

Calcite 0.1 0.2 

Cerussite 81 57 64 62 20 5 32 14 1.1 2 0.3 1 4 0.3 

5 

Clay 0.01 0.003 0.017 0.1 0.018 0.03 0.13 0.1 

Fe-Pb 8 2 10 7 9 6 14 2 0.13 2 2 6 3 51 0.3 7 

oxide 

Fe-Pb 3 1 1 5 5 6 3 1 0.6 0.3 22 30 0.3 0.1 20 

sulfate 

Galena 8 3 17 12 2 20 9 9 3 6 12 100 100 

Lead 0.14 0.01 0.06 0.15 1 0.1 0.04 0.007 

barite 

Lead 0.11 0.03 0.03 0.11 0.3 1 

organic 

Lead 7 4 0.09 27 69 

oxide 4 

Lead 15 6 7 1 1 30 21 24 1 50 26 3.6 

phosphate 

Lead 0.8 0.04 0.5 1.9 1.4 

silicate 

Lead 0.4 0.1 18 

vanidate 

Mn-Pb 72 2 9 5 4 22 2 66 66 0.8 18 2 20.2 

oxide 

Native 2 22 0.7 15 

lead 

Pb(M)O 3 7 4 26 

Pb-As 0.15 0.1 29 6 2 1 31 33 

oxide 
LEAD 164 

3. HEALTH EFFECTS 

Table 3-8. Percent Relative Lead Mass of Mineral Phases Observed in Test 

Materials Assessed for Relative Bioavailability in Immature Swinea
 

1 2 

Test material 

Cal. Gulch Fe/Mn PbO Jasper County low lead yard 

3 4 Jasper County high lead mill 

Aspen residential 

5 

Aspen Berm 

6 

Cal. Gulch Phase I residential soil 

7 8 NIST paint

Jasper County high lead smelter 

9 

Palmerton location 2 

10 Murray smelter soil 11 Palmerton location 4 12 Murray smelter slag 13 14 Bingham Creek residential Bingham Creek channel soil 15 16 Cal. Gulch AV slag Midvale slag 17 Butte soil 18 Cal. Gulch Oregon Gulch tailings 19 Galena-enriched soil 

PbOcerussite 

Slag 1 

1 

1 4 6 7 10 16 

Sulfosalts 

Zn-Pb 

silicate 

2 0.03 

0.4 

a

Test material numbers refer to Figure 3-4. 

Source: EPA 2004c 
LEAD 165 

3. HEALTH EFFECTS 

Table 3-9. Ranking of Relative Bioavailability of Lead Mineral Phases in Soila 

Low bioavailability Medium bioavailability High bioavailability 

(RBA<0.25) (RBA=0.25–0.75) (RBA>0.75) 

Angelsite Lead oxide Cerussite 

Fe(M) oxide Lead phosphate Mn(M) oxide 

Fe(m) sulfate 

Galena 

Pb(m) oxide 

a

Estimates are based on studies of immature swine (see Figure 3-4, Table 3-8). 

M = metal; RBA = relative bioavailability (compared to lead acetate) 

Source: EPA 2004c 
LEAD 166 

3. HEALTH EFFECTS 

females for average lead dosages of 5.13 and 12.1 mg Pb/kg/day in males and 7.39 and 23.2 mg 

Pb/kg/day in females, respectively. In a subsequent follow-up study, absolute bioavailability of ingested 

lead acetate in rats was estimated to be 15% based on measurements of blood lead concentrations after 

oral or intravenous administration of lead acetate (Freeman et al. 1994). Based on this estimate, the 

absolute bioavailability of lead in the soils from the Freeman et al. (1992) study was estimated to be 2.7% 

(Freeman et al. 1994). In rats that received diets containing 17–127 mg lead/kg for 44 days in the form of 

lead acetate, lead sulfide, or lead-contaminated soil, bone and tissue lead levels increased in a dosedependent manner (Freeman et al. 1996). Estimated bioavailability of lead sulfide was approximately 

10% that of lead acetate. Bioavailability of lead in soil from the California Gulch NPL site (Freeman et 

al. 1996), a former mining site, decreased with increasing soil lead concentration in the diet and ranged 

from 7 to 28% of that of lead acetate. The predominant forms of lead in the NPL site soil were identified 

as: iron-lead oxide (40%), manganese-lead oxide (16%), lead phosphate (13%), "slag" (12%), and ironlead sulfate (10%). The addition of "uncontaminated soil" (having a lead concentration of 54±3 mg 

lead/kg soil) to diets containing lead acetate decreased the bioavailability of lead acetate by 

approximately 76%. 

3.3.1.3 Dermal Exposure 

Inorganic Lead. Dermal absorption of inorganic lead compounds is generally considered to be much less 

than absorption by inhalation or oral routes of exposure; however, few studies have provided quantitative 

estimates of dermal absorption of inorganic lead in humans, and the quantitative significance of the 

dermal absorption pathway as a contributor to lead body burden in humans remains an uncertainty. Lead 

was detected in the upper layers of the stratum corneum of lead-battery workers, prior to their shifts and 

after cleaning of the skin surface (Sun et al. 2002), suggesting adherence and/or possible dermal 

penetration of lead. Following skin application of 203Pb-labeled lead acetate in cosmetic preparations 

(0.12 mg Pb in 0.1 mL or 0.18 mg Pb in 0.1 g of a cream) to eight male volunteers for 12 hours, 

absorption was ≤0.3%, based on whole-body, urine and blood 203Pb measurements, and was predicted to 

be 0.06% during normal use of such preparations (Moore et al. 1980). Most of the absorption took place 

within 12 hours of exposure. Lead also appears to be absorbed across human skin when applied to the 

skin as lead nitrate; however, quantitative estimates of absorption have not been reported. Lead (4.4 mg, 

as lead nitrate) was applied (vehicle or solvent not reported) to an occluded filter placed on the forearm of 

an adult subject for 24 hours, after which, the patch was removed, the site cover and the forearm were 

rinsed with water, and total lead was quantified in the cover material and rinse (Stauber et al. 1994). The 

amount of lead recovered from the cover material and rinse was 3.1 mg (70% of the applied dose). Based 
LEAD 167 

3. HEALTH EFFECTS 

on this recovery measurement, 1.3 mg (30%) of the applied dose remained either in the skin or had been 

absorbed in 24 hours; the amount that remained in or on the skin and the fate of this lead (e.g., 

exfoliation) was not determined. Exfoliation has been implicated as an important pathway of elimination 

of other metals from skin (e.g., inorganic mercury; Hursh et al. 1989). Lead concentrations in sweat 

collected from the right arm increased 4-fold following the application of lead to the left arm, indicating 

that some lead had been absorbed (amounts of sweat collected or total lead recovered in sweat were not 

reported). In similar experiments with three subjects, measurements of 203Pb in blood, sweat and urine, 

made over a 24-hour period following dermal exposures to 5 mg Pb as 203Pb nitrate or acetate, accounted 

for <1% of the applied (or adsorbed) dose. This study also reported that absorption of lead could not be 

detected from measurements of lead in sweat following dermal exposure to lead as lead carbonate. 

Information on relative dermal permeability of inorganic and organic lead salts of lead comes from 

studies of in vitro preparations of excised skin; the rank ordering of penetration rates through excised 

human skin were: lead nuolate (lead linoleic and oleic acid complex) > lead naphthanate > lead acetate > 

lead oxide (nondetectable) (Bress and Bidanset 1991). 

Studies conducted in animals provide additional evidence that dermal absorption of inorganic lead is 

substantially lower than absorption from the inhalation or oral route. In a comparative study of dermal 

absorption of inorganic and organic salts of lead conducted in rats, approximately 100 mg of lead was 

applied in an occluded patch to the shaved backs of rats. Based on urinary lead measurements made prior 

to and for 12 days following exposure, lead compounds could be ranked according to the relative amounts 

absorbed (i.e., percent of dose recovered in urine; calculated by ATSDR): lead naphthalene (0.17%), lead 

nitrate (0.03%), lead stearate (0.006%), lead sulfate (0.006%), lead oxide (0.005%), and metal lead 

powder (0.002%). This rank order (i.e., lead naphthalene>lead oxide) is consistent with a rank ordering 

of penetration rates of inorganic and organic lead salts through excised skin from humans and guinea 

pigs: lead nuolate (lead linoleic and oleic acid complex) > lead naphthanate > lead acetate > lead oxide 

(nondetectable) (Bress and Bidanset 1991). 

Following application of lead acetate to the shaved clipped skin of rats, the concentration of lead in the 

kidneys was found to be higher relative to controls, suggesting that absorption of lead had occurred (Laug 

and Kunze 1948). This study also observed that dermal absorption of lead from lead arsenate was 

significantly less than from lead acetate, and that mechanical injury to the skin significantly increased the 

dermal penetration of lead. 
LEAD 168 

3. HEALTH EFFECTS 

Organic Lead. Relative to inorganic lead and organic lead salts, tetraalkyl lead compounds have been 

shown to be rapidly and extensively absorbed through the skin of rabbits and rats (Kehoe and Thamann 

1931; Laug and Kunze 1948). A 0.75-mL amount of tetraethyl lead, which was allowed to spread 

uniformly over an area of 25 cm2

 on the abdominal skin of rabbits, resulted in 10.6 mg of lead in the 

carcass at 0.5 hours and 4.41 mg at 6 hours (Kehoe and Thamann 1931). Tetraethyl lead was reported to 

be absorbed by the skin of rats to a much greater extent than lead acetate, lead oleate, and lead arsenate 

(Laug and Kunze 1948). Evidence for higher dermal permeability of organic lead compounds compared 

to inorganic organic salts of lead also comes from in vitro studies conduced with excised skin. The rank 

order of absorption rates through excised skin from humans and guinea pigs was as follows: tetrabutyl 

lead > lead nuolate (lead linoleic and oleic acid complex) > lead naphthanate > lead acetate > lead oxide 

(nondetectable) (Bress and Bidanset 1991). 

3.3.2 Distribution 

Inorganic Lead. Absorbed inorganic lead appears to be distributed in essentially the same manner 

regardless of the route of absorption (Chamberlain et al. 1978; Kehoe 1987); therefore, the distribution of 

absorbed lead (i.e., by any route) is discussed in this section, rather than in separate sections devoted to 

specific routes of exposure. The expression, body burden is used here to refer to the total amount of lead 

in the body. Most of the available information about the distribution of lead to major organ systems (e.g., 

bone, soft tissues) derives from autopsy studies conducted in the 1960s and 1970s and reflect body 

burdens accrued during periods when ambient and occupational exposure levels were much higher than 

current levels (Barry 1975, 1981; Gross et al. 1975; Schroeder and Tipton 1968). In general, these studies 

indicate that the distribution of lead appears to be similar in children and adults, although a larger fraction 

of the lead body burden of adults resides in bone (see Section 3.3.3 for further discussion). Several 

models of lead pharmacokinetics have been proposed to characterize such parameters as intercompartmental lead exchange rates, retention of lead in various tissues, and relative rates of distribution among 

the tissue groups (see Section 3.3.5 for further discussion of the classical compartmental models and 

physiologically based pharmacokinetic (PBPK) models developed for lead risk assessments). 

Lead in Blood. Concentrations of lead in blood vary considerably with age, physiological state (e.g., 

pregnancy, lactation, menopause) and numerous factors that affect exposure to lead. The NHANES 

provide estimates for average blood lead concentrations in various demographic strata of the U.S. 

population. Samples for the most recent NHANES III were collected during the period 1999–2002. 

Geometric mean PbB of U.S. adults, ages 20–59 years, estimated from the NHANES III 1999–2002, were 
LEAD 169 

3. HEALTH EFFECTS 

1.5 μg/dL (95% CI, 1.5–1.6) (CDC 2005a). Among adults, blood lead concentrations were highest in the 

strata that included ages 60 years and older (2.2 μg/dL; 95% CI, 2.1–2.3). Geometric mean PbB of 

children, ages 1-5 years, was 1.9 (95% CI, 1.8–2.1) for the 1999–2002 survey period; however, the 

geometric mean PbB for non-Hispanic black children is higher than that for Mexican-American and nonHispanic white children, showing that differences in risk for exposure still exist (CDC 2005a). Central 

estimates from NHANES 1999–2002 when compared to those from NHANES III Phase 2 (1991–1994), 

and from Phase 1 of the NHANES III (1988–1991) and NHANES II (1976–1980), indicate a downward 

temporal trend in blood lead concentrations in the United States, over this period. 

The excretory half-life of lead in blood, in adult humans, is approximately 30 days (Chamberlain et al. 

1978; Griffin et al. 1975; Rabinowitz et al. 1976). Lead in blood is primarily in the red blood cells (99%) 

(Bergdahl et al. 1997a, 1998, 1999; Hernandez-Avila et al. 1998; Manton et al. 2001; Schutz et al. 1996; 

Smith et al. 2002). Most of the lead found in red blood cells is bound to proteins within the cell rather 

than the erythrocyte membrane. Approximately 40–75% of lead in the plasma is bound to plasma 

proteins, of which albumin appears to be the dominant ligand (Al-Modhefer et al. 1991; Ong and Lee 

1980a). Lead may also bind to γ-globulins (Ong and Lee 1980a). Lead in serum that is not bound to 

protein exists largely as complexes with low molecular weight sulfhydryl compounds (e.g., cysteine, 

homocysteine) and other ligands (Al-Modhefer et al. 1991). 

Lead in Bone. In human adults, approximately 94% of the total body burden of lead is found in the 

bones. In contrast, bone lead accounts for 73% of the body burden in children (Barry 1975). Lead 

concentrations in bone increase with age throughout the lifetime, indicative of a relatively slow turnover 

of lead in adult bone (Barry 1975, 1981; Gross et al. 1975; Schroeder and Tipton 1968). This large pool 

of lead in adult bone can serve to maintain blood lead levels long after exposure has ended (Fleming et al. 

1997; Inskip et al. 1996; Kehoe 1987; O'Flaherty et al. 1982; Smith et al. 1996). It can also serve as a 

source of lead transfer to the fetus when maternal bone is resorbed for the production of the fetal skeleton 

(Franklin et al. 1997; Gulson et al. 1997b, 1999b, 2003). 

Lead is not distributed uniformly in bone. Lead will accumulate in those regions of bone undergoing the 

most active calcification at the time of exposure. During infancy and childhood, bone calcification is 

most active in trabecular bone, whereas in adulthood, calcification occurs at sites of remodeling in 

cortical and trabecular bone. This suggests that lead accumulation will occur predominantly in trabecular 

bone during childhood, and in both cortical and trabecular bone in adulthood (Aufderheide and Wittmers 

1992). Two physiological compartments appear to exist for lead in cortical and trabecular bone, to 
LEAD 170 

3. HEALTH EFFECTS 

varying degrees. In one compartment, bone lead is essentially inert, having a half-life of several decades. 

A labile compartment exists as well that allows for maintenance of an equilibrium of lead between bone 

and soft tissue or blood (Rabinowitz et al. 1976). Although a high bone formation rate in early childhood 

results in the rapid uptake of circulating lead into mineralizing bone, bone lead is also recycled to other 

tissue compartments or excreted in accordance with a high bone resorption rate (O'Flaherty 1995a). Thus, 

most of the lead acquired early in life is not permanently fixed in the bone (O'Flaherty 1995a). In general, 

bone turnover rates decrease as a function of age, resulting in slowly increasing bone lead levels among 

adults (Barry 1975; Gross et al. 1975; Schroeder and Tipton 1968). An x-ray fluorescence study of tibial 

lead concentrations in individuals older than 10 years showed a gradual increase in bone lead after 

age 20 (Kosnett et al. 1994). In 60–70-year-old men, the total bone lead burden may be ≥200 mg, while 

children <16 years old have been shown to have a total bone lead burden of 8 mg (Barry 1975). 

However, in some bones (i.e., mid femur and pelvic bone), the increase in lead content plateaus at middle 

age and then decreases at higher ages (Drasch et al. 1987). This decrease is most pronounced in females 

and may be due to osteoporosis and release of lead from resorbed bone to blood (Gulson et al. 2002). 

Bone lead burdens in adults are slowly lost by diffusion (heteroionic exchange) as well as by resorption 

(O'Flaherty 1995a, 1995b). 

Evidence for the exchange of bone lead and soft tissue lead stores comes from analyses of stable lead 

isotope signatures of lead in bone and blood. A comparison of blood and bone lead stable isotope 

signatures in five adults indicated that bone lead stores contributed to approximately 40–70% of the lead 

in blood (Smith et al. 1996). During pregnancy, the mobilization of bone lead increases, apparently as the 

bone is catabolized to produce the fetal skeleton. Analysis for kinetics of changes in the stable isotope 

signatures of blood lead in pregnant women as they came into equilibrium with a novel environmental 

lead isotope signature indicated that 10–88% of the lead in blood may derive from the mobilization of 

bone lead stores and approximately 80% of cord blood may be contributed from maternal bone lead 

(Gulson 2000; Gulson et al. 1997b, 1999c, 2003). The mobilization of bone lead during pregnancy may 

contribute, along with other mechanisms (e.g., increased absorption), to the increase in lead concentration 

that has been observed during the later stages of pregnancy (Gulson et al. 1997b; Lagerkvist et al. 1996; 

Schuhmacher et al. 1996). Bone resorption during pregnancy can be reduced by ingestion of calcium 

supplements (Janakiraman et al. 2003). Additional evidence for increased mobilization of bone lead into 

blood during pregnancy is provided from studies in nonhuman primates and rats (Franklin et al. 1997; 

Maldonado-Vega et al. 1996). Direct evidence for transfer of maternal bone lead to the fetus has been 

provided from stable lead isotope studies in Cynomolgus monkeys (Macaca fascicularis) that were dosed 

with lead having a different stable isotope ratio than the lead to which the monkeys were exposed at an 
LEAD 171 

3. HEALTH EFFECTS 

earlier age; approximately 7–39% of the maternal lead burden that was transferred to the fetus appeared to 

have been derived from the maternal skeleton (Franklin et al. 1997). 

In addition to pregnancy, other states of increased bone resorption appear to result in release of bone lead 

to blood; these include lactation and osteoporosis. Analysis for kinetics of changes in the stable isotope 

signatures of blood lead in postpartum women as they came into equilibrium with a novel environmental 

lead isotope signature indicated that the release of maternal bone lead to blood appears to accelerate 

during lactation (Gulson et al. 2003, 2004). Similar approaches have detected increased release of bone 

lead to blood in women, in association with menopause (Gulson et al. 2002). These observations are 

consistent with epidemiological studies that have shown increases in PbB after menopause and in 

association with decreasing bone density in postmenopausal women (Berkowitz et al. 2004; HernandezAvila et al. 2000; Nash et al. 2004; Symanski and Hertz-Picciotto 1995). 

Lead in Soft Tissues. Several studies have compared soft tissue concentrations of lead in autopsy 

samples of soft tissues (Barry 1975, 1981; Gross et al. 1975; Schroeder and Tipton 1968). These studies 

were conducted in the 1960s and 1970s and, therefore, reflect burdens accrued during periods when 

ambient and occupational exposure levels were much higher than current levels. Average PbBs reported 

in the adult subjects were approximately 20 μg/dL in the Barry (1975) and Gross et al. (1975) studies, 

whereas more current estimates of the average for adults in the United States are below 5 μg/dL (Pirkle et 

al. 1998). Levels in other soft tissues also appear to have decreased substantially since these studies were 

reported. For example, average lead concentrations in kidney cortex of male adults were 0.78 μg/g wet 

tissue and 0.79 μg/g, as reported by Barry (1975) and Gross et al. (1975), respectively (samples in the 

Barry study were from subjects who had no known occupational exposures). In a more recent analysis of 

kidney biopsy samples collected in Sweden, the mean level of lead in kidney cortex among subjects not 

occupationally exposed to lead was 0.18 μg/g (maximum, 0.56μg/g) (Barregård et al. 1999). In spite of 

the downward trends in soft tissue lead levels, the autopsy studies provide a basis for describing the 

relative soft tissue distribution of lead in adults and children. Most of the lead in soft tissue is in liver. 

Relative amounts of lead in soft tissues as reported by Schroeder and Tipton (1968), expressed as percent 

of total soft tissue lead, were: liver, 33%; skeletal muscle, 18%; skin, 16%; dense connective tissue, 11%; 

fat, 6.4%; kidney, 4%; lung, 4%; aorta, 2%; and brain, 2% (other tissues were <1%). The highest soft 

tissue concentrations in adults also occur in liver and kidney cortex (Barry 1975; Gerhardsson et al. 

1986a, 1995b; Gross et al. 1975; Oldereid et al. 1993). The relative distribution of lead in soft tissues, in 

males and females, expressed in terms of tissue:liver concentration ratios, were: liver, 1.0 (approximately 

1 μg/g wet weight); kidney cortex, 0.8; kidney medulla, 0.5; pancreas, 0.4; ovary, 0.4; spleen, 0.3; 
LEAD 172 

3. HEALTH EFFECTS 

prostate, 0.2; adrenal gland, 0.2; brain, 0.1; fat, 0.1; testis, 0.08; heart, 0.07; and skeletal muscle, 

0.05 (Barry 1975; Gross et al. 1975). In contrast to lead in bone, which accumulates lead with continued 

exposure in adulthood, concentrations in soft tissues (e.g., liver and kidney) are relatively constant in 

adults (Barry 1975; Treble and Thompson 1997), reflecting a faster turnover of lead in soft tissue, relative 

to bone. 

Maternal-Fetal-Infant Transfer. The maternal/fetal blood lead concentration ratio, indicated from cord 

blood lead measurements, is approximately 0.9 (Carbone et al. 1998; Goyer 1990; Graziano et al. 1990). 

In one of the larger studies of fetal blood lead concentration, maternal and cord blood lead concentration 

were measured at delivery in 888 mother-infant pairs; the cord/maternal ratio was relatively constant, 

0.93, over a PbB range of approximately 3–40 μg/dL (Graziano et al. 1990). A study of 159 motherinfant pairs also found a relatively constant cord/maternal ratio (0.84) over a maternal blood lead range of 

approximately 1–12 μg/dL (Carbone et al. 1998). As noted in the discussion of the distribution of lead in 

bone, measurements of stable lead isotope ratios in pregnant women and cord blood, as they came into 

equilibrium with a novel environmental lead isotope signature, indicated that approximately 80% of lead 

in fetal cord blood appears to derive from maternal bone stores (Gulson et al. 2003). A recent study 

looked at factors that might influence the amount of lead that infants receive (Harville et al. 2005). The 

analysis, conducted on 159 mother-infant pairs, revealed that higher blood pressure and alcohol 

consumption late in pregnancy were associated with more lead in cord blood relative to maternal PbB. In 

addition, higher hemoglobin and sickle cell trait were associated with reduced cord blood lead relative to 

maternal PbB. No associations were found for calcium intake, physical activity, or smoking. 

Maternal lead can also be transferred to infants during breastfeeding. Numerous studies have reported 

lead concentrations in maternal blood and breast milk. In general, these studies indicate that breast 

milk/maternal blood concentration ratios are <0.1, although values of 0.9 have been reported (Ettinger et 

al. 2006; Gulson et al. 1998a). Ettinger et al. (2006) assessed factors influencing breast milk lead 

concentration in a group of 367 women and found that PbB (mean, 8–9 μg/dL; range, 2–30) was a 

stronger predictor of breast milk lead (mean, 0.9–1.4 μg/L; range, 0.2–8 μg/dL) than bone lead, and that 

tibia lead (mean, 9.5 μg/g; range, <1–76.5 μg/dL) was a stronger predictor of breast milk lead than patella 

bone lead (mean, 14.6 μg/dL; range, <1–67.2 μg/dL). Stable lead isotope dilution measurements in 

infant-mother pairs, measured as they came into equilibrium with a novel environmental lead isotope 

signature, suggested that lead in breast milk can contribute substantially to isotope profile of infant blood 

(approximately 40–80%; Gulson et al. 1998b). 
LEAD 173 

3. HEALTH EFFECTS 

Organic Lead. Information on the distribution of lead in humans following exposures to organic lead is 

extremely limited. One hour following 1–2-minute inhalation exposures to 203Pb tetraethyl or tetramethyl 

lead (1 mg/m3

), approximately 50% of the 203Pb body burden was associated with liver and 5% with 

kidney; the remaining 203Pb was widely distributed throughout the body (Heard et al. 1979). The kinetics 

of 203Pb in blood of these subjects showed an initial declining phase during the first 4 hours (tetramethyl 

lead) or 10 hours (tetraethyl lead) after the exposure, followed by a phase of gradual increase in PbB that 

lasted for up to 500 hours after the exposure. Radioactive lead in blood was highly volatile immediately 

after the exposure and transitioned to a nonvolatile state thereafter. These observations may reflect an 

early distribution of organic lead from the respiratory tract, followed by a redistribution of de-alkylated 

lead compounds (see Section 3.3.3 for further discussion of alkyl lead metabolism). 

In a man and woman who accidentally inhaled a solvent containing 31% tetraethyl lead (17.6% lead by 

weight), lead concentrations in the tissues, from highest to lowest, were liver, kidney, brain, pancreas, 

muscle, and heart (Bolanowska et al. 1967). In another incident, a man ingested a chemical containing 

59% tetraethyl lead (38% lead w/w); lead concentration was highest in the liver followed by kidney, 

pancreas, brain, and heart (Bolanowska et al. 1967). 

3.3.3 Metabolism 

Inorganic Lead. Metabolism of inorganic lead consists of formation of complexes with a variety of 

protein and nonprotein ligands. Major extracellular ligands include albumen and nonprotein sulfhydryls 

(see Section 3.3.2 for further discussion). The major intracellular ligand in red blood cells is ALAD (see 

Section 3.3.2 for further discussion). Lead also forms complexes with proteins in the cell nucleus and 

cytosol (see Section 3.4.2 for further discussion). 

Organic Lead. Alkyl lead compounds are actively metabolized in the liver by oxidative dealkylation 

catalyzed by cytochrome P-450. Relatively few studies that address the metabolism of alkyl lead 

compounds in humans have been reported. Occupational monitoring studies of workers who were 

exposed to tetraethyl lead have shown that tetraethyl lead is excreted in the urine as diethyl lead, ethyl 

lead, and inorganic lead (Turlakiewicz and Chmielnicka 1985; Vural and Duydu 1995; Zhang et al. 1994). 

Trialkyl lead metabolites were found in the liver, kidney, and brain following exposure to the tetraalkyl 

compounds in workers; these metabolites have also been detected in brain tissue of nonoccupational 

subjects (Bolanowska et al. 1967; Nielsen et al. 1978). In volunteers exposed by inhalation to 0.64 and 

0.78 mg lead/m3

 of 203Pb-labeled tetraethyl and tetramethyl lead, respectively, lead was cleared from the 
LEAD 174 

3. HEALTH EFFECTS 

blood within 10 hours, followed by a re-appearance of radioactivity back into the blood after 

approximately 20 hours (Heard et al. 1979). The high level of radioactivity initially in the plasma 

indicates the presence of tetraalkyl/trialkyl lead. The subsequent rise in blood radioactivity, however, 

probably represents water-soluble inorganic lead and trialkyl and dialkyl lead compounds that were 

formed from the metabolic conversion of the volatile parent compounds (Heard et al. 1979). 

3.3.4 Excretion 

Independent of the route of exposure, absorbed lead is excreted primarily in urine and feces; sweat, saliva, 

hair and nails, and breast milk are minor routes of excretion (Chamberlain et al. 1978; Griffin et al. 1975; 

Hursh and Suomela 1968; Hursh et al. 1969; Kehoe 1987; Rabinowitz et al. 1976; Stauber et al. 1994). 

Fecal excretion accounts for approximately one-third of total excretion of absorbed lead (fecal/urinary 

excretion ratio of approximately 0.5), based on intravenous injection studies conducted in humans 

(Chamberlain et al. 1978). A similar value for fecal/urinary excretion ratio, approximately 0.5, has been 

observed following inhalation of submicron lead particles (Chamberlain et al. 1978; Hursh et al. 1969). 

3.3.4.1 Inhalation Exposure 

Inorganic Lead. Inorganic lead inhaled as submicron particles is deposited primarily in the bronchiolar 

and alveolar regions of the respiratory tract, from where it is absorbed and excreted primarily in urine and 

feces (Chamberlain et al. 1978; Hursh et al. 1969; Kehoe 1987). Fecal/urinary excretion ratios were 

approximately 0.5 following inhalation of submicron lead-bearing particles (Chamberlain et al. 1978; 

Hursh et al. 1969). Higher fecal-urinary ratios would be expected following inhalation of larger particle 

sizes (e.g., >1 μm) as these particles would be cleared to the gastrointestinal tract from where a smaller 

percentage would be absorbed (Kehoe 1987; see Section 3.3.1.2). 

Organic Lead. Lead derived from inhaled tetraethyl and tetramethyl lead is excreted in exhaled air, 

urine, and feces (Heard et al. 1979). Following 1–2-minute inhalation exposures to 203Pb tetraethyl 

(1 mg/m3

), in four male subjects, 37% of inhaled 203Pb was initially deposited in the respiratory tract, of 

which approximately 20% was exhaled in the subsequent 48 hours (Heard et al. 1979). In a similar 

experiment conducted with (203Pb) tetramethyl lead, 51% of the inhaled 203Pb dose was initially deposited 

in the respiratory tract, of which approximately 40% was exhaled in 48 hours. Lead that was not exhaled 

was excreted in urine and feces. Fecal/urinary excretion ratios were 1.8 following exposure to tetraethyl 

lead and 1.0 following exposure to tetramethyl lead (Heard et al. 1979). Occupational monitoring studies 

of workers who were exposed to tetraethyl lead have shown that tetraethyl lead is excreted in the urine as 
LEAD 175 

3. HEALTH EFFECTS 

diethyl lead, ethyl lead, and inorganic lead (Turlakiewicz and Chmielnicka 1985; Vural and Duydu 1995; 

Zhang et al. 1994). 

3.3.4.2 Oral Exposure 

Inorganic Lead. Much of the available information on the excretion of ingested lead in adults derives 

from studies conducted on five male adults who received daily doses of 207Pb nitrate for periods up to 

210 days (Rabinowitz et al. 1976). The dietary intakes of the subjects were reduced to accommodate the 

tracer doses of 207Pb without increasing daily intake, thus preserving a steady state with respect to total 

lead intake and excretion. Total lead intakes (diet plus tracer) ranged from approximately 210 to 

360 μg/day. Urinary excretion accounted for approximately 12% of the daily intake (range for five 

subjects: 7–17%) and fecal excretion, approximately 90% of the daily intake (range, 87–94%). Based on 

measurements of tracer and total lead in saliva, gastric secretions, bile, and pancreatic secretions (samples 

collected from three subjects by intubation), gastrointestinal secretion of lead was estimated to be 

approximately 2.4% of intake (range, 1.9–3.3%). In studies conducted at higher ingestion intakes, 1– 

3 mg/day for up to 208 weeks, urinary lead excretion accounted for approximately 5% of the ingested 

dose (Kehoe 1987). 

3.3.4.3 Dermal Exposure 

Inorganic lead is excreted in sweat and urine following dermal exposure to lead nitrate or lead acetate 

(Moore et al. 1980; Stauber et al. 1994). 

3.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 
LEAD 176 

3. HEALTH EFFECTS 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-5 shows a conceptualized representation of a PBPK model. 
3. HEALTH EFFECTS 

Figure 3-5. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a Hypothetical 

Chemical Substance 

Inhaled chem ical E xhaled chem ical 

L u n gs 

L iv er 

F a t 

S lo w ly 

p e rfu s e d 

tis su e s 

R ic h ly 

p e rfu s e d 

tis su e s 

K id n e y 

S k in 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

V m a x 

K m 

In g e stion 

GI 

T rac t 

F e c e s 

U rin e

 C h em ic als 

contactin g skin 

LEAD 177 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan et al. 1994 
LEAD 178 

3. HEALTH EFFECTS 

If PBPK models for lead exist, the overall results and individual models are discussed in this section in 

terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations. 

Early lead modeling applications relied on classical pharmacokinetics. Compartments representing 

individual organs or groups of organs that share a common characteristic were defined as volumes, or 

pools, that are kinetically homogeneous. For example, the body could be represented by a central 

compartment (e.g., blood plasma), and one or two peripheral compartments, which might be “shallow” or 

“deep” (i.e., they may exchange relatively rapidly or relatively slowly with blood plasma) (O'Flaherty 

1987). One of the first of such models was proposed by Rabinowitz et al. (1976) based on a study of the 

kinetics of ingested stable lead isotope tracers and lead balance data in five healthy adult males. The 

Rabinowitz model includes three compartments: a central compartment representing blood and other 

tissues and spaces in rapid equilibrium with blood (e.g., interstitial fluid); a shallow tissue compartment, 

representing soft tissues and rapidly exchanging pools within the skeleton; and a deep tissue compartment, representing, primarily, slowly exchanging pools of lead within bone. Excretion pathways 

represented in the model included urinary, from the central compartment, and bile, sweat, hair, and nails, 

from the shallow tissue compartment. A diagram of the model is shown in Figure 3-6, along with the lead 

content and reported mean residence times and the rates of lead movement between compartments 

(residence times are the reciprocal of the sum of the individual elimination rate constants). The model 

predicts pseudo-first order half-times for lead of approximately 25, 28, and 104

 days in the central, 

shallow tissue, and deep compartments, respectively. The slow kinetics of the deep tissue compartment 

leads to the prediction that it would contain most of the lead burden after lengthy exposures (e.g., years), 

consistent with lead measurements made in human autopsy samples (see Section 3.3.2 Distribution). 

Note that this model did not simulate the distribution of lead within blood (e.g., erythrocytes and plasma), 

nor did it simulate subcompartments within bone or physiological processes of bone turnover that might 

affect kinetics of the deep tissue compartment. 

Marcus (1985b) reanalyzed the data from stable isotope tracer studies of Rabinowitz et al. (1976) and 

derived an expanded multicompartment kinetic model for lead (Figure 3-7). The model included separate 

compartments for cortical (slow, t1/2 1.2x104

–3.5x104 days) and trabecular (fast, t1/2 100–700 days), an 

approach subsequently adopted in several models (Bert et al. 1989; EPA 1994a, 1994b; Leggett 1993; 

O’Flaherty 1993, 1995a). A more complex representation of the lead disposition in bone included 

explicit simulation of diffusion of lead within the bone volume of the osteon and exchange with blood at 

the canaliculus (Marcus 1985a; Figure 3-8). The bone diffusion model was based on lead kinetics data 

from studies conducted in dogs. Marcus (1985c) also introduced nonlinear kinetics of exchange of lead 
3. HEALTH EFFECTS 

Figure 3-6. Lead Metabolism Model* 

DIET + AIR 

 ̃ 48 μg/day 

3 

DEEP TISSUE 

(BONE) 

 ̃ 200 mg 

T1/2 ̃ 104 days 

 ̃ 7 μg/day 

 ̃ 7 μg/day 

1 

BLOOD 

1.9 mg 

T1/2 ̃ 25 days 

 ̃ 15 μg/day 

2 

SHALLOW TISSUE 

(SOFT TISSUE) 

 ̃ 2 μg/day 

 ̃ 0.6 mg 

T1/2 ̃ 28 days 

URINE BILE, HAIR, 

 ̃ 36 μg/day SWEAT, NAILS... 

 ̃ 12 μg/day 

LEAD 179 

*Schematic model for lead kinetics, in which distribution is represented as a central (blood) compartment and 

peripheral soft-tissue (fast = t1/2 28 days) and deep tissue (slow = t1/2 10,000 days) compartments. 

Source: Rabinowitz et al. 1976 
3. HEALTH EFFECTS 

Figure 3-7. Compartments and Pathways of Lead Exchange in the Marcus (1985b) 

Model* 

Diet Lead Air Lead Other Sources 

BLOOD 

Cortical 

Bone 

Trabecular 

Bone 

Soft 

Tissue 

Sweat, 

Bile, etc. 

Urine, 

etc. 

Hair 

Hair 

Loss 

LEAD 180 

*Schematic model for lead kinetics, in which bone is represented as a cortical (slow=t1/2 1.2x104–3.5x104 days) and 

trabecular (fast=t1/2 100–700 days) compartments. 

Source: Marcus 1985b 
3. HEALTH EFFECTS DIFFUSION

a

r b

Figure 3-8. Schematic Model for Lead Kinetics in Marcus (1985a) Bone Model* 

BLOOD 

LEAD INPUT 

KIDNEY 

LIVER OTHER 

SOFT 

TISSUE 

URINE, 

etc. 

FECES, 

etc. BONE 

BLOOD 

LEAD INPUT 

KIDNEY 

LIVER OTHER 

SOFT 

TISSUE 

URINE, 

etc. 

FECES, 

etc. 

DIFFUSION 

a 

r b

BONE 

LEAD 181 

*Schematic model for lead kinetics, in which bone is represented as an extended cylindrical canalicular territory. The 

canalicular territory has a radius b, and surrounds the canaliculus of radius a. Lead diffuses across radius r, between 

the fluid in the canaliculus (which is in communication with blood in the Haversian canal, not shown) and the bone 

volume of the canalicular territory. 

Source: Marcus 1985a 
LEAD 182 

3. HEALTH EFFECTS 

between plasma and erythrocytes. The blood model included four blood subcompartments: diffusible 

lead in plasma, protein-bound lead in plasma, a "shallow" erythrocyte pool, and a "deep" erythrocyte pool 

(see Figure 3-9). This model predicted the curvilinear relationship between plasma and blood lead 

concentrations observed in humans (see Section 3.3.2 Distribution for further discussion of plasmaerythrocyte lead concentrations). 

Additional information on lead biokinetics, bone mineral metabolism, and lead exposures has led to 

further refinements and expansions of these earlier modeling efforts. Three pharmacokinetic models, in 

particular, are currently being used or are being considered for broad application in lead risk assessment: 

(1) the O'Flaherty Model, which simulates lead kinetics from birth through adulthood (O'Flaherty 1993, 

1995a); (2) the Integrated Exposure Uptake BioKinetic (IEUBK) Model for Lead in Children developed 

by EPA (1994a, 1994b); and (3) the Leggett Model, which simulates lead kinetics from birth through 

adulthood (Leggett 1993). Of the three approaches, the O'Flaherty Model has the fewest lead-specific 

parameters and relies more extensively on physiologically based parameters to describe volumes, flows, 

composition, and metabolic activity of blood and bone that determine the disposition of lead in the human 

body. Both the IEUBK Model and the Leggett Model are classic multicompartmental models; the values 

of the age-specific transfer rate constants for lead are based on kinetics data obtained from studies 

conducted in animals and humans, and may not have precise physiological correlates. Thus, the structure 

and parameterization of the O'Flaherty Model is distinct from both the IEUBK Model and Leggett Model. 

All three models represent the rate of uptake of lead (i.e., amount of lead absorbed per unit of time) as 

relatively simple functions (f) of lead intake (e.g., uptake=intake x A, or uptake=intake x f[intake]). The 

values assigned to A or other variables in f(intake) are, in general, age-specific and, in some models, 

environmental medium-specific. However, the models do not modify the representation of uptake as 

functions of the many other physiologic variables that may affect lead absorption (e.g., nutritional status). 

While one can view this approach as a limitation of the models, it also represents a limitation of the data 

available to support more complex representations of lead absorption. 

The IEUBK Model simulates multimedia exposures, uptake, and kinetics of lead in children ages 0– 

7 years; the model is not intended for use in predicting lead pharmacokinetics in adults. The O'Flaherty 

and Leggett models are lifetime models, and include parameters that simulate uptake and kinetics of lead 

during infancy, childhood, adolescence, and adulthood. Lead exposure (e.g., residence-specific 

environmental lead concentrations, childhood activity patterns) is not readily described by current 

versions of these models. By contrast, the IEUBK Model includes parameters for simulating exposures 

and uptake to estimate average daily uptake of lead (μg/day) among populations of children potentially 
3. HEALTH EFFECTS 

Figure 3-9. Compartmental Model for Lead in Plasma and Red Blood Cells in the 

Marcus (1985c) Model* 

Other Sources Loss 

(Urine) 

Loss 

(Feces, 

Sweat, Hair, 

Other 

Tissues Gut Plasma 

etc.) 

Red Blood 

Cells 

Shallow 

Red Blood 

Cells 

Deep 

Blood 

Lead Ingested 

LEAD 183 

*Schematic model for lead kinetics in which blood is represented as plasma (central exchange compartment) and red 

blood cells, the latter having shallow and deep pools. 

Source: Marcus 1985c 
LEAD 184 

3. HEALTH EFFECTS 

exposed via soil and dust ingestion, air inhalation, lead-based paint chip ingestion, tap water ingestion, 

and diet. 

All three models have been calibrated, to varying degrees, against empirical physiological data on animals 

and humans, and data on blood lead concentrations in individuals and/or populations (EPA 1994a, 1994c; 

Leggett 1993; O'Flaherty 1993). However, applications in risk assessment require that the models 

accurately predict blood lead distributions in real populations, in particular the “upper tails” (e.g., 

95th percentile), when input to the models consists of data that describe site-specific exposure conditions 

(e.g., environmental lead concentrations, physicochemical properties of soil and dust) (Beck et al. 2001; 

Griffin et al. 1999). In evaluating models for use in risk assessment, exposure data collected at hazardous 

waste sites have been used to drive model simulations (Bowers and Mattuck 2001; Hogan et al. 1998). 

The exposure module in the IEUBK Model makes this type of evaluation feasible. 

The focus on relying on blood lead concentrations for model evaluation and calibration derives from 

several concerns. The empirical basis for a relationship between low levels of lead exposure and 

behavioral dysfunction largely consists of prospective epidemiological studies relating various indices of 

dysfunction with blood lead concentration (see Section 3.2.2). In this context, blood lead concentration 

has been related to health effects of lead, and this is the main reason that the focus of interest in the 

models has been on estimating blood lead concentrations. Also, the most available data with which to 

calibrate and validate the models has been data relating exposure and/or lead intake to blood 

concentration. Thus, there is greater confidence in the validity of the models for estimating blood 

concentrations, rather than lead levels in other physiologic compartments. Although the principal adverse 

health effects of lead have been related to concentrations of lead in blood, other biomarkers of lead 

exposure, such as bone lead concentrations, are also of value in assessing associations between lead 

exposure and health; hence, there is a need for models that predict concentrations of lead in tissues other 

than blood (see Section 3.2.2). 

The following three pharmacokinetic models are discussed in great detail below: (1) the O'Flaherty 

Model (O'Flaherty 1993, 1995a); (2) the IEUBK Model for Lead in Children (EPA 1994a, 1994b); and 

(3) the Leggett Model (Leggett 1993). 
LEAD 185 

3. HEALTH EFFECTS 

3.3.5.1 O'Flaherty Model 

The O'Flaherty Model simulates lead exposure, uptake, and disposition in humans, from birth through 

adulthood (O'Flaherty 1993, 1995a). Figure 3-10 shows a conceptualized representation of the O'Flaherty 

Model, including the movement of lead from exposure media (i.e., intake via inhalation or ingestion) to 

the lungs and gastrointestinal tract, followed by the subsequent exchanges between blood plasma, liver, 

kidney, richly-perfused tissues, poorly-perfused tissues, bone compartments, and excretion from liver 

and/or kidney. The model simulates both age- and media-specific absorption. Because many of the 

pharmacokinetic functions are based on body weight and age, the model can be used to estimate blood 

lead concentrations across a broad age range, including infants, children, adolescents, and adults. The 

model uses physiologically based parameters to describe the volume, composition, and metabolic activity 

of blood, soft tissues, and bone that determine the disposition of lead in the human body. 

Description of the model. The O'Flaherty Model simulates lead absorption and disposition from 

birth through adulthood. A central feature of the model is the growth curve, a logistic expression relating 

body weight to age. The full expression relating weight to age has five parameters (constants), so that it 

can readily be adapted to fit a range of standardized growth curves for men and women. Tissue growth 

and volumes are linked to body weight; this provides explicit modeling of concentrations of lead in 

tissues. Other physiologic functions (e.g., bone formation) are linked to body weight, to age, or to both. 

Lead exchange between blood plasma and bone is simulated as parallel processes occurring in cortical 

(80% of bone volume) and trabecular bone (20% of bone volume). Uptake and release of lead from 

trabecular bone and metabolically active cortical bone are functions of bone formation and resorption 

rates, respectively. Rates of bone formation and resorption are simulated as age-dependent functions, 

which gives rise to an age-dependence of lead kinetics in bone. The model simulates an age-related 

transition from immature bone, in which bone turn-over (formation and resorption) rates are relatively 

high, to mature bone, in which turn-over is relatively slow. Changes in bone mineral turnover associated 

with senescence (e.g., postmenopausal osteoporosis) are not represented in the model. In addition to 

metabolically active regions of bone, in which lead uptake and loss is dominated by bone formation and 

loss, a region of slow kinetics in mature cortical bone is also simulated, in which lead uptake and release 

to blood occur by heteroionic exchange with other minerals (e.g., calcium). Heteroionic exchange is 

simulated as a radial diffusion in bone volume of the osteon. All three processes are linked to body 

weight, or the rate of change of weight with age. This approach allows for explicit simulation of the 

effects of bone formation (e.g., growth) and loss, changes in bone volume, and bone maturation on lead 
3. HEALTH EFFECTS 

Respiratory tract 

Blood plasma 

Well-perfused tissues 

Poorly-perfused tissues 

Cortical bone 

Trabecular bone 

Liver 

Kidney 

Air 

Diet, Dust, 

Paint, Soil, 

Water 

Gastrointestinal tract 

Elimination pools of 

the body 

Intake from environmental 

Media (μg/lead/year) 

Body compartment 

Urine Feces 

Figure 3-10. Compartments and Pathways of Lead Exchange in the O’Flahert

Model* 

LEAD 186 

y
 

*Schematic model for lead kinetics in which lead distribution is represented by flows from blood plasma to liver, 

kidney, richly-perfused tissues, poorly-perfused tissues, and cortical and trabecular bone. The model simulates 

tissue growth with age, including growth and resorption of bone mineral. 

Sources: O’Flaherty 1991b, 1993, 1995a 
LEAD 187 

3. HEALTH EFFECTS 

uptake and release from bone. Exchanges of lead between blood plasma and soft tissues (e.g., kidney and 

liver) are represented as flow-limited processes. The model simulates saturable binding of lead in 

erythrocytes; this replicates the curvilinear relationship between plasma and erythrocyte lead 

concentrations observed in humans (see Sections 3.3.2 and 3.4.1). Excretory routes include kidney to 

urine and liver to bile. Total excretion (clearance from plasma attributable to bile and urine) is simulated 

as a function of glomerular filtration rate. Biliary and urinary excretory rates are proportioned as 70 and 

30% of the total plasma clearance, respectively. 

The O'Flaherty Model simulates lead intake from inhalation and ingestion. Inhalation rates are agedependent. Absorption of inhaled lead is simulated as a fraction (0.5) of the amount inhaled, and is 

independent of age. The model simulates ingestion exposures from infant formula, soil and dust 

ingestion, and drinking water ingestion. Rates of soil and dust ingestion are age-dependent, increasing to 

approximately 130 mg/day at age 2 years, and declining to <1 mg/day after age 10 years. Gastrointestinal 

absorption of lead in diet and drinking water is simulated as an age-dependent fraction, declining from 

0.58 of the ingestion rate at birth to 0.08 after age 8 years. These values can be factored to account for 

relative bioavailability when applied to absorption of lead ingested in dust or soil. 

Risk assessment. The O'Flaherty Model has several potential applications to risk assessments at 

hazardous waste sites. The model can be used to predict the blood lead concentrations in a broad age 

range, including infants, children, and adults. The model may be modified to simulate the 

pharmacokinetics of lead in potential sensitive subpopulations, including pregnant women and fetuses, as 

well as older adults. The model does not contain a detailed exposure module; however, model 

simulations have been run holding physiological variables fixed and allowing soil and dust lead 

concentrations to vary in order to estimate the range of environmental lead concentrations that would be 

expected to yield close correspondence between predicted and observed blood lead concentrations 

(O'Flaherty 1993, 1995a). 

The O'Flaherty Model, as described in O’Flaherty (1993, 1995a), utilizes point estimates for parameter 

values and yields point estimates as output; however, a subsequent elaboration of the model has been 

developed that utilizes a Monte Carlo approach to simulate variability in exposure, absorption, and 

erythrocyte lead binding capacity (Beck et al. 2001). This extension of the model can be used to predict 

the probability that children exposed to lead in environmental media will have blood lead concentrations 

exceeding a health-based level of concern (e.g., 10 μg/dL). 
LEAD 188 

3. HEALTH EFFECTS 

The model was designed to operate with an exposure time step on 1 year (the smallest time interval for a 

single exposure event). However, the implementation code allows constructions of simulations with an 

exposure time step as small as 1 day, which would allow simulation of rapidly changing intermittent 

exposures (e.g., an acute exposure event). 

Validation of the model. The O'Flaherty Model was initially calibrated to predict blood, bone, and 

tissue lead concentrations in rats (O'Flaherty 1991a), and subsequently modified to reflect anatomical and 

physiological characteristics in children (O'Flaherty 1995a), adults (O'Flaherty 1993), and Cynomolgus 

monkeys (M. fasicularis) (O’Flaherty et al. 1998). Model parameters were modified to correspond with 

available information on species- and age-specific anatomy and physiological processes described above. 

In general, the model has been shown to reproduce blood lead observations in children and adults well, 

except in instances where lead is ingested at very high concentrations (O'Flaherty 1993, 1995a). 

Target tissues. Output from the O'Flaherty Model is an estimate of age-specific blood lead 

concentrations. The O'Flaherty Model has also been used to predict lead concentrations in bone and other 

tissue compartments (O'Flaherty 1995a), in order to evaluate correspondence between predicted tissue 

concentrations and observed concentrations in different populations of children and adults. 

Species extrapolation. The mathematical structure of the O'Flaherty Model for humans is designed 

to accept parameter values that reflect the physiology and metabolism of different species (O'Flaherty 

1993). Although the model has been calibrated to predict compartmental lead masses for human children 

and adults; the model for humans was derived from a model for rats (O'Flaherty 1991a), and has been 

successfully extrapolated, with modification, to nonhuman primates (O’Flaherty et al. 1998). Crucial to 

the extrapolation of the model across species are the parameters describing bone formation, resorptions, 

and volume. Certain parameter values describing bone physiology and metabolism are likely to be 

relatively independent of species; for example, volume fractions of cortical bone and trabecular bone 

appear to be similar across species (i.e., 80% cortical, 20% trabecular) (Gong et al. 1964). However, 

while the potential for bone resorption and accretion of new bone is present in all species, the magnitude 

and age dependence of these processes are variable with species (O'Flaherty 1995a). These factors would 

have to be evaluated in extrapolating the model to other species. 

Interroute extrapolation. The O'Flaherty Model simulates intakes and uptake of ingested and 

inhaled lead and includes media-specific estimates of absorption from the gastrointestinal tract. 
LEAD 189 

3. HEALTH EFFECTS 

3.3.5.2 IEUBK Model 

The IEUBK Model for Lead in Children is a classical multicompartmental pharmacokinetics model 

linked to an exposure and probabilistic model of blood lead concentration distributions in populations of 

children ages 0–7 years (EPA 1994a, 1994b; White et al. 1998). Figure 3-11 shows a conceptualized 

representation of the IEUBK Model. The model has four major submodels: (1) exposure model, in 

which average daily intakes of lead (μg/day) are calculated for each inputted exposure concentration (or 

rates) of lead in air, diet, dust, soil, and water; (2) uptake model, which converts environmental mediaspecific lead intake rates calculated from the exposure model into a media-specific time-averaged uptake 

rate (μg/day) of lead to the central compartment (blood plasma); (3) biokinetic model, which simulates 

the transfer of absorbed lead between blood and other body tissues, elimination of lead from the body (via 

urine, feces, skin, hair, and nails), and predicts an average blood lead concentration for the exposure time 

period of interest; and (4) blood lead probability model, which applies a log-normal distribution (with 

parameters geometric mean and geometric standard deviation) to predict probabilities for the occurrence 

of a specified given blood lead concentration in a population of similarly exposed children. 

Description of the Model 

Exposure Model. The exposure model simulates intake of lead (μg/day) for inputted exposures to lead in 

air (μg/m3

), drinking water (μg/L), soil-derived dust (μg/g), or diet (μg/day). The exposure model 

operates on a 1-year time step, the smallest time interval for a single exposure event. The model accepts 

inputs for media intake rates (e.g., air volumes breathing rates, drinking water consumption rate, soil and 

dust ingestion rate). The air exposure pathway is partitioned in exposures to outdoor air and indoor air; 

with age-dependent values for time spent outdoors and indoors (hours/day). Exposure to lead to soilderived dust is also partitioned into outdoor and indoor contributions. The intakes from all ingested 

exposure media (diet, drinking water, soil-derived dust) are summed to calculate a total intake to the 

gastrointestinal tract, for estimating capacity-limited absorption (see description of the uptake model). 

Uptake Model. The uptake model simulates lead absorption for the gastrointestinal tract as the sum of a 

capacity-limited (represented by a Michaelis-Menten type relationship) and unlimited processes 

(represented by a first-order, linear, relationship). These two terms are intended to represent two different 

mechanisms of lead absorption, an approach that is in accord with limited available data in humans and 

animals that suggest a capacity limitation to lead absorption (see Sections 3.3.2 and 3.4.1). One of the 

parameters for the capacity-limited absorption process (that represents that maximum rate of absorption) 
LEAD 190 

3. HEALTH EFFECTS 

Figure 3-11. Structure of the IEUBK Model for Lead in Children* 

Air Diet Water Dust Soil Other 

Respiratory 

Tract 

Gastrointestinal tract 

Exposure Compartment 

Gastrointestinal tract 

Plasma extra-cellular fluid 

Plasma extra-cellular fluid 

Respiratory 

Tract 

Feces 

Feces 

Uptake Compartment 

Trabecular 

bone 

Cortical 

bone 

Red blood 

cells 

Other soft 

tissues Kidney Liver 

Urine 

Skin, 

hair, 

nails 

Biokinetic Compartment 

Elimination pools of Body compartment 

the body 

Body compartment or 

Intake from environmental elimination pool required in 

media (μg/lead/day} more than one component 

*Schematic for integrated lead exposure-kinetics model in which simulated multi-media exposures are linked to 

simulations of lead uptake (i.e., absorption into the plasma-ECF) tissue distribution, and excretion. 

Sources: EPA 1994a, 1994b 
LEAD 191 

3. HEALTH EFFECTS 

is age-dependent. The above representation gives rise to a decrease in the fractional absorption of 

ingested lead as a function of total lead intake as well as an age-dependence of fractional lead absorption. 

Absorption fractions are also medium-specific. At 30 months of age, at low intakes (<200 μg/day), below 

the rates at which capacity-limitation has a significant impact on absorption, the fraction of ingested lead 

in food or drinking water that is absorbed is 0.5 and decreases to approximately 0.11 (intake, 

>5,000 μg/day). For lead ingested in soil or dust, fractional absorption is 0.35 at low intakes 

(<200 μg/day) and decreases to 0.09 (intake, >5,000 μg/day). 

The uptake model assumes that 32% of inhaled lead is absorbed. This value was originally assigned 

based on a scenario of exposure to active smelter emissions, which assumed the particle size distribution 

in the vicinity of an active lead smelter (<1 μm, 12.5%; 1–2.5 μm, 12.5%; 2–15 μm, 20%; 15–30 μm, 

40%; >30 μm, 15%); size-specific deposition fractions for the nasopharyngeal, tracheobronchial, and 

alveolar regions of the respiratory tract; and region-specific absorption fractions. Lead deposited in the 

alveolar region is assumed to be completely absorbed from the respiratory tract, whereas lead deposited in 

the nasopharyngeal and tracheobronchial regions (30–80% of the lead particles in the size range 1– 

15 μm) is assumed to be transported to the gastrointestinal tract. 

Biokinetics Model. The biokinetics model includes a central compartment, six peripheral body 

compartments, and three elimination pools. The body compartments include plasma and extra cellular 

fluid (central compartment), kidney, liver, trabecular bone, cortical bone, and other soft tissue (EPA 

1994a). The model simulates growth of the body and tissues, compartment volumes, and lead masses and 

concentrations in each compartment. Blood lead concentration at birth (neonatal) is assumed to be 

0.85 of the maternal blood lead. Neonatal lead masses and concentrations are assigned to other 

compartments based on a weighted distribution of the neonatal blood lead concentration. Exchanges 

between the central compartment and tissue compartments are simulated as first-order processes, which 

are parameterized with unidirectional, first-order rate constants. Bone is simulated as two compartments: 

a relatively fast trabecular bone compartment (representing 20% of bone volume) and a relatively slow 

cortical bone compartment (representing 80% of the bone volume). Saturable uptake of lead into 

erythrocytes is simulated, with a maximum erythrocyte lead concentration of 120 μg/L. Excretory routes 

simulated include urine, from the central compartment; bile-feces, from the liver; and a lumped excretory 

pathway represented losses from skin, hair and nail, from the other soft tissue compartment. 

Blood Lead Probability Model. Inputs to the IEUBK Model are exposure point estimates that are 

intended to represent time-averaged central tendency exposures. The output of the model is a central 
LEAD 192 

3. HEALTH EFFECTS 

tendency estimate of blood lead concentration for children who might experience the inputted exposures. 

However, within a group of similarly exposed children, blood lead concentrations would be expected to 

vary among children as a result of inter-individual variability in media intakes, absorption, and 

biokinetics. The model simulates the combined impact of these sources of variability as a lognormal 

distribution of blood lead concentration for which the geometric mean (GM) is given by the central 

tendency blood lead concentration outputted from the biokinetics model and the GSD is an input 

parameter. The resulting lognormal distribution also provides the basis for predicting the probability of 

occurrence of given blood lead concentration within a population of similarly exposed children. The 

model can be iterated for varying exposure concentrations (e.g., a series of increasing soil lead 

concentration) to predict the media concentration that would be associated with a probability of 0.05 for 

the occurrence of a blood lead concentration exceeding 10 μg/dL. A subsequent elaboration of the model 

has been developed that utilizes a Monte Carlo approach to simulate variability and uncertainty in 

exposure and absorption (Goodrum et al. 1996; Griffin et al. 1999). This extension of the model provides 

an alterative to the blood lead probability model for incorporating, explicitly, estimates of variability (and 

uncertainty in variability) in exposure and absorption into predictions of an expected probability 

distribution of blood lead concentrations. 

Risk assessment. The IEUBK Model was developed to predict the probability of elevated blood 

lead concentrations in children. The model addresses three components of human health risk assessment: 

(1) the multimedia nature of exposures to lead; (2) lead pharmacokinetics; and (3) significant variability 

in exposure and risk. Thus, the IEUBK Model can be used to predict the probability that children of ages 

up to 7 years who are exposed to lead in multiple environmental media would have blood lead 

concentrations exceeding a given health-based level of concern (e.g., 10 μg/dL). These risk estimates can 

be useful in assessing the possible consequences of alternative lead exposure scenarios following 

intervention, abatement, or other remedial actions. The IEUBK Model was not developed to assess lead 

risks for age groups older than 7 years. The model operates with an exposure time step on 1 year (the 

smallest time interval for a single exposure event) and, therefore, is more suited to applications in which 

long-term (i.e., >1 year) average exposures and blood lead concentrations are to be simulated (Lorenzana 

et al. 2005). 

Validation of the model. An evaluation of the IEUBK Model has been conducted in which model 

predictions of blood lead concentrations in children were compared to observations from epidemiologic 

studies of hazardous waste sites (Hogan et al. 1998). Data characterizing residential lead exposures and 

blood lead concentrations in children living at four Superfund NPL sites were collected in a study 
LEAD 193 

3. HEALTH EFFECTS 

designed by ATSDR and EPA. The residential exposure data were used as inputs to the IEUBK Model 

and the resulting predicted blood lead concentration distributions were compared to the observed 

distributions in children living at the same residences. The IEUBK Model predictions agreed reasonably 

well with observations for children whose exposures were predominantly from their residence (e.g., who 

spent no more than 10 hours/week away from home). The predicted geometric mean blood lead 

concentrations were within 0.7 μg/dL of the observed geometric means at each site. The prediction of the 

percentage of children expected to have blood lead concentrations exceeding 10 μg/dL were within 4% of 

the observed percentage at each site. This evaluation provides support for the validity of the IEUBK 

Model for estimating blood lead concentrations in children at sites where their residential exposures can 

be adequately characterized. Similar empirical comparisons of the IEUBK Model have shown that 

agreement between model predictions and observed blood lead concentrations at specific locations is 

influenced by numerous factors, including the extent to which the exposure and blood lead measurements 

are adequately matched, and site-specific factors (e.g., soil characteristics, behavior patterns, bioavailability) that may affect lead intake or uptake in children (Bowers and Mattuck 2001; EPA 2001c). In 

addition to the above empirical comparisons, the computer code used to implement the IEUBK Model 

(IEUBK version 0.99d) has undergone an independent validation and verification and has been shown to 

accurately implement the conceptual IEUBK Model (Zaragoza and Hogan 1998). 

Target tissues. The output from the IEUBK Model is an estimate of age-specific blood lead 

concentrations. The current version of the IEUBK Model does not save as output the interim parameter 

values determined for lead in other tissues or tissue compartments. 

Species extrapolation. Data in both animals and humans (children and adults) describing the 

absorption, distribution, metabolism, and excretion of lead provide the biological basis of the biokinetic 

model and parameter values used in the IEUBK Model. The model is calibrated to predict compartmental 

lead masses for human children ages 6 months to 7 years, and is not intended to be applied to other 

species or age groups. 

Interroute extrapolation. The IEUBK Model includes an exposure module that simulates agespecific lead exposures via inhalation and ingestion of lead in diet, dust, lead-based paint, soil, and water. 

The total exposure from each route is defined as the total lead uptake (μg/day) over a 1-month period. 

Other routes of exposure may be simulated by the IEUBK Model pending available information from 

which to characterize both the exposure and media-specific absorption variables. Values for variables in 

the biokinetic component of the IEUBK Model are independent of the route of exposure. 
LEAD 194 

3. HEALTH EFFECTS 

3.3.5.3 Leggett Model 

The Leggett Model is a classical multicompartmental pharmacokinetic model of lead uptake and 

disposition in children and adults (Leggett 1993). Figure 3-12 shows a conceptualized representation of 

the model, including the movement of lead from exposure media (i.e., intake via inhalation or ingestion) 

to the lungs and gastrointestinal tract, followed by the subsequent exchanges between diffusible blood 

plasma, soft tissues, bone compartments, and excretion from liver, kidneys, and sweat. A detailed 

exposure module is not linked to the Leggett Model; rather, lead exposure estimates are incorporated into 

the model as age-specific point estimates of average daily intake (μg/day) from inhalation and ingestion. 

A detailed description of the model and its potential application to risk assessment are provided below. 

Description of the model. The Leggett Model includes a central compartment, 15 peripheral body 

compartments, and 3 elimination pools, as illustrated in Figure 3-12. Transport of lead from blood 

plasma to tissues is assumed to follow first-order kinetics. Transfer rate constants vary with age and 

blood lead concentration. Above a nonlinear threshold concentration in red blood cells (assumed to be 

60 μg/dL), the rate constant for transfer to red blood cells declines and constants to all other tissues 

increase proportionally (Leggett 1993). This replicates the nonlinear relationship between plasma and red 

blood observed in humans (see Section 3.4.1). The model simulates blood volume as an age-dependent 

function, which allows simulation of plasma and blood lead concentrations. Lead masses are simulated in 

all other tissues (tissue volumes are not simulated). 

Unidirectional, first-order transfer rates (day-1) between compartments were developed for six age groups, 

and intermediate age-specific values are obtained by linear interpolation. The total transfer rate from 

diffusible plasma to all destinations combined is assumed to be 2,000 day-1, based on isotope tracer 

studies in humans receiving lead via injection or inhalation. Values for transfer rates in various tissues 

and tissue compartments are based on measured deposition fractions or instantaneous fractional outflows 

of lead between tissue compartments (Leggett 1993). 

The Leggett Model was developed from a biokinetic model originally developed for the International 

Commission on Radiological Protection (ICRP) for calculating radiation doses from environmentally 

important radionuclides, including radioisotopes of lead (Leggett 1993). The Leggett Model simulates 

age-dependent bone physiology using a model structure developed for application to the alkaline earth 

elements, but parameterized using data specific to lead where possible. The model simulates both rapid 
3. HEALTH EFFECTS 

Figure 3-12. Compartments and Pathways of Lead Exchange in the Leggett 

Model* 

Brain 

Liver 2 

Liver 1 

Liver 

Diffusible 

Plasma 

ExtraVascular 

RBC 

Tenacious 

Turnover 

Rapid 

Turnover 

Intermediate 

Turnover 

Other Soft Tissues 

Cortical 

Surface 

Trabecular 

Surface 

Cortical Volume 

NonExchange Exchange 

Trabecular Volume 

NonExchange Exchange 

Skeleton 

Other 

Kidney 

Tissue 

Urinary 

Path 

Kidneys 

Bladder 

Contents 

Urine 

Losses in 

Hair, Nails, 

Skin 

Sweat 

Bound 

Plasma 

Brain 

Liver 2 

Li 

Diffusible 

Plasma 

ExtraVascular Vascular 

RBC 

pid 

rnover

ermediate 

Turnover

pid

ver 1 

Liver 

Tenacious 

Turnover

Ra

Tu

Int

Other Soft Tissues

Tenacious 

Turnover Turnover 

Ra

Turnover

Ra 

Turnover 

Intermediate 

Turnover Turnover 

Other Soft Tissues 

Cortical

Surface

Cortical 

Surface 

Trabecular

Surface

Trabecular 

Surface 

Cortical Volume

NonExchange Exchange

Cortical Volume 

Exchange Exchange 

Trabecular Volume

NonExchange Exchange

Trabecular Volume 

Exchange Exchange 

Skeleton 

Other

Kidney

Tissue

Urinary

Path

Kidneys

Other

Kidney

Tissue

Other 

Kidney 

Tissue 

Urinary

Path

Urinary 

Path 

Kidneys 

Bladder 

Contents Contents 

Urine 

Losses in 

Hair, Nails, 

Skin 

Sweat 

Bound 

Plasma 

RT TractRT Tract 

GI TractGI Tract 

Feces 

LEAD 195 

*Schematic model for lead kinetics in which lead distribution is represented by exchanges between the central 

plasma-ECF and tissue compartments. Bone is represented as having surface (which rapidly exchanges with 

plasma-ECF), and volume compartments; the latter simulates slow exchange with the surface and slow return of lead 

to the plasma-ECF from bone resorption. 

Source: Leggett 1993 
LEAD 196 

3. HEALTH EFFECTS 

exchange of lead with plasma via bone surface and slow loss by bone resorption. Cortical bone volume 

(80% of bone volume) and trabecular bone volume (20% of bone volume) are simulated as bone surface 

compartments, which rapidly exchange with lead the blood plasma, and bone volume, within which are 

exchangeable and nonexchangeable pools. Lead enters the exchangeable pool of bone volume via the 

bone surface and can return to the bone surface, or move to the nonexchangeable pool, from where it can 

return to the blood only when bone is resorbed. Rate constants for transfer of lead from the nonexchangeable pools and blood plasma vary with age to reflect the age-dependence of bone turnover. 

The liver is simulated as two compartments; one compartment has a relatively rapid uptake of lead from 

plasma and a relatively short removal half-life (days) for transfers to plasma and to the small intestine by 

biliary secretion; a second compartment simulates a more gradual transfer to plasma of approximately 

10% of lead uptake in liver. The kidney is simulated as two compartments, one that exchanges slowly 

with blood plasma and accounts for lead accumulation kidney tissue and a second compartment that 

receives lead from blood plasma and rapidly transfers lead to urine, with essentially no accumulation 

(urinary pathway). Other soft tissues are simulated as three compartments representing rapid, 

intermediate, and slow turnover rates (without specific physiologic correlates). Other excretory pathways 

(hair nails and skin) are represented as a lumped pathway from the intermediate turnover rate soft tissue 

compartment. 

The Leggett Model simulates lead intakes from inhalation, ingestion, or intravenous injection. The latter 

was included to accommodate model evaluations based on intravenous injection studies in humans and 

animal models. The respiratory tract is simulated as four compartments into which inhaled lead is 

deposited and absorbed with half-times of 1, 3, 10, and 48 hours. Four percent of the inhaled lead is 

assumed to be transferred to the gastrointestinal tract. These parameter values reflect the data on which 

the model was based, which were derived from studies in which human subjects inhaled submicron leadbearing particles (Chamberlain et al. 1978; Hursh and Mercer 1970; Hursh et al. 1969; Morrow et al. 

1980; Wells et al. 1975). These assumptions would not necessarily apply to exposures to large airborne 

particles (see Section 3.3.1.1). Absorption of ingested lead simulated as an age-dependent fraction of the 

ingestion rate, declining from 0.45 at birth to 0.3 at age 1 year (to age 15 years), and to 0.15 after age 

25 years. 

Risk assessment. The Leggett Model has several potential applications to risk assessment at 

hazardous waste sites. The model can be used to predict blood lead concentrations in both children and 

adults. The model allows the simulation of lifetime exposures, including assumptions of blood lead 
LEAD 197 

3. HEALTH EFFECTS 

concentrations at birth (from which levels in other tissue in the first time step after birth are calculated). 

Thus, exposures and absorption of lead prior to any given period of time during the lifetime can be 

simulated with the Leggett Model. The model operates with an exposure time step on 1 day (the smallest 

time interval for a single exposure event), which allows simulation of rapidly changing intermittent 

exposures (Khoury and Diamond 2003; Lorenzana et al. 2005). The model does not contain a detailed 

exposure module and, therefore, requires assumptions regarding total lead intake from multiple exposure 

media. In addition, the model utilizes point estimates for intakes and yields point estimates as output 

(e.g., blood lead concentration) and predicted blood lead distributions in exposed populations. 

Validation of the model. Output from the Leggett Model has been compared with data in children 

and adult subjects exposed to lead in order to calibrate model parameters. The model appears to predict 

blood lead concentrations in adults exposed to relatively low levels of lead; however, no information 

could be found describing efforts to compare predicted blood lead concentrations with observations in 

children. 

Target tissues. The output from the Leggett Model is an estimate of age-specific PbB concentrations. 

The current version of the Leggett Model does not save as output the interim parameter values determined 

for lead in other tissues or tissue compartments. 

Species extrapolation. Data on both animals and humans (children and adults) describing the 

absorption, distribution, metabolism, and excretion of lead provide the biological basis of the biokinetic 

model and parameter values used in the Leggett Model. The model is calibrated to predict compartmental 

lead masses only for humans, both children and adults. 

Interroute extrapolation. The values for pharmacokinetic variables in the Leggett Model are 

independent of the route of exposure. Based on the description of the inputs to the model provided by 

Leggett (1993), lead intake from different exposure routes is defined as a total lead intake from all routes 

of exposure. 

3.3.5.4 Model Comparisons 

The O’Flaherty, IEUBK, and Leggett Models differ considerably in the way each represents tissues, 

exchanges of lead between tissues, and lead exposure. Figure 3-13 compares the PbBs predicted by each 

model for a hypothetical child who ingests 100 μg lead/day in soil for a period of 1 year beginning at the 
LEAD 198 

3. HEALTH EFFECTS 

Figure 3-13. Blood Lead Concentrations in Children Predicted by the O’Flaherty, 

IEUBK, and Leggett Models* 

25 

Base 

20 Leggett Model 

IEUBK Model 

15 O'Flaherty Model 

10 

5 

0 

0 1 2 3 4 5 6 7 

Age (year) 

*The simulations are of a hypothetical child who has a PbB of 2 g/dL at age 2 years, and then experiences a 1-year 

exposure to 100 g Pb/day. The 100 g/day exposure was simulated as an exposure to lead in soil in the IEUBK 

Model. Default bioavailability assumptions were applied in all three models. Blood Lead (ug/dL) 
LEAD 199 

3. HEALTH EFFECTS 

age of 2 years (e.g., equivalent to ingestion of 100 μg soil/day at a soil lead concentration of 1,000 mg 

lead/g soil). The 100-μg/day exposure is superimposed on a baseline exposure that yields a PbB of 

approximately 2 μg/dL at 2 years of age. All three models predict an increase in PbB towards a quasisteady state during the exposure period, followed by a decline towards the pre-exposure baseline PbB 

with a half-time of approximately 1 month. Predicted PbBs at the end of the 12-month soil exposure 

period were 6, 10, and 23 μg/dL for the IEUBK, O’Flaherty, and Leggett Models, respectively. 

Differences in the magnitude of the predicted impact of the soil exposure on PbB reflect differences in 

assumptions about lead biokinetics and cannot be attributed solely to different assumptions about lead 

bioavailability. Bioavailability assumptions in the three models for the age range 2–3 years are: 

O’Flaherty Model, 45% (50% at age 2 years, decreasing to 40% at age 3 years); IEUBK Model, 30% (soil 

lead at low intakes); and Leggett Model, 30%. A comparison of model predictions for a similar exposure 

during adulthood (100 μg Pb/day for 1 year, beginning at age 25) is shown in Figure 3-14. Predicted 

PbBs at the end of the12-month soil exposure period were: 3 and 8 μg/dL for the O’Flaherty and Leggett 

Models, respectively. Both the O’Flaherty and Leggett Models predict a smaller change in PbB in adults, 

compared to children, for a similar increment in exposure. This is attributed, in part, to assumptions of 

lower lead bioavailability in adults (i.e., O’Flaherty, 8%; Leggett, 15%). 

3.3.5.5 Slope Factor Models 

Slope factor models have been used as simpler alternatives to compartmental models for predicting PbBs, 

or the change in PbB, associated with a given exposure (Abadin et al. 1997a; Bowers et al. 1994; Carlisle 

and Wade 1992; EPA 2003b, Stern 1994, 1996). In slope factor models, lead biokinetics is represented 

with a simple linear relationship between the PbB and either lead uptake (biokinetic slope factor, BSF) or 

lead intake (intake slope factor, ISF). The models take the general mathematical forms: 

PbB = E ⋅ ISF 

PbB = E ⋅ AF ⋅ BSF 

where E is a expression for exposure (e.g., soil intake x soil lead concentration) and AF is the absorption 

fraction for lead in the specific exposure medium of interest. Intake slope factors are based on ingested 

rather than absorbed lead and, therefore, integrate both absorption and biokinetics into a single slope 

factor, whereas models that utilize a biokinetic slope factor to account for absorption in the relationship 

include an absorption parameter. Slope factors used in various models are presented in Table 3-10. Of 
LEAD 200 

3. HEALTH EFFECTS 

Figure 3-14. Blood Lead Concentrations in Adults Predicted by the O’Flaherty 

and Leggett Models* 

0 

2 

4 

6 

8 

10 

21 22 23 24 25 26 27 28 29 30 

Age (year) 

Blood Lead (ug/dL) 

Leggett Model 

O'Flaherty Model 

*The simulations are of a hypothetical adult who has a PbB of 2 g/dL at age 25 years, and then experiences a 

1-year exposure to 100 g Pb/day. Default bioavailability assumptions were applied in all three models. 
LEAD 201 

3. HEALTH EFFECTS 

Table 3-10. Comparison of Slope Factors in Selected Slope Factor Models 

Model Receptor Intake 

Slope factor 

Biokinetics 

Absorption 

fraction 

Bowers et al. 1994 Adult ND 0.375 0.08 

Carisle and Wade 1992 Child Soil/dust: 0.07 

Water: 0.04 

ND ND 

Carisle and Wade 1992 Adult Soil/dust: 0.018 

Water: 0.04 

ND ND 

EPA 1996 Adult ND 0.4 0.12 

Stern 1994 

Stern 1996 

Child 

Adult 

Residential: 

T (0.056, 0.16, 0.18) 

Non-residential: 

U (0.014, 0.034) 

ND 

ND 

ND 

ND 

ND = No data; T = triangular probability distribution function (PDF); U = uniform PDF 
LEAD 202 

3. HEALTH EFFECTS 

the various models presented in Table 3-9, two Bowers et al. (1994) and EPA (2003b) models implement 

BSFs. The slope factors used in both models (approximately 0.4 μg/dL per μg Pb/day) are similar to 

biokinetic slope factors predicted from the O’Flaherty Model (0.65 μg/dL per μg Pb uptake/day) and 

Legget Model (0.43 μg/dL per μg Pb uptake/day) for simulations of adult exposures (Maddaloni et al. 

2005). In general, intake slope factors are derived from epidemiologic observations. A review of slope 

factors relating medium-specific exposures and blood lead concentrations derived from epidemiologic 

studies is provided in Appendix D (Abadin et al. 1997a). 

3.4 MECHANISMS OF ACTION 

3.4.1 Pharmacokinetic Mechanisms 

Absorption 

Gastrointestinal Absorption of Inorganic Lead. Gastrointestinal absorption of inorganic lead occurs 

primarily in the duodenum (Mushak 1991). The exact mechanisms of absorption are unknown and may 

involve active transport and/or diffusion through intestinal epithelial cells (transcellular) or between cells 

(paracellular), and may involve ionized lead (Pb+2) and/or inorganic or organic complexes of lead. In 

vitro studies of lead speciation in simulated human intestinal chyme indicate that the concentration of 

ionized lead is negligible at lead concentrations below 10-3 M (207 mg/L) and that lead phosphate and 

bile acid complexes are the dominant forms when inorganic lead salts (e.g., lead nitrate) are added to 

chyme (Oomen et al. 2003a). However, these complexes may be sufficiently labile to provide ionized 

lead for transport across cell membranes (Oomen et al. 2003b). Saturable mechanisms of absorption have 

been inferred from measurements of net flux kinetics of lead in the in situ perfused mouse intestine, the in 

situ ligated chicken intestine, and in in vitro isolated segments of rat intestine (Aungst and Fung 1981; 

Barton 1984; Flanagan et al. 1979; Mykkänen and Wasserman 1981). By analogy to other divalent 

cations, saturable transport mechanisms for Pb+2 may exist within the mucosal and serosal membranes 

and within the intestinal epithelial cell. For calcium and iron, these are thought to represent membrane 

carriers (e.g., Ca2+-Mg2+-ATPase, Ca2+/Na+

 exchange, DMT1) or facilitated diffusion pathways (e.g., Ca2+ 

channel) and intracellular binding proteins for Ca2+ (Bronner et al. 1986; Fleming et al. 1998b; Gross and 

Kumar 1990; Teichmann and Stremmel 1990). Numerous observations of nonlinear relationships 

between blood lead concentration and lead intake in humans suggest the existence of a saturable 

absorption mechanism or some other capacity-limited process in the distribution of lead in humans 

(Pocock et al. 1983; Sherlock and Quinn 1986; Sherlock et al. 1984). In immature swine that received 

oral doses of lead in soil, lead dose-blood lead relationships were nonlinear; however, dose-tissue lead 
LEAD 203 

3. HEALTH EFFECTS 

relationships for bone, kidney, and liver were linear. The same pattern (nonlinearity for blood lead and 

linearity for tissues) was observed in swine administered lead acetate intravenously (Casteel et al. 1997). 

These results raise the question of whether there is an effect of dose on absorption or on some other 

aspect of the biokinetics of lead. 

Gastrointestinal absorption of lead is influenced by dietary and nutritional calcium and iron status. An 

inverse relationship has been observed between dietary calcium intake and blood lead concentration 

(Mahaffey et al. 1986; Ziegler et al. 1978). Complexation with calcium (and phosphate) in the 

gastrointestinal tract and competition for a common transport protein have been proposed as possible 

mechanisms for this interaction (Barton et al. 1978a; Heard and Chamberlain 1982). Absorption of lead 

from the gastrointestinal tract is enhanced by dietary calcium depletion or administration of 

cholecalciferol. This "cholecalciferol-dependent" component of lead absorption appears to involve a 

stimulation of the serosal transfer of lead from the epithelium, not stimulation of mucosal uptake of lead 

(Mykkänen and Wasserman 1981, 1982). This is similar to the effects of cholecalciferol on calcium 

absorption (Bronner et al. 1986; Fullmer and Rosen 1990). 

Iron deficiency is also associated with increased blood lead concentration in children (Mahaffey and 

Annest 1986; Marcus and Schwartz 1987). In rats, iron deficiency increases the gastrointestinal 

absorption of lead, possibly by enhancing binding of lead to iron binding proteins in the intestine 

(Morrison and Quaterman 1987). Iron (FeCl2) added to the mucosal fluid of the everted rat duodenal sac 

decreases serosal transfer, but not mucosal uptake of lead (Barton 1984). 

Thus, interactions between iron and lead also appear to involve either intracellular transfer or basolateral 

transfer mechanisms. When mRNA for DMT1, a mucosal membrane carrier for iron, was suppressed in 

Caco 2 cells (a human gastrointestinal cell line) the rate of iron and cadmium uptake decreased by 50% 

compared to cells in which DMT1 mRNA was not suppressed; however, DMT1 mRNA suppression did 

not alter the rate of lead uptake by Caco 2 cells, indicating that lead may enter Caco 2 cells through a 

mechanism that is independent of DMT1 (Bannon et al. 2003). The above observations suggest that ratelimiting saturable mechanisms for lead absorption are associated with transfer of lead from cell to blood 

rather than with mucosal transfer. Similar mechanisms may contribute to lead-iron and lead-calcium 

absorption interactions in humans, and, possibly interactions between lead and other divalent cations such 

as cadmium, copper, magnesium and zinc. 
LEAD 204 

3. HEALTH EFFECTS 

Distribution 

Red Blood Cells. Lead in blood is rapidly taken by red blood cells, where it binds to several intracellular 

proteins. Although the mechanisms by which lead crosses cell membranes have not been fully elucidated, 

results of studies in intact red blood cells and red blood cell ghosts indicate that there are two, and 

possibly three, pathways for facilitated transfer of lead across the red cell membrane. The major proposed 

pathway is an anion exchanger that is dependent upon HCO3

-

 and is blocked by anion exchange inhibitors 

(Bannon et al. 2000, Simons 1985, 1986a, 1986b, 1993). A second minor pathway, which does not 

exhibit HCO3

-

 dependence and is not sensitive to anion exchange inhibitors, may also exist (Simons 

1986b). Lead and calcium may also share a permeability pathway, which may be a Ca2+-channel 

(Calderon-Salinas et al. 1999). Lead is extruded from the erythrocyte by an active transport pathway, 

most likely a (Ca2+, Mg2+)-ATPase (Simons 1988). 

ALAD is the primary binding ligand for lead in erythrocytes (Bergdahl et al. 1997a, 1998; Sakai et al. 

1982; Xie et al. 1998). Lead binding to ALAD is saturable; the binding capacity has been estimated to be 

approximately 850 μg/dL red blood cells (or approximately 40 μg/dL whole blood) and the apparent 

dissociation constant has been estimated to be approximately 1.5 μg/L (Bergdahl et al. 1998). Two other 

lead-binding proteins have been identified in the red cell, a 45 kDa protein (Kd 5.5 μg/L) and a smaller 

protein(s) having a molecular weight <10 kDa (Bergdahl et al. 1996, 1997a, 1998). Of the three principal 

lead-binding proteins identified in red blood cells, ALAD has the strongest affinity for lead (Bergdahl et 

al. 1998) and appears to dominate the ligand distribution of lead (35–84% of total erythrocyte lead) at 

blood lead levels below 40 μg/dL (Bergdahl et al. 1996, 1998; Sakai et al. 1982). 

Lead binds to and inhibits the activity of ALAD (Gercken and Barnes 1991; Gibbs et al. 1985; Sakai et al. 

1982, 1983). Synthesis of ALAD appears to be induced in response to inhibition of ALAD and, 

therefore, in response to lead exposure and binding of lead to ALAD (Boudene et al. 1984; Fujita et al. 

1982). Several mechanisms may participate in the induction of ALAD, including (1) inhibition of ALAD 

directly by lead; (2) inhibition by protoporphyrin, secondary to accumulation of protoporphyrin as a result 

of lead inhibition of ferrochelatase; and (3) accumulation of ALA, secondary to inhibition of ALAD, 

which may stimulate ALAD synthesis in bone marrow cells (Boudene et al. 1984; Fujita et al. 1982). 

ALAD is a polymorphic enzyme with two alleles (ALAD 1 and ALAD 2) and three genotypes: 

ALAD 1,1, ALAD 1,2, and ALAD 2,2 (Battistuzzi et al. 1981). Higher PbBs were observed in 

individuals with the ALAD 1,2 and ALAD 2,2 genotypes compared to similarly exposed individuals with 
LEAD 205 

3. HEALTH EFFECTS 

the ALAD 1,1 genotype (Astrin et al. 1987; Hsieh et al. 2000, Schwartz et al. 2000b; Wetmur et al. 1991). 

This observation has prompted the suggestion that the ALAD-2 allele may have a higher binding affinity 

for lead than the ALAD 1 allele (Bergdahl et al. 1997b), a difference that could alter lead-mediated 

outcomes. Several studies have been conducted to specifically evaluate whether ALAD genotypes are 

associated with differences in partitioning of lead between red blood cells and plasma, differences in 

distribution of lead to other tissue compartments, and altered susceptibility to lead toxicity. Further 

details on ALAD and other polymorphisms involved in lead toxicity are presented in Section 3.8, 

Populations that are Unusually Susceptible. 

Lead in Blood Plasma. Lead binds to several constituents in plasma and it has been proposed that lead in 

plasma exists in four states: loosely bound to serum albumin or other proteins with relatively low affinity 

for lead, complexed to low molecular weight ligands such as amino acids and carboxylic acids, tightly 

bound to a circulating metalloprotein, and as free Pb2+ (Al-Modhefer et al. 1991). Free ionized lead (i.e., 

Pb2+) in plasma represents an extremely small percentage of total plasma lead. The concentration of Pb2+ 

in fresh serum, as measured by an ion-selective lead electrode, was reported to be 1/5,000 of the total 

serum lead (Al-Modhefer et al. 1991). Approximately 40–75% of lead in the plasma is bound to plasma 

proteins, of which albumin appears to be the dominant ligand (Al-Modhefer et al. 1991; Ong and Lee 

1980a). Lead may also bind to γ-globulins (Ong and Lee 1980a). Lead in serum that is not bound to 

protein exists largely as complexes with low molecular weight sulfhydryl compounds (e.g., cysteine, 

homocysteine). Other potential low molecular weight lead-binding ligands in serum may include citrate, 

cysteamine, ergothioneine, glutathione, histidine, and oxylate (Al-Modhefer et al. 1991). 

Lead in Bone. Approximately 95% of lead in adult tissues, and approximately 70% in children, resides 

in mineralized tissues such as bone and teeth (Barry 1975, 1981). A portion of lead in bone readily 

exchanges with the plasma lead pool and, as a result, bone lead is a reservoir for replenishment of lead 

eliminated from blood by excretion (Alessio 1988; Chettle et al. 1991; Hryhirczuk et al. 1985; Nilsson et 

al. 1991; Rabinowitz et al. 1976). Lead forms highly stable complexes with phosphate and can replace 

calcium in the calcium-phosphate salt, hydroxyapatite, which comprises the primary crystalline matrix of 

bone (Lloyd et al. 1975). As a result, lead deposits in bone during the normal mineralization process that 

occurs during bone growth and remodeling and is released to the blood during the process of bone 

resorption (O'Flaherty 1991b, 1993). The distribution of lead in bone reflects these mechanisms; lead 

tends to be more highly concentrated at bone surfaces where growth and remodeling are most active 

(Aufderheide and Wittmers 1992). This also gives rise to an age-dependence in bone lead distribution. 

During infancy and childhood, bone calcification is most active in trabecular bone, whereas in adulthood, 
LEAD 206 

3. HEALTH EFFECTS 

calcification occurs at sites of remodeling in cortical and trabecular bone. This suggests that lead 

accumulation will occur predominantly in trabecular bone during childhood, and in both cortical and 

trabecular bone in adulthood (Aufderheide and Wittmers 1992). Bone lead burdens in adults are slowly 

lost by diffusion (heteroionic exchange) as well as by resorption (O'Flaherty 1995a, 1995b). The 

association of lead uptake and release from bone with the normal physiological processes of bone 

formation and resorption renders lead biokinetics sensitive to these processes. Physiological states (e.g., 

pregnancy, menopause, advanced age) or disease states (e.g., osteoporosis, prolonged immobilization) 

that are associated with increased bone resorption will tend to promote the release of lead from bone, 

which, in turn, may contribute to an increase in the concentration of lead in blood (Berkowtiz et al. 2004; 

Bonithon-Kopp et al. 1986c; Hernandez-Avila et al. 2000; Markowitz and Weinberger 1990; Nash et al. 

2004; Silbergeld et al. 1988; Symanski and Hertz-Picciotto 1995; Thompson et al. 1985). 

Soft Tissues. Mechanisms by which lead enters soft tissues have not been fully characterized (Bressler et 

al. 2005). Studies conducted in preparations of mammalian small intestine support the existence of 

saturable and nonsaturable pathways of lead transfer and suggest that lead can interact with transport 

mechanisms for calcium and iron (see Section 3.4.2, Absorption). Lead can enter cells through voltagegated L-type Ca2+ channels in bovine adrenal medullary cells (Legare et al. 1998; Simons and Pocock 

1987; Tomsig and Suszkiw 1991) and through store-operated Ca2+ channels in pituitary GH3, glial C3, 

human embyronic kidney, and bovine brain capillary endothelial cells (Kerper and Hinkle 1997a, 1997b). 

Anion exchangers may also participate in lead transport in astrocytes (Bressler et al. 2005). In addition to 

the small intestine, DMT1 is expressed in the kidney (Canonne-Hergaux et al. 1999); however, little 

information is available regarding the transport of lead across the renal tubular epithelium. In MadinDarby canine kidney cells (MDCK), lead has been shown to undergo transepithelial transport by a 

mechanism distinct from the anion exchanger that has been identified in red blood cells (Bannon et al. 

2000). The uptake of lead into MDCK cells was both time and temperature dependent. Overexpression 

of DMT1 in the human embryonic kidney fibroblast cells (HEK293) resulted in increased lead uptake 

compared to HEK293 cells in which DMT1 was not overexpressed (Bannon et al. 2002). Based on this 

limited information, it appears that DMT1 may play a role in the renal transport of lead. 

Lead in other soft tissues such as kidney, liver, and brain exists predominantly bound to protein. High 

affinity cytosolic lead binding proteins (PbBPs) have been identified in rat kidney and brain (DuVal and 

Fowler 1989; Fowler 1989). The PbBPs of rat are cleavage products of α2μ globulin, a member of the 

protein superfamily known as retinol-binding proteins (Fowler and DuVal 1991). α2μ-Globulin is 

synthesized in the liver under androgen control and has been implicated in the mechanism of male rat 
LEAD 207 

3. HEALTH EFFECTS 

hyaline droplet nephropathy produced by certain hydrocarbons (EPA 1991c; Swenberg et al. 1989); 

however, there is no evidence that lead induces male-specific nephropathy or hyaline droplet 

nephropathy. The precise role for PbBP in the toxicokinetics and toxicity of lead has not been firmly 

established; however, it has been proposed that PbBP may serve as a cytosolic lead "receptor" that, when 

transported into the nucleus, binds to chromatin and modulates gene expression (Fowler and DuVal 1991; 

Mistry et al. 1985, 1986). Other high-affinity lead binding proteins (Kd approximately 14 nM) have been 

isolated in human kidney, two of which have been identified as a 5 kD peptide, thymosin 4 and a 9 kD 

peptide, acyl-CoA binding protein (Smith et al. 1998b). Lead also binds to metallothionein, but does not 

appear to be a significant inducer of the protein in comparison with the inducers of cadmium and zinc 

(Eaton et al. 1980; Waalkes and Klaassen 1985). In vivo, only a small fraction of the lead in the kidney is 

bound to metallothionein, and appears to have a binding affinity that is less than Cd2+, but higher than 

Zn2+ (Ulmer and Vallee 1969); thus, lead will more readily displace zinc from metallothionein than 

cadmium (Goering and Fowler 1987; Nielson et al. 1985; Waalkes et al. 1984). 

Metabolism. Metabolism of inorganic lead consists primarily of reversible ligand reactions, including 

the formation of complexes with amino acids and nonprotein thiols, and binding to various proteins 

(DeSilva 1981; Everson and Patterson 1980; Goering and Fowler 1987; Goering et al. 1986; Ong and Lee 

1980a, 1980b, 1980c; Raghavan and Gonick 1977). 

Tetraethyl and tetramethyl lead undego oxidative dealkylation to the highly neurotoxic metabolites, 

triethyl and trimethyl lead, respectively (Bolanowska 1968; Kehoe and Thamann 1931). In the liver, the 

reaction is catalyzed by a cytochrome P-450 dependent monoxygenase system (Kimmel et al. 1977). 

Complete oxidation of alkyl lead to inorganic lead also occurs (Bolanowska 1968). 

Excretion 

Urinary Excretion. Mechanisms by which inorganic lead is excreted in urine have not been fully 

characterized. Such studies have been hampered by the difficulties associated with measuring 

ultrafilterable lead in plasma and thereby in measuring the rate of glomerular filtration of lead. Renal 

plasma clearance was approximately 20–30 mL/minute in a subject who received a single intravenous 

injection of a 203Pb chloride tracer (Chamberlain et al. 1978). Measurement of the renal clearance of 

ultrafilterable lead in plasma indicates that, in dogs and humans, lead undergoes glomerular filtration and 

net tubular reabsorption (Araki et al. 1986, 1990; Victery et al. 1979). Net tubular secretion of lead has 

been demonstrated in dogs made alkalotic by infusions of bicarbonate (Victery et al. 1979). Renal 
LEAD 208 

3. HEALTH EFFECTS 

clearance of blood lead increases with increasing blood lead concentrations above 25 μg/dL (Chamberlain 

1983). The mechanism for this has not been elucidated and could involve a shift in the distribution of 

lead in blood towards a fraction having a higher glomerular filtration rate (e.g., lower molecular weight 

complex), a capacity-limited mechanism in the tubular reabsorption of lead, or the effects of lead-induced 

nephrotoxicity on lead reabsorption. 

Mechanisms of secretory and absorptive transfer of lead in the kidney have not been characterized. 

Studies conducted in preparations of mammalian small intestine support the existence of saturable and 

nonsaturable pathways of lead transfer and suggest that lead can interact with transport mechanisms for 

calcium and iron. Although these observations may be applicable to the kidney, empirical evidence for 

specific transport mechanisms in the renal tubule are lacking (Diamond 2005). 

Fecal Excretion. In humans, absorbed inorganic lead is excreted in feces (Chamberlain et al. 1978; 

Rabinowitz et al. 1976). The mechanisms for fecal excretion of absorbed lead have not been elucidated; 

however, pathways of excretion may include secretion into the bile, gastric fluid and saliva (Rabinowitz 

et al. 1976). Biliary excretion of lead has also been observed in the dog, rat, and rabbit (Klaassen and 

Shoeman 1974; O'Flaherty 1993). 

3.4.2 Mechanisms of Toxicity 

Target Organ Toxicity. This section focuses on mechanisms for sensitive health effects of major 

concern for lead—cardiovascular/renal effects, hematological effects, and neurological effects, 

particularly in children. 

Cardiovascular Effects. A variety of diverse mechanisms may contribute to the increased blood pressure 

that is observed with chronic exposure to lead. Lead affects important hormonal and neural systems that 

contribute to the regulation of peripheral vascular resistance, heart rate and cardiac output (Carmignani et 

al. 2000; Khalil-Manesh et al. 1993; Ni et al. 2004; Vaziri and Sica 2004). Lead-induced hypertension in 

rats is accompanied by depletion of nitric oxide (NO), which plays an important role in regulating blood 

pressure, through peripheral (i.e., vasodilation, naturesis) and central (anti-sympathetic) mechanisms 

(Gonick et al. 1997; Vaziri et al. 1997). NO depletion induced by lead is thought to derive, at least in 

part, from oxidative stress and associated increased activity of reactive oxygen species (ROS) and 

reactivity with NO (Ding et al. 2001; Vaziri et al. 1999a, 199b). Lead may also disrupt the vasodilatory 

actions of NO by altering cell-signaling mechanisms in endothelial cells. Lead exposure in rats is 
 

LEAD 209 

3. HEALTH EFFECTS 

associated with a down regulation of the expression of soluble guanylate cyclase, the enzyme that 

produces cyclic GMP, which mediates NO-induced vasodilation (Marques et al. 2001). Lead-induced 

hypertension is also associated with abnormalities in the adrenergic system, including increased central 

sympathetic nervous system activity, elevated plasma norepinephrine, and decreased vascular 

β-adrenergic receptor density (Carmignani et al. 2000; Chang et al. 1996; Tsao et al. 2000). Chronic lead 

exposure also activates the renin-angiotensin-aldosterone system, either directly or indirectly, through 

stimulation of the sympathetic nervous system. Chronic exposure to lead elevates plasma renin activity, 

plasma angiotensin-converting-enzyme (ACE), and plasma aldosterone concentrations (Boscolo and 

Carmignani 1988; Carmignani et al. 1988). Lead-induced hypertension is also associated with alterations 

in the regulation of kallikrein-kinin system and the production of associated vasodilatory hormones 

(Carmignani et al. 1999) and alterations in production of renal prostaglandins (Gonick et al. 1998; Hotter 

et al. 1995). Lead exerts direct constrictive effects on vascular smooth muscle, which are thought to be 

mediated by inhibition or Na-K-ATPase activity and associated elevation of intracellular Ca2+ levels, and 

possibly through activation of protein kinase C (Hwang et al. 2001; Kramer et al. 1986; Piccinini et al. 

1977; Watts et al. 1995). 

Renal Effects. Lead in cells binds to a variety of proteins, some of which have been implicated in lead 

toxicity (see Section 3.4.1 for further discussion). A characteristic histologic feature of lead nephrotoxicity is the formation of intranuclear inclusion bodies in the renal proximal tubule (Choie and Richter 

1972; Goyer et al. 1970a, 1970b). Inclusion bodies contain lead complexed with protein (Moore et al. 

1973). Appearance of nuclear inclusion bodies is associated with a shift in compartmentalization of lead 

from the cytosol to the nuclear fraction (Oskarsson and Fowler 1985). Sequestration of lead in nuclear 

inclusion bodies can achieve a lead concentration that is 100 times higher (μg Pb/mg protein) than that in 

kidney cytosol (Goyer et al. 1970a, 1970b; Horn 1970); thus, the bodies can have a profound effect on the 

intracellular disposition of lead in the kidney. 

The sequestration of lead in intranuclear inclusion bodies may limit or prevent toxic interactions with 

other molecular targets of lead. In rats exposed to nephrotoxic doses of lead acetate, few intranuclear 

inclusion bodies occurred in the S3 segment of the proximal tubule, where acute injury was most severe, 

whereas, intranuclear inclusion bodies were more numerous in the S2 segment, where the injury was less 

severe (Murakami et al. 1983). 

The exact identity of the lead-protein complex in inclusion bodies remains unknown, as is the mechanism 

of formation of the inclusion body itself. Although proteins that appear to be unique to lead-induced 
LEAD 210 

3. HEALTH EFFECTS 

inclusion bodies have been isolated, their role in the lead sequestration has not been elucidated (Shelton 

and Egle 1982). Cytosolic proteins may serve as carriers of lead or intermediary ligands for uptake of 

lead into the nucleus. Two cytosolic proteins, which appear to be cleavage products of 2-microglobulin 

(Fowler and DuVal 1991), have been isolated from rat kidney cytosol that have high affinity binding sites 

for lead (Kd=13 and 40 nM, respectively) and can mediate uptake of lead into isolated nuclei (Mistry et 

al. 1985, 1986). These proteins can also participate in ligand exchange reactions with other cytosolic 

binding sites, including δ-aminolevulinic dehydratase, which binds and is inhibited by lead (Goering and 

Fowler 1984, 1985). Other high-affinity lead binding proteins (Kd approximately 14 nM) have been 

isolated in human kidney, two of which have been identified as a 5 kD peptide, thymosin 4 and a 9 kD 

peptide, acyl-CoA binding protein (Smith et al. 1998b). Lead also binds to metallothionein, but does not 

appear to be a significant inducer of the protein in comparison with the inducers of cadmium and zinc 

(Eaton et al. 1980; Waalkes and Klaassen 1985). In vivo, only a small fraction of the lead in the kidney is 

bound to metallothionein, and appears to have a binding affinity that is less than Cd2+, but higher than 

Zn2+ (Ulmer and Vallee 1969); thus, lead will more readily displace zinc from metallothionein than 

cadmium (Goering and Fowler 1987; Nielson et al. 1985; Waalkes et al. 1984). The precise role of 

cytosolic lead binding proteins in inclusion body formation has not been determined, although it has been 

hypothesized that aggregations of 2-microglobulin may contribute to the lead-protein complex observed 

in nuclear inclusion bodies (Fowler and DuVal 1991). 

A consistent feature of lead-induced nephropathy is the finding of structural abnormalities of 

mitochondria of renal proximal tubule cells (Fowler et al. 1980; Goyer 1968; Goyer and Krall 1969). 

Mitochondria isolated from intoxicated rats contain lead, principally associated with the intramembrane 

space or bound to the inner and outer membranes, and show abnormal respiratory function, including 

decreased respiratory control ratio during pyruvate/malate- or succinate-mediated respiration (Fowler et 

al. 1980; Oskarsson and Fowler 1985). Lead inhibits uptake of calcium into isolated renal mitochondria 

and may enter mitochondria as a substrate for a calcium transporter (Kapoor et al. 1985). This would be 

consistent with evidence that lead can interact with calcium binding proteins and thereby affect calciummediated or regulated events in a variety of tissues (Fullmer et al. 1985; Goldstein 1993; Goldstein and 

Ar 1983; Habermann et al. 1983; Platt and Busselberg 1994; Pounds 1984; Richardt et al. 1986; Rosen 

and Pounds 1989; Simons and Pocock 1987; Sun and Suszkiw 1995; Tomsig and Suszkiw 1995; Watts et 

al. 1995). Impairments of oxidative metabolism could conceivably contribute to transport deficits and 

cellular degeneration; however, the exact role this plays in lead-induced nephrotoxicity has not been 

elucidated. 
LEAD 211 

3. HEALTH EFFECTS 

Lead exposure also appears to produce an oxidative stress of unknown, and possibly multi-pathway, 

origin (Daggett et al. 1998; Ding et al. 2001; Hermes-Lima et al. 1991; Lawton and Donaldson 1991; 

Monteiro et al. 1991; Nakagawa 1991; Sandhir et al. 1994; Sugawara et al. 1991). Secondary responses 

to lead-induced oxidative stress include induction of nitric oxide synthase, glutathione S-transferase and 

transketolase in the kidney (Daggett et al. 1998; Moser et al. 1995; Vaziri et al. 2001; Witzmann et al. 

1999; Wright et al. 1998). Depletion of nitric oxide has been implicated as a contributor to lead-induced 

hypertension in the rat (Carmignani et al. 2000; Gonick et al. 1997; Vaziri et al. 1997, 1999a, 1999b) and 

thereby may contribute to impairments in glomerular filtration and possibly in the production of 

glomerular lesions; however, a direct role of this mechanism in lead-induced proximal tubular injury has 

not be elucidated. Both lead and L-N-(G)-nitro arginine methyl ester (L-NAME), an inhibitor of nitric 

oxide synthetase, increased the release of N-acetyl-D-glucosaminidase (NAG) from isolated rat kidneys 

perfused with an albumin-free perfusate (Dehpour et al. 1999). The addition of L-arginine decreased the 

effect of lead on NAG release. This observation is consistent with an oxidative stress mechanism 

possibly contributing to lead-induced enzymuria and increased urinary excretion of NAG (see 

Section 3.2.2, Renal Effects). 

Experimental studies in laboratory animals have shown that lead can depress glomerular filtration rate and 

renal blood flow (Aviv et al. 1980; Khalil-Manesh et al. 1992a, 1992b). In rats, depressed glomerular 

filtration rate appears to be proceeded with a period of increased filtration (Khalil-Manesh et al. 1992a; 

O’Flaherty et al. 1986). The mechanism by which lead alters glomerular filtration rate is unknown and, 

its mechanistic connection to lead-induced hypertension has not been fully elucidated. Glomerular 

sclerosis or proximal tubule injury and impairment could directly affect renin release (Boscolo and 

Carmignani 1988) and/or renal insufficiency could secondarily contribute to hypertension. 

Hematological Effects. The effects of lead on the hematopoietic system have been well documented. 

These effects, which are seen in both humans and animals, include increased urinary porphyrins, 

coproporphyrins, ALA, EP, FEP, ZPP, and anemia. The process of heme biosynthesis is outlined in 

Figure 3-15. Lead interferes with heme biosynthesis by altering the activity of three enzymes: ALAS, 

ALAD, and ferrochelatase. Lead indirectly stimulates the mitochondrial enzyme ALAS, which catalyzes 

the condensation of glycine and succinyl-coenzyme A to form ALA. The activity of ALAS is the ratelimiting step in heme biosynthesis; increase of ALAS activity occurs through feedback derepression. 

Lead inhibits the zinc-containing cytosolic enzyme ALAD, which catalyzes the condensation of two units 

of ALA to form porphobilinogen. This inhibition is noncompetitive, and occurs through the binding of 

lead to vicinal sulfhydryls at the active site of ALAD. Lead bridges the vicinal sulfhydryls, whereas Zn, 
LEAD 212 

3. HEALTH EFFECTS 

Figure 3-15. Effects of Lead on Heme Biosynthesis 

MITOCHONDRION 

MITOCHONDRIAL MEMBRANE 

AMINOLEVULINIC ACID 

(ALA) 

GLYCINE 

+ 

SUCCINYL-CoA 

ALA SYNTHETASE 

(INCREASE) 

Pb (DIRECTLY OR 

BY DEREPRESSION) 

IRON + PROTOPORPHYRIN 

FERROCHELATASE 

HEME 

Pb 

? 

? 

ALA CORPROPORPHYRIN Pb DEHYDRASE (INCREASE) 

(DECREASE) 

PORPHOBILINOGEN 

Source: EPA 1986a 

IRON 
LEAD 213 

3. HEALTH EFFECTS 

which is normally found at the active site, binds to only one of these sulfhydryls. Inhibition of ALAD 

and feedback derepression of ALAS results in accumulation of ALA. Lead decreases, in a noncompetitive fashion, the activity of the zinc-containing mitochondrial enzyme ferrochelatase, which catalyzes the 

insertion of iron (II) into the protoporphyrin ring to form heme. Inhibition of ferrochelatase (a 

mitochondrial enzyme) may occur through binding of lead to the vicinal sulfhydryl groups of the active 

site. Another possible mechanism is indirect, through impaired transport of iron in the mitochondrion, 

due to disruption of mitochondrial structure. Some other enzymes of the heme synthesis pathway contain 

single sulfhydryl groups at their active sites and are not as sensitive to inhibition by lead as are ALAD 

and ferrochelatase (EPA 1986a; Goering 1993). 

Lead inhibition of ferrochelatase results in an accumulation of protoporphyrin IX, which is present in the 

circulating erythrocytes as ZPP, because of the placement of zinc, rather than iron, in the porphyrin 

moiety. ZPP is bound in the heme pockets of hemoglobin and remains there throughout the life of the 

erythrocyte. In the past, assays used in studies of protoporphyrin accumulation measured ZPP or FEP, 

because ZPP is converted to FEP during extraction and older technology could not differentiate FEP from 

ZPP. However, contemporary technology permits the direct quantification of ZPP, a far more clinically 

useful parameter. Because accumulation of ZPP occurs only in erythrocytes formed during the presence 

of lead in erythropoietic tissue, this effect is detectable in circulating erythrocytes only after a lag time 

reflecting maturation of erythrocytes and does not reach steady state until the entire population of 

erythrocytes has turned over, in approximately 120 days (EPA 1986a). 

A marked interference with heme synthesis results in a reduction of the hemoglobin concentration in 

blood. Decreased hemoglobin production, coupled with an increase in erythrocyte destruction, results in 

a hypochromic, normocytic anemia with associated reticulocytosis. Decreased hemoglobin and anemia 

have been observed in lead workers and in children with prolonged exposure at higher PbBs than those 

noted as threshold levels for inhibition or stimulation of enzyme activities involved in heme synthesis 

(EPA 1986a). Inappropriate renal production of erythropoietin due to renal damage, leading to 

inadequate maturation of erythoid progenitor cells, also has been suggested as a contributing mechanism 

for lead-induced anemia (Osterode et al. 1999). 

The increase in erythrocyte destruction may be due in part to inhibition by lead of pyrimidine5'-nucleotidase, which results in an accumulation of pyrimidine nucleotides (cytidine and uridine 

phosphates) in the erythrocyte or reticulocyte. This enzyme inhibition and nucleotide accumulation affect 

erythrocyte membrane stability and survival by alteration of cellular energetics (Angle et al. 1982; EPA 
LEAD 214 

3. HEALTH EFFECTS 

1986a). Formation of the heme-containing cytochromes is inhibited in animals treated intraperitoneally 

or orally with lead compounds. An inverse dose-effect relationship between lead exposure and 

P-450 content of hepatic microsomes and also activity of microsomal mixed-function oxygenases has 

been observed (Goldberg et al. 1978). Increasing duration of exposure to lead was associated with 

decreasing microsomal P-450 content and decreasing microsomal heme content (Meredith and Moore 

1979). In addition, delays in the synthesis of the respiratory chain hemoprotein cytochrome C have been 

noted during administration of lead to neonatal rats (Bull et al. 1979). 

The impairment of heme synthesis by lead may have a far-ranging impact not limited to the hematopoietic 

system. EPA (1986a) provided an overview of the known and potential consequences of the reduction of 

heme synthesis as shown in Figure 3-16. Solid arrows indicate well-documented effects, whereas dashed 

arrows indicate effects considered to be plausible further consequences of the impairment of heme 

synthesis. More detailed information on the exposure levels or blood lead levels at which these impacts 

may be experienced was provided in Section 3.2. 

Neurotoxicity. The literature on mechanisms of neurotoxicity of lead is enormous. Most studies 

conducted in recent years have focused on trying to determine the biochemical or molecular basis of the 

intellectual deficits observed in exposed children using animal models. Trying to cite all of the studies 

that have contributed to our current knowledge is an almost impossible task. Therefore, the major topics 

summarized below have been extracted from experts’ reviews and the reader is referred to references 

cited therein for more detailed information (Bouton and Pevsner 2000; Bressler et al. 1999; Cory-Slechta 

1995, 2003; Gilbert and Lasley 2002; Lasley and Gilbert 2000; Nihei and Guilarte 2002; Suszkiw 2004; 

Toscano and Guilarte 2005; Zawia et al. 2000). 

Lead can affect the nervous system by multiple mechanisms, one of the most important of which is by 

mimicking calcium action and/or disruption of calcium homeostasis. Because calcium is involved as a 

cofactor in many cellular processes, it is not surprising that many cell-signaling pathways are affected by 

lead. One pathway that has been studied with more detail is the activation of protein kinase C (PKC). 

PKC is a serine/threonine protein kinase involved in many processes important for synaptic transmission 

such as the synthesis of neurotransmitters, ligand-receptor interactions, conductance of ionic channels, 

and dendritic branching. The PKC family is made up of 12 isozymes, each with different enzymatic 

cofactor requirements, tissue expression, and cellular distributions. The γ-isoform is one of several 

calcium-dependent forms of PKC and is a likely target for lead neurotoxicity; it is neuron-specific and is 
LEAD 215 

3. HEALTH EFFECTS 

Figure 3-16. Multiorgan Impact of Reduction of Heme Body Pool by Lead 

REDUCTION OF HEME 

BODY POOL 

Pb 

EFFECTS ON NEURONS, 

AXONS, AND SCHWANN 

CELLS 

IMPAIRED CELLULAR 

ENERGETICS 

 ERYTHROPOMETIC 

EFFECTS 

REDUCED HEMOGLOBIN 

SYNTHESIS 

REDUCED NEURAL HEMOPROTEINS (e.g., EFFECTS CYTOCHROMES) 

ANEMIA REDUCED
 

OXYGEN TRANSPORT TO
 

ALL TISSUES
 

DISTURBED IMMUNOREGULATORY ROLE OF 

CALCIUM 

DISTURBED CALCIUM 

METABOLISM 

REDUCED 1.25 (OH)2 – 

VITAMIN D 

RENAL ENDOCRINE 

EFFECTS 

DISTURBED ROLE IN 

TUMORIGENESIS 

CONTROL 

IMPAIRED
 

DETOXIFICATION OF
 

XENOBIOTICS
 

HEPATIC
 

EFFECTS
 

REDUCED HEME FOR 

HEME-REGULATED 

TRANSFORMATIONS 

IMPAIRED METABOLISM
 

OF ENDOGENOUS
 

AGONISTS
 

EXACERBATION OF
 

HYPOXIC EFFECTS OF
 

OTHER STRESS AGENTS
 

CARDIOVASCULAR
 

DYSFUNCTION AND OTHER
 

HYPOXIC EFFECTS

IMPAIRED MYELINATION
 

AND NERVE CONDUCTION
 

IMPAIRED MINERAL 

TISSUE HOMEOSTASIS 

IMPAIRED BONE AND TOOTH 

DEVELOPMENT 

IMPAIRED CALCIUM ROLE 

AS SECOND MESSENGER 

IMPAIRED CALCIUM ROLE 

IN CYCLIC NUCLEOTIDE 

METABOLISM 

IMPAIRED
 

DETOXIFICATION OF
 

ENVIRONMENTAL TOXINS
 

IMPAIRED
 

DETOXIFICATION OF
 

DRUGS
 

IMPAIRED 

HYDROXYLATION OF 

CORTISOL 

DISTURBED INDOLEAMINE 

NEUROTRANSMITTER 

FUNCTION 

IMPAIRED DEVELOPMENT
 

OF NERVOUS SYSTEM
 

ALTERED METABOLISM 

OF TRYPTOPHAN 

ELEVATED BRAIN LEVELS 

OF TRYPTOPHAN, 

SEROTONIN, AND HIAA 

Source: EPA 1986a 
LEAD 216 

3. HEALTH EFFECTS 

involved in long-term potentiation (see below), spatial learning, and memory processes. PKC has the 

capacity to both activate and inhibit PKCs. Studies have shown that micromolar concentrations of lead 

can activate PKC-dependent phosphorylation in cultured brain microvessels, whereas picomolar 

concentrations of lead activate preparations of PKC in vitro. Interestingly, studies in rats exposed to low 

lead levels have shown few significant changes in PKC activity or expression, suggesting that the whole 

animal may be able to compensate for lead PKC-mediated effects compared to a system in vitro. PKC 

induces the formation of the AP-1 transcriptional regulatory complex, which regulates the expression of a 

large number of target genes via AP-1 promoter elements. A gene regulated by lead via AP-1 promoters 

is the glial fibrillary acidic protein (GFAP), an astrocytic intermediate filament protein that is induced 

during periods of reactive astrocytic gliosis. Astrocytes along with endothelial cells make up the blood 

brain barrier (BBB). Studies in rats exposed chronically to low lead levels have reported alterations in the 

normal pattern of GFAP gene expression in the brain, and the most marked long-lasting effects occurred 

when the rats were exposed during the developmental period. In immature brain microvessels, most of 

the protein kinase C is in the cytosol, whereas in mature brain microvessels, this enzyme is membranebound. Activation of protein kinase C in other systems is known to result in a change in distribution from 

cytosol to membrane, and has been observed with exposure of immature brain microvessels to lead. An 

inhibition of microvascular formation has been observed with lead concentrations that are effective in 

activating PKC. Thus, it appears that premature activation of PKC by lead may impair brain 

microvascular formation and function, and at high levels of lead exposure, may account for gross defects 

in the blood-brain barrier that contribute to acute lead encephalopathy. The blood-brain barrier normally 

excludes plasma proteins and many organic molecules, and limits the passage of ions. With disruption of 

this barrier, molecules such as albumin freely enter the brain and ions and water follow. Because the 

brain lacks a well-developed lymphatic system, clearance of plasma constituents is slow, edema occurs, 

and intracranial pressure rises. The particular vulnerability of the fetus and infant to the neurotoxicity of 

lead may be due in part to immaturity of the blood-brain barrier and to the lack of the high-affinity leadbinding protein in astroglia, which sequester lead. 

Another enzyme altered by lead is calmodulin, a major intracellular receptor for calcium in eukaryotes. 

Normally, calcium induces a conformational change in calmodulin that converts the protein to an active 

form; lead improperly activates the enzyme. Some studies suggest that activation of calmodulin by lead 

results in protein phosphorylation in the rat brain and brain membrane preparations and can alter proper 

functioning of cAMP messenger pathways. It has been shown that calmodulin can mediate gene 

expression via calmodulin-dependent kinases. The effects of lead on gene expression via activation of 
LEAD 217 

3. HEALTH EFFECTS 

calmodulin are not as marked as those via PKC because activation of calmodulin requires 100-fold more 

lead than activation of PKC. 

Lead also can substitute for zinc in some enzymes and in zinc-finger proteins, which coordinate one or 

more zinc cations as cofactors. The substitution of lead for zinc in zinc-finger proteins can have 

significant effects on de novo expression of the bound proteins and in any genes transcriptionallyregulated by a particular protein. Lead has been found to alter the binding of zinc-finger transcriptional 

regulator Sp1 to its specific DNA sequences. This is accompanied by aberrant expression of Sp1 target 

genes such as myelin basic protein and proteolipid protein. Another gene regulated by Sp1 is the 

β-amyloid precursor protein (APP) gene. Recently, it was shown that lead exposure in neonatal rats 

transiently induces APP mRNA, which is overexpressed with a delay of 20 months after exposure to lead 

ceased. In contrast, APP expression, Sp1 activity, as well as APP ans β-amyloid protein levels, were 

unresponsive to lead during old age, suggesting that exposures occurring during brain development may 

predetermine the expression and regulation of APP later in life. It has been suggested that the multiple 

responses to lead exposure are due to lead specifically targeting zinc-finger proteins found in enzymes, 

channels, and receptors. 

Lead affects virtually every neurotransmitter system in the brain, but most information on changes is 

available on the glutamatergic, dopaminergic, and cholinergic systems. Of these, special attention has 

been paid to the glutamatergic system and its role in hippocampal long-term potentiation (LTP). 

Hippocampal LTP is a cellular model of learning and memory characterized by a persistent increase in 

synaptic efficacy following delivery of brief tetanic stimulation (high-frequency stimulation). LTP 

provides a neurophysiological substrate for learning and storing information and is thought to utilize the 

same synaptic mechanisms as the learning process. LTP is established only with complex patterns of 

stimulation but not with single pulse stimulation. While it has been studied primarily in the hippocampal 

subregions CA1 and dentate gyrus, it can also be evoked in cortical areas. Exposure of intact animals or 

tissue slices to lead diminishes LTP by a combination of three actions: increasing the threshold for 

induction, reducing the magnitude of potentiation, and shortening its duration by accelerating its rate of 

decay. This effect on LTP involves actions of lead on glutamate release (presynaptic effects) and on the 

N-methyl-D-aspartate (NMDA) receptor function. Studies have shown that the effects of lead vary as a 

function of the developmental exposure period and that lead exposure early in life is critical for 

production of impaired LTP in adult animals. LTP is more readily affected by lead during early 

development, but exposure initiated after weaning also affects synaptic plasticity. Studies also have 

shown that both LTP magnitude and threshold exhibit a U-shape type response with increasing lead 
LEAD 218 

3. HEALTH EFFECTS 

doses. While LTP is primarily a glutamatergic phenomenon, it can be modulated through input from 

extrahippocampal sources including noradrenergic, dopaminergic, and cholinergic sources. 

Studies in animals treated with lead (PbB 30–40 μg/dL) have shown that induction of pair-pulse 

facilitation in dentate gyrus is impaired. Since the phenomenon is mediated primarily by increased 

glutamate release, the reasonable assumption is that lead reduces glutamate release. Support for this 

assumption is also derived from studies in which depolarization-induced hippocampal glutamate release 

was reduced in awake animals with similar PbBs. This inhibition of glutamate release was shown to be 

due to lead-related decrements in a calcium-dependent component. The exact mechanism for the 

inhibition of glutamate release by lead is not known, but is consistent with lead at nanomolar 

concentrations preventing maximal activation of PKC, rather than lead blocking calcium influx into the 

presynaptic terminal through voltage-gated calcium channels. Reduced glutamate release can be 

observed in rats exposed from conception through weaning and tested as adults, when lead was no longer 

present, suggesting that a direct action of lead is not necessary and that other mechanisms, such as 

reductions in synaptogenesis, also may be involved. As with LTP, depolarization-evoked hippocampal 

glutamate release in rats treated chronically with several dose levels of lead exhibited a U-shaped 

response. That is, glutamate release was inhibited in rats treated with the lower lead doses, but not in 

those exposed to the higher concentrations of lead. Although speculative, this was interpreted as lead at 

the higher doses mimicking calcium in promoting transmitter release and overriding the inhibitory effects 

of lead that occur at lower lead levels. 

The findings regarding the effects of lead on postsynaptic glutamatergic function have been inconsistent 

across laboratories, but a direct inhibitory action of lead on the NMDA receptor is unlikely at 

environmentally relevant exposure levels. Some studies have shown that continuous exposure of rats 

from gestation to adulthood results in a significant increase in NMDA receptor numbers in cortical areas, 

hippocampus, and forebrain. This was observed in the forebrain at PbB of 14 μg/dL. Other studies, 

however, have reported changes in the opposite direction and the reason for the discrepancy in results 

may be due to the different exposure protocols used. From a functional point of view, it seems plausible 

that a lead-induced reduction in presynaptic transmitter release be compensated by a postsynaptic increase 

in number or density of receptors in order to maintain a viable function. 

The dopaminergic system also has a role in aspects of cognitive function since lesions of dopaminergic 

neurons impair behavior in various types of learning and cognitive tasks. Also, individuals who suffer 

from Parkinson’s disease, a disease associated with dopamine depletion in the striatum, sometimes show 
LEAD 219 

3. HEALTH EFFECTS 

difficulties in cognitive functions. Most of the evidence available suggests that lead may impair 

regulation of dopamine synthesis and release, indicating a presynaptic site of action. Studies in animals 

often report opposing effects of lead on nigrostriatal and mesolimbic dopamine systems regarding 

receptor binding, dopamine synthesis, turnover, and uptake. Postweaning exposure of rats to lead resulted 

in supersensitivity of D1 and D2 dopamine receptors, which can be interpreted as a compensatory 

response to decreased synthesis and/or release of dopamine. Lesions to the nucleus acumbens (a terminal 

dopamine projection area) and the frontal cortex result in perseverative deficits, suggesting that the 

mesolimbic system is preferentially involved in the effects of lead. Results of studies using dopaminergic 

compounds seem to indicate that changes in dopamine systems do not play a role in the effects of lead on 

learning. Instead, it has been suggested that changes in dopaminergic systems may play a role in the 

altered response rates on Fixed-Interval (FI) schedules of reinforcement that have been observed in 

animals exposed to lead. This type of changes has been thought to represent a failure to inhibit 

inappropriate responding. 

It is widely accepted that the cholinergic system plays a role in learning and memory processes. Some 

cognitive deficits observed in patients with Alzheimer’s disease have been attributed to impaired 

cholinergic function in the cortex and hippocampus. Exposure to lead induces numerous changes in 

cholinergic system function, but the results, in general, have been inconsistently detected, or are of 

opposite direction in different studies, which may be attributed to the different exposure protocols used in 

the different studies. However, it is clear that lead blocks evoked release of acetylcholine and diminishes 

cholinergic function. This has been demonstrated in central and peripheral synapses. Studies with the 

neuromuscular junction showed that lead reduces acetylcholine release by blocking calcium entry into the 

terminal. At the same time, lead prevents sequestration of intracellular calcium by organelles, which 

results in increased spontaneous release of the neurotransmitter. Studies in vitro show that lead can block 

nicotinic cholinergic receptors, but it is unclear whether such effects occur in vivo or whether lead alters 

the expression of nicotinic cholinergic receptors in developing brain. Evidence for an involvement in 

lead-induced behavioral deficits has been presented based on the observation that intrahippocampal 

transplants of cholinergic-rich septal and nucleus basalis tissue improve the deficits and that treatment 

with nicotinic agonists can improve learning and memory impairments following perinatal lead treatment 

of rats. Chronic exposure of rats to lead has resulted in decreased muscarinic-receptor expression in the 

hippocampus. Whether or not lead exposure during development alters muscarinic receptor sensitivity is 

unclear as there are reports with opposite results. The preponderance of the binding data suggests that 

lead does not directly affect muscarinic receptors with the exception of visual cortex, where lead may 

have a direct inhibitory effect on muscarinic receptors from rods and bipolar of the retina. 
LEAD 220 

3. HEALTH EFFECTS 

3.4.3 Animal-to-Human Extrapolations 

Studies in rodents, dogs, and nonhuman primates have demonstrated all of the major types of health 

effects of lead that have been observed in humans, including cardiovascular, hematological, neurodevelopmental, and renal effects (EPA 1986a). These studies also provide support for the concept of 

blood lead concentration as a metric of internal dose for use in dose-response assessments in humans. 

The effects of low-level lead exposure on cognitive development and function in humans are difficult to 

discern against the background of genetic, environmental, and socioeconomic factors that would be 

expected to affect these end points in children. Experimental studies in animals have been helpful for 

establishing the plausibility of the hypothesis that low-level exposures to lead can affect cognitive 

function in mammals and for providing insights into possible mechanisms for these effects. Studies in 

rats and nonhuman primates have demonstrated deficits in learning associated with blood lead 

concentrations between 10 and 15 μg/dL, a range that is comparable to those reported in epidemiological 

studies, which found learning deficits in children (Cory-Slechta 2003; Rice 1996b). 

The lead-induced nephropathy observed in humans and rodents shows a comparable early pathology 

(Goyer 1993). However, in rodents, proximal tubular cell injury induced by lead can progress to 

adenocarcinomas of the kidney (see Section 3.2.2). The observation of lead-induced kidney tumors in 

rats may not be relevant to humans. Conclusive evidence for lead-induced renal cancers (or any other 

type of cancer) in humans is lacking, even in populations in which chronic lead nephropathy is evident. 

3.5 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 
LEAD 221 

3. HEALTH EFFECTS 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 
LEAD 222 

3. HEALTH EFFECTS 

Health effects that have been associated with lead exposures during infancy or childhood include anemia 

(Schwartz et al. 1990) (and related disorders of heme synthesis), neurological impairment (e.g., encephalopathy), renal alterations, colic (Chisolm 1962, 1965; Chisolm and Harrison 1956), and impaired 

metabolism of vitamin D (Mahaffey et al. 1982; Rosen and Chesney 1983). Death from encephalopathy 

may occur with PbBs ≥125 μg/dL. In addition to the above effects, the following health effects have been 

associated with lead exposures either in utero, during infancy, or during childhood: delays or impairment 

of neurological development, neurobehavioral deficits including IQ deficits, low birth weight, and low 

gestational age, growth retardation, and delayed sexual maturation in girls (Bellinger et al. 1992; Canfield 

et al. 2004; Coscia et al. 2003; Lanphear et al. 2000a; Ris et al. 2004; Schnaas et al. 2000; Selevan et al. 

2003; Tong et al. 1998; Wu et al. 2003a). These effects, which are discussed in Section 3.2, are 

consistent with findings in animals exposed to lead. Effects of lead observed at relatively high exposures 

such as anemia, colic, and encephalopathy, also occur in adults. There is no evidence that exposure to 

lead causes structural birth defects in humans or in animals, although Needleman et al. (1984) reported an 

association between cord blood lead and the incidence of minor anomalies (hemangiomas and 

lymphangiomas, hydrocele, skin anomalies, undescended testicles) in a study of 5,183 women who 

delivered neonates of at least 20 weeks of gestational age. Exposure to lead during childhood may result 

in neurobehavioral effects that persist into adulthood (e.g., Byers and Lord 1943; Stokes et al. 1998; 

White et al. 1993). 

Children and developing organisms in general, are more susceptible to lead toxicity than adults. This 

higher susceptibility derives from numerous factors. Children exhibit more severe toxicity at lower 

exposures than adults, as indicated by lower PbB concentrations and time-integrated PbB concentrations 

that are associated with toxicity in children (see Section 3.2 for more detailed discussion). This suggests 

that children are more vulnerable to absorbed lead than adults. The mechanism for this increased 

vulnerability is not completely understood. Lead affects processes such as cell migration and 

synaptogenesis, as well as pruning of unnecessary connections between neurons, all key processes during 

brain development. Lead also affects glial cells and the blood brain barrier. Alterations in any of these 

parameters can produce permanent improper connections that will lead to altered specific brain functions. 

Children also absorb a larger fraction of ingested lead than do adults; thus, children will experience a 

higher internal lead dose per unit of body mass than adults at similar exposure concentrations (Alexander 

et al. 1974; Blake et al. 1983; James et al. 1985; Rabinowitz et al. 1980; Ziegler et al. 1978). Absorption 

of lead appears to be higher in children who have low dietary iron or calcium intakes; thus, dietary 

insufficiencies, which are not uncommon in lower socioeconomic children, may contribute to their lead 

absorption (Mahaffey and Annest 1986; Mahaffey et al. 1986; Marcus and Schwartz 1987; Ziegler et al. 
LEAD 223 

3. HEALTH EFFECTS 

1978) (see Section 3.3.1.2 for more detailed discussion of lead absorption in children). Insufficient 

dietary zinc, also not uncommon in children, may contribute to their increased susceptibility to lead, since 

lead impairs the activity of zinc-requiring enzymes in the heme biosynthesis pathway (see Section 3.4.2). 

Infants are born with a lead body burden that reflects the burden of the mother (Goyer 1990; Graziano et 

al. 1990; Schuhmacher et al. 1996). During gestation, lead from the maternal skeleton is transferred 

across the placenta to the fetus (Gulson 2000; Gulson et al. 1997b, 1999b, 2003). Additional lead 

exposure may occur during breast feeding (Gulson et al. 1998b) (see Section 3.3.2 for more detailed 

discussion). This means that lead stored in the mother’s body from exposure prior to conception can 

result in exposure to the fetus or nursing neonate. Behavioral patterns of children can result in higher 

rates of ingestion of soil and dust, both of which are often important environmental depots for lead 

(Barnes 1990; Binder et al. 1986; Calabrese et al. 1989, 1997a; Clausing et al. 1987). Examples of 

activities that tend to promote soil and dust ingestion preferentially in children include playing and 

crawling on the ground and floor, hand-to-mouth activity, mouthing of objects, and indiscriminate eating 

of food items dropped or found on the ground or floor (see Section 6.6 for more detailed discussion). 

Some children engage in pica, or the ingestion of nonfood items (e.g., soil). This behavior can lead to 

excess exposure if a child consumes soil contaminated with lead. 

The toxicokinetics of lead in children appears to be similar to that in adults, with the exception of the 

higher absorption of ingested lead in children. Most of the lead body burden in both children and adults 

is in bone; a slightly large fraction of the body burden in adults resides in bone (Barry 1975). The 

difference may reflect the larger amount of trabecular bone and bone turnover during growth; trabecular 

bone has a shorter retention halftime for lead than does cortical bone (see Section 3.3.2 for details). 

Limited information suggests that organic lead compounds undergo enzymatic (cytochrome P-450) 

biotransformation and that inorganic lead is complexed (nonenzymatically) with proteins and nonprotein 

ligands. However, the information available is insufficient to determine whether the metabolism of lead 

in children is similar to adults. Several models of lead pharmacokinetics in children have been developed 

(EPA 1994a, 1994b; Leggett 1993; O'Flaherty 1993, 1995a); these are described in Section 3.3.5. 

The important biomarkers of exposure that have been explored in children include PbB concentration 

(CDC 1991), bone lead levels (as measured from noninvasive XRF measurements of phalanx, patella, 

tibia, or ulna), and lead levels in deciduous teeth (Hu et al. 1998). Lead in blood has a much shorter 

retention half-time than lead in bone (days compared to years); therefore, PbB concentration provides a 

marker for more recent exposure, while lead in bone appears to reflect longer-term cumulative exposures 

(Borjesson et al. 1997; Nilsson et al. 1991; Schutz et al. 1987). Lead in tooth enamel is thought to reflect 
LEAD 224 

3. HEALTH EFFECTS 

exposures in utero and during early infancy, during which development of tooth enamel and coronal 

dentine is completed. Lead appears to accumulate in dentin after formation of the dentin is complete; 

therefore, lead in dentin is thought to reflect exposures that occur up to the time the tooth is shed (Gulson 

1996; Gulson and Wilson 1994; Rabinowitz 1995; Rabinowitz et al. 1993). A more detailed discussion of 

the above biomarkers of exposure, as well as other less important biomarkers, is presented in 

Section 3.6.1. The most sensitive biomarkers of effects of lead in children relate to the effects of lead on 

heme metabolism, they include ALAD activity, EP, FEP, and ZPP; however, these are not specific for 

lead (Bernard and Becker 1988; CDC 1991; Hernberg et al. 1970). EP has been used as a screening test. 

However, it is not sensitive below a PbB of about 25 μg/dL. These and other biomarkers of effects of 

lead are discussed in Section 3.6.2. 

Methods for preventing or decreasing the absorption of lead following acute exposures to potentially toxic 

levels of lead include removal of the child from the exposure source, removal of lead-containing dirt and 

dust from the skin, and, if the lead has been ingested, standard treatments to induce vomiting. Ensuring a 

diet that is nutritionally adequate in calcium and iron may decrease the absorbed dose of lead associated 

with a given exposure level, because lead absorption appears to be higher in children who have low levels 

of iron or calcium in their diets (Mahaffey and Annest 1986; Mahaffey et al. 1986; Marcus and Schwartz 

1987; Ziegler et al. 1978). Diets that are nutritionally adequate in zinc also may be helpful for reducing 

the risks of lead toxicity because zinc may protect against lead-induced inhibition of zinc-dependent 

enzymes, such as ALAD (Chisolm 1981; Johnson and Tenuta 1979; Markowitz and Rosen 1981). 

Methods for reducing the toxicity of absorbed lead include the injection or oral administration of 

chelating or complexing agents (e.g., EDTA, penicillamine, dimercaptosuccinic acid [DMSA]) (CDC 

1991). These agents form complexes with lead that are more rapidly excreted and thereby decrease the 

body burden of lead. These methods for reducing the toxic effects of lead are described in greater detail 

in Section 3.9. Several studies (described in Section 3.9) have examined whether lead-lowering 

interventions, such as with chelators, are paralleled by improvement in health outcomes reportedly altered 

by lead (Dietrich et al. 2004; Liu et al. 2002; Rogan et al. 2001; Ruff et al. 1993). The conclusion of 

these studies was that chelation therapy is not indicated in children with moderate PbB (≤40 μg/dL). 

3.6 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 
LEAD 225 

3. HEALTH EFFECTS 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic 

substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target 

molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The 

preferred biomarkers of exposure are generally the substance itself, substance-specific metabolites in 

readily obtainable body fluid(s), or excreta. However, several factors can confound the use and 

interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures 

from more than one source. The substance being measured may be a metabolite of another xenobiotic 

substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic 

compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental 

conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the 

body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous 

substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as 

copper, zinc, and selenium). Biomarkers of exposure to lead are discussed in Section 3.6.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by lead are discussed in Section 3.6.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.8, Populations That Are Unusually Susceptible. 
LEAD 226 

3. HEALTH EFFECTS 

3.6.1 Biomarkers Used to Identify or Quantify Exposure to Lead 

The ideal biomarker of lead exposure would be a measurement of total lead body burden. Biomarkers of 

exposure in practical use today are measurements of total lead levels in tissues or body fluids, such as 

blood, bone, urine, or hair; or measurement of certain biological responses to lead (e.g., zinc protoporphyrin). Tetraalkyl lead compounds may also be measured in the breath. Of these, blood lead 

concentration (PbB) is the most widely used and considered to be the most reliable biomarker for general 

clinical use and public health surveillance. Currently, blood lead measurement is the screening test of 

choice to identify children with elevated PbBs (CDC 1991). Venous sampling of blood is preferable to 

finger prick sampling, which has a considerable risk of surface lead contamination from the finger if 

proper finger cleaning is not carried out. In children, PbBs between 10 and 14 μg/dL should trigger 

community-wide childhood lead poisoning prevention activities (CDC 1991). Since the elimination halftime of lead in blood is approximately 30 days, PbBs generally reflect relatively recent exposure and 

cannot be used to distinguish between low-level intermediate or chronic exposure and high-level acute 

exposure. In 1997, the CDC issued new guidance on screening children for lead poisoning that 

recommends a systematic approach to the development of appropriate lead screening in states and 

communities (CDC 1997c). The objective of the new guidelines is maximum screening of high-risk 

children and reduced screening of low-risk children, as contrasted with previous guidelines (CDC 1991), 

which recommended universal screening. 

Blood Lead Concentration. Measurement of PbB is the most widely used biomarker of lead exposure. 

Elevated blood lead concentration (e.g., >10 μg/dL) is an indication of excessive exposure in infants and 

children (CDC 1991) and is considered to be excessive for women of child-bearing age (ACGIH 1998). 

The biological exposure index (BEI) for lead in blood of exposed workers is 30 μg/dL (ACGIH 2004). 

The NIOSH recommended exposure limit (REL) for workers (50 μg/m3

 air, 8-hour TWA) is established 

to ensure that the blood lead concentration does not exceed 60 μg/dL (NIOSH 2005). 

The extensive use of blood lead as a dose metric reflects mainly the greater feasibility of incorporating 

blood lead measurements into clinical or epidemiological studies, compared to other potential dose 

indicators, such as lead in kidney, plasma, urine, or bone (Skerfving 1988). PbB measurements have 

several limitations as measures of lead body burden. Blood comprises <2% of the total lead burden; most 

of the lead burden resides in bone (Barry 1975). The elimination half-time of lead in blood is 

approximately 30 days (Chamberlain et al. 1978; Griffin et al. 1975; Rabinowitz et al. 1976); therefore, 

the lead concentration in blood relatively reflects, mainly, the exposure history of the previous few 
LEAD 227 

3. HEALTH EFFECTS 

months and does not necessarily reflect the larger burden and much slower elimination kinetics of lead in 

bone (Graziano 1994; Lyngbye et al. 1990b). The relationship between lead intake and PbB is 

curvilinear; the increment in PbB per unit of intake decreases with increasing PbB (Ryu et al. 1983; 

Sherlock and Quinn 1986; Sherlock et al. 1982, 1984). Lead intake-blood lead relationships also vary 

with age as a result of age-dependency of gastrointestinal absorption of lead, and vary with diet and 

nutritional status (Mushak 1991). A practical outcome of the above characteristics of PbB is that PbB can 

change relatively rapidly (e.g., weeks) in response to changes in exposure; thus, PbB can be influenced by 

short-term variability in exposure that may have only minor effects on lead body burden. A single blood 

lead determination cannot distinguish between lower-level intermediate or chronic exposure and higherlevel acute exposure. Similarly, a single measurement may fail to detect a higher exposure that occurred 

(or ended) several months earlier. Time-integrated measurements of PbB may provide a means for 

accounting for some of these factors and thereby provide a better measure of long-term exposure (Roels et 

al. 1995). 

Bone and Tooth Lead Measurements. The development of noninvasive XRF techniques for measuring 

lead concentrations in bone has enabled the exploration of bone lead as a biomarker of lead exposure in 

children and in adults (Batuman et al. 1989; Hu 1991b; Hu et al. 1989, 1990, 1995; Rosen et al. 1993; 

Wedeen 1988, 1990, 1992). Lead in bone is considered a biomarker of cumulative exposure to lead 

because lead accumulates in bone over the lifetime and most of the lead body burden resides in bone. 

Lead is not distributed uniformly in bone. Lead will accumulate in those regions of bone undergoing the 

most active calcification at the time of exposure. During infancy and childhood, bone calcification is 

most active in trabecular bone, whereas in adulthood, calcification occurs at sites of remodeling in 

cortical and trabecular bone. This suggests that lead accumulation will occur predominantly in trabecular 

bone during childhood, and in both cortical and trabecular bone in adulthood (Aufderheide and Wittmers 

1992). Patella, calcaneus, and sternum XRF measurements primarily reflect lead in trabecular bone, 

whereas XRF measurements of midtibia, phalanx, or ulna reflect primarily lead in cortical bone. Lead 

levels in cortical bone may be a better indicator of long-term cumulative exposure than lead in trabecular 

bone, possibly because lead in trabecular bone may exchange more actively with lead in blood than does 

cortical bone. This is consistent with estimates of a longer elimination half-time of lead in cortical bone, 

compared to trabecular bone (Borjesson et al. 1997; Brito et al. 2005; Nilsson et al. 1991; Schutz et al. 

1987). Longitudinal measures of bone lead over a 3-year period showed no significant decline in cortical 

bone lead, whereas trabecular bone lead declined by approximately 15% (Kim et al. 1997). Estimates of 

cortical bone lead elimination half-times (5–50 years) show a dependence on lead burden, with longer 

half-times in people who have higher bone lead burdens (Brito et al. 2005). Further evidence that cortical 
LEAD 228 

3. HEALTH EFFECTS 

bone lead measurements may provide a better reflection of long-term exposure than do measurements of 

trabecular bone comes from studies in which cortical and trabecular bone lead measurements have been 

compared to PbB. Lead levels in trabecular bone (in adults) correlate more highly with contemporary 

PbB than do levels of lead in cortical bone (Erkkila et al. 1992; Hernandez-Avila et al. 1996; Hu et al. 

1996b, 1998; Watanabe et al. 1994). Cortical bone lead measurements correlate well with time-integrated 

PbB measurements, which would be expected to be a better reflection of cumulative exposure than 

contemporary blood lead measurements (Borjesson et al. 1997; Roels et al. 1994). Bone lead levels tend 

to increase with age (Hu et al. 1996b; Kosnett et al. 1994; Roy et al. 1997), although the relationship 

between age and bone lead may be stronger after adolescence (Hoppin et al. 1997). These observations 

are consistent with cortical bone reflecting cumulative exposures over the lifetime. 

Relationships between bone lead levels and health outcomes have been studied in several epidemiology 

studies, but not as extensively as have other biomarkers of exposure such as PbB. These studies suggest 

that bone lead levels may be predictors of certain health outcomes, including neurodevelopmental and 

behavioral outcomes in children and adolescents (Campbell et al. 2000a; Needleman et al. 1996, 2002; 

Payton et al. 1998); and hypertension and declines in renal function in adults (Cheng et al. 2001; Gerr et 

al. 2002; Hu et al. 1996a, 1998; Korrick et al. 1999; Rothenberg et al. 2002a; Tsaih et al. 2004). 

Tooth lead has been considered a potential biomarker for measuring long-term exposure to lead (e.g., 

years) because lead that accumulates in tooth dentin and enamel appears to be retained until the tooth is 

shed or extracted (Ericson 2001; Gomes et al. 2004; Omar et al. 2001; Rabinowitz et al. 1989; Steenhout 

and Pourtois 1987). Formation of enamel and coronal dentin of deciduous teeth is complete prior to the 

time children begin to crawl; however, lead in shed deciduous teeth is not uniformly distributed. 

Differences in lead levels and stable isotope signatures of the enamel and dentin suggest that lead uptake 

occurs differentially in enamel and dentin after eruption of the tooth (Gulson 1996; Gulson and Wilson 

1994). Lead in enamel is thought to reflect primarily lead exposure that occurs in utero and early infancy, 

prior to tooth eruption. Dentin appears to continue to accumulate lead after eruption of the tooth, 

therefore, dentin lead is thought to reflect exposure that occurs up to the time the teeth are shed or 

extracted (Gulson 1996; Gulson and Wilson 1994; Rabinowitz 1995; Rabinowitz et al. 1993). 

Accumulation of lead in dentin of permanent teeth may continue for the life of the tooth (Steenhout 1982; 

Steenhout and Pourtois 1981). Because it is in direct contact with the external environment, enamel lead 

levels may be more influenced than dentin lead by external lead levels and tooth wear (Purchase and 

Fergusson 1986). 
LEAD 229 

3. HEALTH EFFECTS 

An analysis of eight cross-sectional and/or prospective studies that reported tooth lead and PbBs of the 

same children found considerable consistency among the studies (Rabinowitz 1995). The mean tooth 

lead levels ranged from <3 to >12 μg/g. In a study of 63 subjects, dentin lead was found to be predictive 

of concentrations of lead in the tibia, patella, and mean bone lead 13 years after tooth lead assessment in 

half of them (Kim et al. 1996b). The authors estimated that a 10 μg/g increase in dentin lead levels in 

childhood was predictive of a 1 μg/g increase in tibia lead levels, a 5 μg/g in patella lead levels, and a 

3 μg/g increase in mean bone lead among the young adults. 

Plasma Lead Concentration. The concentration of lead in plasma is extremely difficult to measure 

accurately because levels in plasma are near the quantitation limits of most analytical techniques (e.g., 

approximately 0.4 μg/L at blood lead concentration of 100 μg/L (Bergdahl and Skerfving 1997; Bergdahl 

et al. 1997a) and because hemolysis that occurs with typical analytical practices can contribute substantial 

measurement error (Bergdahl et al. 1998, 2006; Cavalleri et al. 1978; Smith et al. 1998a). Recent 

advances in inductively-coupled plasma mass spectrometry (ICP-MS) offer sensitivity sufficient for 

measurements of lead in plasma (Schütz et al. 1996). The technique has been applied to assessing lead 

exposures in adults (Cake et al. 1996; Hernandez-Avila et al. 1998; Manton et al. 2001; Smith et al. 2002; 

Tellez-Rojo et al. 2004). A direct comparison of lead concentrations in plasma and serum yielded similar 

results (Bergdahl et al. 2006); however, the interchangeability of plasma and serum lead measurements 

for biomonitoring of lead exposure or body burden had not been thoroughly evaluated in large numbers of 

subjects (Bergdahl et al. 2006; Manton et al. 2001; Smith et al. 2002). 

Urinary Lead. Measurements of urinary lead levels have been used to assess lead exposure (e.g., Fels et 

al. 1998; Gerhardsson et al. 1992; Lilis et al. 1968; Lin et al. 2001; Mortada et al. 2001; Roels et al. 

1994). However, like PbB, urinary lead excretion reflects, mainly, recent exposure and, thus, shares 

many of the same limitations for assessing lead body burden or long-term exposure (Sakai 2000; 

Skerfving 1988). The measurement is further complicated by variability in urine volume, which can 

affect concentrations independent of excretion rate (Diamond 1988) and the potential effects of 

decrements in kidney function on excretion, in association with high, nephrotoxic lead exposures or 

kidney disease (Lilis et al. 1968; Wedeen et al. 1975). Urinary lead concentration increases exponentially 

with PbB and can exhibit relatively high intra-individual variability, even at similar PbBs (Gulson et al. 

1998a; Skerfving et al. 1985). Urinary diethyl lead has been proposed as a qualitative marker of exposure 

to tetraethyl lead (Turlakiewicz and Chmielnicka 1985; Vural and Duydu 1995; Zhang et al. 1994). 
LEAD 230 

3. HEALTH EFFECTS 

The measurement of lead excreted in urine following an injection (intravenous or intramuscular) of the 

chelating agent, calcium disodium EDTA (EDTA provocation) has been used to detect elevated body 

burden of lead in adults (Biagini et al. 1977; Lilis et al. 1968; Wedeen 1992; Wedeen et al. 1975) and 

children (Chisolm et al. 1976; Markowitz and Rosen 1981), and is considered to be a reliable measure of 

the potentially toxic fraction of the lead body burden (WHO 1995). The assay is not a substitute for blood 

lead measurements in the clinical setting. Children whose PbBs are ≥45 μg/dL should not receive a 

provocative chelation test; they should be immediately referred for appropriate chelation therapy (CDC 

1991). Further limitations for routine use of the test are that EDTA must be given parenterally and 

requires timed urine collections. A study conducted in rats found that intraperitoneal administration of a 

single dose of EDTA following 3–4-month exposures to lead in drinking water increased levels of lead in 

the liver and brain (Cory-Slechta et al. 1987) raising concern for similar effects in humans who undergo 

the EDTA provocation test. The use of EDTA to assess bone stores of lead (Wedeen 1992) are largely 

being supplanted by more direct, noninvasive procedures for measuring lead in bone. 

Lead in Saliva and Sweat. Lead is excreted in human saliva and sweat (Lilley et al. 1988; Rabinowitz et 

al. 1976; Stauber and Florence 1988; Stauber et al. 1994). However, sweat has not been widely adopted 

for monitoring lead exposures. Lilley et al. (1988) found that lead concentrations in sweat were elevated 

in lead workers; however, sweat and blood lead concentrations were poorly correlated. This may reflect 

excretion of lead in or on the skin that had not been absorbed into blood. Studies conducted in rats have 

found relatively strong correlations between lead concentrations in plasma and saliva (e.g., r2

>0.9), 

compared to blood lead and saliva; therefore, saliva may serve as a better predictor of plasma lead than 

blood lead concentration (Timchalk et al. 2006). 

Hair and Nail Lead. Lead is incorporated into human hair and hair roots (Bos et al. 1985; Rabinowitz et 

al. 1976) and has been explored as a possibly noninvasive approach for estimating lead body burden 

(Gerhardsson et al. 1995b; Wilhelm et al. 1989). The method is subject to error from contamination of 

the surface with environmental lead and contaminants in artificial hair treatments (i.e., dyeing, bleaching, 

permanents) and is a relatively poor predictor of PbB, particularly at low concentrations (<12 μg/dL) 

(Campbell and Toribara 2001; Drasch et al. 1997; Esteban et al. 1999). Nevertheless, levels of lead in 

hair were positively correlated with children’s classroom attention deficit behavior in a study (Tuthill 

1996). Lead in hair was correlated with liver and kidney lead in a study of deceased smelter workers 

(Gerhardsson et al. 1995b). Nail lead has also been utilized as a marker (Gerhardsson et al. 1995b). 
LEAD 231 

3. HEALTH EFFECTS 

Semen Lead. Correlations between concentrations of lead in semen and blood have been reported and 

vary in strength across studies (Alexander et al. 1998a, 1998b; Farias et al. 2005; Telisman et al. 2000). 

This variation may relate, in part, to analytical challenges in the measurement of the relatively low 

concentrations of lead in semen. Using ICP-MS and rigorous collection methods to avoid contamination, 

Farias et al. (2005) reported a detection limit of 0.2 μg/L semen. Mean semen lead concentration in a 

group of 160 adults (age range: 19–48 years) who were not exposed to lead occupationally was 2.66 μg/L 

(range: 0.08–19.42) and significantly correlated with blood lead concentration (mean: 10.8 μg/dL, range: 

4.5–40.2) and tibia bone lead (mean: 14.51 μg/g, range: non-detect–44.71 μg/g). 

Stable Lead Isotopes. Analysis of the relative abundance of stable isotopes of lead in blood and other 

accessible body fluids (e.g., breast milk, urine) has been used to differentiate exposures from multiple 

sources (Flegal and Smith 1995). Relative abundances of stable isotopes of lead (204Pb, 206Pb, 207Pb, and 

208Pb) in lead ores vary with the age of the ore (which determines the extent to which the parent isotopes 

have undergone radioactive decay to stable lead). Humans have lead isotope abundance profiles that 

reflect the profiles of lead deposits to which they have been exposed. Conversely, if exposure is to lead 

from a predominant deposit, that source can be identified by the relative abundance profile in blood (or 

other biological sample). Similarly, if exposure abruptly changes to a lead source having a different 

isotope abundance profile, the kinetics of the change in profile in the person can be measured, reflecting 

the kinetics of uptake and distribution of lead from the new source (Gulson et al. 2003; Maddaloni et al. 

1998; Manton et al. 2003). Numerous examples of the application of stable isotope abundance 

measurements for studying sources of lead exposures have been reported (Angle et al. 1995; Graziano et 

al. 1996; Gulson and Wilson 1994; Gulson et al. 1996; Manton 1977, 1998). 

Effect Biomarkers Used to Assess Exposure to Lead. Certain physiological changes that are associated 

with lead exposure have been used as biomarkers of exposure (see Section 3.6.2). These include 

measurement of biomarkers of impaired heme biosynthesis (blood zinc protoporphyrin, urinary 

coproporphyrin, erythrocyte ALAD activity). These types of measurements have largely been supplanted 

with measurement of blood lead concentration for the purpose of assessing lead exposure. 

3.6.2 Biomarkers Used to Characterize Effects Caused by Lead 

One of the most sensitive effects of lead exposure is the inhibition of the heme biosynthesis pathway, 

which is necessary for the production of red blood cells. Hematologic tests such as hemoglobin 

concentration may suggest toxicity, but this is not specific for lead (Bernard and Becker 1988). However, 
LEAD 232 

3. HEALTH EFFECTS 

inhibition of ferrochelatase in the heme pathway causes accumulation of protoporphyrin in erythrocytes 

(CDC 1985). Most protoporphyrin in erythrocytes (about 90%) exists as ZPP. This fraction is 

preferentially measured by hematofluorometers. Extraction methods measure all of the protoporphyrin 

present, but strip the zinc from the ZPP during the extraction process. For this reason, extraction results 

are sometimes referred to as (zinc) FEP. Although the chemical forms measured by the two methods 

differ slightly, on a weight basis they are roughly equivalent; thus, results reported as EP, ZPP, or FEP all 

reflect essentially the same analyte. An elevated EP level is one of the earliest and most reliable 

indicators of impairment of heme biosynthesis and reflects average lead levels at the site of erythropoiesis 

over the previous 4 months (Janin et al. 1985). The concentration of EP rises above background at PbBs 

of 25–30 μg/dL, above which, there is a positive correlation between PbB and EP (CDC 1985; Gennart et 

al. 1992a; Roels and Lauwerys 1987; Soldin et al. 2003; Wildt et al. 1987). Lead toxicity is generally 

considered to be present when a PbB ≥10 μg/dL is associated with an EP level of ≥35 μg/dL (CDC 1991; 

Somashekaraiah et al. 1990). This effect is detectable in circulating erythrocytes only after a lag time 

reflecting maturation in which the entire population of red blood cells has turned over (i.e., 120 days) 

(EPA 1986a; Moore and Goldberg 1985). Similarly, elevated erythrocyte protoporphyrin can reflect iron 

deficiency, sickle cell anemia, and hyperbilirubinemia (jaundice). Therefore, reliance on EP levels alone 

for initial screening could result in an appreciable number of false positive cases (CDC 1985; Mahaffey 

and Annest 1986; Marcus and Schwartz 1987). Conversely, since EP does not go up until the PbB 

exceeds 25 μg/dL, and the level of concern is 10 μg/dL, relying on EP measures would result in many 

false negative cases. Some have estimated that relying only on ZPP screening to predict future lead 

toxicity would miss approximately 3 cases with toxic blood lead concentrations in every 200 workers at 

risk (Froom et al. 1998). A limitation of measuring porphyrin accumulation is that porphyrin is labile 

because of photochemical decomposition; thus, assay samples must be protected from light. However, 

other diseases or conditions such as porphyria, liver cirrhosis, iron deficiency, age, and alcoholism may 

also produce similar effects on heme synthesis (Somashekaraiah et al. 1990). 

ALAD, an enzyme occurring early in the heme pathway, is also considered a sensitive indicator of lead 

effect (Graziano 1994; Hernberg et al. 1970; Morris et al. 1988; Somashekaraiah et al. 1990; Tola et al. 

1973). ALAD activity is negatively correlated with PbBs of 5–95 μg/dL, with >50% inhibition occurring 

at PbBs >20 μg/dL (Hernberg et al. 1970; Morita et al. 1997; Roels and Lauwerys 1987). However, 

ALAD activity may also be decreased with other diseases or conditions such as porphyria, liver cirrhosis, 

and alcoholism (Somashekaraiah et al. 1990). ALAD was found to be a more sensitive biomarker than 

urinary ALA and ZPP at PbBs between 21 and 30 μg/dL (Schuhmacher et al. 1997). A marked increase 

in urinary excretion of ALA, the intermediate that accumulates from decreased ALAD, can be detected 
LEAD 233 

3. HEALTH EFFECTS 

when PbB exceeds 35 μg/dL in adults and 25–75 μg/dL in children (NAS 1972; Roels and Lauwerys 

1987; Sakai and Morita 1996; Schuhmacher et al. 1997). 

Another potential biomarker for hematologic effects of lead is the observation of basophilic stippling and 

premature erythrocyte hemolysis (Paglia et al. 1975, 1977). Lead can impair the activity of pyrimidine 

5'-nucleotidase, resulting in a corresponding increase in pyrimidine nucleotides in red blood cells, which 

leads to a deficiency in maturing erythroid elements and thus, decreased red blood cells. However, this 

effect is nonspecific; it is encountered with benzene and arsenic poisoning (Smith et al. 1938) and in a 

genetically-induced enzyme-deficiency syndrome (Paglia et al. 1975, 1977). Furthermore, since 

basophilic stippling is not universally found in chronic lead poisoning, it is relatively insensitive to lesser 

degrees of lead toxicity (CDC 1985). The activity of adenine dinucleotide synthetase (NADS) in 

erythrocytes has also been explored as a biomarker for predicting PbBs >40 μg/dL; NADS activity is 

negatively correlated with PbB over the range 5–80 μg/dL (Morita et al. 1997). 

A multisite study of populations living near four NPL sites was conducted to assess the relationship 

between exposure (PbB and area of residence) and biomarkers of four organ systems: immune function 

disorders, kidney dysfunction, liver dysfunction, and hematopoietic dysfunction (Agency for Toxic 

Substances and Disease Registry 1995). The geometric mean PbB in those living in the target areas was 

4.26 μg/dL (n=1,645) compared with 3.45 μg/dL for a group living in comparison areas (n=493). In 

children <6 years old, the corresponding means were 5.37 versus 3.96 μg/dL. In subjects ≥15 years old, 

the target and comparison values were 3.06 and 3.63 μg/dL, respectively. Ninety percent of target and 

93% of comparison area participants had PbBs <10 μg/dL. Lead in soil and in water was found to be 

higher in comparison areas than in the target areas, but lead in house dust and in interior paint was higher 

in the target areas. PbB correlated with lead in soil and dust, but not with lead in paint and water. 

Multivariate regression analyses showed that of all the biomarkers analyzed, PbB was significantly 

associated with and predictive of hematocrit in adults 15 years of age or older and with increased mean 

serum IgA in children 6–71 months of age. The biological significance of these associations is unclear 

since both hematocrit and IgA levels were well within normal ranges and were hardly different than levels 

in subjects from the comparison areas. 

Reduction in the serum 1,25-dihydroxyvitamin D concentration has been reported as an indicator of 

increased lead absorption or lead concentrations in the blood (Rosen et al. 1980). Lead inhibits the 

formation of this active metabolite of vitamin D, which occurs in bone mineral metabolism (EPA 1986a; 

Landrigan 1989). Children with PbBs of 12–120 μg/dL showed decreased serum 1,25-dihydroxyvita­
LEAD 234 

3. HEALTH EFFECTS 

min D concentrations comparable to those found in patients with hypoparathyroidism, uremia, and 

metabolic bone disease (Mahaffey et al. 1982; Rosen et al. 1980). This biomarker is clearly not specific 

for lead exposure and several diseases can influence this measurement. 

One of the most sensitive systems affected by lead exposure is the nervous system. Encephalopathy is 

characterized by symptoms such as coma, seizures, ataxia, apathy, bizarre behavior, and incoordination 

(CDC 1985). Children are more sensitive to neurological changes. In children, encephalopathy has been 

associated with PbBs as low as 70 μg/dL (CDC 1985). An early sign of peripheral manifestations of 

neurotoxicity is gastrointestinal colic, which can occur with PbBs above 50 μg/dL. The most sensitive 

peripheral index of neurotoxicity of lead is reported to be slowed conduction velocity in small motor 

fibers of the ulnar nerve in workers with PbBs of 30–40 μg/dL (Landrigan 1989). Other potential 

biomarkers of lead suggested for neurotoxicity in workers are neurological and behavioral tests, as well as 

cognitive and visual sensory function tests (Williamson and Teo 1986). However, these tests are not 

specific to elevated lead exposure. 

Functional deficits associated with lead-induced nephrotoxicity increase in severity with increasing PbB. 

Effects on glomerular filtration evident at PbBs below 20 μg/dL, enzymuria and proteinuria occurs above 

30 μg/dL, and severe deficits in function and pathological changes occur in association with PbBs 

exceeding 50 μg/dL (see Table 3-3 and Figure 3-3). Biomarkers for these changes include elevation of 

serum creatinine, urinary enzymes (e.g., NAG), or protein (albumin, β2μ-globulin, α1μ-globulin, retinol 

binding protein). However, none of these markers are specific for lead-induced nephrotoxicity. A 

characteristic histologic feature of lead nephrotoxicity is the formation of intranuclear inclusion bodies in 

the renal proximal tubule (Choie and Richter 1972; Goyer et al. 1970a, 1970b). 

3.7 INTERACTIONS WITH OTHER CHEMICALS 

The toxicokinetics and toxicological behavior of lead can be affected by interactions with essential 

elements and nutrients (for a review, see Mushak and Crocetti 1996). In humans, the interactive behavior 

of lead and various nutritional factors is particularly significant for children, since this age group is not 

only sensitive to the effects of lead, but also experiences the greatest changes in relative nutrient status. 

Nutritional deficiencies are especially pronounced in children of lower socioeconomic status; however, 

children of all socioeconomic strata can be affected. 
LEAD 235 

3. HEALTH EFFECTS 

Available data from a number of reports document the association of lead absorption with suboptimal 

nutritional status. In infants and children 1–6 years of age, lead retention (as measured by PbB content) 

was inversely correlated with calcium intake, expressed either as a percentage of total or on a weight basis 

(Johnson and Tenuta 1979; Mahaffey et al. 1986; Sorrell et al. 1977; Ziegler et al. 1978). Dietary intakes 

of calcium and vitamin D were significantly (p<0.001) lower in children with PbBs >60 μg/dL (Johnson 

and Tenuta 1979). The gastrointestinal uptake of 203Pb was monitored in eight adult subjects as a function 

of dietary calcium and phosphorus intakes (Heard and Chamberlain 1982). The label absorption rate was 

63% without supplementation of these minerals in fasting subjects, compared with 10% in subjects 

supplemented with 200 mg calcium plus 140 mg phosphorus, the amounts present in an average meal. 

Calcium and phosphorus alone reduced lead uptake by a factor of 1.3 and 1.2, respectively; both together 

yielded a reduction factor of 6. Copper, iron, and zinc have also been postulated to affect lead absorption 

(Klauder and Petering 1975). 

Children with elevated PbB (12–120 μg/dL) were found to have significantly lower serum concentrations 

of the vitamin D metabolite 1,25-dihydroxyvitamin D compared with age-matched controls (p<0.001), 

and showed a negative correlation of serum 1,25-dihydroxyvitamin D with lead over the range of blood 

lead levels measured (Mahaffey et al. 1982; Rosen et al. 1980). 

Zinc is in the active site of ALAD and can play a protective role in lead intoxication by reversing the 

enzyme-inhibiting effects of lead. Children with high PbBs (50–67 μg/dL) were reported to consume less 

zinc than children with lower PbB (12–29 μg/dL) (Johnson and Tenuta 1979). In a group of 13 children, 

Markowitz and Rosen (1981) reported that the mean serum zinc levels in children with plumbism were 

significantly below the values seen in normal children; chelation therapy reduced the mean level even 

further. An inverse relationship between ALA in urine and the amount of chelatable or systemically 

active zinc was reported in 66 children challenged with EDTA and having PbBs ranging from 45 to 

60 μg/dL (Chisolm 1981). Zinc sulfate administration to a lead-intoxicated man following calcium 

disodium EDTA therapy restored the erythrocyte ALAD activity that was inhibited by lead (Thomasino et 

al. 1977). 

Forty-three children with elevated PbB (>30 μg/dL) and EP (>35 μg/dL) had an increased prevalence of 

iron deficiency (Yip et al. 1981). An inverse relationship between chelatable iron and chelatable body 

lead levels as indexed by urinary ALA levels was observed in 66 children with elevated PbB (Chisolm 

1981). Another study reported that the lead absorption rate was 2–3 times greater in iron-deficient adults 

compared to subjects who were iron-replete (Watson et al. 1980). Daily nutritional intake of dietary fiber, 
LEAD 236 

3. HEALTH EFFECTS 

iron, and thiamine were negatively correlated with PbB in male workers occupationally exposed to lead in 

a steel factory (Ito et al. 1987). Results from the NHANES II national survey showed that in children low 

iron status increases the lead hematotoxic dose response curves (Marcus and Schwartz 1987) and that iron 

deficiency plus elevated PbB produce a greater degree of hematotoxicity compared with either factor 

alone (Mahaffey and Annest 1986). A study of 299 children from 9 months to 5 years old from an urban 

area found a significant negative association between PbB and dietary iron intake (Hammad et al. 1996). 

Graziano et al. (1990) studied a population of pregnant women in Kosovo, Yugoslavia. They found that 

serum ferritin concentrations were associated with lower PbBs, suggesting that dietary iron may inhibit 

lead absorption. A study of 319 children ages 1–5 from Sacramento, California found that iron-deficient 

children had an unadjusted geometric mean PbB 1 μg/dL higher than iron-replete children (Bradman et al. 

2001). The difference persisted after adjusting for potential confounders by multivariate regression; the 

largest difference in PbB was approximately 3μg/dL and was present among those living in the most 

contaminated areas. While the studies mentioned above point to a link between iron deficiency and lead 

poisoning, it is unclear whether there is a causal link or whether iron deficiency is just a marker of high 

environmental lead. Also considered should be the possibility that children who do not get adequate 

nutrition (including iron) may be more prone to ingestion of paint chips and this may confound the type 

of study that attempts to associate iron deficiency with lead poisoning. A longitudinal analysis of 

1,275 children whose blood was screened for lead and complete blood count on two consecutive visits to 

a clinic suggested that the risk of subsequent lead poisoning associated with iron deficiency is 4–5 times 

greater than the baseline risk of lead poisoning (Wright et al. 2003c). The subject of lead/iron interactions 

was recently reviewed by Kwong et al. (2004). 

The relationship between nutritional factors, other than those mentioned above, and PbB of preschool 

children was examined by Lucas et al. (1996). The objective of the study was to determine whether total 

caloric intake, dietary fat, dietary protein, and carbohydrates are associated with PbB while simultaneously controlling for other nutrient and environmental exposures. The cohort comprised 296 children 

aged 9–72 months, predominantly black (82%), from an urban area. The mean PbB was 11.4 μg/dL 

(range, 1–55 μg/dL). After adjusting for confounders, the study found significant positive associations 

for total caloric intake and dietary fat with PbB. Lucas et al. (1996) speculated that bile secreted into the 

gastrointestinal to aid in the digestion and absorption of fat may increase lead absorption, as shown in rats 

(Cikrt and Tichy 1975). The influence of total caloric intake may just reflect increased intake of lead 

through contaminated food. 
LEAD 237 

3. HEALTH EFFECTS 

Reports of lead-nutrient interactions in experimental animals have generally described such relationships 

in terms of a single nutrient, using relative absorption or tissue retention in the animal to index the effect. 

Most of the data are concerned with the impact of dietary levels of calcium, iron, phosphorus, and 

vitamin D. These interaction studies are summarized in Table 3-11. 

People who live near waste sites may be simultaneously exposed to more than one chemical, and there is 

concern that chemicals in a mixture may interact with each other in such a manner that the toxicity of 

chemical A may be increased in the presence of chemical B. Studies have shown that both the toxicity 

and toxicokinetics of lead can be influenced by the presence of other chemicals that are commonly found 

together with lead at hazardous waste sites, particularly other metals. The studies available indicate that 

the outcome of the interaction of lead with other metals depends on many factors such as exposure levels, 

timing of exposure, and end point examined, to name a few. As a result, global statements cannot be 

made. However, it appears that, in general, zinc and copper are protective of the effects of lead. For 

details on the interactive effects of lead with other metals, the reader is referred to the Interaction Profile 

for Arsenic, Cadmium, Chromium, and Lead (Agency for Toxic Substances and Disease Registry 2004a), 

Interaction Profile for Lead, Manganese, Zinc, and Copper (Agency for Toxic Substances and Disease 

Registry 2004b), and Interaction Profile for Chlorpyrifos, Lead, Mercury, and Methylmercury (Agency 

for Toxic Substances and Disease Registry 2006). 

3.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to lead than will most persons 

exposed to the same level of lead in the environment. Reasons may include genetic makeup, age, health 

and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These parameters 

result in reduced detoxification or excretion of lead, or compromised function of organs affected by lead. 

Populations who are at greater risk due to their unusually high exposure to lead are discussed in 

Section 6.7, Populations with Potentially High Exposures. 

Certain subgroups of the population may be more susceptible to the toxic effects of lead exposure. These 

include crawling and house-bound children (<6 years old), pregnant women (and the fetus), the elderly, 

smokers, alcoholics, and people with genetic diseases affecting heme synthesis, nutritional deficiencies, 

and neurological or kidney dysfunction. This is not an exhaustive list and reflects only current data 

available; further research may identify additional susceptible subgroups. 
LEAD 238 

3. HEALTH EFFECTS 

Table 3-11. Effects of Nutritional Factors on Lead Uptake in Animals 

Factor Species Index of effect Interactive effect References 

Calcium 

Calcium 

Calcium 

Calcium 

Calcium 

Calcium 

Iron 

Iron 

Iron 

Iron 

Protein 

Protein 

Protein 

Milk 

components 

Milk 

components 

Zinc 

Rat 

Rat 

Rat 

Pig 

Horse 

Lamb 

Rat 

Rat 

Rat 

Mouse 

Rat 

Rat 

Rat 

Rat 

Rat 

Rat 

Lead in tissues and severity of 

effect at low levels of dietary 

calcium 

Lead retention 

Lead in tissues at high levels 

of dietary calcium during 

pregnancy 

Lead in tissues at low levels 

of dietary calcium 

Lead in tissues at low levels 

of dietary calcium 

Lead in tissues at low levels 

of dietary calcium 

Tissue levels and relative 

toxicity of lead 

Lead absorption in everted 

duodenal sac preparation 

In utero or milk transfer of 

lead in pregnant or lactating 

rats 

Lead retention 

Body lead retention 

Tissue levels of lead 

Lead uptake by tissues 

Lead absorption 

Lead absorption 

Lead absorption 

Low dietary calcium (0.1%) 

increase lead absorption 

and severity of effects 

Retention increased in 

calcium deficiency 

Reduced release of lead 

from bone 

Increased absorption of 

lead with low dietary 

calcium 

Increased absorption of 

lead with low dietary 

calcium 

Increased absorption of 

lead with low dietary 

calcium 

Iron deficiency increases 

lead absorption and toxicity 

Reduction in intubated iron 

increases lead absorption; 

increased levels decrease 

lead uptake 

Iron deficiency increases 

both in utero and milk 

transfer of lead to sucklings 

Iron deficiency has no 

effect on lead retention 

Low dietary protein either 

reduces or does not affect 

retention in various tissues 

Casein diet increases lead 

uptake compared to 

soybean meal 

Both low and high protein 

in diet increases lead 

absorption 

Lactose-hydrolyzed milk 

does not increase lead 

absorption, but ordinary 

milk does 

Lactose in diet enhances 

lead absorption compared 

to glucose 

Low zinc in diets increases 

lead absorption 

Mahaffey et al. 

1973; Six and Goyer 

1970 

Barton et al. 1978a 

Bogden et al. 1995 

Hsu et al. 1975 

Willoughby et al. 

1972 

Morrison et al. 1977 

Six and Goyer 1972 

Barton et al. 1978b 

Cerklewski 1980 

Hamilton 1978 

Quarterman et al. 

1978 

Anders et al. 1982 

Barltrop and Khoo 

1975 

Bell and Spickett 

1981 

Bushnell and 

DeLuca 1981 

Cerklewski and 

Forbes 1976 
LEAD 239 

3. HEALTH EFFECTS 

Table 3-11. Effects of Nutritional Factors on Lead Uptake in Animals 

Factor Species Index of effect Interactive effect References 

Zinc Rat Lead transfer in utero and in Low-zinc diet of mother Cerklewski 1979 

milk during lactation increases lead transfer 

in utero and in maternal 

milk 

Zinc Rat Tissue retention Low zinc diet enhances Bushnell and Levin 

brain lead levels 1983 

Copper Rat Lead absorption Low copper in diet Klauder and 

increases lead absorption Petering 1975 

Phosphorus Rat Lead uptake in tissues Reduced phosphorus Barltrop and Khoo 

increases 203Pb uptake 1975 

2.7-fold 

Phosphorus Rat Lead retention Low dietary phosphorus Quarterman and 

enhances lead retention; Morrison 1975 

no effect on lead resorption 

in bone 

Phosphorus Rat Lead retention Low dietary phosphorus Barton and Conrad 

enhances both lead 1981 

retention and lead 

deposition in bone 

Vitamin D Rat Lead absorption using everted Increasing vitamin D Smith et al. 1978 

sac techniques increases intubated lead 

absorption 

Vitamin D Rat Lead absorption using everted Both low and excess levels Barton et al. 1980 

sac techniques of vitamin D increase lead 

uptake by affecting motility 

Thiamin Mouse Whole-body lead retention	 Increased retention with Kim et al. 1992 

increased thiamin 

concentration 

Lipid Rat Lead absorption Increases in lipid (corn oil) Barltrop and Khoo 

content up to 40% 1975 

enhance lead absorption 

203Pb = Lead 203 
LEAD 240 

3. HEALTH EFFECTS 

Children. Children are at the greatest risk for experiencing lead-induced health effects, particularly in the 

urbanized, low-income segments of this pediatric population. Young children (<5 years old) have been 

documented to absorb lead via the gastrointestinal tract more efficiently (50% relative absorption) than 

adults (15% relative absorption) (Chamberlain et al. 1978). The use of leaded seams in cans used for 

canned food is not nearly as prevalent as it once was, so this is no longer as important a source of dietary 

exposure to lead. Behavior such as thumb sucking and pica result in an elevated transfer of leadcontaminated dust and dirt to the gastrointestinal tract (Schroeder and Hawk 1987). Also, children 

frequently have a greater prevalence of nutrient deficiency (Yip et al. 1981; Ziegler et al. 1978). For 

example, the diets of young children are commonly deficient in zinc, a condition that exacerbates some of 

the toxic effects of lead. Children have also been documented to have lower blood thresholds for the 

hematological and neurological effects induced by lead exposure. In addition, the resultant encephalopathy, central nervous system deficits, and neurologic sequelae tend to be much more severe in children 

than adults (Bellinger et al. 1989a; Bradley et al. 1956; Wang et al. 1989). Breast-fed infants of leadexposed mothers are also a susceptible group since lead is also secreted in the breast milk (Dabeka et al. 

1988; Ettinger et al. 2006; Gulson et al. 1998a). Calcium supplementation during lactation has been 

shown to decrease both maternal PbB and lead concentration in breast milk (Ettinger et al. 2006; 

Hernandez-Avila et al. 2003). 

Susceptibility to lead toxicity is influenced by dietary levels of calcium, iron, phosphorus, vitamins A and 

D, dietary protein, and alcohol (Calabrese 1978). Low dietary ingestion of calcium or iron increased the 

predisposition to lead toxicity in animals (Barton et al. 1978a; Carpenter 1982; Hashmi et al. 1989; Six 

and Goyer 1972; Waxman and Rabinowitz 1966). Iron deficiency combined with lead exposure acts 

synergistically to impair heme synthesis and cell metabolism (Waxman and Rabinowitz 1966). 

Nutritional surveys indicate that children of low-income groups consume less than recommended dietary 

allowances of calcium and iron. Dietary deficiencies of these two minerals have been shown to increase 

the risk of lead poisoning (Bradman et al. 2001; Johnson and Tenuta 1979; Wright et al. 2003c; Yip et al. 

1981; Ziegler et al. 1978). Thus, nutrient deficiencies in conjunction with a developmental predisposition 

to absorb lead makes this subset of children at a substantially elevated risk. More information on 

children’s susceptibility to lead is presented in Section 3.5. 

Embryo/Fetus. The embryo/fetus are at increased risk because of transplacental transfer of maternal lead 

(Bellinger et al. 1987a; Moore et al. 1982). Thompson et al. (1985) reported the case of a woman whose 

PbB increased to 74 μg/dL over the course of pregnancy resulting in the baby’s PbB level of 55 μg/dL 

and showing clinical signs of intoxication. No evidence of increased exposure to external lead source 
LEAD 241 

3. HEALTH EFFECTS 

during this period was apparent, but it was found that the mother had excessive exposure to lead 30 years 

prior to the pregnancy. Bone resorption during pregnancy can be reduced by ingestion of calcium 

supplements (Janakiraman et al. 2003). Lead has been demonstrated in animal studies to increase the 

incidence of fetal resorptions (McClain and Becker 1972) and to induce adverse neurobehavioral effects 

in offspring exposed in utero (Section 3.2.4). 

Women. Studies of women suggest that conditions of pregnancy, lactation, and osteoporosis may 

intensify bone demineralization, thus mobilizing bone lead into the blood resulting in increased body 

burdens of lead (Silbergeld et al. 1988). For example, women show an increased rate of bone lead loss 

with age relative to men (Drasch et al. 1987). Women with postmenopausal osteoporosis may be at an 

increased risk since lead inhibits activation of vitamin D, uptake of calcium, and several aspects of bone 

cell function to aggravate the course of osteoporosis. An increased release of bone lead to blood occurs in 

women, in association with menopause (Gulson et al. 2002). These observations are consistent with 

epidemiological studies that have shown increases in PbB after menopause and in association with 

decreasing bone density in postmenopausal women (Berkowtiz et al. 2004; Bonithon-Kopp et al. 1986c; 

Ewers et al. 1990; Hernandez-Avila et al. 2000; Korrick et al. 2002; Markowitz and Weinberger 1990; 

Nash et al. 2004; Silbergeld et al. 1988; Symanski and Hertz-Picciotto 1995). Long-term effects of lead 

exposure were also reported by Hu (1991b) who found that pregnant women who had experienced 

childhood plumbism had a higher rate of spontaneous abortion or stillbirth than matched controls, and 

their offspring were more likely to experience learning disabilities. 

Elders. The aged population may be at an increased risk for toxic effects of lead as suggested by two 

studies that found an association between decreased neurobehavioral performance and PbB in aging 

subjects with PbB around 5 μg/dL (Muldoon et al. 1996; Payton et al. 1998). A more recent study of 

526 participants of the Normative Aging Study with a mean age of 67.1 years and mean PbB of 6.3 μg/dL 

reported that patellar lead was significantly associated with psychiatric symptoms such as anxiety, 

depression, and phobic anxiety (Rhodes et al. 2003). In yet an additional study of Normative Aging 

Study participants (mean PbB, 4.5 μg/dL), it was found that both bone and blood lead were associated 

with poor test performance (Wright et al. 2003c). According to the investigators, these findings are 

consistent with the theory that bone lead chronically remobilizes into blood, thus accelerating cognitive 

decline. 

People with Genetic Diseases and Gene Polymorphisms. The toxic effects of lead exposure become 

exacerbated in individuals with inherited genetic diseases, such as thalassemia, which is characterized by 
LEAD 242 

3. HEALTH EFFECTS 

an abnormality in the rate of hemoglobin synthesis (Calabrese 1978). Individuals with glucose6-phosphate dehydrogenase (G6PD) deficiency are also unusually susceptible and may exhibit hemolytic 

anemia following lead exposure (Calabrese 1978). In a study of 148 subjects, Cocco et al. (1991) found 

that chronic lead poisoning tended to decrease total cholesterol and LDL in both G6PD-deficient and 

G6PD-nondeficient populations, but positive slopes were seen for cholesterol esters in G6PD deficient 

subjects and for HDL in G6DP normal subjects. Another study from the same group found that mortality 

from all causes and cancer mortality were lower among lead smelter workers with the G6PD-deficient 

phenotype compared to coworkers with the wild phenotype; the study comprised 867 workers with the 

wild phenotype and 213 with the deficient phenotype (Cocco et al. 1996). Because of the relatively small 

number of subjects with the deficient phenotype, the study may have lacked statistical power to examine 

deaths among this group. It has also been postulated that children with sickle cell disease have an 

increased risk of developing neuropathy with exposure to lead (Erenberg et al. 1974). People with 

metabolic disorders associated with the synthesis of porphyrins (important intermediates in the synthesis 

of hemoglobin, cytochromes, and vitamin B12), collectively known as porphyrias, are especially 

susceptible to lead exposure since lead inhibits two critical enzymes, ALAD and ferrochelatase, 

concerned with heme synthesis in erythrocytes (Hubermont et al. 1976; Silbergeld et al. 1982). The 

presence of genetic disorders that induce excessive ALA synthetase activity in addition to lead exposure 

produce higher than normal levels of ALA, resulting in excessive ALA excretion, accumulation, and lack 

of negative feedback on the ALA synthetase activity from heme (Calabrese 1978). 

ALAD is a polymorphic enzyme with two alleles (ALAD-1 and ALAD-2) and three genotypes: 

ALAD 1,1;, ALAD 1,2; and ALAD 2,2 (Battistuzzi et al. 1981). Various single nucleotide 

polymorphisms of the ALAD gene have been reported (Chia et al. 2005). Approximately 80% of 

Caucasians have the ALAD 1,1 genotype, 19% have the ALAD 1,2 genotype, and only 1% have the 

ALAD 2,2 genotype (Astrin et al. 1987; Battistuzzi et al. 1981). Studies of the relationship between 

ALAD genotype and blood lead levels have yielded conflicting results. Higher blood lead levels were 

observed in individuals with the ALAD 1,2 and ALAD 2,2 genotypes compared to similarly exposed 

individuals with the ALAD 1,1 genotype (Astrin et al. 1987; Hsieh et al. 2000; Schwartz et al. 2000b; 

Wetmur et al. 1991). There are also reports of children with the ALAD 2,2 having higher PbB than 

noncarriers (Pérez-Bravo et al. 2004; Shen et al. 2001). However, results of several other studies have 

found no association between blood lead levels and ALAD genotype in lead-exposed workers (Alexander 

et al. 1998b; Bergdahl et al. 1997b; Schwartz 1995; Schwartz et al. 1997a, 1997b; Smith et al. 1995; 

Süzen et al. 2003), although ALAD-2 carriers were 2.3 times more likely to have blood levels ≥40 μg/dL 

(Schwartz et al. 1997a). The observations of higher blood level levels in ALAD 2 carriers has prompted 
LEAD 243 

3. HEALTH EFFECTS 

the suggestion that the ALAD-2 allele may have a higher binding affinity for lead than the ALAD-1 allele 

(Bergdahl et al. 1997b), a difference that could alter lead-mediated outcomes. Several studies have been 

conducted to specifically evaluate whether ALAD genotypes are associated with differences in 

partitioning of lead between red blood cells and plasma, differences in distribution of lead to other tissue 

compartments, and altered susceptibility to lead toxicity. 

Studies investigating the effects of ALAD polymorphism on the distribution of lead in the blood have 

also yielded conflicting results. In lead-exposed workers, a higher percentage of erythrocyte lead was 

bound to ALAD in carriers of the ALAD-2 allele (84%) compared to carriers of the ALAD-1 allele (81%) 

(Bergdahl et al. 1997b). Although this difference is small, it did reach statistical significance (p<0.03), 

supporting the hypothesis that the ALAD-2 allele has a higher binding affinity for lead than the 

ALAD-1 allele. However, higher whole blood levels were not observed for ALAD-2 carriers compared 

to ALAD-1 homozygotes. Furthermore, no ALAD allele-specific differences were detected for the ratio 

of blood lead to plasma lead. Results of studies by Fleming et al. (1998a) substantiate earlier reports of 

higher blood lead levels for carriers of the ALAD-2 allele and indicate that ALAD polymorphism has an 

effect on the distribution of lead in the blood and, ultimately, to other tissue compartments. Serum lead 

levels for carriers of the ALAD-2 allele were higher than for ALAD-1 homozygotes (ALAD-2 carriers = 

0.335±0.025 μg/dL; ALAD-1 homozygotes = 0.285±0.009 μg/dL), an 18% difference that approached 

statistical significance (p<0.06) (Fleming et al. 1998a). 

Based on the higher plasma lead levels observed for ALAD-2 carriers, it is reasonable to project that 

distribution of lead to other tissue compartments could be higher for ALAD-2 carriers, in which case, the 

ALAD genotype could exert effects on the dose-response relationship for lead. In lead-exposed workers, 

urinary excretion of lead following oral administration of DMSA was less in ALAD-2 carriers than in 

ALAD-1 homozygotes (p=0.07), suggesting that carriers of the ALAD-2 allele may have lower levels of 

lead, or, at least, lower amounts of lead accessible to complexation with DMSA (Schwartz et al. 1997b). 

Studies investigating the effects of ALAD polymorphism on the distribution of lead to bone have also 

yielded conflicting results. No ALAD allele-specific differences were observed for the net accumulation 

of lead in bone (Bergdahl et al. 1997b, Fleming et al. 1998a; Lee et al. 2001) or for patellar bone (Lee et 

al. 2001; Theppeang et al. 2004). However, ALAD-2 carriers accumulated slightly more lead in bone 

than ALAD-1 homozygotes (p=0.06) (Fleming et al. 1998a). Higher bone lead levels were reported in 

lead-exposed workers carrying the ALAD-2 gene compared to ALAD-1 homozygotes (Smith et al. 1995). 

The cortical-trabecular bone lead differential (patellar minus tibial lead concentration) in 

ALAD-1 homozygotes was lower than in ALAD-2 carriers (p=0.06). In these same workers, blood urea 
 

 

LEAD 244 

3. HEALTH EFFECTS 

nitrogen (BUN) and uric acid (UA) were elevated in ALAD-2 carriers (BUN, p=0.03; UA, p=0.07), 

indicating that ALAD-2 carriers could be more susceptible to the renal toxicity of lead. However, in a 

multivariate logistic regression model that included PbB and ALAD genotype (along with age and alcohol 

consumption), increases in BUN and serum uric acid concentration were significantly associated with 

increases in PbB (regression coefficient, 0.13 mg/dL per μg Pb/dL; p=0.005), but not ALAD genotype 

(p=0.06). Wu et al. (2003a) also found apparent effects of ALAD genotype on the relationship between 

bone lead levels and serum uric acid levels in a study conducted as part of the Normative Aging Study. 

Increasing patella bone lead levels above a threshold of 15 μg/g was positively associated with serum uric 

acid levels among ALAD 1-1/2-2 heterozygotes; however, among ALAD 1-1 homozygotes, the threshold 

for the association was 101 μg/g. In contrast, young adults with ALAD 1-2 genotype did better on 

cognitive tests given the same amount of lead exposure (Bellinger et al. 1994), suggesting possible agespecific interactions. Chia et al. (2005) examined interactions between PbB and the presence of various 

single nucleotide polymorphisms (SNP) in the ALAD gene on various kidney outcomes among a group of 

lead workers in Vietnam (n=323). This study found significant interactions between increasing PbB and 

the HpyCH4 SNP on increasing urinary retinal binding protein, α1μ-globulin, β2μ-globulin, and albumin. 

Lee et al. (2001) examined the possible influence of ALAD genotype on systolic and diastolic blood 

pressure in a cohort of Korean lead workers (789 workers, 135 controls). Lead body burden measures 

(i.e., PbB, tibia blood lead, DMSA-chelatable lead) and blood pressures were not significantly different 

between ALAD 1-1 and ALAD 1-2 genotypes. 

The finding of associations between ALAD-2 and bone lead concentrations and ALAD-2 and markers of 

renal toxicity suggest that differential binding of lead to ALAD-2 may influence both the toxicokinetics 

and certain aspects of the toxicodynamics of lead. No information is available on the distribution of lead 

to other tissue compartments relative to ALAD genotype. Thus, based on the limited data available, it 

appears that ALAD polymorphism may be a genetic factor in the kinetic behavior of lead in the body. 

However, the exact nature and significance of ALAD polymorphism remains to be elucidated. A recent 

meta-analysis of 24 studies that included lead workers, the general population, and children found a 

statistically significant association beween ALAD-2 carriers and higher PbB in lead-exposed workers 

(Scinicariello et al. 2007). However, the ALAD-2 genotype did not appear to be a significant determinant 

of PbB among adults with PbBs <10 μg/dL. The study also found that ALAD-2 carriers appeared to be 

protected against adverse hematopoietic effects of lead as measured by hemoglobin levels, possibly 

because of decreased lead bioavailability to enzymes of the heme pathway. 
 

LEAD 245 

3. HEALTH EFFECTS 

The role of the vitamin D receptor (VDR) polymorphism in lead intoxication also has been studied. The 

VDR gene regulates the production of calcium-binding proteins and is reported to account for up to 75% 

of the total genetic effect on bone density (Onalaja and Claudio 2000). The VDR exists in several 

polymorphic forms in humans (Morrison et al. 1992). Restriction enzyme digestion of the VDR results in 

three genotypes commonly termed bb, when the restriction site is present, BB when the site is absent, and 

Bb when the two alleles are present. Schwartz et al. (2000a) studied the association of tibial lead and 

VDR genotype in 504 former organolead manufacturing workers in the United States. Tibial and blood 

lead concentrations were relatively low, with means of 14.4 ppm, and 4.6 μg/dL, respectively. Analyses 

of unadjusted data showed that there were only small differences in tibial lead concentrations by VDR 

genotype. However, in a multiple linear regression model of tibial lead concentrations, subjects with the 

B allele had larger increases in tibial lead concentrations with increasing age. In addition, whereas in 

subjects with the bb genotype, tibial lead declined since their last exposure to lead, subjects with Bb and 

BB showed increases in tibial lead. A study of 798 Korean lead workers whose mean tibial lead 

concentration and mean PbB were 37.2 ppm and 32 μg/dL, respectively, reported that lead workers with 

the VDR B allele had significantly higher PbB, chelatable lead level, and tibial lead than did workers with 

the VDR bb genotype (Schwartz et al. 2000b). A more recent study of this cohort reported that workers 

with the VDR B allele had significantly higher patellar lead than lead workers with the VDR bb genotype 

(Theppeang et al. 2004). 

Two other genetic polymorphisms have been studied in the context of potential influence on lead 

associations with blood pressure. The endothelial nitric oxide synthase (eNOS) converts L-arginine into 

nitric oxide in the endothelium, resulting in the relaxation of vascular smooth muscle and contributes to 

the regulation of peripheral vascular resistance and blood pressure. Theppeang et al. (2004) reported that, 

in a cohort of Korean lead workers, there was no association of the endothelial nitric oxide synthase 

(eNOS) gene with patella lead. Polymorphisms in the α2 subunit of Na+-K+ ATPase (ATP1A2) have 

also been shown to influence associations between lead exposure and blood pressure (Glenn et al. 2001). 

Another genetic susceptibility that has been studied in relation to lead toxicity is that of the hemochromatosis gene. Results published so far provided seemingly conflicting results. Hemochromatosis is 

a disease in which the absorption of iron is increased, resulting in excess iron depositing in many internal 

organs, particularly the liver, and leading to progressive damage (Onalaja and Claudio 2000). The gene 

codes for a protein designated HFE and has two variants: C282Y and H63D. Wright et al. (2004) studied 

730 men from the Normative Aging Study and found that the presence of a hemochromatosis variant, 

either C282Y or H63D, predicted lower bone and blood lead concentration. Based on the fact that iron 
LEAD 246 

3. HEALTH EFFECTS 

status is inversely related to lead absorption, Wright et al. (2004) hypothesized that the results may be 

secondary to increased iron stores among HFE variant carriers leading to decreased lead absorption in the 

gastrointestinal tract. Previously, Barton et al. (1994) found that homozygous individuals who suffered 

from hemochromatosis had higher PbB than individuals who did not have the gene. An additional study 

found no difference in PbB between subjects with hemochromatosis and controls (Åkesson et al. 2000). 

Wright et al. (2004) speculated that the different results could be due to the different characteristics of the 

participants studied in terms of age, health status, and sex. 

Finally, the possible association between Apolipoprotein E (APOE) genotype and susceptibility to lead 

toxicity also has been studied. APOE is an intracellular transporter of cholesterol and fatty acids that is 

synthesized by astrocytes in the brain and that plays a key role in the structure of cell membranes and 

myelin. There are three alleles of the APOE gene: E2, E3, and E4. Wright et al. (2003b) evaluated the 

relationship between the APOE gene and infant neurodevelopment in a sample of 311 mother-infant pairs 

living in and around Mexico City. The primary outcome assessed in the study was the 24-month MDI of 

the Bayley Scale. The authors also evaluated the modifying effect of APOE genotype on the association 

between PbB in umbilical cord and MDI score. After adjustment for potential confounders, infants 

carrying at least one copy of the APOE4 allele scored 4.4 points higher in the MDI than E3/E2 carriers. 

Furthermore, APOE genotype modified the dose–response relationship between umbilical PbB and MDI 

score in a manner that suggested that those with APOE4 were more protected against lead exposure than 

E3/E2 carriers. The APOE genotype also was reported to influence the relation between tibia lead and 

neurobehavioral test scores in a group of 529 former organolead workers (Stewart et al. 2002). The 

authors used linear regression to model the relations between each of 20 neurobehavioral test scores and 

tibia lead, a binary variable for APOE genotype. In 19 of the 20 regression models, the coefficients for 

the APOE and tibia lead interaction were negative. This meant that the slope for the relation between 

tibia lead and each neurobehavioral test was more negative for individuals with at least one APOE4 allele 

than for those who did not have an APOE4 allele. Stewart et al. (2002) concluded that some persistent 

effects of lead may be more toxic in individuals who have at least one APOE4 allele. The apparent 

contrast between the results of Stewart et al. (2002) and Wright et al. (2003b) may reflect age-specific 

gene-lead interactions. 

Alcoholics and Smokers. Alcoholics, and people who consume excess amounts of alcohol, may be at 

increased risk of hematological, neurological, and hepatotoxic effects. In animal studies, lead and alcohol 

synergistically inhibited blood ALAD activity and hepatic glutamic oxaloacetic transaminase (GOT, 

AST) and glutamic pyruvic transaminase (GPT, ALT) activity, depressed dopamine and 5-hydroxy­
LEAD 247 

3. HEALTH EFFECTS 

tryptamine levels in rat brain, increased lead burdens in tissue organs, and elevated blood ZPP (Dhawan et 

al. 1989; Flora and Tandon 1987). Smokers are also at elevated risks of lead intoxication since cigarette 

smoke contains lead and other heavy metals such as cadmium and mercury (Calabrese 1978), which have 

been shown to be synergistic in experimental animals (Congiu et al. 1979; Exon et al. 1979; Fahim and 

Khare 1980). 

People with Neurologic Dysfunction or Kidney Disease. This population is unusually susceptible to lead 

exposure. The neurologic and renal systems are the primary target organs of lead intoxication, which may 

become overburdened at much lower threshold concentrations to elicit manifestations of lead intoxication 

(Benetou-Marantidou et al. 1988; Chisolm 1962, 1968; Lilis et al. 1968; Pollock and Ibels 1986). 

3.9 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to lead. However, because some of the treatments discussed may be experimental and 

unproven, this section should not be used as a guide for treatment of exposures to lead. When specific 

exposures have occurred, poison control centers and medical toxicologists should be consulted for 

medical advice. The following texts provide specific information about treatment following exposures to 

lead: 

Ellenhorn MJ. 1997. Medical toxicology: Diagnosis and treatment of human poisoning. Metals and 

related compounds. 2nd ed. Baltimore, MD: Williams and Wilkins, 1563-1579. 

Homan CS, Brogan GX, Orava RS. 1998. Emergency toxicology: Lead toxicity. Philadelphia, PA: 

Lippincott-Raven, 363-378. 

Leikin JB, Paloucek FP. 2002. Poisoning and toxicology handbook. 3rd ed. Hudson, OH: Lexi-Comp, 

Inc., 725-731. 

3.9.1 Reducing Peak Absorption Following Exposure 

Individuals potentially exposed to lead can prevent inhalation exposure to particles by wearing the 

appropriate respirator. The mechanism and rate of lead absorption from the gastrointestinal tract is not 

completely understood, but it is believed that absorption occurs in the small intestine by both active and 

passive transport following solubilization of lead salts by gastric acid (see Section 3.3, Toxicokinetics). 

Lead is poorly absorbed from the gastrointestinal tract; however, toxic effects can result from the 

relatively small amount of lead that is absorbed. It has been estimated that adults absorb approximately 
LEAD 248 

3. HEALTH EFFECTS 

10% of an administered dose, whereas children absorb 4–50% of ingested lead (see Section 3.3, 

Toxicokinetics). Lead absorption from the gut appears to be blocked by calcium, iron, and zinc. 

Although no treatment modalities to reduce lead absorption have yet been developed that make use of 

these observations, it is recommended that a child's diet contain ample amounts of iron and calcium to 

reduce the likelihood of increased absorption of lead and that children eat regular meals since more lead is 

absorbed on an empty stomach (CDC 1991). Good sources of iron include liver, fortified cereal, cooked 

legumes, and spinach, whereas milk, yogurt, cheese, and cooked greens are good sources of calcium 

(CDC 1991). 

General recommendations to reduce absorption of lead following acute exposure include removing the 

individual from the source of exposure and decontaminating exposed areas of the body. Contaminated 

skin is washed with soap and water, and eyes exposed to lead are thoroughly flushed with water or saline 

(Stutz and Janusz 1988). Once lead is ingested, it is suggested that syrup of ipecac be administered to 

induce emesis. Administration of activated charcoal following emesis has not been proven to reduce 

absorption of any lead remaining in the gastrointestinal system, but is frequently recommended (Kosnett 

2004; Stutz and Janusz 1988). Gastric lavage has been used to remove ingested lead compounds. Whole 

gut lavage with an osmotically neutral polyethylene glycol electrolyte solution (GO-Lytely®, Co-lyte®) 

has successfully removed ingested lead-containing pottery glazes according to anecdotal case reports. 

However, this procedure is not universally accepted. Patients who ingest lead foreign objects should be 

observed for the possible, although rare, development of signs or symptoms of lead poisoning until the 

ingested object has been proven to have passed through the gut. Surgical excision has been recommended 

when lead bullets or shrapnel are lodged near joint capsules (reaction with synovial fluid leads to systemic 

uptake of lead in some cases) (Kosnett 2004). The blood lead level can be monitored and used as an 

indication for surgical removal of the projectile. 

3.9.2 Reducing Body Burden 

Lead is initially distributed throughout the body and then redistributed to soft tissues and bone. In human 

adults and children, approximately 94 and 73% of the total body burden of lead is found in bones, 

respectively. Lead may be stored in bone for long periods of time, but may be mobilized, thus achieving 

a steady state of intercompartmental distribution (see Section 3.3.2). 

All of the currently available methods to obviate the toxic effects of lead are based on their ability to 

reduce the body burden of lead by chelation. All of the chelating agents bind inorganic lead, enhance its 
LEAD 249 

3. HEALTH EFFECTS 

excretion, and facilitate the transfer of lead from soft tissues to the circulation where it can be excreted. 

Since the success of chelation therapy depends on excretion of chelated lead via the kidney, caution 

should be used when treating a patient with renal failure. The standard chelating agents currently in use 

are dimercaprol (British Anti-Lewisite, or BAL), CaNa2-EDTA (or EDTA), penicillamine, and 

2,3-dimercaptosuccinic acid (DMSA; Succimer®). Most of the information below regarding chelators has 

been extracted from Homan et al. (1998). 

Dimercaprol (BAL) is the chelator of choice in the presence of renal compromise. Sulfhydryl ligands in 

BAL form stable chelate-metal compounds intra- and extracellularly. The onset of action for BAL is 

30 minutes. BAL increases fecal excretion of lead as chelated lead is excreted predominantly in bile 

within 4–6 hours; BAL also increases urinary excretion of chelated lead. The use of BAL is indicated in 

cases of high lead levels without symptoms, in acute encephalopathy, and in symptomatic plumbism 

characterized by abdominal pain, anemia, headache, peripheral neuropathy, ataxia, memory loss, lethargy, 

anorexia, dysarthria, and encephalopathy. BAL is administered intramuscularly as a 10% solution in oil 

and the recommended dosage is 50–75 mg/m2

 every 4 hours. The full course is 3–5 days. Contraindications for the use of BAL include liver failure, since BAL chelates are excreted primarily in bile. 

Also, patients with glucose-6-phosphate dehydrogenase deficiency develop hemolysis if BAL is 

administered. Concurrent administration of iron is contraindicated due to the high toxicity of the BALiron chelate. BAL also is contraindicated in subjects with a history of peanut oil allergy and in 

pregnancy. A number of adverse reactions have been described in BAL user including nausea, vomiting, 

hypertension, tachycardia, headache, increased secretions, anxiety, abdominal pain, and fever. 

Premedication with diphenylhydramine may mitigate these effects. Elevated liver function tests and 

sterile abscesses may also occur. 

CaNa2-EDTA (or EDTA) works by forming a stable metal-chelate complex that is excreted by the kidney. 

It increases renal excretion of lead 20–50 times. Numerous adverse effects have been described due to 

treatment with EDTA including rash, fever, fatigue, thirst, myalgias, chills, and cardiac dysrhythmias. 

EDTA should be used together with BAL (4 hours after the first dose of BAL) because acute lead 

encephalopathy may progress if EDTA given alone secondary to lead from soft tissue lead mobilization 

resulting in increased PbB. Since EDTA chelates zinc, patients with low zinc stores may be adversely 

affected by EDTA. Since EDTA also chelates other metals, administration of EDTA (or BAL) to persons 

occupationally exposed to cadmium may result in increased renal excretion of cadmium and renal 

damage. The dosage recommended for children is 1,000–1,500 mg/m2

/24 hours in 0.5% procaine i.m. to 

avoid fluid overload, although the preferred route of administration of EDTA is intravenously. This dose 
LEAD 250 

3. HEALTH EFFECTS 

may be given in up to six divided daily doses. For adults, the recommended dose is 1.5 g/24 hours in two 

divided doses. The full course for EDTA therapy is 5 days, but the course may be repeated if the patient 

is still symptomatic or when PbB is >50μg/dL. 

D-Penicillamine is an orally-administered lead chelator whose mechanism of action is unknown, and that 

increased urinary excretion of lead. The FDA has not approved the use of d-penicillamine during 

pregnancy. Administration of d-penicillamine is contraindicated in subjects allergic to penicillin because 

of cross-reactivity with the latter. Among the adverse effects are rash, fever, anorexia, nausea, vomiting, 

leucopenia, thrombocytopenis, eosinophilia, hemolytic anemia, Stevens-Johnson syndrome (severe 

erythema multiforme), nephrotoxicity, and proteinuria. Furthermore, continued exposure to lead will 

result in continued absorption of lead at a higher rate. The recommended dose is 10 mg/kg/24 hours for 

7 days, but may be increased to 10–15 mg/kg every 12 hours over 2–4 weeks. One way to minimize 

toxicity is to start medication at 1⁄4 the dosage and gradually increase it to full dosage over 3–4 weeks. 

The CDC recommends giving children an entire dose on an empty stomach 2 hours before breakfast and 

to give adults an entire dose in two or three divided doses on an empty stomach 2 hours before meals. 

2,3-Dimercaptosuccinic acid (DMSA; Succimer®) has a mechanism of action similar to BAL, but is far 

less toxic than BAL. DMSA is currently approved for asymptomatic children with PbB <45 μg/dL and an 

experimental protocol is available for mild encephalopathy and use in the adult. DMSA can be used with 

concurrent administration of iron. DMSA has been shown to be as effective as EDTA in increasing the 

urinary excretion of lead. Minimal adverse effects that have been reported include anorexia, nausea, 

vomiting, and rashes. DMSA increases the excretion of zinc, but to a much lesser extent than other 

chelators, and has minimal effects on Ca, Fe, Mg, and Cu. The recommended dosage is 10 mg/kg 

3 times/day for 5 days, then 10 mg/kg 3 times/day for 14 days. 

The following are treatment guidelines for lead exposure in children developed by the American 

Academy of Pediatrics (Berlin et al. 1995). 

1. Chelation treatment is not indicated in patients with blood lead levels of less than 

25 μg/dL, although environmental intervention should occur. 

2. Patients with blood levels of 25 to 45 μg/dL need aggressive environmental 

intervention but should not routinely receive chelation therapy, because no evidence 

exists that chelation avoids or reverses neurotoxicity. If blood lead levels persist in 

this range despite repeated environmental study and abatement, some patients may 

benefit from (oral) chelation therapy by enhanced lead excretion. 
LEAD 251 

3. HEALTH EFFECTS 

3. Chelation therapy is indicated in patients with blood lead levels between 45 and 

70 μg/dL. In the absence of clinical symptoms suggesting encephalopathy (e.g., 

obtundation, headache, and persisting vomiting), patients may be treated with 

succimer at 30 mg/kg per day for 5 days, followed by 20 mg/day for 14 days. 

Children may need to be hospitalized for the initiation of therapy to monitor for
 

adverse effects and institute environmental abatement. Discharge should be 

considered only if the safety of the environment after hospitalization can be 

guaranteed. An alternate regimen would be to use CaNa2EDTA as inpatient therapy 

at 25 mg/kg for 5 days. Before chelation with either agent is begun, if an abdominal 

radiograph shows that enteral lead is present, bowel decontamination may be 

considered as an adjunct to treatment. 

4. Patients with blood lead levels of greater than 70 μg/dL or with clinical symptoms 

suggesting encephalopathy require inpatient chelation therapy using the most 

efficacious parenteral agents available. Lead encephalopathy is a life-threatening 

emergency that should be treated using contemporary standards or intensive care 

treatment of increased intracranial pressure, including appropriate pressure 

monitoring, osmotic therapy, and drug therapy in addition to chelation therapy. 

Therapy is initiated with intramuscular dimercaprol (BAL) at 25 mg/kg per day 

divided into six doses. The second dose of BAL is given 4 hours later, followed 

immediately by intravenous CaNa2EDTA at 50 mg/day as a single dose infused 

during several hours or as a continuous infusion. Current labeling of CaNa2EDTA
 

does not support the intravenous route of administration, but clinical experience 

suggests that it is safe and more appropriate in the pediatric population. The 

hemodynamic stability of these patients, as well as changes in neurologic status that 

may herald encephalopathy, needs to be closely monitored. 

5. Therapy needs to be continued for a minimum of 72 hours. After this initial
 

treatment, two alternatives are possible: (1) the parenteral therapy with two drugs 

(CaNa2EDTA and BAL) may be continued for a total of 5 days; or (2) therapy with 

CaNa2EDTA alone may be continued for a total of 5 days. If BAL and CaNa2EDTA 

are used for the full 5 days, a minimum of 2 days with no treatment should elapse 

before considering another 5-day course of treatment. In patients with lead 

encephalopathy, parenteral chelation should be continued with both drugs until they 

are clinically stable before therapy is changed. 

6. After chelation therapy, a period of reequilibration of 10 to 14 days should be 

allowed, and another blood lead concentration should be obtained. Subsequent 

treatment should be based on this determination, following the categories presented 

above. 

3.9.3 Interfering with the Mechanism of Action for Toxic Effects 

Lead has multiple mechanisms of action at many different levels that affect many enzyme systems and 

cellular processes throughout the body. Thus, while it seems plausible that specific effects could be 

prevented or at least minimized, it is unlikely that one could prevent all of the physiological alterations 

that have been attributed to exposure to lead. However, several studies have examined whether leadlowering interventions, such as with chelators, are paralleled by improvement in health outcomes 
LEAD 252 

3. HEALTH EFFECTS 

reportedly altered by lead. For example, Ruff et al. (1993) studied a group of 154 children with PbB 

between 25 and 55 μg/dL who were treated with CaNa2EDTA if eligible and/or with orally administered 

iron supplement if iron deficient. The outcome measured was a global index of cognitive functioning. It 

was found that within a period of 6 months, improvement in performance was significantly related to 

decreases in PbB, but there was no effect of chelation treatment. Ruff et al. (1993) speculated that a 

reduction or elimination of exposure may have led to decreases in PbB, and this may have occurred for 

chelated and nonchelated children. 

Rogan et al. (2001) studied a group of 780 children enrolled in a randomized, placebo-controlled, doubleblind trial of up to three 26-day courses of treatment with succimer. The PbB for the group ranged from 

20 to 44 μg/dL. Although treatment with succimer lowered PbB by a mean of 4.5 μg/dL during the 

6 months after initiation of treatment, it did not improve scores on tests of cognition, behavior, or 

neuropsychological function in children with PbB below 45 μg/dL. Rogan et al. (2001) noted that the 

failure to demonstrate a significant difference in test scores could have been due to the small difference in 

PbB between the two groups. Re-analysis of these data using change in PbB as the independent variable 

showed that improvement in test scores was associated with greater falls in PbB only in the placebo group 

and suggested that factors other than declining PbB were responsible for cognitive improvement (Liu et 

al. 2002). A further evaluation of this cohort at the age of 7 years showed that chelation therapy with 

succimer, although lowering mean PbB for approximately 6 months, produced no benefit in cognitive, 

behavioral, and neuromotor end points (Dietrich et al. 2004). Also in this cohort, treatment with succimer 

did not have a beneficial effect on blood pressure (Chen et al. 2006) or growth during or after treatment 

(Peterson et al. 2004). In fact, from baseline to 9 months, children receiving succimer were on the 

average 0.27 cm shorter than children receiving placebo, and 0.43 cm shorter during 34 months of followup. The conclusion of this series of studies reached by the investigators was that chelation therapy is not 

indicated in children with moderate PbB (≤40 μg/dL). Additional information regarding the safety and 

efficacy of succimer in children can be found in O’Connor and Rich (1999) and Chisolm (2000). 

In a study similar to those described above, Kordas et al. (2005) tested the hypothesis that iron and zinc 

supplementation could improve behavior ratings in a population of first-grade children who attended a 

school near a metal foundry in Torreón, Mexico. The mean PbB for the whole sample was 11.5 μg/dL 

(SD, ±6.1 μg/dL). The overall prevalency of iron and zinc deficiency was 21.7 and 28.9%, respectively. 

During the trial, which lasted 6 months, parents and teachers provided ratings of child behavior using the 

Conners Rating Scales. Neither iron nor zinc (combined or separately) induced a marked reduction in 

PbB. Although all parent ratings and some teacher ratings improved with time, the change was unrelated 
LEAD 253 

3. HEALTH EFFECTS 

to treatment and the clinical significance was unclear. The only beneficial change was that children 

receiving any zinc had a higher likelihood of no longer receiving clinically-significant teacher ratings of 

oppositional behaviors. 

A series of studies in monkeys provide relevant information regarding lead exposure and succimer. In 

adult Rhesus monkeys treated chronically with lead to maintain a target PbB of 35–40 μg/dL, treatment 

with succimer was ineffective in reducing brain lead levels (Cremin et al. 1999). However, cessation of 

exposure reduced brain lead levels by 34% both in succimer- and placebo-treated monkeys. In addition, 

the concentration of lead in the prefrontal cortex prior to treatment with succimer was significantly 

correlated with the integrated PbB (AUC) over the period of exposure to lead, but not with the single 

pretreatment PbB sample collected concurrently with the brain biopsy. These results indicated that 

succimer treatment did not reduce brain lead levels beyond the cessation of lead exposure alone. A 

subsequent study in this series showed that treatment with succimer did not reduce skeletal levels of lead 

and that the efficacy of succimer in reducing PbB did not persist beyond the completion of treatment due 

to posttreatment rebounds in PbB from endogenous sources (Smith et al. 2000). 

3.10 ADEQUACY OF THE DATABASE 

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of lead is available. Where adequate information is not 

available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the 

initiation of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of lead. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.10.1 Existing Information on Health Effects of Lead 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to lead 

are summarized in Figure 3-17. The purpose of this figure is to illustrate the existing information 
3. HEALTH EFFECTS 

Figure 3-17. Existing Information on Health Effects of Lead 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Inhalation 

Oral 

Dermal 

Human 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Inhalation 

Oral 

Dermal 

Animal 

Existing Studies 

LEAD 254 
LEAD 255 

3. HEALTH EFFECTS 

concerning the health effects of lead. Each dot in the figure indicates that one or more studies provide 

information associated with that particular effect. The dot does not necessarily imply anything about the 

quality of the study or studies, nor should missing information in this figure be interpreted as a “data 

need”. A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data 

Needs Related to Toxicological Profiles (Agency for Toxic Substances and Disease Registry 1989), is 

substance-specific information necessary to conduct comprehensive public health assessments. 

Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from 

the scientific literature. 

There is a wealth of information regarding the health effects of lead in humans and in animals. In fact, 

lead may be a chemical for which there is as much information in humans as there is in animals. Human 

data consist of studies of children and adults, occupational exposures, and exposures of the general 

population. A number of studies of children are studies of cohorts that have been followed for years, and 

these have provided the most valuable information. Children and developing organisms, in general, are 

more vulnerable to the toxic effects of lead than adults, and therefore, much of the lead research in the 

past decades has focused on these populations. The most sensitive end points for lead toxicity are the 

developing nervous system, and the cardiovascular, renal, and hematological systems, but lead can affect 

any system or organ in the body. The most significant routes of exposure to lead for humans are the 

inhalation and oral routes; the latter is the main route of exposure for young children mainly due to their 

hand-to-mouth activities. The toxicity of lead is not route-specific. Studies in animals support the 

findings in humans and have been of great utility in elucidating the underlying mechanisms of lead 

toxicity. 

3.10.2 Identification of Data Needs 

Acute-Duration Exposure. There are relatively few data available for acute exposures in humans 

and most are derived from cases of accidental or intentional ingestion of lead-containing dirt or leadbased paint in adults and children. Exposure to high amounts of lead can induce encephalopathy, a 

general term that describes various diseases that affect brain function. Symptoms develop following 

prolonged exposure and include dullness, irritability, poor attention span, epigastric pain, constipation, 

vomiting, convulsions, coma, and death (Chisolm 1962, 1965; Chisolm and Harrison 1956; Kehoe 1961; 

Kumar et al. 1987). The utility of further acute-duration exposure studies in animals for the sole purpose 

of obtaining dose-response relationships is questionable. However, further short-term studies or studies 
LEAD 256 

3. HEALTH EFFECTS 

in vitro designed to elucidate mechanisms of action for the various toxicities discussed below might be 

useful. 

Intermediate-Duration Exposure. Intermediate and chronic exposures in humans should be 

considered together because the duration of exposure is not usually known. Specific studies that have 

evaluated a variety of end points are presented below under Chronic-Duration Exposure and Cancer. As 

with acute-duration exposure, additional standard 90-day toxicity studies in animals are unlikely to 

produce new key information about the toxicity of lead, but studies could be designed to elucidate 

mechanisms of action involved in the specific toxicities described below. For example, exposures during 

different developmental periods can help identify critical periods of vulnerability for immunocompetence, 

development of sex organs, or neurobehavioral parameters. 

Chronic-Duration Exposure and Cancer. The effects of chronic-duration exposure to lead in 

humans and in animals have been relatively well-studied. In humans, exposure to lead has been 

associated with (only representative citations are included) cardiovascular effects (Nawrot et al. 2002; 

Schwartz 1995; Staessen et al. 1994), hematological effects (Chisolm et al. 1985; Hernberg and Nikkanen 

1970; Roels and Lauwerys 1987; Roels et al. 1976), musculoskeletal effects (Holness and Nethercott 

1988; Marino et al. 1989; Pagliuca et al. 1990), effects on teeth in children (Gemmel et al. 2002; Moss et 

al. 1999), renal effects (Kim et al. 1996a; Muntner et al. 2003), alterations in serum hormone levels 

(Gustafson et al. 1989; López et al. 2000; Singh et al. 2000a), cataracts (Schaumberg et al. 2004), 

alterations in electroretinograms (Cavalleri et al. 1982; Otto and Fox 1993; Rothenberg et al. 2002a), 

altered vitamin D metabolism (Rosen et al. 1980), alterations in immunological parameters (Fischbein et 

al. 1993; Karmaus et al. 2005; Lutz et al. 1999; Pinkerton et al. 1998; Sata et al. 1998; Sun et al. 2003; 

Ündeger et al. 1996), neurobehavioral effects in adults (Awad El Karim et al. 1986; Baker et al. 1979, 

1983; Haenninen et al. 1979; Holness and Nethercott 1988; Lucchini et al. 2000; Matte et al. 1989; 

Pagliuca et al. 1990; Pollock and Ibels 1986; Schwartz et al. 2005; Stollery 1996; Stollery et al. 1991) and 

children (Bellinger et al. 1992; Canfield et al. 2003; Chiodo et al. 2004; Kordas et al. 2006; Lanphear et 

al. 2000a; Ris et al. 2004; Schnaas et al. 2000; Téllez-Rojo et al. 2006; Tong et al. 1998; Wasserman et al. 

2003), reproductive effects in females (Borja-Aburto et al. 1999; Nordstrom et al. 1979; Torres-Sánchez 

et al. 1999) and males (Gennart et al. 1992b; Hernández-Ochoa et al. 2005; Lancranjan et al. 1975; 

Sállmen et al. 2000a), altered children’s growth (Dietrich et al. 1987a; Hernández-Avila et al. 2002; 

Schwartz et al. 1986), delayed sexual maturation in girls (Selevan et al. 2003; Wu et al. 2003a), decreased 

erythropoietin in children (Graziano et al. 2004), genotoxic effects in workers (Forni et al. 1976; Fracasso 

et al. 2002; Nordenson et al. 1978; Vaglenov et al. 2001; Wu et al. 2002), and possibly increased risk of 
LEAD 257 

3. HEALTH EFFECTS 

lung cancer and stomach cancer in lead workers (Steenland and Boffetta 2000). It is unlikely that 

additional standard chronic-duration exposure studies in animals would provide new key information on 

the toxicity of lead, but special studies that examine biochemical and morphological effects of lead may 

provide new information on mechanisms of action of lead, particularly for the effects of greatest concern 

such as neurobehavioral alterations in children. However, as indicated below under Epidemiological 

Studies, the children and adolescents from the prospective studies should continue to undergo periodic 

comprehensive evaluations. 

There are several studies of cancer on lead-exposed workers (Anttila et al. 1995; Cocco et al. 1997, 

1998a, 1998b; Cooper et al. 1985; Fanning 1988; Gerhardsson et al. 1986b; Lundstrom et al. 1997; 

Malcolm and Barnett 1982; Wong and Harris 2000), which provided inconclusive evidence of 

carcinogenicity. A meta-analysis of eight major occupational studies on cancer mortality or incidence in 

workers with high lead exposure concluded that there is some limited evidence of increased risk of lung 

cancer and stomach cancer, although there might have been confounding with arsenic exposure in the 

study with highest relative risk of lung cancer (Steenland and Boffetta 2000). The results also showed 

weak evidence for an association with kidney cancer and gliomas. Follow-up of the cohorts from the 

prospective lead studies may provide information on possible shifts in age-related cancer incidence and 

on associations between perinatal exposure to lead and increased cancer risk. 

Exposure of rodents to lead has produced mainly renal tumors (Azar et al. 1973; Koller et al. 1985; Van 

Esch and Kroes 1969). In a study in mice exposed to lead during pregnancy, the offspring developed 

renal proliferative lesions and renal tumors; no renal tumors occurred in controls (Waalkes et al. 1995). 

Replication of these findings would be useful. In addition, studies could be conducted in which animals 

are exposed at different times during pregnancy to determine the existence of potential windows of 

vulnerability. Silbergeld et al. (2000) suggest that the hypothesis that lead-induced cancer is secondary to 

cytotoxicity and target organ damage needs further testing. Silbergeld et al. (2000) also identified the 

need for studies examining the potential role of lead-zinc interactions in transcription regulation and DNA 

protection using reporter gene systems and combined exposures to lead and other mutagens. Other types 

of studies suggested include evaluation of the effects of lead on the expression of specific genes, such as 

oncogenes and suppressor genes, and evaluation of the potential role of lead-induced inhibition of DNA 

repair on systems where the fidelity of DNA replication can be directly studied. 

Genotoxicity. Lead is a clastogenic agent, as shown by the induction of chromosomal aberrations, 

micronuclei, and sister chromatid exchanges in peripheral blood cells from lead workers (i.e., Duydu et al. 
LEAD 258 

3. HEALTH EFFECTS 

2001; Forni et al. 1976; Nordenson et al. 1978; Vaglenov et al. 1998, 2001). In vitro mutagenicity studies 

in microorganisms have yielded mostly negative results for lead, and additional studies of this type are 

unlikely to provide new key information. The lines of research suggested previously with regard to 

cancer also apply for genotoxicity. In addition, studies of chromosomal changes in germ cells involved in 

gametogenesis would provide valuable information on potential transgenerational effects of lead. 

Reproductive Toxicity. Some studies of humans occupationally or environmentally exposed to lead 

have reported associations between PbB and abortion and pre-term delivery in women (Borja-Aburto et 

al. 1999; Nordstrom et al. 1979) and alterations in sperm and decreased fertility in men (Gennart et al. 

1992b; Sállmen et al. 2000a; Shiau et al. 2004). For the effects in males, the threshold PbB appears to be 

in the range of 30–40 μg/dL. Additional research might be warranted to study the effects of lead on the 

gonado-hypothalamic-pituitary axis. An earlier study by Cullen et al. (1984) found increased serum FSH 

and LH and borderline low serum testosterone levels in one of seven men with symptomatic occupational 

lead poisoning and a mean PbB of 87.4 μg/dL. Although serum testosterone concentration was normal in 

most of these patients, five had defects in spermatogenesis. Studies in monkeys using protocols designed 

to evaluate age of exposure on lead-induced effects have reported structural alterations in the testis at 

PbBs relevant to the human population (Foster et al. 1996, 1998). Studies in rats exposed to lead 

concentrations that produced relatively high PbB have suggested that continuous lead exposure delays 

sexual maturation by suppressing normal sex steroid surges at birth and during puberty (Ronis et al. 

1998b, 1998c). Replication of these studies in primates would be useful. Also, further research on the 

interaction of lead and protamines could provide valuable information on lead-induced effects in sperm. 

Protamines specifically are bound to sperm DNA and their interaction with lead has been suggested to 

possibly decrease the protection of DNA to mutagens (Quintanilla-Vega et al. 2000). 

Developmental Toxicity. In addition to inducing neurobehavioral alterations in developing 

organisms (see below under Neurotoxicity), exposure to lead has been associated in some studies with 

reduced birth weight and gestational age (Dietrich et al. 1987a; Jelliffe-Pawlowski et al. 2006), reduced 

stature in children (Hernández-Avila et al. 2002; Sanín et al. 2001; Schwartz et al. 1986), and delayed 

sexual maturation in girls (Selevan et al. 2003; Wu et al. 2003a). These findings are supported by results 

from studies in animals (Dearth et al. 2002; Grant et al. 1980; Ronis et al. 1996, 1998a, 1998b, 1998c, 

2001). It would be useful to collect data on growth of children from the ongoing lead prospective studies, 

although some information is available from the Cincinnati Prospective Study (Shukla et al. 1989, 1991), 

the Cleveland Prospective Study (Greene and Ernhart 1991), and a study of children from Boston (Kim et 

al. 1995). Because of the enormous influence of nutrition on growth and on lead toxicity, it would be 
LEAD 259 

3. HEALTH EFFECTS 

advantageous to conduct studies of populations of children as homogeneous as possible with respect to 

nutrition, even if the cohort size is less than optimal. A study in rats reported that lead reduced somatic 

longitudinal bone growth and bone strength during the pubertal period by a mechanism that appeared not 

to involve disruption of the growth hormone axis (Ronis et al. 2001). Further studies in animals as well 

as in bone cells in vitro should help elucidate the mechanism(s) of lead on growth. 

Studies have shown that exposure of rats and mice to lead during various developmental periods alters 

sexual maturation of both male and female animals (Dearth et al. 2002; Iavicoli et al. 2004; Ronis et al. 

1996, 1998a, 1998b, 1998c). Therefore, it would be desirable to evaluate adolescents of both sexes who 

are participating in the ongoing prospective lead studies to determine possible delays in sexual 

maturation, and if found, determine which lead biomarker best predicts the outcome. Follow-up of the 

children studied by Selevan et al. (2003) and Wu et al. (2003a) or the cohorts studied longitudinally could 

provide information on whether lead exposure during infancy has long-term effects on parameters such as 

fertility in males and females or on female’s ability to maintain pregnancy. Dearth et al. (2004) recently 

reported that Fisher 344 rats are more sensitive than Sprague-Dawley rats regarding puberty-related 

effects. Researchers should be aware of this strain difference when comparing results between these two 

strains of rats. As with other lead-induced toxicities, the role of some polymorphisms (i.e., ALAD 

genotype) on growth and sexual maturation could be evaluated. 

Immunotoxicity. Altered immune parameters have been described in lead workers. Reported effects 

have included changes in some T-cell subpopulations (Fischbein et al. 1993; Pinkerton et al. 1998; Sata et 

al. 1998; Ündeger et al. 1996), altered response to T-cell mitogens (Mishra et al. 2003), and reduced 

chemotaxis of polymorphonuclear leukocytes (Valentino et al. 1991). Three studies of children reported 

significant associations between PbB and increases in serum IgE levels (Karmaus et al. 2005; Lutz et al. 

1999; Sun et al. 2003). IgE is the primary mediator for type-I hypersensitivity and is involved in various 

allergic diseases such as asthma; therefore, the suggestion has been raised that in utero exposure to lead 

may be a risk factor for childhood asthma (Dietert et al. 2002). Perinatal exposure of rodents to lead also 

has induced increased IgE levels in the offspring (Miller et al. 1998; Snyder et al. 2000). Additional 

studies in which animals are exposed at different developmental periods are necessary to identify 

vulnerable periods during development and to determine potential long-term consequences of exposures 

during discrete periods of development (Dietert et al. 2002, 2004). Also, studies that compare the effects 

of lead on immunological end points in different species, different strains, and animals of both sexes 

would provide valuable information, as there is some evidence that the immune response may depend on 

the species, strain, and/or gender (Bunn et al. 2001a, 2001b, 2001c). In addition, further information on 
LEAD 260 

3. HEALTH EFFECTS 

how lead-induced changes in immune balance (Heo et al. 1998; McCabe et al. 1999) affect the immune 

response profile and the host’s defense capabilities would be valuable. This is important because there is 

evidence that suggests that lead or other chemicals during development may cause inappropriate 

Th1 development and a potentially serious imbalance toward Th2-associated capacity resulting in 

elevated IgE production and increased risk for atopy and asthma (Peden 2000). 

Neurotoxicity. The nervous system is a sensitive target for lead toxicity in humans (for representative 

references, see Chronic-Duration Exposure and Cancer, above) and in animals. Of special concern are the 

results of recent studies that have reported neurobehavioral deficits in children associated with PbBs 

<10 μg/dL and an apparent lack of threshold down to even the lowest PbBs recorded in these studies 

(Bellinger and Needleman 2003; Canfield et al. 2003; Chiodo et al. 2004; Kordas et al. 2006; Lanphear et 

al. 2000a, 2005; Téllez-Rojo et al. 2006). Some of these studies found that the slope of the dose-response 

is steeper at lower PbBs than at higher PbBs; that is, the effects of lead on cognitive function is greater in 

children with lower PbB than in children with higher PbB. However, a mechanism that could produce 

this result has not yet been identified, and this represents a data need. The neurotoxicity of lead is the 

result of multiple modes of action and research needs can be identified at almost any level of action, from 

studies of basic biochemical and physiological mechanisms (i.e., transport of lead across biological 

barriers in general and nerve membranes in particular) to studies of populations. There are several 

ongoing prospective studies of lead in children (i.e., Bellinger et al. 1992; Ris et al. 2004; Schnaas et al. 

2000; Tong et al. 1998; Wasserman et al. 2003) and it is assumed that follow-up of some of these cohorts 

will continue. With regard to these and other studies in humans, researchers have identified some specific 

needs. For example, there is a need to develop new and more sensitive tests of specific 

neuropsychological functions (Bellinger 1995). Also, not enough research has been conducted in adults 

using measures of cumulative exposure to lead. Another area where additional research would be 

valuable is to determine the extent to which lead contributes as a risk factor to disease and dysfunction. 

There is a limited number of studies that have linked lead to amyotrophic lateral sclerosis (Kamel et al. 

2002), essential tremor (Louis et al. 2003), schizophrenia (Opler et al. 2004), and Parkinson’s disease 

(Gorell et al. 1997, 1999). Also, the possibility that lead contributes to attention deficit disorder has never 

been adequately addressed, despite the increased levels of diagnosis of this disorder in children over the 

past 20 years. Studies in animal models of these diseases can provide valuable information to answer 

such questions. With regard to the interpretation of studies with seemingly differing results, it would be 

important to identify the basis of individual differences in sensitivity to neurotoxicants (Bellinger 2000). 

In addition, epidemiological studies should be designed in a manner that permits more rigorous 

assessments of effect modification. In order to minimize confounding and effect modification, 
LEAD 261 

3. HEALTH EFFECTS 

researchers should make greater use of more focused sampling frames that ensure adequate representation 

of specific subgroups of interest (Bellinger 2000). Additional information is needed to characterize the 

nature of the relationships between lead and nutritional factors, as well as determining what dietary 

modifications might be particularly beneficial in alleviating lead uptake and or effects. Banks et al. 

(1997) suggest that further studies using electrophysiological methods in infancy and early childhood can 

add to knowledge about the effects of lead on specific sensory systems such as vision and audition, as 

well as on higher, more cortically-controlled cognitive processes. 

With regard to studies in animals, further studies of the specific behavioral nature of lead-induced 

learning impairments and of the behavioral mechanisms contributing to such effects would be valuable 

(Cory-Slechta 1995). Such studies in conjunction with microdialysis and microinjection techniques could 

provide critical information related to the roles of various neurotransmitter systems and different brain 

regions in behavioral manifestations (Cory-Slechta 1995). Such research may also shed light on possible 

interactions between neurotransmitter systems that might contribute to lead effects and allow researchers 

to examine the efficacy of potential behavioral or chemical therapeutic approaches for reversing 

behavioral impairments (Cory-Slechta 2003). Additional studies of the roles of developmental periods of 

lead exposure and the levels of lead exposure should be conducted to resolve the possibility of differential 

mechanisms at different stages of the life cycle (Cory-Slechta 1997). Further development of molecular 

techniques to study the action of lead on the function of specific components of proteins associated with 

synaptic transmission also would be helpful (Atchison 2004; Suszkiw 2004). Additional research on 

lead-gene interactions is critical to further the understanding of these issues. 

Epidemiological and Human Dosimetry Studies. There are dozens of epidemiological studies 

that investigated the health effects of lead in both adults and children. The studies listed above under 

Chronic-Duration Exposure and Cancer and others cited throughout Section 3.2, Discussion of Health 

Effects, provide information on lead-induced effects on multiple systems and organs, but the most 

sensitive targets for lead toxicity are the nervous system, heme synthesis, and kidney function. Children 

are more sensitive than adults to lead toxicity and a great number of studies conducted in the last decades 

have focused on the evaluation of neurobehavioral effects of lead in children that have been associated 

with relative low blood lead levels (i.e., <10 μg/dL) (Bellinger and Needleman 2003; Canfield et al. 2003; 

Chiodo et al. 2004; Kordas et al. 2006; Lanphear et al. 2000a, 2005; Téllez-Rojo et al. 2006). Although 

the preponderance of the evidence suggests that lead exposure in children is associated with small 

decrements in intelligence, there are studies that have not found such an association. In this regard, a 

major information need regarding epidemiological studies of lead is identifying the basis of individual 
LEAD 262 

3. HEALTH EFFECTS 

differences in sensitivity to lead toxicity. Another important issue that future studies need to consider is 

the presence of modifying factors. Bellinger (2000) states that effect modification is a property of a true 

association and should be distinguished from confounding. Effect modification can explain 

inconsistencies in findings, and if it exists, failure to address it will lead to an error in inference. Maternal 

stress and environmental enrichment have recently been identified as modifying factors of lead-induced 

behavioral effects in studies in animals (Cory-Slechta 2006; Cory-Slechta et al. 2004; Guilarte et al. 2003; 

Schneider et al. 2001) and continued research in these areas may provide valuable information for 

understanding effects in humans. Effects of lead through alterations in corticoids may have enormous 

implications since changes in the hypothalamic-pituitary-adrenal axis could be a mechanism for multiple 

effects of lead, including those on the immune system as well as on the brain. 

Most of the research gaps identified in the preceding sections could also be listed in this section. For 

example, it is expected that children from some of the prospective studies of lead will continue to be 

evaluated periodically with appropriate neurobehavioral tests. As children in these cohorts (or in newly 

identified cohorts) go through adolescence and eventually into adulthood, it would be desirable also to 

evaluate other end points for potential late-appearing effects. Such evaluations may include, but not be 

limited to, immunocompetence, sexual development, fertility, kidney and cardiovascular functions, or 

cancer incidence. The usefulness of studies involving adult populations exposed to lead as adults (i.e., 

lead workers) in understanding neurotoxicity of lead in children is questionable. This is because the 

impact of a brain lesion experienced as an adult can be dramatically different than that of a lesion incurred 

during periods in which the brain is still undergoing substantial changes (Bellinger 2004). However, 

studies regarding other end points of interest would be useful. For example, associations between lead 

exposure and decreases in glomerular filtration rate have been observed, but not fully characterized (Kim 

et al. 1996a; Muntner et al. 2003; Payton et al. 1994; Staessen et al. 1990, 1992; Weaver et al. 2003a). 

Major uncertainties in the dose-response relationship include: (1) the appropriate exposure biomarker 

(i.e., PbB or bone lead concentration); and (2) the strength of the interactions between glomerular 

filtration rate, blood pressure, and certain diseases such as diabetes. Regarding cardiovascular effects, 

meta-analyses of the association between blood pressure and PbB have found an average effect size of 

approximately 1 mmHg increase in blood pressure per doubling of PbB (Nawrot et al. 2002; Schwartz 

1995; Staessen et al. 1994); however, more recent studies have observed a larger effect in older 

populations and associations between blood pressure and bone lead concentrations that is stronger than 

the association with PbB (Cheng et al. 2001; Korrick et al. 1999; Nash et al. 2003). Major uncertainties 

in the dose-response relationship for blood pressure effects include: (1) the appropriate exposure 
LEAD 263 

3. HEALTH EFFECTS 

biomarker (i.e., PbB or bone lead concentration); and (2) the strength of the association in older males and 

post-menopausal women. 

Biomarkers of Exposure and Effect. 

Exposure. Inorganic lead can be measured in blood, serum, urine, sweat, cerebrospinal fluid, tissues, 

bone, teeth, and hair and nails (see Section 3.6.1). While measurements of lead in any of the above 

tissues can be useful as an indicator of excessive exposure to lead, quantitative associations with exposure 

levels and health effects have been most rigorously explored for blood lead concentration (PbB). 

Currently, PbB is the most widely used biomarker of lead exposure in humans. However, because of the 

relatively rapid elimination of lead from blood (elimination half-time <30 days), PbB reflects exposures 

that occurred within a few months previous to the measurement. The need exists for the development of a 

biomarker that would accurately reflect the total body burden from both acute and chronic durations at 

both low- and high-level exposures. Bone lead concentration may serve as a more reliable biomarker of 

long-term exposure because lead is eliminated slowly from bone (elimination half-time of decades). It 

may also provide a better reflection of long-term time-integrated plasma lead concentration (Cake et al. 

1996; Chuang et al. 2001; Tellez-Rojo et al. 2004). This may explain why bone lead concentration has 

been observed to be a better predictor of cardiovascular/renal effects in older populations than is PbB 

(Cheng et al. 1998, 2001; Korrick et al. 1999; Tsaih et al. 2004). Further characterization of bone lead 

concentration as a biomarker of exposure for various effect end points in adults may improve lead doseresponse assessment and characterization of health risks from exposure to lead in humans. 

The development of inductively-coupled plasma mass spectrometry (ICP-MS) (see Chapter 7) has 

provided adequate analytical sensitivity to measure plasma lead concentrations with greater confidence 

than in the past (Schutz et al. 1996). Recent studies using this technique have shown that plasma lead 

concentrations in adults correlate more strongly with bone lead levels than do PbB (Cake et al. 1996; 

Chuang et al. 2001; Hernandez-Avila et al. 1998; Tellez-Rojo et al. 2004). Since most of the body lead 

burden resides in bone, measurements of plasma lead concentration may turn out to be a better predictor 

of lead body burden than measurements of PbB. This observation has not been explored in children, and 

few studies have attempted to explore relationships between plasma lead concentration and health 

outcomes in children. 

Effect. No clinical disease state is pathognomonic for lead exposure. The neurotoxic and hematopoietic 

effects of lead are well recognized. The primary biomarkers of effect for lead are EP, ALAD, basophilic 
LEAD 264 

3. HEALTH EFFECTS 

stippling and premature erythrocyte hemolysis, and presence of intranuclear lead inclusion bodies in the 

kidneys. Of these, activity of ALAD is a sensitive indicator of lead exposure (see Section 3.6.1). 

Biomarkers for the nephrotoxic effects of lead in humans include elevation of serum creatinine, urinary 

enzymes (e.g., NAG), or protein (albumin, β2μ-globulin, α1μ-globulin, retinol binding protein; see 

Table 3-3 and Figure 3-3). However, none of these markers are specific for lead-induced nephrotoxicity. 

More specific biomarkers of effects for lead may improve the assessment of health risks derived from 

exposure to lead. 

Absorption, Distribution, Metabolism, and Excretion. Inhalation of airborne lead-bearing 

surface dusts can be an important exposure pathway for human. However, available studies of the 

deposition and absorption of inhaled lead in humans are of exposures of adults to submicron lead-bearing 

particles (Chamberlain et al. 1978; Hursh and Mercer 1970; Hursh et al. 1969; Morrow et al. 1980; Wells 

et al. 1975). No studies are available on deposition and absorption of larger particles that might be 

encountered from inhalation of airborne surface dusts. No data are available on the deposition and 

absorption of inhaled lead in children. However, models of age-related changes in airway geometry and 

physiology predict that particle deposition in the various regions of the respiratory tract in children may 

be higher or lower than in adults depending on particle size; for submicron particles, fractional deposition 

in 2-year-old children has been estimated to be 1.5 times greater than in adults (Xu and Yu 1986). 

Ingestion of lead can occur as a result of consuming lead-containing food, drinking water, and beverages, 

from ingesting lead-containing dusts, and from swallowing lead deposited in the upper respiratory tract 

after inhalation exposure. Children can ingest lead-containing dusts, lead-based paint, and other nonfood 

materials through their normal mouthing activity and pica (abnormal ingestion of nonfood items). 

Fractional absorption of ingested lead appears to vary in magnitude with age, being as much as 5– 

10 times greater in infants and young children than in adults (Alexander et al. 1974; Chamberlain et al. 

1978; James et al. 1985; Ziegler et al. 1978). However, there are no data on the absorption of lead in 

older children and adolescents; thus, it is uncertain whether lead absorption in this population is more 

similar to that of adults or to that of infants and young children. While no absorption studies have been 

conducted on subjects in this age group, the kinetics of the change in stable isotope signatures of blood 

lead in mothers and their children, as both come into equilibrium with a novel environmental lead isotope 

profile, suggest that children ages 6–11 years and their mothers may absorb a similar percentage of 

ingested lead (Gulson et al. 1997b). 
LEAD 265 

3. HEALTH EFFECTS 

Ingested soil lead is less readily absorbed than ingested water-soluble lead acetate (Casteel et al. 1997; 

EPA 2004b; Freeman et al. 1996). This difference may reflect a lower solubility of soil lead because of 

its chemical or physical form; for example, there is an inverse relationship between lead particle size and 

gastrointestinal absorption (Barltrop and Meek 1979). There is one published study that assessed the 

bioavailability of lead in adults who ingested hazardous waste site soil (Maddaloni et al. 1998). 

Additional studies of this type would provide an improved basis for estimating lead uptake in people who 

are exposed to lead in soil and soil-derived dusts. A variety of other factors are known to influence the 

absorption of ingested lead, including the chemical form of the ingested lead, the presence of food in the 

gastrointestinal tract, diet, and nutritional status with respect to calcium, vitamin D, and iron (Mushak 

1991); however, for the most part, the mechanisms by which these interactions occur are not fully 

understood. This reflects, in part, a lack of understanding of the mechanisms by which lead is absorbed in 

the gastrointestinal tract and studies aimed at elucidating such mechanisms are needed. A better 

understanding of absorption mechanisms is critical to developing physiologically based models that 

accurately simulate relationships between lead exposure and lead in blood and other target and biomarker 

tissues. 

Few studies are available on the absorption after dermal exposure of inorganic lead compounds in 

humans. In contrast, alkyl lead compounds have been shown to be rapidly and extensively absorbed 

through the skin of rabbits and rats (Kehoe and Thamann 1931; Laug and Kunze 1948). Recent studies 

provide evidence for rapid dermal absorption of inorganic lead in adults; however, these studies have not 

quantified the fraction of applied dose that was absorbed (Stauber et al. 1994; Sun et al. 2002). The 

quantitative significance of the dermal absorption pathway as a contributor to lead body burden remains 

an uncertainty. In children who may experience extensive dermal contact with lead in soil, sand, or 

surface water and suspended sediment (e.g., beach or shoreline exposure scenario), even a low percent 

absorption across the skin may represent a significant internal dose. Therefore, additional studies 

designed to quantify dermal absorption of inorganic lead compounds from both aqueous media and from 

soil, in particular, studies that enable measurements to be extrapolated to children, are important for 

estimating internal doses that children might receive in relatively common exposure scenarios. 

Several models of the toxicokinetics of lead in humans have been developed (Bert et al. 1989; EPA 

1994a, 1994c; Leggett 1993; Marcus 1986a, 1986b, 1986c; O'Flaherty 1993; Rabinowitz et al. 1976). 

Major uncertainties in these models include: (1) absence of calibration data for the kinetics of lead in 

blood and bone in children in association with exposures that have been quantified with high certainty; 

(2) absence of calibration data on bone lead concentrations in adolescents and adults in association with 
LEAD 266 

3. HEALTH EFFECTS 

exposures that have been quantified with high certainty; (3) absence of data on the absolute 

bioavailability of ingested lead in older children and adolescents; (4) incomplete understanding of lead 

kinetics during periods of changing bone metabolism, including adolescence, pregnancy, and menopause; 

and (5) incomplete understanding of inter- and intra-individual variability in model parameters values in 

humans. In addition, there is a need for models that predict concentrations of lead in tissues other than 

blood. 

Comparative Toxicokinetics. The immature swine has been used extensively as a model for 

assessing relative bioavailability of lead in ingested soil in humans (Casteel et al. 1997; EPA 2004c) and 

for evaluating in vitro approaches to assessing bioaccessibility of lead (EPA 2004c; Ruby et al. 1999). 

However, no studies are available in which the absolute or relative bioavailability of ingested lead has 

been quantitatively compared in swine and humans. Such studies would be useful for validating both the 

in vivo swine model and the in vitro bioaccessibility model. 

Methods for Reducing Toxic Effects. The extent of lead absorption in the gastrointestinal tract 

depends on numerous factors including nutritional factors and the presence or absence of other metals that 

interact with lead (Kwong et al. 2004; Mahaffey and Annest 1986; Mahaffey et al. 1986; Ziegler et al. 

1978). Thus, further studies that could identify additional factors that affect lead absorption would be 

valuable. These factors may be nutritional factors or specific pathologic conditions. Chelators have been 

used in the management of lead poisoning, particularly in children (Berlin et al. 1995; Homan et al. 

1998). However, further research should address questions such as what blood lead levels warrant 

chelation therapy and whether chelation therapy may redistribute lead from bone to other tissues. 

Moreover, the effectiveness of chelation therapy in reducing neuropsychologic impairment in children 

with clinically inapparent lead poisoning is questionable, as shown in a series of recent studies (Dietrich 

et al. 2004; Liu et al. 2002; Rogan et al. 2001). Clinical studies of oral chelation should monitor not only 

PbB, but also the possibility of ongoing lead exposure, the child’s age, sources of lead exposure, length of 

exposure, and general health status. Also, the potential benefits of chelation in reducing chronic 

impairments in adults are completely unknown. Lead inhibits heme synthesis by inhibiting the enzyme 

ALAD, and this results in a diffuse effect that involves many systems and organs. Even if ALAD 

inhibition could be prevented, because of the ability of lead to inhibit and/or substitute for calcium in 

many cellular processes (such as neurotransmitter exocytosis), it is unlikely that one could prevent all of 

the physiological alterations that have been attributed to exposure to lead. 
LEAD 267 

3. HEALTH EFFECTS 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 

Many of the known health effects that have been associated with low-level lead exposure have been 

detected in children who experienced lead exposures both in utero and postnatally. Considerable 

uncertainty remains about the relative contribution of in utero and postnatal exposures to the development 

of health outcomes that are expressed later in childhood. This information is important for distinguishing 

those health outcomes that might be mitigated during the postnatal period from those that must be 

mitigated by limiting in utero exposure. Considerable uncertainty also remains about the long-term 

consequences of the lead-related neurobehavioral deficits detected in infants and children with respect to 

manifestation of chronic neurobehavioral problems in adolescence and adulthood. An additional 

important issue that needs to be studied is the potential prevalence of elevated bone lead stores in women 

of reproductive age and the associated risk that this poses to fetal development by mobilization of 

maternal bone stores during pregnancy. 

The interaction between exposure intensity and duration of exposure in the development of neurobehavioral deficits is not understood, in part because of a lack of biomarkers of long-term lead exposure. 

The strongest evidence for health effects of low-level lead exposures on neurodevelopmental deficits is 

based on relationships between measured health outcomes and PbB. Although these studies suggest that 

a significant amount of the variability in the health outcomes (e.g., neurobehavioral deficits) can be 

attributed to variability in PbB, a substantial amount of variability in the outcomes usually cannot be 

assigned to PbB, even after many known potential confounders have been considered (i.e., Needleman 

and Gatsonis 1990; Pocock et al. 1994; Schwartz 1994; Winneke et al. 1996). 

Efforts to explore alternative biomarkers of exposure that provide a better reflection of long-term 

cumulative exposure may be of value for exploring the above issues. Two potential biomarkers of longterm exposure are bone lead measurements and plasma lead measurements (Cake et al. 1996; Erkkila et 

al. 1992; Hernandez-Avila et al. 1996; Hu et al. 1996b, 1998; Watanabe et al. 1994). Recent advances in 

XRF techniques have made it possible to estimate lead levels in bone. Such measurements hold promise 

as biomarkers of long-term cumulative exposure during childhood. However, standard techniques for 

measuring bone lead have not yet been developed. Moreover, there continues to be uncertainty about 

how to interpret bone lead measurements in terms of lead exposure, their relationship to PbB 

concentrations, and their relationships to the various health effects that have been associated with lead 
LEAD 268 

3. HEALTH EFFECTS 

exposure in children. Thus, while dose-response relationships based on PbB are becoming understood, 

much less is known about bone lead-response relationships. This information is important for gaining a 

better understanding of the relationship between cumulative exposures and toxicity. The development of 

ICP-MS (see Chapter 7) has provided adequate analytical sensitivity to measure plasma lead concentrations with greater confidence than in the past. Studies using this technique have shown that plasma 

lead concentrations in adults correlate more strongly with bone lead levels than does PbB (Cake et al. 

1996; Hernandez-Avila et al. 1998). Since most of the body lead burden resides in bone, measurements 

of plasma lead concentration may turn out to be a better predictor of lead body burden than are 

measurements of PbB. This observation has not been explored in children, and few studies have 

attempted to explore relationships between plasma lead concentration and health outcomes in children. 

Studies in animals have provided abundant support for the plausibility of the neurodevelopmental effects 

of lead that have been associated with lead exposure in children, and researchers have begun to identify 

potential mechanisms (i.e., Cory-Slechta 1995, 2003; Rice 1993, 1996a). However, mechanistic 

connections between behavioral deficits, or changes observed in animals, and those that have been 

associated with lead exposure in children have not been completely elucidated. Understanding of such 

connections would be valuable for developing better and more relevant animal models of lead toxicity. 

Studies of the effects of lead on bone metabolism indicate that, in addition to being a reservoir for the lead 

body burden, bone may also be a toxicological target (Hamilton and O’Flaherty 1994, 1995). Studies in 

rats have shown effects of lead on bone mineralization and bone growth. The effects observed in rats 

may be relevant to our understanding of the mechanisms for the growth deficits that have been associated 

with low-level in utero and childhood lead exposures (Ballew et al. 1999; Frisancho and Ryan 1991; 

Shukla et al. 1989, 1991). Additional studies of the effects of lead on bone metabolism in humans and in 

animal models would improve our understanding of the toxicological significance of lead in bone. 

Further research on the relationship between paternal lead exposure and fetal/infant development should 

be conducted. Additional information on relationships between nutritional deficits and vulnerability of 

the fetus and child to lead would be valuable. 

Absorption of ingested lead is higher in infants and young children than in adults; however, available data 

on lead absorption during the ages between childhood and adulthood are very limited (Alexander et al. 

1974; Ziegler et al. 1978). The higher absorption of lead in childhood contributes to the greater 

susceptibility of children to lead; therefore, it is important to know at what age the higher absorption 
LEAD 269 

3. HEALTH EFFECTS 

status of the child changes to the lower absorption status observed in adults. Limited data suggest that 

this conversion may occur early in adolescence. This information is particularly important for accurately 

simulating biokinetics of lead in older children and adolescents. Additional information on interactions 

between nutritional deficiencies and lead absorption and other aspects of lead biokinetics would be 

valuable. 

Dermal absorption of inorganic lead compounds occurs, but the quantitative significance of the dermal 

absorption pathway as a contributor to lead body burden remains an uncertainty, although it is generally 

considered to be much lower than absorption by the inhalation or oral routes of exposure. In children 

who experience extensive dermal contact with lead in soil, sand, or surface water and suspended sediment 

(e.g., beach or shoreline exposure scenario), even a low percent absorption across the skin may represent 

a significant internal dose. Therefore, additional studies designed to quantify dermal absorption of 

inorganic lead compounds from both aqueous media and soil, in particular, studies that enable 

measurements to be extrapolated to children, are important for estimating internal doses that children 

might receive in relatively common exposure scenarios. 

The kinetics of bone formation and remodeling are important factors in the overall biokinetics of lead. 

Most of the body burden of lead resides in bone; a portion of the maternal bone lead stores is transferred 

to the fetus during gestation and incorporated into fetal bone during the development of the fetal skeleton 

(Franklin et al. 1997; Gulson et al. 1997b, 1999b, 2003). Thus, changes in maternal bone metabolism 

(e.g., formation and remodeling) are likely to have a significant impact on in utero exposure of the fetus. 

Approximately 80% of lead in cord blood appears to derive from maternal bone stores (Gulson et al. 

2003). Further information about the kinetics of the mobilization of maternal bone lead, or its 

incorporation into the fetal skeleton is critical for developing models that accurately simulate in utero 

exposures and maternal lead biokinetics during pregnancy and for understanding how changes in maternal 

bone metabolism might affect the susceptibility of the fetus to lead toxicity. Bone formation undergoes 

rapid changes during infancy, childhood, and adolescence. These changes may give rise to periods of 

greater or lower susceptibility to environmental lead; however, little is known about the potential 

consequences of these changes on the biokinetics of lead in children. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 
LEAD 270 

3. HEALTH EFFECTS 

3.10.3 Ongoing Studies 

Ongoing studies pertaining to lead have been identified and are shown in Table 3-12. 
LEAD 271 

3. HEALTH EFFECTS 

Table 3-12. Ongoing Studies on Lead 

Investigator Affiliation Research Description Sponsor 

Audesirk GJ 

Benoff SH 

Berkowitz GS 

Blum CB 

Bornschein RL 

Brain JD 

Burchiel SW 

Burt BA 

Cecil KM 

Cohen MD 

Cory-Slechta DA 

Ehrich M, 

Meldrum JB, Parran D, 

Magnin-Bissel G, and 

Inzana KD 

Ercal N 

University of Colorado 

at Denver/Health 

Science Center, 

Denver, Colorado 

Jewish Research 

Institute, Manhasset, 

New York 

Mount Sinai School of 

Medicine, New York, 

New York 

Columbia University 

Health Sciences, New 

York, New York 

University of 

Cincinnati, Cincinnati, 

Ohio 

Harvard School of 

Public Health, Boston, 

Massachusetts 

University of New 

Mexico School of 

Medicine, 

Albuquerque, New 

Mexico 

University of Michigan 

Dental School, Ann 

Arbor, Michigan 

Children's Hospital 

Medical Center, 

Cincinnati, Ohio 

New York University 

School of Medicine, 

Tuxedo, New York 

University of 

Rochester, Rochester, 

New York 

Virginia Polytechnic 

Institute, College of 

Veterinary Medicine, 

Blacksburg, Virginia 

University of Missouri, 

Rolla, Missouri 

Differential lead toxicity in 

neurons and astrocytes 

Developing an 

understanding of toxic 

metal action in the human 

testis 

Lead mobilization during 

pregnancy and lactation in 

urban women 

Bioavailability of soil lead 

and arsenic in humans 

Treatment of lead exposed 

children follow up 

Transport of lead, 

manganese, iron, and 

cadmium from the 

environment to critical 

organs 

Effects of immunotoxic 

xenobiotics on human 

peripheral blood 

Lead exposure/dietary 

factors in children's oral 

health 

MR assessment of brain 

function altered by lead 

exposure 

Investigation of how 

properties of metals may 

govern toxicities in the 

lungs 

Behavioral toxicity of lead-­

a pharmacological analysis 

Insecticide exposure and 

the permeability of the 

blood-brain barrier to lead 

Role of selenocystine in 

lead toxicity 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 

National Center for Research 

Resources 

National Institute of 

Environmental Health 

Sciences 

National Institutes of Health 

National Institutes of Health 

National Center for Research 

Resources 

National Institute of Dental 

and Craniofacial Research 

National Institute of 

Environmental Health 

Sciences 

National Institute of General 

Medical Sciences 

National Institute of 

Environmental Health 

Sciences 

Department of Agriculture 

National Institute of 

Environmental Health 

Sciences 
LEAD 

3. HEALTH EFFECTS 

272 

Investigator 

Table 3-12. Ongoing Studies on Lead 

Affiliation Research Description Sponsor 

Evanylo GK, 

Daniels WL, and 

Zelazny LW 

Fox DA 

Gao F-B 

Garshick E 

Gonick H 

Godwin HA 

Gray LC 

Graziano JH 

Guilarte TR 

Harry GJ 

Hassett JJ 

Henkens RW 

Hu H 

Virginia Polytechnic 

Institute, Crop and Soil 

Environmental 

Sciences, Blacksburg, 

Virginia 

University of Houston, 

Houston, Texas 

J David Gladstone 

Institutes, San 

Francisco, California 

Department of 

Veterans Affairs, 

Medical Center, 

Brockton, 

Massachusetts 

Department of 

Veterans Affairs, 

Medical Center, West 

Los Angeles, California 

Northwestern 

University, Evanston, 

Illinois 

University of Texas, 

Health Science Center, 

Houston, Texas 

Columbia University 

Health Sciences, New 

York, New York 

Johns Hopkins 

University, Baltimore, 

Maryland 

Not specified 

University of Illinois, 

Natural Resources and 

Environmental 

Sciences, Urbana, 

Illinois 

Alderon Biosciences, 

Inc., Durham, North 

Carolina 

Harvard University 

School of Public 

Health, Boston, 

Massachusetts 

Chemistry and 

bioavailability of waste 

constituents in soils 

Low-level prenatal lead 

exposure and retinal 

toxicity 

Genetic analysis of heavy 

metals neurotoxicity 

Lead intoxicationprevalence and its relation 

to anemia in India 

Influence of lead on blood 

vessel contraction 

Mechanisms of lead 

toxicity 

Effects of lead on deficits 

in hearing rapid changes in 

sound 

Health effects and 

geochemistry of arsenic 

and lead 

NMDA receptor function in 

lead neurotoxicity 

Environmental effects and 

development of neuron 

and glia 

Continued studies on 

bioavailability of lead in 

soil 

One-step rapid screening 

for childhood lead 

poisoning 

Dietary supplements and 

suppression of bone 

resorption and lead 

mobilization 

Department of Agriculture 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Neurological Disorders and 

Stroke 

Department of Veterans 

Affairs 

Department of Veterans 

Affairs 

National Institute of General 

Medical Sciences 

National Institute on Deafness 

and Other Communication 

Disorders 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 

Department of Agriculture 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 
LEAD 

3. HEALTH EFFECTS 

273 

Investigator 

Table 3-12. Ongoing Studies on Lead 

Affiliation Research Description Sponsor 

Hu H 

Hu H 

Hu H 

Ike JO 

Kamel F 

Knight JQ 

Korrick SA 

Korrick SA 

Lanphear BP 

Lawrence DA 

Lubin BH 

Lurie D 

Lutz PM 

Mori S 

Brigham and Women's 

Hospital, Boston, 

Massachusetts 

Brigham and Women's 

Hospital, Boston, 

Massachusetts 

Brigham and Women’s 

Hospital, Boston, 

Massachusetts 

Fisk University, 

Nashville, Tennessee 

Not specified 

Safer Pest Control 

Project, Chicago, 

Illinois 

Harvard University 

School of Public 

Health, Boston, 

Massachusetts 

Brigham and Women's 

Hospital, Boston, 

Massachusetts 

Children’s Hospital 

Medical Center, 

Cincinnati, Ohio 

Wadsworth Center, 

Rensselaer, New York 

University of California 

San Francisco, 

California 

University of Montana, 

Center of 

Environmental Health 

Sciences, Missoula, 

Montana 

University of Missouri 

Rolla, Rolla, Michigan 

Johns Hopkins 

University, Baltimore, 

Maryland 

Lead, blood pressure, 

neurologic and renal 

function in two study 

populations 

Lead-gene interactions 

and cognition 

Development of 

Parkinson’s disease and 

the exposure to lead 

Lead toxicity and 

serotonergic system in 

developing rat brain 

Lead and other 

neurotoxins as risk factors 

for amyotrophic lateral 

sclerosis 

Asthma and lead 

prevention in Chicago 

public housing 

In utero PCB, pesticide 

and metal exposure and 

childhood cognition 

Lead exposure, genetics 

and osteoporosis 

epidemiology 

Neurobehavioral effects of 

prevalent toxicants in 

children 

Immunotoxic effects of 

lead on cytokine 

expression 

Erythrocyte isozyme 

biomarkers of low lead 

overburden 

Lead on development of 

auditory temporal process 

Immunity in children with 

exposure to environmental 

lead 

MR-based study of 

hypomyelination by lead 

poisoning 

National Center for Research 

Resources 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 

National Institute of General 

Medical Sciences 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 

National Center for Research 

Resources 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 

National Center for Research 

Resources 

National Center for Research 

Resources 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 
LEAD 

3. HEALTH EFFECTS 

274 

Investigator 

Table 3-12. Ongoing Studies on Lead 

Affiliation Research Description Sponsor 

Neary JT 

Oteiza P 

Pettit DL 

Pevsner JA 

Pitts DK 

Pollitt E 

Poretz RD 

Puzas JE 

Rajanna B 

Ris MD 

Rogan W 

Rosen HN 

Ruden DM 

Department of 

Veterans Affairs, 

Medical Center, Miami, 

Florida 

University of California, 

Davis, California 

Albert Einstein College 

of Medicine, Yeshiva 

University, New York, 

New York 

Kennedy Krieger 

Research Institute, 

Inc., Baltimore, 

Maryland 

Wayne State 

University, College of 

Pharmacy and AHP, 

Wayne State 

University, Detroit, 

Michigan 

University of California, 

Independent, Davis, 

California 

Rutgers University, 

Biochemistry and 

Microbiology, New 

Brunswick, New Jersey 

University of 

Rochester, Rochester, 

New York 

Alcorn State 

University, Lorman, 

Mississippi 

Children's Hospital 

Medical Center, 

Cincinnati, Ohio 

Not specified 

Beth Israel Deaconess 

Medical Center, 

Boston, Massachusetts 

University of Alabama 

at Birmingham, 

Birmingham, Alabama 

Molecular mechanisms of 

lead neurotoxicity 

Exposure during gestation 

and infancy and its impact 

on neurobehavioral and 

learning capacities 

Micromapping of lead 

induced changes to NMDA 

receptors 

Effects of lead on calciumbinding proteins in rats 

Lead toxicity—midbrain 

dopaminergic system 

The relationship between 

lead and iron and 

behavioral development in 

infants and young children 

A mechanism for leadinduced neurotoxicity 

Lead toxicity in the 

skeleton and its role in 

osteoporosis 

Mechanism of lead 

neurotoxicity 

Early exposure to lead and 

adult antisocial outcome 

Toxicity of lead in 

children—clinical trial 

Lead and skeletal health in 

Boston area women 

QTL and microarray 

mapping lead sensitivity 

genes 

Department of Veterans 

Affairs 

Not specified 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 

Department of Agriculture 

Department of Agriculture 

National Institute of 

Environmental Health 

Sciences 

National Institute of General 

Medical Sciences 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 

National Center for Research 

Resources 

National Institute of 

Environmental Health 

Sciences 
LEAD 

3. HEALTH EFFECTS 

275 

Investigator 

Table 3-12. Ongoing Studies on Lead 

Affiliation Research Description Sponsor 

Schwab AP and 

Joern BC 

Schwartz BS 

Schwarz D 

Shine JP 

Soliman KFA 

Sparrow D 

Sparrow D 

Timchalk C 

Todd AC 

Watson GE, II 

Weisskopf MG 

White RF 

Purdue University, 

Agronomy, West 

Lafayette, Indiana 

Johns Hopkins 

University, Baltimore, 

Maryland 

Children's Hospital of 

Philadelphia, 

Philadelphia, 

Pennsylvania 

Harvard University, 

School of public 

Health, Boston, 

Massachusetts 

Florida Agricultural and 

Mechanical University, 

Tallahassee, Florida 

Department of 

Veterans Affairs, 

Medical Center, 

Boston, Massachusetts 

Department of 

Veterans Affairs, 

Medical Center, 

Boston, Massachusetts 

Battelle Memorial 

Institute, Pacific 

Northwest 

Laboratories, Richland, 

Washington 

Mount Sinai, School of 

Medicine, New York, 

New York 

Department of 

Dentistry, University of 

Rochester, Rochester, 

New York 

Harvard University, 

School of Public 

Health, Boston, 

Massachusetts 

Department of 

Veterans Affairs, 

Medical Center, 

Boston, Massachusetts 

Bioavailability and 

chemical lability of lead in 

agricultural soils amended 

with metal-containing 

biosolids 

Role of lead in the decline 

in cognitive function in 

older adults 

Treatment of lead in 

children 

Transport and fate of 

metals from mine wastes 

Neonatal lead exposure 

effects on the adrenal 

cortex function 

Neurochemical and 

genetic markers of lead 

toxicity 

Lead biomarkers, aging, 

and chronic disease 

Innovative biomonitoring 

for lead in saliva 

African-Americans, 

hypertension and lead 

exposure 

A longitudinal study of lead 

exposure and dental caries 

New biomarkers of 

neurotoxicity 

Functional neuroimaging in 

lead exposed adults 

Department of Agriculture 

National Institute of Aging 

National Center for Research 

Resources 

National Institute of 

Environmental Health 

Sciences 

National Institute of General 

Medical Sciences 

Department of Veterans 

Affairs 

Department of Veterans 

Affairs 

National Institute of 

Environmental Health 

Sciences 

National Institute of Diabetes 

and Digestive and Kidney 

Diseases 

National Institute of Dental 

and Craniofacial Research 

National Institute of 

Environmental Health 

Sciences 

Department of Veterans 

Affairs, Research And 

Development 
LEAD 276 

3. HEALTH EFFECTS 

Table 3-12. Ongoing Studies on Lead 

Investigator Affiliation Research Description Sponsor 

Worobey J Rutgers University, 

Nutritional Sciences, 

New Brunswick, New 

Jersey 

Wright RO Harvard School of 

Public Health, Boston, 

Massachusetts 

Wright RO Brigham And Women's 

Hospital, Boston, 

Massachusetts 

Behavioral outcomes in 

children screened for lead 

burden and nutritional risk 

Metals, nutrition, and 

stress in child 

development 

Neurochemical and 

genetic markers of lead 

toxicity 

Department of Agriculture 

National Institute of 

Environmental Health 

Sciences 

National Institute of 

Environmental Health 

Sciences 

MR = magnetic resonance; NMDA = N-methyl-D-aspartate; PCBs = polychlorinated biphenyls; QTL = quantitative trait 

loci 

Source: FEDRIP 2005 
LEAD 277 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Lead is a naturally occurring element and is a member of Group 14 (IVA) of the periodic table. Natural 

lead is a mixture of four stable isotopes, 208Pb (51–53%), 206Pb (23.5– -27%), 207Pb (20.5–23%), and 204Pb 

(1.35–1.5%). Lead isotopes are the stable decay product of three naturally radioactive elements: 206Pb 

from uranium, 207Pb from actinium, and 208Pb from thorium. 

Lead is not a particularly abundant element, but its ore deposits are readily accessible and widely 

distributed throughout the world. Its properties, such as corrosion resistance, density, and low melting 

point, make it a familiar metal in pipes, solder, weights, and storage batteries. The chemical identities of 

lead and several of its compounds are given in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Lead exists in three oxidation states: Pb(0), the metal; Pb(II); and Pb(IV). In the environment, lead 

primarily exists as Pb(II). Pb(IV) is only formed under extremely oxidizing conditions and inorganic 

Pb(IV) compounds are not found under ordinary environmental conditions. While organolead(II) 

compounds are known, organolead chemistry is dominated by the tetravalent (+4) oxidation state. 

Metallic lead, Pb(0) exists in nature, but its occurrence is rare. 

Lead’s extensive use is largely due to its low melting point and excellent corrosion resistance in the 

environment. When exposed to air and water, films of lead sulfate, lead oxides, and lead carbonates are 

formed; these films act as a protective barrier that slows or halts corrosion of the underlying metal. Lead 

is amphoteric, forming plumbous and plumbic salts in acid and plumbites and plumbates in alkali. Lead 

is positioned slightly above hydrogen in the electromotive series and therefore should theoretically 

replace hydrogen in acids. However, the potential difference is small and the high hydrogen overvoltage 

prevents replacement (King and Ramachandran 1995; Sutherland and Milner 1990). 

Data on the physical and chemical properties of lead and several of its compounds are given in Table 4-2. 
LEAD 278 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Lead and Compounds 

Characteristic Leada Lead acetatea Lead azideb Lead bromidec 

Synonyms Lead metal; Lead(2+) acetic acid; Lead (2+) azide; Lead (II) bromided 

plumbum; pigment plumbous acetate Lead diazinde 

metal 

Trade name CI77575 Salt of Saturn; sugar RD 1333 No data 

of lead; Unichem 

PBA 

Chemical formula Pb C4H6O4Pb N6Pb Br2Pb 

Chemical structuree Pb O O Pb(N3)2 PbBr2 

Pb2+ O- -O 

Identification numbers: 

CAS registry 7439-92-1 301-04-2 13424-46-9 10031-22-8 

 NIOSH RTECS OF7525000b

 AI5250000b OF8650000 No data 

 EPA hazardous D008 U144, D008 No data No data 

 waste 

OHM/TADS 7216776 7217255 No data No data 

 DOT/UN/NA/IMCO NA UN 1616, IMO 6.1 UN 0129 No data 

shipping 

HSDB 231 1404 No data No data 

NCI No data No data No data No data 
LEAD 279 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Lead and Compounds 

Lead 

Characteristic Lead chloridea Lead chromatea fluoroboratea Lead iodidea 

Synonyms Lead(2+) chloride; Chromic acid Borate(1-), Lead diiodide; 

lead (II) chloride; (H2CrO4) lead(2+) tetrafluoro, lead(II) iodide; 

plumbous chloride salt; lead chromate lead(2+); lead plumbous iodide 

(VI); Yellow 34 borofluoride; lead 

boron fluoride; lead 

tetrafluoroborate 

Trade name No data Canary Chrome No data No data 

Yellow 40-2250; 

Cologne Yellow; 

King's Yellow 

Chemical formula Cl2Pb CrO4Pb B24F8Pb I2Pb 

Chemical structuree PbCl2 PbCrO4 Pb(BF4)2 PbI2 

Identification numbers: 

 CAS registry 7758-95-4 7758-97-6 13814-96-5 10101-63-0 

 NIOSH RTECS OF9450000b

 GB2975000b ED2700000b OG1515000b

 EPA hazardous No data D007, D008 D008 D008 

 waste 

OHM/TADS 7217256 No data 7217378 No data 

 DOT/UN/NA/IMCO NA 2291 No data NA 2291; 1MO 6.1 NA 2811 

shipping 

HSDB 6309 1650 1991 636 

NCI No data No data No data No data 
LEAD 280 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Lead and Compounds 

Lead molybdenum 

Characteristic chromateb Lead nitratea Lead oxidea 

Synonyms Chromic acid, lead and Lead dinitrate; nitric acid Lead(2+) oxide; 

molybdenum salt; lead(2+) salt; lead (II) lead oxide, yellow 

molybdenum-lead nitrate; plumbous nitrate lead monoxide; 

chromate; molybdenum litharge; massicot 

orange; Scarlet chrome; 

Red 104 

Trade name C.I. Pigment Red 104 No data CI 77577; CI 

Pigment Yellow 46 

Chemical formula CRMoOPb N2O6Pb OPb 

Chemical structuree No data Pb(NO3)2 PbO 

Identification numbers: 

 CAS registry 12709-98-7 10099-74-8 1317-36-8 

 NIOSH RTECS OG1625000 OG2100000b

 OG1750000b

 EPA hazardous No data D008 D008 

 waste 

OHM/TADS No data 7217257 No data 

 DOT/UN/NA/IMCO No data UN 1469, IMO 5.1 No data 

shipping 

HSDB No data 637 638 

NCI No data No data No data 
LEAD 

4. CHEMICAL AND PHYSICAL INFORMATION 

281 

Characteristic 

Table 4-1. Chemical Identity of Lead and Compounds 

Lead phosphatea Lead styphnatef Lead sulfatea 

Synonyms Lead(2+) phosphate; 1,3-benzenediol, 2,4,6- Sulfuric acid 

phosphoric acid lead(2+) trinitro, lead (2+) salt (1:1); lead(2+) salt; lead 

salt resorcinol, 2,4,6-trinitro; (II) sulfate 

lead (2+) salt (1:1); lead (II) 

styphnate 

Trade name Perlex Paste 500; Perlex No data CI 77630; Fast 

Paste 600A; CI 77622 White; Lead 

Bottoms; 

Mulhouse White 

Chemical formula O8P2Pb3 C6H3N3O8·Pb O4PbS 

Chemical structuree

 Pb3(PO4)2 O­ PbSO4 

O2N NO2 

Pb2+ ONO2 

Identification numbers: 

 CAS registry 7446-27-7 15245-44-0 7446-14-2 

 NIOSH RTECS OG3675000b

 No data OG4375000b

 EPA hazardous D008, U145 No data No data 

 waste 

OHM/TADS No data No data No data 

 DOT/UN/NA/IMCO No data No data UN 1794; NA 

shipping 1794; IMO 8.0 

HSDB 2637 No data 6308 

NCI No data No data No data 
LEAD 282 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Lead and Compounds 

Characteristic Lead sulfidea Tetraethyl leada Lead carbonatea 

Synonyms Lead monosulfide; Lead, tetraethyl; TEL; Carbonic acid lead 

lead(2+) sulfide; Lead (II) tetraethyllead; tetraethyl- salt; cerussite 

sulfide; plumbous sulfide; plumbane 

natural galena 

Trade name No data No data No data 

Chemical formula PbS C8H20Pb PbCO3 

Chemical structuree

 PbS PbCO3 

Pb 

Identification numbers: 

 CAS registry 1314-87-0 78-00-2 598-63-0 

 NIOSH RTECS OG4550000 TP4550000 OF9275000 

 EPA hazardous D008 P110; D008 D008 

 waste 

 OHM/TADS 7800071 7216922 No data 

 DOT/UN/NA/IMCO NA 2291; IMO 6.1 NA 1649; IMO 6.1 No data 

shipping 

HSDB 639 841 1649 

NCI No data C54988 No data 

a

HSDB 2007 

b

RTECS 2007 

c

Lewis 1993 

d

Lenga 1988 

e

ChemIDplus 2005 

f

EPA 2006 

CAS = Chemical Abstracts Services; DOT/UN/NA/IMO = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for 

Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; 

RTECS = Registry of Toxic Effects of Chemical Substances 
LEAD 283 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Lead and Compounds 

Property Leada Lead acetatea Lead azideb Lead bromideb 

Molecular weight 

Color 

Physical state 

Melting point 

Boiling point 

207.20 

Bluish-gray 

Solid 

327.4 °C 

1,740 °C 

325.28 

White 

Solid 

280 °C 

Decomposes 

above 200 °C 

291.25 367.04 

White White 

Needles or powder Crystalline powder 

No data 373 °C 

Explodes at 350 °C 916 °C 

Density at 20 °C 

Odor 

Odor threshold: 

11.34 g/cm3 

None 

 3.25 g/cm3 

Slightly acetic 

No data 

No data 

6.66 g/cm3 d 

No data 

Water No data No data No data No data 

Air No data No data No data No data 

Solubility: 

Water at 25 °C Insoluble 443,000 mg/L at 

520 °C 

230 mg/L at 18 °C 8,441 mg/L at 20 °C 

Nitric acid Soluble No data No data No data 

 Hot conc. Soluble No data No data No data 

sulfuric acid 

 Organic 

solvents 

Insoluble Soluble in glycerol, 

very slight in 

alcohol 

Acetic acidc Insoluble in alcohol 

Partition coefficients: 

 Log Kow 

 Log Koc 

Vapor pressure 

No data 

No data 

1.77 mmHg at 

1,000 °C 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

1 mm Hg at 513 °C 

Henry’s law 

constant 

No data No data No data No data 

Autoignition 

temperature 

Flashpoint 

Flammability 

limits 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

Not flammable 

No data 

No data 

No data 

Conversion 

factorsj 

Not relevante

 Not relevante Not relevante Not relevante 

Explosive limits No data Lead acetate-lead 

bromate double 

No data No data 

Valence state 0f 

salt is explosive 

+2 +2 +2 
LEAD 284 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Lead and Compounds 

Property Lead chloridea Lead chromatea Lead fluoroborateb Lead iodidea 

Molecular weight 278.11 323.19 380.81 461.01 

Color White (Orange-)yellow Colorless Bright or golden 

yellow 

Physical state Solid Solid Crystalline powder Hexagonal 

crystals; powder 

Melting point 501 °C 844 °C No data 402 °C 

Boiling point 950 °C Decomposesc

 No data Decomposes at 

872 °C 

Density at 20 °C 5.85 g/cm3

 6.12 g/cm3 at 15 °C 1.75 g/cm3 6.16 g/cm3 

Odor No data Faint odor (solution) Odorless No data 

Odor threshold No data No data No data No data 

Solubility: 

Water at 25 °C 9,900 mg/L at 20 °C 0.2 mg/L No data 630 mg/L at 

20 °C 

Nitric acid No data Soluble in dilute acid No data No data 

 Hot conc. No data No data No data No data 

sulfuric acid 

 Organic Insoluble in alcoholc Insoluble in acetic Decomposes in Insoluble in 

solvents acid alcoholc alcoholb 

Partition coefficients: 

 Log Kow No data No data No data No data 

 Log Koc No data No data No data No data 

Vapor pressure 1 mm Hg at 547 °C No data No data 1 mm Hg at 

479 °C 

Henry’s law No data No data No data No data 

constant 

Autoignition No data No data No data No data 

temperature 

Flashpoint No data No data No data No data 

Flammability No data Flammable with Not ignited readily Not flammable 

limits combustible organic 

or other oxidizable 

materials 

Conversion Not relevante

 Not relevante Not relevante Not relevante 

factors 

Explosive limits No data No data No data No data 

Valence state +2 +2 +2 +2 
LEAD 285 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Lead and Compounds 

Lead molybdenum 

Property chromatea Lead nitratea

 Lead oxidea 

Molecular weight 886.26g 331.21 223.20 

Color No data Colorless or white Reddish-yellow; yellow 

(above 489 °C) 

Physical state No data Solid Solid 

Melting point No data Decomposes at 470 °C 888 °C 

Boiling point No data No data Decomposes at 1,472 °C 

Density at 20 °C No data 4.53 g/cm3

 9.3 g/cm3 (Litharge); 

8.0 g/cm3

 (Massicot)d 

Odor No data Odorless No data 

Odor threshold: No data No data No data 

Solubility: 

Water at 25 °C No data 376,500 mg/L at 0 °C 17 mg/L at 20 °C 

565,000 mg/L at 20 °C 

Nitric acid No data Insoluble Soluble (Litharge)

 Hot conc. No data No data No data 

sulfuric acid 

 Organic No data 1 g in 2,500 mL absolute alcohol; Soluble in alkali chlorides; 

solvents 1 g in 75 mL absolute alcohol soluble in alkali (Massicot); 

insoluble in alcohol 

Partition coefficients: 

 Log Kow No data No data No data 

 Log Koc No data No data No data 

Vapor pressure No data No data No data 

Henry’s law No data No data No data 

constant 

Autoignition No data No data No data 

temperature 

Flashpoint No data No data No data 

Flammability No data Fire risk with organics Not readily ignited 

limits 

Conversion Not relevante

 Not relevante Not relevante 

factors 

Explosive limits No data Explosive with easily oxidizable 2B3 drops 90% 

substances, and lead nitrate-lead peroxyformic acid causes 

hypophosphite double salt violent explosion 

Valence state +2 +2 +2 
LEAD 286 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Lead and Compounds 

Property Lead phosphatea Lead styphnateh Lead sulfatea 

Molecular weight 811.54 450.29g 303.26 

Color White Orange-yellow White 

(monohydrate) 

Physical state Solid Monoclinic crystals Solid 

Melting point 1,014 °C No data 1,170 °C 

Boiling point No data No data No data 

Density at 20 °C 6.9B7.3 g/cm3 d No data 6.2 g/cm3c 

Odor No data No data No data 

Odor threshold: No data No data No data 

Solubility: 

Water at 25 °C 0.14 mg/L at 20 °C Insoluble 42.5 mg/L 

Nitric acid Soluble No data More than in water 

 Hot conc. No data No data Slightly soluble 

sulfuric acid 

 Organic Soluble in fixed alkali No data Insoluble in alcohol 

solvents hydroxides; insoluble in 

alcohol 

Partition coefficients: 

 Log Kow No data No data No data 

 Log Koc No data No data No data 

Vapor pressure No data No data No data 

Henry’s law No data No data No data 

constant 

Autoignition No data No data No data 

temperature 

Flashpoint No data No data No data 

Flammability No data Detonates at 260 °C Not flammable 

limits 

Conversion Not relevante

 Not relevante Not relevant 

factors 

Explosive limits No data No data No data 

Valence state +2 +2 +2 
LEAD 287 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Lead and Compounds 

Property Lead sulfidea Tetraethyl leada Lead carbonatea 

Molecular weight 239.27 323.45 267.2 

Color Black, blue, or silvery Colorless Colorless rhombic crystals 

Physical state Cubic or metallic Oily liquid Solid 

crystals; powder 

Melting point 1,114 °C No data 315 °C (decomposes) 

Boiling point Sublimes at 1,281 °C 200 °C; 227.7 °C (with No data 

decomposition) 

Density at 20 °C 7.57–-7.59 g/cm3

 1.653 g/cm3 6.6 g/cm 

Odor No data No data No data 

Odor threshold: No data No data No data 

Solubility: 

Water at 25 °C 0.86 mg/L at 13 °C 0.29 mg/L 1.1 mg/L 

Nitric acid Soluble No data Soluble 

 Hot conc. Soluble (in acid) No data Soluble 

sulfuric acid 

 Organic Nitric acid, hot diluted Benzene, ethanol, diethyl Insoluble in ammonia and 

solvents hydrochloric acidb

; ether, gasoline petroleum alcohol 

insoluble in alcohol ether 

Partition coefficients: 

 Log Kow No data 4.15 No data 

 Log Koc No data No data No data 

Vapor pressure 10 mmHg at 975 °C 0.26 mm Hg at 25 °C No data 

Henry’s law No data No data No data 

constant 

Autoignition No data No data No data 

temperature 

Flashpoint No data 93 °C (closed cup); 85 °C No data 

(open cup) 

Flammability Noncombustible 1.8% Not flammable 

limits 

Conversion Not relevant Not relevant Not relevant 

factors 

Explosive limits No data Potentially, above 80 °C No data 

Valence state +2 +4 +2 

a

HSDB 2007 

b

Budavari et al. 1989 

c

Lide 1996 

d

Temperature not specified. 

e

Since these compounds exist in the atmosphere in the particulate state, their concentrations are expressed as 

μg/m3

 only. f

Howe 1981 

g

Molecular weight calculated from atomic weights. 

h

Lewis 1993 
LEAD 288 

4. CHEMICAL AND PHYSICAL INFORMATION 

This page is intentionally blank. 
LEAD 289 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 PRODUCTION 

The most important lead ore is galena (PbS) followed by anglesite (PbSO4) and cerussite (PbCO3). The 

latter two minerals are formed from the weathering of galena. Five lead mines in Missouri plus leadproducing mines in Alaska, Idaho, Montana, and Washington produce most of the primary lead. In 2003, 

Alaska and Missouri (“lead-belt” in southeastern part of the state) accounted for 96% of domestic mine 

production. Lead can be recovered from ore deposits of lead, zinc, lead-zinc, and silver. Lead ore is 

mined underground except when it is mined with copper ores, which are typically open pit mines. The 

United States is third in world lead production after Australia and China. Together with Peru, Canada, 

and Mexico, these six countries account for 82% of the world's mine production. 

Primary lead is obtained from mined ore. The crude ore is first beneficiated, which involves processes 

such as crushing, dense-medium separation, grinding, and froth floatation to obtain concentrates with 

higher lead concentrations. Primary metal is generally produced from the sulfide concentrate by a twostep process involving (1) an oxidative roast to remove sulfur with the formation of PbO and (2) blast 

furnace reduction of the PbO. Lead concentrates produced from ore were processed into primary metal at 

two smelter refineries operated by a company in Missouri. 

Secondary lead is obtained from scrap lead. Ninety-nine percent of secondary production of lead was 

produced at 23 plants in the United States, 15 of which had annual capacities of 15,000 tons or more. In 

2003, secondary lead accounted for 82% of refined lead production. Secondary lead is obtained primarily 

from recycled lead-acid batteries. Almost all of the lead recycled in 2003 was produced by 7 companies 

operating 15 plants in Alabama, California, Florida, Indiana, Louisiana, Minnesota, Missouri, New York, 

Tennessee, and Texas (USGS 2003). 

Tables 5-1 and 5-2 list facilities in each state that respectively manufacture, process, or use lead and lead 

compounds, the intended use, and the range of maximum amounts of these substances that are stored on 

site. The data listed in Tables 5-1 and 5-2 are derived from the Toxics Release Inventory (TRI04 2006). 

Only certain types of facilities were required to report. Therefore, this is not an exhaustive list. In 

comparing Toxics Release Inventory (TRI) data with that of previous years, it is important to note that 

starting in 2001 the threshold for reporting lead was reduced to 100 pounds. Previously, reporting was 

only required of facilities that manufactured or processed 25,000 pounds or more annually or that used 

10,000 pounds or more annually. Additionally, in 1998, additional industries were required to report, 
LEAD 290 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Lead 

Number Minimum Maximum 

of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AK 10 100 99,999 1, 5, 7, 9, 12, 13, 14 

AL 126 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AR 74 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AZ 76 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CA 281 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CO 56 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CT 104 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

DC 4 100 99,999 1, 8, 11, 12, 13 

DE 15 100 9,999,999 2, 3, 7, 8, 9, 11, 12, 13, 14 

FL 119 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

GA 117 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

GU 3 0 999 1, 5, 12 

HI 15 0 999,999 1, 7, 8, 11, 12, 13, 14 

IA 91 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ID 37 0 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 13, 14 

IL 217 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

IN 174 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KS 61 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

KY 107 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

LA 77 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MA 103 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MD 51 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

ME 39 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

MI 176 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MN 84 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MO 112 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MS 74 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MT 19 0 99,999 1, 2, 5, 6, 7, 8, 9, 12, 13, 14 

NC 138 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ND 17 0 99,999 1, 2, 3, 5, 7, 8, 9, 10, 12, 13, 14 

NE 58 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NH 44 0 999,999 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 13, 14 

NJ 161 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NM 28 0 49,999,999 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 14 

NV 55 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

NY 178 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OH 268 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OK 93 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OR 75 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 
LEAD 291 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Lead 

Number Minimum Maximum 

of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

PA 238 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

PR 31 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12 

RI 50 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

SC 113 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

SD 21 0 499,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

TN 156 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

TX 223 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 63 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

VA 109 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

VI 3 100 99,999 1, 5, 12, 14 

VT 17 0 9,999,999 2, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WA 90 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WI 129 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WV 64 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14 

WY 15 0 999,999 1, 4, 7, 8, 9, 12, 13, 14 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 

Source: TRI04 2006 (Data are from 2004) 
LEAD 292 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-2. Facilities that Produce, Process, or Use Lead Compounds 

Number Minimum Maximum 

of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AK 30 0 999,999,999 1, 2, 4, 5, 7, 9, 10, 12, 13, 14 

AL 159 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AR 111 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

AZ 129 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CA 324 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CO 87 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

CT 111 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

DE 38 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

FL 136 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

GA 187 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

GU 5 0 9,999 1, 2, 3, 4, 5, 7, 9, 12, 13, 14 

HI 11 0 99,999 1, 2, 5, 7, 9, 12, 13, 14 

IA 107 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ID 41 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

IL 287 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

IN 259 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KS 104 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KY 148 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

LA 116 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MA 148 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MD 80 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ME 33 0 999,999 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 13, 14 

MI 209 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MN 103 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MO 161 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MP 4 0 9,999 1, 2, 3, 4, 5, 7, 9, 12, 13, 14 

MS 93 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MT 43 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 9, 12, 13, 14 

NC 156 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ND 17 0 999,999 1, 2, 5, 7, 9, 10, 12, 13, 14 

NE 65 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NH 51 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NJ 182 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NM 55 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

NV 74 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NY 197 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OH 330 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OK 96 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 
LEAD 293 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-2. Facilities that Produce, Process, or Use Lead Compounds 

Number Minimum Maximum 

of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

OR 92 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

PA 331 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

PR 38 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

RI 59 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

SC 123 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

SD 24 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

TN 166 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

TX 288 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 88 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

VA 120 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

VI 7 0 999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 12 

VT 18 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 11, 12, 13, 14 

WA 113 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WI 136 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WV 70 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 

WY 36 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 

Source: TRI04 2006 (Data are from 2004) 
LEAD 294 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

including metal mining, coal mining, electrical utilities, and Resource Conservation and Recovery Act 

(RCRA)/Solvent Recovery. Table 5-3 lists the producers of primary lead metal and selected lead 

compounds. Companies listed are those producing lead compounds in commercial quantities, exceeding 

5,000 pounds or $10,000 in value annually. Table 5-4 shows the U.S. production volumes for lead for 

1999 through 2003. During this time, the primary lead production declined while secondary lead 

production was fairly constant. 

5.2 IMPORT/EXPORT 

No lead in ore and concentrates and base bullion were imported into the United States in 2003, while 

175,000 metric tons were imported in pigs, bars, and reclaimed scrap. Imports were down from 

1999 when 12,300 metric tons, 90 metric tons, and 311,000 metric tons were imported in ore and 

concentrates; base bullion; and pigs bars and reclaimed scrap, respectively. In 2003, 36,000 metric tons, 

lead content of lead pigments and compounds were imported in the United States (USGS 2003). 

Exports of lead in ore and concentrates and lead materials, excluding scrap, rose from 93,500 and 

103,000 metric tons in 1999 to 253,000 and 123,000 metric tons, respectively, in 2003. In 2003, 

92,800 metric tons of lead scrap were exported (USGS 2003). 

5.3 USE 

Lead may be used in the form of metal, either pure or alloyed with other metals, or as chemical 

compounds. The commercial importance of lead is based on its ease of casting, high density, low melting 

point, low strength, ease of fabrication, acid resistance, electrochemical reaction with sulfuric acid, and 

chemical stability in air, water, and soil (King and Ramachandran 1995; Shea 1996; Sutherland and 

Milner 1990). Lead is used in the manufacture of storage batteries; lead alloys used in bearings, brass and 

bronze and some solders; sheets and pipe for nuclear and x-ray shielding, cable covering, noise control 

materials; chemical resistant linings; ammunition; and pigments and lead compounds used in glass 

making, ceramic glazes, plastic stabilizers, caulk, and paints. Consumption of lead in lead-acid batteries, 

including SLI (Start, Light, Ignition) batteries used in cars, trucks, and other vehicles and industrial type 

lead acid batteries is the major use of lead today. In 2003, the U.S. consumption for lead was: 84.2%, 

storage batteries; 3.5%, ammunition, shot, and bullets; 2.6%, other oxides (paint, glass and ceramic 

products, other pigments and chemicals); 2.3%, casting metals (electrical machinery and equipment, 

motor vehicles and equipment, other transportation equipment, and nuclear radiation shielding); and 

1.7%, sheet lead (building construction, storage tanks, process vessels, etc., and medical radiation 
LEAD 295 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-3. Current U.S. Manufacturers of Lead Metal and Selected Lead 

Compoundsa 

Company Location 

Lead metalb: 

Doe Run Resources Corp. St. Louis, Missouri 

Lead chromate (Yellow 34): 

Dominion Colour Corp. (USA) Paterson, New Jersey 

 Engelhard Corporation Louisville, Kentucky 

Nichem Corp. Chicago, Illinois 

 Rockwood Pigments, NA, Inc. Beltsville, Maryland 

Wayne Pigment Corporation Milwaukee, Wisconsin 

Lead fluoborate: 

Atotech USA Inc Rock Hill, South Carolina 

General Chemical Corporation Claymont, Delaware 

OMG Fidelity, Inc. Newark, New Jersey 

Solvay Fluorides, LLC. St. Louis, Missouri 

Lead molybdenum chromate (Red 104): 

 Englehard Corporation Louisville, Kentucky 

Wayne Pigment Corporation Milwaukee, Wisconsin 

Lead nitrate: 

GFS Chemicals, Inc. Columbus, Ohio 

Lead oxide, yellow: 

Eagle-Picher Industries, Inc Joplin, Missouri 

Hammond Group, Inc. Hammond, Indiana, 

Pottstown, Pennsylvania 

OMNI Oxide Lancaster, Ohio 

Lead sulfate:

 Nichem Corp.c

 Chicago, Illinois 

Hammond Group, Inc.d

 Hammond, Indiana 

Eagle-Pitcher Industries, Inc.e

 Joplin, Missouri 

a

Derived from SRI 2004 unless otherwise noted. SRI reports production of chemicals produced in commercial 

quantities (defined as exceeding 5,000 pounds or $10,000 in value annually) by the companies listed. b

USGS 2004. Primary producer 

c

Lead sulfate, Dibasic lead sulfate (2PbO.PBSO4) and Tribasic lead sulfate (3PbO.PbSO4) d

Dibasic lead sulfate (2PbO.PBSO4) and tribasic lead sulfate (3PbO.PbSO4) e

Tribasic lead sulfate (3PbO.PbSO4) 
LEAD 296 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-4. U.S. Lead Production 1999–2003 

Production 1999 

Production volumes in metric tons 

2000 2001 2002 2003 

Mined (recovered): domestic ores, 

recoverable lead content 

503,000 449,000 454,000 440,000 449,000 

Primary (refined): domestic/foreign 

ores and base bullion 

350,000 341,000 290,000 262,000 245,000 

Secondary (refined): lead content 1,110,000 1,130,000 1,100,000 1,120,000 1,150,000 

Source: USGS 2003 
LEAD 297 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

shielding) (USGS 2003). Certain dispersive uses of lead that led to widespread exposure, such as 

tetraethyl lead in gasoline, water pipe, solder in food cans, lead shot and sinkers, and in house paints, have 

been or are being phased out due to environmental and health concerns (Larrabee 1998). 

Prior to the EPA beginning to regulate the lead content in gasoline during the early 1970s, approximately 

250,000 tons of organic lead (e.g., tetraethyl lead) were added to gasoline on an annual basis in the United 

States (Giddings 1973). These lead-based “anti-knock” additives increased the octane rating of the 

gasoline and as a result increased engine efficiency (Giddings 1973). In 1971, the average lead content 

for a gallon of gasoline purchased in the United States was 2.2 grams per gallon (Giddings 1973). After 

determining that lead additives would impair the performance of emission control systems installed on 

motor vehicles, and that lead particle emission from motor vehicles presented a significant health risk to 

urban populations, EPA, in 1973, initiated a phase-down program designed to minimize the amount of 

lead in gasoline over time. By 1988, the phase-down program had reduced the total lead usage in 

gasoline to <1% of the amount of lead used in the peak year of 1970 (EPA 1996a). 

In 1990, a Congressional amendment to the Clean Air Act (CAA) banned the use of gasoline containing 

lead or lead additives as fuel in motor vehicles. On February 2, 1996, the EPA incorporated the statutory 

ban in a direct final rule which defined unleaded gasoline as gasoline containing trace amounts of lead up 

to 0.05 gram per gallon (EPA 1996a). The definition still allowed trace amounts of lead but expressly 

prohibited the use of any lead additive in the production of unleaded gasoline. The term “lead additive” 

was defined to include pure lead as well as lead compounds (EPA 1996a). Although the regulatory action 

of Congress banned the use of leaded gasoline as fuel in motor vehicles, it did not restrict other potential 

uses of gasoline containing lead or lead additives (EPA 1996a). Gasoline produced with lead additives 

continues to be made and marketed for use as fuels in aircraft, race cars, and non-road engines such as 

farm equipment engines and marine engines, to the extent allowed by law (EPA 1996a), but tetraethyl 

lead has not been produced in the United States since March 1991. All gasoline sold for motor vehicle 

use since January 1, 1996, has been unleaded (EPA 1997). 

Table 5-5 lists the uses of the specific lead compounds identified in Chapter 4. 

Lead arsenate, basic lead arsenate, and lead arsenite were formerly used as herbicides, insecticides, or 

rodenticides. Until the 1960s, they were widely used to control pests in fruit orchards, especially apple 

orchards (EPA 2002; PAN Pesticides Database 2004; Peryea 1998; Wisconsin Department of Health and 
LEAD 298 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-5. Current and Former Uses of Selected Lead Compounds 

Compound Uses 

Lead acetate	 Dyeing of textiles, waterproofing, varnishes, lead driers, chrome pigments, gold 

cyanidation process, insecticide, anti-fouling paints, analytical reagent, hair dye 

Lead azide Primary detonating compound for high explosives 

Lead bromide	 Photopolymerization catalyst, inorganic filler in fire-retardant plastics, general purpose 

welding flux 

Lead chloride	 Preparation of lead salts, lead chromate pigments, analytical reagent 

Lead chromate	 Pigment in industrial paints, rubber, plastics, ceramic coatings; organic analysis 

Lead fluoborate Salt for electroplating lead; can be mixed with stannous fluoborate to electroplate any 

composition of tin and lead as an alloy 

Lead iodide Bronzing, printing, photography, cloud seeding 

Lead molybdate Analytical chemistry, pigments 

Lead nitrate Lead salts, mordant in dyeing and printing calico, matches, mordant for staining 

mother of pearl, oxidizer in the dye industry, sensitizer in photography, explosives, 

tanning, process engraving, and lithography 

Lead oxide, black Storage batteries, ceramic cements and fluxes, pottery and glazes, glass, chromium 

pigments, oil refining, varnishes, paints, enamels, assay of precious metal ores, 

manufacture of red lead, cement (with glycerol), acid-resisting compositions, matchhead compositions, other lead compounds, rubber accelerator 

Lead phosphate Stabilizing agent in plastics 

Lead styphnate Primary explosive 

Lead sulfate Storage batteries, paints, ceramics, pigments, Electrical and other vinyl compounds 

requiring high heat stability 

Lead sulfide Ceramics, infrared radiation detector, semi-conductor, ceramic glaze, source of lead 

Tetraethyl lead	 Anti-knock agent in aviation gasoline 

Sources: Boileau et al. 1987; Carr 1995; EPA 2001 
LEAD 299 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Family Services 2002). All insecticidal use of lead arsenate was officially banned on August 1, 1988. 

However, all registrations for its insecticidal use had lapsed before that time. 

5.4 DISPOSAL 

Although certain uses of lead preclude recycling (e.g., use as a gasoline additive), lead has a higher 

recycling rate than any other metal (Larrabee 1998). In 2002, about 81% of refined lead production in the 

United States was recovered from recycled scrap. The primary source was recycled lead-acid batteries. 

About 6% of recycled lead was obtained from other sources, namely new scrap, obtained from primary 

lead production, building construction materials, cable covering, and solder. About 99% of the 

1.10 million tons of lead recycled in 2002 was produced by 7 companies operating 15 secondary smelterrefineries in Alabama, California, Florida, Indiana, Louisiana, Minnesota, Missouri, New York, 

Pennsylvania, Tennessee, and Texas. An estimated 90–95% of the lead consumed in the United States is 

considered to be recyclable. In 1996, 77.1% of U.S. lead consumption was satisfied by recycled lead 

products (mostly lead-acid batteries). This compares to 69.5% in 1990 and 55.2% in 1980 (Larrabee 

1997, 1998; USGS 2002). 

Disposal of wastes containing lead or lead compounds is controlled by a number of federal regulations 

(see Chapter 8). Lead is listed as a toxic substance under Section 313 of the Emergency Planning and 

Community Right to Know Act (EPCRA) under Title III of the Superfund Amendments and 

Reauthorization Act (SARA) (EPA 2001e). Lead-containing waste products include storage batteries, 

ammunition waste, ordnance, sheet lead, solder, pipes, traps, and other metal products; solid waste and 

tailings from lead mining; items covered with lead-based paint; and solid wastes created by mineral ore 

processing, iron and steel production, copper and zinc smelting, and the production and use of various 

lead-containing products (EPA 1982a). 

Presently, 37 states have enacted legislation to encourage recycling of lead-acid batteries. These states 

have adopted laws that prohibit disposal of lead-acid batteries in municipal solid waste streams and 

require all levels of the collection chain to accept spent lead-acid batteries. Four other states ban only the 

land-filling and incineration of lead-acid batteries. Battery recycling rates are determined by comparing 

the amount of lead recycled from batteries with the quantity available for recycling in a given year. 

Recycling facilities can usually provide data on the amount of lead produced from scrapped batteries; 

however, the amount of lead available for recycling is largely influenced by the battery's useful life span. 

Therefore, to determine the amount of lead available from batteries for a given year requires historical 
LEAD 300 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

data on battery production and average lead content, as well as import and export data on new batteries, 

vehicles containing batteries, scrap lead and scrapped batteries (Larrabee 1998). According to the Battery 

Council International, 97% of all lead-acid batteries are recycled and new batteries contain between 

60 and 80% recycled lead and plastic (Battery Council International 2003). 
LEAD 301 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Lead has been identified in at least 1,272 of the 1,684 hazardous waste sites that have been proposed for 

inclusion on the EPA National Priorities List (NPL) (HazDat 2006). However, the number of sites 

evaluated for lead is not known. The frequency of these sites can be seen in Figure 6-1. Of these sites, 

1,258 are located within the United States, 2 are located in Guam, 10 are located in the Commonwealth of 

Puerto Rico, and 2 are located in the Virgin Islands (not shown). 

Lead is dispersed throughout the environment primarily as the result of anthropogenic activities. In the 

air, lead is in the form of particles and is removed by rain or gravitational settling. The solubility of lead 

compounds in water is a function of pH, hardness, salinity, and the presence of humic material. Solubility 

is highest in soft, acidic water. The sink for lead is the soil and sediment. Because it is strongly adsorbed 

to soil, it generally is retained in the upper layers of soil and does not leach appreciably into the subsoil 

and groundwater. Lead compounds may be transformed in the environment to other lead compounds; 

however, lead is an element and cannot be destroyed. Anthropogenic sources of lead include the mining 

and smelting of ore, manufacture of lead-containing products, combustion of coal and oil, and waste 

incineration. Many anthropogenic sources of lead, most notably leaded gasoline, lead-based paint, lead 

solder in food cans, lead-arsenate pesticides, and shot and sinkers, have been eliminated or strictly 

regulated due to lead’s persistence and toxicity. Because lead does not degrade, these former uses leave 

their legacy as higher concentrations of lead in the environment. 

Plants and animals may bioconcentrate lead, but lead is not biomagnified in the aquatic or terrestrial food 

chain. 

The general population may be exposed to lead in ambient air, foods, drinking water, soil, and dust. 

Segments of the general population at highest risk of health effects from lead exposure are preschool-age 

children and pregnant women and their fetuses. Within these groups, relationships have been established 

between lead exposure and adverse health effects. Other segments of the general population at high risk 

include individuals living near sites where lead was produced or disposed. 

Human exposure to lead above baseline levels is common. Baseline refers to the naturally-occurring level 

of lead in soil or dust that is not due to the influence of humans. Some of the more important lead 

LEAD 303 

6. POTENTIAL FOR HUMAN EXPOSURE 

exposures have occurred as a result of living in urban environments, particularly in areas near stationary 

emission sources (e.g., smelters); consumption of produce from family gardens; renovation of homes 

containing lead-based paint; pica (an abnormal eating habit in children); contact with interior lead paint 

dust; occupational exposure; secondary occupational exposure (e.g., families of workers using lead); 

smoking; and wine consumption. Higher than normal exposures may also occur to residents living in 

close proximity to NPL sites that contain elevated levels of lead. The highest and most prolonged lead 

exposures are found among workers in the lead smelting, refining, and manufacturing industries. 

The primary source of lead in the environment has historically been anthropogenic emissions to the 

atmosphere. In 1984, combustion of leaded gasoline was responsible for approximately 90% of all 

anthropogenic lead emissions. EPA gradually phased out the use of lead alkyls in gasoline, and by 1990, 

auto emissions accounted for only 33% of the annual lead emissions (EPA 1996b). Use of lead additives 

in motor fuels was totally banned after December 31, 1995 (EPA 1996a). The ban went into effect on 

February 2, 1996. Atmospheric deposition is the largest source of lead found in soils. Lead is transferred 

continuously between air, water, and soil by natural chemical and physical processes such as weathering, 

runoff, precipitation, dry deposition of dust, and stream/river flow; however, soil and sediments appear to 

be important sinks for lead. Lead particles are removed from the atmosphere primarily by wet and dry 

deposition. The average residence time in the atmosphere is 10 days. Over this time, long-distance 

transport, up to thousands of kilometers, may take place. Lead is extremely persistent in both water and 

soil. The speciation of lead in these media varies widely depending upon such factors as temperature, pH, 

and the presence of humic materials. Lead is largely associated with suspended solids and sediments in 

aquatic systems, and it occurs in relatively immobile forms in soil. 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005i). This is not an exhaustive list. Manufacturers, processors, 

and users of lead and lead compounds are required to report information to the TRI only if they employ 

10 or more full-time employees; if they operate in certain industrial sectors; and if their facility produces, 

imports, processes, or uses at least 100 pounds of lead, (exclusive of that contained in stainless steel, 

brass, or bronze alloys), or lead compounds in a calendar year. Prior to 2001, the threshold for reporting 

was much higher for persistent, bioaccumulative, toxic (PBT) chemicals such as lead. Facilities then had 

to report only when they manufactured, imported, or processed >25,000 pounds or used >10,000 pounds 

of lead or lead compounds in a calendar year. This higher threshold still applies to lead contained in 
LEAD 304 

6. POTENTIAL FOR HUMAN EXPOSURE 

stainless steel, brass, or bronze alloys. The threshold for lead is determined using the weight of the metal, 

whereas the threshold for lead compounds is determined by the weight of the entire compound. Prior to 

1998, only facilities classified within the SIC codes 20–39 (Manufacturing Industries) were required to 

report. After 1998, the industrial sector required to report was enlarged to include other industrial sectors, 

such as metal mining, coal mining, electrical utilities, and hazardous waste treatment (EPA 2001a). 

While lead is a naturally-occurring chemical, it is rarely found in its elemental form. It occurs in the 

Earth’s crust primarily as the mineral galena (PbS), and to a lesser extent as anglesite (PbSO4) and 

cerussite (PbCO3). Lead minerals are found in association with zinc, copper, and iron sulfides as well as 

gold, silver, bismuth, and antimony minerals. It also occurs as a trace element in coal, oil, and wood. 

Typical lead concentration in some ores and fuels are: copper ores, 11,000 ppm; lead and zinc ores, 

24,000 ppm; gold ores, 6.60 ppm; bituminous coal, 3–111 ppm; crude oil, 0.31 ppm; No. 6 fuel oil, 

1 ppm; and wood, 20 ppm (EPA 2001a). 

Lead released from natural sources, such as volcanoes, windblown dust, and erosion, are minor compared 

with anthropogenic sources. Industrial sources of lead can result from the mining and smelting of lead 

ores, as well as other ores in which lead is a by-product or contaminant. In these processes, lead may be 

released to land, water, and air. Electrical utilities emit lead in flue gas from the burning of fuels, such as 

coal, in which lead is a contaminant. Because of the large quantities of fuel burned by these facilities, 

large amounts of lead can be released. For example, using the EPA emission factor for lignite coal, 

4.2x10-4 pounds of lead/ton of coal, a boiler burning a million pounds of lignite coal will release 

420 pounds of lead into the atmosphere (EPA 2001a). Many of the anthropogenic sources of lead have 

been eliminated or phased out because of lead’s persistence, bioaccumulative nature, and toxicity. These 

include, most notably, lead in gasoline, lead-based paint, and lead-containing pesticides, and lead in 

ammunition and sinkers. Because lead does not degrade, these former uses leave their legacy as higher 

concentrations of lead in the environment. 

According to the TRI, in 2004, a total of 12,112,037 pounds of lead were released to the environment 

from 4,347 reporting facilities (TRI04 2006). Another 4,767,316 pounds were transferred off-site. 

Table 6-1 lists amounts of lead released from these facilities grouped by state. In addition, a total of 

405,285,570pounds of lead compounds were released to the environment from 4,294 reporting facilities 

and another 20,809,590 pounds were transferred off-site (TRI04 2006). Table 6-2 lists amounts of lead 
LEAD 305 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or 

Use Leada
 

Reported amounts released in pounds per yearb 

Total release 

On- and offStatec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek site 

AK 7 292 2 0 39,203 13 39,497 13 39,510 

AL 115 11,377 625 39 1,857,435 904 1,800,604 69,778 1,870,382 

AR 52 2,642 193 0 56,661 35,279 46,126 48,649 94,775 

AZ 77 652 6,112 0 56,020 43,185 55,184 50,786 105,969 

CA 290 2,208 1,669 359 35,634 47,985 31,094 56,761 87,855 

CO 49 424 59 143 115,238 22,117 94,378 43,604 137,981 

CT 69 286 36 0 138 11,454 311 11,603 11,914 

DC 2 0 0 0 403 0 0 403 403 

DE 3 3 1 0 0 0 4 0 4 

FL 156 4,640 371 0 152,932 10,593 152,988 15,548 168,536 

GA 123 3,786 150 0 78,219 37,659 76,673 43,140 119,813 

GU 1 120 0 0 0 0 120 0 120 

HI 10 784 1 1 125,691 1,681 126,477 1,682 128,159 

IA 76 3,999 446 140 5,939 50,150 8,280 52,395 60,674 

ID 20 580 29 0 4,397,661 831 4,398,246 855 4,399,101 

IL 220 20,391 1,713 401 156,127 14,987 22,120 171,499 193,619 

IN 191 6,973 1,411 176 784,642 825,635 19,525 1,599,312 1,618,837 

KS 45 5,123 64 99 42,320 5,206 26,399 26,413 52,812 

KY 85 13,914 377 1,250 84,887 101,249 91,819 109,859 201,678 

LA 59 1,386 1,913 279 2,400 795 4,914 1,858 6,772 

MA 103 722 34 0 3,200 12,226 2,188 13,994 16,182 

MD 38 587 34 0 11,669 2,731 10,399 4,622 15,021 

ME 18 516 159 0 1,386 15 1,363 714 2,077 

MI 182 8,600 526 0 101,768 11,209 14,625 107,478 122,103 

MN 97 629 519 0 3,058 800 630 4,376 5,006 

MO 90 2,581 262 157 142,943 1,733 125,168 22,508 147,676 

MS 57 1,986 393 27 44,196 449 43,659 3,392 47,050 

MT 7 366 11 0 332,755 669 332,252 1,549 333,801 

NC 141 2,197 563 0 223,107 8,242 212,004 22,104 234,108 

ND 10 406 474 0 8,313 200 4,470 4,922 9,392 

NE 54 6,788 70 0 5,155 5,535 7,692 9,855 17,547 

NH 34 364 121 0 2,171 3,449 644 5,461 6,105 

NJ 73 1,612 169 0 1,299 37,414 2,921 37,573 40,494 

NM 17 90 0 0 32,544 3,413 32,634 3,413 36,047 

NV 21 2,522 0 0 96,301 2,563 98,588 2,798 101,386 

NY 169 4,296 7,241 1 26,877 38,864 18,677 58,602 77,279 
LEAD 306 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or 

Use Leada
 

Reported amounts released in pounds per yearb 

Total release 

On- and offStatec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek site 

OH 311 21,200 6,974 28,852 2,396,501 831,963 2,294,828 990,663 3,285,490 

OK 59 6,250 25 162 84,903 712 55,964 36,088 92,052 

OR 54 389 17 0 198,334 1,019 198,327 1,432 199,759 

PA 229 18,426 2,534 0 44,891 336,150 49,233 352,768 402,001 

PR 22 41 0 0 0 420 41 420 461 

RI 25 58 46 0 0 2,176 70 2,209 2,280 

SC 78 6,116 492 19,107 34,974 18,570 11,829 67,430 79,259 

SD 17 105 26 0 11,103 1 11,208 28 11,236 

TN 107 8,958 832 198 24,456 33,552 15,650 52,346 67,996 

TX 232 19,573 2,036 133,133 339,613 39,359 453,503 80,211 533,714 

UT 37 539 74 0 154,967 26,984 145,376 37,189 182,565 

VA 91 6,437 1,152 0 385,614 26,809 32,753 387,259 420,012 

VI 2 114 0 0 426 23 516 47 563 

VT 6 14 18 0 0 2,658 14 2,676 2,691 

WA 76 861 1,545 0 864,384 12,312 855,186 23,917 879,102 

WI 178 10,688 1,015 0 79,703 32,974 11,181 113,200 124,380 

WV 42 1,538 46 0 50,653 6,245 46,684 11,798 58,482 

WY 10 66 0 0 27,052 0 27,003 115 27,118 

Total 4,337 215,216 42,581 184,525 13,725,870 2,711,160 12,112,037 4,767,316 16,879,353 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used. 

d

Number of reporting facilities.
 e

The sum of fugitive and point source releases are included in releases to air by a given facility. f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal 

and metal compounds). 

g

Class I wells, Class II-V wells, and underground injection. 

h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills. i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for 

disposal, unknown 

j

The sum of all releases of the chemical to air, land, water, and underground injection wells. k

Total amount of chemical transferred off-site, including to POTWs. 

RF = reporting facilities; UI = underground injection 

Source: TRI04 2006 (Data are from 2004) 
LEAD 307 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Releases to the Environment from Facilities that Produce, Process, or 

Use Lead Compoundsa
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek off-site 

AK 13 11,686 792 8,493,212 141,141,748 3 149,643,055 4,387 149,647,441 

AL 108 30,437 10,300 1,001 1,709,923 786,593 1,450,722 1,087,531 2,538,253 

AR 71 7,871 1,744 0 174,136 192,907 137,497 239,162 376,659 

AZ 60 14,142 214 0 5,510,961 9,540 5,499,714 35,144 5,534,857 

CA 276 9,530 1,462 123 4,989,235 124,884 3,760,943 1,364,291 5,125,234 

CO 53 6,310 820 0 6,775,795 2,753 6,577,849 207,830 6,785,679 

CT 72 1,842 50,808 0 55,894 46,837 2,552 152,828 155,380 

DE 13 2,930 1,161 0 72,923 16,714 31,159 62,568 93,728 

FA 110 23,635 2,624 0 505,968 21,557 444,097 109,687 553,784 

FL 133 19,762 2,502 0 439,521 15,659 337,497 139,948 477,445 

GU 3 4 1 0 4 0 10 0 10 

HI 13 3,902 22 11 1,304 206 3,935 1,510 5,444 

IA 62 19,705 1,919 3 250,083 104,373 54,916 321,167 376,084 

ID 31 4,652 682 0 2,432,819 3,756 2,421,469 20,439 2,441,908 

IL 223 27,715 6,780 1,139 2,252,474 166,469 1,752,530 702,047 2,454,577 

IN 183 54,164 7,662 1,202 3,736,474 1,318,189 1,273,823 3,843,869 5,117,691 

KS 54 11,010 309 0 104,267 83,899 100,975 98,510 199,485 

KY 82 22,586 1,937 40 908,615 41,149 865,666 108,660 974,327 

LA 76 16,143 26,110 0 1,104,894 3,061 948,072 202,136 1,150,209 

MA 135 4,088 243 0 304,852 38,052 9,549 337,686 347,234 

MD 38 4,202 1,873 9 261,495 56,339 235,657 88,260 323,918 

ME 29 1,346 1,373 0 12,061 9,811 11,991 12,601 24,592 

MI 136 23,248 9,161 80 711,353 94,813 296,369 542,284 838,653 

MN 74 9,093 948 0 254,293 132,931 89,773 307,491 397,264 

MO 111 181,782 10,114 0 28,889,783 3,098 27,669,492 1,415,285 29,084,777 

MP 3 1 0 0 1 0 2 0 2 

MS 59 14,205 1,624 254,800 112,794 3,928 330,719 56,634 387,352 

MT 20 6,339 393 3,098 15,029,303 851 15,030,211 9,772 15,039,984 

NC 154 19,778 2,287 13 452,288 365,461 422,797 417,030 839,828 

ND 10 7,745 14 66 130,165 80 86,306 51,764 138,070 

NE 28 4,918 135 0 52,093 32,663 52,489 37,321 89,810 

NH 31 490 71 0 55,741 911 743 56,469 57,213 

NJ 98 7,008 8,201 0 496,387 222,789 153,985 580,400 734,385 

NM 22 1,252 881 0 596,749 17,894 583,007 33,768 616,776 

NV 32 4,073 541 4 105,668,551 5,296 105,667,734 10,731 105,678,465 

NY 129 16,840 9,737 0 744,058 168,013 687,725 250,922 938,648 

OH 263 60,447 13,753 15,937 1,905,688 568,837 801,235 1,763,427 2,564,663 

OK 47 54,622 363 401 290,227 73,571 338,813 80,372 419,184 

OR 61 2,037 3,165 0 55,083 530 11,787 49,027 60,814 
LEAD 308 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Releases to the Environment from Facilities that Produce, Process, or 

Use Lead Compoundsa
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek off-site 

PA 246 69,995 6,769 987 3,479,169 1,229,509 1,714,804 3,071,625 4,786,428 

PR 18 2,948 18 0 394 2,936 3,028 3,268 6,296 

RI 24 38 67 1 3,701 805 44 4,568 4,612 

SC 84 16,757 2,239 0 354,464 28,224 255,034 146,649 401,683 

SD 17 1,936 762 0 1,446,132 386 1,446,330 2,884 1,449,215 

TN 108 16,735 4,380 0 8,765,194 35,448 8,635,566 186,192 8,821,758 

TX 236 45,373 5,779 1,089 2,492,627 54,544 2,015,842 583,571 2,599,413 

UT 36 14,630 277 0 59,676,521 298,324 59,596,136 393,616 59,989,752 

VA 98 14,524 4,397 558 381,233 35,396 267,225 168,883 436,108 

VI 2 389 0 0 0 0 389 0 389 

VT 10 25 50 0 2,712 7,136 41 9,882 9,923 

WA 87 6,775 6,896 0 2,788,908 792,545 2,759,956 835,168 3,595,124 

WI 136 11,702 2,165 0 389,469 56,300 110,108 349,527 459,636 

WV 59 4,743 1,970 54 810,502 9,651 597,011 229,908 826,919 

WY 17 5,336 20 0 112,415 309 97,189 20,891 118,080 

Total 4,294 923,449 218,510 8,773,829 408,893,442 7,285,930 405,285,570 20,809,590 426,095,160 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used. 

d

Number of reporting facilities.
 e

The sum of fugitive and point source releases are included in releases to air by a given facility. f

Surface water discharges, waste water treatment0(metals only), and publicly owned treatment works (POTWs) 

(metal and metal compounds).

g

Class I wells, Class II0V wells, and underground injection. 

h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on0site landfills, land treatment, surface 

impoundments, other land disposal, other landfills. i

Storage only, solidification/stabilization (metals only), other off0site management, transfers to waste broker for 

disposal, unknown 

j

The sum of all releases of the chemical to air, land, water, and underground injection wells. k

Total amount of chemical transferred off0site, including to POTWs. 

RF = reporting facilities; UI = underground injection 

Source: TRI04 2006 (Data are from 2004) 
LEAD 309 

6. POTENTIAL FOR HUMAN EXPOSURE 

compounds released from these facilities grouped by state. The TRI data should be used with caution 

because only certain types of facilities are required to report. This is not an exhaustive list. 

Lead has been identified in a variety of environmental media (air, surface water, groundwater, soil, and 

sediment) collected at 1,272 of the 1,684 current and former NPL hazardous waste sites (HazDat 2006). 

Lead is the most frequently found metal at hazardous waste sites (Reed et al. 1995). 

6.2.1 Air 

According to the TRI, in 2004, a total of 215,216 pounds of lead were released to air from 4,337 reporting 

facilities (TRI04 2006). Table 6-1 lists amounts of lead released from these facilities grouped by state. In 

addition, a total of 923,449 pounds of lead compounds were released to air from 4,294 reporting facilities 

(TRI04 2006). Table 6-2 lists amounts of lead compounds released from these facilities grouped by state. 

Releases of lead and lead compounds to air constitute, respectively, 1.78 and 4 0.23% of all on-site 

releases. The TRI data should be used with caution because only certain types of facilities are required to 

report. This is not an exhaustive list. 

Lead has been identified in air samples collected at 96 of the 1,272 NPL hazardous waste sites where it 

was detected in some environmental medium (HazDat 2006). 

The emissions of lead and lead compounds to the atmosphere reported to TRI has declined from 

2.8 million pounds in 1988 to about 1.1 million pounds in 2004 as new industries were added to TRI 

reporting requirements (TRI04 2006). In 2000, before the reporting thresholds were drastically reduced, 

air emissions were 1.5 million pounds. In the past, transportation, particularly automotive sources, were 

the major contributor to air emissions of lead. Today, industrial processes, especially metal processing, 

are the major sources of lead emissions to the atmosphere with the highest lead concentrations found 

around smelters and battery manufacturers (EPA 2003a). Based on emission estimates, EPA reports a 

93% reduction in lead emissions to the atmosphere between 1982 and 2002 and a 5% reduction between 

1993 and 2002. Air quality levels for lead, namely the maximum quarterly mean concentrations, declined 

93% between 1983 and 2002 and 57% between 1993 and 2002. EPA estimated that 78% of emissions in 

2001 were from industrial processes, 12% from transportation, and 10% from fuel combustion. It should 

be noted that aviation gasoline and racing fuels are not regulated for lead content and can use significant 

quantities of lead (EPA 2003a). Historical trends of lead emissions in the United States are provided in 

Table 6-3 (EPA 2007a). 
LEAD 310 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Historic Levels of Lead Emissions to the Atmosphere 

in the United States 

Pounds of lead emitted annually 

1970 1975 1980 1985 1990 1995 2000 2005 2006 

4.4x108 3.2x108

 1.5x108 4.6x107 1.0x107 8.0x106 4.0x106 6.0x106 4.0x106 

Source: EPA 2007a 
LEAD 311 

6. POTENTIAL FOR HUMAN EXPOSURE 

EPA (2000) estimated lead emission between 1990 and 1993 from all sources, not just those covered by 

TRI, which is limited to certain industries. During this period, lead emissions were estimated to average 

3,307 tons/year. The major contributors to these emissions were: metals processors (840 tons/year), 

chemical manufacturers (181 tons/year), other manufacturing operations (553 tons/year), waste disposal 

and recycling (270 tons/year), onroad (e.g., automobiles, trucks, buses, and motorcycles) mobile sources 

(418 tons/year), and nonroad (e.g., airplanes, boats, railway engines, lawnmowers, and off-road vehicles) 

mobile sources (778 tons/year). 

A study that estimated the historical rate of atmospheric metal fluxes into Central Park Lake, New York 

City by analyzing sediment cores for levels of trace metals, indicated that lead fluxes were extremely high 

throughout the 20th century, reaching maximum values (>70 μg cm-2 year-1) from the late 1930s to the 

early 1960. This occurred decades before the maximum emissions from the use of leaded gasoline 

(Chillrud et al. 1999). The trends closely resemble the history of solid waste incineration in the city. 

These results, and the widespread use of solid waste incineration during that time, suggest that this may 

have been the dominant source of lead in urban areas. The decline in the prevalence of small incinerators, 

increased recycling, and the decline in the use of lead in a variety of consumer and commercial products 

would indicate that atmospheric releases of lead from solid waste incineration is a much less important 

source of lead emissions today than it was in the past. 

As indicated in Table 6-4, by 1988, transportation (i.e., automotive) emissions were no longer the 

dominant source of lead emitted to the atmosphere. When such emissions were prevalent, >90% (mass 

basis) of automotive lead emissions from leaded gasoline were in the form of inorganic particulate matter 

(e.g., lead bromochloride [PbBrCl]) and <10% (mass basis) were in the form of organolead vapors (e.g., 

lead alkyls). In 1984 the average lead content of gasoline was 0.44 g lead/gallon (EPA 1986a); however, 

as of January 1986, the allowable lead content of leaded gasoline dropped to 0.1 g lead/gallon (EPA 

1985d). Between January and June of 1990, the actual average lead concentration in leaded gasoline was 

0.085 g lead/gallon, indicating consumption of approximately 230,000 kg of lead for the production of 

2.74 billion gallons of leaded gasoline. In the early 1980s EPA allowed up to 0.05 g of lead in a gallon of 

unleaded gasoline (EPA 1982b). 

In 1996, estimated mobile transportation source emissions of lead into air for the 48 contiguous states 

decreased from an average of 1,196 tons/year derived for 1990–1993 to 546.1 tons/year in 1996 (EPA 

2000, 2001b). The estimates are based on data obtained from the 1996 National Toxics Inventory. The 

onroad estimate of 18.9 tons/year for 1996 was a dramatic decrease from the average estimate of 
LEAD 312 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. National Lead Emission Estimates (in 103 Metric Tons/Year), 

1979–1989 

Source 

category 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 

Transportation 94.6 59.4 46.9 46.9 40.8 34.7 15.5 3.5 3.0 2.6 2.2 

Fuel 

combustion 4.9 3.9 2.8 1.7 0.6 0.5 0.5 0.5 0.5 0.5 0.5 

Industrial 

processes 5.2 3.6 3.0 2.7 2.4 2.3 2.3 1.9 1.9 2.0 2.3 

Solid waste 4.0 3.7 3.7 3.1 2.6 2.6 2.8 2.7 2.6 2.5 2.3 

Totala 108.7 70.6 56.4 54.4 46.4 40.1 21.1 8.6 8.0 7.6 7.2 

a

The sums of categories may not equal the total because of rounding. 

Source: derived from EPA 1991e 
LEAD 313 

6. POTENTIAL FOR HUMAN EXPOSURE 

418 tons/year given for 1990–1993 (EPA 2000, 2001b). Likewise, nonroad emissions decreased from an 

average of 778 tons/year in 1990–1993 to 527.2 tons/year in 1996. These decreases were the result of the 

complete phase-out of leaded gasoline in 1996. Projected estimates of lead emissions in 2007 for onroad 

and nonroad sources were 22.0 and 585.2 tons/year, respectively. The major onroad lead emissions in 

1996 were generated from light-duty gasoline vehicles (13.9 tons/year) and light-duty gasoline trucks 

(5.0 tons/year). The major generators of lead emissions in 1996 from nonroad sources were airports 

(526.1 tons/year). 

Emissions of lead from electric utility steam generating plants totaled 71.37 tons/year in 1994 (EPA 

1998b). The emissions varied depending on the fuel used in the electric generating facility; coal 

(62 tons/year), oil (8.9 tons/year), and natural gas (0.47 tons/year). It is projected that total lead emissions 

from electric steam generating plants will increase to 93.08 tons/year in 2010. This increase will be due 

to increased demand for electric power and an increased use of coal and natural gas as fuel sources to 

generate electricity. Lead emissions for coal, oil, and natural powered electric steam utilities are 

projected to be 87, 5.4, and 0.68 tons/year, respectively, in 2010. 

Releases from lead-based paints are frequently confined to the area in the immediate vicinity of painted 

surfaces, and deterioration or removal of the paint by sanding or sandblasting can result in high localized 

concentrations of lead dust in both indoor and outdoor air. 

The largest volume of organolead vapors released to the atmosphere results from industrial processes; 

prior to its phaseout and ban, leaded gasoline containing tetraethyl lead as an anti-knock additive was also 

a major contributor. Tetraalkyl lead vapors are photoreactive, and their presence in local atmospheres is 

transitory. Halogenated lead compounds are formed during combustion by reaction of the tetraalkyl lead 

compounds with halogenated lead scavenger compounds. These halogenated lead compounds ultimately 

give rise to lead oxides and carbonates in the environment (EPA 1985b). Tetraalkyl lead compounds 

once contributed 5–10% of the total particulate lead present in the atmosphere. Organolead vapors were 

most likely to occur in occupational settings (e.g., gasoline transport and handling operations, gas 

stations, and parking garages) and high-traffic areas (Nielsen 1984). 

6.2.2 Water 

According to the TRI, in 2004, a total of 42,581 pounds of lead were released to water from 

4,337 reporting facilities (TRI04 2006). Table 6-1 lists amounts of lead released from these facilities 
LEAD 314 

6. POTENTIAL FOR HUMAN EXPOSURE 

grouped by state. In addition, a total of 218,510 pounds of lead compounds were released to water from, 

4,294 reporting facilities (TRI04 2006). Table 6-2 lists amounts of lead compounds released from these 

facilities grouped by state. Releases of lead and lead compounds to water constitute, respectively, 

0.35 and 0.05 % of all on-site releases. The TRI data should be used with caution because only certain 

types of facilities are required to report. This is not an exhaustive list. 

Of the known aquatic releases of lead, the largest ones are from the steel and iron industries and lead 

production and processing operations (EPA 1982a). Urban runoff and atmospheric deposition are 

significant indirect sources of lead found in the aquatic environment. Lead reaching surface waters is 

sorbed to suspended solids and sediments (EPA 1982a). 

Lead is released into surface water from lead shot and lead sinkers. A study of a shooting range in 

Southwestern Virginia found that the dissolved lead content of surface water ranged up to 473 ppb with 

the highest concentrations closest to the backstop (Craig et al. 1999). Upstream from the site the lead 

concentration was 0.5 ppb. In 1991, the U.S. Fish and Wildlife Service banned the use of lead shot when 

hunting waterfowl, such as geese or ducks, in order to avoid releasing lead directly to surface water. 

Although aquatic releases of lead from industrial facilities are expected to be small with respect to 

emissions to land and air, lead may be present in significant levels in drinking water. In areas receiving 

acid rain (e.g., northeastern United States) the acidity of drinking water may increase; this increases the 

corrosivity of the water, which may, in turn, result in the leaching of lead from water systems, particularly 

from older systems during the first flush of water through the pipes (McDonald 1985). In addition, the 

grounding of household electrical systems to the plumbing can increase corrosion rates and the 

subsequent leaching of lead from the lead solder used for copper pipes. The age of a home or building 

and the type of plumbing installed will be a major factor regarding the levels of lead in drinking water 

(EPA 2005h). Lead-contaminated drinking water is most problematic in buildings and residences that are 

either very old or very new. It was not uncommon to use lead pipes for interior plumbing purposes at the 

start of the 20th century in the United States. Also, lead piping was often used for the service connections 

that join residences to public water supplies (this practice ended only recently in some localities). 

Plumbing installed before 1930 is most likely to contain lead pipes. In most new homes, copper pipes 

have replaced lead pipes and lead-free solder is used. However, lead-free means that solders and flux 

may not contain >0.2% lead, while pipes, pipe fittings, and well pumps may not contain >8% lead. New 

brass faucets and fittings can also leach lead, which is released directly into the water. Lead levels 
LEAD 315 

6. POTENTIAL FOR HUMAN EXPOSURE 

decrease as the residence ages because as time passes, mineral deposits form a coating on the inside of the 

pipes, which insulates the water from the lead. 

Lead has been identified in groundwater samples collected at 949 of the 1,272 NPL hazardous waste sites, 

and in surface water samples collected at 567 of the 1,272 NPL hazardous waste sites where it was 

detected in some environmental medium (HazDat 2006). 

6.2.3 Soil 

According to the TRI, in 2004, a total of 13,725,870 pounds of lead were released to the land, both on-site 

and off-site, by 4,337 reporting facilities (TRI04 2006). Table 6-1 lists amounts of lead released from 

these facilities grouped by state. In addition, a total of 408,893,442 pounds of lead compounds were 

released to land, both on-site and off-site, by 4,294 reporting facilities (TRI04 2006). Table 6-2 lists 

amounts of lead compounds released from these facilities grouped by state. In addition, 184,525 and 

8,773,829 pounds of lead and lead compounds, respectively, were injected underground. Ninety-seven 

percent of lead compounds injected underground were by one facility, Kennecott Greens Creek Mining 

Co. in Juneau, Alaska. The TRI data should be used with caution because only certain types of facilities 

are required to report. This is not an exhaustive list. 

While the majority of lead releases are to land, they constitute much lower exposure risks than releases to 

air and water. In 1997, before new industries were added to TRI, 95% of lead and lead compound 

releases to land reported to TRI were from the primary metals industrial sector, primarily metal smelters. 

In 2004, metal mining, coal mining, electrical utilities, and Resource Conservation and Recovery Act 

(RCRA)/solvent recoveries (hazardous waste facilities), as well as primary metals, are the industrial 

sectors contributing most heavily to releases to land. Many of these facilities with large releases, such as 

metal mines, are located in sparsely populated areas. Hazardous waste facilities are highly regulated. 

Most of the lead released to land becomes tightly bound and immobile. 

Lead-containing material from home and commercial use may be sent to municipal landfills. It is 

important to note that land is the ultimate repository for lead, and lead released to air and water ultimately 

is deposited in soil or sediment. For example, lead released to the air from leaded gasoline or in stack gas 

from smelters and power plants will settle on soil, sediment, foliage, or other surfaces. The heaviest 

contamination occurs near the highway, in the case of leaded gasoline, or near the facility, in the case of a 

power plant or smelter. 
LEAD 316 

6. POTENTIAL FOR HUMAN EXPOSURE 

Lead has been identified in soil samples collected at 901 of the 1,272 NPL hazardous waste sites, and in 

sediment samples collected at 605 of the 1,272 NPL hazardous waste sites where it was detected in some 

environmental medium (HazDat 2006). 

6.2.4 Paint 

Although the sale of residential lead-based paint was banned in the United States in 1978, flaking paint, 

paint chips, and weathered powdered paint, which are most commonly associated with deteriorated 

housing stock in urban areas, remain major sources of lead exposure for young children residing in these 

houses, particularly for children afflicted with pica (the compulsive, habitual consumption of nonfood 

items) (Bornschein et al. 1986; EPA 1986a). Lead concentrations of 1–5 mg/cm2 have been found in 

chips of lead-based paint (Billick and Gray 1978), suggesting that consumption of a single chip of paint 

would provide greater short-term exposure than any other source of lead (EPA 1986a). An estimated 40– 

50% of occupied housing in the United States may contain lead-based paint on exposed surfaces (Chisolm 

1986). 

In the late 1980s, the U.S. Department of Housing and Urban Development (HUD) conducted a national 

survey of lead-based paint in housing. The EPA subsequently sponsored a comprehensive technical 

report on the HUD-sponsored survey to provide estimates of the extent of lead-based paint in housing. In 

the EPA report, a home is considered to have lead-based paint if the measured lead concentration on any 

painted surface is ≥1.0 mg/cm2

. The EPA report estimates that 64 million (±7 million) homes, or 83% 

(±9%) of privately-owned housing units built before 1980, have lead-based paint somewhere in the 

building. Approximately 12 million (±5 million) of these homes are occupied by families with children 

under the age of 7 years. Approximately 49 million (±7 million) privately owned homes have lead-based 

paint in their interiors. By contrast, approximately 86% (±8%) of all pre-1980 public housing family 

units have lead-based paint somewhere in the building (EPA 1995c). 

Damaged lead-based paint is associated with excessive dust lead levels. Approximately 14 million homes 

(19% of pre-1980 housing) have >5 square feet of damaged lead-based paint, and nearly half (47%) of 

those homes have excessive dust lead levels (EPA 1995c). 

In the Cincinnati prospective lead study of public and private low- and moderate-income housing, the lead 

concentration ranges were: painted interior walls, 0.1–35 mg/cm2

; interior home surface dust, 0.04– 
LEAD 317 

6. POTENTIAL FOR HUMAN EXPOSURE 

39 mg/m2 and 72–16,200 μg/g; interior home dustfall, 0.0040–60 mg/m2/30 days; exterior dust scrapings, 

20–108,000 μg/g; and dust on children's hands, 1–191 μg. The lead levels in older private deteriorating or 

dilapidated housing were higher than the levels in newer public and rehabilitated housing (Clark et al. 

1985). 

Releases from lead-based paints are frequently confined to the area in the immediate vicinity of painted 

surfaces, and deterioration or removal of the paint can result in high localized concentrations of lead in 

dust in air (from sanding and sandblasting) and on exposed surfaces. A study was conducted in New 

Orleans where power sanding is a common practice during repainting old houses and median, 

90th percentile, and maximum lead concentrations in 31 study houses were 35, 126, and 257 mg/g, 

respectively (Mielke et al. 2001). Lead concentrations in dust and soil samples from one study of a house 

where the paint chips contained about 90 mg Pb/g were very high. If the house had been sanded down to 

bare wood, 7.4 kg of lead would have been released to the environment. Disturbance of older structures 

containing lead-based paints is now a significant contributor to total lead releases. 

The authors of a report of findings from the Third National Health and Nutrition Examination Survey 

(NHANES III), conducted in 1988–1991, comment that of the multiple sources of exposure, lead-based 

paint is the principal high-dose source of lead. Exposure occurs not only through the direct ingestion of 

flaking and chalking paint, but also through the inhalation of dust and soil contaminated with paint 

(Brody et al. 1994). According to a study by the New York State Department of Health, renovation and 

remodeling activities that disturb lead-based paints in homes can produce significant amounts of lead 

dust, which can be inhaled or ingested (CDC 1997d). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

In the atmosphere, non-organic compounds of lead exist primarily in the particulate form. The median 

particle distribution for lead emissions from smelters is 1.5 μm with 86% of the particle sizes under 

10 μm (Corrin and Natusch 1977). The smallest lead-containing particulate matter (<1 μm) is associated 

with high-temperature combustion processes. Upon release to the atmosphere, lead particles are 

dispersed and ultimately removed from the atmosphere by wet or dry deposition. Approximately 40–70% 

of the deposition of lead is by wet fallout; 20–60% of particulate lead once emitted from automobiles is 

deposited near the source. An important factor in determining the atmospheric transport of lead is particle 

size distribution. Large particles, particularly those with aerodynamic diameters of >2 μm, settle out of 
LEAD 318 

6. POTENTIAL FOR HUMAN EXPOSURE 

the atmosphere fairly rapidly and are deposited relatively close to emission sources (e.g., 25 m from the 

roadway for those size particles emitted in motor vehicle exhaust in the past); smaller particles may be 

transported thousands of kilometers. The dry deposition velocity for lead particles with aerodynamic 

diameters of 0.06–2.0 μm was estimated to range between 0.2 and 0.5 cm/second in a coniferous forest in 

Sweden, with an overall particle-size weighted dry deposition velocity of 0.41 cm/second (Lannefors et 

al. 1983). However, the use of an average net deposition velocity of 0.6 cm/second and an average 

atmospheric residence time of 10 days has been recommended by the National Academy of Sciences 

(NAS 1980). The amount of lead scavenged from the atmosphere by wet deposition varies widely; wet 

deposition can account for 40–70% of lead deposition depending on such factors as geographic location 

and amount of emissions in the area (Nielsen 1984). An annual scavenging ratio (concentration in 

precipitation, mg/L, to concentration in air, μg/m3

) of 0.18x10-6 has been calculated for lead, making it the 

lowest value among seven trace metals studied (iron, aluminum, manganese, copper, zinc, cadmium); this 

indicates that lead (which initially exists as fine particles in the atmosphere) is removed from the 

atmosphere by wet deposition relatively inefficiently. Wet deposition is more important than dry 

deposition for removing lead from the atmosphere; the ratio of wet to dry deposition was calculated to be 

1.63, 1.99, and 2.50 for sites in southern, central, and northern Ontario, Canada, respectively (Chan et al. 

1986). While lead particles from automobile emissions are quite small (<0.1 μm in diameter), they may 

coagulate, resulting in larger particulates (Chamberlain et al. 1979). Lead has been found in sediment 

cores of lakes in Ontario and Quebec, Canada far from any point sources of lead releases, suggesting that 

long-range atmospheric transport was occurring (Evans and Rigler 1985). However, the results reported 

by Allen-Gil et al. (1997) do not support the contention of long-range transport of lead from smelters in 

the Arctic, based on lead concentrations in sediments obtained from Arctic lakes in the United States. In 

fact, data summarized by Berndtsson (1993) indicate that local sources dominate the deposition of lead; 

lead is primarily deposited <10 kilometers from emission sources. 

The amount of soluble lead in surface waters depends upon the pH of the water and the dissolved salt 

content. Equilibrium calculations show that at pH >5.4, the total solubility of lead is approximately 

30 μg/L in hard water and approximately 500 μg/L in soft water. Sulfate ions, if present in soft water, 

limit the lead concentration in solution through the formation of lead sulfate. Above pH 5.4, the lead 

carbonates, PbCO3 and Pb2(OH)2CO3, limit the amount of soluble lead. The carbonate concentration is in 

turn dependent upon the partial pressure of carbon dioxide, pH, and temperature (EPA 1986a). 

A significant fraction of lead carried by river water is expected to be in an undissolved form, which can 

consist of colloidal particles or larger undissolved particles of lead carbonate, lead oxide, lead hydroxide, 
LEAD 319 

6. POTENTIAL FOR HUMAN EXPOSURE 

or other lead compounds incorporated in other components of surface particulate matters from runoff. 

Lead may occur either as sorbed ions or surface coatings on sediment mineral particles, or it may be 

carried as a part of suspended living or nonliving organic matter in water. The ratio of lead in suspended 

solids to lead in dissolved form has been found to vary from 4:1 in rural streams to 27:1 in urban streams 

(NSF 1977). 

The fate of lead in soil is affected by the adsorption at mineral interfaces, the precipitation of sparingly 

soluble solid forms of the compound, and the formation of relatively stable organic-metal complexes or 

chelates with soil organic matter. These processes are dependent on such factors as soil pH, soil type, 

particle size, organic matter content of soil, the presence of inorganic colloids and iron oxides, cation 

exchange capacity (CEC), and the amount of lead in soil (NSF 1977; Reddy et al. 1995). Soil samples 

were extracted from the Powder River Basin in Wyoming to determine the relative distribution and 

speciation of lead and other metals in acidic environments (Reddy et al. 1995). At near neutral pH, 

organic carbon-lead complexes were the predominant species in the soil water extracts. At low pH, 

dissolved lead in ionic form (Pb2+) and ion pairs (e.g., PbSO4) were the predominant species. It was 

concluded that the mobility of lead will increase in environments having low pH due to the enhanced 

solubility of lead under acidic conditions. The accumulation of lead in most soils is primarily a function 

of the rate of deposition from the atmosphere. Most lead is retained strongly in soil, and very little is 

transported through runoff to surface water or leaching to groundwater except under acidic conditions 

(EPA 1986a; NSF 1977). Clays, silts, iron and manganese oxides, and soil organic matter can bind 

metals electrostatically (cation exchange) as well as chemically (specific adsorption) (Reed et al. 1995). 

Lead is strongly sorbed to organic matter in soil, and although not subject to leaching, it may enter surface 

waters as a result of erosion of lead-containing soil particulates. Lead bromochloride, the primary form of 

lead emitted from motor vehicles, which once burned leaded gasoline in the presence of organohalogen 

scavenger compounds, are converted to the less soluble lead sulfate either by reactions in the atmosphere 

or by reactions at the soil surface, thus limiting it’s mobility in soil. It has been determined that lead 

oxides, carbonates, oxycarbonates, sulfates, and oxysulfates become the most prominent constituents of 

aged automobile exhaust particles (i.e., those collected at locations more remote from traffic sources) (Ter 

Haar and Bayard 1971). Lead may also be immobilized by ion exchange with hydrous oxides or clays or 

by chelation with humic or fulvic acids in the soil (Olson and Skogerboe 1975). In soils with pH ≥5 and 

with at least 5% organic matter content, atmospheric lead is retained in the upper 2–5 cm of undisturbed 

soil. Inorganic lead may be bound into crystalline matrices of rocks and remain essentially immobile; it 

can also occur in water entrapped in soil macro- and micropores (Reed et al. 1995). Lead complexes and 

precipitates in soil. In soil with high organic matter content and a pH of 6–8, lead may form insoluble 
LEAD 320 

6. POTENTIAL FOR HUMAN EXPOSURE 

organic lead complexes; if the soil has less organic matter at the same pH, hydrous lead oxide complexes 

may form or lead may precipitate out with carbonate or phosphate ions. At a pH of 4–6, the organic lead 

complexes become soluble and leach out or may be taken up by plants (EPA 1986a). Entrainment or 

suspension of soil particles in moving air is another route of lead transport (EPA 1982c). This process 

may be important in contributing to the atmospheric burden of lead around some lead smelting facilities 

and NPL sites that contain elevated levels of lead in soil. 

The downward movement of elemental lead and inorganic lead compounds from soil to groundwater by 

leaching is very slow under most natural conditions except for highly acidic situations (NSF 1977). The 

conditions that induce leaching are the presence of lead in soil at concentrations that either approach or 

exceed the CEC of the soil, the presence of materials in soil that are capable of forming soluble chelates 

with lead, and a decrease in the pH of the leaching solution (e.g., acid rain) (NSF 1977). Favorable 

conditions for leaching may be present in some soils near lead smelting and NPL sites. Tetraalkyl lead 

compounds, such as tetraethyl lead, are insoluble in water and would not be expected to leach in soil. 

However, they can be transported through a soil column when it is present in a migrating plume of 

gasoline (USAF 1995). In aqueous media, tetraalkyl lead compounds are first degraded to their 

respective ionic trialkyl lead species and are eventually mineralized to inorganic lead (Pb2+) by biological 

and chemical degradation processes (Ou et al. 1995). 

Plants and animals may bioconcentrate lead, but biomagnification is not expected. In general, the highest 

lead concentrations are found in aquatic and terrestrial organisms with habitats near lead mining, 

smelting, and refining facilities; storage battery recycling plants; areas affected by high automobile and 

truck traffic; sewage sludge and spoil disposal areas; sites where dredging has occurred; areas of heavy 

hunting and fishing (lead from spent shot or sinkers); and in urban and industrialized areas. Lead may be 

present on plant surfaces as a result of atmospheric deposition; its presence in internal plant tissues 

indicates biological uptake from the soil and leaf surfaces. Although the bioavailability of lead in soil to 

plants is limited because of the strong adsorption of lead to soil organic matter, the bioavailability 

increases as the pH and the organic matter content of the soil are reduced. Plants grown in leadcontaminated soils were shown to accumulate low levels of lead in the edible portions of the plant from 

adherence of dusts and translocation into the tissues (Finster et al. 2004). Thirty-two different types of 

fruits or vegetables were grown in urban gardens with soils containing high lead levels (27–4,580 mg/kg). 

Samples were harvested and washed with either water or detergents and analyzed for lead content. Only 

one fruiting vegetable among 52 samples contained lead levels greater than the detection limit of 10 μg/g 
LEAD 321 

6. POTENTIAL FOR HUMAN EXPOSURE 

in the edible portion. However, 39% of the leafy vegetables and herbs had lead levels >10 μg/g in the 

edible shoot portion following washing of the vegetables with detergent and water (Finster et al. 2004). 

Lead may be taken up in edible plants from the soil via the root system, by direct foliar uptake and 

translocation within the plant, and by surface deposition of particulate matter. The amount of lead in soil 

that is bioavailable to a vegetable plant depends on factors such as cation exchange capacity, pH, amount 

of organic matter present, soil moisture content, and type of amendments added to the soil. Background 

agricultural soil lead concentrations for major growing areas of the United States have been determined 

(Holmgren et al. 1993). 

The influence of various combinations of soil amendments on lead uptake by soybeans was studied for a 

metal-contaminated alluvial soil (Pierzynski and Schwab 1993). Addition of limestone was found to be 

most effective in reducing the bioavailability of metals (including lead) as indicated by the reduction in 

labile soil metals, increased yields, and decreased soybean tissue metal content. Uptake of metals by 

lettuce and radishes grown in a loam soil spiked with cadmium chloride and lead nitrate (from 100 to 

1,000 mg/kg) was also studied (Nwosu et al. 1995). Results indicated that the mean uptake of lead by 

lettuce increased as the concentration of lead rose in the soil mixture. However, the uptake was low and 

this finding is inconsistent with other reports. Lead was not bioaccumulated by either plant regardless of 

soil lead concentrations. The response of kidney bean growth to the concentration and chemical form of 

lead in soils obtained near a zinc smelter in Japan has been studied (Xian 1989). It was found that the 

amount of lead in the total plant (approximately 35–80 μg) correlated strongly with the concentration of 

lead in the soil (0–240 mg/kg). The best relationship was found between the amount of metal uptake and 

the concentration of exchangeable and carbonate forms of lead in the soil. 

Uptake of lead in animals may occur as a result of inhalation of contaminated ambient air or ingestion of 

contaminated plants. However, lead is not biomagnified in aquatic or terrestrial food chains. Older 

organisms tend to contain the greatest body burdens of lead. In aquatic organisms, lead concentrations 

are usually highest in benthic organisms and algae, and lowest in upper trophic level predators (e.g., 

carnivorous fish). Exposure of a fresh-water fish to several sublethal concentrations of lead for a period 

of 30 days showed significant accumulation of lead in the blood and tissues. The lead accumulation in 

tissues was found to increase with lead in water up to a concentration of 5 mg/L (μg/mL); at concentrations of 10 and 20 mg/L, the lead accumulation in the tissues, although indicating an increase, was not 

proportional to the lead concentration in water (Tulasi et al. 1992). High bioconcentration factors (BCFs) 

were determined in studies using oysters (6,600 for Crassostrea virginica), fresh-water algae (92,000 for 
LEAD 322 

6. POTENTIAL FOR HUMAN EXPOSURE 

Senenastrum capricornutum), and rainbow trout (726 for Salmo gairdneri). However, most median BCF 

values for aquatic biota are significantly lower: 42 for fish, 536 for oysters, 500 for insects, 725 for algae, 

and 2,570 for mussels (Eisler 1988). Lead is toxic to all aquatic biota, and organisms higher up in the 

food chain may experience lead poisoning as a result of eating lead-contaminated food. Organolead 

compounds, such as trialkyl and tetraalkyl lead compounds, are more toxic than inorganic forms and have 

been shown to bioconcentrate in aquatic organisms. 

Biomagnification of organolead compounds has not been found to occur. Depuration is relatively rapid, 

with half-life values of 30–45 hours for rainbow trout exposed to tetramethyl lead. Tetraalkyl lead 

compounds are more toxic than trialkyl lead compounds, and ethyl forms are more toxic than methyl 

forms (Eisler 1988). Isolation of a Pseudomonas aeruginosa strain designated CHL004, which is able to 

remove lead from solidified media and soil, has been reported (Vesper et al. 1996). The rate of uptake of 

lead nitrate by CHL004 was very rapid initially and then decreased greatly. 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Information available regarding the chemistry of lead in air is limited. Before the ban on sales of leaded 

gasoline, lead particles were emitted to the atmosphere from automobile exhaust as lead halides (mostly 

PbBrCl) and as double salts with ammonium halides (e.g., 2PbBrCl·NH4Cl, Pb3[PO4]2, and PbSO4) 

(Biggins and Harrison 1979; Ter Haar and Bayard 1971). After 18 hours, approximately 75% of the 

bromine and 30–40% of the chlorine was released, and lead carbonates, oxycarbonates and oxides were 

produced. These lead oxides are subject to further weathering to form additional carbonates and sulfates 

(Olson and Skogerboe 1975). Lead particles are emitted from mines and smelters primarily in the form of 

elemental lead and lead-sulfur compounds, PbSO4, PbO·PbSO4, and PbS (Corrin and Natusch 1977; EPA 

1986a; Spear et al. 1998). The lead emitted from the combustion of waste oil was found to be in the form 

of PbCl2, PbO, and elemental lead (Pb0

) (Nerin et al. 1999). In the atmosphere, lead exists primarily in 

the form of PbSO4 and PbCO3. It is not completely clear how the chemical composition of lead changes 

during dispersion (EPA 1986a). 

Tetraalkyl lead compounds, once added to gasoline, are no longer present in significant quantities in the 

air. However, their degradation products are still present. Based on the vapor pressure of tetraethyl lead 

(0.26 mm Hg at 25 °C) and tetramethyl lead (26.0 mm Hg at 20 °C), these two compounds exist almost 

entirely in the vapor phase in the atmosphere (Eisenreich et al. 1981). When exposed to sunlight, they 
LEAD 323 

6. POTENTIAL FOR HUMAN EXPOSURE 

decompose rapidly to trialkyl and dialkyl lead compounds, and eventually to inorganic lead oxides by a 

combination of direct photolysis, reaction with hydroxyl radicals, and reaction with ozone. The half-life 

of tetraethyl lead in reactions with hydroxyl radicals during summer is approximately 5.7 hours, based on 

a rate constant of 6.8x10-11 cm3

/molecule - sec (Nielsen et al. 1991). The half-life for tetramethyl lead is 

about 65 hours based on a rate constant of 5.9x10-12 cm3

/molecule - sec. In the winter, both compounds 

have half-lives of up to several days since the concentration of atmospheric hydroxyl radicals is lower 

than in summer months (DeJonghe and Adams 1986). Trialkyl compounds occur almost entirely in the 

vapor phase and have life-times in air that are 3 times longer than for the corresponding tetraalkyl 

compounds (Hewitt and Harrison 1986, 1987). Dialkyl compounds occur almost entirely in particulate 

form. Because of the relatively high water solubility of trialkyl and dialkyl lead compounds, washout in 

wet deposition would be the major process for removing these compounds from air. Dialkyl lead 

compounds would be removed from the air by dry deposition. Adsorption of tetraethyl and tetramethyl 

lead to atmospheric particles does not appear to be an important fate process (DeJonghe and Adams 1986; 

EPA 1985a). Monitoring studies in England indicate that urban air advected to rural areas may contain up 

to 5% of total lead as alkyl lead; this percentage may increase to 20% for maritime air, with trialkyl lead 

being the predominant species (Hewitt and Harrison 1987). 

6.3.2.2 Water 

The chemistry of lead in aqueous solution is highly complex because this element can be found in 

multiple forms. Lead has a tendency to form compounds of low solubility with the major anions found in 

natural waters. The amount of lead dissolved in surface waters is dependent on the pH and the dissolved 

salt content of the water. The maximum solubility of lead in hard water is about 30 μg/L at pH>5.4 and 

the maximum solubility of lead in soft water is approximately 500 μg/L at pH>5.4 (EPA 1977). In the 

environment, the divalent form (Pb2+) is the stable ionic species of lead. Hydroxide, carbonate, sulfide, 

and, more rarely, sulfate may act as solubility controls in precipitating lead from water. At pH<5.4, the 

formation of lead sulfate limits the concentration of soluble lead in water, while at pH>5.4, the formation 

of lead carbonates limits the amount of soluble lead (EPA 1979). The relatively volatile organolead 

compound, tetramethyl lead, may form as a result of biological alkylation of organic and inorganic lead 

compounds by microorganisms in anaerobic lake sediments; however, if the water over the sediments is 

aerobic, volatilization of tetramethyl lead from the sediments is not considered to be important because 

the tetramethyl lead will be oxidized (EPA 1979). 
LEAD 324 

6. POTENTIAL FOR HUMAN EXPOSURE 

The speciation of lead was found to differ in fresh water and seawater. In fresh water, lead may partially 

exist as the divalent cation (Pb2+) at pHs below 7.5, but complexes with dissolved carbonate to form 

insoluble PbCO3 under alkaline conditions (Long and Angino 1977). Even small amounts of carbonate 

ions formed in the dissolution of atmospheric CO2 are sufficient to keep lead concentrations in rivers at 

the 500 μg/L solubility limit (EPA 1979). Lead chloride and lead carbonate are the primary complexes 

formed in seawater (Long and Angino 1977). The speciation of lead in water is also dependent on the 

presence of other ligands in water. Lead is known to form strong complexes with humic acid and other 

organic matter (Denaix et al. 2001; Gao et al. 1999; Guibaud et al. 2003). Lead-organic matter complexes 

are stable to a pH of 3 with the affinity increasing with increasing pH, but decreasing with increased 

water hardness (EPA 1979). In seawater, there is the presence of lead complexed to Fe-Mn oxides, which 

is due to the content of these oxides in seawater (Elbaz-Poulichet et al. 1984). Sorption of lead to polar 

particulate matter in freshwater and estuarine environments is an important process for the removal of 

lead from these surface waters. The adsorption of lead to organic matter, clay and mineral surfaces, and 

coprecipitation and/or sorption by hydrous iron and manganese oxides increases with increasing pH (EPA 

1979). 

In water, tetraalkyl lead compounds, such as tetraethyl lead and tetramethyl lead, are subject to photolysis 

and volatilization. Degradation proceeds from trialkyl species to dialkyl species, and eventually to 

inorganic lead oxides. Removal of tetraalkyl lead compounds from seawater occurs at rates that provide 

half-lives measurable in days (DeJonghe and Adams 1986). Some of the degradation products include 

trialkyl lead carbonates, hydroxides, and halides. These products are more persistent than the original 

tetraalkyl lead compounds. 

6.3.2.3 Sediment and Soil 

Lead in its naturally-occurring mineral forms is a very minor component of many soils in the United 

States. Additional sources of lead are incorporated to soils from atmospheric wet and dry deposition. 

Since the ban on leaded gasoline, the major source of lead emissions to the environment arise from 

industrial processes (EPA 1996b). Smelters in Pennsylvania, Missouri, and Nebraska are among the top 

10 emitters. Lead particles emitted from mining operations and smelters are primarily in the form of leadsulfur compounds PbSO4, PbO·PbSO4, and PbS (EPA 1986a). In the atmosphere, lead most likely exists 

primarily as PbSO4 and PbCO3 and is deposited onto soil as lead sulfates and lead carbonates. Organic 

tetraalkyl lead compounds, once used extensively in motor fuel, are emitted from automobiles primarily 

in the form of lead bromochloride, which is ultimately transformed to lead sulfate. The organolead 
LEAD 325 

6. POTENTIAL FOR HUMAN EXPOSURE 

compounds also undergo photolysis and other reactions in the atmosphere to form lead carbonates, 

oxycarbonates, and oxides. Once these compounds encounter components of the soil, further reactions 

can occur, resulting in a complex variety of lead compounds. The speciation of lead in soils is dependent 

upon the properties of the soil. In a calcareous soil, PbSO4 and PbCO3 were shown to account for 

<5% of the total lead content, whereas in road side dust, PbSO4, elemental lead, Pb3O4, PbO·PbSO4, and 

2PbCO3·Pb(OH)2 were present in significant quantities (Chaney et al. 1988). It was also reported that 

after adding 3,000–4,000 mg/kg of lead in the form of PbSO4, subsequent extractions revealed that the 

lead sulfate was rapidly transformed to other lead compounds in the soil (Chaney et al. 1988). 

Nearly all forms of lead that are released to soil from anthropogenic sources, such as PbSO4, PbCO3, PbS, 

Pb(OH)2, PbCrO4, and PbClBr, are transformed by chemical and biotic processes to adsorbed forms in 

soil (Chaney et al. 1988). The transformation process involves the formation of lead complexes with 

binding sites on clay minerals, humic acid and other organic matter, and hydrous iron oxides (Chaney et 

al. 1988; Chuan et al. 1996; Sauve et al. 1997). The ability of soils to bind lead is dependent on soil pH 

and the cation exchange capacity of the soil components (e.g., hydrous iron oxides on clay and organic 

matter) (Chaney et al. 1988; EPA 1986a). Only a small fraction (0.1–1%) of lead appears to remain 

water-soluble in soil (Khan and Frankland 1983). The solubility of lead in soil is dependent on pH, being 

sparingly soluble at pH 8 and becoming more soluble as the pH approaches 5 (Chuan et al. 1996). 

Between pH 5 and 3.3, large increases in lead solubility in soil are observed. These changes in lead 

solubility appear to correlate with the pH-dependent adsorption and dissolution of Fe-Mn oxyhydroxides. 

In addition to pH, other factors that influence lead solubility in soil are total lead content and the 

concentrations of phosphate and carbonate in soils (Bradley and Cox 1988; Ge et al. 2000; Pardo et al. 

1990; Sauve et al. 1997). 

Since the ban on the use of leaded gasoline, atmospheric lead deposition to soil has decreased 

considerably. However, the deposited organolead compounds and their transformation products remain in 

the soil. Limited data indicate that tetraethyl and tetramethyl lead are converted into water-soluble lead 

compounds in soil through microbial metabolism (Ou et al. 1994). Using an Arredondo fine sand from 

Florida (92% sand, 7% silt, 1% clay, 11.8 g/kg organic carbon, pH 5.5), tetraethyl lead was shown to 

degrade sequentially to monoionic triethyl lead, diionic diethyl lead, and eventually Pb+2 (Ou et al. 1994). 

Experiments were conducted using non sterilized and autoclaved soil samples. The presence of 

monoionic triethyl lead and diionic diethyl lead was generally lower in the autoclaved samples, 

suggesting that both abiotic and biotic mechanisms are responsible for the degradation of tetraethyl lead. 

At the end of a 28-day incubation period, no tetraethyl lead was present in the soil; however, there were 
LEAD 326 

6. POTENTIAL FOR HUMAN EXPOSURE 

significant quantities of monoionic triethyl lead and diionic diethyl lead, which suggest that the 

degradation products are more persistent than the original species. Although tetraethyl and tetramethyl 

lead are not expected to leach significantly through soil, their more water-soluble metabolites may be 

subject to leaching (EPA 1985a). 

In a study of lead migration in forest soils in Vermont, Miller and Friedland (1994) used lead deposition 

time series and measurements of organic soil horizon lead content made in 1966, 1980, and 1990 to 

compute dynamic response times for lead storage in several types of soil. The authors concluded that 

maximum lead concentrations in organic soil occurred around 1980, with concentrations of about 85 μg/g 

in soils of the northern hardwood forests of the study area and about 200 μg/g in soils of the spruce-fir 

forests. The large surge of atmospheric lead deposited in these forests during the time when leaded 

gasoline was routinely used in motor vehicles is being redistributed in the soil profile rather than being 

retained in the organic horizon. Based on an analysis of lead transit times through mineral soil horizons, 

the pulse of lead may begin to be released to upland streams sometime in the middle of the next century 

(Miller and Friedland 1994). However, Wang et al. (1995) observed that lead migration in forest soils is 

slowed considerably due to a decrease in solubility when lead moves from the soil surface horizon to 

streams. Their results suggest that lead is effectively trapped in the subsurface soil horizons, which may 

greatly reduce its release to streams. 

Lead content in plants is largely the result of atmospheric deposition. This is due to the strong retention 

of particulate matter on plant surfaces that is difficult to remove through washing (EPA 1977). Some 

plants are capable of taking up lead from soil through their root systems, although this uptake does not 

appear to be appreciable (IARC 1980; Nwosu et al. 1995). The distribution of lead in plants is mainly in 

the roots and much less in the stems or leaves (Deng et al. 2004; Nan and Cheng 2001). Eventually, the 

lead will be returned to soil when these plants decay unless they are harvested (to possibly enter the food 

chain) or removed (EPA 1986a). 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to lead depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. Concentrations of lead 

in unpolluted atmospheres and in pristine surface waters are often so low as to be near the limits of 

current analytical methods. In reviewing data on lead levels monitored or estimated in the environment, it 

should also be noted that the amount of chemical identified analytically is not necessarily equivalent to 
LEAD 327 

6. POTENTIAL FOR HUMAN EXPOSURE 

the amount that is bioavailable. The analytical methods available for monitoring lead in a variety of 

environmental media are detailed in Chapter 7. 

6.4.1 Air 

Lead levels in the ambient air have been monitored in a number of remote, urban, and nonurban areas of 

the United States and other countries (EPA 1986a). Atmospheric lead concentrations vary widely, but 

usually decrease with vertical and horizontal distance from emission sources; they are generally 0.3– 

0.8 times lower indoors than outdoors, with an average ratio of 0.5. Lead levels in ambient air range from 

7.6x10-5 μg/m3

 in remote areas such as Antarctica (Maenhaut et al. 1979) to >10 μg/m3 near stationary 

sources such as smelters. Due to decreases in lead emissions to the atmosphere from automobiles, the 

level of lead in air has declined significantly over the past 3 decades. Monitoring data from a composite 

of 147 sampling sites throughout the United States indicated that the maximum quarterly average lead 

levels in urban air were 0.36 μg/m3

 during 1984 and 0.2–0.4 μg/m3 during 1986 (EPA 1986a, 1989e). 

Between 1979 and 1983, lead concentrations in precipitation in Minnesota decreased from 29 to 4.3 μg/L 

at urban locations and from 5.7 to 1.5 μg/L at rural locations, indicating a reduction in lead emissions of 

>80%. This reduction resulted primarily from the decreased use of leaded gasoline and the use of more 

efficient emission controls on stationary lead sources (Eisenreich et al. 1986). 

Since 1979, elemental concentrations of fine particles have been monitored in remote areas of the United 

States in networks operated for the National Park Service (NPS) and the EPA (Eldred and Cahill 1994). 

Lead at all sites decreased sharply through 1986, corresponding to the shift to unleaded gasoline, but has 

since leveled off at 1–2 ng/m3 (0.001–0.002 μg/m3

), which is approximately 18% of the 1982 mean. The 

elevated lead concentrations (up to 5 ng/m3

) since 1986 at 3 of the 12 sites are thought to be associated 

with mining activity. 

In the 1960s, the National Air Surveillance Network (NASN) was established to monitor ambient air 

quality levels of total particulate solids and trace metals, including lead, at sites in larger American cities. 

In 1981 some old sites were eliminated and new ones were added to give 139 urban sites for air 

monitoring purposes. In 1988, the average lead concentration for all 139 sites was 0.085 μg/m3

, well 

below the National Ambient Air Quality Standard of 1.5 μg/m3

, quarterly average concentration, that has 

been established for lead (EPA 1996b). Data from the EPA National Air Quality Monitoring Program 

indicated that the 2002 average air quality concentration for lead is about 94% lower than in the early 

1980s, with a mean atmospheric concentration below 0.05 μg/m3

 in 2002 (EPA 2005k). In 1988, the 
LEAD 328 

6. POTENTIAL FOR HUMAN EXPOSURE 

average concentration of 18-point-source sites was 0.4 μg/m3, down from 2.9 μg/m3 in 1979, and the 

average concentration for urban sites was 0.1 μg/m3

, down from 0.8 μg/m3 in 1979 (EPA 1990). This 

decrease was undoubtedly caused by decreased use of leaded gasoline in the period leading up to its total 

ban after December 1995. Composite urban air concentrations of lead for 1989 and 1991 were 0.11 and 

0.08 μg/m3 (EPA 1996b). Although lead concentration in urban air continues to decline, there are 

indications that the rate of decline has slowed. Between 1976 and 1995, ambient concentrations of lead in 

the United States declined by 97%. Between 1994 and 1995, national average lead concentrations 

remained unchanged at 0.04 μg/m3

 even though lead emissions declined 1% (EPA 1996b). 

Concentrations of lead in ambient air that result from emission, both mobile and stationary, have been 

estimated to average 0.0058 μg/m3

 in 1996, while the concentration of lead attributed to mobile sources 

alone was 0.0035 μg/m3

 (EPA 2001a). 

Lead concentrations in air and dust in the indoor environment were measured in residential homes as part 

of the National Human Exposure Assessment Survey (NHEXAS) in EPA Region V (Indiana, Illinois, 

Michigan, Minnesota, Ohio, and Wisconsin). Mean (±1 standard deviation [SD]) and median 

concentrations of lead in indoor air from 213 residences were 15.2 ng/m3

 (37.6 ng/m3) and 6.17 ng/m3, 

respectively, with a maximum value of 293.5 ng/m3

 (Bonanno et al. 2001). The median lead 

concentration in outdoor air was 8.84 ng/m3

 (Clayton et al. 2002). Lead concentrations were higher in 

households where one or more residents smoked indoors (mean concentration of 21.8 ng/m3

) as compared 

to households with nonsmoking residents (mean concentration of 7.79 ng/m3

) (Bonanno et al. 2001). In 

dust collected from the living areas of 238 residences, the mean (±1 SD) and median lead concentrations 

were 467.4 μg/g (2,100 μg/g) and 131.6 μg/g, respectively, with a maximum value of 30,578 μg/g. Dust 

samples collected from window sills had mean (±1 SD) and median lead concentrations of 987 μg/g 

(2,723 μg/g) and 207.5 μg/g, respectively, with a maximum value of 21,120 μg/g. For both indoor air and 

dust measurements, higher concentrations of lead were correlated with dilapidated and suburban homes. 

In another analysis of the NHEXAS EPA Region V data, Pellizzari et al. (1999) looked at potential 

differences in lead concentrations in indoor air and personal air exposures between minorities (e.g., 

Hispanics and African-Americans) and nonminorities (e.g., Caucasian). Some differences were noted in 

the mean (±1 SD) lead concentrations between minorities of 57 ng/m3

 (±24 ng/m3) and nonminorities of 

22 ng/m3

 (±3.4 ng/m3) in personal air exposures, although the differences were not significant (p=0.147). 

Similarly, differences were noted between minorities (26±12 ng/m3

) and nonminorities (13±2.6 ng/m3) in 

indoor air, although these too were not significantly different (p=0.266). When the age of the home was 
LEAD 329 

6. POTENTIAL FOR HUMAN EXPOSURE 

considered in the analysis, it was found that lead concentrations were significantly (p=0.036) higher in 

homes built before 1940 than in homes built between 1960 and 1979, with mean (±1 SD) values of 

46 ng/m3

 (±1.6 ng/m3) and 13 ng/m3 (±2.1 ng/m3), respectively. The lead concentrations measured in 

indoor air in homes built before 1940 were not significantly different from mean (±1 SD) lead 

concentrations of 22 ng/m3

 (±5.1 ng/m3) and 23 ng/m3 (±5.1 ng/m3) measured in indoor air in homes built 

between 1940 and 1959 and between 1980 and 1995, respectively. 

6.4.2 Water 

Lead has been monitored in surface water, groundwater, and drinking water throughout the United States 

and other countries. The concentration of lead in surface water is highly variable depending upon sources 

of pollution, lead content of sediments, and characteristics of the system (pH, temperature, etc.). Levels 

of lead in surface water and groundwater throughout the United States typically range between 5 and 

30 μg/L, although levels as high as 890 μg/L have been measured (EPA 1986a). Mean levels of lead in 

surface water measured at 50,000 surface water stations throughout the United States are 3.9 μg/L (based 

on 39,490 occurrences) (Eckel and Jacob 1988). The median lead level in natural river water is 5 μg/L, 

with a range of 0.6–120 μg/L (Bowen 1966). Lead levels in seawater are estimated as 0.005 μg/L (EPA 

1982c). Lead concentrations in surface water are higher in urban areas than in rural areas (EPA 1982c). 

Using the EPA Storage and Retrieval (STORET) database, from January 1, 2005 to May 16, 2005, lead 

had been detected in surface water in Washington, Utah at concentrations of 20.5 and 142 μg/L and 

surface water from Salt Lake City, Utah at 7.75 μg/L (EPA 2005j). Lead was not detected above the 

detection limits in 224 other surface water samples obtained from various locations in Utah and Iowa over 

the sampling period (EPA 2005j). 

Urban storm water runoff is an important source of lead entering receiving waterways. Lead is found in 

building material (brick, concrete, painted and unpainted wood, roofing, and vinyl), and automotive 

sources (brakes, used oil), which contribute to runoff (Davis et al. 2001). The largest contributing sources 

were siding and roofing. 

Based on a survey of 900 public water supply systems, EPA (1988b) estimated that 99% of the 

219 million people in the United States using public water supplies are exposed to drinking water with 

levels of lead <5 μg/L and approximately 2 million people are served by drinking water with levels of 

lead >5 μg/L. A survey of 580 cities in 47 states indicated that the national mean concentration of lead in 

drinking water was 29 μg/L after a 30-second flushing period (EPA 1986a, 1989e); however, it was 
LEAD 330 

6. POTENTIAL FOR HUMAN EXPOSURE 

estimated that in 1988 the average lead content of drinking water decreased to 17 μg/L (Cohen 1988). In 

1986, the Safe Drinking Water Act Amendments banned the use of lead solder or flux containing 

>0.2% lead and the use of lead pipes or fittings that contained >8% lead (EPA 1986a, 1989e). 

In a more recent Federal Register notice (EPA 1991d), EPA examined the occurrences of lead in source 

water and distributed water. By resampling at the entry point to the distribution system, few samples 

were found to contain lead at levels above 5 μg/L. EPA now estimates that approximately 

600 groundwater systems may have water leaving the treatment plant with lead levels above 5 μg/L. 

Based on several data sets, it is estimated that <1% of the public water systems in the United States have 

water entering the distribution system with lead levels above 5 μg/L. These systems are estimated to 

serve <3% of the population that receives drinking water from public systems (EPA 1991d). 

Lead levels ranging between 10 and 30 μg/L can be found in drinking water from households, schools, 

and office buildings as a result of plumbing corrosion and subsequent leaching of lead. The combination 

of corrosive water and lead pipes or lead-soldered joints in either the distribution system or individual 

houses can create localized zones of high lead concentrations that exceed 500 μg/L (EPA 1989d). 

Quantitative data on the nationwide range of lead levels in drinking water drawn from the tap (which 

would include lead corrosion by-product) were insufficient to assign a national value at the time of the 

1991 EPA publication. One set of data comprised of 782 samples taken in 58 cities in 47 states shows 

that the average lead level in tap water was 13 μg/L with 90% of the values below 33 μg/L (EPA 1991d). 

In the NHEXAS study that was conducted during 1995–1996, lead concentrations were measured in tap 

drinking water (flushed for 15 minutes) taken from 82 homes in Arizona (O’Rourke et al. 1999), 441– 

444 homes in EPA Region V (Thomas et al. 1999), and 381 homes in Maryland (Ryan et al. 2000). 

Median lead concentrations of 0.4, 0.37, and 0.33 μg/L were determined in the Arizona, EPA Region V, 

and Maryland regional studies, respectively. Mean values (±1 SD) of 0.84 μg/L (±1.8 μg/L) and 

1.08 μg/L (±2.01 μg/L) were calculated for the EPA Region V and Maryland studies, respectively, and 

are much lower than the mean concentrations of lead in drinking water determined in previous EPA 

estimates. 

According to EPA's National Compliance Report for calendar year 1998 (EPA 1999), the vast majority of 

people in the nation received water from systems that had no reported violations of the maximum 

contaminant level and treatment technique requirements or significant monitoring and reporting 

requirements. Lead and copper are regulated in a treatment technique that requires systems to take tap 
LEAD 331 

6. POTENTIAL FOR HUMAN EXPOSURE 

water samples at sites with lead pipes or copper pipes that have lead solder and/or are served by lead 

service lines. The water system is required to take treatment steps if the action level (15 μg/L for lead) is 

exceeded in >10% of tap water samples. 

A survey of 1,484 drinking water samples taken from various districts of the American Water Works 

Service Company showed that average lead levels in a 1-L first-draw sample for copper, galvanized, and 

plastic pipes were 9, 4.2, and 4.5 μg/L, respectively. These data show that even plumbing that did not use 

lead solder for copper pipes (e.g., plastic pipes) contained significant levels of lead, primarily from the 

brass faucet fixtures, which are used in almost all plumbing. The brass fixtures may account for 

approximately one-third of the lead in the first-draw water (Lee et al. 1989). Lead levels are also known 

to increase when tap water is heated in boiling kettles that contain lead in their heating elements. Lead 

concentrations in tap water were found to vary depending on the age of nine homes in New Jersey. In 

homes built in the 1980s, median lead concentrations in the first-draw sample were higher (17.9 μg/L) 

than in first-draw samples (1.86 μg/L) taken from homes built in the 1970s (Murphy and Hall 2000). 

Leaching of lead from kitchen plumbing fixtures was given as the reason for the high lead concentrations 

in the first-draw samples. An additional water draw (>2 L) found decreased lead concentrations in tap 

water for all homes. However, the median concentration of lead in samples taken from homes built in the 

1980s was higher (2.45 μg/L) than in samples taken from 1970s homes (0.14 μg/L). The lead 

concentrations in these higher volume samples are attributed to lead leaching from solder joints in 

basement piping and the water meter on the public water service line that may be more prevalent in the 

more recently built homes. 

Concentrations of lead in water at NPL sites can be at much higher levels. For example, in 1986, an NPL 

hazardous waste site was identified in Genesee County, Michigan, that contained a landfill and nine 

surface impoundments. The facility had accepted sludge and residual waste from a chemical warehouse 

as well as other hazardous wastes. Water samples taken from the impoundments had a maximum lead 

concentration of 25 mg/L (EPA 1986b). 

6.4.3 Sediment and Soil 

Sediments contain considerably higher levels of lead than corresponding surface waters. Concentrations 

of lead in river sediments have been estimated at about 23 mg/kg (EPA 1982c; Fitchko and Hutchinson 

1975), and concentrations of lead in coastal sediments range from 1 to 912 mg/kg with a mean value of 

87 mg/kg (EPA 1982c; Nriagu 1978). Data from the STORET (1973–1979) database of Eastern and 
LEAD 332 

6. POTENTIAL FOR HUMAN EXPOSURE 

Midwestern river basins indicates maximum lead concentrations in river sediments of 440–1,000 mg/kg, 

and mean lead concentrations of 27–267 mg/kg (EPA 1982c). More current data obtained from the EPA 

STORET database (from January 1, 2004 to May 16, 2005), showed that lead has been detected in 

sediment samples from Honolulu, Hawaii (0.75–6.2 mg/kg), various locations of South Carolina (<1– 

21 mg/kg), Dade County, Florida (4.7–17.9 mg/kg), and various locations in Tennessee (6–50 mg/kg) 

(EPA 2005k). Surface sediment concentrations in Puget Sound ranged from 13 to 53 mg/kg (Bloom and 

Crecelius 1987). An analysis of sediments taken from 10 lakes in Pennsylvania indicated that the 

elevated lead values were not derived from leaching of lead from the native rocks as a result of acid 

deposition, but rather originated from anthropogenic lead deposition (probably from automotive 

emissions) on the soil surface and subsequent runoff of soil particulates into the lake (Case et al. 1989). 

Local sources of lead releases can also contribute significantly to lead content in sediments (Gale et al. 

2004). For example, lead concentrations in sediments located near mines and or sites containing mine 

tailings in the old lead belt of Missouri were greatly elevated, 10,550–12,400 mg/kg sediment (dry 

weight) compared to unaffected sediments (72–400 mg/kg dry weight) (Gale et al. 2002). 

The natural lead content of soil derived from crustal rock, mostly as galena (PbS), typically ranges from 

<10 to 30 μg/g soil. However, the concentration of lead in the top layers of soil varies widely due to 

deposition and accumulation of atmospheric particulates from anthropogenic sources. The concentration 

of soil lead generally decreases as distance from contaminating sources increases. The estimated lead 

levels in the upper layer of soil beside roadways are typically 30–2,000 μg/g higher than natural levels, 

although these levels drop exponentially up to 25 m from the roadway (EPA 1986a). Soil adjacent to a 

smelter in Missouri had lead levels in excess of 60,000 μg/g (Palmer and Kucera 1980). Soils adjacent to 

houses with exterior lead-based paints may have lead levels of >10,000 μg/g (EPA 1986a). As a result of 

lead reactions with the soil, extractable lead in surface soil samples (0–5 cm depth) from an agricultural 

area near a car battery manufacturing plant (taken at 0.3 km from the source) decreased from 117 μg/g to 

1 μg/g within 1 year after the plant stopped operating (Schalscha et al. 1987). Soil collected by scraping 

the top 2.5 cm of soil surface near homes and streetside in Louisiana and Minnesota contained median 

lead concentrations of >840 μg/g in New Orleans and 265 μg/g in Minneapolis. In contrast, the small 

towns of Natchitoches, Louisiana, and Rochester, Minnesota, had soil lead concentrations of <50 and 

58 μg/g, respectively. These data suggest that lead-contaminated soil is a major source of lead exposure 

in urban areas (Mielke 1993). As would be expected, soils in elementary school properties were also 

found to have the same pattern of lead levels as the soils in the surrounding residences. Lead 

concentrations in soils collected from inner-city schools in New Orleans were higher (median 
LEAD 333 

6. POTENTIAL FOR HUMAN EXPOSURE 

concentration of 96.5 μg/g) than soils collected from mid-city (30.0 μg/g) and outer-city (16.4 μg/g) 

elementary schools (Higgs et al. 1999). 

Studies conducted in Maryland and Minnesota indicate that within large, light-industrial, urban settings 

such as Baltimore, the highest soil lead levels generally occur near inner-city areas, especially where high 

traffic flows have long prevailed (Mielke et al. 1983, 1984/1985, 1989) and that the amount of lead in the 

soil is correlated with the size of the city (Mielke 1991). In 1981, soil lead levels in the Minneapolis/St. 

Paul inner-city area were 60 times higher (423 μg/g) than levels found in rural Minnesota (6.7 μg/g), with 

almost all the increase (95%) resulting from the combustion of leaded gasoline. A study conducted in 

Minneapolis, Minnesota, after the lead content of gasoline had been significantly reduced, found that 

median soil lead levels taken from the foundations of homes, in yards, and adjacent to the street were 700, 

210, and 160 μg/g, respectively; median soil lead concentrations in comparable samples from the smaller 

city of Rochester, Minnesota, did not exceed 100 μg/g at any location tested (Mielke et al. 1989). The 

Minneapolis data suggested that average lead levels were elevated in soil samples taken from the 

foundations of homes, but that lead levels were low (<50 μg/g) in areas where children could be expected 

to play, such as parks that were located away from traffic, but were higher in play areas around private 

residences. Soil samples taken from around the foundations of homes with painted exteriors had the 

highest lead levels (mean concentrations of 522 μg/g), but levels around homes composed of brick or 

stucco were significantly lower (mean concentration 158 μg/g) (Schmitt et al. 1988). Severely 

contaminated soils (levels as high as 20,136 μg/g) were located near house foundations adjacent to private 

dwellings with exterior lead-based paint. Elevated soil lead concentrations were found in larger urban 

areas with 27, 26, 32, and 42% of the soil samples exceeding 300 μg/g lead in Duluth, inner-city North 

Minneapolis, inner-city St. Paul, and inner-city South Minneapolis, respectively. Only 5% of the soil 

samples taken from the smaller urban areas of Rochester and St. Cloud, Minnesota, had lead levels 

>150 μg/g. It has been suggested that the higher lead levels associated with soils taken from around 

painted homes in the inner city are the result of greater atmospheric lead content, resulting from the 

burning of leaded gasoline in cars and the washdown of building surfaces to which the small lead 

particles adhere by rain (Mielke et al. 1989). A state-wide Minnesota study concluded that exterior leadbased paint was the major source of contamination in severely contaminated soils located near the 

foundations of private residences and that aerosol lead accounted for virtually all of the contamination 

found in soils removed from the influence of lead-based paint. Contamination due to lead-based paint 

was found to be “highly concentrated over a limited area, while contamination due to aerosol lead was 

found to be less concentrated, but more widespread” (MPCA 1987). 
LEAD 334 

6. POTENTIAL FOR HUMAN EXPOSURE 

Lead was analyzed in dust wipes and soil samples from 67 public housing projects containing 

487 dwelling units across the United States (Succop et al. 2001). A total of 5,906 dust wipes and 

1,222 soil samples were included in the data set. The median soil levels were 194 ppm near the 

foundation, 177 ppm near the walkways, and 145 ppm elsewhere in the yard. The maximum level, 

3,900 ppm, was found in a foundation sample. Median dust lead loading from kitchens, living rooms, and 

two children’s bedrooms were 151, 936, and 8,560 μg m-2 for floor window sills and window troughs, 

respectively. Thirteen percent of the floor samples and 30% of the window sill samples from the rooms 

exceeded the HUD Interim Dust Lead Standards of 431 and 2,690 μg m-2 for floor and window sill 

samples, respectively. 

Blood lead levels (PbBs) in children have been shown to correlate with lead concentration in soils in 

urban areas. In a study of children in New Orleans, Mielke et al. (1999) found that those living in areas 

classified as high (median soil lead concentrations >310 μg/kg) and low (median soil lead concentrations 

<310 μg/kg) metal census tract regions correlated well with median PbB above and below 9 μg/dL, 

respectively. In an analysis of data collected in an ATSDR study of children living near four NPL sites, it 

was concluded that a PbB of 5.99 μg/dL could be predicted for children exposed to soil lead levels of 

500 mg/kg (Lewin et al. 1999). However, there was a high degree of uncertainty and variability 

associated with the predicted correlation between blood and soil lead levels, suggesting the contribution 

of other factors to PbB, such as lead levels in household dust, interior paint, and drinking water. 

In a study of associations between soil lead levels and childhood blood lead levels (PbBs) in urban New 

Orleans and rural Lafourche Parish in Louisiana, childhood PbBs appeared more closely associated with 

soil lead levels than with age of housing. In the study, over 2,600 lead-containing soil and 6,000 PbB 

samples were paired by their median values and pre-1940 housing percentages for 172 census tracts. 

Census tracts with low median lead-containing soil levels were associated with new housing, but census 

tracts with high median lead-containing soil levels were split evenly between old and new housing. The 

same pattern was also observed for childhood PbBs. High lead-containing soil levels were associated 

with high PbB, and low lead-containing soil levels were associated with low PbB. Risk factors for lead 

exposure were found to be low in Lafourche Parish, where there was no census tract in which median 

PbB was >9 μg/dL and no indication of a statistical association between median PbB and either median 

lead levels in soil or age of housing (Mielke et al. 1997a). 

In the state of Maine, soil samples taken from areas where the risk of lead contamination was considered 

high (within 1–2 feet of a foundation of a building >30 years old) indicated that 37% of the samples had 
LEAD 335 

6. POTENTIAL FOR HUMAN EXPOSURE 

high lead concentrations (>1,000 μg/g). In 44% of the private dwellings, high lead levels were found in 

the soil adjacent to the foundation; high levels were found in only 10% of the public locations 

(playgrounds, parks, etc.). In addition, the largest percentage (54%) of highly contaminated soil was 

found surrounding homes built prior to 1950; homes built after 1978 did not have any lead contamination 

in the soil (Krueger and Duguay 1989). Environmental health studies conducted near four NPL sites 

measured mean concentrations of lead in soil ranging from 317 to 529 mg/kg, and mean concentrations of 

lead in dust ranging from 206 to 469 mg/kg (Agency for Toxic Substances and Disease Registry 1995). 

In 1972, household dust samples taken near nonferrous ore smelters in El Paso, Texas, which were known 

to emit 1,012 metric tons of lead/year, had lead levels of 22,191 μg/g (geometric mean) and 973 μg/g at 

distances from the smelter of 1.6 km and 6.4 km, respectively (Landrigan and Baker 1981). 

Lead was measured in soil from a port facility where galena ore concentrate and smelter dross arriving by 

rail were offloaded, stored, and reloaded onto seagoing vessels from 1974 through 1985. The lead 

concentrations ranged from 1,900 to 183,000 mg/kg (μg/g) (Ruby et al. 1994). 

In 1986, an NPL hazardous waste site that contained a landfill and nine surface impoundments was 

identified in Genesee County, Michigan. The facility had accepted sludge and residual waste from a 

chemical warehouse as well as other hazardous wastes. Lead was present in sludge samples taken from 

the impoundments at a maximum concentration of 11.6 mg/L, in sediment samples at a maximum 

concentration of 4,770 mg/kg dry weight, and in soil samples at 1,560 mg/kg (EPA 1986b). 

6.4.4 Paint 

Weathering of lead-based paint can contribute to the lead content of dust and soil. A 1974 study indicated 

that elevated PbBs in children were most likely a result of ingesting lead-contaminated soil, and that the 

most likely source was lead-based paint rather than lead from automotive exhaust (Ter Haar and Aronow 

1974). A state-wide Minnesota study concluded that exterior lead-based paint was the major source of 

contamination in severely contaminated soils located near the foundations of private residences (MPCA 

1987). A soil lead study in Minneapolis, Minnesota, found that soil samples taken from around the 

foundations of homes with painted exteriors had a mean concentration of 522 μg/g while soil samples 

taken from around the foundations of brick or stucco had a mean concentration of 158 μg/g (Schmitt et al. 

1988). Lead-based paint, removed from surfaces by burning (gas torch or hot air gun), scraping, or 
LEAD 336 

6. POTENTIAL FOR HUMAN EXPOSURE 

sanding have been found to result, at least temporarily, in higher levels of exposure for families residing 

in these homes. 

6.4.5 Other Sources 

Concentrations of lead (wet weight basis) in samples of 11 raw edible plants have been reported for 

growing areas in the United States that are uncontaminated by human activities other than normal 

agricultural practices (Wolnik et al. 1983a, 1983b). Results are as follows: plant (mean μg/g wet 

weight); lettuce (0.013); peanut (0.010); potato (0.009); soybean (0.042); sweet corn (0.0033); wheat 

(0.037); field corn (0.022); onion (0.005); rice (0.007); spinach (0.045); and tomato (0.002). 

Lead has been detected in a variety of foods. Lead may be introduced into food through uptake from soil 

into plants or atmospheric deposition onto plant surfaces, during transport to market, processing, and 

kitchen preparation (EPA 1986a). In the FDA Total Diet Study (TDS) 1991–1996, food was purchased 

4 times/year from each of four geographic regions of the United States and a market basket consisting of 

about 260 foods from three representative cities within the geographical region analyzed for different 

elements, including lead (Capar and Cunningham 2000). Lead was below the limit of quantitation in all 

TDS food in the following food categories: milk and cheese; eggs; meat, poultry, and fish; legumes and 

nuts; grain and cereal products; vegetables; mixed dishes and meals; desserts; snacks; fats and dressings; 

and infant and junior foods. Only five products had quantifiable concentrations of lead, namely: canned 

peaches (0.032 mg/kg), canned pineapple (0.013 mg/kg), canned fruit cocktail (0.031 mg/kg), sweet 

cucumber pickles (0.036 mg/kg), and dry table wine (0.023 mg/kg). Typical concentrations of lead in 

various foods are shown in Table 6-5 for the TDS 1991–1996. Results of a previous FDA TDS in which 

samples were collected in 27 cities between October 1980 and March 1983 are shown for comparison 

(Gartrell et al. 1986a). 

Other factors such as absorption of lead from cooking water and cookware can influence the amount of 

lead in cooked vegetables. Ceramic dishes may contain lead in their glazes, and lead in glass has been 

shown to leach into wine. The degree to which lead is released from food once it is consumed also 

influences a person’s uptake of lead. 

A survey conducted in five Canadian cities during 1986–1988 in which food was purchased from retail 

stores and analyzed for lead in composite samples (n=756), determined the lead levels in 11 food 

categories as well as the average dietary intake of different population groups (Dabeka and McKenzie 
LEAD 337 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Lead Levels in Various Food Categories 

Mean concentration (μg/g) 

Food category TDS 1980–1982a TDS 1991–1996b 

Dairy products 0.006 

Milk and cheese <0.02–<0.05 

Eggs <0.03 

Meat, fish, and poultry 0.016 nd–<0.05 

Grain and cereal products 0.023 nd–<0.05 

Vegetables 0.010–0.041 nd–<0.05 

Legumes and nuts 0.124 nd–<0.05 

Fruits 0.046–0.060 nd–0.032 

Mixed dishes and meals nd–<0.04 

Desserts nd–<0.04 

Snacks <0.05 

Oils, fats, shortenings, and dressings 0.017 nd–<0.04 

Sugar, adjuncts, condiments, and sweeteners 0.028 <0.03–0.036 

Infant and junior foods nd–<0.04 

Beverages 0.010 nd–0.0.023 

a

Gartrell et al. 1986b 

b

Capar and Cunningham 2000 

nd = not detectable (<0.008 μg/g); TDS = Total Dietary Study 
LEAD 338 

6. POTENTIAL FOR HUMAN EXPOSURE 

1995). Results of this study are found in Table 6-6. The lead level in all of the foods ranged from <0.4 to 

523.4 ng/g with a mean of 23.2 ng/g for all food categories. The highest mean Pb levels were found in 

canned luncheon meats (163 ng/g), canned beans (158 ng/g), canned citrus fruit (126 ng/g), and canned 

peaches (133 ng/g). In canned foods, mean Pb levels decreased from 73.6 ng/g in 1985 to 46 ng/g in 

1988, at which time it was estimated that 97–99% of Canadian canned foods were in lead-free cans. 

Canning foods in lead-soldered cans may increase levels of lead 8–10-fold; however, the impact of 

canning appears to be decreasing as a result of a decrease in the use of lead-soldered cans. The use of 

three-piece lead-soldered cans ceased in 1991; however, older lead- soldered cans may still be present in 

some households. In 1974, for example, the lead level in evaporated milk in lead-soldered cans was 

0.12 μg/g; in 1986, after these cans were phased out, the lead level in evaporated milk dropped to 

0.006 μg/g (Capar and Rigsby 1989). A survey conducted in five Canadian cities during 1986–1988 in 

which food was purchased from retail stores and analyzed for lead in composite samples (n=756), 

determined the lead levels in 11 food categories as well as the average dietary intake of different 

population groups (Dabeka and McKenzie 1995). Results of this study are found in Table 6-6. The lead 

level in all of the foods ranged from <0.4 to 523.4 ng/g with a mean of 23.2 ng/g for all food categories. 

The highest mean Pb levels were found in canned luncheon meats (163 ng/g), canned beans (158 ng/g), 

canned citrus fruit (126 ng/g), and canned peaches (133 ng/g). In canned foods, mean Pb levels decreased 

from 73.6 ng/g in 1985 to 46 ng/g in 1988, at which time it was estimated that 97–99% of Canadian 

canned foods were in lead-free cans. Canning foods in lead-soldered cans may increase levels of lead 8– 

10-fold; however, the impact of canning appears to be decreasing as a result of a decrease in the use of 

lead-soldered cans. The use of three-piece lead-soldered cans ceased in 1991; however, older leadsoldered cans may still be present in some households. In 1974, for example, the lead level in evaporated 

milk in lead-soldered cans was 0.12 μg/g; in 1986, after these cans were phased out, the lead level in 

evaporated milk dropped to 0.006 μg/g (Capar and Rigsby 1989). 

The U.S. Fish and Wildlife Service reported on the concentration of metals in a total of 315 composite 

samples of whole fish sampled from 109 stations nationwide from late 1994 to early 1995. For lead, the 

geometric mean, maximum, and 85th percentile concentrations (μg/g wet weight) were 0.11, 4.88, and 

0.22, respectively. The mean concentration of lead was significantly lower than in the 1980–1981 survey. 

Lead concentrations in fish have declined steadily from 1976 to 1984, suggesting that reductions of 

leaded gasoline and controls on mining and industrial discharges have reduced lead in the aquatic 

environment (Schmitt and Brumbaugh 1990). 
LEAD 339 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Lead Levels in Canadian Foods 1986–1988 

Concentration (ng/g) 

Food category Number of samples Mean Median Maximum 

Milk and milk products 64 7.7 3.9 44.7 

Meat and poultry 89 20.2 8.2 523.2 

Fish 28 19.3 13.7 72.8 

Soups 20 15.5 8.7 48.7 

Bakery goods and cereals 120 13.7 10.5 66.4 

Vegetables 190 24.4 8.7 331.7 

Fruits and fruit juices 127 44.4 15.9 372.7 

Fats and oils 15 9.6 <8.8 19.7 

Sugar and candies 35 18.3 10.3 111.6 

Beverages 35 9.9 <3.1 88.8 

Miscellaneous 33 41.7 23.4 178.9 

All categories 756 23.2 9.2 523.4 

Source: Dabeka and McKenzie 1995 
LEAD 340 

6. POTENTIAL FOR HUMAN EXPOSURE 

In order to reduce lead exposure from consumption of lead-contaminated fish and shellfish, consumption 

advisories are issued by states recommending that individuals restrict their consumption of specific fish 

and shellfish species from certain waterbodies where lead concentrations in fish and shellfish tissues 

exceed the human health level of concern. This level of concern is set by individual state agencies and 

used to issue advisories recommending no consumption, or restricted consumption, of contaminated fish 

and shellfish from certain waterbody types (e.g., lakes and/or rivers). In 1995, the EPA Office of Water 

issued guidance to states on sampling and analysis procedures to use in assessing the health risks from 

consuming locally caught fish and shellfish. The risk assessment method proposed by EPA was 

specifically designed to assist states in developing fish consumption advisories for recreational and 

subsistence fishers (EPA 1995b). These two groups within the general population consume larger 

quantities of fish and shellfish than the general population and frequently fish the same waterbodies 

routinely. Because of this, these populations are at greater risk of exposure to lead and other chemical 

contaminants if the waters they fish are contaminated. In 2007, 8 advisories restricting the consumption 

of lead-contaminated fish and shellfish were in effect in 5 states (Hawaii, Idaho, Washington, Kansas, and 

Missouri) and 1 territory (American Samoa) (EPA 2007b). 

Elevated levels of lead in the blood of cattle grazing near a lead smelter have been reported, although no 

implications regarding lead in beef were made. The mean lead levels for the herd were highest near the 

smelter and decreased with distance. Ingestion of soil along with the forage was thought to be a large 

source of additional metal (Neuman and Dollhopf 1992). Evidence has also been shown for transfer of 

lead to milk and edible tissue in cattle poisoned by licking the remains of storage batteries burned and left 

in a pasture (Oskarsson et al. 1992). Levels of lead in muscle of acutely sick cows that were slaughtered 

ranged from 0.23 to 0.5 mg/kg (wet weight basis). Normal lead levels in bovine meat from Swedish 

farms are <0.005 mg/kg. For eight cows that were less exposed, levels of lead in milk taken 2 weeks after 

the exposure were 0.08±0.04 mg/kg. The highest lead level found in the milk of eight cows studied for 

18 weeks was 0.22 mg/kg. Lead in most milk samples decreased to values <0.03 mg/kg 6 weeks after 

exposure. Two affected cows delivered a calf at 35 and 38 weeks after the exposure. There was a high 

lead level in the blood of the cows at the time of delivery, which suggests mobilization of lead in 

connection with the latter stages of gestation and delivery. Lead levels in colostrum were increased as 

compared to mature milk samples taken 18 weeks after exposure. The concentration of lead in milk 

produced after delivery decreased rapidly with time and was almost down to the limit of detection in 

mature milk. 
LEAD 341 

6. POTENTIAL FOR HUMAN EXPOSURE 

The FDA investigated the prevalence and concentration of lead in a variety of dietary supplements with 

an emphasis on botanical-based products (Dolan et al. 2003). The concentration of lead in the 95 major 

product components tested was <20–48,600 μg/kg and the median concentration was 403 μg/kg. Levels 

of lead found in 11 products would result in exposures that exceed the tolerable lead intakes for children 

and women of child-bearing age, particularly pregnant women, 6 and 25 μg Pb/day. Of the 136 brands of 

nutritional supplements containing calcium (calcium supplements, mineral-vitamin supplements, antacids, 

and baby formulas) purchased in California in 1996, two-thirds failed to meet the 1999 California criteria 

for acceptable lead levels in consumer products, >1.5 μg lead/g calcium (Scelfo and Flegal 2000). The 

lowest levels were found in infant formulas and antacids, which all contained either synthesized or refined 

calcium. Lead concentrations were undetectable (<0.02 μg/g) in all infant formulas tested. Of the natural 

calcium supplements, none of the dolomite brands (n=5), five of the oyster shell brands (n=26), and half 

of the bonemeal brands (n=9) met the 1999 California criteria, while two dolomite brands and one oyster 

shell brand exceeded the federal limit, 7.5 μg Pb/g calcium. 

Many non-Western folk remedies used to treat diarrhea or other ailments may contain substantial amounts 

of lead. Examples of these include: Alarcon, Ghasard, Alkohl, Greta, Azarcon, Liga, Bali Goli, 

Pay-loo-ah, Coral, and Rueda. In addition, an adult case of lead poisoning was recently attributed to an 

Asian remedy for menstrual cramps known as Koo Sar. The pills contained lead at levels as high as 

12 ppm (CDC 1998). The source of the lead was thought to be in the red dye used to color the pills. 

Lead was the most common heavy metal contaminant/adulterant found in samples (n=54) of Asian 

traditional remedies available at health food stores and Asian groceries in Florida, New York, and New 

Jersey (Garvey et al. 2001). Sixty percent of the remedies tested would give a daily dose of lead in excess 

of 300 mg when taken according to labeling instructions. Lead poisoning has been caused by ingestion of 

a Chinese herbal medicine to which metallic lead was added to increase its weight and sales price (Wu et 

al. 1996). Ayurveda is a traditional form of medicine practiced in India and other South Asian countries; 

the medications used often contain herbs, minerals, metals, or animal products and are made in 

standardized and nonstandardized formulations (CDC 2004). During 2000–2003, 12 cases of lead 

poisoning among adults were reported in five states due to the use of ayurveda medications obtained from 

ayurvedic physicians (CDC 2004). 

Because lead concentrations in urban soil can be very high, a pilot study was conducted in an urban 

neighborhood in Chicago in order to gauge the levels of lead in an array of fruits, vegetables, and herbs 

(Finster et al. 2004). The soil lead concentrations where the plants were sampled varied from 27 to 

4,580 ppm (median 800 ppm, geometric mean 639 ppm). Detectable lead levels in the edible fruit, 
LEAD 342 

6. POTENTIAL FOR HUMAN EXPOSURE 

vegetables, and herbs sampled ranged from 11 to 81 ppm. Only one fruiting vegetable (cucumber 

81 ppm) among the 52 sampled had detectable levels of lead in the edible portion. However, 12 of the 

31 leafy vegetables and herbs sampled contained lead in the edible shoot part of the plant (range, 11– 

60 ppm). The lead concentrations in the four samples of root vegetables ranged from 10 to 21 ppm. No 

significant correlation was found between the lead concentrations in the edible portion of plant and the 

soil lead level. 

Tamarindo jellied fruit candy from Mexico, and lozeena, a bright orange powder from Iraq used to color 

rice and meat, have been implicated in lead poisoning (CDC 1998). The lozeena, containing 7.8–8.9% 

lead, was purchased in Iraq and brought into the United States. Tamarindo candy and jam products, 

restricted from importation into the United States since 1993, were purchased by a woman visiting her 

family in Mexico. Although no product was available for testing, several commercial retail lots of 

tamarindo and tejocote jellied fruit candy were embargoed by the state of California in 1993 because of 

high lead levels. The fruit candies were packaged in stoneware or ceramic jars. The lead-based glazing 

applied to the jars appeared to have been the major source of the lead, although some of the fruits from 

plastic-lined jars also contained substantial amounts of lead. 

Lead may leach from lead crystal decanters and glasses into the liquids they contain. Port wine that 

contained an initial concentration of 89 μg/L lead was stored for 4 months in crystal decanters containing 

up to 32% lead oxide. At the end of 4 months lead concentrations in the port were 5,331, 3,061, and 

2,162 μg/L in decanters containing 32, 32, and 24% lead oxide, respectively. Lead was also found to 

elute from lead crystal wine glasses within minutes. Mean lead concentrations in wine contained in 

12 glasses rose from 33 μg/L initially to 68, 81, 92, and 99 μg/L after 1, 2, 3, and 4 hours, respectively 

(Graziano and Blum 1991). 

Lead is also present in tobacco at concentrations of approximately 2.5–12.2 μg/cigarette, of which 

approximately 2–6% may actually be inhaled by the smoker (WHO 1977). This lead may have been due 

to the use of lead arsenate pesticides or lead-containing vehicle exhaust contaminating the tobacco plants. 

While no recent data were found on the concentration of lead in tobacco, higher levels of lead in indoor 

air and PbBs are associated with households with smokers (Bonanno et al. 2001; Mannino et al. 2003). 

Hair dyes and some cosmetics may contain lead compounds (Cohen and Roe 1991). Hair dyes 

formulated with lead acetate may have lead concentrations 3–10 times the allowable concentration in 

paint. Measured lead concentrations of 2,300–6,000 μg of lead/gram of product have been reported 
LEAD 343 

6. POTENTIAL FOR HUMAN EXPOSURE 

(Mielke et al. 1997b). Lead acetate is soluble in water and easily transferred to hands and other surfaces 

during and following application of a hair dye product. Measurements of 150–700 μg of lead on each 

hand following application have been reported (Mielke et al. 1997b). In addition to transfer of lead to the 

hand-to-mouth pathway of the person applying the product, lead is transferred to any other surface (comb, 

hair dryer, outside of product container, counter top, etc.) that comes into contact with the product. It is 

also on the hair it is applied to and the hands applying it. Objects coming into contact with hair dyed with 

a lead-containing product also become contaminated. A dry hand passed through dry hair dyed with a 

lead-containing product in cream form has been shown to pick up about 786 μg of lead. A dry hand 

passed through dry hair dyed using foam or liquid lead-containing hair dye products picked up less lead: 

69 μg/hand for foam products and 73 μg/hand for liquid products (Mielke et al. 1997b). 

Cases of lead poisoning have been related to less common sources of exposure. Illicit "moonshine" 

whiskey made in stills composed of lead-soldered parts (e.g., truck radiators) may contain high levels of 

lead. Detectable levels of lead with a maximum concentration of 5.3 mg/L were found in 7 of 12 samples 

of Georgia moonshine whiskey (Gerhardt et al. 1980). Of the 115 suspected moonshine samples seized 

by local law enforcement between 1995 and 2001 and analyzed by the Bureau of Alcohol, Tobacco, and 

Firearms, 33 samples (28.7%) contained lead levels >300 μg/dL. The median and maximum levels were 

44.0 and 53,200 μg/dL, respectively (Parramore et al. 2001). 

Use of lead ammunition may result in exposure to lead dust generated during gun or rifle discharge at 

levels up to 1,000 μg/m3

 (EPA 1985c), from lead pellets ingested by or imbedded in animals that are used 

as food sources, and from lead pellets or fragments imbedded in humans from shooting incidents (Burger 

et al. 1998; Johnson and Mason 1984; Raymond et al. 2002). Exposures to airborne lead dust from 

firearm discharge in indoor shooting ranges has been shown to result in increases in blood lead 

concentration that are 1.5–2 times higher than preexposure concentrations (Greenberg and Hamilton 

1999; Gulson et al. 2002). However, the use of copper-jacketed bullets, nonlead primers, and wellventilated indoor firing ranges lessen the impact of airborne lead on blood lead levels (Gulson et al. 

2002). 

A lead poisoning hazard for young children exists in imported vinyl miniblinds that have had lead added 

to stabilize the plastic. Over time, the plastic deteriorates to produce lead dust that can be ingested when 

the blinds are touched by children who then put their hands in their mouths (CPSC 1996). The U.S. 

Consumer Product Safety Commission (CPSC) has requested that manufacturers change the 

manufacturing process to eliminate the lead. As a consequence, vinyl miniblinds should now be lead­
LEAD 344 

6. POTENTIAL FOR HUMAN EXPOSURE 

free. The CPSC recommends that consumers with young children remove old vinyl miniblinds from their 

homes and replace them with new miniblinds made without added lead or with alternative window 

coverings. 

Inexpensive metallic jewelry items specifically intended for children and teenagers have been shown to 

contain varying levels of lead (Maas et al. 2005). A total of 311 chemical assays conducted using 

285 jewelry items purchased in 20 different stores in California revealed that a considerable amount of 

lead was added to the items, presumably to increase their weight or to impart some type of metallic 

coating to the surface of the item. The mean weight percentage of lead for all 311 assays was 30.6%. Of 

the 311 samples tested, 169 contained at least 3% lead by weight in at least one portion of the jewelry 

piece and 123 of the samples were found to contain >50% lead by weight (Maas et al. 2005). In addition, 

62 pieces of the purchased jewelry were tested for surface levels of lead that could potentially be 

transferred dermally through the routine handling of these pieces. Using standard laboratory wipes, the 

surface of the jewelry pieces were wiped for a total of 20 seconds and subsequently analyzed for lead 

content. Mean lead levels in the wipes ranged from 0.06 to 541.97 μg. The authors characterized the 

potential lead exposure from these dermal transfer experiments as either low exposure (<1 μg of lead 

transferred to the laboratory wipe), moderate exposure (1–10 μg of lead transferred to the laboratory 

wipe), high exposure (10–50 μg of lead transferred to the laboratory wipe), and very high exposure 

(>50 μg of lead transferred to the laboratory wipe). Approximately 35% of the 62 pieces tested were 

characterized as having low exposure, 48% were characterized as moderate exposure, 11% were 

characterized as high exposure, and 5% were characterized as very high exposure (Maas et al. 2005). 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Exposure of the general population to lead is most likely to occur through the ingestion of contaminated 

food and drinking water, and by the inhalation of lead particulates in ambient air. Direct inhalation of 

lead accounts for only a small part of the total human exposure; however, lead that is adsorbed to soil may 

be inhaled as dust and reentrainment of lead-contaminated dust is common. Fruits, vegetables, and grains 

may contain levels of lead in excess of background levels as a result of plant uptake of lead from soils and 

direct deposition of lead onto plant surfaces (EPA 1986a). Between 1979 and 1989, lead-soldered food 

cans were virtually eliminated as a source of lead contamination of canned food. The CDC has concluded 

that the most common source of lead exposure for children (Section 6.6) is lead-based paint that has 

deteriorated into paint chips and lead dusts and that the most common sources of lead exposure for adults 

are occupational (CDC 1997b). 
LEAD 345 

6. POTENTIAL FOR HUMAN EXPOSURE 

Those who use recreational shooting ranges may be exposed to lead and soluble lead compounds, such as 

carbonates and sulfates, in soil. Surface soil concentrations of lead at a range in Michigan were 10– 

100 times greater than background level of 25 mg/kg; mobilization of lead appeared to be occurring and 

may present a threat to groundwater and surface water (Murray et al. 1997). 

Exposure may also result from engaging in hobbies that use lead. For example, molten lead can be used 

in casting ammunition and making fishing weights or toy soldiers; leaded solder is used in making stained 

glass; leaded glazes and frits are used in making pottery; artists' paints may contain lead; lead compounds 

are used as coloring agents in glassblowing; and lead may be present in platinum printing and screen 

printing materials (Grabo 1997). 

In 1982–1983, the baseline value for daily intake of lead by inhalation in a nonurban environment was 

estimated to be 0.5 μg/day for a 2-year-old child, 1.0 μg/day for an adult working indoors, and 2.0 μg/day 

for adults working outdoors; these figures are based on an average atmospheric lead concentration of 

0.1 μg/m3

 and an indoor/outdoor lead concentration ratio of 0.5. In an urban environment, the indoor/ 

outdoor lead concentration ratio was assumed to be approximately 0.8, yielding an estimated lead 

exposure of 1.0 μg/m3

 for adults. This estimate assumed a 2-hour/day exposure to an outdoor lead 

concentration of 0.75 μg/m3

, a 20-hour/day exposure to an indoor lead concentration of 0.6 μg/m3, a 

2-hour/day exposure to 5 μg/m3

 in high traffic, and an average daily intake of air by an adult of 20 m3. 

These estimates indicate that urban and nonurban residents inhaled approximately the same amount of 

lead dust (EPA 1986a). Drastic reductions in the lead content of gasoline since 1986 have resulted in a 

64% decrease in lead emissions to the atmosphere (see Section 6.4.1). 

Using the EPA National Air Quality Monitoring System, the average maximum 24-hour atmospheric lead 

concentration in the United States was 0.84 μg/m3

 in 2004 (EPA 2005k). There were two maximum 

24-hour monitoring values measured in 2004 in which the 10 μg/m3

 level was exceeded (11.76 and 

11.53 μg/m3

 in Muncie, Indiana). All other atmospheric lead levels measured throughout the rest of the 

United States were <10 μg/m3

 threshold in 2004. 

Between 1979 and 1989 there was a virtual elimination of the use of lead-soldered food cans, with a 

concomitant drop in lead levels in food. The contribution of various food categories to the average daily 

intakes of lead for adults, based on an analysis of 27 market basket samples taken nationwide for a 1980– 

1982 Total Diet Study, are shown in Table 6-7 (Gartrell et al. 1986b). This value is only slightly higher 
LEAD 346 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-7. Contribution of Various Food Categories to the Average Daily Intake 

(AVDI) of Lead in Adults (1980–1982) 

Food category AVDI (μg/day) 

Dairy products 4.54 

Meat, fish, and poultry 4.09 

Grain and cereal products 9.84 

Potatoes 1.39 

Leafy vegetables 0.94 

Leafy legumes 9.18 

Root vegetables 1.39 

Garden fruit 4.44 

Fruits 10.00 

Oils, fats, and shortenings 1.23 

Sugar and adjuncts 2.34 

Beverages 6.86 

Total 56.50 

Source: Gartrell et al. 1986b 
LEAD 347 

6. POTENTIAL FOR HUMAN EXPOSURE 

than the estimated lead intake of 54 μg/day found in a Canadian 24-hour duplicate diet study conducted 

during 1981. The average lead content of the 10 food groups used in the Canadian study ranged from 

0.088 μg/g for drinking water to 0.654 μg/g for cheese (Dabeka et al. 1987). 

Based on data from the FDA’s Total Diet Food Studies (Bolger et al. 1991; Gunderson 1988), dietary 

values for average daily intake of lead by different population groups from 1980 to 1990 have been 

estimated (Table 6-8). The estimates of lead intake presented in Table 6-8 are based on measurements of 

lead in foods prepared for consumption and on consumption patterns for those foods (or food groups) 

from dietary surveys in which survey participant data were grouped by age and sex. The Total Diet Food 

Studies conducted between 1982 and 1988 determined daily intakes of a variety of pesticides, industrial 

chemicals, and elements for eight age and sex groups. In 1984, lead residues were found in 193 of the 

201 foods analyzed. A comparison of daily intakes of lead by age group (6 months, 2 years, and adult) 

showed that lead intakes dropped by approximately 50% for each group between 1980 and 

1984 (Gunderson 1988) and continued to decrease through 1990 for all age and sex groups (Bolger et al. 

1991). Data from the 1990–1991 Total Diet Survey indicate that dietary lead intake ranged from 1.8 to 

4.2 μg/day for all age groups combined, primarily as a result of reduced lead solder in cans and the phaseout of leaded gasoline. Further reductions in lead exposure will be more difficult to identify and achieve 

(Bolger et al. 1991, 1996). The daily dietary intake of lead estimated from the 1986–1988 Canadian 

Survey was 24 μg/day for all ages, male and female (Dabeka and McKenzie 1995). The highest 

contribution among 11 food categories to Pb intake was beverages (20.9%) and bakery goods and cereals 

(20.6%). The FDA Total Diet Survey (TDS) 1991–1996 tested 18 market baskets consisting of about 

260 foods collected from three cities (representing standard metropolitan statistical areas) within four 

different geographical regions (Capar and Cunningham 2000). Mean and median Pb concentrations in all 

foods were 0.005 and 0 mg/kg, respectively. These results are similar to those in previous TDS 1982– 

1988 and 1990–1991 surveys except those in canned foods. The lower Pb concentrations in canned foods 

for TDS 1991–1996 is attributed to the reduction and ultimate ban in 1995 on the use of lead-soldered 

food cans in the United States. 

More recent data on lead intakes from the U.S. diet come from the results of the NHEXAS studies. Mean 

and median dietary intakes of lead for study participants in the EPA Region V study were calculated to be 

0.25 and 0.10 μg/kg body weight/day, respectively, or 17.5 and 7.0 μg/day for a 70-kg adult, respectively 

(Thomas et al. 1999). These results were obtained from measurement of concentrations in water and 

dietary samples. The median dietary lead intake for the Region V population agrees with the 0.09– 

0.10 μg/kg body weight/day calculated in the FDA TDS (1986–1991) (Gunderson 1995), but is 
LEAD 348 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-8. Daily Average Intake of Lead (μg Lead/Day) 

Age Sex 1980a 1982a 1984a 1986a 1988a 1990–1991b 

6–11 Months Male/female ≈34 20 16.7 10 5 1.82 

2 Years Male ≈45 25.1 23.0 12.8 5.0 1.87 

Female No data No data No data No data No data No data 

14–16 Years Female No data No data 28.7 15.2 6.1 2.63 

Male No data No data 40.9 21.8 8.2 3.24 

25–30 Years Female No data 32.0 28.7 14.8 7.9 3.28 

Male 84 45.2 40.9 21.2 10.0 4.17 

60–65 Years Female No data No data 30.4 15.6 No data 3.05 

Male No data No data 37.6 19.1 No data 3.46 

a

Bolger et al. 1991 

b

Bolger et al. 1996 
LEAD 349 

6. POTENTIAL FOR HUMAN EXPOSURE 

substantially lower than the average in the 1986–1988 Canadian study of 0.4 μg/kg body weight/day 

(calculated from an average intake of 24 μg/day for a 60-kg person (Dabeka and McKenzie 1995). 

Higher mean daily intakes of lead of 8.14 mg/day were reported from the NHEXAS Maryland study 

(Ryan et al. 2001). This intake was determined from the consumption levels determined in the NHEXAS 

Maryland study and the concentration in food from the 1997 ATSDR Toxicological Profile for Lead, 

11.0 ppb. This intake would be much lower if the more recent levels of lead in food as reported in Capar 

and Cunningham (2000) were used. The mean and median concentrations of lead in combined solids and 

liquids in the EPA Region V study were 4.5 and 3.1 μg/kg, respectively. The mean (median) Pb intakes 

from dietary, water, and inhalation routes were 10.9 (7.3), 1.7 (0.66), and 0.333 (0.156) μg/day, 

respectively. While water lead contributed significantly to dietary intake, dietary intake was greater than 

that calculated for intake from home tap water. Mean and median flushed tap water from Region V 

homes contained 0.84 and 0.33 μg/L, while standing tap water contained 3.9 and 1.9 μg/L of lead, 

respectively. 

In another approach to determining daily lead intake within subpopulations in the United States, 

Moschandreas et al. (2002) used the Dietary Exposure Potential Model (DEPM) and data obtained from 

Combined National Residue Database (CNRD) to estimate dietary lead intake based on food consumption 

patterns in 19 subpopulation groups. The food items used in the model are based on 11 food groups 

consisting of approximately 800 exposure core foods that represent 6,500 common food items. The 

results of their model (Table 6-9) yielded an average dietary lead intake in the U.S. population of 

1.009 μg/kg body weight/day, or 70.6 μg/day for a 70-kg adult. Of the various subpopulation groups, 

nonnursing infants and children ages 1–6 years had much higher lead intakes/kg body weight than the 

general population, 3.117 and 1.952 μg/kg body weight, respectively. 

The NHEXAS Arizona study evaluated exposure to lead for a study population from multiple media and 

pathways (O’Rourke et al. 1999). The concentrations of lead in the various media sampled are presented 

in Table 6-10 and the estimated total human exposure to the study population and various subpopulations 

is shown in Table 6-11. The daily total lead intake to the study population from all media ranged from 

11 to 107 μg/day, with a mean of 36 μg/day. This compares with a range of 15–312 μg/day reported by 

the World Health Organization (WHO 1995). 

Moonshine consumption was strongly associated with elevated PbBs (Morgan and Parramore 2001). A 

2000 study found a median PbB of 11 μg/dL among 35 moonshine consumers versus 2.5 μg/dL in 

68 randomly-selected nonmoonshine consumers. Gulson et al. (2001b) studied the contribution of lead 
LEAD 350 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-9. Dietary Exposure Estimates of U.S. Populations to Lead Based on the 

Dietary Exposure Potential Model (DEPM) 

Subpopulation Lead intake (μg/kg body weight/day) 

U.S. population 1.009 

Age/gender 

 Nonnursing infants 3.117 

 Children 1–6 1.952 

 Children 7–12 1.164 

 Females 13–19 0.824 

 Females 20+ 0.920 

 Females 55+ 0.946 

 Males 13–19 0.890 

 Males 20+ 0.895 

 Males 55+ 0.918 

Ethnicity 

 Hispanic 1.177 

 Non-Hispanic white 1.095 

 Non-Hispanic black 0.797 

 Non-Hispanic other 0.871 

Geographic regiona

 North central 0.611 

 Northeast 0.968 

Southern 0.966 

 Western 1.133 

Family incomeb

 Poverty 0–130% 1.094 

 Poverty 131%+ 0.986 

a

The regional classification is as defined by the U.S. Department of Agriculture, and is based upon U.S. Census 

Bureau regions. 

b

Annual household income as a percentage of the Poverty Index 

Source: Moschandreas et al. 2002 
LEAD 351 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-10. Lead Concentrations for Various Media From the 

NHEXAS Arizona Study 

Number of Percent Lead concentration—percentile 

90 Media th samples BDL Units 50th 75th 

Air—indoors 119 100 ng/m3 BDL BDL BDL 

Air—outdoors 116 100 ng/m3

 BDL BDL BDL 

Dust 135 86 μg/g BDL BDL 131.0 

Soil 139 85 μg/g BDL BDL 118.1 

Food 159 0.6 μg/kg 6.4 9.2 16.1 

Beverage 154 29 μg/kg 1.9 4.1 7.1 

Drinking water consumed 73 51 μg/L BDL 0.4 2.0 

Tap water consumed 82 1 μg/L 0.4 0.9 1.3 

BDL = below detection limit 

Source: O’Rourke et al. 1999 
LEAD 352 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-11. Total Lead Exposure of Subject Population From the 

NHEXAS Arizona Study 

Lead intake (μg/day) 

Exposure population Number of subjects Mean Median Range 

All subjects 176 36 31 11–107 

Adult male (>18 years of age) 55 42 37 16–107 

Adult female (>18 years of age) 86 35 30 11–96 

Children (<18 years of age) 35 27 25 15–45 

Hispanic 54 40 34 14–107 

Non-Hispanic 119 34 29 11–-96 

Source: O’Rourke et al. 1999 
LEAD 353 

6. POTENTIAL FOR HUMAN EXPOSURE 

from calcium supplements to blood lead in 21 adults divided into three treatment groups over a 6-month 

period. One treatment group received a complex calcium supplement (carbonate/phosphate/citrate), 

another group received calcium carbonate, and the last, the control group, received no supplement. The 

isotopic composition of the supplements differed from that of the subject’s blood allowing the 

investigators to estimate the contribution of the supplements to PbBs. While the changes from baseline to 

treatment in isotopic composition were significant in the treatment groups, there was no discernable 

increase in PbB concentration during the study. The change in isotopic contribution, however, indicates 

that there is a limited input of lead from the diet into the blood in adults. These results are consistent in 

other investigations that showed minimal gastrointestinal absorption of lead in the presence of calcium in 

adults. 

Plastic food wrappers may be printed with pigments that contain lead chromates. Plastic wrappers used 

for 14 different national brands of bread collected in New Jersey contained a mean concentration of 

26 mg of lead for a bag size of 2,000 cm2

. A survey of 106 homemakers who buy such breads indicated 

that 39% of them reused the bags and 16% of the respondents turned the bags inside out to reuse them, 

suggesting that the potential exists for lead leaching from the paint into the stored food (Weisel et al. 

1991). 

Another source of dietary lead is the use of inadequately glazed or heavily worn earthenware vessels for 

food storage and cooking. Due to the number of incidences of lead poisoning that have resulted from the 

use of earthenware vessels, the FDA has established action levels of 0.5 μg/mL lead for pitchers to 

5.0 μg/mL for cups and mugs soaked for 24 hours in a 4% acetic acid solution (FDA 1992). However, 

inadequately glazed pottery manufactured in other countries continues to pose a significant health hazard. 

Likewise, homemade or craft pottery and porcelain-glazed vessels have been found to release large 

quantities of lead, particularly if the glaze is chipped, cracked, or improperly applied. In addition, glaze 

on vessels that are washed repeatedly may deteriorate, and a vessel that previously met FDA standards 

may become unsafe (CDC 1985; EPA 1986a). 

Blood lead levels measured as a part of the NHANES revealed that between 1976 and 1991, the mean 

PbBs of the U.S. population aged from 1 to 74 years dropped 78%, from 12.8 to 2.8 μg/dL. The 

prevalence of PbBs ≥10 μg/dL also decreased sharply from 77.8 to 4.3%. The major cause of the 

observed decline in PbBs is most likely the removal of 99.8% of lead from gasoline and the removal of 

lead from soldered cans (Pirkle et al. 1994). PbBs were consistently higher for younger children than for 

older children, for older adults than for younger adults, for males than for females, for blacks than for 
LEAD 354 

6. POTENTIAL FOR HUMAN EXPOSURE 

whites, and for central-city residents than for noncentral-city residents. PbBs also correlated with low 

income, low educational attainment, and residence in the Northeast region of the United States. Data 

analyses of the PbBs from NHANES surveys 1991–1994 and 1999–2002 are provided in 

Table 6-12 (CDC 2005a). Geometric means as well as 95% confidence intervals were calculated, and the 

results were organized by age, race/ethnicity, and sex. For 1999–2002, the overall prevelance of elevated 

PbBs (≥10 μg/dL) was 0.7%, down from 2.2% in the 1991–1994 survey. Children aged 1–5 years had the 

highest prevelance, 1.6%, of all age groups for levels ≥10 μg/dL in the 1999–2002 survey. This 

percentage is down from 4.4% in the 1991–1994 NHANES survey (CDC 2005a). Approximately 

310,000 children in this age group were at risk of exposure to harmful levels of lead. The largest decline 

(72%) in elevated PbB in the two surveys, from 11.2 to 3.1%, was among non-Hispanic black children 

aged 1–5 years. In 2000, the year that had been targeted for the elimination of PbBs, >25 μg/dL in 

children aged 6 months–5 years, a total of 8,723 children had been identified with PbBs ≥25 μg/dL. Lead 

surveillance data collected by states between 1997 and 2001 also show a decline in the number of 

children aged 1–5 years with PbBs ≥10 μg/dL from 130,512 in 1997 to 74,887 in 2001 (Meyer et al. 

2003). 

The Adult Blood Lead Epidemiology and Surveillance (ABLES) program, which tracks cases of adult 

(aged ≥16 years) elevated PbBs from workplace exposure, reported updated results from 25 participating 

states for the period 1998–2001 (Roscoe et al. 2002). During that period, the prevalence of adults with 

PbBs ≥25 μg/dL was 13.4 per 100,000 employed adults, compared with 15.2 per 100,000 for 1994–1997. 

For adults with blood lead levels ≥40 μg/dL, the prevalence rate was 2.9 per 100,000 during 1998–2001, 

compared with 3.9 per 100,000 for 1994–1997. ABLES surveillance data from 2004 tracked the blood 

lead levels of females of childbearing age (16–44 years) in 37 different states (CDC 2007). The results 

indicated that 0.06 per 100,000 had PbBs ≥40 μg/dL, 0.7 per 100,000 had PbBs ≥25 μg/dL, 3.9 per 

100,000 had PbBs ≥10 μg/dL, and 10.9 per 100,000 had PbBs ≥5 μg/dL (CDC 2007). 

A 1992 survey of lead in blood of 492 Inuit adults from the Arctic region of Quebec, Canada resulted in 

geometric mean lead concentrations of 0.42 μmol/L, with a range of 0.04–2.28 μmol/L. Analysis of 

variance revealed that smoking, age, and consumption of waterfowl were associated with elevated lead 

levels (Dewailly et al. 2001). A Swedish study was aimed at characterizing PbBs in 176 men and 

248 women, 49–92 years of age (Baecklund et al. 1999). Blood lead levels ranged from 5.6 to 150 μg 

Pb/L (median 27 μg Pb/L) and were higher in men than in women (median 30 versus 24 μg Pb/L). In 

both men and women, PbBs decreased between 50 and 70 years of age, which was thought to be a result 

of decreased energy intake. In women, PbBs peaked at 50–55 years of age, which is probably related to 
LEAD 355 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-12. Geometric Mean Blood Lead Levels (μg/dL) and the 95th Percentile 

Confidence Interval, by Race/Ethnicity, Sex, and Age 

Sex/age Number in All racial/ethnic White, non- Black, non- Mexican 

(years) sample groups Hispanic Hispanic American 

NHANES 1991–1994 geometric mean (95% confidence interval) 

Both sexes 

≥1 13,472 2.3 (2.1–2.4) 2.2 (2.0–2.3) 2.8 (2.5–3.0) 2.4 (2.3–2.6) 

1–5 2,392 2.7 (2.5–3.0) 2.3 (2.1–2.6) 4.3 (3.6–5.0) 3.1 (2.7–3.5) 

6–19 2,960 1.7 (1.5–1.8) 1.5 (1.4–1.7) 2.3 (2.1–2.6) 2.0 (1.8–2.1) 

20–59 5,596 2.2 (2.1–2.3) 2.1 (2.0–2.2) 2.6 (2.4–2.8) 2.5 (2.4–2.6) 

≥60 2,524 3.4 (3.2–3.5) 3.3 (3.2–3.4) 4.3 (3.7–4.9) 3.1 (2.7–3.6) 

Males 

≥1 6,204 2.8 (2.6–2.9) 2.6 (2.5–2.8) 3.6 (3.3–4.0) 3.1 (2.9–3.3) 

1–5 1,211 2.8 (2.5–3.1) 2.3 (2.1–2.6) 4.7 (3.9–5.5) 3.3 (2.9–3.6) 

6–19 1,443 1.9 (1.7–2.1) 1.7 (1.5–1.9) 2.7 (2.4–3.1) 2.3 (2.0–2.5) 

20–59 2,365 2.9 (2.7–3.1) 2.7 (2.5–3.0) 3.6 (3.2–3.9) 3.4 (3.2–3.6) 

≥60 1,185 4.2 (4.0–4.4) 4.0 (3.8–4.2) 6.3 (5.4–7.1) 4.1 (3.5–4.8) 

Female 

≥1 7,268 1.9 (1.8–2.0) 1.8 (1.7–1.9) 2.2 (2.0–2.4) 1.9 (1.8–2.1) 

1–5 1,181 2.7 (2.4–2.9) 2.3 (2.0–2.6) 4.0 (3.2–4.8) 2.9 (2.4–3.4) 

6–19 1,517 1.5 (1.3–1.7) 1.4 (1.2–1.6) 2.0 (1.7–2.2) 1.7 (1.5–1.9) 

20–59 3,231 1.7 (1.6–1.8) 1.6 (1.5–1.7) 1.9 (1.8–2.1) 1.8 (1.7–1.9) 

≥60 1,339 2.9 (2.7–3.0) 2.8 (2.7–3.0) 3.3 (2.8–3.8) 2.5 (2.1–2.9) 

NHANES 1999–2002 geometric mean (95% confidence interval) 

Both sexes 

≥1 16,825 1.6 (1.5–1.6) 1.5 (1.5–1.6) 1.8 (1.7–1.9) 1.6 (1.6–1.7) 

1–5 1,160 1.9 (1.8–2.1) 1.8 (1.6–2.0) 2.8 (2.5–3.1) 1.9 (1.8–2.0) 

6–19 6,283 1.1 (1.1–1.2) 1.1 (1.0–1.1) 1.5 (1.4–1.6) 1.3 (1.2–1.4) 

20–59 5,876 1.5 (1.5–1.6) 1.5 (1.4–1.5) 1.7 (1.6–1.8) 1.8 (1.6–1.9) 

≥60 3,056 2.2 (2.1–2.3) 2.2 (2.1–2.3) 2.7 (2.5–2.8) 2.1 (1.9–2.3) 

Males 

≥1 8,202 1.9 (1.8–2.0) 1.9 (1.8–1.9) 2.1 (1.4–1.6) 2.0 (1.9–2.2) 

1–5 846 1.9 (1.8–2.1) 1.8 (1.6–2.0) 2.8 (2.5–3.2) 2.0 (1.8–2.1) 

6–19 3,158 1.3 (1.3–1.4) 1.2 (1.1–1.3) 1.7 (1.5–1.8) 1.5 (1.4–1.6) 

20–59 2,689 2.0 (1.9–2.0) 1.9 (1.8–2.0) 2.1 (2.0–2.3) 2.3 (2.2–2.5) 

≥60 1,509 2.7 (2.6–2.8) 2.6 (2.5–2.7) 3.4 (3.1–3.6) 2.6 (2.3–2.8) 

Female 

≥1 8,623 1.3 (1.3–1.3) 1.3 (1.2–1.3) 1.5 (1.4–1.6) 1.3 (1.2–1.4) 

1–5 764 1.9 (1.8–2.1) 1.8 (1.5–2.1) 2.8 (2.5–3.2) 1.8 (1.7–2.0) 

6–19 3,125 1.0 (0.9–1.0) 0.9 (0.8–1.0) 1.3 (1.2–1.5) 1.1 (1.0–1.2) 

20–59 3,187 1.2 (1.2–1.2) 1.2 (1.1–1.2) 1.4 (1.3–1.5) 1.3 (1.2–1.4) 

≥60 1,547 1.9 (1.8–2.0) 1.9 (1.8–2.0) 2.3 (2.1–2.4) 1.8 (1.6–2.0) 

Source: CDC 2005a 
LEAD 356 

6. POTENTIAL FOR HUMAN EXPOSURE 

postmenopausal bone mineralization. Increases in PbBs after age 70 was thought to be a result from 

higher lead exposure in the past for this group. Nash et al. (2004) reported median adjusted PbBs that 

were 25–30% higher than for premenopausal women (2.0 μg/dL). Users of hormone replacement therapy 

had significant lower median PbBs. Lead stored in the bones of women is released into the blood during 

post menopausal bone mineral resorption. 

Mourning doves and other game birds consume lead pellets from hunting fields for grit. Recreational and 

subsistence hunters and their families who consume large amounts of these birds may ingest lead from 

this source (Burger et al. 1998). 

Lead is a component of tobacco and tobacco smoke, and smokers often have higher lead blood levels than 

nonsmokers (Bonanno et al. 2001; Mannino et al. 2003). Using data from the NHEXAS EPA Region V 

study, PbB levels in smokers and nonsmokers were analyzed and a correlation between tobacco smoke 

and exposure levels was observed (Bonanno et al. 2001). The mean PbBs in smokers, nonsmokers 

exposed to environmental tobacco smoke (ETS), and nonsmokers without ETS were 2.85, 2.06, and 

1.81 μg/dL, respectively (Bonanno et al. 2001). 

Table 6-13 provides geometric means and selected percentiles of lead levels in the urine in segments of 

the U.S. population (CDC 2003, 2005b). These data will continue to be updated as new information 

becomes available. 

Information on occupational exposure to lead is obtained primarily from the National Occupational 

Exposure Survey (NOES) and industry surveys of workers. While occupational exposure is widespread, 

environmental monitoring data on levels of exposure in many occupations are not available. OSHA has 

established a permissible exposure limit (PEL) for lead of 50 μg/m3

 for workplace air (OSHA 2005d; 

Tripathi and Llewellyn 1990). NIOSH has estimated that >1 million American workers were 

occupationally exposed to inorganic lead in >100 occupations (NIOSH 1978a). According to NOES, 

conducted by NIOSH between 1980 and 1983, an estimated 25,169 workers were exposed to tetraethyl 

lead (not used in gasoline since December 31, 1995); approximately 57,000 employees were exposed to 

various lead oxides mostly in nonferrous foundries, lead smelters, and battery plants; 3,902 workers were 

exposed to lead chloride; and 576,579 workers were exposed to some other form of lead in the workplace 

in 1980 (NIOSH 1990). Workers who operate and maintain solid waste incinerators are also exposed to 

air lead levels as high as 2,500 μg/m3

 (Malkin et al. 1992). 
LEAD 357 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-13. Geometric Mean and Selected Percentile Urine Concentrations (μg/L) 

of Lead in the U.S. Population From 1999 to 2002 

Group and survey 

years 

Geometric 

mean 50th 75th 

Percentile 

90th 95th Sample size 

Age 6 and older 

1999–2000 

2001–2002 

0.766 

0.677 

0.800 

0.600 

1.30 

1.20 

2.10 

2.00 

2.90 

2.60 

2,465 

2,690 

6–11 Years 

1999–2000 1.07 1.00 1.50 2.40 3.40 340 

2001–2002 0.753 0.800 1.20 2.00 2.60 368 

12–19 Years 

1999–2000 0.659 0.600 1.10 1.70 2.20 719 

2001–2002 0.564 0.600 0.900 1.50 1.90 762 

20 Years and older 

1999–2000 

2001–2002 

0.752 

0.688 

0.700 

0.700 

1.40 

1.20 

2.10 

1.90 

2.90 

2.80 

1,406 

1,560 

Males 

1999–2000 

2001–2002 

0.923 

0.808 

0.900 

0.700 

1.60 

1.30 

2.40 

2.40 

3.40 

3.20 

1,227 

1,335 

Females 

1999–2000 

2001–2002 

0.642 

0.573 

0.600 

0.500 

1.20 

1.00 

1.90 

1.50 

2.40 

2.20 

1,238 

1,335 

Mexican Americans 

1999–2000 1.02 1.00 1.70 2.80 4.10 884 

2001–2002 0.833 0.80 1.50 2.40 3.20 683 

Non-Hispanic blacks 

1999–2000 1.11 1.10 1.90 2.90 4.20 568 

2001–2002 0.940 0.900 1.50 2.60 3.70 667 

Non-Hispanic whites 

1999–2000 0.695 0.700 1.30 1.90 2.60 882 

2001–2002 0.610 0.600 1.00 1.80 2.40 1,132 

Source: CDC 2003, 2005b 
LEAD 358 

6. POTENTIAL FOR HUMAN EXPOSURE 

Potentially high levels of lead may occur in the following industries: lead smelting and refining 

industries, battery manufacturing plants, steel welding or cutting operations, construction, rubber products 

and plastics industries, printing industries, firing ranges, radiator repair shops and other industries 

requiring flame soldering of lead solder (EPA 1986a; Feldman 1978; Goldman et al. 1987; NIOSH 

1978a). In these work areas, the major routes of lead exposure are inhalation and ingestion of leadbearing dusts and fumes. In the smelting and refining of lead, mean concentrations of lead in air can 

reach 4,470 μg/m3

; in the manufacture of storage batteries, mean airborne concentrations of lead from 

50 to 5,400 μg/m3

 have been recorded; and in the breathing zone of welders of structural steel, an average 

lead concentration of 1,200 μg/m3

 has been found (Fu and Boffetta 1995). Evaluations by NIOSH from 

1979 to 1990 in radiator repair shops found that 68% of the workers sampled had airborne lead exposures 

exceeding the OSHA standard of 0.05 mg/m3

 (Tharr 1993). Also, past studies of PbBs of 56 radiator 

shop mechanics in the Boston area revealed that 80% had PbBs >30 μg/dL and 16 had PbBs exceeding 

50 μg/dL (Tharr 1993). 

Studies have been conducted to determine exposure of firearm instructors to lead at outdoor firing ranges 

when either nonjacketed (pure lead) or jacketed (copper-coated) bullets were used. Instructors are likely 

to have higher exposure than shooters because they spend more time at the range. In studies at an outdoor 

range in Virginia, the mean breathing zone lead level when nonjacketed bullets were fired was 

67.1 μg/m3

 for one instructor and 211.1 μg/m3 for another (Tripathi and Llewellyn 1990). When jacketed 

bullets were used, breathing zone levels decreased to 8.7 μg/m3

 or less. PbBs of the instructors did not 

exceed the OSHA return standard of 1.93 μmol/L (40 μg/dL) or removal standard of 2.4 μmol/L 

(50 μg/dL) in either case. When shooters fired conventional lead bullets, their mean exposures to 

airborne lead were 128 μg/m3

 in the personal breathing zone and 68 μg/m3 in the general area. When 

totally copper-jacketed lead bullets were fired, the mean breathing zone and general area air sample 

concentrations were 9.53 and 5.80 μg/m3

, respectively (Tripathi and Llewellyn 1990). At an outdoor 

uncovered range in Los Angeles, instructors who spent an average of 15–20 hours/week behind the firing 

line were found to be exposed to breathing zone lead concentrations of 460 and 510 μg/m3

 measured as 

3-hour, time-weighted averages. The PbB of one instructor reached 3.38 μmol/L (70 μg/dL). After 

reassignment to other duties, repeat testing indicated his PbB had dropped to 1.35 μmol/L (28 μg/dL) 

(Goldberg et al. 1991). 

In 1991, NIOSH conducted a survey of the Federal Bureau of Investigations (FBI) Firearms Training Unit 

firing ranges and related facilities to determine occupational lead exposures among FBI and Drug 

Enforcement Agency (DEA) firing range personnel (NIOSH 1996). Sixty-one personal breathing-zone 
LEAD 359 

6. POTENTIAL FOR HUMAN EXPOSURE 

and 30 area samples for airborne lead were collected. Exposures ranged up to 51.7 μg/m3 (mean, 

12.4 μg/m3

), 2.7 μg/m3 (mean, 0.6 μg/m3), and 4.5 μg/m3 (mean, 0.6 μg/m3) for range instructors, 

technicians, and gunsmiths, respectively. Exposure of custodians ranged from nondetectable to 

220 μg/m3

 during short-term cleaning of a large indoor range. Carpet dust sampling of dormitory rooms 

of students who practiced at the firing ranges revealed statistically significant (p<0.0005) higher dust-lead 

concentrations when compared to nonstudent dormitories (dust-lead concentration range of 116–546 μg/g 

with a geometric mean of 214 μg/g in the student's rooms versus a dust-lead concentration range of 50– 

188 μg/g with a geometric mean of 65 μg/g for the nonstudent rooms). This suggested that the students 

were contaminating their living quarters with lead. 

Field surveys of three radiator repair shops in the Cincinnati area revealed that local exhaust ventilation 

(LEV) systems are effective in controlling airborne lead levels. The highest concentration of airborne 

lead measured during a brief period of continuous soldering in a shop equipped with an LEV was only 

7.1 μg/m3

. In a shop where no LEV was used, the 13 personal samples averaged 209 μg/m3 with a 

maximum of 810 μg/m3

 measured for a 56-minute sample worn while tearing down and resoldering a 

single radiator (Tharr 1993). 

Airborne dusts settle onto food, water, clothing, and other objects, and may subsequently be transferred to 

the mouth. A study suggests that lead, applied to the skin as lead acetate or lead nitrate, was rapidly 

absorbed through the skin and was detected in sweat, blood, and urine within 6 hours of application 

(Stauber et al. 1994). In this study, 4.4 mg of lead was applied to the skin under a covered wax/plastic 

patch on the forearms of human subjects; of the applied dose, 1.3 mg of lead was not recovered from skin 

washings. The amount that actually remained in (or on) the skin and the mass balance of the fate of this 

lead was not determined; it may have been dermally absorbed or eliminated from the skin by exfoliation 

of epidermal cells. Thus, while this study provides evidence for dermal absorption of lead, it did not 

quantify the fraction of applied dose that was absorbed. The quantitative significance of the dermal 

absorption pathway as a contributor to lead body burden remains uncertain. 

In these occupational areas, good housekeeping and good ventilation have a significant impact on the 

extent of worker exposure. Workers who were (or are) involved in the production of gasoline additives, 

tetraethyl lead and tetramethyl lead (now banned from highway use in the United States) are exposed to 

both inorganic lead and alkyl lead. The major potential hazard to these workers appears to be from 

dermal exposure since alkyl leads may be absorbed through the skin (Bress and Bidanset 1991; EPA 

1986a). Others who may be occupationally exposed to lead are artists and crafts persons who may be 
LEAD 360 

6. POTENTIAL FOR HUMAN EXPOSURE 

exposed to lead used in paints, ceramic glazes, and lead solder for sculpture and stained glass (Fischbein 

et al. 1992; Hart 1987) and welders where lead concentrations in the welding fumes generated by gas 

metal arc welding of carbon steel ranged from 1.0 to 17.6 μg/m3

, well below the established PEL for the 

workplace (Larson et al. 1989). A study conducted at two lead battery factories in Taiwan revealed a high 

correlation between ambient air concentration of lead and PbBs in workers; improvement of hygienic 

practices proved to be more effective at lowering PbBs than reducing the ambient air lead concentration 

(Lai et al. 1997). 

Lead exposure is frequently monitored by biological testing (e.g., determination of urinary lead levels, 

PbBs, urinary coproporphyrin levels, or δ-aminolevulinic acid [ALA] levels) rather than monitoring the 

workplace environment for lead concentrations (EPA 1986a; NIOSH 1978a). An employer survey of 

California industries that use lead indicated that 229,434 employees were potentially exposed to lead in 

the workplace; of these workers, 59,142 (25%) had received routine biological monitoring (i.e., 

determination of PbBs), and only 24,491 (10%) were in positions where environmental monitoring 

(workplace air lead levels) had ever been conducted. In addition, approximately 12% of the potentially 

exposed individuals were in the construction industry (OSHA 1993; Rudolph et al. 1990). 

Workers in an electronic components plant that makes ceramic-coated capacitors and resistors using 

leaded glass for the ceramic coating were found to be exposed to ambient lead levels ranging from 61 to 

1,700 μg/m3

, and to have PbBs ranging from 16 to 135 μg/dL. Approximately 30% of the workforce was 

found to be on medical leave as a result of their PbBs exceeding 40 μg/dL. An analysis of PbBs among 

family members of the exposed workers gave revealed levels of 10.2 μg/dL compared with 6.2 μg/dL for 

families of nonexposed workers, indicating possible secondary occupational exposure from workers to 

their families (Kaye et al. 1987). 

Data from the NHANES III was used to compile statistics regarding the PbBs in U.S. workers (Yassin et 

al. 2004). The greatest levels tended to occur in mechanical and construction trades, while the lowest 

levels were observed for workers involved in professional labor categories such as managerial positions 

and health care professionals. Lead levels increased with age, decreased with education level, and male 

workers had a much higher geometric mean blood level, 3.3 μg/dL, than female workers, 1.8 μg/dL. 

Tables 6-14 and 6-15 summarize the results from these data for different industries and occupations. 

Okun et al. (2004) evaluated trends in occupational lead exposure in U.S. industries following the 

establishment of the general industrial lead standard in 1978 and the construction lead standard in 1993. 

They used data collected by OSHA under their compliance and consultation programs. On the basis of 
LEAD 361 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-14. Median, Range, and Weighted Geometric Mean Blood Lead Levels in 

U.S. Workers, Ages 18–64 in 1988–1994 

μg/dL 

Occupation Number of workers Median Range WGM (GSD) 

Vehicle mechanics 169 5.10 0.70–28.10 4.80 (3.88) 

Food service workers 700 2.30 0.70–27.00 2.00 (2.69) 

Management, professional, 

technical and sales 4,768 2.20 0.70–39.40 2.13 (4.05) 

Personal service workers 1,130 2.90 0.70–25.90 2.48 (4.52) 

Agricultural workers 498 3.80 0.70–23.40 2.76 (4.02) 

Production workers: machine 

operators, material movers, etc. 1,876 3.30 0.70–52.90 2.88 (4.24) 

Laborers other than construction 137 4.70 0.70–21.80 3.47 (3.36) 

Transportation workers 530 3.85 0.70–22.30 3.49 (5.10) 

Mechanics other than vehicles 227 4.10 0.70–16.60 3.50 (4.91) 

Construction trades people 470 4.30 0.70–16.90 3.66 (4.64) 

Construction workers 122 4.70 1.20–36.00 4.44 (7.84) 

Health service workers 499 2.00 0.70–22.40 1.76 (2.24) 

All 11,126 2.80 0.70–52.90 2.42 (6.93) 

GSD = geometric standard deviation; WGM = weighted geometric mean 

Source: Yassin et al. 2004 
LEAD 362 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-15. Median, Range, and Weighted Geometric Mean Blood Lead Levels in 

U.S. Workers, Ages 18–64 by Industrial Categoriesa 

Number of Blood lead (μg/dL) 

Industry workers Median Range WGM (GSD) 

Repair services (SIC 75–76) 188 4.80 0.70–28.10 4.54 (5.05) 

Wholesale and retail trade (SIC 50–59) 2,229 2.50 0.70–39.40 2.25 (3.38) 

Finance, insurance, and real estate (SIC 60– 1,117 2.40 0.70–28.70 2.30 (2.74) 

65, 67) 

Agriculture (SIC 01–02, 07–08) 493 3.80 0.70–23.40 2.68 (4.09) 

Transportation and utility (SIC 40–49) 764 3.10 0.70–22.30 2.58 (3.49) 

Manufacturing (SIC 20–32, 34–39) 2,008 3.10 0.70–41.80 2.66 (4.51) 

Metal (SIC 33) 188 3.80 0.70–52.90 3.50 (2.91) 

Construction (SIC 15–17) 671 4.40 0.70–36.00 3.68 (5.66) 

Mining (SIC 10, 12–14 41 3.90 1.10–12.90 4.66 (6.23) 

Services (SIC 770, 72–73, 78–79, 80–84, 86– 3,449 2.30 0.70–23.70 2.05 (4.39) 

89, 91–97) 

All 11,148 2.80 0.70–52.90 2.42 (6.93) 

a

Working population aged 18–64: U.S. Third National Health and Nutrition Examination Survey, 1988–1994 

GSD = standard deviation of geometric mean, SIC = standard industrial code; WGM = weighted geometric mean 

Source: Yassin et al. 2004 
LEAD 363 

6. POTENTIAL FOR HUMAN EXPOSURE 

these data, there has been a decline in occupational lead exposures for general industry facilities since 

1979. The median exposure level for these facilities declined 5–10-fold. With the exception of retail 

trade, these declines were for the major industry divisions and the majority of four-digit SIC codes 

including some high risk industries. A decline was not observed in the construction industry, but in this 

case, the data are only for a limited number of years. 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

The American Academy of Pediatrics (AAP) (1998) has concluded that although monitoring data 

demonstrate a decline in the prevalence of PbBs, lead remains a common, preventable, environmental 

health threat. The AAP supports the CDC guidelines endorsing universal screening in certain areas and 

targeted screening for children at high risk (CDC 1997c). Many children continue to be at risk for 

ingestion of lead-based paint and of soil and dust contaminated through the deterioration of lead-based 

paint and the residues from combustion of leaded gasoline. A 1974 study indicated that elevated PbBs in 

children were most likely a result of ingesting lead-contaminated soil, and that the most likely source was 

lead-based paint rather than lead from automotive exhaust (Ter Haar and Aronow 1974). However, 

subsequent data have shown that children with the highest PbBs live in areas with high traffic flow where 

lead particles in the air may fall directly to the soil or adhere to the outer surfaces of building and wash to 

the soil with rain (Mielke et al. 1989). Studies of children in Minnesota showed that PbBs in children 

were correlated with soil lead levels, which were highest in inner-city areas; soil lead levels and PbBs 

were not correlated with the age of housing, although the presence of lead-based paint or lead abatement 

procedures may be of significance for individual children (Mielke et al. 1989). The CDC has concluded 
LEAD 364 

6. POTENTIAL FOR HUMAN EXPOSURE 

that the most common source of lead exposure for children is lead-based paint that has deteriorated into 

paint chips and lead dusts (CDC 1997b). 

The results of successive NHANES monitoring studies suggest that from 1976 to 2002, PbBs have 

declined, but were consistently higher for younger children than for older children (CDC 1997b, 1997d, 

2003, 2005a, 2005b; Pirkle et al. 1994). In general, PbBs also correlated with low income, low 

educational attainment, and residence in the Northeast region of the United States. Data from Phase II of 

NHANES III (conducted during October 1991 to September 1994) and the most recent data (1999–2002) 

indicate that PbBs in the U.S. population aged ≥1 year continued to decrease and that PbBs among 

children aged 1–5 years were more likely to be elevated among those who were poor, non-Hispanic black, 

living in large metropolitan areas, or living in older housing (with potential exposure to lead from leadbased paint) (CDC 1997b, 2003. 2005a, 2005b; Pirkle et al. 1998). During 1991–1994, the overall 

geometric mean PbB of the population aged ≥1 year was 2.3 μg/dL. Among those aged 1–5 years, 

approximately 4.4% had PbBs ≥10 μg/dL, representing an estimated 930,000 children in the general 

population with levels high enough to be of concern (CDC 1997b). In addition, 1.3% of children aged 1– 

5 years had PbBs ≥15 μg/dL and 0.4% had PbBs ≥20 μg/dL. For the NHANES III Phase II data, the 

geometric mean PbBs were higher for children aged 1–2 years (3.1 μg/dL) than for children aged 3– 

5 years (2.5 μg/dL) (CDC 1997b). For the most recent 1999–2002 NHANES sample, the geometric mean 

PbB for children ≥1 year was 1.6 μg/dL and among those aged 1–5 years, approximately 1.6% had PbBs 

≥10 μg/dL (CDC 2005a). These data have been summarized in Table 6-12. 

The U.S. Navy instituted a pediatric lead surveillance program in 1995 because of public health concerns 

over pediatric PbBs (Bohnker et al. 2003). The database contained 38,502 samples from 1995 to 

2001 with 1.6% containing levels ≥10 μg/dL. Samples were obtained at the time of the 12-month wellchild visit. Results were similar to those for the NHANES survey. 

Fetuses are at even greater risk. As discussed in Section 3.5, lead can readily cross the placenta; 

therefore, exposure of women to lead during pregnancy results in uptake by the fetus. Furthermore, since 

the physiological stress of pregnancy may result in mobilization of lead from maternal bone, fetal uptake 

of lead can occur from a mother who was exposed to lead before pregnancy, even if no lead exposure 

occurs during pregnancy. Prenatal exposure may be related to postnatal mental retardation, impaired 

postnatal neurobehavioral development, and reduced birth weight and gestational age (EPA 1986a). 
LEAD 365 

6. POTENTIAL FOR HUMAN EXPOSURE 

Maternal PbBs during pregnancy were significantly higher for a group of 1,428 immigrant women 

(geometric mean, 2.3 μg/dL) than for a group of 504 non-immigrant women (geometric mean, 1.9 μg/dL) 

in a study conducted at a medical center in South Central Los Angeles, one of the most economically 

depressed regions in California. Immigrant PbBs were strongly dependent on time elapsed since 

immigration to the United States, with PbBs being highest in those women who had immigrated most 

recently. Elevated PbBs in immigrant women were also associated with pica and with low dietary 

calcium during pregnancy (Rothenberg et al. 1999a, 1999b). 

Lead concentrations in maternal and umbilical cord blood have been reported by Greek researchers for 

50 parturient women at delivery. Twenty-five of the women lived in industrial areas with high air 

pollution, and 25 lived in agricultural areas with low air pollution. The mean lead concentrations 

(expressed as mean±SD) for the women living in areas with high air pollution were 3.72±0.47 μg/dL in 

maternal blood and 2.0±0.34 μg/dL in umbilical cord blood (correlation coefficient, r=0.57). The mean 

lead concentrations for the women living in areas with low air pollution were 2.05±0.56 μg/dL in 

maternal blood and 1.29±0.36 μg/dL in umbilical cord blood (correlation coefficient, r=0.70). The 

authors concluded that the placenta demonstrates a dynamic protective function that is amplified when 

maternal PbBs are raised (Vasilios et al. 1997). 

Concentrations of lead in umbilical cord blood of two groups of women giving birth in a Boston Hospital 

in 1980 and 1990 have also been reported. Mean lead concentrations of umbilical cord blood were 

6.56±3.19 μg/dL for the 1980 group and 1.19±1.32 μg/dL for the 1990 group (Hu et al. 1996b). 

In a study of blood samples collected from 113 mothers of 23 different nationalities and from their 

neonates (cord blood), mean maternal PbBs were 14.9±2.14 μg/dL (range, 6.6–27.8 μg/dL) and mean 

cord PbBs were 13±2.5 μg/dL (range, 6.0–30 μg/dL). Sixteen percent of mothers and nearly 10% of cord 

blood samples had PbBs >20 μg/dL (Al Khayat et al. 1997b). 

Malcoe et al. (2002) assessed lead sources and their effect on blood lead in rural Native American and 

white children living in a former mining region. Blood samples, residential environmental samples (soil, 

dust, paint, water) and caregiver interviews (hand-mouth behaviors, socioeconomic conditions) were 

obtained from a representative sample of 245 children ages 1–6. There were no ethnic differences in the 

results. However poor children were especially vulnerable. Regression analysis showed that mean floor 

dust lead loading >10.1 μg/ft2

 and yard soil lead >165.3 mg/kg were independently associated with blood 

lead levels ≥10 μg/dL. 
LEAD 366 

6. POTENTIAL FOR HUMAN EXPOSURE 

FDA estimated that in 1990, toddlers (2-year-olds) received 16% of their total lead exposure from food 

(5 μg/day), 1% from soil, 7% from water, and 75% from dust. EPA estimated that in 1990 lead intake 

from U.S. drinking water would be 11.9 μg/day for a 6-year-old child and 7.5 μg/day for an infant <1 year 

old (Cohen 1988). A study of lead in the diet of Canadian infants found an average intake by children 0– 

1 years of age to be 16.5 μg/day when both food and water ingestion were considered (Dabeka and 

McKenzie 1988). 

Lead intoxication has been observed in children, but rarely in adults, in residential settings (Sedman 

1989). The geometric mean blood lead level for children has dropped dramatically since the late 1970s. 

Results summarizing the CDC NHANES II and NHANES III, Phases I and II, study of blood lead levels 

for children aged 1–5 years are provided in Table 6-16 (CDC 1997b, 1997d, 2005a). 

In 1982–1983, the baseline value for daily intake of lead by inhalation in a nonurban environment was 

estimated to be 0.5 μg/day for a 2-year-old child. The baseline value was based on an average 

atmospheric lead concentration of 0.1 μg/m3

 and an indoor/outdoor lead concentration ratio of 0.5. In an 

urban environment, the indoor/outdoor ratio was assumed to be approximately 0.8 (EPA 1986a). Drastic 

reductions in the lead content of gasoline since 1986 have resulted in a 64% decrease in lead emissions to 

the atmosphere (see Section 6.4.1). 

The lead content of dusts can be a significant source of exposure, especially for young children. Baseline 

estimates of potential human exposure to dusts, including intake due to normal hand-to-mouth activity, 

are 0.2 g/day for children 1–6 years old versus 0.1 g/day for adults when both indoor and outdoor 

ingestion of soil including dust is considered (EPA 1989c). For children who engage in pica behavior, the 

ingestion rate of soil can be as high as 5 g/day. Although ingestion of lead-containing paint may lead to 

elevated PbBs in young children, the major source of moderately elevated PbBs (30–80 μg/dL) in inner 

city children is most likely to be contaminated household dust and subsequent hand contamination and 

repetitive mouthing (Charney et al. 1980). Weathering of lead-based paint can contribute to the lead 

content of dust and soil. Lead levels of indoor dust and outdoor soil were found to be strongly predictive 

of PbBs in over 200 urban and suburban infants followed from birth to 2 years of age; however, the PbBs 

were not correlated with indoor air or tap water lead levels, nor the size of nearby roadways. Indoor dust 

lead levels and soil lead levels in the homes of children with high PbBs (>8.8 μg/dL) were 72 μg/wipe 

(window sill dust) and 1,011 μg/g, respectively; children with low PbBs (<3.7 μg/dL) were exposed to 

22 μg/wipe and 380 μg/g, respectively. In addition, 79% of the homes of children with high PbBs had 
LEAD 367 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-16. Blood Levels of Lead in Children (1–5 Years) in 1976–2002 

NHANES 

Children (1–5 Years) 1976–1980 1988–1991 1991–1994 1999–2002 

Geometric mean (μg/dL) 15.0 3.6 2.7 1.9 

Blood lead ≥10 μg/dL 88.2% 8.9% 4.4% 1.6% 

NHANES = National Health and Nutrition Examination Survey 

Sources: CDC 1997b, 1997d, 2005a; Pirkle 1994 
LEAD 368 

6. POTENTIAL FOR HUMAN EXPOSURE 

been renovated, while only 56% of the homes of children with low PbBs had been renovated, suggesting 

that renovating the interior of homes previously painted with leaded paint may increase, at least 

temporarily, a child's exposure to lead dust (Rabinowitz et al. 1985). Regular use of dust control methods 

(e.g., wet mopping of floors, damp-sponging of horizontal surfaces, high-efficiency vacuum cleaner) has 

been shown in some, although not all, cases to reduce indoor dust, lead dust, and blood lead levels in 

some, although not all, older homes containing leaded paints (Lanphear et al. 2000b; Rhoads et al. 1999). 

Decreases of between 17 and 43% in blood lead concentrations were observed in children where regular 

dust control methods had been used to reduce indoor levels of lead (Rhoads et al. 1999). 

Lanphear and Roghmann (1997) and Lanphear et al. (1996a, 1996b, 1998b) studied factors affecting 

PbBs in urban children and found the following independent predictors of children's PbBs: dust lead 

loading in homes, African-American race/ethnicity, soil lead levels, ingestion of soil or dirt, lead content 

and condition of painted surfaces, and water lead levels (Lanphear et al. 1996a). Differences in housing 

conditions and exposures to lead-containing house dust appear to contribute to the racial differences in 

urban children's PbBs. In addition, white children were more likely to put soil in their mouths (outdoor 

exposure) and suck their fingers, and African-American children were more likely to put their mouths on 

window sills (indoor exposure) and to use a bottle. Exterior lead exposures were more significant for 

white children, and interior lead exposures were more significant for African-American children 

(Lanphear et al. 1996b). Mouthing behaviors are an important mechanism of lead exposure among urban 

children (Lanphear and Roghmann 1997). Community characteristics such as residence within a city, 

proportion of African Americans, lower housing value, housing built before 1950, higher population 

density, higher rates of poverty, lower percent of high school graduates, and lower rates of owneroccupied housing have been used to identify children with elevated blood levels (Lanphear et al. 1998b). 

An analysis of children's PbBs and multiple measures of lead concentrations in household dust, water, 

soil, and paint has been used to predict the effect of changing concentrations of lead in environmental 

media on children's PbBs. An increase in dust lead loading from background to 200 μg/ft2

 was estimated 

to produce an increase of 23.3% in the percentage of children estimated to have a PbB >10 μg/dL; an 

increase in water lead concentration from background to 15 μg/L was estimated to produce an increase of 

13.7% in the percentage of children estimated to have a PbB level >10 μg/dL; and an increase in soil lead 

concentration from background to 400 μg/g was estimated to produce an increase of 11.6% in the 

percentage of children estimated to have a PbB level >10 μg/dL (Lanphear et al. 1998a). 

Outdoor lead dust was found to be a more potent contaminant of children's hands than indoor dust at day 

care centers in New Orleans; boys, in general, had higher hand lead levels than girls. The conclusions 
LEAD 369 

6. POTENTIAL FOR HUMAN EXPOSURE 

were based on lead analysis of hand wipe samples taken before and after children played outdoors at four 

different day care centers (a private inner-city site, a private outer-city site, a public inner-city site, and a 

public outer-city site). The private inner-city site had a severely contaminated outdoor play area with 

measured soil lead concentrations ranging from 287 to 1,878 mg/kg. The outdoor play area at the public 

inner-city site, where children exhibited the lowest hand lead measurements of any site in the study, had 

been completely paved over with concrete or rubberized asphalt and had well-maintained equipment 

(Viverette et al. 1996). 

EPA conducted the Urban Soil Lead Abatement Demonstration Project (USLADP), also known as the 

“Three City Lead Study,” in Boston, Baltimore, and Cincinnati (EPA 1996c). The purpose was to 

determine whether abatement of lead in soil could reduce PbBs of inner-city children. No significant 

evidence was found that soil abatement had any direct impact on children’s PbBs in either the Baltimore 

or Cincinnati studies. In the Boston study, however, a mean soil lead reduction of 1,856 ppm resulted in a 

mean decline of 1.28 μg/dL PbB at 11 months postabatement (Weitzman et al. 1993). Phase II extended 

the study to 2 years and included soil abatement of the two comparison areas from Phase I (Aschengrau et 

al. 1994). Combined results from Phase I and II suggested a higher impact of soil remediation on PbBs 

(2.2–2.7 μg/dL). EPA reanalyzed the data from the USLADP in an integrated report (EPA 1996c). They 

concluded that when soil is a significant source of lead in the child’s environment, under certain 

conditions, the abatement of that soil will result in a reduction in exposure and consequently, PbB level. 

Crump (1997) criticized the Boston data, including EPA’s integrated report, for poor selection of 

statistical methods, failure to adequately examine confounding variables, selective interpretation of 

results, and lack of control group in phase II of the study. Regardless, his reevaluation of the data, based 

on randomization analysis, resulted in a significant, yet modest effect of soil abatement (1.37 μg/dL) 

consistent with the conclusions of Weitzman et al. (1993) (1.28 μg/dL). Clearly, the results of the 

USLADP suggest that a number of factors are important in determining the influence of soil remediation 

on PbBs in children. These include the site-specific exposure scenario, the magnitude of the remediation, 

and the magnitude of additional sources of lead exposure. 

Authors of a study of PbBs in children in Toronto, Canada, before and after abatement of leadcontaminated soil and house dust found that they could neither strongly support nor refute beneficial 

effects of abatement. The failure to reach a definite conclusion from the results of the study, which 

included data from 12 cross-sectional blood-screening surveys that were conducted over an 8-year period, 

was due in part to a low response rate (32–75%) to questionnaires used to determine behavioral, 
LEAD 370 

6. POTENTIAL FOR HUMAN EXPOSURE 

household, lifestyle, neighborhood, and environmental factors relating to study participants (Langlois et 

al. 1996). 

A study by Davis et al. (1992, 1994) used electron microprobe analysis of soil and waste rock from Butte, 

Montana, to help explain the low PbBs observed in young children living in that mining community. 

They hypothesized that, if soils were ingested, the lead bioavailability would be constrained by alteration 

and encapsulation of the lead-bearing minerals of the Butte ore body (galena, anglesite, cerussite, and 

plumbojarosite), which would limit the available lead-bearing surface area. Kinetic limitations relative to 

the residence time of soil in the gastrointestinal tract also affect the bioavailability of lead (Ruby et al. 

1992). The inherent chemical properties of soil-lead adsorption sites may reduce the bioavailability of 

soil-lead compared to soluble lead salts and lead compounds ingested without soil (Freeman et al. 1992). 

It has been shown that lead in impacted unleaded and leaded automobile exhaust particulate matter is 

readily leachable, but lead in paint may not be as leachable (Que Hee 1994). Thus, the differential 

availability may cause differential lead bioaccessibility and hence bioavailability. The extent of 

absorption of lead into the tissues of young Sprague-Dawley rats has been determined (Freeman et al. 

1992). The animals were fed various concentrations of lead-contaminated mining waste soil mixed with a 

purified diet for 30 days. The overall percentage bioavailability values, based on lead acetate as the 

standard, were: 20% based on blood data; 9% based on bone data; and 8% based on liver data. These 

low bioavailabilities agree favorably with the low blood levels (average, 3.5 μg/dL) found in children in 

Butte, Montana (Freeman et al. 1992). EPA (1989c) uses 0.2 g/day as a typical soil ingestion rate 

(including both dirt and dust) for children 1–6 years of age. 

Seasonal variations in PbBs in children have been observed in a number of studies. Mean PbBs in the 

State of New York have been shown to increase by 15–30% in the late summer as compared to mean 

values obtained during late winter/early spring (Haley and Talbot 2004). Blood lead measurements taken 

from children aged 0–6 years in Syracuse, New York over a 48-month period beginning in January 1992, 

showed a regular yearly periodicity in blood lead concentrations, which peaked in the late summer 

(Johnson and Bretsch 2002). These seasonal variations in PbBs have been attributed to ingestion of lead 

in soil. Indeed, the work of Johnson and Bretsch (2002), which looked at the relationship between PbBs 

measured in children and soil lead concentrations within small regional grids (600 m by 600 m) laid out 

over the City of Syracuse, New York, showed a correlation between the geometric mean PbBs and the 

median soil lead concentrations (r2

>0.65). 
LEAD 371 

6. POTENTIAL FOR HUMAN EXPOSURE 

In addition to the ingestion of hand soil/dust through normal hand-to-mouth activity, some children 

engage in pica behavior (consumption of nonfood items), which can put them at increased risk through 

ingestion of large amounts of soil contaminated with lead. It has been estimated that an average child 

may ingest between 20 and 50 mg of soil/day and that a pica child may ingest 5,000 mg or more of 

soil/day (LaGoy 1987; Mielke et al. 1989). If the soil contains 100 μg/g of lead, an average child may be 

exposed to 5 μg of lead/day from this source alone (Mielke et al. 1989), and a pica child may be exposed 

to >100 times that amount. At the EPA's Soil Screening Guidance concentration of 400 mg Pb/kg soil, a 

13-kg child who consumes 5 g of soil during a pica episode would have a dose from soil of 0.2 mg Pb/kg 

of body weight, which is 10 times the nonlethal toxic dose (Calabrese et al. 1997b; Stuik 1974). Yard soil 

containing lead concentrations >500 mg/kg has been associated with a mean PbB ≥10 μg/dL in children 

6–71 months of age in a multi-site study (Agency for Toxic Substances and Disease Registry 1995). 

Improper removal of lead from housing known to contain lead-based paint can significantly increase lead 

levels in dust, thus causing lead toxicity in children living in the home during the lead-removal process. 

Four such cases have been documented (Amitai et al. 1987). In January 1995, the New York State 

Department of Health identified 320 children in 258 households in New York State (excluding New York 

City) with PbBs ≥20 μg/dL that were considered to be attributable to residential renovation and 

remodeling (CDC 1997d). 

Trace metals, including lead, have been detected in human breast milk, so breast-feeding could deliver 

lead to an infant. Levels of lead in human milk vary considerably depending on the mother’s exposure 

and occupation. For example, levels of lead in the milk of a mother who had worked in a battery factory 

for the first 6 months of pregnancy varied from 4 to 63 μg/L in samples taken soon after the birth of the 

child up to 32 weeks later. These concentrations were similar to those in control samples even though the 

PbB of the mother was about 3 times higher than that of the control subject. The pharmacokinetic model 

for lead may be complex since >90% of the lead body burden is stored in bone tissue and lead is strongly 

bound to hemoglobin, which may impede its partition to milk (Wolff 1983). On the other hand, an 

analysis of 210 human milk samples taken across Canada showed a mean lead level of 1.01 μg/L. 

Women who resided in homes that were >30 years old, lived in high-traffic areas for >5 years, or had 

drunk three or more cups of coffee in the preceding 24 hours prior to taking the milk sample, had higher 

lead levels. The increased lead levels resulting from coffee drinking were thought to be the result of 

mobilization by the coffee of the lead stored in tissues and bone (Dabeka et al. 1988). In a paper by 

Abadin et al. (1997b), results of several additional studies of lead in human milk are summarized and 

discussed from a public health perspective. Among other citations, the median lead in milk 
LEAD 372 

6. POTENTIAL FOR HUMAN EXPOSURE 

concentrations from 41 volunteers in Sweden was 2 μg/L (Larsson et al. 1981); the mean value for urban 

residents of Germany in 1983 was 9.1 μg/L (Sternowsky and Wessolowski 1985); and the concentration 

in 3-day postpartum milk samples from 114 women in Malaysia averaged 47.8 μg/L (Ong et al. 1985). 

Gulson et al. (1998a, 2001c) used measured lead isotope ratios (207Pb/206Pb and 206Pb/204Pb) in mothers' 

breast milk and in infants' blood to establish that, for the first 60–90 days postpartum, the contribution 

from breast milk to blood lead in the infants varied from 36 to 80%. Lead release during maternal bone 

loss and maternal diet appear to be the major sources of lead in breast milk fed infants. Other sources of 

lead, such as air, soil, and dust are considered to contribute minimally to lead concentrations in infant 

blood. Mean lead concentration (±SD) in breast milk for participants in the study was 0.73±0.70 μg/kg. 

Sowers et al. (2002b) examined the relationship between lead concentrations in breast milk, maternal 

blood lead concentration, and maternal bone loss in 15 mothers who breast-fed compared to 30 mothers 

who bottle-fed commercial formula. The data showed a modest correlation (p<0.07) between maternal 

blood lead and breast milk concentrations at 1–2 months postpartum. However, a stronger correlation 

(p<0.001) was observed between the mean extent of bone loss (5.6%) and lead concentrations in breast 

milk in women who breast-fed between 1.5 and 6 months postpartum. 

In a review of data on occupational chemicals that may contaminate breast milk (Byczkowski et al. 1994), 

it is stated that lead may be excreted in milk in amounts lethal to the infant and that the metal may be 

mobilized from bone stores to milk during the lactation period. Even when the concentration of lead in 

mother’s milk is low, the absorption of metals into the systemic circulation of infants is generally high 

when they are on a milk diet. To better understand the sensitivity of the nursing infant to chemicals, 

epidemiological studies, chemical monitoring, and model development and application are needed. 

Lead has also been reported in home-prepared reconstituted infant formula. Two of 40 samples collected 

in a Boston-area study had lead concentrations >15 μg/L. In both cases, the reconstituted formula had 

been prepared using cold tap water run for 5–30 seconds, drawn from the plumbing of houses >20 years 

old. Three preparation practices for infant formula should be avoided: (1) excessive water boiling, 

(2) use of lead-containing vessels, and (3) morning (first-draw) water (Baum and Shannon 1997). Gulson 

et al. (1997a) measured lead in household water throughout the day when the plumbing system of an 

unoccupied test house was not flushed. Water concentration data ranged from 119 μg/L for the initial 

(first-draw) sample to 35–52 μg/L for hourly samples to 1.7 μg/L for a fully flushed sample. The water 

concentration data were used in the EPA's Integrated Exposure Uptake and Biokinetic (IEUBK) Model 
LEAD 373 

6. POTENTIAL FOR HUMAN EXPOSURE 

for Lead in Children to predict PbBs in infants drinking water (or formula reconstituted using water) 

drawn from the same tap. Predicted PbBs in infants only exceeded 10 μg/L when 100% of the water 

consumed contained 100 μg Pb/L (Gulson et al. 1997a). 

Lead-containing ceramic ware used in food preparation has also been associated with childhood lead 

exposure in children of Hispanic ethnicity in San Diego County, California. One study (Gersberg et al. 

1997) used the IEUBK to determine that dietary lead exposure from beans prepared in Mexican ceramic 

bean pots may account for a major fraction of blood lead burden in children whose families use such 

ceramic ware. 

Workers occupationally exposed to lead apparently carry lead home on clothing, bodies, or tools. PbBs 

of children in households of occupationally exposed workers were almost twice those of children in 

neighboring homes whose parents were not occupationally exposed to lead (median ranges were 10– 

14 and 5–8 μg/dL, respectively) (Grandjean and Bach 1986). Young children (<6 years old) of workers 

exposed to high levels of lead in workplace air at an electronic components plant (61–1,700 μg 

lead/m3

 ambient concentrations) had significantly elevated PbBs (13.4 μg/dL) compared with children 

from the same locale whose parents did not work in the electronics plant (7.1 μg/dL) (Kaye et al. 1987). 

Based upon data collected from 1987–1994, children aged 1–5 years (n=139) of workers whose 

occupation resulted in lead exposure had a geometric mean PbB of 9.3 μg/dL as compared to a U.S. 

population geometric mean of 3.6 μg/dL (Roscoe et al. 1999). Of this group, 52% of the children had 

PbBs ≥10 μg/dL compared to 8.9% of the U.S. population and 21% had PbBs ≥20 μg/dL compared to 

1.1% of the U.S. population (Roscoe et al. 1999). Exposures of lead workers' families have been 

identified in nearly 30 different industries and occupations. Industries in which exposure of family 

members has been reported most often include lead smelting, battery manufacturing and recycling, 

radiator repair, electrical components manufacturing, pottery and ceramics, and stained glass making 

(NIOSH 1995). Children of lead-exposed construction workers may also be at increased risk (Whelan et 

al. 1997). 

Children may be exposed to lead because of activities associated with certain hobbies and artistic 

activities practiced by adults in the home. Some of the more obvious hobbies and activities involving use 

of lead-containing materials (casting, stained glass, pottery, painting, glassblowing, screenprinting) are 

discussed in Section 6.5. Activities involving use of lead-containing materials should always be done in 

an area well-ventilated with outdoor air and should never be done with children in the same room or in 
LEAD 374 

6. POTENTIAL FOR HUMAN EXPOSURE 

close proximity. Recent data by Maas et al. (2005) indicate that high levels of lead are prevalent in 

inexpensive cosmetic jewelry that is sold to the general public at retail stores (see Section 6.4.5). 

Children may be exposed to lead from other hobby or recreational activities that are not as obviously 

dangerous. For example, two case studies (one in North Carolina and one in Arizona) of lead poisoning 

in children from homes in which environmental surveys indicated no identifiable lead hazards have been 

reported. More extensive investigations revealed that both children had been observed on several 

occasions with pool cue chalk in their mouths. Subsequent chemical analysis of 23 different types of pool 

cue chalk identified three types as having lead concentrations in excess of 7,000 mg/kg (Miller et al. 

1996). 

Accidental or intentional ingestion of folk remedies containing lead (discussed in Section 6.4.5) 

represents another source for potential lead-poisoning in children. Acute lead encephalopathy in early 

infancy has been reported in a Middle Eastern study for 14 infants following the use of Bint al Thahab, a 

traditional medicine containing 91% lead monoxide, and for 5 infants following application of leadcontaining kohl/surma, a preparation used as eye makeup (Al Khayat et al. 1997a). Hair dyes formulated 

with lead acetate represent a potential source for lead-poisoning both by accidental ingestion and by handto-mouth activity following contact with lead-contaminated surfaces, including dyed hair of adults 

(Mielke et al. 1997b). 

Children may be exposed to lead through the inhalation of second-hand smoke. Mannino et al. (2003) 

employed data from the NHANES III and analyzed PbBs of children aged 4–16 who were exposed to 

high, low, and intermediate levels of second-hand smoke. Serum levels of the nicotine biomarker 

cotinine were used to classify the children into one of the three second-hand smoke exposure categories. 

The geometric mean PbBs were 1.5, 1.9, and 2.6 μg/dL for children with low (≤0.050–0.104 ng/mL), 

intermediate (0.105–0.562 ng/mL), and high (0.563–14.9 ng/mL) serum cotinine levels, respectively 

(Mannino et al. 2003). 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

In addition to workers exposed to lead in the workplace, several other population groups at risk for 

potential exposure to high levels of lead can be identified: preschool-age children and fetuses (see 

Section 6.6), individuals living near sites where lead was produced or sites where lead was disposed, and 

individuals living near one of the 1,272 NPL hazardous waste sites where lead has been detected in some 
LEAD 375 

6. POTENTIAL FOR HUMAN EXPOSURE 

environmental media (EPA 1986b; HazDat 2006; Murgueytio et al. 1998) also may be at risk for 

exposure to high levels of lead. Since lead is often detected in tobacco and tobacco smoke, persons who 

use chewing tobacco or smoke, may have higher PbB levels than persons that do not use these products 

(Bonanno et al. 2001). 

General population exposure is most likely to occur through the ingestion of food and water that are 

contaminated with lead; however, some individuals and families may be exposed to additional sources of 

lead in their homes. This is particularly true of older homes that may contain lead-based paint. In an 

attempt to reduce the amount of exposure due to deteriorating leaded paint, the paint is commonly 

removed from homes by burning (gas torch or hot air gun), scraping, or sanding. These activities have 

been found to result, at least temporarily, in higher levels of exposure for families residing in these 

homes. In addition, those individuals involved in the paint removal process (i.e., do-it-yourself 

renovators and professionals who remove lead) can be exposed to such excessive levels that lead 

poisoning may occur (Chisolm 1986; Fischbein et al. 1981; Rabinowitz et al. 1985). 

Special populations at risk of high exposure to tetraethyl lead include workers at hazardous waste sites 

and those involved in the manufacture and dispensing of tetraethyl lead (Bress and Bidanset 1991). 

Populations living near any of the 1,272 NPL sites that were identified as having lead present in the 

environmental media may be at risk for exposure to high levels of lead (HazDat 2006). However, the 

available data are insufficient to allow characterization of the sizes of these populations or intake levels of 

lead to which they may be exposed. 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of lead is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of lead. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 
LEAD 376 

6. POTENTIAL FOR HUMAN EXPOSURE 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of lead and its 

compounds are sufficiently characterized to permit an estimation of the environmental fate of lead to be 

made (Howe 1981; Lide 1996; Budavari et al. 1989; Sax 1984; Sax and Lewis 1987). Availabilities of 

the various forms need to be modeled and the connectivities to bioaccessabilities and bioavailabilities 

determined. 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2004, became available in May of 2006. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

Lead is produced and imported for widespread use in the United States. Therefore, the potential for 

human exposure in the workplace, the home, the environment, and at waste sites may be substantial. 

Lead is produced from both primary (i.e., mined ore) and secondary (i.e., scrap metal and wastes) sources, 

and is imported by the United States. In 1997, production from primary and secondary sources was 

343,000 metric tons and 1.1 million metric tons, respectively (Smith 1998), and imports reached 

265,000 metric tons (Larrabee 1998; Smith 1998). Approximately 1.6 million metric tons of lead were 

consumed in the United States in 1997 (Smith 1998). Of lead used in 1997, 86.9% was used for storage 

batteries, 7.8% was used in metal products, and 5.3% was used in miscellaneous applications (Smith 

1998). Because of the adverse health effects associated with exposure to lead, its use in paints, ceramic 

products, gasoline additives (now banned), and solder has declined dramatically in recent years. In 1997, 

exports of lead metal totaled 37,400 metric tons, and exports of lead waste and scraps totaled 

88,400 metric tons (Larrabee 1998; Smith 1998). Exports of lead in ore and concentrates and lead 

materials, excluding scrap, rose from 93,500 and 103,000 metric tons in 1999 to 253,000 and 

123,000 metric tons, respectively, in 2003. In 2003, 92,800 metric tons of lead scrap were exported 

(USGS 2003). 
LEAD 377 

6. POTENTIAL FOR HUMAN EXPOSURE 

Although certain uses of lead preclude recycling (e.g., use as a gasoline additive), lead has a higher 

recycling rate than any other metal (Larrabee 1998). An estimated 90–95% of the lead consumed in the 

United States is considered to be recyclable. In the United States, 77.1% of the lead requirements were 

satisfied by recycled lead products (mostly lead-acid batteries) in 1996. This compares to 69.5% in 

1990 and 55.2% in 1980 (Larrabee 1997, 1998). 

Industrial wastes, as well as consumer products, containing lead are disposed of in municipal and 

hazardous waste landfills. Current information on the amounts being disposed of is needed to evaluate 

the potential for exposure to lead. 

The federal government regulates the release and disposal of lead. EPA has established national ambient 

air quality standards for lead. Under the Safe Drinking Water Act, EPA limits the level of lead in 

drinking water. Industrial emissions are regulated by the Clean Water Act. Lead and certain of its 

compounds are designated hazardous substances; CERCLA requires that the person in charge of a vessel 

or facility notify the National Response Center immediately when there is a release of a hazardous 

substance in an amount equal to or greater than the reportable quantity for that substance. Such data 

should be useful in determining potential for exposure and relating it to health effects. 

Environmental Fate. Lead released to the atmosphere partitions to surface water, soil, and sediment 

(EPA 1986a; NAS 1980; Nielsen 1984; NSF 1977). Lead is transported in the atmosphere and in surface 

water. Organolead compounds are transformed in the atmosphere by photodegradation (DeJonghe and 

Adams 1986); however, the atmospheric transformation of inorganic lead compounds is not completely 

understood (EPA 1986a). Organolead compounds are transformed in surface waters by hydrolysis and 

photolysis (EPA 1979). Inorganic lead compounds are strongly adsorbed to minerals and organic matter 

in soils and sediments (Chaney et al. 1988; Chuan et al. 1996; EPA 1986a; Gerritse et al. 1981; Sauve et 

al. 1997). Some work has been conducted to assess the speciation of lead in air, water, and soil (Chaney 

et al. 1988; Corrin and Natusch 1977; EPA 1986a; Long and Angino 1977; Nerin et al. 1999; Spear et al. 

1998). Lead is a naturally occurring element and is extremely persistent in the environment. Additional 

information on the atmospheric transformations of organic and inorganic lead compounds in the 

atmosphere would provide a basis for determining the lead compounds to which humans are most likely 

to be exposed. Additional data regarding the chemical speciation and the transformation pathways of lead 

in soils and water with varying properties such as pH, oxygen content and salinity are necessary to fully 

understand the environmental fate of lead in soils and water. 
LEAD 378 

6. POTENTIAL FOR HUMAN EXPOSURE 

Bioavailability from Environmental Media. Available pharmacokinetic data indicate that lead is 

absorbed by humans following inhalation of particulate lead in ambient air and ingestion of contaminated 

foods, drinking water, and soil (Chamberlain et al. 1978; EPA 1986a; Morrow et al. 1980). In addition, 

children may ingest paint chips that contain lead (MPCA 1987). The bioavailability of lead from soil or 

dust on the hand after mouthing activity needs to be modeled. Absorption following dermal exposure is 

much more limited, although absorption of organolead compounds through the skin occurs (Kehoe and 

Thamann 1931; Laug and Kunze 1948; Moore et al. 1980). Dermal absorption models of lead would be 

useful in modeling total exposure pathways of lead. 

Food Chain Bioaccumulation. Lead is bioaccumulated by terrestrial and aquatic plants and animals 

(Eisler 1988). However, lead is not biomagnified in terrestrial or aquatic food chains (Eisler 1988). No 

additional information is needed. 

Exposure Levels in Environmental Media. Environmental monitoring data are available for lead 

in ambient air, indoor air, surface water, groundwater, drinking water, sediments, soils, and foodstuffs 

(Eckel and Jacob 1988; EPA 1982c, 1986a, 1988b, 1989d, 1989e, 1990; Lee et al. 1989; Maenhaut et al. 

1979; Mielke 1993; Mielke et al. 1983, 1984/1985, 1989). More current data (1995–1996) on lead in 

ambient and indoor air, drinking water, and foodstuffs for residents in Arizona, EPA Region V (Illinois, 

Indiana, Michigan, Minnesota, Ohio, and Wisconsin), and Maryland are available through the NHEXAS 

(Bonanno et al. 2001; Clayton et al. 2002; O’Rourke et al. 1999; Pellizzari et al. 1999; Ryan et al. 2000; 

Thomas et al. 1999). Estimates of human intake from inhalation of ambient air and ingestion of 

contaminated foods and drinking water are available (Dabeka et al. 1987; EPA 1986a, 1991d; Gartrell et 

al. 1986b; Gunderson 1988). Additional information on the concentrations of lead compounds in 

environmental media, particularly at hazardous waste sites, and an estimate of human intake would be 

helpful in establishing human exposure to lead. Absorption of lead through the skin may be a significant 

exposure pathway (Stauber et al. 1994) and may be deserving of further study. Lead has been found in 

tobacco and tobacco smoke and higher levels of lead have been detected in indoor air of the homes of 

smokers when compared to non smokers (Bonanno et al. 2001; Mannino et al. 2003). It is unclear 

whether the source of this lead is from plant uptake, atmospheric deposition of lead compounds to the 

surface of tobacco plants, or from tobacco plants being grown in soils that had previously been treated 

with arsenate pesticides. A study to determine the source of this lead in tobacco is needed in order to help 

reduce the risk of lead exposure to smokers and those that may inhale second hand smoke. 
LEAD 379 

6. POTENTIAL FOR HUMAN EXPOSURE 

Reliable monitoring data for the levels of lead in contaminated media at hazardous waste sites are needed 

so that the information obtained on levels of lead in the environment can be used in combination with the 

known body burden of lead to assess the potential risk of adverse health effects in populations living in 

the vicinity of hazardous waste sites. 

Exposure Levels in Humans. Lead can be measured in human blood, hair, perspiration, teeth, 

bones, feces, and urine (Aguilera de Benzo et al. 1989; Batuman et al. 1989; Blakley and Archer 1982; 

Blakley et al. 1982; Christoffersson et al. 1986; Delves and Campbell 1988; Ellen and Van Loon 1990; 

Exon et al. 1979; Hu et al. 1989, 1990, 1991; Jason and Kellogg 1981; Manton and Cook 1984; NIOSH 

1977b, 1977c; Que Hee and Boyle 1988; Que Hee et al. 1985a; Wielopolski et al. 1986). The most 

common method of assessing human exposure involves measurement of lead in blood (PbB) (Aguilera de 

Benzo et al. 1989; Delves and Campbell 1988; Manton and Cook 1984; NIOSH 1977b, 1977c; Que Hee 

et al. 1985a). PbBs have been correlated with ambient air exposure levels and dust, and dietary intake 

levels (Rabinowitz et al. 1985). In their critical evaluation of reports of historic occupational aerosol 

exposure to lead, Vincent and Werner (2003) recommended that exposure measurements be made using 

sampling techniques and strategies that relate to the health effects underlying the need for exposure 

assessment. Additionally, sufficient detail must be included so that the quality and value of the data can 

be judged. This is necessary so the data can be pooled for broad hazard surveillance purposes. 

Additional information on the biological monitoring of populations living in the vicinity of hazardous 

waste sites would be helpful in estimating exposure of these populations to lead compounds. The 

relationships between the major biological monitoring media should be determined. Alkyl lead 

compounds can be measured in exhaled breath and the diethyllead metabolite of tetraethyl lead can be 

measured in urine. The most recent NHANES Report, containing data from 1999 to 2002 and released in 

2005, contains blood lead levels for the U.S. population (CDC 2005a, 2005b). The data pertaining to lead 

levels in the U.S. population are summarized in Tables 6-12 and 6-13. This information is necessary for 

assessing the need to conduct health studies on these populations. 

Exposures of Children. Estimates are available for intake by children through ingestion of 

contaminated soils, dust, paint chips (EPA 1989c), and breast milk (Wolff 1983). However, some of 

these estimates are not current or well understood. To better understand the sensitivity of the nursing 

infant to chemicals such as lead, epidemiological studies, chemical monitoring, and model development 

and application are needed (Byczkowski et al. 1994). The bioavailability of lead from soil or dust on the 

hand after mouthing activity needs to be modeled. Lead levels in blood (CDC 2005a, 2005b) and urine 
LEAD 380 

6. POTENTIAL FOR HUMAN EXPOSURE 

(CDC 2003, 2005b) of children are available from the NHANES monitoring data, and have been 

summarized in Tables 6-12 and 6-13. 

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data 

Needs: Children’s Susceptibility. 

Exposure Registries. No exposure registries for lead were located. This substance is not currently 

one of the compounds for which a sub-registry has been established in the National Exposure Registry. 

The substance will be considered in the future when chemical selection is made for sub-registries to be 

established. The information that is amassed in the National Exposure Registry facilitates the 

epidemiological research needed to assess adverse health outcomes that may be related to exposure to this 

substance. 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2005) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. These 

studies are summarized in Table 6-17. 
LEAD 381 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-17. Ongoing Research Regarding the Environmental Fate and Exposure 

of Humans to Lead 

Investigator Affiliation Research description Sponsor 

Blum CB Columbia 

University, New 

York, New York 

The estimation of bioavailability to lead and arsenic 

from soil currently use assumptions based on 

bioavailability data from animal or in vitro models. 

Using the technique of stable Pb isotope dilution, a 

method was developed for estimating soil Pb 

bioavailability in humans. This model examines 

changes in the ratio of 206Pb to 207Pb in blood, 

following the ingestion of trace quantities of Pbcontaminated soils. 

National Institute 

of Environmental 

Health Sciences 

Cochran JK 

and Veron A 

SUNY at Stony 

Brook, Stony 

Brook, New York 

This three-year award for United States-France 

collaboration in environmental geochemistry 

involves State University of New York at Stony 

Brook and the Centre Europeen de Recherche et 

d'Enseignement de Geosciences in Marseilles, 

France. The investigators will determine the history 

of input rates and sources of stable lead to coastal 

National Science 

Foundation 

areas. 

Basta NK and 

Lower SK 

Ohio State 

University, 

Columbus, Ohio 

The goals of this project are to: (1) determine the 

ability of chemical speciation methods that measure 

heavy metal bioavailability; (2) estimate ecotoxicity 

of contaminated soil; (3) determine the effect of soil 

chemical properties on chemical speciation and 

heavy metal bioavailability in contaminated soil and 

the ability of soil chemical properties to define 

ecotoxicity categories in development of ecological 

soil screening levels; (4) determine the ability of 

diammonium phosphate to reduce bioavailable 

chemical species of heavy metal contaminants in 

soil. 

Department of 

Agriculture 

Spraks DL University of 

Delaware, 

Newark, 

Delaware 

The goals of this project are to (1) determine the 

effect of reaction conditions and residence time on 

sorption/release of important metals/metalloids (Cu, 

Cd, Cr, Ni, Pb, As) on soil components and 

Delaware soils; and (2) ascertain metal/metalloid 

reaction mechanisms on soil components/soils 

using molecular level spectroscopic (e.g., x-ray 

absorption fine structure [XAFS] and microscopic 

[atomic force microscopy (AFS]) techniques. 

Metal/metalloid sorption studies will be examined as 

a function of residence time, pH, and total metal 

loading on soil components/soils, using a pH-stat 

batch method. 

Department of 

Agriculture 

Source: FEDRIP 2005 
LEAD 382 

6. POTENTIAL FOR HUMAN EXPOSURE 

This page is intentionally blank. 
LEAD 383 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring lead, its metabolites, and other biomarkers of exposure and effect to lead. 

The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to identify 

well-established methods that are used as the standard methods of analysis. Many of the analytical 

methods used for environmental samples are the methods approved by federal agencies and organizations 

such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods 

presented in this chapter are those that are approved by groups such as the Association of Official 

Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, 

analytical methods are included that modify previously used methods to obtain lower detection limits 

and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

Blood, Urine, Serum, Cerebrospinal Fluid. Several analytical methods are available to analyze the level 

of lead in biological samples. The most common methods employed are flame atomic absorption 

spectrometry (AAS), graphite furnace atomic absorption spectrometry (GFAAS), anode stripping 

voltametry (ASV), inductively coupled plasma-atomic emission spectroscopy (ICP/AES), and inductively 

coupled plasma mass spectrometry (ICP/MS). According to Grandjean and Olsen (1984) and Flegal and 

Smith (1995), GFAAS and ASV are the methods of choice for the analysis of lead. In order to produce 

reliable results, background correction, such as Zeeman background correction that minimizes the impact 

of the absorbance of molecular species, must be applied. Limits of detection for lead using AAS are on 

the order of μg/mL (ppm) for flame AAS measurements, while flameless AAS measurements can detect 

blood lead levels at about 1 ng/mL (Flegal and Smith 1995). A detection limit of 0.05 ng/mL has been 

achieved for lead in blood samples analyzed by GFAAS (Flegal and Smith 1995). ICP/MS is also a very 

powerful tool for trace analysis of lead and other metals. Although ICP/MS instruments are more costly 

than GFAA instruments, their ability to analyze multiple metals from a single sample, low detection 

limits, reliability, and ease of use have increasingly made them popular for trace metal analysis. Other 

specialized methods for lead analysis are x-ray fluorescence spectroscopy (XRFS), neutron activation 

analysis (NAA), differential pulse anode stripping voltametry, and isotope dilution mass spectrometry 

(IDMS). The most reliable method for the determination of lead at low concentrations is IDMS (EPA 

1986a; Grandjean and Olsen 1984), but due to the technical expertise required and high cost of the 

equipment, this method is not commonly used. It is primarily used for the development of certified 

standard reference materials by which other methods can determine their reliability since results of lead 
LEAD 384 

7. ANALYTICAL METHODS 

analyses from numerous laboratories often do not agree (Fell 1984). Details of several methods used for 

the analysis of lead in biological samples are presented in Table 7-1. 

Concentrations of lead in blood, urine, serum, and cerebrospinal fluid have been used as indicators of 

exposure to lead. Measurement of lead in blood is the most common method of assessing exposure. 

OSHA mandates biological monitoring of blood as a measure of workplace exposure to lead (Goyer 

2001). Blood lead is also considered the most useful tool for screening and diagnostic testing (Moore 

1995); the half-life of lead in blood is approximately 36 days (Todd et al. 1996). A second half-life is 

generally considered to be approximately 4 years (Graziano 1994) and reflects the replenishment of lead 

in the blood from the bone storage compartment. Sample preparation usually consists of wet ashing 

(digesting) the sample with strong acid and heat, and redissolving the residue in dilute acid prior to 

analysis so that all lead species are converted quantitatively to the same lead compound (NIOSH 1977c). 

Preparation methods not requiring wet ashing have also been used with good results (Aguilera de Benzo 

et al. 1989; Delves and Campbell 1988; Manton and Cook 1984; NIOSH 1977b; Que Hee et al. 1985a; 

Zhang et al. 1997). For samples analyzed by ICP/MS, ASV, AAS, and GFAAS, sensitivity is in the lowto sub-ppb (0.1–15 ppb) with good accuracy and precision (Aguilera de Benzo et al. 1989; Delves and 

Campbell 1988; NIOSH 1977b, 1977c; Que Hee et al. 1985a; Zhang et al. 1997). The presence of 

phosphate, ethylenediaminetetraacetic acid (EDTA), and oxalate can sequester lead and cause low 

readings in flame AAS (NIOSH 1994c). A comparison of IDMS, ASV, and GFAAS showed that all 

three of these methods can be used to reliably quantify lead levels in blood (Que Hee et al. 1985a). 

ACGIH recommends quantification of blood lead by GFAAS. ESA, Inc. has introduced a simple to use, 

portable device for performing blood lead measurements using a finger stick or a venous sample (ESA 

1998). Results can be obtained in about 3 minutes. For analysis of urine, chelation and solvent 

extraction, followed by atomic absorption for quantification is the recommended method (ACGIH 1986). 

Estimated accuracy reported for an IDMS technique was excellent (Manton and Cook 1984). Sensitivity 

and precision were not reported by the authors, but they are generally considered to be excellent (EPA 

1986a; Grandjean and Olsen 1984). 

An indirect fluorescent method to quantify the level of Pb+2 in intracellular fluids has been published 

(Dyatlov et al. 1998). Although there are no commercially available fluorescent probes specific to Pb2+, 

the fluorescent probe (fluo-3) frequently used to quantify levels of Ca2+ was employed as a means to 

estimate Pb2+ levels in calcium containing solution. The presence of Pb2+ depresses the fluorescent signal 
LEAD 385 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Lead in Biological Materials 

Sample Accuracy 

Sample Analytical detection (percent 

matrix Preparation method method limit recovery) Reference 

Blood Dilution with Triton X-100®; GFAAS 2.4 μg/L 93–105 Aguilera et 

addition of nitric acid and al. 1989 

diammonium phospate 

Blood Dilution of sample with ICP/MS 15 μg/L 96–111 Delves and 

ammonium solution containing Campbell 

Triton X-100 1988 

Blood Dilution of sample in 0.2% GFAAS ≈15 μg/L 97–150 Que Hee et 

Triton X-100 and water al. 1985a 

Blood wet ashing, dilution ICP/MS 0.1 ppb 94–100 Zhang et al. 

GFAAS 4 ppb 90–108 1997 

Blood and Mixing of urine sample with AAS 0.05 μg/g 99 (±10.8%) NIOSH 

urine HNO3; filtration, chelation of (NIOSH Method (blood) or 1994e 

lead in whole blood or filtered 8003) 0.05 μg/mL 

urine with APDC, extraction (urine) 

with MIBK 

Blood and 206Pb addition and sample acid IDMS No data 98–99 Manton and 

urine digestion; lead coprecipitation Cook 1984 

by addition of Ba(NO3)2, 

followed by electrodeposition 

on platinum wire 

Blood and Digestion of sample with ICP/AES (Method 0.01 μg/g 113 NIOSH 

tissue HNO3/HClO4 /H2SO4; heat 8005) (blood) 1994b 

0.2 μg/g 

(tissue) 

Blood Addition of 50 μL of blood into Gold electrode 1.4 μg/dL No data ESA 1998 

reagent, mixing, and sensor 

transferring to sensor strip 

(commercial test kit) 

Urine Collect 50 mL urine sample ICP/AES (Method 0.1 μg/ 100 NIOSH 

and add 5 mL concentrated 8310) sample (50– 1994f 

HNO3 as preservative. 200 mL 

Extraction-filter samples sample 

through cellulose membrane, volume) 

adjust pH to 8, ash filters and 

resins in low temperature 

oxygen plasma for 6 hours 

Serum 

blood, and 

Filtration of sample if needed; 

blood requires digestion in a 

ICP/AES 10B50 μg/L 85 (serum) 

>80 (urine, 

Que Hee 

and Boyle 

urine Parr bomb; dilution of serum or blood) 1988 

urine with acid or water 
LEAD 386 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Lead in Biological Materials 

Sample Accuracy 

Sample Analytical detection (percent 

matrix Preparation method method limit recovery) Reference 

Urine Dilution of sample; reaction Spectrophotometry No data No data Tomokuni 

(δ-amino­ with ethylacetoacetate and and Ichiba 

levulinic ethylacetate to form δ-amino­ 1988 

acid) levulinic acid-pyrrole; reaction 

with Erhlich's reagent 

Urine Acidification of sample; HPLC/FL 10 μg/L No data Tabuchi et 

(δ-amino­ separate δ-aminolevulinic acid al. 1989 

levulinic on HPLC; reaction with 

acid) formaldehyde and 

acetylacetone 

Plasma, Derivatization of HPLC/FL 3 μg/L No data Oishi et al. 

Urine δ-aminolevulinic acid with 1996 

(δ-amino­ formaldehyde and 

levulinic acetylacetone to form 

acid) fluorescent compounds; 

separation using HPLC 

Serum and 206Pb addition and sample acid IDMS No data 80–120 Manton and 

cerebro­ digestion; lead isolation by ion- Cook 1984 

spinal fluid exchange, elution, and 

deposition onto platinum wire 

Feces Dessication and pulverization ICP/AES 10–50 μg/L >86 Que Hee 

of sample; digestion with hot and Boyle 

acid in Paar bomb 1988 

Testes, Dicing of sample and digestion ICP/AES 10–50 μg/L >80 Que Hee 

liver, in hot acid in a Paar bomb; and Boyle 

spleen, evaporation; redissolution in 1988 

kidney HCl/HNO3 

Spleen, Wet digestion of sample with GFAAS No data No data Blakley and 

liver, and HNO3-HClO4 mixture; Bomb GFAAS 20 μg/g 85– Archer 

kidney; digestion of sample with acid (bomb); 107 (bomb); 1982; Ellen 

Liver, and heat or digestion with acid 5 μg/g (dry 75–107 (dry and Van 

kidney, and dry ashing; dissolution in ashing) ashing) 82– Loon 1990 

muscle acid; dilution with water DPASV No data 120 

Tissues Dry ashing of sample; AAS No data No data Exon et al. 

(brain, dissolution in HNO3 1979 

heart, lung, 

kidney, 

liver, and 

testes) 

Tissues Freeze drying of samples; NAA No data No data Hewitt 1988 

subjection to thermal neutron 

irradiation; chemical separation 

of elements 

Brain Wet ashing of sample with ASV No data No data Jason and 

mixture of acids, mixing with Kellogg 

Metex®

 and analysis 1981 
LEAD 387 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Lead in Biological Materials 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection 

limit 

Accuracy 

(percent 

recovery) Reference 

Bone Partially polarized photon 

directed at second phalanx of 

left forefinger (noninvasive 

technique) 

K-XRF 20 μg/g No data Christoffersson et al. 

1986 

Bone Partially polarized photon 

directed at anteromedial skin 

L-XRF 20 μg/g No data Wielopolski 

et al. 1986 

surface of mid-tibia (noninvasive technique) 

Teeth Cleaning and sectioning of 

tooth; digestion with HNO3; 

evaporation; redissolution in 

buffer solution 

ASV No data 83–114 Rabinowitz 

et al. 1989 

Teeth Dry ashing of sample; 

crushing; dry ashing again; 

dissolution in HNO3 

AAS No data 90–110 Steenhout 

and 

Pourtois 

1981 

Hair Cleaning of sample with 

acetone/ methanol; digestion 

with acid mixture and heat; 

GFAAS 0.16 μg/g 99 Wilhelm et 

al. 1989 

diammonium phosphate 

addition as matrix modifier 

Bone 109Cd gamma-ray irradiation 

with source at 2.5 cm from skin 

K-XRF 2 μg/g No data Hu et al. 

1989, 1990, 

of proximal tibia 1991 

Hair Cleaning of sample with 

hexane, ethanol, and water; 

ICP/AES No data No data Thatcher et 

al. 1982 

wet ashing with HNO3 and 

H2O2 

AAS = atomic absorption spectroscopy; APDC = ammonium pyrrolidine dithiocarbamate; ASV = anode stripping 

voltammetry; Ba(NO3)2 = barium nitrate; 109Cd = cadmium 109 radioisotope; DPASV = differential pulse anodic 

stripping voltammetry; GFAAS = graphite furnace atomic absorption spectroscopy; H2O2 = hydrogen peroxide; 

HCl = hydrogen chloride; H2SO4 = sulfuric acid; HClO4 = perchloric acid; HNO3 = nitric acid; HPLC/FL = high 

performance liquid chromatography/fluorimetry; ICP/AES = inductively coupled plasma/atomic emission 

spectroscopy; ICP/MS = inductively coupled plasma-mass spectrometry; IDMS = isotope dilution mass spectrometry; 

K-XRF = K-wave X-ray fluorescence; L-XRF = L-wave X-ray fluorescence; MIBK = methyl isobutyl ketone; 

NAA = neutron activation analysis; NaOH = sodium hydroxide; NIOSH = National Institute for Occupational Safety 

and Health; 206Pb = lead 206 
LEAD 388 

7. ANALYTICAL METHODS 

observed in the emission spectrum of the fluo-3 Ca2+ complex at 530 nm, and the concentration of Pb2+ in 

solution was correlated with the observed decrease of intensity in the emission spectra. 

Several biomarkers exist for monitoring exposure to lead. A number of biochemical assays are available 

for the assessment of lead exposure and toxicity in the human body using standard clinical laboratory 

techniques. Details of such assays are reported in several reviews (EPA 1986a; Grandjean and Olsen 

1984; Stokinger 1981) and are also available in standard clinical laboratory methods manuals. The 

commonly used assays are coproporphyrin, 1,25-dihydroxyvitamin D, ALA (δ-aminolevulinic acid), and 

EP (erythrocyte protoporphyrin) concentrations and ALAD (ALA dehydratase) activity. All of these 

assays are sensitive, reliable, and well established; however, erythrocyte protoporphyrin and ALAD 

activity appear to be the most useful and sensitive for determining exposure to lead. A recent review 

(Porru and Alessio 1996) indicated that ALAD activity was proportional to blood lead concentration 

ranging from 10 to 40 μg/dL, and EP concentration was proportional to blood lead over the range of 30– 

80 μg/dL. The EP concentration was said to be useful for assessing exposure experienced over the past 

3 to 4 months. Urinary ALA, however, was not proportional to blood lead until the blood concentrations 

reached 60–70 μg/dL, a concentration too high to be of use for early screening since other clinical 

symptoms should already be evident. A colorimetric method for detection of ALA in urine, in which the 

pyrrole from ALA is formed and reacted with Ehrlich's reagent to form a colored end product, has been 

used successfully (Tomokuni and Ichiba 1988). ALA has also been determined in urine using highperformance liquid chromatography (HPLC) followed by quantification of a fluorescent end product 

(Tabuchi et al. 1989). A similar approach to ALA determination in blood and urine was described by 

Oishi et al. (1996) and was more sensitive than the method of Tabuchi et al. (1989). Erythrocyte 

protoporphyrin bound to zinc has been quantified using hemofluorimetry (Braithwaite and Brown 1987). 

An HPLC/fluorescent method has been reported for determination of coproporphyrin in urine (Tomokuni 

et al. 1988). Other biological assays that have been used as indicators of lead exposure are serum 

immunoglobulins and salivary IgA (Ewers et al. 1982). While all of these biological assays are reliable 

and have been verified for clinical laboratory use, they are not specific for lead. 

Tissues. Lead has been quantified in a variety of tissues, including liver, kidney, brain, heart, lung, 

muscle, and testes. Techniques for measuring lead in tissues are similar to those used for blood and urine. 

When AAS, GFAAS, or ASV are used for analysis, the samples may be wet ashed, digested with acid, or 

bomb digested (Blakley and Archer 1982; Blakley et al. 1982; Ellen and Van Loon 1990; Exon et al. 

1979; Jason and Kellogg 1981; Que Hee and Boyle 1988). The information located did not allow an 

adequate comparison between these methods. Parr bomb digestions are recommended for estimation of 
LEAD 389 

7. ANALYTICAL METHODS 

metals in biological tissues (Que Hee and Boyle 1988). Sensitivities reported for GFAAS and ICP/AES 

are in the low ppm range (5–20 ppm) (Ellen and Van Loon 1990) and are probably comparable for the 

other techniques. Differential anodic stripping pulse voltametry (DPASV) and NAA have also been used 

to analyze tissues for lead. Sample preparation for DPASV is the same as those for AAS, GFAAS, and 

ASV. Its accuracy and precision are comparable to results using GFAAS, and its sensitivity is slightly 

greater (Ellen and Van Loon 1990). Determination of lead in tissue samples following freeze drying, 

neutron irradiation, and chemical separation has been reported. An advantage of this method is that the 

sample does not have to be dissolved. No further information was reported for the method (Hewitt 1988). 

Hair, Teeth, and Bone. Noninvasive methods using x-ray fluorescence can be used for the determination 

of lead concentration in bones. Lead accumulates over a lifetime in bones, so these measurements 

represent a metric cumulative dose, whereas measurements of lead in blood represent a more recent dose. 

Typical analyses encompass L x-rays of the tibia produced using an x-ray generator (Wielopolski et al. 

1986); K x-rays in the second phalanx of the index finger using a cobalt source and a germanium silicon 

detector (Christoffersson et al. 1986); and in vivo bone K x-ray fluorescence (Batuman et al. 1989; Hu et 

al. 1989, 1990, 1991, 1998). The K x-ray fluorescence technique has been more widely used and 

validated than the L x-ray method, which has limitations regarding its utility for the determination of lead 

levels in bone (Hu et al. 1998; Preiss and Tariq 1992). The more energetic K x-rays penetrate the cortical 

bone deeper (2 cm) than the soft L x-rays, and are therefore more suitable for determining the average 

lead content over the whole bone thickness (Wedeen 1990). The better penetration also alleviates errors 

resulting from the measurement of overlying skin and makes the method relatively insensitive to 

movement of the subject during the 15-minute sampling period (Landrigan and Todd 1994). The level of 

lead in bone has been reported to be a good indicator of stored lead in body tissue (Ahlgren et al. 1976; 

Bloch et al. 1976; Rosen et al. 1987; Skerfving et al. 1993). The sensitivity of the technique is in the low 

ppm range and the precision is acceptable. Advantages are that no sample preparation is required and the 

technique can safely and easily be done on live subjects. A limitation of x-ray fluorescence 

measurements is that its precision is dependent upon the mass of the bone being studied (Hu et al. 1998). 

Therefore, thin bones of children have greater measurement errors than mature bones found in adults. 

Teeth have been analyzed for lead using AAS and ASV (Rabinowitz et al. 1989; Steenhout and Pourtois 

1981). Samples must be dry ashed or digested with acid prior to analysis. Precision and accuracy of both 

AAS and ASV are good. Detection limits were not reported by the authors. A detection limit in the subppm range (0.16 ppm) and high accuracy were reported for GFAAS analysis of hair samples (Wilhelm et 

al. 1989). ICP/AES has also been used to analyze hair for lead, but lack of data prevents a comparison 

with the AAS method (Thatcher et al. 1982). 
LEAD 390 

7. ANALYTICAL METHODS 

The isotopic distribution of lead (IDMS) in shed teeth from children has been shown to be useful in 

studies of the history of exposure to lead, including the definition of the source of the exposure, e.g., mine 

dust vs. food (Gulson and Wilson 1994), so IDMS certainly has important applicability, if not for routine 

determinations. ICP/MS, however, is easier, more sensitive, allows for multi-element analysis, and 

provides isotopic data. 

7.2 ENVIRONMENTAL SAMPLES 

The primary methods of analyzing for lead in environmental samples are AAS, GFAAS, ASV, ICP/AES, 

and XRFS (EPA 1993). Less commonly employed techniques include ICP/MS, gas chromatography/photoionization detector (GC/PID), IDMS, DPASV, electron probe x-ray microanalysis 

(EPXMA), and laser microprobe mass analysis (LAMMA). The use of ICP/MS for the analysis of trace 

metals (including lead) has increased in recent years due to its high sensitivity and ease of sample 

preparation. ICP/MS is generally 3 orders of magnitude more sensitive than ICP/AES; however, it is 

more costly than other spectroscopic methods and is not universally available (Al-Rashdan et al. 1991; 

California Department of Fish and Game 2004). Chromatography (GC, HPLC) in conjunction with 

ICP/MS can also permit the separation and quantification of organometallic and inorganic forms of lead 

(Al-Rashdan et al. 1991). In analyzing lead concentrations in the atmosphere, a distinction between the 

levels of inorganic lead, which exists predominantly in the particulate phase, and alkyl lead, which occurs 

predominantly in the vapor phase, is necessary. Particulate-phase lead can be separated from the gas 

phase using a filter technique. The filter collects the particulate matter and allows the dissolved material 

to pass through for separate analysis of each form. As with the analysis of biological samples, the 

definitive method of analysis for lead is IDMS. Table 7-2 summarizes several methods for determining 

lead in a variety of environmental matrices. 

Air. Various methods have been used to analyze for particulate lead in air. The primary methods, AAS, 

GFAAS, and ICP/AES are sensitive to levels in the low μg/m3

 range (0.1–20 μg/m3) (Birch et al. 1980; 

EPA 1988b; NIOSH 1981, 1994a, 1994c, 2003; Scott et al. 1976). Accuracy and precision are generally 

good. GFAAS is considered to be more sensitive than AAS; however, AAS is not subject to as much 

interference from matrix effects as GFAAS (NIOSH 1977a, 1977d). Detection of particulate lead by 

generation of the lead hydride has been used to increase the sensitivity of the AAS technique (Nerin et al. 

1989). Excellent accuracy and precision was reported for this method. ASV has a wide range as well as 

high sensitivity. It is relatively inexpensive compared to other methods (NIOSH 1977a). 
LEAD 391 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Lead in Environmental Samples 

Accuracy 

Sample Analytical Sample (percent 

matrix Preparation method method detection limit recovery) Reference 

Air Collection of particulate GFAAS 0.02 μg/ 85–115 NIOSH 

(particulate matter onto membrane filter; (NIOSH sample (1– 1994d 

lead) digestion with HNO3/H2O2; Method 7105) 1,500 L 

dilution with distilled water sample) 

Air Collection of particulate AAS flame 2.6 μg/sample 97–100 NIOSH 

(particulate matter onto membrane filter; (Method 7082) (200–1,500 L 1994c 

lead) wet ashing with HNO3 sample) 

Air Collection of particulate ICP/AES 25 ng/mL 101–109 NIOSH 2003 

(particulate matter onto cellulose acetate (NIOSH 

lead) membrane filter; wet ashing Method 7300) 

with HNO3/HClO4 

Air Collection of particulate ICP/AES No data No data EPA 1988a 

(particulate matter onto filter; extraction 

lead) with HNO3/HCl, heat, and 

sonication 

Air 

(particulate 

Collection of particulate 

matter onto filter; dry ashing; 

AAS 

AES 

0.1 μg/m3 

0.15 μg/m3 

93 

102 

Scott et al. 

1976 

lead) extraction with HNO3/HCl; 

dilution with HNO3 

Air Collection of sample onto AAS 8 ng/L 100–101 Nerin et al. 

(particulate cellulose acetate filter; 1989 

lead) dissolution in HNO3 with 

heat; addition of 

HCl/H2O2 and reaction in 

hydride generator with 

sodium borohydride to 

generate lead hydride 

Air 

(particulate 

Collection of sample onto 

filter; addition of 206Pb to 

IDMS 0.1 ng/m3 No data Volkening et 

al. 1988 

lead) filter; dissolution of filter in 

NaOH; acidification; 

separation of lead by electrodeposition; dissolution in 

acid 

Air Collection of particles onto XRD 60 μg/m3

 102.6 NIOSH 

(particulate filter, suspension in THF, 1994a 

PbS) recollection onto silver filter 

Air Collection of sample onto EPXMA No data No data Van Borm et 

(particulate nucleopore polycarbonate LAMMA No data No data al. 1990 

lead) filter; coating of filter sections 

with carbon 
LEAD 392 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Lead in Environmental Samples 

Accuracy 

Sample Analytical Sample (percent 

matrix Preparation method method detection limit recovery) Reference 

Air 

(tetramethyl 

and tetraethyl 

lead) 

Air 

(particulate 

and organolead) 

Air 

(particulate 

and organolead) 

Surface 

contamination 

(lead and its 

compounds) 

Water (particulate and 

dissolved 

lead) 

Water (TAL) 

Water (TAL) 

Water (alkyl 

lead) 

Adsorption of volatile 

compounds in filtered 

sample onto XAD-2 resin, 

desorption with pentane 

Collection of particulate 

matter collected onto glass 

fiber filter; passage of filtered 

gases through iodine 

monochloride bubblers; wet 

ashing of particulate matter; 

conversion of lead 

compounds in bubbler 

solution to dithiazone 

complex in presence of 

EDTA-salts and extraction 

with carbon tetrachloride 

solution followed by acid 

extraction 

Collection of particulate 

matter collected onto 

nucleopore filters; filtered 

gases cryogenically trapped 

and thermally desorbed 

Wiping of defined area 

surface using a moistened 

gauze pad; digestion of 

sample using nitric acid; 

dilution. 

Filtration of water through a 

0.45 μm membrane filter 

(dissolved lead); particulate 

material dissolved by wet 

ashing (insoluble lead) 

Extraction with hexane 

Purging of sample with gas 

followed by cryogenically 

trapping volatile species onto 

solid sorbent GC column 

Complexation of sample with 

diethyldithiocarbamate; 

extraction with pentane; 

removal of water; butylation; 

extraction with nonane 

GC/PID 

(NIOSH 

Method 

2534 [TML] 

and 

2533 [TEL]) 

GFAAS 

XRF 

(particulate) 

GC/GFAAS 

(gaseous) 

ICP/AES 

GFAAS 

ICP/AES (EPA 

Method 200.7) 

GC/AAS 

GC/AAS 

GC/AAS 

0.4 μg/sample 97 NIOSH 

(15–100 L 1994g; 

sample) (TML); 1994h 

0.1 μg/ 

sample (30– 

200 L sample) 

(TEL) 

No data No data Birch et al. 

(particulate); (particulate); 1980 

0.25 ng/m3

 (ga 95– 

seous) 99 (gaseous) 

0.3 μg/m3 46–>90 De Jonghe 

et al. 1981 

0.2 ng/m3 90–100 

2 μg/sample No data NIOSH 

0.1 μg/sample 1994a 

42 μg/L 94–125 EPA 1983 

0.5 μg/L 88–90 Chau et al. 

1979 

0.5 ng/g No data Chau et al. 

1980 

1.25 ng/L 90–108 Chakraborti 

et al. 1984 
LEAD 393 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Lead in Environmental Samples 

Accuracy 

Sample Analytical Sample (percent 

matrix Preparation method method detection limit recovery) Reference 

Water Filtration of water through a AAS (EPA 0.1 mg/L 99.8–125.7 EPA 1983 

(particulate 0.45 μm membrane filter Method 239.1) 

and dissolved (dissolved lead); particulate GFAAS (EPA 1 μg/L 88–95 

lead) material dissolved by wet Method 239.2) 

ashing (insoluble lead) 

Water (total Digestion of sample with AAS 1.0 ng/g No data Chau et al. 

lead) acid and heat; dilution with 1979 

water 

Water Acidification, addition of (Standard No data No data NEMI 2005b 

(dissolved or ammoniacal citrate-cyanide Method 3500­

total) reducing solution; extraction PbB) 

with chloroform containing 

dithizone. 

Water Filtration, acidification, AAS (Standard 0.5 mg/L No data NEMI 2005a 

aspiration into a flame Method 3111B) 

Water Digestion, analysis	 GFAAS 1 μg/L 101% NEMI 2005c 

(Standard 

Method 3113B) 

Water and Filtration/acidification and ICP/AES 10 μg/L 109% NEMI 2005d 

waste water analysis for dissolved; (Standard 

(dissolved, digestion followed by Method 3120B) 

total) analysis for total 

Water, Filtration or digestion as ICP/MS (EPA No data 71–137% EPA 1994d 

extracts or appropriate (depends on Method 6020) (11–23% 

digests of matrix, dissolved or total, RSD) for 

waste acid leachable, etc.) aqueous 

solutions; 

90B104% 

(6B28% RSD) 

for solid 

samples 

Water Filtration; addition of ETAAS 0.14 μg/L 89–101 Xu and 

Ni(NO3)2 and Liang 1997 

NH4H2PO4matrix modifiers 

Water (total Filtration of sample followed ICP/AES 10B50 μg/L >80 Que Hee 

lead) by analysis; digestion of filter and Boyle 

with acid 1988 

Soil Drying of soil sample ICP/AES 0.09 μg/g 97–103 Schmitt et 

followed by sieving; al. 1988 

digestion with HNO3; 

centrifugation 
LEAD 394 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Lead in Environmental Samples 

Accuracy 

Sample Analytical Sample (percent 

matrix Preparation method method detection limit recovery) Reference 

Dust Wiping of hard surface of ICP/AES Varies No data ASTM 1998f 

known dimension; acid AAS (ASTM E 

digestion GFAAS 1728); 

ASTM 

1998b 

(ASTM E 

1644); 

ASTM 

1998a 

(ASTM E 

1613) 

Soil Drying of soil followed by ICP/AES Varies No data ASTM 

homogenization, digestion AAS 1998e 

with nitric acid and hydrogen GFAAS (ASTM E 

peroxide, dilution 1727) ; 

ASTM 

1998d 

(ASTM E 

1726) ; 

ASTM 

1998a 

(ASTM E 

1613) 

Soil Drying of soil sample AAS No data No data Mielke et al. 

followed by sieving, 1983 

digestion with HNO3, 

filtration 

Soil Drying of sample and sieving XRF No data 65–98 Krueger and 

for XRF; digestion of sieved AAS No data 63–68 Duguay 

sample with HNO3 and heat 1989 

for AAS 

Soil Drying of sample, dry AAS 2 μg/g 79–103 Beyer and 

ashing, digestion with acid, Cromartie 

and dilution with water 1987 

Soil Digestion with HNO3 and FI-HG-AAS 2 μg/L 98–101 Samanta 

H2O2; evaporation; and 

redissolution with HNO3; Chakraborti 

filtration 1996. 

Soil, wastes, Acid digestion of sample, AAS (EPA 0.1 mg/L No data EPA 1986c 

and ground- dilution with water, and method 7420) 

water filtration GFAAS (EPA 1 μg/L No data 

method 7421) 

Soil, dust, and Digestion of sample with hot AAS 12 ng/g >80 Que Hee et 

paint acid; evaporation of water; al. 1985b 

redissolution in HNO3 
LEAD 395 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Lead in Environmental Samples 

Accuracy 

Sample Analytical Sample (percent 

matrix Preparation method method detection limit recovery) Reference 

Sediment Digestion of sample with hot GFAAS No data 92–95 Bloom and 

HNO3/H2SO4 Crecelius 

1987 

Sediment, fish Homogenization of fish; GC/AAS 0.01 μg/g 81–85 Chau et al. 

(TAL) addition of EDTA to sample; (sediment) 72–76 1979 

extraction with hexane; 0.025 μg/g 

centrifugation; isolation off 

organic layer for analysis 

Sediment, Purging of sample with gas GC/AAS 0.1 ng/g (solid) No data Chau et al. 

(fish), followed by cryogenically 1980 

vegetation trapping volatile species onto 

(TAL) solid sorbent GC column 

Sediment, Digestion of sample with AAS 50 ng/g No data Chau et al. 

fish, acid and heat; dilution with (sediment) 1980 

vegetation water 10 ng/g (fish No data 

(total lead) and 

vegetation) 

Dried paint Sample collection using heat ICP/AES Varies No data ASTM 

gun, cold scraping, or coring AAS 1998g 

methods; microwave GFAAS (ASTM 

digestion with nitric acid and E 1729); 

hydrochloric acid ASTM 

1998c 

(ASTM 

E 1645); 

ASTM 

1998a 

(ASTM 

E 1613) 

Milk Addition of 50 μL GFAAS No data No data Michaelson 

(C2H5)4NOH in ethanol to and 

25 μL milk followed by Sauerhoff 

heating and dilution with 1974 

water to 125 μL 

Evaporated Dry ashing of sample; ASV 0.005 μg/g 99 Capar and 

milk dissolution in HNO3 Rigsby 1989 

Mussel, Digestion of sample with GFAAS 4 ng/g 94–95 Aroza et al. 

tomato acid or acid plus catalyst; 1989 

generation of lead hydride 

Agricultural Dry ashing of sample with DPASV 0.4 ng/g 85–106 Satzger et 

crops H2SO4 and HNO3; dilution al. 1982 

with water 
LEAD 396 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Lead in Environmental Samples 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection limit 

Accuracy 

(percent 

recovery) Reference 

Grains, milk 

mussel, fish 

Bomb digestion of sample 

with acid and heat or 

digestion with acid and dry 

ashing; dissolution in acid; 

dilution with water 

GFAAS 

DPASV 

20 μg/g 

(bomb); 5 μg/g 

(dry ash) 

 No data 

85–107 

75–107 

82–120 

Ellen and 

Van Loon 

1990 

Edible oils Microwave digestion with 

acid mixture; 

ICP/AES 50 ng/g 75–107 Allen et al. 

1998 

(NH4)2PO4 added as matrix 

modifier 

GFAAS 30 ng/g 78–117 

Citrus leaves 

and paint 

Chopping or pulverization of 

sample; digestion with hot 

acid; evaporation of water; 

redissolution in acid 

ICP/AES 10–50 μg/L 75–82 (citrus 

leaves); 89– 

96 (paint) 

Que Hee 

and Boyle 

1988 

Feathers Clean feathers with non ionic 

detergent; rinse with 

deionized water for 2– 

ICP/MS 10 ppb No data California 

Department 

of Fish and 

3 minutes. Game 2004 

AA = atomic absorption; AAS = atomic absorption spectroscopy; AES = atomic emissions spectroscopy; 

ASV = anode stripping voltammetry; (C2H5)4NOH = tetraethylammonium hydroxide; DPASV = differential pulse 

anodic stripping voltammetry; EDTA = ethylenediamine tetraacetic acid; EPA = Environmental Protection Agency; 

EPXMA = electron probe X-ray micro-analysis; ETAAS = electrothermal atomic absorption spectroscopy; GC = gas 

chromatography; GFAAS = graphite furnace atomic absorption spectrometry; HCl = hydrochloric acid; 

HClO4 = perchloric acid; HNO3 = nitric acid; H2O2 = hydrogen peroxide; H2SO4 = sulfuric acid; ICP/AES = inductively 

coupled plasma-atomic emission spectroscopy; ICP/MS = inductively coupled plasma-mass spectrometry; 

IDMS = isotope dilution mass spectrometry; LAMMA = laser microprobe mass analysis; MS = mass spectrometry; 

NaOH = sodium hydroxide; NG = nanogram; NIOSH = National Institute for Occupational Safety and Health; 206Pb = lead 206; PID = photoionization detector; TAL = tetraalkyl leads; TEL = tetraethyl lead; 

THF = tetrahydrofuran; TML = tetramethyl lead; XRD = X-ray diffraction; XRF = X-ray fluorescence 
LEAD 397 

7. ANALYTICAL METHODS 

Advantages of ICP/AES are that it has a wide range and allows analysis of several elements at once. 

However, the technique is expensive in terms of equipment and supplies (NIOSH 1981). XRFS has been 

used to analyze for particulate lead in air (DeJonghe et al. 1981). While sensitivity was good, recovery 

was highly variable and relatively low compared to other methods. The highest sensitivity was obtained 

with IDMS, as expected (Volkening et al. 1988). As previously stated, this is the definitive method for 

determining lead in environmental, as well as biological samples. Two sophisticated methods, EPXMA 

and LAMMA, have been used to determine the inorganic lead species present in particulate matter in air 

(Van Borm et al. 1990). 

Determination of lead vapor in air requires prior filtering of the air to exclude particulate lead, and 

trapping of the gaseous components. Gaseous lead is also referred to as organic lead or alkyl lead, the 

most common being the tetraalkyl species. Organic lead species may be trapped by liquid or solid 

sorbents, or cryogenically (Birch et al. 1980; DeJonghe et al. 1981; NIOSH 1978b). Gas chromatography 

(GC) is used to separate the different alkyl species. Detection by GFAAS and PID has been reported 

(DeJonghe et al. 1981; NIOSH 1978b). GFAAS detection is more sensitive than PID, but both have good 

accuracy. 

Water. As with air, water can be analyzed for both particulate and dissolved (organic) lead. Particulate 

lead collected on a filter is usually wet ashed prior to analysis. Comparison of the GFAAS and AAS 

methods for particulate lead showed the former technique to be about 100 times more sensitive than the 

latter, although both offer relatively good accuracy and precision (EPA 1983). ICP/MS has been used to 

determine lead in water (EPA 1994d). Chelation/extraction can also be used to recover lead from 

aqueous matrices (APHA 1998). GC/AAS has been used to determine organic lead, present as various 

alkyl lead species, in water (Chakraborti et al. 1984; Chau et al. 1979, 1980). Sample preparation for 

organic lead analysis was either by organic solvent extraction (Chakraborti et al. 1984; Chau et al. 1979) 

or purge-and-trap (Chau et al. 1980). Sensitivity was in the ppb to ppt range and reliability was similar 

for all three methods. Total lead can be determined by digesting samples with acid and analyzing by 

either AAS or the more sensitive GFAAS (EPA 1986c). 

Dusts, Sediments, and Soil. Both total and organic lead have been determined in dusts, sediments, and 

soils. In most cases, the sample must be digested with acid to break down the organic matrix prior to 

analysis (ASTM 1998b, 1998d; Beyer and Cromartie 1987; Bloom and Crecelius 1987; EPA 1986c; 

Krueger and Duguay 1989; Mielke et al. 1983; Que Hee and Boyle 1988; Que Hee et al. 1985b; Samanta 

and Chakraborti 1996; Schmitt et al. 1988); however, organic extraction (Chau et al. 1979) and purge­
LEAD 398 

7. ANALYTICAL METHODS 

and-trap (Chau et al. 1980) have also been used. The primary detection methods are ICP/AES, AAS, or 

GFAAS (GFAAS being more sensitive, but also more susceptible to interference). When quantification 

of organic lead is desired, GC is employed to separate the alkyl lead species (Chau et al. 1979, 1980). 

Precision and accuracy are acceptable for these atomic absorption-based methods (Beyer and Cromartie 

1987; Bloom and Crecelius 1987; Chau et al. 1979; EPA 1986c; Krueger and Duguay 1989; Que Hee et 

al. 1985b). ICP/AES is reported to be more sensitive and reliable than atomic absorption techniques 

(Schmitt et al. 1988), but sample collection and preparation methods have been shown to strongly 

influence the reliability of the overall method (Que Hee et al. 1985b). Sampling of house dust and hand 

dust of children requires special procedures (Que Hee et al. 1985b). XRFS appears to provide a simpler 

method of measuring lead in soil matrices; however, the available data do not permit an assessment of the 

techniques sensitivity and reliability for soil analysis (Krueger and Duguay 1989). XRFS has been shown 

to permit speciation of inorganic and organic forms of lead in soil for source elucidation (Manceau et al. 

1996). 

Other Matrices. Lead has been determined in several other environmental matrices, including paint, fish, 

vegetation, agricultural crops, and various foods. As with soil, the methods of choice are ICP/AES, AAS, 

or GFAAS. Samples may be prepared using one of the methods described for sediment and soil or by wet 

or dry ashing (Aroza et al. 1989; ASTM 1998d; Capar and Rigsby 1989; Que Hee and Boyle 1988; Que 

Hee et al. 1985b; Satzger et al. 1982). ASV and DPASV have also been used with good sensitivity (ppb) 

and reliability to analyze for lead in other environmental media (Capar and Rigsby 1989; Ellen and Van 

Loon 1990; Satzger et al. 1982). 

7.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of lead is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of lead. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 
LEAD 399 

7. ANALYTICAL METHODS 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. Methods are available for 

measuring inorganic lead in blood, serum, urine, cerebrospinal fluid, tissues, bone, teeth, and hair 

(Aguilera de Benzo et al. 1989; Batuman et al. 1989; Blakley and Archer 1982; Blakley et al. 1982; 

Christoffersson et al. 1986; Delves and Campbell 1988; Ellen and Van Loon 1990; Exon et al. 1979; Hu 

et al. 1989, 1990, 1991; Jason and Kellogg 1981; Manton and Cook 1984; NIOSH 1977b, 1977c, 1994c, 

2003; Que Hee and Boyle 1988; Que Hee et al. 1985a; Wielopolski et al. 1986; Zhang et al. 1997). 

Available methods for determining lead in body fluids are sensitive and reliable for measuring 

background exposure levels, as well as exposure levels at which health effects have been observed to 

occur. Blood lead levels have been found to correlate best with exposure concentrations (Moore 1995; 

Rabinowitz et al. 1985). Methods of quantifying lead in tissues, bone, teeth, and hair are generally 

reliable, but are only sensitive at relatively high exposure concentrations. Since the elimination half-time 

of lead in blood is approximately 30 days, PbBs generally reflect relatively recent exposures. Lead in 

bone is considered a biomarker of cumulative exposure to lead because lead accumulates in bone over the 

lifetime and most of the lead body burden resides in bone. There is a need for more sensitive methods of 

detection for matrices so that correlations between lead levels in these media and exposure concentrations 

can be more reliably determined. Several nonspecific biomarkers are used to assess exposure to lead. 

These include ALAD activity and ALA, EP, coproporphyrin, and 1,25-dihydroxyvitamin D 

concentrations (Braithwaite and Brown 1987; EPA 1986a; Grandjean and Olsen 1984; Oishi et al. 1996; 

Porru and Alessio 1996; Stokinger 1981; Tabuchi et al. 1989; Tomokuni and Ichiba 1988; Tomokuni et 

al. 1988). Lead interferes with the conversion of zinc protoporphyrin (ZPP) to heme by the enzyme 

ferrochelatase and a correlation has been observed between lead blood levels and ZPP; therefore, levels of 

ZPP can also be used as a biomarker of lead exposure (Goyer 2001). The methods for determining these 

biomarkers are generally sensitive and reliable. No additional research for these biomarkers appears to be 

needed. There is a need to identify and quantify those molecules responsible for lead transport within the 

body; the measurement of lead associated with these compounds could provide additional information 

about exposure. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Numerous analytical methods are available for measuring inorganic and organic lead 
LEAD 400 

7. ANALYTICAL METHODS 

compounds in air, water, sediments, dust, paint, soil, fish, agricultural products, and foodstuffs (NEMI 

2005a, 2005b, 2005c, 2005d; Eckel and Jacob 1988; EPA 1982a, 1986a, 1988b, 1989d, 1989e, 1990, 

1994d; Lee et al. 1989; Maenhaut et al. 1979; Mielke 1993; Mielke et al. 1983, 1984/1985, 1989). Most 

of these are sensitive and reliable for determining background concentrations of lead compounds in the 

environment and levels at which health effects might occur. The most frequently used methods are AAS, 

GFAAS, ASV, and ICP/AES, the methods recommended by EPA and NIOSH (ASTM 1998a; Birch et al. 

1980; EPA 1988b; NIOSH 1981, 1994c, 2003; Scott et al. 1976). The definitive method is IDMS, which 

is used to produce reference standards by which laboratories can determine the reliability of their analyses 

(Volkening et al. 1988). No additional analytical methods for determining low levels of lead compounds 

in environmental media are needed. Additional method development work is needed if individual lead 

species in environmental media are to be accurately determined. ICP/MS based methods should be 

critically examined. 

7.3.2 Ongoing Studies 

Ongoing studies regarding analytical methods for lead were reported in the Federal Research in Progress 

database (FEDRIP 2005), and are summarized in Table 7-3. 
LEAD 401 

7. ANALYTICAL METHODS 

Table 7-3. Ongoing Research Regarding the Analytical Methods for Lead in 

Environmental and Biological Samples 

Investigator Affiliation Research description Sponsor 

Chillrud S Columbia 

University, New 

York, New York 

Core-Geochemistry Laboratory: A laboratory is 

being developed to support several ongoing 

research projects, including projects involving the 

analytical measurement of lead in environmental 

samples and human tissue. The instrumentation 

that will be used includes a VG sector 

National 

Institute of 

Environmental 

Health 

Sciences 

54-30 Thermal Ionization Mass Spectrometer 

(TIMS), a Hitachi Z8200 Graphite Furnace Atomic 

Absorption Spectrophotometer (GFAAS), a VG 

High-Resolution inductively coupled plasma-mass 

spectrometry (ICP-MS). 

Mutti A University of 

Parma, Parma 

Italy 

Metals in exhaled breath condensate as chronic 

obstructive pulmonary disease (COPD) biomarkers: 

Develop biomarkers for COPD involving the analysis 

of exhaled breath condensate for the presence of 

lead by electro-thermal atomic absorption 

spectroscopy (ETAAS) and ICP-MS. 

National Heart, 

Blood, and 

Lung Institute 

Parsons PJ New York State 

Department of 

Health, Human 

Toxicology and 

Molecular 

Epidemiology 

Bone Lead Standardization Program: The aim of 

this proposal is to create a Standardization Program 

for Bone Lead measurements (BLSP) obtained via 

reference methods and via in vivo x-ray 

fluorescence (XRF). 

National 

Institute of 

Environmental 

Health 

Sciences 

Source: FEDRIP 2005 
LEAD 402 

7. ANALYTICAL METHODS 

This page is intentionally blank. 
LEAD 403 

8. REGULATIONS AND ADVISORIES 

The international and national regulations and guidelines regarding lead and lead compounds in air, water, 

and other media are summarized in Table 8-1. 

ATSDR has not derived MRLs for lead. The EPA has not developed a reference concentration (RfC) for 

lead. EPA has also decided that it would be inappropriate to develop a reference dose (RfD) for inorganic 

lead (and lead compounds) because some of the health effects associated with exposure to lead occur at 

blood lead levels as low as to be essentially without a threshold (IRIS 2005). 

EPA has assigned lead a weight-of-evidence carcinogen classification of B2, probable human carcinogen, 

based on inadequate information in humans and sufficient data in animals (IRIS 2005). The International 

Agency for Research on Cancer (IARC) has classified inorganic lead compounds as probably 

carcinogenic to humans (Group 2A) based on limited evidence of carcinogenicity in humans and 

sufficient evidence in animals (IARC 2004). IARC also determined that organic lead compounds are not 

classifiable as to their carcinogenicity to humans (Group 3) based on inadequate evidence of 

carcinogenicity in humans and animals (IARC 2004). The Department of Health and Humans Services 

(DHHS) has determined that lead and lead compounds are reasonably anticipated to be human 

carcinogens based on limited evidence from studies in humans and sufficient evidence from studies in 

experimental animals (NTP 2005). The American Conference of Governmental Industrial Hygienists 

(ACGIH) has categorized elemental lead and certain inorganic lead compounds, assessed as lead, as 

A3 carcinogens: carcinogenic in experimental animals at a relatively high dose not considered relevant to 

worker exposure. The data obtained from epidemiologic studies suggest that, except for uncommon 

routes or levels of exposure, these substances are unlikely to cause cancer in humans (ACGIH 2004). 

ACGIH has categorized lead chromate, assessed on the basis of both lead and chromium, as an 

A2 carcinogen. Although substances in this category are carcinogenic in experimental animals at dose 

levels that are considered relevant to worker exposure, the data from epidemiologic studies are 

insufficient to confirm an increased risk of cancer in exposed humans (ACGIH 2004). 

OSHA requires employers of workers who are occupationally exposed to a toxic or hazardous substance 

to institute engineering controls and work practices that maintain or reduce their exposure to a level that is 

at or below the permissible exposure limit (PEL) established for the substance. For occupational 

exposures to lead, the employer must use engineering controls and work practices to achieve an 
LEAD 404 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Lead and Lead Compounds 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

 IARC Carcinogenicity classification IARC 2004 

WHO 

Lead compounds, inorganic 

Lead compounds, organic 

Air quality guidelines 

Group 2Aa 

Group 3b 

0.5 μg/m3

 WHO 2000 

Drinking water quality guidelines 0.01 mg/L WHO 2004 

NATIONAL 

Regulations and Guidelines: 

a. Air 

ACGIH TLV (TWA) 

Lead, inorganic 0.05 mg/m3 

ACGIH 2004 

EPA Hazardous air pollutant Yes EPA 2004b 

42 USC 7412 

NIOSH 

OSHA 

National primary and secondary ambient 

air quality standardsc 

REL (TWA)d

 IDLH 

PEL (8-hour TWA) for toxic and 

1.5 μg/m3

 0.05 mg/m3 

100 mg/m3 

50 μg/m3

 EPA 2005b 

40 CFR 50.12 

NIOSH 2005 

 OSHA 2005d 

hazardous substances for lead 29 CFR 1910.1025 

b. Water 

PEL (8-hour TWA) for general industry 

for tetraethyl leade 

PEL (8-hour TWA) for construction 

industry for tetraethyl leade 

PEL (8-hour TWA) for shipyard industry 

for tetraethyl leade 

0.075 mg/m3 

0.1 mg/m3 

0.1 mg/m3

 OSHA 2005c 

29 CFR 1910.1000 

 OSHA 2005b 

29 CFR 1926.55 

 OSHA 2005a 

29 CFR 1915.1000 

EPA Designated as hazardous substances in 

accordance with Section 311(b)(2)(A) of 

the Clean Water Act 

Yes EPA 2005a 

40 CFR 116.4 

Lead acetate, lead chloride, lead 

fluoroborate, lead iodide, lead nitrate, 

lead sulfate, lead sulfide, and tetraethyl 

lead 

National primary drinking water 

standards 

EPA 2002 

MCLG Zero 

MCL 

Action level 

Reportable quantities of hazardous 

substances designated pursuant to 

Section 311 of the Clean Water Act 

Treatment techniquef 

0.015 mg/L 

10 pounds EPA 2005c 

40 CFR 117.3 

Lead acetate, lead chloride, lead 

fluoroborate, lead iodide, lead nitrate, 

lead sulfate, lead sulfide, and tetraethyl 

lead 
LEAD 405 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Lead and Lead Compounds 

Agency Description Information Reference 

NATIONAL (cont.)

 EPA Residential lead hazards standards – EPA 2005l 

TSCA Section 403 

Floors 

Interior window sills 

40 μg/ft2 

250 μg/ft2 

Bare soil in children’s play areas 400 ppm 

Bare soil in rest of yard 1,200 ppm average 

c. Food 

FDA Action level (μg/mL leaching solution) FDA 2000 

Ceramicware 

Flatware (average of 6 units) 3.0 μg/mL 

Small hollowware (other than cups 2.0 μg/mL 

and mugs) (any 1 of 6 units) 

Large hollowware (other than pitchers) 1.0 μg/mL 

(any 1 of 6 units) 

Cups and mugs (any 1 of 6 units) and 0.5 μg/mL
 

pitchers (any 1 of 6 units) 

Silver-plated hollowware 

Product intended for use by adults 7 μg/mL 

(average of 6 units) 

Product intended for use by infants 0.5 μg/mL 

and children (any 1 of 6 units) 

Bottled drinking water 0.005 mg/L FDA 2004 

21 CFR 165.110 

d. Other 

 ACGIH Carcinogenicity classification ACGIH 2004 

A3g Lead 

Biological exposure indices (lead in 30 μg/100 mL 

blood)h 

ATSDR Action level for children 10 μg/dL Agency for Toxic 

Substances and 

Disease Registry 

1997 

EPA Carcinogenicity classification Group B2i IRIS 2005 

Oral slope factor Not available 

Inhalation unit risk Not available

 RfC Not available

 RfD Not applicablej 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous 10 pounds EPA 2005d 

substance 40 CFR 302.4 

Reportable quantity 

Lead, lead acetate, lead chloride, 

lead fluoroborate, lead iodide, lead 

nitrate, lead phosphate, lead sulfate, 

lead sulfide, and tetraethyl lead 
LEAD 406 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Lead and Lead Compounds 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA Superfund, emergency planning, and 

community right-to-know 

Effective date of toxic chemical release 01/01/87 EPA 2005g 

reporting for lead 40 CFR 372.65 

Extremely hazardous substances EPA 2005e 

Tetraethyl lead 

Reportable quantity 10 pounds 

40 CFR 355, 

Appendix A 

Threshold planning quantities 100 pounds 

Superfund, emergency planning, and 

community right-to-know 

Threshold amounts for manufacturing 100 pounds EPA 2005f 

(including importing), processing, and 40 CFR 372.28 

otherwise using such toxic chemicals 

NTP Carcinogenicity classification Reasonably NTP 2005 

anticipated to be 

human carcinogens 

a

Group 2A: probably carcinogenic to humans 

b

Group 3: not classifiable as to carcinogenicity to humans 

c

National primary and secondary ambient air quality standards for lead and its compounds, measured as elemental 

lead by a reference method based on Appendix G to 40 CFR 50.12, or by an equivalent method, are: 1.5 μg/m3

, 

maximum arithmetic mean averaged over a calendar quarter. d

The REL also applies to other lead compounds (as Pb), including metallic lead, lead oxides, and lead salts 

(including organic salts such as lead soaps but excluding lead arsenate). The NIOSH REL for lead (10-hour TWA) is 

0.050 mg/m3; air concentrations should be maintained so that worker blood lead remains less than 0.060 mg 

Pb/100 g of whole blood. 

e

Skin designation 

f

Treatment Technique: lead is regulated by a Treatment Technique that requires systems to control the 

corrosiveness of their water. If more than 10% of tap water samples exceed the action level, water systems must 

take additional steps. For lead, the action level is 0.015 mg/L. 

g

A3: confirmed animal carcinogen with unknown relevance to humans 

h

BEI: Women of child-bearing potential, whose blood exceeds 10 μg/dL, are at risk of delivering a child with a blood 

Pb over the current CDC guideline of 10 μg/dL. If the blood Pb of such child remains elevated, they may be at 

increased risk of cognitive deficits. 

i

Group B2: probable human carcinogen 

j

See IRIS record for complete oral RfD discussion (IRIS 2005). 

ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic Substances and 

Disease Registry; BEI = biological exposure indices; CDC = Centers for Disease Control and Prevention; 

CERCLA = Comprehensive Environmetnal Response, Compensation, and Liability Act; CFR = Code of Federal 

Regulations; EPA = Environmental Protection Agency; FDA = Food and Drug Administration; IARC = International 

Agency for Research on Cancer; IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information 

System; MCL = maximum contaminant level; MCLG = maximum contaminant level goal; NIOSH = National Institute 

for Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health 

Administration; PEL = permissible exposure limit; REL = recommended exposure limit; RfC = inhalation reference 

concentration; RfD = oral reference dose; TSCA = Toxic Substances Control Act; TLV = threshold limit values; 

TWA = time-weighted average; USC = United States Code; WHO = World Health Organization 
LEAD 407 

8. REGULATIONS AND ADVISORIES 

occupational exposure of 50 μg/m3 (0.006 ppm) or lower, based on an 8-hour TWA (OSHA 2005d). 

When employee exposures to lead cannot be maintained ≤50 μg/m3

 through engineering and work 

practice controls, the employer is required to provide the employees with respirators as a means of 

supplemental control. The specifications for different types of respirators and the conditions for their use 

are provided in the Code of Federal Regulations at 29 CFR 1910.1025. OSHA specifies 30 μg/m3

 of air 

as the action level for employee exposure to airborne concentrations of lead (OSHA 2005d). Under the 

requirements for medical surveillance and biological monitoring, the blood lead level (PbB) of employees 

exposed to lead above the action level for >30 days/year must be monitored at least every 6 months. The 

frequency for sampling an employee’s PbB increases to once every 2 months if the results of his or hers 

previous blood analysis indicated a PbB ≥40 μg/dL (OSHA 2005d). OSHA requires continuing the 

2-month sampling protocol until the employee’s PbB is below 40 μg/dL for two consecutive samplings. 

If an employee is working in an area where exposure to lead is at or above the action level, and the 

employee’s periodic blood test or a follow-up test indicates a PbB ≥50 μg/dL, the employer is required to 

remove the employee from that work area (OSHA 2005d). The relocation of an employee may also be 

instituted if the average of the three most recent blood tests or the average of all blood tests given over the 

most recent 6-month period indicates a PbB ≥50 μg/dL. If however, the last single blood test taken 

during this period indicates a PbB ≤40 μg/dL, relocation of the employee may not be required (OSHA 

2005d). Except for the construction industry and certain aspects of the agricultural industry, more 

detailed requirements for limiting all occupational exposures to lead, including shipyard employment 

(OSHA 2005f), can be found in 29 CFR 1910.1025 (OSHA 2005d). On May 4, 1993, OSHA published 

an interim final rule, which reduced the permitted level of occupational exposure to lead for construction 

workers from an 8-hour TWA of 200 μg/m3

 to an 8-hour TWA of 50 μg/m3 (OSHA 1993). As with other 

industries, the action level for occupational exposure to lead in the construction industry is 

30 μg/m3

 (OSHA 2005e). More detailed requirements for protecting construction workers from 

occupational exposures to lead can be found in 29 CFR 1926.62 (OSHA 2005e). 

The EPA regulates lead under the Clean Air Act (CAA) and has designated lead as a hazardous air 

pollutant (HAP) (EPA 2004b). In the early 1970s, after determining that lead additives would impair the 

performance of emission control systems installed on motor vehicles and that lead particle emissions from 

motor vehicles presented a significant health risk to urban populations, the EPA began regulating the lead 

content in gasoline (EPA 1996a). In 1973, EPA instituted a phase-down program designed to minimize 

the lead content of leaded gasoline over time. By 1988, the total lead usage in gasoline had been reduced 

to <1% of the amount of lead used in the peak year of 1970 (EPA 1996a). The EPA defined unleaded 

gasoline as gasoline produced without the use of any lead additive and containing not more than 0.05 g of 
LEAD 408 

8. REGULATIONS AND ADVISORIES 

lead per gallon and not more than 0.0005 g of phosphorous per gallon. The 0.05 g per gallon criterion 

was allowed because EPA determined that this maximum trace level would provide adequate protection 

for catalyst emission control devices (i.e., prevent deterioration in emission control systems) and would 

be practicable for the petroleum industry. In 1990, Congress added Section 211(n) to the CAA and 

provided that after December 31, 1995, it would be unlawful to offer, sell, dispense, or transport, for use 

as fuel in any motor vehicle, any gasoline that contains lead or lead additives. The effective date for this 

prohibition was January 1, 1996 (EPA 1996a). On February 2, 1996, the EPA published a direct final 

rule revising its regulation for consistency with the CAA prohibitions; however, EPA’s definition of 

unleaded gasoline still allowed the sale of gasoline containing trace amounts of lead up to 0.05 g/gallon. 

The current definition, however, expressly prohibits the use of any lead additive in the production of 

unleaded gasoline. The term “lead additive” was defined to include pure lead as well as lead compounds 

(EPA 1996a). 

Lead is regulated by the Clean Water Effluent Guidelines and Standards, which are promulgated under 

the authority of the Clean Water Act (CWA). The regulations provide limitations on pollutant 

concentrations in waste water discharges from point source categories and represent the degree of 

reduction in pollutant concentration that is attainable through demonstrated technologies for new and 

existing sources. The regulations also provide standards of performance for new sources as well as 

pretreatment standards for new and existing sources. The effluent limitations establish the maximum 

discharge of pollutants allowed for 1 day and for a monthly average. The CWA establishes the basic 

structure for regulating the discharge of pollutants to waterways and is designed to ensure that all waters 

are sufficiently clean to protect public health and/or the environment. However, if waters and their 

sediments become contaminated from sources such as atmospheric deposition and discharges from 

industrial, municipal, or agricultural operations, toxic substances could concentrate in the tissue of fish 

and wildlife. Advisories have been developed and issued to warn people about the health risks of 

consuming lead-contaminated fish, shellfish, or wildlife and provide guidance as to the amount of fish or 

wildlife that can be safely consumed. Each state, Native American Tribe, or U.S. Territory establishes its 

own criteria for issuing fish and wildlife advisories. A fish or wildlife advisory will specify which waters 

(lake, rivers, estuaries, or coastal areas) or hunting areas have restrictions. The advisory provides 

information on the species and size range of the fish or wildlife of concern. The advisory may completely 

ban eating fish and shellfish, or recommend consumption limits (numbers of fish meals per specified time 

period) considered to be safe to eat. For example, an advisory may recommend that a person eat a certain 

type of fish no more than once a month. Advisories may specify the tissues of the fish or wildlife that can 

be safely eaten or proper preparation and cooking practices to help decrease exposure to lead. The fish or 
LEAD 409 

8. REGULATIONS AND ADVISORIES 

wildlife advisory is typically more restrictive to protect pregnant women, nursing mothers, and young 

children. Published information in the form of brochures on fish and wildlife advisories is available from 

state public health departments, natural resources departments, or fish and game departments. Signs may 

be posted in certain fishing and hunting areas frequently used by recreational fishers and hunters to warn 

them about specific contamination problems (EPA 1995b). Currently, 10 advisories are in effect in five 

states (Hawaii, Louisiana, Missouri, Ohio, and Tennessee), and one U.S. Territory (American Samoa) 

restricting the consumption of lead-contaminated fish and shellfish (EPA 2004d). No advisories were 

issued for wildlife. 

In an effort to protect human health by reducing the lead levels in drinking water at consumers' taps to as 

close to the maximum contaminant level goal (MCLG) of zero, water system authorities are required to: 

(1) install or improve corrosion control to minimize lead levels at the tap while ensuring that treatment 

does not cause the water system to violate any national primary drinking water regulation; (2) install 

treatment to reduce lead in source water entering the distribution system; (3) replace lead service lines 

when >10% of targeted tap samples exceed 0.015 mg/L lead in drinking water if corrosion control and/or 

source water treatment does not bring lead levels below the lead action level; and (4) conduct public 

education programs if lead levels are above the action level (EPA 1991a). 

The EPA also regulates the lead content in hazardous wastes as prescribed by the Resource Conservation 

and Recovery Act (RCRA). A solid waste may be defined as hazardous if it exhibits any of the four 

characteristics (ignitability, corrosivity, reactivity, and toxicity) used to identify hazardous wastes. A 

solid waste containing lead or lead compounds may be defined as a hazardous waste if it exhibits the 

characteristic of toxicity. The waste is said to exhibit the toxicity characteristic if the lead concentration 

in the extract obtained by subjecting a sample of the waste to the Toxicity Characteristic Leaching 

Procedure (TCLP) exceeds 5.0 mg/L (EPA 1990). On December 18, 1998, EPA issued a proposed rule 

under the Toxic Substances Control Act (TSCA) to provide new standards for the management and 

disposal of lead-based paint debris generated by individuals involved in abatements, renovations, and 

demolition of target housing and from lead removal and demolition of public and commercial buildings 

(EPA 1998a). As a result of the proposed rule and to avoid duplication and inconsistency in the 

management of lead-based paint debris, EPA also issued, on the same day a proposed rule that would 

temporarily suspend the applicability of the toxicity characteristic to these types of debris (EPA 1998b). 

The Lead-Based Paint Poisoning Prevention Act, as amended by the National Consumer Information and 

Health Promotion Act of 1976, mandates that the use of lead-based paint in residential structures 
LEAD 410 

8. REGULATIONS AND ADVISORIES 

constructed or rehabilitated by any federal agency or with federal assistance in any form be prohibited 

(HUD 1998). By definition, residential structures include non-dwelling facilities operated by the owner 

and commonly used by children under 6 years old, such as childcare centers. The Act also authorized the 

Department of Housing and Urban Development (HUD) to promulgate regulations to eliminate leadbased paint from HUD-associated housing built prior to 1978. The regulatory definition of lead-based 

paint is “any paint or other surface coating that contains lead equal to or in excess of 1.0 mg/cm2

 or 

0.5 percent by weight” (HUD 1997, 1998). For paints manufactured after June 22, 1977, however, 

Section 501(3) of the Act defines lead-based as any paint where the nonvolatile content contains 0.06% 

lead by weight. Purchasers and tenants of HUD-associated housing constructed before 1978 must be 

notified that the dwelling was constructed prior to 1978 and may contain lead-based paint. Information 

concerning the hazards of lead-based paint, the symptoms and treatment of lead-based paint poisoning, 

the precautions to be taken to avoid poisoning, and maintenance and removal techniques must also be 

provided (HUD 1998). The Residential Lead-Based Paint Hazard Reduction Act of 1992 (also known as 

Title X of the Housing and Community Development Act) requires sellers, landlords, and agents to 

provide the same type of information to potential purchasers or tenants of other “target housing” (i.e., 

constructed prior to 1978). Exceptions to these requirements include housing for elderly or disabled 

persons, unless a child <6 years of age is expected to reside in the dwelling; and dwellings without 

bedrooms such as studio/efficiency apartments, individual room rentals, dormitories, and military 

barracks (HUD 1998). Title IX also mandates a broad range of interrelated lead exposure activities, some 

of which require inter-agency collaboration. 

In addition to HUD, the primary federal agencies responsible for promulgating regulations implementing 

the mandates of Title X are the EPA, the Department of Health and Human Services (DHHS) and the 

Department of Labor’s Occupational Safety and Health Administration (OSHA). Title X amends TSCA 

by adding Title IV, entitled “Lead Exposure Reduction”. Title IV provides the authority for developing 

standards that reduce lead-based paint hazards in housing and environmental media (EPA 1998a). 

Section 402 of Title IV requires the EPA to promulgate regulations for accrediting training programs and 

certification of persons engaging in “lead-based paint activities” such as for lead abatement and 

renovation. The aim of the ruling is to ensure that individuals conducting these activities are properly 

trained and certified. The EPA/HUD training and certification program provides for five categories of 

lead-based paint professionals: supervisors, workers, inspectors, risk assessors, and project designers; 

and three categories of activities: inspection, risk assessment, and abatement. Section 403 of Title IV 

requires EPA to develop standards for lead-based paint hazards in most pre-1978 housing and childoccupied facilities and to address by regulation(s) the definition of “lead-based paint hazards", “lead­
LEAD 411 

8. REGULATIONS AND ADVISORIES 

contaminated dust", and “lead-contaminated soil”. On June 3, 1998, EPA issued several proposed 

standards in a notice of proposed rulemaking. It was proposed that lead-based paint hazards be described 

as “paint in poor condition” and defined as >10 ft2

 of deteriorated paint on exterior surface areas and 

>2 ft2

 on interior surface areas (EPA 1998b). The proposed standard for a lead-dust hazard is an average 

level of lead in dust of ≥40 μg/ft2

 on uncarpeted floors and ≥250 μg/ft2 on interior window sills (EPA 

2005l). For soils, an average concentration of 400 ppm/yard was the proposed standard at which the 

public should be made aware of the risk associated with exposure to lead (EPA 1998b). 

Section 404 of Title IV concerns the authorization requirements for state and tribal programs. States and 

Native American tribes can seek authorization from EPA to implement their own lead training, 

accreditation, and certification programs. On August 26, 1996, EPA published the final rule establishing 

the requirements that state or tribal programs must meet for authorization to administer and enforce the 

standards and regulations promulgated in accordance with Title IV (EPA 1998c). According to “The 

Lead Listing” provided by the National Lead Service Providers Listing System, as of July 1, 1998, 

22 states have established operational lead programs that actively certify lead service providers. Local, 

certified (licensed) lead-based paint inspectors, risk assessors, and laboratories can be located by calling 

the National Lead Information Center and Clearinghouse (1-800-LEAD-FYI [1-800-532-3394]) or 

through the Internet at http://www.leadlisting.org (HUD 1997). The Lead Listing is operated by a private 

entity for HUD’s Office of Lead Hazard Control. 

Section 406 of Title IV directs the EPA to develop consumer information concerning the hazards of 

exposure to lead and procedures to be followed during housing renovations or remodeling. On 

June 1, 1998, the EPA issued its final rule on the requirements for lead hazard education prior to 

conducting renovations in target housing (EPA 1998a). It is important to note that while the federal 

disclosure program requires property owners to make others aware of the potential lead hazards in or on 

their property, the program does not require the property owner to conduct inspections or risk assessments 

prior to selling or leasing property. Regulations responding to the mandates of Title IV are codified at 

40 CFR 745; Lead-Based Paint Poisoning Prevention in Certain Residential Structures. 

Lead also appears on the FDA’s list of poisonous and deleterious substances, which was established to 

control levels of contaminants in human food and animal feed. The action levels established for these 

substances represent limits at or above which the FDA will take legal action to remove the affected 

consumer products from the market (FDA 2000). In 1993, the FDA has established an action level for 

lead in fruit beverages (80 μg/kg) packaged in lead-soldered cans (FDA 1998b); in 1995, the use of lead­
LEAD 412 

8. REGULATIONS AND ADVISORIES 

soldered cans was banned by the FDA. Lead solders are alloys of metals that contain lead and are used in 

the construction of metal food cans. The FDA considers any food packaged in containers that use lead in 

can solders to be adulterated and in violation of the Federal Food, Drug, and Cosmetic Act (FDA 1995). 

As of February 8, 1996, the FDA considers wine in bottles capped with tin-coated lead foil capsules to be 

adulterated (FDA 1996). Tin-coated lead foil has been used as a covering applied over the cork and neck 

areas of wine bottles to prevent insect infestations, as a barrier to oxygen, and for decorative purposes. 

Because it can be reasonably expected that lead could become a component of the wine, the use of these 

capsules is also a violation of the Federal Food, Drug, and Cosmetic Act (FDA 1996). The FDA has 

reviewed several direct human food ingredients and has determined them to be “generally recognized as 

safe” when used in accordance with current good manufacturing practices. Some of these ingredients 

contain allowable concentrations of lead ranging from 0.1 to 10 ppm (FDA 1998a). 

The Lead Contamination Control Act of 1988 mandates that the Consumer Product Safety Commission 

(CPSC): (1) require the repair or recall of drinking water coolers containing lead in parts that come in 

contact with drinking water; (2) prohibit the sale of drinking water coolers that are not lead-free; 

(3) require that states establish programs to assist educational agencies in testing and remediating lead 

contamination of drinking water in schools; and (4) require that EPA certify testing laboratories and 

provide for coordination by the CDC of grants for additional lead screening and referral programs for 

children and infants (Congressional Record 1988). The CPSC has declared paints and similar surface 

coating having a lead content that exceeds the 0.06% by weight limit to be “banned hazardous products” 

(CPSC 1977). Paints and surface coatings with lead concentrations exceeding the 0.06% limit are defined 

as “lead-containing paint". Except for applications to motor vehicles and boats, once lead-containing 

paints are applied to toys or other articles intended for use by children and articles of furniture 

manufactured for consumer use, these items also become “banned hazardous products” (CPSC 1977). 

These products may be exempt from the ban if, at a minimum, the main label on the product includes the 

single word “Warning” and the statement: “Contains Lead. Dried Film of This Paint May Be Harmful If 

Eaten or Chewed” (CPSC 1977). 

The CDC determined in 1991 that PbBs >10 μg/dL in children were to be considered elevated (CDC 

1991). In its annual publication of threshold limit values (TLVs) and biological exposure indices (BEIs), 

the ACGIH notes that women of child-bearing age who have a PbB exceeding the CDC guideline value 

are at risk of delivering children with a PbB >10 μg/dL (ACGIH 1998). In its report to Congress, NIOSH 

summarizes occupational exposure information and provides recommendations for workers (NIOSH 

1997b). 
LEAD 413 

8. REGULATIONS AND ADVISORIES 

The ACGIH also notes that if a child’s PbB remains elevated, the child may be at increased risk of 

cognitive deficits (ACGIH 1998). The ACGIH has adopted BEIs for various substances. The BEI for a 

substance is an industrial hygiene reference value to be used in evaluating potential health hazards. It is 

important to note that BEIs are guideline values, and that they are not intended for use as measures of 

adverse effects or for diagnosis of occupational illness (ACGIH 1998). They represent the level of 

substance most likely to be observed in specimens (e.g., blood or urine) collected from a healthy worker 

who has been exposed to a chemical at its TLV. The TLV refers to the airborne concentration of a 

substance at which nearly all workers may be repeatedly exposed, day after day, without adverse health 

affects. BEIs apply to 8-hour exposures occurring 5 days/week. The BEI for lead is 30 μg/dL (ACGIH 

2004). The recommended exposure level (REL) for lead in the air adopted by the NIOSH is 

0.05 mg/m3

 (NIOSH 2005). NIOSH also recommends maintaining air concentrations so that worker 

blood lead remains at <60 μg/dL (NIOSH 1997a). 
LEAD 414 

8. REGULATIONS AND ADVISORIES 

This page is intentionally blank. 
_______________________ 

LEAD 415 

9. REFERENCES 

Abadin HG, Hibbs BF, Pohl HR. 1997b. Breast-feeding exposure of infants to cadmium, lead, and 

mercury: A public health viewpoint. Toxicol Ind Health 15(4):1-24. 

Abadin HG, Wheeler JS, Jones DE, et al. 1997a. A framework to guide public health assessment 

decisions at lead sites. J Clean Technol Environ Toxicol Occup Med 6:225-237. 

Abbate C, Buceti R, Munao F, et al. 1995. Neurotoxicity induced by lead levels: An 

electrophysiological study. Int Arch Occup Environ Health 66:389-392. 

ACGIH. 1986. Documentation of the threshold limit values and biological exposure indices. 5th ed. 

Cincinnati, OH: American Conference of Governmental Industrial Hygienists, BEI-19 to BEI-23. 

ACGIH. 1998. 1998 TLVs and BEIs. Threshold limit values for chemical substances and physical 

agents. Biological exposure indices. Cincinnati, OH: American Conference of Governmental Industrial 

Hygienist. 

ACGIH. 2004. Lead. Threshold limit values for chemical substances and physical agents and biological 

exposure indices. Cincinnati, OH: American Conference of Governmental Industrial Hygienists. 

Adebonojo FO. 1974. Hematologic status of urban black children in Philadelphia: Emphasis on the 

frequency of anemia and elevated blood lead levels. Clin Pediatr 13:874-888. 

Adhikari N, Sinha N, Narayan R, et al. 2001. Lead-induced cell death in testes of young rats. J Appl 

Toxicol 21:275-277. 

Adinolfi M. 1985. The development of the human blood-CSF-brain barrier. Dev Med Child Neurol 

27:532-537. 

Agency for Toxic Substances and Disease Registry. 1989. Decision guide for identifying substancespecific data needs related to toxicological profiles; notice. Fed Regist 54(174):37618-37634. 

Agency for Toxic Substances and Disease Registry. 1995. Multisite lead and cadmium exposure study 

with biological markers incorporated. Atlanta, GA: U.S. Department of Health and Human Services, 

Public Health Service, Agency for Toxic Substances and Disease Registry. 

Agency for Toxic Substances and Disease Registry. 1997. Public health statement for lead. Atlanta, 

GA: U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic 

Substances and Disease Registry. 

Agency for Toxic Substances and Disease Registry. 2004a. Interaction profile for arsenic, cadmium, 

chromium, and lead. Atlanta, GA: Agency for Toxic Substances and Disease Registry. 

http://www.atsdr.cdc.gov/interactionprofiles/ip04.html. July 22, 2005. 

Agency for Toxic Substances and Disease Registry. 2004b. Interaction profile for lead, manganese, zinc, 

and copper. Atlanta, GA: Agency for Toxic Substances and Disease Registry. 

http://www.atsdr.cdc.gov/interactionprofiles/ip06.html. July 22, 2005. 

*Not cited in text 
LEAD 416 

9. REFERENCES 

Agency for Toxic Substances and Disease Registry. 2006. Interaction profile for chlorpyrifos, lead, 

mercury, and methylmercury. Atlanta, GA: Agency for Toxic Substances and Disease Registry. 

http://www.atsdr.cdc.gov/interactionprofiles/IP-11/ip11.pdf. June 14, 2007. 

Aguilera de Benzo Z, Fraile R, Carrion N, et al. 1989. Determination of lead in whole blood by 

electrothermal atomization atomic absorption spectrometry using tube and platform atomizers and 

dilution with Triton X-100. J Anal Atom Spectrom 4:397-400. 

Ahamed M, Verma S, Kumar A, et al. 2005. Environmental exposure to lead and its correlation with 

biochemical indices in children. Sci Total Environ 346(1-3):48-55. 

Ahlgren L, Liden S, Mattson, et al. 1976. X-ray fluorescence analysis of lead in human skeleton in vivo. 

Scand J Work Environ Health 2:82-86. 

*Ahmed NS, El-Gendy KS, El-Refaie AK et al. 1987. Assessment of lead toxicity in traffic controllers 

of Alexandria, Egypt, road intersections. Arch Environ Health 42:92-95. 

Aiba Y, Ohshiba S, Horiguchi S, et al. 1999. Peripheral hemodynamics evaluated by acceleration 

plethysmography in workers exposed to lead. Ind Health 37:3-8. 

Åkesson A, Stal P, Vahter M. 2000. Phlebotomy increases cadmium uptake in hemochromatosis. 

Environ Health Perspect 108:289-291. 

Al-Hakkak ZSH, Hamamy HA, Murad AMB, et al. 1986. Chromosome aberrations in workers at a 

storage battery plant in Iraq. Mutat Res 171:53-60. 

Al Khayat A, Habibullah J, Koutouby A, et al. 1997b. Correlation between maternal and cord blood lead 

levels. Int J Environ Health Res 7(4):323-328. 

Al Khayat A, Menon NS, Alidina MR. 1997a. Acute lead encephalopathy in early infancy-clinical 

presentation and outcome. Ann Trop Paediatr 17(1):39-44. 

Al-Modhefer AJA, Bradbury MWB, Simmons TJB. 1991. Observations on the chemical nature of lead 

in human blood serum. Clin Sci 81:823-829. 

Al-Neamy FR, Almehdi AM, Alwash R, et al. 2001. Occupational lead exposure and amino acid profiles 

and liver function tests in industrial workers. Int J Environ Health Res 11(2):181-188. 

Al-Rashdan A, Heitkemper D, Caruso JA. 1991. Lead speciation by HPLC-ICP-AES and HPLC-ICPMS. J Chromatogr Sci 29(3):98-102. 

Al-Saleh I, Nester M, DeVol E, et al. 2001. Relationship between blood lead concentrations, 

intelligence, and academic achievement of Saudi Arabian schoolgirls. Int J Hyg Environ Health 204:165­

174. 

Al-Saleh I, Shinwari N, Mashour A, et al. 2005. Is lead considered as a risk factor for high blood 

pressure during menopause period among Saudi women? Int J Hyg Environ Health 208(5):341-356. 

Alessio L. 1988. Relationships between “chelatable lead” and the indicators of exposure and effect in 

current and past occupational life. Sci Total Environ 71:293-299. 
LEAD 417 

9. REFERENCES 

Alessio L, Bertazzi PA, Monelli O, et al. 1976. Free erythrocyte protoporphyrin as an indicator of the 

biological effect of lead in adult males: II. Comparison between free erythrocyte protoporphyrin and 

other indicators of effect. Int Arch Occup Environ Health 37:89-105. 

Alexander FW, Delves HT. 1981. Blood lead levels during pregnancy. Int Arch Occup Environ Health 

48:35-39. 

Alexander BH, Checkoway H, Costa-Mallen P, et al. 1998b. Interaction of blood lead and δaminolevulinic acid dehydratase genotype on markers of heme synthesis and sperm production in lead 

smelter workers. Environ Health Perspect 106:213-216. 

Alexander BH, Checkoway H, Faustman EM, et al. 1998a. Contrasting associations of blood and semen 

lead concentrations with semen quality among lead smelter workers. Am J Ind Med 34:464-469. 

Alexander BH, Checkoway H, van Netten C, et al. 1996. Semen quality of men employed at a lead 

smelter. Occup Environ Med 53:411-416. 

Alexander FW, Clayton BE, Delves HT. 1974. Mineral and trace-metal balances in children receiving 

normal and synthetic diets. QJ Med 43:89-111. 

Allen LB, Siitonen PH, Thompson HC. 1998. Determination of copper, lead, and nickel in edible oils by 

plasma and furnace atomic spectroscopies. J Am Oil Chem Soc 75(4):477-481. 

Allen-Gil SM, Gubala CP, Landers DH, et al. 1997. Heavy metal accumulation in sediment and 

freshwater fish in U.S. arctic lakes. Environ Toxicol Chem 16(4):733-741. 

Alomran AH, Shleamoon MN. 1988. The influence of chronic lead exposure on lymphocyte 

proliferative response and immunoglobulin levels in storage battery workers. J Biol Sci Res 19:575-585. 

Altman PL, Dittmer DS. 1974. Biological handbooks: Biology data book. Vol. III. 2nd ed. Bethesda, 

MD: Federation of American Societies for Experimental Biology, 1987-2008, 2041. 

Altmann L, Sveinsson K, Kraemer U, et al. 1998. Visual functions in 6-year-old children in relation to 

lead and mercury levels. Neurotoxicol Teratol 20(1):9-17. 

Alvares AP, Kapelner S, Sassa S, et al. 1975. Drug metabolism in normal children, lead-poisoned 

children, and normal adults. Clin Pharmacol Ther 17:179-183. 

American Academy of Pediatrics. 1998. Screening for elevated blood lead levels. Policy statement. 

Committee on environmental health. Pediatrics 101(6):1072-1078. 

Amitai Y, Graef JW, Brown MJ, et al. 1987. Hazards of deleading homes of children with lead 

poisoning. Am J Dis Child 141:758-760. 

Anders E, Bagnell CR, Krigman M, et al. 1982. Influence of dietary protein composition on lead 

absorption in rats. Bull Environ Contam Toxicol 28:61-67. 

Andersen ME, Krishnan K. 1994. Relating in vitro to in vivo exposures with physiologically based 

tissue dosimetry and tissue response models. In: Salem H, ed. Animal test alternatives: Refinement, 

reduction, replacement. New York: Marcel Dekker, Inc., 9-25. 
LEAD 418 

9. REFERENCES 

Andersen ME, Clewell HJ III, Gargas ML, et al. 1987. Physiologically based pharmacokinetics and the 

risk assessment process for methylene chloride. Toxicol Appl Pharmacol 87:185-205. 

Anderson RJ. 1987. Peripheral nerve conduction velocities and excitability. In: Lowndes HE, ed. 

Electrophysiology in neurotoxicology, Vol. 11. Piscataway, NJ: Department of Pharmacology and 

Toxicology, 51-69. 

Angle CR, Kuntzelman DR. 1989. Increased erythrocyte protoporphyrins and blood lead--a pilot study 

of childhood growth patterns. J Toxicol Environ Health 26:149-156. 

Angle CR, McIntire MS. 1978. Low level lead and inhibition of erythrocyte pyrimidine nucleotidase. 

Environ Res 17:296-302. 

Angle CR, Manton WI, Stanek KL. 1995. Stable isotope identification of lead sources in preschool 

children: The Omaha study. Clin Toxicol 33(6):657-662. 

Angle CR, Marcus A, Cheng I-H, et al. 1984. Omaha childhood blood lead and environmental lead: A 

linear total exposure model. Environ Res 35:160-170. 

Angle CR, McIntire MS, Swanson MS, et al. 1982. Erythrocyte nucleotides in children--increased blood 

lead and cytidine triphosphate. Pediatr Res 16:331-334. 

Annesi-Maesano I, Pollitt R, King G, et al. 2003. In utero exposure to lead and cord blood total IgE. Is 

there a connection? Allergy 58:589-594. 

Anttila A, Heikkila P, Nykyri E, et al. 1996. Risk of nervous system cancer among workers exposed to 

lead. J Occup Environ Med 38(2):131-136. 

Anttila A, Heikkila P, Pukkala E, et al. 1995. Excess lung cancer among workers exposed to lead. Scand 

J Work Environ Health 21:460-469. 

APHA. 1998. Method 3111. Metals by flame atomic absorption spectrometry. In: Clesceri LS, 

Greenberg AE, Eaton AD, eds. Standard methods for the examination of water and wastewater. 20th ed. 

Washington, DC: American Public Health Association. American Water Works Association. Water 

Environmental Federation, 3-13 to 3-22. 

Apostoli P, Bellini A, Porru S, et al. 2000a. The effect of lead on male fertility: A time to pregnancy 

(TTP) study. Am J Ind Med 38:310-315. 

Apostoli P, Maranelli G, Cas LD, et al. 1990. Blood lead and blood pressure: A cross sectional study in 

a general population group. Cardiologia 35(7):597-603. 

Araki S, Aono H, Yokoyama K, et al. 1986. Filterable plasma concentration, glomerular filtration, 

tubular reabsorption and renal clearance of heavy metals and organic substances in metal workers. Arch 

Environ Health 41:216-221. 

Araki S, Honma T, Yanagihara S, et al. 1980. Recovery of slowed nerve conduction velocity in leadexposed workers. Int Arch Occup Environ Health 46:151-157. 

Araki S, Murata K, Aono H. 1987. Central and peripheral nervous system dysfunction in workers 

exposed to lead, zinc and copper. Int Arch Occup Environ Health 59:177-187. 
LEAD 419 

9. REFERENCES 

Araki S, Sata F, Katsuyuki M. 1990. Adjustment for urinary flow rate and improved approach to 

biological monitoring. Int Arch Environ Health 62:471-477. 

Araki S, Sato H, Yokoyama K, et al. 2000. Subclinical neurophysiological effects of lead: A review on 

peripheral, central, and autonomic nervous system effects in lead workers. Am J Ind Med 37:193-204. 

Ariza ME, Bijur GN, Williams MV. 1998. Lead and mercury mutagenesis: Role of H2O2, superoxide 

dismutase, and xanthine oxidase. Environ Mol Mut 31:352-361. 

Arnvig E, Grandjean P, Beckmann J. 1980. Neurotoxic effects of heavy lead exposure determined with 

psychological tests. Toxicol Lett 5:399-404. 

Aroza I, Bonilla M, Madrid Y, et al. 1989. Combination of hydride generation and graphite furnace 

atomic absorption spectrometry for the determination of lead in biological samples. J Anal Atmos 

Spectro 4:163-166. 

Aschengrau A, Beiser A, Bellinger D, et al. 1994. The impact of soil lead abatement on urban children’s 

blood lead levels: Phase II results from the Boston lead-in-soil demonstration project. Environ Res 

67:125-148. 

Assennato G, Paci C, Baser ME, et al. 1987. Sperm count suppression without endocrine dysfunction in 

lead-exposed men. Arch Environ Health 42:124-127. 

ASTM. 1998a. ASTM E 1613. Standard test method for analysis of digested samples for lead by 

inductively coupled plasma atomic emission spectrometry (ICP-AES). Flame atomic absorption (FAAS), 

or graphite furnace atomic absorption (GFAA) techniques. In: Annual book of ASTM standards. 

Philadelphia, PA: American Society for Testing and Materials, 669-674. 

ASTM. 1998b. ASTM E 1644. Standard practice for hot plate digestion of dust wipe samples for the 

determination of lead by atomic spectrometry. In: Annual book of ASTM standards. Philadelphia, PA: 

American Society for Testing and Materials, 684-687. 

ASTM. 1998c. ASTM E 1645. Standard practice for the preparation of dried paint samples for 

subsequent lead analysis by atomic spectrometry. In: Annual book of ASTM standards. Philadelphia, 

PA: American Society for Testing and Materials, 688-692. 

ASTM. 1998d. ASTM E 1726. Standard practice for sample digestion of soils for the determination of 

lead by atomic spectrometry. In: Annual book of ASTM standards. Philadelphia, PA: American 

Society for Testing and Materials, 918-921. 

ASTM. 1998e. ASTM E 1727. Standard practice for field collection of soil samples for lead 

determination by atomic spectrometry techniques. In: Annual book of ASTM standards. Philadelphia, 

PA: American Society for Testing and Materials, 922-924. 

ASTM. 1998f. ASTM E 1728. Standard practice for field collection of settled dust samples using wipe 

sampling methods for lead determination by atomic spectrometry techniques. In: Annual book of ASTM 

standards. Philadelphia, PA: American Society for Testing and Materials, 925-927. 
LEAD 420 

9. REFERENCES 

ASTM. 1998g. ASTM E 1729. Standard practice for field collection of dried paint samples for lead 

determination by atomic spectrometry techniques. In: Annual book of ASTM standards. Philadelphia, 

PA: American Society for Testing and Materials, 928-930. 

Astrin KH, Bishop DF, Wetmur JG, et al. 1987. Delta-aminolevulinic acid dehydratase isozymes and 

lead toxicity. Ann NY Acad Sci 514:23-29. 

Atchison WD. 2004. Neurotoxicants and synaptic function: Session VII-B summary and research needs. 

Neurotoxicology 25:515-519. 

Aufderheide AC, Wittmers LE. 1992. Selected aspects of the spatial distribution of lead in bone. 

Neurotoxicology 13:809-820. 

Aungst BJ, Fung HL. 1981. Kinetic characterization of an in vitro lead transport across the rat small 

intestine. Toxicol Appl Pharmacol 61:38-47. 

Aungst BJ, Doice JA, Fung H-L. 1981. The effect of dose on the disposition of lead in rats after 

intravenous and oral administration. Toxicol Appl Pharmacol 61:48-57. 

Aviv A, John E, Bernstein J, et al. 1980. Lead intoxication during development: Its late effect on kidney 

function and blood pressure. Kidney Int 17:430-437. 

Awad El Karim MA, Hamed AS, Elhaimi YAA, et al. 1986. Effects of exposure to lead among lead-acid 

battery factory workers in Sudan. Arch Environ Health 41:261-265. 

Azar A, Snee RD, Habibi K. 1975. An epidemiologic approach to community air lead exposure using 

personal air samplers. In: Griffin TB, Knelson JH, eds. Lead. Stuttgart, West Germany: Georg Thieme 

Publishers, 254-290. 

Azar A, Trochimowicz HJ, Maxfield ME. 1973. Review of lead studies in animals carried out at Haskell 

Laboratory: Two year feeding study and response to hemorrhage study. In: Barth D, Berlin A, Engel R, 

et al., eds. Environmental health aspects of lead: Proceedings, International Symposium, October 1972, 

Amsterdam, The Netherlands. Luxembourg: Commission of the European Communities, 199-210. 

Baecklund M, Pedersen NL, Bjorkman L, et al. 1999. Variation in blood concentrations of cadmium and 

lead in the elderly. Environ Res 80(3):222-230. 

Bagci C, Bozkurt AI, Cakmak EA, et al. 2004. Blood lead levels of the battery and exhaust workers and 

their pulmonary function tests. Int J Clin Pract 58(6):568-572. 

Baghurst PA, McMichael AJ, Tong S, et al. 1995. Exposure to environmental lead and visual-motor 

integration at age 7 years: The Port Pirie cohort study. Epidemiology 6(2):104-109. 

Baghurst PA, McMichael AJ, Wigg NR, et al. 1992. Environmental exposure to lead and children's 

intelligence at the age of seven years. New Engl J Med 327:1279-1284. 

Baghurst PA, Robertson EF, McMichael AJ, et al. 1987. The Port Pirie cohort study: Lead effects on 

pregnancy outcome and early childhood development. Neurotoxicology 8:395-401. 

Baker EL, Feldman RG, White RF, et al. 1983. The role of occupational lead exposure in the genesis of 

psychiatric and behavioral disturbances. Acta Psychiatr Scand Suppl 67:38-48. 
LEAD 421 

9. REFERENCES 

*Baker EL, Goyer RA, Fowler BA, et al. 1980. Occupational lead exposure, nephropathy, and renal 

cancer. Am J Ind Med 1:138-148. 

Baker EL, Hayes CG, Landrigan PH, et al. 1977. A nationwide survey of heavy metal absorption in 

children living near primary copper, lead, and zinc smelters. Am J Epidemiol 106(4):261-273. 

Baker EL, Landrigan PJ, Barbour AG, et al. 1979. Occupational lead poisoning in the United States: 

Clinical and biochemical findings related to blood lead levels. Br J Ind Med 36:314-322. 

Balbus-Kornfeld JM, Stewart W, Bolla KI, et al. 1995. Cumulative exposure to inorganic lead and 

neurobehavioural test performance in adults: An epidemiological review. Occup Environ Med 52(1):2­

12. 

Ballew C, Khan LK, Kaufmann R, et al. 1999. Blood lead concentration and children's anthropometric 

dimensions in the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. J 

Pediatr 134:623-630. 

Balo J, Bajtai A, Szenda B. 1965. [Experimental adenomas of the kidney produced by chronic 

administration of lead phosphate.] Magyar Onkol 9:144-151. (Hungarian) 

Baloh RW, Spivey GH, Brown CP, et al. 1979. Subclinical effects of chronic increased lead absorption-­

a prospective study: 11. Results of baseline neurologic testing. J Occup Med 21:490-496. 

Banks EC, Ferretti LE, Shucard DW. 1997. Effects of low level lead exposure on cognitive function in 

children: A review of behavioral, neuropsychological and biological evidence. Neurotoxicology 

18(1):237-282. 

Bannon DI, Abounader R, Lees PSJ, et al. 2003. Effect of DMT1 knockdown on iron, cadmium, and 

lead uptake in Caco-2 cells. Am J Physiol Cell Physiol 284:C44-C50. 

Bannon DI, Olivi L, Bressler J. 2000. The role of anion exchange in the uptake of Pb by human 

erythrocytes and Madin-Darby canine kidney cells. Toxicology 147:101-107. 

Bannon DI, Portnoy ME, Olivi L, et al. 2002. Uptake of lead and iron by divalent metal transport 1 in 

yeast and mammalian cells. Biochem Biophys Res Commun 295:978-984. 

Barltrop D, Khoo HE. 1975. The influence of nutritional factors on lead absorption. Postgrad Med J 

51:795-800. 

Barltrop D, Meek F. 1979. Effect of particle size on lead absorption from the gut. Arch Environ Health 

34:280-285. 

Barnes RM. 1990. Childhood soil ingestion: How much dirt do kids eat? Anal Chem 62:1023-1033. 

Barnes DG, Dourson M. 1988. Reference dose (RfD): Description and use in health risk assessments. 

Regul Toxicol Pharmacol 8:471-486. 

Barratt CLR, Davies AG, Bansal MR, et al. 1989. The effects of lead on the male rat reproductive 

system. Andrologia 21:161-166. 
LEAD 422 

9. REFERENCES 

Barregård L, Svalander C, Schütz A, et al. 1999. Cadmium, mercury, and lead in kidney cortex of the 

general Swedish population: A study of biopsies from living kidney donors. Environ Health Perspect 

107(11):867-871. 

Barry PSI. 1975. A comparison of concentrations of lead in human tissue. Br J Ind Med 32:119-139. 

Barry PSI. 1981. Concentrations of lead in the tissues of children. Br J Ind Med 38:61-71. 

Barth A, Schaffer AW, Osterode W, et al. 2002. Reduced cognitive abilities in lead-exposed men. Int 

Arch Occup Environ Health 75:394-398. 

Barton JC. 1984. Active transport of lead-210 by everted segments of rat duodenum. Am J Physiol 

247:G193-G198. 

Barton JC, Conrad ME. 1981. Effect of phosphate on the absorption and retention of lead in the rat. Am 

J Clin Nutr 34:2192-2198. 

Barton JC, Conrad ME, Harrison L, et al. 1978a. Effects of calcium on the absorption and retention of 

lead. J Lab Clin Med 91:366-376. 

Barton JC, Conrad ME, Harrison L, et al. 1980. Effects of vitamin D on the absorption and retention of 

lead. Am J Physiol 238:G124-G130. 

Barton JC, Conrad ME, Nuby S, et al. 1978b. Effects of iron on the absorption and retention of lead. J 

Lab Clin Med 92:536-547. 

Barton JC, Patton MA, Edwards CQ, et al. 1994. Blood lead concentrations in hereditary 

hemochromatosis. J Lab Clin Med 124(2):193-198. 

Basaran N, Ündeger U. 2000. Effects of lead on immune parameters in occupationally exposed workers. 

Am J Ind Med 38:349-354. 

Batra N, Nehru B, Bansal MP. 2001. Influence of lead and zinc on rat male reproduction at 'biochemical 

and histopathological levels'. J Appl Toxicol 21:507-512. 

Battery Council International. 2003. Battery recycling. Chicago, IL: Battery Council International. 

http://www.batterycouncil.org/recycling.html. May 12, 2005. 

Battistuzzi G, Petrucci R, Silvagni L, et al. 1981. Delta-aminolevulinate dehydrase: A new genetic 

polymorphism in man. Ann Hum Gen 45:223-229. 

Batuman V, Wedeen RP, Bogden JD, et al. 1989. Reducing bone lead content by chelation treatment in 

chronic lead poisoning: An in vivo X-ray fluorescence and bone biopsy study. Environ Res 48:70-75. 

Bauchinger M, Schmid E. 1972. Chromosomenanalvsen in zellkulturen des chinesischen hamsters nach 

applikation von bleiacetat. Mutat Res 14:95-100. 

Bauchinger M, Dresp J, Schmid E, et al. 1977. Chromosome analyses of children after ecological lead 

exposure. Mutat Res 56:75-79. 
LEAD 423 

9. REFERENCES 

Baum CR, Shannon MW. 1997. The lead concentration of reconstituted infant formula. J Toxicol Clin 

Toxicol 35(4):371-5. 

Beck BD, Mattuck RL, Bowers TS, et al. 2001. The development of a stochastic physiologically-based 

pharmacokinetic model for lead. Sci Total Environ 274:15-19. 

Beek B, Obe G. 1974. Effect of lead acetate on human leukocyte chromosomes in vitro. Experientia 

30:1006-1007. 

Beek B, Obe G. 1975. The human leukocyte test system: VI. The use of sister chromatid exchanges as 

possible indicators for mutagenic activities. Humangenetik 29:127-134. 

Bell RR, Spickett JT. 1981. The influence of milk in the diet on the toxicity of orally ingested lead in 

rats. Food Cosmet Toxicol 19:429-436. 

Bellinger DC. 1995. Interpreting the literature on lead and child development: The neglected role of the 

“experimental system”. Neurotoxicol Teratol 17:201-212. 

Bellinger DC. 2000. Effect modification in epidemiologic studies of low-level neurotoxicant exposures 

and health outcomes. Neurotoxicol Teratol 22:133-140. 

Bellinger DC. 2004. Lead. Pediatrics 113(4):1016-1022. 

Bellinger DC, Needleman HL. 1983. Lead and the relationship between maternal and child intelligence. 

J Pediatr 102:523-527. 

Bellinger DC, Needleman HL. 2003. Intellectual impairment and blood lead levels. N Engl J Med 

349(5):500-502. 

Bellinger DC, Hu H, Titlebaum L, et al. 1994. Attentional correlates of dentin and bone lead levels in 

adolescents. Arch Environ Health 49(2):98-105. 

Bellinger DC, Leviton A, Needleman HL, et al. 1986a. Low-level lead exposure and infant development 

in the first year. Neurobehav Toxicol Teratol 8:151-161. 

Bellinger DC, Leviton A, Rabinowitz M, et al. 1986b. Correlates of low-level lead exposure in urban 

children at two years of age. Pediatrics 77:826-833. 

Bellinger DC, Leviton A, Waternaux C, et al. 1985a. A longitudinal study of the developmental toxicity 

of low-level lead exposure in the prenatal and early postnatal periods. In: Lekkas TD, ed. International 

conference on heavy metals in the environment, Athens, Greece, September, Vol. 1. Edinburgh, United 

Kingdom: CEP Consultants, Ltd., 32-34. 

Bellinger DC, Leviton A, Watemaux C, et al. 1985b. Methodological issues in modeling the relationship 

between low-level lead exposure and infant development: Examples from the Boston lead study. 

Environ Res 38:119-129. 

Bellinger DC, Leviton A, Waternaux C, et al. 1987a. Longitudinal analyses of prenatal and postnatal 

lead exposure and early cognitive development. N Engl J Med 316:1037-1043. 
LEAD 424 

9. REFERENCES 

Bellinger DC, Leviton A, Waternaux C, et al. 1989a. Low-level lead exposure and early development in 

socioeconomically advantaged urban infants. In: Smith M, Grant LD, Sors A, eds. Lead exposure and 

child development: An international assessment. Lancaster, UK: Kluwer Academic Publishers, 345­

356. 

Bellinger DC, Leviton A, Waternaux C, et al. 1989b. Low-level lead exposure, social class, and infant 

development. Neurotoxicol Teratol 10:497-504. 

Bellinger DC, Needleman HL, Leviton A, et al. 1984. Early sensory-motor development and prenatal 

exposure to lead. Neurobehav Toxicol Teratol 6:387-402. 

Bellinger DC, Sloman J, Leviton A, et al. 1987b. Low level lead exposure and child development: 

Assessment at age 5 of a cohort followed from birth. In: Lindberg SE, Hutchinson TC, eds. 

International Conference on Heavy Metals in the Environment. New Orleans, LA, September, Vol. 1. 

Edinburgh, UK: CEP Consultants, Ltd., 49-53. 

Bellinger DC, Sloman J, Leviton A, et al. 1991. Low-level lead exposure and children's cognitive 

function in the preschool years. Pediatrics 87:219-227. 

Bellinger DC, Stiles KM, Needleman HL. 1992. Low-level lead exposure, intelligence and academic 

achievement: A long-term follow-up study. Pediatrics 90:855-861. 

Benetou-Marantidou A, Nakou S, Michelovannis J. 1988. Neurobehavioral estimation of children with 

life-long increased lead exposure. Arch Environ Health 43:392-395. 

Bergdahl IA, Skerfving S. 1997. Partition of circulating lead between plasma and red cells does not 

seem to be different for internal and external sources of lead. Letter to the editor. Am J Ind Med 32:317­

318. 

Bergdahl IA, Gerhardsson L, Liljelind IE, et al. 2006. Plasma-lead concentration: Investigations into its 

usefulness for biological monitoring of occupational lead exposure. Am J Ind Med 49(2):93-101. 

Bergdahl IA, Gerhardsson L, Schutz A, et al. 1997b. Delta-aminolevulinic acid dehydratase 

polymorphism: Influence on lead levels and kidney function in humans. Arch Environ Health 52(2):91­

96. 

Bergdahl IA, Grubb A, Schutz A, et al. 1997a. Lead binding to δ-aminolevulinic acid dehydratase 

(ALAD) in human erythrocytes. Pharmacol Toxicol 81:153-158. 

Bergdahl IA, Schutz A, Grubb A. 1996. Application of liquid chromatography-Inductively coupled 

plasma mass spectrometry to the study of protein-bond lead in human erythrocytes. J Anal Atom 

Spectrom 11:735-738. 

Bergdahl IA, Sheveleva M, Schutz A, et al. 1998. Plasma and blood lead in humans: Capacity-limited 

binding to δ-aminolevulinic acid dehydratase and other lead-binding components. Toxicol Sci 46:247­

253. 

Bergdahl IA, Vahter M, Counter SA, et al. 1999. Lead in plasma and whole blood from lead-exposed 

children. Environ Res 80:25-33. 
LEAD 425 

9. REFERENCES 

Berkowitz GS, Wolff MS, Lapinski RH, et al. 2004. Prospective study of blood and tibia lead in women 

undergoing surgical menopause. Environ Health Perspect 112(17):1673-1678. 

Berlin CM, Gorman RL, May DG, et al. 1995. Treatment guidelines for lead exposure in children. 

Pediatrics 96(1):155-160. 

Bernard BP, Becker CE. 1988. Environmental lead exposure and the kidney. Clin Toxicol 26:1-34. 

Bernard AM, Vyskocil A, Roels H, et al. 1995. Renal effects in children living in the vicinity of a lead 

smelter. Environ Res 68:91-95. 

Berndtsson R. 1993. Small-scale spatial patterns of bulk atmospheric deposition. J Environ Qual 

22:349-360. 

Bert JL, Van Dusen LJ, Grace JR. 1989. A generalized model for the prediction of lead body burdens. 

Environ Res 48:117-127. 

Betts PR, Astley R, Raine DN. 1973. Lead intoxication in children in Birmingham. Br Med J 1:402­

406. 

Beyer WN, Cromartie EJ. 1987. A survey of Pb, Cu, Zn, Cd, Cr, As, and Se in earthworms and soil from 

diverse sites. Environ Monit Assess 8:27-36. 

*Bhattacharya A, Shukla R, Bornschein R, et al. 1988. Postural disequilibrium quantification in children 

with chronic lead exposure: A pilot study. Neurotoxicology 9:327-340. 

Bhattacharya A, Shukla R, Dietrich KN, et al. 1993. Functional implications of postural disequilibrium 

due to lead exposure. Neurotoxicology 14:179-190. 

*Bhattacharya A, Smelser DT, Berger O, et al. 1998. The effect of succimer therapy in lead intoxication 

using postural balance as a measure: A case study in a nine year old child. Neurotoxicology 19(1):57-64. 

Biagini G, Caudarelia R, Vangelista A. 1977. Renal morphological and functional modification in 

chronic lead poisoning. In: Brown SS, ed. Clinical chemistry and chemical toxicology of metals. 

Elsevier/North-Holland Biomedical Press, 123-126. 

Biggins PDE, Harrison RM. 1979. Atmospheric chemistry of automotive lead. Environ Sci Technol 

13:558-565. 

Billick IH, Gray VE. 1978. Lead based paint poisoning research: Review and evaluation 1971-1977. 

Washington, DC: U.S. Department of Housing and Urban Development. 

Binder S, Sokal D, Maugham D. 1986. Estimating soil ingestion: The use of tracer elements in 

estimating the amount of soil ingestion by young children. Arch Environ Health 41:341-345. 

Birch J, Harrison RM, Laxen DPH. 1980. A specific method for 24-48 hour analysis of tetraalkyl lead in 

air. Sci Total Environ 14:31-42. 

Bizarro P, Acevedo S, Nino-Cabrera G, et al. 2003. Ultrastructural modifications in the mitochondrion 

of mouse Sertoli cells after inhalation of lead, cadmium or lead–cadmium mixture. Reprod Toxicol 

17:561-566. 
LEAD 426 

9. REFERENCES 

Blake KCH, Mann M. 1983. Effect of calcium and phosphorus on the gastrointestinal absorption of 

203Pb in man. Environ Res 30:188-194. 

Blake KCH, Barbezat GO, Mann M. 1983. Effect of dietary constituents on the gastrointestinal 

absorption of 203Pb in man. Environ Res 30:182-187. 

Blakley BR, Archer DL. 1982. Mitogen stimulation of lymphocytes exposed to lead. Toxicol Appl 

Pharmacol 62:183-189. 

Blakley BR, Archer DL, Osborne L. 1982. The effect of lead on immune and viral interferon production. 

Can J Comp Med 46:43-46. 

Bleecker ML, Ford DP, Lindgren KN, et al. 2003. Association of chronic and current measures of lead 

exposure with different components of brainstem auditory evoked potentials. Neurotoxicology 24:625­

631. 

Bleecker ML, Ford DP, Lindgren KN, et al. 2005. Differential effects of lead exposure on components 

of verbal memory. Occup Environ Med 62(3):181-187. 

Bloch P, Garavaglia G, Mitchell G, et al. 1976. Measurement of lead content of children's teeth in situ 

by x-ray fluorescence. Phys Med Biol 20:56-63. 

Bloom NS, Crecelius EA, 1987. Distribution of silver, mercury, lead, copper, and cadmium in Central 

Puget Sound sediments. Mar Chem 21:377-390. 

Böckelmann I, Pfister EA, McGauran N, et al. 2002. Assessing the suitability of cross-sectional and 

longitudinal cardiac rhythm tests with regard to identifying effects of occupational chronic lead exposure. 

J Occup Environ Med 44:59-65. 

Bogden JD, Kemp FW, Han S, et al. 1995. Dietary calcium and lead interact to modify maternal blood 

pressure, erythropoiesis, and fetal and neonatal growth in rats during pregnancy and lactation. J Nutr 

125:990-1002. 

Bohnker BK, Schwartz E, McGinnis J, et al. 2003. Effects of pediatric blood lead surveillance on Navy 

population health (1995-2001). Mil Med 168(5):391-393. 

Boileau J, Fauquignon C, Napoly C. 1987. Explosives. In: Ullmann's encyclopedia of industrial 

chemistry. 5th edition. New York, NY: VCH Publishers, 143-172. 

Bolanowska W. 1968. Distribution and excretion of triethyllead in rats. Br J Ind Med 25:203-208. 

Bolanowska W, Piotrowski J, Garczynski H. 1967. Triethyllead in the biological material in cases of 

acute tetraethyllead poisoning. Arch Toxicol 22:278-282. 

Bolger PM, Carrington CD, Capar SG, et al. 1991. Reductions in dietary lead exposure in the United 

States. Chem Speciation Bioavail 3(314):31-36. 

Bolger PM, Yess NJ, Gunderson EL, et al. 1996. Identification and reduction of sources of dietary lead 

in the United States. Food Addit Contam 13(1):53-60. 
LEAD 427 

9. REFERENCES 

Bonanno LJ, Freeman NCG, Greenburg M, et al. 2001. Multivariate analysis on levels of selected 

metals, particulate matter, VOC, and household characteristics and activities from the midwestern states 

NHEXAS. Appl Occup Environ Hyg 16(9):859-874. 

Bonde JP, Kolstad H. 1997. Fertility of Danish battery workers exposed to lead. Int J Epidemiol 

26(6):1281-1288. 

Bonde JP, Joffe M, Apoatoli P, et al. 2002. Sperm count and chromatin structure in men exposed to 

inorganic lead: Lowest adverse effect levels. Occup Environ Med 59:234-242. 

Bonithon-Kopp C, Huel G, Grasmick C, et al. 1986c. Effects of pregnancy on the inter-individual 

variations in blood lead levels of lead, cadmium and mercury. Biol Res Preg 7:37-42. 

*Bonithon-Kopp C, Huel G, Moreau T. 1986a. [Lead and psychomotor development in children: A 

critical analysis of arguments of epidemiologic origin.] Neuropsychiatr Enfanc Adolesc 34:383-394. 

(French) 

*Bonithon-Kopp C, Huel G, Moreau T, et al. 1986b. Prenatal exposure to lead and cadmium and 

psychomotor development of the child at 6 years. Neurobehav Toxicol Teratol 8:307-310. 

*Borella P, Picco P, Masellis G. 1986. Lead content in abortion material from urban women in early 

pregnancy. Int Arch Occup Environ Health 57:93-99. 

Borja-Aburto VH, Hertz-Picciotto I, Lopez MR, et al. 1999. Blood lead levels measured prospectively 

and risk of spontaneous abortion. Am J Epidemiol 150:590-597. 

Borjesson J, Gerhardsson L, Schuetz A, et al. 1997. In vivo measurements of lead in fingerbone in active 

and retired lead smelters. Int Arch Occup Environ Health 69(2):97-105. 

Bornschein RL, Grote J, Mitchell T, et al. 1989. Effects of prenatal lead exposure on infant size at birth. 

In: Smith M, Grant LD, Sors A, eds. Lead exposure and child development: An international 

assessment. Lancaster, UK: Kluwer Academic Publishers, 307-319. 

Bornschein RL, Succop PA, Krafft KM, et al. 1986. Exterior surface dust lead, interior house dust lead 

and childhood lead exposure in an urban environment. In: Hemphil DD, ed. Trace substances in 

environmental health. Vol. 20. Columbia, MO: University of Missouri 322-332. 

Bos AJJ, can der Stap CCAH, Valkovic V, et al. 1985. Incorporation routes of elements into human hair: 

Implications for hair analysis used for monitoring. Sci Total Environ 42:157-169. 

Boscolo P, Carmignani M. 1988. Neurohumoral blood pressure regulation in lead exposure. Environ 

Health Perspect 78:101-106. 

*Boscolo P, Galli G, Iannaccone A, et al. 1981. Plasma renin activity and urinary kallikrein excretion in 

lead-exposed workers as related to hypertension and nephropathy. Life Sci 28:175-184. 

Bost L, Primatesta P, Dong W, et al. 1999. Blood lead and blood pressure: Evidence from the health 

survey for England 1995. J Hum Hypertens 13(22):123-128. 

Boudene C, Despaux-Pages N, Comoy E, et al. 1984. Immunological and enzymatic studies of 

erythrocytic 8-aminolevulinate dehydratase. Int Arch Occup Environ Health 55:87-96. 
LEAD 428 

9. REFERENCES 

Boudene C, Malet D, Masse R. 1977. Fate of 210Pb inhaled by rats. Toxicol Appl Pharmacol 41:271­

276. 

Bouton C, Pevsner J. 2000. Effects of lead on gene expression. Neurotoxicology 21(6):1045-1056. 

Bowen HJM. 1966. Trace elements in biochemistry. New York, NY: Academic Press, 31-32. 

Bowers TS, Beck BD. 2006. What is the meaning of non-linear dose-response relationships between 

blood lead concentrations and IQ? Neurotoxicology 27:520-524. 

Bowers TS, Mattuck RL. 2001. Further comparisons of empirical and epidemiological data with 

predictions of the integrated exposure uptake biokinetic model for lead in children. Hum Ecol Risk 

Assess 7(6):1699-1713. 

Bowers TS, Beck BD, Karam HS. 1994. Assessing the relationship between environmental lead 

concentrations and adult blood lead levels. Risk Anal 14(2):183-189. 

Bradley JE, Baumgartner RJ. 1958. Subsequent mental development of children with lead 

encephalopathy, as related to type of treatment. J Pediatr 53:311-315. 

Bradley SB, Cox JJ. 1988. The potential availability of cadmium, copper, iron, lead, manganese, nickel, 

and zinc in standard river sediment (NBS 1645). Environ Technol Lett 9:733-739. 

Bradley JE, Powell AE, Niermann W, et al. 1956. The incidence of abnormal blood levels of lead in a 

metropolitan pediatric clinic: With observation on the value of coproporphyrinuria as a screening test. J 

Pediatr 49:1-6. 

Bradman A, Eskenazi B, Sutton P, et al. 2001. Iron deficiency associated with higher blood lead in 

children living in contaminated environments. Environ Health Perspect 109(10):1079-1084. 

Brady HR, Brenner BM, Clarkson MR, et al. 2000. Acute renal failure. In: Brenner BM, ed. The 

kidney. New York, NY: W.B. Saunders Co., 1202. 

Braithwaite RA, Brown SS. 1987. The need for accuracy in trace metal analysis: A case study of 

childhood exposure to lead. Occup Environ Health 9:35-49. 

Braunstein GD, Dahlgren J, Loriaux DL. 1978. Hypogonadism in chronically lead-poisoned men. 

Infertility 1:33-51. 

Bress WC, Bidanset JH. 1991. Percutaneous in vivo and in vitro absorption of lead. Vet Hum Toxicol 

33:212-214. 

Bressler J, Kim K, Chakraborti T, et al. 1999. Molecular mechanisms of lead neurotoxicity. Neurochem 

Res 24(4):595-600. 

Bressler JP, Olivi L, Kim Y, et al. 2005. Plasma membrane transporters for lead and cadmium. J Appl 

Pharmacol 13(1):1-6. 

Brewer GJ, Hill GM, Dick RD, et al. 1985. Interactions of trace elements: Clinical significance. J Am 

Coll Nutr 4:33-38. 
LEAD 429 

9. REFERENCES 

Brito JA, McNeill FE, Webber CE, et al. 2005. Grid search: An innovative method for the estimation of 

the rates of lead exchange between body compartments. J Environ Monit 7(3):241-247. 

Brockel BJ, Cory-Slechta DA. 1998. Lead, attention, and impulsive behavior: Changes in a fixed-ratio 

waiting-for-reward paradigm. Pharmacol Biochem Behav 60(2):545-552. 

Brody DJ, Pirkle JL, Kramer RA, et al. 1994. Blood lead levels in the US population. Phase 1 of the 

Third National Health and Nutrition Examination Survey (NHANES III, 1988 to 1991). J Am Med 

Assoc 272:277-283. 

Bronner F, Pansu S, Stein WD. 1986. An analysis of intestinal calcium transport across the rat intestine. 

Am J Physiol 250:G561-G569 

Bruce WR, Heddle JA. 1979. The mutagenic activity of 61 agents as determined by the micronucleus, 

Salmonella and sperm abnormality assays. Can J Genet Cytol 21:319-334. 

Buc HA, Kaplan JC. 1978. Red-cell pyrimidine 5'-nucleotidase and lead poisoning. Clin Chim Acta 

87:49-55. 

Buchanan LH, Counter SA, Ortega F, et al. 1999. Distortion product oto-acoustic emissions in Andean 

children and adults with chronic lead intoxication. Acta Otolaryngol (Stockh)119:652-658. 

Buchet JP, Roels H, Bernard A, et al. 1980. Assessment of renal function of workers exposed to 

inorganic lead, cadmium, or mercury vapor. J Occup Med 22:741-750. 

Budavari S, O’Neil MJ, Smith A, et al. eds. 1989. The Merck index. An encyclopedia of chemicals, 

drugs, and biologicals. 11th ed. Rahway, NJ: Merck & Co., Inc., 851-854. 

Bull RJ, Lutkenhoff SD, McCarty GE, et al. 1979. Delays in the postnatal increase of cerebral 

cyochrome concentrations in lead-exposed rats. Neuropharmacology 18:83-92. 

Bulsma JB, De France HF. 1976. Cytogenetic investigations in volunteers ingesting inorganic lead. Int 

Arch Occup Environ Health 28:145-148. 

Bunn TL, Dietert RR, Ladics GS, et al. 2001c. Developmental immunotoxicology assessment in the rat: 

Age, gender, and strain comparisons after exposure to lead. Toxicol Meth 11:41-58. 

Bunn TL, Parsons PJ, Kao E, et al. 2001a. Exposure to lead during critical windows of embryonic 

development: Differential immunotoxic outcome based on stage of exposure and gender. Toxicol Sci 

64:57-66. 

Bunn TL, Parsons PJ, Kao E, et al. 2001b. Gender-based profiles of developmental immunotoxicity to 

lead in the rat: Assessment in juveniles and adults. J Toxicol Environ Health A 64:223-240. 

Burger J, Kennamer RA, Brisbin IL, et al. 1998. A risk assessment for consumers of mourning doves. 

Risk Anal 18(5):563-573. 

Bushnell PJ, Bowman RE. 1979a. Effects of chronic lead ingestion on social development in infant 

Rhesus monkeys. Neurobehav Toxicol 1:207-219. 
LEAD 430 

9. REFERENCES 

Bushnell PJ, Bowman RE. 1979b. Persistence of impaired reversal learning in young monkeys exposed 

to low levels of dietary lead. J Toxicol Environ Health 5:1015-1023. 

Bushnell PJ, Levin ED. 1983. Effects of zinc deficiency on lead toxicity in rats. Neurobehav Toxicol 

Teratol 5:283-288. 

Bushnell PJ, Bowman RE, Allen JR, et al. 1977. Scotopic vision deficits in young monkeys exposed to 

lead. Science 196:333-335. 

Byczkowski JZ, Gearhart JM, Fisher JW. 1994. Occupational exposure of infants to toxic chemicals via 

breast milk. Nutrition 10(1):43-48. 

Byers RK, Lord EE. 1943. Late effects of lead poisoning on mental development. Am J Dis Child 

66(5):471-494. 

Cake KM, Bowins RJ, Vaillancourt C, et al. 1996. Partition of circulating lead between serum and red 

cells is different for internal and external sources of exposure. Am J Ind Med 29:440-445. 

Calabrese EJ. 1978. Pollutants and high-risk groups: The biological basis of increased human 

susceptibility to environmental and occupational pollutants. New York, NY: John Wiley and Sons, 43­

49, 71-72, 106-107, 135-138. 

Calabrese EJ, Barnes R, Stanek EJ III, et al. 1989. How much soil do young children ingest: An 

epidemiological study. Regul Toxicol Pharmacol 10:123-137. 

Calabrese EJ, Stanek EJ, James RC, et al. 1997b. Soil ingestion: A concern for acute toxicity in 

children. Environ Health Perspect 105:1354-1358. 

Calabrese EJ, Stanek EJ, Pekow P, et al. 1997a. Soil ingestion estimates for children residing on a 

Superfund site. Ecotoxicol Environ Saf 36:258-268. 

Calderon-Salinas JV, Quintanar-Escorcia MA, Gonzalez-Martinez MT, et al. 1999. Lead and calcium 

transport in human erythrocyte. Hum Exp Toxicol 18:327-332. 

California Department of Fish and Game. 2004. Analysis of lead in California condor feathers: 

Determination of exposure and depuration during feather growth. Sacramento, CA: California 

Department of Fish and Game. 

Campara P, D'Andrea F, Micciolo R, et al. 1984. Psychological performance of workers with blood-lead 

concentration below the current threshold limit value. Int Arch Occup Environ Health 53:233-246. 

Campbell JR, Toribara TY. 2001. Hair-root lead to screen for lead toxicity. J Trace Elem Exp Med 

14:69-72. 

*Campbell BC, Beattie AD, Moore MR, et al. 1977. Renal insufficiency associated with excessive lead 

exposure. Br Med J 1:482-485. 

*Campbell BC, Meredith PA, Scott JJC. 1985. Lead exposure and changes in the renin-angiotensinaldosterone system in man. Toxicol Lett 25:25-32. 
LEAD 431 

9. REFERENCES 

Campbell JR, Moss ME, Raubertas RF. 2000a. The association between caries and childhood lead 

exposure. Environ Health Perspect 108(11):1099-1102. 

Campbell JR, Rosier RN, Novotny L, et al. 2004. The association between environmental lead exposure 

and bone density in children. Environ Health Perspect 112(11):1200-1203. 

Campbell TF, Needleman HL, Riess JA, et al. 2000b. Bone lead levels and language processing 

performance. Dev Neuropsychol 18(2):171-186. 

Canfield RL, Gendle MH, Cory-Slechta DA. 2004. Impaired neuropsychological functioning in leadexposed children. Dev Neuropsychol 26(1):513-540. 

Canfield RL, Henderson CR, Cory-Slechta DA, et al. 2003. Intellectual impairment in children with 

blood lead concentrations below 10 microgram per deciliter. N Engl J Med 348(16):1517-1526. 

Canonne-Hergaux F, Gruenheid S, Ponka P, et al. 1999. Cellular and subcellular localization of the 

Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood 93(12):4406­

4417. 

Capar SG, Cunningham WC. 2000. Element and radionuclide concentrations in food: FDA total diet 

study 1991-1996. J AOAC Int 83(11):157-177. 

Capar SG, Rigsby EJ. 1989. Survey of lead in canned evaporated milk. J Assoc Off Anal Chem 72:416­

417. 

Carbone R, Laforgia N, Crollo E, et al. 1998. Maternal and neonatal lead exposure in southern Italy. 

Biol Neonate 73:362-366. 

Cardenas A, Roels H, Bernard AM, et al. 1993. Markers of early renal changes induced by industrial 

pollutants. II. Application to workers exposed to lead. Br J Ind Med 50:28-36. 

Cardozo dos Santos A, Colacciopo S, Bo CMRD, et al. 1994. Occupational exposure to lead, kidney 

function tests, and blood pressure. Am J Ind Med 26:635-643. 

Carlisle JC, Wade MJ. 1992. Predicting blood lead concentrations from environmental concentrations. 

Regul Toxicol Pharmacol 16:280-289. 

Carmignani M, Boscolo M, Poma P, et al. 1999. Kininergic system and arterial hypertension following 

chronic exposure to inorganic lead. Immunopharmacology 44:105-110. 

Carmignani M, Boscolo P, Preziosi P. 1988. Cardiovascular actions of lead in rats as related to the level 

of chronic exposure. Arch Toxicol Supp 12:326-329. 

Carmignani M, Volpe AR, Boscolo P, et al. 2000. Catcholamine and nitric oxide systems as targets of 

chronic lead exposure in inducing selective functional impairment. Life Sci 68:401-415. 

Carmouche JJ, Puzas JE, Zhang X, et al. 2005. Lead exposure inhibits fracture healing and is associated 

with increased chondrogenesis, delay in cartilage mineralization, and a decrease in osteoprogenitor 

frequency. Environ Health Perspect 113:749-755. 
LEAD 432 

9. REFERENCES 

Carpenter SJ. 1982. Enhanced teratogenicity of orally administered lead in hamsters fed diets deficient 

in calcium or iron. Toxicology 24:259-271. 

Carr DS. 1995. Lead compounds: Lead salts. In: Kirk-Othmer encyclopedia of chemical technology. 

4th edition. New York, NY: John Wiley and Sons, 132-152. 

Carta P, Carta R, Girei E, et al. 2003. [Cognitive and performance capacity among adolescents living 

near a lead and zinc smelter.] G Ital Med Lav Ergon 25(Suppl 3):43-45. 

Case JM, Reif CB, Timko A. 1989. Lead in the bottom sediments of Lake Nuangola and fourteen other 

bodies of water in Luzerne County, Pennsylvania. J PA Acad Sci 63:67-72. 

Casteel WS, Cowart RP, Weis CP, et al. 1997. Bioavailability of lead to juvenile swain dosed with soil 

from the Smuggler Mountain NLP site of Aspen, Colorado. Fundam Appl Toxicol 36:177-187. 

Cavalleri A, Minoia C, Pozzoli L, et al. 1978. Determination of plasma lead levels in normal subjects 

and in lead-exposed workers. Br J Ind Med 35:21-26. 

Cavalleri A, Trimarchi F, Gelmi C, et al. 1982. Effects of lead on the visual system of occupationally 

exposed subjects. Scand J Work Environ Health 8:148-151. 

CDC. 1985. Preventing lead poisoning in young children. Atlanta, GA: U.S. Department of Health and 

Human Services, Public Health Service, Centers for Disease Control and Prevention. Publication No. 99­

2230, 7-19. 

CDC. 1991. Preventing lead poisoning in young children. Atlanta, GA: U.S. Department of Health and 

Human Services, Public Health Service, Centers for Disease Control and Prevention. 

*CDC. 1997a. Adult blood lead epidemiology and surveillance-United States Fourth Quarter 1996. 

Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 46(16):358-359, 367. 

CDC. 1997b. Update: Blood lead levels. Centers for Disease Control and Prevention. MMWR Morb 

Mortal Wkly Rep 46(7):141-146. 

CDC. 1997c. Screening young children for lead poisoning: Guidance for state and local public health 

officials. Centers for Disease Control and Prevention. Atlanta, GA: U.S. Department of Health & 

Human Services. 

CDC. 1997d. Children with elevated blood lead levels attributed to home renovation and remodeling 

activities - New York 1993-1994. Centers for Disease Control and Prevention. MMWR Morb Mortal 

Wkly Rep 45(51&52):1120-1123. 

CDC. 1998. Lead poisoning associated with imported candy and powdered food coloring - California 

and Michigan. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 

47(48):1041-1043. 

CDC. 2003. Second national report on human exposure to environmental chemicals. Centers for 

Disease Control and Prevention. Atlanta, GA: U.S. Department of Health and Human Services. 

CDC. 2004. Lead poisoning associated with ayurvedic medications - five states, 2000-2003. Centers for 

Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 53(26):582-584. 
LEAD 433 

9. REFERENCES 

CDC. 2005a. Blood lead levels - United States, 1999-2002. Centers for Disease Control and Prevention. 

MMWR Morb Mortal Wkly Rep 54(20):513-516. 

CDC. 2005b. Third national report on human exposure to environmental chemicals. Centers for Disease 

Control and Prevention. Atlanta, GA: U.S. Department of Health and Human Services. 

CDC. 2007. Lead exposure among females of childbearing age-United States, 2004. MMWR Morb 

Mortal Wkly Rep 56(16):397-400. http://www.cdc.gov/mmwr/PDF/wk/mm5616.pdf. June 05, 2007. 

Cerklewski FL. 1979. Influence of dietary zinc on lead toxicity during gestation and lactation in the 

female rat. J Nutr 109:1703-1709. 

Cerklewski FL. 1980. Reduction in neonatal lead exposure by supplemental dietary iron during gestation 

and lactation in the rat. J Nutr 110:1453-1457. 

Cerklewski FL, Forbes RM. 1976. Influence of dietary zinc on lead toxicity in the rat. J Nutr 106:689­

696. 

Chakraborti D, DeJonghe WRA, Mol WE, et al. 1984. Determination of ionic alkyllead compounds in 

water by gas chromatography/atomic absorption spectrometry. Anal Chem 56:2692-2697. 

Chamberlain A. 1983. Effect of airborne lead on blood lead. Atmos Environ 17:677-692. 

Chamberlain A, Heard C, Little MJ, et al. 1978. Investigations into lead from motor vehicles. Harwell, 

United Kingdom: United Kingdom Atomic Energy Authority. Report no. AERE-9198. 1979. The 

dispersion of lead from motor exhausts. Philos Trans R Soc Lond A 290:557-589. 

Chamberlain A, Heard C, Little P, et al. 1979. The dispersion of lead from motor exhausts. Philos Trans 

R Soc Lond A 290:557-589. 

Chan WH, Tang JS, Chung DH, et al. 1986. Concentration and deposition of trace metals in Ontario 

1982. Water Air Soil Pollut 29:373-389.
 

Chaney RL, Mielke HW, Sterret SB. 1988. Speciation, mobility and bioavailability of soil lead. Environ 

Geochem Health 9:105-129. 

Chang H-R, Chen S-S, Chen T-J, et al. 1996. Lymphocyte β-2-adrenergic receptors and plasma 

catecholamine levels in lead-exposed workers. Toxicol Appl Pharmacol 139:1-5.
 

Charney E, Sayre J, Coulter M. 1980. Increased lead absorption in inner city children: Where does the 

lead come from? Pediatrics 65:226-231.
 

Chau YK, Wong PTS, Bengert GA, et al. 1979. Determination of tetraalkyl-lead compounds in water, 

sediments, and fish samples. Anal Chem 51:186-188. 

Chau YK, Wong PTS, Kramar O, et al. 1980. Occurrence of tetraalkylead compounds in the aquatic 

environment. Bull Environ Contam Toxicol 24:265-269. 

ChemIDplus. 2005. Lead and lead compounds. Bethesda, MD: U.S. National Library of Medicine. 
LEAD 434 

9. REFERENCES 

Chen A, Dietrich KN, Ware JH, et al. 2005. IQ and blood lead from 2 to 7 years of age: Are the effects 

in older children the residual of high blood lead concentrations in 2-year-olds? Environ Health Perspect 

113(5):597-601. 

Chen A, Rhoads GG, Cai B, et al. 2006. The effect of chelaton on blood pressure in lead-exposed 

children: A randomized study. Environ Health Perspect 114(4):579-583. 

Cheng Y, Schwartz J, Sparrow D, et al. 2001. Bone lead and blood lead levels in relation to baseline 

blood pressure and the prospective development of hypertension. Am J Epidemiol 153(2):164-171. 

Cheng Y, Schwartz J, Vokonas PS, et al. 1998. Electrocardiographic conduction disturbances in 

association with low-level lead exposure (the Normative Aging Study). Am J Cardiol 82:594-599. 

Chettle DR, Scott MC, Somervaille LJ. 1991. Lead in bone: Sampling and quantitation using K X-rays 

excited by 109Cd. Environ Health Perspect 91:45-55. 

Chia KS, Jeyaratnam J, Lee J, et al. 1995b. Lead-induced nephropathy: Relationship between various 

biological exposure indices and early markers of nephrotoxicity. Am J Ind Med 27:883:895. 

Chia KS, Jeyaratnam J, Tan C, et al. 1995a. Glomerular function of lead-exposed workers. Toxicol 

Letters 77:319-328. 

Chia KS, Mutti A, Tan C, et al. 1994. Urinary N-acetyl-D-glucosaminidase activity in workers exposed 

to inorganic lead. Occup Environ Med 51:125-129. 

Chia SE, Chia HP, Ong CN, et al. 1996b. Cumulative concentrations of blood lead and postural stability. 

Occup Environ Med 53(4):264-268. 

Chia SE, Chia KS, Chia HP, et al. 1996a. Three-year follow-up of serial nerve conduction among leadexposed workers. Scand J Work Environ Health 22(5):374-80. 

Chia SE, Zhou H, Tham MT, et al. 2005. Possible influence of δ-aminolevulinic acid dehydratase 

polymorphism and susceptibility to renal toxicity of lead: A study of a Vietnamese population. Environ 

Health Perspect 113(10):1313-1317. 

Chillrud SN, Bopp RF, Simpson HJ, et al. 1999. Twentieth century atmospheric metal fluxes into 

Central Park Lake, New York City. Environ Sci Technol 33(5):657-662. 

Chiodo LM, Jacobson SW, Jacobson JL. 2004. Neurodevelopmental effects of postnatal lead exposure at 

very low levels. Neurotoxicol Teratol 26(3):359-371. 

Chisolm JJ. 1962. Aminoaciduria as a manifestation of renal tubular injury in lead intoxication and a 

comparison with patterns of aminoaciduria seen in other diseases. J Pediatr 60:1-17. 

Chisolm JJ. 1965. Chronic lead intoxication in children. Dev Med Child Neurol 7:529-536. 

Chisolm JJ. 1968. The use of chelating agents in the treatment of acute and chronic lead intoxication in 

childhood. J Pediatr 73:1-38. 
LEAD 435 

9. REFERENCES 

Chisolm JJ. 1981. Dose-effect relationships for lead in young children: Evidence in children for 

interactions among lead, zinc, and iron. In: Lynam DR, Piantanida LG, Cole JF, eds. Environmental 

lead: Proceedings on the second international symposium on environmental lead research, December, 

1978, Cincinnati, Ohio. New York, NY: Academic Press, 1-7. 

Chisolm JJ. 1986. Removal of lead paint from old housing: The need for a new approach. Am J Public 

Health 76:236-237. 

Chisolm JJ. 2000. Safety and efficacy of meso-2,3-dimercaptosuccinic acid (DMSA) in children with 

elevated blood lead concentrations. Clin Toxicol 38(4):365-375. 

Chisolm JJ, Harrison HE. 1956. The exposure of children to lead. Pediatrics 18:943-958. 

*Chisolm JJ, Harrison HC, Eberlein WR, et al. 1955. Aminoaciduria, hypophosphatemia, and rickets in 

lead poisoning: Study of a case. Am J Dis Child 89:159-168. 

Chisolm JJ, Mellits ED, Barrett MB. 1976. Interrelationships among blood lead concentration, 

quantitative daily ALA-U and urinary lead output following calcium EDTK. In: Nordberg GF, ed. 

Proceedings of third meeting of the subcommittee on the toxicology of metals under the Permanent 

Commission and International Association on Occupational Health, November 1974, Tokyo, Japan. 

Amsterdam, Netherlands: Elsevier Publishing Co., 416-433. 

Chisolm JJ, Thomas DJ, Hamill TG. 1985. Erythrocyte porphobilinogen synthase activity as an indicator 

of lead exposure to children. Clin Chem 31:601-605. 

Choie DD, Richter GW. 1972. Lead poisoning: Rapid formation of intranuclear inclusions. Science 

177:1194-1195. 

Chowdhury AR, Chinoy NJ, Gautam AK, et al. 1986. Effect of lead on human semen. Adv Contracept 

Deliv Syst 2:208-211. 

Christoffersson JO, Ahlgren L, Schutz A, et al. 1986. Decrease of skeletal lead levels in man after end of 

occupational exposure. Arch Environ Health 41:312-318. 

Chu NF, Liou SH, Wu TN, et al. 1999. Reappraisal of the relation between blood lead concentration and 

blood pressure among the general population in Taiwan. Occup Environ Med 56:30-33. 

Chuan MC, Shu GY, Liu JC. 1996. Solubility of heavy metals in a contaminated soil: Effects of redox 

potential and pH. Water Air Soil Pollut 90:543-556. 

Chuang HY, Chao KY, Tsai SY. 2005. Reversible neurobehavioral performance with reductions in 

blood lead levels-A prospective study on lead workers. Neurotoxicol Teratol 27(3):497-504. 

Chuang HY, Schwartz J, Gonzales-Cossio T, et al. 2001. Interrelations of lead levels in bone, venous 

blood, and umbilical cord blood with exogenous lead exposure through maternal plasma lead in 

peripartum women. Environ Health Perspect 109(5):527-532. 

Cikrt M, Tichy M. 1975. Role of bile in intestinal absorption of 203Pb in rats. Experientia 31:1320-3121. 

Clark CS, Bornschein RL, Succop P, et al. 1985. Conditions and type of housing as an indicator of 

potential environmental lead exposure and pediatric blood lead levels. Environ Res 38:46-53. 
LEAD 436 

9. REFERENCES 

Clausing P, Brunekreef B, van Wijen JH. 1987. A method for estimating soil ingestion by children. Int 

Arch Occup Environ Health 59:73-82. 

Clayton CA, Pellizzari ED, Quackenboss JJ. 2002. National Human Exposure Assessment Survey: 

Analysis of exposure pathways and routes for arsenic and lead in EPA Region 5. J Expo Anal Environ 

Epidemiol 12:29-43. 

Clewell HJ III, Andersen ME. 1985. Risk assessment extrapolations and physiological modeling. 

Toxicol Ind Health 1(4):111-131. 

Coate D, Fowles R. 1989. Is there statistical evidence for a blood lead-blood pressure relationship? J 

Economics 8:173-184. 

Cocco P, Carta P, Flore C, et al. 1996. Mortality of lead smelter workers with the glucose-6-phosphate 

dehydrogenase-deficient phenotype. Cancer Epidemiol Biomarkers Prev 5(3):223-225. 

Cocco P, Cocco E, Anni MS, et al. 1991. Occupational exposure to lead and blood cholesterol in 

glucose-6-phosphate dehydrogenase deficient and normal subjects. Res Commun Chem Pathol 

Pharmacol 72(1):81-95. 

Cocco P, Dosemeci M, Heineman EF. 1998a. Brain cancer and occupational exposure to lead. J Occup 

Environ Med 40(11):937-942. 

Cocco P, Hua F, Boffetta P, et al. 1997. Mortality of Italian lead smelter workers. Scand J Work 

Environ Health 23(1):15-23. 

Cocco P, Ward MH, Dosemeci M. 1998b. Occupational risk factors for cancer of the gastric cardia. J 

Occup Environ Med 40(10):855-861. 

Cohen J. 1988. Revisions to dietary lead estimates for case-study exposure analyses. Memo to the files. 

Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of Air Quality Planning and 

Standards. September 9, 1988. 

Cohen AJ, Roe FJC. 1991. Review of lead toxicology relevant to the safety assessment of lead acetate as 

a hair colouring. Food Chem Toxicol 29(7):485-507. 

Congiu L, Corongiu FP, Dore M, et al. 1979. The effect of lead nitrate on the tissue distribution of 

mercury in rats treated with methylmercury chloride. Toxicol Appl Pharmacol 51:363-366. 

Congressional Record. 1988. Lead contamination control act of 1988. Congressional Record-House. 

(October 5, 1988):49645-49648. 

Cools A, Salle HJA, Verberk MM, et al. 1976. Biochemical response of male volunteers ingesting 

inorganic lead for 49 days. Int Arch Occup Environ Health 38:129-139. 

*Cooney GH, Bell A, McBride W, et al. 1989a. Low-level exposures to lead: The Sydney lead study. 

Dev Med Child Neurol 31:640-649. 

*Cooney GH, Bell A, McBride W, et al. 1989b. Neurobehavioral consequences of prenatal low level 

exposures to lead. Neurotoxicol Teratol 11:95-104. 
LEAD 437 

9. REFERENCES 

Cooper WC. 1988. Deaths from chronic renal disease in US battery and lead production workers. 

Environ Health Perspect 78:61-63. 

Cooper WC, Wong O, Kheifets L. 1985. Mortality among employees of lead battery plants and lead 

producing plants, 1947-1980. Scand J Work Environ Health 11:331-345. 

Corrin ML, Natusch DFS. 1977. Physical and chemical characteristics of environmental lead. In: 

Boggess WR, Wixson BG, eds. Lead in the environment. Washington, DC: National Science 

Foundation, 7-31. 

*Cory-Slechta DA. 1990. Lead exposure during advanced age: Alterations in kinetics and biochemical 

effects. Toxicol Appl Pharmacol 104:67-78. 

Cory-Slechta DA. 1995. Relationships between lead-induced learning impairments and changes in 

dopaminergic, cholinergic, and glutamatergic neurotransmitter system functions. Ann Rev Pharmacol 

Toxicol 35:391-415. 

Cory-Slechta DA. 1997. Relationships between Pb-induced changes in neurotransmitter system function 

and behavioral toxicity. Neurotoxicology 18(3):673-688. 

Cory-Slechta DA. 2003. Lead-induced impairments in complex cognitive function: Offerings from 

experimental studies. Neuropsychol Dev Cogn C Child Neuropsychol 9(1):54-75. 

Cory-Slechta DA. 2006. Interactions of lead exposure and stress: Implications for cognitive 

dysfunction. Int Rev Res Ment Retard 30:87-139. 

Cory-Slechta DA, Thompson T. 1979. Behavioral toxicity of chronic postweaning lead exposure in the 

rat. Toxicol Appl Pharmacol 47:151-159. 

Cory-Slechta DA, Bissen ST, Young AM, et al. 1981. Chronic post-weaning lead exposure and response 

duration performance. Toxicol Appl Pharmacol 60:78-84. 

Cory-Slechta DA, Virgolini MB, Thiruchelvam M, et al. 2004. Maternal stress modulates the effects of 

developmental lead exposure. Environ Health Perspect 112(6):717-730. 

Cory-Slechta DA, Weiss B, Cox C. 1983. Delayed behavioral toxicity of lead with increasing exposure 

concentrations. Toxicol Appl Pharmacol 71:342-352. 

Cory-Slechta DA, Weiss B, Cox C. 1985. Performance and exposure indices of rats exposed to low 

concentrations of lead. Toxicol Appl Pharmacol 78:291-299. 

Cory-Slechta DA, Weiss B, Cox C. 1987. Mobilization and redistribution of lead over the course of 

calcium disodium ethylenediamine tetraacetate chelation therapy. J Pharmacol Exp Ther 243:804-813. 

*Coscia GC, Discalzi G, Ponzetti C. 1987. Immunological aspects of occupational lead exposure. Med 

Lav 78:360-364. 

Coscia JM, Ris MD, Succop PA, et al. 2003. Cognitive development of lead exposed children from ages 

6 to 15 years: An application of growth curve analysis. Neuropsychol Dev Cogn C Child Neuropsychol 

9(1):10-21. 
LEAD 438 

9. REFERENCES 

Costa LG, Aschner M, Vitalone A, et al. 2004. Developmental neuropathology of environmental agents. 

Annu Rev Pharmacol Toxicol 44:87-110. 

Costa M, Cantoni O, DeMars M, et al. 1982. Toxic metals produce S-phase-specific cell cycle block. 

Res Commun Chem Pathol Pharmacol 38:405-419. 

Coste J, Mandereau L, Pessione F, et al. 1991. Lead-exposed workmen and fertility: A cohort study on 

354 subjects. Eur J Epidemiol 7:154-158. 

Counter SA. 2002. Brainstem neural conduction biomarkers in lead-exposed children of Andean leadglaze workers. J Occup Environ Med 44(9):855-864. 

Counter SA, Buchanan LH. 2002. Neuro-ototoxicity in Andean adults with chronic lead and noise 

exposure. J Occup Environ Med 44:30-38. 

Counter SA, Buchanan LH, Ortega F, et al. 1997a. Normal auditory brainstem and cochlear function in 

extreme pediatric plumbism. J Neurol Sci 152(1):85-92. 

Counter SA, Buchanan LH, Ortega F, et al. 2000. Blood lead and hemoglobin levels in Andean children 

with chronic lead intoxication. Neurotoxicology 21(3):301-308. 

Counter SA, Vahter M, Buchanan LH, et al. 1997b. High lead exposure and auditory sensory-neural 

function in Andean children. Environ Health Perspecp 105:522-526. 

CPSC. 1977. Ban of lead-containing products bearing lead-containing paint. Consumer Product Safety 

Commission. Code of Federal Regulations. 16 CFR 1303. 

CPSC. 1996. CPSC finds lead poisoning hazard for young children in imported vinyl miniblinds. U.S. 

Consumer Product Safety Commission. http://www.cpsc.gov/cpscpub/prerel/prhtml96/96150.html. 

February 25, 1999. 

Craig JR, Rimstidt JD, Bonnaffon CA, et al. 1999. Surface water transport of lead at shooting range. 

Bull Environ Contam Toxicol 63:312-319. 

Cramer K, Goyer RA, Jagenburg R, et al. 1974. Renal ultrastructure, renal function, and parameters of 

lead toxicity in workers with different periods of lead exposure. Br J Ind Med 31:113-127. 

Cremin JD, Luck ML, Laughlin NK, et al. 1999. Efficacy of succimer chelation for reducing brain lead 

in a primate model of human lead exposure. Toxicol Appl Pharmacol 161:283-293. 

Crump K. 1997. Evaluation of the Boston study of effectiveness of soil abatement in reducing children’s 

blood lead, with particular emphasis upon the EPA (1996) reevaluation. ICF Kaiser: Ruston, LA. 

Report to Seeger, Potter, Richardson, Luxton, Joselow & Brooks. March 13, 1997. 

Cullen MR, Kayne RD, Robins JM. 1984. Endocrine and reproductive dysfunction in men associated 

with occupational inorganic lead intoxication. Arch Environ Health 39:431-440. 

Dabeka RW, McKenzie AD. 1988. Lead and cadmium levels in commercial infant foods and dietary 

intake by infants 0-1 year old. Food Addit Contam 5:333-342. 
LEAD 439 

9. REFERENCES 

Dabeka RW, McKenzie AD. 1995. Survey of lead, cadmium, fluoride, nickel, and cobalt in food 

composites and estimation of dietary intakes of these elements by Canadians in 1986-1988. J AOAC Int 

78(4):897-909. 

Dabeka RW, Karpinski KF, McKenzie AD, et al. 1988. Survey of lead and cadmium in human milk and 

correlation of levels with environmental and food factors. Sci Total Environ 71:65-66. 

Dabeka RW, McKenzie AD, Lacroix GMA. 1987. Dietary intakes of lead, cadmium, arsenic and 

fluoride by Canadian adults: A 24-hour duplicate diet study. Food Addit Contam 4:89-102. 

Daggett DA, Oberley TD, Nelson SA, et al. 1998. Effects of lead on rat kidney and liver: GST 

expression and oxidative stress. Toxicology 128:191-206. 

Dalpra L, Tibiletti MG, Nocera G, et al. 1983. SCE analysis in children exposed to lead emission from a 

smelting plant. Mutat Res 120:249-256. 

Damm D, Grandjean P, Lyngbye T, et al. 1993. Early lead exposure and neonatal jaundice: Relation to 

neurobehavioral performance at 15 years of age. Neurotoxicol Teratol 15:173-181. 

Danadevi K, Rozati R, Banu BS, et al. 2003. DNA damage in workers exposed to lead using comet 

assay. Toxicology 187:183-193. 

Davis JM, Svendsgaard DJ. 1987. Lead and child development. Nature 329:297-300. 

Davis JM, Svendsgaard DJ. 1990. Nerve conduction velocity and lead: A critical review and metaanalysis. In: Johnson BL, Anger WK, Durao A, et al., eds. Advances in neurobehavioral toxicology. 

Chelsea, MI: Lewis Publishers, 353-376. 

Davis A, Ruby MV, Bergstrom PD. 1992. Bioavailability of arsenic and lead in soils from the Butte, 

Montana, mining district. Environ Sci Technol 26:461-468. 

Davis A, Ruby MV, Bergstrom, PD. 1994. Factors controlling lead bioavailability in the Butte mining 

district, Montana, USA. Environ Geochem Health 16:147-157. 

Davis A, Shokouhian M, Ni S. 2001. Loading estimates of lead, copper, cadmium, and zinc in urban 

runoff from specific sources. Chemosphere 44:997-1009. 

Dearth RK, Hiney JK, Srivastava V, et al. 2002. Effects of lead (Pb) exposure during gestation and 

lactation on female pubertal development in the rat. Reprod Toxicol 16:343-352. 

Dearth RK, Hiney JK, Srivastava V, et al. 2004. Low level lead (Pb) exposure during gestation and 

lactation: Assessment of effects on pubertal development in Fisher 344 and Sprague-Dawley female rats. 

Life Sci 74:1139-1148. 

De Gennaro LD. 2002. Lead and the developing nervous system. Growth Dev Aging 66:43-50. 

Dehpour AR, Essalat M, Ala S, et al. 1999. Increase by NO synthase inhibitor of lead-induced release of 

N-acetyl-beta-D-glucosaminidase from perfused rat kidney. Toxicology 132:119-125. 

DeJonghe WRA, Adams FC. 1986. Biogeochemical cycling of organic lead compounds. Adv Environ 

Sci Technol 17:561-594. 
LEAD 440 

9. REFERENCES 

DeJonghe WRA, Chakraborti D, Adams FC. 1981. Identification and determination of individual 

tetraalkyl lead species in air. Environ Sci Technol 15:1217-1222. 

Deknudt G, Gerber GB. 1979. Chromosomal aberrations in bone-marrow cells of mice given a normal or 

a calcium-deficient diet supplemented with various heavy metals. Mutat Res 68:163-168. 

Deknudt G, Colle A, Gerber GB. 1977. Chromosomal abnormalities in lymphocytes from monkeys 

poisoned with lead. Mutat Res 45:77-83. 

de Kort WLAM, Zwennis WCM. 1988. Blood lead and blood pressure: Some implications for the 

situation in the Netherlands. Environ Health Perspect 78:67-70 

de Kort WL, Verschoor MA, Wibowo AAE, et al. 1987. Occupational exposure to lead and blood 

pressure: A study of 105 workers. Am J Ind Med 11:145-156. 

de la Burde B, Choate MS. 1972. Does asymptomatic lead exposure in children have latent sequelae? J 

Pediatr 81:1088-1091. 

de la Burde B, Choate MS. 1975. Early asymptomatic lead exposure and development at school age. J 

Pediatr 87:638-642. 

Delves HT, Campbell MJ. 1988. Measurements of total lead concentrations and of lead isotope ratios in 

whole blood by use of inductively coupled plasma source mass spectrometry. J Anal At Spectrom 3:343­

348. 

Denaix L, Semlali RM, Douay F. 2001. Dissolved and colloidal transport of Cd, Pb, and Zn in a silt 

loam soil affected by atmospheric industrial deposition. Environ Pollut 113:29-38. 

Deng H, Ye ZH, Wong MH. 2004. Accumulation of lead, zinc, copper and cadmium by 12 wetland 

plant species thriving in metal-contaminated sites in China. Environ Pollut 132:29-40. 

Den Hond E, Nawrot T, Staessen JA. 2001. Relationship between blood pressure and blood lead in 

NHANES III. J Hypertens 19(2):S57. 

Den Hond E, Nawrot T, Staessen JA. 2002. The relationship between blood pressure and blood lead in 

NHANES III. J Hum Hypertens 16:563-568. 

DeSilva PE. 1981. Determination of lead in plasma and studies on its relationship to lead in 

erythrocytes. Br J Ind Med 38:209-217. 

Dewailly E, Ayotte P, Bruneau S, et al. 2001. Exposure of the Inuit population of Nunavik (Arctic 

Quebec) to lead and mercury. Arch Environ Health 56(4):350-357. 

Dhawan M, Flora SJS, Singh S, et al. 1989. Chelation of lead during, co-exposure to ethanol. Biochem 

Int 19:1067-1075. 

Diamond GL. 1988. Biological monitoring of urine for exposure to toxic metals. In: Clarkson TW, 

Nordberg G, Sager PF, et al., eds. Scientific basis and practical applications of biological monitoring of 

toxic metals. New York, NY: Plenum Press, 515-529. 
LEAD 441 

9. REFERENCES 

Diamond GL. 2005. Risk assessment of nephrotoxic metals. In: Tarloff J, Lash L, eds. The toxicology 

of the kidney. London: CRC Press, 1099-1132. 

Dick RD, Pinkerton LE, Krieg EF, et al. 1999. Evaluation of postural stability in workers exposed to 

lead at a secondary lead smelter. Neurotoxicology 20(4):595-607. 

Dieter MP, Matthews HB, Jeffcoat RA, et al. 1993. Comparison of lead bioavailability in F344 rats fed 

lead acetate, lead oxide, lead sulfide, or lead ore concentrate from Skagway, Alaska. J Toxicol Environ 

Health 39:79-93. 

Dietert RR, Lee JE, Bunn TL. 2002. Developmental immunotoxicology: Emerging issues. Hum Exp 

Toxicol 21:479-485. 

Dietert RR, Lee JE, Hussain I, et al. 2004. Developmental immunotoxicology of lead. Toxicol Appl 

Pharmacol 198:86-94. 

Dietrich KN, Berger OG, Succop PA. 1993b. Lead exposure and the motor development status of urban 

six-year-old children in the Cincinnati Prospective study. Pediatrics 91:301-307. 

Dietrich KN, Berger OG, Succop PA, et al. 1993a. The developmental consequences of low to moderate 

prenatal and postnatal lead exposure: Intellectual attainment in the Cincinnati lead study cohort following 

school entry. Neurotoxicol Teratol 15:37-44. 

Dietrich KN, Krafft KM, Bier M, et al. 1986. Early effects of fetal lead exposure: Neurobehavioral 

findings at 6 months. Int J Biosoc Med Res 8:151-168. 

Dietrich KN, Krafft KM, Bier M, et al. 1989. Neurobehavioral effects of foetal lead exposure: The first 

year of life. In: Smith M, Grant LD, Sors A, eds. Lead exposure and child development: An 

international assessment. Lancaster, UK: Kluwer Academic Publishers, 320-331. 

Dietrich KN, Krafft KM, Bornschein RL, et al. 1987a. Low-level fetal lead exposure effect on 

neurobehavioral development in early infancy. Pediatrics 80:721-730. 

Dietrich KN, Krafft KM, Shukla R, et al. 1987b. The neurobehavioral effects of early lead exposure. 

Monogr Am Assoc Ment Defic 8:71-95. 

Dietrich KN, Ris MD, Succop PA, et al. 2001. Early exposure to lead and juvenile delinquency. 

Neurotoxicol Teratol 23:511-518. 

Dietrich KN, Succop PA, Berger OG, et al. 1991. Lead exposure and the cognitive development of 

urban preschool children: The Cincinnati cohort lead study at age 4 years. Neurotoxicol Teratol 13:203­

211. 

Dietrich KN, Ware JH, Salganik M, et al. 2004. Effect of chelation therapy on the neuropsychological 

and behavioral development of lead-exposed children after school entry. Pediatrics 114(1):19-26. 

Ding Y, Gonick HC, Vaziri ND, et al. 2001. Lead-induced hypertension. Increased hydroxyl radical 

production. Am J Hypertens 14:169-173. 

Ding Y, Vaziri ND, Gonick HC. 1998. Lead-induced hypertension: II. Response to sequential infusions 

of l- arginine, superoxide dismutase, and nitroprusside. Environ Res 76(2):107-113. 
LEAD 442 

9. REFERENCES 

Dixon S, Tohn E, Rupp R, et al. 1999. Achieving dust lead clearance standards after lead hazard control 

projects: An evaluation of the HUD-recommended cleaning procedure and an abbreviated alternative. 

Appl Occup Environ Hyg 14(5):339-334. 

Dolan SP, Nortrup DA, Bolger PM, et al. 2003. Analysis of dietary supplements for arsenic, cadmium, 

mercury, and lead using inductively coupled plasma mass spectrometry. J Agric Food Chem 51(5):1307­

1312. 

Dolenc P, Staessen JA, Lauwerys RR, et al. 1993. Short report: Low-level lead exposure does not 

increase the blood pressure in the general population. J Hypertens 11:589-593. 

Drasch G, Bohm J, Baur C. 1987. Lead in human bones: Investigation of an occupationally nonexposed 

population in southern Bavaria (F.R.G.): I. Adults. Sci Total Environ 64:303-315. 

*Drasch G, Kretschmer E, Lochner C. 1988. Lead and sudden infant death: Investigations on blood 

samples of SID babies. Eur J Pediatr 147:79-84. 

Drasch G, Wanghofer E, Roider G. 1997. Are blood, urine, hair, and muscle valid biomonitors for the 

internal burden of men with the heavy metals mercury, lead and cadmium? Trace Elem Electrolytes 

14(3):116-123. 

Duggan MJ, Inskip MJ. 1985. Childhood exposure to lead in surface dust and soil: A community health 

problem. Public Health Rev 13:1-54. 

Dundar B, Oktem F, Arslan MK, et al. 2006. The effect of long-term low-dose lead exposure on thyroid 

function in adolescents. Environ Res 101(1):140-145. 

Dunkel VC, Zieger E, Brusick D, et al. 1984. Reproducibility of microbial mutagenicity assays: 1. 

Tests with Salmonella typhimurim and Escherichia coli using a standardized protocol. Environ Mutagen 

6 (Suppl. 2):1-254. 

Dursun N, Tutus A. 1999. Chronic occupational lead exposure and thyroid function. J Trace Elem Exp 

Med 12:45-49. 

DuVal GE, Fowler BA. 1989. Preliminary purification and characterization studies of a low molecular 

weight, high affinity cytosolic lead-binding protein in rat brain. Biochem Biophys Res Commun 

159:177-184. 

Duydu Y, Suzen HS, Aydin A, et al. 2001. Correlation between lead exposure indicators and sister 

chromatid exchange (SCE) frequencies in lymphocytes from inorganic lead exposed workers. Arch 

Environ Contam Toxicol 41:241-246. 

Dyatlov VA, Platoshin AV, Lawrence DA, et al. 1998. Lead potentiates cytokine- and glutamatemediated increases in permeability of blood-brain barrier. Neurotoxicology 19:283-292. 

Dye BA, Hirsch R, Brody DJ. 2002. The relationship between blood lead levels and periodontal bone 

loss in the United States, 1988-1994. Environ Health Perspect 110(10):997-1002. 
LEAD 443 

9. REFERENCES 

Eaton DL, Stacey NH, Wong KL, et al. 1980. Dose response effects of various metal ions on rat liver 

metallothionein, glutathione, heme oxygenase, and cytochrome P-450. Toxicol Appl Pharmacol 55:393­

402. 

Eckel WP, Jacob TA. 1988. Ambient levels of 24 dissolved metals in U.S. surface and ground waters. 

Am Chem Soc Div Environ Chem 28:371-372. 

Ehle A. 1986. Lead neuropathy and electrophysiological studies in low level lead exposure: A critical 

review. Neurotoxicity 7:203-216. 

Ehle AL, McKee DC. 1990. Neuropsychological effect of lead in occupationally exposed workers: A 

critical review. Crit Rev Toxicol 20(4):237-255. 

Ehrlich R, Robins T, Jordaan E, et al. 1998. Lead absorption and renal dysfunction in a South African 

battery factory. Occup Environ Med 55:453-460. 

Eisenreich SJ, Looney BB, Thornton JD. 1981. Airborne organic contaminants in the Great Lakes 

ecosystem. Environ Sci Technol 15:30-38. 

Eisenreich SJ, Metzer NA, Urban NR, et al. 1986. Response of atmospheric lead to decreased use of lead 

in gasoline. Environ Sci Technol 20:171-174. 

Eisler R. 1988. Lead hazards to fish, wildlife, and invertebrates: A synoptic review. Laurel, MD: U.S. 

Department of the Interior, Fish and Wildlife Service. Biol Report 85 (1.14). 

Elbaz-Poulichet F, Holliger P, Huang WW, et al. 1984. Lead cycling in estuaries, illustrated by the 

Gironde Estuary, France. Nature 308:409-414. 

Eldred RA, Cahill TA. 1994. Trends in elemental concentrations of fine particles at remote sites in the 

United Sates of America. Atmos Environ 28:1009-1019. 

Ellen G, Van Loon JW. 1990. Determination of cadmium and lead in foods by graphite furnace atomic 

absorption spectrometry with Zeeman background correction: Test with certified reference materials. 

Food Addit Contam 7:265-273. 

Ellenhorn MJ, ed. 1997. Lead. In: Medical toxicology: Diagnosis and treatment of human poisoning. 

Metals and related compounds. 2nd ed. Baltimore, MD: Williams and Wilkins, 1563-1579. 

Elwood PC, Davey-Smith G, Oldham PD, et al. 1988a. Two Welsh surveys of blood lead and blood 

pressure. Environ Health Perspect 78:119-121. 

Elwood PC, Yarnell JWG, Oldham PD, et al. 1988b. Blood pressure and blood lead in surveys in Wales. 

Am J Epidemiol 127:942-945. 

Emory E, Ansari Z, Pattillo R, et al. 2003. Maternal blood lead effects on infant intelligence at age 7 

months. Am J Obstet Gynecol 188(4):S26-32. 

EPA. 1977. Standards of performance for secondary lead smelters. U.S. Environmental Protection 

Agency. Code of Federal Regulations. 40 CFR 60; Subpart L. 
LEAD 444 

9. REFERENCES 

EPA. 1979. Water-related environmental fate of 129 priority pollutants. Volume 1: Introduction and 

technical background, metals and inorganic pesticides and PCBs. Washington, DC: U.S. Environmental 

Protection Agency. EPA440479029a, 13-1 - 43-19. 

EPA 1982a. Standards of performance for lead-acid battery manufacturing plants. U.S. Environmental 

Protection Agency. Code of Federal Regulations. 40 CFR 60. Subpart KK. 

EPA. 1982b. Test methods. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 

CFR 80.3. 

EPA. 1982c. Exposure and risk assessment for lead. Washington, DC: U.S. Environmental Protection 

Agency, Office of Water Regulations and Standards, Monitoring and Data Support Division. 

EPA440485010, PB85220606. 

EPA. 1983. Methods for chemical analysis of water and wastes. Methods 239.1 and 239.2. Cincinnati, 

OH: U.S. Environmental Protection Agency, Office of Research and Development, Environmental 

Monitoring and Support Laboratory. EPA600479020. 

EPA. 1985a. Controls applicable to gasoline refiners and importers. U.S. Environmental Protection 

Agency. Code of Federal Regulations. 40 CFR 80.20. 

EPA. 1985b. Determination of reportable quantities. U.S. Environmental Protection Agency. Code of 

Federal Regulations. 40 CFR 117.3. 

EPA. 1985c. Lead exposures in the human environment. Research Triangle Park, NC: U.S. 

Environmental Protection Agency, Environmental Criteria and Assessment Office. EPA600D86185, 

PB86241007. 

EPA. 1985d. Regulation of fuels and fuel additives; gasoline lead content. Fed Regist 50(45):9386­

9399. 

EPA. 1986a. Air quality criteria for lead. Research Triangle Park, NC: U.S. Environmental Protection 

Agency, Office of Research and Development, Office of Health and Environmental Assessment, 

Environmental Criteria and Assessment Office. EPA600883028F. 

EPA. 1986b. Superfund record of decision (EPA Region 5): Forest waste disposal site, Genesee County, 

Michigan. PB87189890. 

EPA. 1986c. Test methods for evaluating solid waste SW-846: Physical/chemical methods. Method 

Nos. 7420 and 7421. Washington, DC: U.S. Environmental Protection Agency, Office of Solid Waste 

and Emergency Response. 

EPA. 1988a. Specific toxic chemical listings. U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 372.65. 

EPA. 1988b. Hazard constituents. U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 261, Appendix VIII. 

EPA. 1989c. Exposure factors handbook. Washington, DC: U.S. Environmental Protection Agency, 

Office of Health and Environmental Assessment. EPA600889043. 
LEAD 445 

9. REFERENCES 

EPA. 1989d. National primary drinking water regulations. U.S. Environmental Protection Agency. 

Code of Federal Regulations. 40 CFR 141, 142. 

EPA. 1989e. Supplement to the 1986 EPA air quality criteria for lead. Vol. 1: Addendum. Research 

Triangle Park, NC: U.S. Environmental Protection Agency, Office of Health and Environmental 

Assessment. ECAO-R-0297, EPA600889049A, PB89181374. 

EPA. 1990. Toxicity characteristic. U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 261.24, Table 1. 

EPA. 1991a. Control of lead and copper. U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 141, Subpart I (40 CFR 141.80 - 40 CFR 141.90). 

*EPA. 1991b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 142.19. 

EPA. 1991c. Reference air concentrations. Health based limits for exclusion of waste-derived residues. 

U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 266, Appendices IV and 

VII. 

EPA. 1991d. Maximum contaminant level goals and national primary drinking water regulations for lead 

and copper. Fed Regist 56:26461-26564. 

EPA. 1991e. National air quality and emissions trends report 1989. Research Triangle Park, NC: U.S. 

Environmental Protection Agency, Office of Air Quality Planning and Standards. EPA450491003. 

EPA. 1993. Pb-based paint laboratory operations guidelines: Analysis of Pb in paint, dust, and soil. 

Washington, DC: U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics. 

EPA747R92006. 

EPA. 1994a. Guidance manual for the integrated exposure uptake biokinetic model for lead in children. 

U.S. Environmental Protection Agency. EPA540R93081, PB93963510. 

EPA. 1994b. Technical support document: Parameters and equations used in integrated exposure uptake 

biokinetic model for lead in children (v0.99d). U.S. Environmental Protection Agency. EPA540R94040, 

PB94963505. 

EPA. 1994c. Validation strategy for the integrated exposure uptake biokinetic model for lead in children. 

U.S. Environmental Protection Agency. EPA540R94039, PB94963504. 

EPA. 1994d. Method 6020: Inductively coupled plasma-mass spectrometry, revision 0 (1994), SW-846. 

Test methods for evaluating solid waste, Volume 1A: Laboratory manual, physical/chemical methods. 

Washington, DC: U.S. Environmental Protection Agency, Office of Solid Waste and Emergency 

Response. 

*EPA. 1995a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 421, 

Subparts P-AB, and AE. 

EPA. 1995b. Guidance for assessing chemical contaminant data for use in fish advisories. Washington, 

DC: U.S. Environmental Protection Agency, Office of Science and Technology, Office of Water. 

EPA823R95007. 
LEAD 446 

9. REFERENCES 

EPA. 1995c. Report on the national survey of lead based paint in housing - base report. U.S. 

Environmental Protection Agency, Office of Pollution Prevention and Toxics. EPA747R95003. 

http://www.hud.gov/lea/leadwnlo.html. January 15, 2005. 

EPA. 1996a. U.S. Environmental Protection Agency. Fed Regist 61:3832. 

EPA. 1996b. National air quality and emissions trends report 1995. Office of Air Quality Planning and 

Standards. U.S. Environment Protection Agency. 

EPA. 1996c. Urban soil lead abatement demonstration project. Washington, DC: U.S. Environmental 

Protection Agency, Office of Research and Development. EPA600P93001. 

EPA. 1997. Controls and prohibitions. U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 80.22. http://frwebgate.access.gpo.gov/cgi-bin/getcfr.cgi?YEAR=1997&TITLE=40&PART=80&SECTION=22&SUBPART=&TYPE=TEXT. May 22, 

2007. 

EPA. 1998a. Lead; requirements for hazard education before renovation of target housing; final rule. 

U.S. Environmental Protection Agency. Fed Regist 63:29908. 

EPA. 1998b. Lead; identification of dangerous levels of lead; notice of proposed rulemaking. U.S. 

Environmental Protection Agency. Fed Regist 63:30302. 

EPA. 1998c. Lead-based paint poisoning prevention in certain residential structures. U.S. 

Environmental Protection Agency. Code of Federal Regulations. 440 CFR 745. 

EPA. 1999. National characteristics of drinking water systems serving populations under 10,000. U.S. 

Environmental Protection Agency. EPA816R99010. 

http://www.epa.gov/safewater/ndwac/smallsys/smallsys.pdf. November 06, 2007. 

EPA. 2000. National air pollutant emission trends, 1900-1998. Research Triangle Park, NC: U.S. 

Environmental Protection Agency. EPA454R00002. 

EPA. 2001a. Lead and lead compounds. Guidance for reporting releases and other waste management 

quantities of toxic chemicals. Washington, DC: U.S. Environmental Protection Agency. 

EPA. 2001b. The projection of mobile source air toxics from 1996 to 2007: Emissions and 

concentrations. U.S. Environmental Protection Agency. EPA420R01038. 

EPA. 2001c. Final human health risk assessment for the Coeur d'Alene Basin extending from Harrison 

to Mullan on the Coeur d'Alene River and Tributaries remedial investigation/feasibility study. 

Washington, DC: U.S. Environmental Protection Agency, Idaho Department of Environmental Quality. 

EPA. 2001d. National air quality and emissions trend report, 1999. Research Triangle Park, NC: U.S. 

Environmental Protection Agency. EPA454R01004. 

EPA. 2001e. Emergency planning and community right-to-know act-section 313: Guidance for 

reporting releases and other waste management quantities of toxic chemicals: Lead and lead compounds. 

Washington, DC: U.S. Environmental Protection Agency. EPA2660B01027. 
LEAD 447 

9. REFERENCES 

EPA. 2002. National primary drinking water regulations. Washington, DC: U.S. Environmental 

Protection Agency. EPA816F02013. http://www.epa.gov/safewater/mcl.html. February 15, 2005. 

EPA. 2003a. National air quality and emissions trends report. 2003 Special studies edition. Research 

Triangle Park, NC: U.S. Environmental Protection Agency. EPA454R03005. 

EPA. 2003b. Recommendations of the technical review workgroup for lead for an approach to assessing 

risks associated with adult expsoures to lead in soil. Washington, DC: U.S. Environmental Protection 

Agency. EPA540R03001. 

*EPA. 2004a. Air Emissions Trends-Continued Progress Through 2003. Washington, DC: U.S. 

Environmental Protection Agency. http://www.epa.gov/airtrends/reports.html. March 17, 2005. 

EPA. 2004b. Hazardous air pollutants. Washington, DC: U.S. Environmental Protection Agency. 

United States Code 42 USC 7412. http://www.epa.gov/ttn/atw/orig189.html. February 15, 2005. 

EPA. 2004c. Estimation of relative bioavailability of lead in soil and soil-like materials using in vivo 

and in vitro methods. Washington, DC: U.S. Environmental Protection Agency. OSWER 9285777. 

EPA. 2004d. Fact sheet: National listing of fish advisories. Washington, DC: Office of Water, U.S. 

Environmental Protection Agency. EPA823F04016. 

EPA. 2005a. Designated as hazardous substances in accordance with Section 311(b)(2)(A) of the Clean 

Water Act. Washington, DC: U.S. Environmental Protection Agency. Code of Federal Regulations. 40 

CFR 116.4. http://www.epa.gov/ttn/atw/orig189.html. February 15, 2005. 

EPA. 2005b. National primary and secondary ambient air quality standards for lead. Washington, DC: 

U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 50.12. 

http://www.epa.gov/epacfr40/chapt-I.info/chi-toc.htm. February 15, 2005. 

EPA. 2005c. Reportable quantities of hazardous substances designated pursuant to Section 311 of the 

Clean Water Act. Washington, DC: U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 117.3. http://www.epa.gov/epacfr40/chapt-I.info/chi-toc.htm. February 16, 2005. 

EPA. 2005d. Superfund, emergency planning, and community right-to-know programs. Designation, 

reportable quantities, and notifications. Washington, DC: U.S. Environmental Protection Agency. Code 

of Federal Regulations. 40 CFR 302.4. http://www.epa.gov/epacfr40/chapt-I.info/chi-toc.htm. February 

15, 2005. 

EPA. 2005e. Superfund, emergency planning, and community right-to-know programs. Extremely 

hazardous substances and their threshold planning quantities. Washington, DC: U.S. Environmental 

Protection Agency. Code of Federal Regulations. 40 CFR 355, Appendix A. 

http://www.epa.gov/epacfr40/chapt-I.info/chi-toc.htm. February 15, 2005. 

EPA. 2005f. Superfund, emergency planning, and community right-to-know programs. Lower 

thresholds for chemicals of special concern. Washington, DC: U.S. Environmental Protection Agency. 

Code of Federal Regulations. 40 CFR 372.28. http://www.epa.gov/epacfr40/chapt-I.info/chi-toc.htm. 

February 16, 2005. 
LEAD 448 

9. REFERENCES 

EPA. 2005g. Superfund, emergency planning, and community right-to-know programs. Toxic chemical 

release reporting. Washington, DC: U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 372.65. http://www.epa.gov/epacfr40/chapt-I.info/chi-toc.htm. February 16, 2005. 

EPA. 2005h. Lead in drinking water. Washington, DC: U.S. Environmental Protection Agency. 

http://www.epa.gov/safewater/lead/leadfacts.html. April 19, 2005. 

EPA. 2005i. Toxic chemical release inventory reporting forms and instructions: Revised 2004 version. 

Section 313 of the Emergency Planning and Community Right-to-Know Act (Title III of the Superfund 

Amendments and Reauthorization Act of 1986). U.S. Environmental Protection Agency. Office of 

Environmental Information. EPA260B05001. 

EPA. 2005j. EPA STORET database. Washington, DC: U.S. Environmental Protection Agency. 

http://www.epa.gov/storet/dbtop.html. May 20, 2005. 

EPA. 2005k. EPA national air quality monitoring system. Washington, DC: U.S. Environmental 

Protection Agency. http://www.epa.gov/air/data/. May 20, 2005. 

EPA. 2005l. Residential lead hazards standards - TSCA Section 403. Washington, DC: U.S. 

Environmental Protection Agency. http://www.epa.gov/opptintr/lead/leadhaz.htm. May 26, 2005. 

EPA. 2006. Substance registry system. Lead (II) styphnate. U.S. Environmental Protection Agency. 

http://iaspub.epa.gov/srs/srs_proc_qry.navigate?P_SUB_ID=198986. June 11, 2007. 

EPA. 2007a. Air quality and emissions-progress continues in 2006. U.S. Environmental Protection 

Agency. http://www.epa.gov/airtrends/econ-emissions.html. June 14, 2007. 

EPA. 2007b. The national listing of fish advisories. Advisory report output. U.S. Environmental 

Protection Agency. http://map1.epa.gov/. June 07, 2007. 

Erenberg G, Rinsler SS, Fish BG. 1974. Lead neuropathy and sickle cell disease. Pediatrics 54:438-441. 

Erfurth EM, Gerhardsson L, Nilsson A, et al. 2001. Effects of lead on the endocrine system in lead 

smelter workers. Arch Environ Health 56(5):449-455. 

Ericson JE. 2001. Enamel lead biomarker for prenatal exposure assessment. Environ Res 87:136-140. 

Erkkila J, Armstrong R, Riihimaki V, et al. 1992. In vivo measurements of lead in bone at four 

anatomical sites: Long term occupational and consequent endogenous exposure. Br J Ind Med 49:631­

644. 

Ernhart CB, Greene T. 1990. Low-level lead exposure in prenatal and early preschool periods: 

Language development. Arch Environ Health 45:342-354. 

*Ernhart CB, Landa B, Schell NB. 1981. Subclinical levels of lead and developmental deficit--a 

multivariate follow-up reassessment. Pediatrics 67:911-919. 

Ernhart CB, Morrow-Tlucak M, Marler MR, et al. 1987. Low level lead exposure in the prenatal and 

early preschool periods: Early preschool development. Neurotoxicol Teratol 9:259-270. 
LEAD 449 

9. REFERENCES 

Ernhart CB, Morrow-Tlucak M, Wolf AW. 1988. Low level lead exposure and intelligence in the 

preschool years. Sci Total Environ 71:453-459. 

Ernhart CB, Wolf AW, Kennard MJ, et al. 1985. Intrauterine lead exposure and the status of the neonate. 

In: Lekkas TD, ed. International conference on heavy metals in the environment, Athens, Greece. 

September, Vol. 1. Edinburgh, United Kingdom: CEP Consultants, Ltd, 35-37. 

Ernhart CB, Wolf AW, Kennard MJ, et al. 1986. Intrauterine exposure to low levels of lead: The status 

of the neonate. Arch Environ Health 41:287-291. 

ESA. 1998. LeadCare childhood blood lead testing. Chelmsford, MA: ESA, Inc. 

http://www.esainc.com/esaproducts/esaleadcare.html. October 15, 1998. 

Escribano A, Revilla M, Hernandez ER, et al. 1997. Effect of lead on bone development and bone mass: 

A morphometric, densitometric, and histomorphometric study in growing rats. Calcif Tissue Int 

60(2):200-203. 

Eskew AE, Crutcher JC, Zimmerman SL, et al. 1961. Lead poisoning resulting from illicit alcohol 

consumption. J Forensic Sci 6:337-350. 

Esteban E, Rubin CH, Jones RL, et al. 1999. Hair and blood substrates for screening children for lead 

poisoning. Arch Environ Health 54(6):436-440. 

Ettinger AS, Tellez-Rojo MM, Amarasiriwardena C, et al. 2006. Influence of maternal bone lead burden 

and calcium intake on levels of lead in breast milk over the course of lactation. Am J Epidemiol 

163(1):48-56. 

Evans RD, Rigler FH. 1985. Long distance transport of anthropogenic lead as measured by lake 

sediments. Water Air Soil Pollut 24:141-151. 

Everson J, Patterson CC. 1980. “Ultra-clean” isotope dilution/mass spectrometric analyses for lead in 

human blood plasma indicate that most reported values are artificially high. Clin Chem 26:1603-1607. 

Ewers U, Brockhaus A, Dolgner R, et al. 1990. Levels of lead and cadmium in blood of 55-66 year old 

women living in different areas of Northrhine-Westphalia-Chronological trend 1982-1988. Zentralb Hyg 

Umveltmed 189:405-418. 

Ewers U, Stiller-Winkler R, ldel H. 1982. Serum immunoglobulin, complement C3, and salivary IgA 

level in lead workers. Environ Res 29:351-357. 

Exon JH, Koller LD, Kerkvliet NI. 1979. Lead-cadmium interaction: Effects on viral-induced mortality 

and tissue residues in mice. Arch Environ Health 34:469-475. 

Factor-Litvak P, Graziano JH, Kline JK, et al. 1991. A prospective study of birthweight and length of 

gestation in population surrounding a lead smelter in Kosovo, Yugoslavia. Int J Epidemiol 20:722-728. 

Factor-Litvak P, Kline JK, Popovac D, et al. 1996. Blood lead and blood pressure in young children. 

Epidemiology 7(6):633-637. 

Factor-Litvak P, Slavkovich V, Liu X, et al. 1998. Hyperproduction of erythropoietin in nonanemic 

lead-exposed children. Environ Health Perspect 106(6):361-364. 
LEAD 450 

9. REFERENCES 

Factor-Litvak P, Wasserman G, Kline JK, et al. 1999. The Yugoslavia prospective study of 

environmental lead exposure. Environ Health Perspect 107:9-15. 

Fahim MS, Khare NK. 1980. Effects of subtoxic levels of lead and cadmium on urogenital organs of 

male rats. Arch Androl 4:357. 

*Fahim MS, Fahim Z, Hall DG. 1976. Effects of subtoxic lead levels on pregnant women in the state of 

Missouri. Res Commun Chem Pathol Pharmacol 13:309-331. 

Faith RE, Luster MI, Kimmel CA. 1979. Effect of chronic developmental lead exposure on cellmediated immune functions. Clin Exp lmmunol 35:413-420. 

Falcón M, Vinas P, Luna A. 2003. Placental lead and outcome of pregnancy. Toxicology 185:59-66. 

Fanning D. 1988. A mortality study of lead workers, 1926-1985. Arch Environ Health 43:247-251. 

Farias P, Echavarria M, Hernandez-Avila M, et al. 2005. Bone, blood and semen lead in men with 

environmental and moderate occupational exposure. Int J Environ Health Res 15(1):21-31. 

Fayerweather WE, Karns ME, Nuwayhid IA, et al. 1997. Case-control study of cancer risk in tetraethyl 

lead manufacturing. Am J Ind Med 31:28-35. 

FDA. 1992. Lead in ceramic foodware; revised compliance policy guide; availability. Washington, DC: 

Department of Health and Human Services, U.S. Food and Drug Administration. Fed Regist 57:29734. 

FDA. 1995. Substances prohibited from use in human food. Substances prohibited from indirect 

addition to human food through food-contact surfaces. U.S. Food and Drug Administration. Code of 

Federal Regulations. 21 CFR 189.240. 

FDA. 1996. Tin-coated lead foil capsules for wine bottles. U.S. Food and Drug Administration. Code 

of Federal Regulations. 21 CFR 189.301. 

FDA. 1998a. Direct food substances affirmed as generally recognized as safe. U.S. Food and Drug 

Administration. Code of Federal Regulations. 21 CFR 184. 

FDA. 1998b. Hazard analysis and critical control point (HACCP); procedures for the safe and sanitary 

processing and importing of juice. U.S. Food and Drug Administration. Fed Regist 63(79):20449-20486. 

http://www.cfsan.fda.gov/lrd/fr98424a.html. May 25, 2007. 

FDA. 2000. Action levels for poisonous or deleterious substances in human food and animal feed. 

Washington, DC: Food and Drug Administration. http://www.cfsan.fda.gov/lrd/fdaact.html. February 

15, 2005. 

FDA. 2004. Bottled water. U.S. Environmental Protection Agency. Code of Federal Regulations.21 

CFR 165.110 

http://a257.g.akamaitech.net/7/257/2422/12feb20041500/edocket.access.gpo.gov/cfr_2004/aprqtr/pdf/21c 

fr165.110.pdf. September 22, 2007. 

FEDRIP. 2005. FEDRIP literature search for lead. Palo Alto, CA: Federal Research in Progress. 

Dialog Information Service. 
LEAD 451 

9. REFERENCES 

Feldman RG. 1978. Urban lead mining: Lead intoxication among deleaders. N Engl J Med 

298(20):1143-1145. 

Fell GS. 1984. Review article: Lead toxicity: Problems of definition and laboratory evaluation. Ann 

Clin Biochem 21:453-460. 

Fels LM, Wünsch M, Baranowski J, et al. 1998. Adverse effects of chronic low level lead exposure on 

kidney function - a risk group study in children. Nephrol Dial Transplant 13:2248-2256. 

Fergusson DM, Fergusson JE, Horwood LJ, et al. 1988. A longitudinal study of dentine lead levels, 

intelligence, school performance and behavior: Part III. Dentine lead levels and attention activity. J 

Child Psychol Psychiatry 29:811-824. 

Fewtrell LJ, Pruss-Ustun A, Landrigan P, et al. 2004. Estimating the global burden of disease of mild 

mental retardation and cardiovascular diseases from environmental lead exposure. Environ Res 94:120­

133. 

Finster ME, Gray KA, Binns HJ. 2004. Lead levels of edibles grown in contaminated residential soils: 

A field survey. Sci Total Environ 320:245-257. 

Fischbein A, Anderson KE, Sassa S, et al. 1981. Lead poisoning from do-it- yourself heat guns for 

removing lead-based paint: Report of two cases. Environ Res 24:425-431. 

Fischbein A, Tsang P, Luo J, et al. 1993. Phenotypic aberrations of CD3 and CD4 cells and functional 

impairments of lymphocytes at low-level occupational exposure to lead. Clin Immunol Immunopathol 

66:163-168. 

Fischbein A, Wallace J, Sassa S, et al. 1992. Lead poisoning from art restoration and pottery work 

unusual exposure source and household risk. J Environ Path Toxicol Oncol 11(1):7-11. 

Fitchko J, Hutchinson TC. 1975. A comparative study of heavy metal concentrations in river mouth 

sediments around the Great Lakes. J Great Lakes Res 1:46-78. 

Flanagan PR, Hamilton DL, Haist J, et al. 1979. Inter-relationships between iron and absorption in irondeficient mice. Gastroenterology 77:1074-1081. 

Flegal AR, Smith DR. 1995. Measurements of environmental lead contamination and human exposure. 

Rev Environ Contam Toxicol 143:1-45. 

Fleming DEB, Boulay D, Richard NS, et al. 1997. Accumulated body burden and endogenous release of 

lead in employees of a lead smelter. Environ Health Perspect 105(2):224-233. 

Fleming DEB, Chettle DR, Wetmur JG, et al. 1998b. Effect of the δ-aminolevulinate dehydratase 

polymorphism on the accumulation of lead in bone and blood in lead smelter workers. Environ Res 

77:49-61. 

Fleming MD, Romano MA, Su MA, et al. 1998a. Nramp2 is mutated in the anemic Belgrade (b) rat: 

Evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci U S A 95:1148-1153. 
LEAD 452 

9. REFERENCES 

Flora SJS, Tandon SK. 1987. Effect of combined exposure to lead and ethanol on some biochemical 

indices in the rat. Biochem Pharm 36:537-541. 

Fomon SJ. 1966. Body composition of the infant: Part I: The male reference infant. In: Falkner F, ed. 

Human development. Philadelphia, PA: WB Saunders, 239-246. 

Fomon SJ, Haschke F, Ziegler EE, et al. 1982. Body composition of reference children from birth to age 

10 years. Am J Clin Nutr 35:1169-1175. 

Forbes GB, Reina JC. 1972. Effect of age on gastrointestinal absorption (Fe, Sr, Pb) in the rat. J Nutr 

102:647-652. 

Forni A, Camiaghi G, Sechi GC. 1976. Initial occupational exposure to lead: Chromosome and 

biochemical findings. Arch Environ Health 31:73-78. 

Foster WG. 1992. Reproductive toxicity of chronic lead exposure in the female Cynomolgus monkey. 

Reprod Toxicol 6:123-131. 

Foster WG, McMahon A, Rice DC. 1996. Sperm chromatin structure is altered in Cynomolgus monkeys 

with environmentally relevant blood lead levels. Toxicol Ind Health 12(5):723-735. 

Foster WG, Singh A, McMahon A, et al. 1998. Chronic lead exposure effects in the Cynomolgus 

monkey (Macaca fascicularis) testis. Ultrastruct Pathol 22(1):63-71. 

Fowler BA. 1989. Biological roles of high affinity metal-binding proteins in mediating cell injury. 

Comments Toxicol 3:27-46. 

Fowler BA, DuVal G. 1991. Effects of lead on the kidney: Roles of high-affinity lead-binding proteins. 

Environ Health Perspect 91:77-89. 

Fowler BA, Kimmel CA, Woods JS, et al. 1980. Chronic low-level lead toxicity in the rat: III. An 

integrated assessment of long-term toxicity with special reference to the kidney. Toxicol Appl Pharmacol 

56:59-77. 

Fox DA, Chu LWF. 1988. Rods are selectively altered by lead: II. Ultrastructure and quantitative 

histology. Exp Eye Res 46:613-625. 

Fox DA, Farber DB. 1988. Rods are selectively altered by lead: I. Electrophysiology and biochemistry. 

Exp Eye Res 46:597-611. 

Fox DA, Katz LM. 1992. Developmental lead exposure selectively alters the scotopic ERG component 

of dark and light adaptation and increases rod calcium content. Vision Res 32:249-255. 

Fox DA, Rubinstein SD. 1989. Age-related changes in retinal sensitivity, rhodopsin content and rod 

outer segment length in hooded rats following low-level lead exposure during development. Exp Eye Res 

48:237-249. 

Fox DA, Campbell ML, Blocker YS. 1997. Functional alterations and apoptotic cell death in the retina 

following developmental or adult lead exposure. Neurotoxicology 18(3):645-664. 
LEAD 453 

9. REFERENCES 

Fox DA, Katz LM, Farber DB. 1991. Low level developmental lead exposure decreases the sensitivity, 

amplitude and temporal resolution of rods. Neurotoxicology 12:641-654. 

Fracasso ME, Perbellini L, Solda S, et al. 2002. Lead induced DNA strand breaks in lymphocytes of 

exposed workers: Role of reactive oxygen species and protein kinase C. Mutat Res 515:159-169. 

Franklin CA, Inskip MJ, Baccanale CL, et al. 1997. Use of sequentially administered stable lead 

isotopes to investigate changes in blood lead during pregnancy in a nonhuman primate (Macaca 

fascicularis). Fundam Appl Toxicol 39:109-119. 

Franks PA, Laughlin NK, Dierschke DJ, et al. 1989. Effects of lead on luteal function in Rhesus 

monkeys. Biol Reprod 41:1055-1062. 

Freeman GB, Dill JA, Johnson JD, et al. 1996. Comparative absorption of lead from contaminated soil 

and lead salts by weanling Fischer 344 rats. Fundam Appl Toxicol 33:109-119. 

Freeman GB, Johnson JD, Killinger JM, et al. 1992. Relative bioavailability of lead from mining waste 

soil in rats. Fundam Appl Toxicol 19:388-398. 

Freeman GB, Johnson JD, Liao SC, et al. 1994. Absolute bioavailability of lead acetate and mining 

waste lead in rats. Toxicology 91:151-163. 

Friedlander MA. 1981 Blood pressure and creatinine clearance in lead-exposed children: Effect of 

treatment. Arch Environ Health 36:310-315. 

Frisancho AR, Ryan AS. 1991. Decreased stature associated with moderate blood lead concentrations in 

Mexican-American children. Am J Clin Nutr 54:516-519. 

Froom P, Kristal-Boneh E, Benbassat J, et al. 1998. Predictive values of determinations of zinc 

protoporphyrin for increase blood lead concentrations. Clin Chem 44:1283-1288. 

Froom P, Kristal-Boneh E, Benbassat J, et al. 1999. Lead exposure in battery-factory workers is not 

associated with anemia. J Occup Environ Med 41(2):120-123. 

Fu H, Boffetta P. 1995. Cancer and occupational exposure to inorganic lead compounds: A metaanalysis of published data. Occup Environ Med 52(2):73-81. 

Fujita H, Sato K, Sano S. 1982. Increase in the amount erythrocyte δ-aminolevulinic acid dehydratase in 

workers with moderate lead exposure. Int Arch Occup Environ Health 50:287-297. 

Fukunaga M, Kurachi Y, Mizuguchi Y. 1982. Action of some metal ions at yeast chromosomes. Chem 

Pharm Bull 30:3017-3019. 

Fullmer CS, Rosen JF. 1990. Effect of dietary calcium and lead status on intestinal calcium absorption. 

Environ Res 51:91-99. 

Fullmer CS, Edelstin S, Waserman RH. 1985. Lead-binding properties of intestinal calcium-binding 

proteins. J Biol Chem 260:6816-6819. 

Fulton M, Raab G, Thomson G, et al. 1987. Influence of blood lead on the ability and attainment of 

children in Edinburgh. Lancet 1:1221-1226. 
LEAD 454 

9. REFERENCES 

Gale NL, Adams CD, Wixson BG, et al. 2002. Lead concentrations in fish and river sediments in the old 

lead belt of Missouri. Environ Sci Technol 36:4262-4268. 

Gale NL, Adams CD, Wixson BG, et al. 2004. Lead, zinc, copper, and cadmium in fish and sediments 

from the Big River and Flat River Creek of Missouri’s Old Lead Belt. Environ Geochem Health 26:37­

49. 

Gant VA. 1938. Lead poisoning. Ind Med 7:679-699. 

Gao K, Pearce J, Jones J, et al. 1999. Interaction between peat, humic acid and aqueous metal ions. 

Environ Geochem Health 21:13-26. 

Gartrell MJ, Craun JC, Podrebarac DS, et al. 1986a. Pesticides, selected elements, and other chemicals 

in infant and toddler total diet samples, October 1980-March 1982. J Assoc Off Anal Chem 69:123-145. 

Gartrell MJ, Craun JC, Podrebarac DS, et al. 1986b. Pesticides, selected elements, and other chemicals 

in adult total diet samples, October 1980-March 1982. J Assoc Off Anal Chem 69:146-161. 

Gartside PS. 1988. The relationship of blood lead levels and blood pressure in NHANES II: Additional 

calculations. Environ Health Perspect 78:31-34. 

Garvey GJ, Hahn G, Lee RV, et al. 2001. Heavy metal hazards of Asian traditional remedies. Int J 

Environ Health Res 11(1):63-71. 

Gasiorek K, Bauchinger M. 1981. Chromosome changes in human lymphocytes after separate and 

combined treatment with divalent salts of lead, cadmium, and zinc. Environ Mutat 3:513-518. 

Ge Y, Murray P, Hendershot WH. 2000. Trace metal speciation and bioavailability in urban soils. 

Environ Pollut 107:137-144. 

Gemmel A, Tavares M, Alperin S, et al. 2002. Blood lead level and dental caries in school-age children. 

Environ Health Perspect 110(10):625-630. 

Gennart J-P, Bernard A, Lauwerys R. 1992a. Assessment of thyroid, testes, kidney and autonomic 

nervous system function in lead-exposed workers. Int Arch Occup Environ Health 64:49-57. 

Gennart J-P, Buchet J-P, Roels H, et al. 1992b. Fertility of male workers exposed to cadmium, lead or 

manganese. Am J Epidemiol 135:1208-1219. 

Gercken B, Barnes RM. 1991. Determination of lead and other trace element species in blood by size 

exclusion chromatography and inductively coupled plasma/mass spectrometry. Anal Chem 63:283-287. 

Gerhardsson L, Brune D, Nordberg GF, et al. 1986a. Distribution of cadmium, lead, and zinc in lung, 

liver, and kidney in long-term exposed smelter workers. Sci Total Environ 50:65-85. 

Gerhardsson L, Chettle DR, Englyst V, et al. 1992. Kidney effects in long term exposed lead smelter 

workers. Br J Ind Med 49:186-192. 

Gerhardsson L, Endlyst V, Lundstrom NG, et al. 1995b. Lead in tissues of deceased lead smelter 

workers. J Trace Elem Med Biol 9:136-143. 
LEAD 455 

9. REFERENCES 

Gerhardsson L, Hagmar L, Rylander L, et al. 1995a. Mortality and cancer incidence among secondary 

lead smelter workers. Occup Environ Med 52:667-672. 

Gerhardsson L, Lundstrom NG, Nordberg G, et al. 1986b. Mortality and lead exposure: A retrospective 

cohort study of Swedish smelter workers. Br J Ind Med 43:707-712. 

Gerhardt RE, Crecelius EA, Hudson JB. 1980. Trace element content of moonshine. Arch Environ 

Health 35:332-334. 

Gerlach RF, Cury JA, Krug FJ, et al. 2002. Effect of lead on dental enamel formation. Toxicology 

14(175(1-3)):27-34. 

Gerlach RF, Toledo DB, Novaes PD, et al. 2000. The effect of lead on the eruption rates of incisor teeth 

in rats. Arch Oral Biol 45:951-955. 

Gerr F, Letz R, Stokes L, et al. 2002. Association between bone lead concentration and blood pressure 

among young adults. Am J Ind Med 42:98-106. 

Gerritse RG, Vriesema R, Dalenberg H, et al. 1981. Trace element mobility in soils effect of sewage 

sludge. Heavy Met Environ Int Conf 4th 1:180-184. 

Gersberg RM, Gaynor K, Tenczar D, et al. 1997. Quantitative modeling of lead exposure from glazed 

ceramic pottery in childhood lead poisoning cases. Int J Environ Health Res 7(3):193-202. 

Gibbs PNB, Gore MG, Jordan PM. 1985. Investigation of the effect of metal ions on the reactivity of 

thiol groups in human 5-aminolaevulinate dehydratase. Biochem J 225:573-580. 

Giddings JC, ed. 1973. Lead in gasoline. In: Chemistry, man, and environmental change: An 

integrated approach. New York, NY: Harper & Row, Publishers, Inc., 351-353. 

Gilbert ME, Lasley SM. 2002. Long-term consequences of developmental exposure to lead or 

polychlorinated biphenyls: Synaptic transmission and plasticity in the rodent CNS. Environ Toxicol 

Pharmacol 12:105-117. 

Giwercman A, Carlsen E, Keiding N, et al. 1993. Evidence for increasing incidence of abnormalities of 

the human testis: A review. Environ Health Perspect Suppl 101(2):65-71. 

Glenn BS, Stewart WF, Links JM, et al. 2003. The longitudinal association of lead with blood pressure. 

Epidemiology 14:30-36. 

Glenn BS, Stewart WF, Schwartz BS, et al. 2001. Relation of alleles of the sodium- potassium adenosine 

triphosphatase α2 gene with blood pressure and lead exposure. Am J Epidemiol 153:537-545. 

Glickman L, Valciukas JA, Lilis R, et al. 1984. Occupational lead exposure: Effects on saccadic eye 

movements. Int Arch Occup Environ Health 54:115-125. 

Goering PL. 1993. Lead-protein interactions as a basis for lead toxicity. Neurotoxicology 14:45-60. 

Goering PL, Fowler BA. 1984. Regulation of lead inhibition of delta-aminolevulinic acid dehydratase by 

a high affinity renal lead-binding protein. J Pharmacol Exp Ther 231:66-71. 
LEAD 456 

9. REFERENCES 

Goering PL, Fowler BA. 1985. Mechanisms of renal lead-binding protein protection against leadinhibition of delta-aminolevulinic acid dehydratase. J Pharmacol Exp Ther 234:365-371. 

Goering PL, Fowler BA. 1987. Metal constitution of metallothionein influences inhibition of deltaaminolevulinic acid dehydratase (porphobiligen synthase) by lead. Biochem J 245:339-345. 

Goering PL, Mistry P, Fowler BA. 1986. A high affinity lead binding protein attenuates lead inhibition 

of delta-aminolevulinic acid dehydratase: Comparison with a renal lead-binding protein. J Pharmacol 

Exp Ther 237:220-225. 

Goldberg AM, Meredith PA, Miller S, et al. 1978. Hepatic drug metabolism and heme biosynthesis in 

lead-poisoned rats. Br J Pharmacol 62:529-536. 

Goldberg RL, Hicks AM, O'Leary LM, et al. 1991. Lead exposure at uncovered outdoor firing ranges. J 

Occup Med 33(6):718-719. 

Goldman RH, Baker EL, Hannan M, et al. 1987. Lead poisoning in automobile radiator mechanics. N 

Engl J Med 317:214-218. 

Goldstein GW. 1993. Evidence that lead acts as a calcium substitute in second messenger metabolism. 

Neurotoxicology 14:97-102. 

Goldstein GW, Ar D. 1983. Lead activates calmodulin sensitive processes. Life Sci 33:1001-1006. 

Gomaa A, Howard H, Bellinger D, et al. 2002. Maternal bone lead as an independent risk factor for fetal 

neurotoxicity: A prospective study. Pediatrics 110(1):110-118. 

Gomes VE, Rosario de Sousa ML, Barbosa F, et al. 2004. In vivo studies on lead content of deciduous 

teeth superficial enamel of preschool children. Sci Total Environ 320:25-35. 

Gong JK, Arnold JS, Cohn SH. 1964. Composition of trabecular and cortical bone. Anatmol Rec 

149:325-331. 

Gonick HC, Ding Y, Bondy SC, et al. 1997. Lead-induced hypertension. Interplay of nitric oxide and 

reactive oxygen species. Hypertension 30:1487-1492. 

Gonick HC, Ding Y, Bondy SC, et al. 1998. Effect of low lead exposure on eicosanoid excretion in rats. 

Prost Lipid Med 55:77-82. 

Gonzalez-Riola J, Hernandez ER, Escribano A, et al. 1997. Effect of lead on bone and cartilage in 

sexually mature rats: A morphometric and histomorphometry study. Environ Res 74(1):91-93. 

Goodman M, LaVerda N, Clarke C, et al. 2002. Neurobehavioural testing in workers occupationally 

exposed to lead: Systematic review and meta-analysis of publications. Occup Environ Med 59:217-223. 

Goodrum PE, Diamond GL, Hassett JM, et al. 1996. Monte Carlo modeling of childhood lead exposure: 

Development of a probabilistic methodology for use with the USEPA IEUBK model for lead in children. 

Hum Ecol Risk Assess 2(4):681-708. 
LEAD 457 

9. REFERENCES 

Gorell JM, Johnson CC, Rybicki BA, et al. 1997. Occupational exposures to metals as risk factors for 

Parkinson's disease. Neurology 48(3):650-658. 

Gorell JM, Johnson CC, Rybicki BA, et al. 1999. Occupational exposure to manganese, copper, lead, 

iron, mercury and zinc and the risk of Parkinson's disease. Neurotoxicology 20(2-3):239-248. 

Goyer RA. 1968. The renal tubule in lead poisoning. I. Mitochondrial swelling and aminoaciduria. Lab 

Invest 19:71-77. 

Goyer RA. 1971. Lead toxicity: A problem in environmental pathology. Am J Pathol 64:167-179. 

Goyer RA. 1986. Toxic effect of metals. In: Klaassen CD, ed. Casarett and Doull's toxicology: The 

basic science of poisons. 3rd ed. New York, NY: Macmillan Publishing Co., 582-588, 598-605. 

Goyer RA. 1989. Mechanisms of lead and cadmium nephrotoxicity. Toxicol Lett 46:153-162. 

Goyer RA. 1990. Transplacental transport of lead. Environ Health Perspect 89:101-105. 

Goyer RA. 1993. Lead toxicity: Current concerns. Environ Health Perspect 100:177-187. 

Goyer RA. 2001. Lead. In: Bingham E, Cohrssen B, Powell CH, eds. Patty's toxicology. 5th edition. 

New York, NY: John Wiley & Sons, Inc., 611-675. 

Goyer RA, Krall R. 1969. Ultrastructural transformation in mitochondria isolated from kidneys of
 

normal and lead-intoxicated rats. J Cell Biol 41:393-400. 

Goyer RA, Leonard DL, Moore JF, et al. 1970a. Lead dosage and the role of the intranuclear inclusion 

body. Arch Environ Health 20:705-711. 

Goyer RA, May P, Cates MM, et al. 1970b. Lead and protein content of isolated intranuclear inclusion 

bodies from kidneys of lead-poisoned rats. Lab Invest 22(3):245-251. 

Grabo TN. 1997. Unknown toxic exposures. Arts and crafts materials. AAOHN 45(3):124-130.
 

Grandjean P. 1979. Occupational lead exposure in Denmark: Screening with the haematofluorometer. 

Br J Ind Med 36:52-58. 

Grandjean P, Bach E. 1986. Indirect exposures: The significance of bystanders at work and at home. 

Am Ind Hyg Assoc J 47:819-824. 

Grandjean P, Lintrup J. 1978. Erythrocyte-Zn-protoporphyrin as an indicator of lead exposure. Scand J 

Clin Lab Invest 38:669-675. 

Grandjean P, Olsen B. 1984. Lead. In: Vercruysse A, ed. Techniques and instrumentation in analytical 

chemistry. Volume 4: Evaluation of analytical methods in biological systems: Part B. Hazardous metals 

in human toxicology. New York, NY: Elsevier Science Publishing Co., Inc., 153-169. 

Grandjean P, Hollnagel H, Hedegaard L, et al. 1989. Blood lead-blood pressure relations: Alcohol 

intake and hemoglobin as confounders. Am J Epidemiol 129:732-739. 
LEAD 458 

9. REFERENCES 

Grandjean P, Jorgensen PJ, Viskum S, et al. 1991. Temporal and interindividual variation in 

erythrocytezine-protoporphyrin in lead exposed workers. Br J Ind Med 48:254-257. 

Grandjean P, Wulf HC, Niebuhr E. 1983. Sister chromatid exchange in response to variations in 

occupational lead exposure. Environ Res 32:199-204. 

Grant LD, Kimmel CA, West GL, et al. 1980. Chronic low-level lead toxicity in the rat: II. Effects on 

postnatal physical and behavioral development. Toxicol Appl Pharmacol 56:42-58. 

Graziano JH. 1994. Validity of lead exposure markers in diagnosis and surveillance. Clin Chem 

40:1387-1390. 

Graziano JH, Blum C. 1991. Lead exposure from lead crystal. Lancet 333:141-142. 

Graziano JH, Blum CB, Lolacono NJ, et al. 1996. A human in vivo model for determination of lead 

bioavailability using stable isotope dilution. Environ Health Perspect 104:176-179. 

Graziano JH, Popovac D, Factor-Litvak P, et al. 1990. Determinants of elevated blood lead during 

pregnancy in a population surrounding a lead smelter in Kosovo, Yugoslavia. Environ Health Perspect 

89:95-100. 

Graziano JH, Slavkovic V, Factor-Litvak P, et al. 1991. Depressed serum erythropoietin in pregnant 

women with elevated blood lead. Arch Environ Health 46(6):347-350. 

Graziano JH, Slavkovich V, Liu X, et al. 2004. A prospective study of prenatal and childhood lead 

exposure and erythropoietin production. J Occup Environ Med 46:924-929. 

Greenberg M, Hamilton R. 1999. Lack of blood lead elevations in police officers following small arms 

qualification on an indoor range [Abstract]. J Toxicol Clin Toxicol 37(5):627. 

Greene T, Ernhart CB. 1991. Prenatal and preschool age lead exposure: Relationship with size. 

Neurotoxicol Teratol 13:417-427. 

Griffin S, Goodrum PE, Diamond GL, et al. 1999. Application of a probabilistic risk assessment 

methodology to a lead smelter site. Hum Ecol Risk Assess 5(4):845-868. 

Griffin TB, Coulston F, Wills H. 1975. [Biological and clinical effects of continuous exposure to 

airborne particulate lead.] Arh Hig Toksikol 26:191-208. (Yugoslavian) 

Grobler SR, Rossouw RJ, Kotze D. 1988. Effect of airborne lead on the blood lead levels of rats. S Afr 

J Sci 84:260-262. 

Gross M, Kumar R. 1990. Physiology and biochemistry of vitamin D-dependent calcium binding 

proteins. Am J Physiol 259:F195-F209. 

Gross SB, Pfitzer EA, Yeager DW, et al. 1975. Lead in human tissues. Toxicol Appl Pharmacol 32:638­

651. 

Grosse SD, Matte TD, Schwartz J, et al. 2002. Economic gains resulting from the reduction in children's 

exposure to lead in the United States. Environ Health Perspect 110(6):563-569. 
LEAD 459 

9. REFERENCES 

Gruber HE, Gonick HC, Khalil-Manesh F, et al. 1997. Osteopenia induced by long-term, low- and highlevel exposure of the adult rat to lead. Miner Electrolyte Metab 23 (2):65-73. 

Guibaud G, Tixier N, Bouju A, et al. 2003. Relation between extracellular polymers' composition and its 

ability to complex Cd, Cu and Pb. Chemosphere 52:1701-1710. 

Guilarte TR, Toscano CD, McGlothan JL, et al. 2003. Environmental enrichment reverses cognitive and 

molecular deficits induced by developmental lead exposure. Ann Neurol 53:50-56. 

Gulson BL. 1996. Tooth analyses of sources and intensity of lead exposure in children. Environ Health 

Perspect 104:306-312. 

Gulson BL. 2000. Revision of estimates of skeletal contribution to blood during pregnancy and 

postpartum period. J Lab Clin Med 136:250-251. 

Gulson BL, Wilson D. 1994. History of lead exposure in children revealed from isotopic analyses of 

teeth. Arch Environ Health 49(4):279-283. 

*Gulson BL, Gray B, Mahaffey KR, et al. 1999a. Comparison of the rates of exchange of lead in the 

blood of newly born infants and their mothers with lead in their current environment. J Lab Clin Med 

133:171-178. 

Gulson BL, James M, Giblin AM, et al. 1997a. Maintenance of elevated lead levels in drinking water 

from occasional use and potential impact on blood leads in children. Sci Total Environ 205(2-3):271-275. 

Gulson BL, Jameson CW, Mahaffey KR, et al. 1997b. Pregnancy increases mobilization of lead from 

maternal skeleton. J Lab Clin Med 130(1):51-62. 

Gulson BL, Jameson CW, Mahaffey KR, et al. 1998a. Relationships of lead in breast milk to lead in 

blood, urine, and diet of the infant and mother. Environ Health Perspect 106(10):667-674. 

Gulson BL, Mahaffey KR, Jameson CW, et al. 1998b. Mobilization of lead from the skeleton during the 

postnatal period is larger than during pregnancy. J Lab Clin Med 131:324-329. 

Gulson BL, Mahaffey KR, Jameson CW, et al. 1999c. Impact of diet on lead in blood and urine in 

female adults and relevance to mobilization of lead from bone stores. Environ Health Perspect 

107(4):257-263. 

Gulson BL, Mizon KJ, Korsch MJ, et al. 1996. Impact on blood lead in children and adults following 

relocation from their source of exposure and contribution of skeletal tissue to blood lead. Bull Environ 

Contam Toxicol 56:543-550. 

*Gulson BL, Mizon KJ, Korsch MJ, et al. 2001a. Dietary intakes of selected elements from longitudinal 

6-day duplicate diets for pregnant and nonpregnant subjects and elemental concentrations of breast milk 

and infant formula. Environ Res 87:160-174. 

Gulson BL, Mizon KJ, Korsch MJ, et al. 2003. Mobilization of lead from human bone tissue during 

pregnancy and lactation - a summary of long-term research. Sci Total Environ 303:79-104. 

Gulson BL, Mizon KJ, Palmer JM, et al. 2001b. Contribution of lead from calcium supplements to blood 

lead. Environ Health Perspect 109(3):283-288. 
LEAD 460 

9. REFERENCES 

Gulson BL, Mizon KJ, Palmer JM, et al. 2001c. Longitudinal study of daily intake and excretion of lead 

in newly born infants. Environ Res 85:232-245. 

Gulson BL, Mizon KJ, Palmer JM, et al. 2004. Blood lead changes during pregnancy and postpartum 

with calcium supplementation. Environ Health Perspect 12(15):1499-1507. 

Gulson BL, Palmer JM, Bryce A. 2002. Changes in blood lead of a recreational shooter. Sci Total 

Environ 293(1-3):143-150. 

Gulson BL, Pounds JG, Mushak P, et al. 1999b. Estimation of cumulative lead releases (lead flux) from 

the maternal skeleton during pregnancy and lactation. J Lab Clin Med 134(6):631-640. 

Gump BB, Stewart P, Reihman J, et al. 2005. Prenatal and early childhood blood lead levels and 

cardiovascular functioning in 9 1/2 year old children. Neurotoxicol Teratol 27(4):655-665. 

Gunderson EL. 1988. FDA total diet study, April 1982-April 1984, dietary intakes of pesticides, selected 

elements and other chemicals. J Assoc Off Anal Chem 71:1200-1209. 

Gunderson EL. 1995. FDA Total diet study, July 1986-April 1991, Dietary intakes of pesticides, 

selected elements, and other chemicals. J AOAC Int 78(6):1353-1363. 

Gurer-Orhan H, Sabir HU, Ozgunes H. 2004. Correlation between clinical indicators of lead poisoning 

and oxidative stress parameters in controls and lead-exposed workers. Toxicology 195:147-154. 

Gustafson A, Hedner P, Schutz A, et al. 1989. Occupational lead exposure and pituitary function. Int 

Arch Occup Environ Health 61:277-281. 

Guzelian PS, Henry CJ, Olin SS, eds. 1992. Similarities and differences between children and adults: 

Implications for risk assessment. Washington, DC: International Life Sciences Institute Press. 

*Haas T, Wieck AG, Schaller KH, et al. 1972. [The usual lead load in new-born infants and their 

mothers.] Zentralbl Bakteriol [B] 155:341-349. (German) 

Habermann HC, Crowell K, Janicki P. 1983. Lead and other metals can substitute for Ca2

 in calmodulin. 

Arch Toxicol 54:61-70. 

Haeger-Aronsen B, Schutz A, Abdulla M. 1976. Antagonistic effect in vivo of zinc on inhibition of δaminolevulinic acid dehydratase by lead. Arch Environ Health 31:215-220. 

Haenninen H, Hernberg S, Mantere P, et al. 1978. Psychological performance of subjects with low 

exposure to lead. J Occup Med 20:683-689. 

Häenninen H, Mantere P, Hernberg S, et al. 1979. Subjective symptoms in low-level exposure to lead. 

Neurotoxicology 1:333-347. 

Haley VB, Talbot TO. 2004. Seasonality and trend in blood lead levels of New York State children. 

BMC Pediatr 4:8. 

Hamilton DL. 1978. Interrelationships of lead and iron retention in iron- deficient mice. Toxicol Appl 

Pharmacol 46:651-661. 
LEAD 461 

9. REFERENCES 

Hamilton JD, O'Flaherty EJ. 1994. Effects of lead exposure on skeletal development in rats. Fundam 

Appl Toxicol 22(4):594-604. 

Hamilton JD, O'Flaherty EJ. 1995. Influence of lead on mineralization during bone growth. Fundam 

Appl Toxicol 26(2):265-271. 

Hammad TA, Sexton M, Langenberg P. 1996. Relationship between blood lead and dietary iron intake 

in preschool children. A cross-section study. Ann Epidemiol 6(1):30-33. 

Hammond PB, Bornschein RL, Succop P. 1985. Dose-effect and dose-response relationships of blood 

lead to erythrocytic protoporphyrin in young children. Environ Res 38:187-196. 

Hänninen H, Aitio A, Kovala T, et al. 1998. Occupational exposure to lead and neuropsychological 

dysfunction. Occup Environ Med 55:202-209. 

Hansen ON, Trillingsgaard A, Beese I, et al. 1989. A neuropsychological study of children with elevated 

dentine lead level: Assessment of the effect of lead in different socioeconomic groups. Neurotoxicol 

Teratol 11:205-213. 

Harlan WR. 1988. The relationship of blood lead levels to blood pressure in the US population. Environ 

Health Perspect 78:9-13. 

Harlan WR, Landis JR, Schmouder RL, et al. 1985. Blood lead and blood pressure: Relationship in the 

adolescent and adult U.S. population. JAMA 253:530-534. 

Hart C. 1987. Art hazards: An overview for sanitarians and hygienists. J Environ Health 49:282-286. 

*Harvey PG, Hamlin MW, Kumar R, et al. 1984. Blood lead, behavior and intelligence test performance 

in preschool children. Sci Total Environ 40:45-60. 

Harvey PG, Hamlin MW, Kumar R, et al. 1988. Relationships between blood lead, behavior, 

psychometric and neuropsychological test performance in young children. Br J Dev Psychol 6:145-156. 

Harville EW, Hertz-Picciotto I, Schramm M, et al. 2005. Factors influencing the difference between 

maternal and cord blood lead. Occup Environ Med 62:263-269. 

Hashmi NS, Kachru DN, Khandelwal S, et al. 1989. Interrelationship between iron deficiency and lead 

intoxication: Part 2. Biol Trace Elem Res 22:299-307. 

*Hawk BA, Schroeder SR, Robinson G, et al. 1986. Relation of lead and social factors to IQ of low-SES 

children: A partial replication. Am J Ment Defic 91:178-183. 

HazDat. 2006. HazDat database: ATSDR’s Hazardous Substance Release and Health Effects Database. 

Atlanta, GA: Agency for Toxic Substances and Disease Registry. www.atsdr.cdc.gov/hazdat.html. 

October 14, 2006. 

He L, Poblenz AT, Medrano CJ, et al. 2000. Lead and calcium produce rod photoreceptor cell apoptosis 

by opening the mitochondrial permeability transition pore. J Biol Chem 275:12175-12184. 
LEAD 462 

9. REFERENCES 

Healy MA, Harrison PG, Aslam M, et al. 1982. Lead sulfide and traditional preparations: Routes for 

ingestion, and solubility and reactions in gastric fluid. J Clin Hosp Pharmacol 7:169-173. 

Heard MJ, Chamberlain AC. 1982. Effect of minerals and food on uptake of lead from the 

gastrointestinal tract in humans. Hum Toxicol 1:411-416. 

Heard MJ, Chamberlain AC. 1983. Uptake of lead by humans and effects of minerals and food. Sci 

Total Environ 30:245-253. 

Heard MJ, Wells AC, Newton D, et al. 1979. Human uptake and metabolism of tetra ethyl and 

tetramethyl lead vapour labelled with 203Pb. In: International Conference on Management and Control of 

Heavy Metals in the Environment, London, England, September. Edinburgh, United Kingdom: CEP 

Consultants, Ltd., 103-108. 

Hense HW, Filipiak B, Keil U. 1993. The association of blood lead and blood pressure in population 

surveys. Epidemiology 4:173-179. 

Heo Y, Lee BK, Ahn KD, et al. 2004. Serum IgE elevation correlates with blood lead levels in battery 

manufacturing workers. Hum Exp Toxicol 23:209-213. 

Heo Y, Lee WT, Lawrence DA. 1998. Differential effects of lead and cAMP on development and 

activities of TH1- and Th2-lymphocytes. Toxicol Sci 43:172-185. 

Herber RFM. 1980. Estimation of blood lead values from blood porphyrin and urinary deltaaminolevulinic acid levels in workers. Int Arch Occup Environ Health 45:169-179. 

Hermes-Lima M, Pereira B, Bechara EJH. 1991. Are free radicals involved in lead poisoning? 

Xenobiotica 21:1085-1090. 

Hernandez-Avila M, Gonzalez-Cossio T, Hernandez-Avila JE, et al. 2003. Dietary calcium supplements 

to lower blood lead levels in lactating women: A randomized placebo-controlled trial. Epidemiology 

14(2):206-212. 

Hernandez-Avila M, Gonzalez-Cossio T, Palazuelos E, et al. 1996. Dietary and environmental 

determinants of blood and bone lead levels in lactating postpartum women living in Mexico City. 

Environ Health Perspect 104:1076-1082. 

Hernández-Avila M, Peterson KE, Gonzalez-Cossio T, et al. 2002. Effect of maternal bone lead on 

length and head circumference of newborns and 1-month-old infants. Arch Environ Health 57(5):482­

488. 

Hernandez-Avila M, Smith D, Meneses F, et al. 1998. The influence of bone and blood lead on plasma 

lead levels in environmentally exposed adults. Environ Health Perspect 106(8):473-477. 

Hernandez-Avila M, Villalpano CG, Palazuelos E, et al. 2000. Determinants of blood lead levels across 

the menopausal transition. Arch Environ Health 53:355-360. 

Hernandez-Ochoa I, Carcia-Vargas G, Lopez-Carrillo L, et al. 2005. Low lead environmental exposure 

alters semen quality and sperm chromatin condensation in northern Mexico. Reprod Toxicol 20(2):221­

228. 
LEAD 463 

9. REFERENCES 

Hernberg S, Nikkanen J. 1970. Enzyme inhibition by lead under normal urban conditions. Lancet 1:63­

64. 

Hernberg S, Nikkanen J, Mellin G, et al. 1970. δ-Aminolevulinic acid dehydrase as a measure of lead 

exposure. Arch Environ Health 21:140-145. 

Hertz-Picciotto I, Croft J. 1993. Review of the relation between blood lead and blood pressure. 

Epidemiol Rev 15:352-373. 

Hewitt PJ. 1988. Accumulation of metals in the tissues of occupationally exposed workers. Environ 

Geochem Health 10:113-116. 

Hewitt CN, Harrison RM. 1986. Formation and decomposition of trialkyllead compounds in the 

atmosphere. Environ Sci Technol 20(8):797-802. 

Hewitt CN, Harrison RM. 1987. Atmospheric concentrations and chemistry of alkyl lead compounds 

and environmental alkylation of lead. Environ Sci Technol 21:260-266. 

Higgs FJ, Mielke HW, Brisco M. 1999. Soil lead at elementary public schools: Comparison between 

school properties and residential neighbourhoods of New Orleans. Environ Geochem Health 21:27-36. 

Hirata M, Kosaka H. 1993. Effects of lead exposure on neurophysiological parameters. Environ Res 

63:60-69. 

Hodgkins DG, Robins TG, Hinkamp DL, et al. 1992. A longitudinal study of the relation of lead in 

blood to lead in air concentrations among battery workers. Br J Ind Med 49:241-248. 

Hoffman DJ, Niyogi SK. 1977. Metal mutagens and carcinogens affect RNA synthesis rates in a distinct 

manner. Science 198:513-514. 

Hogan K, Marcus A, Smith R, et al. 1998. Integrated exposure uptake biokinetic model for lead in 

children: Empirical comparisons with epidemiological data. Environ Health Perspect 106:1557-1567. 

Hogstedt C, Hane M, Agrell A, et al. 1983. Neuropsychological test results and symptoms among 

workers with well-defined long-term exposure to lead. Br J Ind Med 40:99-105. 

Holmgren GGS, Meyer MW, Chaney RL, et al. 1993. Cadmium, lead, cooper, and nickel in agricultural 

soils of the United States of America. J Environ Qual 22:335-348. 

Holness DL, Nethercott JR. 1988. Acute lead intoxication in a group of demolition workers. Appl Ind 

Hyg 3:338-341. 

Homan CS, Brogan GX, Orava RS. 1998. Lead toxicity. In: Viccellio P, ed. Emergency toxicology. 

Philadelphia, PA: Lippincott-Raven Publishers, 363-378. 

Hong CD, Hanenson IB, Lerner S, et al. 1980. Occupational exposure to lead: Effects on renal function. 

Kidney Int 18:489-494. 

Hoppin JA, Aro A, Hu H, et al. 1997. In vivo bone lead measurement in suburban teenagers. Pediatrics 

100(3 Pt 1):365-370. 
LEAD 464 

9. REFERENCES 

Horn J. 1970. [Isolation and examination of inclusion bodies of the rat kidney after chronic lead 

poisoning.] Virchows Arch B Cell Pathol 6:313-317. (German) 

Hotter G, Fels LM, Closa D, et al. 1995. Altered levels of urinary prostanoids in lead-exposed worker. 

Toxicol Lett 77:309-312. 

Howe HE. 1981. Lead. In: Kirk-Othmer encyclopedia of chemical technology. 3rd ed., Vol. 14. New 

York, NY: John Wiley and Sons, 98-139. 

Hryhirczuk DO, Rabinowitz RB, Hessl SM, et al. 1985. Elimination kinetics of blood lead in workers 

with chronic lead intoxication. Am J Ind Med 8:33-42. 

HSDB. 2007. Lead. Hazardous Substances Data Bank. National Library of Medicine. 

http://toxnet.nlm.nih.gov. June 13, 2007. 

Hsiao C-Y, Wu H-DI, Lai J-S, et al. 2001. A longitudinal study of the effects of long-term exposure to 

lead among lead battery factory workers in Taiwan (1989-1999). Sci Total Environ 279:151-158. 

Hsieh LL, Liou SH, Chen YH, et al. 2000. Association between aminolevulinate dehydrogenase 

genotype and blood lead levels in Taiwan. J Occup Environ Med 42(2):151-155. 

Hsu FS, Krook L, Pond WG, et al. 1975. Interactions of dietary calcium with toxic levels of lead and 

zinc in pigs. J Nutr 105:112-118. 

Hsu PC, Hsu CC, Liu MY, et al. 1998a. Lead-induced changes in spermatozoa function and metabolism. 

J Toxicol Environ Health A 55:45-64. 

Hsu PC, Liu MY, Hsu CC, et al. 1998b. Effects of vitamin E and/or C on reactive oxygen speciesrelated lead toxicity in the rat sperm. Toxicology 128:169-179. 

Hu H. 1991a. A 50-year follow-up of childhood plumbism. Hypertension, renal function, and 

hemoglobin levels among survivors. Am J Dis Child 145:681-687. 

Hu H. 1991b. Knowledge of diagnosis and reproductive history among survivors of childhood 

plumbism. Am J Public Health 81:1070-1072. 

Hu H, Aro A, Payton M, et al. 1996a. The relationship of bone and blood lead to hypertension. The 

normative study. JAMA 275:1171-1176. 

Hu H, Aro A, Rotnitzky A. 1995. Bone lead measured by x-ray fluorescence: Epidemiologic methods. 

Environ Health Perspect 103(Suppl 1):105-110. 

Hu H, Hashimoto D, Besser M. 1996b. Levels of lead in blood and bone of women giving birth in a 

Boston hospital. Arch Environ Health 51(1):52-58. 

Hu H, Milder FL, Burger DE. 1989. X-ray fluorescence: Issues surrounding the application of a new 

tool for measuring burden of lead. Environ Res 49:295-317. 

Hu H, Milder FL, Burger DE. 1990. X-ray fluorescence measurements of lead burden in subjects with 

low-level community lead exposure. Arch Environ Health 45(6):335-341. 
LEAD 465 

9. REFERENCES 

Hu H, Pepper L, Goldman R. 1991. Effect of repeated occupational exposure to lead, cessation of 

exposure, and chelation on levels of lead in bone. Am J Ind Med 20:723-735. 

Hu H, Rabinowitz M, Smith D. 1998. Bone lead as a biological marker in epidemiologic studies of 

chronic toxicity: Conceptual paradigms. Environ Health Perspect 106(1):1-8. 

Hu H, Tellez-Rojo MM, Bellinger D, et al. 2006. Fetal lead exposure at each stage of pregnancy as a 

predictor of infant mental health. Environ Health Perspect 114(11):1730-1735. 

Hu H, Watanabe H, Payton M, et al. 1994. The relationship between bone lead and hemoglobin. JAMA 

272(19):1512-1517. 

Hu H, Wu M-T, Cheng Y, et al. 2001. The δ-aminolevulinic acid dehydratase (ALAD) polymorphism 

and bone and blood lead levels in community-exposed men: The normative aging study. Environ Health 

Perspect 109(8):827-832. 

*Huang JX, He FS, Wu YG, et al. 1988a. Observations on renal function in workers exposed to lead. 

Sci Total Environ 71:535-537. 

Huang XP, Feng ZY, Zhai WL, et al. 1988b. Chromosomal aberrations and sister chromatid exchanges 

in workers exposed to lead. Biomed Environ Sci 1:382-387. 

Hubermont G, Buchet J, Roels H, et al. 1976. Effect of short-term administration of lead to pregnant 

rats. Toxicology 5:379-384. 

HUD. 1997. Guidelines for the evaluation and control of lead-based paint hazards in housing. Chapter 

7: Lead-based paint inspection. 1997 Revision. U.S. Department of Housing and Urban Development. 

HUD. 1998. Lead-based paint poisoning prevention in certain residential structures. U.S. Department of 

Housing and Urban Development. Code of Federal Regulations. 24 CFR 35. 

Hursh JB, Mercer TT. 1970. Measurement of 212Pb loss rate from human lungs. J Appl Physiol 28:268­

274. 

Hursh JB, Suomela J. 1968. Absorption of 212Pb from the gastrointestinal tract of man. Acta Radiol 

7(2):108-120. 

Hursh JB, Clarkson TW, Miles EF, et al. 1989. Percutaneous absorption of mercury vapor by man. Arch 

Environ Health 44(2):120-127. 

Hursh JB, Schraub A, Sattler EL, et al. 1969. Fate of 212Pb inhaled by human subjects. Health Phys 

16:257-267. 

*Huseman CA, Moriarty CM, Angle CR. 1987. Childhood lead toxicity and impaired release of 

thyrotropin-stimulating hormone. Environ Res 42:524-533. 

Huseman CA, Varma MM, Angle CR. 1992. Neuroendocrine effects of toxic and low blood lead levels 

in children. Pediatrics 90:186-189. 
LEAD 466 

9. REFERENCES 

Hwang K-Y, Schwartz BS, Byung-Kook L, et al. 2001. Associations of lead exposure and dose 

measures with erythrocyte protein kinase C activity in 212 current Korean lead workers. Toxicol Sci 

62:280-288. 

Iannaccone A, Boscolo P, Carmignani M. 1981. Neurogenic and humoral mechanisms in arterial 

hypertension of chronically lead-exposed rats. Medicina del Lavoro 72:13-21. 

IARC. 1980. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Vol. 

23: Some metals and metallic compounds. Lyons France: World Health Organization, International 

Agency for Research on Cancer, 325-415. 

IARC. 2004. Overall evaluations of carcinogenicity to humans: As evaluated in IARC Monographs 

volumes 1-82 (at total of 900 agents, mixtures and exposures). Lyon, France: International Agency for 

Research on Cancer. http://www-cie.iarc.fr/monoeval/crthall.html. February 15, 2005. 

Iavicoli I, Carelli G, Stanek EJ, et al. 2004. Effects of low doses of dietary lead on puberty onset in 

female mice. Reprod Toxicol 19(1):35-41. 

Inskip MJ, Franklin CA, Baccanale CL, et al. 1996. Measurement of the flux of lead from bone to blood 

in a nonhuman primate (Macaca fascicularis) by sequential administration of stable lead isotopes. 

Fundam Appl Toxicol 33:235-245. 

IPCS. 1995. Inorganic lead. International Programme on Chemical Safety. Environmental Health 

Criteria 165 ed. Geneva, Switzerland: WHO (World Health Organization). 

IRIS. 2005. Lead. U.S. Environmental Protection Agency. Washington, DC: Integrated Risk 

Information System. http://www.epa.gov/iris/. March 26, 2005. 

Ishida M, Ishizaki M, Yamada Y. 1996. Decreases in postural change in finger blood flow in ceramic 

painters chronically exposed to low level lead. Am J Ind Med 29(5):547-553. 

Ito Y, Niiya Y, Otani M, et al. 1987. Effect of food intake on blood lead concentration in workers 

occupationally exposed to lead. Toxicol Lett 37:105-114. 

Iwata T, Yano E, Karita K, et al. 2005. Critical dose of lead affecting postural balance in workers. Am J 

Epidemiol 48(5):319-325. 

Jackson LW, Correa-Villasenor A, Lees PS, et al. 2004. Parental lead exposure and total anomalous 

pulmonary venous returrn. Birth Defects Res A Clin Mol Teratol 70(4):185-193. 

Jacquet P, Tachon P. 1981. Effects of long-term lead exposure on monkey leukocyte chromosomes. 

Toxicol Lett 8:165-169. 

Jacquet P, Leonard A, Gerber GB. 1977. Cytogenetic investigations on mice treated with lead. J Toxicol 

Environ Health 2:619-624. 

Jagetia GC, Aruna R. 1998. Effect of various concentrations of lead nitrate on the induction of 

micronuclei in mouse bone marrow. Mutat Res 415:131-137. 

James AC, Stahlhofen W, Rudolf G, et al. 1994. Deposition of inhaled particles. Ann ICRP 24(1­

3):231-299. 
LEAD 467 

9. REFERENCES 

James HM, Hilburn ME, Blair JA. 1985. Effects of meals and meal times on uptake of lead from the 

gastrointestinal tract of humans. Hum Toxicol 4:401-407. 

Janakiraman V, Ettinger A, Mercado-Garcia A, et al. 2003. Calcium supplements and bone resorption in 

pregnancy: A randomized crossover trial. Am J Prev Med 24(3):260-264. 

Janin Y, Couinaud C, Stone A, et al. 1985. The “lead-induced colic” syndrome in lead intoxication. 

Surg Ann 17:287-307. 

Jason KM, Kellogg CK. 1981. Neonatal lead exposure: Effects on development of behavior and striatal 

dopamine neurons. Pharmacol Biochem Behav 15:641-649. 

Jelliffe-Pawlowski LL, Miles SQ, Courtney JG, et al. 2006. Effect of magnitude and timing of maternal 

pregnancy blood lead (Pb) levels on birth outcomes. J Perinatol 26(3):154-162. 

Jemal A, Graubard BI, Devesa SS, et al. 2002. The association of blood lead level and cancer mortality 

among whites in the United States. Environ Health Perspect 110(4):325-329. 

Jin Y, Liao Y, Lu C, et al. 2006. Health effects in children aged 3-6 years induced by environmental lead 

exposure. Ecotoxicol Environ Saf 63(2):313-317. 

Joffe M, Bisanti L, Apostoli P, et al. 2003. Time to pregnancy and occupational lead exposure. Occup 

Environ Med 60:752-758. 

Johanson CE. 1980. Permeability and vascularity of the developing brain: Cerebellum vs cerebral 

cortex. Brain Res 190:3-16. 

Johnson BL, Mason RW. 1984. A review of public health regulations on lead. Neurotoxicity 5:1-22. 

Johnson DL, Bretsch JK. 2002. Soil lead and children's blood lead levels in Syracuse, NY, USA. 

Environ Geochem Health 24:375-385. 

Johnson NE, Tenuta K. 1979. Diets and lead blood levels of children who practice pica. Environ Res 

18:369-376. 

*Joselow MM, Flores J. 1977. Application of the zinc protoporphyrin (ZP) test as a monitor of 

occupational exposure to lead. Am Ind Hyg Assoc J 38:63-66. 

Joseph CLM, Havstad S, Ownby DR, et al. 2005. Blood lead levels and risk of asthma. Environ Health 

Perspect 113(7):900-904. 

Kamel F, Umbach DM, Munsat TL, et al. 2002. Lead exposure and amyotrophic lateral sclerosis. 

Epidemiology 13:311-319. 

Kapoor SC, Van Rossum GDV, O’Neill KJ et al. 1985. Uptake of inorganic lead in vitro by isolated 

mitochondria and tissue slices of rat renal cortex. Biochem Pharmacol 34:1439-1448. 

Karmaus W, Brooks KR, Nebe T, et al. 2005. Immune function biomarkers in children exposed to lead 

and organochlorine compounds: A cross-sectional study. Environ Health 4:5. 

http://www.ehjournal.net/content/4/1/5. February 1, 2007. 
LEAD 468 

9. REFERENCES 

Kaufmann RB, Staes CJ, Matte TD. 2003. Deaths related to lead poisoning in the United States, 1979– 

1998. Environ Res 91:78-84. 

Kaye WE, Novotny TE, Tucker M. 1987. New ceramics-related industry implicated in elevated blood 

lead levels in children. Arch Environ Health 42:161-164. 

Kehoe RA. 1961. The metabolism of lead in man in health and disease: Present hygienic problems 

relating to the absorption of lead: The Harben lectures, 1960. J R Inst Public Health Hyg 24:177-203. 

Kehoe RA. 1987. Studies of lead administration and elimination in adult volunteers under natural and 

experimentally induced conditions over extended periods of time. Food Chem Toxicol 25:425-493. 

Kehoe RA, Thamann F. 1931. The behavior of lead in the animal organism: II. Tetraethyl lead. Am J 

Hyg 13:478-498. 

Kerper LE, Hinkle PM. 1997b. Cellular uptake of lead is activated by depletion of intracellular calcium 

stores. J Biol Chem 272(13):8346-8352. 

Kerper LE, Hinkle PM. 1997a. Lead uptake in brain capillary endothelial cells: Activation by calcium 

store depletion. Toxicol Appl Pharmacol 146:127-133. 

Khalil-Manesh F, Gonick HC, Cohen AH, et al. 1992a. Experimental model of lead nephropathy. I. 

Continuous high-dose lead administration. Kidney Int 41:1192-1203. 

Khalil-Manesh F, Gonick HC, Cohen A, et al. 1992b. Experimental model of lead nephropathy. II. 

Effect of removal from lead exposure and chelation treatment with dimercaptosuccinic acid (DMSA). 

Environ Res 58:35-54. 

Khalil-Manesh F, Gonick HC, Weiler EWJ. 1993. Lead-induced hypertension: Possible role of 

endothelial factors. Am J Hypertens 6:723-729. 

Khan DH, Frankland B. 1983. Chemical forms of cadmium and lead in some contaminated soils. 

Environ Pollut Ser B 6:15-31. 

Kharab P, Singh I. 1985. Genotoxic effects of potassium dichromate, sodium arsenite, cobalt chloride 

and lead nitrate in diploid yeast. Mutat Res 155:117-120. 

*Khera AK, Wibberley DG, Dathan JG. 1980a. Placental and stillbirth tissue lead concentration in 

occupationally exposed women. Br J Ind Med 37:394-396. 

*Khera AK, Wibberley DG, Edwards KW, et al. 1980b. Cadmium and lead levels in blood and urine in 

a series of cardiovascular and normotensive patients. Int J Environ Stud 14:309-312. 

Khoury GA, Diamond GL. 2003. Risks to children from exposure to lead in air during remedial or 

removal activities at superfund sites: A case study of the RSR lead smelter superfund site. Toxicol Sci 

72:394. 

Kim JS, Hamilton DL, Blakley BR, et al. 1992. The effects of thiamin on lead metabolism: Organ 

distribution of lead 203. Can J Vet Res 56:256-259. 
LEAD 469 

9. REFERENCES 

Kim R, Hu H, Rotnitzky A, et al. 1995. A longitudinal study of chronic lead exposure and physical 

growth in Boston children. Environ Health Perspect 103:952-957. 

Kim R, Hu H, Rotnitzky A, et al. 1996b. Longitudinal relationship between dentin lead levels in 

childhood and bone lead levels in young adulthood. Arch Environ Health 51(5):375-382. 

Kim R, Landrigan C, Mossmann P, et al. 1997. Age and secular trends in bone lead levels in middleaged and elderly men: Three-year longitudinal follow-up in the normative aging study. Am J Epidemiol 

146(4):586-591. 

Kim R, Rotnitzky A, Sparrow D, et al. 1996a. A longitudinal study of low-level lead exposure and 

impairment of renal function. The normative aging study. JAMA 275:1177-1181. 

Kimber I, Stonard MD, Gidlow DA, et al. 1986. Influence of chronic low- level exposure to lead on 

plasma immunoglobin concentration and cellular immune function in man. Int Arch Occup Environ 

Health 57:117-125. 

Kimmel EC, Fish RH, Casida JE. 1977. Bioorganotin chemistry: Metabolism of organotin compounds 

in microsomal monoxygenase systems and in mammals. J Agric Food Chem 25:1-9. 

King M, Ramachandran V. 1995. Lead. In: Kirk-Othmer encyclopedia of chemical technology. 4th 

edition. New York, NY: John Wiley & Sons, 69-113. 

Kirkby H, Gyntelberg F. 1985. Blood pressure and other cardiovascular risk factors of long-term 

exposure to lead. Scand J Work Environ Health 11:15-19. 

Klaassen CD, Shoeman DW. 1974. Biliary excretion of lead in rats, rabbits, and dogs. Toxicol Appl 

Pharmacol 1(9):434-446. 

Klauder DS, Petering HB. 1975. Protective value of dietary copper and iron against some toxic effects of 

lead in rats. Environ Health Perspect 12:77-80. 

Kohler K, Lilienthal H, Guenther E, et al. 1997. Persistent decrease of the dopamine synthesizing 

enzyme tyrosine hydroxylase in the Rhesus monkey retina after chronic lead exposure. Neurotoxicology 

18(3):623-632. 

Koller LD. 1985. Immunological effects of lead. In: Mahaffey KR, ed. Dietary and environmental 

lead: Human health effects. Amsterdam, The Netherlands: Elsevier Publishers B.V., 339-353. 

Koller K, Brown T, Spurgeon A, et al. 2004. Recent developments in low-level lead exposure and 

intellectual impairment in children. Environ Health Perspect 112(9):987-994. 

Koller LD, Kerkvliet NI, Exon JH. 1985. Neoplasia induced in male rats fed lead acetate, ethylurea and 

sodium nitrite. Toxicologic Pathol 13:50-57 

Komori M, Nishio K, Kitada M, et al. 1990. Fetus-specific expression of a form of cytochrome P-450 in 

human livers. Biochemistry 29:4430-4433. 

Koo WWR, Succop PA, Bornschcin RL, et al. 1991. Serum vitamin D metabolites and bone 

mineralization in young children with chronic low to moderate lead exposure. Pediatrics 87:680-687. 
LEAD 470 

9. REFERENCES 

Kordas K, Canfield RL, Lopez P, et al. 2006. Deficits in cognitive function and achievement in Mexican 

first-graders with low blood lead concentrations. Environ Res 100(3):371-386. 

Kordas K, Stoltzfus RJ, Lopez P, et al. 2005. Iron and zinc supplementation does not improve parent or 

teacher ratings of behavior in first grade Mexican children exposed to lead. J Pediatr 147(5):632-639. 

Koren G, Chang N, Gonen R, et al. 1990. Lead-exposure among mothers and their newborns in Toronto. 

Can Med Assoc J 142:1241-1244. 

Korrick SA, Hunter DJ, Rotnitzky A, et al. 1999. Lead and hypertension in a sample of middle-aged 

women. Am J Public Health 89(3):330-335. 

Korrick SA, Schwartz J, Tsaih SW, et al. 2002. Correlates of bone and blood lead levels among middleaged and elderly women. Am J Epidemiol 156(4):335-343. 

Kosmider S, Petelenz T. 1962. [Electrocardiographic changes in elderly patients with chronic 

professional lead poisoning.] Pol Arch Med Wewn 32:437-442. (Polish) 

Kosnett MJ. 2004. Lead. In: Olson KR, Anderson IB, Benowitz NL, et al, eds. Poisoning & drug 

overdose. 4th ed. New York, NY: McGraw-Hill Companies, Inc., 238-242. 

Kosnett MJ, Becker CE, Osterloh JD, et al. 1994. Factors influencing bone lead concentration in a 

suburban community assessed by noninvasive K x-ray fluorescence. JAMA 271:197-203. 

Kostial K, Kello D, Jugo S, et al. 1978. Influence of age on metal metabolism and toxicity. Environ 

Health Perspect 25:81-86. 

*Kotok D. 1972. Development of children with elevated blood levels: A controlled study. J Pediatr 

80:57-61. 

*Kotok D, Kotok R, Heriot T. 1977. Cognitive evaluation of children with elevated blood lead levels. 

Am J Dis Child 131:791-793. 

Kramer HJ, Gonick HC, Lu E. 1986. In vitro inhibition of Na-K-ATPase by trace metals: Relation to 

renal and cardiovascular damage. Nephron 44:329-336. 

Krieg EF, Chrislip DW, Crespo CJ, et al. 2005. The relationship between blood lead levels and 

neurobehavioral test performance in NHANES III and related occupational studies. Public Health Rep 

120(3):240-251. 

Krishnan K, Andersen ME. 1994. Physiologically based pharmacokinetic modeling in toxicology. In: 

Hayes AW, ed. Principles and methods of toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 149­

188. 

Krishnan K, Andersen ME, Clewell HJ III, et al. 1994. Physiologically based pharmacokinetic modeling 

of chemical mixtures. In: Yang RSH, ed. Toxicology of chemical mixtures: Case studies, mechanisms, 

and novel approaches. San Diego, CA: Academic Press, 399-437. 

Kristal-Boneh E, Coller D, Froom P, et al. 1999. The association between occupational lead exposure 

and serum cholesterol and lipoprotein levels. Am J Public Health 89(7):1083-1087. 
LEAD 471 

9. REFERENCES 

Kromhout D. 1988. Blood lead and coronary heart disease risk among elderly men in Zutphen, The 

Netherlands. Environ Health Perspect 78:43-46. 

Kromhout D, Wibowo AAE, Herber RFM, et al. 1985. Trace metals and coronary heart disease risk 

indicators in 152 elderly men (the Zutphen study). Am J Epidemiol 122:378-385. 

Krueger JA, Duguay KM. 1989. Comparative analysis of lead in Maine urban soils. Bull Environ 

Contam Toxicol 42:574-581. 

*Kuhnert PM, Erhard P, Kuhnert BR. 1977. Lead and δ-aminolevulinic acid dehydratase in RBC's of 

urban mothers and fetuses. Environ Res 14:73-80. 

Kumar BD, Krishnaswamy K. 1995. Detection of occupational lead nephropathy using early renal 

markers. Clin Toxicol 33(4):331-335. 

Kumar S, Jain S, Aggarwal CS, et al. 1987. Encephalopathy due to inorganic lead exposure in an adult. 

Jpn J Med 26:253-254. 

Kutbi II, Ahmed M, Saber A, et al. 1989. Measurement of blood-lead levels in school children of Jeddah 

Saudi Arabia and assessment of sub-toxic levels of lead on some sensitive hematological parameters. J 

Environ Sci Health A24:943-955. 

Kwong WT, Friello P, Semba RD. 2004. Interactions between iron deficiency and lead poisoning: 

Epidemiology and pathogenesis. Sci Total Environ 330:21-37. 

Lacey RF, Moore MR, Richards WN. 1985. Lead in water, infant diet and blood: The Glasgow 

duplicate diet stud. Sci Total Environ 41:235-257. 

Lagerkvist BJ, Ekesrydh S, Englyst V, et al. 1996. Increased blood lead and decreased calcium levels 

during pregnancy: A prospective study of Swedish women living near a smelter. Am J Public Health 

86:1247-1252. 

LaGoy P. 1987. Estimated soil ingestion rates for use in risk assessment. Risk Anal 7:355-359. 

Lai JS, Wu TN, Liou SH, et al. 1997. A study of the relationship between ambient lead and blood lead 

among lead battery workers. Int Arch Occup Environ Health 69(4):295-300. 

Lancranjan I, Popescu HI, Gavanescu O, et al. 1975. Reproductive ability of workmen occupationally 

exposed to lead. Arch Environ Health 30:396-401. 

Landis JR, Flegal KM. 1988. A generalized Mantel-Haenszel analysis of the regression of blood 

pressure on blood lead using NHANES II data. Environ Health Perspect 78:35-41. 

Landrigan PJ. 1989. Toxicity of lead at low dose. Br J Ind Med 46:593-596. 

Landrigan PJ, Baker EL. 1981. Exposure of children to heavy metals from smelters: Epidemiology and 

toxic consequences. Environ Res 25:204-224. 

Landrigan PJ, Todd AC. 1994. Lead poisoning [see comments]. West J Med 161(2):153-159. 
LEAD 472 

9. REFERENCES 

Landrigan PJ, Baker EL, Feldman RG, et al. 1976. Increased lead absorption with anemia and slowed 

nerve conduction in children near a lead smelter. J Pediatr 89:904-910. 

Landrigan PJ, Boffetta P, Apostoli P. 2000. The reproductive toxicity and carcinogenicity of lead: A 

critical review. Am J Ind Med 38:231-243. 

Landrigan PJ, Schechter CB, Lipton JM, et al. 2002. Environmental pollutants and disease in American 

children: Estimates of morbidity, mortality, and costs for lead poisoning, asthma, cancer, and 

developmental disabilities. Environ Health Perspect 110:721-728. 

Langlois P, Smith L, Fleming S, et al. 1996. Blood lead levels in Toronto children and abatement of 

lead-contaminated soil and house dust. Arch Environ Health 51(1):59-67. 

Lannefors H, Hansson HC, Granat L. 1983. Background aerosol composition in southern Sweden -- 

Fourteen micro and macro constituents measured in seven particle size intervals at one site during one 

year. Atmos Environ 17:87-101. 

Lanphear BP, Roghmann KJ. 1997. Pathways of lead exposure in urban children. Environ Res 74(1):67­

73. 

Lanphear BP, Burgoon DA, Rust SW, et al. 1998a. Environmental exposures to lead and urban 

children's blood lead levels. Environ Res 76(2):120-130. 

Lanphear BP, Byrd RS, Auinger P, et al. 1998b. Community characteristics associated with elevated 

blood lead levels in children. Pediatrics 101(2):264-271. 

Lanphear BP, Dietrich K, Auinger P, et al. 2000a. Cognitive deficits associated with blood lead 

concentrations <10 μg/dL in US children and adolescents. Public Health Rep 115(6):521-529. 

Lanphear BP, Eberly S, Howard CR. 2000b. Long-term effect of dust control on blood lead 

concentrations. Pediatrics 106(4):1-4. 

Lanphear BP, Hornung R, Khoury J, et al. 2005. Low-level environmental lead exposure and children's 

intellectual function: An international pooled analysis. Environ Health Perspect 113(7):894-899. 

Lanphear BP, Weitzman M, Eberly S. 1996a. Racial differences in urban children's environmental 

exposures to lead. Am J Public Health 86(10):1460-1463. 

Lanphear BP, Weitzman M, Winter NL, et al. 1996b. Lead-contaminated house dust and urban 

children's blood lead levels. Am J Public Health 86(10):1416-1421. 

Lansdown R, Yule W, Urbanowicz MA, et al. 1986. The relationship between blood lead concentrations, 

intelligence, attainment and behavior in a school population: The second London study. Int Arch Occup 

Environ Health 57:225-235. 

*Laraque D, McCormick M, Norman M, et al. 1990. Blood lead, calcium status, and behavior in 

preschool children. Am J Dis Child 144:186-189. 

Larrabee D. 1997. U.S. industry & trade outlook. New York, NY: McGraw Hill Inc., 14-10 to 14-13. 
LEAD 473 

9. REFERENCES 

Larrabee D. 1998. Comments on chapter 4 of the draft toxicological profile for lead/metals division. 

U.S. Department of Commerce, February 11, 1998. 

Larson JK, Buchan RM, Blehm KD, et al. 1989. Characterization of lead fume exposure during gas 

metal arc welding on carbon steel. Appl Ind Hyg 4:330-333. 

Larsson B, Slorach SA, Hagman U, et al. 1981. WHO collaborative breast feeding study. Acta Paediatr 

Scand 70:281-284. 

Lasky RE, Luck ML, Torre P, et al. 2001. The effects of early lead exposure on auditory function in 

rhesus monkeys. Neurotoxicol Teratol 23:639-649. 

Lasky RE, Maier MM, Snodgrass EB, et al. 1995. The effects of lead on otoacoustic emissions and 

auditory evoked potentials in monkeys. Neurotoxicol Teratol 17:633-644. 

Lasley SM, Gilbert ME. 2000. Glutamatergic components underlying lead-induced impairments in 

hippocampal synaptic plasticity. Neurotoxicology 21(6):1057-1068. 

Laug EP, Kunze FM. 1948. The penetration of lead through the skin. J Ind Hyg Toxicol 30:256-259. 

*Lauwers MC, Hauspie RC, Susanne C, et al. 1986. Comparison of biometric data of children with high 

and low levels of lead in the blood. Am J Phys Anthropol 69:107-116. 

Lauwerys R, Buchet J-P, Roels HA, et al. 1974. Relationship between urinary delta-aminolevulinic acid 

excretion and the inhibition of red cell delta-aminolevulinate dehydratase by lead. Clin Toxicol 7:383­

388. 

Lauwerys R, Buchet J-P, Roels HA, et al. 1978. Placental transfer of lead, mercury, cadmium, and 

carbon monoxide in women: I. Comparison of the frequency distributions of the biological indices in 

maternal and umbilical cord blood. Environ Res 15:278-289. 

Lawton LJ, Donaldson WE. 1991. Lead-induced tissue fatty acid alterations and lipid peroxidation. Biol 

Trace Elem Res 28:83-97. 

Laxen DP, Raab GM, Fulton M. 1987. Children's blood lead and exposure to lead in household dust and 

water--a basis for an environmental standard for lead in dust. Sci Total Environ 66:235-244. 

Lee BK, Lee GS, Stewart WF, et al. 2001. Associations of blood pressure and hypertension with lead 

dose measures and polymorphisms in the vitamin D receptor and δ-aminolevulinic acid dehydratase 

genes. Environ Health Perspect 109(4):383-389. 

Lee RG, Becker WC, Collins DW. 1989. Lead at the tap: Sources and control. J Am Water Works 

Assoc 81:52-62. 

Leeder JS, Kearns GL. 1997. Pharmcogenetics in pediatrics: Implications for practice. Pediatr Clin 

North Am 44(1):55-77. 

Legare ME, Barhoumi R, Hebert E, et al. 1998. Analysis of Pb2

 entry into cultured astroglia. Toxicol 

Sci 46:90-100. 
LEAD 474 

9. REFERENCES 

Leggett RW. 1993. An age-specific kinetic model of lead metabolism in humans. Environ Health 

Perspect 101:598-616. 

Leikin JB, Paloucek FP. 2002. Poisoning and toxicology handbook. 3rd edition. Hudson, OH: LexiComp Inc., 725-731. 

Lenga RE. 1988. The Sigma-Aldrich library of chemical safety data. Edition II, Volume 1. Milwaukee, 

WI: Sigma-Aldrich Corporation, 2071. 

Le Quesne PM. 1987. Clinically used electrophysiological end-points. In: Lowndes HE, ed. 

Electrophysiology in neurotoxicology. Vol. 1. Piscataway, NJ: Department of Pharmacology and 

Toxicology, Rutgers, 103-116. 

Lerda D. 1992. Study of sperm characteristics in persons occupationally exposed to lead. Am J Ind Med 

22:567-571. 

Leung H. 1993. Physiologically-based pharmacokinetic modelling. In: Ballentyne B, Marrs T, Turner 

P, eds. General and applied toxicology. Vol. 1. New York, NY: Stockton Press, 153-164. 

Levey AS, Bosch JP, Lewis JB, et al. 1999. A more accurate method to estimate glomerular filtration 

rate from serum creatinine: A new prediction equation. Ann Intern Med 130(6):461-479. 

Levin ED, Bowman RE. 1986. Long-term lead effects on the Hamilton Search Task and delayed 

alternation in monkeys. Neurobehav Toxicol Teratol 8:219-224. 

Lewin MD, Sarasua S, Jones PA. 1999. A multivariate linear regression model for predicting children's 

blood lead levels based on soil lead levels: A study at four Superfund sites. Environ Res 81:52-61. 

Lewis RJ. 1993. Hawley's condensed chemical dictionary. New York, NY: Van Nostrand Reinhold 

Company, 686-693. 

Li S, Zhengyan Z, Rong L, et al. 2005. Decrease of CD4+

 T-lymphocytes in children exposed to 

environmental lead. Biol Trace Elem Res 105(1-3):19-25. 

Lide DR, ed. 1996. CRC handbook of chemistry and physics. Boca Raton, FL: CRC Press, Inc., 4-119. 

Lidsky TI, Schneider JS. 2003. Lead neurotoxicity in children: Basic mechanisms and clinical 

correlates. Brain 126:5-19. 

Liebelt EL, Schonfeld DJ, Gallagher P. 1999. Elevated blood lead levels in children are associated with 

lower erythropoietin concentrations. J Pediatr 134:107-109. 

Lilienthal H, Winneke G. 1996. Lead effects on the brain stem auditory evoked potentials in monkeys 

during and after the treatment phase. Neurotoxicol Teratol 18:17-32. 

Lilienthal H, Kohler K, Turfeld M, et al. 1994. Persistent increases in scotopic B-wave amplitudes after 

lead exposure in monkeys. Exp Eye Res 59:203-209. 

Lilienthal H, Lenaerts C, Winneke G, et al. 1988. Alternation of the visual evoked potential and the 

electroretinogram in lead-treated monkeys. Neurotoxicol Teratol 10:417-422. 
LEAD 475 

9. REFERENCES 

*Lilis R. 1981. Long-term occupational lead exposure, chronic nephropathy, and renal cancer: A case 

report. Am J Ind Med 2:293-297. 

Lilis R, Eisinger J, Blumberg W, et al. 1978. Hemoglobin, serum iron, and zinc protoporphyrin in leadexposed workers. Environ Health Perspect 25:97-102. 

Lilis R, Fischbein A, Valciukas JA, et al. 1980. Kidney function and lead: Relationships in several 

occupational groups with different levels of exposure. Am J Ind Med 1:405-412. 

Lilis R, Gavrilescu N, Nestorescu B, et al. 1968. Nephropathy in chronic lead poisoning. Br J Ind Med 

25:196-202. 

Lilley SG, Florence TM, Stauber JL. 1988. The use of sweat to monitor lead absorption through the 

skin. Sci Total Environ 76:267-278. 

Lin JL, Tan DT, Hsu KH, et al. 2001. Environmental lead exposure and progressive renal insufficiency. 

Arch Intern Med 161:264-271. 

Lin S, Hwang S, Marshall EG, et al. 1996. Fertility rates among lead workers and professional bus 

drivers: A comparative study. Ann Epidemiol 6:201-208. 

Lindgren KN, Ford DP, Bleecker ML. 2003. Pattern of blood levels over working lifetime and 

neuropsychological performance. Arch Environ Health 58(6):373-379. 

Lindgren KN, Masten VL, Ford DP, et al. 1996. Relation of cumulative exposure to inorganic lead and 

neuropsychological test performance. Occup Environ Med 53(7):472-477. 

Liu X, Dietrich KM, Radcliffe J, et al. 2002. Do children with falling blood lead levels have improved 

cognition? Pediatrics 110(4):787-791. 

Lloyd RD, Mays CW, Atherton DR, et al. 1975. 210Pb studies in beagles. Health Phys 28:575-583. 

Lockett CJ, Arbuckle D. 1987. Lead, ferritin, zinc, and hypertension. Bull Environ Contam Toxicol 

38:975-980. 

Loghman-Adham M. 1997. Renal effects of environmental and occupational lead exposure. Environ 

Health Perspect 105:928-939. 

Long DT, Angino EE. 1977. Chemical speciation of Cd, Cu, Pb, and Zn in mixed freshwater, seawater, 

and brine solutions. Geochim Cosmochim Acta 41:1183-1191. 

Long GJ, Rosen JF. 1994. Lead perturbs 1,25 dihydroxyvitamin D3 modulation of intracellular calcium 

metabolism in clonal rat osteoblastic (ros 17/2.8) cells. Life Sci 54(19):1395-1402. 

Lopez CM, Pineiro AE, Nunez N, et al. 2000. Thyroid hormone changes in males exposed to lead in the 

Buenos Aires area (Argentina). Pharmacol Res Commun 42(6):599-602. 

Lorenzana RM, Troast R, Klotzbach JM, et al. 2005. Issues related to time averaging of exposure in 

modeling risks associated with intermittent exposures to lead. Risk Anal 25:169-178. 
LEAD 476 

9. REFERENCES 

Louis ED, Jurewicz EC, Applegate L, et al. 2003. Association between essential tremor and blood lead 

concentration. Environ Health Perspect 111(14):1707-1711. 

Lucas SR, Sexton M, Langenberg P. 1996. Relationship between blood lead and nutritional factors in 

preschool children: A cross-sectional study. Pediatrics 97(1):74-78. 

Lucchini R, Albini E, Cortesi I, et al. 2000. Assessment of neurobehavioral performance as a function of 

current and cumulative occupational lead exposure. Neurotoxicology 21(5):805-812. 

Lundstrom NG, Nordberg G, Englyst V, et al. 1997. Cumulative lead exposure in relation to mortality 

and lung cancer morbidity in a cohort of primary smelter workers. Scand J Work Environ Health 

23(1):24-30. 

Lustberg M, Silbergeld E. 2002. Blood lead levels and mortality. Arch Intern Med 162:2443-2449. 

Luster MI, Faith RE, Kimmel CA. 1978. Depression of humoral immunity in rats following chronic 

developmental lead exposure. J Environ Pathol Toxicol 1:397-402. 

Lutz PM, Wilson TJ, Ireland J, et al. 1999. Elevated immunoglobulin E (IgE) levels in children with 

exposure to environmental lead. Toxicology 134:63-78. 

*Lyngbye T, Hansen ON, Grandjean P. 1987. The influence of environmental factors on physical 

growth in school age: A study of low level lead exposure. In: Lindberg SE, Hutchinson TC, eds. 

International conference on heavy metals in the environment, Vol. 2, New Orleans, LA. Edinburgh, UK: 

CEP Consultants, Ltd., 210-212. 

*Lyngbye T, Hansen ON, Grandjean P. 1989. Neurological deficits in children: Medical risk factors and 

lead exposure. Neurotoxicol Teratol 10:531-537. 

Lyngbye T, Jorgensen PJ, Grandjean P, et al. 1990b. Validity and interpretation of blood lead levels: A 

study of Danish school-children. Scand J Clin Lab Invest 50:441-449. 

Maas RP, Patch SC, Pandolfo TJ, et al. 2005. Lead content and exposure from children's and adult's 

jewelry products. Bull Environ Contam Toxicol 74:437-444. 

Maddaloni M, Ballew M, Diamond G, et al. 2005. Assessing non-residential lead risks at hazardous 

waste sites. Hum Ecol Risk Assess 11:967-1003. 

Maddaloni M, Lolacono N, Manton W, et al. 1998. Bioavailability of soil-borne lead in adults by stable 

isotope dilution. Environ Health Perspect 106:1589-1594. 

Maenhaut W, Zoller WH, Duce RA, et al. 1979. Concentration and size distribution of particulate trace 

elements in the south polar atmosphere. J Geophys Res 84:2421-2431. 

Mahaffey KR, Annest JL. 1986. Association of erythrocyte protoporphyrin with blood lead level and 

iron status in the Second National Health and Nutrition Examination Survey, 1976-1980. Environ Res 

41:327-338. 

Mahaffey KR, Gartside PS, Glueck CJ. 1986. Blood lead levels and dietary calcium intake in 1- to 11­

year-old children: The Second National Health and Nutrition Examination Survey, 1976 to 1980. 

Pediatrics 78:257-262. 
LEAD 477 

9. REFERENCES 

Mahaffey KR, Goyer R, Haseman JK. 1973. Dose-response to lead ingestion in rats fed low dietary 

calcium. J Lab Clin Med 82:92-100. 

Mahaffey KR, Rosen JF, Chesney RW, et al. 1982. Association between age, blood lead concentration, 

and serum 1,25-dihydroxycholecalciferol levels in children. Am J Clin Nutr 35:1327-1331. 

Maheswaran R, Gill JS, Beevers DG. 1993. Blood pressure and industrial lead exposure. Am J 

Epidemiol 137(6):645-653. 

Maizlish NA, Parra G, Feo O. 1995. Neurobehavioral evaluation of Venezuelan workers exposed to 

inorganic lead. Occup Environ Med 52:408-414. 

Mäki-Paakkanen J, Sorsa M, Vainio H. 1981. Chromosome aberrations and sister chromatid exchanges 

in lead-exposed workers. Hereditas 94:269-275. 

Malcoe LH, Lynch RA, Keger MC, et al. 2002. Lead sources, behaviors, and socioeconomic factors in 

relation to blood lead of native and white children: A community-based assessment of a former mining 

area. Environ Health Perspect Suppl 110:221-231. 

Malcolm D, Barnett HAR. 1982. A mortality study of lead workers: 1925-76. Br J Ind Med 39:404­

410. 

Maldonado-Vega M, Cerbón-Solorzano J, Albores-Medina A, et al. 1996. Lead: Intestinal absorption 

and bone mobilization during lactation. Hum Exp Toxicol 15:872-877. 

Malkin R, Brandt-Rauf P, Graziano J, et al. 1992. Blood lead levels in incinerator workers. Environ Res 

59:265-270. 

Manceau A, Boisset M-C, Sarret G, et al. 1996. Direct determination of lead speciation in contaminated 

soils by EXAFS spectroscopy. Environ Sci Technol 30(5):1540-1552. 

Mannino DM, Albalak R, Grosse S, et al. 2003. Second-hand smoke exposure and blood lead levels in 

U.S. children. Epidemiology 14(6):719-727. 

Mantere P, Haenninen H, Hernberg S. 1982. Subclinical neurotoxic lead effects: Two-year follow-up 

studies with psychological test methods. Neurobehav Toxicol Teratol 4:725-727. 

Manton WI. 1977. Sources of lead in blood. Identification by stable isotopes. Arch Environ Health 

32:149-159. 

Manton WI. 1998. Isotope ratios and the source of lead in lead poisoning. J Toxicol Clin Toxicol 

36(7):705-706. 

Manton WI, Cook JD. 1984. High-accuracy (stable isotope dilution) measurements of lead in serum and 

cerebrospinal fluid. Br J Ind Med 41:313-319. 

Manton WI, Angle CR, Stanek KL, et al. 2003. Release of lead from bone in pregnancy and lactation. 

Environ Res 92:139-151. 
LEAD 478 

9. REFERENCES 

Manton WI, Rothenberg SJ, Manalo M. 2001. The lead content of blood serum. Environ Res 86:263­

273. 

*Maranelli G, Apostoli P. 1987. Assessment of renal function in lead poisoned workers. Occup Environ 

Chem Hazards 344-348. 

Marcus AH. 1985a. Multicompartment kinetic models for lead: I. Bone diffusion models for long-term
 

retention. Environ Res 36:441-458. 

Marcus AH. 1985b. Multicompartment kinetic models for lead: II. Linear kinetics and variable 

absorption in humans without excessive lead exposure. Environ Res 36:459-472. 

Marcus AH. 1985c. Multicompartment kinetic models for lead: III. Lead in blood plasma and 

erythrocytes. Environ Res 36:473-489. 

Marcus AH, Schwartz J. 1987. Dose-response curves for erythrocyte protoporphyrin vs blood lead: 

Effects of iron status. Environ Res 44:221-227. 

Marino PE, Franzblau A, Lilis R, et al. 1989. Acute lead poisoning in construction workers: The failure 

of current protective standards. Arch Environ Health 44:140-145. 

Markowitz ME, Rosen JF. 1981. Zinc (Zn) and copper (Cu) metabolism in CaNa2 EDTA-treated 

children with plumbism. Pediatr Res 15:635. 

Markowitz ME, Weinberger HL. 1990. Immobilization-related lead toxicity in previously lead-poisoned 

children. Pediatrics 86:455-457. 

Marques M, Millas I, Jimenez A, et al. 2001. Alteration of the soluble guanylate cyclase system in the 

vascular wall of lead-induced hypertension in rats. J Am Soc Nephrol 12:2594-2600. 

Martin D, Glass TA, Bandeen-Roche K, et al. 2006. Association of blood lead and tibia lead with blood 

pressure and hypertension in a community sample of older adults. Am J Epidemiol 163(5):467-478. 

Matte TD, Figueroa JP, Burr G, et al. 1989. Lead exposure among lead-acid battery workers in Jamaica. 

Am J Ind Med 16:167-177. 

McBride WG, Black BP, English BJ. 1982. Blood lead levels and behavior of 400 preschool children. 

Med J Aust 10:2(l):26-29. 

McCabe MJ, Singh KP, Reiners JJ. 1999. Lead intoxication impairs the generation of a delayed type 

hypersensitivity response. Toxicology 139:255-264. 

McClain RM, Becker BA. 1972. Effects of organolead compounds on rat embryonic and fetal 

development. Toxicol Appl Pharmacol 21:265-274. 

McDonald ME. 1985. Acid deposition and drinking water. Environ Sci Technol 19:772-776. 

McDonald JA, Potter NU. 1996. Lead's legacy? Early and late mortality of 454 lead-poisoned children. 

Arch Environ Health 51:116-121. 
LEAD 479 

9. REFERENCES 

McMichael AJ, Baghurst PA, Vimpani GV, et al. 1994. Tooth lead levels and IQ in school-age children: 

The Port Pirie cohort study. Am J Epidemiol 140:489-499. 

McMichael AJ, Baghurst PA, Wigg NR, et al. 1988. Port Pirie cohort study: Environmental exposure to 

lead and children's abilities at the age of four years. N Engl J Med 319:468-476. 

McMichael AJ, Vimpani GV, Robertson EF, et al. 1986. The Port Pirie cohort study: Maternal blood 

lead and pregnancy outcome. J Epidemiol Community 40:18-25. 

Meredith PA, Moore MR. 1979. The influence of lead on heme biosynthesis and biodegradation in the 

rat. Biochem Soc Trans 7:637-639. 

Meredith PA, Moore MR, Campbell BC, et al. 1978. Delta-aminolevulinic acid metabolism in normal 

and lead-exposed humans. Toxicology 9:1-9. 

Meyer-Baron M, Seeber A. 2000. A meta-analysis for neurobehavioural results due to occupational lead 

exposure with blood lead concentrations <70 μg/100 ml. Arch Toxicol 73:510-518. 

Meyer PA, Pivetz T, Dignam TA, et al. 2003. Surveillance for elevated blood lead levels among children 

- United States, 1997-2001. MMWR Morb Mortal Wkly Rep 52(10):1-21. 

Michaels D, Zoloth SR, Stern FB. 1991. Does low-level lead exposure increase risk of death? A 

mortality study of newspaper printers. Int J Epidemiol 20:978-983. 

Michaelson A, Sauerhoff MW. 1974. An improved model of lead-induced brain dysfunction in the 

suckling rat. Toxicol Appl Pharmacol 28:88-96. 

Mielke HW. 1991. Lead in residential soils: Background and preliminary results of New Orleans. 

Water Air Soil Pollut 57-58:111-119. 

Mielke HW. 1993. Lead dust contaminated U.S.A. communities: Comparison of Louisiana and 

Minnesota. Appl Geochem (Suppl 2):257-261. 

Mielke HW, Adams JL, Reagan PL, et al. 1989. Soil-dust lead and childhood lead exposure as a 

function of city size and community traffic flow: The case for lead abatement in Minnesota. Environ 

Chem Health 9(Supp):253-271. 

Mielke HW, Anderson JC, Berry KJ, et al. 1983. Lead concentrations in inner-city soils as a factor in the 

child lead problem. Am J Public Health 73:1366-1369. 

Mielke HW, Burroughs S, Wade R, et al. 1984/1985. Urban lead in Minnesota: Soil transect results of 

four cities. Minnesota Academy of Science 50:19-24. 

Mielke HW, Dugas D, Mielke PW, et al. 1997a. Associations between soil lead and childhood blood 

lead in urban New Orleans and rural Lafourche Parish of Louisiana. Environ Health Perspect 105(9):950­

954. 

Mielke HW, Gonzales CR, Smith MK, et al. 1999. The urban environment and children's health: Soils 

as an integrator of lead, zinc, and cadmium in New Orleans, Louisiana, U.S.A. Environ Res 81:117-129. 
LEAD 480 

9. REFERENCES 

Mielke HW, Powell ET, Shah A, et al. 2001. Multiple metal contamination from house paints: 

Consequences of power sanding and paint scraping in New Orleans. Environ Health Perspect 

109(9):973-978. 

Mielke HW, Taylor MD, Gonzales CR, et al. 1997b. Lead-based hair coloring products: Too hazardous 

for household use. J Am Pharm Assn 37:85-89. 

Milburn H, Mitran E, Crockford GW. 1976. An investigation of lead workers for subclinical effects of 

lead using three performance tests. Ann Occup Hyg 19:239-249. 

Miller EK, Friedland AJ. 1994. Lead migration in forest soils: Response to changing atmospheric 

inputs. Environ Sci Technol 28:662-669. 

Miller MB, Curry SC, Kunkel DB, et al. 1996. Pool cue chalk: A source of environmental lead. 

Pediatrics 97(6 Pt 1):916-917. 

Miller TE, Golemboski KA, Ha RS, et al. 1998. Developmental exposure to lead causes persistent 

immunotoxicity in Fischer 344 rats. Toxicol Sci 42:129-135. 

Minder B, Das-Smaal EA, Orlebeke JF. 1998. Cognition in children does not suffer from very low lead 

exposure. J Learn Disabil 31(55):494-502. 

Mishra KP, Singh VK, Rani R, et al. 2003. Effect of lead exposure on the immune response of some 

occupationally exposed individuals. Toxicology 188:251-259. 

Mistry P, Lucier GW, Fowler BA. 1985. High affinity lead binding proteins from rat kidney cytosol 

mediate cell-free nuclear translocation of lead. J Pharmacol Exp Ther 232:462-469. 

Mistry P, Mastri C, Fowler BA. 1986. Influence of metal ions on renal cytosolic lead-binding proteins 

and nuclear uptake of lead in the kidney. Biochem Pharmacol 35:711-713. 

Moller L, Kristensen TS. 1992. Blood lead as a cardiovascular risk factor. Am J Epidemiol 

136(9):1091-1100. 

Monteiro HP, Bechara EJH, Abdalla DSP. 1991. Free radicals involvement in neurological porphyrias 

and lead poisoning. Mol Cell Biochem 103:73-83. 

Moore PV. 1995. Lead toxicity-by the Agency for Toxic Substances and Disease Registry. AAOHN J 

43(8):428-438. 

Moore MR, Goldberg A. 1985. Health implication of the hematopoietic effects of lead. In: Mahaffey 

KR, ed. Dietary and environmental lead: Human health effects. Amsterdam, The Netherlands: Elsevier 

Science Publishers B.V., 261-314. 

Moore MR, Meredith PA. 1979. The carcinogenicity of lead. Arch Toxicol 42:87-94. 

Moore JF, Goyer RA, Wilson M. 1973. Lead-induced inclusion bodies. Solubility, amino acid content, 

and relationship to residual acidic nuclear proteins. Lab Invest 29(5):488-494. 

Moore MR, Goldberg A, Pocock SJ, et al. 1982. Some studies of maternal and infant lead exposure in 

Glasgow. Scott Med J 27:113-122. 
LEAD 481 

9. REFERENCES 

Moore MR, Goldberg A, Yeung-Laiwah AAC. 1987. Lead effects on the heme biosynthetic pathway: 

Relationship to toxicity. Ann NY Acad Sci 514:191-203. 

Moore MR, Meredith PA, Watson WS, et al. 1980. The percutaneous absorption of lead-203 in humans 

from cosmetic preparations containing lead acetate, as assessed by whole-body counting and other 

techniques. Food Cosmet Toxicol 18:399-405. 

*Mooty J, Ferrand CF, Harris P. 1975. Relationship of diet to lead poisoning in children. Pediatrics 

55:636-639. 

Moreau T, Hannaert P, Orssaud G, et al. 1988. Influence of membrane sodium transport upon the 

relation between blood lead and blood pressure in a general male population. Environ Health Perspect 

78:47-51. 

Moreau T, Orssaud G, Juguet B, et al. 1982. [Blood lead levels and arterial pressure: Initial results of a 

cross sectional study of 431 male subjects.] Rev Epidemol Sante Publique 39:395-397. (French) 

Morgan A, Holmes A. 1978. The fate of lead in petrol-engine exhaust particulates inhaled by the rat. 

Environ Res 15:44-56. 

Morgan B, Parramore C. 2001. Elevated blood lead levels associated with the consumption of illicitly 

distilled moonshine. J Toxicol Clin Toxicol 39(5):551. 

Morita Y, Sakai T, Araki S, et al. 1997. Nicotinamide adenine dinucleotide synthetase activity in 

erythrocytes as a tool for the biological monitoring of lead exposure. Int Arch Occup Environ Health 

70(3):195-198. 

Morris C, McCarron DA, Bennett WM. 1990. Low-level lead exposure, blood pressure, and calcium 

metabolism. Am J Kidney Dis 15:568-574. 

Morris V, Markowitz ME, Rosen JF. 1988. Serial measurements of aminolevulinic acid dehydratase in 

children with lead toxicity. J Pediatr 112:916-919. 

Morrison JN, Quarterman J. 1987. The relationship between iron status and lead absorption in rats. Biol 

Trace Element Res 14:115-126. 

Morrison JN, Quarterman J, Humphries WR. 1977. The effect of dietary calcium and phosphate on lead 

poisoning in lambs. J Comp Pathol 87:417-429. 

Morrison NA, Yeoman R, Kelly PJ, et al. 1992. Contribution of trans-acting factor alleles to normal 

physiological variability: Vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Natl 

Acad Sci U S A 89:6665-6669. 

Morrow PE, Beiter H, Amato F, et al. 1980. Pulmonany retention of lead: An experimental study in 

man. Environ Res 21:373-384. 

Morselli PL, Franco-Morselli R, Bossi L. 1980. Clinical pharmacokinetics in newborns and infants: 

Age-related differences and therapeutic implications. Clin Pharmacokin 5:485-527. 
LEAD 482 

9. REFERENCES 

Mortada WI, Sobh MA, El-Defrawy MM, et al. 2001. Study of lead exposure from automobile exhaust 

as a risk for nephrotoxicity among traffic policemen. Am J Nephrol 21:274-279. 

Moschandreas DJ, Karuchit S, Berry MR, et al. 2002. Exposure apportionment: Ranking food items by 

their contribution to dietary exposure. J Expo Anal Environ Epidemiol 12:233-243. 

Moser R, Oberley TD, Daggett DA, et al. 1995. Effects of lead administration on developing rat kidney. 

I. Glutathione S-transferase isoenzymes. Toxicol Appl Pharmacol 131:85-93. 

Moss ME, Lanphear BP, Auinger P. 1999. Association of dental caries and blood lead levels. JAMA 

281(24):2294-2298. 

MPCA. 1987. Soil lead report to the Minnesota State Legislature. St. Paul, MN: Minnesota Pollution 

Control Agency, XII, 13, 28, 29. 

Muijser H, Hoogendijk EM, Hooisma J, et al. 1987. Lead exposure during demolition of a steel structure 

coated with lead-based paints. II. Reversible changes in the conduction velocity of the motor nerves in 

transiently exposed workers. Scand J Work Environ Health 13:56-61. 

Muldoon SB, Cauley JA, Kuller LH, et al. 1996. Effects of blood lead levels on cognitive function of 

older women. Neuroepidemiology 15(2):62-72. 

Muntner P, He J, Vupputuri S, et al. 2003. Blood lead and chronic kidney disease in the general United 

States population: Results from NHANES III. Kidney Int 63:1044-1050. 

Murakami M, Kawamura R, Nishii S, et al. 1983. Early appearance and localization of intranuclear 

inclusions in the segments of renal proximal tubules of rats following ingestion of lead. Br J Exp Pathol 

64:144-155. 

Murata K, Araki S, Yokoyama K, et al. 1995. Autonomic and central nervous system effects of lead in 

female glass workers in China. Am J Ind Med 28(2):233-244. 

Murgueytio AM, Evans GR, Sterling DA, et al. 1998. Relationship between lead mining and blood lead 

levels in children. Arch Environ Health 53(6):414-423. 

Muro LA, Goyer RA. 1969. Chromosome damage in experimental lead poisoning. Arch Pathol 87:660­

663. 

Murphy EA, Hall GS. 2000. Determination of lead sources in water samples using isotope ratios. Bull 

Environ Contam Toxicol 65:314-321. 

Murphy MJ, Graziano JH, Popovac D, et al. 1990. Past pregnancy outcomes among women living in the 

vicinity of a lead smelter in Kosovo, Yugoslavia. Am J Public Health 80:33-35. 

Murray K, Bazzi A, Carter C, et al. 1997. Distribution and mobility of lead in soils at an outdoor 

shooting range. J Soil Contam 6(1):79-93. 

Mushak P. 1991. Gastro-intestinal absorption of lead in children and adults: Overview of biological and 

biophysico-chemical aspects. Chem Speciat Bioavail 3:87-104. 
LEAD 483 

9. REFERENCES 

Mushak P, Crocetti AF. 1996. Lead and nutrition. I. Biologic interactions of lead with nutrients. Nutr 

Today 31:12-17. 

Mykkänen HM, Wasserman RH. 1981. Gastro-intestinal absorption of lead (203Pb) in chicks: Influence 

of lead, calcium and age. J Nutr 111:1757-1765. 

Mykkänen HM, Wasserman RH. 1982. Effect of vitamin D on the intestinal absorption of 203Pb and 

47Ca in chicks. J Nutr 112:520-527. 

Nakagawa K. 1991 Decreased glutathione S-transferase activity in mice livers by acute treatment with 

lead, independent of alteration in glutathione content. Toxicol Lett 56:13-17. 

Nan Z, Cheng G. 2001. Accumulation of Cd and Pb in spring wheat (Triticum aestivum L.) grown in 

calcareous soil irrigated with wastewater. Bull Environ Contam Toxicol 66:748-754. 

NAS. 1972. Lead: Airborne lead in perspective. Washington, DC: National Academy of Sciences, 71­

177, 281-313. 

NAS. 1980. Lead in the human environment. Washington, DC: National Academy of Sciences, 

Committee on Lead in the Human Environment. 

NAS/NRC. 1989. Report of the oversight committee. In: Biologic markers in reproductive toxicology. 

Washington, DC: National Academy of Sciences, National Research Council, National Academy Press. 

Nash D, Magder L, Lustberg M, et al. 2003. Blood lead, blood pressure, and hypertension in 

perimenopausal and postmenopausal women. JAMA 289:1523-1532. 

Nash D, Magder LS, Sherwin R, et al. 2004. Bone density-related predictors of blood lead level among 

peri- and postmenopausal women in the United States: The Third National Health and Nutrition 

Examination Survey, 1988–1994. Am J Epidemiol 160(9):901-911. 

Navas-Acien A, Selvin E, Sharrett AR, et al. 2004. Lead, cadmium, smoking, and increased risk of 

peripheral arterial disease. Circulation 109(25):3196-3201. 

Nawrot TS, Thijs L, Hond EMD, et al. 2002. An epidemiological re-appraisal of the association between 

blood pressure and blood lead: A meta-analysis. J Hum Hypertens 16:123-131. 

Neal R, Aykin-Burns N, Ercal N, et al. 2005. Pb2

 exposure alters the lens αA-crystallin protein profile in 

vivo and induces cataract formation in lens organ culture. Toxicology 212(1):1-9. 

Needleman HL. 2004. Lead poisoning. Annu Rev Med 55:209-222. 

Needleman HL, Gatsonis CA. 1990. Low-level lead exposure and the IQ of children: A meta-analysis 

of modern studies. J Am Med Assoc 263(5):673-678. 

*Needleman HL, Geiger SK, Frank R. 1985. Lead and IQ scores: A reanalysis (letter). Science 

227:701-704. 

Needleman HL, Gunnoe C, Leviton A, et al. 1979. Deficits in psychologic and classroom performance 

of children with elevated dentine lead levels. N Engl J Med 300:689-695. 
LEAD 484 

9. REFERENCES 

Needleman HL, McFarland C, Ness RB, et al. 2002. Bone lead levels in adjudicated delinquents a case 

control study. Neurotoxicol Teratol 24:711-717. 

Needleman HL, Rabinowitz M, Leviton A, et al. 1984. The relationship between prenatal exposure to 

lead and congenital anomalies. JAMA 251:2956-2959. 

Needleman HL, Riess JA, Tobin MJ, et al. 1996. Bone lead levels and delinquent behavior. JAMA 

275(5):363-369. 

Needleman HL, Schell A, Bellinger D, et al. 1990. The long-term effects of exposure to low doses of 

lead in childhood. An 11-year follow-up report. N Engl J Med 322:83-88. 

NEMI. 2005a. Method 3111B. Direct air-acetylene flame method. NEMI method summary. 

Washington, DC: National Environmental Methods Index. 

http://web1.er.usgs.gov/nemi/method_summary.jsp?param_method_id=5703. June 10, 2005. 

NEMI. 2005b. Method 3500-Pb B. Dithizone method. NEMI method summary. Washington, DC: 

National Environmental Methods Index. 

http://web1.er.usgs.gov/nemi/method_summary.jsp?param_method_id=7396. June 10, 2005. 

NEMI. 2005c. Method 3113 B. Metals in water by electrothermal atomic absorption spectrometry. 

NEMI method summary. Washington, DC: National Environmental Methods Index. 

http://web1.er.usgs.gov/nemi/method_summary.jsp?param_method_id=4698. June 10, 2005. 

NEMI. 2005d. Method 3120 B. Metals in water by plasma emission spectroscopy. NEMI method 

summary. Washington, DC: National Environmental Methods Index. 

http://web1.er.usgs.gov/nemi/method_summary.jsp?param_method_id=4699. June 10, 2005. 

Neri LC, Hewitt D, Orser B. 1988. Blood lead and blood pressure: Analysis of cross-sectional and 

longitudinal data from Canada. Environ Health Perspect 78:123-126. 

Nerin C, Domeno C, Garcia JI, et al. 1999. Distribution of Pb, V, Cr, Ni, Cd, Cu and Fe in particles 

formed from the combustion of waste oils. Chemosphere 38(7):1533-1540. 

Nerin C, Olavide S, Cacho J, et al. 1989. Determination of lead in airborne particulate by hybrid 

generation. Water Air Soil Pollut 44:339-345. 

Nestmann ER, Matula TI, Douglas GR, et al. 1979. Detection of the mutagenic activity of lead chromate 

using a battery of microbial tests. Mutat Res 66:357-365. 

Neuman DR, Dollhopf DJ. 1992. Lead levels in blood from cattle residing near a lead smelter. J 

Environ Qual 21:181-184. 

Nevin R. 2000. How lead exposure relates to temporal changes in IQ, violent crime, and unwed 

pregnancy. Environ Res 83:1-22. 

Ng TP, Goh HH, Ong HY, et al. 1991. Male endocrine functions in workers with moderate exposure to 

lead. Br J Ind Med 48:485-491. 

Ni Z, Hou S, Barton CH, et al. 2004. Lead exposure raises superoxide and hydrogen peroxide in human 

endothelial and vascular smooth muscle cells. Kidney Int 66(6):2329-2336. 
LEAD 485 

9. REFERENCES 

Niebuhr E, Wulf HC. 1984. Genotoxic effects. In: Grandjean P, ed. Biological effects of organo-lead 

compounds. Boca Raton, FL: CRC Press, 117-124. 

Nielsen T. 1984. Chapter 6: Atmospheric occurrence of organolead compounds. In: Grandjean P, ed. 

Biological effects of organolead compounds. Boca Raton, FL: CRC Press, 43-62. 

Nielsen OJ, O'Farrell DJ, Treacy JJ, et al. 1991. Rate constants for the gas-phase reactions of hydroxyl 

radicals with tetramethyllead and tetraethyllead. Environ Sci Technol 25(6):1098-1103. 

Nielsen T, Jensen KA, Grandjean P. 1978. Organic lead in normal human brains. Nature 274:602-603. 

Nielson KB, Atkin CL, Winge DR. 1985. Distinct metal-binding configurations in metallothionein. J 

Biol Chem 260:5342-5350. 

Nihei MK, Guilarte TR. 2002. Molecular mechanisms of low-level Pb2 neurotoxicity. In: Massaro EJ, 

eds. Handbook of neurotoxicology. Totowa, NJ: Humana Press, 107-133. 

Nilsson U, Attewell R, Christoffersson JO, et al. 1991. Kinetics of lead in bone and blood after end of 

occupational exposure. Pharmacol Toxicol 69:477-484. 

NIOSH. 1974. Evaluation of behavioral functions in workers exposed to lead. In: Xintaras C, Johnson 

BL, De Groot 1, eds. Behavioral toxicology: Early detection of occupational hazards. Cincinnati, OH: 

U.S. Department of Health, Education and Welfare, National Institute for Occupational Safety and 

Health, 248-266. 

NIOSH. 1977a. Manual of analytical methods. 2nd ed, vol. 1. Method No. P&CAM 173. Cincinnati, 

OH: U.S. Department of Health, Education, and Welfare. Public Health Service, Centers for Disease 

Control, National Institute for Occupational Safety and Health. 

NIOSH. 1977b. Manual of analytical methods. 2nd ed, vol. 1. Method No. P&CAM 208. Cincinnati, 

OH: U.S. Department of Health, Education, and Welfare, Public Health Service, Centers for Disease 

Control, National Institute for Occupational Safety and Health. 

NIOSH. 1977c. Manual of analytical methods. 2nd ed, vol. 1. Method No. P&CAM 262. Cincinnati, 

OH: U.S. Department of Health, Education and Welfare. Public Health Service, Centers for Disease 

Control, National Institute for Occupational Safety and Health. 

NIOSH. 1977d. Manual of analytical methods. 2nd ed, vol. 3. Method No. S341. Cincinnati, OH: U.S. 

Department of Health, Education, and Welfare, Public Health Service, Centers for Disease Control, 

National Institute for Occupational Safety and Health. 

NIOSH. 1978a. Criteria for a recommended standard: Occupational exposure to inorganic lead revised 

criteria. 1978. Cincinnati, OH: U.S. Department of Health. Education, and Welfare, Centers for Disease 

Control, National Institute for Occupational Safety and Health. 

NIOSH. 1978b. Manual of analytical methods. 2nd ed, vol. 4. Method No. 383 and 384. Cincinnati, 

OH: U.S. Department of Health, Education and Welfare, Centers for Disease Control, National Institute 

for Occupational Safety and Health, S383-1 to S383-10, S384-1 to S384-10. 
LEAD 486 

9. REFERENCES 

NIOSH. 1981. Manual of analytical methods. Vol. 7. Method P&CAM 351. Cincinnati, OH: U.S. 

Department of Health and Human Services, Centers for Disease Control, National Institute for 

Occupational Safety and Health, 351-1 to 351-11. 

NIOSH. 1990. Manual of analytical methods. 3rd ed, vol. I. Method No. 7105. Cincinnati, OH: U.S. 

Department of Health and Human Services, Centers for Disease Control, National Institute for 

Occupational Safety and Health. 

NIOSH. 1994a. NIOSH manual of analytical methods, 4th ed. Methods 7082 (lead by flame AAS), 

7105 (lead by HGAAS), 7505 (lead sulfide), 8003 (lead in blood and urine), 9100 (lead in surface wipe 

samples), U.S. Department of Health and Human Services, Centers for Disease Control, National Institute 

for Occupational Safety and Health. 

NIOSH. 1994b. Method 8005. Elements in blood or tissue. NIOSH manual of analytical methods 

(NMAM). Cincinnati, OH: National Institute for Occupational Safety and Health. 

http://www.cdc.gov/niosh/nmam/pdfs/8005.pdf. July 26, 2005. 

NIOSH. 1994c. Method 7082. Lead by flame AAS. NIOSH manual of analytical methods (NMAM). 

Cincinnati, OH: National Institute for Occupational Safety and Health. 

http://www.cdc.gov/niosh/nmam/pdfs/7082.pdf. July 26, 2005. 

NIOSH. 1994d. Method 7105. Lead by GFAAS. NIOSH manual of analytical methods (NMAM). 

Cincinnati, OH: National Institute for Occupational Safety and Health. 

http://www.cdc.gov/niosh/nmam/pdfs/7105.pdf. July 26, 2005. 

NIOSH. 1994e. Method 8003. Lead in blood and urine. NIOSH manual of analytical methods 

(NMAM). Cincinnati, OH: National Institute for Occupational Safety and Health. 

http://www.cdc.gov/niosh/nmam/pdfs/8003.pdf. July 26, 2005. 

NIOSH. 1994f. Method 8310. Metals in urine. NIOSH manual of analytical methods (NMAM). 

Cincinnati, OH: National Institute for Occupational Safety and Health. 

http://www.cdc.gov/niosh/nmam/pdfs/8310.pdf. July 26, 2005. 

NIOSH. 1994g. Method 2533. Tetraethyl lead (as Pb). NIOSH manual of analytical methods (NMAM). 

Cincinnati, OH: National Institute for Occupational Safety and Health. 

http://www.cdc.gov/niosh/nmam/pdfs/2533.pdf. July 26, 2005. 

NIOSH. 1994h. Method 2534. Tetramethyl lead (as Pb). NIOSH manual of analytical methods 

(NMAM). Cincinnati, OH: National Institute for Occupational Safety and Health. 

http://www.cdc.gov/niosh/nmam/pdfs/2534.pdf. July 26, 2005. 

NIOSH. 1995. Report to Congress on workers’ home contamination. Study conducted under the 

Workers’ Family Protection. 

NIOSH. 1996. NIOSH health hazard evaluation report, HETA 91-0346-2572, FBI Academy, Quantico, 

Virginia. Michael E Barsan and Aubrey Miller, U.S. Department of Health and Human Services, Public 

Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety 

and Health. 
LEAD 487 

9. REFERENCES 

NIOSH. 1997a. NIOSH pocket guide to chemical hazards. Washington, DC: U.S. Department of 

Health and Human Services. Public Health Service. Centers for Disease Control and Prevention. 

National Institute for Occupational Safety and Health, 302. 

NIOSH. 1997b. Protecting workers exposed to lead-based paint hazards. A report to congress. DHHS 

(NIOSH) Publication No. 98-112. January 1997. U.S. Department of Health and Human Services, 

Center for Disease Control and Prevention, and National Institute for Occupational Safety and Health, 1­

74. 

NIOSH. 2003. Method 7300. Elements by ICP (Nitric/perchloric acid ashing). NIOSH manual of 

analytical methods (NMAM). Cincinnati, OH: National Institute for Occupational Safety and Health. 

http://www.cdc.gov/niosh/nmam/pdfs/7300.pdf. July 26, 2005. 

NIOSH. 2005. NIOSH pocket guide to chemical hazards. Atlanta, GA: National Institute for 

Occupational Safety and Health. http://www.cdc.gov/niosh/npg/npgdname.html. February 15, 2005. 

Nishioka H. 1975. Mutagenic activities of metal compounds in bacteria. Mutat Res 31:185-189. 

Nordenson I, Beckman G, Beckman L, et al. 1978. Occupational and environmental risks in and around 

a smelter in northern Sweden: IV. Chromosomal aberrations in workers exposed to lead. Hereditas 

88:263-267. 

*Nordstrom S, Beckman L, Nordensen I. 1978. Occupational and environmental risks in and around a 

smelter in northern Sweden: I. Variations in birth weight. Hereditas 88:43-46. 

Nordstrom S, Beckman L, Nordensen I. 1979. Occupational and environmental risks in and around a 

smelter in northern Sweden: V. Spontaneous abortion among female employees and decreased birth 

weight in their offspring. Hereditas 90:291-296. 

NRC. 1993. National Research Council. Pesticides in the diets of infants and children. Washington, 

DC: National Academy Press. 

Nriagu JO. 1978. Lead in soils, sediments and major rock types. In: Nriagu JO, ed. The 

biogeochemistry of lead in the environment. Part A. Ecological cycles. New York, NY: Elsevier/NorthHolland Biomedical Press, 15-72. 

NSF. 1977. Transport and distribution in a watershed ecosystem. In: Boggess WR, ed. Lead in the 

environment. Washington, DC: National Science Foundation. Report No. NSFRA770214, 105-133. 

NTP. 2005. Report on carcinogens. 11th ed. Research Triangle Park, NC: U.S. Department of Health 

and Human Services, National Toxicology Program. http://ntp-server.niehs.nih.gov/ntp/roc/toc11.html. 

February 15, 2004. 

Nwosu JU, Harding AK, Linder G. 1995. Cadmium and lead uptake by edible crops grown in a silt loam 

soil. Bull Environ Contam Toxicol 54:570-578. 

Nye LJJ. 1929. An investigation of the extraordinary incidence of chronic nephritis in young people in 

Queensland. Med J Aust 2:145-159. 

O’Connor ME, Rich D. 1999. Children with moderately elevated lead levels: Is chelation with DMSA 

helpful? Clin Pediatr 38(6):325-331. 
LEAD 488 

9. REFERENCES 

Odland JO, Nieboer E, Romanova N, et al. 1999. Blood lead and cadmium and birth weight among subarctic and arctic populations of Norway and Russia. Acta Obstet Gynecol Scand 78:852-860. 

O’Flaherty EJ. 1986. The rate of decline of blood lead in lead industry workers during medical removal: 

The effect of job tenure. Fundam Appl Toxicol 6:372-380. 

O'Flaherty EJ. 1987. Modeling: An introduction. Pharmacokinetics in risk assessment. Drinking water 

and health. Vol. 8. Washington, DC: U.S. Environmental Protection Agency, 27-35. PB89203319. 

O’Flaherty EJ. 1991a. Physiologically based models for bone-seeking elements. II. Kinetics of lead 

disposition in rats. Toxicol Appl Pharmacol 111:313-331. 

O’Flaherty EJ. 1991b. Physiologically based models for bone-seeking elements. III. Human skeletal 

and bone growth. Toxicol Appl Pharmacol 111:332-341. 

O’Flaherty EJ. 1993. Physiologically based models for bone-seeking elements. IV. Kinetics of lead 

disposition in humans. Toxicol Appl Pharmacol 118:16-29. 

O’Flaherty EJ. 1995a. Physiologically based models for bone-seeking elements. V. Lead absorption 

and disposition in childhood. Toxicol Appl Pharmacol 131:297-308. 

O’Flaherty EJ. 1995b. PBK modeling for metals. Examples with lead, uranium, and chromium. Toxicol 

Lett 82/83:367-372. 

O’Flaherty EJ, Hammond PB, Lerner SI. 1982. Dependence of apparent blood lead half-life on the 

length of previous lead exposure in humans. Fundam Appl Toxicol 2:49-54. 

O’Flaherty EJ, Inskip MJ, Franklin CA, et al. 1998. Evaluation and modification of a physiologically 

based model of lead kinetics using data from a sequential isotope study in Cynomolgus monkeys. 

Toxicol Appl Pharmacol 149:1-16. 

Oishi H, Nomiyama H, Nomiyama K, et al. 1996. Fluorometric HPLC determination of deltaaminolevulinic acid (ALA) in the plasma and urine of lead workers: Biological indicators of lead 

exposure. J Anal Toxicol 20(2):106-110. 

Okun A, Cooper G, Bailer AJ, et al. 2004. Trends in occupational lead exposure since the 1978 OSHA 

lead standard. Am J Ind Med 45(6):558-572. 

Oldereid NB, Thomassen Y, Attramadal A, et al. 1993. Concentrations of lead, cadmium and zinc in the 

tissues of reproductive organs of men. J Reprod Fertil 99:421-425. 

Olson KW, Skogerboe RK. 1975. Identification of soil lead compounds from automotive sources. 

Environ Sci Technol 9:227-230. 

Omae K, Sakurai H, Higashi T, et al. 1990. No adverse effects of lead on renal function in lead-exposed 

workers. Ind Health 28:77-83. 

Omar M, Ibrahim M, Assem H, et al. 2001. Teeth and blood lead levels in Egyptian schoolchildren: 

Relationship to health effects. J Appl Toxicol 21:349-352. 
LEAD 489 

9. REFERENCES 

Onalaja AO, Claudio L. 2000. Genetic susceptibility to lead poisoning. Environ Health Perspect Suppl 

108:23-28. 

Ong CN, Lee WR. 1980a. Distribution of lead-203 in human peripheral blood in vitro. Br J Ind Med 

37:78-84 

Ong CN, Lee WR. 1980c. High affinity of lead for fetal hemoglobin. Br J Ind Med 37:292-298. 

Ong CN, Lee WR. 1980b. Interaction of calcium and lead in human erythrocytes. Br J Ind Med 37:70­

77. 

*Ong CN, Endo G, Chia KS, et al. 1987. Evaluation of renal function in workers with low blood lead 

levels. In: Fao V, Emmett EA, Maroni M, et al., eds. Occupational and environmental chemical hazards. 

Chichester: Ellis Horwood Limited, 327-333. 

Ong CN, Phoon WO, Law HY, et al. 1985. Concentrations of lead in maternal blood, cord blood, and 

breast milk. Arch Dis Child 60:756-759. 

Oomen AG, Tolls J, Sips AJAM, et al. 2003a. Lead speciation in artificial human digestive fluid. Arch 

Environ Contam Toxicol 44:107-115. 

Oomen AG, Rompelberg CJM, Bruil MA, et al. 2003b. Development of an in vitro digestion model for 

estimation of bioaccessibility of soil contaminants. Arch Environ Contam Toxicol 44(3):281-287. 

Opler MGA, Brown AS, Graziano J, et al. 2004. Prenatal lead exposure, δ-aminolevulinic acid, and 

schizophrenia. Environ Health Perspect 112(5):548-552. 

O’Riordan ML, Evans HJ. 1974. Absence of significant chromosome damage in males occupationally 

exposed to lead. Nature 247:50-53. 

O’Rourke MK, Van de Water PK, Jin S, et al. 1999. Evaluations of primary metals from NHEXAS 

Arizona: Distributions and preliminary exposures. J Expo Anal Environ Epidemiol 9:435-445. 

Orssaud G, Claude JR, Moreau T, et al. 1985. Blood lead concentration and blood pressure. Br Med J 

290:244. 

OSHA. 1993. Lead exposure in construction. Interim Final Rule. U.S. Department of Labor. 

Occupational Safety and Health Administration. May 4, 1993. Fed Regist 58:26590. 

OSHA. 2005a. Air contaminants. Occupational safety and health standards for shipyard employment. 

Washington, DC: Occupational Safety and Health Administration. Code of Federal Regulations. 29 

CFR 1915.1000. http://www.osha.gov/comp-links.html. February 15, 2005. 

OSHA. 2005b. Gases, vapors, fumes, dusts, and mists. Safety and health regulations for construction. 

Washington, DC: Occupational Safety and Health Administration. Code of Federal Regulations. 29 

CFR 1926.55, Appendix A. http://www.osha.gov/comp-links.html. February 15, 2005. 

OSHA. 2005c. Limits for air contaminants. Occupational safety and health standards. Washington, DC: 

Occupational Safety and Health Administration. Code of Federal Regulations. 29 CFR 1910.1000. 

http://www.osha.gov/comp-links.html. February 15, 2005. 
LEAD 490 

9. REFERENCES 

OSHA. 2005d. Toxic and Hazardous Substances. Occupational safety and health standards. 

Washington, DC: Occupational Safety and Health Administration. Code of Federal Regulations. 29 

CFR 1910.1025. http://www.osha.gov/comp-links.html. March 25, 2005. 

OSHA. 2005e. Occupational safety and health standards for shipyard. Washington, DC: Occupational 

Safety and Health Administration. Code of Federal Regulations. 40 CFR 1915.1025. 

http://www.osha.gov/comp-links.html. May 26, 2005. 

OSHA. 2005f. Occupational safety and health standards for shipyard. Washington, DC: Occupational 

Safety and Health Administration. Code of Federal Regulations. 40 CFR 1926.62. 

http://www.osha.gov/comp-links.html. May 26, 2005. 

Oskarsson A, Fowler BA. 1985. Effects of lead inclusion bodies on subcellular distribution of lead in rat 

kidney: The relationship to mitochondrial function. Exp Mol Pathol 43:397-408. 

Oskarsson A, Jorhem L, Sundberg J, et al. 1992. Lead poisoning in cattle-transfer of lead to milk. Sci 

Total Environ 111:83-94. 

Osman K, Pawlas K, Schutz A, et al. 1999. Lead exposure and hearing effects in children in Katowice, 

Poland. Environ Res 80:1-8. 

Osterode W, Barnas U, Geissler K. 1999. Dose dependent reduction of erythroid progenitor cells and 

inappropriate erythropoietin response in exposure to lead: New aspects of anaemia induced by lead. 

Occup Environ Med 56:106-109. 

Otto D, Fox DA. 1993. Auditory and visual dysfunction following lead exposure. Neurotoxicology 

14(2-3):191-208. 

*Otto D, Benignus VA, Muller K, et al. 1981. Effects of age and body lead burden on CNS function in 

young children: I. Slow cortical potentials. Electroencephalogr Clin Neurophysiol 52:229-239. 

*Otto D, Benignus V, Muller K, et al. 1982. Effects of low to moderate lead exposure on slow cortical 

potential in young children: Two year follow-up study. Neurobehav Toxicol Teratol 4:733-737. 

Otto D, Robinson G, Baumann S, et al. 1985. Five-year follow-up study of children with low-tomoderate lead absorption: Electrophysiological evaluation. Environ Res 38:168-186. 

Ou L-T, Jing W, Thomas JE. 1995. Biological and chemical degradation of ionic ethyllead compounds 

in soil. Environ Toxicol Chem 14(4):545-551. 

Ou LT, Thomas JE, Jing TW. 1994. Biological and chemical degradation of tetraethyl lead in soil. Bull 

Environ Contam Toxicol 52:238-245. 

Owen GM, Brozek J. 1966. Influence of age, sex and nutrition on body composition during childhood 

and adolescence. In: Falkner F, ed. Human development. Philadelphia, PA: WB Saunders, 222-238. 

Paglia DE, Valentine WN, Dahigren JG. 1975. Effects of low-level lead exposure on pyrimidine 5'­

nucleotidase and other erythrocyte enzymes: Possible role of pyrimidine 5'-nucleotidase in the 

pathogenesis of lead-induced anemia. J Clin Invest 56:1164-1169. 
LEAD 491 

9. REFERENCES 

Paglia DE, Valentine WN, Fink K. 1977. Lead poisoning: Further observations on erythrocyte 

pyrimidine-nucleotidase deficiency and intracellular accumulation of pyrimidine nucleotides. J Clin 

Invest 60:1362-1366. 

Pagliuca A, Mufti GJ, Baldwin D, et al. 1990. Lead-poisoning: Clinical, biochemical, and 

hematological aspects of a recent outbreak. J Clin Path 43:277-281. 

Palmer KT, Kucera CL. 1980. Lead contamination of sycamore and soil from lead mining and smelting 

operations in eastern Missouri. J Environ Qual 9:106-111. 

PAN Pesticides Database. 2004. PAN pesticides database-chemicals. San Francisco, CA: Pesticide 

Action Network. http://www.pesticideinfo.org/List_Chemicals.jsp?. March 23, 2005. 

Pardo R, Barrado E, Perez L, et al. 1990. Determination and speciation of heavy metals in sediments of 

the Pisuerga River. Water Res 24(3):373-379. 

Parkinson DK, Hodgson MJ, Bromet EJ, et al. 1987. Occupational lead exposure and blood pressure. Br 

J Ind Med 44:744-748. 

Parkinson DK, Ryan C, Bormet J, et al. 1986. A psychiatric epidemiologic study of occupational lead 

exposure. Am J Epidemiol 123:261-269. 

Parramore CS, Morgan BW, Ethridge MW. 2001. Lead contaminated moonshine: A report of ATF 

analyzed samples. J Toxicol Clin Toxicol 39(5):520. 

Pasternak G, Becker CE, Lash A, et al. 1989. Cross-sectional neurotoxicology study of lead-exposed 

cohort. Clin Toxicol 27:37-51. 

Payton M, Hu H, Sparrow D, et al. 1994. Low-level lead exposure and renal function in the normative 

aging study. Am J Epidemiol 140(9):821-829. 

Payton M, Riggs KM, Spiro A III, et al. 1998. Relations of bone and blood lead to cognitive function: 

The VA normative aging study. Neurotoxicol Teratol 20(1):19-27. 

Peden DB. 2000. Development of atopy and asthma: Candidate environmental influences and important 

periods of exposure. Environ Health Perspect 108(suppl 3):475-482. 

Pellizzari ED, Perritt RL, Clayton CA. 1999. National human exposure assessment survey (NHEXAS): 

Exploratory survey of exposure among population subgroups in EPA region V. J Expo Anal Environ 

Epidemiol 9:49-55. 

Pérez-Bravo F, Ruz M, Moran-Jimenez MJ, et al. 2004. Association between aminolevulinate dehydrase 

genotypes and blood lead levels in children from a lead-contaminated area in Antofagasta, Chile. Arch 

Environ Contam Toxicol 47:276-280. 

Pergande M, Junk K, Precht S, et al. 1994. Changed excretion or urinary proteins and enzymes by 

chronic exposure to lead. Nephrol Dial Transplant 9:613-618. 

Perneger TW, Nieto FJ, Whelton PK, et al. 1993. A prospective study of blood pressure and serum 

creatinine: Results from the ‘clue’ study and the ARIC study. JAMA 269:488-93. 
LEAD 492 

9. REFERENCES 

Peryea FJ. 1998. Historical use of lead arsenate insecticides, resulting soil contamination and 

implications for soil remediation. Wenatchee, WA: Tree Fruit Research and Extension Center, 

Washington State University. 

Peterson KE, Salganik M, Campbell C, et al. 2004. Effect of succimer on growth of preschool children 

with moderate blood lead levels. Environ Health Perspect 112(2):233-237. 

Piccinini F, Favalli L., Chiari MC. 1977. Experimental investigations on the contraction induced by lead 

in arterial smooth muscle. Toxicology 8:43-51. 

Pierzynski GM, Schwab AP. 1993. Bioavailability of zinc, cadmium, and lead in a metal contaminated 

alluvial soil. J Environ Qual 22:247-254. 

Pinkerton LE, Biagini RE, Ward EM, et al. 1998. Immunologic findings among lead-exposed workers. 

Am J Ind Med 33(4):400-408. 

Pinto de Almeida AR, Carvalho FM, Spinola AG, et al. 1987. Renal dysfunction in Brazilian lead 

workers. Am J Nephrol 7:455-458. 

Piomelli S, Seaman C, Zullow D, et al. 1982. Threshold for lead damage to heme synthesis in urban 

children. Proc Natl Acad Sci 7:3335-3339. 

Pirkle JL, Brody DJ, Gunter EW, et al. 1994. The decline in blood lead levels in the United States. The 

National Health and Nutrition Examination Surveys (NHANES). JAMA 272:284-291. 

Pirkle JL, Kaufmann RB, Brody DJ, et al. 1998. Exposure of the U.S. population to lead, 1991-1994. 

Environ Health Perspect 106(11):745-750. 

Pirkle JL, Schwartz J, Landis JR, et al. 1985. The relationship between blood lead levels and blood 

pressure and its cardiovascular risk implications. Am J Epidemiol 121:246-258. 

Platt B, Busselberg D. 1994. Combined actions of Pb2

, Zn2, and Al3 on voltage-activated calcium 

channel currents. Cell Mol Neurobiol 14:831-840. 

Pocock SJ, Ashby D, Smith MA. 1987. Lead exposure and children's intellectual performance. Int J 

Epidemiol 16:57-67. 

*Pocock SJ, Ashby D, Smith MA. 1989. Lead exposure and children's intellectual performance: The 

Institute of Child Health/Southhampton Study. In: Smith M, Grant LD, Sors A, eds. Lead exposure and 

child development: An international assessment. Hingham, MA: Kluwer Academic Publishers, 149­

165. 

Pocock SJ, Shaper AG, Ashby D, et al. 1984. Blood lead concentration, blood pressure, and renal 

function. Br Med J 289:872-874. 

*Pocock SJ, Shaper AG, Ashby D, et al. 1985. Blood lead and blood pressure in middle-aged men. In: 

Lekkas TD, ed. International Conference on Heavy Metals in the Environment, Vol. 1, Athens, Greece, 

September. Edinburgh, United Kingdom: CEP Consultants, Ltd., 303-305. 

Pocock SJ, Shaper AG, Ashby D, et al. 1988. The relationship between blood lead, blood pressure, 

stroke, and heart attacks in middle-aged British men. Environ Health Perspect 78:23-30. 
LEAD 493 

9. REFERENCES 

Pocock SJ, Shaper AG, Walker M, et al. 1983. Effects of tap water lead, water hardness, alcohol, and 

cigarettes on blood lead concentrations. J Epidemiol Community Health 37:1-7. 

Pocock SJ, Smith M, Baghurst P. 1994. Environmental lead and children's intelligence: A systematic 

review of the epidemiological evidence. Br Med J 309:1189-1197. 

Pollock CA, Ibels LS. 1986. Lead intoxication in paint removal workers on the Sidney Harbour Bridge. 

Med J Aust 145:635-639. 

Poma A, Pittaluga E, Tucci A. 2003. Lead acetate genotoxicity on human melanoma cells in vitro. 

Melanoma Res 13(6):563-566. 

Porru S, Alessio L. 1996. The use of chelating agents in occupational lead poisoning. Occup Med 

46(1):41-48. 

*Poulos L, Qammaz S, Athanaselis S, et al. 1986. Statistically significant hematopoietic effects of low 

blood lead levels. Arch Environ Health 41:384-386. 

Pounds JG. 1984. Effect of lead intoxication on calcium homeostasis and calcium-mediated cell 

function: A review. Neurotoxicology 5:295-332. 

Pounds JG, Long GJ, Rosen JF. 1991. Cellular and molecular toxicity of lead in bone. Environ Health 

Perspect 91:17-32. 

Pounds JG, Marlar RJ, Allen JR. 1978. Metabolism of lead-210 in juvenile and adult Rhesus monkeys 

Macaca mulatta. Bull Environ Contam Toxicol 19:684-691. 

Preiss IL, Tariq MA. 1992. On the use of L X-ray fluorescence for bone lead evaluation. J Radioanal 

Nucl Chem 164:381-387. 

Proctor SP, Rotnitzky A, Sparrow D, et al. 1996. The relationship of blood lead and dietary calcium to 

blood pressure in the normative aging study. Int J Epidemiol 25(3):528-536. 

Prpic-Majic D, Bobic J, Simic D, et al. 2000. Lead absorption and psychological function in Zagreb 

(Croatia) school children. Neurotoxicol Teratol 22:347-356. 

Pueschel SM, Kopito L, Schwachman H. 1972. Children with an increased lead burden: A screening 

and follow-up study. JAMA 222:462-466. 

Purchase NG, Fergusson JE. 1986. Lead in teeth: The influence of the tooth type and the sample within 

a tooth on lead levels. Sci Total Environ 52:239-250. 

Purdy RE, Smith JR, Ding Y, et al. 1997. Lead-induced hypertension is not associated with altered 

vascular reactivity in vitro. Am J Hypertens 10:997-1003. 

Quarterman J, Morrison JN. 1975. The effects of dietary calcium and phosphorus on the retention and 

excretion of lead in rats. Br J Nutr 34:351-362. 

Quarterman J, Morrison E, Morrison JN, et al. 1978. Dietary protein and lead retention. Environ Res 

17:68-77. 
LEAD 494 

9. REFERENCES 

Que Hee SS. 1994. Availability of elements in leaded/unleaded automobile exhausts, a leaded paint, a 

soil, and some mixtures. Arch Environ Contam Toxicol 27:145-153. 

Que Hee SS, Boyle JR. 1988. Simultaneous multi-elemental analysis of some environmental and 

biological samples by inductively coupled plasma atomic emission spectrometry. Anal Chem 60:1033­

1042. 

Que Hee SS, MacDonald TJ, Bornschein RL. 1985a. Blood lead by furnace-Zeeman atomic absorption 

spectrophotometrv. Microchem J 32:55-63. 

Que Hee SS, Peace B, Clark CS, et al. 1985b. Evolution of efficient methods to sample lead sources, 

such as house dust and hand dust, in the homes of children. Environ Res 38:77-95. 

Quintanilla-Vega B, Hoover DJ, Bal W, et al. 2000. Lead interaction with human protamine (HP2) as a 

mechanism of male reproductive toxicity. Chem Res Toxicol 13:594-600. 

Rabinowitz MB. 1995. Relating tooth and blood lead levels in children. Bull Environ Contam Toxicol 

55:853-857. 

Rabinowitz MB, Bellinger D, Leviton A, et al. 1987. Pregnancy hypertension, blood pressure during 

labor, and blood lead levels. Hypertension 10:447-451. 

Rabinowitz MB, Kopple JD, Wetherill GW. 1980. Effect of food intake on fasting gastrointestinal lead 

absorption in humans. Am J Clin Nutr 33:1784-1788. 

Rabinowitz MB, Leviton A, Bellinger D. 1985. Home refinishing, lead paint and infant blood lead 

levels. Am J Public Health 75:403-404. 

Rabinowitz MB, Leviton A, Bellinger D. 1989. Blood lead-tooth lead relationship among Boston 

children. Bull Environ Contam Toxicol 43:485-492. 

Rabinowitz MB, Leviton A, Bellinger D. 1993. Relationships between serial blood lead levels and 

exfoliated tooth dentin lead levels: Models of tooth lead kinetics. Calcif Tissue Int 53(5):338-41. 

Rabinowitz MB, Leviton A, Needleman H. 1986. Occurrence of elevated protoporphyrin levels in 

relation to lead burden in infants. Environ Res 39:253-257. 

Rabinowitz MB, Wetherill GW, Kopple JD. 1976. Kinetic analysis of lead metabolism in healthy 

humans. J Clin Invest 58:260-270. 

Raghavan SRV, Gonick HC. 1977. Isolation of low-molecular-weight lead-binding protein from human 

erythrocytes. Proc Soc Exp Biol Med 155:164-167. 

Ramel C, Magnusson J. 1979. Chemical induction of nondisjunction in Drosophila. Environ Health 

Perspect 3:59-66. 

Ratzon N, Froom P, Leikin E, et al. 2000. Effect of exposure to lead on postural control in workers. 

Occup Environ Med 57:201-203. 
LEAD 495 

9. REFERENCES 

Ravnskov U. 1992. Cholesterol lowering trials in coronary heart disease: Frequency of citation and 

outcome. Br Med J 305:15-19. 

Raymond LW, Ford MD, Coldham GJ, et al. 2002. Maternal-fetal lead poisoning in a convenience store 

cashier: Effects of a 15-year old bullet. J Investig Med 50(1):54A. 

Reagan PL, Silbergeld EK. 1990. Establishing a health based standard for lead in residential soils. Trace 

Subst Environ Health 23:199-238. 

Reddy KJ, Wang L, Gloss SP. 1995. Solubility and mobility of copper, zinc and lead in acidic 

environments. Plant Soil 171:53-58. 

Reed BE, Moore RE, Cline SR. 1995. Soil flushing of a sandy loam contaminated with Pb(II), PbS04 

(s), PbCo3 (3) or Pb-naphthalene: Column results. J Soil Contam 4(3):243-267. 

Refowitz RM. 1984. Thyroid function and lead: No clear relationship. J Occup Med 26(8):579-583. 

Reigart JR, Graber CD. 1976. Evaluation of the humoral immune response of children with low level 

lead exposure. Bull Environ Contam Toxicol 16:112-117. 

Reimer W, Tittelbach U. 1989. Verhalten von herzfrequenz, blutdruck und systolischen zeitintervallen in 

ruhe und während einhandarbeit bei bleiexponierten und kontrollpersonen. Z Gesamte Hyg 35:491-492. 

Rhoads GG, Ettinger AS, Weisel CP, et al. 1999. The effect of dust lead control on blood lead in 

toddlers: A randomized trial. Pediatrics 103(3):551-555. 

Rhodes D, Spiro A, Aro A, et al. 2003. Relationship of bone and blood lead levels to psychiatric 

symptoms: The normative aging study. J Occup Environ Med 45:1144-1151. 

Rice DC. 1984. Behavioral deficit (delayed matching to sample) in monkeys exposed from birth to low 

levels of lead. Toxicol Appl Pharmacol 75:337-345. 

Rice DC. 1985. Chronic low-lead exposure from birth produces deficits in discrimination reversal in 

monkeys. Toxicol Appl Pharmacol 77:201-210. 

Rice DC. 1990. Lead-induced behavioral impairment on a spatial discrimination reversal task in 

monkeys exposed during different periods of development. Toxicol Appl Pharmacol 106:327-333. 

Rice DC. 1992. Behavioral effects of lead in monkeys tested during infancy and adulthood. 

Neurotoxicol Teratol 14:235-245. 

Rice DC. 1993. Lead-induced changes in learning: Evidence for behavioral mechanisms from 

experimental animal studies. Neurotoxicology 14(2-3):167-178. 

Rice DC. 1996a. Behavioral effects of lead: Commonalities between experimental and epidemiologic 

data. Environ Health Perspect Suppl 104:337-351. 

Rice DC. 1996b. Effect of long-term lead exposure on hematology, blood biochemistry, and growth 

curves in monkeys. Neurotoxicology 18:221-236. 
LEAD 496 

9. REFERENCES 

Rice DC. 1997. Effects of lifetime lead exposure in monkeys on detection of pure tones. Fundam Appl 

Toxicol 36(2):112-118. 

Rice DC. 1998. Effects of a lifetime lead exposure on spatial and temporal visual function in monkeys. 

Neurotoxicology 19(6):893-902. 

Rice DC, Gilbert SG. 1985. Low-level lead exposure from birth produces behavioral toxicity (DRL) in 

monkeys. Toxicol Appl Pharmacol 80:421-426. 

Rice DC, Gilbert SG. 1990a. Lack of sensitive period for lead-induced behavioral impairment on a 

spatial delayed alternation task in monkeys. Toxicol Appl Pharmacol 103:364-373. 

Rice DC, Gilbert SG. 1990b. Sensitive periods for lead-induced behavioral impairment (nonspatial 

discrimination reversal) in monkeys. Toxicol Appl Pharmacol 102:101-109. 

Rice DC, Karpinski KF. 1988. Lifetime low-level lead exposure produces deficits in delayed alternation 

in adult monkeys. Neurotoxicol Teratol 10:207-214. 

Rice DC, Willes RF. 1979. Neonatal low-level lead exposure in monkeys (Macaca fascicuiaris): Effect 

on two choice non-spatial form discrimination. J Environ Pathol Toxicol 2:1195-1203. 

Richardt G, Federolf G, Haberman E. 1986. Affinity of heavy metal ions to intracellular Ca2

-binding 

proteins. Biochem Pharmacol 35:1331-1335. 

Ris MD, Dietrich KN, Succop PA, et al. 2004. Early exposure to lead and neuropsychological outcome 

in adolescence. J Int Neuropsychol Soc 10:261-270. 

Roberts TM, Hutchinson TC, Paciga J. 1974. Lead contamination around secondary smelters: 

Estimation of dispersal and accumulation by humans. Science 186:1120-1123. 

Robins JM, Cullen MR, Connors BB, et al. 1983. Depressed thyroid indexes associated with 

occupational exposure to inorganic lead. Arch Intern Med 143:220-224. 

Robinson GS, Baumann S, Kleinbaum D, et al. 1985. Effects of low to moderate lead exposure on 

brainstem auditory evoked potentials in children: Environmental health document 3. Copenhagen, 

Denmark: World Health Organization Regional Office for Europe, 177-182. 

*Robinson GS, Keith RW, Bornschein RL, et al. 1987. Effects of environmental lead exposure on the 

developing auditory system as indexed by the brainstem auditory evoked potential and pure tone hearing 

evaluations in young children. In: Lindberg SE, Hutchinson TC., eds. International Conference on 

Heavy Metals in the Environment, Vol. 1, New Orleans, LA. September. Edinburgh, UK: CEP 

Consultants, Ltd., 223-225. 

Robison SH, Cantoni O, Costa M. 1984. Analysis of metal-induced DNA lesions and DNA-repair 

replication in mammalian cells. Mutat Res 131:173-181. 

Rodamilans M, Osaba MJ, To-Figueras J, et al. 1988. Lead toxicity on endocrine testicular function in 

an occupationally exposed population. Hum Toxicol 7:125-128. 
LEAD 497 

9. REFERENCES 

Roels HA, Lauwerys R. 1987. Evaluation of dose-effect and dose-response relationships for lead 

exposure in different Belgian population groups (fetus, child, adult men and women). Trace Elem Med 

4:80-87. 

Roels HA, Balis-Jacques MN, Buchet J-P, et al. 1979. The influence of sex and of chelation therapy on 

erythrocyte protoporphyrin and urinary δ-aminolevulinic acid in lead-exposed workers. J Occup Med 

21:527-539. 

Roels HA, Buchet J, Lauwerys R, et al. 1976. Impact of air pollution by lead on the hemebiosynthetic 

pathway in school-age children. Arch Environ Health 31:310-316. 

Roels HA, Buchet J, Lauwerys R, et al. 1980. Exposure to lead by the oral and the pulmonary routes of 

children living in the vicinity of a primary lead smelter. Environ Res 22:81-94. 

*Roels HA, Hubermont G, Buchet J, et al. 1978. Placental transfer of lead, mercury, cadmium, and 

carbon monoxide in women: III. Factors influencing the accumulation of heavy metals in the placenta 

and the relationship between metal concentration in the placenta and in maternal and cord blood. Environ 

Res 16:236-247. 

Roels HA, Konings J, Green S, et al. 1995. Time-integrated blood lead concentration is a valid surrogate 

for estimating the cumulative lead dose assessed by tibial lead measurement. Environ Res 69(2):75-82. 

Roels HA, Lauwerys R, Buchet J-P, et al. 1975. Response of free erythrocyte porphyrin and urinarydelta-aminolevulinic acid in men and women moderately exposed to lead. Int Arch Arbeitsmed 34:97­

108. 

Roels HA, Lauwerys R, Konings J, et al. 1994. Renal function and hyperfiltration capacity in lead 

smelter workers with high bone lead. Occup Environ Med 51:505-512. 

Rogan WJ, Dietrich KN, Ware JH, et al. 2001. The effect of chelation therapy with succimer on 

neuropsychological development in children exposed to lead. N Engl J Med 344(19):1421-1426. 

Rogan WJ, Hogan M, Chi P. 1978. Blood pressure and lead levels in children. J Environ Pathol Toxicol 

2:517-519. 

Romeo R, Aprea C, Boccalon P, et al. 1996. Serum erthropoietin and blood lead concentrations. Int 

Arch Occup Environ Health 69:73-75. 

Ronis MJJ, Aronson J, Gao GG, et al. 2001. Skeletal effects of developmental lead exposure in rats. 

Toxicol Sci 62:321-329. 

Ronis MJJ, Badger TM, Shema SJ, et al. 1996. Reproductive toxicity and growth effects in rats exposed 

to lead at different periods during development. Toxicol Appl Pharmacol 136:361-371. 

Ronis MJJ, Badger TM, Shema SJ, et al. 1998a. Effects on pubertal growth and reproduction in rats 

exposed to lead perinatally or continuously throughout development. J Toxicol Environ Health 

53(4):327-341. 

Ronis MJJ, Badger TM, Shema SJ, et al. 1998c. Endocrine mechanisms underlying the growth effects of 

developmental lead exposure in the rat. J Toxicol Environ Health 54:101-120. 
LEAD 498 

9. REFERENCES 

Ronis MJJ, Gandy J, Badger T. 1998b. Endocrine mechanisms underlying reproductive toxicity in the 

developing rat chronically exposed to dietary lead. J Toxicol Environ Health 54:77-99. 

Roscoe RJ, Ball W, Curran JJ, et al. 2002. Adult blood lead epidemiology and surveillance-United 

States, 1998-2001. MMWR Morb Mortal Wkly Rep 51(11):1-10. 

Roscoe RJ, Gittleman JL, Deddens JA, et al. 1999. Blood lead levels among children of lead-exposed 

workers: A meta-analysis. Am J Med 36(4):475-481. 

Rosen JF, Chesney RW. 1983. Circulating calcitriol concentration in health and disease. J Pediatr 

103:1-17. 

Rosen JF, Pounds JG. 1989. Quantitative interactions between Pb2

 and Ca2 homeostasis in cultured 

osteoclastic bone cells. Toxicol Appl Pharmacol 98:530-543. 

*Rosen I, Wildt K, Guilberg B, et al. 1983. Neurophysiological effects of lead exposure. Scand J Work 

Environ Health 9:431-441. 

Rosen JF, Chesney RW, Hamstra AJ, et al. 1980. Reduction in 1,25-dihydroxyvitamin D in children 

with increased lead absorption. N Engl J Med 302:1128-1131. 

Rosen JF, Crocetti AF, Balbi K, et al. 1993. Bone lead content assessed by L-line x-ray fluorescence in 

lead-exposed and non-lead-exposed suburban populations in the United States. Proc Natl Acad Sci USA 

90:2789-2792. 

Rosen JF, Markowitz ME, Jenks ST, et al. 1987. L-X-ray fluorescence (XRF): A rapid assessment of 

cortical bone lead (Pb) in Pb-toxic children. Pediatr Res 21:287A. 

Rosen JF, Zarate-Salvador C, Trinidad EE. 1974. Plasma lead levels in normal and lead-intoxicated 

children. J Pediatr 84:45-48. 

Rosenkranz HS, Poirier LA. 1979. Evaluation of the mutagenicity and DNA-modifying activity of 

carcinogens and noncarcinogens in microbial systems. J Natl Cancer Inst 62:873-892. 

Rosenman KD, Sims A, Luo Z, et al. 2003. Occurrence of lead-related symptoms below the current 

Occupational Safety and Health Act allowable blood lead levels. J Occup Environ Med 45(5):546-555. 

Rothenberg SJ, Rothenberg JC. 2005. Testing the dose-response specification in epidmiology: Public 

health and policy consequences for lead. Environ Health Perspect 113:1190-1195. 

*Rothenberg SJ, Cansino S, Sepkoski C, et al. 1995. Prenatal and perinatal lead exposures alter acoustic 

cry parameters of neonate. Neurotoxicol Teratol 17(2):151-160. 

Rothenberg SJ, Karchmer S, Schnaas L, et al. 1994a. Changes in serial blood lead levels during 

pregnancy. Environ Health Perspect 102(10):876-880. 

Rothenberg SJ, Kondrashov V, Manalo M, et al. 2002b. Increases in hypertention and blood pressure 

during pregnancy with increased bone lead levels. Am J Epidemiol 156:1079-1087. 

Rothenberg SJ, Manalo M, Jiang J, et al. 1999a. Blood lead level and blood pressure during pregnancy 

in South Central Los Angeles. Arch Environ Health 54(6):382-389. 
LEAD 499 

9. REFERENCES 

Rothenberg SJ, Manalo M, Jiang J, et al. 1999b. Maternal blood lead level during pregnancy in South 

Central Los Angeles. Arch Environ Health 54(3):151-157. 

Rothenberg SJ, Poblano A, Garza-Morales S. 1994b. Prenatal and perinatal low level lead exposure 

alters brainstem auditory evoked responses in infants. Neurotoxicology 15:695-700. 

Rothenberg SJ, Poblano A, Schnaas L. 2000. Brainstem auditory evoked response at five years and 

prenatal and postnatal blood lead. Neurotoxicol Teratol 22:503-510. 

Rothenberg SJ, Schnaas L, Cansino-Ortiz S, et al. 1989. Neurobehavioral deficits after low level lead 

exposure in neonates: The Mexico City pilot study. Neurotoxicol Teratol 11:85-93. 

Rothenberg SJ, Schnaas L, Perroni E, et al. 1999c. Pre- and postnatal lead effect on head circumference: 

A case for critical periods. Neurotoxicol Teratol 21:1-11. 

Rothenberg SJ, Schnaas L, Salgado-Valladares M, et al. 2002a Increased ERG a- and b-wave amplitudes 

in 7- to 10-year-old children resulting from prenatal lead exposure. Invest Ophthalmol Vis Sci 

43(6):2036-2044. 

Roy MM, Gordon CL, Beaumont LF, et al. 1997. Further experience with bone lead content 

measurements in residents of southern Ontario. Appl Radiat Isot 48:391-396. 

RTECS. 2007. Lead. Registry of Toxic Effects on Chemical Substances. National Institute of 

Occupational Safety and Health. MDL Information Systems, Inc. June 8, 2007. 

Ruby MV, Davis A, Kempton JH, et al. 1992. Lead bioavailability: Dissolution kinetics under 

simulated gastric conditions. Environ Sci Technol 26:1242-1248. 

Ruby MV, Davis A, Nicholson A. 1994. In situ formation of lead phosphates in soils as a method to 

immobilize lead. Environ Sci Technol 28:646-654. 

Ruby MV, Schoof R, Brattin W, et al. 1999. Advances in evaluating the oral bioavailability of 

inorganics in soil for use in human health risk assessment. Environ Sci Technol 33(21):3697-3705. 

Rudolph L, Sharp DS, Samuels S, et al. 1990. Environmental and biological monitoring for lead 

exposure in California workplaces. Am J Public Health 80:921-934. 

Ruff HA, Bijur PE, Markowitz M, et al. 1993. Declining blood lead levels and cognitive changes in 

moderately lead-poisoned children. JAMA 259(13):1641-1646. 

*Ruff HA, Markowitz ME, Bijur PE, et al. 1996. Relationships among blood lead levels, iron 

deficiency, and cognitive development in two-year-old children. Environ Health Perspect 104(2):180­

185. 

Rummo JH, Routh DK, Rummo NJ, et al. 1979. Behavioral and neurological effects of symptomatic and 

asymptomatic lead exposure in children. Arch Environ Health 34:120-125. 

*Ryan CM, Morrow L, Parkinson D, et al. 1987. Low level lead exposure and neuropsychological 

functioning in blue collar males. Int J Neurosci 36:29-39. 
LEAD 500 

9. REFERENCES 

Ryan PB, Huet N, MacIntosh DL. 2000. Longitudinal investigation of exposure to arsenic, cadmium, 

and lead in drinking water. Environ Health Perspect 108(8):731-735. 

Ryan PB, Scanlon KA, MacIntosh DL. 2001. Analysis of dietary intake of selected metals in the 

NHEXAS-Maryland investigation. Environ Health Perspect 109(2):121-128. 

Ryu JE, Ziegler EE, Nelson SE, et al. 1983. Dietary intake of lead and blood lead concentration in early 

infancy. Am J Dis Child 137:886-891. 

Sachs HK, Moel DI. 1989. Height and weight following lead poisoning in childhood. Am J Dis Child 

143:820-822. 

Saenger P, Markowitz ME, Rosen JF. 1984. Depressed excretion of 6β-hydroxycortisol in lead-toxic 

children. J Clin Endocrinol Metab 58:363-367. 

Sakai T. 2000. Biomarkers of lead exposure. Ind Health 38:127-142. 

Sakai T, Morita Y. 1996. δ-aminolevulinic acid in plasma or whole blood as a sensitive indicator of lead 

effects, and its relation to the other heme-related parameters. Int Arch Occup Environ Health 68(2):126­

132. 

Sakai T, Yanagihara S, Kunugi Y, et al. 1982. Relationships between distribution of lead in erythrocytes 

in vivo and in vitro and inhibition of ALA-D. Br J Ind Med 39:382-387. 

Sakai T, Yanagihara S, Kunugi Y, et al. 1983. Mechanisms of ALA-D inhibition by lead and of its 

restoration by zinc and dithiothreitol. Br J Ind Med 40:61-66. 

Sallmén M, Anttila A, Lindbohm M-L, et al. 1995. Time to pregnancy among women occupationally 

exposed to lead. J Occup Environ Med 37:931-934. 

Sallmén M, Lindbohm ML, Anttila A, et al. 2000a. Time to pregnancy among the wives of men 

occupationally exposed to lead. Epidemiology 11:141-147. 

Sallmén M, Lindbohm ML, Nurminen M. 2000b. Paternal exposure to lead and infertility. 

Epidemiology 11:148-152. 

Samanta G, Chakraborti D. 1996. Flow injection hydride generation atomic absorption spectrometry (FIHG-AAS) and spectrophotometric methods for determination of lead in environmental samples. Environ 

Technol 17(12):1327-1337. 

Sandhir R, Julka D, Gill KD. 1994. Lipoperoxidative damage on lead exposure in rat brain and its 

implications on membrane bound enzymes. Pharmacol Toxicol 74:66-71. 

Sanín LH, Gonzalez-Cossio T, Romieu I, et al. 2001. Effect of maternal lead burden on infant weight 

and weight gain at one month of age among breastfed infants. Pediatrics 107(55):1016-1023. 

Sarasua SM, Vogt RF, Henderson LO, et al. 2000. Serum immunoglobulins and lymphocyte subset 

distributions in children and adults living in communities assessed for lead and cadmium exposure. J 

Toxicol Environ Health A 60:1-15. 
LEAD 501 

9. REFERENCES 

Sarto F, Stella M, Acqua A. 1978. [Cytogenic studies in 20 workers occupationally exposed to lead.] 

Med Lav 69:172-180. (Italian) 

Sata F, Araki S, Tanigawa T, et al. 1998. Changes in T cell subpopulations in lead workers. Environ 

Res 76(1):61-64. 

Satzger RD, Clow CS, Bonnin E, et al. 1982. Determination of background levels of lead and cadmium 

in raw agricultural crops by using differential pulse anodic stripping voltammetry. J Assoc Off Anal 

Chem 65:987-991. 

Sauk JJ, Smith T, Silbergeld EK, et al. 1992. Lead inhibits secretion of osteonectin/sparc without 

significantly altering collagen or hsp47 production in osteoblast-like ros 17/2.8 cells. Toxicol Appl 

Pharmacol 116(2):240-247. 

Sauve S, McBride MB, Hendershot WH. 1997. Speciation of lead in contaminated soils. Environ Pollut 

98(2):149-155. 

Sax NI. 1984. Dangerous properties of industrial materials. 6th ed. New York, NY: Van Nostrand 

Reinhold Company, 2641. 

Sax NI, Lewis RJ. 1987. Hawley's condensed chemical dictionary. New York, NY: Van Nostrand 

Reinhold Company, 687-694. 

Scelfo GM, Flegal AR. 2000. Lead in calcium supplements. Environ Health Perspect 108(4):309-313. 

Schalscha EB, Morales M, Pratt P. 1987. Lead and molybdenum in soils and forage near an atmospheric 

source. J Environ Qual 16:313-315. 

Schaumberg DA, Mendes F, Balaram M, et al. 2004. Accumulated lead exposure and risk of age-related 

cataract in men. JAMA 292(22):2750-2754. 

Schmid E, Bauchinger M, Pietruck S, et al. 1972. [Cytogenic action of lead in human peripheral 

lymphocytes in vitro and in vivo.] Mutat Res 16:401-406. (German) 

Schmitt CJ, Brumbaugh WG. 1990. National contaminant biomonitoring program: Concentration of 

arsenic, cadmium, cooper, lead, mercury, selenium, and zinc in U.S. freshwater fish, 1976-1984. Arch 

Environ Contam Toxicol 19:731-747. 

Schmitt MDC, Trippler DL, Wachtler JN, et al. 1988. Soil lead concentrations in residential Minnesota 

as measured by ICP AES. Water Air Soil Pollut 39:157-168. 

Schnaas L, Rothenberg SJ, Flores MF. 2006. Reduced intellectual development in children with prenatal 

lead exposure. Environ Health Perspect 114(5):791-797. 

Schnaas L, Rothenberg SJ, Perroni E, et al. 2000. Temporal pattern in the effect of postnatal blood lead 

level on intellectual development of young children. Neurotoxicol Teratol 22:805-810. 

Schneider JS, Lee MH, Anderson DW, et al. 2001. Enriched environment during development is 

protective against lead-induced neurotoxicity. Brain Res 896:48-55. 
LEAD 502 

9. REFERENCES 

Schneitzer L, Osborn HH, Bierman A, et al. 1990. Lead poisoning in adults from renovation of an older 

home. Ann Emerg Med 19:415-420. 

Schober SE, Mirel LB, Graubard BI, et al. 2006. Blood lead levels and death from all causes, 

cardiovascular disease, and cancer: Results from the NHANES III mortality study. Environ Health 

Perspect 114(10):1538-1541. 

Schroeder HA, Tipton IH. 1968. The human body burden of lead. Arch Environ Health 17:965-978. 

Schroeder SR, Hawk B. 1987. Psycho-social factors, lead exposure and IQ. Monogr Am Assoc Ment 

Defic S:97-137. 

*Schroeder SR, Hawk B, Otto DA, et al. 1985. Separating the effects of lead and social factors on IQ. 

Environ Res 38:144-154. 

Schuhmacher M, Hernandez M, Domingo JL, et al. 1996. A longitudinal study of lead mobilization 

during pregnancy: Concentration in maternal and umbilical cord blood. Trace Elements and Electrolytes 

13:177-181. 

Schuhmacher M, Paternain JL, Domingo JL, et al. 1997. An assessment of some biomonitors indicative 

of occupational exposure to lead. Trace Elem Electrolytes 14(3):145-149. 

Schumacher C, Brodkin CA, Alexander B, et al. 1998. Thyroid function in lead smelter workers: 

Absence of subacute or cumulative effects with moderate lead burdens. Int Arch Occup Environ Health 

71:453-458. 

Schütz A, Bergdahl IA, Ekholm A, et al. 1996. Measurement by ICP-MS of lead in plasma and whole 

blood of lead workers and controls. Occup Environ Med 53:736-740. 

Schutz A, Skerfving S, Ranstam J, et al. 1987. Kinetics of lead in blood after the end of occupational 

exposure. Scand J Work Environ Health 13:221-231. 

Schwanitz G, Gebhart E, Rott HD, et al. 1975. [Chromosome investigations in subjects with 

occupational lead exposure.] Deutsch Med Wschr 100:1007-1011. (German) 

Schwanitz G, Lenhert G, Gebhart E. 1970. [Chromosome damage after occupational exposure to lead.] 

Deutsch Med Wschr 95:1636-1641. (German) 

Schwartz J. 1988. The relationship between blood lead and blood pressure in the NHANES II survey. 

Environ Health Perspect 78:15-22. 

Schwartz J. 1994. Low-level lead exposure and children's IQ: A meta-analysis and search for a 

threshold. Environ Res 65:42-55. 

Schwartz J. 1995. Lead, blood pressure, and cardiovascular disease in men. Arch Environ Health 50:31­

37. 

Schwartz J, Otto DA. 1987. Blood lead, hearing thresholds, and neurobehavioral development in 

children and youth. Arch Environ Health 42:153-160. 

Schwartz J, Otto DA. 1991. Lead and minor hear impairment. Arch Environ Health 46:300-305. 
LEAD 503 

9. REFERENCES 

Schwartz BS, Stewart WF. 2000. Different associations of blood lead, meso 2,3-dimercaptosuccinic acid 

(DMSA)-chelatable lead, and tibial lead levels with blood pressure in 543 organolead manufacturing 

workers. Arch Environ Health 55:85-92. 

Schwartz BS, Lee BK, Bandeen-Roche K, et al. 2005. Occupational lead exposure and longitudinal 

decline in neurobehavioral test scores. Epidemiology 16(1):106-113. 

Schwartz BS, Lee BK, Lee GS, et al. 2000a. Associations of blood lead, dimercaptosuccinic acidchelatable lead, and tibia lead with polymorphisms in the Vitamin D receptor and d-aminolevulinic acid 

dehydratase genes. Environ Health Perspect 108:949-954. 

Schwartz BS, Lee BK, Lee GS, et al. 2001. Associations of blood lead, dimercaptosuccinic acidchelatable lead, and tibia lead with neurobehavioral test scores in South Korean lead workers. Am J 

Epidemiol 153:453-464. 

Schwartz BS, Lee B-K, Stewart W, et al. 1997a. Associations of subtypes of hemoglobin with deltaaminolevulinic acid dehydratase genotype and dimercaptosuccinic acid-chelatable lead levels. Arch 

Environ Health 52(2):97-103. 

Schwartz BS, Lee BK, Stewart W, et al. 1997b. δ-aminolevulinic acid dehydratase genotype modifies 

four hour urinary lead excretion after oral administration of dimercaptosuccinic acid. Occup Environ 

Med 54(4):241-246. 

Schwartz BS, Stewart WF, Bolla KI, et al. 2000b. Past adult lead exposure is associated with 

longitudinal decline in cognitive function. Neurology 55:1144-1150. 

Schwartz J, Angle C, Pitchcr H. 1986. Relationship between childhood blood lead levels and stature. 

Pediatrics 77:281-288. 

Schwartz J, Landrigan PJ, Baker EL Jr. 1990. Lead-induced anemia: Dose-response relationships and 

evidence for a threshold. Am J Public Health 80:165-168. 

Schwartz J, Landrigan PJ, Feldman RG, et al. 1988. Threshold effect in lead-induced peripheral 

neuropathy. J Pediatr 112:12-17. 

Scinicariello F, Murray HE, Moffett DB, et al. 2007. Lead and δ-aminolevulinic acid dehydratase 

polymorphism: Where does it lead? A meta-analysis. Environ Health Perspect 115(1):35-41. 

Scott DR, Hemphill DC, Hoiboke LE, et al. 1976. Atomic absorption and optical emission analysis of 

NASN atmospheric particulate samples for lead. Environ Sci Technol 9:877-880. 

Secchi GC, Erba L, Cambiaghi G. 1974. Delta-aminolevulinic acid dehydrase, activity of erythrocytes 

and liver tissue in man: Relationship to lead exposure. Arch Environ Health 28:130-132. 

Sedman RM. 1989. The development of applied action levels for soil contact: A scenario for the 

exposure of humans to soil in a residential setting. Environ Health Perspect 79:291-313. 

Selander S, Cramer K. 1970. Interrelationships between lead in blood, lead in urine, and ALA in urine 

during lead work. Br J Ind Med 27:28-39. 
LEAD 504 

9. REFERENCES 

Selbst M, Sokas R, Hennetig F, et al. 1993. The effect of blood lead on blood pressure in children. J 

Envrion Pathol Toxicol Oncol 12:213-218. 

Selevan SG, Landrigan PJ, Stern FB, et al. 1985. Mortality of lead smelter workers. Am J Epidemiol 

122:673-683. 

Selevan SG, Landrigan PJ, Stern FB, et al. 1988. Lead and hypertension in a mortality study of lead 

smelter workers. Environ Health Perspect 78:65-66. 

Selevan SG, Rice DC, Hogan KA, et al. 2003. Blood lead concentration and delayed puberty in girls. N 

Engl J Med 348(16):1527-1536. 

Seppalainen AM, Hernberg S, Vesanto R, et al. 1983. Early neurotoxic effects of occupational lead 

exposure: A prospective study. Neurotoxicology 4:181-192. 

Setchell BP, Waites GMH. 1975. The blood-testis barrier. In: Creep RO, Astwood EB, Geiger SR, eds. 

Handbook of physiology: Endocrinology V. Washington, DC: American Physiological Society, 143­

172. 

Seto DSY, Freeman JM. 1964. Lead neuropathy in childhood. Am J Dis Child 107:337-342. 

Shaper AG, Pocock SJ, Walker M, et al. 1981. British regional heart study: Cardiovascular risk factors 

in middle-aged men in 24 towns. Br Med J 283:179-186. 

Sharp DS, Benowitz NL, Osterloh JD, et al. 1990. Influence of race, tobacco use, and caffeine use on the 

relationship between blood pressure and blood lead concentration. Am J Epidemiol 131(5):845-854. 

Sharp DS, Osterloh J, Becker CE, et al. 1988. Blood pressure and blood lead concentration in bus 

drivers. Environ Health Perspect 78:131-137. 

Sharp DS, Smith AH, Holman BL, et al. 1989. Elevated blood pressure in treated hypertensives with 

low-level lead accumulation. Arch Environ Health 44:18-22. 

Shea EE. 1996. Lead regulation handbook. Rockville, MD: Government Institutes. 

Shelton KR, Egle PM. 1982. The proteins of lead-induced intranuclear inclusion bodies. J Biol Chem
 

257(19):11802-11807. 

Shen XM, Wu SH, Yan CH, et al. 2001. δ-Aminolevulinate dehydratase polymorphism and blood lead 

levels in Chinese children. Environ Res 85:185-190. 

Shen XM, Yan C-H, Guo D, et al. 1998. Low-level prenatal lead exposure and neurobehavioral 

development of children in the first year of life: A prospective study in Shanghai. Environ Res 79:1-8. 

Sherlock JC, Quinn MJ. 1986. Relationship between blood and lead concentrations and dietary lead 

intake in infants: The Glasgow Duplicate Diet Study 1979-1980. Food Addit Contam 3:167-176. 

Sherlock JC, Ashby D, Delves HT, et al. 1984. Reduction in exposure to lead from drinking water and 

its effect on blood lead concentrations. Hum Toxicol 3:383-392. 
LEAD 505 

9. REFERENCES 

Sherlock JC, Smart G, Forbes GI, et al. 1982. Assessment of lead intakes and dose-response for a 

population in Ayr exposed to a plumbosolvent water supply. Hum Toxicol 1:115-122. 

Shiau CY, Wang JD, Chen PC. 2004. Decreased fecundity among male lead workers. Occup Environ 

Med 61:915-923. 

Shih RA, Glass TA, Bandeen-Roche K, et al. 2006. Environmental lead exposure and cognitive function 

in community-dwelling older adults. Neurology 67(9):1556-1562. 

*Shukla R, Bornschein RL, Dietrich KN, et al. 1987. Effects of fetal and early postnatal lead exposure 

on child's growth in stature--the Cincinnati lead study. In: Lindberg SE, Hutchinson TC, eds. 

International Conference on Heavy Metals in the Environment, Vol. 1. New Orleans, LA. Edinburgh, 

UK: CEP Consultants, Ltd., 210-212. 

Shukla R, Bornschein RL, Dietrich KN, et al. 1989. Fetal and infant lead exposure: Effects on growth in 

stature. Pediatrics 84:604-612. 

Shukla R, Dietrich KN, Bornschein RL, et al. 1991. Lead exposure and growth in the early preschool 

child: A follow-up report from the Cincinnati lead study. Pediatrics 88:886-892. 

Siegel M, Forsyth B, Siegel L, et al. 1989. The effect of lead on thyroid function in children. Environ 

Res 49:190-196. 

Silbergeld EK. 1987. Role of altered heme synthesis in chemical injury to the nervous system. Ann N Y 

Acad Sci 514:297-308. 

Silbergeld EK. 2003. Facilitative mechanisms of lead as a carcinogen. Mutat Res 533:121-133. 

Silbergeld EK, Hruska RE, Bradley D, et al. 1982. Neurotoxic aspects of porphyrinopathies: Lead and 

succinylacetone. Environ Res 29:459-471. 

Silbergeld EK, Quintanilla-Vega B, Gandley RE. 2003. Mechanisms of male mediated developmental 

toxicity induced by lead. Adv Exp Med Biol 518:37-48. 

Silbergeld EK, Schwartz J, Mahaffey K. 1988. Lead and osteoporosis: Mobilization of lead from bone 

in postmenopausal women. Environ Res 47:79-94. 

Silbergeld EK, Waalkes M, Rice JM. 2000. Lead as a carcinogen: Experimental evidence and 

mechanisms of action. Am J Ind Med 38:316-323. 

Silva PA, Hughes P, Williams S, et al. 1988. Blood lead, intelligence, reading attainment, and behavior 

in eleven year old children in Dunedin, New Zealand. J Child Psychol Psychiatry 29:43-52. 

*Silver W, Rodriguez-Torres R. 1968. Electrocardiographic studies in children with lead poisoning. 

Pediatrics 41:1124-1127. 

Simmon VF. 1979a. In vitro assays for recombinogenic activity of chemical carcinogens and related 

compounds with Saccharomyces cerevisiae D3. J Natl Cancer Inst 62:901-909. 

Simmon VF. 1979b. In vitro mutagenicity assays of chemical carcinogens and related compounds with 

Salmonella typhimurium. J Natl Cancer Inst 62:893-899. 
LEAD 506 

9. REFERENCES 

Simons TJB. 1985. Influence of lead ions on cation permeability in human red cell ghosts. J Membr 

Biol 84:61-71. 

Simons TJB. 1986b. Passive transport and binding of lead by human red blood cells. J Physiol 378:267­

286. 

Simons TJB. 1986a. The role of anion transport in the passive movement of lead across the human red 

cell membrane. J Physiol 378:287-312. 

Simons TJB. 1988. Active transport of lead by the calcium pump in human red cell ghosts. J Physiol 

405:105-113. 

Simons TJB. 1993. Lead transport and binding by human erythrocytes in vitro. Toxicol Lett 423:307­

313. 

Simons TJB, Pocock G. 1987. Lead enters bovine adrenal medullary cells through calcium channels. J 

Neurochem 48:383-389. 

Singh B, Chandran V, Bandhu HK, et al. 2000a. Impact of lead exposure on pituitary-thyroid axis in 

humans. BioMetals 13:187-192. 

Singh B, Dhawan D, Nehru B, et al. 1994. Impact of lead pollution on the status of other trace metals in 

blood and alterations in hepatic functions. Biol Trace Elem Res 40:21-29. 

Sirover, MA, Loeb LA. 1976. Infidelity of DNA synthesis in vitro: Screening for potential metal 

mutagens or carcinogens. Science 194:1434-1436. 

Six KM, Goyer RA. 1970. Experimental enhancement of lead toxicity by low dietary calcium. J Lab 

Clin Med 76:933-942. 

Six KM, Goyer RA. 1972. The influence of iron deficiency on tissue content and toxicity of ingested 

lead in the rat. J Lab Clin Med 79:128-136. 

Skerfving S. 1988. Biological monitoring of exposure to inorganic lead. In: Clarkson TW, Friberg L, 

Nordberg GF, et al., eds. Biological monitoring of toxic metals. New York, NY: Plenum Press, 169­

197. 

Skerfving S, Ahlgren L, Christoffersson J-O, et al. 1985. Metabolism of inorganic lead in man. Nutr 

Res Suppl 2:601-607. 

Skerfving S, Nilsson U, Schutz A, et al. 1993. Biological monitoring of inorganic lead. Scand J Work 

Environ Health 19(1):59-64. 

Skoczynska A, Smolik R, Jelen M. 1993. Lipid abnormalities in rats given small doses of lead. Arch 

Toxicol 67:200-204. 

Smith GR. 1995. Lead. In: Minerals yearbook: Volume I. Metals and minerals. Reston, VA: U.S. 

Department of the Interior, U.S. Geological Survey. 

http://minerals.usgs.gov/minerals/pubs/commodity/lead/380495.pdf. May 24, 2005. 
LEAD 507 

9. REFERENCES 

Smith GR. 1998. Lead: Lead statistics and information, mineral commodity summary, 1998. U.S. 

Department of the Interior, U.S. Geological Survey. 

http://minerals.er.usgs.gov/minerals/pubs/commodity/lead/. October 11, 1998. 

Smith CM, Deluca HF, Tanaka Y, et al. 1978. Stimulation of lead absorption by vitamin D 

administration. J Nutr 108:843-847. 

Smith CM, Deluca HF, Tanaka Y, et al. 1981. Effect of lead ingestion on functions of vitamin D and its 

metabolites. J Nutr 111:1321-1329. 

Smith CM, Wang X, Hu H, et al. 1995. A polymorphism in the δ-aminolevulinic acid dehydratase gene 

may modify the pharmacokinetics and toxicity of lead. Environ Health Perspect 103:248-253. 

Smith D, Hernandez-Avila M, Tellez-Rojo MM, et al. 2002. The relationship between lead in plasma 

and whole blood in women. Environ Health Perspect 110(3):263-268. 

Smith DR, Ilustre RP, Osterloh JD. 1998a. Methodological considerations for the accurate determination 

of lead in human plasma and serum. Am J Ind Med 33:430-438. 

Smith DR, Kahng MW, Quintanilla-Vega B, et al. 1998b. High-affinity renal lead-binding proteins in 

environmentally-exposed humans. Toxicol Appl Pharmacol 115:39-52. 

Smith D, Osterloh JD, Flegal AR. 1996. Use of endogenous, stable lead isotopes to determine release of 

lead from the skeleton. Environ Health Perspect 104(1):60-66. 

Smith D, Woolard D, Luck ML, et al. 2000. Succimer and the reduction of tissue lead in juvenile 

monkeys. Toxicol Appl Pharmacol 166:230-240. 

Smith FL II, Rathmell TK, Marcil GE. 1938. The early diagnosis of acute and latent plumbism. Am J 

Clin Pathol 8:471-508. 

Smith M, Delves T, Tansdown R, et al. 1983. The effects of lead exposure on urban children: The 

Institute of Child Health/Southampton study. Dev Med Child Neurol 25(suppl 47):1-54. 

Snyder JE, Filipov NM, Parsons PJ, et al. 2000. The efficiency of maternal transfer of lead and its 

influence on plasma IgE and splenic cellularity of mice. Toxicol Sci 57:87-94. 

Sokas RK, Simmens S, Sophar K, et al. 1997. Lead levels in Maryland construction workers. Am J Ind 

Med 31:188-194. 

Sokol RZ, Wang S, Wan YJY, et al. 2002. Long-term, low-dose lead exposure alters the gonadotropinreleasing hormone system in the male rat. Environ Health Perspect 110(9):871-874. 

Soldin OP, Pezzullo JC, Hanak B, et al. 2003. Changing trends in the epidemiology of pediatric lead 

exposure: Interrelationship of blood lead and ZPP concentrations and a comparison to the US population. 

Ther Drug Monit 25:415-420. 

Solliway BM, Schaffer A, Pratt H, et al. 1996. Effects of exposure to lead on selected biochemical and 

hematological variables. Pharmacol Toxicol 78:18-22. 
LEAD 508 

9. REFERENCES 

Somashekaraiah BV, Venkaiah B, Prasad ARK. 1990. Biochemical diagnosis of occupational exposure 

to lead toxicity. Bull Environ Contam Toxicol 44:268-275. 

Sonmez F, Donmez O, Sonmez HM, et al. 2002. Lead exposure and urinary N-acetyl B D 

glucosaminidase activity in adolescent workers in auto repair workshops. J Adolesc Health 30:213-216. 

Sorrell M, Rosen JF, Roginskv M. 1977. Interactions of lead, calcium, vitamin D, and nutrition in lead 

burdened children. Arch Environ Health 32:160-164. 

Sowers M, Jannausch M, Scholl T, et al. 2002a. Blood lead concentrations and pregnancy outcomes. 

Arch Environ Health 57(5):489-495. 

Sowers M, Scholl T, Hall G, et al. 2002b. Lead in breast milk and maternal bone turnover. Am J Obstet 

Gynecol 187(3):770-776. 

Spear TM, Svee W, Vincent JH, et al. 1998. Chemical speciation of lead dust associated with primary 

lead smelting. Environ Health Perspect 106(9):565-571. 

Spivey GH, Baloh RW, Brown CP, et al. 1980. Subclinical effects of chronic increased lead absorption-­

a prospective study: III. Neurologic findings at follow-up examination. J Occup Med 22:607-612. 

SRI. 2004. 2004 Directory of chemical producers. Menlo Park, CA: SRI Consulting.:787, 788, 689, 

690. 

Staessen JA, Buchet J-P, Ginucchio G, et al. 1996a. Public health implications of environmental 

exposure to cadmium and lead: An overview of epidemiological studies in Belgium. J Cardiovasc Risk 

3:26-41. 

Staessen JA, Bulpitt CJ, Roels H, et al. 1984. Urinary cadmium and lead concentrations and their 

relation to blood pressure in a population with low exposure. Br J Ind Med 41:241-248. 

Staessen JA, Lauwerys RR, Buchet JP, et al. 1992. Impairment of renal function with increasing blood 

lead concentrations in the general population. The cadmibel study group. N Engl J Med 327(3):151-156. 

Staessen JA, Lauwerys RR, Bulpitt CJ, et al. 1994. Is a positive association between lead exposure and 

blood pressure supported by animal experiments? Curr Opin Nephrol Hypertens 3(3):257-263. 

Staessen JA, O'Brien ET, Thijs L, et al. 2000. Modern approaches to blood pressure measurement. 

Occup Environ Med 57:510-520. 

Staessen JA, Roels H, Fagard R. 1996b. Lead exposure and conventional and ambulatory blood 

pressure. JAMA 275:1563-1570. 

Staessen JA, Yeoman WB, Fletcher AE, et al. 1990. Blood lead concentration, renal function, and blood 

pressure in London civil servants. Br J Ind Med 47:442-447. 

Stanek K, Manton W, Angle C, et al. 1998. Lead consumption of 18- to 36-month-old children as 

determined from duplicate diet collections: Nutrient intakes, blood lead levels, and effects on growth. J 

Am Diet Assoc 98(2):155-158. 
LEAD 509 

9. REFERENCES 

Stark AD, Quah RF, Meigs JW, et al. 1982. The relationship of environmental lead to blood-lead levels 

in children. Environ Res 27:372-383. 

Stauber JL, Florence TM. 1988. A comparative study of copper, lead, cadmium and zinc in human sweat 

and blood. Sci Total Environ 74:235-247. 

Stauber JL, Florence TM, Gulson BL, et al. 1994. Percutaneous absorption of inorganic lead 

compounds. Sci Total Environ 145:55-70. 

Steenhout A. 1982. Kinetics of lead storage in teeth and bones: An epidemiologic approach. Arch 

Environ Health 37(4):224-231. 

Steenhout A, Pourtois M. 1981. Lead accumulation in teeth as a function of age with different 

exposures. Br J Ind Med 38:297-303. 

Steenhout A, Pourtois M. 1987. Age-related lead kinetics in children. In: Trace elements in human 

health and disease, Second Nordic symposium, Odense, Denmark, August 17-21, 1987. Copenhagen, 

Denmark: World Health Organization, 144-147. 

Steenland K, Boffetta P. 2000. Lead and cancer in humans: Where are we now? Am J Ind Med 38:295­

299. 

Steenland K, Selevan S, Landrigan P. 1992. The mortality of lead smelter workers: An update. Am J 

Public Health 82:1641-1644. 

Stern AH. 1994. Derivation of a target level of lead in soil at residential sites corresponding to a de 

minimis contribution to blood lead concentration. Risk Anal 14(6):1049-1056. 

Stern AH. 1996. Derivation of a target concentration of Pb in soil based on elevation of adult blood 

pressure. Risk Anal 16:201-210. 

Sternowsky HJ, Wessolowski R. 1985. Lead and cadmium in breast milk. Arch Toxicol 57:41-45. 

Stewart WF, Schwartz BS, Davatzikos C, et al. 2006. Past adult lead exposure is linked to 

neurodegeneration measured by brain MRI. Neurology 66:1476-1484. 

Stewart WF, Schwartz BS, Simon D, et al. 1999. Neurobehavioral function and tibial and chelatable lead 

levels in 543 former organolead workers. Neurology 52:1610-1617. 

Stewart WF, Schwartz BS, Simon D, et al. 2002. ApoE genotype, past adult lead exposure, and 

neurobehavioral function. Environ Health Perspect 110(5):501-505. 

Stokes L, Letz R, Gerr F, et al. 1998. Neurotoxicity in young adults 20 years after childhood exposure to 

lead: The Bunker Hill experience. Occup Environ Med 55:507-516. 

Stokinger HE. 1981. Lead. In: Clayton GD, Clayton FE, eds. Patty's industrial hygiene and toxicology. 

Vol. 2A: Toxicology. New York, NY: John Wiley and Sons, 1687-1728. 

Stollery BT. 1996. Reaction time changes in workers exposed to lead. Neurotoxicol Teratol 18(4):477­

483. 
LEAD 510 

9. REFERENCES 

Stollery BT, Banks HA, Broadbent DE, et al. 1989. Cognitive functioning in lead workers. Br J Ind 

Med 46:698-707. 

Stollery BT, Broadbent DE, Banks HA, et al. 1991. Short term prospective study of cognitive 

functioning in lead workers. Br J Ind Med 48:739-749. 

Stretesky PB, Lynch MJ. 2001. The relationship between lead exposure and homicide. Arch Pediatr 

Adolesc Med 155:579-582. 

Stuik EJ. 1974. Biological response of male and female volunteers to inorganic lead. Int Arch 

Arbeitsmed 33:83-97. 

Stutz DR, Janusz SJ. 1988. Hazardous materials injuries: A handbook for pre-hospital care. 2nd ed. 

Beltsville, MD: Bradford Communications Corporation, 314-315. 

Succop P, Clark S, Tseng CY, et al. 2001. Evaluation of public housing lead risk assessment data. 

Environ Geochem Health 23:1-15. 

Sugawara E, Nakamura K, Miyake T, et al. 1991. Lipid peroxidation and concentration of flutathione in 

erythrocytes from workers exposed to lead. Br J Ind Med 48:239-242. 

Sun LR, Suszkiw JB. 1995. Extracellular inhibition and intracellular enhancement of Ca2

 currents by Pb2 

in bovine adrenal chromaffin cells. J Neurophysiol 74:574-581. 

Sun CC, Wong TT, Hwang YH, et al. 2002. Percutaneous absorption of inorganic lead compounds. Am 

Ind Hyg Assoc J 63:641-646. 

Sun L, Hu J, Zhao Z, et al. 2003. Influence of exposure to environmental leadon serum immunoglobulin 

in preschool children. Environ Res 92:124-128. 

Suszkiw JB. 2004. Presynaptic disruption of transmitter release by lead. Neurotoxicology 25:599-604. 

Sutherland CA, Milner EF. 1990. Lead. In: Elvers B, Hawkins S, Schulz G, eds. Ullmann's 

encyclopedia of industrial chemistry. 5th edition. New York, NY: VCH Publishers, 193-236. 

Süzen HS, Duydu Y, Aydin A, et al. 2003. Influence of the delta-aminolevulinic acid dehydratase 

(ALAD) polymorphism on biomarkers of lead exposure in Turkish storage battery manufacturing 

workers. Am J Ind Med 43:165-171. 

Swenberg JA, Short B, Borghoff S, et al. 1989. The comparative pathobiology of I2-globulin 

nephropathy. Toxicol Appl Phamacol 97:35-46. 

Symanski E, Hertz-Picciotto I. 1995. Blood lead levels in relation to menopause, smoking, and 

pregnancy history. Am J Epidemiol 141(11):1047-1058. 

Tabuchi T, Okayama A, Ogawa Y, et al. 1989. A new HPLC fluorimetric method to monitor urinary 

delta-aminolevulinic acid (ALA-U) levels in workers exposed to lead. Int Arch Occup Environ Health 

61:297-302. 

Tachi K, Nishimae S, Saito K. 1985. Cytogenic effects of lead acetate on rat bone marrow cells. Arch 

Environ Health 40:144-147. 
LEAD 511 

9. REFERENCES 

Talcott PA, Koller LD. 1983. The effect of inorganic lead and/or a polychlorinated biphenyl on the 

developing immune system of mice. J Toxicol Environ Health 12:337-352. 

Taupeau C, Poupon J, Treton D, et al. 2003. Lead reduces messenger RNA and protein levels of 

cytochrome P450 aromatase and estrogen receptor beta in human ovarian granulosa cells. Biol Reprod 

68:1982-1988. 

Tchernitchin NN, Clavero A, Mena MA, et al. 2003. Effect of chronic exposure to lead on estrogen 

action in the prepubertal rat uterus. Environ Toxicol 18:268-277. 

Teichmann R, Stremmel W. 1990. Iron uptake by human upper small intestine microvillous membrane 

vesicles. Indication for a facilitated transport mechanism mediated by a membrane iron-binding protein. 

J Clin Invest 86:2145-2153. 

Telisman S, Cvitkovic P, Jurasovic J, et al. 2000. Semen quality and reproductive endocrine function in 

relation to biomarkers of lead, cadmium, zinc, and copper in men. Environ Health Perspect 108:45-53. 

Téllez-Rojo MM, Bellinger DC, Arroyo-Quiroz C, et al. 2006. Longitudinal associations between blood 

lead concentrations lower than 10 μg/dl and neurobehavioral development in environmentally exposed 

children in Mexico City. Pediatrics 118(2):e323-e330. 

Téllez-Rojo MM, Hernández-Avila M, Lamadrid-Figueroa H, et al. 2004. Impact of bone lead and bone 

resorption on plasma and whole blood lead levels during pregnancy. Am J Epidemiol 160(7):668-678. 

Ter Haar GL, Aronow R. 1974. New information on lead in dirt and dust as related to the childhood lead 

problem. Environ Health Perspect 7:83-89. 

Ter Haar GL, Bayard MA. 1971. Composition of airborne lead particles. Nature 232:553-554. 

Thacker SB, Hoffman DA, Smith J, et al. 1992. Effect of low-level body burdens of lead on the mental 

development of children: Limitations of meta-analysis in a review of longitudinal data. Arch Environ 

Health 47(5):336-346. 

Tharr D. 1993. Lead contamination in radiator repair shops. Appl Occup Environ Hyg 8(5):434-438. 

Thatcher RW, Lester ML, McAlaster R, et al. 1982. Effects of low levels of cadmium and lead on 

cognitive functioning in children. Arch Environ Health 37:159-166. 

Theppeang K, Schwartz BS, Lee BK, et al. 2004. Associations of patella lead with polymorphisms in the 

vitamin D receptor, γ-aminolevulinic acid dehydratase and endothelial nitric oxide synthase genes. J 

Occup Med 46:528-537. 

Thier R, Bonacker D, Stoiber T, et al. 2003. Interaction of metal salts with cytoskeletal motor protein 

systems. Toxicol Lett 11:75-81. 

Thomas KW, Pellizzari ED, Berry MR. 1999. Population-based dietary intakes and tap water 

concentrations for selected elements in the EPA Region V National Human Exposure Assessment Survey 

(NHEXAS). J Expo Anal Environ Epidemiol 9:402-413. 
LEAD 512 

9. REFERENCES 

Thomasino JA, Zuroweste E, Brooks SM, et al. 1977. Lead, zinc and erythrocyte delta-aminolevulinic 

acid dehydratase: Relationships in lead toxicity. Arch Environ Health 32:244-247. 

Thompson GN, Robertson EF, Fitzgerald S. 1985. Lead mobilization during pregnancy. Med J Aust 

143:131. 

Timchalk C, Lin Y, Weitz KK, et al. 2006. Disposition of lead (Pb) in saliva and blood of SpragueDawley rats following a single or repeated oral exposure to Pb-acetate. Toxicology 222(1-2):86-94. 

Todd AC, Wetmur JG, Moline JM, et al. 1996. Unraveling the chronic toxicity of lead: An essential 

priority for environmental health. Environ Health Perspect 104(1):141-146. 

Tola S, Hernberg S, Asp S, et al. 1973. Parameters indicative of absorption and biological effect in new 

lead exposure: A prospective study. Br J Ind Med 30:134-141. 

Tomokuni K, Ichiba M. 1988. A simple method for colorimetric determination of urinary δaminolevulinic acid in workers exposed to lead. Sangyo Igaku 30:52-53. 

Tomokuni K, Ichiba M, Hirai Y. 1988. Species difference of urinary excretion of delta-aminolevulinic 

acid and coproporphyrin in mice and rats exposed in lead. Toxicol Lett 41:255-259. 

Tomsig JL, Suszkiw JB. 1991. Permeation of Pb2

 through calcium channels: Fura-2 measurements of 

voltage- and dihydrophyridine-sensitve Pb2

 entry in isolated bovine chromaffin cells. Biochim Biophys 

Acta 1069:197-200. 

Tomsig JL, Suszkiw JB. 1995. Multisite interactions between Pb2 and protein kinase C and its role in 

norepinephrine release from bovine adrenal chromaffin cells. J Neurochem 64:2667-2673. 

Tong S, Baghurst P, McMichael A, et al. 1996. Lifetime exposure to environmental lead and children's 

intelligence at 11-13 years: The Port Pirie cohort study. BMJ 312(7046):1569-1575. 

Tong S, Baghurst PA, Sawyer MG, et al. 1998. Declining blood lead levels and changes in cognitive 

function during childhood. JAMA 280(22):1915-1919. 

Tong S, McMichael AJ, Baghurst PA. 2000. Interactions between environmental lead exposure and 

sociodemographic factors on cognitive development. Arch Environ Health 55(5):330-355. 

*Toriumi H, Kawai M. 1981. Free erythrocyte protoporphyrin (FEP) in a general population, workers 

exposed to low-level lead, and organic-solvent workers. Environ Res 25:310-316. 

Torres-Sánchez LE, Berkowitz G, Lopez-Carrillo L, et al. 1999. Intrauterine lead exposure and preterm 

birth. Environ Res 81:297-301. 

Toscano CD, Guilarte TR. 2005. Lead neurotoxicity: From exposure to molecular effects. Brain Res 

Brain Res Rev 49(3):529-554. 

Treble RG, Thompson RS. 1997. Preliminary results of a survey of lead levels in human liver tissue. 

Bull Environ Contam Toxicol 59:688-695. 
LEAD 513 

9. REFERENCES 

TRI04. 2006. TRI explorer: Providing access to EPA’s toxics release inventory data. Washington, DC: 

Office of Information Analysis and Access. Office of Environmental Information. U.S. Environmental 

Protection Agency. Toxics Release Inventory. http://www.epa.gov/triexplorer/. October 23, 2006. 

Triebig G, Weitle D, Valentin H. 1984. Investigations on neurotoxicity of chemical substances at the 

workplace: V. Determination of the motor and sensory nerve conduction velocity in persons 

occupationally exposed to lead. Int Arch Occup Environ Health 53:189-204. 

Tripathi RK, Llewellyn GC. 1990. Deterioration of air quality in firing ranges: In: A review of airborne 

lead exposures. Biodeterioration research 3: Mycotoxins, biotoxins, wood decay, air quality, cultural 

properties, general biodeterioration, and degradation. New York, NY: Wiley and Sons, 445-457. 

Tsaih SW, Korrick S, Schwartz J, et al. 2004. Lead, diabetes, hypertension, and renal function: The 

normative aging study. Environ Health Perspect 112(11):1178-1182. 

Tsao D-A, Yu H-S, Cheng J-T, et al. 2000. The change of β-adrenergic system in lead-induced 

hypertension. Toxicol Appl Pharmacol 163:127-133. 

Tulasi SJ, Reddy PUM, Rao JV. 1992. Accumulation of lead and effects on total lipids and lipid 

derivatives in the freshwater fish Anabas testudineus (Bioch). Ecotoxicol Environ Safety 23:33-38. 

Tuppurainen M, Wagar G, Kurppa K. 1988. Thyroid function as assessed by routine laboratory tests of 

workers with long-term lead exposure. Scand J Work Environ Health 14:175-180. 

Turlakiewicz Z, Chmielnicka J. 1985. Diethyllead as a specific indicator of occupational exposure to 

tetraethyllead. Br J Ind Med 42:682-685. 

Tuthill RW. 1996. Hair lead levels related to children's classroom attention-deficit behavior. Arch 

Environ Health 51:214-220. 

Ulmer DD, Vallee BL. 1969. Effects of Lead on Biochemical Systems. In: Hemphill DD, ed. Trace 

substances in environmental health. University of Missouri Press, 7-27. 

Ündeger U, Basaran N, Canpinar H, et al. 1996. Immune alterations in lead-exposed workers. 

Toxicology 109(2-3):167-172. 

USAF. 1995. The fate and behavior of lead alkyls in the subsurface environment. Tyndall AFB, FL: 

U.S. Air Force. AL/EQ-TR-1994-0026. 

USGS. 2002. Lead: Recycling-metals. U.S. Geological Survey, 62.7. 

http://minerals.usgs.gov/minerals/pubs/commodity/recycle/recycmyb02r.pdf. March 28, 2005. 

USGS. 2003. Lead. Minerals yearbook. U.S. Geological Survey. 

http://minerals.usgs.gov/minerals/pubs/commodity/lead/leadmyb03.pdf. March 28, 2005. 

USGS. 2004. Lead. Mineral commodity summaries. U.S. Geological Survey 

http://minerals.usgs.gov/minerals/pubs/commodity/lead/index.html#mcs. April 3, 2005 

Vaglenov A, Carbonell E, Marcos R. 1998. Biomonitoring of workers exposed to lead. Genotoxic 

effects, its modulation by polyvitamin treatment and evaluation of induced radioresistance. Mutat Res 

418:79-92. 
LEAD 514 

9. REFERENCES 

Vaglenov A, Creus A, Laltchev S, et al. 2001. Occupational exposure to lead and induction of genetic 

damage. Environ Health Perspect 109(3):295-298. 

Valciukas JA, Lilis R, Eisinger J, et al. 1978. Behavioral indicators of lead neurotoxicity: Results of a 

clinical field survey. Int Arch Occup Environ Health 41:217-236. 

Valentino M, Governa M, Marchiseppe I, et al. 1991. Effects of lead on polymorphonuclear luekocyte 

(PMN) functions in occupationally exposed workers. Arch Toxicol 65:685-688. 

Valverde M, Fortoul TI, Diaz-Barriga F, et al. 2002. Genotoxicity induced in CD-1 mice by inhaled 

lead: Differential organ response. Mutagenesis 17(1):55-61. 

Van Borm W, Wouters L, Van Grieken R, et al. 1990. Lead particles in an urban atmosphere: An 

individual particle approach. Sci Total Environ 90:55-66. 

Van Esch EJ, Kroes R. 1969. The induction of renal tumors by feeding basic lead acetate to mice and 

hamsters. Br J Cancer 23:765-771. 

Vasilios D, Theodor S, Konstantinos S, et al. 1997. Lead concentrations in maternal and umbilical cord 

blood in areas with high and low air pollution. Clin Exp Obstet Gynecol 24(4):187-189. 

Vaziri ND, Ding Y. 2001. Effect of lead on nitric oxide synthase expression in coronary endothelial 

cells: Role of superoxide. Hypertension 37:223-226. 

Vaziri ND, Sica DA. 2004. Lead-induced hypertension: Role of oxidative stress. Curr Hypertens Rep 

6:314-320. 

Vaziri ND, Ding Y Ni Z, et al. 1997. Altered nitric oxide metabolism and increased oxygen free radical 

activity of lead-induced hypertension: Effect of lazaroid therapy. Kidney Int 52:1042-1046. 

Vaziri ND, Ding Y, Ni Z. 1999b. Nitric oxide synthase expression in the course of lead-induced 

hypertension. Hypertension 34:558-562. 

Vaziri ND, Ding Y, Ni Z. 2001. Compensatory up-regulation of nitric-oxide synthase isoforms in leadinduced hypertension; reversal by a superoxide dismutase-mimetic drug. J Pharmacol Exp Ther 

298(2):679-685. 

Vaziri ND, Liang K, Ding Y. 1999a. Increased nitric oxide inactivation by reactive oxygen species in 

lead-induced hypertension. Kidney Int 56:1492-1498. 

Verberk MM, Willems TE, Verplanke AJ, et al. 1996. Environmental lead and renal effects in children. 

Arch Environ Health 51(1):83-87. 

Verschoor M, Wibowo A, Herber R, et al. 1987. Influence of occupational low-level lead exposure on 

renal parameters. Am J Ind Med 12:341-351. 

Vesper SJ, Donovan-Brand R, Paris KP, et al. 1996. Microbial removal of lead from solid media and 

soil. Water Air Soil Pollut 86:207-219. 
LEAD 515 

9. REFERENCES 

Victery W, Vander AJ, Markel LK, et al. 1982a. Lead exposure begun in utero decreases renin and 

angiotensin II in adult rats. Proc Soc Exp Biol Med 170:63-67. 

Victery W, Vander AJ, Mouw DR. 1979. Effect of acid-base status on renal excretion and accumulation 

of lead in dogs and rats. Am J Physiol 6:F398-F407. 

Victery W, Vander AJ, Shulak JM, et al. 1982b. Lead, hypertension, and the renin-angiotensin system in 

rats. J Clin Med 99:354-362. 

Vieira I, Sonnier M, Cresteil T. 1996. Developmental expression of CYP2E1 in the human liver: 

Hypermethylation control of gene expression during the neonatal period. Eur J Biochem 238:476-483. 

*Vimpani GV, Baghurst PA, Wigg NR, et al. 1989. The Port Pirie cohort study-Cumulative lead 

exposure and neurodevelopmental status at age 2 years: Do HOME scores and maternal IQ reduce 

apparent effects of lead on Bayley mental scores? In: Smith M, Grant LD, Sors A, eds. Lead exposure 

and child development: An international assessment. Hingham, MA: Kluwer Academic Press, 332-344. 

Vincent JH, Werner MA. 2003. Critical evaluation of historical occupational aerosol exposure records: 

Applications to nickel and lead. Ann Occup Hyg 47(1):49-59. 

Viverette L, Mielke HW, Brisco M, et al. 1996. Environmental health in minority and other underserved 

populations: Benign methods for identifying lead hazards at day care centers of New Orleans. Environ 

Geochem Health 18(1):41-45. 

Volkening J, Baumann H, Heumann KG. 1988. Atmospheric distribution of particulate lead over the 

Atlantic Ocean from Europe to Antarctica. Atmos Environ 22:1169-1174. 

*Voors AW, Johnson WD, Shuman MS. 1982. Additive statistical effects of cadmium and lead on heart 

related disease in a North Carolina autopsy series. Arch Environ Health 37:98-102. 

Vupputuri S, He J, Muntner P, et al. 2003. Blood lead level is associated with elevated blood pressure in 

blacks. Hypertension 41:463-468. 

Vural N, Duydu Y. 1995. Biological, monitoring of lead in workers exposed to tetraethyllead. Sci Total 

Environ 171:183-187. 

Vyskocil A, Panci J, Tusl M, et al. 1989. Dose-related proximal tubular dysfunction in male rats 

chronically exposed to lead. J Appl Toxicol 9:395-400. 

Waalkes MP, Klaassen CD. 1985. Concentration of metallothionein in major organs of rats after 

administration of various metals. Fund Appl Toxicol 5:473-477. 

Waalkes MP, Diwan BA, Ward JM, et al. 1995. Renal tubular tumors and atypical hyperplasias in 

B6C3F1 mice. Cancer Res 55:5265-5271. 

Waalkes MP, Harvey MJ, Klaassen CD. 1984. Relative in vitro affinity of hepatic metallothionein for 

metals. Toxicol Lett 20:33-39. 

Wada O, Yano Y, Ono T, et al. 1973. The diagnosis of different degrees of lead absorption in special 

references to choice and evaluation of various parameters indicative of an increased lead absorption. Ind 

Health 11:55-67. 
LEAD 516 

9. REFERENCES 

Wadi SA, Ahmad G. 1999. Effects of lead on the male reproductive system in mice. J Toxicol Environ 

Health A 56:513-521. 

Wang EX, Bormann FH, Benoit G. 1995. Evidence of complete retention of atmospheric lead in the 

soils of northern hardwood forested ecosystems. Environ Sci Technol 29:735-739. 

Wang L, Xu SE, Zhang GD, et al. 1989. Study of lead absorption and its effect on children's 

development. Biomed Environ Sci 2:325-330. 

*Ward NI, Watson R, Brvce-Smith D. 1987. Placental element levels in relation to fetal development for 

obstetrically normal births: A study of 37 elements: Evidence for the effects of cadmium, lead, and zinc 

on fetal growth and for smoking as a source of cadmium. Int J Biosoc Res 9:63-81. 

Wasserman GA, Factor-Litvak P, Liu X, et al. 2003. The relationship between blood lead, bone lead and 

child intelligence. Neuropsychol Dev Cogn C Child Neuropsychol 9(1):22-34. 

Wasserman G, Graziano JH, Factor-Litvak P, et al. 1992. Independent effects of lead exposure and iron 

deficiency anemia on developmental outcome at age 2 years. J Pediatr 121(3):695-703. 

Wasserman GA, Graziano JH, Factor-Litvack P, et al. 1994. Consequences of lead exposure and iron 

supplementation on childhood development at age 4 years. Neurotoxicol Teratol 16:233-240. 

Wasserman GA, Liu X, Lolacono NJ, et al. 1997. Lead exposure and intelligence in 7-year-old children: 

The Yugoslavia prospective study. Environ Health Perspect 105(9):956-962. 

Wasserman GA, Liu X, Popovac D, et al. 2000a. The Yugoslavia prospective lead study: Contributions 

of prenatal and postnatal lead exposure to early intelligence. Neurotoxicol Teratol 22:811-818. 

Wasserman GA, Staghezza-Jaramillo B, Shrout P, et al. 1998. The effect of lead exposure on behavior 

problems in preschool children. Am J Public Health 88(3):481-486. 

Watanabe H, Hu H, Rotnitzky A. 1994. Correlates of bone and blood lead levels in carpenters. Am J Ind 

Med 26:255-264. 

Watson GE, Davis BA, Raubertas RF, et al. 1997. Influence of maternal lead ingestion on caries in rat 

pups. Nat Med 3(9):1024-1025. 

Watson WS, Hume R, Moore MR. 1980. Oral absorption of lead and iron. Lancet 2:236-237. 

Watson WS, Morrison J, Bethel MIF, et al. 1986. Food iron and lead absorption in humans. Am J Clin 

Nutr 44:248-256. 

Watts SW, Chai S, Webb RC. 1995. Lead acetate-induced contraction in rabbit mesenteric artery: 

Interaction with calcium and protein kinase C. Toxicology 99:55-65. 

Waxman HS, Rabinowitz M. 1966. Control of reticulocyte polyribosome content and hemoglobin 

synthesis by heme. Biochim Biophys Acta 129:369-379. 

Weaver VM, Jaar BG, Schwartz BS, et al. 2005a. Associations among lead dose biomarkers, uric acid, 

and renal function in Korean lead workers. Environ Health Perspect 113(1):36-42. 
LEAD 517 

9. REFERENCES 

Weaver VM, Lee BK, Ahn KD, et al. 2003a. Associations of lead biomarkers with renal function in 

Korean lead workers. Occup Environ Med 60:551-562. 

Weaver VM, Lee BK, Todd AC, et al. 2005b. Associations of patella lead and other lead biomarkers 

with renal function in lead workers. J Occup Environ Med 47(3):235-243. 

Weaver VM, Schwartz BS, Ahu KD, et al. 2003b. Associations of renal function with polymorphisms in 

the gamma-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in 

Korean lead workers. Environ Health Perspect 111(13):1613-1619. 

Wedeen RP. 1988. Bone lead, hypertension, and lead nephropathy. Environ Health Perspect 78:57-60. 

Wedeen RP. 1990. In vivo tibial XFR measurement of bone lead. Arch Environ Health 45(2):69-71. 

Wedeen RP. 1992. Removing lead from bone: Clinical implications of bone lead stores. 

Neurotoxicology 13:843-852. 

Wedeen RP, Maesaka JK, Weiner B, et al. 1975. Occupational lead nephropathy. Am J Med 59:630­

641. 

Wedeen RP, Mallik DK. Batuman V. 1979. Detection and treatment of occupational lead nephropathy. 

Arch Intern Med 139:53-57. 

Weis CP, LaVelle JM. 1991. Characteristics to consider when choosing an animal model for the study of 

lead bioavailability. Chem Speciat Bioavail 3:113-119. 

Weisel C, Demak M, Marcus S, et al. 1991. Soft plastic bread packaging: Lead content and reuse by 

families. Am J Public Health 81(6):756-758. 

Weiss ST, Munoz A, Stein A, et al. 1986. The relationship of blood lead to blood pressure in 

longitudinal study of working men. Am J Epidemiol 123:800-808. 

Weiss ST, Munoz A, Stein A, et al. 1988. The relationship of blood lead to systolic blood pressure in a 

longitudinal study of policemen. Environ Health Perspect 78:53-56. 

Weisskopf MG, Wright RO, Schwartz J, et al. 2004. Cumulative lead exposure and prospective change 

in cognition among elderly men: The VA Normative Aging Study. Am J Epidemiol 160(12):1184-1193. 

Weitzman M, Aschengrau A, Bellinger D, et al. 1993. Lead-contaminated soil abatement and urban 

children’s blood lead levels. JAMA 269(13):1647-1654. 

Wells AC, Venn JB, Heard MJ. 1975. Deposition in the lung and uptake to blood of motor exhaust 

labelled with 203Pb. Inhaled Particles IV. Proceedings of a Symposium of the British Occupational 

Hygiene Society. Oxford, England: Pergamon Press, 175–189. 

West JR, Smith HW, Chasis H. 1948. Glomerular filtration rate, effective renal blood flow, and maximal 

tubular excretory capacity in infancy. J Pediatr 32:10-18. 
LEAD 518 

9. REFERENCES 

Wetmur JG, Lehnert G, Desnick RJ. 1991. The δ-aminolevulinate dehydratase polymorphism: Higher 

blood lead levels in lead workers and environmentally exposed children with 1-2 and 2-2 isozymes. 

Environ Res 56:109-119. 

Whelan EA, Piacitelli GM, Gerwel B, et al. 1997. Elevated blood lead levels in children of construction 

workers. Am J Public Health 87(8):1352-1355. 

White PD, Van Leeuwen P, Davis BD, et al. 1998. The conceptual structure of the integrated exposure 

uptake biokinetic model for lead in children. Environ Health Perspect 106:1513-1530. 

White RF, Diamond R, Proctor S, et al. 1993. Residual cognitive deficits 50 years after lead poisoning 

during childhood. Br J Ind Med 50:613-622. 

WHO. 1977. United Nations Environmental Programme: Lead: Environmental Health Criteria 3. 

Geneva, Switzerland: World Health Organization, 112. 

WHO. 1995. Environmental transport, distribution and transformation. Geneva, Switzerland: World 

Health Organization, 60-65. 

WHO. 2000. Air quality guidelines. 2nd edition. Geneva, Switzerland: World Health Organization. 

http://www.euro.who.int/air/Activities/20050104_1. February 15, 2005. 

WHO. 2004. Guidelines for drinking-water quality. 3rd edition. Geneva, Switzerland: World Health 

Organization. http://www.who.int/water_sanitation_health/dwq/gdwq3/en/. February 15, 2005. 

Wibberley DG, Khera AK, Edwards JH, et al. 1977. Lead levels in human placentae from normal and 

malformed births. J Med Genet 14:339-345. 

Widdowson EM, Dickerson JWT. 1964. Chemical composition of the body. In: Comar CL, Bronner F, 

eds. Mineral metabolism: An advanced treatise. Volume II: The elements Part A. New York, NY: 

Academic Press. 

Wielopolski L, Ellis K, Vaswani A, et al. 1986. In vivo bone lead measurements: A rapid monitoring 

method for cumulative lead exposure. Am J Ind Med 9:221-226. 

*Wigg NR, Vimpani GV, McMichael AJ, et al. 1988. Port Pirie cohort study: Childhood blood lead and 

neuropsychological development at age two years. J Epidemiol Community Health 42:213-219. 

Wildt K, Berlin M, Isberg PE. 1987. Monitoring of zinc protoporphyrin levels in blood following 

occupational lead exposure. Am J Ind Med 12:385-398. 

Wildt K, Eliasson R, Berlin M. 1983. Effects of occupational exposure to lead on sperm and semen. In: 

Clarkson TW, Nordberg GF, Sager PR, eds. Reproductive and developmental toxicity of metals. 

Proceedings of a Joint Meeting, Rochester, NY. New York, NY: Plenum Press, 279-300. 

Wilhelm M, Lombeck I, Hafner D, et al. 1989. Hair lead levels in young children from the F.R.G. J 

Trace Elem Electrolytes Health Dis 3:165-170. 

Willems MI, Deschepper GG, Wibowo AAE, et al. 1982. Absence of an effect of lead acetate on sperm 

morphology, sister chromatid exchange or on micronuclei formation in rabbits. Arch Toxicol 50:149­

157. 
LEAD 519 

9. REFERENCES 

Williamson AM, Teo RKC. 1986. Neurobehavioral effects of occupational exposure to lead. Br J Ind 

Med 43:374-380. 

Willoughby RA, MacDonald E, McSherry BJ, et al. 1972. Lead and zinc poisoning and the interaction 

between Pb and Zn poisoning in the foal. Can J Comp Med 36:348-359. 

Winneke G, Kraemer U. 1984. Neuropsychological affects of lead in children: Interactions with social 

background variables. Neuropsychobiology 11:195-202. 

Winneke G, Altmann L, Kramer U, et al. 1994. Neurobehavioral and neurophysiological observations in 

six year old children with low lead levels in East and West Germany. Neurotoxicology 15(3):705-713. 

*Winneke G, Beginn U, Ewert T, et al. 1985a. Comparing the effects of perinatal and later childhood 

lead exposure on neurophysiological outcome. Environ Res 38:155-167. 

*Winneke G, Brockhaus A, Collet W, et al. 1985b. Predictive value of different markers of leadexposure for neuropsychological performance. In: Lekkas TD, ed. International Conference on Heavy 

Metals in the Environment, Athens, Greece. September, Vol. 1. Edinburgh, United Kingdom: CEP 

Consultants, Ltd., 44-47. 

Winneke G, Brockhous A, Ewers U, et al. 1990. Results from the European multicenter study on lead 

neurotoxicity in children: Implications for risk assessment. Neurotoxicol Teratol 12:553-559. 

Winneke G, Lilienthal H, Kramer U. 1996. The neurobehavioural toxicology and teratology of lead. 

Arch Toxicol Suppl 18:57-70. 

Wisconsin Department of Health and Family Services. 2002. Lead arsenate pesticides. Madison, WI: 

Department of Health and Family Services. 

Witzmann FA, Fultz CD, Grant RA, et al. 1999. Regional protein alterations in rat kidneys induced by 

lead exposure. Electrophoresis 20:943-951. 

*Wolf AW, Ernhart CB, White CS. 1985. Intrauterine lead exposure and early development. In: Lekkas 

TD, ed. International conference: Heavy metals in the environment, Athens, Greece, Vol. 2. Edinburgh, 

UK: CEP Consultants, Ltd., 153-155. 

Wolf AW, Jimenez E, Lozoff B. 1994. No evidence of developmental III effects of low-level lead 

exposure in a developing country. Develop Behav Pediatr 15(4):224-231. 

Wolf C, Wallnöfer A, Waldhor T, et al. 1995. Effect of lead on blood pressure in occupationally 

nonexposed men. Am J Ind Med 27:897-903. 

Wolff MS. 1983. Occupationally derived chemicals in breast milk. Am J Ind Med 4:259-281. 

Wolnik KA, Fricke FL, Capar SG, et al. 1983a. Elements in major raw agricultural crops in the United 

States. 1. Cadmium and lead in lettuce, peanuts, potatoes, soybeans, sweet corn, and wheat. J Agric 

Food Chem 31:1240-1244. 
LEAD 520 

9. REFERENCES 

Wolnik KA, Fricke FL, Capar SG, et al. 1983b. Elements in major raw agricultural crops in the United 

States. 3. Cadmium, lead, and eleven other elements in carrots, field corn, onions, rice, spinach, and 

tomatoes. J Agric Food Chem 33:807-811. 

Wong O, Harris F. 2000. Cancer mortality study of employees at lead battery plants and lead smelters, 

1947-1995. Am J Ind Med 38:255-270. 

Woźniak K, Blasiak J. 2003. In vitro genotoxicity of lead acetate: Induction of single and double DNA 

strand breaks and DNA-protein cross-links. Mutat Res 535:127-139. 

Wright LS, Kornguth SE, Oberley TD. 1998. Effects of lead on glutathione S-transferase expression in 

rat kidney: A dose-response study. Toxicol Sci 46:254-259. 

Wright RO, Hu H, Silverman EK, et al. 2003a. Apolipoprotein E genotype predicts 24-month bayley 

scales infant development score. Pediatr Res 54(6):819-825. 

Wright RO, Silverman EK, Schwartz J, et al. 2004. Association between hemochromatosis genotype and 

lead exposure among elderly men: The normative aging study. Environ Health Perspect 112(6):746-750. 

Wright RO, Tsaih SW, Schwartz J, et al. 2003b. Association between iron deficiency and blood lead 

level in a longitudinal analysis of children followed in an urban primary care clinic. J Pediatr 142:9-14. 

Wright RO, Tsaih SW, Schwartz J, et al. 2003c. Lead exposure biomarkers and mini-mental status exam 

scores in older men. Epidemiology 14(6):713-718. 

Wu FY, Chang PW, Wu CC, et al. 2002. Correlations of blood lead with DNA-protein cross-links and 

sister chromatid exchanges in lead workers. Cancer Epidemiol Biomarkers Prev 11:287-290. 

Wu MT, Kelsey K, Schwartz J. 2003a. A δ-aminolevulinic acid dehydratase (ALAD) polymorphism 

may modify the relationship of low-level lead exposure to uricemia and renal function: The Normative 

Aging Study. Environ Health Perspect 111(3):335-340. 

Wu T, Buck GM, Mendola P. 2003b. Blood lead levels and sexual maturation in U.S. girls: The Third 

National Health and Nutrition Examination Survey, 1988-1994. Environ Health Perspect 111(5):737­

741. 

Wu T, Yang K-C, Wang C-M. 1996. Lead poisoning caused by contaminated Cordyceps, a Chinese 

herbal medicine: Two case reports. Sci Total Environ 182:193-195. 

Xian X. 1989. Response of kidney bean to concentration and chemical form of cadmium, zinc, and lead 

in polluted soils. Environ Pollut 57:127-137. 

Xie Y, Chiba M, Shinohara A, et al. 1998. Studies on lead-binding protein and interaction between lead 

and selenium in the human erythrocytes. Ind Health 36:234-239. 

Xu GB, Yu CP. 1986. Effects of age on deposition of inhaled aerosols in the human lung. Aerosol Sci 

Technol 5:349-357. 

Xu Y, Liang Y. 1997. Combined nickel and phosphate modifier for lead determination in water by 

electrothermal atomic absorption spectrometry. J Anal Atom Spectrom 12(4):471-474. 
LEAD 521 

9. REFERENCES 

Yankel AJ, von Lindern IH, Walter SD. 1977. The Silver Valley lead study: The relationship of 

childhood lead poisoning and environmental exposure. J Air Pollut Contr Assoc 27:763-767. 

Yassin AS, Martonik JF, Davidson JL. 2004. Blood lead levels in U.S. workers, 1988-1994. J Occup 

Environ Med 46:720-728. 

Yeh JH, Chang YC, Wang JD. 1995. Combined electroneurographic and electromyographic studies in 

lead workers. Occup Environ Med 52(6):415-419. 

Yip R, Norris TN, Anderson AS. 1981. Iron status of children with elevated blood lead concentrations. 

J Pediatr 98:922-925. 

Yokoyama K, Araki S, Murata K, et al. 1997. Subclinical vestibulo-cerebellar, anterior cerebellar lobe 

and spinocerebellar effects in lead workers in relation to concurrent and past exposure. Neurotoxicology 

18(2):371-380. 

Yokoyama K, Araki S, Yamashita K, et al. 2002. Subclinical cerebellar anterior lobe, vestibulocerebellar and spinocerebellar afferent effects in young female lead workers in China: Computerized 

posturography with sway frequency analysis and brainstem auditory evoked potentials. Ind Health 

40:245-253. 

Yu CC, Lin JL, Lin-Tan DT. 2004. Environmental exposure to lead and progression of chronic renal 

diseases: A four-year prospective longitudinal study. J Am Soc Nephrol 15:1016-1022. 

Zaragoza L, Hogan K. 1998. The integrated exposure uptake biokinetic model for lead in children: 

Independent validation and verification. Environ Health Perspect 106(6):1551-1556. 

Zawia NH, Crumpton T, Brydie M, et al. 2000. Disruption of the zinc finger domain: A common target 

that underlies many of the effects of lead. Neurotoxicology 21(6):1069-1080. 

Zelikoff JT, Li JH, Hartwig A, et al. 1988. Genetic toxicology of lead compounds. Carcinogenesis 

9:1727-1732. 

Zhang W, Zhang GG, He HZ, et al. 1994. Early health effects and biological monitoring in persons 

occupationally exposed to tetraethyllead. Int Arch Occup Environ Health 65:395-399. 

Zhang Z-W, Shimbo S, Ochi N, et al. 1997. Determination of lead and cadmium in food and blood by 

inductively coupled plasma mass spectrometry: A comparison with graphite furnace atomic absorption 

spectrometry. Sci Total Environ 205(2-3):179-187. 

Ziegler EE, Edwards BB, Jensen RL, et al. 1978. Absorption and retention of lead by infants. Pediatr 

Res 12:29-34. 

Zimmerman-Tanselia C, Campara P, D’Andrea F, et al. 1983. Psychological and physical complaints of 

subjects with low exposure to lead. Hum Toxicol 2:615-623. 

Zollinger HU. 1953. [Kidney adenomas and carcinomas in rats caused by chronic lead poisoning and 

their relationship to corresponding human neoplasms.] Virchows Arch A Pathol Anat 323:694-710. 

(German) 
LEAD 522 

9. REFERENCES 

Zou C, Zhao Z, Tang L, et al. 2003. The effect of lead on brainstem auditory evoked potentials in 

children. Chin Med J 116(4):565-568. 
LEAD 523 

10. GLOSSARY 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 
LEAD 524 

10. GLOSSARY 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 
LEAD 525 

10. GLOSSARY 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 
LEAD 526 

10. GLOSSARY 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 
LEAD 527 

10. GLOSSARY 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 
LEAD 528 

10. GLOSSARY 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 
LEAD A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 
LEAD A-2 

APPENDIX A 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-32, Atlanta, Georgia 30333. 
LEAD B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1.	 What effects are known to occur in humans? 

2. What effects observed in animals are likely to be of concern to humans? 

3. What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 
LEAD B-2 

APPENDIX B 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 
LEAD B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1) Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2) Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3) Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4) Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5) Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6) Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7) System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8) NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 
LEAD B-4 

APPENDIX B 

(9) LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10) Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11) CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12) Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13) Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14) Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)	 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3

 or ppm and oral exposure is reported in 

mg/kg/day. 

(16) NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 

18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17) CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 
LEAD B-5 

APPENDIX B 

(18)	 Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19)	 Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 
3 

4 

SAMPLE 

1 →	 Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

LOAEL (effect) Exposure 

Key to frequency/ NOAEL Less serious Serious (ppm) 

figurea Species duration System (ppm) (ppm) Re

2 → INTERMEDIATE EXPOSURE 

5 

→ Systemic ↓ 

18 Rat 

→ 

CHRONIC EXPOSURE Cancer 38 Rat 39 Rat 40 Mouse 

6↓ 13 wk 5 d/wk 6 hr/d 18 mo 5 d/wk 7 hr/d 89–104 wk 5 d/wk 6 hr/d 79–103 wk 5 d/wk 6 hr/d 

7 8 9 

↓ ↓ ↓ 

3b Resp 10 (hyperplasia) 

11 ↓ 20 (CEL, multiple 

organs) 

10 (CEL, lung tumors, 

nasal tumors) 

10 (CEL, lung tumors, 

hemangiosarcomas) 

10 

↓ 

NitWoNTNT

12 →	 a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent ex

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

LEAD B-8 

APPENDIX B 

This page is intentionally blank. 
LEAD C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD benchmark dose 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/Intergovernmental Maritime Dangerous Goods Code 
LEAD C-2 

APPENDIX C 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 
LEAD C-3 

APPENDIX C 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 
LEAD C-4 

APPENDIX C 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
LEAD C-5 

APPENDIX C 

> greater than ≥ greater than or equal to 

= equal to 

< less than ≤ less than or equal to 

% percent α alpha β beta γ gamma δ delta μm micrometer μg microgram q1 

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 
LEAD C-6 

APPENDIX C 

This page is intentionally blank. 
LEAD D-1 

APPENDIX D. A FRAMEWORK TO GUIDE PUBLIC HEALTH ASSESSMENT 

DECISIONS AT LEAD SITES 

ABSTRACT 

The Agency for Toxic Substances and Disease Registry (ATSDR) provides health consultations 

and assessments at hazardous waste sites. Many of these sites have potentially significant levels 

of lead contamination for which the Agency must assess the health implications of exposure. 

Typically, environmental data are used to predict blood lead (PbB) levels in order to determine at 

which sites, if any, follow-up action is needed. Estimating blood lead levels from environmental 

lead concentrations, however, can be problematic. Several approaches have been developed, 

including classical ingestion rate determinations and comparison to animal studies, prevalence 

studies extrapolated to comparable sites, regression analysis of known exposure followed by 

slope factor estimates of similar levels of exposure, and the Environmental Protection Agency’s 

(EPA) Integrated Exposure Uptake Biokinetic Model (IEUBK). Uncertainty is attendant to each of 

these approaches due, in part, to the limited nature of the environmental sampling data and the 

various site-specific factors. In this manuscript we describe an approach ATSDR developed to 

utilize regression analysis with multi-route uptake parameters to estimate blood lead levels. 

The profound toxicity of lead has been acknowledged for many years. Developmental effects associated 

with female lead workers and wives of lead workers were well known during the 18th and 19th centuries, 

and much of what is taken for granted today regarding lead poisoning in children has been known for 

more than ninety years. None the less, production of lead compounds, mining and smelting of lead ore 

and secondary lead sources, and widespread use of lead-containing products continued to increase 

during the 20th century. These manufacturing, mining, and smelting activities resulted in the 

contamination of many industrial and residential areas. In addition, leaded gasoline and lead-based 

paint contributed to the dispersal of lead throughout the environment. During the 1970s and 1980s, 

federal agencies targeted programs and resources to reduce lead exposure in the United States. These 

primary prevention activities resulted in regulations governing air emissions, drinking water standards, the 

phase-out of lead in gasoline, and the banning of lead-based paint and leaded solder. Although these 

efforts have all contributed to reducing lead exposure to the general population, past uses have resulted 

in the contamination of many areas, many of which still have the potential for adversely affecting the 

public health. 

Introduction 

One of the mandates of the Agency for Toxic Substances and Disease Registry (ATSDR) (under the 

Comprehensive Environmental Response, Compensation, and Liability Act, Section 104(i)(3), or 

Superfund) is to address the potential for adverse effects on public health resulting from lead exposure. 

Lead has been identified as a contaminant in at least 1,026 of the National Priorities List (NPL) sites and 

is currently ranked first on the Priority List of Hazardous Substances (ATSDR 1996a). Consequently, 

ATSDR must address public health concerns regarding lead exposure at hazardous waste sites. 

ATSDR’s specific responsibilities related to blood lead screening at lead-contaminated hazardous waste 

sites include: (1) evaluation of site-specific environmental lead exposure information, (2) identification of 

populations potentially exposed to lead, (3) decision about whether or not to conduct blood lead 

screening, (4) evaluation of blood lead screening results, and (5) determination of whether the U.S. 

Environmental Protection Agency’s (EPA) proposed site remediation plans are sufficient to protect public 

health. 

Evaluation of these environmental data is associated with a high level of biomedical judgment regarding 

appropriate public health actions. In this manuscript, we describe a framework developed to guide such 

judgment and one that can be used to evaluate the need for a site-specific public health action, which 

may include blood lead screening. This approach utilizes regression analysis along with uptake 

parameters and potential results of exposure in an effort to estimate blood lead levels in at-risk 

populations. 
LEAD D-2 

APPENDIX D 

Superfund specifically directs ATSDR to ascertain significant human exposure levels for hazardous 

substances. Minimal risk levels (MRLs) were developed as part of the strategy to address this mandate. 

An MRL is "an estimate of the daily human exposure to a dose of a chemical that is likely to be without an 

appreciable risk of adverse, noncancerous effects over a specified duration of exposure” (ATSDR 1996b) 

and is analogous to the reference doses and the reference concentrations developed by EPA. MRLs are 

derived from no-observed-adverse-effect levels or lowest-observed-adverse-effect levels and are 

intended to assist in determining the safety of communities near hazardous waste sites. For example, an 

exposure level below the MRL suggests that there is little likelihood of adverse, noncancer human health 

effects occurring, whereas an exposure level exceeding the MRL alerts the health assessor that a more 

detailed evaluation using site-specific and chemical-specific information is required. Although the 

database for lead is large, empirical data from which to obtain a threshold for the effects of lead are 

lacking. With no observable threshold yet identified, the derivation of conventional health assessment 

tools such as MRLs is not feasible (De Rosa et al. 1991). In addition, a great deal of the human health 

effects data are expressed in terms of blood lead (PbB) levels rather than exposure dose, the usual 

comparison value. Using more traditional methodologies would overlook this significant body of literature, 

as well as the Centers for Disease Control (CDC, now the Centers for Disease Control and Prevention) 

guidelines1

. A predictive tool relating environmental levels to PbBs is needed. 

In response to this mandate, the Agency has been seeking ways to further refine the tools necessary for 

assessing the public health implications from exposure to hazardous substances. MRLs provide a 

guidance for single routes of exposure to a single substance. But, clearly, multi-route, multi-substance 

exposure considerations are needed not only for lead but for other substances. To this end, a framework 

for determining significant human exposure levels was developed (Mumtaz et al. 1995). The 

development of health-based guidance for lead is consistent with this concept. It should be noted that 

this effort and others to associate environmental levels with PbBs and consequently make health 

decisions are simply screening tools. Many issues must be considered on a site-by-site basis and used 

in conjunction with this guidance. Some of these issues are outlined below. 

Exposure and Bioavailability Issues. Primary routes of exposure to lead are via inhalation and 

ingestion. Lead exposure occurs through inhalation of airborne lead particles with deposition rates in 

adults of 30%–50% depending on factors such as particle size and ventilation rate (EPA 1986). Once 

deposited in the lower respiratory tract, lead appears to be almost completely absorbed (Morrow et al. 

1980). 

Oral intake of lead is a more important route of exposure for children and can occur from ingestion of 

contaminated food, soil, dust, water, or lead-based paint chips. For young children (1–6 years of age), 

soil and dust are important pathways for exposure. Ingestion of soil and dust can occur through normal 

hand-to-mouth activity. Lead-based paint, often found in older homes, and flaking or peeling off walls, 

can also contribute significantly to exposure in young children. Through normal aging and weathering, 

intact lead-based paint can contribute to the contamination of dust or soil 

The extent and rate of gastrointestinal absorption of lead is mediated by several factors including fasting, 

physical and chemical form of lead, and dietary status of the individual (Aungst et al. 1981; Grobler et al. 

1988; Baltrop and Meek 1979; Chamberlain et al. 1978; Mahaffey et al. 1982; Rabinowitz et al. 1976). 

Animal studies indicate that nutritional deficiencies in a number of essential elements (e.g., calcium, iron, 

zinc, copper, phosphorus) may impact the toxicokinetic and toxicological behavior of lead (ATSDR 1993; 

Chaney et al. 1989). In infants and children, lead retention has been shown to be inversely correlated 

with calcium intake (Johnson and Tenuta 1979; Sorrell et al. 1977; Ziegler et al. 1978). Zinc has been 

1

The weight of evidence suggests that PbBs of "10–15 μg/dL and possibly lower" are the levels of concern (ATSDR 1993; Davis 

1990; EPA 1986). The Department of Health and Human Services (DHHS) has determined that primary prevention activities should begin at 

blood lead levels of 10 μg/dL in children (CDC 1991). 
LEAD D-3 

APPENDIX D 

shown to have a protective effect against lead toxicity in a number of animal species (Goyer 1986; 

Haeger-Aronsen et al. 1976; Brewer et al. 1985; Cerklewski and Forbes 1976). 

The physical and chemical characteristics of the lead/soil matrix and the particular lead species have also 

been shown to affect the bioavailability of lead. Studies measuring lead concentration at various soil and 

dust particle sizes have shown that higher lead concentrations are often found in the smaller-sized 

fractions. The results of these studies have been summarized by Duggan and Inskip (1985). This is 

particularly important for young children because smaller particles (<100 μm in diameter) also tend to 

adhere more readily to hands. Additionally, lead from smaller particles is more readily absorbed from the 

gastrointestinal tract (Baltrop and Meek 1979). It has been suggested that lead at mining waste sites is 

less bioavailable and therefore poses less of a human health hazard than lead found at smelter sites or in 

urban areas (Hemphill et al. 1991; Steele et al. 1990). These differences in bioavailability have been 

attributed to these biochemical/ biophysical differences of the lead source. Lead particles at mining sites 

are typically of larger size and consist of the less soluble lead sulfides. However, recent data suggest 

that this may not always be the case and that a site-by-site evaluation is necessary to determine the lead 

hazards to the surrounding populations (Gulson et al. 1994; Mushak 1991). See Mushak (1991) for a 

review of physical/chemical issues regarding lead bioavailability. 

Age is also an important factor in that young children absorb lead more efficiently than adults (50% 

versus 15%) (Chamberlain et al. 1978). Fasting has a significant effect on absorption of lead. Retention 

of ingested lead is about 60% under fasting conditions compared with 4% when lead is ingested with a 

balanced meal (James et al. 1985). 

Behavioral factors must also be considered. The normal hand to mouth activity of young children results 

in an increase in lead intake from hand soil/dust particles. In addition, children who exhibit pica behavior 

are at increased risk because they may ingest more lead-contaminated soil/dust. Health assessors 

should also be aware of distinct sources of lead within a household or community, such as certain 

hobbies that would expose one to lead (e.g. using molten lead for casting ammunition, leaded solder for 

making stained glass, leaded glazes for pottery), the use of folk remedies or lead-glazed pottery, or eating 

imported canned foods that might contain elevated lead from lead solder used in the can seams. 

 Approach 

Numerous longitudinal and cross-sectional studies have attempted to correlate environmental lead levels 

with blood lead levels (Table 1). These studies have provided a number of regression analyses and 

corresponding slope factors (δ) for various media including air, soil, dust, water, and food. The specifics 

of each of these have been extensively discussed and evaluated elsewhere (Brunekreef 1984; Duggan 

and Inskip 1985; EPA 1986; Reagan and Silbergeld 1990; Xintaras 1992). In an attempt to use this 

valuable body of data, ATSDR has developed an integrated exposure regression analysis (Abadin and 

Wheeler, 1993). This approach utilizes slope values from select studies to integrate all exposures from 

various pathways, thus providing a cumulative exposure estimate expressed as total blood lead. 
LEAD D-4 

APPENDIX D 

Table 1. Summary of blood slope factors from various environmental media. 

Population Slope Comments Reference 

Air Slope Factors μg/dL per μg Pb/m3 

Adults; N = 43 1.75 ± 0.35 Experimental study; EPA analysis Griffin et al. 1975 

Adults; N=5 1.59–3.56 Experimental study; EPA analysis Rabinowitz et al. 1976 

Adults; N=10 2.7 Experimental study; EPA analysis Chamberlain et al. 1978 

Children; 1–18 years of 1.92 ± 0.60 Omaha cross-sectional study; smelter Angle et al. 1984 

age; N=831; 1,074 blood 

samples 

Children; N=148 2.46 ± 0.58 Belgium cross-sectional study; Roels et al. 1980 

smelter; EPA analysis 

Children; N=880 1.53 ± 0.064 Kellogg/Silver Valley cross-sectional Yankel et al. 1977 

study; EPA analysis; smelter 

Adult males; 5 groups, 

30/group 

2.57 ± 0.04 Cross-sectional study; air 

concentrations of 1 μg/m3 

Azar et al. 1975 

Adult males; 5 groups, 

30/group 

1.12 Reanalysis of Azar 1975 by Snee 

1982; at air concentration of 1 μg/m3 

Azar et al. 1975 

Adult males; 5 groups, 

30/group 

1–2.39 Analysis of Azar 1975 by EPA; at 

1 μg/m3 

Azar et al. 1975 

Adults; N=44 1.14 Occupational longitudinal study over Hodgkins et al. 1992 

30 months; air concentration 

<30 μg/m3 
LEAD D-5 

APPENDIX D 

Table 1. Summary of blood slope factors from various environmental media (continued). 

Population Slope Comments Reference 

Water Slope Factors 

Infants, N=131 

Children, N=495 

Adult males, N=7,735 

Adult Females, N=114 

Diet Slope Factors: 

Infants and toddlers; N=29 

Adults; N=31 

Adults; N=15 

Adult males; N=15 

μg/dL per μg Pb/L 

0.26 at <15 μg/L 

0.04 at >15 μg/L 

0.16 at <15 μg/L 

0.03 at >15 μg/L 

0.06 

0.03 

μg/dL per μg Pb/day 

0.24 

0.034--females 

0.014–0.017--males 

0.018–0.022--females 

0.027 

Scottish study of infants; EPA 

analysis 

Scottish study; EPA analysis 

24 British towns sampled; water lead 

levels <100 μg/L 

Duplicate diet study; Ayr, Scotland; 

EPA analysis 

Breast-fed and formula-fed; EPA 

analysis 

Duplicate diet study; Ayr, Scotland 

Experimental study; blood leads were 

not allowed to equilibrate 

Experimental study 

Lacey et al. 1985 

Laxen et al. 1987 

Pocock et al. 1983 

Sherlock et al. 1982 

Ryu et al. 1983; EPA 1990 

Sherlock et al. 1982 

Stuik et al. 1974 

Cools et al. 1976 
LEAD D-6 

APPENDIX D 

Table 1. Summary of blood slope factors from various environmental media (continued). 

Population Slope Comments Reference 

Soil Slope Factors μg/dL per μg Pb/kg 

Mixed 0.002–0.016 Review of the literature Reagan and Silbergeld 1990 

Children; 1–18 years of 0.0068 ± 0.00097 Omaha study; urban/suburban Angle et al. 1984 

age; N=831; 1,074 blood 

 samples 

Children; 1–72 months of -0.00016–0.00223 (near New Haven, CT; EPA analysis. The Stark et al. 1982 

age; N=377; 926 blood house) largest slopes were from the children 

leads 0.00073–0.0023 at curb) under 1 year 

Children; N=880 0.0011 (avg. for all ages) Kellogg/Silver Valley cross-sectional Yankel et al. 1977 

0.0025 (for 2–3 year olds) study; smelter; EPA analysis 

U.S. males age 18–65 years 0.001–0.003 Slope derived from Monte Carlo Stern 1996 

old (NHANES III) analysis 

Dust Slope Factors: μg/dL per mg Pb/kg 

Children; 1–18 years of 0.00718 ± 0.00090 Omaha study; urban/suburban; Angle et al. 1984 

age; N=831; 1074 blood housedust 

samples 

Children; 1–6 years of age; 0.008 Homes of lead workers; housedust Baker 1977 

N=32 

Children; 2 years of age; 0.004 Area of high lead soil; housedust Baltrop et al. 1974 

N=82 

Adults and children; N=80 0.0086–0.0096 (housedust); Smelter Roberts et al. 1974 

0.0021–0.0067 (outside 

dust) 

Children; N=377; 1– 0.00402 ± 0.0017 (0–1 year New Haven, CT; EPA analysis Stark et al. 1982 

72 months of age; old); 0.00182 ± 

926 blood lead levels 0.00066 (2–3 years old) 

0.00022±0.00077 (4– 

7 years old) 

Source: adapted from Duggan and Inskip 1985; EPA 1986, 1989 
LEAD D-7 

APPENDIX D 

The general form of the model is: 

PbB=δSTPbS + δDTPbD + δWTPbW + δAOTPbAO + δAITPbAI + δFTPbF 

where, 

PbS=soil lead concentration 

PbD=dust lead concentration 

PbW=water lead concentration 

PbAO=outside air lead concentration 

PbAI = inside air concentration 

PbF=food lead concentration 

T=relative time spent 

δ=the respective slope factor for specific media 

A worktable that can be used to calculate a cumulative exposure estimate on a site-specific basis is 

provided in Table 2. To use the table, environmental levels for outdoor air, indoor air, food, water, soil, 

and dust are needed. In the absence of such data (as may be encountered during health assessment 

activities), default values can be used. In most situations, default values will be background levels unless 

data are available to indicate otherwise. Based on the U.S. Food and Drug Administration’s (FDA’s) Total 

Diet Study data, lead intake from food for infants and toddlers is about 5 μg/day (Bolger et al. 1991). In 

some cases, a missing value can be estimated from a known value. For example, EPA (1986) has 

suggested that indoor air can be considered 0.03 x the level of outdoor air. Suggested default values are 

listed in Table 3. 

Empirically determined and/or default environmental levels are multiplied by the percentage of time one is 

exposed to a particular source and then multiplied by an appropriate regression slope factor. This 

assumes slope factor studies were based upon continuous exposure. The slope factors can be derived 

from regression analysis studies that determine PbBs for a similar route of exposure. Typically, these 

studies identify standard errors describing the regression line of a particular source of lead exposure. 

These standard errors can be used to provide an upper and lower confidence limit contribution of each 

source of lead to PbB. The individual source contributions can then be summed to provide an overall 

range estimate of PbB. While it is known that such summing of standard errors can lead to errors of 

population dynamics, detailed demographic analysis (e.g., Monte Carlo simulations) would likely lead to a 

model without much utility. As a screening tool, the estimates provided here have much greater utility 

than single value central tendency estimates, yet still provide a simple-to-use model that allows the health 

assessor an easy means to estimate source contributions to PbB. 

As an example, Table 4 provides environmental monitoring data for a subset of data from the Multisite 

Lead and Cadmium Exposure Study (ATSDR 1995). Default values are used for air and dietary lead. 

The data are input as described in equation 1 with suggested slope factors from Table 2. The resulting 

media-specific contributions to PbB, the range of predicted PbBs, and the actual PbBs are given in 

Table 5. 

The purpose of screening tools, such as MRLs or estimates derived from this approach, is to alert health 

assessors to substances that may pose risk to the exposed population. In addition, these approaches 

economize the use of resources by eliminating substances for which there is little likelihood of human 
LEAD D-8 

APPENDIX D 

Table 2. Worktable for calculation of PbB from environmental and dietary lead. 

Media Concentration 

Relative 

 Time 

Spent 

Slope 

Factor 

Blood Lead 

Low High 

Outdoor Air 

Indoor Air 

Food 

Water 

Soil 

Dust 

Total 

Table 3. Suggested default values to be used for missing data. 

Media Default Reference 

Outdoor Air 0.1–0.2 μg/m3 Eldred and Cahill 1994 

Indoor Air 0.03–0.06 μg/m3 

(0.3 x outdoor 

concentration) 

EPA 1986 

Food 5 μg/day Bolger et al. 1991 

Water 4 μg/L EPA 1991 

Soil 10–70 mg/kg Shacklette and Boerngen 

1972 

Dust 10–70 mg/kg Shacklette and Boerngen 

1972 
LEAD D-9 

APPENDIX D 

Table 4. Media concentrations for three sites: A, B, and C.

 SITE 

Media A B C 

Soil (mg/kg) 290 768 580 

Dust (mg/kg) 383 580 560 

Air (μg/m3

) 0.06-0.2 0.06-0.2 0.06-0.2 

Water (μg/L) 1 1 1 

Food (μg/day) 5 5 5 

Table 5. Contribution of environmental lead to blood lead for three sites: A, B, and C.

 SITE 

Media A 

contribution to PbB 

(μg/dL) 

B 

contribution to PbB 

(μg/dL) 

C 

contribution to PbB 

(μg/dL) 

Soil 1.1-2.8 3-7.4 2.3-5.6 

Dust 1.7-3.8 2.6-5.7 2.5-5.5 

Air 0.1-0.2 0.1-0.2 0.1-0.2 

Water 0.26 0.26 0.26 

Food 1.2 1.2 1.2 

Predicted range of PbB (μg/dL) 4.4-8.3 7-14.8 6.4-12.8 

Actual PbB 4.8 10.6 13.1 

Slope values used were based on Angle et al. (1984): soil = 0.0068 ± 3SE; dust = 0.00718 ± 3SE; air = 1.92 ± 3SE. 

Slope value for water was 0.26, based on Lacey et al. 1985 (reanalyzed by EPA 1986). 

Slope value for food was 0.24, based on Ryu et al. 1983 (reanalyzed by Marcus in EPA 1990). 

Default concentrations were used for air and food. 
LEAD D-10 

APPENDIX D 

health effects so that efforts can be concentrated on those compounds of importance. Interpretation of 

the results from Table 5 would indicate that the potential exists that children at sites B and C have 

elevated PbBs as defined by the CDC guidelines. Further action on these sites would, therefore, be 

warranted based on the individual site-specific demographic information and the CDC recommended 

follow-up services. These might include education, follow-up testing, and social services (CDC 1997). 

Results from site A, however, would indicate to the health assessor that the environmental data would not 

likely adversely affect PbBs of resident children; resources can then be shifted to the other substances at 

the site. 

Summary and Discussion 

A number of methods and models have been used at sites to estimate potential risks from exposure to 

lead. One method is the use of prevalence data for estimating PbBs. In this case, PbB measurements 

can be made at a site and extrapolated to other sites with similar environmental and demographic data. 

Limitations of this method include site-to-site variability with respect to, among other things, children’s 

behavioral patterns, age, and bioavailability issues. Estimation of past exposures can be problematic 

because of redistribution of Pb out of the blood compartment since PbB is only an indicator of recent 

exposure (<90 days). 

More traditional approaches have calculated exposure doses from a particular medium via a specific 

route (ATSDR, 1992). Such exposure doses can then be compared with a reference value derived for 

the same substance via the same route of exposure. Usual assumptions are ingestion rates of 100 mg 

dust/day and 200 mg soil/day, child body weight of 15 kg, and continuous exposure scenarios. This 

approach assumes a threshold for the effects of lead and does not reflect the fullest possible use of the 

wealth of human data on PbBs. 

Pharmacokinetic models have been developed that attempt to relate environmental levels to PbBs 

(Leggett 1993; O’Flaherty 1995). The Integrated Exposure Uptake Biokinetic Model (IEUBK) developed 

by EPA is one of the most extensive efforts to date to make population-based predictions of PbBs based 

upon environmental data. The model incorporates both exposure/uptake parameters and a biokinetic 

component to estimate the PbB distribution in the exposed population (EPA 1994). 

The framework described here provides a useful screening tool. Preliminary efforts to test its predictive 

power have shown promise (unpublished data). The framework’s strengths lie in its simplicity and 

flexibility to take into consideration environmental and biological variability between sites through the 

selection of slope factors from similar sites. For example, slope factors from a lead mining study can be 

used to address concerns at a mining community or, as more refined regression coefficients become 

available, they can be used in a site-specific manner to assist in making appropriate decisions. The 

framework also offers a simple approach that allows the health assessor to readily identify factors that 

may be contributing to elevated PbBs. In this manner, it provides for multi-media evaluation of all source 

contributions and utilizes a basic approach for determining significant human effect levels. This helps the 

health assessor determine source contributions of most significance and suggests plausible remediation 

avenues. These insights, coupled with biomedical judgment, can serve as valuable screening tools to 

identify those sites meriting further evaluation. 
LEAD D-11 

APPENDIX D 

References 

Abadin HG, Wheeler JS. 1993. Guidance for risk assessment of exposure to lead: A site-specific, multimedia approach. In: Hazardous waste and public health: International congress on the health effects of 

hazardous waste. Princeton, NJ: Princeton Scientific Publishing Company, Inc., 477-485. 

Angle CR, Marcus A, Cheng I-H, McIntire MS. 1984. Omaha childhood blood lead and environmental 

lead: A linear total exposure model. Environ Res 35:160-170. 

ATSDR. 1992. Public health assessment guidance manual. US Department of Health and Human 

Services, Public Health Service, Agency for Toxic Substances and Disease Registry. Atlanta, GA. 

ATSDR. 1993. Toxicological profile for lead. Atlanta, GA: US Department of Health and Human 

Services, Public Health Service, Agency for Toxic Substances and Disease Registry. 

ATSDR. 1995. Multisite lead and cadmium exposure study with biological markers incorporated. 

Atlanta, GA: US Department of Health and Human Services, Public Health Service, Agency for Toxic 

Substances and Disease Registry. 

ATSDR. 1996a. 1995 CERCLA priority list of hazardous substances that will be the subject of 

toxicological profiles and support document. Atlanta, GA: US Department of Health and Human 

Services, Public Health Service, Agency for Toxic Substances and Disease Registry. 

ATSDR. 1996b. Minimal risk levels for priority substances and guidance for derivation; republication. 

Federal Register, Vol. 61, No. 125, June 27, 1996. 

Aungst BJ, Dolce JA, Fung H-L. 1981. The effect of dose on the disposition of lead in rats after 

intravenous and oral administration. Toxicol Appl Pharmacol 61:48-57. 

Azar A, Snee RD, Habibi K. 1975. An epidemiologic approach to community air lead exposure using 

personal air samplers. In: Griffin TB, Knelson JH, eds. Lead. Stuttgart, West Germany: Georg Thieme 

Publishers, 254-290. 

Baker EL, Hayes CG, Landrigan PH, et al. 1977. A nationwide survey of heavy metal absorption in 

children living near primary copper, lead, and zinc smelters. Am J Epidemiol 106(4):261-273. 

Barltrop D, Strehlow CD, Thorton I, et al. 1974. Significance of high soil lead concentrations for childhood 

lead burdens. Environ Health Perspect 7:75-82. 

Barltrop D, Meek F. 1979. Effect of particle size on lead absorption from the gut. Arch Environ Health 

34:280-285. 

Bolger PM, Carrington CD, Capar SG, Adams MA. 1991. Reductions in dietary lead exposure in the 

United States. Chemical Speciation and Bioavailability 3(3/4):31-36. 

Brewer GJ, Hill GM, Dick RD, et al. 1985. Interactions of trace elements: Clinical significance. J Am 

Coll Nutr 4:33-38. 

Brunekreef BD. 1984. The relationship between air lead and blood lead in children: A critical review. 

Sci Total Environ 38:79-123. 

Cerklewski FL, Forbes RM. 1976. Influence of dietary zinc on lead toxicity in the rat. J Nutr 106:689

696. 

­
LEAD D-12 

APPENDIX D 

Chaney RL, Mielke HW, Sterrett SB. 1989. Speciation, mobility and bioavailability of soil lead. Environ 

Geochem Health 9[Suppl]:105-129. 

CDC. 1991. Preventing lead poisoning in young children. Atlanta, GA: US Department of Health and 

Human Services, Public Health Service, Centers for Disease Control. 

CDC. 1997. Screening young children for lead poisoning: Guidance for state and local public health 

officials-DRAFT. Atlanta, GA: US Department of Health and Human Services, Public Health Service, 

Centers for Disease Control and Prevention. 

Cools A, Salle HJA, Verberk MM, et al. 1976. Biochemical response of male volunteers ingesting 

inorganic lead for 49 days. Int Arch Occup Environ Health 38:129-139. 

Davis MJ. 1990. Risk assessment of the developmental neurotoxicity of lead. Neurotoxicology 11:285­

292. 

De Rosa CT, Choudhury H, Peirano WB. 1991. An integrated exposure/pharmacokinetic based 

approach to the assessment of complex exposures: Lead: A case study. Toxicol Ind Health 7(4):231­

247. 

Duggan MJ, Inskip MJ. 1985. Childhood exposure to lead in surface dust and soil: A community health 

problem. Public Health Rev 13:1-54. 

Eldred RA, Cahill TA. 1994. Trends in elemental concentrations of fine particles at remote sites in the 

United Sates of America. Atmos Environ 28:1009-1019. 

EPA. 1986. Air quality criteria for lead. Research Triangle Park, NC: US Environmental Protection 

Agency, Office of Research and Development, Office of Health and Environmental Assessment, 

Environmental Criteria and Assessment Office. EPA 600/8-83-028F. 

EPA. 1991. Maximum contaminant level goals and national primary drinking water regulations for lead 

and copper. Federal Register 56:26461-26564. 

EPA. 1990. Uptake of lead from formula and food by infants: Reanalysis of the Ryu et al. data. Draft final 

report. US Environmental Protection Agency, Office of Pesticides and Toxic Substances Exposure 

Evaluation Division, Office of Toxic Substances. 

EPA. 1994. Guidance manual for integrated exposure uptake biokinetic model for lead in children. US 

Environmental Protection Agency, Office of Solid Waste and Emergency Response. EPA/540/R-93/081. 

Goyer RA. 1986. Toxic effect of metals. In: Klaassen CD, et al., eds. Casarett and Doull's Toxicology: 

The basic science of poisons. 3rd ed. New York, NY: Macmillan Publishing Co, 582-588, 598-605. 

Griffin TB, Coulston F, Golberg L, et al. 1975. Clinical studies on men continuously exposed to airborne 

particulate lead. In: Griffin TB, Knelson JG, eds. Lead. Stuttgart, West Germany: Georg Thieme 

Publisher, 221-240. 

Grobler SR, Rossouw RJ, Kotze D. 1988. Effect of airborne lead on the blood lead levels of rats. S Afr J 

Sci 84:260-262. 

Gulson BL, Davis JJ, Mizon KJ, Korsch MJ, Law AJ. 1994. Lead bioavailability in the environment of 

children: Blood lead levels in children can be elevated in a mining community. Arch Environ Health 

49(5):326-331. 

Haeger-Aronsen B, Schutz A, Abdulla M. 1976. Antagonistic effect in vivo of zinc on inhibition of δaminolevulinic acid dehydratase by lead. Arch Environ Health 31(4):215-220. 
LEAD D-13 

APPENDIX D 

Heard MJ, Chamberlain AC. 1982. Effect of minerals and food on uptake of lead from the 

gastrointestinal tract in humans. Hum Toxicol 1:441-415. 

Hemphill CP, Ruby MV, Beck BD, Davis A, Bergstrom PD. 1991. The bioavailability of lead in mining 

wastes: physical/chemical considerations. Chem Speciation and Bioavailability 3(3/4):135-148. 

Hodgkins DG, Robins TG, Hinkamp DL, et al. 1992. A longitudinal study of the relation of lead in blood to 

lead in air concentrations among battery workers. Br J Ind Med 49:241-248. 

James HM, Hilburn ME, Blair JA. 1985. Effects of meals and meal times on uptake of lead from the 

gastrointestinal tract in humans. Hum Toxicol 4:401-407. 

Johnson NE, Tenuta K. 1979. Diets and lead blood levels of children who practice pica. Environ Res 

18:369-376. 

Lacey RF, Moore MR, Richards WN. 1985. Lead in water, infant diet and blood: The Glasgow duplicate 

diet stud. Sci Total Environ 41:235-257. 

Laxen DP, Raab GM, Fulton M. 1987. Children's blood lead and exposure to lead in household dust and 

water--a basis for an environmental standard for lead in dust. Sci Total Environ 66:235-244. 

Leggett RW. 1993. An age-specific kinetic model of lead metabolism in humans. Environ Health 

Perspect 101:598-616. 

Mahaffey KR, Rosen JF, Chesney RW, et al. 1982. Association between age, blood lead concentration, 

and serum 1,25-dihydroxycholecalciferol levels in children. Am J Clin Nutr 35:1327-1331. 

Morrow PE, Beiter H, Amato F, Gibb FR. 1980. Pulmonary retention of lead: An experimental study in 

man. Environ Res 21:373-384. 

Mumtaz MM, Cibulas W, De Rosa CT. 1995. An integrated framework to identify significant human 

exposures (SHELs). Chemosphere 31(1):2485-2498. 

Mushak P. 1991. Gastro-intestinal absorption of lead in children and adults: Overview of biological and 

biophysico-chemical aspects. Chem Speciation and Bioavailability 3(3/4):87-104. 

O'Flaherty EJ. 1995. Physiologically based models for bone-seeking elements. V Lead absorption and 

disposition in childhood. Toxicol Appl Pharmacol 131:297-308. 

Pocock SJ, Shaper AG, Walker M, et al. 1983. Effects of tap water lead, water hardness, alcohol, and 

cigarettes on blood lead concentrations. J Epidemiot Communitv Health 37:1-7. 

Rabinowitz MB, Wetherill GW, Kopple JD. 1976. Kinetic analysis of lead metabolism in healthy humans. 

J Clin Invest 58:260-270. 

Reagan PL, Silbergeld EK. 1990. Establishing a health based standard for lead in residential soils. 

Trace Subst Environ Health 23:199-238. 

Roberts TM, Hutchinson TC, Paciga J. 1974. Lead contamination around secondary smelters: 

Estimation of dispersal and accumulation by humans. Science 186:1120-1123. 

Roels HA, Buchet J-P, Lauwerys RR, et al. 1980. Exposure to lead by the oral and the pulmonary routes 

of children living in the vicinity of a primary lead smelter. Environ Res 22:81-94. 

Ryu JE, Ziegler EE, Nelson SE, Fomon SJ. 1983. Dietary intake of lead and blood lead concentration in 

early infancy. Am J Dis Child 137:886-891. 
LEAD D-14 

APPENDIX D 

Shacklette HT and Boerngen JG. 1972. Elemental composition of surficial materials in the conterminous 

United States. Washington DC: US Department of the Interior, Geological Survey; Geological Survey 

professional paper no. 1270. 

Sherlock JC, Smart G, Forbes GI, et al. 1982. Assessment of lead intakes and dose-response for a 

population in Ayr exposed to a plumbosolvent water supply. Human Toxicol 1:115-122. 

Sorrell M. Rosen JF, Roginsky M. 1977. Interactions of lead, calcium, vitamin D, and nutrition in lead 

burdened children. Arch Environ Health 32:160-164. 

Stark AD, Quah RF, Meigs JW, et al. 1982. The relationship of environmental lead to blood-lead levels in 

children. Environ Res 27:372-383. 

Steele MJ, Beck BD, Murphy BL, Strauss HS. 1990. Assessing the contribution from lead in mining 

wastes to blood lead. Regul Toxicol Pharmacol 11:158-190. 

Stern AH. 1996. Derivation of a target concentration of Pb in soil based on elevation of adult blood 

pressure. Risk Analysis 16:201-210. 

Stuik EJ. 1974. Biological response of male and female volunteers to inorganic lead. Int Arch 

Arbeitsmed 33:83-97. 

Xintaras C. 1992. Analysis paper: Impact of lead-contaminated soil on public health. US Department of 

Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry. 

Atlanta, GA. 

Yankel AJ, von Lindern IH, Walter SD. 1977. The Silver Valley lead study: The relationship of childhood 

lead poisoning and environmental exposure. J Air Pollut Contr Assoc 27:763-767. 

Ziegler EE, Edwards BB, Jensen RL, Mahaffey KR, Fomon SJ. 1978. Absorption and retention of lead 

by infants. Pediatr Res 12:29-34. 
LEAD E-1 

APPENDIX E. INDEX 

absorbed dose.............................................................................................................................. 37, 239, 241 

acetylcholine .............................................................................................................................................234 

active transport.................................................................................................................................. 216, 218 

adenocarcinomas.......................................................................................................................................235 

adrenal gland.............................................................................................................................................181 

adsorbed .................................................................................................................... 176, 318, 342, 362, 397 

adsorption.................................................................................................................. 336, 337, 341, 342, 390 

aerobic.......................................................................................................................................................341 

alanine aminotransferase (see ALT) ...........................................................................................................80 

ALT (see alanin aminotransferase) ..................................................................................................... 80, 263 

ambient air .................................................. 20, 164, 318, 338, 344, 345, 362, 379, 397, 398, 399, 425, 427 

anaerobic...................................................................................................................................................341 

anemia......................................... 8, 10, 23, 32, 73, 75, 76, 99, 152, 225, 228, 237, 247, 258, 265, 266, 289 

aspartate aminotransferase (see AST).........................................................................................................80 

AST (see aspartate aminotransferase)................................................................................................. 80, 263 

bioavailability .......................................... 169, 171, 174, 175, 199, 206, 212, 213, 214, 260, 282, 283, 289, 

337, 338, 390, 398, 400, 401 

bioconcentration factor .............................................................................................................................339 

biokinetic .....................35, 167, 168, 192, 201, 204, 205, 206, 207, 208, 211, 213, 214, 216, 217, 220, 286 

biomarker ........................... 22, 29, 35, 38, 53, 70, 81, 87, 93, 158, 195, 239, 240, 241, 242, 243, 246, 248, 

249, 276, 279, 280, 281, 282, 284, 285, 290, 292, 394, 403, 408, 419, 421 

blood cell count...........................................................................................................................................75 

breast milk........................................................................... 79, 164, 181, 183, 246, 256, 382, 391, 392, 400 

cancer .......................................... 8, 9, 25, 51, 59, 64, 90, 159, 161, 162, 235, 236, 258, 274, 275, 279, 423 

carcinogen....................................................................................................................... 9, 25, 163, 423, 427 

carcinogenic ............................................................................................................ 9, 25, 163, 164, 423, 427 

carcinogenicity........................................................................................................ 9, 25, 163, 274, 423, 427 

carcinomas ................................................................................................................................................163 

cardiovascular ............... 22, 25, 28, 29, 33, 51, 52, 53, 60, 61, 63, 70, 72, 92, 222, 235, 270, 273, 279, 280 

cardiovascular effects.................................................................................................... 52, 70, 222, 273, 280 

chromosomal aberrations ............................................................................................ 25, 154, 156, 158, 275 

clearance ............................................................... 31, 69, 81, 85, 86, 87, 88, 89, 90, 92, 165, 199, 221, 231
 

cognitive function ............................................. 26, 27, 28, 29, 109, 112, 120, 121, 233, 235, 268, 277, 292 

death............................................................................................ 9, 24, 50, 51, 100, 106, 116, 159, 161, 271 

deoxyribonucleic acid (see DNA)..................................................................................................... 157, 160 

developmental effects ....................................................................................................................... 148, 284 

DNA (see deoxyribonucleic acid)......................... 24, 25, 146, 156, 157, 159, 160, 163, 232, 240, 274, 275 

dopamine................................................................................................................................... 100, 234, 263 

elimination half-time................................................................................................. 241, 242, 243, 280, 419 

elimination rate .........................................................................................................................................188 

endocrine...................................................................................................................................................154 

endocrine effects .........................................................................................................................................94 

erythema....................................................................................................................................................266 

estrogen receptor.......................................................................................................................................144 

estrogenic ..................................................................................................................................................144 

fetal tissue .................................................................................................................................................143 

fetus........................................................................... 143, 164, 178, 179, 231, 235, 238, 253, 256, 286, 383 

follicle stimulating hormone (see FSH) ................................................................................................ 23, 94 

fractional absorption .................................................................................................................................204 
LEAD E-2 

APPENDIX E 

FSH (see follicle stimulating hormone) ............................................ 23, 94, 97, 98, 144, 146, 147, 148, 275 

gastrointestinal effects ................................................................................................................................72 

general population.................................... 21, 22, 25, 31, 37, 38, 50, 56, 60, 77, 87, 96, 102, 140, 149, 154, 

156, 162, 240, 260, 270, 318, 358, 362, 368, 383 

genotoxic................................................................................................................................... 154, 158, 274 

genotoxicity....................................................................................................................................... 158, 275 

groundwater .............................................................. 3, 5, 318, 326, 332, 336, 337, 346, 347, 363, 398, 414
 

growth retardation.....................................................................................................................................237 

half-life...................................................................................................... 178, 179, 210, 240, 339, 340, 404 

hematological effects ...................................................................................... 32, 73, 77, 153, 222, 225, 273 

hematopoietic............................................................................................................ 225, 229, 248, 260, 281 

hepatic effects .............................................................................................................................................80 

hydrolysis..................................................................................................................................................397 

hydroxyl radical ........................................................................................................................................340 

immune system ......................................................................................................... 102, 104, 105, 106, 279 

immunological .......................................................................................................................... 102, 273, 277 

Kow ............................................................................................................................ 300, 301, 302, 303, 304 

lymphatic ..................................................................................................................................................231 

melanoma..................................................................................................................................................160 

menstrual........................................................................................................................................... 144, 359 

micronuclei ......................................................................................................................... 25, 154, 158, 275 

milk ........................................... 141, 164, 181, 254, 255, 256, 264, 353, 356, 357, 358, 391, 392, 415, 416 

mucociliary ...............................................................................................................................................165 

muscarinic receptor........................................................................................................................... 234, 235 

musculoskeletal effects ............................................................................................................... 77, 151, 273 

neonatal............................................................................................................. 128, 130, 167, 204, 229, 232 

neurobehavioral................................ 24, 27, 28, 33, 107, 108, 109, 110, 111, 117, 119, 121, 127, 128, 129, 

130, 237, 257, 262, 273, 275, 277, 279, 284, 291, 384 

neurochemical.............................................................................................................................................28 

neurodevelopmental.................................................................................... 25, 123, 129, 235, 243, 284, 285 

neurological effects............................................................................................. 52, 106, 116, 139, 222, 256
 

neurophysiological............................................................................................................................ 114, 232 

neurotransmitter .......................................................................................................... 32, 232, 234, 278, 284 

nicotinic cholinergic receptor ...................................................................................................................234 

non-Hodgkin’s lymphoma ..........................................................................................................................51 

norepinephrine ..........................................................................................................................................223 

nuclear............................................................................................................................... 146, 223, 224, 311 

ocular effects...............................................................................................................................................99 

odds ratio......................................................................................................................................... 30, 61, 68 

passive transport........................................................................................................................................263 

pharmacodynamic.....................................................................................................................................185 

pharmacokinetic............................................... 164, 177, 184, 185, 187, 188, 192, 195, 196, 199, 201, 205, 

207, 211, 236, 238, 391, 398 

photolysis .......................................................................................................................... 340, 341, 342, 397 

placenta ..................................................................................................................................... 238, 383, 384 

rate constant ...................................................................................................................... 192, 204, 207, 340 

renal effects................................................................... 29, 31, 52, 81, 85, 89, 222, 223, 225, 235, 273, 280 

reproductive effects............................................................................................................. 97, 142, 147, 273 

respiratory effects........................................................................................................................................52 

retention .................................................................................... 164, 177, 238, 239, 250, 252, 254, 255, 343 

solubility ................................................................... 165, 166, 169, 282, 318, 335, 336, 340, 341, 342, 343 
LEAD E-3 

APPENDIX E 

spermatozoa ...................................................................................................................................... 146, 147 

systemic effects................................................................................................................................... 52, 100 

T3.............................................................................................................................................. 94, 95, 96, 97 

T4.............................................................................................................................................. 23, 94, 95, 96 

thyroid........................................................................................................................... 23, 34, 62, 94, 95, 96 

thyroid stimulating hormone (see TSH)................................................................................................ 23, 94 

thyroxine ............................................................................................................................................... 23, 94 

toxicokinetic.......................................................................................... 26, 37, 221, 238, 250, 252, 260, 283 

triiodothyronine...........................................................................................................................................94 

TSH (see thyroid stimulating hormone).............................................................................. 23, 94, 95, 96, 97
 

tumors ............................................................................................................................. 9, 25, 163, 235, 274 

vapor phase ....................................................................................................................................... 340, 410 

vapor pressure ...........................................................................................................................................340 

volatilization .............................................................................................................................................341