Toxicological Profile for

Lead

August 2020
LEAD ii

DISCLAIMER

Use of trade names is for identification only and does not imply endorsement by the Agency for Toxic 

Substances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human 

Services.
LEAD iii

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 these toxic substances described therein. Each peer-reviewed profile identifies and 

reviews the key literature that describes a 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 relevance to public health discussion which would allow a public health professional to 

make a real-time determination of whether the presence of a particular substance in the environment 

poses a potential threat to human health. 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 the protection of 

public health are identified by ATSDR.

Each profile includes the following:

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

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

human exposure for the substance due to associated acute, intermediate, and chronic 

exposures;

(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, intermediate, 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. Staffs 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 was made available for public review. Final responsibility for the contents and views expressed in 

this toxicological profile resides with ATSDR.

Patrick N. Breysse, Ph.D., CIH

Director, National Center for Environmental Health and

Agency for Toxic Substances and Disease Registry

Centers for Disease Control and Prevention
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*Legislative Background

The toxicological profiles are developed under the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section 

104(i)(1) directs the Administrator of ATSDR to “...effectuate and implement the health related 

authorities” of the statute. This includes the preparation of toxicological profiles for hazardous 

substances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that 

pose the most significant potential threat to human health, as determined by ATSDR and the EPA. 

Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a 

toxicological profile for each substance on the list. In addition, ATSDR has the authority to prepare 

toxicological profiles for substances not found at sites on the NPL, in an effort to “...establish and 

maintain inventory of literature, research, and studies on the health effects of toxic substances” under 

CERCLA Section 104(i)(1)(B), to respond to requests for consultation under section 104(i)(4), and as 

otherwise necessary to support the site-specific response actions conducted by ATSDR.
LEAD v

VERSION HISTORY

Date Description

August 2020 Final toxicological profile released

May 2019 Draft for public comment toxicological profile released

August 2007 Final toxicological profile released

April 1993 Final toxicological profile released
LEAD vi

CONTRIBUTORS & REVIEWERS

CHEMICAL MANAGER TEAM

Henry Abadin, M.S.P.H. (Lead) Julie M. Klotzbach, Ph.D.

Jessilynn Taylor, M.S., CDR USPHS Gary L. Diamond, Ph.D.

Melanie Buser, M.P.H. Mario Citra, Ph.D.

Franco Scinicariello, M.D., M.P.H. Lara L. Chappell, Ph.D.

Jennifer Przybyla, Ph.D. Laura A. McIlroy, B.A.

ATSDR, Division of Toxicology and Human Health 

Sciences, Atlanta, GA

SRC, Inc., North Syracuse, NY

REVIEWERS

Interagency Minimal Risk Level Workgroup: 

Includes ATSDR; National Center for Environmental Health (NCEH); National Institute for Occupational 

Safety and Health (NIOSH); U.S. Environmental Protection Agency (EPA); National Toxicology 

Program (NTP).

Additional reviews for science and/or policy: 

ATSDR, Division of Community Health Investigations; ATSDR, Office of Science; NCEH, Division of 

Laboratory Science; NCEH, Division of Environmental Health Science and Practice; Occupational Safety 

and Health Administration (OSHA); Department of Defense (DoD); EPA; NIOSH.

PEER REVIEWERS

1. Howard Hu, M.D., M.P.H., Sc.D., Department of Environmental Health Sciences, University of 

Michigan School of Public Health, Ann Arbor, Michigan

2. Anthony Knafla, M.Sc., DABT, P. Biol., Founder/Senior Scientist & Manager, Equilibrium 

Environmental Inc., Calgary, Canada

3. Nelly Mañay, Ph.D., Professor, Department of Toxicology and Environmental Hygiene, Faculty 

of Chemistry, University of the Republic of Uruguay, Montevideo, Uruguay

These experts collectively have knowledge of toxicology, chemistry, and/or health effects. All reviewers 

were selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, 

Compensation, and Liability Act, as amended.

ATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the 

profile based on comments. The peer reviewers’ comments and responses to these comments are part of 

the administrative record for this compound.

The listing of peer reviewers should not be understood to imply their approval of the profile's final 

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

CONTENTS

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

FOREWORD...............................................................................................................................................iii

VERSION HISTORY...................................................................................................................................v

CONTRIBUTORS & REVIEWERS...........................................................................................................vi

CONTENTS................................................................................................................................................vii

LIST OF FIGURES ......................................................................................................................................x

LIST OF TABLES.......................................................................................................................................xi

CHAPTER 1. RELEVANCE TO PUBLIC HEALTH .................................................................................1

1.1 OVERVIEW AND U.S. EXPOSURES.........................................................................................1

1.2 SUMMARY OF HEALTH EFFECTS...........................................................................................3

1.3 MINIMAL RISK LEVELS (MRLs)..............................................................................................9

CHAPTER 2. HEALTH EFFECTS............................................................................................................10

2.1 INTRODUCTION........................................................................................................................10

2.2 ACUTE LEAD TOXICITY.........................................................................................................18

2.3 DEATH ........................................................................................................................................19

2.4 BODY WEIGHT..........................................................................................................................28

2.5 RESPIRATORY ..........................................................................................................................33

2.6 CARDIOVASCULAR.................................................................................................................39

2.7 GASTROINTESTINAL...............................................................................................................74

2.8 HEMATOLOGICAL ...................................................................................................................75

2.9 MUSCULOSKELETAL..............................................................................................................87

2.10 HEPATIC.....................................................................................................................................96

2.11 RENAL ......................................................................................................................................102

2.12 DERMAL...................................................................................................................................116

2.13 OCULAR ...................................................................................................................................116

2.14 ENDOCRINE.............................................................................................................................117

2.15 IMMUNOLOGICAL .................................................................................................................121

2.16 NEUROLOGICAL.....................................................................................................................133

2.17 REPRODUCTIVE .....................................................................................................................200

2.18 DEVELOPMENTAL.................................................................................................................218

2.19 CANCER....................................................................................................................................247

2.20 GENOTOXICITY......................................................................................................................256

2.21 GENERAL CELLULAR MECHANISMS OF ACTION..........................................................262

2.21.1 Perturbation of Ion Homeostasis.........................................................................................262

2.21.2 Protein Binding/Sequestration.............................................................................................270

2.21.3 Oxidative Stress ..................................................................................................................271

2.21.4 Inflammation.......................................................................................................................274

2.21.5 Epigenetic Effects ...............................................................................................................275

2.21.6 Apoptosis.............................................................................................................................276

CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL 

INTERACTIONS..................................................................................................................277

3.1 TOXICOKINETICS...................................................................................................................277

3.1.1 Absorption...........................................................................................................................278

3.1.2 Distribution .........................................................................................................................289
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3.1.3 Metabolism .......................................................................................................................... 298

3.1.4 Excretion ............................................................................................................................. 299

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 302

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ... 321

3.3 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 326

3.3.1 Biomarkers of Exposure ...................................................................................................... 327

3.3.2 Biomarkers of Effect ........................................................................................................... 335

3.4 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 338

3.5 METHODS FOR REDUCING TOXIC EFFECTS ................................................................... 339

3.5.1 Reducing Absorption Following Exposure ......................................................................... 340

3.5.2 Reducing Body Burden ....................................................................................................... 342

CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ........................................................... 345

4.1 CHEMICAL IDENTITY ........................................................................................................... 345

4.2 PHYSICAL AND CHEMICAL PROPERTIES ........................................................................ 348

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 355

5.1 OVERVIEW .............................................................................................................................. 355

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 358

5.2.1 Production ........................................................................................................................... 358

5.2.2 Import/Export ...................................................................................................................... 366

5.2.3 Use ...................................................................................................................................... 366

5.2.4 Disposal ............................................................................................................................... 369

5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 370

5.3.1 Air ....................................................................................................................................... 371

5.3.2 Water ................................................................................................................................... 377

5.3.3 Soil ...................................................................................................................................... 379

5.3.4 Paint..................................................................................................................................... 380

5.4 ENVIRONMENTAL FATE ...................................................................................................... 382

5.4.1 Transport and Partitioning ................................................................................................... 382

5.4.2 Transformation and Degradation ........................................................................................ 389

5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 393

5.5.1 Air ....................................................................................................................................... 395

5.5.2 Water ................................................................................................................................... 398

5.5.3 Sediment and Soil ............................................................................................................... 401

5.5.4 Paint..................................................................................................................................... 403

5.5.5 Other Media ........................................................................................................................ 404

5.6 GENERAL POPULATION EXPOSURE.................................................................................. 411

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 428

CHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 430

6.1 INFORMATION ON HEALTH EFFECTS ............................................................................... 430

6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 431

6.3 ONGOING STUDIES ................................................................................................................ 435

CHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 437

CHAPTER 8. REFERENCES .................................................................................................................. 442
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APPENDICES

APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR LEAD................................................ B-1 

APPENDIX C. INGESTION OF LEAD DEBRIS .................................................................................. C-1 

APPENDIX D. QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... D-1 

APPENDIX E. GLOSSARY ................................................................................................................... E-1 

APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS .................................................. F-1
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LIST OF FIGURES

2-1. Overview of the Number of Studies Examining Associations Between PbB and Health Effects......17

2-2. Change in the Systolic Pressure Associated with a Doubling of the Blood Lead 

Concentration (PbB)...........................................................................................................................46

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

Concentration (PbB)...........................................................................................................................47

2-4. Pb Interactions in the Heme Synthesis Pathway.................................................................................86

2-5. Multiorgan Impact of Reduction of Heme Body Pool by Lead..........................................................87

2-6. Immunological Pathways by which Pb Exposure Potentially may Increase Risk of ImmuneRelated Diseases...............................................................................................................................132

2-7. Relationship Between Blood Lead Concentration (PbB) and Birth Weight at PbB ≤10 μg/dL.......231

3-1. Compartments and Pathways of Lead (Pb) Exchange in the O’Flaherty Model..............................305

3-2. Structure of the IEUBK Model for Lead (Pb) in Children ...............................................................309

3-3. Compartments and Pathways of Lead (Pb) Exchange in the Leggett Model ...................................313

3-4. Blood Lead Concentrations (PbBs) in Children Predicted by the IEUBK, Leggett, and 

O’Flaherty Models and AALM ........................................................................................................319

3-5. Blood Lead Concentrations (PbBs) in Adults Predicted by the Leggett and O’Flaherty 

Models and AALM...........................................................................................................................319

5-1. Number of NPL Sites with Lead Contamination..............................................................................355

5-2. Number of NPL Sites with Lead Compound Contamination...........................................................356

5-3. Annual Maximum 3-Month Average Representing the National Trend ..........................................396
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LIST OF TABLES

2-1. Summary of Epidemiological Studies Evaluating Death ...................................................................22

2-2. Summary of Epidemiological Studies Evaluating Effects on Body Weight at Mean Blood 

Lead Concentrations (PbB) ≤10 μg/dL ..............................................................................................30

2-3. Effects on Body Weight Associated with Mean Blood Lead Concentrations (PbBs) ≤10 μg............33

2-4. Overview of Respiratory Effects in Adults and Children Chronically Exposed to Lead (Pb) ...........35

2-5. Summary of Epidemiological Studies Evaluating Respiratory Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL.........................................................................................................36

2-6. Overview of Cardiovascular Effects in Adults and Children Associated with Chronic 

Exposure to Lead (Pb)........................................................................................................................41

2-7. Characteristics of the Study Population in Meta-Analyses of Effects of Lead (Pb) on Blood 

Pressure...............................................................................................................................................43

2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dL................................................................................................49

2-9. Summary of Epidemiological Studies Evaluating Atherosclerosis at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL.........................................................................................................65

2-10. Summary of Epidemiological Studies Evaluating Heart Disease at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL.......................................................................................................66

2-11. Summary of Epidemiological Studies Evaluating Mortality due to Cardiovascular Disease 

at Mean Blood Lead Concentrations (PbB) ≤10 μg/dL....................................................................70

2-12. Associations Between Bone Pb and Blood Pressure Outcomes.......................................................71

2-13. Associations Between Bone Pb and Cardiac Function, Disease, and Mortality...............................73

2-14. Summary of Studies Evaluating Gastrointestinal Symptoms Associated with Chronic 

Exposure to Lead (Pb)......................................................................................................................76

2-15. Overview of Hematological Effects Associated with Chronic Exposure to Lead (Pb)....................79

2-16. Summary of Epidemiological Studies Evaluating Hematological Effects at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dL..............................................................................................82

2-17. Overview of Musculoskeletal Effects Associated with Chronic Exposure to Lead (Pb) .................89

2-18. Summary of Epidemiological Studies Evaluating Musculoskeletal Effects at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dL..............................................................................................91

2-19. Summary of Epidemiological Studies Evaluating Hepatic Effects Associated with Blood 

Lead Concentration (PbB)................................................................................................................98

2-20. Effects on Liver Function Tests Associated with Chronic Exposure to Lead (Pb) ........................101
LEAD xii

2-21. Overview of Renal Effect Associated with Chronic Exposure to Lead (Pb)..................................104

2-22. Summary of Epidemiological Studies Evaluating Renal Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL.....................................................................................................106

2-23. Associations Between Bone Pb and Renal Function......................................................................115

2-24. Overview of Endocrine Effects Associated with Chronic Exposure to Lead (Pb).........................119

2-25. Effects on Thyroid Hormones Associated with Blood Lead Concentration (PbB)........................119

2-26. Overview of Immunological Effects Associated with Chronic Exposure to Lead (Pb).................123

2-27. Summary of Epidemiological Studies Evaluating Immunological Effects at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dL............................................................................................127

2-28. Overview of Neurological Effects in Children Associated with Chronic Exposure to Lead 

(Pb).................................................................................................................................................136

2-29. Overview of Neurological Effects in Adults Associated with Chronic Exposure to Lead 

(Pb).................................................................................................................................................138

2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean 

Blood Lead Concentration (PbB) ≤10 μg/dL .................................................................................141

2-31. Associations Between Bone Pb and Neurological Outcomes in Children .....................................175

2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at 

Mean Blood Lead Concentration (PbB) ≤10 μg/dL.......................................................................177

2-33. Associations Between Bone Pb and Neurological Outcomes in Adults.........................................191

2-34. Overview of Effects on the Male Reproductive System Associated with Chronic Exposure 

to Lead (Pb)....................................................................................................................................203

2-35. Effects on Reproductive Hormones Associated with Chronic Exposure to Lead (Pb) in 

Males..............................................................................................................................................204

2-36. Summary of Epidemiological Studies Evaluating Effects on the Male Reproductive System 

at Mean Blood Lead Concentration (PbB) ≤10 μg/dL ...................................................................206

2-37. Overview of Effects on the Female Reproductive System and Pregnancy Outcomes 

Associated with Chronic Exposure to Lead (Pb)............................................................................211

2-38. Summary of Epidemiological Studies Evaluating Effects on the Female Reproductive 

System at Mean Blood Lead Concentration (PbB) ≤10 μg/dL.......................................................212

2-39. Overview of Developmental Effects Associated with Chronic Exposure to Lead (Pb).................220

2-40. Effects on Birth Outcomes at Blood Lead Concentration (PbB) ≤10 μg/dL..................................221

2-41. Summary of Epidemiological Studies Evaluating Birth Outcomes Effects of Mean Blood 

Lead Concentration (PbB) ≤10 μg/dL............................................................................................223
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2-42. Overview of Decreased Anthropometric Measures in Children at Blood Lead

Concentration (PbB) ≤10 μg/dL ..................................................................................................... 233

2-43. Summary of Epidemiological Studies Evaluating Anthropometric Measurements in Infants

and Children with Mean Blood Lead Concentration (PbB) ≤10 μg/dL ......................................... 235

2-44. Summary of Epidemiological Studies Evaluating the Onset of Puberty at Children with

Mean Blood Lead Concentration (PbB) ≤10 μg/dL ....................................................................... 242

2-45. Associations Between Maternal Bone Pb and Birth Outcome and Postnatal Growth .................... 246

2-46. Summary of Epidemiological Studies Evaluating Cancer Endpoints and Blood Lead

Concentration (PbB) .......................................................................................................................250

2-47. Overview of Epidemiology Studies Evaluating Genotoxicity Associated with Chronic

Exposure to Lead (Pb) .................................................................................................................... 258

2-48. Results of Genotoxicity Studies at Blood Lead Concentration (PbB) ≤10 μg/dL .......................... 260

2-49. Effects of Lead (Pb) on Function of Various Proteins .................................................................... 266

3-1. Ranking of Relative Bioavailability of Lead (Pb) Mineral Phases in Soil ....................................... 286

3-2. Comparison of Slope Factors in Selected Slope Factor Models ....................................................... 320

3-3. Influence of Other Metals and Metalloids on Lead (Pb) Toxicity .................................................... 338

3-4. Recommended Actions Based on Child Blood Lead Level (PbB) ................................................... 341

3-5. Recommended Actions for Workers Based on Blood Lead Level (PbB) ........................................ 342

4-1. Chemical Identity of Lead and Compounds ..................................................................................... 345

4-2. Physical and Chemical Properties of Lead and Compounds ............................................................ 350

5-1. U.S. Manufacturers of Lead Metal and Selected Lead Compounds ................................................. 359

5-2. U.S. Lead Production 2015–2018 ..................................................................................................... 362

5-3. Facilities that Produce, Process, or Use Lead ................................................................................... 362

5-4. Facilities that Produce, Process, or Use Lead Compounds ............................................................... 364

5-5. Current and Former Uses of Selected Lead Compounds .................................................................. 368

5-6. Releases to the Environment from Facilities that Produce, Process, or Use Lead ........................... 372

5-7. Releases to the Environment from Facilities that Produce, Process, or Use Lead Compounds ....... 374

5-8. Historic Levels of Lead Emissions to the Atmosphere in the United States (in Thousand

Metric Tons) ..................................................................................................................................... 376

5-9. U.S. Surface Water Discharges of Lead and Lead Compounds (Pounds/Year) ............................... 378
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5-10. Canada Surface Water Discharges of Lead and Lead Compounds (Tonnes).................................379

5-11. Lowest Limit of Detection Based on Standards.............................................................................394

5-12. Lead Levels in Water, Soil, and Air of National Priorities List (NPL) Sites .................................395

5-13. Summary Data for Lead Monitors Across the United States, 2008–2010 (μg/m3

) ........................396

5-14. Percentile Distribution of Mean Lead (TSP) Concentrations (μg/m3

) Measured in Ambient 

Air at Locations Across the United States......................................................................................397

5-15. Lead Levels in Foods Commonly Eaten by Toddlers and Infants..................................................404

5-16. Selected Mean Lead Concentrations in Food from the FDA Total Diet Study ..............................405

5-17. Estimated Median and Maximum Lead Exposures........................................................................407

5-18. Lead Content in Ayurvedic Medications and Other Health Remedies...........................................408

5-19. Lowest Limit of Detection Based on Standards.............................................................................411

5-20. Geometric Mean Blood Lead Levels (μg/dL) and the 95th Percentile Confidence Interval, 

by Race/Ethnicity, Sex, and Age for the Years for 2011–2016......................................................415

5-21. Geometric Mean Urine Lead Levels (μg/dL) and the 95th Percentile Confidence Interval, by 

Race/Ethnicity, Sex, and Age.........................................................................................................416

5-22. Industries by Sector with Most Workers having Blood Lead Concentrations (PbBs) 

≥25 μg/dL, 2010–2016 ...................................................................................................................417

5-23. Number and Rate per 100,000 Children Aged <5 Years with Blood Lead Levels 5–9 μg/dL 

in the Childhood Blood Lead Surveillance System, United States, 2010–2014.............................418

5-24. Geometric Mean Urine Lead Levels (μg/dL) and the 95th Percentile Confidence Interval by 

Smoking Status...............................................................................................................................420

5-25. Measurements of Lead in Indoor Dust in the United States from 2006 to 2011 ............................424

6-1. Ongoing Studies on Lead (Pb)..........................................................................................................435

7-1. Regulations and Guidelines Applicable to Lead (Pb).......................................................................437
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CHAPTER 1. RELEVANCE TO PUBLIC HEALTH

1.1 OVERVIEW AND U.S. EXPOSURES

Lead (Pb) is an element that is found in concentrated and easily accessible Pb ore deposits that are widely 

distributed throughout the world. A major source of Pb in the U.S. environment has historically been 

anthropogenic emissions to the atmosphere from combustion of leaded gasoline, which was phased out of 

use after 1973 and then banned in 1995 (with the exception of fuels for piston-driven aircraft) (EPA 

1996a). Pb continued to be used as an anti-knock agent in National Association for Stock Car Auto 

Racing (NASCAR) fuels until it was phased out beginning in 2008. Deteriorating Pb-based paints from 

weathered surfaces (which produce highly concentrated Pb debris and dusts) in older housing stock 

(pre-1978) continues to be a source of childhood Pb poisoning in the United States (CDC 1991, 2012d). 

The combination of corrosive water and Pb pipes or Pb-soldered joints in either the distribution system or 

individual houses can create localized zones of high Pb water concentrations (EPA 1989b, 2007a; HannaAttisha et al. 2016). Other anthropogenic sources of Pb have included mining and smelting of ore; 

manufacture of and use of Pb-containing products (e.g., Pb-based paints, pigments, and glazes; electrical 

shielding; plumbing; storage batteries; solder; and welding fluxes); manufacture and application of 

Pb-containing pesticides; combustion of coal and oil; and waste incineration.

Pb does not degrade in the environment, although it can exist in various chemical forms (see Section 5.4 

for a more detailed discussion of the environmental fate of Pb). Particulate matter containing Pb can be 

transported through air, water, and soil. In general, atmospheric deposition is the largest source of Pb

found in soils not impacted by other local non-air sources (e.g., dust from deteriorating leaded paint). Pb

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 Pb. Pb adsorbs strongly to most soils, which limits the rate of 

leaching. Soil acidity (pH) and composition are the most important factors affecting solubility, mobility, 

and phytoavailability of Pb in soil. Other conditions that increase Pb mobility in soil are reducing 

conditions and high chloride content.

The general population may be exposed to Pb in ambient air, foods, drinking water, soil, and dust. Pb has 

also been found in a variety of other consumer products including storage batteries, solders, pottery 

glazes, leaded crystal glassware, cosmetics, hair dyes, jewelry, gun shot and ammunition, relic fishing 

sinkers, tire weights, and imported children’s toys, traditional or folk remedies, and candy/food 
LEAD 2

1. RELEVANCE TO PUBLIC HEALTH

packaging. For adults, exposure to levels of Pb beyond background is usually associated with 

occupational exposures. For children, exposure to high levels of Pb is associated with living in areas 

contaminated by Pb (e.g., soil or indoor dust in older homes with Pb-based paint). The primary source of 

Pb exposure to children is from surface dusts (on the ground or entrained) that contain Pb from a variety 

of sources including deteriorated Pb-based paint (CDC 2009; Lanphear et al. 1998a; Succop et al. 1998). 

Environmental Pb is particularly accessible to children because of their more intensive hand-to-mouth 

activity and the proximity of the child breathing zone to Pb entrained from surface dusts. Because Pb is 

transported from soil very slowly, historic sources of deposition of Pb to soil continue to contribute to 

current exposures (Laidlaw and Filipelli 2008; Laidlaw et al. 2012). Based on a multimedia Pb exposure 

modeling analysis for children 1–5 years old at upper percentiles of blood Pb (PbB) levels in the U.S. 

population, soil and dust ingestion are dominant exposure pathways, but for lower percentiles, other age 

groups (e.g., younger children), or specific local U.S. locations, the main other exposure sources/

pathways could be important, such as drinking water and food (Zartarian et al. 2017).

PbB has been used as a biomarker of Pb exposure, and periodic surveys of PbB of the U.S. population are 

conducted by the Centers for Disease Control and Prevention (CDC). Based on data from the National 

Health and Nutrition Examination Survey (NHANES) (2015–2016, CDC 2018a, 2019), the geometric 

mean PbB in a representative sample of U.S. adults, ≥20 years old, was 0.920 μg/dL (95% confidence 

interval [CI] 0.862, 0.982). The geometric mean blood PbB of a representative sample of U.S. children, 

1–5 years old, was 0.758 μg/dL (95% CI 0.675, 0.850). PbBs in the U.S. have decreased considerably in 

the last several decades as a result of removal of Pb from gasoline and restrictions placed on the use of Pb

in residential paints (Brody et al. 1994; CDC 2011, 2018a; Pirkle et al. 1994, 1998; Schwartz and Pitcher 

1989).

Seasonal variations in blood lead concentration (PbB) levels in children have been observed, with a 

general trend of increasing PbB during late summer and early fall (Gulson et al. 2008; Johnson and 

Bretsch 2002; Laidlaw et al. 2005). Seasonal patterns in behavior (e.g., outdoor activities) and weather 

that promotes re-entrainment and transport of dust Pb (humidity and wind velocity) may contribute to the 

observed seasonal patterns in PbB (Laidlaw et al. 2005, 2012) and provide additional evidence for surface 

dusts being a major contributor to child Pb exposure and PbB.
LEAD 3

1. RELEVANCE TO PUBLIC HEALTH

1.2 SUMMARY OF HEALTH EFFECTS

The toxicity of Pb to humans has been known for over 2,000 years, and is not disputed. Early 

epidemiological studies focused on overt toxicity associated with high occupational exposures. However, 

during the past few decades, there has been a growing awareness that low-level environmental exposure 

resulting in PbB <10 μg/dL is associated with adverse effects, particularly in children. PbB levels 

associated with adverse effects vary by endpoint. Adverse effects occur at PbB <5 μg/dL and for the 

most studied endpoints (neurological, renal, cardiovascular, hematological, immunological, reproductive, 

and developmental), effects occur at the lowest PbBs studied (≤5 μg/dL). CDC (2018b) states that “no 

safe blood lead level in children has been identified.” As a result, U.S. public health policy has changed 

to focus on eliminating lead poisoning as a public health problem. CDC considers PbB to be elevated in 

children when it exceeds a reference value defined as the 97.5th percentile for the U.S. population. The 

current CDC reference value, based on data from the NHANES 2007–2008 and 2009–2010, is 5 μg/dL. 

Therefore, the primary objective of current research is on health effects associated with PbB ≤5 μg/dL. 

The literature evaluating the health effects of Pb is enormous, and includes an extensive database in 

humans, including children and infants. Information on health effects reviewed below is taken from 

epidemiological studies that identify the major lines of evidence regarding health effects in humans. 

Although the literature on adverse effects of Pb in laboratory animals also is extensive, due to the large 

number of available epidemiological studies, results of animal studies were not considered for the 

identification of health effects associated with Pb. This potentially leaves out discussion of effects that 

may have been observed in animal models that have not been studied in humans and that may be future 

targets of human epidemiology and clinical toxicology studies. Animal studies were included in 

discussion of mechanisms of toxicity of Pb and toxicokinetics.

To quantify exposure, epidemiological studies on the toxicity of Pb rely on internal exposure metrics, 

rather than measurements of external exposures (e.g., concentration of Pb in water or air) or ingested 

dose. The most common internal dose metric for Pb is the concentration of Pb in blood (PbB, typically 

expressed in terms of μg/dL). Blood Pb concentration reflects both ongoing exposure and Pb stores in 

bone, which can be transferred to blood. Because of the relatively rapid elimination of Pb from blood 

compared to bone, blood Pb will reflect mainly the exposure history of the previous few months and not 

necessarily the larger burden of Pb in bone (see Section 3.1). As a result, a single PbB measurement may 

not be a reliable metric for Pb body burden or cumulative exposure. Longitudinal measurements of PbB 

can be used to construct a cumulative blood Pb index (CBLI), which may be a better reflection of 
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1. RELEVANCE TO PUBLIC HEALTH

exposure history; however, the CBLI will not capture shorter-term variation in exposure that may occur 

between measurements. Direct, noninvasive measurements of bone Pb concentrations have been used as 

a metric of long-term exposure on the basis that most of the absorbed Pb retained in the body will reside 

in bone (see Section 3.1). The health effects of Pb are the same, regardless of the route of exposure (e.g., 

inhalation or ingestion). Given that exposure is quantified by internal exposure metrics (e.g., PbB, bone 

Pb), epidemiological studies do not attempt to define the route of exposure. Environmental exposure to 

Pb occurs continuously over a lifetime and Pb is retained in the body for decades. Because internal dose 

metrics cannot define the complete history of exposure, the exposure duration and timing that correlates 

most strongly with the observed health effect are typically unknown or highly uncertain.

Toxic effects of Pb have been observed in every organ system that has been rigorously studied. Clinical 

significance of some of the organ system effects at low levels of exposure and blood Pb is more 

substantial than for others (e.g., neurological, renal, cardiovascular, hematological, immunological, 

reproductive, and developmental effects). This is not surprising because the mechanisms that induce 

toxicity are common to all cell types and because Pb is widely distributed throughout the body. Adverse 

health effects have been observed in these systems at PbB ≤10 μg/dL. Exposure thresholds for effects on 

specific organ systems have not been identified (i.e., no safe level has been identified). Cognitive deficits 

in children occurring at the lowest PbBs (≤5 μg/dL) are the best substantiated effects. However, data for 

some organ systems results are inconsistent, and insufficient data are available to provide information on 

dose-response relationships. It is also important to note that effects observed in adults, especially older 

adults, may be due to higher environmental or occupational exposures in the past; therefore, exposure 

history is an important consideration in epidemiological studies on the health effects of Pb.

The most extensively studied health outcomes, as described below, are neurological, renal, 

cardiovascular, hematological, immunological, reproductive, and developmental effects. Neurological 

effects of Pb are of greatest concern because effects are observed in infants and children and may result in 

life-long decrements in neurological function. Infants are born with a Pb burden derived from maternal 

transfer in utero and subsequently can continue to absorb maternal Pb from ingestion of breast milk. 

Children are also more vulnerable because of behaviors that increase ingestion of Pb surface dusts 

(e.g., hand-to-mouth activity) and because gastrointestinal absorption of ingested Pb is higher in children 

compared to adults, possibly due to a combination of physiological differences and differences in diet and 

nutrition. The following briefly summarizes health effects of chronic exposure to Pb observed in humans. 

More detailed information, including reference citations, is provided in Chapter 2. 
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Neurological Effects in Children. Numerous prospective and large cross-section studies in 

children provide consistent evidence of decrements in neurological function, including decrements in 

cognitive function (learning and memory), altered behavior and mood (attention, hyperactivity, 

impulsivity, irritably, delinquency), and altered neuromotor and neurosensory function (visual-motor 

integration, dexterity, postural sway, changes in hearing and visual thresholds). These effects have been 

associated with a PbB range from ≤5 to >50 μg/dL, with numerous studies providing evidence for effects 

at PbB ≤5 μg/dL. Taken together, studies support the concept that Pb affects cognitive function in 

children prenatally and/or environmentally exposed to low levels of Pb. No threshold for these effects 

has been identified (i.e., no safe level has been identified). Decrements in cognitive function increase 

with PbB, and several PbB-effect models predict that larger decrements in cognitive function would occur 

when PbB increases from 1 to 10 μg/dL, compared to when PbB increases from levels >10 μg/dL. Supralinear dose-response relationships for neurological outcomes are discussed in greater detail in 

Section 2.16 (Neurological). At higher PbB (>30 μg/dL), other neurotoxic effects have been observed, 

including alterations in nerve function (decrements in fine and gross motor skills, peripheral neuropathy) 

and encephalopathy.

Neurological Effects in Adults. Epidemiological studies in adults demonstrate decrements in 

neurological function associated with PbB. All of the cognitive and neurobehavioral effects of Pb 

observed in children also have been observed in adults associated with PbB ranging from ≤10 to 

>50 μg/dL, with evidence of effects occurring at PbB ≤5 μg/dL. At higher PbB (>30 μg/dL), other 

observed neurotoxic effects include peripheral neuropathy, psychiatric symptoms (depression, panic 

disorders, anxiety, hostility, confusion, anger, and schizophrenia), and changes in regional brain volumes 

and neurochemistry. It is not clear if cognitive decrements are related to exposures that occurred during 

adulthood or during periods of nervous system development (e.g., prenatal and childhood exposures) or if 

effects are due to cumulative exposure. Results of a few studies that have followed children to early 

adulthood show an association between child PbB and behavioral and neuroanatomical changes in adults, 

suggesting a possible impact of exposures on childhood to adult outcomes.

Renal Effects. Adverse renal effects of Pb are well-established in numerous epidemiological studies. 

Studies show consistent evidence of renal damage and reduced renal function associated with a wide 

range of PbB (≤10–50 μg/dL), with several studies providing evidence for effects at PbB ≤5 μg/dL. 

Deficits in renal function include enzymuria, proteinuria, impaired transport of organic anions and 

glucose, and depressed glomerular filtration rate (GFR). At higher PbB (>30 μg/dL), Pb-induced 

nephrotoxicity is characterized by proximal tubular nephropathy, glomerular sclerosis, interstitial fibrosis, 
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and tubular necrosis. Note that Pb-induced decrements in renal function can lead to higher Pb body 

burden due to decreased excretion of Pb (i.e., reverse causality). In addition, other causes of decreased 

renal function could result in an increased body burden of Pb.

Cardiovascular Effects. A large number of epidemiological studies in adults show adverse 

cardiovascular effects associated with a PbB range from ≤5 to >50 μg/dL. Effects on blood pressure is 

the most-studied cardiovascular outcome, with studies showing increased systolic and diastolic blood 

pressure, with some evidence of effects occurring at PbB ≤5 μg/dL. A few studies show increased blood 

pressure in children and pregnant women. Nawrot et al. (2002) estimated that with doubling of PbB (for 

example, from 5 to 10 μg/dL), systolic and diastolic blood pressure would increase by 1 and 

0.6 millimeters of mercury, respectively. Other cardiovascular effects include increased risk of 

hypertension and heart disease, atherosclerosis, altered cardiac conduction, cardiac disease, and increased 

mortality due to cardiovascular disease. A recent study concluded that low-level environmental Pb 

exposure is an important risk factor for cardiovascular disease mortality (Lanphear et al. 2018).

Hematological Effects. The toxicity of Pb to the hematological system of humans has been 

established in numerous studies in adults and children. Exposure to Pb causes dose-dependent decreases 

in heme synthesis through inhibition of the enzyme delta-aminolevulinic acid dehydratase (δ-ALAD). At 

PbB ≤10 μg/dL, decreased blood hemoglobin is observed; however, it should be noted that the magnitude 

of this decrease is typically small and may not represent a biologically significant change. As PbB 

increases, further decreases in blood hemoglobin and loss of erythrocytes due to a Pb-induced increased 

membrane fragility results in the development of anemia (NAS 2013). Other effects of Pb on the 

hematological system include decreased activity of other erythrocyte enzymes (pyrimidine 

5’-nucleotidase or red blood cell membrane Ca2+/Mg2+ATPase) and altered levels of plasma 

erythropoietin (a hormone that stimulates red blood cell formation); however, fewer studies on these 

endpoints have been published and study results are mixed.

Immunological Effects. Epidemiological studies provide evidence that Pb exposure can perturb the 

immune systems of children and adults. Evidence for this derives from changes in various indicators of 

humoral and cell-mediated immunity in association with increasing PbB. Effects have been observed in 

populations that had average PbB <10 μg/dL. These effects are consistent with more extensive studies 

conducted in animal models and isolated immune cells that have shown that Pb can perturb the humoral 

and cell-mediated immune systems, leading to sensitization, autoimmunity, and inflammation (EPA 

2014c; NAS 2013).
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Reproductive Effects in Males. Health effects of Pb on the male reproductive system have been 

evaluated in numerous epidemiological studies. Effects include damage to sperm (decreased sperm 

count, concentration, motility, and viability, and increased immature sperm concentration and percentage 

of morphologically abnormal sperm), possible alterations in serum levels of reproductive hormones 

(testosterone, estradiol, luteinizing hormone [LH], and follicle-stimulating hormone [FSH]), decreased 

fertility, and histopathological changes to the testes. Severity of these effects increases with PbB. Studies 

conducted in populations with mean PbB ≤10 μg/dL provide evidence of damage to sperm, although 

effects are more consistently observed at PbB >10 μg/dL. Regarding effects on serum levels of 

reproductive hormones, results of available studies for PbB ranging from ≤10 to >50 μg/dL are 

inconsistent; thus, Pb-induced effects on circulating reproductive hormones are not firmly established. At 

higher PbB (>10 μg/dL), a few studies provide evidence of more severe effects, including decreased 

fertility and histopathological damage to testes.

Reproductive Effects in Females. Compared to studies of male reproductive effects, the 

epidemiologic literature database for effects of Pb on the female reproductive system is smaller, with 

most epidemiological studies conducted in populations with mean PbB ≤10 μg/dL. Studies provide some 

evidence of alterations in serum reproductive hormone levels (estradiol, LH, and FSH), decreased 

fertility, increased spontaneous abortion, increased preterm birth, and earlier age at onset of menopause. 

However, results are inconsistent, with several studies reporting no association between PbB and female 

reproductive effects.

Developmental Effects (Excluding Neurodevelopmental). Numerous epidemiological studies 

have evaluated developmental outcomes, with most studies conducted in populations with maternal 

and/or umbilical cord PbB ≤10 μg/dL. Some studies provide evidence of decreased birth size (weight, 

length, head circumference), decreased child growth (weight, height, head circumference, trunk length, 

leg length, arm length, body mass index [BMI]), and delayed onset of puberty in males and females. 

Although it is difficult to assess dose-dependence for developmental effects within the relatively narrow 

range of PbB (≤10 μg/dL) in most studies, dose-related decreases in birth weight have been observed in 

populations with PbB ≤10 μg/dL. Although studies provide evidence of associations between PbB and 

developmental outcomes, results are inconsistent and several studies, including prospective studies, show 

no associations with non-neurodevelopmental outcomes.
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Other Health Effects Associated with Pb. In addition to the effects summarized above, health 

effects to other organ systems have been reported. The epidemiological databases for these effects are 

much less extensive than for the effects reviewed above. Effects described below occur over a wide range 

of PbBs, including PbB ≤10 μg/dL. However, results for most endpoints are inconsistent and insufficient 

data are available to provide information on dose-response relationships.

• Respiratory Effects. Associations have been observed between PbB and decreased lung 

function, increased bronchial hyperreactivity, symptoms of respiratory disease, and increased 

risk of respiratory diseases (e.g., asthma and obstructive lung disease). 

• Endocrine Effects (Excluding Reproductive Hormones). Studies in adults, adolescents, and 

children show effects on thyroid function, cortisol levels, vitamin D levels, and serum levels of 

growth factors. Effects on thyroid function are the most studied effect, although results do not 

demonstrate a consistent pattern of effect.

• Hepatic Effects. Most studies were conducted in workers with PbB >10 μg/dL. Several studies 

show altered plasma levels of liver enzymes, although no consistent pattern of effects has been 

observed. Liver enlargement and increased gall bladder wall thickness have been associated 

with PbB.

• Musculoskeletal Effects. Studies provide evidence of bone loss, increased markers of bone 

metabolism/turn over, and adverse periodontal and dental effects (periodontal bone loss, tooth 

loss, periodontal disease, dental caries) in adults and children.

• Gastrointestinal Effects. Gastrointestinal colic is a predominant clinical symptom of acute Pb 

poisoning. Epidemiological studies provide evidence of gastrointestinal symptoms (abdominal 

colic/pain, nausea, vomiting, diarrhea, and/or constipation) associated with PbB ranging from 

8 μg/dL to approximately 100 μg/dL. However, most studies are survey or cross-sectional 

studies of small populations of workers.

• Body Weight Effects. A few studies evaluating effects of PbB ≤10 μg/dL on body weight 

provide some evidence of decreased body weight in children and adults, although inconsistent 

results have been reported.

• Ocular Effects (Excluding Neurological Effects). Limited data provide some evidence that 

exposure to Pb is associated with macular degeneration in adults and increased risk of cataracts.

Cancer. Numerous epidemiological studies have evaluated associations between Pb exposure and 

cancer. Although studies provide limited evidence of carcinogenicity of Pb in humans, results are 

inconsistent, with several negative studies, and interpretation of data may be limited due to confounding 
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factors (e.g., smoking status, family history of cancer, co-exposure to other carcinogens). At PbB 

≤10 μg/dL, increased risks were reported for all cancers and lung cancer. At PbB >10 μg/dL, increased 

risks were observed for all cancer, respiratory tract cancer, stomach cancer, intestinal cancer, cancer of 

the larynx, and glioma.

The Department of Health and Human Services classified Pb and Pb compounds as reasonably anticipated 

to be human carcinogens (NTP 2016). In 1988, EPA classified Pb as a probable human carcinogen based 

on sufficient evidence in animals; evidence in humans was considered inadequate (IRIS 2004). The 

International Agency for Research on Cancer (IARC) has classified inorganic Pb compounds as probably 

carcinogenic to humans (Group 2A) based on sufficient evidence in animals and limited evidence in 

humans; evidence for organic Pb compounds was considered to be inadequate in humans and animals 

(IARC 2006). 

1.3 MINIMAL RISK LEVELS (MRLs)

As reviewed in Section 1.2, epidemiological studies have evaluated the health effects of Pb in all organ 

systems. For the most studied endpoints (neurological, renal, cardiovascular, hematological, 

immunological, reproductive, and developmental), effects occur at the lowest PbBs studied (≤5 μg/dL). 

Because the lowest PbBs are associated with serious adverse effects (e.g., declining cognitive function in 

children), MRLs for Pb have not been derived.
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2.1 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 (Pb). It 

contains descriptions and evaluations of 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 at the end of this profile.

To help public health professionals and others identify potential health effects in persons with elevated PbB, 

the information in this section is organized by health effect.

As discussed in Appendix B, a literature search was conducted to identify relevant studies examining health 

effect endpoints. Figure 2-1 provides an overview of the database of epidemiology studies included in this 

chapter of the profile. 

Since development of the 2007 Toxicological Profile on Lead (ATSDR 2007), results of numerous 

epidemiological studies have prompted growing attention to the adverse health effects of Pb exposures 

that result in blood Pb concentrations (PbB) of <10 μg/dL (EPA 2014c). Awareness of the potential 

adverse consequences of such exposures has led to changes in U.S. public health policy, with a focus on 

eliminating lead poisoning as a public health problem (CDC 2012d; EPA 2016b). In 2012, CDC accepted 

their Advisory Committee on Childhood Lead Poisoning Prevention (ACCLPP) recommendation to 

establish a PbB reference value for Pb, replacing the 10 μg/dL level of concern. The reference value is 

based on the 97.5th percentile of the PbB distribution among children 1–5 years of age in the United 

States, using data generated by NHANES (CDC 2012d). At that time, the PbB reference was 

approximately 5 μg/dL (NHANES 2007–2010) (CDC 2018a). ACCLPP recommended that the reference 

value be updated every 4 years using the two most recent NHANES cycles and would be used in 

recommendations for follow-up evaluations and identification of high-risk childhood populations (CDC 

2012d). It is likely that PbB values among children will continue to decline; therefore, the primary focus 

of this toxicological profile is on health effects associated with low Pb exposure (i.e., those observed at 

PbB ≤5 μg/dL). Detailed information on effects at PbB ≤10 μg/dL is also presented to examine potential 
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exposure-response relationships. Information on health effects observed at higher PbB levels 

(>10 μg/dL) is also included to provide a comprehensive overview of the adverse effects of Pb. 

Literature Search Strategy. The literature on health effects of Pb in humans is enormous, with countless 

epidemiological studies in workers and the general population, including children. Due to the extent of 

the Pb database in humans, it is impossible to cite all, or even most, of the studies on health effects of Pb; 

thus, this profile does not attempt to provide a comprehensive review of all literature; instead, the profile 

summarizes the major lines of epidemiological evidence regarding health effects in humans. Although 

the literature database on adverse effects of Pb in laboratory animals is also extensive, given the large 

number of studies available in humans, animal studies are not included in this toxicological profile. For a 

recent review of studies in animal models, the reader should consult the EPA’s Integrated Science 

Assessment for Lead (EPA 2014c). 

The following were used as primary sources to identify literature on health effects of Pb: 

• The previous Toxicological Profile for Lead (ATSDR 2007) was used to identify literature 

published through 2007.

• The EPA (2014c) Integrated Science Assessment for Lead was used to identify literature 

published from 2006 to 2013.

• Literature searches were conducted from 2013 to 2019 to identify studies published after EPA 

(2014c).

In addition, recent reviews by NTP (2012) and NAS (2013) were consulted. As anticipated, the literature 

search revealed an extensive epidemiological database of literature published since 2013. To narrow the 

evaluation to those studies of greatest utility identifying health effects of low exposures to Pb, a series of 

inclusion criteria were defined; only studies meeting the criteria were considered for inclusion in the 

toxicological profile. These criteria are described further in Appendix B. Data from selected studies were 

tabulated and discussed in subsequent sections of this chapter. 

Duration of Exposure. Typically, toxicological profiles organize the discussion of health effects 

according to exposure duration categories. However, this is not a particularly informative approach to the 

discussion of Pb epidemiology. The epidemiologic study of Pb toxicity in human populations has relied 

on internal dose metrics (e.g., PbB, bone Pb) for evaluating associations between health outcomes. These 

metrics are considered to represent relatively recent exposure history, in the case of PbB, and longer-term 
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cumulative exposure, in the case of CBLI or bone Pb. However, neither metric offers a confident 

estimate of exposure duration or of changes in Pb exposure over time (including peak exposure periods 

that may have occurred in the past), and, in general, the complete exposure history is not known. Health 

outcomes associated with acute exposures is available from clinical case studies of Pb poisoning (see 

Section 2.2). However, even in these cases, the exposure duration that proceeded the identification of the 

case is rarely known with certainty.

Routes of Exposure. For the general population, exposure to Pb occurs primarily via the oral route, with 

some contribution from the inhalation route, whereas inhalation exposures can be more important in 

occupational settings, depending on particle size. In addition, occupational exposure to organic Pb 

compounds may involve dermal absorption as a significant exposure route. This profile does not attempt 

to separate health effects by route of exposure. As noted previously, epidemiology studies have relied on 

internal dose metrics (e.g., PbB, bone Pb), which reflect Pb body burden (to varying degrees), irrespective 

of the route of exposure. The primary systemic toxic effects of Pb are the same regardless of the route of 

entry into the body,

Exposure Metric. To quantify exposure in humans, data are expressed in terms of absorbed Pb, and not 

in terms of external exposure levels (e.g., concentration in water) or dose (e.g., mg/kg/day). The most 

common metric of absorbed dose for Pb is the concentration of lead in blood (PbB), although other 

measures of exposure (e.g., concentration of Pb in bone, hair, teeth, or urine) are used; however, 

measurements of Pb in urine, teeth, and hair are not as reliable as measurements in blood or bone. PbB 

mainly reflects exposure history of the previous few months and does not necessarily reflect the larger 

burden and much slower elimination kinetics of Pb in bone (see Section 3.1). Pb in bone is considered a 

biomarker of cumulative or long-term exposure because Pb accumulates in bone over the lifetime and 

most of the Pb body burden resides in bone. Most of the body burden of Pb (the total amount of Pb in the 

body) is distributed to the bone, with approximately 94 and 76% of the body burden found in bone in 

adults and children, respectively. The remainder is distributed to blood and soft tissues. However, the

concentration of Pb in blood can vary considerably with age and physiology/lifestage (e.g., pregnancy, 

lactation, menopause). For this reason, measurement of Pb in bone has seen wider application in 

epidemiological studies of adults in which measures of cumulative lifetime exposures are of interest. 

However, bone Pb measurements require specialized radiologic equipment (e.g., K-shell x-ray 

fluorescence; XRF) and, as a result, are used less commonly than PbB in human epidemiology. Since 

most of the epidemiology has relied on PbB as the dose metric, this profile has focused on describing 

dose-response relationships based on PbB to facilitate comparisons across studies and endpoints. This 
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approach also aligns with public health practices, which rely on PbB for evaluating elevated exposures to 

Pb (CDC 2012d; EPA 2016b). However, it is recognized that some health outcomes may be correlated 

with cumulative exposure, in which case, bone Pb may be a better dose metric than PbB. For these 

outcomes, short-term variation in PbB may contribute to exposure classification error (i.e., the same PbB 

could be observed in individuals who have different bone Pb). The exposure history of the subjects may 

also be an important factor in determining associations observed between outcomes and blood or bone Pb. 

Some studies of historically exposed occupational populations (e.g., former workers) have found stronger 

associations between bone Pb and health outcomes than with PbB, while some studies of concurrently 

exposed populations have found stronger associations with PbB (Shih et al. 2007). 

Confounding Factors and Effect Modifiers. Bias can occur in epidemiological studies when the 

background risk of the outcome being measured is not the same in the exposed and reference groups. 

Confounders are variables that affect the measured outcome and are also associated with the Pb exposure 

metric (e.g., PbB, bone Pb). For example, Pb body burden increases with age; therefore, age can be a 

confounding factor if it is also a risk factor for the outcome (e.g., renal or cardiovascular disease). Not 

adjusting for confounders may attenuate or strengthen the apparent associations between Pb exposure and 

the outcome, depending on whether it is a negative or positive confounding variable. Effect modifiers are 

variables that affect the measured outcome independently of the Pb exposure metric. For example, renal 

disease from any cause can affect blood pressure and, thereby, could interact with Pb to change blood 

pressure. Effect modifiers can also be confounders, if they are associated with the Pb exposure metric 

(e.g., socio-economic status [SES] and cognitive development). Recall bias may also contribute to 

uncertainties and should be considered as a confounding factor. For example, interviews of parents are a 

standard method for estimating potential co-variables that might affect child development in prospective 

studies, as there are no alternatives for studies in children. Thus, inaccurate recall may potentially 

influence study outcomes. Failure to account for important effect modifiers can result in underestimation 

or overestimation of the apparent strength of the association, depending on the direction of the effect of 

the modifying variable. Confounding factors and effect modifiers are discussed in greater detail in 

sections that describe specific categories of health effects. Epidemiological studies provide information 

about the strengths of statistical associations between exposure metrics (e.g., blood Pb) and health 

outcomes. However, statistical associations do not necessarily reflect causal associations. Evidence for 

causal associations can include demonstration of exposure-response relationships, occurrence of the 

outcome or its precursors in controlled studies conducted in experimental models (in vivo and in vitro), 

and consistency of observed statistical associations with known modes of action of Pb.
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Overview of Health Effects of Pb. The health effects of Pb are diverse, and exposure to Pb is associated 

with toxicity to every organ system. This is not surprising because the mechanisms of action associated 

with Pb-induced toxicity, including perturbations of ion homeostasis and transport, protein binding, 

oxidative stress, and inflammation, are common to all cell types. In addition, Pb is widely distributed 

throughout the body, and has been measured in all tissues evaluated (see Section 3.1.2). For all organ 

systems, toxicity has been observed at PbB ≤10 μg/dL. Neurological effects of Pb are of greatest concern 

because effects are observed in infants and children; furthermore, these effects may result in life-long 

decrements in neurological function. Children are also more vulnerable because of behaviors that 

increase ingestion of Pb surface dusts (e.g., hand-to-mouth activity) and because gastrointestinal 

absorption of ingested Pb is higher in children compared to adults, possibly due to a combination of 

physiological differences and differences in diet and nutrition. The weight-of-evidence for all adverse 

health effects is strongly supported by studies in animal models and in vitro systems; see EPA (2014c) for 

a review of this literature.

Effects observed in association with PbB are briefly described below. Note that for some of the effects 

listed below, study results are not consistent, which limits interpretation of observations; this is reviewed 

in more detail in subsequent sections for each organ system in Chapter 2. The most extensive 

epidemiological databases examining Pb are for neurological, renal, cardiovascular, hematological, 

immunological, reproductive, and developmental effects. 

• Neurological Effects:

o Children. Decreased cognitive function; altered mood and behaviors that may contribute 

to learning deficits, altered neuromotor and neurosensory function, peripheral 

neuropathy, and encephalopathy.

o Adults. Decreased cognitive function including attention, memory, and learning; altered 

neuromotor and neurosensory function; altered mood and behavior; and decreased 

peripheral nerve conduction velocity.

• Renal Effects. Decreased GFR, proteinuria, enzymuria, impaired tubular transport, and 

histopathological damage.

• Cardiovascular Effects. Increased systolic and diastolic blood pressure, increased risk of 

hypertension, atherosclerosis, altered cardiac conduction, increased risk of heart disease, and 

increased mortality due to cardiovascular disease.
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2. HEALTH EFFECTS

• Hematological Effects. Inhibition of δ-ALAD leading to decreased blood hemoglobin and 

anemia, decreased activity of other erythrocyte enzymes, and altered plasma erythropoietin 

(EPO) levels.

• Immunological Effects. Perturbation of humoral and cell-mediated immune systems, decreased 

resistance to disease, sensitization, autoimmunity, and inflammation.

• Reproductive Effects:

o Males. Effects on sperm, alterations in semen quality, decreased fertility, 

histopathological damage to the testes, and possible altered serum concentrations of 

reproductive hormones.

o Females. Possible alterations in serum concentrations of reproductive hormones, 

decreased fertility, spontaneous abortion, preterm birth, and earlier age at the onset of 

menopause.

• Developmental Effects. Decreased birth weight and size, decreased anthropometric measures 

in children, and delayed onset of puberty in males and females.

Other health outcomes associated with PbB include the following:

• Respiratory Effects. Decreased lung function, increased bronchial hyperreactivity, increased 

risk of asthma, and obstructive lung disease.

• Hepatic Effects. Possible increases in plasma liver enzymes and cholesterol, enlarged liver, and 

increased thickness of gall bladder wall.

• Endocrine Effects. Possible alterations in serum of thyroid hormones, altered cortisol 

responses, alteration in serum growth factors, and decreased serum vitamin D levels.

• Gastrointestinal Effects. Abdominal pain/colic, nausea, vomiting, and diarrhea and/or 

constipation.

• Musculoskeletal Effects. Bone loss, osteoporosis, dental caries, tooth loss, and periodontitis.
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• Ocular Effects. Possible macular degeneration and cataracts.

• Cancer. Increased risk of cancer, including all cancers, cancer of the respiratory tract, intestinal 

tract, and larynx, and glioma.

Many specific health effect endpoints have been evaluated in numerous studies. To provide the 

reader with a weight-of-evidence for these endpoints, the profile indicates if results are consistent 

and corroborated in numerous studies or if results are inconsistent (or mixed). 

Figure 2-1 shows the numbers of epidemiological studies included in this chapter of the toxicological 

profile, based on health outcome studied. The number of studies evaluating effects at PbB ≤10 μg/dL 

also is indicated. The PbB ≤10 μg/dL was selected to evaluate effects at the lowest PbB (e.g., ≤5 μg/dL) 

and to evaluate potential exposure-response relationships for PbB ≤10 μg/dL. As noted above, due to the 

enormous number of epidemiological studies published, the profile does not attempt to provide a 

comprehensive review of all literature. Therefore, this figure should not be interpreted as depicting all 

epidemiological studies that have been published on Pb toxicity.
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2. HEALTH EFFECTS

Figure 2-1. Overview of the Number of Studies Examining Associations Between PbB and Health Effectsa

 

Most studies examined the potential cardiovascular, renal, and neurological effects of lead

A subset of studies evaluating health effects for PbB ≤10 μg/dL compared to all PbB studies (counts represent studies examining endpoint)

aIncludes studies discussed in Chapter 2. A total of 694 epidemiological studies (including those finding no effect) have examined toxicity; some studies examined 

multiple endpoints.
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2.2 ACUTE LEAD TOXICITY

Overview. No controlled studies in humans have evaluated the acute toxicity of Pb (acute Pb poisoning). 

Available information is anecdotal, obtained from numerous case reports. Thus, data are not sufficient to 

establish a dose-response relationship for acute toxicity relative to PbB. Acute Pb toxicity is 

characterized by symptoms of abdominal pain/colic, vomiting, constipation, peripheral neuropathy, and 

cerebral edema and encephalopathy, which can lead to seizures, coma, and death. Children are more 

susceptible than adults to acute Pb poisoning. Additional information on toxicity of ingested Pb debris 

(e.g., Pb shot) is provided in Appendix C. 

Rather than reviewing numerous case reports, the information presented below was taken from the 

following reviews: Beers et al. (1999); Chisolm (1977); Klaassen (2001); Landrigan (1995); NAS (1972); 

Needleman (2004); and Skerfving and Bergdahl (2015). Citations are only specifically noted below if 

quantitative information is discussed.

Confounding Factors, Effect Modifiers, and Uncertainties. There are several uncertainties from case 

reports on acute toxicity of Pb. Therefore, it is difficult to establish dose-response relationships for acute 

toxicity relative to PbB. Uncertainties include: 

• Baseline PbB data are rarely available.

• There is a lack of quantitative data on the dose of Pb ingested.

• No information on the fractional absorption of ingested Pb. 

• Time from ingestion of Pb to development of symptoms of acute Pb toxicity is often unknown. 

• Time from ingestion of Pb to first clinical evaluation and PbB assessment is often unknown. 

• Gastrointestinal symptoms and general malaise are typically the first symptoms of acute Pb 

toxicity to appear; these general symptoms are often attributed to other causes, leading to an 

initial misdiagnosis or delay in diagnosis. 

• Data to develop PbB time-concentration curves are incomplete.

• Numerous factors may contribute to individual susceptibility to acute Pb exposure, including age, 

intercurrent illness, underlying developmental issues, dietary and nutritional status, concurrent 

medication use, and exposure to other chemicals. 

Clinical Presentation of Acute Pb Toxicity. The onset of acute toxicity is rapid, usually occurring within 

1–5 days of exposure. The main organ systems involved are the gastrointestinal, hematological, and 
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2. HEALTH EFFECTS

neurological systems. Signs and symptoms increase in severity with increasing PbB, ranging from mild 

to severe. Gastrointestinal effects include abdominal colic/pain, nausea, vomiting, diarrhea, and 

constipation. Massive loss of gastrointestinal fluids can lead to dehydration. Hematological effects 

include decreased hemoglobin synthesis, anemia, and acute hemolytic crisis characterized by anemia and 

hemoglobinuria. Numerous neurological symptoms are associated with acute Pb toxicity, including 

headache, hyperirritability, decreased activity, paresthesia, muscle pain and weakness, ataxic gait, 

decreased consciousness, cerebral edema leading to seizures and coma, encephalopathy, and death. Other 

reported symptoms include astringency of the mouth, metallic taste in the mouth, and thirst.

Susceptibility of Children. Children are more susceptible than adults to Pb poisoning because the 

fractional absorption of ingested Pb is higher than in adults and the developing central nervous system is 

more vulnerable to toxicity compared to a fully developed nervous system (Needleman 2004). In addition 

to being more sensitive than adults, acute toxicity in children may have long-lasting effects. For example, 

children who recover from acute encephalopathy can have long-term decreases in cognitive abilities, 

attention deficits, and impaired behavior. Children are also susceptible due to increased exposure.

Dose-Response Relationship for Acute Toxicity Relative to PbB. As noted above, data from case reports 

are not sufficient to establish a dose-response relationship for acute toxicity relative to PbB. Some 

general observations can be made from available reports; however, dose-response relationships are highly 

uncertain and may not apply to individuals acutely exposed to Pb. At PbB <30 μg/dL, signs and 

symptoms of acute toxicity typically are not observed. This should not be interpreted to mean that no 

Pb-induced adverse effects (e.g., decreased hemoglobin synthesis) occur at PbB <30 μg/dL, but that 

symptoms causing individuals to seek medical intervention (e.g., abdominal colic and vomiting) typically 

are not observed at PbB <30 μg/dL. As PbBs increase to >30 μg/dL, signs and symptoms of 

gastrointestinal and neurological toxicity are observed, with severity increasing with PbB. Pb-induced 

encephalopathy has been reported at PbB <100 μg/dL, but is more commonly associated with PbB 

>100 μg/dL (NAS 1972). In a review of 96 cases of death due to acute Pb poisoning in children, death 

occurred at PbB >100 μg/dL (NAS 1972). 

2.3 DEATH

Overview. Numerous epidemiological studies have investigated associations between Pb exposure and 

death. Studies include exposure of workers and general populations, and report a wide range of PbB 

levels. In the general population, studies have shown significant associations between PbB and mortality 
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due to disease of blood and blood-forming organs. In occupationally exposed individuals, mortality due 

to infection, endocrine diseases, and digestive diseases were associated with PbB in male workers, but not 

female workers, while mortality due to respiratory disease was associated with PbB in a cohort of male 

workers. In addition, studies of the general population and Pb occupations show an association between 

PbB and cumulative “all-cause” mortality (including cancer). However, results are inconsistent and 

interpretation may be limited due to confounding factors. Studies assessing associations between PbB 

and mortality due to cardiovascular diseases and cancer are discussed in Sections 2.5 and 2.19, 

respectively, and are not reviewed here.

The following causes of death have been associated with PbB: 

• ≤10 μg/dL:

o Increased risk of death from all causes (including cancer and cardiovascular disease); 

evaluated in a few studies with generally consistent results.

• >10 μg/dL:

o Increased risk of death from all causes (including cancer and cardiovascular disease); 

evaluated in several studies with positive associations in some studies.

o Increased risk of death from chronic or unspecified nephritis or non-malignant kidney 

disease; evaluated in several studies with positive associations in some studies.

o Increase risk of death from infection; demonstrated in one study.

o Increased risk of death from endocrine disease; demonstrated in one study.

o Increased risk of death from digestive disease; evaluated in several studies with positive 

associations in some studies.

o Increased risk of death from diseases of the blood and blood forming organs; demonstrated in 

one study.

o Increased risk of death from respiratory diseases (emphysema, pneumonia, and other 

respiratory diseases); evaluated in several studies with positive associations in some studies.

Confounding Factors and Effect Modifiers. Numerous factors can influence results of epidemiological 

studies evaluating associations between Pb exposure and mortality, including age, sex, BMI, ethnicity, 

poverty level, education, alcohol consumption, smoking status, hypertension, diabetes, family history of 

diseases, activity level, total cholesterol, postmenopausal status, nutritional status, and co-exposure with 

other metals (i.e., arsenic or cadmium). Failure to account for these factors may attenuate or strengthen 
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the apparent associations between Pb exposure and the outcome, depending on the direction of the effect 

of the variable on the outcome.

Measures of Exposure. Studies examining the association between Pb exposure and mortality evaluate 

exposure by measurement of PbB. 

Characterization of Effects. Numerous epidemiological studies have assessed associations between PbB 

and mortality. Studies of general populations and workers are briefly summarized in Table 2-1. In the 

general population, at PbB ≤10 μg/dL, a positive dose-response relationship was suggested for all-cause 

mortality and mortality due to coronary heart disease (Khalil 2009, 2010; Menke et al. 2006; Schober et 

al. 2006), although Weisskopf et al. (2009) did not show an increased risk for all-cause mortality. At 

>10 μg/dL, results of occupational exposure and general population studies are mixed and do not 

establish a pattern of effects or exposure-response relationships. In the general population, findings of the 

Lustberg and Silbergeld (2002) study suggested dose-response for PbB and all-cause mortality. In Pb 

workers, a dose-effect relationship was observed for all-cause mortality and mortality due to endocrine 

disease, infection, and digestive disease (Chowdhury et al. 2014; Kim et al. 2015), although Malcolm and 

Barnett (1982) did not observe a dose-effect relationship between Pb and all-cause mortality in Pb battery 

workers.
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Table 2-1. Summary of Epidemiological Studies Evaluating Deatha

Reference and study population PbB (μg/dL) Mortality outcome Effectsb

PbB ≤10 μg/dL

Cheung et al. 2013

Cross-sectional study; n=3,482 

(NHANES III)

Mean: 4.44 All-cause mortalityc OR: 1.045 (1.013 1.079)*

Khalil 2010; Khalil et al. 2009

Prospective cohort study; n=533 women 

(age 65–87 years)

Quintiles

• Q1: <4

• Q2: 4

• Q3: 5

• Q4: 6–7

• Q5: >7

All-cause mortalityc HR Q1 (reference)

HR Q2: 0.80 (0.45,1.42)

HR Q3: 0.70 (0.39, 1.24)

HR Q4: 0.60 (0.34, 1.06)

HR Q5: 1.20 (0.69, 2.09)

p-trend=0.905

Spline for 5th knot: p=0.009*

Wald test: p=0.0843

Khalil et al. 2009

Prospective cohort study; n=533 women 

(age 65–87 years)

Mean: 5.3

<8 (n=453)

≥8 (n=79)

All-cause mortalityc Adjusted HR ≥8 μg/dL: 1.59 (1.02, 

2.49); p=0.041*

All-cause mortality 

excluding deaths due to 

cancer and cardiovascular 

disease

Adjusted HR ≥8 μg/dL: 1.22 (0.48, 3.10); 

p=0.673

Menke et al. 2006

Longitudinal study; n=13,946 (NHANES 

1988–1994; mean age 44.4 years)

Mean: 2.58

Tertiles: 

• T1: <1.93

• T2: 1.94–3.62

• T3: ≥3.63

All-cause mortalityc Adjusted HR

T1 (reference)

T2: 0.91 (0.72, 1.15)

T3: 1.25 (1.04, 1.51)*

p-trend=0.002*

Neuberger et al. 2009

Retrospective cohort study; mortality data 

from Oklahoma State Department of Health; 

1999–2001

5.8 Tuberculosis SMR: 0.0 (0.0, 10.80)

Bronchitis, emphysema, 

asthma

SMR: 1.10 (0.863, 13.84)

Kidney disease SMR: 0.984 (0.573, 1.576)

Schober et al. 2006

Longitudinal study; n=9,757 (NHANES III; 

age ≥40 years)

Tertiles

• T1: <5; mean 2.6

• T2: 5–9; mean 6.3 

• T3: >10, mean 11.8

All-cause mortalityc RR T2: 1.24 (1.05, 1.48)*

RR T3: 1.59 (1.28, 1.98)*; 

p-trend<0.001
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Table 2-1. Summary of Epidemiological Studies Evaluating Deatha

Reference and study population PbB (μg/dL) Mortality outcome Effectsb

Weisskopf et al. 2009

Longitudinal study; n=868 men (Normative 

Aging Study; age 21–80 years)

Mean (SD): 5.6 (3.4)

Tertiles:

• T1: <4

• T2: 4–6

• T3: >6

All-cause mortalityc Adjusted HR 

• T1: 1 (reference)

• T2: 0.99 (0.71, 1.37)

• T3: 1.01 (0.71, 1.44)

• p-trend=0.92

PbB >10 μg/dL

Barry and Steenland 2019

Retrospective study; n=58,368 male 

workers (10-year follow-up of Chowdhury et 

al. 2014)

Q1: 0–<5

Q2: 5–<25

Q3: 25–<40

Q4: ≥40

T1: 0–<25

T2: 25–<40

T3: ≥40

All-cause mortalityc HR Q4: 1.38 (1.24, 1.53)*

Chronic obstructive 

pulmonary disease

HR Q4: 1.46 (0.94, 2.28)

Chronic renal disease HR T3: 1.81 (0.91, 3.57)

Cerebrovascular disease 

(stroke)

SMR Q4: 0.73 (0.58, 0.91)

Ischemic heart disease SMR Q4: 0.70 (0.63, 0.77)

Chowdhury et al. 2014

Survey study; n=58,368 male workers 

(mean age 38.9 years)

Quartiles

• Q1: 0–<5

• Q2: 5–<25

• Q3: 25–<40

• Q4: ≥40

All-cause mortalityc SMR Q4: 0.80 (0.75, 0.84)*

SMR overall: 0.69 (0.66, 0.71)

Chronic obstructive 

pulmonary disease

SMR Q4: 0.86 (0.64, 1.12)

SMR overall: 0.65 (0.54, 0.78)

Chronic renal disease SMR Q4: 1.01 (0.58, 1.64)

SMR overall: 0.65 (0.44, 0.93)

Cooper 1988; Cooper et al. 1985

Cohort study; n=4,519 battery workers; 

2,300 smelters

Mean

• Battery (n=1326): 62.7

• Smelters (n=537): 79.7

Nonmalignant respiratory 

disease

Battery PMR: 0.90 (0.74, 1.10)

Smelter PMR: 0.76 (0.53, 1.11)

Cirrhosis of the liver Battery PMR:1.29 (0.96, 1.73)

Smelter PMR: 0.63 (0.35, 1.15)

Chronic or unspecified 

nephritis

Battery PMR: 2.06 (1.26, 3.18)*; 

p<0.01

Smelter PMR: 1.86 (0.80, 3.66)

Chronic nephritis Battery PMR: 1.48 (0.88, 2.49)

Smelter PMR: 1.20 (0.50, 2.86)
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2. HEALTH EFFECTS

Table 2-1. Summary of Epidemiological Studies Evaluating Deatha

Reference and study population PbB (μg/dL) Mortality outcome Effectsb

Kim et al. 2015

Cross-sectional study; n=81,067 inorganic 

Pb workers (54,788 males; 26,279 females; 

age 20–≤50 years)

Mean

• Males: 8.8

• Females 5.8

Tertiles:

• T1: <10

• T2: 10–20

• T3: >20

All-cause mortalityc Males: RR T3: 1.36 (1.03, 1.79)*; 

p<0.05

Females: RR T3: 1.30 (0.41, 4.16)

Non-malignant death Males: RR T3: 0.95 (0.56, 1.51)

Females RR T3: 0.99 (0.13, 7.19)

Infection Males: RR T2: 3.73 (1.06, 13.06)*; 

p<0.05

Females: not reported

Endocrine disease Males: RR T3: 4.25 (0.90, 20.04)*; 

p<0.1

Females: not reported

Respiratory disease Males: RR T2: 1.46 (0.28, 7.49)

Females: RR T2: 3.49 (0.31, 39.05)

Digestive disease Males: RR T3: 3.23 (1.33, 7.86)*; 

p<0.05

Females: RR T2: 3.66 (0.33, 40.70)

Lundstrom et al. 1997

Retrospective cohort study; 

n=3,979 workers

Mean:

• In 1950: 62.2

• In 1987: 33.2

All-cause mortalityc Total cohort SMR: 0.9 (0.8, 1.0)

Respiratory disease Total cohort SMR: 0.4 (0.2, 0.8)

Digestive organs Total cohort SMR: 0.6 (0.3, 1.1)

Lustberg and Silbergeld 2002

Longitudinal study; n=4,292; age 30–

74 years (NHANES II)

Tertiles:

• T1 (n=818): <10

• T2 (n=2,735): 10–19

• T3 (n=637): 20–29

All-cause mortalityc RR T2: 1.17 (0.90, 1.52)

RR T3: 1.46 (1.14, 1.86)*

Malcolm and Barnett 1982

Retrospective cohort study; n=754 Pb 

battery workers

Group1 (non-occupational 

exposed): not reported

Group 2: (light occupational Pb

exposure): mean 57

Group 3: (high occupational Pb

exposure): not reported

All-cause mortalityc Group 3 SMR: 1.07; p=0.134
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Table 2-1. Summary of Epidemiological Studies Evaluating Deatha

Reference and study population PbB (μg/dL) Mortality outcome Effectsb

McDonald and Potter 1996

Prospective cohort study; n=454 pediatric 

patients diagnosed with Pb poisoning, 

Massachusetts, 1923–1966, followed 

through 1991; age of diagnosis <1–9 years

Mean 113 Diseases of the blood and 

blood forming organs

SMR: 9.68 (1.95, 28.28)*

Nervous-system and 

sense-organ diseases

SMR: 2.86 (0.57, 8.35)

Respiratory diseases SMR: 1.95 (0.78, 4.02)

Pneumonia SMR: 2.10 (0.68, 4.90)

Digestive system diseases SMR: 1.37 (0.44, 3.21)

Genitourinary system 

diseases

SMR: 1.69 (0.02, 9.43)

Chronic nephritis SMR: 5.00 (0.06, 27.82)

All-cause mortalityc SMR: 1.74 (1.40, 2.15)*

McElvenny et al. 2015

Cohort study; n=9,122 workers; mean age 

29.2 years

Mean: 44.3

Range: 2.3–321.5

All-cause mortalityc Males: SMR 1.10 (1.06, 1.14)*

Females: SMR 1.00 (0.91, 1.09)

Total SMR: 1.09 (1.05, 1.12)*

Respiratory system 

diseases

Males: SMR: 1.17 (1.06,1.30)*

Females: SMR: 1.24 (0.98, 1.57)

Total SMR: 1.18 (1.08, 1.30)*

Digestive system diseases Males: SMR: 1.22 (1.03, 1.45)*

Females: SMR: 0.84 (0.52, 1.35)

Total SMR: 1.16 (0.99, 1.36)

Genitourinary diseases Males: SMR: 1.02 (0.72,1.44)

Females: SMR: 0.67 (0.28, 1.60)

Total SMR: 0.95 (0.69, 1.31)

Non-malignant kidney 

disease

Males: SMR: 1.30 (0.76, 2.24)

Total SMR: 1.29 (0.79. 2.11
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Table 2-1. Summary of Epidemiological Studies Evaluating Deatha

Reference and study population PbB (μg/dL) Mortality outcome Effectsb

Selevan et al. 1985

Retrospective cohort study; n=1,987 male 

workers

Mean: 56.3 All tuberculosis SMR: 1.39 (0.69, 2.49)

Diseases of the central 

nervous system

SMR: 0.84 (0.61, 1.12)

Diseases of the respiratory 

system

SMR: 1.25 (0.92, 1.66)

Other respiratory diseases SMR: 1.87 (1.28, 2.64)*

Diseases of the digestive 

system

SMR: 0.51 (0.26, 0.89)

Diseases of the 

genitourinary system

SMR: 0.93 (0.42, 1.77)

Chronic and unspecified 

nephritis and other renal 

sclerosis

SMR: 1.92 (0.88, 3.64)

All other SMR: 0.88 (0.67, 1.14)

Steenland et al. 1992

Cohort study (same cohort as Selevan et al. 

1985); n=1,990 male smelter workers

Mean: 56.3 All-cause mortalityc SMR: 1.07 (1.00, 1.14)*

Non-malignant respiratory 

disease

SMR: 1.44 (1.16, 1.77)*

Emphysema SMR: 2.20 (1.45, 3.20)*

Pneumonia and other 

respiratory disease

SMR: 1.88 (1.34, 2.56)*

Acute kidney disease SMR: 0.91 (0.02, 5.07)

Chronic kidney disease SMR: 1.26 (0.54, 2.49)

Steenland et al. 2017

Cohort study; n=88,187 Pb workers (United 

States n=58,313, United Kingdom n=9,122, 

Finland n=20,752)

Median: 26

Tertiles:

• T1: 20–<30

• T2: 30–<409

• T3: >40

All-cause mortalityc HR T1: 1.15 (1.10, 1.21)*

Stroke HR T1: 1.24 (1.03, 1.50)*

Ischemic heart disease HR T1: 1.14 (1.04, 1.26)*

Chronic obstructive 

pulmonary disease

HR T1: 1.43 (1.10, 1.86)*

Chronic kidney disease HR T3: 1.54 (0.77, 3.08)
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Table 2-1. Summary of Epidemiological Studies Evaluating Deatha

Reference and study population PbB (μg/dL) Mortality outcome Effectsb

Wong and Harris et al. 2000

Cohort study; n=4,519 battery workers; 

2,300 smelters (same cohort as Cooper et 

al. 1985)

Mean:

• All workers: 64.0

• Battery workers: 62.7

• Smelters: 79.7

All-cause mortalityc SMR: 1.045 (1.012, 1.08)*; p<0.01

aStudies assessing death due to cardiovascular disease and cancer are discussed in Sections 2.5 and 2.19, respectively. 

bAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

c

Includes cancer and/or cardiovascular deaths.

CI = confidence interval; HR = hazard ratio; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; Pb = lead; PbB = blood lead 

concentration; PMR = proportionate mortality ratio; RR = rate ratio or relative risk; SD = standard deviation; SMR = standard mortality ratio
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2. HEALTH EFFECTS

2.4 BODY WEIGHT

Overview. Compared to other health effect endpoints, there is little information on Pb exposure and body 

weight measures. However, a few epidemiological studies have evaluated effects of Pb exposure on body 

weight in children, adolescents, and adults. The studies reviewed below focused on effects at PbB 

≤10 μg/dL. Inverse associations have been observed between PbB and BMI, and decreased risks of being 

overweight or obese have been reported. However, some studies did not observe associations and one 

study reported a positive association between PbB and the risk of obesity in women.

Note that studies evaluating the effects of exposure to Pb on birth weight are reviewed in Section 2.18 

(Developmental). 

The following effects on body weight have been associated with PbB ≤10 μg/dL:

• Decreased BMI and risk of being overweight or obese in children and adolescents; observed in a 

few studies.

• Decreased BMI and risk of being overweight or obese in adults; not corroborated.

• Increased risk of obesity in women; not corroborated.

Measures of Exposure. Most studies evaluating effects of chronic Pb exposure on body weight evaluate 

exposure by measurement of PbB. A few other studies examining associations between Pb exposure and 

body weight used Pb concentration in urine, bone, and/or dentin as biomarkers of exposure; however, 

these studies did not report PbB (Kim et al. 1995; Liu et al. 2019a; Padilla et al. 2010; Shao et al. 2017).

Confounding Factors and Effect Modifiers. Numerous factors contribute to body weight (or BMI), 

including age, sex, race, nutrition, diet, daily activity level, intercurrent illness, genetic pre-disposition for 

body type, income level, education, and alcohol and tobacco use. Failure to account for these factors may 

attenuate or strengthen the apparent associations between Pb exposure and the outcome, depending on the 

direction of the effect of the variable on the outcome. 
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2. HEALTH EFFECTS

Effects at Blood Pb Levels ≤10 μg/dL. Results of studies evaluating effects of PbB ≤10 μg/dL on body 

weight are briefly summarized in Table 2-2 and an overview of results is provided in Table 2-3; study 

details are provided in the Supporting Document for Epidemiological Studies for Lead, Table 1. Studies 

have been conducted in children and adolescents (Burns et al. 2017; Cassidy-Bushrow et al. 2016; Hauser 

et al. 2008; Scinicariello et al. 2013) and adults (Scinicariello et al. 2013; Wang et al. 2015). The largest 

study evaluating associations between PbB and body weight is a study of children, adolescents, and adults 

participating in NHANES, 1999–2006; this study included adjustments for numerous confounding factors 

(see the Supporting Document for Epidemiological Studies for Lead, Table 1) (Scinicariello et al. 2013). 

In children and adolescents (n=10,693), results show an inverse association between PbB and BMI-Z 

score and risk of being overweight or obese. In a smaller study in children (n=131), inverse associations 

were observed between PbB and BMI and BMI-Z score (Cassidy-Bushrow et al. 2016). Other studies in 

small populations of boys showed no associations between weight, BMI and/or BMI-Z score (Burns et al. 

2017; Hauser et al. 2008). Results of studies in adults are mixed. The largest study in adults (n=15,899) 

shows inverse associations between PbB and BMI and risk of being overweight and obese, with a 

negative trend (p-trend: ≤0.01) over quartiles (Scinicariello et al. 2013). No association was observed 

between PbB and BMI in a small study on women (n=107) (Ronco et al. 2010) or a larger study in men 

(n=2235) (Wang et al. 2015). In contrast, the risk of being obese was increased in a large population 

(n=3323) of women (Wang et al. 2015). Thus, except for the Wang et al. (2015) study, available studies 

show either no association or an inverse association between PbB ≤10 μg/dL and body weight and/or 

BMI. 

Mechanisms of Action. The mechanisms involved in the development of Pb-induced changes in body 

weight have not been established. However, alterations of the hypothalamic-pituitary-adrenal axis, stressinduced elevations in glucocorticoid levels, oxidative stress, and altered lipid metabolism have been 

proposed (reviewed by Scinicariello et al. 2013; Shao et al. 2017; Wang et al. 2015). 
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Table 2-2. Summary of Epidemiological Studies Evaluating Effects on Body Weight at Mean Blood Lead 

Concentrations (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Burns et al. 2017

Prospective cohort of 481 Russian 

boys enrolled at age 8–9 years and 

followed until age 18 years

Median 3.0 HT-Z score Adjusted β (95% CI), HT-Z score per unit 

lnPbB: -0.26 (-0.40, -0.13); p<0.001*

BMI-Z score Adjusted β (95% CI), BMI-Z score per unit 

lnPbB: -0.14 (-0.31, 0.04); p=0.12

Cassidy-Bushrow et al. 2016

Birth cohort of 131 children, 2–

3 years of age 

Mean (SD): 2.45 (2.53) BMI Adjusted RR (95% CI) for BMI ≥85th

percentile 0.57 (0.33, 0.98); p=0.041*

BMI-Z score Adjusted β (95% CI) for BMI Z-score: -0.35

(-0.60, -0.10); p=0.012*

Hauser et al. 2008

Cross-sectional study of 489 boys, 8–

9 years of age 

Mean: 3 Weight Adjusted β (95% CI), per unit log-PbB: -0.761 

(-1.54, 0.02); p=0.067

BMI Adjusted β (95% CI), per unit log-PbB: -0.107 

(-0.44, 0.23); p=0.53

Ronco 2010

Cross-sectional study of 107 women 

of childbearing age (median age: 

27 years) from Chile; data collection 

period not reported

Median 

• All: 1.0

• Low weight: 1.7 

• Normal weight: 2.3

• Overweight: 1.0

BMI No differences in PbB were observed between 

BMI categories
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Table 2-2. Summary of Epidemiological Studies Evaluating Effects on Body Weight at Mean Blood Lead 

Concentrations (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Scinicariello et al. 2013

Cross-sectional study of children and 

adolescents (n=10,693; age 3–

19 years) adults (n=15,899, age 

≥20 years) using NHANES data 

(1999–2006) 

Gmean (SE)

• Children/adolescents: 

1.12 (0.02)

• Adults: 1.59 (0.02)

• Quartiles (all):

o Q1: ≤0.70

o Q2: 0.71–1.09

o Q3: 1.10–1.60

o Q4: ≥1.61

BMI-Z score

(children and adolescents)

Adjusted β (SE) (BMI Z-score per PbB 

quartile):

• Q3: −0.15 (0.06); p=0.01*

• Q4: -0.33 (0.07); p ≤ 0.01*

• p-trend: ≤0.01*

Overweight

(children and adolescents)

Adjusted OR for Q4: 0.67 (0.52, 0.88)*

Obesity

(children and adolescents)

Adjusted OR 

• Q3: 0.70 (0.54, 0.90)*

• Q4: 0.42 (0.30, 0.59)*

BMI (adults) Adjusted β (SE) (BMI per quartile):

• Q2: −0.90 (0.20); p ≤ 0.01*

• Q3: −1.41 (0.22); p ≤0.01*

• Q4: −2.58 (0.25); p ≤0.01*

• p-trend: ≤0.01*

Overweight (adults) Adjusted OR for Q4: 0.79 (0.65–0.95)*

Obesity (adults) Adjusted OR

• Q2: 0.76 (0.66–0.87)*

• Q3: 0.66 (0.56–0.77)*

• Q4: 0.42 (0.35–0.50)*
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Table 2-2. Summary of Epidemiological Studies Evaluating Effects on Body Weight at Mean Blood Lead 

Concentrations (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Wang et al. 2015

Cross-sectional study of 5,558 adults 

(men: 2,235, ages 39–65 years; 

women: 3,323, ages 40–65 years) 

from 16 locations in China

PbB:

Men

• Median: 4.40

• Quartiles:

o Q1: ≤29.00

o Q2: 29.01–44.00

o Q3: 44.01–62.16

o Q4: ≥62.17

Women:

• Median: 3.78

• Quartiles:

o Q1: ≤25.13

o Q2: 25.14–37.79

o Q3: 37.80–54.35

o Q4: ≥54.36

BMI β (SE) per PbB quartile

• Men

o Q4: 0.01 (0.20)

o p-trend: 0.82

• Women

o Q4: 0.59 (0.17); p<0.05*

o p-trend: <0.001*

Overweight Adjusted OR

• Men

o Q4: 0.95 (0.72,1.26)

o p-trend: 0.74

• Women

o Q4: 1.16 (0.92, 1.46)

o p-trend: 0.07

Obesity Adjusted OR

• Men

o Q4: 0.88 (0.48, 1.61)

o p-trend: 0.99

• Women

o Q4: 1.86 (1.16, 2.98)*

o p-trend: <0.01*

aSee the Supporting Document for Epidemiological Studies for Lead, Table 1 for more detailed descriptions of studies. bAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

BMI = body mass index; BMI-Z = BMI z-scores; CI = confidence interval; Gmean = geometric mean; HT-Z = height z-scores; NHANES = National Health and 

Nutrition Examination Survey; OR = odds ratio; Pb = lead; RR = risk ratio; SD = standard deviation; SE = standard error
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2. HEALTH EFFECTS

Table 2-3. Effects on Body Weight Associated with Mean Blood Lead 

Concentrations (PbBs) ≤10 μga

Mean PbB 

(μg/dL) Population (n)b Weight BMI

BMI-Z 

score Overweight Obese Reference

3.0 C (481 boys) – – 0 – – Burns et al. 2017

2.45 C (131) – ↓ ↓ – – Cassidy-Bushrow 

et al. 2016

3 C (489 boys) 0 0 – – – Hauser et al. 2008

1.0 A (107 women) – 0 – – – Ronco et al. 2010

1.12 C, Ad (10,693)c – – ↓ ↓ ↓ Scinicariello et al. 

2013

1.59 A (15,899)c – ↓ – ↓ ↓ Scinicariello et al. 

2013

4.40 A (2,235, men) – 0 – 0 0 Wang et al. 2015

3.78 A (3,323, women) – 0 – 0 ↑ Wang et al. 2015

a↑ = increased; ↓ = decreased; 0 = no change; – = not assessed. bUnless otherwise specified, study was conducted in males and females.

cParticipants from the National Health and Nutrition Examination Survey 1999–2006.

A = adults; Ad = adolescents; BMI = body mass index; BMI-Z = BMI z-scores; C = children

2.5 RESPIRATORY

Overview. Few epidemiological studies have evaluated respiratory effects associated with exposure to 

Pb; those that are available include cross-sectional studies in adults and prospective and cross-sectional 

studies in children. Associations have been observed between PbB and decreased lung function, 

increased bronchial hyperreactivity, increased number and severity of symptoms of respiratory disease, 

and increased risk of respiratory diseases (e.g., asthma and obstructive lung disease). Although most 

studies found associations between respiratory effects and PbB, other studies did not observe associations. 

The following respiratory effects have been associated with PbB: 

• ≤10 μg/dL:

o Decreased lung function; corroborated in a few studies, including studies in children.

o Increased bronchial hyperreactivity.

o Increased risk of asthma and obstructive lung disease; evaluated in a few studies with mixed 

results.
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2. HEALTH EFFECTS

• >10 μg/dL:

o Decreased lung function.

o Symptoms of respiratory disease (e.g., shortness of breath).

o Increased risk/prevalence of asthma; evaluated in a few studies with mixed results.

Measures of Exposure. Studies evaluating the association between respiratory effects and Pb exposure 

evaluate exposure by measurement of PbB.

Confounding Factors and Effect Modifiers. The etiology for most respiratory diseases is multifactorial; 

therefore, several factors may contribute to clinical findings. Factors that may contribute to the 

development of respiratory diseases include poor housing conditions, exposure to allergens (e.g., pet 

dander, seasonal allergies), exposure to tobacco smoke and other respiratory irritants, and asthma 

compounded by obesity (Ali and Ulirk 2013). In addition, Aligne et al. (2000) reported that children 

living in urban settings have an increased risk of asthma. Failure to account for these factors may 

attenuate or strengthen the apparent associations between Pb exposure and the outcome, depending on the 

direction of the effect of the variable on the outcome.

Characterization of Effects. General trends for studies showing a relationship between PbB and 

respiratory effects are shown in Table 2-4. Compared to other toxicological endpoints (e.g., neurological 

or cardiovascular effects), few studies have evaluated adverse respiratory effects associated with PbB. 

Data are from cross-sectional studies in adults (Bagci et al. 2004; Bener et al. 2001; Chung et al. 2015; 

Min et al. 2008a; Pugh Smith and Nriagu 2011; Rokadia and Agarwal 2013), and prospective (Joseph et 

al. 2005; Rabinowitz et al. 1990) and cross-sectional (Wells et al. 2014) studies in children. Over a range 

of PbBs that includes PbB ≤10 μg/dL and PbB >50 μg/dL, studies provide evidence for effects in Pb 

workers compared to controls or associations between PbB and decreased pulmonary function tests 

indicative of obstructive pulmonary disease (forced expiratory volume in 1 second [FEV1], FEV1/forced 

vital capacity [FVC] ratio, forced expiratory flow at 25–75% of FVC [FEF25–75]), increased bronchial 

hyperreactivity (indicative of asthma), symptoms of respiratory disease (cough, shortness of breath), and 

increased risk of respiratory diseases (e.g., asthma and obstructive lung disease). With the exception of a 

prospective study in children, which showed no increased risk of asthma at umbilical cord PbB ≥10 μg/dL 

compared to <10 μg/dL (Rabinowitz et al. 1990), studies showed positive associations between PbB and 

respiratory effects.
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Table 2-4. Overview of Respiratory Effects in Adults and Children Chronically 

Exposed to Lead (Pb)

Mean blood lead 

concentration 

(PbB) (μg/dL) Effects associated with Pb exposure References

≤10 Decreased lung function Chung et al. 2015; Leem et al. 2015; 

Little et al. 2017; Zeng et al. 2017

Increased bronchial responsiveness Min et al. 2008a

Lung disease (asthma and obstructive lung 

disease)

Joseph et al. 2005; Rokadia and 

Agarwal 2013; Wang et al. 2017a; Wells 

et al. 2014; Zeng et al. 2016

>10–30 Lung disease (asthma) Pugh Smith and Nriagu 2011

>30–50 Decreased lung function Bagci et al. 2004

>50 Symptoms of lung disease (phlegm) Bener et al. 2001

Lung disease (asthma) Bener et al. 2001

Effect at Blood Pb Levels ≤10 μg/dL. Results of studies evaluating respiratory effects of PbB ≤10 μg/dL 

are summarized in Table 2-5, with study details provided in the Supporting Document for 

Epidemiological Studies for Lead, Table 2. Studies show associations between PbB ≤10 μg/dL and 

decreased lung function, increased bronchial hyperreactivity, and increased risk of asthma; findings are 

consistent with obstructive lung disease. In a cross-sectional study in adults from China with mean PbB 

of 2.50 μg/dL, an inverse association was observed for the FEV1/FVC ratio in a population; results are 

consistent with obstructive airway disease (Chung et al. 2015). In a large pooled cross-sectional study,

Korean adults showed a decrease in the FEV1/FVC ratio in the highest exposure quartile (Leem et al. 

2015). A small study in children with a mean PbBs of 5.53 μg/dL show inverse associations between 

PbB and pulmonary functions tests, including FEV1 and FVC (Little et al. 2017). Increased bronchial 

reactivity in response to methacholine challenge, consistent with a diagnosis of asthma, was observed in 

adults with mean PbB of 2.96 μg/dL (Min et al. 2008a). In addition, risk of obstructive lung disease was 

observed in a large NHANES population of adults with a mean PbB of 1.73 μg/dL (Rokadia and Agarwal 

2013). Studies in children examining associations between PbB and risk of asthma do not provide 

consistent results. A large prospective study showed an increased risk of asthma in black children with 

PbB <5 and ≥5 μg/dL compared to white children with PbB <5 μg/dL; however, no increased risk was 

observed for white children with PbB ≥5 μg/dL compared to white children with PbB <5 μg/dL (Joseph 

et al. 2005). The underlying causes for the racial disparity of results have not been established. However, 

the study authors noted the following as possible contributors: socio-economic factors; racial differences 

in IgE; differences in housing conditions and indoor Pb sources (e.g., Pb paint); and genetic variability in 

susceptibility to Pb toxicity (e.g., vitamin D receptor gene). In cross-sectional studies, asthma risk was 
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2. HEALTH EFFECTS

Table 2-5. Summary of Epidemiological Studies Evaluating Respiratory Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Decreased lung function

Chung et al. 2015

Cross-sectional study; n=870 adults

Mean: 2.50

Tertiles:

• T1: <2.03

• T2: 2.03–2.81

• T3: >2.81

FVC% Correlation coefficient: 0.070

FEV1% Correlation coefficient: 0.00

FEV1/FVC ratio Correlation coefficient: -0.115; p<0.01*

OR T3: 0.006 (0, 0.286)*

p-trend: 0.03*

Leem et al. 2015

Pooled cross-sectional study; 

n=5,972 adults

Mean:

• Men: 2.92

• Women: 2.33

Quartiles (men and women)

• Q1: ≤1.85 (reference)

• Q2: 1.86–2.43

• Q3: 2.44–3.16

• Q4: ≥3.17

FEV1/FVC ratio Difference (SE) between reference and Q4: 

-0.6 (0.3); p=0,025*

Little et al. 2017

Cross-sectional study; n=184 boys and 

189 girls (age ≥10–≤15.9 years)

Mean:

• Boys: 5.27

• Girls: 3.82

FVC Boys, β (SE), per log10 increase in PbB:

-5.11 (4.47); p=0.25

Girls, β (SE), per log10 increase in PbB:

-12.90 (5.25); p=0.02*

Zeng et al. 2017

Cross-sectional study; n=200 children

(ages 5–7 years)

PbB:

Median

• Control: 3.57 

• Exposed: 5.53

FEV1 Regression coefficient for exposed: -

0.02 (-0.100, 0.043)

FVC Regression coefficient for exposed: 

FVC: -0.015 (-0.093, 0.063)

Increased bronchial responsiveness

Min et al. 2008a

Cross-sectional study; n=523 adults

Mean (SD): 2.96 (1.59) BR A 1 μg/dL increase in PbB was associated 

with a higher BR; β (SE): 0.018 (0.007)*
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2. HEALTH EFFECTS

Table 2-5. Summary of Epidemiological Studies Evaluating Respiratory Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Asthma

Joseph et al. 2005

Prospective study; n=4,634 children 

(ages 3 months to 3 years)

Mean

• White: 3.2

• Black: 5.5

Asthma All compared to PbB <5 μg/dL in white children

HR white (PbB ≥5): 2.3 (0.8, 6.7); p=0.12

HR black (PbB <5): 1.8 (1.3, 2.4); p<0.01*

HR black (PbB ≥5): 1.5 (1.2, 1.8); p<0.01*

HR black (PbB ≥10): 3.0 (1.2, 7.1); p=0.01*

Rokadia and Agarwal 2013c

Pooled cross-sectional study; 

n=9,575 adults (8,411 without OLD; 

1,164 with OLD)

Mean

• Non-OLD: 1.18

• OLD: 1.73

OLD OR for all OLD: 1.94 (1.10, 3.42)*

OR for mild OLD: 1.21 (0.55, 2.65)

OR for moderate-severe OLD: 3.49 (1.70, 

7.15)*

Wang et al. 2017a

Cross-sectional study; n=930 children

(mean age: 5.74 years)

Gmean (GSD)

• All: 1.86 (1.21)

• Boys: 1.89 (1.22)

• Girls: 1.83 (1.20)

Asthma OR (all participants), <5 versus ≥5 μg/dL: 

5.50 (1.69, 17.94); p=0.005*

OR (boys), <5 versus ≥5 μg/dL: 6.40 (1.49, 

27.42); p=0.012*

OR (girls), <5 versus ≥5 μg/dL: 4.73 (0.44, 

50.60); p=0.199

Wells et al. 2014c

Cross-sectional study; NHANES 2005–

2006; n=1,430 children (ages 4–

12 years)

Gmean: 1.07 Asthma OR for asthma with atopy: 0.97 (0.61, 1.55)

OR for asthma with no atopy: 1.07 (0.86, 1.33)
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2. HEALTH EFFECTS

Table 2-5. Summary of Epidemiological Studies Evaluating Respiratory Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Zeng et al. 2016

Cross-sectional study; n=470 children

(ages 3–8 years)

Median 

• Haojiang area: 4.75

• Guiyu area: 6.24

Asthma OR for asthma at PbB ≥5 μg/dL: 9.50 (1.16, 

77.49); p<0.01*

aSee the Supporting Document for Epidemiological Studies for Lead, Table 2 for more detailed descriptions of studies. bAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

cStudy population was from NHANES.

BR = bronchial responsiveness; CI = confidence interval; FEV1 = forced expiratory volume in 1 second (L/s); FEV1% = percent of predicted FEV1; FVC = forced 

vital capacity (L); FVC% = percent of predicted FVC; Gmean = geometric mean; GSD = geometric standard deviation; HR = hazard ratio; NHANES = National 

Health and Nutrition Examination Survey; OLD = obstructive lung disease; OR = odds ratio; Pb = lead; SD = standard deviation; SE = standard error
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2. HEALTH EFFECTS

increased in Taiwanese children, with elevated risks in the total population and for boys, but not for girls 

(Wang et al. 2017a) and in Chinese children with PbB ≥5 μg/dL (Zeng et al. 2016). In contrast, a large 

cross-sectional study of children participating in NHANES did not observe an association between PbB 

(mean 1.07 μg/dL) and asthma, with or without atopy (Wells et al. 2014). 

Mechanisms of Action. General mechanisms of toxicity of Pb (reviewed in Section 2.21) are likely 

involved in the development of toxicity to the respiratory system. EPA (2014c) specifically noted that 

oxidative stress through reactive oxygen species (ROS), resulting in tissue damage and inflammation and 

immune effects, is a plausible mechanism for the underlying cause of respiratory damage. Increased 

ROS, along with depletion of antioxidants, results in inflammation and production and release of 

metabolites and cytokines. Immune-mediated inflammation is observed with asthma and bronchial 

hyperreactivity. 

2.6 CARDIOVASCULAR

Overview. A large number of epidemiological studies showing adverse effects on the cardiovascular 

system associated with Pb exposure have been published. Most studies evaluated effects in adults, 

although a few studies in children have been conducted. The effect of Pb exposure on blood pressure is 

the most studied cardiovascular outcome, with results providing consistent evidence of positive 

associations between Pb exposure and blood pressure. Other cardiovascular endpoints (atherosclerosis, 

cardiac conduction, cardiovascular disease, and mortality due to cardiovascular disease) also show 

positive and inverse associations with PbB, although the majority of studies had positive associations. In 

some cases, although no associations between PbB and cardiovascular outcomes were observed, 

associations were observed for bone Pb, a biomarker of cumulative Pb exposure that, among individuals 

with high historical Pb exposures, typically remains elevated for many years after the PbB declines to 

≤10 μg/dL; these cases are noted in the discussions below. 

The following cardiovascular effects have been associated with PbB: 

• ≤10 μg/dL:

o Greater systolic and diastolic blood pressure:

 In adults; corroborated in multiple studies.

 In children; evaluated in a few studies.

 During pregnancy; evaluated in a few studies.
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2. HEALTH EFFECTS

o Greater risk of hypertension:

 In adults, including during pregnancy; evaluated in numerous studies.

o Greater risk of atherosclerosis; evaluated in a few studies.

o Altered cardiac conduction; evaluated in a few studies.

o Greater risk of mortality due to cardiovascular diseases; evaluated in a few studies with

mixed results.

• >10 μg/dL:

o Increased systolic and diastolic blood pressure:

 In adults; corroborated in multiple studies and meta-analyses.

 In children; evaluated in a few studies.

o Increased risk of hypertension; corroborated in multiple studies.

o Atherosclerosis; evaluated in a few studies.

o Increased risk or prevalence of heart disease; evaluated in a few studies.

o Increased mortality due to cardiovascular diseases; corroborated in multiple studies.

Measures of Exposure. PbB and bone Pb concentrations have been used as biomarkers to evaluate 

cardiovascular effects of Pb exposure. However, PbB may not provide the ideal biomarker for long-term 

exposure to target tissues that contribute a hypertensive effect of Pb. Because the development of 

cardiovascular effects has a long latency period, associations between PbB and cardiovascular disease at 

concurrent PbB ≤10 μg/dL may be related to higher past Pb exposures. Bone Pb, a metric of cumulative 

or long-term exposure to Pb, appears to be a better predictor of Pb-induced elevations in blood pressure 

and alterations in cardiac conduction than PbB.

Confounding Factors and Effect Modifiers. Numerous factors affect blood pressure, including age, 

body mass, race, smoking, alcohol consumption, ongoing or family history of cardiovascular/renal 

disease, LDL cholesterol levels, and various dietary factors (e.g., dietary calcium). In addition, renal 

disease, as well as Pb-induced renal damage, can lead to cardiovascular effects, including increased blood 

pressure (EPA 2014c; NTP 2012); thus, interpretation of studies examining cardiovascular outcomes is 

complicated by the link between cardiovascular and renal function. Failure to account for these factors 

may attenuate or strengthen the apparent associations between Pb exposure and the outcome, depending 

on the direction of the effect of the variable on the outcome (e.g., Møller and Kristensen 1992). For 

example, adjusting for alcohol consumption will decrease the apparent association between PbB and 

blood pressure, if alcohol consumption contributes to Pb intake and, thereby, PbB (Bost et al. 1999; 

Hense et al. 1993; Hertz-Picciotto and Croft 1993; Wolf et al. 1995). Varying approaches and breadth of 
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2. HEALTH EFFECTS

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). Ambulatory measurements also can decrease bias in estimates related to increases in blood 

pressure that can accompany clinic visits (Yang et al. 2018). 

Characterization of Effects. General trends between studies showing a relationship between PbB and 

cardiovascular effects are shown in Table 2-6. Over the PbB range of ≤10–>50 μg/dL, results of 

epidemiological studies provide evidence for increased blood pressure and hypertension, atherosclerosis 

(increased intimal medial thickening and peripheral artery disease), heart disease (myocardial infarction, 

ischemic heart disease, left ventricular hypertrophy, cardiac arrhythmias, and angina), and increased risk 

of mortality due to cardiovascular diseases. The effect of Pb exposure on blood pressure is the most 

studied cardiovascular outcome. A review by Navas-Acien et al. (2007) concluded that available 

literature provides evidence that “is sufficient to infer a causal relationship of Pb exposure and 

hypertension” and evidence that “is suggestive but not sufficient to infer a causal relationship of Pb

exposure with clinical cardiovascular outcomes” (cardiovascular, coronary heart disease, and stroke 

mortality; and peripheral arterial disease). Well-controlled studies in laboratory animals provide 

additional support regarding effects of Pb on blood pressure; see EPA (2014c) for additional information.

Table 2-6. Overview of Cardiovascular Effects in Adults and Children Associated 

with Chronic Exposure to Lead (Pb)

Mean blood lead 

concentration 

(PbB) (μg/dL)

Effects associated with Pb 

exposure References

≤10 Increased blood pressure and 

hypertension 

Almeida Lopes et al. 2017; Al-Saleh et al. 2005; 

Barry et al. 2019; Bost et al. 1999; Bushnik et al. 

2014; Cheng et al. 2001; Chu et al. 1999; Den 

Hond et al. 2002; Disha et al. 2019; 

Elmarsafawy et al. 2006; Faramawi et al. 2015; 

Gambelunghe et al. 2016; Gerr et al. 2002; 

Glenn et al. 2003; Gump et al. 2005, 2011; 

Hense et al. 1993; Hu et al. 1996a; Korrick et al. 

1999; Lee et al. 2016a, 2016b; Martin et al. 

2006; Muntner et al. 2005; Nash et al. 2003; 

Obeng-Gyasi and Obeng-Gyasi 2018; Park et al. 

2009b; Perlstein et al. 2007; Proctor et al. 1996; 

Rothenberg et al. 2002; Schwartz 1995; 

Scinicariello et al. 2010, 2011; Vupputuri et al. 

2003; Wells et al. 2011; Yang et al. 2017, 2018; 

Yazbeck et al. 2009; Zhang et al. 2011; Zota et 

al. 2013
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2. HEALTH EFFECTS

Table 2-6. Overview of Cardiovascular Effects in Adults and Children Associated 

with Chronic Exposure to Lead (Pb)

Mean blood lead 

concentration 

(PbB) (μg/dL)

Effects associated with Pb 

exposure References

Atherosclerosisa Ari et al. 2011; Muntner et al. 2005; Navas-Acien 

et al. 2004; 

Heart diseaseb and cardiac 

function

Chen et al. 2017; Cheng et al. 1998; Eum et al. 

2011; Jain et al. 2007; Jing et al. 2019; Park et 

al. 2009a

Mortality due to cardiovascular 

disease

Aoki et al. 2016; Khalil et al. 2009; Lanphear et 

al. 2018; Menke et al. 2006; Schober et al. 2006; 

Weisskopf et al. 2009

>10–30 Increased blood pressure and 

hypertension

Coate and Fowles 1989; Factor-Litvak et al. 

1999; Grandjean et al. 1989; Han et al. 2018; 

Harlan et al. 1985; Møller and Kristensen 1992; 

Pirkle et al. 1985; Rabinowitz et al. 1987

Atherosclerosisa Pocock et al. 1988; Poreba et al. 2011, 2012

Heart diseaseb and cardiac 

function

Karakulak et al. 2019; Poreba et al. 2013

Mortality due to cardiovascular 

disease

Barry and Steenland 2019; Lustberg and 

Silbergeld 2002; Min et al. 2017; Schober et al. 

2006; Steenland et al. 2017

>30–50 Increased blood pressure and 

hypertension

Aiba et al. 1999; Al-Saleh et al. 2005; FactorLitvak et al. 1996, 1999; Ghiasvand et al. 2013; 

Glenn et al. 2006; Rapisarda et al. 2016; 

Weaver et al. 2008; Weiss et al. 1986, 1988

Atherosclerosisa Karakulak et al. 2017

Heart diseaseb Bockelmann et al. 2002; Jain et al. 2007; 

Kieltucki et al. 2017

Mortality due to cardiovascular 

disease

Barry and Steenland 2019; Gerhardsson et al. 

1995a; Steenland et al. 2017

>50 Increased blood pressure and 

hypertension

Kirby and Gyntelberg 1985; Were et al. 2014

Atherosclerosisa Kirby and Gyntelberg 1985

Mortality due to cardiovascular 

disease

Cooper 1988; Cooper et al. 1985; Fanning 1988; 

Gerhardsson et al. 1995a; McDonald and Potter 

1996

aAtherosclerosis includes increased intimal medial thickening and peripheral artery disease. bHeart disease includes myocardial infarction, ischemic heart disease, left ventricular hypertrophy, cardiac 

arrhythmias, and angina.

Numerous studies provide a weight of evidence for associations between PbB and increased blood 

pressure over a wide PbB range in adults (Table 2-6). Results of meta-analyses estimate small but 

consistent increases in blood pressure per doubling of PbB. The largest meta-analysis of 31 studies 

published between 1980 and 2001 included a total of 58,518 subjects (Nawrot et al. 2002); blood pressure 
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2. HEALTH EFFECTS

data from studies included in the analysis are shown in Table 2-7 and Figures 2-2 and 2-3. Nawrot et al. 

(2002), in an update of an earlier meta-analysis by Staessen et al. (1994), estimated the increase in 

systolic pressure per doubling of PbB to be 1 mmHg (95% CI 0.5, 1.4) and the increase in diastolic 

pressure to be 0.6 mmHg (95% CI 0.4, 0.8). The range of mean (or median) PbBs for studies included in 

the analysis was 2.28–63.82 μg/dL. Although a PbB mean was not estimated for the entire study 

population, only nine studies had a mean PbB <10 μg/dL; therefore, it is likely that the overall PbB mean 

for the entire study population was >10 μg/dL. Similar outcomes were observed in two other metaanalyses (Schwartz 1995; Staessen et al. 1994). A meta-analysis 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) increase in diastolic 

pressure per doubling of PbB. Schwartz (1995) conducted a 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 (SE) 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. The estimated increase in blood pressure per doubling 

of PbB in these meta-analyses is small; however, on a population basis, the consequences of increased 

blood pressure includes increased risks of serious and potentially fatal effects, including atherosclerosis, 

stroke, and myocardial infarction. Increased blood pressure during pregnancy has been associated with 

PbB and bone Pb (Rothenberg et al. 2002; Wells et al. 2011; Yazbeck et al. 2009); these studies are 

discussed in more detail below (Effect at Blood Pb Levels ≤10 μg/dL). 

Table 2-7. Characteristics of the Study Population in Meta-Analyses of Effects of 

Lead (Pb) on Blood Pressure

Reference Numbera Populationb

Men 

(%)c HTd

Age

(years)e SBPf DBPf

Lead 

(μg/dL)g

1h Pocock et al. 1984i,j; 

Shaper et al. 1981

7,379 GP 100 Y 49

(40–59)

145 82 15.13

(2.07–66.3)a,e

2 Kromhout 1988i,j; 

Kromhout et al. 1985i

152 GP 100 Y 67

(57–76)

154 92 18.23

(10.77–

27.97)a,c

3 Moreau et al. 1982j, 

1988; Orssaud et al. 

1985i,j

431 WC 100 Y 41

(24–55)

131 75 18.23

(8.91–49.94)a,e

4 Weiss et al. 1986i, 1988i 89 WC 100 Y 47

(30–64)

122 83 24.45

(18.65–

29.01)m,x
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2. HEALTH EFFECTS

Table 2-7. Characteristics of the Study Population in Meta-Analyses of Effects of 

Lead (Pb) on Blood Pressure

Reference Numbera Populationb

Men 

(%)c HTd

Age

(years)e SBPf DBPf

Lead 

(μg/dL)g

5 de Kort and Zwennis 

1988i,j; de Kort et al. 

1987i

105 BC 100 N 40

(25–80)

136 83 29.22

(4.35–83.29)a,e

6 Lockett and Arbuckle 

1987i

116 BC 100 Y 32

(?–?)

119 80 37.5

(14.92–

95.52)a,e

7 Parkinson et al. 1987i 428 BC 100 Y 36

(18–60)

127 80 27.97

(6.01–49.52)a,c

8 Rabinowitz et al. 1987i 3,851 GP 0 Y 28

(18–38)

121 76 7.04

(3.73–10.15)a,c

9 Elwood et al. 1988ai,j, 

1988bk

1,136 GP 100 Y 56

(49–65)

146 87 12.64

(6.01–26.11)g,c

10 Elwood et al. 1988a, 

1988bi,j,l

1,721 GP 50 Y 41

(18–64)

127 78 10.15

(4.56–23.21)g,c

11 Gartside et al. 1988i; 

Harlan 1988; Harlan et 

al. 1985; Pirkle et al. 

1985; Ravnskov 1992m

6,289 GP 53 Y 30

(10–74)

127 80 13.47

(2.07–95.93)g,e

12 Neri et al. 1988i,j,n 288 BC 100 ? ? 

(?–?)

? ? 45.17

(6.01–65.06)a,e

13 Neri et al. 1988i,o 2,193 GP ? Y 45

(25–65)

? ? 23.41

(0–47.03)m,e

14 Grandjean et al. 1989, 

1991i,p

1,050 GP 48 Y 40

(40–40)

? ? 11.6

(3.94–60.09)a,e

15 Reimer and Tittelbach 

1989i

58 BC 100 ? 32

(?–?)

134 81 39.99

(12.85–

70.24)a,c

16 Apostoli et al. 1990i 525 GP 48 Y 45

(21–60)

132 84 13.05

(2.07–28.18)a,e

17 Morris et al. 1990i,j 251 GP 58 Y ? 

(23–79)

? ? 7.46

(4.97–38.95)a,e

18 Sharp et al. 1988i,j, 

1989i, 1990i

249 WC 100 N 43

(31–65)

128 83 6.63

(2.07–14.92)p,e

19 Staessen et al. 1984i,q 531 WC 75 Y 48

(37–58)

126 78 11.4

(4.14–35.22)g,e

20 Møller and Kristensen 

1992i,j,r

439 GP 100 Y 40

(40–40)

? ? 13.68

(4.97–60.09)a,e

21 Hense et al. 1993i,j 3,364 GP 51 Y 48

(28–67)

129 80 7.87

(1.24–37.09)a,e

22 Maheswaran et al. 1993i 809 BC 100 Y 43

(20–65)

129 84 31.7

(0–98.01)a,e

23 Menditto et al. 1994 1,319 GP 100 Y 63

(55–75)

140 84 11.19

(6.22–24.66)
LEAD 45

2. HEALTH EFFECTS

Table 2-7. Characteristics of the Study Population in Meta-Analyses of Effects of 

Lead (Pb) on Blood Pressure

Reference Numbera Populationb

Men 

(%)c HTd

Age

(years)e SBPf DBPf

Lead 

(μg/dL)g

24 Hu et al. 1996a; Proctor 

et al. 1996s

798 GP 100 Y 66

(43–93)

134 80 5.59

(0.41–35.02)p,e

25 Staessen et al. 1996ai, 

1996bi,t

728 GP 49.3 Y 46

(20–82)

130 77 9.12

(1.66–72.52)g,e

26 Sokas et al. 1997u 186 BC 99 Y 43

(18–79)

130 85 7.46

(2.07–30.04)p,e

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)a,e

29 Rothenberg et al. 

1999a, 1999b

1,627 GP 0 Y 27

(?–?)

110 59 2.28

(?–?)g

30 Schwartz et al. 2000c 543 BC 100 Y 58

(41–73)

128 77 4.56

(1.04–20.1)a,e

31 Den Hond et al. 2001v 13,781 GP 53.2 Y 48

(20–90)

125 73 3.11

(0.62–55.94)g,e

aNumber of persons in whom relevant data were available.

bStudy population: BC = blue collar workers; GP = sample from general population; WC = white collar employees.

cMen: Percentage of men.

dHT: Indicates whether the sample included (Y = yes) or did not include (N = no) hypertensive patients. 

eAge: Mean age or midpoint of age span (range or approximate range given between parentheses).

f

SBP, DBP: Mean systolic and diastolic blood pressures. gLead: 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. hNumber refers to reference in Figures 2-2 and 2-3. i

Included in the Staessen et al. (1994) meta-analysis.

j

Included in the Schwartz (1995) meta-analysis. kCaerphilly Study.

l

Welsh Heart Program.

mNHANES (National Health and Nutrition Examination Survey). nFoundry workers.

oCanadian Health Survey.

pGlostrup Population Study, cross-sectional analysis (1976). qLondon Civil Servants.

r

Glostrup Population Study, longitudinal analysis (1976–1987). sNormative Aging Study.

t

PheeCad (Public Health and Environmental Exposure to Cadmium) Study. uBecause of missing information, only the effect in whites is included.

vNHANES III.

Source: Nawrot et al. 2002
LEAD 46

2. HEALTH EFFECTS

Figure 2-2. Change in the Systolic Pressure Associated with a Doubling of the 

Blood Lead Concentration (PbB)*

*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 2-7 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

-20 -10 0 10 20 30

SBP

(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
LEAD 47

2. HEALTH EFFECTS

Figure 2-3. Change in the Diastolic Pressure Associated with a Doubling of the 

Blood Lead Concentration (PbB)*

*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 2-7 for more details on study groups.

B = blacks; C = Caerphilly Study; CS = civil servants; FW = foundry workers; HP = Welsh Heart Program; 

I = immigrants; N = non-immigrants; P = Public Health and Environmental Exposure to Cadmium Study; W = whites

-15 -10 -5 0 5 10 15 20 25

DBP

(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
LEAD 48

2. HEALTH EFFECTS

Within individual studies, dose-effect relationships are evident at PbB ≤10 μg/dL. A positive dose-effect 

was observed for PbB and diastolic blood pressure (Zota et al. 2013). An observed positive dose-effect 

was observed for tibia Pb concentration and hypertension (Hu et al. 1996a). No dose-effect was observed 

for PbB and pulse pressure (PP), although a positive dose-effect was observed for tibia Pb and PP 

(Perlstein et al. 2007). In a cross-sectional study of women, diastolic hypertension was observed to have 

a positive dose-effect when pre- and postmenopausal women were analyzed together and when 

postmenopausal women were analyzed alone. In contrast, a dose-effect relationship was not observed for 

PbB and hypertension in a cross-sectional study of men and women (Muntner et al. 2005). A positive 

dose-effect relationship was observed for PbB and peripheral artery disease (PAD) (Muntner et al. 2005). 

In men, tibia blood levels had a positive dose-effect relationship with QT interval, but a negative doseeffect relationship with atrioventricular conduction defect (Eum et al. 2011). Studies have also found 

positive dose-effect relationships between mortality due to cardiovascular disease, myocardial infarction, 

and stroke and PbB (Menke et al. 2006; Schober et al. 2006). 

Several studies have evaluated associations between PbB and cardiovascular function in children (Ahn et 

al. 2018; Factor-Litvak et al. 1999, 1996; Gump et al. 2005, 2011; Kapuku et al. 2006; Khalil et al. 2009, 

2010; Lustberg and Silbergeld 2002; Menke et al. 2006; Schober et al. 2006; Zhang et al. 2011). Results 

show alterations in cardiovascular function, including increases in blood pressure and altered 

cardiovascular function under stress (decreased stroke volume and cardiac output) over a PbB range from 

<10 to approximately 40 μg/dL. 

Effect at Blood Pb Levels ≤10 μg/dL. Studies investigating relationships between PbB ≤10 μg/dL and 

cardiovascular effects have evaluated effects on blood pressure (including hypertension), atherosclerosis, 

heart disease (alterations in cardiac conduction and ischemic heart disease), and death due to 

cardiovascular disease.

Increased blood pressure and hypertension. Numerous studies of large populations show associations 

between PbB ≤10 μg/dL and increased systolic and/or diastolic blood pressure and increased risk of 

hypertension and prehypertension (see Table 2-8). The lowest mean PbB associated with increased 

systolic and diastolic is 1.33 μg/dL (Obeng-Gyasi and Obeng-Gyasi 2018). A few studies did not show 

associations between PbB and blood pressure parameters; however, positive associations between bone 

Pb concentrations and blood pressure at concomitant PbB ≤10 μg/dL were observed (Barry et al. 2019; 

Gerr et al. 2002; Hu et al. 1996a; Korrick et al. 1999; Zhang et al. 2011). Studies are briefly summarized 
LEAD 49

2. HEALTH EFFECTS

Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

Women and men combined (not stratified by sex)c 

Almeida Lopes et al. 2017

Population-based study; n=948 adults 

(≥40 years of age)

Gmean: 1.97

Quartiles:

• Q1: ≤1.32

• Q2: 1.32–1.93

• Q3: 1.93–2.76

• Q4: >2.76

SBP Change in SBP, Q4: -0.00 (-0.00, -0.00); 

p-trend: 0.002*

DBP Change in DBP, Q4: 0.06 (0.04, 0.09); 

p-trend: <0.001*

Hypertension OR, Q4: 2.54 (1.17, 5.53)*

Faramawi et al. 2015d

Cross-sectional study; n=13,757

Mean: 3.44 SBP β (SE), mmHg for change in blood pressure 

SD per μg/dL: 0.07 (0.02); p<0.01*

DBP β (SE), for change in blood pressure SD per 

μg/dL: 0.04 (0.03); p=0.08

Gambelunghe et al. 2016

Cross-section study; n=4,452 adults

Mean: 2.8 

Quartiles:

• Q1: 0.15–1.9

• Q2: 1.9–2.5

• Q3: 2.5–3.3

• Q4: 3.3–25.8

SBP Regression coefficient, β, Q4 versus Q1–Q3 

(mmHg): 1.7; p=0.01*

DBP Regression coefficient, β, Q4 versus Q1–Q3 

(mmHg): 1.3; p<0.001*

Hypertension OR, Q4 versus Q1–Q3: 1.3 (1.1–1.5); 

p=0.004*

Lee et al. 2016b

Cross-sectional study; n=8,493 adults

Study population mean not 

reported

Quartiles:

• Q1: 0.206–1.539

• Q2: 1.540–2.056

• Q3: 2.057–2.716

• Q4: 2.717–24.532

Prehypertension OR, versus Q1:

• Q2: 1.24 (1.04, 1.48)*

• Q3: 1.27 (1.06, 1.52)*

• Q4: 1.30 (1.07, 1.60)*

• p-trend: 0.0152*

Martin et al. 2006

Cross-sectional study; n=964 (ages 50–

70 years)

Mean: 3.5 SBP β, mmHg per 1 μg/dL: 0.99 (0.47,1.51); 

p<0.01*

DBP β, mmHg per 1 μg/dL: 0.51 (0.24, 0.79); 

p<0.01*
LEAD 50

2. HEALTH EFFECTS

Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

Zota et al. 2013d

Cross-sectional study; n=8,194 (ages 

40–65 years) 

Mean: 1.69

Quintiles:

• Q1: ≤1.05

• Q2: 1.06–1.44

• Q3: 1.45–1.90

• Q4: 1.91–2.69

• Q5: >2.70

Elevated SBP 

(≥140 mmHg)

OR (Q5): 1.23 (0.92, 1.65); p-trend: 0.06

Elevated DBP 

(≥90 mmHg)

OR (Q3): 1.56 (1.11, 2.19)*

OR (Q4): 1.80 (1.24, 2.60)*

OR (Q5): 1.77 (1.25, 2.50)*

p-trend 0.0002

Obeng-Gyasi and Obeng-Gyasi 2018

Cross-sectional study; n=22,747 adults

Mean: 1.33 SBP β, increase in blood pressure (mmHg) per 

unit increased in ln PbB: 0.238 (0.122, 

0.355); p=0.0001*

DBP β, increase in blood pressure (mmHg) per 

unit increased in ln PbB: 0.132 (0.049, 

0.215); p=0.002*

Women and men (stratified by sex)c

Bost et al. 1999

Cross-sectional study; n=2,563 males 

and 2,763 females

Mean

• M: 3.7

• F: 2.6

SBP M: no association with PbB (regression 

coefficient not reported)

F: no association with PbB (regression 

coefficient not reported)

DBP M: β, per doubling of PbB: 0.78 (0.01, 1.55)*

F: regression coefficients not reported

Bushnik et al. 2014

Population-based survey; 

n=2,214 males and 2,336 females

Mean

• All: 1.64

• Non-hypertensive: 1.59

• Hypertensive: 1.74

SBP All β, mmHg per 1 μg/dL: 1.85 (-0.20, 3.90); 

p=0.075

M β, mmHg per 1 μg/dL: 2.17 (-0.08, 4.42); 

p=0.058

F β, mmHg per 1 μg/dL: 0.76 (-2.72, 4.24); 

p=0.656

DBP All β, mmHg per 1 μg/dL: 1.91 (0.75, 3.08); 

p=0.002*

M β, mmHg per 1 μg/dL: 2.36 (0.94, 3.79); 

p=0.002*
LEAD 51

2. HEALTH EFFECTS

Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

F β, mmHg per 1 μg/dL: 1.43 (-0.51, 3.38); 

p=0.142

Hypertension All β, mmHg per 1 μg/dL: -3.87 (-7.46, -0.29); 

p=0.035*

M β, mmHg per 1 μg/dL: -6.37 (-15.02, 2.29); 

p=0.142

F β, mmHg per 1 μg/dL: -4.18 (-8.78, 0.42); 

p=0.073

Chu et al. 1999

Population-based survey study; 

n=1,471 males and 1,329 females

Mean

• M: 7.3

• F: 5.7

SBP M β (SE), mmHg per 1 log10 μg/dL: 

0.185 (0.076); p=0.015*

F β (SE), mmHg per 1 log10

μg/dL: -0.057 (0.109); p=0.603

DBP M β (SE), mmHg per 1 log10 μg/dL: 

0.075 (0.053); p=0.159

F β (SE), mmHg per 1 log10

μg/dL: -0.083 (0.072); p=0.250

Hense et al. 1993

Population-based survey study; 

n=1,703 males and 1,661 females

Mean

• M: 8.3

• F: 6.0

SBP M β, mmHg per 1 μg/dL: 0.29 (0.08, 0.49)*

F β, mmHg per 1 μg/dL: 0.17 (-0.14, 0.48)

DBP M β, mmHg per 1 μg/dL: 0.08 (-0.06, 0.23)

F β, mmHg per 1 μg/dL: 0.29 (0.09, 0.49)*
LEAD 52

2. HEALTH EFFECTS

Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

Lee et al. 2016a

Cross-sectional study; n=5,920 men 

and 6,059 women

Gmean (95% CI)

• Men: 2.396

• Women: 1.919

Tertiles:

• Men

o T1: <2.096

o T2: 2.096–2.886

o T3: >2.886

• Women

o T1: <1.516

o T2: 1.516–2.147

o T3: >2.14

SBP M difference, T3 versus T1: 0.25 (-0.90, 1.41)

F difference, T3 versus T1: 1.48 (0.29, 2.67)

DBP M difference, T3 versus T1 : 0.73 (-0.12, 1.60)

F difference, T3 versus T1: 1.059 (0.308, 

1.811)

Hypertension M OR, T3: 0.88 (0.72, 1.07)

F OR, T3: 1.26 (0.999, 1.58)

Prehypertension M OR, T3: 0.95 (0.79, 1.16)

F OR, T3: 1.22 (1.01, 1.48)*

Men onlyc

An et al. 2017

Cross-sectional study; n=310 male 

smelters (21–61 years of age)

Gmean: 5.839 SBP β, per doubling of PbB: -0.636 (-2.661, 1.389); 

p=0.537

DBP β, per doubling of PbB: -1.182 (-2.763, 0.399);

p=0.142

Barry et al. 2019

Cross-sectional study; n=211 male Pb 

workers

Median (range): 2.5 (0–34.0)

• Quartiles

o Q1: <1.6

o Q2: 1.6–2.5

o Q3: 2.6–4.2

o Q4: ≥4.3

Bone Pb (tibia) median, μg/g 

(range): 13.8 (0–127.3)

• Bone Pb quartiles:

o Q1: <9.6

o Q2: 9.6–13.7

o Q3: 13.8–19.5

o Q4: ≥19.6

SBP Regression coefficient (SE) for

PbB Q4: 7.33 (4.40); p=0.10

PbB continuous: 0.19 (0.30) 0.52

Bone Pb Q4: 5.32 (5.26); p=0.31

Bone Pb continuous: 0.36 (0.15); p=0.02*
LEAD 53

2. HEALTH EFFECTS

Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

Cheng et al. 2001e

Longitudinal study; n=833 men

Analysis for hypertension limited to 

474 participants who had no history of 

definite hypertension; analysis for SBP 

limited to 519 participants who were 

free from definite hypertension at 

baseline

PbB mean (all): 6.09

Tibia Pb (μg/g)

• Borderline: 23.46

• Definite: 22.69

Patella Pb (μg/g)

• Borderline: 33.73

• Definite: 32.72

Hypertension (borderline 

and definite) 

RR, per 1 SD increase in PbB: 1.00 (0.76, 1.33)

RR, per 1 SD increase in tibia Pb: 1.22 (0.95, 

1.57)

RR, per 1 SD increased in patella Pb: 1.29 

(1.04, 1.61); p<0.05*

SBP RR, per 1 SD increase in PbB: -0.13 (-1.35, 

1.09)

RR, per 1 SD increase in tibia Pb: 1.37 (0.02, 

2.73); p<0.05*

RR, per 1 SD increased in patella Pb: 0.57

(-0.71, 1.84) 

Elmarsafawy et al. 2006e

Cross-sectional study; n=471

Mean

• Low Ca2+ intake: 6.6

• High Ca2+ intake: 6.6

Hypertension Low Ca2+: OR: 1.07 (1.00, 1.15)*

High Ca2+: OR: 1.03 (0.97, 1.11)

Glenn et al. 2003

Occupational longitudinal study; n=496

Mean: 4.6 SBP β (SE; 95% CI), per 1 SD increased in PbB: 

0.64 (0.25; 0.14, 1.14)*

DBP β (SE; 95% CI); per 1 SD increased in PbB: 

0.09 (0.17; -0.24, 0.43)

Hu et al. 1996ae

Case-control study of men (n=146) with 

hypertension and controls (n=444)

Mean 

• Cases: 6.9

• Controls: 6.1

Hypertension Risk of hypertension based on tibia Pb: 

logistic β (SE): 0.19 (0.0078); p=0.01* 

PbB was not associated with hypertension

OR for 1 μg/g change in tibia Pb: 1.019 

(1.004, 1.035)*

OR for quintile range (8–37 μg/g): 1.5 (1.1, 

1.8)*

Perlstein et al. 2007e

Cross-sectional study; n=593

Mean: 6.12 PP PbB: no trend over quintiles (p=0.82)

Bone Pb: p-trend=0.02*
LEAD 54

2. HEALTH EFFECTS

Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

Proctor et al. 1996e

Cross-sectional study; ≤74 years 

(n=681); >74 years (n=117)

Mean:

• All: 6.5

• ≤74 years: 6.5

• >74 years: 6.3

SBP All β, mmHg per 1 ln μg/dL PbB: 0.85 (-1.1, 

2.7); p>0.05

≤74 β, mmHg per 1 ln μg/dL PbB: 1.2 (-0.86, 

3.2); p>0.05

DBP All β, mmHg per 1 ln μg/dL PbB: 1.2 (0.11, 

2.2); p≤0.05*

≤74 β, mmHg per 1 ln μg/dL PbB: 1.6 (0.42, 

2.7); p≤0.01*

Yang et al. 2018

Cross-sectional study; n=236 Pb 

workers

Gmean (IQR): 4.50 (2.60–

9.15)

SBP Regression (β) coefficients, expressed as 

change pressure (mmHg) per 2-fold increase in 

PbB: 

• Office blood pressure: 0.79 (-0.17, 1.76)

p=0.11

24-hour ambulatory pressure: 0.29 (-0.82, 1.41)

p=0.60

DBP Regression (β) coefficients, expressed as 

change pressure (mmHg) per 2-fold increase in 

PbB: 

• Office: 0.87 (0.03, 1.72) p=0.043*

• 24-hour ambulatory: -0.25 (-0.97, 0.48)

p=0.50

Hypertension OR:

• Office: 0.89 (0.62–1.28); p=0.052

• 24-hour ambulatory: 1.21 (0.94–1.57);

p=0.14

Women onlyc

Al-Saleh et al. 2005

Case-control study of women with 

hypertension (n=100) and control 

subjects (n=85)

Mean

• Hypertension: 4.75

• Controls: 4.56

Hypertension OR for PbB ≥3.85 compared to PbB <3.85: 

5.27 (0.93, 29.86); p=0.06
LEAD 55

2. HEALTH EFFECTS

Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

Korrick et al. 1999

Case-control study of women with 

hypertension (n=89) and control 

subjects (n=195)

Mean (all): 3 Hypertension PbB: no increased risk (ORs not reported)

Patella Pb OR per 1 μg/g increase in PbB: 

1.03 (1.00, 1.05); p=0.02*

Nash et al. 2003

Cross-sectional study; n=2,165 all; 

1,084 premenopausal, and 

663 postmenopausal

Mean (all): 2.9

Quartiles; mean (range) 

• Q1: 1.0 (0.5–1.6)

• Q2: 2.1 (1.7–2.5)

• Q3: 3.2 (2.6–3.9)

• Q4: 6.4 (4.0–31.1)

SBP All β (SE), mmHg per 1 ln μg/dL PbB: 

0.32 (0.16); p=0.03*

Premenopausal β (SE), mmHg per 1 ln μg/dL 

PbB: 0.14 (0.26); p=0.59

Postmenopausal β (SE), mmHg per 1 ln μg/dL 

PbB: 0.42 (0.21); p=0.29

DBP All β (SE): 0.25 (0.09), mmHg per 1 ln μg/dL 

PbB; p=0.009*

Premenopausal β (SE), mmHg per 1 ln μg/dL 

PbB: 0.38 (0.25); p=0.12

Postmenopausal β (SE) mmHg per 1 ln 

μg/dL PbB: 0.14 (0.13); p=0.04*

Hypertension Percent of total population with 

hypertension: p-trend<0.001* (Q1: 19.4; Q2: 

20.6; Q3: 25.5 Q4: 28.3)

Women and men stratified by racec

Den Hond et al. 2002d

Cross-sectional study n=4,685 MW; 

5,138 FW; 1,761 MB; and 2,197 FB

Mean

• MW: 3.6

• FW: 2.1

• MB: 4.2

• FB: 2.3

SBP MW β, per doubling of PbB: 0.3 (-0.2, 0.7); 

p=0.29

FW β, per doubling of PbB: 0.1 (-0.4, 0.5); 

p=0.80

MB β, per doubling of PbB: 0.9 (0.04,1.8); 

p=0.04*

FB β, per doubling of PbB: 1.2 (0.4,2.0); 

p=0.004*

DBP MW β, per doubling of PbB: -0.6 (-0.9, -0.3); 

p=0.0003*
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Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

FW β, per doubling of PbB: -0.2 (-0.5, 0.1); 

p=0.13

MB β, per doubling of PbB: 0.3 (-0.3, 1.0); 

p=0.28

FB β, per doubling of PbB: 0.5 (0.01, 1.1); 

p=0.047*

Muntner et al. 2005d

Cross-sectional study; n=9,961 (men 

and women), stratified by race

(W, B, MA)

Mean: 1.64

Quartiles: 

• Q1: <1.06

• Q2: 1.06–1.63

• Q3: 1.63–2.47

• Q4: ≥2.47

Hypertension W (Q4) OR: 1.10 (0.87, 1.41); p-trend=0.61

B (Q4) OR: 1.44 (0.89, 2.32); p-trend=0.06

MA (Q4) OR: 1.54 (0.99, 2.39); p-trend=0.04*

Park et al. 2009bd

Cross-sectional study; n=12,500 all, 

2,130 MW (<50 years old); 2,152 MW 

(≥50 years old); 1,048 MB (<50 years 

old); 540 MB (≥50 years old); 2,429 FW 

(<50 years old); 2,180 FW (≥50 years 

old); 1,409 FB (<50 years old); and 

612 FB (≥50 years old) 

Mean

• MW (<50 years old) 4.02

• MW (≥50 years old) 4.92

• MB (<50 years old) 4.55

• MB (≥50 years old) 7.57

• FW (<50 years old) 2.09

• FW (≥50 years old) 3.53

• FB (<50 years old) 2.52

• FB (≥50 years old) 4.49

Hypertension MW OR: 1.06 (0.92, 1.22)

FW OR: 1.16 (1.04, 1.29)*

MB OR: 1.17 (0.98, 1.38)

FB OR: 1.19 (1.04, 1.38)*

M (<50 years old) OR: 0.98 (0.80, 1.22) 

M (>50 years old) OR: 1.20 (1.02, 1.41)*

F (<50 years old) OR: 1.23 (1.04, 1.46)* 

F (>50 years old) OR: 1.09 (0.94, 1.26)

Scinicariello et al. 2010d

Cross-sectional study; 

n=6,016 (stratified by race)

Mean

• W 2.87

• B 3.59

• MA 3.33

SBP W β (SE), mmHg per ln μg/dL PbB: 1.05 

(0.37); p=0.01*

B β (SE), mmHg per ln μg/dL PbB: 2.55 

(0.49); p=0.001* 

MA β (SE), mmHg per ln μg/dL PbB: 0.84 

(0.46); p=0.08

DBP W β (SE), mmHg per ln μg/dL PbB: -0.14 

(0.49); p=0.77
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Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

B β (SE), mmHg per ln μg/dL PbB: 1.99 

(0.44); p=0.0002*

MA β (SE), mmHg per ln μg/dL PbB: 0.74 

(0.74); p=0.06

Scinicariello et al. 2011d

Cross-sectional study; n=16,222 all; 

4,538 MW; 4,319 FW; 1,767 MB; 

1,854 FB; 1,925 MMA; and 1,819 FMA

Mean

• All 1.41

• MW 2.20

• FW 1.55

• MB 2.44

• FB 1.81

• MMA 2.47

• FMA 1.56

SBP All β (SE), per ln μg/dL PbB: 1.07 (0.35); 

p<0.05*

MW β (SE), per ln μg/dL PbB: 0.87 (0.53); 

p>0.05

FW β (SE), per ln μg/dL PbB: 0.89 (0.55); 

p>0.05

MB β (SE), per ln μg/dL PbB: 2.30 (0.71); 

p<0.05*

FB β (SE), per ln μg/dL PbB: 2.40 (1.14); 

p<0.05*

MMA β (SE), per ln μg/dL PbB: 0.10 (0.70); 

p>0.05

FMA β (SE), per ln μg/dL PbB: -0.03 (0.64); 

p>0.05

DBP All β (SE): 0.71 (0.27): p<0.05*

MW β (SE): 0.90 (0.45): p<0.05*

FW β (SE): 0.95 (0.38): p<0.05*

MB β (SE): 2.75 (0.82); p<0.05*

FB β (SE), per ln μg/dL PbB: 0.30 (0.81); 

p>0.05

MMA β (SE), per ln μg/dL PbB: -1.34 (0.66); 

p<0.05*

FMA β (SE), per ln μg/dL PbB: -0.74 (0.44); 

p>0.05
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Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

Vupputuri et al. 2003d

Cross-sectional study; n=14,952 total; 

n=5,360 MW; 5,188 FW; 2,104 MB; and 

2,300 FB

Mean

• MW 4.4

• FW 3.0

• MB 5.4

• FB 3.4

SBP MW β, per 1 SD (3.3 μg/dL) increase of PbB: 

0.29 (-0.24, 0.83)

FW β, per 1 SD (3.3 μg/dL) increase of PbB: 

0.34 (-0.49, 1.17)

MB β, per 1 SD (3.3 μg/dL) increase of PbB: 

0.82 (0.19, 1.44); p<0.05*

FB β, per 1 SD (3.3 μg/dL) increase of PbB: 

1.55 (0.47, 2.64); p<0.01*

DBP MW β, per 1 SD (3.3 μg/dL) increase of PbB: 

0.01 (-0.38, 0.40); p≥0.05

FW β, per 1 SD (3.3 μg/dL) increase of 

PbB: -0.04 (-0.56, 0.47) p≥0.05

MB β, per 1 SD (3.3 μg/dL) increase of PbB: 

0.64 (0.08, 1.20); p<0.05*

FB β, per 1 SD (3.3 μg/dL) increase of PbB: 

1.07 (0.37, 1.77); p<0.01*

Hypertension MW OR: 1.04 (0.93, 1.16); p=0.47

FW OR: 1.32 (1.14, 1.52) p<0.001*

MB OR: 1.08 (0.99, 1.19); p=0.08

FB OR: 1.39 (1.21, 1.61); p<0.001*
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Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

Children and young adultsc

Ahn et al. 2018

Cross-sectional study; n=1,776 

adolescents (ages 10–18 years)

Mean (95% CI): 1.192 (1.165, 

1.219)

Quartiles

• Males

o Q1: <1.07

o Q2: 1.07–1.341

o Q3: 1.342–1.655

o Q4: >1.655

• Females

o Q1: <0.839

o Q2: 0.839–1.076

o Q3: 1.077–1.371

o Q4: >1.371

DBP Mean difference with doubling of PbB, 

continuous variable: -0.680 (-1.581, 0.221)

SBP Mean difference with doubling of PbB, 

continuous variable: -0.099 (-1.098, 0.898)

Prehypertension OR, continuous variable: 0.906 (0.629, 1.305)

Gerr et al. 2002

Cross-sectional study; n=508 young 

adults (ages 19–29 years)

PbB mean associated with the 

following bone Pb 

concentrations:

• <1 μg/g: 1.91 (1.58)

• 1–5 μg/g: 2.31 (2.06)

• 6–10 μg/g: 2.43 (2.36)

• >10 μg/g: 3.15 (2.28)

SBP Increase (mmHg) associated with bone Pb 

>10 μg/g (SE): 4.26 (1.48); p=0.004*

DBP Increase (mmHg) associated with bone Pb 

>10 μg/g (SE): 2.80 (1.25); p=0.03*

Gump et al. 2005

Prospective study; n=122 children 

assessed at 9 years of age

Cord PbB mean: 2.97 SBP β (SE), mmHg log μg/dL: 12.16 (4.96); 

p=0.016*

DBP β (SE), mmHg per log μg/dL: 8.45 (4.54); 

p=0.066

Gump et al. 2011

Cross-sectional study; n=140 children 

(ages 9–11 years)

Mean: 1.01 

Quartiles: 

• Q1: 0.14–0.68

• Q2: 0.69–0.93

• Q3: 0.94–1.20

• Q4: 1.21–3.76

SBP Under acute stress, p-trend over quartiles: 0.31

DBP Under acute stress, p-trend over quartiles: 0.29

TPR Under acute stress, p-trend over quartiles: 

0.03*
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Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

Zhang et al. 2011

Prospective longitudinal study; 

n=457 mother-child pairs; children 

evaluated at ages 7–15 years

• Mean umbilical cord: 5.51

• Mean child concurrent:

2.96

• Median maternal postnatal

tibia Pb (μg/g): 9.3

SBP Maternal tibia Pb, boys, β, mmHg increased per 

maternal tibia Pb (13 μg/g): -0.34 (-1.98, 1.30)

Maternal tibia Pb, girls, β mmHg increased 

per maternal tibia Pb (13 μg/g): 2.11 (0.69, 

3.52); p=0.025*

DBP Maternal tibia Pb, boys, β, mmHg increased per 

maternal tibia Pb (13 μg/g): -0.83 (-2.05, 0.38)

Maternal tibia Pb, girls, β, mmHg increased 

per maternal tibia Pb (13 μg/g): 1.60 (0.28, 

2.91); p=0.007*

Blood pressure during pregnancyc

Disha et al. 2019

Cross-sectional study; n=44 healthy 

pregnant women; n=23 pre-eclamptic 

women

PbB:

Mean 

• Control: 2.38

• Pre-eclampsia: 3.42

SBP Pearson correlation (mmHg): 0.71; 

p<0.0001*

DBP Pearson correlation (mmHg): 0.57; p=0.004*

Rothenberg et al. 2002

Longitudinal study; n=667 pregnant 

women

Mean: 1.9

Bone (calcaneus) Pb (μg/g) 

mean:10.7

SBP Ln-PbB, β: -0.04 (-1.26, 1.18) 

Bone Pb, β: 0.70 (0.04, 1.36)*

DBP Ln-PbB, β: 0.20 (-0.78, 1.18)

Bone Pb, β: 0.54 (0.01, 1.08)*

Wells et al. 2011

Cross-sectional study; n=285 pregnant 

women during labor

Umbilical cord PbB

• mean: 0.66

• Quartiles:

o Q1: <0.46

o Q2: 0.47–0.65

o Q3: 0.66–0.95

o Q4: 0.96–6.47

SBP Q4 versus Q1 increase in SBP in mmHg at 

admission: 6.87 (1.51, 12.21); p<0.05*

Q4 versus Q4 maximum increase in SBP in 

mmHg: 7.72 (1.83, 13.60); p<0.05*

DBP Q4 versus Q1 increase in DBP in mmHg at 

admission: 4.40 (0.21, 8.59); p<0.05*

Q4 versus Q4 maximum increase in DBP in 

mmHg: Q4: 8.33 (1.14, 15.53); p<0.05*
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Table 2-8. Summary of Epidemiological Studies Evaluating Effects on Blood Pressure at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dL

Reference and study population PbB (μg/dL) Outcome evaluated Resulta,b

Yazbeck et al. 2009

Cross-sectional study; n=971 pregnant 

women

Mean 

• Participants with PIH: 2.2

• Participants without PIH:

1.9

PIH OR for PIH for an increase of 1 log10 μg/dL 

in PbB; 3.29 (1.11, 9.74); p=0.03*

aAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the table. bIf bone Pb is noted under results, study did not show associations between PbB and blood pressure parameters; however, results showed associations between 

bone Pb concentrations and increased blood pressure at concomitant PbB ≤10 μg/dL.

cSee the Supporting Document for Epidemiological Studies for Lead, Table 3 for more detailed descriptions of studies. dStudy population was from NHANES.

eStudy population was from the Normative Aging Study.

B = black; CI = confidence interval; CL = confidence limit; DBP = diastolic blood pressure; F = female(s); Gmean = geometric mean; M = male(s); MA = Mexican 

American; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; Pb = lead; PIH = pregnancy-induced hypertension; PP = pulse 

pressure; RR = rate ratio; SBP = systolic blood pressure; SD = standard deviation; SE = standard error; TPR = total peripheral resistance; W = white
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in Table 2-8, with additional details provided in the Supporting Document for Epidemiological Studies for 

Lead, Table 3.

The magnitude of effect on blood pressure observed in individual large-scale, cross-sectional studies is 

consistent with results of meta-analyses (see discussion above on Characterization of Effects). For 

example, Martin et al. (2006) reported that systolic and diastolic blood pressure increased by 0.99 (95% 

CI 0.47, 1.51; p<0.01) mmHg and 0.51 (95% CI 0.24, 0.79; p<0.01) mmHg, respectively, per 1 μg/dL 

increase in PbB. 

Several studies have examined the relationship between PbB and blood pressure with study populations 

stratified according to gender, race, and/or age. For example, within study populations, positive 

associations were observed between PbB and systolic and diastolic blood pressure in men but not in 

women (Bushnik et al. 2014; Chu et al. 1999; Hense et al. 1993). A cross-sectional study reported an 

increased risk of prehypertension (defined as a diastolic blood pressure of at least 80 mmHg but below 

90 mmHg or a systolic blood pressure of at least 120 mmHg but below 140 mmHg) in women but not in 

men, although PbB was lower (p<0.05) in women (1.9 μg/dL) than men (2.4 μg/dL) (Lee et al. 2016a). 

However, other studies did not find differences between men and women (Bost et al. 1999; Scinicariello 

et al. 2011). Stratification by sex and age indicates additional differences between men and women. For 

example, Park et al. (2009b) reported a greater risk of hypertension in men >50 years of age (odds ratio 

[OR] 1.20; 95% CI 1.02, 1.41), but not in men <50 years of age (OR 0.98; 95% CI 0.80, 1.22), whereas in 

women, the opposite effect of age was observed, with a greater risk of hypertension in women <50 years 

of age (OR 1.23; 95% CI 1.04, 1.46) but not >50 years of age (OR 1.09; 95% CI 0.94, 1.26). Studies that 

stratify populations by race have found race differences in effect sizes on blood pressure. Large-scale 

cross-sectional studies based on data from NHANES have found larger effect sizes in non-Hispanic 

blacks and Mexican-Americans than in whites (Den Hond et al. 2002; Muntner et al. 2005; Scinicariello 

et al. 2011; Vupputuri et al. 2003). Cross-sectional studies based on data from NHANES have 

consistently shown elevations of systolic blood pressure in association with increasing PbB among black 

males and females, with less consistency in findings for other demographic groups or for diastolic blood 

pressure (Den Hond et al. 2002; Nash et al. 2003; Scinicariello et al. 2010, 2011; Vupputuri et al. 2003). 

Scinicariello et al. (2011) estimated increases in systolic blood pressure ranging from 1.07 to 2.4 per 1 ln 

increase in PbB (equivalent to approximately 0.7–1.66 per doubling of PbB). The largest effects sizes 

were observed in black males (2.3; SE 0.71 per ln PbB) and black females (2.4; SE 1.14). Den Hond et 

al. (2002) estimated the effect size for systolic blood pressure in black males and females to be 0.9 mmHg 

(95% CI 0.04, 1.8) and 1.2 mmHg (95% CI 0.4, 2.0) per doubling of PbB, respectively. Vupputuri et al. 
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2. HEALTH EFFECTS

(2003) estimated the effect size for systolic blood pressure in black males and females to be 0.82 mmHg 

(95% CI 0.19, 1.44) and 1.55 mmHg (95% CI 0.47, 2.64) per 1 standard deviation (SD) increase 

(3.3 μg/dL) of PbB, respectively. As discussed above (see Confounding Factors and Effect Modifiers), 

numerous co-variables and confounders affect studies of associations between PbB and blood pressure, 

complicating comparisons between studies. 

Few studies have evaluated effects of chronic Pb exposure in children or young adults on blood pressure 

parameters at PbB at ≤10 μg/dL (Ahn et al. 2018; Gerr et al. 2002; Gump et al. 2005, 2011; Zhang et al. 

2011). Studies are briefly summarized in Table 2-8, with additional details provided in the Supporting 

Document for Epidemiological Studies for Lead, Table 3. Population sizes in these studies are small 

(n=122–1,776) compared to studies in adults. Positive associations were observed between concurrent 

PbB and increased systolic and diastolic blood pressure in young adults (Gerr et al. 2002). Two 

prospective studies suggest that prenatal exposure to Pb is associated with increased blood pressure in 

childhood (Gump et al. 2005; Zhang et al. 2011). Umbilical cord PbB was positively associated with 

increased systolic, but not diastolic, blood pressure in children (Gump et al. 2005). Maternal postnatal 

bone Pb concentration was associated with increased systolic and diastolic blood pressure in girls, but not 

boys; however, no association was observed between umbilical cord PbB or patella Pb concentration and 

increased blood pressure (Zhang et al. 2011). No association between PbB and diastolic or systolic blood 

pressure or risk of prehypertension in a larger population of adolescents (n=1,776) with a mean PbB of 

1.19 μg/dL (Ahn et al. 2018).

Effects of Pb on blood pressure and hypertension at PbB at ≤10 μg/dL have also been evaluated during 

pregnancy (Disha et al. 2019; Rothenberg et al. 2002; Wells et al. 2011; Yazbeck et al. 2009). Studies are 

briefly summarized in Table 2-8, with additional details provided in the Supporting Document for 

Epidemiological Studies for Lead, Table 3. Increases in systolic and diastolic blood pressure during 

pregnancy and labor were associated with PbB ≤10 μg/dL umbilical cord PbB, or bone Pb concentrations 

with concomitant PbB ≤10 μg/dL (Rothenberg et al. 2002; Wells et al. 2011; Yazbeck et al. 2009). 

Pregnancy-induced hypertension has been positively associated with PbB ≤10 μg/dL (Yazbeck et al. 

2009). A small cross-sectional study reported a positive association between PbB and increased systolic 

and diastolic blood pressure in women with pre-eclampsia (Disha et al. 2019). 

Atherosclerosis. Few studies have evaluated associations between PbB ≤10 μg/dL and atherosclerosis 

(Ari et al. 2011; Muntner et al. 2005; Navas-Acien et al. 2004). Studies are briefly summarized in 

Table 2-9, with additional details provided in the Supporting Document for Epidemiological Studies for 
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Lead, Table 3. Ari et al. (2011) reported a positive correlation between PbB and intimal medial 

thickening of the greater carotid artery in non-diabetic hemodialysis patients at a concurrent PbB of 

0.41 μg/dL. Peripheral artery disease was positively associated with PbB levels ≥2.47 μg/dL, with a 

positive trend across quartiles, in a study of a large NHANES 1999–2002 (age 18 years or older) 

population (Muntner et al. 2005), whereas analyses restricted to adult (≥40 years old) participants of 

NHANES 1999–2000 reported a positive trend for the risk of peripheral artery disease, although ORs for 

PbB quartiles (highest PbB quartile >2.90 μg/dL) were not associated with peripheral artery disease 

(Navas-Acien et al. 2004). 

Cardiac function and heart disease. Several studies have investigated cardiac function and heart disease, 

including a series of studies conducted in men from the Normative Aging Study in the greater Boston, 

Massachusetts area that evaluated associations between PbB ≤10 μg/dL and alterations in cardiac 

conduction and ischemic heart disease (Cheng et al. 1998; Eum et al. 2011; Jain et al. 2007; Park et al. 

2009a). Studies are briefly summarized in Table 2-10, with additional details provided in the Supporting 

Document for Epidemiological Studies for Lead, Table 2. Studies on the Normative Aging Study 

population show positive associations between bone Pb concentrations (at concomitant PbB ≤10 μg/dL) 

and changes to electrocardiograms (prolonged QT and QRS intervals) and atrioventricular conduction 

defect; however, no associations were observed between PbB and conduction abnormalities (Cheng et al. 

1998; Eum et al. 2011; Park et al. 2009a). For ischemic heart disease, increased risks were associated 

with PbB and with tibia and patella Pb concentrations (Jain et al. 2007). A 1 SD increase in PbB was 

associated with a 1.27-fold increase in risk for ischemic heart disease (Jain et al. 2007). In addition to the 

evaluations of the Normative Aging Study population, a large cross-sectional study of 2,163 men and

3,185 women found an increased risk of cardiovascular disease (including coronary artery disease, 

myocardial infarction, and stroke) for women in the two highest exposure PbB quartiles (Q3: 3.77–

5.460 μg/dL; Q4: ≥5.461 μg/dL), although risk was not increased for men in any PbB quartile (Q4: 

≥6.25 μg/dL) (Chen et al. 2017). Other studies have evaluated left ventricular function and structure, 

heart rate variability, and QRS-T wave angle (Jing et al. 2019l Yang et al. 2017; Yu et al. 2019a). A 

small (n=179) prospective study in adults with a mean PbB of 4.18 μg/dL showed an inverse association 

between PbB and left ventricular systolic function, but not left ventricular diastolic function or left 

ventricular structure (Yang et al. 2017). Results of a small (n=328) cross-sectional study in newly hired 

male Pb workers did not observe an association between PbB (mean 4.54 μg/dL) and heart rate variability 

(Yu et al. 2019a). A large (n=7,179) study of NHANES III participants showed that PbB was associated 
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Table 2-9. Summary of Epidemiological Studies Evaluating Atherosclerosis at Mean Blood Lead Concentration 

(PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Ari et al. 2011

Clinical study; n=50 adult male and 

female hemodialysis patients and 

48 age- and sex-matched controls

Mean

• Hemodialysis patients:

0.41

• Controls: 0.10

Greater carotid artery 

intima-media thickness

β (SE), mm per μg/dL PbB: 0.101 (0.040); 

p=0.013*

Muntner et al. 2005c

Cross-sectional study; 

n=9,961participants

Mean: 1.64 

Quartiles: 

• Q1: <1.06

• Q2: 1.06–1.63

• Q3: 1.63–2.47

• Q4: ≥2.47

PAD OR for prevalence in Q4: 1.92 (1.02–3.61)* 

p-trend (across quartiles): <0.001*

Navas-Acien et al. 2004c

Cross-sectional study; 

n=2,125 participants

Mean: 2.07 

Quartiles:

• Q1: <1.45

• Q2: 1.45–2.07

• Q3: 2.07–2.90

• Q4: >2.90

PAD OR for prevalence in Q4: 2.88 (0.87, 9.47)

p-trend (across quartiles) for risk: 0.02*

aSee the Supporting Document for Epidemiological Studies for Lead, Table 3 for more detailed descriptions of studies. bAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs cStudy population was from NHANES.

CI = confidence interval; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; PAD = peripheral artery disease; pb = lead; 

SE = standard error
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Table 2-10. Summary of Epidemiological Studies Evaluating Heart Disease at Mean Blood Lead Concentration 

(PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb,c

Chen et al. 2017

Cross-sectional study; 

n=5,348 adults (men: 2,163; women: 

3,185) aged ≥18 years 

Quartiles: 

• Men

o Q1: ≤2.900

o Q2: 2.901–4.400

o Q3: 4.401–6.248

o Q4: ≥6.249

• Women

o Q1: ≤2.50

o Q2: 2.501–3.770

o Q3:3.771–5.460

o Q4: ≥5.461

Cardiovascular 

disease

ORs:

Men, Q4: 1.01 (0.58, 1.78); p-trend: 0.59

Women, Q3: 1.65 (1.03, 2.66)*

Women, Q4, 1.93 (1.22, 3.04); p-trend: <0.01*

Cheng et al. 1998d

Longitudinal study; n=775 men 

(n=277 for men <65 years of age)

PbB mean: 5.8

Bone Pb, μg/g, mean (SD)

• Tibia: 22.2 (13.4)

• Patella: 30.8 (19.2)

QT interval β, msec per 10-fold increase in PbB: -0.65

(-10.40, 9.10); p=0.90

β, msec per 10-fold increase in tibia Pb: 

5.03 (0.83, 9.22); p=0.02*

β, msec per 10-fold increase in patella Pb: 3.00 

(0.16, 5.84); p=0.04*

QRS interval β, msec per 1 unit increase in PbB: -3.49 (-10.72, 

3.75); p=0.35

β, msec per 1-fold increase in tibia Pb: 

4.83 (1.83, 7.83); p<0.01*

β, msec per 1-fold increase in patella Pb: 

2.23 (0.10, 4.36); p=0.04*

IVCD OR for a 10-fold increase in tibia Pb: 2.23 (1.28, 

3.90); p<0.01*
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Table 2-10. Summary of Epidemiological Studies Evaluating Heart Disease at Mean Blood Lead Concentration 

(PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb,c

Eum et al. 2011d

Prospective longitudinal study; 

n=600 men

PbB baseline mean: 5.8

PbB Tertiles:

• T1: <4

• T2: 4–6

• T3: >6

Tibia Pb (μg/g) baseline mean:

21.6

Tertiles:

• T1: <16

• T2: 16–23

• T3: >23

QT interval PbB OR for T3: 1.31 (0.69, 2.48); p-trend: 0.41

Tibia OR for T3: 2.53 (1.22, 5.25)*; p-trend: 

0.003*

Atrioventricular 

conduction defect

PbB OR for T3: 0.52 (0.19, 1.45); p-trend: 0.16

Tibia OR for T3: 0.23 (0.06, 0.87); p-trend: 0.03

Jain et al. 2007d

Longitudinal prospective study; 

n=837 men

PbB baseline mean

• Non-cases 6.2

• Cases 7.0

Patella Pb (μg/g) baseline mean

• Non-cases 30.6

• Cases 36.8

Ischemic heart 

disease

PbB β per 1 SD increase in PbB: 1.27 (1.01, 

1.59)*

PbB HR per 1 log increased in PbB: 1.45 (1.01, 

2.06); p=0.05*

Patella Pb HR per 1 log increased in bone Pb: 

2.64 (1.09, 6.37); p=0.05*

Park et al. 2009ad

Longitudinal prospective study; 

n=613 men

• PbB median (IQR): 5 (4–7)

• Patella Pb (μg/dL), median

(IQR): 26 (18–37)

• Tibia Pb (μg/dL), median

(IQR): 19 (14–27)

QT interval PbB β for msec increase per IQR: 1.3 (-0.76, 

3.36)

Patella β for msec increase per IQR: 2.64 (0.13, 

5.15)*

Tibia β for msec increase per IQR: 2.85 (0.29, 

5.40)*

Yang et al. 2017

Prospective study; n=179 adults 

(50.3% women); follow-up period 

11.9 years

PbB baseline Gmean: 4.19 Left ventricular 

systolic function

β, per doubling of PbB for ejection fraction (%): 

0.150 (-1.019, 1.320); p=0.800

β, per doubling of PbB for global longitudinal 

strain (%): -0.392 (-0.753, -0.030); p=0.034*

β, per doubling of PbB for regional 

longitudinal strain (%): -0.618 (-1.167, -0.068); 

p=0.028*
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Table 2-10. Summary of Epidemiological Studies Evaluating Heart Disease at Mean Blood Lead Concentration 

(PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb,c

β, per doubling of PbB for regional 

longitudinal strain rate (per second): -0.056 

(-0.097, -0.015); p=0.008*

β, per doubling of PbB for regional radial strain 

(%): -1.825 (-3.740, 0.090); p=0.062

β, per doubling of PbB for regional radial 

strain rate (per second): -0.113 

(-0.226, -0.0002); p=0.050*

Left ventricular 

structure

β, per doubling of PbB for left ventricular mass 

(g/m2): -1.399 (-4.504, 1.707); p=0.375

β, per doubling of PbB for end-diastolic diameter 

(cm): -0.064 (-0.134, 0.006); p=0.072

β, per doubling of PbB for relative wall thickness: 

0.0065 (-0.0031, 0.0162); p=0.185

Yu et al. 2019a

Cross-sectional study; n=328 newly 

hired male Pb workers

Mean: 4.54 Heart rate variability Regression (β) coefficients (95% CI) per 10-fold 

increase in PbB:

• Supine position: 3.0 (-20.4, 33.0); p=0.82

• Standing position: -6.0 (-26.2, 19.7); p=0.61

• Orthostatic change: -8.8 (-31.8, 17.5); p=0.47

aSee the Supporting Document for Epidemiological Studies for Lead, Table 3 for more detailed descriptions of studies. bAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

c

If bone Pb is noted under results, study did not show associations between PbB and blood pressure parameters; however, results showed associations between 

bone Pb concentrations and increased blood pressure at concomitant PbB ≤10 μg/dL.

dStudy population was from the Normative Aging Study.

CI = confidence interval; Gmean = geometric mean; HR = hazard ratio; IQR = intraquartile range; IVCD = intraventricular conduction defect; OR = odds ratio; 

Pb = lead; SD = standard deviation
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with an abnormal QRS-T wave angle in men (mean PbB: 4.10 μg/dL), but not in women (mean PbB: 

2.93 μg/dL) (Jing et al. 2019). 

Mortality due to cardiovascular disease. Mortality due to cardiovascular disease at PbB ≤10 μg/dL has 

been examined in large prospective and longitudinal studies, which provide mixed results. Studies are 

briefly summarized in Table 2-11, with additional details provided in the Supporting Document for 

Epidemiological Studies for Lead, Table 3. Three of these were conducted in large studies of men and 

women participating in NHANES (Aoki et al. 2016; Lanphear et al. 2018; Menke et al. 2006; Schober et 

al. 2006). Aoki et al. (2016), Lanphear et al. (2018), and Menke et al. (2006) observed positive 

associations of mortality due to cardiovascular disease, including ischemic heart disease, myocardial 

infarction, and stroke and at PbB ≤10 μg/dL, including positive trends for mortality with increasing PbB. 

In contrast, Schober et al. (2006) did not find increased cardiovascular mortality risk at PbB <10 μg/dL, 

although risk was increased at PbB ≥10 μg/dL and a positive trend for mortality was observed with 

increasing PbB. For PbB, no increased risk or positive trend for morality due to cardiovascular was 

observed in men from the Normative Aging Study (Weisskopf et al. 2009). In women, the risk of 

mortality due to coronary heart disease was increased at PbB ≥8 μg/dL compared to PbB <8 μg/dL 

(Khalil et al. 2009).

Associations Between Bone Pb and Cardiovascular Effects. Several studies have evaluated associations 

between bone Pb concentration and blood pressure and cardiac outcomes. Results provide evidence that 

long-term exposure to Pb produces adverse effects on the cardiovascular system. 

Increased blood pressure and hypertension. Numerous studies show associations between bone Pb 

concentration and increased blood pressure and increased risk of hypertension (see Table 2-12). The most 

studied population is older men participating in the Normative Aging Study. Results consistently show 

positive associations between tibia Pb and systolic blood pressure (Cheng et al. 2001), pulse pressure 

(Jhun et al. 2015; Perlstein et al. 2007; Zhang et al. 2010), and risk of hypertension (Cheng et al. 2001; 

Elmarsafawy et al. 2006; Hu et al. 1996a; Peters et al. 2007). The association between bone Pb and 

elevated pulse pressure suggests that Pb may alter cardiovascular function through loss of arterial 

elasticity (Jhun et al. 2015; Perlstein et al. 2007; Zhang et al. 2010). Associations between patella Pb and 

blood pressure outcomes have been somewhat less consistent, with some studies showing positive 

associations (Hu et al. 1997; Jhun et al. 2015; Perlstein et al. 2007; Peters et al. 2007; Zhang et al. 2010) 

and other studies showing no associations (Cheng et al. 2001; Elmarsafawy et al. 2006). Other study 
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Table 2-11. Summary of Epidemiological Studies Evaluating Mortality due to Cardiovascular Disease at Mean 

Blood Lead Concentrations (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Aoki et al. 2016c

Prospective study; n=18,602

Mean: 1.73 Mortality due to 

cardiovascular disease

RR, per 10-fold increase in PbB: 1.44 (1.05, 

1.98)*

Khalil et al. 2009

Prospective study; n=533 women

Mean: 5.3 Mortality due to coronary heart 

disease

PbB ≥8.0 compared to women with PbB <8.0. 

HR: 3.08 (1.23, 7.70); p=0.016*

Menke et al. 2006c

Longitudinal study; n=13,946

Baseline mean: 2.58

Tertiles:

• T1: <1.93

• T2: 1.94–3.62

• T3: ≥3.63

Mortality due to cardiovascular 

disease

HR for T3 versus T1: 1.55 (1.08, 2.24)*; 

p-trend: 0.003*

Mortality due to myocardial 

infarction

HR for T3 versus T1: 1.89 (1.04, 3.43)*; 

p-trend: 0.007*

Mortality due to stroke HR for T3 versus T1: 2.51 (1.20, 5.26)*; 

p-trend: 0.017*

RR for T3 versus T1: 1.55 (1.16, 2.07)*; 

p-trend: <0.01*

Lanphear et al. 2018c

Longitudinal study; n=14,289

Mean: 2.71 Mortality due to cardiovascular 

disease

HR for PbB increase from 1.0 to 6.7 μg/dL: 

1.70 (1.30, 2.22)*

Mortality due to ischemic heart 

disease

HR for PbB increase from 1.0 to 6.7 μg/dL: 

2.08 (1.52, 2.85)*

Weisskopf et al. 2009d

Longitudinal study; n=868 men

Mean: 5.6 

Tertiles 

• T1: <4

• T2: 4–6

• T3: >6

Mortality due to cardiovascular 

disease

HR for T3 versus T1: 1.10 (0.67, 1.80); p-trend: 

0.72

aSee the Supporting Document for Epidemiological Studies for Lead, Table 3 for more detailed descriptions of studies. bAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

cStudy population was from NHANES.

dStudy population was from the Normative Aging Study.

CI = confidence interval; HR = hazard ratio; NHANES = National Health and Nutrition Examination Survey; Pb = lead; RR = risk ratio
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populations examined include adults (Martin et al. 2006), young adults (Gerr et al. 2002), current and 

former Pb workers (Glenn et al. 2003; Lee et al. 2001), women (Korrick et al. 1999), pregnant women 

(Rothenberg et al. 2002), and mother-child pairs (Zhang et al. 2011). Although study results are not 

consistent, positive associations between bone Pb and blood pressure and risk of hypertension have been 

reported. Navas-Acien et al. (2008) conducted a meta-analysis of 10 studies (see Table 2-12 for studies 

included in the analysis) to evaluate associations between tibia and patella Pb and blood pressure 

outcomes. Positive associations were observed between tibia Pb and systolic blood pressure and 

hypertension risk, but no associations were observed between tibia Pb and diastolic blood pressure or 

between patella Pb and systolic blood pressure, diastolic blood pressure, or hypertension risk. 

Table 2-12. Associations Between Bone Pb and Blood Pressure Outcomes

Reference Population

Blood pressure outcome

Systolic 

blood 

pressure

Diastolic 

blood 

pressure

Pulse 

pressure Hypertension

Cheng et al. 

2001a

833 menb ↑ T

0 P

– – ↑ T

0 P

Elmarsafawy 

et al. 2006

471 menb – – – ↑ T (at low dietary 

calcium)

0 P (at high dietary 

calcium)

Gerr et al. 

2002a

508 young adultsc ↑ T ↑ T – –

Glenn et al. 

2003a

496 male Pb workersd ↑ T

↑ P

0 T

0 P

– –

Glenn et al. 

2006a

575 adult Pb workerse ↓ T 0 T – –

Hu et al. 

1996aa

590 – – – ↑ T

↑ P

Jhun et al. 

2015

727 menb – – ↑ T

↑ P

–

Korrick et al. 

1999a

689 women (214 

cases; 475 controls)f

– – – 0 T

↑ P

Lee et al. 

2001a

924 adult Pb workers 

(789 cases; 

135 controlse

↑ T 0 T – ↑ T

Martin et al. 

2006a

964 adults 0 T 0 T – ↑ T

Perlstein et 

al. 2007

593 menb – – ↑ T

↑ P

–
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Table 2-12. Associations Between Bone Pb and Blood Pressure Outcomes

Reference Population

Blood pressure outcome

Systolic 

blood 

pressure

Diastolic 

blood 

pressure

Pulse 

pressure Hypertension

Peters et al. 

2007

512 menb – – – ↑ T (with high stress)

↑ P (with high stress)

Rothenberg 

et al. 2002a

1,006 pregnant women – – – ↑ C (3rd trimester)

0 T (3rd trimester)

Schwartz et 

al. 2000ca

543 male Pb workersd 0 T 0 T – 0 T

Weaver et al. 

2008

652 Pb workerse 0 P 0 P – 0 P

Zhang et al. 

2010

612 menb – – ↑ T

↑ P

–

Zhang et al. 

2011

457 mother-child pairsg ↑ T (girls)

0 T (boys)

↑ T (girls)

0 T (boys)

– –

aIncluded in the Navas-Acien et al. (2008) meta-analysis. bParticipants in the Normative Aging Study. 

c19–29 years of age. dCurrent and former Pb workers in the United States.

eCurrent and former Pb workers in South Korea. 

f

Nurses Health Study.

gBased on maternal bone Pb measurement.

↑ = positive association; ↓ = inverse association; 0 = no association; – = not reported; C = calcaneus bone; 

P = patella; Pb = lead; T = tibia

Cardiac function. Several studies evaluating associations between bone Pb and cardiac function, disease, 

and mortality were conducted in participants of the Normative Aging Study (see Table 2-13). For tibia 

Pb, positive associations have been observed for QT and QRS intervals (Cheng et al. 1998; Eum et al. 

2011; Park et al. 2009a), atrioventricular and intraventricular block (Cheng et al. 1998), and ischemic 

heart disease (Jain et al. 2007). For patella Pb, positive associations were observed for QT and QRS 

intervals (Cheng et al. 1998; Park et al. 2009a). Both tibia Pb and patella Pb were positively associated 

with ischemic heart disease (Jain et al. 2007), and patella and tibia Pb were associated with an increased 

risk of coronary heart disease (Ding et al. 2016, 2019). However, no association was observed between 

tibia or patella Pb and all cardiovascular mortality or mortality due to ischemic heart disease (Weisskopf 

et al. 2009). 
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Table 2-13. Associations Between Bone Pb and Cardiac Function, Disease, and 

Mortality

Reference Population

Outcome

Function Disease Mortality

Cheng et al. 

1998

775 mena ↑ T (QT and QRS 

intervals;

AV block; IV block)

↑ P (QT and QRS 

intervals)

0 P (AV block; IV block)

– –

Ding et al. 2016 589 mena – ↑ P (CHD) –

Ding et al. 2019 594 mena – ↑ T (CHD)

↑ P (CHD)

–

Eum et al. 2011 600 mena ↑ T (QT and QRS 

intervals)

0 P (QT and QRS 

intervals)

– –

Jain et al. 2007 837 mena – ↑ T (IHD)

↑ P (IHD)

–

Park et al. 2006 413 mena 0 T (HRV with MetS)

0 T (HRV without MetS)

↑ P (HRV with MetS)

0 P (HRV without MetS)

– –

Park et al. 

2009a

613 mena ↑ T (QT interval)

↑ P (QT interval)

– –

Weisskopf et al. 

2009

868 mena – – 0 T (all cardiovascular or IHD 

deaths)

0 P (all cardiovascular or IHD 

deaths)

aParticipants in the Normative Aging Study.

↑ = positive association; ↓ = inverse association; 0 = no association; – = not reported; AV = atrioventricular; 

CHD = coronary heart disease; HRV = heart rate variability; IHD = ischemic heart disease (defined as myocardial 

infarction or angina pectoris); IV = intraventricular; MetS = metabolic syndrome (three or more of the following: 

obesity, diabetes, hypertension, and dyslipidemia); P = patella; Pb = lead; T = tibia 

Mechanisms of Action. Several studies and recent reviews include discussions of mechanisms that may 

be involved in Pb-induced effects on cardiovascular function (Faramawai et al. 2015; Ghiasvand et al. 

2013; Mitra et al. 2017; Nawrot et al. 2002; Shiue et al. 2014; Weisskopf et al. 2009; Xu et al. 2015; Zota 

et al. 2013). Control of cardiovascular function is multi-factorial; therefore, numerous mechanisms are 

likely involved in Pb-induced cardiovascular effects. Specific mechanisms for cardiovascular effects 

include: impairment of renal function; effects on vascular smooth muscle, including constrictive effects 

and disruption of NO-induced vasodilatory actions; increase of sympathetic nervous system activity; 
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altered chemoreceptor activity; and altered regulation of the renin-angiotensin-aldosterone axis and the 

renal kallikrein system. In addition, general mechanisms of toxicity of Pb, including oxidative stress, 

inflammation, and altered transport of ions across cellular membranes, also are likely to be involved (see 

Section 2.21).

2.7 GASTROINTESTINAL

Overview. Few epidemiological studies have evaluated gastrointestinal effects associated with chronic 

exposure to Pb. Almost all available studies were conducted in small numbers of workers with PbB 

>10 μg/dL, although one study included a group of workers with PbB ≤10 μg/dL. Study results 

consistently show gastrointestinal symptoms (abdominal colic/pain, nausea, vomiting, diarrhea, and/or 

constipation) associated with PbB ranging from 8.04 μg/dL to approximately 100 μg/dL. As reviewed in 

Section 2.2 (Acute Lead Toxicity), acute exposure to Pb is associated with gastrointestinal symptoms and 

intestinal paralysis.

The following gastrointestinal effects have been associated with PbB:

• ≤10 μg/dL:

o Gastrointestinal symptoms (abdominal colic/discomfort).

• >10 μg/dL: 

o Gastrointestinal symptoms (abdominal colic/pain, nausea, vomiting, diarrhea and/or 

constipation); corroborated in a few studies.

Measures of Exposure. Studies examining the association between gastrointestinal effects of Pb 

exposure evaluate exposure by measurement of PbB.

Confounding Factors and Effect Modifiers. Most epidemiological studies on gastrointestinal effects of 

Pb are survey or cross-sectional studies of small populations of workers. In general, studies did not 

consider factors, such as age, diet, nutritional factors, alcohol use, and potential exposure to other 

occupational chemicals or limitations such as study design (cross-sectional and survey). Failure to 

account for these factors may attenuate or strengthen the apparent associations between Pb exposure and 

the outcome, depending on the direction of the effect of the variable on the outcome.
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Characterization of Effects. In contrast to the large number of epidemiological studies evaluating effects 

of Pb on other organ systems (e.g., neurological and cardiovascular outcomes), few epidemiological 

studies have investigated the gastrointestinal effects of chronic exposure to Pb (see Table 2-14). With the 

exception of a survey study conducted in 497 workers (Rosenman et al. 2003), studies were conducted in 

small worker populations (n=69–155). Increased gastrointestinal symptoms (abdominal colic/pain, 

nausea, vomiting, diarrhea, and/or constipation) were observed in all studies. The lowest PbB associated 

with increased gastrointestinal symptoms showed an increased percentage of workers reporting 

abdominal colic and discomfort at a mean PbB of 8.04 μg/dL, compared to controls (PbB 5.76 μg/dL) 

(Kuruvilla et al. 2006). For example, 18.9% of painters reported abdominal colic compared to 0 in the 

control group.

Effect at Blood Pb Levels ≤10 μg/dL. See discussion above on Kuruvilla et al. (2006).

Mechanisms of Action. General mechanisms of toxicity of Pb (reviewed in Section 2.21) are likely 

involved in the development of gastrointestinal toxicity. EPA (2014c) specifically noted that oxidative 

stress through ROS could result in gastrointestinal toxicity; as a result, damage to the intestinal mucosa 

epithelium is possible. 

2.8 HEMATOLOGICAL

Overview. Pb-induced toxicity to the hematological system has long been established. Pb inhibits heme 

synthesis, leading to the development of microcytic, hypochromic anemia. Numerous epidemiological 

studies have evaluated hematological effects associated with exposure to Pb in adults and children. Most 

studies were cross-sectional in design and evaluated effects on heme synthesis and subsequent changes in 

erythrocyte hemoglobin parameters and anemia. Studies in adults (general populations and workers) and 

children consistently show inhibition of heme synthesis enzymes, particularly δ-ALAD, and subsequent 

decreases in blood hemoglobin, red blood cell parameters (e.g., mean cell hemoglobin, mean cell 

volume), and development of anemia. Other hematological effects observed in epidemiological studies 

include alterations in erythrocyte function (decreased activities of pyrimidine 5’-nucleotidase and 

membrane Ca2+/Mg2+ATPase), changes in serum EPO concentration, and decreased platelet count.
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Table 2-14. Summary of Studies Evaluating Gastrointestinal Symptoms Associated with Chronic Exposure to 

Lead (Pb)

Reference and study population PbB (μg/dL) Outcomes evaluateda Effectsb

Awad el Karin et al. 1986

Cross-sectional study; n=92 

exposed; 40 controls

Range of means (by job 

category): 48.1–80.7

Controls mean: 21.2 

Abdominal colic • Exposed (% reporting symptom) 41.3;

exposed versus control p=0.01*

• Control (% reporting symptom): 7.5 

Constipation • Exposed (% reporting symptom) 41.4;

exposed versus control p=0.01*

• Control (% reporting symptom): 10.0

Baker et al. 1979

Survey study; n=160 Pb workers

Range of means (by job 

category): 41.8–87.2

Gastrointestinal 

symptoms

• Mean PbB at which symptoms are present: 

101.24 μg/dL (p<0.01)*

• PbB, symptom absent: 65.98 μg/dL

Abdominal pain • PbB, symptoms present: 100.77 μg/dL 

(p<0.01)*

• PbB, symptom absent: 68.25 μg/dL

Kuruvilla et al. 2006

Cross-sectional study; n=155; 

exposed workers: n=105 (52 battery 

workers; 53 painters); controls: n=50 

Mean

• Battery workers:42.40

• Painters: 8.04

• Controls: 5.76

Abdominal colic • Battery workers (% reporting symptom): 

17.3; p<0.01*

• Painters (% reporting symptom):18.9; 

p<0.01*

• Controls (% reporting symptom): 0

Abdominal discomfort • Battery workers (% reporting symptom): 

19.2; p<0.01*

• Painters (% reporting symptom): 26.4; 

p<0.001* 

• Controls (% reporting symptom): 2

Vomiting • Battery workers (% reporting symptom): 1.9

• Painters (% reporting symptom): 1.9

• Controls (% reporting symptom): 0

Constipation • Battery workers (% reporting symptom): 0

• Painters (% reporting symptom): 1.9

• Controls (% reporting symptom): 2
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Table 2-14. Summary of Studies Evaluating Gastrointestinal Symptoms Associated with Chronic Exposure to 

Lead (Pb)

Reference and study population PbB (μg/dL) Outcomes evaluateda Effectsb

Matte et al. 1989

Survey study; n=69 

(46 manufacturing and 23 battery 

repair workers)

• Mean: not reported

• Workers stratified by PbB

<60 and ≥60

Nausea • PbB <60 (% reporting symptom): 7

• PbB ≥60 (% reporting symptom): 14

• PR (95% CI): 2.0 (0.5, 7.9)

Abdominal pain • PbB <60 (% reporting symptom): 12

• PbB ≥60 (% reporting symptom): 18

• PR (95% CI): 1.5 (0.5, 4.6)

Rosenman et al. 2003

Survey study; n=497 workers

• Range 10–70

• Stratification by PbB:

o 10–24 (n=139)

o 25–29 (n=98)

o 30–39 (n=171)

o 40–49 (n=58)

o 50–59 (n=22)

o ≥60 (n=9)

Abdominal pain AdjOR (95% CI) for PbB:

• 10–24: 1 (reference)

• 25–29: 0.62 (0.28, 1,37)

• 30–39: 0.98 (0.53, 1.82)

• 40–49: 2.15 (1.03, 4.49)*

• 50–59: 1.54 (0.52, 5.23)

• ≥60: NR

aGastrointestinal symptoms include abdominal colic, nausea, vomiting, diarrhea, and/or constipation. bAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

AdjOR = adjusted odds ratio (adjusted by age, ethnicity group, company screening, and smoking status); CI = confidence interval; NR = not reported; PbB = blood 

lead concentration; PR: prevalence ratio
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The following hematological effects have been associated with PbB: 

• ≤10 μg/dL:

o Inhibition of δ-ALAD; demonstrated in a few studies.

o Decreased blood hemoglobin; evaluated in several studies with mixed results.

o Decreased platelet count.

o Decreased plasma EPO in adult males.

• >10 μg/dL:

o Dose-dependent decreased heme synthesis due to inhibition of δ-ALAD and other heme 

metabolism enzymes; demonstrated in numerous studies.

o Anemia and decreased blood hemoglobin; demonstrated in numerous studies.

o Decreased activity of other erythrocyte enzymes (pyrimidine 5’-nucleotidase or red blood cell 

membrane Ca2+/Mg2+ATPase); demonstrated in a few studies.

o Altered plasma EPO concentration:

 Decreased in adult males; evaluated in a few studies with mixed results.

 Decreased in pregnant females; demonstrated in one study, but findings not corroborated.

 Mixed results (both increases and decreases observed) in children; evaluated in a few 

studies.

Measures of Exposure. Studies evaluating the association between hematological effects and Pb 

exposure most commonly evaluate exposure by measurement of PbB.

Confounding Factors and Effect Modifiers. In general, available epidemiological studies on 

hematological effects do not control for factors, including concomitant exposure to other chemicals, that 

may affect the hematological system. In addition, dietary insufficiency of iron is the primary cause of 

microcytic, hypochromic anemia; however, few studies evaluated this as an effect modifier. Age and 

renal function are also confounding factors, as impairment of renal function can affect renal EPO 

synthesis and PbB. Failure to account for these factors may attenuate or strengthen the apparent 

associations between Pb exposure and the outcome, depending on the direction of the effect of the 

variable on the outcome.

Characterization of Effects. General trends for studies showing a relationship between PbB and 

hematological effects are shown in Table 2-15. Most epidemiological studies of hematological effects 

have examined effects on heme metabolism and its consequences, with fewer studies examining other 
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hematological endpoints (altered serum levels of EPO, altered erythrocyte function, and decreased platelet 

count). As noted above, Pb-induced toxicity to the hematological system, specifically inhibition of heme 

synthesis enzymes and resulting anemia and decreased erythrocyte hemoglobin, have long been 

established. Numerous epidemiological studies in adults and children provide consistent evidence that 

δ-ALAD activity is inversely correlated with PbB over a PbB range of <10–>50 μg/dL (see Table 2-15) 

with δ-ALAD inhibition and subsequent effects of inhibition showing concentration-dependence for PbB 

(Murata et al. 2009; Schwartz et al. 1990). A few studies have reported other hematological effects, 

including decreased platelet count in Pb workers at PbB of 5.4 μg/dL (Conterato et al. 2013) and 

>41 μg/dL (Barman et al. 2014). Inhibition of non-heme metabolism enzymes in erythrocytes was also 

associated with PbB. In Pb workers, membrane Ca2+/Mg2+ATPase was inhibited at a PbB range of 

approximately 29–42 μg/dL (Abam et al. 2008), and pyrimidine 5’-nucleotidase was inhibited at a PbB of 

>50 μg/dL (Buc and Kaplan 1978). Pyrimidine 5’-nucleotidase also was inhibited in children (aged 1–

5 years) with a PbB range of 30–72 μg/dL (Angle et al. 1982).

Table 2-15. Overview of Hematological Effects Associated with Chronic 

Exposure to Lead (Pb)

Mean blood lead 

concentration (PbB) 

(μg/dL)

Effects associated 

with Pb exposure References

≤10 Altered heme synthesisa Ahamed et al. 2006; Ergurhan-Ilhan et al. 2008; 

Wang et al. 2010

Anemia and/or 

decreased measures of 

RBC hemoglobinb

Ahamed et al. 2006; Conterato et al. 2013; OliveroVerbel et al. 2007; Queirolo et al. 2010; Riddell et al. 

2007; Ukaejiofo et al. 2009

Increased hemoglobin Chen et al. 2019

Decreased platelet 

count

Conterato et al. 2013

Decreased EPO Sakata et al. 2007 

>10–30 Altered heme synthesisa Ahamed et al. 2005, 2006; Counter et al. 2008, 

2009; Grandjean and Lintrup 1978; La-Llave-Leon et 

al. 2017; Lauwerys et al. 1978; Mohammad et al. 

2008; Murata et al. 2009; Piomelli et al. 1982 

Rabinowitz et al. 1985; Roels et al. 1975, 1976; 

Roels and Lauwerys 1987; Schumacher et al. 1997; 

Stuik 1974

Anemia and/or 

decreased measures of 

RBC hemoglobinb

Adebonojo 1974; Ahamed et al. 2007; Karita et al. 

2005; Li et al. 2018; Schwartz et al. 1990; Shah et al. 

2010

Altered RBC functionc Abam et al. 2008; Huel et al. 2008

Decreased platelet 

count

Barman et al. 2014

Decreased EPO Graziano et al. 1991, Liebelt et al. 1999
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Table 2-15. Overview of Hematological Effects Associated with Chronic 

Exposure to Lead (Pb)

Mean blood lead 

concentration (PbB) 

(μg/dL)

Effects associated 

with Pb exposure References

Increased EPO Factor-Litvak et al. 1999;

>30–50 Altered heme synthesisa Ademuyiwa et al. 2005; Alessio et al. 1976; 

Conterato et al. 2013; Fukumoto et al. 1983; Griffin 

et al. 1975; Murata et al. 2009; Roels et al. 1976; 

Secchi et al. 1974; Solliway et al. 1996

Anemia and/or 

decreased measures of 

RBC hemoglobinb

Chwalba et al. 2018; Conterato et al. 2013; 

Dobrakowski et al. 2016; Schwartz et al. 1990; 

Solliway et al. 1996

Altered RBC function Abam et al. 2008; Angle et al. 1982; Buc and Kaplan 

1978

Increased reticulocytes Kalahasthi and Barman 2016

Decreased EPO Romeo et al. 1996

Increased EPO Factor-Litvak et al. 1998; Graziano et al. 2004;

>50 Altered heme synthesisa Cools et al. 1976; Gurer-Orhan et al. 2004; Jin et al. 

2006; Meredith et al. 1978; Murata et al. 2009; 

Pagliuca et al. 1990; Schwartz et al. 1990

Anemia and/or 

decreased measures of 

RBC hemoglobinb

Baker et al. 1979; Lilis et al. 1978; Malekirad et al. 

2013; Grandjean1979; Patil et al. 2006; Roels et al.

1979

Decreased EPO Romeo et al. 1996

Altered RBC functionc Buc and Kaplan 1978

aInhibition of heme synthesis measured by decreased δ-ALAD activity, elevated RBC levels or urinary levels of heme 

precursors (e.g., protoporphyrin, erythrocyte protoporphyrin, free erythrocyte protoporphyrin), and/or increased RBC 

zinc protoporphyrin/heme ratio. bDecreased blood hemoglobin, hematocrit, erythrocyte count, mean corpuscular hemoglobin, mean corpuscular 

hemoglobin concentration, and/or mean cell volume.

cAltered erythrocyte function includes inhibition of pyrimidine 5’-nucleotidase or decreased RBC membrane 

Ca2+/Mg2+ATPase.

ALAD = aminolevulinic acid dehydratase; EPO = serum erythropoietin; RBC = red blood cell

Several studies have evaluated the relationship between PbB and serum EPO levels in adults (Graziano et 

al. 1991; Osterode et al. 1999; Romeo 1996; Sakata et al. 2007) and children (Factor-Litvak 1998, 1999; 

Graziano et al. 2004; Liebelt et al. 1999). Erythropoietin is a glycoprotein hormone produced in renal 

proximal tubules that regulates steady-state and accelerated erythrocyte production. As a compensatory 

response to conditions producing low blood oxygen (e.g., anemia), proximal tubular cells release EPO, 

resulting in stimulated erythrocyte production. However, if renal function is compromised due to disease 

or toxicity (e.g., Pb-induced renal damage), the compensatory increases in serum EPO may be diminished 

or absent. Results of three cross-sectional studies in adult male workers are inconsistent, showing 
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decreased serum EPO levels at PbB 6.4–65.1 μg/dL (Romeo et al. 1996; Sakata et al. 2007), but no effect 

on EPO at a PbB of 45.5 μg/dL (Osterode et al. 1999). Study populations in these cross-sectional studies 

were small (n for exposed groups=10–27). In a subgroup of 48 pregnant women (selected from a larger 

cohort of 1,502 pregnant women), serum EPO was decreased; the range of PbB means based on 

hemoglobin stratifications was 23.1–36.2 μg/dL (Graziano et al. 1991). Studies in children have yielded 

mixed results on associations between PbB and serum EPO. Results of a series of prospective studies of 

children (n=280) in former Yugoslavia indicate that serum EPO levels in Pb-exposed children exhibit 

age-dependence (Factor-Litvak et al. 1998, 1999; Graziano et al. 2004). Serum EPO was increased in 

children 4.5 (mean PbB: 39.3 μg/dL) and 6.5 years of age (mean PbB: 36.2 μg/dL), but not in children 

9.5 (mean PbB: 28.1 μg/dL) or 12 years of age (mean PbB: 30.6 μg/dL) (Factor-Litvak et al. 1998, 1999; 

Graziano et al. 2004). The study authors suggested that the capacity for compensatory increases in EPO 

in response to Pb-induced anemia declines over time, possibly due to Pb-induced damage to the renal 

proximal tubule. In contrast to increases in EPO levels observed in the Yugoslavian cohort, Liebelt et al. 

(1999) showed decreased EPO levels in a group of children ages 1–6 years (n=95) who had a mean PbB 

of 18 μg/dL. 

Effect at Blood Pb Levels ≤10 μg/dL. Epidemiological studies evaluating hematological effects of PbB 

≤10 μg/dL are summarized in Table 2-16, with additional details provided in the Supporting Document 

for Epidemiological Studies for Lead, Table 4. Studies were conducted in small populations (n for 

exposed groups=25–391), except for two larger (n=855–2,861) cross-sectional studies in children (Liu et 

al. 2015a; Riddell et al. 2007). In general, studies show inverse associations between PbB ≤10 μg/dL and 

δ-ALAD activity and blood hemoglobin in adults and children, although results are mixed. Negative 

correlations between PbB and δ-ALAD activity (measured by plasma δ-ALAD activity or zinc 

protoporphyrin:heme ratio) have been observed in children (Wang et al. 2010), adolescent males 

(Ahamed et al. 2006), and adults (Wang et al. 2010) at mean PbB of 5.95–9.96 μg/dL; however, no effect 

on δ-ALAD activity was observed in children with a mean PbB of 7.11 μg/dL (Ahamed et al. 2005). 

Differences in δ-ALAD activity were observed for male automotive repair workers (mean PbB: 

7.9 μg/dL) and male controls (mean PbB: 2.6 μg/dL). Additionally, two studies in adults showed that 

blood hemoglobin concentration was lower in Pb workers (mean PbB: 5.4–7.0 μg/dL) compared to 

controls (mean PbB: 1.5–3.0 μg/dL) (Conterato et al. 2013; Ukaejiofo et al. 2009). In contrast, blood 

hemoglobin and erythrocyte count were increased in adults living near an electronic waste site (median 

PbB 8.7 μg/dL), compared to controls (median PbB 8.7 μg/dL) (Chen et al. 2019). In children with mean 
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Table 2-16. Summary of Epidemiological Studies Evaluating Hematological Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Heme metabolism

Ahamed et al. 2005

Cross-sectional study; n=62 children 

(ages 4–12 years)

Mean (SD)

• Group 1: 3.93 (0.61)

• Group 2: 7.11 (1.25)

δ-ALAD activity No difference between groups:

• Group 1: 4.82 (1.25)

• Group 2: 4.56 (1.20)

Ahamed et al. 2006

Cross-sectional study;

n=39 adolescent males (ages 15–

18 years)

Mean (SD): 9.96 (3.63)

Range: 4.62–18.64

δ-ALAD activity A negative correlation between PbB and blood 

δ-ALAD activity: r= -0.592; p<0.001*

Ergurhan-Ilhan et al. 2008

Cross-sectional study; n=25 male 

automotive repair workers (mean age 

16.8 years): 24 male controls (mean 

age 16.3 years)

Mean (SD)

• Controls: 2.6 (2.0)

• Workers: 7.9 (5.2)

ALAD index • Controls: 0.40 (0.34)

• Workers: 0.73 (0.47); p=0.048*

ZPP:heme ratio • Controls: 26.4 (7)

• Workers: 37.2 (15.9); p=0.045*

Wang et al. 2010

Cross-sectional study; n=307 children 

(ages 4–13 years) and 391 adults

(ages 16–77 years) from China

Median

• Children: 6.83

• Adults: 5.95

δ-ALAD activity Pearson correlation coefficients:

• Children: -0.256; p<0.05*

• Adults: -0.213; p<0.05*

ZPP Pearson correlation coefficients:

• Children: 0.135; p<0.05*

• Adults: 0.083; p<0.05*

Blood hemoglobin/erythrocyte count

Chen et al. 2019

Cross-sectional study; n=158 exposed 

adults living near an electronic waste 

area (mean age: 44 years); 

n=109 controls (mean age: 47 years)

Median (P25, P75)

• Control: 5.1 (3.9, 8.4)

• Exposed: 8.7 (6.2, 12.2)

Hb Median (P25, P75), g/dL

• Control: 123.0 (107.0, 143.0)

• Exposed: 137.0 (119.5, 150.0), p=0.001*

Erythrocyte count RBC count (x103), median (P25, P75):

• Control: 4.2 (3.5, 4.6)

• Exposed: 4.5 (4.1, 4.8), p=0.001*
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Table 2-16. Summary of Epidemiological Studies Evaluating Hematological Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Conterato et al. 2013

Cross-sectional study; n=50 painters; 

36 controls

Mean (SE)

• Control: 1.5 (0.1)

• Painters: 5.4 (0.4)

Hb Mean (SE), μg/dL

• Control: 15.4 (0.2)

• Painters: 15.0 (0.1); p<0.05*

Liu et al. 2015a

Cross-sectional study; n=855 children 

(age range: 3–7 years)

PbB quartiles:

• Q1: 2.20–5.16

• Q2: 5.16–7.33

• Q3: 7.33–10.62

• Q4: 10.62–37.78

Erythrocyte Pb quartiles:

• Q1: 5.98–13.52

• Q2: 13.52–19.35

• Q3: 19.35–28.42

• Q4: 28.42–101.01

Hb Change in Hb compared to Q1:

• PbB Q3: 1.45 (-0.28, 3.18)

• Erythrocyte Pb

o Q3: -3.01 (-4.71,1.31); p<0.05*,c

o Q4: -3.97 (-5.68, -2.27); p<0.05*

Olivero-Verbel et al. 2007

Cross-sectional study, n=189 children 

(age range 5–9 years) 

Mean (SE): 5.49 (0.23) Hb Spearman correlation coefficient: 0.069; p=0.348

Queirolo et al. 2010

Cross-sectional study; n=222 children 

(age: 5–45 months)

Mean (SD): 9.0 (6.0) Hb Blood Hb <10.5 g/L was a predictor of PbB; 

β (95% CI): 2.40 (0.77, 4.03); p<0.01*

Riddell et al. 2007

Cross-sectional study; 

n=2,861 children (age 6 months–

5 years)

Mean: 6.9 Hb A 1 g/dL increase in Hb was associated with a 3% 

decrease in PbB (p=0.043)*

Ukaejiofo et al. 2009 

Cross-sectional study; n=81 Pb 

workers; 30 controls

Mean (SD)

• Controls: 3.00 (0.19)

• Workers: 7.00 (0.07)

Hb Mean (SE), g/dL

• Controls: 12.96 (0.089)

• Workers: 12.05 (1.62); p<0.001*
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Table 2-16. Summary of Epidemiological Studies Evaluating Hematological Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Zentner et al. 2006

Cross-sectional study; n=55 newborns 

Umbilical mean (SD): 3.9 

(3.6)

Hb Pearson correlation coefficient: -0.04; p=0.721

Other hematological effects

Conterato et al. 2013

Cross-sectional study; n=50 painters; 

36 controls

Mean (SE)

• Control: 1.5 (0.1)

• Painters: 5.4 (0.4)

Platelet count Mean (SE), %

• Control: 244.3 (8.3)

• Painters: 203.7 (6.5); p<0.05*

Sakata et al. 2007

Cross-sectional studies: n=27 exposed 

workers; 9 controls

Mean (SD); range

• Controls: 2.4 (1.1)

• Workers: 6.4 (2.2)

EPO Mean (SD), mU/mL:

• Controls:18.8 (4.6)

• Workers: 12.7 (3.5); p<0.01*

aSee the Supporting Document for Epidemiological Studies for Lead, Table 4 for more detailed descriptions of studies. bAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs. cThe discrepancy between the 95% confidence limits and the p-value appears to be caused by an error in the reporting of the upper confidence limit (i.e., -1.31, 

rather than 1.31).

ALAD index = log(active δ-ALAD/non-activated δ-ALAD); δ-ALAD = δ-aminolevulinic acid dehydratase; CI = confidence interval; EPO = serum erythropoietin; 

Hb = hemoglobin; Pb = lead; SD = standard deviation; SE = standard error; ZPP = zinc-protoporphyrin
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PbB of 6.9–9.0 μg/dL, there was an inverse association between blood hemoglobin concentrations and 

PbB (Queirolo et al. 2010; Riddell et al. 2007) and erythrocyte Pb concentration (Liu et al. 2015a). At 

lower PbB in newborns (PbB 3.9 μg/dL) and children (PbB 5.5 μg/dL), no correlation was found; 

however, these study populations were small (n=50–189) (Olivero-Verbel et al. 2007; Zentner et al. 

2006). Thus, data are not adequate to establish an exposure-response relationship for decreased 

hemoglobin at PbB ≤10 μg/dL. Studies in small groups of workers (n=27–50) showed lower platelet 

count (PbB 5.4 μg/dL) and serum EPO concentrations (PbB 6.4 μg/dL) compared to controls (Conterato 

et al. 2013; Sakata et al. 2007). Although these findings have not been evaluated in other studies with 

PbB ≤10 μg/dL, similar effects have been observed at PbB >10 μg/dL.

Mechanisms of Action. Pb inhibits heme synthesis by inhibiting δ-ALAD and ferrochelatase (see

Figure 2-4). As a consequence, the activity of the rate-limiting enzyme of the pathway, δ-aminolevulinic 

synthetase (δ-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 (δ-ALA), increased blood and plasma δ-ALA, increased erythrocyte protoporphyrin (EP), 

and decreased hemoglobin. The impairment of heme synthesis by Pb may have a far-ranging impact not 

limited to the hematopoietic system. EPA (1986) provided an overview of the known and potential 

consequences of the reduction of heme synthesis as shown in Figure 2-5. Solid arrows indicate welldocumented effects, whereas dashed arrows indicate effects considered to be plausible further 

consequences of the impairment of heme synthesis.

In addition to decreased hemoglobin synthesis, general mechanisms of toxicity of Pb (reviewed in 

Section 2.21) are likely involved in the development of adverse effects to the hematological system. EPA 

(2014c) specifically noted effects of oxidative stress (altered antioxidant enzymes, decreased cellular 

glutathione, and lipid peroxidation) as an important mechanism for hematological effects. As reviewed in 

Section 3.2.3 (Toxicokinetics, Distribution), 99% of Pb in blood is distributed to erythrocytes, providing a 

toxicokinetic mechanism for hematological effects (Bergdahl et al. 1997a, 1998, 1999; Hernandez-Avila 

et al. 1998; Manton et al. 2001; Schutz et al. 1996; Smith et al. 2002).
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Figure 2-4. Pb Interactions in the Heme Synthesis Pathway

Abbreviations as noted in Ahamed and Siddiqui (2007): δ-ALAS = delta-aminolevulinic acid synthetase; 

δ-ALAD = delta-aminolevulinic dehydratase; CoA = coenzyme A

*Activity of enzymes inhibited by lead.

Source: Reprinted from Ahamed and Siddiqui (2007) with permission from Elsevier.

Succinyl CoA

+

Glycine

δ-Aminolevulinic acid (δ-ALA)

CYTOPLASM

M

I

T

O

C

H

O

N

D

R

I

O

N

δ-ALAS*

δ-ALAD*

Porphobilinogen Uroporphobilinogen Coporphobilinogen III

Protophobilinogen III

Protophorphyrin IX

Heme

Ferrochelatase*

Fe++

 

 
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2. HEALTH EFFECTS

Figure 2-5. Multiorgan Impact of Reduction of Heme Body Pool by Lead

EXACERBATION OF 

HYPOXIC EFFECTS OF 

OTHER STRESS AGENTS

EFFECTS ON NEURONS, 

AXONS, AND SCHWANN 

CELLS

IMPAIRED MYELINATION 

AND NERVE CONDUCTION

IMPAIRED DEVELOPMENT 

OF NERVOUS SYSTEM

IMPAIRED MINERAL 

TISSUE HOMEOSTASIS

IMPAIRED CALCIUM ROLE 

IN CYCLIC NUCLEOTIDE 

METABOLISM

IMPAIRED 

DETOXIFICATION OF 

ENVIRONMENTAL TOXINS

IMPAIRED 

DETOXIFICATION OF 

DRUGS

ALTERED METABOLISM 

OF TRYPTOPHAN

IMPAIRED 

HYDROXYLATION OF 

CORTISOL

ELEVATED BRAIN LEVELS 

OF TRYPTOPHAN, 

SEROTONIN, AND HIAA

DISTURBED INDOLEAMINE 

NEUROTRANSMITTER 

FUNCTION

IMPAIRED BONE AND TOOTH 

DEVELOPMENT

CARDIOVASCULAR 

DYSFUNCTION AND OTHER 

HYPOXIC EFFECTS

ANEMIA REDUCED 

OXYGEN TRANSPORT TO 

ALL TISSUES

IMPAIRED CELLULAR 

ENERGETICS

DISTURBED IMMUNOREGULATORY ROLE OF 

CALCIUM

DISTURBED CALCIUM 

METABOLISM

DISTURBED ROLE IN 

TUMORIGENESIS 

CONTROL

IMPAIRED 

DETOXIFICATION OF 

XENOBIOTICS

IMPAIRED CALCIUM ROLE 

AS SECOND MESSENGER

IMPAIRED METABOLISM 

OF ENDOGENOUS 

AGONISTS

REDUCED 

HEMOPROTEINS (e.g., 

CYTOCHROMES)

REDUCED HEMOGLOBIN 

SYNTHESIS

REDUCED 1.25 (OH)2 – 

VITAMIN D

REDUCED HEME FOR 

HEME-REGULATED 

TRANSFORMATIONS

REDUCTION OF HEME 

BODY POOL

 ERYTHROPOMETIC

 EFFECTS

NEURAL 

EFFECTS

RENAL ENDOCRINE

 EFFECTS

HEPATIC 

EFFECTS

Pb

Source: EPA 1986a 

2.9 MUSCULOSKELETAL

Overview. Few epidemiological studies have evaluated musculoskeletal effects associated with Pb 

exposure; thus, limited data are available to fully describe the exposure-response relationship or evaluate 

the weight-of-evidence for certain effects. Studies provide evidence of bone loss, increased markers of 

bone metabolism/turnover, and adverse periodontal and dental effects (periodontal bone loss, tooth loss, 

periodontal disease, dental caries). However, within dose ranges (≤10, 10–30, 30–50, and >50 μg/dL), 
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few studies examined the same endpoints. Available studies include a prospective study in women and 

cross-sectional studies in adults and children, with some studies in large populations. 

The following musculoskeletal effects have been associated with PbB: 

• ≤10 μg/dL:

o Bone loss or markers of increased bone or joint tissue metabolism.

o Periodontal bone loss.

o Tooth loss.

o Dental caries.

o Periodontitis.

• >10 μg/dL:

o Muscle soreness/weakness.

o Osteoporosis/decreased bone mineral density (BMD) in adults.

o Increased BMD in children.

o Periodontal disease.

o Dental caries.

Measures of Exposure. Most studies examining the association between musculoskeletal effects and Pb 

exposure have evaluated exposure by measurement of PbB, although some studies also evaluated 

exposure by bone Pb concentration.

Confounding Factors and Effect Modifiers. A complicating factor in the interpretation of studies 

examining associations between PbB and bone loss or measures of bone metabolism is that increased 

bone metabolism (bone turnover or loss) can result in higher PbB due to Pb released from bone into the 

blood (reverse causality). This contributes to confounding from other factors that are associated with 

bone loss, including nutrition, age, pregnancy and menopause, and activity. Results of studies examining 

Pb-induced periodontal or dental effects need to account for dental hygiene, diet/nutrition, and previous 

dental interventions. For example, interpretation of results on associations between dental caries and PbB 

would be uncertain if daily fluoride intake or prophylactic dental treatments (e.g., fluoride treatments or 

coating of molars during childhood) were not considered as confounding factors. Studies that rely on in 

vivo estimates of bone Pb (e.g., XRF) as the exposure metric for changes in BMD should also consider 

the potential for changes in BMD affecting the measurement of the concentration of Pb in bone mineral 

(Hu et al. 2007).
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Characterization of Effects. Studies evaluating musculoskeletal effects associated with PbB provide 

evidence of bone loss, altered bone or joint tissue metabolism, and adverse periodontal and dental effects 

(periodontal bone loss, tooth loss, periodontal disease, dental caries). Due to the small number of studies, 

it is difficult to establish exposure-response relationships; in addition, within specific dose-ranges (≤10, 

10–30, 30–50, and >50 μg/dL), few studies examined the same endpoints. Effects associated with 

chronic Pb exposure are shown in Table 2-17. In adults, decreased BMD has been observed over a PbB 

range of ≤10–>50 μg/dL (Campbell and Auinger 2007; Dongre et al. 2013; Khalil et al. 2008; Lee and 

Park 2018), although BMD was not decreased in women at PbB ≤10 μg/dL (Pollack et al. 2013). BMD 

was increased in a single study in children with a mean PbB of 23.6 μg/dL (Campbell et al. 2004). The 

study authors suggested that the effect may represent accelerated bone maturation due to Pb-induced 

inhibition of parathyroid hormone-related peptide and transforming growth factor β-1. The study authors 

also noted that the accelerated bone maturation may be a predisposing factor for osteoporosis later in life. 

Sun et al. (2008a, 2008b) showed that PbB was associated with increased prevalence of osteoporosis 

(mean PbB men: 20.22 μg/dL; women 15.50 μg/dL). Periodontal disease (including periodontitis), 

periodontal bone loss, tooth loss, and dental caries have been reported over a PbB range of ≤10–30 μg/dL 

(Arora et al. 2009; Campbell et al. 2000a; Dye et al. 2002; Gemmel et al. 2002; Kim and Lee 2013; Kim 

et al. 2017a; Moss et al. 1999; Youravong and Teanpaisan 2015). Most studies examining periodontal 

and dental effects of Pb are conducted in populations with PbB ≤10 μg/dL. Muscle soreness and 

weakness has also been reported, although at higher PbB (40–49 μg/dL) (Rosenman et al. 2003).

Table 2-17. Overview of Musculoskeletal Effects Associated with Chronic 

Exposure to Lead (Pb)

Mean blood lead 

concentration (PbB) (μg/dL)

Effects associated with Pb 

exposure References

≤10 Bone loss/increased bone 

metabolism

Khalil et al. 2008; Lee and Park 2018; 

Machida et al. 2009; Nelson et al. 

2009

Tooth loss Arora et al. 2009

Periodontal bone loss Dye et al. 2002

Periodontitis Kim and Lee 2013

Dental caries Gemmel et al. 2002; Kim et al. 2017a; 

Moss et al. 1999
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Table 2-17. Overview of Musculoskeletal Effects Associated with Chronic 

Exposure to Lead (Pb)

Mean blood lead 

concentration (PbB) (μg/dL)

Effects associated with Pb 

exposure References

>10–30 Osteoporosis Sun et al. 2008a, 2008b

Decreased bone mineral density 

(adults)

Campbell and Auinger 2007

Increased bone mineral density 

(children)

Campbell et al. 2004

Periodontal disease Youravong and Teanpaisan 2015

Dental caries Campbell et al. 2000a

>30–50 Muscle soreness/weakness Rosenman et al. 2003

Decreased bone mineral density Campbell and Auinger 2007

>50 Decreased bone mineral density Dongre et al. 2013

Effects at Blood Pb Levels ≤10 μg/dL. Epidemiological studies of musculoskeletal effects associated 

with PbB ≤10 μg/dL have examined effects on bone and periodontal and dental health; studies are briefly 

summarized in Table 2-18, with additional details provided in the Supporting Document for 

Epidemiological Studies for Lead, Table 5. A prospective study in women reported an increased rate of 

bone loss at PbB ranges of 4–7 and 8–21 μg/dL and an increased risk of non-spine fractures at a PbB 

range of 8–21 μg/dL (Khalil et al. 2008). In cross-sectional studies, markers of bone metabolism were 

positively associated with PbB in women at mean PbBs of <2 and 2.9 μg/dL, although no relationship 

was observed for these markers and PbB in men (mean PbB: 1.2 μg/dL) (Machida et al. 2009; Nelson et 

al. 2011). In non-occupationally exposed men and women (n=443), PbB (mean 4.44 μg/dL) was 

negatively associated with BMD (Lee and Park 2018). However, no associations between PbB and BMD 

have been observed in cross-sectional studies in women at slightly lower PbB median PbB (1.8–

2.2 μg/dL) (Machida et al. 2009; Pollack et al. 2013). Studies examining periodontal and dental effects 

include large (n=2,805–10,033) cross-sectional studies in adults and children (Dye et al. 2002; Kim and 

Lee 2013; Kim et al. 2017a; Moss et al. 1999). Positive associations have been observed between PbB 

and presence of dental furcations in male and female adults (mean PbB: 1.9–3.3 μg/dL) (Dye et al. 2002), 

periodontitis in adult males (PbB mean 3.1 μg/dL), but not females (mean PbB: 2.2) (Kim and Lee 2013), 

and dental 
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Table 2-18. Summary of Epidemiological Studies Evaluating Musculoskeletal Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb,c

Bone metabolism

Khalil et al. 2008

Prospective cohort study; n=533 

women (age range: 65–87 years). 

PbB:

Mean (SD): 5.3 (2.3)

Tertiles:

• T1 (n=122): ≤3 

(reference)

• T2 (n=332): 4–7

• T3 (n=79): 8–21

Bone loss Percentage rate of calcaneus bone loss

• T1: -1.01 (-1.27, -0.74)*

• T2: -1.41 (-1.57, -1.24)*

• T3: -1.49 (-1.86, -1.10)*; p=trend: 0.03

Non-spine fractures HR T3: 2.50 (1.25, 5.03)*; p-trend: 0.016

Lee and Park 2018

Cross-sectional study; n=443 adults 

(age range: 39–69 years)

PbB:

Gmean: 4.44

BMD Regression coefficient, β (SE), for BMD: -1.27 

(0.48); p<0.01*

Machida et al. 2009

Cross-sectional study; n=1,225 female 

Japanese farmers (age range: 35–

75 years)

PbB:

Median 

• Premenopausal 

(n=261): 1.6

• Perimenopausal 

(n=319): 2.0

• Younger 

postmenopausal 

(n=397): 1.8

• Older postmenopausal 

(n=248): 1.7

BALP Spearman’s correlation coefficients

• All women: 0.143; p=0.000*

• Perimenopausal women: 0.234; p=0.000*

OC Spearman’s correlation coefficients

• All women: 0.191; p=0.000*

• Perimenopausal women: 0.391; p=0.000*

NTx Spearman’s correlation coefficients

• All women: 0.181; p=0.000*

• Perimenopausal women: 0.261; p=0.000*

BMD Spearman’s correlation coefficients

• All women: -0.016; p=0.570

• Perimenopausal women: -0.101; p=0.071
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Table 2-18. Summary of Epidemiological Studies Evaluating Musculoskeletal Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb,c

Nelson et al. 2011

Cross-sectional study; n=329 males 

(mean age: 65 years) and 

n=342 females (mean age: 62 years) 

Median (range)

• Males: 2.2 (0.5–25.1)

• Females: 1.9 (0.5–25.4)

uNTX-I β, change in biomarker per 5 μg/dL increase in 

ln-PbB

• Males: 1.06 (0.95, 1.18)

• Females: 1.45 (1.21, 1.74)*

uCTX-II β, change in biomarker per 5 μg/dL increase in 

ln-PbB

• Males: 1.07 (0.97, 1.18)

• Females: 1.28 (1.04, 1.58)*

C2C (65 years) β, change in biomarker per 5 μg/dL increase in 

ln-PbB

• Males: 1.00 (0.94, 1.04)

• Females: 1.00 (0.92, 1.08)

CPII β, change in biomarker per 5 μg/dL increase in 

ln-PbB

• Males: 0.99 (0.93, 1.05)

• Females: 1.09 (0.97, 1.22)

HA β, change in biomarker per 5 μg/dL increase in 

ln-PbB

• Males: 1.01 (0.88, 1.05)

• Females: 0.96 (0.71, 1.29)

COMP β, change in biomarker per 5 μg/dL increase in 

ln-PbB

• Males: 1.08 (1.00, 1.18)*

• Females: 0.96 (0.87, 1.06)

Pollack et al. 2013

Cross-sectional study; 

n=249 premenopausal women (ages 

18–44 years)

Mean (SD): 1.03 (0.64) BMD β per log-unit increase in PbB: 0.004 (-0.029, 0.020)
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Table 2-18. Summary of Epidemiological Studies Evaluating Musculoskeletal Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb,c

Periodontal and dental effects

Arora et al. 2009

Cross-sectional study; n=333 men 

(age range: 50–94 years)

PbB Tertiles

• T1: ≤4.0 (reference)

• T2: 4.2–6.4

• T3: 7.0–35.0

Bone Pb (μg/g)

Tertiles for tibia

• T1: ≤15.0 (reference)

• T2: 16.0–23.0

• T3: 24.0–96.0

Tertiles for patella

• T1: ≤22.0 (reference)

• T2: 23.0–36.0

• T3: 37.0–126.0

Tooth loss OR PbB (compared to T1)

• T3: 0.88 (0.52, 1.50); p-trend=0.57

OR Tibia Pb (compared to T1)

• T2: 1.81 (1.02, 3.18)*

• T3: 3.03 (1.60, 5.76)*; p-trend=0.001*

OR Patella Pb (compared to T1)

• T3: 2.41 (1.30, 4.49)*; p-trend 0.005*

Dye et al. 2002

Cross-sectional study in 

10,033 participants in NHANES III 

(ages 20–69 years)

Mean (SE)

• Males: 3.3 (0.12)

• Females: 1.9 (0.05)

Presence of dental 

furcations

β (SE), for presence of dental furcations 

(combined men and women): 0.13 (0.05); 

p=0.005*
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Table 2-18. Summary of Epidemiological Studies Evaluating Musculoskeletal Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb,c

Gemmel et al. 2002

Cross-sectional study in 498 children 

(age range: 6–10 years) from rural 

(n=239) and urban (n=259) settings.

Mean (SD)

• Rural: 1.7 (1.0)

• Urban: 2.9 (2.0)

Dental caries Regression coefficient (SE):

• Rural: -0.15 (0.09); p=0.09

• Urban: -0.22 (0.08); p=0.005*

Kim and Lee 2013

Cross-sectional study; n=3,966 adults 

(≥20 years of age) 

PbB:

Mean (SE):

• Men

o no periodontitis: 

2.625 (0.028)

o periodontitis: 3.118 

(0.057); p<0.001

• Women, 

o no periodontitis: 

1.906 (0.025)

o periodontitis: 2.222 

(0.052); p<0.001

Periodontitis OR (95% CI), per doubling of PbB:

• Men: 1.699 (1.154, 2.503)*

• Women: 1.242 (0.833, 1.850)

Kim et al. 2017a

Cross-sectional study; 

n=2,805 school-aged children (age 

range: ≤9–≥12 years)

PbB:

Gmean: 1.53

Range: 0.11–4.89

Dental caries PR for combined teeth with caries and filled teeth 

• Deciduous teeth: 1.14 (1.02, 1.27)*

• Permanent teeth: 0.83 (0.69, 0.99)
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Table 2-18. Summary of Epidemiological Studies Evaluating Musculoskeletal Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb,c

Moss et al. 1999

Cross-sectional study; 

n=24,901 participants (2–5 years old: 

n=3,547; 6–11 years old: n=2,894; 

≥12 years: n=18,460) in NHANES III 

Mean (SE):

• Age 2–5 years: 2.9

(0.12)

• Age 6–11 years: 2.1

(0.08)

• Age 12–17 years:

2.5 (0.06)

Dental caries in 

children (ages 5–

17 years)

OR per 5 μg/dL increased in PbB: 1.8 (1.3, 2.5)*

aSee the Supporting Document for Epidemiological Studies for Lead, Table 5 for more detailed descriptions of studies. bAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

cIf bone Pb is noted under results, study did not show associations between PbB and musculoskeletal effects; however, results showed associations between 

bone Pb concentrations and musculoskeletal effects at concomitant PbB ≤10 μg/dL.

BALP = bone-specific alkaline phosphatase (marker of bone metabolism); BMD = bone mineral density; C2C = serum cleavage neoepitope of type II collagen 

(marker of joint tissue metabolism); CI = confidence interval; COMP = serum cartilage oligomeric matrix protein (marker of joint tissue metabolism); CPII = serum 

type II procollagen synthesis C-propeptide (marker of joint tissue metabolism); Gmean = geometric mean; HA = serum hyaluronic acid (marker of joint tissue 

metabolism); HR = hazard ratio; NHANES = National Health and Nutrition Examination Survey; NTx = N-telopeptide cross-linked collagen type I (marker of bone 

metabolism); OC = osteocalcin (marker of bone metabolism); OR = odds ratio; Pb = lead; PR = prevalence ratio; SD = standard deviation; SE = standard error; 

uCTX-II = C-telopeptide urine fragments of type II collagen (marker of joint tissue metabolism); uNTX-I = urine cross-linked N telopeptide of type I collagen 

(marker of joint tissue metabolism)
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caries in children ages 6–17 years (PbB 2.1–2.4 μg/dL) (Moss et al. 1999). Kim et al. (2017a) reported 

that the prevalence of dental caries and filled teeth in children was increased for deciduous teeth, but not 

for permanent teeth; the mean PbB was 1.53 μg/dL, with all PbB <5 μg/dL. One study in adult males 

showed an association between bone Pb and tooth loss, but not PbB and tooth loss (Arora et al. 2009).

Mechanisms of Action. In bone and teeth, Pb substitutes for calcium (see Section 3.1.2, Toxicokinetics, 

Distribution). As reviewed by EPA (2014c) and Mitra et al. (2017), several mechanisms may be involved 

in the development of bone and periodontal/dental effects. Possible mechanisms include the following:

• Alterations in plasma growth hormones and calcitropic hormones (e.g., 1,25-[OH]2D3) leading to 

altered bone cell differentiation and function.

• Suppression in bone cell proliferation due to altered growth factors and hormones, including 

growth hormone, epidermal growth factor, transforming growth factor-beta 1 (TGF-β), and 

parathyroid hormone-related protein.

• Alterations in vitamin D-stimulated production of osteocalcin production, with inhibition of 

secreted bone-related proteins (e.g., osteonectin and collagen).

• Increased chondrogenesis through alterations of multiple signaling pathways, including TGF-β, 

bone morphogenic protein, activator protein-1, and nuclear factor kappa B. 

• Inhibition of the posteruptive enamel proteinases. 

• Decreased microhardness of tooth surface enamel.

2.10 HEPATIC

Overview. Few epidemiological studies have evaluated hepatic effects associated with exposure to Pb, 

with most available studies comparing hepatic effects in small numbers of workers with PbB >10 μg/dL 

to controls with PbB lower than workers. Results of studies evaluating effects of Pb on liver function 

tests are inconsistent and do not demonstrate exposure-response relationships. Liver enlargement and 

increased gall bladder wall thickness was observed in workers with mean PbB of ≥28.66 μg/dL. 

Observed effects are consistent with oxidative stress. Histopathological effects of the liver associated 

with Pb have not been established.

The following hepatic effects have been associated with PbB >10 μg/dL:

• Greater plasma liver enzymes; evaluated in a few studies with mixed results.
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• Greater total cholesterol.

• Enlarged liver and increased thickness of gall bladder wall.

Measures of Exposure. Studies examining the association between hepatic effects Pb exposure evaluate 

exposure by measurement of PbB.

Confounding Factors and Effect Modifiers. Most epidemiological studies on hepatic effects of Pb were 

of small populations of workers using cross-sectional designs. In general, studies did not consider 

factors, such as age, diet, concurrent diseases, and potential exposure to other workplace chemicals that 

could affect hepatic function in association with, or independent of, Pb exposure. Failure to account for 

these factors may attenuate or strengthen the apparent associations between Pb exposure and the outcome, 

depending on the direction of the effect of the variable on the outcome.

Characterization of Effects. In contrast to the large number of epidemiological studies evaluating effects 

of Pb on other organ systems (e.g., neurological and cardiovascular outcomes), few studies have 

investigated the hepatic effects of Pb. Brief study descriptions are provided in Table 2-19. Available 

studies were conducted in small populations (n=23–100) of workers with mean PbB of 5.4–77.5 μg/dL. 

The most serious effects reported for Pb-induced hepatic damage are liver enlargement and greater gall 

bladder wall thickness observed in workers with low PbB (28.66 μg/dL) and high PbB (40.58 μg/dL), 

respectively, compared to the control group (PbB 8.34 μg/dL) (Kasperczyk et al. 2013). However, these 

findings have not been corroborated in other studies. The study authors stated that no signs consistent 

with liver necrosis were observed. A cross-sectional study of a Chinese population evaluated the 

association between PbB and non-alcoholic fatty liver disease in China (Zhai et al. 2017). In women, a 

positive association between PbB and non-alcoholic fatty liver disease was observed in the two highest 

PbB quartiles (4.50–6.59 and >6.59 μg/dL; upper range not reported); no association was observed for 

men in the highest PbB quartile (>7.29 μg/dL; upper range not reported).

Most studies evaluated hepatic toxicity by liver function tests measuring plasma levels of liver enzymes. 

As shown in Table 2-20, results on effects of Pb on liver function tests are inconsistent and do not 

demonstrate exposure-response relationships. For example, Patil et al. (2007) reported greater alanine 

aminotransferase (ALT) and aspartate aminotransferase (AST) in spray painters with a mean PbB of 

22.32 μg/dL, but no change in ALT or AST in battery workers or silver jewelry workers with higher 

mean PbB (53.64 and 48.56 μg/dL, respectively), compared to controls (mean PbB: 12.52 μg/dL). 

Similarly, AST was elevated in painters with a mean PbB of 5.4 μg/dL, but no change in AST was 
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Table 2-19. Summary of Epidemiological Studies Evaluating Hepatic Effects Associated with Blood Lead 

Concentration (PbB)

Reference and study population PbB (μg/dL) Outcomes evaluated Effectsb,c

Al-Neamy et al. 2001

Cross-sectional study; 

n=100 workers; 100 controls

Mean (SD)

• Workers: 77.5 (42.8)

• Controls: 19.8 (12.3)

LFTs • Greater: LDH, AP 

• No difference: ALT, AST, GGT, bilirubin, 

albumin 

Can et al. 2008

Cross-sectional study; n=22 battery 

workers; 38 muffler repair workers; 

24 controls 

Mean (SD)

• Battery workers: 36.83 (8.13)

• Muffler workers: 26.99 (9.42)

• Controls: 14.81 (3.01)

LFTs Battery workers:

• Greater LDH, AP, TC

Muffler workers:

• Greater” LDH, AP

Chen et al. 2019

Cross-sectional study; 

n=158 exposed adults living near an 

electronic waste area; 109 controls

Median (P25, P75)

• Control: 5.1 (3.9, 8.4)

• Exposed: 8.7 (6.2–12.2)

LFTs • Greater: GGT

• No difference: AST, ALT, LDH

Conterato et al. 2013

Cross-sectional study; 

n=50 painters; 23 battery workers; 

and 36 controls

Mean (SE)

• Painters: 5.4 (0.4)

• Battery workers 49.8 (4.0)

• Controls: 1.5 (0.1) 

LFTs Painters:

• Greater: AST

• No difference: GGT

Battery workers: 

• No difference: AST, GGT

Hsiao et al. 2001

Longitudinal study (baseline 1989; 

follow-up 1999); n=30 battery 

workers

Baseline: 60

Follow-up: 30

LFTs No correlation of PbB to ALT
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Table 2-19. Summary of Epidemiological Studies Evaluating Hepatic Effects Associated with Blood Lead 

Concentration (PbB)

Reference and study population PbB (μg/dL) Outcomes evaluated Effectsb,c

Kasperczyk et al. 2013

Cross-sectional study; n (from Pb-Zn 

processing facility): 57 low Pb 

exposure; 88 high Pb exposure; and 

36 controls

Mean (SD); range

• Low Pb: 28.66 (6.60); 20–35

• High Pb: 40.58 (6.74); 35–60

• Control: 8.34 (2.91)

Liver size • Low PbB: Greater 

• High BPb: Greater 

Gall bladder wall 

thickness

• Low PbB: Greater 

• High PbB: Greater 

LFTs • Low PbB:

o No difference: ALT, AST, LDH, GGT, 

bilirubin

• High PbB:

o No difference: ALT, LDH, AST, bilirubin 

o Greater AST, GGT 

Khan et al. 2008

Cross-sectional study; 

n=87 workers; 61 controls

Median (range)

• Workers: 29.1 (9.0–61.1)

• Controls: 8.3 (1.0–21.7)

LFTs • Greater ALT, GGT, albumin 

• No change: AP, bilirubin 

Kristal-Boneh et al. 1999

Cross-sectional study; 

n=56 exposed; 87 controls

Mean (SD)

• Workers: 42.3 (14.9)

• Controls: 2.7 (3.6)

Cholesterol and 

lipoproteins

• Greater: TC, HDL

• No change: LDL, TG, HDL:TC ratio 

Patil et al. 2007

Cross-sectional study; n=30 battery 

workers; 30 silver jewelry workers; 

30 spray paintersa; 35 controls

Mean (SD)

• Battery workers: 53.63 

(16.98)

• Silver jewelry workers: 48.56 

(7.39)

• Spray painters: 22.32 (8.87)

• Controls: 12.52 (4.08)

LFTs Battery workers: 

• Greater percentage change: albumin, 

bilirubin 

• No change: ALT, AST 

Silver jewelry workers: 

• Lesser percentage change: albumin 

compared to controls

• No change: ALT, AST, bilirubin compared to 

controls

Spray painters: 

• Greater percentage change: ALT, AST 

• Decreased percentage change: albumin 

• No change: bilirubin 
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Table 2-19. Summary of Epidemiological Studies Evaluating Hepatic Effects Associated with Blood Lead 

Concentration (PbB)

Reference and study population PbB (μg/dL) Outcomes evaluated Effectsb,c

Zhai et al. 2017

Cross-sectional study; n=214 men 

and 610 women with non-alcoholic 

fatty liver disease

Quartiles (Q)

Men:

• Q1: ≤3.60

• Q2: 3.61–5.29

• Q3: 5.30–7.28

• Q4: ≥7.29

Women:

• Q1: ≤2.97

• Q2: 2.98–4.49

• Q3: 4.50–6.59

• Q4: ≥6.60

Non-alcoholic fatty liver 

disease

• Mend: no association were observed for any

PbB quartile

• Womend: positive association between PbB

at the two highest quartiles; OR (95% CI)

o Q3: 1.495 (1.024, 2.181)*

o Q4: 1.613 (1.082, 2.405)*

o p for trend: 0.019

aReporting inconsistencies regarding number of spray painters evaluated; reported as 30 and 35.

bAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

cUnless otherwise specified, comparisons are to control groups.

dComparison to lowest PbB quartile.

ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; CI = confidence interval; GGT = gamma-glutamyl 

transpeptidase; HDL = high-density lipoprotein; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; LFT = liver function test (plasma activity of hepatic 

enzymes); Pb = lead; Q = quartiles; SD = standard deviation; SE = standard error; TC = total cholesterol; TG = triglycerides; Zn = zinc
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Table 2-20. Effects on Liver Function Tests Associated with Chronic Exposure to 

Lead (Pb)a

Mean PbB (μg/dL) Population (n)b ALT AST GGT LDH AP Reference

5.4 P (50) – ↑ 0 – – Conterato et al. 2013

8.7 G (158) 0 0 ↑ 0 ↑ Chen et al. 2019

22.32 P (35)c ↑ ↑ – – – Patil et al. 2007

26.99 Pb-A (38) 0 0 0 ↑ ↑ Can et al. 2008

28.66 Pb-Zn (57) 0 0 0 0 0 Kasperczyk et al. 2013

29.1 Pb (87) ↑ – ↑ – 0 Khan et al. 2008

30 B (30) 0 – – – – Hsiao et al. 2001

36.83 B (22) 0 0 0 ↑ 0 Can et al. 2008

40.58 Pb-Zn (88) 0 ↑ ↑ 0 ↑ Kasperczyk et al. 2013

48.56 J (30) 0 0 – – – Patil et al. 2007

9.8 B (23) 0 0 0 – – Conterato et al. 2013

53.63 B (30) 0 0 – – – Patil et al. 2007

77.5 Pb (100) 0 0 0 ↑ ↑ Al-Neamy et al. 2001

aReporting inconsistencies regarding number of spray painters evaluated; reported as 30 and 35.

↑ = increased; 0 = no change; – = not assessed; ALT = alanine aminotransferase; AP = alkaline phosphatase;

AST = aspartate aminotransferase; B = battery workers; G = general population; GGT = gamma-glutamyl 

transpeptidase; J = silver jewelry workers; LDH = lactate dehydrogenase; MDA: malondialdehyde; P = painters; 

Pb = Pb-exposed industrial workers; Pb-A = Pb-exposed auto workers; Pb-Zn = Pb-zinc processers

observed in battery workers with a mean PbB of 49.8 μg/dL, compared to controls with a mean PBB of 

1.5 μg/dL (Conterato et al. 2013). Effects in painters with lower PbB compared to other workers with 

higher PbB may be due to co-exposure to other occupational chemicals. In a cross-sectional study of 

residents living close to an electronic waste site in China, PbB (median PbB: 8.7 μg/dL) was associated 

with an increase in gamma-glutamyl transpeptidase (GGT) compared to controls (median PbB: 

5.1 μg/dL), although no effects were observed for ALT or AST (Chen et al. 2019). In addition to liver 

enzymes, total serum cholesterol and high-density lipoprotein (HDL)-cholesterol were greater in workers 

with a mean PbB of 26.99–42.3 μg/dL, compared to controls with a mean PbB 2.7–14.81 μg/dL (Can et 

al. 2008; Kristal-Boneh et al. 1999).

Effect at Blood Pb Levels ≤10 μg/dL. See discussion above on Conterato et al. (2013), Chen et al. 

(2019), and Zhai et al. (2017). 

Mechanisms of Action. General mechanisms of toxicity of Pb (reviewed in Section 2.21) are likely 

involved in the development of hepatic toxicity. EPA (2014c) specifically noted that oxidative stress 
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through ROS can result in damaged function and histopathological damage to the liver, including 

peroxidation of lipid membranes.

2.11 RENAL

Overview. Numerous epidemiologic studies in adults show that exposure to Pb can cause altered kidney 

function and contribute to the development of chronic kidney disease (CKD). A few studies in children 

also show decreases in renal function. Pb-induced nephrotoxicity is characterized by proximal tubular 

nephropathy, glomerular sclerosis, and interstitial fibrosis (Diamond 2005; Goyer 1989; LoghmanAdham 1997). Functional deficits in humans that have been associated with excessive Pb exposure 

include enzymuria, low- and high-molecular weight proteinuria, impaired transport of organic anions and 

glucose, and depressed GFR. 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). Studies show 

consistent evidence of renal damage and reduced renal function associated over a wide range of PbB 

(≤10–>50 μg/dL), with the overall dose-effect pattern suggesting an increasing severity of nephrotoxicity 

associated with increasing PbB.

The following renal effects have been associated with PbB:

• ≤10 μg/dL:

o Decreased GFR; corroborated in numerous studies.

o Proteinuria; demonstrated in a few studies. 

o Chronic kidney disease (CKD); demonstrated in two studies.

• >10 μg/dL:

o Decreased GFR; corroborated in numerous studies.

o Enzymuria; corroborated in numerous studies.

o Proteinuria; corroborated in numerous studies.

o Impaired tubular transport; demonstrated in a few studies.

o Histopathological damage; demonstrated in a few studies.

Measures of Effect. Endpoints demonstrating renal damage include various measures of glomerular and 

tubular dysfunction. Effects on GFR typically are assessed from measurements of creatinine clearance, 

serum creatinine concentration, or blood urea nitrogen (BUN). Increased excretion of albumin 
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2. HEALTH EFFECTS

(albuminuria) is an indication of damage to the glomerular endothelium or basement membrane, resulting 

in increased filtration of albumin, or impaired function of the proximal tubule, resulting in decreased 

reabsorption of filtered albumin. Increased excretion of low molecular weight serum proteins (e.g., 2μG 

or retinol-binding protein) are an indication of impaired reabsorption of protein in the proximal tubule. 

Increased excretion of enzymes associated with the renal tubule (renal tubular enzymuria) is an indication 

of injury to renal tubular cells resulting in release of membrane or intracellular enzymes into the tubular 

fluid. Pb-induced renal tubular enzymuria is most commonly evaluated from measurements of urinary 

N-acetyl-D-glucosaminidase (NAG). Increased excretion of NAG has been found in Pb-exposed workers 

in the absence of increased excretion of other proximal tubule enzymes (e.g., alanine aminopeptidase, 

alkaline phosphatase, glutamyltransferase) (Pergande et al. 1994). Indices of impaired transport include 

altered 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). Proximal tubular injury can also be 

confirmed through histopathological examination of renal tissue, although few studies provide this 

information (Biagini et al. 1977; Cramer et al. 1974; Wedeen et al. 1975, 1979).

Measures of Exposure. Most studies evaluating renal damage use PbB as the biomarker for exposure, 

although more recent epidemiological studies have explored associations between toxicity and bone Pb 

concentrations. These studies provide a basis for establishing PbB, and, in some cases, bone Pb 

concentration ranges associated with specific nephrotoxicity outcomes.

Confounding Factors and Effect Modifiers. Inconsistencies in the reported outcomes for renal effects 

across studies may derive from several causes, including failure to account for confounding factors and 

effect modifiers. Various factors can affect kidney function, including age, underlying diseases (e.g., 

hypertension), and concomitant exposure to other nephrotoxicants (e.g., cadmium). Results of 

epidemiological studies of general populations have shown an effect of age on the relationship between 

GFR (assessed from creatinine clearance of serum creatinine concentration or cystatin C) and PbB (Kim 

et al. 1996a; Muntner et al. 2003; Payton et al. 1994; Staessen et al. 1990, 1992). Pb-induced decrements 

in renal function can lead to higher Pb body burden due to decreased excretion of Pb (i.e., reverse 

causality) (Bellinger 2011; Diamond et al. 2019; Evans and Elinder 2011; Marsden 2003). Thus, reverse 

causality potentially confounds interpretation of the dose-response relationship between PbB and 

decreased renal function. Pb exposure has also been associated with increases in GFR (Hsiao et al. 2001; 

Roels et al. 1994). This may represent a benign outcome or a potentially adverse hyperfiltration, which 

may contribute to subsequent adverse renal effects. Hypertension can be both a confounder in studies of 

associations between Pb exposure and creatinine clearance (Perneger et al. 1993) and a covariable with Pb 
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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). Renal damage can cause increased blood pressure, 

which in turn can result in further damage to the kidneys. In addition, varying uncertainty also exists 

across studies in exposure history of subjects and in the biomarkers assessed.

Characterization of Effects. A large number of studies showing decrements in renal function associated 

with Pb exposure in humans have been published (Table 2-21). Most of these studies are of adults whose 

exposures were of occupational origin; however, a few environmental, mixed, and/or unknown exposures 

are represented, and a few studies of children are also included. Although these studies demonstrate 

adverse renal effects across the PbB range, some studies did not find associations (Buchet et al. 1980; de 

Kort et al. 1987; Fadrowski et al. 2010; Gennart et al. 1992; Huang et al. 2002; Karimooy et al. 2010; 

Mujaj et al. 2019; Omae et al. 1990). However, collectively, the body of evidence demonstrates that 

long-term exposure to Pb is nephrotoxic. General trends regarding the relationship between PbB and 

qualitative aspects of the kidney response are shown in Table 2-21. Decreased GFR and proteinuria have 

been observed in association with PbB ≤10 μg/dL; the significance of these studies is discussed in greater 

detail below. Enzymuria and proteinuria have been observed in association with PbB >10–≤50 μg/dL. 

Functional deficits, including enzymuria, proteinuria, impaired transport, and depressed GFR have been 

observed at PbB >50 μg/dL. Histopathological findings, including tubular atrophy, focal sclerosis of 

glomeruli, and periglomerular and interstitial fibrosis have also been observed at PbB >50 μg/dL. The 

overall dose-effect pattern suggests an increasing severity of nephrotoxicity associated with increasing 

PbB, with effects on glomerular filtration evident at PbBs <10 μg/dL, enzymuria and proteinuria 

becoming evident >10 μg/dL, and severe deficits in function and pathological changes occurring in 

association with PbBs >50 μg/dL.

Table 2-21. Overview of Renal Effect Associated with Chronic Exposure to Lead 

(Pb)

Mean blood lead 

concentration 

(PbB) (μg/dL)

Effects 

associated with 

Pb exposure References

≤10 Increased GFR de Burbure et al. 2006

Decreased GFR Åkesson et al. 2005; Fadrowski et al. 2010; Harari et al. 2018; Lin 

et al. 2001; Khan et al. 2010a; Kim et al. 1996a; Lin et al. 2003; 

Lin et al. 2006a, 2006b; Muntner et al. 2003; Navas-Acien et al. 

2009; Payton et al. 1994; Pollack et al. 2015; Spector et al. 2011; 

Staessen et al. 1992, 2001; Yu et al. 2004
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Table 2-21. Overview of Renal Effect Associated with Chronic Exposure to Lead 

(Pb)

Mean blood lead 

concentration 

(PbB) (μg/dL)

Effects 

associated with 

Pb exposure References

Proteinuria

chronic kidney 

disease

Navas-Acien et al. 2009; Harari et al. 2018; Pollack et al. 2015

>10–≤30 Decreased GFR Kim et al. 1996a; Staessen et al. 1990

Enzymuria Bernard et al. 1995; Chia et al. 1994; Sonmez et al. 2002; Sun et 

al. 2008b

Proteinuria Bernard et al. 1995; Chia et al. 1995a, 1995b

>30–≤50 Increased GFR Hsiao et al. 2001; Roels et al. 1994

Decreased GFR Orisakwe et al. 2007; Weaver et al. 2003a, 2003b, 2005a; 

Wedeen et al. 1975

Enzymuria Cardenas et al. 1993; Cardozo dos Santos et al. 1994; Fels et al. 

1994; Garcon et al. 2007; Gerhardsson et al. 1992; Kim et al. 

1996a; Kumar and Krishnaswamy 1995; Lin and Tai-yi 2007; 

Mortada et al. 2001; Pergande et al. 1994; Roels et al. 1994; 

Verberk et al. 1996; Verschoor et al. 1987; Weaver et al. 2003a, 

2003b, 2005a

Proteinuria Factor-Litvak et al. 1999; Fels et al. 1998; Garcon et al. 2007; 

Gerhardsson et al. 1992; Kumar and Krishnaswamy 1995; 

Mortada et al. 2001; Pergande et al. 1994; Verschoor et al. 1987

Impaired tubular 

transport

Pinto de Almeida et al. 1987

>50 Decreased GFR Baker et al. 1979; Biagini et al. 1977; Cramer et al. 1974; Ehrlich 

et al. 1998; Hong et al. 1980; Lilis et al. 1968, 1980; Onuegbu et 

al. 2011; Wedeen et al. 1975, 1979

Enzymuria Cabral et al. 2012; Gao et al. 2010; Garcon et al. 2007

Proteinuria Cabral et al. 2012; Gao et al. 2010; Garcon et al. 2007

Impaired tubular 

transport

Biagini et al. 1977; Ehrlich et al. 1998; Hong et al. 1980; Wedeen 

et al. 1975

Histopathological 

changes

Biagini et al. 1977; Cramer et al. 1974; Wedeen et al. 1975, 1979

GFR = glomerular filtration rate

Effects at Blood Pb Levels ≤10 μg/dL. Studies of renal function in populations with PbB ≤10 μg/dL 

provide evidence for effects of Pb on GFR in children and adults. Results are summarized in Table 2-22, 

with study details provided in the Supporting Document for Epidemiological Studies for Lead, Table 6. 

Most studies found that increasing PbB was associated with decreased GFR; however, one study found 

evidence for increasing GFR in children (de Burbure et al. 2006). 
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Table 2-22. Summary of Epidemiological Studies Evaluating Renal Effects at Mean Blood Lead Concentration 

(PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluatedc Resultd

Åkesson et al. 2005

Cross-sectional study; n=820 adult 

women

Median: 2.2 CCr Linear regression β coefficient (mL/minute per 

μg/dL): -0.018 (95% CI -0.03, -0.006)*

GFR Linear regression β coefficient (mL/minute per 

μg/dL): -0.02 (95% CI -0.03, -0.009)*

UPHC Linear regression β coefficient (μg/L per μg/dL): 

reported as NS

UNAG Linear regression β coefficient (U/g creatinine per 

μg/dL): reported as NS

Barry et al. 2019

Cross-sectional study; n=211 adult men 

Median: 2.5 GFR Linear regression coefficient (SE) for: 

PbB Q4: -2.71 (4.16); p=0.52

PbB continuous: -0.13 (0.28); p=0.65

Bone Pb Q4: -5.66 (4.86); p=0.25

Bone Pb Continuous: -0.15 (0.11); p=0.18

de Burbure et al. 2006

Cross-sectional study; n>800 children 

(ages 8.5–12.3 years)

Mean range (three 

locations)

Control: 2.81–3.81

Exposure: 3.64–6.51

SCr Decreased 7% (p<0.01) in Q4 (PbB 

>5.59 μg/dL), compared to Q1 (PbB 

<2.85 μg/dL)*

Sβ2M Decreased 9% (p<0.01) in Q4 (PbB 

>5.86 μg/dL), compared to Q1 (PbB 

<3.10 μg/dL)*

Fadrowski et al. 2010

Cross-sectional study; 

n=769 adolescents (ages 12–20 years)

Median: 1.5

Quartiles:

• Q1: <1.0

• Q2: 1.0–1.5

• Q3: 1.6–2.9

• Q4: >2.9

GFR • Change in GFR (mL/minute/1.73 m2) Q4 

compared to Q1: 

-6.6 (-12.6, -0.7)*

• p-Trend across Q1–Q4=0.009*

• Mean difference in GFR associated with a 

2-fold increase in blood lead 

level: -2.9 (-5.0, -0.7)*
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Table 2-22. Summary of Epidemiological Studies Evaluating Renal Effects at Mean Blood Lead Concentration 

(PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluatedc Resultd

Harari et al. 2018

Prospective cohort study; 

n=2,567 adults; with a 16-year follow-up 

period 

Median at baseline (range): 

2.5 (0.15–25.8)

Quartiles (range): 

• Q1: 1.5 (0.15–1.85)

• Q2: 2.2 (1.85–2.47)

• Q3: 2.9 (2.47–3.30)

• Q4: 4.6 (3.30–25.8)

GFR At follow-up, GFR for Q1 decreased from 89 to 

62 mL/minute from baseline

Additional decreases in GFR, mL/minute/

1.73 m2, per quartile:

• Q3: -2.6 (-4.0, -1.2); p<0.001*

• Q4: -2.3 (-3.8, -0.85); p=0.002*

• p-trend: <0.001*

CKD HR for Q4 compared to combined Q1–Q3: 

1.49 (1.07–2.08); p=0.02*

Kim et al. 1996a

Retrospective cohort study;

n=459 men

Mean: 9.9 SCr • Regression coefficient (SE) for all 

participants (μmol/L per μg/dL): 

0.033 (0.012); p=0.005*

• Regression coefficient (SE) for PbB 

≤10 (μmol/L per μg/dL): 0.060 (0.019); 

p=0.002*

Khan et al. 2010

Cross sectional study children (ages 1–

6 years) of Pb workers (n=123) and 

controls (n=123)

Median

• Control: 6.7 

• Exposed: 8.10

SCr • Serum creatinine (μmol/L): control: 52; 

exposed: 56; p≤0.01*

• Spearman’s correlation coefficient: r=0.13; 

p≤0.05*

Lin et al. 2001

Prospective, longitudinal study; 

n=110 patients with chronic renal 

insufficiency

Low PbB mean: 3.9

High PbB mean: 6.6

CCr • 18 Months CCr (mL/second) mean±SD: low 

Pb: 0.72±0.25; high Pb: 0.59±0.22 μg/dL 

(p=0.007)*

• 21 Months CCr (mL/second) mean±SD: low 

Pb: 0.70±0.24; High Pb: 0.57±0.22 μg/dL 

(p=0.006)*

• 24 Months CCr (mL/second) mean±SD: low 

Pb: 0.70±0.24; High Pb: 0.55±0.22 μg/dL 

(p=0.001)*
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Table 2-22. Summary of Epidemiological Studies Evaluating Renal Effects at Mean Blood Lead Concentration 

(PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluatedc Resultd

Lin et al. 2003

Prospective, longitudinal study; 

n=202 patients with chronic renal 

insufficiency

Baseline: 5.3

After 24-month 

observation, prior to 

chelatione

• Placebo: 5.9

• Chelation: 6.1

GFR • GFR (mL/minute/1.73 m2) following 

treatment (mean±SD): placebo 25.5±12.3; 

chelation 34.4±14.7 (p=0.01)*

• Change in GFR (mL/minute/1.73 m2) 

following treatment (mean±SD): 

placebo -6.0±5.8; chelation 2.1±5.7 

(p>0.001)*

Lin et al. 2006a

Prospective, longitudinal study; 

n=124 patients with chronic renal 

insufficiency

After 24-month 

observation, prior to 

chelatione

• Placebo: 3.0

• Chelation: 2.6

GFR • GFR (mL/minute/1.73 m2) following 

treatment (mean±SD): placebo 38.0±8.9; 

chelation 47.9±17.0 (p=0.0493)*

• Change in GFR (mL/minute/1.73 m2) 

following treatment (mean±SD): 

placebo -4.6±4.3; chelation 6.6±10.7 

(p>0.0005)*

UP (24-hour) • Urine protein (g) following chelation: placebo 

1.11±1.63; chelation: 0.92±1.16 (p=0.6236)

Lin et al. 2006b

Prospective, longitudinal study; 

n=238 patients with type II diabetes and 

progressive diabetic neuropathy

End of 12-month 

observation, prior to 

chelatione

• Placebo: 5.9

• Chelation: 7.5

GFR • GFR (mL/minute/1.73 m2) following 

treatment (mean±SD): placebo 13.1±4.5; 

chelation 18.0±7.3 (p=0.0352)*

• Decrements in GFR (mL/minute/1.73 m2) 

following treatment (mean±SD): placebo 

13.2±7.6; chelation 4.4±6.8 (p>0.0045)*

Lin-Tan et al. 2007

Placebo-controlled clinical study; n=116 

non-diabetic patients with chronic 

kidney disease

Mean after 51-month 

chelation

• Placebo: 6.0

• Chelation: 3.5 

GFR • GFR (mL/minute/1.73 m2) following 

treatment (mean±SD): placebo 23.7±10.8; 

Chelation 35.4±17.0 (p<0.0001)*

• Change in GFR (mL/minute/1.73 m2) 

following treatment (mean±SD): 

placebo -12.7±8.4; chelation -1.8±8.8 

(p>0.0001)*

UP (24-hour) UP (mean±SD): placebo 0.96±1.04; chelation: 

0.81±0.86 (p=0.3369)
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Table 2-22. Summary of Epidemiological Studies Evaluating Renal Effects at Mean Blood Lead Concentration 

(PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluatedc Resultd

Mujaj et al. 2019

Cross-sectional study; n=447 newly 

hired male workers 

Mean: 4.34 GFR β, per doubling of PbB: -0.281 (-3.07, 2.50); 

p=0.84

ACR β, per doubling of PbB: -0.071 (-0.14, 0.59); 

p=0.06

Muntner et al. 2003

Cross-sectional study; 

n=4,813 hypertensive; 

n=10,398 normotensive adultsg

Normotensive

Mean: 3.30±0.10

Quartiles

• Q1 (reference): 0.7–1.6

• Q2: 1.7–2.8

• Q3: 2.9–4.6

• Q4: 4.7–52.9

Hypertensive

Mean: 4.21±0.14 

Quartiles:

• Q1 (reference): 0.7–2.4

• Q2: 2.5–3.8

• Q3: 3.9–5.9

• Q4: 6.0–56.0

GFR Estimated GFR, mL/minute (mean±SD)

• Normotensive: 115±0.7

• Hypertensive: 95±0.7 (p<0.001)*

SCr OR for elevated SCr in hypertensive patients:

Q2: 1.47 (1.03, 2.10)*

Q3: 1.80 (1.34, 2.42)*

Q4: 2.41 (1.46, 3.97)*

p-trend: <0.001*

CKD OR for elevated CKD in hypertensive patients:

Q2: 1.44 (1.00, 2.09)

Q3: 1.85 (1.32, 2.59)*

Q4: 2.60 (1.52, 4.45)*

p-trend: <0.001*

Navas-Acien et al. 2009f

Cross-sectional study; n=14,778 adults

Mean: 1.58

Quartiles:

• Q1 (reference): ≤1.1

• Q2: >1.1–1.6

• Q3: >1.6–2.4

• Q4: >2.4

GFR ORs for reduced GFR

• Q2: 1.10 (0.80, 1.51)

• Q3: 1.36 (0.99, 1.85)

• Q4: 1.56 (1.17, 2.08)*

• p-trend: <0.001*

Albuminuria ORs for albuminuria

• Q2: 0.83 (0.66, 1.04)

• Q3: 0.92 (0.76, 1.12)

• Q4: 1.19 (0.96, 1.47)

• p-trend: <0.001*
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Table 2-22. Summary of Epidemiological Studies Evaluating Renal Effects at Mean Blood Lead Concentration 

(PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluatedc Resultd

Payton et al. 1994

Cross-sectional study; n=744 men

Mean: 8.1 CCr Regression coefficient, β (SE), mL/minute per 

μg/dL: -0.0403 (0.0198); p=0.0426*

Pollack et al. 2015

Prospective cohort study; 

n=257 premenopausal women

Median: 0.88

Tertiles:

• T1 (reference): <0.72

• T2: 0.72–1.10

• T3: >1.10

GFR • Regression β coefficient (% change per 

twofold increase in PbB): 

-3.73 (-6.55, -0.83)*

• Regression β coefficient (% change per 

2-fold increase in PbB) by tertile:

o T2: -8.28 (-14.07, -2.5); p<0.05*

o T3: -6.79 (-13.10, -0.49); p<0.05*

SCr Regression β coefficient (% change per 2-fold 

increase in PbB): 3.47 (0.86, 6.16)

BUN Regression β coefficient (% change per 2-fold 

increase in PbB): -0.13 (-4.97, 4.96)

Blood albumin Regression β coefficient (% change per 2-fold 

increase in PbB): -0.38 (-1.28, 0.52)

Blood glucose Regression β coefficient (% change per 2-fold 

increase in PbB): 0.93 (-0.28, 2.15)

Blood protein Regression β coefficient (% change per 2-fold 

increase in PbB): -0.76 (-1.61, 0.09)
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Table 2-22. Summary of Epidemiological Studies Evaluating Renal Effects at Mean Blood Lead Concentration 

(PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluatedc Resultd

Spector et al. 2011f

Cross-sectional study; n=3,941 adults

Mean (all): 1.7 

Mean (≥60 years)

Tertiles (all):

• T1 (reference): ≤1.3

• T2: >1.3–2.2

• T3: >2.2

GFR • All participants: change in GFR 

(mL/minute/1.73 m2) per 2-fold increase in 

PbB: -1.9 (-3.2, -0.7)*

• All participants: OR for reduced GFR by 

tertiles

o T2: -1.6 (-4.2, 1.0)

o T3: -3.3 (-5.3, -1.4)*

o p-trend: 0.001*

• Participants ≥60 years: change in GFR 

(mL/minute/1.73 m2) per 2-fold increase in 

PbB: -4.5 (-5.6, -3.3)

Staessen et al. 1992

Cross-sectional study; n=1,981 adults 

(965 men; 1,016 women)

Mean men: 11.4

Mean women: 7.5 

CCr Partial regression coefficient (SE) for CCr 

(mL/minute per log μg Pb/L):

• Men: -13.1 (4.0); p≤0.001*

• Women: -30.1 (3.4); p≤0.001*

Staessen et al. 2001

Cross-sectional study; n=200 17-yearold adolescent girls

Mean control: 1.4

Mean exposed area 1: 1.8

Mean exposed area 2: 2.7

Serum cystatin C Change in per 2-fold increase in PbB: +3.6% 

(1.5, 5.7)*

Urine β2-microblobulin Change per 2-fold increase in PbB: +16.0% 

(2.7, 31)*

Tsaih et al. 2004

Prospective study; n=448 (66–72 years 

of age); n=26 participants with diabetes, 

and n=115 participants with 

hypertension

Mean at baseline: 6.5 

Mean at follow-up: 4.5

SCr Baseline regression β coefficients (mg/dL per ln 

μg/dL):

• All participants: 0.009 (SE 0.006)

• Participants with diabetes: 0.076 (SE 

0.023); p<0.05*

• Participants with hypertension: 0.008 (0.010); 

Follow-up (4–8 years) regression β coefficients 

(mg/dL per ln μg/dL): 

• Participants with diabetes: 0.223 (SE 0.183); 

Participants with hypertension: 0.352 

(0.097); p<0.05*
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Table 2-22. Summary of Epidemiological Studies Evaluating Renal Effects at Mean Blood Lead Concentration 

(PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluatedc Resultd

Yu et al. 2004

Prospective longitudinal study; 

n=121 patients with chronic renal 

insufficiency; progression of renal 

insufficiency was evaluated for 

48 months

Mean: 4.2 GFR Change in GFR (mL/minute/1.73 m2 per 

1 μg/dL): -4.0 (p=0.0148)*

aSee the Supporting Document for Epidemiological Studies for Lead, Table 6 for more detailed descriptions of studies. bParticipants had no known occupational exposure to Pb.

cA variety of methods are used to estimate GFR (Chao et al. 2015). Each has limitations for application to both clinical evaluations and epidemiology. The 

preferred method is to measure the clearance of substance from plasma that is known to be eliminated solely by glomerular filtration and is not reabsorbed in the 

renal tubule. Typically, in the clinical setting, this is accomplished with intravenous administration of GFR markers, such as 125I-iothalmate, for the radiocontrast 

agent (e.g., iohexol). These procedures are feasible in the clinical setting, but not in epidemiology studies in which invasive procedures and administration of 

such agents is not practical or possible. Clearance of endogenous creatinine is an alternative that has had wide use in epidemiology. However, it requires 

concurrent measurements of serum creatinine and the rate of urinary excretion of creatinine, which can be accurately determined only with a carefully timed urine 

sample that can represent the amount of glomerular filtrate formed over a given time interval. Achieving accurately timed urine samples requires a rigidly 

implemented and supervised collection protocol, which is not always feasible, particularly in large-scale epidemiology studies. Alternatives to clearance methods 

are measurement of endogenous metabolites in plasma whose clearance approximates GFR. Typically, this is achieved with endogenous creatinine or 

cystatin C. The serum concentration of these two metabolites strongly correlates with GFR; however, the relationship between concentration and GFR is also 

affected by other variables, including age, sex, race, and creatinine muscle mass. Several approaches have been developed to improve estimates of GFR from 

serum creatinine that attempt to account for these co-variables. These methods rely on multiple variable regression models that relate GFR to serum creatinine 

and other significant determinants of GFR (Cockcroft and Gault 1976; Levey et al. 1999, 2009). An evaluation of two of the more commonly used methods for 

estimating GFR from serum creatinine, the CKD-EPI and MDRD equations, found that both achieved a median difference between calculated and measured GFR 

(from clearance measurements) that range from 2 to 6 mL/minute per 1.73 m2 (Levey et al. 2009). The interquartile range in the difference was approximately 18 

mL/minute per 1.73 m2 in a validation dataset consisting of data for 3,986 study subjects. This suggests that approximately 25% of the GFR estimates from these 

methods are expected to be in error of the true GFR by >18 mL/minute (or approximately 15% of the GFR in a healthy adult, 120 mL/minute). dAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

eBlood lead estimated by EDTA mobilization.

f

Population from NHANES.

ACR = albumin-to-creatinine ratio; BUN = blood urea nitrogen; CCr = creatinine clearance; CI = confidence interval; CKD = chronic kidney disease; 

CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; EDTA = ethylenediaminetetraacetic acid; GFR = glomerular filtration rate; HR = hazard ratio; 

MDRD = Modification of Diet in Renal Disease; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; Pb = lead; Sβ2M = serum 

β2-microglobulin; SCr = serum creatinine concentration; SD = standard deviation; SE = standard error; UNAG = urine N-acetyl-β-D-glucosaminidase; UP = urine 

protein; UPHC = urine human complex-forming protein (α1-microglobulin) 
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2. HEALTH EFFECTS

A few studies have examined associations between low PbB and GFR in children and adolescents (de 

Burbure et al. 2006; Fadrowski et al. 2010; Khan et al. 2010a; Staessen et al. 2001). de Burbure et al. 

(2006) examined serum creatinine in a cross-sectional study of approximately 800 children (age range 

8.5–12.3 years) who resided near nonferrous smelters. Serum creatinine and cystatin C decreased 

(indicating an increase in GFR) by approximately 7% in the upper quartile PbB group (mean 7.8 μg/dL) 

compared to the lowest quartile (<2.84 μg/dL). Fadrowski et al. (2010) examined adolescents (12–

20 years, n=769). GFR (estimated from serum cystatin C) decreased with increasing PbB. In the upper 

quartile PbB group (>2.9 μg/dL), the decrease was 6.6 mL/minute/1.73m2

, which represented 

approximately a 6% decrease in GFR. In a smaller study of younger children of Pb-exposed workers 

(ages 1–6 years; n=123; PbB: 8.1 μg/dL), serum creatinine was higher compared to controls (ages 1–

6 years; n=123; PbB: 6.7 μg/dL) (Khan et al. 2010), indicating decreased GFR. Several factors may have 

contributed to the different outcomes in these studies (decrease or increase in GFR), including a different 

age range of the study groups, different approaches to adjusting outcome metrics for confounders, and 

different exposures (e.g., co-exposure to Pb, cadmium, and mercury in the de Burbure et al. 2006 study).

A smaller study of adolescents (17 years of age, n=200) also found evidence for higher serum cystatin C 

(indicating lower GFR) in a group with a mean PbB of 2.7 μg/dL compared to a group with a mean PbB 

of 1.4 μg/dL (Staessen et al. 2001).

A larger number of studies have been conducted in adult populations (Table 2-22). These include several 

prospective studies (Harari et al. 2018; Lin et al. 2001, 2003, 2006a, 2006b; Lin-Tan et al. 2007; Pollack 

et al. 2015; Tsaih et al. 2004; Yu et al. 2004). Most of these studies have examined changes in GFR in 

patients who had ongoing renal disease and depressed GFR (Lin et al. 2001, 2003, 2006a, 2006b; Lin-Tan 

et al. 2007; Yu et al. 2004). In adult participants with a median baseline PbB of 2.5 μg/dL, GFR 

decreased from 89 to 62 mL/minute after 16 years; GFR further decreased with increasing PbB (Harari et 

al. 2018). In addition, the risk of CKD was increased in participants with a median PbB of 4.6 μg/dL 

compared to participants with a PbB range of 0.15–3.30 μg/dL. In adult patients who had indications of 

renal insufficiency (e.g., serum creatinine concentration >1.5 mg/dL), GFR increased following repeated 

chelation therapy with calcium disodium ethylenediaminetetraacetic acid (EDTA) (Lin et al. 2003, 

2006b). Yu et al. (2004) estimated the decline in GFR in patients with renal insufficiency to be 

approximately 4 mL/minute/1.73 m2 per 1 μg/dL increase in PbB. A prospective study of premenopausal 

women estimated the decline in GFR to be approximately 3.73% per doubling of PbB (Pollack et al. 

2015). The median PbB in the cohort was 0.88 μg/dL. A prospective study of older males found an 

association between increased serum creatinine (indicative in decreasing GFR) and PbB in subjects 
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2. HEALTH EFFECTS

diagnosed with hypertension or diabetes. Mean PbBs were 6.5 μg/dL at baseline and 4.5 μg/dL at followup (Tsaih et al. 2004). 

Several large cross-sectional studies have examined associations between PbB and GFR in adults 

(Table 2-22). Three large studies relied on data collected in the NHANES (Munter et al. 2003; 

Navas-Acien et al. 2009; Spector et al. 2011). The Munter et al. (2003) study, which included 

4,813 hypertensive subjects and 10,938 normotensive subjects, found an association between increasing 

PbB and decreasing GFR in the hypertensive group. Navas-Acien et al. (2009) included 14,788 adult 

subjects and reported decreased GFR (<60 mL/minute/1.73 m2

) among participants in the highest PbB 

quartile (mean >2.4 μg/dL). Spector et al. (2011) included 3,941 adults. In the age group ≥60 years, the 

estimate for the decline in GFR was 4.5 mL/minute/1.73 m2 per doubling of PbB. The mean PbB in this 

group was 2.2 μg/dL. Several smaller cross-sectional studies have also found associations between 

increasing PbB and decreasing GFR in adult populations in which mean or median PbBs were <10 μg/dL 

(Åkesson et al. 2005; Payton et al. 1994; Staessen et al. 1992). Collectively, these studies indicate that Pb 

exposure is associated with decreasing GFR, and effects on GFR are evident in populations with PbB 

<10 μg/dL. People with on-going renal disease or hypertension may be more vulnerable to the effects of 

Pb. Estimates of the decline in GFR associated with increasing PbB vary across studies, with some 

studies indicating declines of 3–6 mL/minute/1.73 m2 at PbB <10 μg/dL (Pollack et al. 2015; Spector et 

al. 2011; Yu et al. 2004). However, as noted above, the estimates may be inflated by reverse causality for 

associations between decreasing GFR and increasing Pb body burden.

Associations Between Bone Pb and Renal Effects. Studies evaluating associations between bone Pb and 

renal function are summarized in Table 2-23. Weaver et al. (2003a, 2005a, 2005b, 2006, 2009) conducted 

a series of studies evaluating associations between bone Pb and metrics of renal GFR (e.g., serum 

creatinine concentration, creatinine clearance calculated from serum creatinine concentration, BUN) and 

renal tubular injury (urinary NAG) in current and former Pb workers in South Korea. These studies 

provide evidence that tibia Pb is positively associated with serum creatinine concentration in older 

workers (Weaver et al. 2003a, 2005a, 2005b) and in male, but not female, workers (Weaver et al. 2009); 

and negatively associated with tibia Pb and creatinine clearance in male workers (Weaver et al. 2009) and 

in workers with vitamin D receptor (VDR) genotypes BB and Bb (Weaver et al. 2006). Tibia Pb was also 

positively associated with urinary NAG in older workers (Weaver et al. 2005a). Studies of participants of 

the longitudinal Normative Aging Study have found positive associations between tibia Pb and serum 

creatinine concentration in participants with diabetes (Tsaih et al. 2004) and with ALAD genotypes 1-2 

and 2-2 (Wu et al. 2003a). One cross-sectional study did not find an association between tibia Pb and 
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estimated GFR (Barry et al. 2019). A small case-control study did not find an association between tibia 

Pb and end-stage renal disease. Taken together, the results suggest that long-term exposure to Pb is 

associated with diminished renal function.

Table 2-23. Associations Between Bone Pb and Renal Function

Reference Population

Effect

GFR SCr CCr NAG RBP BUN ESRD

Barry et al. 

2019

211 adult 

men

0 (T) – – – – – –

Muntner et 

al. 2007

55 adult 

ESRD 

patients; 

53 controls

– – – – – – 0 T

Tsaih et al. 

2004

448 mena – 0 T

↑ T (diabetics)

0 P

0 P (diabetics)

– – – – –

Weaver et 

al. 2003a

803 adult Pb 

workers; 

135 controlsb

– 0 T (all workers)

↑ T (>46 yearsc)

0 Tc 0 Tc 0 Tc 0 Tc –

Weaver et 

al. 2005a

803 adult Pb 

workersb

– ↑ T (>46 yearsc) – ↑ T 

(>46 years)c

– – –

Weaver et 

al. 2005b

795 adult Pb 

workersb

– ↑ T (>40.6 years) – – – – –

Weaver et 

al. 2006

647 adult Pb 

workersb

– 0 T (VDRd)

0 T (VDRe)

0 P (VDRd)

0 P (VDRe)

0 T 

(VDRd)

↓ T 

(VDRe)

0 P 

(VDRd)

0 P 

(VDRe)

– – – –

Weaver et 

al. 2009

398 adult 

male and 

139 female 

Pb workersb

– ↑ T (M)

0 T (F)

↓ T (M)

0 T (F)

– – 0 T (M)

↑ T (F)

–
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Table 2-23. Associations Between Bone Pb and Renal Function

Reference Population

Effect

GFR SCr CCr NAG RBP BUN ESRD

Wu et al. 

2003a

709 mena – ↑ T (ALADf)

0 P

0 T

↓ P

– – – –

aParticipants in the Normative Aging Study. 

bCurrent and former Pb workers in South Korea. 

cData were analyzed for all study participants and by age tertiles (Tertile 1: ≤36 years old; Tertile 2: 36.1–46 years 

old; Tertile 3: >46 years old). Any association observed in a specific age tertile are noted. If no association was 

observed for all participants and for all age tertiles, this is noted with a single entry of 0.

dVitamin D receptor genotype bb. eVitamin D receptor genotypes BB and Bb.

f

Interaction between ALAD genotype (ALAD 1-2/2-2 versus ALAD 1-1).

↑ = positive association; ↓ = inverse association; 0 = no association; – = not reported; ALAD = aminolevulinic acid 

dehydratase; BUN = blood urea nitrogen; CCr = creatinine clearance; ESRD = end-stage renal disease; F = female; 

M = male; NAG = N-acetyl-D-glucosaminidase; P = patella; Pb = lead; RBP = retinol binding protein; SCr = serum 

creatinine concentration; T = tibia; VDR = vitamin D receptor

Mechanisms of Action. Several mechanisms have been established or proposed as mechanisms for 

kidney damage associated with exposure to Pb, including general mechanisms of Pb-induced toxicity 

(reviewed in Section 2.21). Mechanisms of renal damage associated with Pb exposure were recently 

reviewed in detail by EPA (2014c), including oxidative stress, inflammation, apoptosis of glomerular and 

tubular cells, alterations in renal gangliosides (plasma membrane lipids that play a role in the control of 

GFR), changes in renal vascular tone, and alterations in the renin-angiotensin-aldosterone system. As 

discussed in Pb Section 3.1.2 (Toxicokinetics, Distribution), Pb is distributed to the kidney, providing a 

toxicokinetic mechanism for direct effects to the kidney. 

2.12 DERMAL

No epidemiological studies evaluating adverse dermal effects of chronic exposure to Pb were identified.

2.13 OCULAR

Few epidemiological studies have evaluated non-neurological ocular effects of Pb exposure, with studies 

examining associations with macular degeneration (Erie et al. 2009; Park et al. 2015) and cataract 

development (Schaumberg et al. 2004). In a cross-sectional study of 3,865 participants with a mean PbB 

of 2.69 μg/dL participating in the Korea National Health and Nutrition Examination study (2008–2011), 
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the risks of age-related early (adjusted OR 1.12; 95% CI 1.02, 1.23; p=0.009) and late (adjusted OR 1.25; 

95% CI 1.05, 1.50; p=0.015) macular degeneration were increased (Park et al. 2015). A cross-sectional 

study of human donor eyes with (n=25) and without (n=36) age-related macular degeneration found no 

association between Pb concentration in the retinal pigment epithelium-choroid complex and subjects 

with age-related macular degeneration and normal subjects (Erie et al. 2009). A prospective study of

642 men participating in the Normative Aging Study found no association between PbB (range: 1.0–

35.0 μg/dL) and risk of cataracts, although the risk of cataracts was increased in association with tibia Pb 

levels (Schaumberg et al. 2004). A prospective cohort study of 634 male participants of the Normative 

Aging Study found an association between patellar bone Pb concentration and incidence of primary openangle glaucoma, with an HR of 5.06 (95% CI 1.61, 15.88; p=0:005) (Wang et al. 2018). 

2.14 ENDOCRINE

Effects of chronic exposure to Pb on reproductive hormones are reviewed in Section 2.17 (Reproductive). 

Overview. Effects on endocrine systems have been evaluated in several epidemiological studies in adults 

(general populations and workers), adolescents, and children. Investigations have focused on effects on 

thyroid function, cortisol levels, vitamin D levels, serum levels of other growth factors, and diabetes. 

Associations between PbB and thyroid function, assessed by measurement of serum thyroid hormone 

levels, is the most investigated endocrine outcome, although results do not demonstrate a consistent 

pattern of effect or dose-response relationships. Other endocrine endpoints have been evaluated in only a 

few studies.

The following endocrine effects have been associated with PbB: 

• ≤10 μg/dL:

o Altered serum levels of thyroid hormones (thyroxine [T4], triiodothyronine [T3], thyroidstimulating hormone [TSH]); evaluated in multiple studies. Few effects were observed and 

results do not demonstrate consistent patterns of effects or exposure-response relationships.

o Altered salivary cortisol awakening response in pregnant women.

o Increased stress-induced salivary cortisol response in children.

o Decreased serum levels of insulin-like growth factor-1 (IGF-1) in children.
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• >10 μg/dL:

o Altered serum levels of thyroid hormones (T4, T3, TSH); evaluated in a few studies; results 

do not demonstrate consistent patterns of effects or exposure-response relationships.

o Increased thyroid peroxidase antibodies.

o Decreased serum levels of vitamin D; evaluated in a few studies in children with consistent 

results.

Measures of Exposure. Studies evaluating the association between endocrine effects and Pb exposure 

evaluate exposure by measurement of PbB.

Confounding Factors and Effect Modifiers. Results of epidemiological studies on endocrine effects 

have not been consistent. In general, statistical analyses were not rigorous and potential confounding 

factors and effect modifiers were not fully considered. Exposure to other metals and other chemical with 

endocrine effects is an important confounding factor to consider when interpreting study results. 

Although a few studies were of large populations (e.g., NHANES participants); most studies examined 

relatively small populations and used cross-sectional designs. 

Characterization of Effects. General trends for studies showing a relationship between PbB and 

endocrine effects are shown in Table 2-24. Several studies have evaluated associations between PbB and 

effects on serum levels of thyroid hormones (T4, T3, and TSH) at mean PbB ranging from <1 to 

71 μg/dL; an overview of study results is presented in Table 2-25. Based on evaluation of thyroid 

hormones, it is unclear if PbB is associated with altered thyroid function. At PbB ≤10 μg/dL, results of 

epidemiological studies, including cross-sectional studies of large NHANES populations, show 

associations between PbB and some alterations in serum levels of thyroid hormones; however, results do 

not demonstrate apparent patterns or exposure response relationships (see discussion below on Effect at 

Blood Pb Levels ≤10 μg/dL). Increased thyroid peroxidase (TPO) antibodies were observed at PbB 

≤10 μg/dL, although TSH was not increased. Epidemiological studies at PbB >10 μg/dL, conducted in 

smaller populations (n=25–309), show more effects on thyroid hormones than observed at PbB 

≤10 μg/dL. However, similar to studies at lower PbB, results are inconsistent. Kahn et al. (2014) found 

decreased T4 (p<0.0001) and increased TPO antibodies (p=0.0002) during the second trimester of 

pregnancy in women (n=144) with mean PbB 20.00 μg/dL compared to women (n=147) with PbB of 

5.57 μg/dL; no increase in TSH was observed. The adjusted OR (95% CI) for testing positive for TPO 

antibodies was 2.41 (1.563, 3.82). Results indicate that autoimmunity is a potential mechanism for 

altered thyroid function. This finding has not been corroborated in other studies.
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Table 2-24. Overview of Endocrine Effects Associated with Chronic Exposure to 

Lead (Pb)

Mean PbB 

(μg/dL)

Effects associated with Pb 

exposure References

≤10 Altered levels of thyroid hormonesa,

and increased TPO antibodies 

Abdelouahab et al. 2008; Dundar et al. 2006; Luo and 

Hendryx 2014; Mendy et al. 2013; Nie et al. 2017; 

Yorita Christensen 2013

Altered salivary cortisol levels Braun et al. 2014; Gump et al. 2008

Decreased serum IGF-1 Fleisch et al. 2013

>10–30 Altered levels of thyroid hormonesa

and increased TPO antibodies

Gustafson et al. 1989; Kahn et al. 2014; Lamb et al. 

2008; Lopez et al. 2000

>30–50 Decreased serum vitamin D level Luo and Hendryx 2014; Mahaffey et al. 1982; Rosen et 

al. 1980

>50 Altered levels of thyroid hormonesa Lopez et al. 2000; Pekcici et al. 2010; Robins et al. 

1983; Singh et al. 2000; Tuppurainen et al. 1988 

Decreased serum vitamin D level Rosen et al. 1980

aThyroid hormones: T4, T3, and/or TSH.

IGF-1 = insulin-like growth factor-1; PbB = blood lead concentration; T3 = triiodothyronine; T4 = thyroxine; 

TSH = thyroid-stimulating hormone; TPO = thyroid peroxidase

Table 2-25. Effects on Thyroid Hormones Associated with Blood Lead 

Concentration (PbB)

Mean PbB 

(μg/dL)

Number of 

participants 

T4 T3

Total Free Total Free TSH Reference

PbB ≤10 μg/dL

0.93 1,109 adolescentsa 0 0 0 0 0 Chen et al. 2013

1.3 1,587 adultsa ↓ 0 0 0 0 Yorita Christensen 2013

1.52 4,652 adultsa ↓ 0 0 0 0 Mendy et al. 2013

1.74 87 women 0 – 0 – ↓ Abdelouahab et al. 2008

1.75 4,409 adultsa 0 0 0 0 0 Chen et al. 2013

1.82 6,231 adultsa – 0 – ↑ 0 Luo and Hendryx 2014

3.5 3,350 women – – – – 0 Nie et al. 2017

4.1 2,278 men – – – – 0 Nie et al. 2017

6.3b 24 infantsb – 0 – – 0 Iijama et al. 2007

7.3 42 adolescents – ↓ – 0 0 Dundar et al. 2006

PbB >10 μg/dL

20.00 291 adults – ↓ – – 0 Kahn et al. 2014

20.56 309 pregnancyc – ↓ – – – Lamb et al. 2008

24.1 151 adults 0 0 – – 0 Schumacher et al. 1998

25 68 children 0 0 – – – Siegel et al. 1989
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Table 2-25. Effects on Thyroid Hormones Associated with Blood Lead 

Concentration (PbB)

Mean PbB 

(μg/dL)

Number of 

participants 

T4 T3

Total Free Total Free TSH Reference

31 77 adults – 0 – 0 0 Erfurth et al. 2001

<33.19c 6,231 adultsa 0 – – ↑ 0 Luo and Hendryx 2014

39.5 25 adults ↑ – – – ↑ Gustafson et al. 1989 

50.9 75 adults ↑ ↓ 0 – 0 Lopez et al. 2000

51.9 47 adults ↓ ↓ – – 0 Robins et al. 1983

51.9 58 adults 0 – ↓ – ↑ Singh et al. 2000

56.1 176 adults ↓ ↓ 0 – 0 Tuppurainen et al. 1988

71.1 65 adults – ↑ – ↑ ↑ Pekcici et al. 2010

aNHANES population.

bUmbilical cord PbB; assessments in infants.

cMean not reported.

↑ = Increased; ↓ = decreased; 0 = no change; – = not assessed; NHANES = National Health and Nutrition 

Examination Survey; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone

Studies also have investigated alterations in serum levels of vitamin D at PbB >30 μg/dL (Mahaffey et al. 

1982). In children and adolescents, serum levels of 1,25-dihydroxycholecalciferol were negatively 

associated with PbB over a range of 30–120 μg/dL (Mahaffey et al. 1982). Similar results were observed 

for vitamin D in children with PbB >50 μg/dL (Rosen et al. 1980). However, in children with PbB 

<10 μg/dL, no associations between PbB and vitamin D levels were observed (Kemp et al. 2007) (see 

discussion below on Effect at Blood Pb Levels ≤10 μg/dL). Studies investigating associations between 

PbB and other endocrine outcomes (salivary cortisol levels, serum levels of growth factors and diabetes) 

were conducted in populations with PbB ≤10 μg/dL (see discussion below on Effect at Blood Pb Levels 

≤10 μg/dL).

Effect at Blood Pb Levels ≤10 μg/dL. Epidemiological studies of endocrine effects associated with PbB 

≤10 μg/dL have examined thyroid function, as assessed by serum levels of thyroid hormones 

(Abdelouahab et al. 2008; Chen et al. 2013; Dundar et al. 2006; Iijama et al. 2007; Luo and Hendryx 

2014; Mendy et al. 2013; Yorita Christensen 2013), cortisol levels and cortisol responses to stress (Braun 

et al. 2014; Gump et al. 2008), vitamin D levels (Kemp et al. 2007), IGF-1 levels (Fleisch et al. 2013), 

and diabetes (Moon 2013); study details are summarized in Supporting Document for Epidemiological 

Studies for Lead, Table 7. Studies examining thyroid function, including several large cross-sectional 

studies of NHANES populations (Chen et al. 2013; Mendy et al. 2013; Luo and Hendryx 2014; Yorita 

Christensen 2013), report inconsistent results; see Table 2-25. Results of NHANES studies at low PbB 
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(range of means: 0.93–1.82 μg/dL) are mixed, showing decreased total T4 and no change for free T4 

(Mendy et al. 2013; Yorita Christensen 2013), and no change for total or free T4 (Chen et al. 2013; Luo 

and Hendryx 2014). The NHANES studies did not show associations between PbB and T3 or TSH 

levels, except for an increase in FT3 (Luo and Hendryx 2014). In smaller studies, decreased TSH and 

increased free T4 were observed at PbB of 3.10 and 7.3 μg/dL, respectively (Abdelouahab et al. 2008; 

Dundar et al. 2006). In a large, cross-sectional study, increased TPO antibodies were observed in women 

with PbBs >2.9 μg/dL, with a significant positive trend (p=0.008) for increased TSH; in men, there was 

no association (Nie et al. 2017). Thus, few effects on measures of thyroid function have been observed at 

PbB ≤10 μg/dL, and results do not demonstrate consistent patterns of effects or exposure-response 

relationships. Results of studies examining other endocrine effects associated with PbB have not been 

corroborated. Study findings include: associations between PbB and decreased cortisol awakening 

response during pregnancy at PbB ≥5.1 μg/dL (Braun et al. 2014); enhanced salivary cortisol response to 

cold stress in children at PbB 1.1–6.2 μg/dL (Gump et al. 2008); no association between PbB and basal 

cortisol levels or cortisol levels under stress (Ngueta et al. 2018); no association between PbB and serum 

vitamin D in children at PbB means 4.94–6.54 μg/dL (Kemp et al. 2007); decreased serum IGF-1 in 

children at PbB 5–9 μg/dL (Fleisch et al. 2013); and no association between PbB and diabetes in children 

at mean PbB 4.08 μg/dL (Moon 2013). 

Mechanisms of Action. Adverse effects on the endocrine system (non-reproductive effects) associated 

with chronic Pb exposure have not been established; therefore, mechanisms of toxicity have not been 

identified. Thyroid function could be decreased through stimulation of autoimmunity to the thyroid 

gland, as shown by increased thyroid peroxidase antibodies (Kahn et al. 2014). In addition, general 

mechanisms of toxicity (reviewed in Section 2.21) of Pb would likely be involved in any endocrine 

toxicity.

2.15 IMMUNOLOGICAL

Overview. This section of the profile summarizes the immunological effects of Pb, exclusive of asthma, 

which is summarized in Section 2.5. Studies conducted in animal models have shown that Pb can perturb 

the humoral and cell-mediated immune systems, leading to decreased resistance to disease, sensitization, 

autoimmunity, and inflammation (EPA 2014c). These studies support epidemiological evidence of 

associations between Pb exposures (as indexed to PbB) and changes in biomarkers of humoral and cellmediated immunity. 
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The following immunological effects have been associated with PbB:

• ≤10 μg/dL:

o Increases in susceptibility to infections.

o Sensitization to allergens.

o Changes in indicators of humoral immunity (immunoglobulins, B-cells); demonstrated in 

several studies.

o Changes in indicators of cell-mediated immunity (T-cells, eosinophils, neutrophils); 

demonstrated in several studies.

o Changes in indicators of inflammatory response (circulating inflammation cytokines).

• >10 μg/dL:

o Changes in indicators of humoral immunity (immunoglobulins, B-cells).

o Changes in indicators of cell-mediated immunity (T-cells, natural killer [NK]-cells, 

neutrophils).

o Changes in indicators of inflammatory response (inflammatory response of activated 

monocytes).

o Decreases in circulating complement.

Measures of Exposure. Studies of associations between Pb exposure and immunological outcomes have 

relied on PbB as a biomarker of exposure. Most studies have been cross-sectional in design, which 

increases uncertainty in the interpretation of the results since the exposure history of the subjects is not 

necessarily indicated by the cross-sectional PbB measurement.

Confounding Factors and Effect Modifiers. The immune system is responsive to a multitude of 

environmental and physiological factors, which can be confounding factors or effect modifiers in studies 

of associations between Pb exposure and immunological outcomes. Factors that have been considered in 

some studies, but not consistently across studies, include age, sex, smoking, physical activity, allergen 

exposures, history of inflammatory disease, SES factors, recreational activities, and co-exposures to other 

chemicals. Immunological outcomes observed in epidemiological studies may also be secondary to other 

systemic effects of Pb (e.g., hematological, splenic gene expression) that affect the immune system.

Characterization of Effects. Table 2-26 lists epidemiological studies that have found associations 

between PbB and immunological outcomes, grouped by population PbB (typically mean or geometric 
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mean). Several studies have found alterations in immunological endpoints in association with PbB over 

the range <10–>50 μg/dL. 

Table 2-26. Overview of Immunological Effects Associated with Chronic 

Exposure to Lead (Pb)

Mean PbB 

(μg/dL)

Effects associated with Pb 

exposure References

≤10 Increased susceptibility to 

infections

Krueger and Wade 2016; Park et al. 2019

Sensitization to allergens Jedrychowski et al. 2011; Pizent et al. 2008

Changes in indicators of 

humoral immunitya

Hon et al. 2009, 2010; Karmaus et al. 2005; Min and Min 

2015; Pizent et al. 2008; Sarasua et al. 2000; Wells et al. 

2014; Xu et al. 2015

Changes in indicators of cellmediated immunitybBoscolo et al. 2000; Conterato et al. 2013; Hsiao et al. 

2011; Karmaus et al. 2005; Sarasua et al. 2000; Wells et 

al. 2014

Changes in indicators of 

inflammatory responsec

Kim et al. 2007, Sirivarasai et al. 2013; Songdej et al. 2010

>10–30 Changes in indicators of 

humoral immunitya

Heo et al. 2004, Lutz et al. 1999; Sun et al. 2003; Wang et 

al. 2017a

Changes in indicators of cellmediated immunitybAlomran and Shleamoon 1988; Bergeret et al. 1990; 

Boscolo et al. 1999; Di Lorenzo et al. 2006; Fischbein et al. 

1993; Kimber et al. 1986; Mishra et al. 2003; Queiroz et al. 

1993, 1994; Sata et al. 1998; Valentino et al. 1991, 2007; 

Zhao et al. 2004

Changes in indicators of 

inflammatory responsec

Valentino et al. 2007

>30–50 Changes in indicators of 

humoral immunitya

Ewers et al. 1982; Heo et al. 2004; Pinkerton et al. 1998

Changes in indicators of cellmediated immunitybConterato et al. 2013; Fischbein et al. 1993; Garcia-Leston 

et al. 2012; Niu et al. 2015; Pinkerton et al. 1998

>50 Changes in indicators of 

humoral immunitya

Basaran and Undeger 2000

Changes in indicators of cellmediated immunitybBasaran and Undeger 2000; Mishra et al. 2010; Undeger 

et al. 1996

Decreases in circulating 

complement levels

Ewers et al. 1982; Undeger et al. 1996

aImmunoglobulins, B-cells. bT-cells, natural killer (NK) cells, eosinophils, neutrophils and related receptors and cytokines. cCirculating cytokines (e.g., C-reactive protein [CRP], interleukin-6 [IL-6], tumor necrosis factor-alpha [TNFα]).

Humoral immunity. Numerous epidemiological studies have examined associations between Pb exposure 

and circulating levels of immunoglobulins. These studies provide evidence that exposure to Pb is 

associated with increases in circulating IgE in children (Hon et al. 2009, 2010; Karmaus et al. 2005; Lutz 
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et al. 1999; Sun et al. 2003; Wang et al. 2017a) and in adults (Heo et al. 2004; Sarasua et al. 2000). IgE is 

an important mediator of hypersensitivity reactions and inflammation and Pb-induced perturbations in IgE 

may contribute to associations between Pb exposure and sensitization and inflammation. Although some 

studies have found changes in levels of other immunoglobins, the evidence for these effects is not as 

strong as for IgE (Alomran and Shleamoon 1988; Anetor and Adeniyi 1998; Ewers et al. 1982; Kimber et 

al. 1986; Pinkerton et al. 1998; Queiroz et al. 1994b; Ündeger et al. 1996). The association between 

circulating IgE levels and PbB appears to extend to PbB levels <10 μg/dL (Karmaus et al. 2005; Min and 

Min 2015; Pizent et al. 2008; Sarasua et al. 2000; Wells et al. 2014).

T-cells. T-cells are important mediators of immunity to self-cells (e.g., cancer cells and cells infected 

with virus) and for activation of B-cells and humoral immunity. Epidemiological studies provide 

evidence that exposure to Pb is associated with decreases in T-cell abundance in children (Karmaus et al. 

2005; Lutz et al. 1999; Sarasua et al. 2000; Zhao et al. 2004) and increases in abundance in adults 

(Boscolo et al. 1999, 2000; Sarasua et al. 2000). Several studies in adults found no consistent effect on 

T-cell abundance (Fischbein et al. 1993; Mishra et al. 2010; Pinkerton et al. 1998; Ündeger et al. 1996; 

Yücesoy et al. 1997b). Most of the studies on T-cell abundance did not differentiate specific classes of 

T-cell population affected; however, evidence is stronger for effects on CD3+ cells (Karmaus et al. 2005; 

Lutz et al. 1999; Sarasua et al. 2000; Zhao et al. 2004), with some studies finding effects on abundances 

of CD4+ (T helper) or CD8+ (T cytotoxic) cells (Boscolo et al. 1999, 2000; Karmaus et al. 2005; Sarasua 

et al. 2000). The association between circulating T-cell abundance and PbB appears to extend to PbB 

levels ≤10 μg/dL (Boscolo et al. 2000; Karmaus et al. 2005; Sarasua et al. 2000). 

Neutrophils. Neutrophils are phagocytic cells that function in the immune defense against bacterial 

infections. Epidemiological studies have found associations between Pb exposure and neutrophil 

function. The effects on cultured human PMNs in populations that had mean PbB >10 μg/dL includes 

suppression of chemotaxis, phagocytosis, respiratory oxidative burst, and antigen killing (Alomran and 

Shleamon 1988; Bergeret et al. 1990; Fischbein et al. 1993; Kimber et al. 1986; Queiroz et al. 1993, 1994; 

Valentino et al. 1991). In a worker population having mean PbB ≤10 μg/dL, increasing PbB was 

associated with decreases in circulating neutrophil abundance (Conterato et al. 2013), whereas in a worker 

population having mean PbB >10 μg/dL, PbB was associated with increases in neutrophil abundance (Di

Lorenzo et al. 2006) and decreases in circulating complement levels (Ewers et al. 1982; Undeger et al. 

1996). 
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NK cells. NK cells contribute to the immune defense (cytotoxicity) against tumor cells and viral infected 

cells. Although a few studies have found associations between PbB and NK cell abundance (Boscolo et 

al. 1999, 2000), most studies have found no associations (Fischbein et al. 1993; Garcia-Leston et al. 2011; 

Karmaus et al. 2005; Kimber et al. 1986; Mishra et al. 2003; Pinkerton et al. 1998; Sarasua et al. 2000;

Undeger et al. 1996; Yucesoy et al. 1997) at population mean PbBs ≤10 or >10 μg/dL.

Lymphocyte activation. A few epidemiological studies have found associations between exposure to Pb 

and increased lymphocyte activation (HLA-DR expression) and proliferation in children (Lutz et al. 1999) 

and adults (Alomran and Shleamon 1988; Boscolo et al. 1999; Cohen et al. 1989; Fischbein et al. 1993; 

Kimber et al. 1986; Mishra et al. 2003). These studies found effects in populations that had PbB 

>10 μg/dL.

Sensitization. Epidemiological studies provided evidence for associations between exposure to Pb and 

sensitization. This evidence includes increased risk of atopy to airborne allergens in children 

(Jedrychowski et al. 2011) and adults (Pizent et al. 2008). Consistent with findings in animal studies 

which found that Pb exposure suppresses delayed type hypersensitivity (DTH), Hsiao et al. (2011) found 

that higher PbB was associated with decreases in circulating levels of IFN-γ a T-helper cytokine known 

to be important in DTH). The above effects related to sensitization have been observed in populations 

that had mean PbB ≤10 μg/dL.

Inflammation. A few epidemiological studies have examined possible associations between Pb exposure 

and biomarkers of inflammation. Results for these studies suggest that Pb exposure can modify the 

control of inflammatory responses, including modifying macrophage NO release and ROS production in 

macrophages harvested from exposed children (Pineda-Zavaleta et al. 2004), and in adults, decreases in 

abundance of circulating monocytes (Conterato et al. 2013; Pinkerton et al. 1998), and lower circulating 

levels of HLA-DR+ (Fischbein et al. 1993) in adults. Three studies found evidence for effects indicative 

of enhancement or stimulation of inflammation in adults at mean PbB ≤10 μg/dL. Outcomes included

increases in circulating tumor necrosis factor-alpha (TNFα) (Kim et al. 2007) and C-reactive protein 

(CRP) in men (Songdej et al. 2010; Sirivarasai et al. 2013).

Effect at Blood Pb Levels ≤10 μg/dL. Epidemiological studies that have evaluated immunological effects 

associated with PbB ≤10 μg/dL are summarized in Table 2-27, with additional details provided in the 

Supporting Document for Epidemiological Studies for Lead, Table 8. Outcomes that have been observed 

in populations with PbB ≤10 μg/dL include susceptibility to infections, sensitization in children and 
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adults, humoral and cell-mediated immunity in children and adults, and inflammation in children and 

adults.

Susceptibility to infections. A cross-sectional study of data from NHANES (1999–2012) found a trend 

for increasing OR for being seropositive for H. pylori, T. gondii, and Hepatitis B virus in a population that 

has a geometric mean PbB of 1.5 μg/dL (Krueger and Wade 2016). 

Humoral immunity. Several studies have found associations between circulating IgE levels and PbB in 

populations with mean or geometric mean PbB levels ≤10 μg/dL (Karmaus et al. 2005; Min and Min 

2015; Pizent et al. 2008; Sarasua et al. 2000; Wells et al. 2014). In general, these studies found increases 

in serum IgE levels in association with increasing PbB in children (Karmaus et al. 2005; Sarasua et al. 

2000; Wang et al. 2017a; Wells et al. 2014) and adults (Min and Min 2015; Pizent et al. 2008). A crosssectional study of children (3–7 years of age) found an association between increasing PbB and 

decreasing Hepatitis B virus antibody titers (Xu et al. 2015).

T-cells, neutrophils, and NK cells. Several studies have found associations between T-cell abundance and 

PbB in populations with mean or geometric mean PbB levels ≤10 μg/dL. In studies of children, T-cell 

abundances decreased (Karmaus et al. 2005), whereas in a study of adults, T-cell abundance increased 

(Boscolo et al. 2000). In a study of Pb workers, neutrophil abundance was lower in Pb workers compared 

to controls (Contertato et al. 2013). The worker populations included a group of painters in which the 

mean PbB was 5.4±0.4 (SE) μg/dL, compared to the control group (1.5±0.1, SE). A study of a population 

of atopic adult women with median PbB 6.6 μg/dL (25th–75th percentile range: 4.9–7.9), found an 

association between increasing PbB and increasing abundance of NK cells (CD4+CD45RO+; Boscolo et 

al. 2000).

Sensitization. Exposures to Pb that resulted in population geometric mean PbB ≤10 μg/dL was associated 

with increased risk of atopy to airborne allergens in children (Jedrychowski et al. 2011) and adults (Pizent 

et al. 2008). Higher PbB was associated with decreases in circulating levels of IFN-γ (a T-helper 

cytokine known to be important in DTH) in a population of children with a mean PbB of 8.8±0.45 (SD) 

μg/dL (Hsaio et al. 2011). 
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Table 2-27. Summary of Epidemiological Studies Evaluating Immunological Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Sensitization

Jedrychowski et al. 2011

Prospective study; n=224 children (at 

5 years of age) of women recruited in 

the 2nd trimester of pregnancy 

Gmean (95% CI:):

Cord: 1.16 (1.12, 1.22)

Maternal: 1.60 (1.52, 1.67)

Atopy Adjusted RR:

• Cord PbB: 2.28 (1.12, 4.62)*

• Maternal PbB: 1.72 (0.98, 3.00)

Pizent et al. 2008

Cross-sectional study; n=216 adults 

(age range 19–67 years)

Gmean (95% CI:): 

• Male: 3.17 (0.99, 7.23)

• Female: 2.16 (0.56, 7.35)

SPT Adjusted OR for positive SPT: 0.92 (0.86, 0.98)*

Humoral immunity

Karmaus et al. 2005

Cross-sectional study; n=671 children 

(age 7–10 years)

Gmean (95% CI:): 

• Males: 2.78 (1.48, 4.82)

• Females: 2.54 (1.10, 4.38) 

IgE Mean serum IgE levels were higher (p≤0.05) in 

PbB strata >2.84 and >3.41 μg/dL*

B-cells B-cell abundance was lower (p≤0.05) in PbB 

stratum 2.21–2.83 compared to <2.2 μg/dL*

Min and Min 2015

Cross-sectional study; n=4,287 adults 

(age ≥22 years)c

Gmean (95% CI:): 

• 1.46 (1.44, 1.50)

IgE β for 1 log10 increase in IgE per 1 log10 increase in 

PbB:

• Q2 (1.1–1.69 μg/dL): 0.20 (0.05, 0.34)*

• Q3 (1.7–2.6 μg/dL): 0.26 (0.10, 0.42)*

• Q4 (2.61–26.4 μg/dL): 0.35 (0.20, 0.51)*

Pizent et al. 2008

Cross-sectional study; n=216 adults 

(age range 19–67 years)

Gmean (95% CI:): 

• Male: 3.17 (0.99, 7.23)

• Female: 2.16 (0.56, 7.35)

IgE β log increase in IgE per log increase in PbB 

μg/L (SE), females not taking oral contraceptives 

or hormone replacement therapy: 0.600 (0.298); 

p=0.046*
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Table 2-27. Summary of Epidemiological Studies Evaluating Immunological Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Sarasua et al. 2000

Cross-sectional study; 

n=1,561 residents of communities 

with elevated levels of Cd or Pb in 

soil (age range 6 months–75 years) 

(1991)

Gmean (95% CI:): 

• Age 6–35 months:

7.0 (1.7, 16.1)

• Age 36–71 months: 

6.0 (1.6, 14.1)

• Age 6–15 years: 

4.0 (1.1, 9.2) 

IgA β per 1 μg/dL PbB, age 6–35 months: 0.8, p<0.01*

IgG • β per 1 μg/dL PbB, age 6–35 months: 0.8; 

p<0.01*

• β per 1 μg/dL PbB, age 6–15 years: 7.5; 

p=0.02*

IgM β per 1 μg/dL PbB, age 6–35 months: 1.0; p=0.03*

B-cell count β per 1 μg/dL PbB, age 6–35 months: 16.9; 

p<0.01*

B-cell% β per 1 μg/dL PbB, age 6–35 months: 0.19; 

p=0.02*

Wang et al. 2017a

Cross-sectional study; n=930 children 

(mean age: 5.74 years; 469 boys and 

461 girls)

PbB Gmean (GSD)

• All: 1.86 (1.21)

• Boys: 1.88 (1.22)

• Girls: 1.83 (1.20)

IgE • All participants, β per ln-unit increase in PbB 

(2.72 μg/dL): 0.26 (0.009, 0.50); p=0.042*

• Boys, β per ln-unit increase in PbB 

(2.72 μg/dL): 0.40 (0.03, 0.76); p=0.036*

• Girl, β per ln-unit increase in PbB (2.72 μg/dL):

0.02 (-0.35, 0.40); p=0.901

Wells et al. 2014

Cross-sectional study; 

n=1,788 children (age 2–12 years)c

Gmean (95% CI:): 

• 1.13 (1.04, 1.22)

IgE β per 1 μg/dL PbB for % increase per 1 μg/dL: 

10.27 (3.52, 17.47)*

Xu et al. 2015

Cross-sectional study; n=590 children 

(age 3–7 years)

Gmean (SD of log PbB): 

• Male: 6.61 (0.19)

• Female: 6.16 (0.18)

Hepatitis B virus Antibody titers decreased with increasing PbB 

β signal to cut-off ratio per 1 μg/dL (SE) at two 

assessment dates: 

• 2011: -0.4467 (0.0225); p<0.001*

• 2012: 0.3661 (0.0193); p<0.001*
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Table 2-27. Summary of Epidemiological Studies Evaluating Immunological Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Cell-mediated immunity

Boscolo et al. 2000

Cross-sectional study; n=30 atopic 

women (age range 19–49 years) and 

30 non-atopic women

Median:

• Atopic: 6.4 (4.9, 7.9)

• Control: 5.5 (4.4, 6.7)

T-cell abundance Positive correlation between PbB and T-cell 

abundances in non-atopic subjects (r for cell count):

• CD4+CD45RO-: 0.464; p<0.05*

• CD3+ CD8+: 0.430; p<0.05*

• CD3- HLA-DR+>: 0.435; p<0.05*

Conterato et al. 2013

Cross-section study of battery 

manufacture workers (n=59), and 

automobile painters (n=23); ages 15–

61 years

Median:

• Battery workers: 49.8 (4.0)

• Painters: 5.4 (0.4)

• Controls: 1.5 (0.1)

Neutrophil abundance Mean (SE), 103/mm3:

• Battery workers: 2.87 (0.27); p<0.05*

• Painters: 3.07 (0.13); p<0.05*

• Controls: 3.75 (2.49)

Hsiao et al. 2011

Cross-sectional study; n=214 children 

(primary school grades 5–6)

Mean (SD):

• Allergic and residing near 

oil refinery: 

8.80 (0.45)

• Non-allergic and residing 

near oil refinery: 

5.23 (0.36)

• Other rural or urban 

groups, allergic or not: 

3.16–3.83

Compared to all other groups, allergic group residing 

near the refinery had: 

IFN-γ >96% decrease in serum IFN-γ; p<0.05*

IL-12 >96% decrease; p<0.05*

IL-4 >500% increase; p<0.05*

IL-25 >500% increase; p<0.05*

Karmaus et al. 2005

Cross-sectional study; n=67 children 

(age 7–10 years)

Gmean (95% CI:): 

• Males: 2.78 (1.48, 4.82)

• Females: 2.54 (1.10, 4.38)

T-cell and TC Lower (p≤0.05) in PbB stratum 2.21–2.83 

compared to <2.2 μg/dL*
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Table 2-27. Summary of Epidemiological Studies Evaluating Immunological Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Sarasua et al. 2000

Cross-sectional study; n=1,561; age 

range 6 months–75 years)

Gmean (95% CI:L): 

Age 

• 6–35 months: 7.0 (1.7, 

16.1)

• 36–71 months: 6.0 (1.6, 

14.1)

• Age 6–15 years: 4.0 (1.1, 

9.2) 

T-cell% β per 1 μg/dL PbB: -0.18; p=0.03*

T-cell count β per 1 μg/dL PbB: 7.2; p=0.59

NK-cell% β per 1 μg/dL PbB: 0.00; p=0.99

NK-cell count β per 1 μg/dL PbB: 1.3; p=0.60

Wells et al. 2014

Cross-sectional study; 

n=1,788 children (age 2–12 years)c

Gmean (95% CI:): 

1.13 (1.04, 1.22)

Eosinophils % β for % increase per 1 μg/dL: 

4.61 (2.44, 6.83)*

Inflammation

Kim et al. 2007

Cross-sectional study; n=300 adults 

(mean age 24±2 years) 

Mean (range):

• Q1: 1.46 (0.337,1.885)

• Q2: 2.22 (1.886, 2.511)

• Q3: 2.77 (2.513, 3.103)

• Q4: 3.93 (3.110, 10.470)

In males for PbB stratum >2.51 relative to lower PbB 

stratum. % per 1 μg/dL increase in PbB:

TNFα 23% (4, 55); p=0.015*

WBC 15% (0, 35); p=0.004*

IL-6 26% (0, 55%); p=0.082

Sirivarasai et al. 2013

Cross-sectional study; n=924 male 

adults (mean age 43 years) 

Mean: 5.45

Quartiles, mean (range):

• Q1: 2.44 (1.23, 3.47)

• Q2: 3.95 (3.48, 4.55)

• Q3: 5.77 (4.56, 6.47)

• Q4: 9.21 (6.48, 24.62)

CRP CRP was higher in upper quartile PbB stratum 

compared to Q1 and Q2 (p<0.001). In Q4 stratum, 

adjusted OR was elevated for GSTM1 and GSTT1 

null genotypes:

• -GSTM1-/- and GSTT1-/-: 1.98 (1.47, 2.55)*

• -GSTM1-/-: 1.32 (1.03, 1.69)*

• -GSTT1-/-: 1.65 (1.17, 2.35)*
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Table 2-27. Summary of Epidemiological Studies Evaluating Immunological Effects at Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study population PbB (μg/dL) Outcome evaluated Resultb

Songdej et al. 2010

Cross-sectional study; n=9,145 adults 

(age >40 years)c

Gmean: 1.89 OR for <1.16 versus >3.09 μg/dL:

CRP • Males: 2.85 (1.49, 5.45)*

• Females: 0.57 (0.43, 0.76)

Fibrinogen • Males: 1.15 (0.61, 2.16)

• Females: 0.87 (0.57, 1.33)

WBC • Males: 1.55 (0.96, 2.49)

• Females: 0.84 (0.62, 1.13)

aSee the Supporting Document for Epidemiological Studies for Lead, Table 8 for more detailed descriptions of studies. bAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

cStudy of NHANES participants.

Cd = cadmium; CI = confidence interval; CL = confidence limit; CRP = C-reactive protein; Gmean = geometric mean; GSTM1 = glutathione S-transferase Mu 1;

GSTT1 = glutathione S-transferase theta 1; IFN-γ = interferon gamma; Ig = immunoglobulin antibody; IL = interleukin; NHANES = National Health and Nutrition 

Examination Survey; NK = natural killer; OR = odds ratio; Pb = lead; SD = standard deviation; SE = standard error; SPT = skin prick test; TNFα = tumor necrosis 

factor-alpha; WBC = white blood cell
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Inflammation. A few studies have found evidence for increases in circulating TNFα (Kim et al. 2007) and 

CRP (Songdej et al. 2010; Sirivarasai et al. 2013) in adults at mean PbB <10 μg/dL. These outcomes are 

indicative of enhancement or stimulation of inflammation. 

Mechanisms of Action. Studies conducted in animal models and cell cultures have shown that Pb can 

disrupt the immune response through diverse mechanisms (EPA 2014c). Figure 2-6 shows the various 

potential pathways by which Pb may perturb the immune system and increase risk of atopy and 

inflammation, autoimmunity, and host resistance. In addition to its effects on T-cells, dendritic cells, and 

macrophages, Pb may also alter immune function at many other processes in the pathways shown in

Figure 2-6. 

Figure 2-6. Immunological Pathways by which Pb Exposure Potentially may 

Increase Risk of Immune-Related Diseases

Note: As shown in the figure, immunological pathways may increase risk of diseases such as cancer and 

inflammatory diseases in the cardiovascular, renal, and hepatic systems.

Source: EPA 2014c

Pb

Increased risk of atopic and

inflammatory diseases

Increased risk of 

autoimmunity

Decreased host

resistance

T cells Dendritic Cells Macrophages and 

Other Innate Immune Cells

• Elevated IL-4 and IL-5

• Suppressed INF-γ

• Elevated IL-10

• Suppressed IL-12

• Elevated TNF-α

• Overproduction of ROS

• Depleted antioxidant defenses

Reduced:

• Phagocytosis

• Nitric oxide production

• Peroxynitrite production

• Lysosomal activity

Removal of normal

myelomonocytic

suppression

Damaged epithelial

and mucosal barriers

Inappropriate T cell

Proliferation

activation

Tissue damage

and de novo

antigen appearance

Increased risk of

other inflammatory

diseases

Increased tissue

inflammation

(e.g., lung, gut, skin)

Increased lipid and 

DNA oxidation in tissues Skewed

Th2-biased

responses

Suppressed

Th1-mediated

antitumor

host defense B cells

Increased

tumor cell

formation

Increased risk of

later-life cancer

Increased IgE

production
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2.16 NEUROLOGICAL

Overview. The literature on the neurobehavioral effects of Pb is extensive. With the improvement in 

analytical methods to detect Pb in the various biological media and in study designs, the concentrations of 

Pb, particularly in blood, associated with alterations in neurobehavioral outcomes continue to decrease, 

suggesting that there may be no threshold for the effects of Pb on intellectual function (CDC 2012d). Due 

to the enormous size of the database on neurobehavioral effects of Pb, this discussion has been limited to 

representative and/or major studies published on specific topics crucial to understanding dose-response 

relationships in the lower exposure ranges (e.g., PbB ≤10 μg/dL). For additional information, the reader 

is referred to a recent review of this topic (EPA 2014c). 

Numerous epidemiological studies have evaluated effects of Pb on neurological function in children and 

adults. These studies show consistent evidence of associations between decrements in cognitive and 

neuromotor/neurosensory function with PbBs that range from ≤10 to >50 μg/dL. The PbB-effect 

relationship for cognitive effects in children extends well below 10 μg/dL, with no evidence for a 

threshold. In several PbB-effect models, the slope for decrements in cognitive function in children show 

greater increases at lower PbB ranges. These models predict that larger decrements in cognitive function 

would occur when PbB increases from 1 to 10 μg/dL, than when PbB increases to levels >10 μg/dL. All 

of the cognitive and neurobehavioral effects of Pb observed in children have also been observed in adults; 

however, it is not certain what life-stage exposures contribute most to outcomes in adults. A few studies 

that have followed children to early adulthood provide evidence of associations between childhood Pb 

exposure (e.g., PbB) and behavioral and neuroanatomical changes in adults, suggesting a possible role of 

exposures in childhood to adult outcomes. Other studies have found evidence of associations between 

cumulative Pb exposures (e.g., bone Pb) and neurological outcomes in adults. 

The following neurobehavioral effects in children have been associated with PbB: 

• ≤10 μg/dL:

o Decreased cognitive function including full scale IQ (FSIQ). 

o Altered mood and behaviors that may contribute to learning deficits, including attention 

deficits, hyperactivity, autistic behaviors, conduct disorders, and delinquency. 

o Altered neuromotor and neurosensory function, including gross and fine motor skills, visualmotor integration, and hearing threshold. 
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• >10 μg/dL:

o Decreased cognitive function including FSIQ.

o Altered mood and behaviors, including attention deficits, hyperactivity, autistic behaviors, 

conduct disorders, and delinquency.

o Altered neuromotor and neurosensory function, including gross and fine motor skills, visualmotor integration, hearing threshold, and visual evoked potentials.

o Peripheral neuropathy.

o Encephalopathy.

The following neurobehavioral effects in adults have been associated with increasing PbB:

• ≤10 μg/dL:

o Decreased cognitive function including attention, memory, and learning.

o Altered neuromotor and neurosensory function including decreased reaction time and 

walking speed, tremor, and increased risk of amyotrophic lateral sclerosis (ALS).

o Altered mood and behavior including risk of various psychiatric symptoms including anxiety, 

depression, and schizophrenia.

• >10 μg/dL:

o Reduced brain volume and altered brain neurochemistry.

o Decreased cognitive function.

o Altered neuromotor and neurosensory function.

o Decreased peripheral nerve conduction velocity.

Measures of Exposure. Studies conducted in children have relied heavily on PbB as an exposure metric. 

Although bone or tooth Pb measurements may be informative, few studies have been conducted in 

children (Bellinger et al. 1994; Campbell et al. 2000b; Fergusson et al. 1993; Kim et al. 1995; Needleman 

et al. 1979, 1990, 1996, 2002; Wasserman et al. 2003). Maternal bone Pb has been used as an exposure 

metric for evaluating outcomes in children (Gomaa et al. 2002; Xu et al. 2015). Bone Pb has been used as 

metric of cumulative exposure in a growing number of epidemiological studies of adults (see 

Section 3.3.1, Biomarkers of Exposure). An association between a health outcome and bone Pb does not 

necessarily infer an association between the outcome and PbB (or vice versa) as indicated by studies in 

which associations are not consistent for the two metrics. These differences may reflect the relative 

importance of cumulative exposure on the given outcome, or differences in error associated with 

measurements of blood and bone Pb concentrations. A review by Shih et al. (2007) concluded that 
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negative associations between Pb and cognitive function are stronger for bone Pb (specifically tibia Pb) 

for environmental exposures and for PbB for occupational exposures.

Confounding Factors and Effect Modifiers. Various factors have the potential to contribute to bias in 

estimates of associations between PbB and neurobehavioral outcomes. Failure to account for these 

factors may attenuate or strengthen the apparent associations between Pb exposure and the outcome, 

depending on the direction of the effect of the variable on the outcome. Neurological function can be 

influenced by numerous factors that may also correlate with Pb exposure in the population studied. A 

contributor to these correlations is the influence of SES-related factors on Pb exposure. Confounding 

factors that are typically evaluated in all high-quality studies include maternal education and IQ, SES, and 

HOME score (parental care). However, other factors have also been explored in some studies, including 

maternal substance abuse (including prenatal alcohol) and psychopathology, birth weight, exposure to 

tobacco smoke, nutritional status, and ALAD allele type. The relatively strong correlation between SES 

and PbB can result in overcontrol in studies of populations that have wide SES variability. Overcontrol 

will tend to attenuate the estimated association between PbB and the outcome (Bellinger 2004). 

However, SES may also modify the effect of Pb on neurological function (Bellinger et al. 1990; Ris et al. 

2004; Tong et al. 2000). If this were to occur, then SES would also be an effect-modifier.

Characterization of Effects in Children. A large number of studies showing decrements in neurological 

function in children have been published (Table 2-28). Collectively, these studies support the concept 

that Pb affects cognitive function in children prenatally exposed to PbB ≤10 μg/dL, with numerous

studies providing evidence for effects at PbB ≤5 μg/dL. Neurobehavioral functions that have been 

associated with PbB ≤10 μg/dL include decrements in cognitive function (learning and memory), altered 

behavior and mood (e.g., attention, hyperactivity, impulsivity, irritability, delinquency), and altered 

neuromotor and neurosensory function (visual-motor integration, dexterity, postural sway, changes in 

hearing and visual thresholds). These outcomes also have been observed in association with PbB 

>10 μg/dL. In children who have been followed to early adulthood, mean childhood PbBs of 13 μg/dL 

were associated with altered brain volume and neurochemistry (Brubaker et al. 2010; Cecil et al. 2008, 

2011). PbBs >30 μg/dL are associated with a variety of decrements in cognitive function, behavior (e.g., 

depression, aggression), and nerve function (e.g., decrements in fine and gross motor skills, peripheral 

neuropathy). Encephalopathy has been observed in children who have experienced severe Pb poisoning 

typical of PbB >80 μg/dL (NAS 1972).
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Table 2-28. Overview of Neurological Effects in Children Associated with 

Chronic Exposure to Lead (Pb)

Mean PbB 

(μg/dL)

Effects associated with 

Pb exposure References

≤10 Intellectual deficitsa Blackowicz et al. 2016; Baghurst et al. 1992; Bellinger and 

Needleman 2003; Bellinger et al. 1992; Boucher et al. 2014; 

Braun et al. 2012; Canfield et al. 2003; Chandramouli et al. 

2009; Chiodo et al. 2004; Desrochers-Couture et al. 2018; 

Dietrich et al. 1986, 1987, 1989, 1991, 1992, 1993a; Emory et 

al. 2003; Evens et al. 2015; Geier et al. 2017; Gomaa et al. 

2002; Hong et al. 2015; Hu et al. 2006; Jedrychowski et al. 

2009; Jusko et al. 2008; Kordas et al. 2011; Krieg et al. 2010; 

Lanphear et al. 2000a, 2005, 2019; Lin et al. 2013; Liu et al. 

2014b; Mazumdar et al. 2011; McLaine et al. 2013; Min et al. 

2009; Miranda et al. 2009; Polanska et al. 2018; Rodrigues et 

al. 2016; Rooney et al. 2018; Ruebner et al. 2019; Schnaas et 

al. 2006; Shadbegian et al. 2019; Sobin et al. 2015; Tellez-Rojo 

et al. 2006; Vigeh et al. 2014; Wang et al. 2008; Wasserman et 

al. 1994, 1997, 2003; Zhang et al. 2013; Zhou et al. 2017

Altered mood and 

behaviorb

Arbuckle et al. 2016; Boucher et al. 2012; Braun et al. 2006, 

2008; Choi et al. 2016; Dietrich et al. 2001; Froehlich et al. 

2009; Fruh et al. 2019; Geier et al. 2018; He et al. 2019; Hong 

et al. 2015; Huang et al. 2016; Ji et al. 2018; Joo et al. 2017, 

2018; Kim et al. 2013a, 2016; Liu et al. 2014a, 2015b; Park et 

al. 2016; Sioen et al. 2013; Stroustrup et al. 2016; Wang et al. 

2008; Winter and Sampson 2017

Altered neuromotor 

neurosensory functionc

Chiodo et al. 2004; Dietrich et al. 1987, 1989, 1993b; Ethier et 

al. 2012; Fraser et al. 2006; Kim et al. 2013b; Liu et al. 2018b; 

Osman et al. 1999; Silver et al. 2016; Tellez-Rojo et al. 2006 

Altered brain anatomical 

development and activity

Cecil et al. 2008, 2011

>10–30 Intellectual deficitsa Baghurst et al. 1992; Bellinger et al. 1987, 1990, 1991; Chen et 

al. 2005, 2007; Dietrich et al. 1992, 1993a; Factor-Litvak et al. 

1999; Hornung et al. 2009; Kordas et al. 2006; Magzamen et al. 

2013, 2015; Marques et al. 2014; McMichael et al. 1988; Roy et 

al. 2011; Schnaas et al. 2000; Shen et al. 1998; Tong et al. 

1996; Wasserman et al. 1994, 1997, 2000, 2003

Altered mood and 

behaviorb

Amato et al. 2013; Chen et al. 2007; Dietrich et al. 1993b, 2001; 

Lin et al. 2019; McFarlane et al. 2013; Neugebauer et al. 2015; 

Nkomo et al. 2017; Rothenberg et al. 1989; Roy et al. 2009; Wu 

et al. 2018

Altered neuromotor 

neurosensory functionc

Baghurst et al. 1995; Bhattacharya et al. 2006; Otto et al. 1985; 

Palaniappan et al. 2011; Parajuli et al. 2013, Ris et al. 2004; 

Robinson et al. 1985; Schwartz and Otto 1987, 1991
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Table 2-28. Overview of Neurological Effects in Children Associated with 

Chronic Exposure to Lead (Pb)

Mean PbB 

(μg/dL)

Effects associated with 

Pb exposure References

>30–50 Intellectual deficitsa do Nascimento et al. 2014; Royal et al. 2013

>50 Intellectual deficitsa Hou et al. 2013

Altered mood and 

behaviorb

Hou et al. 2013

Altered neuromotor 

neurosensory functionc

Hou et al. 2013; 

Peripheral neuropathyd Erenberg et al. 1974; Landrigan et al. 1976; Schwartz et al. 

1988; Seto and Freeman 1964

>80 Encephalopathy NAS 1972

aIntellectual deficits include decreased IQ, cognitive function, verbal comprehension, language development, 

perceptual organization, processing speed, decreased math and reading aptitude, educational attainment, school 

performance, and memory.

bAltered mood and behavior includes hyperactivity, ADHD, decreased adaptive skills and emotional functioning, 

externalizing behaviors, internalizing behaviors, social problems, delinquent behavior, impulsive behavior, irritability, 

autistic behavior, altered sleep, and associations between child PbB and adult behavior (see McFarlane et al. 

(2013).

cAltered neuromotor neurosensory function includes decreased integrated motor activities, gross motor skills; fine 

motor speed and dexterity, and visual-motor integration. dPeripheral neuropathy includes decreased motor and sensory nerve conduction velocity.

ADHD = attention-deficit/hyperactivity disorder; IQ = intelligence quotient; PbB = blood lead concentration

Characterization of Effects in Adults. A large number of studies showing decrements in neurological 

function in adults have been published (Table 2-29). These studies have found neurobehavioral effects in 

populations whose PbBs were ≤10 μg/dL. Neurobehavioral functions that have been associated with PbB 

≤10 μg/dL include decreased cognitive function, altered behavior and mood, and altered neuromotor and 

neurosensory function. These outcomes also have been observed in association with PbB >10 μg/dL. 

PbBs in the range of 10–20 μg/dL, measured either during childhood or in adulthood, have been 

associated with decreased brain volume and changes in brain neurochemistry (Brubaker et al. 2010; Cecil 

et al. 2008; 2011; Hsieh et al. 2009). PbBs >30 μg/dL are associated with a variety of decrements in 

cognitive function, behavior and nerve function, including postural sway and stability; decreased walking 

speed; decreased visuospatial function and visual-motor performance; decrements in hearing; peripheral 

neuropathy; psychiatric symptoms (depression, panic disorders, anxiety, hostility, confusion, anger, and 

schizophrenia); and changes in regional brain volumes and neurochemistry. 
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Table 2-29. Overview of Neurological Effects in Adults Associated with Chronic 

Exposure to Lead (Pb)

Mean PbB 

(μg/dL) Effects associated with Pb exposure References

≤10 Intellectual deficitsa Muldoon et al. 1996; Payton et al. 1998; 

Power et al. 2014; Seo et al. 2014; Shih et al. 

2006; Weisskopf et al. 2007; Weuve et al. 

2006; Wright et al. 2003b

Altered mood and behaviorb Bouchard et al. 2009; Buser and Scinicariello 

2017; Golub et al. 2010; Opler et al. 2004; 

Rajan et al. 2007, 2008; Rhodes et al. 2003

Altered neuromotor neurosensory functionc Hwang et al. 2009; Ji et al. 2013; Krieg et al. 

2005

Neurological diseases (ALS) Fang et al. 2010

>10–30 Intellectual deficitsa Mantere et al. 1982; Reuben et al. 2017

Altered mood and behaviorb Beckley et al. 2018; Yoon and Ahn et al. 2016

Altered neuromotor neurosensory functionc Chuang et al. 2007; Yokoyama et al. 1997

Altered brain architecture and metabolism Brubaker et al. 2010; Cecil et al. 2008, 2011; 

Hsieh et al. 2009

>30–50 Intellectual deficitsa Baker et al. 1983; Barth et al. 2002; Campara 

et al. 1984; Fazli et al. 2014; Goodman et al. 

2002; Hogstedt et al. 1983; Meyer-Baron and 

Seeber 2000; Schwartz et al. 2005; Vlasak et 

al. 2019

Altered mood and behaviorb Baker et al. 1983; Lucchini et al. 2000; 

Maizlish et al. 1995; Malekirad et al. 2013; 

Parkinson et al. 1986

Altered neuromotor neurosensory functionc Baker et al. 1983; Barth et al. 2002; Chia et 

al. 1996; Choi et al. 2012; Ghiasvand et al. 

2016; Haenninen et al. 1978; Iwata et al. 

2005

Altered nerve conduction Araki et al. 1980, 1987, 2000; Chia et al. 

1996; Hirata and Kosaka et al. 1993; 

Pasternak et al. 1989; Stollery et al. 1989, 

1991
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Table 2-29. Overview of Neurological Effects in Adults Associated with Chronic 

Exposure to Lead (Pb)

Mean PbB 

(μg/dL) Effects associated with Pb exposure References

>50 Intellectual deficitsa Arnvig et al. 1980; Campara et al. 1984; 

Fenga et al. 2016; Matte et al. 1989; 

Valciukas et al. 1978

Altered mood and behaviorb Awad el Karim et al. 1986; ZimmermanTansella et al. 1983

Altered neuromotor neurosensory functionc Hanninen et al. 1998

Altered nerve conduction Triebig et al. 1984

Altered brain architecture Jiang et al. 2008

aIntellectual deficits include decreased IQ, cognitive function, learning ability, verbal reasoning, logic, memory, and 

concentration.

bAltered mood and behavior include depression, panic disorders, anxiety, hostility, confusion, anger, and 

schizophrenia.

cAltered neuromotor neurosensory function includes postural sway; postural stability, decreased walking speed, 

decreased visuospatial function and visual-motor performance, hearing loss, and altered hearing threshold.

ALS = amyotrophic lateral sclerosis; PbB = blood lead concentration

Effects at Blood Pb Levels ≤10 μg/dL in Children. Numerous prospective and large cross-sectional 

studies provide a weight of evidence for decreased cognitive function, altered mood and behavior, and 

altered neuromotor and neurosensory function in children in association with exposures that result in PbB

<10 μg/dL, with some studies showing effects at PbB ≤5 μg/dL. Study details are reviewed in the 

Supporting Document for Epidemiological Studies for Lead, Table 9. The cognitive outcome metric that 

has been most extensively studied and compared across studies is FSIQ. Tests of memory, learning, and 

executive function have also been used to assess cognitive function. Studies that attempt to identify 

associations between PbB and cognitive function must control for major factors known to influence or 

correlate with cognitive development and function, including SES, parental education and IQ, quality of 

caregiving, nutrition, and birth weight. Many of these same factors correlate with PbB and can confound 

associations between PbB and outcomes. Relationships between PbB and outcomes appear to be 

nonlinear. The Lanphear et al. (2005) pooled analysis and re-analyses (Crump et al. 2013; EPA 2014e) 

predict a nonlinear dose-response relationship for Pb in which the slope for the decrement in cognitive 

function in children increases with decreasing PbB. The biological significance of the observed supralinear response has been the subject of several reviews and commentaries (Bowers and Beck 2006; 

Hornung and Lanphear 2014; Jusko et al. 2006). Decrements in cognitive function in children have been 

associated with increasing PbB measured at various life stages, including prenatal and various metrics of 
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child PbB including peak, concurrent, and cumulative. No specific life stage has been conclusively 

identified as the critical time period for exposure. 

Cognitive function in infancy. Several prospective studies have evaluated cognitive function in infancy 

and early child cohorts having mean PbB <10 μg/dL (Table 2-30). In general, these studies provide 

evidence for decrements in cognitive function in association with increasing PbB. Several studies used 

the Mental Development Index (MDI) score from the Bayley Scales of Infant Development (BSID), 

allowing comparison of results across studies (Dietrich et al. 1986, 1987, 1989; Gomaa et al. 2002; Hu et 

al. 2006; Jedyrychowski et al. 2009; Liu et al. 2014b). Each study found decreases in MDI scores 

measured from 6 to 36 months in association with increasing prenatal (e.g., maternal) or neonatal PbB. 

Cohort mean PbB ranged from 1.2 to 7.1 μg/dL. In a cohort that had a mean PbB of 1.23 μg/dL (range 

0.44–6.9 μg/dL), the change in MDI score measured at 24 months of age was -7.6 (95% confidence limit 

[CL] -14.7, -0.62) points per 1 log10 increase in cord PbB (Jedrychowski et al. 2009). The largest effect 

size was reported for a cohort that had a mean PbB of 8±3.8 (SD) μg/dL; the change in MDI score 

measured at age 6 months was -15±5.1 (SE, p<0.03) points per cord lnPbB (Dietrich et al. 1986). Studies 

that repeatedly measured MDI scores longitudinally within the same birth cohorts found that the 

associations observed at 6 months persisted to later ages (Dietrich et al. 1986, 1987, 1989, 1991; 

Jedyrychowski et al. 2009; Liu et al. 2014b). The association between Pb and declining cognitive 

behavior appears to be exacerbated by maternal prenatal psychosocial stress. A small prospective study 

conducted in Shanghai, China (139 mother-infant pairs) found larger effect sizes on language 

development in mothers who demonstrated higher prenatal stress (Zhou et al. 2017).

Cognitive function in early childhood - FSIQ. Prospective studies initiated at time of pregnancy or birth 

have consistently found decrements in child FSIQ in association with increasing cohort mean PbB 

<10 μg/dL measured at various stages of development (Table 2-30). Collectively, these studies provide 

evidence for effect sizes ranging from -1 to -6 FSIQ points in association with a 10-fold increase in PbB 

and larger effect sizes in cohorts or cohort strata having a lower mean PbB. These studies do not 

consistently point to a specific life stage as being more or less vulnerable, as negative associations with 

FSIQ have been observed with PbB measured during pregnancy, infancy, and childhood, and measured 

previous to or concurrently with the FSIQ evaluation. Results of an adult follow-up of a birth cohort 

suggest that FSIQ decrements observed in childhood may persist to adulthood (Mazumdar et al. 2011). 
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Intellectual deficits

Baghurst et al. 1992

Prospective cohort, n=494 children 

followed from birth to age 7 years

Quartile range:

• Birth: 4.3, 15.0

• Mean 0–2 years: 11.6, 

27.1

• Mean 0–3 years: 12.2, 

28.2

• Mean 0–4 years: 12.2, 

27.7

• Lifetime average 

(7 years):10.8, 24.8

FSIQ β (SE) for PbB metrics per each ln PbB increase:

• Prenatal: 0.6 (1.4), p=0.68

• Mean 0–2 years: -4.6 (2.1), p=0.03*

• Mean 0–3 years: -4.8 (2.3), p=0.04*

• Mean 0–4 years: -4.6 (2.4), p=0.05*

• Lifetime average: -3.7 (2.5), p=0.14

Blackowicz et al. 2016

Retrospective study; n=12,319 thirdgrade Hispanic children

Mean (SD):

• 4.16 (2.03)

ISAT RR for failure on ISAT for 1 or 5 μg/dL increase in 

PbB:

Reading ISAT: 

• 1 μg/dL increase: 1.07 (1.05, 1.10)*

• 5 μg/dL increase: 1.43 (1.25, 1.63)*

Math ISAT

• 1 μg/dL increase: 1.09 (1.06, 1.12)*

• 5 μg/dL increase: 1.53 (1.32, 1.78)*

Bellinger et al. 1992; Bellinger and 

Needleman 2003

Prospective cohort, n=148 children 

followed from birth to age 10 years

Mean (SE):

• 6 months: 6.7 (7.0)

• 1 years: 7.7 (6.5)

• 2 years: 6.5 (4.9)

FSIQ β (SE) for PbB metrics per each 1 μg/dL increase 

in PbB:

• Prenatal: -2.55 (2.56), p=0.57

• 6 months: -0.13 (0.15), p=0.39

• 2 years: -0.58 (0.21), p<0.007*

• Peak <10 μg/dL: -1.56 (p=0.03)*

• Peak >10 μg/dL: -0.58 (p=NA)

Boucher et al. 2014

Prospective cohort, n=93 infants

Umbilical cord PbB:

• Mean (SD): 4.8 (3.5)

• Range: 0.5–17.8

FTII-fixed duration β 0.21 (0.07, 0.35); p≤0.01*
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Braun et al. 2012

Prospective cohort, n=1,035 motherinfant pairs 

Median (5th, 95th percentile) 

at age:

• 1 years: 4.2 (1.3, 10.6)

• 2 years: 4.6 (1.5, 13.4)

• 3 years: 5.5 (2.3, 13.8)

• 4 years: 5.9 (2.5, 12.8)

GCI Coefficient for change in GCI (measured at year 4) 

per 10 μg/dL increase in PbB for PbB measured at 

each year:

• PbB at 1 year: -2.5 (-5.6, 0.5)

• PbB at 2 years: -3.8 (-6.3, -1.4)*

• PbB at 3 years: -0.7 (-3.1, 1.6)

• PbB at 4 years: -2.5 (-5.1, 0.1)

Canfield et al. 2003

Prospective cohort, n=172 children, 

followed from age 24–40 months to 

5 years 

Mean (SD):

Lifetime average at age 5: 

7.4 (4.3)

Peak: 11.1 (7.1)

Concurrent with FSIQ: 5.8 

(4.1)

FSIQ β per IQ for each 1 μg/dL increase in PbB at 

5 years of age:

Full cohort (n=172):

• Lifetime average: -0.57 (-0.93, -0.20); 

p=0.003*

• Peak: -0.26 (-0.47, -0.05); p=0.02*

• Concurrent: -0.61 (-0.99, -0.24); p <0.001*

Peak PbB <10 (n=101)

• Lifetime average: -1.52 (-2.94, -0.09); 

p=0.04*

• Peak: -1.44 (-2.55, -0.33); p=0.01*

• Concurrent: -1.79 (-3.00, -0.60); p=0.004*

Chandramouli et al. 2009

Prospective study; n=488 children 

followed from age 4–30 months (born 

1992) to age 7–8 years 

Mean (SD) at age 

30 months: 4.22 (3.12)

Reading • PbB 2–5 μg/dL OR: 0.88 (0.54, 1.43); p=0.608

• PbB 5–10 μg/dL OR: 0.51 (0.32, 0.82); 

p=0.006*

Writing • PbB 2–5 μg/dL OR: 1.08 (0.69, 1.71); p=0.729

• PbB 5–10 μg/dL OR:0.49 (0.31, 0.78); 

p=0.003*

Standard assessment test 

scores

A 2-fold increase in PbB was associated with a 

0.3-point (95% CI -0.5, -0.1) decrease in scores. 
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Chiodo et al. 2004

Prospective study; n=237 children, age 

7.5 years

Mean (SD, range):

5.4 (3.3, 1–25)

FSIQ β (SE):

• <3 μg/dL: -0.10; p≤0.1*

• <5 μg/dL: -0.12; p≤0.1*

• <7.5 μg/dL: -0.14; p≤0.05*

• <10 μg/dL: -0.18; p≤0.01*

• Cohort: -0.20; p≤0.01*

Desrochers-Couture et al. 2018

Prospective study; n=609 motherinfant pairs with follow-up at age 3–

4 years

Gmean (SD)

• Cord: 0.76 (1.7)

• Child: 0.70 (1.7)

FSIQ Associations with PbB (β per 1 SD PbB:

Cord PbB

• Male: -2.65 (-4.66, -0.48) p=0.04*

• Female: -0.18 (-1.63, 1.21) p=0.83

Child PbB

• Male: -0.07 (-2.10, 2.17), p=0.96

• Female: 0.52 (-1.23, 2.40), p=0.63

Dietrich et al. 1986 

Prospective study; n=280 motherinfant pairs 

Prenatal (maternal):

• Mean (SD): 8.0 (3.8)

• Range: 1–27

Neonatal (age 10 days):

• Mean (SD): 4.5 (2.9)

• Range: 1–22

MDI Associations with maternal PbB (n=245), β per 

lnPbB (SE): -14.978 (6.114); p<0.02*

Associations with neonatal PbB (n=280), β per 

lnPbB (SE): -15.110 (5.083); p<0.003*

In males: F (1,122): 4.95; p=0.03*

Dietrich et al. 1987

Prospective study; n=185 motherinfant pairs 

Mean (SD, range):

• Prenatal (maternal): 

8.3 (3.8, 1–27)

• Neonatal (10 days): 4.9 

(3.3, 1–24)

• Neonatal (3 months): 

6.3 (3.8, 1–22)

• Neonatal (6 months): 

8.1 (5.2, 1–36)

MDI β per lnPbB (SE):

• 3-month: -12.113 (4.727); p=0.01*

• 6-month: -2.117 (0.916); p=0.02*

PDI • β (SE): -13.248 (4.250); p=0.002*

Motor maturity • β (SE): -0.570 (0.260); p=0.03*
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Dietrich et al. 1989

Prospective study; n=192 motherinfant pairs 

Mean (SD, range):

• Prenatal (maternal): 

8.2 (3.6, 1–27)

• Neonatal (10 days): 4.8 

(3.1, 1–23)

• Neonatal (3 months): 

6.0 (3.5, 1–20)

• Neonatal (6 months): 

7.9 (4.8, 1–35)

• Neonatal (9 months): 

11.5 (6.9, 2–57)

• Neonatal (12 months): 

14.2 (7.3<4–47)

MDI Structural Equation Model indicated associations 

(p≤0.05) between increasing prenatal PbB and 

12-month MDI through decreasing birth weight.

Standardized regression coefficients: 

• Prenatal PbB → birth weight: -0.15, p≤0.05*

• Birth weight → 12-month MDI: 0.18, p≤0.05*

Dietrich et al. 1991

Prospective study; n=258 4-year-old 

children 

Mean (SD, range):

(based on Dietrich et al. 

1992)

• Maternal (6–7 months): 

8.2 (3.8, 1–27)

• Neonatal (10 days): 4.8 

(3.3, 1–26)

K-ABC scores Coefficients per μg/dL neonatal PbB:

• Mental processing composite: -0.63; 

p<0.01*

• Sequential processing: -0.68, p<0.01*

• Simultaneous processing: -0.50; p<0.05* 

• Nonverbal: -0.63; p<0.01*

• Achievement: -0.28; p<0.05*

Dietrich et al. 1992

Prospective study; n=259 5-year-old 

children

Mean (SD, range):

• Maternal (6–7 months): 

8.2 (3.8, 1–27)

• Neonatal (10 days): 4.8 

(3.3, 1–26)

• Postnatal (5 years): 

11.9 (6.4, 3–38)

FWS scores Coefficients per μg/dL neonatal PbB:

• FWS(T): -0.26 p<0.1*

• FWS(L): -0.20, p<0.01*

• FWS(R) -0.13, p<0.1*

Coefficients per μg/dL concurrent PbB:

• FWS(T): -0.11 p<0.1*

• FWS(L): -0.06, p<0.1*

• FWS(R) -0.08, p<0.05*
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Dietrich et al. 1993a

Prospective study; n=253 6–7-year-old 

children 

Mean (SD):

• Maternal: 8.3 (3.7) 

• Birth: 5 (3.4)

• 4–5 years: 11.8 (6.3)

FSIQ Adjusted β (SE) in IQ per each 1 μg/dL:

• Prenatal: 0.15 (0.21), 

• Lifetime average: -0.13 (0.11); 

• Concurrent: -0.33 (0.14); p≤0.05*

Emory et al. 2003

Retrospective study; n=79 AfricanAmerican mother-infant pairs

Mean (SD, 5th–

95th percentile):

• Maternal: 0.72 (0.86, 

0.28–1.18)

FTII, Scaled Novelty Risk 

(risk of mental retardation 

later in life)

Score: PbB (SD):

• Low risk: 0.65 μg/dL (0.80)

• Medium risk: 0.89 μg/dL (0.88)

• High risk: 1.01 μg/dL (0.126)

EPA 2014e

(re-analysis of pooled cohort from 

Lanphear et al. 2005 with corrections 

to the database)

Prospective; pooled-analysis; 

n=1,333 children (4.8–6 years of age) 

from seven prospective studies 

Mean (95% CI):

• Lifetime average: 12.4 

(4.1, 34.8)

• Peak: 18.0 (6.2, 47.0)

• Concurrent with FSIQ: 

9.7 (2.5, 33.2)

FSIQ β in IQ for per each ln PbB (μg/dL) increase in 

PbB (95% CI): 

• 6–24 months: -2.21 (-3.38, -1304)*

• Lifetime average: -3.14 (-4.39, -1.88)*

• Peak: -2.86 (-4.10, -1.61)*

• Concurrent: -2.65 (-3.69, -1.61)*

FSIQ change for concurrent PbB range:

• 2.4–10 μg/dL: -3.8 points (-2.3, -5.3)*

• 10–20 μg/dL: -1.8 points (-1.1, -2.6)*

• 20–30 μg/dL: -1.1 (-0.7, -1.5)*

Evens et al. 2015

Population-based retrospective cohort 

study; n=47,168 children (third 

graders)

Mean (SD): 4.81 (2.22):

Participants with PbB <10: 

100%

ISAT reading scores Regression coefficient (SE): -0.60 (0.03); 

p<0.0001*

Adjusted RR:

• 1 μg/dL: 1.06 (1.05, 1.07)*

• 5 μg/dL: 1.32 (1.26, 1.39)*

Math Regression coefficient (SE): -0.50 (0.03); 

p<0.0001*

Adjusted RR: 

• 1 μg/dL: 1.06 (1.05, 1.07)*

• 5 μg/dL: 1.32 (1.26, 1.39)*
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Geier et al. 2017

Cross-sectional study; 

n=1,411 children, age 6–15 years

Mean (SD): 1.32 (0.95)

<P50: 0.2–1.007

P50–P75: 1.007–1.530

P75–P100: 1.530–13.50

Diagnosed with learning 

disability 

OR per μg/dL: 1.19 (1.00, 1.40) p=0.044*

OR for quartile relative to <50th percentile (<P50):

• P50–75: 1.46 (1.11, 1.92), p=0.0017*

• P75–100: 1.95 (1.16, 3.29), p=0.0033*

Gomaa et al. 2002

Prospective study; n=197 children 

followed from birth to age 2 years 

Umbilical cord mean (SD): 

6.7 (3.4)

Participants with PbB ≥10: 

15.7%

MDI β (SE): -4.48 (2.04); p=0.03*

Hong et al. 2015

Cross-sectional study; 

n=1,001 children (ages 8–11 years) 

Gmean (GSD): 1.80 (1.40)

5th–95th percentile range: 

0.53–6.16

IQ Regression coefficients per 10-fold increase in 

PbB:

• Verbal IQ: -2.64 (-4.98, -0.30); p=0.027*

• Full-scale IQ: -7.23 (-13.39, -1.07); p=0.021*

Hu et al. 2006

Prospective study; n=146 mother-child 

pairs 

Mean±SD (range):

• Umbilical cord: 

6.20±3.88 (0.9–20.0)

• Child 12-month: 

5.22±3.41 (0.9–20.4)

• Child 24-month: 

4.79±3.71 (0.8–36.8)

• Maternal 1st trimester: 

7.07±5.10 (1.49–43.6)

• Maternal 2nd trimester: 

6.08±3.15 (1.58–22.4)

• Maternal 3rd trimester: 

6.86±4.23 (1.53–33.1)

MDI β per 1 SD change in ln PbB:

• Umbilical cord: -0.35 (-4.72, 4.03); p=0.88

• Child 12-month: -2.38 (-6.24, 1.49); p=0.23

• Child 24-month: -1.00 (-3.93, 1.94); p=0.50

• Maternal 1st trimester: -4.13 (-8.10, -0.17); 

p=0.04*

• Maternal 2nd trimester: -4.08 (-8.29, 0.12); 

p=0.06

• Maternal 3rd trimester: -2.42 (-6.38, 1.54); 

p=0.23
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Jedrychowski et al. 2009

Prospective study; n=444 children 

followed prenatally to age 3 years

Umbilical cord PbB

• Gmean: 1.29

• Median: 1.23

• Range: 0.44–6.90

MDI β per lg cord PbB±SE: 

• 12 months: -5.419±2.935 (-11.188, 0.3495); 

p=0.066

• 24 months: -7.653±3.577 (-14.684,-0.623); 

p=0.033*

• 36 months: -6.717±2.964 (-12.546, 

-0.889); p=0.024*

• All participants with PbB <5 (combination 

of all testing times): -6.618±2.499 (-11.517, -

1.719); p=0.008*

Jusko et al. 2008

Prospective study; n=174 children 

recruited at age 24–30 months and 

evaluated for FSIQ at 6 years

Lifetime average: 

• Mean (SD): 7.2 (4.1)

• Range: 1.4–27.1

• Participants <10: 77%

FSIQ • Associations between increasing PbB and 

decreasing FSIQ measured at age 6 years 

(p=0.003)*

• Comparison of children with PbB of 5–

9.9 (high) to those with PbB <5 (low) 

showed a 4.9-point decrease in FSIQ score 

(low: 91.3; high 86.4; p=0.04)*

• Adjusted changes in IQ for each 1 μg/dL 

increase in peak lifetime PbB (p not reported):

o 2.1–10 μg/dL: -1.2

o 10–20 μg/dL: -0.32

o 20–30 μg/dL: -0.15

Kim et al. 2013b

Prospective birth cohort; n=884 mother 

infant pairs

Gmean (GSD):

Early pregnancy: 1.4 (1.5)

Late pregnancy: 1.3 (1.5)

MDI β per 1 μg/dL change in late pregnancy 

PbB: -1.94 (-3.60, -0.29); p=0.02*
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Kordas et al. 2011

Prospective study; n=186 children 

followed prenatally (to age 4 years)

Mean (SD):

• Umbilical cord: 6.6 

(3.3)

• 24 months: 8.1 (4.4)

• 48 months: 8.1 (3.6)

MDI (24 months) • β (SE) Cord PbB: -0.7 (0.3); p<0.05*

• β (SE) Concurrent PbB: -0.1 (0.2)

PDI (24 months) • β (SE) Cord PbB: -0.4 (0.2)

• β (SE) Concurrent PbB: -0.2 (0.2)

GCI (48 months) • β (SE) Cord PbB: -0.2 (0.3)

• β (SE) Concurrent PbB: -0.6 (0.2); p<0.05*

Memory score • β (SE) Cord PbB: 0.1 (0.1)

• β (SE) Concurrent PbB: -0.3 (0.1)

Lanphear et al. 2000a

Cross-sectional study; 

n=4,853 children (ages 6–16 years)

Gmean: 1.9

Participants with PbB

• ≥5: 9.7%

• ≥10: 2.1%

Arithmetic Regression coefficients (SE):

• PbB <2.5: -1.28 (0.98), p=0.20

• PbB <5.0: -1.06 (0.48); p=0.03*

• PbB <7.5: -1.06 (0.39); p=0.01*

• PbB <10: -0.89 (0.32); p=0.008*

Reading Regression coefficients (SE):

• PbB <2.5: -1.71 (0.93); p=0.07

• PbB <5.0: -1.66 (0.36); p<0.001*

• PbB <7.5: -1.53 (0.31); p<0.001*

• PbB <10: -1.44 (0.30); p<0.001*

Block design Regression coefficients (SE):

• PbB <2.5: -0.08 (0.22); p=0.72

• PbB <5.0: -0.05 (0.07); p-0.45

• PbB <7.5: -0.11 (0.06); p=0.04*

• PbB <10: -0.13 (0.06); p=0.03*

Digit span Regression coefficients (SE):

• PbB <2.5: -0.25 (0.17); p=0.17

• PbB <5.0: -0.09 (0.07), p=0.20

• PbB <7.5: -0.09 (0.05); p=0.11

• PbB <10: -0.08 (0.04); p=0.03*
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Lanphear et al. 2005

(same cohorts used for BudtzJorgensen et al. 2013)

Prospective; pooled-analysis; 

n=1,333 children (4.8–6 years of age) 

from seven prospective studies 

Mean (96% CL):

• Lifetime average: 12.4 

(4.1, 34.8)

• Peak: 18.0 (6.2, 47.0)

• Concurrent with FSIQ: 

9.7 (2.5, 33.2)

FSIQ β in IQ for per each ln PbB (μg/dL) increase in 

PbB: 

• 6–24 months: -2.04 (-3.27, -0.81)*

• Lifetime average: -3.04 (-4.33, -1.75)

• Peak: -2.85 (-4.10, -1.60)*

• Concurrent: -2.70 (-3.74, -1.66)*

FSIQ change for lifetime average PbB:

• 2.4–10 μg/dL: -3.9 points (-2.4, -5.3)*

• 10–20 μg/dL: -1.9 points (-1.2, -2.6)*

• 20–30 μg/dL: -1.1 (-0.7, -1.5)*

Lanphear et al. 2019

(re-analysis of data reported in 

Lanphear et al. 2005; same cohorts 

used for Budtz-Jorgensen et al. 2013)

Prospective; pooled-analysis; 

n=1,333 children (4.8–6 years of age) 

from seven prospective studies 

Median (96% CL):

• Lifetime average: 11.9 

(3.6, 34.5)

• Peak: 18.0 (6.2, 47.0)

Concurrent with FSIQ: 9.7 

(2.5, 33.2)

FSIQ β in IQ for per each ln PbB (μg/dL) increase in 

PbB: 

• 6–24 months: -2.21 (-3.38, -1.04)*

• Peak: -2.86 (-4.10, -1.61)*

• Lifetime average: -3.25 (-4.51, -1.99)*

• Concurrent: -2.65 (-3.69, -1.61)*

FSIQ change for concurrent PbB:

• 2.4–10 μg/dL: -3.8 points (-2.3, -5.3)*

• 10–20 μg/dL: -1.8 points (-1.1, -2.6)*

• 20–30 μg/dL: -1.1 (-0.7, -1.5)*

Lin et al. 2013

Prospective (Taiwan Birth Panel 

Study; birth dates: April 2004–January 

2005) of 230 mother-infant pairs from 

Taipei, Taiwan, followed until age 

2 years

Umbilical cord

• Mean (SD): 1.30 (0.75)

• Range: 0.016–4.32

Cognitive score Regression analysis comparing PbB ≥1.645 

(75th percentile) and PbB <1.645. Adjusted β 

(SE):

• Total score: −4.23 (1.82); p<0.05*

• Cognitive: −5.35 (2.19); p<0.05*

• Language: −2.53 (1.89); p≥0.05
LEAD 150

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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Liu et al. 2014b

Prospective study; n=243 infants 

followed from birth to age 3 years

Umbilical cord (mean±SD):

• Low PbB group: 

1.35±0.26

• High PbB group: 

5.63±0.32

MDI Regression coefficients:

• 6 months: -1.647 (-2.094, -1.200); p=0.016*

• 12 months: -1.458 (-1.832, -1.084); p=0.023*

• 24 months: -1.385 (-1.683, -1.087) p=0.033*

• 36 months: -1.291 (-1.550, -1.032); p=0.036*

Increasing PbB at ages 24 and 36 months was 

associated with decreasing MDI scores measured 

at 24 and 36 months, respectively; β: 

• 24 months: -1.403; p=0.026*

• 36 months: -1.298; p=0.036*

PDI Regression coefficients at 36 

months: -1.302 (-1.572, -1.031); p=0.041*

Mazumdar et al. 2011

A prospective of 43 adults followed 

from birth (1979–1981) to age 28–

30 years 

Mean (SD):

• Cord: 6.5 (5.3)

• 6 months: 8.0 (5.3)

• 12 months: 10.0 (6.7)

• Age 2 years: 7.7 (4.0)

• Age 4 years: 6.7 (3.6)

• Age 10 years: 3.0 (2.7)

FSIQ Change in FSIQ per 1 μg/dL increase in PbB. 

β for average late childhood PbB (mean of 4- and 

10-year PbB):

• Unadjusted: -1.89 (-3.30, -0.47), p<0.01*

• Adjusted for maternal IQ: -1.11 (-2.29, 0.06)

• Other adjustments: 95% UCLs <0

McLaine et al. 2013

Population-based retrospective cohort 

study; n=3,406 children 

(kindergarteners)

Median: 4.2

Interquartile range: 2.6, 6.0

PALS-K scores Mean differences (95% CI) in PALS-K scores 

(85% CL), compared to PbB <5:

• PbB 5–9: -4.51 (-6.61, -2.85); p>0.182

• PbB ≥10: -10.13 (-13.30, -6.96); p>0.182

PR for falling below the PALS-K benchmark, 

compared to PbB <4:

• PbB 5–9: 1.21 (1.19, 1.23); p<0.001*

• PbB ≥10: 1.56 (1.51, 1.60); p<0.001*
LEAD 151

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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Min et al. 2009

Prospective study; n=267 children 

followed prenatally age 11 years

Mean (SD):

• 4 years: 7.0 μg/dL (4.1)

FSIQ Regression coefficient (SE):

• 4 years: -0.50 (0.20), p<0.05*

• 9 years: -0.41 (0.19), p<0.05*

• 11 years: -0.54 (0.19); p<0.01*

Miranda et al. 2009

Population-based retrospective cohort 

study; n=57,678 4th grade children 

Mean: 4.8

Median: 4

Range: 1–16

EOG scores Multivariate regression coefficients for PbB (μg/dL) 

of:

• PbB 2: -0.30 (-0.58, -0.01); p<0.0001*

• PbB 3: -0.46 (-0.73, -0.19); p<0.0001*

• PbB 4: -0.52 (-0.79, -0.24); p<0.0001*

• PbB 5: -0.80 (-1.08, -0.51); p<0.0001*

• PbB 6: -0.99 (-1.29, -0.68); p<0.0001* 

• PbB 7: -1.07 (-1.40, -0.74); p<0.0001*

• PbB 8: -1.35 (-1.73, -0.97); p<0.0001*

• PbB 9: -1.20 (-1.64, -0.75); p<0.0001*

• PbB ≥10: -1.75 (-2.09, -1.41); p<0.0001*

Polanska et al. 2018

Prospective study; n=538 mother-child 

pairs with follow-up of 303 children at 

age 2 years

Gmean (SD) (range)

• 2nd trimester: 0.99 

(0.15) (0.29, 2.63)

• Cord: 0.96 (0.16) (0.24, 

5.65)

BSID III β score per μg/dL cord ln PbB:

Cognitive score:

• Females: 0.34 (-1.30, 1.98), p=0.68

• Males: -2.07 (-4.07, -0.06), p=0.04*

Language score:

• Females: -0.29 (-2.23, 1.65), p=0.77

• Males: -0.43 (-2.81, 1.95), p=0.72

Rodrigues et al. 2016

Prospective study; n=812 mother-child 

pairs with follow-up of 5251, children 

at age 2–3 years

Median (P24, P75, 

maximum)

• Sirajdikhan: 7.6 (5.5, 

10.4)

• Pabna: <LOD (<LOD, 

3.8, 13.8)

BSID III β score per μg/L child PbB:

Cognitive score:

• Sirajdikhan: -0.17 (0.09), p=0.05*

• Pabna: 0.02 (0.12), p=0.87
LEAD 152

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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Rooney et al. 2018

Longitudinal study; n=330 children with 

follow-up at age 12 and 17 years

Mean (SD) at age 8–

12 years

• Females: 4.42 (2.19)

• Males: 5.26 (2.73) 

Learning, memory, and 

executive function test

Genetic variants of N-methyl-D-aspartate 

receptors (NMDAR subunits GRIN2A and 

GRIN2B) were effect modifiers on associations 

between increasing PbB (at age 8–12 years) and 

decreasing performance on learning and memory 

and executive functions

Ruebner et al. 2019

Cross-sectional study; n=412 children 

(median age 15.4 years) from 

prospective study of CKD in children

Median (P24, P75): 

1.2 (0.8, 1.8)

FSIQ, CPT β score per μg/dL (95% CI):

FSIQ:

• PbB: -2.1 (-3.9, -0.2), p=0.029*CPT 

variability score:

• PbB: 1.8 (0.2, 3.5), p=0.033*

Schnaas et al. 2006

Prospective study; n=150 followed 

from birth to age 10 years

Maternal during full 

pregnancy

• Gmean (range): 8.0 

(1–33)

Maternal PbB during 

pregnancy weeks 28–36

• Gmean (95% CI): 7.3 

(1.5–17.4)

Child 1–5 years

• Gmean (range): 9.8 

(2.8–36.4)

Child 6–10 years

• Gmean (range): 6.2 

(2.2–18.6)

FSIQ β assessed at age 6–10 years:

• Ln maternal PbB (28 weeks pregnancy): 

-4.00 (-6.37, -1.65); p=0.001*

• Ln child PbB (6–10 

years): -2.45 (-4.09, -0.81); p=0.003*
LEAD 153

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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Shadbegian et al. 2019

Retrospective study; 

n=560,624 children with PbB 

measured at ages 0–5 years and 

cognitive assessments during school 

grades 3–8

Mean (SD)

Whole cohort

• <10 μg/dL: 3.66 (1.90)

• ≤5 μg/dL: 2.89 (1.18)

CEM stratum

≤5 μg/dL: 2.40 (1.24)

Standardized academic 

achievement tests

Percentile score change relative to ≤1 μg/dL CEM 

stratum (SE) for children who had geometric mean 

PbB >1 and ≤5 μg/dL:

Math percentile for PbB strata:

• 2 μg/dL: -0.38 (0.19), p>0.05

• 3 μg/dL: -0.56 (0.20), p<0.01*

• 4 μg/dL: -0.96 (0.23), p<0.001*

• 5 μg/dL: -0.51(0.30), p>0.05

Reading percentile for PbB strata:

• 2 μg/dL: -0.55 (0.19), p<0.01*

• 3 μg/dL: -1.02 (0.20), p<0.001*

• 4 μg/dL: -1.31 (0.23), p<0.001*

• 5 μg/dL: -0.97 (0.30), p>0.001*

Sobin et al. 2015

Cross-sectional study; n=252 children 

(age 5.1–11.8 years)

Mean (SD):

• Females: 2.7 (1.5)

• Males: 2.4 (1.0)

• 96% <5.0 μg/dL

Working memory β (SE): 0.11 (0.03), p<0.01*

Taylor et al. 2017

Prospective study; n=14,062 motherinfant pairs with follow-up of 

404 children at age 4 years and 

n=2,217 children at age 8 years

Mean (SD):

• Maternal (11 weeks): 

3.67 (1.46)

• Child (30 months): 4.22 

(3.12)

FSIQ β for score per μg/dL at age 8 years:

Females:

• Verbal: 0.71 (0.11, 1.32), p=0.021*

• Performance: 0.57 (-0.11, 1.24), p=0.099

• Total: 0.73 (0.13, 1.33), p=0.017

Males:

• Verbal: -0.15 (-0.90, 0.60), p=0.72

• Performance: -0.42 (-1.19, 0.35), p=0.29

• Total: -0.29 (-1.02, 0.44), p=0.44
LEAD 154

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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Tellez-Rojo et al. 2006

Prospective study; n=294 children 

followed from birth to age 2 years

Mean (SD):

• Cord: 4.85 (3.0)

• 12 months: 4.27 (2.14)

• 24 months: 4.28 (2.25)

MDI β per ln PbB 12 months:

• <10 μg/dL: -0.15, p=0.57

• ≥10 μg/dL: -0.71, p=0.17

β per lnPbB 24 months:

• <10 μg/dL: -1.04, p<0.01*

• ≥10 μg/dL: 0.07, p=0.84

Vigeh et al. 2014

Prospective study; n=174 mother-child 

pairs, birth to 36 months

Mean±SD (range):

• 1st trimester: 4.15±2.43 

(1.6–20.5)

• 2nd trimester: 

3.44±1.28 (1.1–7.5)

• 3rd trimester: 3.78±1.40 

(1.5–8.0)

• Umbilical cord: 

2.86±1.09 (1.2–6.9).

ECDI score OR 1st trimester: 1.74 (1.18–2.57); p=0.005*

Wasserman et al. 1994, 1997, 2003

Prospective study; n=332 children age 

4 years, 261 children age 7 years, 167 

children age 10–12 years

Mean (SD):

• Age 4 years: 

9.6, Pristina

39.9, K. Mitrovica

• Age 10–12 years: 

6.1 (1.9), Pristina

30.9 (9.6), K. Mitrovica 

FSIQ β (SE) for each ln PbB increase:

• 4 years: -9.43 (2.44); p=0.000*

• Lifetime AUC 7 years: -8.59 (1.89); p<0.05*

• Lifetime average 10–12 years: -5.31 (1.98); 

p<0.05*

Zhang et al. 2013

Population-based retrospective cohort 

study; n=8,831, 7,708, and 

4,742 students in grades 3, 5, and 8, 

respectively

Mean (SD): 7.12 (7.26)

Analysis: academic 

achievement 

Math • OR 1–5 PbB (μg/dL): 1.42 (1.24, 1.63)*

• OR 6–10 PbB (μg/dL): 2.00 (1.74, 2.30)*

• OR >10 PbB (μg/dL): 2.40 (2.07, 2.77)*

Science • OR 1–5 PbB (μg/dL): 1.33 (1.10, 1.62)*

• OR 6–10 PbB (μg/dL): 2.22 (1.82, 2.72)*

• OR >10 PbB (μg/dL): 2.26 (1.84, 2.78)*

Reading • OR 1–5 PbB (μg/dL): 1.45 (1.27, 1.67)*

• OR 6–10 PbB (μg/dL): 2.21 (1.92, 2.55)*

• OR >10 PbB (μg/dL): 2.69 (2.31, 3.12)*
LEAD 155

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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Zhou et al. 2017

Prospective study; n=139 motherinfant pairs followed from birth to 24–

36 months

Gmean (95% CI)

Mid-late pregnancy: 3.30 

(3.05, 3.57)

Gesell Development 

Scale, prenatal stress 

Global Severity Index 

β for development quotient per μg/dL:

All children:

• Adaptive behavior: 3.60 (-3.64, 10.83)

• Language: -6.76 (-17.29, 3.77)

• Social behavior: -6.45 (-15.55, 2.65)

Children from mothers who exhibited high prenatal 

stress:

• Adaptive behavior: -17.93 (-35.83, -0.03)*

• Language: -33.82 (-60.04, -7.59)*

• Social behavior: -41.00 (-63.11 -18.89)*

Mood and behavior

Arbuckle et al. 2016

Cross-sectional study; 

n=2,097 children aged 6–19 years

Gmean (95% CI)

age 6–11 years: 0.91 

(0.81, 0.99)

age 12–19 years: 0.80 

(0.74, 0.85)

ADD/ADHD ORs for ln(PbB):

• ADD/ADHD: 2.39 (1.32, 4.32)*

• Emotional symptoms: 1.08 (0.68, 1.71)

• Hyperactivity/inattention: 2.33 (1.59, 3.43)*

• Total difficulties: 2.16 (1.33, 3.51)*

Boucher et al. 2012

Prospective study; n=272 children 

(mean age 11.3 years)

Mean±SD (range):

• Umbilical cord: 

4.7±3.3 (0.8–20.9)

• Current: 2.7±2.2 (0.4–

12.8)

ADHD-inattentive type Adjusted ORs: 

• T2 (n=94): 1.06 (0.42, 2.66)

• T3 (n=91): 1.01 (0.38, 2.64)

ADHD-hyperactiveimpulsive type

• T2(n=94): 4.01 (1.06, 15.23)*

• T3(n=91): 5.52 (1.38, 22.12)*

ODD and/or CD • T2 (n=94): 1.90 (0.88, 4.11)

• T3 (n=91): 1.53 (0.67, 3.49)

Behavior problem scores Umbilical cord PbB was not associated with 

associated with behavior problem scores (data not 

reported).
LEAD 156

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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Braun et al. 2006

Cross-sectional study; 

n=4,704 children (ages 4–15 years) 

Quintiles:

• Q1 (reference): ND–

0.7

• Q2: 0.8–1.0

• Q3: 1.1–1.3

• Q4: 1.4–2.0

• Q5: ≥2.0

ADHD Adjusted ORs:

• Q2: 1.1 (0.4, 3.4); p=0.804

• Q3: 2.1 (0.7, 6.8); p=0.195

• Q4: 2.7 (0.9, 8.4);p=0.086

• Q5: 4.1 (1.2, 14.0); p=0.026*

• p-trend: 0.012*

Braun et al. 2008

Cross-sectional study; 

n=3,082 children (ages 8–15 years)

Quartiles:

• Q1 (reference): 0.2–0.7

• Q2: 0.8–1.0

• Q3: 1.1–1.4

• Q4: >2.0

Conduct disorder Adjusted ORs:

• Q2: 7.24 (1.06, 49.47)*

• Q3: 12.37 (2.37, 64.56*)

• Q4: 8.64 (1.87, 40.04)*

Choi et al. 2016

Longitudinal study; n=2,159 children 

(ages 7–9 years) 

Gmean (GSD):

• All participants 

>7 years: 1.62 (1.52)

• Boys: 1.65 (1.75)

• Girls: 1.47 (1.76); 

p<0.001, compared to 

boys

ADHD • RR for PbB ≥2.17 (compared to PbB <2.17): 

1.552 (1.002, 2.403)*

Desrochers-Couture et al. 2019

Longitudinal study; n=212 Inuit 

children followed from birth and 

evaluated at mean age 11.4 and 

18.5 years

Gmean (GSD)

• Cord: 3.80 (1.84)

• Child: 2.34 (1.86)

• Adolescent: 1.63 (2.00)

ADHD β per log2 μg/dL PbB:

Child:

• Externalizing: 0.61 (-0.63, 1.96) 

• Hyperactivity-impulsivity: 0.11 (-0.14, 0.37)

• Oppositional defiant/conduct disorder: 0.02 

(-0.20, 0.21)

Adolescent:

• Externalizing interacting with child 

externalizing: 0.32 (0.08, 0.72)* 
LEAD 157

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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Dietrich et al. 2001

Prospective study; n=195 subjects 

(age 15–17 years) 

Categories: 

Lowest: <10

Low: 10–15

Medium: 16–20

High: >20

SRDBS scores β (SE):

• Prenatal PbB: 0.192 (0.076); p=0.002*

• 78-month PbB: 0.193 (0.061); p=0.002*

• Average child PbB: 0.101 (0.047); p=0.036*

Froehlich et al. 2009

Cross-sectional study; 

n=2,588 children (ages 8–15 years)

Tertiles 

T1: 0.2–0.8 

T2: 0.9–1.3

T3: >1.3

ADHD Adjusted ORs:

• T2: 1.7 (0.97, 2.9); p=0.06

• T3: 2.3 (1.5, 3.8); p=0.001*

Fruh et al. 2019

Prospective study; n=1,006 motherchild pairs with follow-up at age 

8 years; Massachusetts

Erythrocyte Pb:

Median:1.1

25th–75th % range: 0.6

BRIEF and SDQ β for change in score for an IQR increase in 

maternal 2nd trimester erythrocyte Pb:

Parent-rated SDQ:

• Total difficulties: 0.36 (-0.04, 0.77)

• Emotional problems: 0.18 (0.03, 0.33)*

Parent-rated BRIEF score:

• Behavioral regulation index: 0.69 (-0.13, 1.51)

• General executive composite: 0.73 (-0.06, 

1.52)

• Plan organize: 0.85 (0.12, 1.59)* 

Geier et al. 2018

Cross-sectional study; 

n=2,109 children, age 10–19 years

Mean (SD): 1.16 (1.27)

Quartiles, range:

• 0–50th: 0.2–0.88

• 50th–75th: 0.88–

1.26

• 75th–100th: 1.26–

34.8

ADD OR for diagnosis of ADD:

Total sample (per μg/dL): 1.292 (1.025, 1.545) 

p=0.0301*

Upper quartile PbB relative to 0–50th percentile 

as reference:

• 50–75th %: 1.28 (0.82, 2.00), p=0.2466*

• 75–100th %: 1.59 (1.05, 2.39), p=0.0130*
LEAD 158

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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

He et al. 2019

Meta-analysis of seven studies of 

associations between PbB and risk of 

ADHD diagnosis

Range of study means: 

0.73, 8.77

ADHD Mean risk difference (95% CI):

• All studies (7): 0.59 (0.50, 0.68), p<0.0001*

• PbB <3 μg/dL: 0.47 (0.39, 0.56), p<0.0001*

Age 5–12 years compared to age >12 years: 

1.35 (0.28, 2.41), p<0.0001*

Hong et al. 2015

A cross-sectional study; 

n=1,001 children (age 8–11 years)

Gmean (GSD): 1.80 (1.40)

Range: 0.53–6.16

ADHD-hyperactiveimpulsive typePbB (log-transformed) OR: 3.66 (1.18, 6.13); 

p=0.004*

ADHD-inattentive type • OR: 2.72 (-0.12, 5.56); p=0.060

Total score • OR: 6.38 (1.36, 11.40); p=0.013*

Huang et al. 2016

Prospective study of mother-infant 

pairs with follow-up of 578 children at 

age 6–13 years

Mean (SD): 3.4 (3.1) ADHD β per 1 μg/dL: 

• Hyperactivity: 1.2 (0.3, 2.0), p=0.01*

• Restless-impulsive: 1.2 (0.3, 2.0), p=0.007*

• Hyperactive-impulsive: 1.1 (0.2, 2.0), 

p=0.02*

Ji et al. 2018

Prospective study of mother-infant 

pairs recruited beginning 1998 with 

follow-up of 1,479 children at median 

age 9.6 years

Mean (SD): 2.2 (1.6)

• All: 2.2 (1.6)

• ADHD: 2.4 (1.9)

• No neurodevelopmental 

disorder: 2.1 (1.5)

ADHD OR for ADHD diagnosis. 

Males and females: OR per ln PbB (μg/dL): 1.25 

(1.01, 1.56) p=0.045*

OR relative to <2 μg/dL reference:

• 2–4 μg/dL: 1.08 (0.81, 1.44) p=0.622

• 5–10 μg/dL: 1.73 (1.09, 2.73) p=0.019*

OR relative to <5 μg/dL reference: 

• 5–10 μg/dL: 1.66 (1.08, 2.56) p=0.020*

Males:

OR 5–10 μg/dL relative to <5 μg/dL reference: 

• Males: 2.49 (1.46, 4.26) p=0.001*

• Females: 0.68 (0.27, 1.69) p=0.401
LEAD 159

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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Joint effects of sex and PbB:

OR 5–10 μg/dL relative to <5 μg/dL reference: 

• Males: 7.48 (4.29, 13.02) p <0.001*

• Females 0.69 (0.28, 1.71) p=0.426

Joo et al. 2017

Case-control study; n=214 child ADHD 

cases and 214 controls, age 6–

10 years

Gmean (SD): 

Cases: 1.65 (1.45)

Controls: 1.49 (1.48)

OR for ADHD diagnosis; OR per μg/dL:

• All AHDH: 1.28 (0.89, 1.83)

• Inattention: 1.63 (1.03, 2.58), p<0.05*

• Hyperactivity/impulsivity: 1.04 (0.53, 2.07)

Joo et al. 2018

Prospective study; n=1,751 motherinfant pairs with follow-up of 

575 children at age 5 years

Gmean (SD): 

Early pregnancy: 1.28 

(1.48)

Late pregnancy: 1.24 

(1.57)

Cord: 0.90 (1.57)

2 years: 1.55 (1.49)

3 years: 1.43 (1.44)

5 years: 1.29 (1.38

Behavioral problems 

(Child Behavior Checklist)

β for score per μg/dL:

PbB at age 2 years: 

• Females: 3.82 (1.25, 3.69)*

• Males: 0.22 (-1.87, 2.32)

PbB at age 3 years:

• Females: 2.43 (-1.00, 5.87)

• Males: 0.48 (-2.17, 3.12)

PbB at age 5 years:

• Females: 5.72 (0.44, 10.99)*

• Males: 1.37 (-2.06, 4.80)

Kim et al. 2016

Prospective study; n=2,473 children 

(age 7–8 years) 

Mean (95% CI):

• Ages 7–8 years: 1.64 

(1.60, 1.68)

• Ages 9–10 years: 1.58 

(1.55, 1.61)

• Ages 11–12 years: 

1.58 (1.55, 1.61)

ASSQ PbB (log transformed) β (SE):

• 7–8 years: 0.151 (0.061, 0.242)*

• 9–10 years: -0.023 (-0.143, 0.097

• 11–12 years: 0.054 (-0.061, 0.170)

SRS • PbB at 7–8 years: 2.489 (1.378, 3.600)*

• PbB at 9–10 years: 1.295 (-0.235, 2.825)

• PbB at 11–12 years: β (SE): 0.724 (-0.727, 

2.176)
LEAD 160

2. HEALTH EFFECTS

Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Liu et al. 2014a 

Prospective study; n=332 motherinfant pairs 

Mean (SD):

• Low PbB group

o 1st trimester: 1.22 

(0.28)

o 2nd trimester: 1.01 

(0.19)

o 3rd trimester: 1.19 

(0.23)

o Delivery: 1.26 

(0.25)

• High PbB group

o 1st trimester: 6.49 

(0.62)

o 2nd trimester: 5.63 

(0.43)

o 3rd trimester: 6.31 

(0.51)

o Delivery: 6.65 

(0.55)

NBNA score β:

• 1st trimester: -4.86 (-8.831, -0.889); p=0.03*

• 2nd trimester: -3.98 (-8.180, 0.220); p=0.07*

• 3rd trimester: -3.65 (-6.609, 1.309); p=0.21

• Delivery: -3.39 (-7.531, 0.751); p=0.11

Liu et al. 2015b

Prospective study; n=665 children 

(ages 3–13 years) 

Mean (SD): 6.26 (2.54) Sleep onset delay β: 0.033 (0.009, 0.056); p=0.006*

Park et al. 2016

Case-control study of child (mean age 

9 years) ADHD cases (n=114) and 

controls (n=114)

Gmean ± SD (range): 

Cases: 1.90±0.86 (0.37, 

5.35)

Controls 1.59±0.68 (0.18, 

3.41)

Q1: 0.18, 1.12

Q2: 1.13, 1.71

Q2: 1.72, 2.29

Q4: 2.30, 5.35

ADHD OR for ADHD diagnosis:

All subjects: 1.60 (1.04, 2.25), p=0.03*

Relative to Q1:

Q2: 1.26 (0.56, 2.84), p=0.39

Q3: 1.26 (0.55, 2.87), p=0.61

Q4: 2.54 (1.09, 5.94), p=0.03*
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2. HEALTH EFFECTS

Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Sioen et al. 2013

Prospective study; n=270 children, 

followed newborn to 8 years 

Umbilical cord mean (25th–

75th percentiles): 1.43 

(0.73–2.53)

Hyperactivity OR: 2.940 (1.172, 7.380); p=0.022*

Stroustrup et al. 2016

Prospective study, n=948 motherinfant pairs with follow-up of 500 

children at age 24 months

Median (IQR):

2nd trimester: 2.8 (2.7)

Temperament 

(TTS=easy, intermediate,

or difficult); maternal 

postnatal depression 

(EPDS)

OR (95% CI) corresponding to a 1 unit change in 

ln(maternal PbB μg/dL) for TTS score, easy score 

as reference:

• Intermediate: 0.88 (0.59, 1.3)

• Difficult: 1.52 (1.03, 2.26)*

Probability of demonstrating difficult TTS score 

was approximately doubled if EPDS score was 

high

Wang et al. 2008

Case-control study; n=630 children 

(ages 4–12 years)

Means (SE):

• ADHD cases: 8.77 

(3.89)

• Controls: 5.76 (3.36)

• Cases versus control: 

p<0.05

Tertiles:

• T1 (reference): ≤5

• T2: 5–10

• T3: ≥10

ADHD OR:

• T2: 4.92 (3.47, 6.98); p<0.01*

• T3: 6.00 (4.11, 8.77); p<0.01*

Winter and Sampson 2017

Prospective study of birth cohort 

(n=1,255) with follow-up from birth to 

age 18 years (n=208)

Means (SD) at age 

<6 years: 6.14 (4.58)

Impulsivity, anxiety, or 

depression (Child 

Behavior Checklist)

β for score per μg/dL:

• Impulsivity: 0.08 (0.01, 0.16)*

• Anxiety or depression: 0.11 (0.01, 0.21)*
LEAD 162

2. HEALTH EFFECTS

Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Neuromotor neurosensory function

Chiodo et al. 2004

Prospective study; n=237 children 

(age 7.5 years) 

Mean (SD, range):

5.4 (3.3, 1–25)

Battery test performance Tests with declines (β) at <3, <5, <7.5, or 

<10 μg/dL: 

• Block design: <10, <5; p≤0.05*

• Digit span backwards: <7.5; p≤0.05*

• Beery visual-motor integration: <10, <5; 

p≤0.05*

• MFF (number correct): <5; p≤0.05*

• Attention-TRF: <3; p≤0.05*

• Barkley-inattention: <5 <3; p≤0.05*

• Withdrawn-TRF: <7.5, <3; p≤0.05*

• Barkley off-task: <10, <5; p≤0.05*

• Sternberg RT “Yes: <5, <3; p≤0.05*

• Color naming: <5; p≤0.05*

• CPT visual (number correct): none

• Seashore rhythm: <3; p≤0.05*

• Mental rotation RT “forward”: <10, <7.5; 

p≤0.05*

Dietrich et al. 1987

Prospective study; n=185 motherinfant pairs 

Mean (SD, range):

• Prenatal (maternal): 

8.3 (3.8, 1–27)

• Neonatal (10 days): 4.9 

(3.3, 1–24)

• Neonatal (3 months): 

6.3 (3.8, 1–22)

• Neonatal (6 months): 

8.1 (5.2, 1–36)

Motor maturity Associations with 3-month ln PbB, β (SE):

• PDI: -13.248 (4.250); p=0.002*

• Motor maturity: -0.570 (0.260); p=0.03*

Associations with 6-month ln PbB, β (SE):

• PDI: -2.117 (0.916); p=0.02*

• Motor maturity: -0.092 (0.056); p=0.11

PDI Associations with 3-month ln PbB, β (SE):

• PDI: -13.248 (4.250); p=0.002*

Associations with 6-month ln PbB, β (SE):

• PDI: -2.117 (0.916); p=0.02*
LEAD 163

2. HEALTH EFFECTS

Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Dietrich et al. 1989

Prospective study; n=192 motherinfant pairs 

Mean (SD, range):

• Prenatal (maternal): 

8.2 (3.6, 1–27)

• Neonatal (10 days): 4.8 

(3.1, 1–23)

• Neonatal (3 months): 

6.0 (3.5, 1–20)

• Neonatal (6 months): 

7.9 (4.8, 1–35)

• Neonatal (9 months): 

11.5 (6.9, 2–57)

• Neonatal (12 months): 

14.2 (7.3<4–47)

PDI β (SE), 12 months: -14.09 (7.26); p=0.054

SEM indicated associations between increasing 

prenatal PbB and race and 12-month PDI. 

• Prenatal PbB --> 12-month PDI: -0.47, 

p≤0.05*

• Prenatal PbB x race --> birth weight: 0.97, 

p≤0.05*

• Race --> 12-month MDI: -0.72, p≤0.05*

Dietrich et al. 1993b

Prospective study; n=245 children 

(age 6 years)

Mean (SD):

• Prenatal (maternal: 8.4 

(3.8) 

• Neonatal: 4.8 (3.1)

• Life average

• 6 years: 10.1 (5.6)

• Lifetime average 

quartile range: 7–22

Motor performance Tests with (p≤0.05) declines (β) associated with 

neonatal (N), mean lifetime (L) or concurrent (C) 

PbB:

• Bilateral coordination: N, M

• Visual motor control: C

• Upper limb speed and dexterity: C, M, N

• Fine motor composite: C, M, N

Ethier et al. 2012

Prospective longitudinal, 

n=149 children (age 10–13 years)

Mean (SD, range):

• Cord: 4.6 (3.1, 0.8–

19.5)

• 11 years: 2.6 (2.3, 0.4–

12.8)

Delay of N150 latency of 

VEP

Association between increasing cord PbB and 

delay of N150 latency of VEP at multiple contracts. 

Mean latency (estimated from reported bar plot):

• ≥4.15 μg/dL: ~160 ms, p<0.05*

• <4.15 μg/dL: ~153 ms (reference)

Fraser et al. 2006

Prospective study; n=101 children 

(age 5 years)

Mean (SD):

Cord: 4.9 (3.7)

Child: 5.3 (4.9)

Hand movements β -0.30, p≤0.01*

Sway velocity β -0.28, p≤0.01*

Transversal sway β 0.24, p≤0.05*
LEAD 164

2. HEALTH EFFECTS

Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Kim et al. 2013b

Prospective birth cohort, n=884 mother 

infant pairs

Gmean (GSD):

Early pregnancy: 1.4 (1.5)

Late pregnancy: 1.3 (1.5)

PDI β per 1 μg/dL change in PbB: -1.69 (-3.65, -0.27); 

p=0.09

Liu et al. 2018b

Cross-sectional study; n=234 children, 

age 3–7 years

Median (SE)

e-waste location: 4.94 

(0.20)

reference location: 3.85 

(1.81)

Hearing (pure tone 

conduction >25 dB)

OR for hearing loss per μg/dL (95% CI):

• Hearing loss 1.24 (1.029, 1.486) p<0.05*

• Low frequency loss: 1.02 (0.869, 1.190)

• High frequency: 1.08 (0.839, 1.379)

Osman et al. 1999

Retrospective study; n=155 children 

(age 4–14 years)

Median (range):

• 7.2 (1.9–28.1)

Hearing threshold β per 1 change in PbB for right ear for full cohort:

• 0.5 kHz: 0.054 (0.035, 0.074)*

• 1 kHz: 0.044 9 (0.026, 0.062)*

• 2 kHz: 0.048 (0.029, 0.066)*

• 4 kHz: 0.060 (0.039, 0.081)*

• 6 kHz: 0.068 (0.044, 0.092)*

• 8kHz: 0.072 (0.050, 0.094)*

β per 1 change in PbB for left ear:

• 0.5 kHz: 0.051 (0.026, 0.075)*

• 1 kHz: 0.032 (0.014, 0.050)*

• 2 kHz: 0.036 (0.019, 0.053)*

• 4 kHz: 0.039 (0.020, 0.059)*

• 6 kHz: 0.004 (0.044, 0.049)*

• 8kHz: 0.047 (0.024, 0.080)*

Association (p<0.05) between increasing PbB 

and increasing hearing threshold at all 

frequencies in PbB stratum <10 μg/dL 

(thresholds not reported)*
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Polanska et al. 2018

Prospective study; n=539 mother-child 

pairs with follow-up of children at age 

2 years; 280 blood samples and 303 

cord blood samples were randomly 

chosen for analysis

Gmean (SD) (range)

• 2nd trimester: 0.99 

(0.15) (0.29, 2.63)

• Cord: 0.96 (0.16) (0.24, 

5.65)

BSID III β score per μg/dL cord PbB:

Motor score:

• Females: 0.48 (-1.55, 2.52), p=0.64

• Males: -0.70 (-2.90, 1.51), p=0.53

Rodrigues et al. 2016

Prospective study with cross-sectional 

analysis of PbB and fine motor score; 

n=524 children, 20–30 months

Median (P25, P75, 

maximum)

• Sirajdikhan: 7.6 (5.5, 

10.4)

• Pabna: <LOD (<LOD, 

3.8, 13.8)

BSID III β score (SE) per child lnPbB (μg/L):

Fine motor score:

• Sirajdikhan: 0.07 (0.11), p=0.50

• Pabna: -0.07 (0.11), p=0.50

Silver et al. 2016

Prospective study; infants assessed 

for hearing at 2 days and vision at 

6 weeks; maternal blood Pb collected 

at mid pregnancy and late pregnancy 

and in cord blood

Exposure for infants with 

hearing data:

Gmean (SD)

Mid-pregnancy: 2.4 (2.5)

Late-pregnancy: 2.7 (2.3)

Cord: <LOQ

Exposure for infants with 

vision data:

Gmean (SD) 

Mid-pregnancy: 2.4 (2.6) 

(n=1,038);

Late-pregnancy: 2.9 (2.2) 

(n=1,058);

Cord: <LOQ (n=949)

Hearing at age 2 days 

(ABR); vision at age 

6 weeks (GVA)

Percent change in score relative to <2 μg/dL (latepregnancy) reference group

GVA score for PbB strata:

• >3.8 μg/dL: -8.5 (-14.7, -2.4)*

• 2 - 3.8 μg/dL: -7.2 (-13.3, -1.1)*

ABR C-P ratio for PbB strata:

• >3.8 μg/dL: 4.6 (1.8, 7.4)*

• 2 - 3.8 μg/dL: 3.2 (0.0, 5.9)*
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Taylor et al. 2018

Prospective study; n=14,541 motherinfant pairs with follow-up of 

1,558 children at age 7 years

Mean (SD) at gestation 

week 11 

Mean (SD) 3.66 (1.55)

Range: 0.20, 19.14

Motor skills (Movement 

Assessment Battery)

OR for scores per μg/dL prenatal PbB:

• Heal to toe: 0.99 (0.74, 1.33), p=0.93

• Beanbag: 0.88 (0.58, 1.32), p=0.54

• Threading lace: 1.12 (0.83, 1.50), p=0.47

• Peg board (preferred hand): 1.19 (0.88, 1.60), 

p=0.26

• Peg board (non-preferred hand): 1.14 (0.85, 

1.54), p=0.37

Tellez-Rojo et al. 2006

Prospective study; n=294 children 

(followed from birth to age 2 years)

Mean (SD):

• Cord: 4.85 (3.0)

• 12 months: 4.27 (2.14)

• 24 months: 4.28 (2.25)

PDI β per 1 ln change in PbB:

12 months:

• <10 μg/dL: -0.01, p=0.98

• ≥10 μg/dL: -1.19, p=0.01*

24 months:

• <10 μg/dL: -1.18, p<0.01*

• ≥10 μg/dL: 0.04, p=0.89

Zhou et al. 2017

Prospective study; n=139 motherinfant pairs followed from birth to 24–

36 months

Gmean (95% CI)

Mid-late pregnancy: 3.30 

(3.05, 3.57)

Motor skills (Gesell 

Development Scale)

β (95% CI) for development quotient per μg/dL:

All children:

• Gross motor: 3.31 (-6.11, 12.73)

• Fine motor: 0.49 (-11.27, 12.24)

Altered brain structure and chemistry

Cecil et al. 2008

Prospective study; n=157 adults, age 

19–24 years from a birth cohort born 

1979–1984 from Cincinnati, Ohio

Mean (SD, range):

• 6 month–6.5 years: 

13.3 (5.9, 4.6–37.2)

Brain volume Association (p≤0.001) between increasing 

childhood mean PbB and decreasing brain volume 

affecting 1.2% of the total gray matter. Effects 

were greater in males than females. Largest 

effects were in the anterior cingulate cortex.
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Table 2-30. Summary of Epidemiological Studies Evaluating Neurological Effects in Children at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Cecil et al. 2011

Prospective study; n=159 adults, age 

19–24 years from a birth cohort born 

1979–1984 from Cincinnati, Ohio

Mean (SD, range):

• 6 months–6.5 years:

13.3 (6.1, 4.7–37.2)

Brain metabolism Association (p<0.05) between increasing 

childhood mean PbB and decreasing regional 

levels of gray matter N-acetyl aspartate, 

glutamate-glutamine, creatine and 

phosphocreatine, and white matter cholines. 

Areas affected include the basal ganglia, 

cerebellum vermis, parietal white matter, and 

frontal white matter.*

aSee the Supporting Document for Epidemiological Studies for Lead, Table 9 for more detailed descriptions of studies. bParticipants had no known occupational exposure to Pb.

cAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

ABR = brainstem auditory response; ADD = attention deficit disorder; ADHD = attention-deficit/hyperactivity disorder; ASSQ = Autism Spectrum Screening 

Development Questionnaire; AUC = area under the curve; BRIEF = Behavior Rating Inventory of Executive Function; BSID = Bayley Scales of Infant 

Development CD = Conduct Disorder; CEM = Coarsened Exact Matching; CI = confidence interval; CKD = chronic kidney disease; CL = confidence limit; 

C-P = central-to-peripheral; CPT = Continuous Performance Test; ECDI = Early Child Development Inventory; EOG = End of Grade; EPDS = Edinburgh Postnatal

Depression Scale; FSIQ = Full-Scale intelligence quotient; FTII = Fagan Test of Infant Intelligence; FWS = Filtered Word Subtest; GCI = General Cognitive Index;

Gmean = geometric mean; GSD = geometric standard deviation; GVA = grating visual acuity; IQ = intelligence quotient; IQR = interquartile range; ISAT = Illinois

Standard Achievement Test; K-ABC = Kaufman Assessment Battery for Children; LOD = limit of detection; LOQ = limit of quantitation; MDI = Mental

Development Index; MFF = Matching Familiar Figures; MSEL = Mullen Scales of Early Learning; NA = not available; NBNA = Neonatal Behavioral Neurological

Assessment; ND = not detected; ODD = Oppositional Defiant Disorder; OR = odds ratio; PALS-K = Phonological Awareness Literacy Screening-Kindergarten; Pb

= lead; PDI = Psychomotor Development Index; PR = prevalence ratio; RR = relative risk; RT = reaction time; SD = standard deviation; SDQ = Strengths and

Difficulties Questionnaire; SE = standard error; SRDBS = Self-Reported Delinquent Behavior Survey; SRS = Social Responsiveness Scale; TRF = Teacher

Report Form from the Child Behavior Checklist; TTS = Toddler Temperament Scales; UCL = upper confidence limit; VEP = visual evoked potential
LEAD 168

2. HEALTH EFFECTS

FSIQ was assessed at age 28–30 years in 43 members of the Boston prospective study cohort (Bellinger et 

al. 1992). The change in FSIQ was -1.89 points (95% CI: -3.00, -047) per μg/dL increase in late child 

PbB (mean 6.7±3.6 at age 4 years, 3.0±2.7 at age 10 years). After adjustment for maternal IQ, the change 

in FSIQ was -1.11 (95% CI: -2.29, 0.06).

The largest study was a pooled analysis from seven individual prospective studies that evaluated FSIQ 

(Baghurst et al. 1992; Bellinger et al. 1992; Canfield et al. 2003; Dietrich et al. 1993a; Ernhart et al. 1989; 

Schnaas et al. 2000; Wasserman et al. 1997). The pooled cohort consisted for 1,333 children who were 

evaluated for FSIQ between ages 4.8 and 6 years (Lanphear et al. 2005, 2019). Co-variates considered in 

the analysis included study, maternal IQ, HOME score (Home Observation for Measurement of the 

Environment Inventory score), maternal education, marital status, birth weight, birth order, maternal age, 

race, and prenatal tobacco exposure. Of these, maternal IQ, HOME, and birth weight were included in 

the final models. When the full cohort was considered (PbB range 0.1–72 μg/dL), the adjusted change in 

FSIQ was loglinear, with greater changes in IQ per unit change in PbB at lower PbB levels. Several 

blood Pb metrics were explored in regression modeling, and slopes were significant for childhood, peak, 

lifetime average, or concurrent (with IQ testing) PbB. The model that used concurrent PbB had the 

highest r2 (not reported). The covariate adjusted regression β for this model was -2.65 (95% 

CI: -3.69, -1.61) IQ points per 1 lnPbB. The unadjusted β was -4.84 (-5.98, -3.69). The concurrent PbB 

model predicts a decrease of 6.2 points in FSIQ when PbB increased from 1 to 10 μg/dL. In a PbB 

stratum maximum <7.5 μg/dL, the mean change in FSIQ was -2.53 (95% CI -4.48, -0.58) per 1 μg/dL 

change in PbB, and for a PbB stratum maximum ≥7.5 μg/dL, the mean change in FSIQ was -0.15 (95% 

CI -0.23, -0.07) per 1 μg/dL. Re-analyses of the pooled cohort reported in Lanphear et al. (2005) have 

been conducted (Crump et al. 2013; EPA 2014e). EPA (2014e) made several corrections to the dataset 

and obtained β coefficients that were similar to those reported in Lanphear et al. (2005). The results of 

the EPA (2014e) reanalysis are presented in Table 2-30. 

The model that used early childhood PbB (6–24 months) had the highest r2 (0.6433), although the r2 was 

similar to concurrent PbB (0.6414). A benchmark dose (BMD) analysis of the pooled data from Lanphear 

et al. (2005) estimated BMDLs (95% lower one-sided confidence limit on BMD) ranging from 0.1 to 

1 μg/dL for a 1% decrease in FSIQ for the best-fitting models (Budtz-Jorgensen et al. 2013). This BMD 

analysis provides supporting evidence that exposures to Pb may produce effects on cognitive function in 

populations whose PbBs are well below 5 μg/dL, and may extend to levels below 1 μg/dL. 
LEAD 169

2. HEALTH EFFECTS

In addition to the seven prospective studies included in the Lanphear et al. (2005, 2019) pooled analysis, 

more recent prospective studies have evaluated associations between PbB and FSIQ in children (Braun et 

al. 2012; Chiodo et al. 2004; Jusko et al. 2008; Kordas et al. 2011; Min et al. 2009; Schnaas et al. 2006; 

Taylor et al. 2017; Table 2-30). Each of these studies found significant associations between increasing 

PbB and decreasing FSIQ in study populations that had mean PbBs <10 μg/dL. The largest of these 

studies combined four Mexico City birth cohorts for a total of 1,035 mother-infant pairs (Braun et al. 

2012). Cognitive function assessed at age 4 years (McCarthy General Cognitive Index [GCI]) decreased 

with increasing PbB measured at age 2 years. The adjusted effect of concurrent PbB was estimated as -

3.8 (95% CI: -6.3, -1.4) points when PbB increased by 10 μg/dL. Similar to the findings of the Lanphear 

et al. (2005, 2019) study, covariate adjustment decreased the regression β by approximately 40% (from -

6.4 to -3.8). The cohort mean PbB was 4.6 μg/dL (5th–95th percentile range 1.3–13.4). Studies of smaller 

cohorts from Mexico City found similar associations (Kordas et al. 2011; Schnaas et al. 2006). Schnaas 

et al. (2006) estimated the effect size to be a -4.0 (95% CI: -6.37, -1.65) point change in FSIQ measured 

at ages 6–10 years in association with a natural log increase in maternal PbB; the cohort geometric mean 

was 7.3 μg/dL (95% CI: 1.5, 17.4). Kordas et al. (2011) estimated the effect size to be -0.6 (SE 0.2) for a 

1 μg/dL increase in concurrent PbB (mean 8.1 μg/dL ±4.4 SE). Prospective studies conducted in 

Cleveland, Ohio (Min et al. 2009) and Rochester, New York (Jusko et al. 2008) also found similar effect 

sizes for the associations between increasing PbB and decreasing IQ. In the Rochester study, the changes 

in FSIQ were larger at lower PbB, consistent with the outcomes of the Lanphear et al. (2005) study (Jusko 

et al. 2008). For the PbB range 2.1–10 μg/dL, the change in FSIQ measured at age 6 years was -1.2 per 

1 μg/dL increase in PbB. This decreased to -0.32 and -0.15 for the ranges 10–20 and 20–30 μg/dL, 

respectively. In the Cleveland study, the change was -0.50±0.20 (SE) in FSIQ measured at age 4 years 

per 1 μg/dL increase in concurrent PbB (Min et al. 2009). A study conducted in Detroit, Michigan 

estimated the change in FSIQ to be -0.20 per 1 SD change in PbB (Chiodo et al. 2004). The decrement 

was significant (p≤0.05) in PbB strata <7.5 and <10 μg/dL. Not all prospective studies have found 

evidence for decreasing FSIQ in association with increased PbB. One of the largest birth cohorts that has 

been studied is the Avon Longitudinal Study of Parents and Children (ALSPC), conducted in the United 

Kingdom (Taylor et al. 2017). This study followed a cohort of approximately 14,000 births. In a followup of 2,127 children at age 8 years, increasing maternal PbB (mean 3rd trimester PbB 3.67±1.46 SD) was 

associated with an increase in FSIQ in females and no change in FSIQ in males. The changes in FSIQ 

were 0.73 (95% CI: 0.13, 1.01) per 1 μg/dL increase in PbB in females and -0.29 (95% CI: -1.02, 0.44) in 

males. A prospective study of 609 mother-infant pairs, conducted in Canada, found that increasing cord 

PbB was associated with decreasing FSIQ when assessed in male children at age 3–4 years (DesrochersCouture et al. 2018). The change in FSIQ in males was -2.61 points (95% CI: -4.66, -0.48) per 1 μg/dL 
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and the change in females was -0.18 (-1.63, 1.21). The geometric mean cord PbB was 3.80±1.86 

(geometric standard deviation [GSD]).

Cross-sectional studies have also found associations between increasing PbB and FSIQ in children (Hong 

et al. 2015; Ruebner et al. 2019). A study conducted in South Korea evaluated PbB and FSIQ in 

1,001 children 8–11 years of age (Hong et al. 2015). The estimated effect of PbB on FSIQ was -

7.23 points (95% CI: -13.39, -1.07) per 10-fold increase in PbB. The 5th–95th percentile range for the 

cohort PbB was 0.53–6.16 μg/dL. A study of 412 children (median age 15 years) who were diagnosed 

with CKD found an association between increasing child PbB and decreasing FSIQ, after adjustment for 

CKD severity (Ruebner et al. 2019). The estimated effect of PbB on FSIQ was -2.1 (95% CI: -3.9, -0.2).

Cognitive function in early childhood–other than FSIQ. Several studies have examined outcomes other 

than IQ and have found associations between PbB and changes in cognitive function in children whose 

PbBs were <10 μg/dL (Table 2-30). These include prospective studies that used the same outcome 

metric, the BSID MDI, allowing comparison of outcomes across studies (Dietrich et al. 1986, 1987, 1989; 

Kim et al. 2013b; Polanska et al. 2018; Rodrigues et al. 2016; Tellez-Rojo et al. 2006). A prospective 

study of 884 children conducted in South Korea found inverse associations between PbB in late 

pregnancy (geometric mean 1.3±1.5, GSD) and MDI scores measured at age 6 months (Kim et al. 2103b). 

A prospective study of 294 children conducted in Mexico City found inverse associations between 

concurrent PbB (mean 4.27±2.14, SD) and MDI measured at 24 months in a PbB stratum <10 μg/dL 

(Tellez-Rojo et al. 2006). A prospective study conducted in Cincinnati, Ohio (approximately 190 infants) 

found declines in MDI scores at age 6 and 12 months in association with increasing maternal, neonatal, or 

infant PbB (Dietrich et al. 1986, 1987, 1989). A prospective study conducted in Poland (303 infants) 

found declines in MDI scores at age 2 years in males (but not females) in association with increasing cord 

PbB (range 0.24–5.65 μg/dL) (Polanska et al. 2018). A prospective study conducted in Bangladesh 

(324 infants) found declines in MDI scores at age 2–3 years in association with increasing child PbB 

(median 7.6 μg/dL, maximum 10.4 μg/dL) (Rodrigues et al. 2016).

Several large-scale retrospective studies linked academic performance for individual children with their 

corresponding blood Pb data recorded in state or local blood Pb registries (Blackowicz et al. 2016; Evens 

et al. 2015; Miranda et al. 2009; Shadbegian et al. 2019; Zhang et al. 2013; Table 2-30). Evens et al. 

(2015) linked individual 3rd grade Illinois Standard Achievement Test (ISAT) scores and PbB data (birth–

72 months) for a population of 47,158 children in Chicago, Illinois. All children had PbB <10 μg/dL and 

the population mean was 4.8±2.2 μg/dL (SD). Increasing PbB was inversely associated with decreasing 
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covariate adjusted scores in math and reading. The adjusted relative risks (RRs) for failing scores was 

also significant for a 1 or 5 μg/dL increase in PbB. A follow-up to this study of the same data from 

Chicago that focused on Hispanic children who had PbB <10 μg/dL also found that increasing PbB was 

associated with decreasing scores in math and reading and significant RRs for failing scores (Blackowicz 

et al. 2016). Miranda et al. (2009) linked 4th grade reading End of Grade (EOG) scores and PbB data 

collected (birth–36 months) for a population of 57,678 children in North Carolina. The population mean 

PbB was 4.8 μg/dL (range 1–16 μg/dL); 94% of children had PbB <10 μg/dL. Increasing PbB was 

associated with decreasing covariate adjusted scores in all PbB strata, the lowest of which was 2 μg/dL. 

The effect size (change in score/μg/dL PbB) increased with increasing PbB. Another study conducted in 

North Carolina analyzed data on PbB and standardized achievement scores of children in grades 3–8 

(Shadbegian et al. 2019). Increasing PbB was associated with decreasing score percentiles in math and 

reading among children who had PbBs within the range >1–≤5 μg/dL, relative to children who had PbBs

<1 μg/dL. Zhang et al. (2013) linked Michigan Educational Assessment Program (MEAP) scores and 

PbB data (birth–72 months) of age for a population of approximately 21,000 children in Detroit, 

Michigan. Covariate adjusted ORs for failing scores in mathematics, science, and reading were 

significant for PbB strata 1–5, 6–10, and >10 μg/dL. A cross-sectional study of data from NHANES III 

examined associations between PbB and scores on tests of cognitive function (Wide Range Achievement 

Test-Revised [WRAT-R], Wechsler Intelligence Scales for Children-Revised [WISC-R]) in 

approximately 5,000 children 6–16 years of age (Lanphear et al. 2000a). Increasing PbB was 

significantly associated with decreasing scores in reading in blood strata <5.0, <7.5, and <10 μg/dL. 

McLaine et al. (2013) examined associations between PbB (9–72 months) and kindergarten readiness 

assessed from Phonological Awareness Literacy Screening-Kindergarten (PALS-K) scores in 

approximately 3,400 children in Providence, Rhode Island. The population median PbB was 4.2 μg/dL 

(interquartile range 2.9–6.0); 93% of children had PbB <10 μg/dL. Mean difference in covariate adjusted 

scores in blood strata 5–9 and ≥10 μg/dL compared to <4 μg/dL were in the inverse direction and 

adjusted prevalence ratios for test failure was significant in both strata. Genetic variants of N-methylD-aspartate receptors (NMDAR subunits GRIN2A and GRIN2B) were effect modifiers on associations 

between increasing PbB (at age 8–12 years) and decreasing performance tests of learning, memory, and 

executive function at age 17 years (Rooney et al. 2018).

Altered mood and behavior. Numerous studies have examined possible associations between neonatal 

and child PbB risk of behaviors that may contribute to learning deficits, including attention deficits, 

hyperactivity, autistic behaviors, conduct disorders, and delinquency (Table 2-30). 
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Several studies have examined attention-deficit/hyperactivity disorder (ADHD) as an outcome, allowing 

comparisons of outcomes across studies (Arbuckle et al. 2016; Boucher et al. 2012; Braun et al. 2006; 

Choi et al. 2016; Desrochers-Couture et al. 2019; Froehlich et al. 2009; Geier et al. 2018; He et al. 2019; 

Hong et al. 2015; Huang et al. 2016; Ji et al. 2018; Joo et al. 2017; Park et al. 2016; Wang et al. 2008). 

Collectively, the ADHD studies indicate that risk of childhood ADHD increases in association with 

increasing PbB within the range of PbB <10 μg/dL (Table 2-30). Several case-control studies have found 

associations between increasing PbB and increasing OR for ADHD diagnosis in children (Joo et al. 2017; 

Park et al. 2016; Wang et al. 2008). In the largest case-control study (630 cases), conducted in China, 

covariate-adjusted ORs for ADHD in children 4–14 years of age were 4.92 (95% CI 3.47, 6.98) for the 

PbB range 5–10 μg/dL and 6.00 (4.11, 8.77) for PbB ≥10 μg/dL compared to <5 μg/dL (Wang et al. 

2008). Associations between increasing PbB and increasing OR for ADHD diagnosis in children have 

also been found in several prospective studies (Boucher et al. 2012; Huang et al. 2016; Ji et al. 2008). In 

the largest prospective study (1,479 children, median age 9.6 years), conducted in Boston, ORs were 

estimated relative to PbB <2 μg/dL (Ji et al. 2018). The OR for the PbB range of 2–4 μg/dL was 

1.08 (95% CI 0.81, 1.44), and the OR for the PbB range of 5–10 μg/dL was 1.73 (95% CI 1.09, 2.73). 

The OR (5–10 μg/dL relative to <5 μg/dL) for male children (OR 2.49, 95% CI 1.46, 4.26) was larger 

than for female children (OR 0.68, 95% CI 0.27, 1.69). A prospective study of 272 children (mean age 

11 years) conducted in Nunavik, Canada found elevated covariate adjusted ORs of 4.01 (95% CI 1.06, 

15.23) for a PbB stratum 1.6–2.7 μg/dL and 5.52 (95% CI 1.38, 22.12) for the stratum 2.7–12.8 μg/dL 

(Boucher et al. 2012). A longitudinal study examined ADHD outcomes of 2,159 South Korean children 

(ages 7–9 years) who did not exhibit ADHD symptoms at recruitment (Choi et al. 2016). Two years 

following baseline assessment, the covariate adjusted relative risk of ADHD was estimated to be 

1.552 (95% CI 1.002, 2.403) for children having PbB >2.17 μg/dL compared to ≤2.17 μg/dL. The 

geometric mean PbB for the cohort was 1.62 μg/dL ±1.52 (GSD). Several cross-sectional studies have 

also found associations between concurrent PbB and risk of ADHD (Braun et al. 2006; Froehlich et al. 

2009; Hong et al. 2014). A study of data on approximately 4,700 children (age 4–15 years) reported in 

the 1999–2002 NHANES found elevated risk of ADHD in association with concurrent PbB >2 μg/dL and 

a significant trend in risk with increasing PbB (Braun et al. 2006). Froehlich et al. (2009) examined data 

for children 8–15 years of age from the 2001–2004 NHANES. Covariate adjusted ORs of ADHD were 

elevated for the PbB stratum >1.3 μg/dL (compared to ≥0.8 μg/dL). A cross-sectional study conducted in 

South Korea examined associations between PbB and ADHD rating scores of 1,001 children of age 8–

11 years (Hong et al. 2015). One log10 increase of PbB was associated with increases in teacher-rated 

ADHD hyperactivity (OR 3.66; 95% CI 1.18, 6.13) and total ADHD score (OR 6.38; 95% CI 1.36, 

11.40). The cohort geometric mean PbB was 1.8±1.4 μg/dL (SD).
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Prospective studies have also provided evidence for associations between neonatal or early childhood 

PbB and other neurobehavioral outcomes, including neonatal behavior, emotional or temperament 

problems, anxiety or depression, sleep disorders, hyperactivity and impulsivity, autistic behavior, and 

delinquency (Dietrich et al. 2001; Fruh et al. 2019; Huang et al. 2016; Joo et al. 2018; Kim et al. 2016; 

Liu et al. 2014b, 2015b; Sioen et al. 2013; Stroustrup et al. 2016; Winter and Sampson 2017). 

Altered neuromotor-neurosensory function. Numerous studies have examined possible associations 

between neonatal and child PbB and neuromotor or neurosensory function (Table 2-30). Several studies 

used the Psychomotor Development Index (PDI) score from the BSID, allowing comparison of results 

across studies (Dietrich et al. 1987, 1989; Kim et al. 2013b; Tellez-Rojo et al. 2006). Each study found 

inverse associations for PDI scores measured from 6 to 12 months in association with increasing prenatal 

(e.g., maternal) or neonatal PbB. Studies that repeatedly measured PDI scores longitudinally within the 

same birth cohorts found that associations observed at 6 months persisted to later ages (Dietrich et al. 

1987, 1989, 1991; Tellez-Rojo et al. 2006). A prospective study conducted in China administered a 

neurobehavioral test battery to a birth cohort of 237 children at age 7 years (Chiodo at al. 2004). 

Significant declines in performance (p≤0.05) were observed in PbB strata that ranged from <3 μg/dL at 

the lowest to <10 μg/dL; most tests that showed significant declines at <10 μg/dL, also showed declines 

at <5 μg/dL (p≤0.05). A prospective study conducted in Nunavik, Canada evaluated fine motor control in 

a birth cohort at 5 years (Fraser et al. 2006). Significant changes in motor control assessed from sway and 

reaction times were associated with increasing concurrent PbB (p≤0.01). The cohort PbB mean was 

5.3 μg/dL ±4.9 (SD). This birth cohort also exhibited changes in visual evoked potentials that were 

associated in increasing cord PbB (Ethier et al. 2012). The cohort cord PbB mean was 4.6±3.1 (SD). 

However, not all studies have found associations between PbB and neuromotor performance. A followup of a prospective birth cohort of approximately 14,500 pregnancies evaluated motor skills in 1,558 

children at age 7 years (Taylor et al. 2018). Prenatal (gestation week 11) PbB was not associated with 

performance on a movement assessment battery (e.g., heel-to-toe, threading lace, peg board). 

Several studies have examined associations between PbB and neurosensory function in infants or children 

(Ethier et al. 2012; Liu et al. 2018b; Silver et al. 2016). A prospective study conducted in Nunavik, 

Canada found changes in visual evoked potentials at age 5 years that were associated with increasing cord 

PbB (mean 4/6±3.1 μg/dL) (Ethier et al. 2012). A prospective study of 315 mother-infant pairs conducted 

in China found associations between increasing prenatal PbB and brainstem auditory response measured 

at age 2 days and grating visual activity measured at age 6 weeks (Silver et al. 2016). Geometric mean 
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late-pregnancy PbB was 2.7±2.3 (GSD) μg/dL. A cross-sectional study of 234 children (age 3–7 years), 

conducted in China, found that increasing PbB was associated with hearing loss (Liu et al. 2018b). The 

OR for hearing loss was 1.24 (95% CI 1.029, 1.486). The median PbB was 4.94±0.20 (SE) μg/dL.

Altered brain structure and neurochemistry. A follow-up to the Cincinnati prospective study (Dietrich et 

al. 1986) estimated whole brain volumes and imaged brain metabolites in 157–159 adults at age 19–

24 years (Brubaker et al. 2010; Cecil et al. 2008, 2011; Table 2-30). Decreasing covariate adjusted brain 

volume was associated with increased childhood mean PbB (measured between ages 6 months and 

6 years). Brain volume reductions that were associated with childhood PbB compromised approximately 

1.2% of the total gray matter and were more severe in males compared to females. The largest effects 

were observed in the anterior cingulate cortex. This region of the brain is involved in controlling 

executive function, mood, and decision-making. Increasing childhood PbB was also associated with 

decreasing concentrations of various metabolites in the brain known to be important in the supporting 

metabolic structural integrity of neurons (e.g., lipid metabolism and myelin production). These included 

decreased N-acetyl aspartate (NAA) in the basal ganglia and cerebellar hemisphere, decreased glutamateglutamine in the vermis and parietal white matter, decreased creatine and phosphocreatine in the basal 

ganglia, and decreased cholines in the cerebellum, parietal white matter, and frontal white matter. These 

changes in association with childhood PbB suggest that childhood Pb exposure may be indicators of 

longer-term changes in brain glutamate-associated lipid metabolism or neuronal architecture (Cecil et al. 

2011). 

Associations Between Bone Pb and Neurological Effects in Children. Few studies have been conducted 

to assess possible associations between bone Pb and neurological function in children (Table 2-31). 

Prospective studies of outcomes in children of mother-infant pairs have found associations between 

maternal or child bone Pb cognitive function (Campbell et al. 2000b; Gomaa et al. 2002; Needleman et al. 

1996; Wasserman et al. 2003; Xu et al. 2015). Increasing bone Pb measured at age 24 months was 

associated with decrements in cognitive development (Gomaa et al. 2002) and behaviors indicative of 

attention deficit hyperactivity disorder assessed at age 7–15 years (Xu et al. 2015). Increasing child bone 

Pb measured later in childhood (ages 11–14 years) was associated with decrements in language 

processing (Campbell et al. 2000b); full scale, verbal, and performance IQ (Wasserman et al. 2003); and 

delinquent, aggressive, internalizing, externalizing behaviors (Needleman et al. 1996). A case-control 

study of adjudicated delinquency at age 12–18 years found associations between increasing bone Pb and 

delinquency (Needleman et al. 2002). A prospective study found associations between increasing bone 

Pb and difficult temperament at age 24 months (Stroustrup et al. 2016).
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Table 2-31. Associations Between Bone Pb and Neurological Outcomes in 

Children

Reference Population

Neurological outcome

Intellectual 

deficits

Altered 

neuromotor or 

neurosensory 

function

Altered 

mood or 

behavior

Outcome 

measures

Campbell et al. 

2000b

156 males, 

age: 11–14 years

↑ T – – Language 

processing

Gomaa et al. 

2002

197 mother-infant 

pairs

↑ Pa

0 Ta

– – 24-month MDIb

Needleman et al. 

1996

301 males, 

age: 9–13 years

– – ↑ T Delinquent, 

aggressive, 

internalizing, 

externalizing 

behaviors

Needleman et al. 

2002

194 male cases, 

145 controls,

age: 12–18 years

– – ↑ T Adjudicated 

delinquency

Stroustrup et al. 

2016

948 mother-infant 

pairs, 760 children, 

age: 24 months

– – ↑ T Difficult 

temperament

Wasserman et 

al. 2003

167 children, 

age: 10–12 years

↑ T – – IQ (full scale, 

verbal, 

performance)c

Xu et al. 2015 197 mother-infant 

pairs

– – ↑ Pa Attenuation of effect 

of maternal selfesteem on ADHD 

assessed at age 7–

15 yearsd

aMaternal bone lead measured within 1 month of birth.

bBayley Scale.

cWechsler Intelligence Scale for Children-III. dMaternal self-esteem was evaluated with Coopersmith Self-Esteem Inventory. ADHD was evaluated with Conners’ 

Parent Rating Scale-Revised and Behavior Rating Inventory of Executive Function.

↑ = positive association; ↓ = inverse association; 0 = no association; – = not reported; ADHD = Attention deficit 

hyperactivity disorder; C = calcaneus bone; MDI = Mental Developmental Index; P = patella; Pb = lead; T = tibia; 

O = other

Effects at Blood Pb Levels ≤10 μg/dL in Adults. Numerous longitudinal and large cross-sectional studies 

in adults provide a weight of evidence for decreased cognitive function, altered mood and behavior, and 

altered neuromotor and neurosensory function in association with exposures that result in PbB <10 μg/dL, 
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with some studies showing effects in the 3–5 μg/dL range. Study details are reviewed in the Supporting 

Document for Epidemiological Studies for Lead, Table 10. Cognitive, neuromotor, and neurosensory 

outcomes have been evaluated with tests of memory, learning, executive function, reaction time, walking 

speed, and tremor. Pb exposure has been associated with risk of various psychiatric symptoms including 

anxiety, depression, and schizophrenia, and with risk of ALS. In some studies, associations were found 

between outcomes and PbB and/or bone Pb. Several studies have examined cohorts of people who had 

mean ages within the range 50–70 years. Studies of cognitive function in elderly populations must 

control for factors that contribute to age-related decrements in function, including confounding from the 

relationship between age and bone Pb, which increases with age. Longitudinal studies offer advantages 

over cross-sectional studies in that they can provide measurement changes in function of individual 

subjects with age. 

Cognitive function. Numerous studies have examined possible associations between Pb exposure and 

cognitive function in adults (Table 2-32). Most of these studies have found associations between 

increasing Pb exposure, indicated by blood or bone Pb, and indications of decreased cognitive function 

(Muldoon et al. 1996; Payton et al. 1998; Power et al. 2014; Przybyla et al. 2017; Seegal et al. 2013; Seo 

et al. 2014; Shih et al. 2006; Weisskopf et al. 2007; Weuve et al. 2006, 2009; Wright et al. 2003b). 

However, not all studies have found associations (Kreig et al. 2005; Yu et al. 2019b). One of the largest 

cross-sectional studies analyzed data from NHANES III (1988–1994) found no associations between PbB 

and performance on neurobehavioral tests (Krieg et al. 2005). This study compared scores from several 

tests from the Neurobehavioral Evaluation System (NBES) and concurrent PbB in approximately 

5,700 adults (age 20–50 years). Implemented tests measured processing speed, attention, learning, and 

memory (reaction time, symbol-digit substitution, serial digit learning). The geometric mean PbB was 

2.51 μg/dL (range 0.7–42) and 96% of the cohort was <10 μg/dL. No significant associations (defined as 

p≤0.05) between PbB and cognitive outcomes were found. However, associations between PbB and 

cognitive performance may be stronger in elderly adults. An examination of a smaller cohort from the 

NHANES 1999–2000, restricted to ages ≥60 years (n=498), found an association between increasing PbB 

and decreasing scores on short-term memory (digit symbol test) (Przybyla et al. 2017). The geometric 

mean PbB in this study was 2.17 μg/dL. Several studies have examined smaller cohorts from longitudinal 

studies designed to evaluate health in aging populations. Studies of male cohorts from the Normative 

Aging Study have found significant (p≤0.05) associations between increasing blood and/or bone Pb and 
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Table 2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Cognitive abilities

Krieg et al. 2005

Cross-sectional study; n=5,662 adults, 

age 20–59 years

Gmean (range): 2.51 (0.7, 

41.8)

Simple visual reaction time No associations between PbB and performance 

scores

• Mean reaction time: p=0.24

Symbol-digit substitution • Mean total latency: p=0.27

• Number of errors: p=0.82

Serial digit learning • Trials to criterion: p=0.26

• Total score: p=0.24

Muldoon et al. 1996

Cross-sectional study; n=530 adult 

women, mean age 70 years 

Mean (SD): 

• All: 4.8 (0.4)

• Rural: 4.5 (0.4)

• Urban: 5.4 (0.4)

• Low: <4

• Medium: 4–7

• High: >7

Trailmaking B • Urban

o Medium PbB OR: 0.97 (0.40, 2.40)

o High PbB OR: 0.79 (0.20, 3.04)

• Rural

o Medium PbB OR: 2.05 (1.05, 4.02)*

o High PbB OR: 2.60 (1.04, 6.49)*

Digit symbol (correct) • Urban

o Medium PbB OR: 0.61 (0.25, 1.50)

o High PbB OR: 0.64 (0.16, 2.47)

• Rural

o Medium PbB OR: 2.03 (1.06, 3.88)*

o High PbB OR: 3.73 (1.57, 8.84)*

Incidental memory • Urban

o Medium PbB OR: 0.50 (0.22, 1.16)

o High PbB OR:0.99 (0.28, 1.16)

• Rural

o Medium PbB: OR: 1.37 (0.77, 2.41)

o High PbB: OR: 1.89 (0.83, 3.41)
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Table 2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Payton et al. 1998

Longitudinal study; n=141 males, 

mean age 67 years

Mean (SD): 

• 5.5 (3.5)

• Q1: 1.4

• Q2: 3.5

• Q3: 5.4

• Q4: 9.8

Pattern recognition • β: 0.074 (0.032), p=0.02*

Vocabulary • β: -0.841 (0.20), p=0.0001*

Word list memory • β: -0.182 (0.086), p=0.036*

Boston naming test • β: -0.036 (0.016), p=0.028*

Verbal fluency • β: -0.230 (0.120), p=0.09

Power et al. 2014

Longitudinal study; n=584 adults 

females, mean age 61 years

Mean (SD): 

• 2.9 (1.9)

Tibia Pb (μg/g): Mean 

(SD):

• 10.5 (9.7)

Patella Pb (μg/g) mean 

(SD):

• 12.6 (11.7)

Overall cognition β for 1-age year change in score per 1 SD PbB:

-0.013 (-0.044, 0.017)

Verbal memory β for 1-age year change in score per 1 SD PbB: 

0.006 (-0.037, 0.050)

Przybyla et al. 2017

Cross-sectional study; n=498 adults, 

age 60–84 years

Gmean (range): 2.17 (0.4, 

16.4)

Digit symbol (correct) β per lnPbB μg/dL: -0.10 (-0.20, -0.006), p=0.04

Seo et al. 2014

Cross-sectional study; n=31 retired 

female Pb workers, mean age 

60.4 years, and 34 controls 

Gmean (range): 

Exposed: 4.07 (0.88–13.5)

Controls: 2.00 (1.24–6.47) 

Verbal memory Accuracy % (SD), exposed versus control: 

• 1-back test: 55.9 (19.8) versus 65.4 (19.4), 

p=0.056

• 2-back test: 61.4 (20.1) versus 77.2 (15.6), 

p=0.001*
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Table 2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Shih et al. 2006

Cross-sectional study; n=985 adults, 

mean age 59.4 years

Mean (SD): 

• 3.46 (2.23)

Tibia Pb (μg/g) mean (SD): 

• 18.72 (11.24)

Language • Β per 1 μg/g tibia Pb: -0.0083 (0.0023), 

p≤0.01*

Processing speed • β per 1 μg/g tibia Pb: -0.0042 (0.0021), 

p<0.01* 

Eye-hand • β per 1 μg/g tibia Pb: -0.0079 (0.0020), 

p≤0.01*

Executive function • β per 1 μg/g tibia Pb: -0.0075 (0.0019), 

p≤0.01*

Verbal memory and learning • β per 1 μg/g tibia Pb: -0.0078 (0.0024), 

p≤0.01*

Visual memory • β per 1 μg/g tibia Pb: -0.0067 (0.0023), 

p≤0.01*

Visuoconstruction • β per 1 μg/g tibia Pb: -0.0122 (0.0027), 

p≤0.01*

Weisskopf et al. 2007

Longitudinal study cohort, 

n=1,089 males, mean age 68.7 years 

Median (IQ range): 

• 5 (3–6)

Tibia Pb (μg/g) median (IQ 

range): 

• 20 (13–28)

Patella Pb (μg/g) median 

(IQ range): 

• 25 (17–37)

Vocabulary β per 3 μg/dL increase in PbB: -1.26 

(-2.08, -0.44), p=0.003*

Visuoconstruction (patella 

Pb)

β per IQR: -0.067 (-0.11, -0.02), p=0.0041*

Pattern comparison latency 

(tibia Pb)

β: 0.079 (0.04, 0.12), p=0.0004*

Weuve et al. 2006

Longitudinal study cohort, 

n=915 males, mean age 68.7 years

Median (IQ range): 

• 5.2 (2.9)

• 94% <10

Cognitive function Change in MMSE score per IQR in PbB, 

3 μg/dL:

• ALAD-2: IQR: -0.29 (-0.56, -0.02)*

• ALAD wildtype: IQR: -0.05 (-0.16, 0.06)

Weuve et al. 2009

Longitudinal study cohort, 

n=587 females, mean age 61 years

Mean (SD): 

• 2.9 (1.9)

Tibia Pb (μg/g) median 

(SD): 

• 10.5 (9.7)

Cognitive function Change in score per 1 SD in PbB or bone Pb:

• PbB: -0.016 (-0.071, 0.039), p=0.57

• Tibia: -0.051 (-0.099, -0.003), p=0.04*

• Patella Pb: -0.033 (-0.080, 0.014), p=0.17
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Table 2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Patella Pb (μg/g) median 

(SD): 

• 12.6 (11.6)

Wright et al. 2003b

Longitudinal study cohort, 

n=736 males, mean age 68.2 years

Mean (SD): 

• All: 4.5 (2.5)

• Q1: 2.5

• Q2: 4.0

• Q3: 5.9

• Q4: 8.9

Tibia Pb (μg/g) median 

(SD): 

• 22.4 (15.3)

Patella Pb (μg/g) median 

(SD): 

• 29.5 (21.2)

MMSE score Adjusted OR with 1 μg/dL increase in PbB or 

1 μg/g increase in bone Pb:

• PbB: 1.21 (1.07, 1.36)*

• Patella Pb: 1.02 (1.00, 1.03)* 

• Tibia Pb: 1.02 (1.00, 1.04)*

Effect of age increased with increasing PbB. 

β for age with increasing Pb for PbB quartile:

• Q1 -0.04 (-0.07, -0.02)*

• Q2 -0.04 (-0.08, -0.01)*

• Q3 -0.09 (-0.13, -0.06)*

• Q4 -0.12 (-0.17, -0.02)*

Yu et al. 2019b

Cross-sectional study; n=339 males, 

mean age 28.6 years

Gmean (IQR): 2.47 (2.00, 

3.00)

Digit symbol (mean total 

latency)

β per log10 PbB: 5.4% (-0.4, 11.5), p=0.066

Stroop reaction time 

incongruent trials

β per log10 PbB: 5.1% (-4.5, 15.6), p=0.30

Stroop reaction time 

congruent trials

β per log10 PbB: -1.2% (-10.4, 9.0), p=0.81

Stroop interference effect β per log10 PbB: 23.0% (-15.4, 78.9), p=0.28
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Table 2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Mood and behavior

Bouchard et al. 2009

Cross-sectional study; n=1,987 adults 

(age 20–39 years) 

Gmean±GSD (range):

• 1.24 (1.96)

• 99%≤10

• Q1: 0.6

• Q2: 0.9

• Q3: 1.2

• Q4: 1.3

• Q5: 3.0

Major depressive disorder • Adjusted ORs for PbB for Q5 relative to 

Q1: 2.32 (1.13, 4.75); p-trend=0.05*

• Eliminating current smokers, adjusted 

ORs for PbB for Q5 relative to Q1: 

2.93 (1.24, 6.92); p-trend=0.03*

Panic disorder • Adjusted ORs for PbB for Q5 relative to 

Q1: 4.94 (1.32, 18.48); p-trend=0.02*

• Eliminating current smokers, adjusted 

ORs for PbB for Q5 relative to Q1: 

9.57 (1.28, 71.43); p-trend=0.01*

Generalized anxiety 

disorder

• Adjusted ORs for PbB for Q5 relative to 

Q1: 1.53 (0.39, 5.96); p-trend=0.78

• Eliminating current smokers, adjusted ORs 

for PbB for Q5 relative to Q1: 1.59 (0.19, 

13.31); p-trend=0.44

Buser and Scinicariello 2017

Cross-sectional study of 3,905 adults 

(age ≥20 years) from NHANES 2011–

2012

Cohort stratified into PbB 

quartiles: 

• Q1: <0.7

• Q2: 0.70–1.06

• Q3: 1.07–1.67

• Q4: >1.67

Depression Adjusted OR for depression symptoms in adult 

females (age 20–47 years) associated with 

increasing PbB: 

• Q3: 1.86 (1.01, 3.41, p<0.05*

• Q4: 2.97 (1.01, 8.74), p<0.05*

Fan et al. 2020

Cross-sectional study; n=994 adults, 

age >60 years

Mean (SD): 3.229 (2.357)

• Q1: <2.027

• Q2: 2.027, 2.677

• Q3: 2.677, 3.058

Q4: ≥3.058

Depression symptoms 

(score on 30-point Geriatric 

Depression Scale ≥11)

OR for depression for PbB quartiles relative to 

Q1:

• Q2: 1.28 (0.79, 2.08), p=0.315

• Q3: 1.36 (0.84, 2.22), p=0.216

• Q4: 2.03 (1.23, 3.35), p=0.006*

• p-trend=0.007*
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Table 2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Golub et al. 2010

Cross-sectional study; 4,195 adults 

(age ≥20 years) from NHANES 2005–

2006

Cohort stratified into PbB 

quartiles: 

• Q1: ≤0.88

• Q2: 0.89–1.40

• Q3: 1.41–2.17

• Q4: 2.18–26.4

Adjusted OR for depression symptoms was 

elevated in PbB quartile 3 (95% CI):

• Q3: 1.25 (1.07, 1.47)*

Li et al. 2017a

Cross-sectional study; 

n=1,931 pregnancies (age 13–

42 years)

Gmean (range): 3.99 (0.80, 

14.84)

Depression symptoms β per log10 PbB: 

• Full cohort: 0.03 (-0.05, 0.10), p=0.466

• PbB ≤2.57: 0.34 (0.12, 0.56), p=0.002*

• PbB >2.57: -0.09 (-0.19, 0.02), p=0.113

Anxiety symptoms β per log10 PbB: 

• Full cohort: 0.01 (-0.06, 0.08), p=0.770

• PbB ≤2.57: 0.25 (0.04, 0.46), p=0.019*

• PbB >2.57: -0.08 (-0.18, 0.02), p=0.136

Depression or anxiety 

symptoms (Global Severity 

Index)

β per log10 PbB: 

• Full cohort: 0.01 (-0.05, 0.07), p=0.815

• PbB ≤2.57: 0.22 (0.05, 0.40), p=0.013*

• PbB >2.57: -0.07 (-0.16, 0.01), p=0.100

Opler et al. 2004

Case-control study; 

n=44 schizophrenia cases and 

75 matched controls from birth cohorts 

Cohort stratified into <15 or 

≥15 μg/dL based on 2nd

trimester ALA 

measurements

Schizophrenia Adjusted OR for schizophrenia associated with 

high (≥15 μg/dL) prenatal PbB: 2.43 (0.99, 

5.96), p=0.051

Opler et al. 2008

Case-control study; 

n=71 schizophrenia cases and 

129 matched controls 

Cohort stratified into <15 or 

≥15 μg/dL based on 2nd

trimester ALA 

measurements

Schizophrenia Adjusted OR for schizophrenia associated 

with high (≥15 μg/dL) prenatal PbB: 1.92 

(1.05, 3.87), p=0.03*
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Table 2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Rajan et al. 2007

Longitudinal study cohort, 

n=1,075 males, mean age 67.1 years 

Mean (SD): 

• All: 6.2 (4.1)

Tibia Pb (μg/g) median 

(SD): 

• 22.1 (13.8)

Patella Pb (μg/g) median 

(SD): 

• 31.4 (19.6)

Somatization, tibia Pb Adjusted OR for inter quartile increases in 

tibia Pb (14 μg/g) or patella Pb (20 μg/g): 1.21 

(1.01, 1.46)*

Global severity index, 

patella Pb

OR: 1.23 (1.02, 1.47)*

Rhodes et al. 2003

Longitudinal study cohort, 

n=526 males, mean age 67.1 years 

Mean (SD): 

• 6.3 (4.2)

Tibia Pb (μg/g) median 

(SD): 

• 21.9 (13.5)

Patella Pb (μg/g) median 

(SD): 

• 32.1 (19.8)

Phobic anxiety Adjusted OR for inter quintile increases in 

patella Pb (8.9 μg/dL: 1.91 (1.01, 3.61)*

Combined symptoms Adjusted OR for inter quintile increases:

• PbB OR: 2.91 (1.39, 6.09)*

• Tibia Pb OR: 2.08 (1.06, 4.07)*

• Patella Pb OR: 3.62 (1.62, 8.08)*

Scinicariello and Buser 2015

Cross-sectional study of 2,892 adults 

(age 20–39 years) from NHANES 

2007–2010

PbB:

Gmean (GSD)

• 0.96 (0.02).

Depression Adjusted OR for depression symptoms was not 

associated with increasing PbB (ORs were not 

reported).
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Table 2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Neuromotor neurosensory function

Casjens et al. 2018

Longitudinal study; n=1,188 males, 

age 55–86 years at follow-up

Median (% >9)

• Baseline: 3.29 (2.27%)

• 11-year follow-up: 2.59

(0.84%)

Olfaction (score on 12-point 

odor identification test ≤7)

Proportional OR for PbB stratum relative 

<5.0 μg/dL:

Baseline:

• 5–<9 μg/dL: 0.91 (0.65, 1.28)

• ≥9 μg/dL: 1.96 (0.94, 4.11)

Follow-up: 

• 5.0–<9.0 μg/dL: 1.04 (0.55, 1.94)

• ≥9.0 μg/dL: 1.57 (0.47, 5.19)

Dexterity (finger tapping 

errors)

OR (95% CI) for impaired performance 

<5.0 μg/dL:

• 5.0 to <9.0 μg/dL: 0.87 (0.53, 1.44)

• ≥9.0 μg/dL: 1.35 (0.49, 3.70)

Follow-up:

• 5.0–<9.0 μg/dL: 2.63 (1.26, 5.94)*

• ≥9.0 μg/dL: 0.80 (0.14, 4.59)

Hwang et al. 2009

Cross-sectional study; n=259 male 

steel workers, mean age 36.0 years

Mean (SD):

5.43 (3.46)

Hearing loss Adjusted OR for hearing loss (>25 dB) at 3,000–

8,000 Hz in PbB categories relative to ≤4 μg/dL:

Loss at 3,000 Hz

• 4–7 μg/dL: 0.75 (0.17, 3.29)

• ≥7 μg/dL: 4.49 (1.28, 15.8); p<0.005*

Loss at 4,000 Hz:

• 4–7 μg/dL: 3.54 (1.40, 8.97)* (p-value not 

reported) 

• ≥7 μg/dL: 6.26 (2.35, 16.6); p<0.005*

Loss at 6,000 Hz:

• 4–7 μg/dL: 2.11 (0.94, 4.47)

• ≥7 μg/dL: 3.06 (1.27, 7.39); p<0.05*
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Table 2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Huh et al. 2018

Cross-sectional study; n=2,387 adults, 

age 19–85 years

Gmean (95% CI): 2.46 

(2.41, 2.52)

Hearing loss (pure tone 

threshold >25 dB)

OR per doubling of PbB (95% CI):

• Low frequency: 0.91 (0.52, 1.61)

• Speech frequency: 1.21 (0.72, 2.04)

• High frequency: 1.88 (1.11, 3.17)*

Ji et al. 2013

Cross-sectional study; n=1,795 males 

and 1,798 females, age >50 years 

(median 61.2) 

Mean (SD):

• Females: 2.17 (0.06)

• Males: 3.18 (0.12)

Walking speed Mean change in walking speed (ft/sec) for PbB 

quintile relative to Q1 (≤1.2 μg/dL):

• PbB 1.3–≤1.6. β: -0.024 (-0.112, 0.064), 

p=0.58

• PbB 1.7–≤2.1, β: -0.027 (-0.118, 0.063), 

p=0.54

• PbB 2.2–≤2.9, β: -0.104 (-0.187, -0.021), 

p=0.02*

• PbB 3.3–≤53.0, β: -0.114 (-0.191, -0.038), 

p=0.01*

• p-trend=0.005*

Ji et al. 2015

Longitudinal study cohort, 

n=807 males, mean age 69 years

Mean (SD): 5.0 (2.7)

• % <10: 96%

Bone Pb, μg/g (SD)

• Patella: 28.0 (18.4) 

Tibia: 21.2 (13.3)

Tremor OR for tremor by PbB quintile:

• Q5 (8–28), PbB: 0.84 (0.38, 1.86), p=0.72

• Q5 (40–165), patella Pb: 0.83 (0.31, 2.19), 

p=0.41

• Q5 (30–126): tibia Pb: 1.08 (0.46, 2.53), 

p=0.60
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Table 2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Kang et al. 2018

Cross-sectional study; n=6,409 adults, 

age 20–87 years

Cohort stratified into PbB 

quartiles

Females, weighted mean 

(SE)

• Q1: 1.12 (0.01)

• Q2: 1.61 (0.01)

• Q3: 2.11 (0.01)

• Q4: 3.03 (0.03)

Males, weighted mean 

(SE)

• Q1: 1.56 (0.01)

• Q2: 2.22 (0.01)

• Q3: 2.82 (0.01)

• Q4: 4.22 (0.08)

Hearing loss (females) • Q2: 0.947 (0.606 1.477)

• Q3: 1.013 (0.698, 1.471)

• Q4: 1.502 (1.027, 2.196)*

Hearing loss (males) • Q2: 1.368 (1.006, 1.859)*

• Q3: 1.402 (1.005, 1.955)*

• Q4: 1.629 (1.161, 2.287)*

Muldoon et al. 1996

Cross-sectional study; n=530 adult 

women, mean age 70 years

Mean (SD): 

• All: 4.8 (0.4)

• Rural: 4.5 (0.4)

• Urban: 5.4 (0.4)

• Low: <4

• Medium: 4–7

• High: >7

Pegboard OR for poor performance (low PbB reference) in 

the rural cohort:

ANOVA, p=0.98

• Medium PbB OR: 1.37 (0.71, 2.65)

• High PbB OR: 1.16 (0.45, 3.01)

Upper extremity ANOVA, p<0.01, in the rural cohort

• Medium PbB: OR: 1.39 (0.73, 2.65)

• High PbB: OR: 2.43 (1.01, 5.83)*

Lower extremity ANOVA, p<0.01, in the rural cohort

• Medium PbB OR: 1.29 (0.68, 2.47

• High PbB OR: 2.84 (1.19, 6.74)*
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Table 2-32. Summary of Epidemiology Studies Evaluating Neurodevelopmental Effects in Adults at Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Neurological disease

Fang et al. 2010

Case-control study; n=184 male ALS 

cases and 194 matched controls, 

mean age 63 years 

Mean (range):

• Controls: 1.76 (0.32–

6.90)

• Cases: 2.41 (0.72–

7.58)

ALS Adjusted OR for ALS for doubling of PbB:

• All cases (n=184): 1.9 (1.3, 2.7)*

• Excluding progressive muscular atrophy

and primary lateral sclerosis (n=151): 1.8

(1.2, 2.5)*

Kamel et al. 2002

Case-control study; n=109 ALS cases 

and 256 matched controls, age 30–

80 years

Mean (range):

• Cases: 3 of 194 had

PbB >10

• Controls: <10 μg/dL

ALS • Adjusted OR for ALS (for a 1-μg/dL

increase in PbB: 1.9 (1.4, 2.6)*

• Adjusted OR for ALS relative to <2 μg/dL:

o 3–4 μg/dL: 14.3 (3.0, 69.3)*

o 5–14 μg/dL: 24.5 (4.3, 139.3)*

aSee the Supporting Document for Epidemiological Studies for Lead, Table 10 for more detailed descriptions of studies. bParticipants had no known occupational exposure to Pb.

cAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

ALA = aminolevulinic acid; ALAD-2 = delta-aminolevulinic acid dehydratase allele; ALS = amyotrophic lateral sclerosis; ANOVA = analysis of variance; 

CI = confidence interval; CL = confidence limit; Gmean = geometric mean; GSD = geometric standard deviation; IQ = intelligence quotient; IQR = interquartile 

range; MMSE = Mini-Mental Status Examination; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; Pb = lead; SD = standard 

deviation; SE = standard error
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decreasing scores on cognitive tests, including short-term memory, verbal memory, and visuoconstruction 

(Payton et al. 1998; Weisskopf et al. 2007; Weuve et al. 2006). Cohort sizes in these studies ranged from 

approximately 600 to 1,100 and the mean PbB ranged from 2.9±1.9 to 5.5±3.5 μg/dL. Weuve et al. 

(2006) found that decreases in cognitive performance were associated with PbB in a cohort of ALAD-2 

carriers, but not in a cohort that carried the wildtype ALAD allele. Studies of female cohorts 

(approximately 600 subjects) from the longitudinal Nurses’ Health Study have found mixed outcomes 

(Power et al. 2014; Weuve et al. 2009). Weuve et al. (2009) found significant association between 

increasing tibia Pb, but not PbB, and scores on a telephone survey of cognitive function (the Telephone 

Interview for Cognitive Status, TIC). The TIC has been used to assess memory and executive function 

and has been used to evaluate dementia. The effect size was -0.051 (95% CI -0.099, -0.003) points per 

1 SD of tibia Pb. Power et al. (2014) used the same telephone survey instrument and found no 

associations between blood or bone Pb and cognitive function; the effect size for PbB was -0.013 (95% 

CI: -0.044, 0.017) and the cohort mean PbB was 2.9±1.9 (SD) μg/dL. A cross-sectional study of 

approximately 1,000 adults from the Boston Memory Study found inverse associations (p≤0.05) between 

performance on cognitive tests and increasing tibia Pb, but not for PbB (Shih et al. 2006). The cohort 

mean blood Pb was 3.46±2.2 (SD) μg/dL. Cognitive function evaluated included language, processing 

speed, executive function, verbal memory and learning, and visuoconstruction. The effect sizes were 

substantially attenuated by race/ethnicity and years of educational and were no longer significant (p<0.05) 

when adjusted for these covariates. A cross-sectional study of approximately 500 adult females from the 

Study of Osteoporotic Fractures found significant associations (p≤0.05) between performance on 

cognitive tests and increasing PbB (Muldoon et al. 1996). The odds of performing worse on visual 

attention and short-term memory tests were significantly decreased (p≤0.05) in a PbB stratum 4–7 and to 

>7 μg/dL compared to stratum <4 μg/dL. A cross-sectional study of 339 newly hired male Pb workers 

did not find significant associations between PbB (p≥0.05) and performance on tests that measured 

attention, memory, and processing speed (Stroop test, Symbol Digit Test) (Yu et al. 2019b). The 

geometric mean PbB was 2.47 μg/dL.

Altered mood and behavior. Several studies have examined associations between Pb exposure assessed 

from blood or bone Pb and symptoms of psychiatric disorders (Table 2-32). Several studies have 

analyzed cross-sectional data from NHANES to explore associations between depression symptoms and 

PbB (Bouchard et al. 2009; Buser and Scinicariello 2017; Golub et al. 2010; Scinicariello and Buser 

2015). Three studies found associations between PbB and depression in adult populations that had 

geometric mean PbBs that were 2–3 μg/dL compared to populations that have PbBs <1 (Bouchard et al. 

2009; Buser and Scinicariello 2017; Golub et al. 2010). Buser and Scinicariello (2017) found stronger 
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associations in adult women than in men. Cross-sectional studies in other populations have found 

significant associations between PbB and symptoms of depression or anxiety (Fan et al. 2020; Li et al. 

2017a). The Fan et al. (2020) study was restricted to adults >60 years (n=994) and found that increasing 

PbB was associated with increasing scores on the Geriatric Depression Scale. The OR for categorization 

as depressed was 2.04 (95% CI: 1.23, 3.35) in the upper quartile PbB stratum (≥3.06 μg/dL). The Li et al. 

(2017a) study examined a cross-sectional cohort of 1,931 pregnancies (age range 13–42 years) for 

depression, anxiety, and psychological stress. Increasing PbB was associated with increasing scores on 

depression and anxiety assessments; however, the association was stronger in the PbB stratum 

≤2.57 μg/dL compared to a higher stratum >2.57 μg/dL. Associations between psychiatric disorders and 

Pb exposure metrics have also been studied in longitudinal studies (Rajan et al. 2007; Rhodes et al. 2003). 

Two studies of cohorts from the Normative Aging Study found significant ORs for blood or bone Pb and 

various psychiatric symptoms in males (mean age 67±7, SD), including somatization, phobic anxiety, and 

composite indices of distress. Mean PbBs in these cohorts were 6±4 (SD) μg/dL. Associations between 

PbB and psychiatric disorders have also been found in case-control studies (Opler et al. 2004, 2008). The 

largest was a study of 71 schizophrenia cases and 129 matched controls (Opler et al. 2008). The adjusted 

OR for schizophrenia was 1.92 (95% CI 1.05, 3.87) for the PbB stratum ≥15 μg/dL compared to 

15 μg/dL. Because individual PbB data were not available, subjects were categorized into the high 

(<15 μg/dL) or low (15 μg/dL) PbB categories based on measurements of serum ALA and a regression 

model relating PbB and ALA derived from a different population (Graziano et al. 1990). Although the 

accuracy of the method for assigning subjects from Graziano et al. (1990) into low or high categories was, 

on average, approximately 90%, uncertainty in the actual regression model is likely to have resulted in 

some misclassification of individuals. 

Altered neuromotor neurosensory function. Several studies have examined associations between Pb 

exposure assessed from blood or bone Pb and performance on tests of neuromotor or neurosensory 

function (Table 2-32). The largest study analyzed data from NHANES III (1988–1994) and found no 

association (p=0.34) between concurrent PbB and simple visual reaction time in a cohort of 5,700 adults 

(age 20–50 years; Krieg et al. 2005). The geometric mean PbB was 2.51 μg/dL (range 0.7–42) and 96% 

of the cohort was <10 μg/dL. A more recent analysis of data from NHANES (1999–2002) examined 

walking speed in cohorts of approximately 1,800 males or females and found a significant association 

between increasing PbB and decreasing walking speed in females in a PbB stratum 2.2–≤2.9 μg/dL 

compared to 1.6 μg/dL; there was a significant trend with increasing PbB (Ji et al. 2013). This outcome is 

consistent with a smaller cross-sectional study of women (mean age 70±4 years) that found significant 

decreases in upper and lower extremity reaction times in association with increasing PbB (Muldoon et al. 
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1996). A longitudinal study of a cohort from the Normative Aging Study found no significant 

associations between bone or blood Pb and hand tremor in males (mean age 60±7 years; Ji et al. 2015). 

The mean PbB for the cohort was 5.0±2.7 (SD) μg/dL. A longitudinal study of males (n=1,188), age 

range 50–86 years, conducted in Germany, found associations between increasing PbB and decreasing 

performance scores on tests of dexterity (Casjens et al. 2018). The median PbBs were 3.29 μg/dL at the 

start of the study (2.27% >9 μg/dL) and 2.29 μg/dL (0.84% >9 μg/dL) at the 11-year follow-up. This 

study examined several metrics of dexterity (finger tapping and aiming, line tracing, steadiness). The 

association with Pb was strongest for the finger tapping test. The OR for impaired performance on the 

finger tapping test at the follow-up was 2.63 (95% CI: 1.26, 5.94) for the PbB stratum 5.0–<9 μg/dL and 

0.80 (95% CI: 0.14, 4.59) for the PbB stratum >9 μg/dL.

Several studies have examined associations between PbB and sensory function in adults, including 

olfaction (Casjens et al. 2018) and hearing (Huh et al. 2018; Hwang et al. 2009; Kang et al. 2018). Two 

studies examined association between PbB and hearing using data from the Korean National Health and 

Nutrition Examination Study (KNHANES) (Huh et al. 2018; Kang et al. 2018). Both studies found 

associations between increasing PbB and high-frequency hearing loss. The larger of the two studies 

(n=6,409) estimated ORs for high-frequency hearing loss in females and males in the age range 19–

85 years. The ORs were 1.629 (95% CI: 1.161, 2.287) in the highest male PbB quartile (mean PbB:

4.2 μg/dL±0.04 SE) and 1.502 (95% CI: 1.027, 2.196) in the highest female PbB quartile (mean PbB:

3.03 μg/dL ±0.03 SE). A smaller cross-sectional study of steel workers (n=259) also found associations

been increasing PbB and hearing loss that extended from 3,000 to 8,000 Hz in the PbB stratum ≥7 μg/dL 

(Hwang et al. 2009). Performance on an odor identification test was not associated with PbB in a 

longitudinal study of males (n=1,188), age range 50–86 years (Casjens et al. 2018).

Neurological diseases. Possible associations between Pb exposure and risk of ALS have been examined 

in case-control studies (Fang et al. 2010; Kamel et al. 2002). A case-control study of 184 male ALS cases 

and 194 matched controls found a significant association between increasing PbB and ALS (Fang et al. 

2010). The mean PbB for cases was 2.41 μg/dL (range 0.72–7.58 μg/dL). A case-control study of 

109 ALS cases (43 females, 66 males) and 194 matched controls estimated the OR for ALS to be 

1.9 (95% CI: 1.4, 2.6) for a 1 μg/dL increase in PbB (Kamel et al. 2002).

Associations Between Bone Pb and Neurological Effects in Adults. Decrements in neurological 

function in adults have also been associated with bone Pb (Table 2-33). In general, these studies provide 

further support for associations between Pb exposure and neurobehavioral function, including decrements 
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in cognitive function, altered neuromotor and neurosensory function, and altered behavior and mood. 

Most of these studies are of cohorts from longitudinal health studies: Boston Memory Study (BandeenRoche et al. 2009; Glass et al. 2009; Shih et al. 2006), Nurses’ Health Study (Power et al. 2014; Weuve et 

al. 2009), or Normative Aging Study (Eum et al. 2013; Farooqui et al. 2017; Grashow et al. 2013a, 2013b, 

2015; Ji et al. 2015; Park et al. 2010; Payton et al. 1998; Power et al. 2014; Rajan et al. 2007, 2008; 

Rhodes et al. 2003; Schwartz et al. 2005; Wang et al. 2007, 2018; Weisskopf et al. 2004, 2007; Wright et 

al. 2003b). These studies have provided both cross-sectional and longitudinal assessments of associations 

between bone Pb (and PbB) and neurological function in adult populations. Longitudinal designs are 

particularly important because they allow age-related declines in cognitive function to be assessed. 

Longitudinal studies have found that associations between bone Pb and cognitive function (learning, 

memory) persist when adjustments are made for age (Bandeen-Roche et al. 2009; Dorsey et al. 2006; 

Eum et al. 2013; Grashow et al. 2013a; Khalil et al. 2009; Payton et al. 1998; Power et al. 2014; Rajan et 

al. 2008; Schwartz et al. 2005; Seegal et al. 2013; Shih et al. 2006; Stewart et al. 2002; van Wijngaarden 

et al. 2009; Weisskopf et al. 2007; Weuve et al. 2009, 2013; Wright et al. 2003b). Rates of decrement in 

cognitive function with age have been found to be more severe in association with increasing bone Pb 

(Farooqui et al. 2017; Power et al. 2014; Schwartz et al. 2005; Wang et al. 2007; Weisskopf et al. 2004, 

2007; Wright et al. 2003b). 

Table 2-33. Associations Between Bone Pb and Neurological Outcomes in 

Adults

Reference Population

Neurological outcome

Intellectual 

deficits

Altered 

neuromotor or 

neurosensory 

function

Altered 

mood or 

behavior

Outcome 

measures

Bandeen-Roche 

et al. 2009

965 adults, 

age: 50–

70 yearsa

↑ T – – Learning, memory, 

executive function, 

eye-hand 

coordination

Coon et al. 2006 121 adult cases, 

414 controls,

age: 50–

>80 years

– ↑ 0d – Parkinson’s disease

Dorsey et al. 

2006

652 adult Pb

workers, 

age: 20–70 years

↑ P

↑ T

↑ P

↑ T

↑ P

↑ T

Reaction time, 

executive function,

manual dexterity, 

vibration threshold, 

depression
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Table 2-33. Associations Between Bone Pb and Neurological Outcomes in 

Adults

Reference Population

Neurological outcome

Intellectual 

deficits

Altered 

neuromotor or 

neurosensory 

function

Altered 

mood or 

behavior

Outcome 

measures

Eum et al. 2013 789 adult malesb,

age: 68 years 

(median)

↑ P

↑ T

– – Memory, verbal and 

written skills, 

executive function

Eum et al. 2015 100 adult cases, 

194 controls,

age: 60 years 

(mean)

– ↑ P

↑ T

– Interaction between 

Pb, amyotrophic 

lateral sclerosis and 

hemochromatosis 

gene 

polymorphisms

Farooqui et al. 

2017

741 males, age: 

68 years (mean)

↑ P

0 T

– – Memory, 

visuospatial ability, 

attention, language, 

orientation

Glass et al. 2009 1,001 adultsa,

age: 50–70 years

↑ T ↑ T – Interaction between 

Pb and 

psychosocial hazard 

scale for eye-hand 

coordination, 

executive function, 

language

Grashow et al. 

2013a

51 adult malesb,

age: 75 years 

(mean)

↑ P

0 T

– – Fear conditioning

Grashow et al. 

2013b

362 adult malesb,

age: 69 years 

(mean)

– ↑ P

↑ T

– Manual dexterity

Grashow et al. 

2015

164 adult malesb,

age: 80 years 

(mean)

– 0 P

↑ T

– Olfactory function

Ji et al. 2015 672 adult malesb,

age: 50–98 years

– 0 P

0 T

– Tremor (no 

association in 

adjusted models)

Kamel et al. 

2002

109 adult cases, 

256 controls,

age: 30–80 years

– 0 P

0 T

– Amyotrophic lateral 

sclerosis (no 

association in 

adjusted models)

Khalil et al. 2009 83 adult workers 

and 51 controls, 

age: >55 years

↑ T – – Learning, memory
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Table 2-33. Associations Between Bone Pb and Neurological Outcomes in 

Adults

Reference Population

Neurological outcome

Intellectual 

deficits

Altered 

neuromotor or 

neurosensory 

function

Altered 

mood or 

behavior

Outcome 

measures

Park et al. 2010 448 adult malesb,

age: 65 years 

(mean)

– ↑ P

↑ T

– Hearing function

Payton et al. 

1998

141 adult malesb,

age: 67 years 

(mean)

↑ T – – Memory, visualspatial performance

Power et al. 

2014

584 adult 

femalesc,

age: 60–74 years

0 P

0 T

– – Learning, memory, 

executive function

Rajan et al. 2007 1,075 adult 

malesb,

age: 48–94 years

– – ↑ P

↑ T

Psychiatric 

symptoms

Rajan et al. 2008 982 adult malesb,

age: 49–>72 

years

0 P

↑ T

– – Visual-spatial 

performance

Rhodes et al. 

2003

536 adult malesb,

age: 48–70 years

– – ↑ P

↑ T

Anxiety

Schwartz et al. 

2000b

535 Pb workers,

age: 56 years 

(mean)

↑ T ↑ T – Memory, executive 

function, manual 

dexterity

Schwartz et al. 

2001

803 exposed Pb

workers and 

135 controls,

age: 40 years 

(mean)

0 T 0 T 0 T Learning, memory, 

executive function, 

manual dexterity, 

grip strength, mood 

and depression

Schwartz et al. 

2005

576 exposed Pb

workers,

age: 41 years 

(mean)

↑ T ↑ T ↑ T Executive function, 

manual dexterity, 

vibration threshold, 

depression

Seegal et al. 

2013

241 capacitor 

workers,

age: 64 years 

(mean)

↑ T ↑ T – Learning, memory, 

executive function, 

manual dexterity

Shih et al. 2006 991 adultsa,

age: 50–70 years

↑ T ↑ T – Learning, memory, 

executive function, 

manual dexterity
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Table 2-33. Associations Between Bone Pb and Neurological Outcomes in 

Adults

Reference Population

Neurological outcome

Intellectual 

deficits

Altered 

neuromotor or 

neurosensory 

function

Altered 

mood or 

behavior

Outcome 

measures

Stewart et al. 

2002

529 Pb workers,

age: 40–

>70 years

↑ T ↑ T – Learning, memory, 

executive function, 

reaction time, 

manual dexterity

van Wijngaarden 

et al. 2009

47 adults,

age: 55–67 years

↑ C – – Learning, memory

Wang et al. 2007 358 adult malesb,

age: 67 years 

(median)

↑ T – – Interaction between 

Pb and 

hemochromatosis 

gene 

polymorphisms on 

learning, memory, 

executive function

Wang et al. 2018 634 males, age: 

67 years (mean)

– ↑ P

↑ T

– Glaucoma

Weisskopf et al. 

2004

466 adult malesb,

age: 68 years 

(mean)

↑ P – – Memory, verbal and 

written skills, 

executive function

Weisskopf et al. 

2007

761 adult malesb,

age: 69 years 

(mean)

↑ P

↑ T

– – Memory, visualspatial performance

Weisskopf et al. 

2010

330 adult cases 

and 308 controls,

age: 67 years 

(mean)

– ↑ T – Parkinson’s disease

Weuve et al. 

2009

587 adult 

femalesc,

age: 47–74 years

0 P

↑ T

– – Learning, memory

Weuve et al. 

2013

101 cases and 

50 controls,

age: 55–80 years

0 P

↑ T

– – Learning, memory 

(stronger 

association with Pb

among Parkinson’s 

disease cases)
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Table 2-33. Associations Between Bone Pb and Neurological Outcomes in 

Adults

Reference Population

Neurological outcome

Intellectual 

deficits

Altered 

neuromotor or 

neurosensory 

function

Altered 

mood or 

behavior

Outcome 

measures

Wright et al. 

2003b

736 adult malesb,

age: 68 years 

(mean)

↑ P

↑ T

– – Memory, verbal and 

written skills, 

executive function

aBoston Memory Study.

bNormative Aging Study. 

c

Nurses Health Study.

dWhole-body Pb predicted from bone Pb.

↑ = positive association; ↓ = inverse association; 0 = no association; – = not reported; C = calcaneus bone; 

P = patella; Pb = lead; T = tibia; O = other

Bone Pb has been associated with declines in neuromotor and neurosensory function. Neuromotor 

outcomes that have been associated with bone Pb include tremor, Parkinson’s disease, and ALS (Coon et 

al. 2006; Eum et al. 2015; Weisskopf et al. 2010; Weuve et al. 2013). Neurosensory outcomes include 

decrements in olfactory and hearing function, vibration threshold, and manual dexterity (Dorsey et al. 

2006; Grashow et al. 2013b, 2015; Park et al. 2010; Schwartz et al. 2000b; 2005; Shih et al. 2006; Stewart 

et al. 2002). Bone Pb has also been associated with increased risk or odds of psychiatric symptoms such 

as anxiety and depression (Dorsey et al. 2006; Rajan et al. 2007; Rhodes et al. 2003; Schwartz et al. 

2005).

Mechanisms of Action. Numerous cellular mechanisms are likely involved in Pb-induced alterations in 

neurological function. Pb disrupts cellular function through diverse mechanisms, including displacement 

of metal ion co-factors from protein, enzyme inhibition, inhibition of ion transport, disruption of cell and 

mitochondrial membrane potentials, disruption of intracellular calcium homeostasis oxidative stress, and 

inflammation and endocrine disruption (see Section 2.21). All of these Pb mechanisms have been 

demonstrated in neuronal tissues, although there is no consensus on which mechanisms dominate. 

Evidence for various mechanisms that may participate in Pb neurotoxicity are summarized in this section. 

The reader is referred to references cited therein for more detailed information (Bouton and Pevsner 2000; 

Bressler et al. 1999; Cory-Slechta 1995, 2003; EPA 2014c; Gilbert and Lasley 2002; Lasley and Gilbert 

2000; Mitra et al. 2017; Nihei and Guilarte 2002; Suszkiw 2004; Toscano and Guilarte 2005; Zawia et al. 

2000; Zhang et al. 2015).
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Pb 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 

Pb. One pathway that has been studied in 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 calciumdependent forms of PKC and is a likely target for Pb neurotoxicity; it is neuron-specific and is involved in 

long-term potentiation (see below), spatial learning, and memory processes. Pb has the capacity to both 

activate and inhibit PKCs. Studies have shown that micromolar concentrations of Pb can activate PKCdependent phosphorylation in cultured brain microvessels, whereas picomolar concentrations of Pb

activate preparations of PKC in vitro. Interestingly, studies in rats exposed to low Pb levels have shown 

few significant changes in PKC activity or expression, suggesting that the whole animal may be able to 

compensate for Pb 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 Pb 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. 

Studies in rats exposed chronically to low Pb 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 membrane-bound. 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 Pb. An inhibition of 

microvascular formation has been observed with Pb concentrations that are effective in activating PKC. 

Thus, it appears that premature activation of PKC by Pb may impair brain microvascular formation and 

function, and at high levels of Pb exposure, may account for gross defects in the blood-brain barrier that 

contribute to acute Pb 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 Pb may be due in part to 
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immature brain microvessels, which affect the blood brain barrier, and to the lack of the high-affinity 

Pb-binding protein in astroglia, which sequester Pb.

Another enzyme altered by Pb 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; Pb improperly activates the enzyme. Some studies suggest that activation of calmodulin by Pb

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 Pb on gene expression via activation of 

calmodulin are not as marked as those via PKC because activation of calmodulin requires 100-fold more 

Pb than activation of PKC.

Pb 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 Pb for zinc in zinc-finger proteins can have significant 

effects on de novo expression of the bound proteins and in any genes transcriptionally-regulated by a 

particular protein. Pb 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 Pb exposure in neonatal rats transiently induces APP mRNA, 

which is overexpressed with a delay of 20 months after exposure to Pb has ceased. In contrast, APP 

expression, and Sp1 activity, as well as APP and β-amyloid protein levels, were unresponsive to Pb

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 Pb

exposure are due to Pb specifically targeting zinc-finger proteins found in enzymes, channels, and 

receptors.

Pb affects virtually every neurotransmitter system in the brain, but most information on changes is 

available on the glutamatergic, dopaminergic, cholinergic, and gamma-aminobutyric acid (GABA)

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 
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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 Pb 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 Pb on glutamate release 

(presynaptic effects) and on the N-methyl-D-aspartate (NMDA) receptor function. Pb exposure inhibits 

release of glutamine from pre-synaptic endings, which may be mediated, in part, by altered pre-synaptic 

vesicle formation or activation. Studies have shown that the effects of Pb vary as a function of the 

developmental exposure period and that Pb exposure early in life is critical for production of impaired 

LTP in adult animals. LTP is more readily affected by Pb 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 Pb 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 Pb (PbB 30–40 μg/dL) have shown that induction of pair-pulse facilitation 

in the dentate gyrus is impaired. Since the phenomenon is mediated primarily by increased glutamate 

release, the reasonable assumption is that Pb 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 PbB. This inhibition of glutamate release was shown to be due to Pb-related 

decrements in a calcium-dependent component. The exact mechanism for the inhibition of glutamate 

release by Pb is not known, but is consistent with Pb at nanomolar concentrations preventing maximal 

activation of PKC, rather than Pb blocking calcium influx into the presynaptic terminal through voltagegated calcium channels. Reduced glutamate release has been observed in rats exposed from conception 

through weaning and tested as adults, when Pb was no longer present, suggesting that a direct action of 

Pb 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 Pb exhibited a U-shaped response. That is, glutamate release was inhibited in 

rats treated with the lower Pb doses, but not in those exposed to the higher concentrations of Pb. 

Although speculative, this was interpreted as Pb at the higher doses mimicking calcium in promoting 

transmitter release and overriding the inhibitory effects of Pb that occur at lower Pb levels. 

The findings regarding the effects of Pb on postsynaptic glutamatergic function have been inconsistent 

across laboratories, but a direct inhibitory action of Pb on the NMDA receptor is unlikely at 

environmentally relevant exposure levels. Some studies have shown that continuous exposure of rats 
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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 Pb-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 

difficulties in cognitive functions. Most of the evidence available suggests that Pb may impair regulation 

of dopamine synthesis and release, indicating a presynaptic site of action. Studies in animals often report 

opposing effects of Pb on nigrostriatal and mesolimbic dopamine systems regarding receptor binding, 

dopamine synthesis, turnover, and uptake. Postweaning exposure of rats to Pb 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 accumbens (a terminal dopamine projection 

area) and the frontal cortex resulted in perseverative deficits, suggesting that the mesolimbic system is 

preferentially involved in the effects of Pb. Results of studies using dopaminergic compounds seem to 

indicate that changes in dopamine systems do not play a role in the effects of Pb 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 Pb. This 

type of change 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 Pb 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 Pb 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 Pb reduces acetylcholine release by blocking calcium entry into the 

terminal. At the same time, Pb prevents sequestration of intracellular calcium by organelles, which 

results in increased spontaneous release of the neurotransmitter. Studies in vitro show that Pb can block 

nicotinic cholinergic receptors, but it is unclear whether such effects occur in vivo or whether Pb alters the 
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expression of nicotinic cholinergic receptors in the developing brain. Evidence for an involvement in 

Pb-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 Pb treatment 

of rats. Chronic exposure of rats to Pb has resulted in decreased muscarinic-receptor expression in the 

hippocampus. Whether or not Pb exposure during development alters muscarinic receptor sensitivity is 

unclear as there are reports with opposite results. The preponderance of the binding data suggests that Pb

does not directly affect muscarinic receptors with the exception of the visual cortex, where Pb may have a 

direct inhibitory effect on muscarinic receptors from rods and bipolar cells of the retina. 

Pb exposure decreases spontaneous and evoked release of GABA in rats and in hippocampal cultures and 

brain slices. In general, GABA functions in the brain as a post-synaptic inhibitory transmitter. The role 

of changes in GABA release in the neurotoxicity of Pb has not been firmly established. 

Various other mechanisms may also contribute to Pb neurotoxicity. Exposure to Pb has also been shown 

to stimulate inflammation in a variety of tissues, including neuronal tissue (see Section 2.21). 

Contributing mechanisms include alterations in levels of ROS, activation of nuclear activation factor 

NFβ, cytokine release, and alterations in prostaglandin metabolism. Pb exposure has been shown to 

alter neuronal nitric oxide signaling (NOS) and the hormone levels regulated by the hypothalamicpituitary-thyroid axis.

2.17 REPRODUCTIVE

Overview. Numerous epidemiological studies have evaluated effects of Pb on male and female 

reproductive function. In males, most exposures were occupational, with mean PbB >10 μg/dL. In 

general, studies in males show consistent evidence of reproductive effects on sperm (production, motility, 

viability, and morphology), semen quantity and composition, serum reproductive hormone levels, and 

fertility, with severity of effects increasing with increasing PbB. In contrast to exposure of males, most 

exposures of females were non-occupational, with mean PbB ≤10 μg/dL. Studies investigating effects on 

serum reproductive hormone levels, fertility, spontaneous abortion, and preterm birth provide mixed 

results; thus, dose-dependence of effects in females is difficult to assess.
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The following reproductive effects in males have been associated with PbB:

• ≤10 μg/dL:

o Increased serum testosterone; evaluated in a few studies with mixed results.

o Effects on sperm (decreased sperm count, concentration, motility, and viability, and increased 

immature sperm concentration and percentage of morphologically abnormal sperm); 

evaluated in a few studies with mixed results.

• >10 μg/dL:

o Altered serum concentrations of reproductive hormones (testosterone, FSH, LH); evaluated in 

several studies with mixed results. 

o Effects on sperm (decreased sperm count, concentration, motility, viability, and increased 

immature sperm concentration and percentage of morphologically abnormal sperm); 

corroborated in several studies. 

o Alterations in semen quality (decreased semen volume and altered composition of seminal 

fluid); evaluated in a few studies.

o Decreased fertility; evaluated in a few studies.

o Histopathological changes to the testes (peritubular fibrosis, oligospermia, and vacuolization 

of Sertoli cells); evaluated in a few studies.

The following reproductive effects in females have been associated with PbB:

• ≤10 μg/dL:

o Increased serum levels of estradiol, FSH, and LH; studies have mixed results.

o Decreased fertility; studies have mixed results.

o Increased spontaneous abortion; studies have mixed results.

o Increased preterm birth; studies have mixed results.

o Earlier age at onset of menopause; demonstrated in a few studies.

• >10 μg/dL:

o Decreased fertility; studies have mixed results.

o Increased preterm birth; studies have mixed results.

Measures of Exposure. Most studies evaluating effects on male and female reproductive systems used 

PbB as the biomarker for exposure. More recent studies in men have explored the relationship between 

the concentration of Pb in semen or spermatozoa and adverse effects (Table 2-34). It has been suggested 
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that semen levels of Pb may be a better biomarker for assessment of male reproductive effects, 

particularly at low PbB, because no relationship between PbB and Pb levels in semen or spermatozoa has 

been observed (Hernandez-Ochoa et al. 2005; Mendiola et al. 2011). In women, other biomarkers of 

exposure include concentration of Pb in plasma (Lamadrid-Figueroa et al. 2007), red blood cells (Perkins 

et al. 2014), placenta (Gundacker et al. 2010), and plasma/blood ratio (Lamadrid-Figueroa et al. 2007).

Confounding Factors and Effect Modifiers. Numerous factors may add uncertainty in the interpretation 

of studies examining associations between PbB and reproductive effects, including overall health, body 

weight, nutrition, and SES. Exposures to other substances, including recreational drugs, alcohol, 

therapeutic agents, industrial chemicals, insecticides, and pesticides, also may affect fertility (Foster and 

Gray 2008). Failure to account for these factors may attenuate or strengthen the apparent associations 

between Pb exposure and the outcome, depending on the direction of the effect of the variable on the 

outcome. Some studies examining effects on sperm (discussed below) were conducted on samples 

obtained at fertility clinics; therefore, other causes for sperm effects could be effect modifiers (additional 

details are provided in the Supporting Document for Epidemiological Studies for Lead, Table 11). In 

addition, because sperm counts can vary by geographical location, it is important that control and exposed 

groups are matched for geographic location.

Characterization of Effects in Males. General trends regarding the relationship between PbB and male 

reproductive effects are shown in Table 2-34. Overall, the dose-effect pattern suggests an increasing 

severity of toxicity associated with increasing PbB, with effects on sperm at ≤10 μg/dL (discussed in 

more detail below). At increasing PbB, effects become more severe, with decreased fertility observed at 

PbB >10 μg/dL and histopathological changes of the testes at PbB of approximately 30 μg/dL. Effects on 

sperm, including decreased sperm count, concentration, motility, viability, and increased immature sperm 

concentration and percentage of morphologically abnormal sperm, have been observed at PbB of ≤10–

>50 μg/dL (Alexander et al. 1998a; Assennato et al. 1987; Bonde et al. 2002; Cullen et al. 1984; 

Famurewa and Ugwuja 2017; Hernández-Ochoa et al. 2005; Kasperczyk et al. 2008; Lancranjan et al. 

1975; Lerda 1992; Li et al. 2015; Meeker et al. 2008; Moran-Martinez et al. 2013; Telisman et al. 2007; 

Wildt et al. 1983). However, a few studies showed no association between PbB and adverse effects on 

sperm (Lancranjan et al. 1975; Mendiola et al. 2011). The significance of the observed changes to sperm 

on fertility is uncertain. Decreased semen volume and altered composition of seminal fluid have been 

observed at PbB >10 μg/dL (Bonde et al. 2002; Naha and Chowdhury 2006; Telisman et al. 2000; Wildt 

et al. 1983). Decreased fertility has been reported in association with PbB >10–>50 μg/dL (Sallmén et al. 

2000; Shiau et al. 2004), although no effect on fertility was observed in one study of workers with PbB 
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>40 μg/dL (Coste et al. 1991). Histopathological assessment of biopsied testicular tissue from Pb 

workers (mean PbB: 29.0 μg/dL) showed peritubular fibrosis, oligospermia, and vacuolization of Sertoli 

cells (Braunstein et al. 1978). Evaluations of associations between PbB and serum levels of reproductive 

hormones show inconsistent results (Table 2-35). At PbB ≤10 μg/dL, positive associations between PbB 

and serum testosterone levels have been observed (Kresovich et al. 2015; Lewis and Meeker 2015; 

Meeker et al. 2010; Telisman et al. 2007), whereas inverse associations or no effects were reported at PbB 

>10 μg/dL. No effects on FSH or LH were reported at PbB ≤10 μg/dL, and inconsistent results were 

observed at PbB >10 μg/dL. Changes in serum levels of reproductive hormones may indicate disruption 

of the hypothalamic-pituitary-gonadal axis; however, due to inconsistent findings, an association between 

PbB and endocrine disruption in males has not been firmly established.

Table 2-34. Overview of Effects on the Male Reproductive System Associated 

with Chronic Exposure to Lead (Pb)

Mean blood lead 

concentration 

(PbB) (μg/dL) Effects associated with Pb exposure References

≤10 Effects on sperm (decreased sperm 

concentration, motility, and viability; increased 

morphologic abnormalities)

Famurewa and Ugwuja 2017;

Hernández-Ochoa et al. 2005; Li et al. 

2015; Meeker et al. 2008; Telisman et 

al. 2007 

Effects on hormones (increased serum levels 

of testosterone, estradiol, LH, FSH, and 

SHBG; decreased serum prolactin and SHBG

Chen et al. 2016; Kresovich et al. 

2015; Lewis and Meeker 2015; 

Meeker et al. 2010; Telisman et al. 

2007

>10–30 Effects on sperm (decreased sperm count, 

concentration, density, motility, viability; 

morphologic abnormalities)

Alexander et al. 1998a; Bonde et al. 

2002; Moran-Martinez et al. 2013

Effects on semen (decreased volume) Bonde et al. 2002

Decreased fertility Sallmén et al. 2000

>30–50 Effects on sperm (decreased count, 

concentration, motility, viability; morphologic 

abnormalities)

Hsu et al. 2009; Lancranjan et al. 

1975; Lerda 1992; Telisman et al. 

2000

Effects on composition of seminal fluid Telisman et al. 2000

Effects on hormones (increased estradiol, LH, 

FSH; decreased testosterone)

Braunstein et al. 1978; Ng et al. 1991; 

Telisman et al. 2000

Histopathological changes to testes 

(peritubular fibrosis, oligospermia, 

vacuolization of Sertoli cells)

Braunstein et al. 1978

Decreased fertility Sallmén et al. 2000; Shiau et al. 2004
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Table 2-34. Overview of Effects on the Male Reproductive System Associated 

with Chronic Exposure to Lead (Pb)

Mean blood lead 

concentration 

(PbB) (μg/dL) Effects associated with Pb exposure References

>50 Effects on sperm (decreased count, 

concentration, motility, viability; morphologic 

abnormalities) 

Assennato et al. 1987; Cullen et al. 

1984; Kasperczyk et al. 2008; 

Lancranjan et al. 1975; Lerda 1992; 

Naha and Chowdhury 2006; Wildt et 

al. 1983

Effects on semen (decreased volume; altered 

composition)

Naha and Chowdhury 2006; Wildt et 

al. 1983

Effects on hormones (altered serum levels of 

testosterone, FSH, LH, prolactin)

Assennato et al. 1987; Rodamilans et 

al. 1988

Decreased fertility Sallmén et al. 2000

FSH = follicle-stimulating hormone; LH = luteinizing hormone; SHBG = sex hormone binding globulin

Table 2-35. Effects on Reproductive Hormones Associated with Chronic 

Exposure to Lead (Pb) in Males

PbB

(μg/dL)

Hormone

T FSH LH E P A SHBG Reference

≤10 ↑ 0 – – – 0 0 Kresovich et al. 2015

↑ 0 0 – – – 0 Meeker et al. 2010

↑ – – ↑ 0 – – Telisman et al. 2007

↑ – – – – – – Lewis and Meeker 2015

↑ ↑ ↑ 0 – – ↑ Chen et al. 2016

0 0 0 – – – – Mendiola e al. 2011

10–30 0 0 0 – – – – Hsieh et al. 2009

0 0 0 – – – Alexander et al. 1998a

30–50 ↓ 0 0 – 0 – – Braunstein et al. 1978

0 0 0 – 0 – – Erfurth et al. 2001 

0 ↓ ↓ – – – – Gustafson et al. 1989

0 ↑ ↑ – – – – McGregor and Mason 1990

↓ ↑ ↑ 0 – – Ng et al. 1991

↑ – – – Telisman et al. 2000

0 0 0 0 – – – Sadeghnaiit Haghighi et al. 2013

↓ – – – – – – Rodamilans et al. 1988

0 = no effect; ↑ = increased serum level; ↓ = decreased serum level; – = not evaluated; A = androstenedione; 

E = estradiol; FSH = follicle stimulating hormone; LH = luteinizing hormone; P = prolactin; SHBG = sex hormone 

binding globulin; T = testosterone
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2. HEALTH EFFECTS

Effects in Males at Blood Pb Levels ≤10 μg/dL. Cross-sectional studies evaluating adverse effects of 

non-occupational exposures to Pb on the male reproductive system show that damage to sperm, decreased 

semen volume, and increased serum testosterone are associated with mean PbB ≤10 μg/dL or with Pb 

concentrations in semen or spermatozoa when PbBs are ≤10 μg/dL. Results are summarized in

Table 2-36, with study details provided in the Supporting Document for Epidemiological Studies for 

Lead, Table 11. None of the studies evaluated associations between PbB and male fertility parameters 

(i.e., pregnancy). Three studies assessed larger populations, including two studies using NHANES data 

(Kresovich et al. 2015; Lewis and Meeker 2015) and one study of a Chinese population (Chen et al. 

2016). However, in general, study populations were small (n=61–240). In addition, for a few studies, 

participants were selected from infertility clinics and it is unclear how this may have biased study results 

(Meeker et al. 2008, 2010; Mendiola et al. 2011). Despite these limitations, taken together, results of 

non-occupational exposure studies support that adverse effects to the male reproductive system occur at 

PbB ≤10 μg/L.

Sperm and semen. A significant association between an increase in PbB ≤10 μg/dL and increasing 

percentages of morphologically abnormal sperm, wide sperm, and round sperm was observed in a 

population of Croatian men (Telisman et al. 2007). The mean PbB was 4.92 μg/dL; although the 

maximum PbB value in this study was 14.9 μg/dL, over 90% of participants had PbB <10 μg/dL. Li et al. 

(2015) found small, but significant inverse associations between PbB and sperm count, sperm 

concentration, motile sperm, and morphologically normal sperm in 154 men from a reproductive clinic in 

Taiwan. The median PbB was 2.78 μg/dL (SD 1.85); range and percentiles were not reported. Sperm 

count was associated with PbB in a small population of infertile men with mean PbB 1.71–2.05 μg/dL 

(Famurewa and Ugwuja 2017). Other studies have shown associations between Pb levels in semen and/or 

spermatozoa and increased percentages of morphologically abnormal sperm and decreased sperm motility 

and viability, although no associations were observed between PbB and these outcomes (HernandezOchoa et al. 2005; Mendiola et al. 2011); mean PbB levels were 9.3 μg/dL in the Hernandez-Ochoa et al. 

(2005) study and 2.8 μg/dL in the Mendiola et al. (2011) study. No associations were observed between 

PbB and sperm concentration, motility, or morphologic abnormalities in men at a median PbB of 

1.5 μg/dL (Meeker et al. 2008). Semen volume (mL) was inversely associated with PbB at a mean PbB 

of 9.3 μg/dL; however, 48% of participants had PbB >10 μg/dL (Hernandez-Ochoa et al. 2005). 
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Table 2-36. Summary of Epidemiological Studies Evaluating Effects on the Male Reproductive System at Mean 

Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Effects on serum hormone levels

Chen et al. 2016

Cross-sectional study; n=2,286

Median (IQR): 4.40 (2.90–

6.23)

Quartiles:

• Q1: <2.9 (n=558)

• Q2: 2.9–4.39 (n=572)

• Q3: 4.4–6.2 (n=585)

• Q4: >6.2 (n=571)

Testosterone β coefficient (SE) Q4: 0.033 (0.010); p<0.01*

FSH β coefficient (SE) Q4: 0.030 (0.015); p<0.05*

LH β coefficient (SE) Q4: 0.028 (0.013); p<0.05*

E β coefficient (SE) Q4: -0.003 (0.017)

SHBG β coefficient (SE) Q4: 0.038 (0.012); p<0.01*

Kresovich et al. 2015

Cross-sectional study; n=869

Median:2.0

Quartiles:

• Q1: ≤1.4 (reference)

• Q2: 1.4–2.1

• Q3: 2.10–3.20

• Q4: >3.20

Testosterone • β coefficient ng/mL per μg/dL (SE) 

• Q3: 0.54 (0.21); p<0.05*

• Q4: 0.79 (0.22); p<0.05*; 

p-trend=0.00268*

Lewis and Meeker 2015

Cross-sectional study; n=484

Gmean:1.06

Quartiles:

• Q1: <0.71

• Q2: 0.71–1.00

• Q3: 1.00–1.59

• Q4: 1.59–33.67

Testosterone • Percent change in serum testosterone 

concentration associated with a 

doubling (100% increase) in PbB: 

6.65% (2.09, 11.41); p<0.004)*; p-trend 

across quartiles=0.003*
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Table 2-36. Summary of Epidemiological Studies Evaluating Effects on the Male Reproductive System at Mean 

Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Meeker et al. 2010

Cross-sectional study; n=219

Median:1.5

Quartiles

• Q1: <1.1 (reference)

• Q2: 1.1–1.5

• Q3: 1.5–2.0

• Q4: >2.0–16.2

Testosterone Regression coefficient Q4 (ng/dL per 

μg/dL): 39.9 (3.32, 76.4)*

FSH Regression coefficient Q4 (mIU/mL per μg/dL): 

0.07 (-0.18, 0.31)

LH Regression coefficient Q4 (mIU/m per μg/dL): 

0.08 (-0.14, 0.29)

Inhibin B Regression coefficient Q4 (pg/mL per μg/dL): -

7.79 (-29.0, 13.4)

SHBG Regression coefficient Q4 (nmol/L per μg/dL): 

0.07 (-0.10, 0.23)

FAI Regression coefficient Q4 (per μg/dL): 

0.08 (-0.05, 0.21)

Mendiola et al. 2011

Case-control study; n=61

Gmean: 2.8 Testosterone β coefficient (ng/mL per μg/L): -0.12 (-0.40, 

0.14)

FSH β coefficient (IU/L per μg/L): -0.20 (-0.64, 0.25)

LH β coefficient (IU/L per μg/L): -0.07 (-0.49, 0.31)

Telisman et al. 2007

Cross-sectional study; n=240

Median: 4.92 Testosterone β coefficient (nmol/L per μg/L): 0.21; 

p<0.003*

Estradiol β coefficient (nmol/L per μg/L): 0.22; 

p<0.0008*

Prolactin β coefficient (μg per μg/L): -0.18; p<0.007

Sperm and semen quality

Famurewa and Ugwuja 2017

Cross-sectional study; n=75 men with 

infertility

PbB:

Mean

• Normospermic: 1.49 

• Azoospermic: 1.71 

• Oligospermic: 2.05 

Semen volume Pearson correlation R value: -0.132; p=0.27

Sperm count Pearson correlation R value: -0.280; p=0.02*

Sperm motility Pearson correlation R value: -0.092; p=0.44

Sperm morphology Pearson correlation R value: -0.081; p=0.50
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Table 2-36. Summary of Epidemiological Studies Evaluating Effects on the Male Reproductive System at Mean 

Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Hernandez-Ochoa et al. 2005

Cross-sectional study; n=68

Mean: 9.3

SPZ Pb: 0.047 ng/106 cells

SF Pb: 2.02 μg/L

Log sperm concentration β coefficient SPZ Pb (106 cells/mL per ng/106

cells): -17.17 (p<0.05)*

Sperm motility β coefficient PbB (% per μg/dL): -0.006

β coefficient SPZ Pb: (% per ng/106

cells): -2.12 (p<0.05)*

Sperm morphology 

(abnormal)

β coefficient PbB (% per μg/dL): -0.001

β coefficient SPZ Pb (% per ng/106

cells): -1.42 (p<0.05)*

Sperm viability β coefficient PbB (% per μg/dL): -0.095

β coefficient SPZ Pb (% per ng/106

cells): -0.130 (p<0.05)*

Semen volume β coefficient PbB (mL per μg/dL): -0.043

β coefficient SF Pb (mL per 

μg/L): -0.183 mL; p<0.05*

Li et al. 2015

Cross-sectional study; n=154

Mean: 

All participants: 2.78 

Low-quality semen group: 

3.43

High-quality semen group: 

2.38 

Low quality sperm OR: 1.040 (1.011, 1.069); p=0.0061*

Decreased sperm 

concentration

OR: 1.046 (1.015, 1.078); p=0.0032*

Decreased sperm number OR: 1.041 (1.012, 1.071); p=0.0048*

Decreased motile sperm OR: 1.057 (1.026, 1.089; p=0.0003*

Decreased 

morphologically normal 

sperm

OR: 1.071 (1.025, 1.118; p=0.0021*

Meeker et al. 2008

Cross-sectional study; n=219

Median:1.50

• Quartiles (Q): 

o Q1: <1.10

o Q2: 1.10–1.50

o Q3: 1.50–2.00

o Q4: 2.00–16.2

Sperm concentration Regression coefficient (106/mL per μg/dL) 

Q4: 0.02 (-0.39, 0.43)

Sperm motility Regression coefficient (% per μg/dL) 

Q4: 1.10 (-4.56, 6.75)

Sperm morphology Regression coefficient (% per μg/dL) 

Q4: -0.16 (-1.58, 1.26)

Semen volume Regression coefficient (mL per μg/dL) 

Q4: 0.17 (-0.41, 0.74)
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Table 2-36. Summary of Epidemiological Studies Evaluating Effects on the Male Reproductive System at Mean 

Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Mendiola et al. 2011

Case-control study; n=61

Gmean: 2.8

Median: 2.9

Sperm concentration β coefficient (106/mL per μg/L): 0.08 (-4.1, 5.2)

Immobile sperm β coefficient (% per μg/L): -0.49 (-1.8, 0.62)

morphologically normal 

sperm

β coefficient(% per μg/L): -0.8 (-3.5, 3.4)

Telisman et al. 2007

Cross-sectional study; n=240

Median: 4.92 Immature sperm β coefficient (106/mL per μg/L): 0.13 (p<0.07) 

Pathologic sperm β coefficient (% per μg/L): 0.31 (p<0.0002)*

Wide sperm β coefficient (% per μg/L): 0.32 (p<0.0001)*

Round sperm β coefficient (% per μ: 0.16 (p<0.03)*

aSee the Supporting Document for Epidemiological Studies for Lead, Table 11 for more detailed descriptions of studies. bParticipants had no known occupational exposure to Pb.

cAsterisk and bold indicate association with PB; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

CI = confidence interval; E = estradiol; FAI = free androgen index; FSH = follicle-stimulating hormone; Gmean = geometric mean; Inhibin B = gonadal dimeric 

polypeptide hormone; IQR = interquartile range; LH = luteinizing hormone; OR = odds ratio; Pb = lead; SE = standard error; SF = seminal fluid; SHBG = sex 

hormone-binding globulin; SPZ = spermatozoa
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Serum testosterone levels. Significant associations have also been observed between PbB ≤10 μg/dL and 

increased serum testosterone levels (Table 2-34). Studies using NHANES data found significant positive 

associations between PbB and serum testosterone levels (Kresovich et al. 2015; Lewis and Meeker 2015). 

Examined by PbB quartiles, Kresovich et al. (2015) observed significant positive associations between 

PbB and serum testosterone (ng/L) for PbBs of 2.10–3.20 and >3.2 μg/dL; the median PbB of the study 

population was 2.0 μg/dL. A doubling of PbB was positively associated with a 6.65% change in serum 

testosterone; the mean PbB of the study population was 1.06 μg/dL (Lewis and Meeker 2015). The 

toxicological significance of the observed associations between PbB and serum testosterone has not been 

established. 

Characterization of Effects in Females. As noted above, most epidemiological studies evaluated effects 

at PbB ≤10 μg/dL, with few studies of PbB >10 μg/dL. Studies of PbB ≤10 μg/dL are discussed in detail 

in the section below. General trends for studies showing a relationship between PbB ≤10–50 μg/dL and 

female reproductive effects are shown in Table 2-37. Effects associated with PbB include increased 

serum levels of estradiol, FSH, and LH at PbB ≤10 μg/dL (Chang et al. 2006; Krieg 2007), decreased 

fertility at PbB ≤10 μg/dL (Chang et al. 2006), increased time to pregnancy at PbB >30–40 μg/dL 

(Sallmén et al. 1995), increased spontaneous abortion at PbB ≤10–30 μg/dL (Borja-Aburto et al. 1999; 

Yin et al. 2008), decreased number of gestational days at PbB >10–40 μg/dL (Jelliffe-Pawlowski et al. 

2006), and increased preterm birth at PbB ≤10–50 μg/dL (McMichael et al. 1986; Jelliffe-Pawlowski et 

al. 2006; Rabito et al. 2014). Although epidemiological studies demonstrate effects on reproductive 

function, results are inconsistent, with several studies reporting no association between PbB and female 

reproductive effects (Baghurst et al. 1987; Bloom et al. 2010, 2011, 2015; Garcia-Esquinas et al. 2014; 

Jackson et al. 2007; Murphy et al. 1990; Perkins et al. 2014; Pollack et al. 2011; Sallmén et al. 1995; 

Taylor et al. 2015; Vigeh et al. 2010). Dose-dependence has not been firmly established within the 

relatively narrow range of PbB (≤10 μg/dL) in most studies. 
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Table 2-37. Overview of Effects on the Female Reproductive System and 

Pregnancy Outcomes Associated with Chronic Exposure to Lead (Pb)

Mean blood lead 

concentration 

(PbB) (μg/dL) Effects associated with Pb exposure References

≤10 Increased serum hormones (estradiol, FSH, LH) Chang et al. 2006; Chen et al. 

2016; Krieg 2007

Decreased fertility Chang et al. 2006

Increased spontaneous abortion Yin et al. 2008

Increased preterm birth Li et al. 2017b; Rabito et al. 2014

Earlier age at menopause Eum et al. 2014; Popovic et al. 

2005

>10–30 Increased spontaneous abortion Borja-Aburto et al. 1999

Decreased number of gestational days Jelliffe-Pawlowski et al. 2006

Increased preterm birth McMichael et al. 1986

>30–40 Increased time to pregnancy Sallmén et al. 1995

Decreased number of gestational days Jelliffe-Pawlowski et al. 2006

Increased preterm birth Jelliffe-Pawlowski et al. 2006

>40–50 Increased preterm birth Jelliffe-Pawlowski et al. 2006

FSH = follicle-stimulating hormone; LH = luteinizing hormone

Effects in Females at Blood Pb Levels ≤10 μg/dL. As discussed above, most epidemiology studies 

evaluating adverse effects of Pb on female reproductive function reported mean PbB ≤10 μg/dL. 

Although some studies provide evidence showing associations between PbB ≤10 μg/dL and effects on 

serum reproductive hormones (Chang et al. 2006; Chen et al. 2016; Krieg 2007), fertility (Chang et al. 

2006), spontaneous abortion (Lamadrid-Figueroa et al. 2007; Yin et al. 2008), and preterm birth (Li et al. 

2017b; Rabito et al. 2014; Taylor et al. 2015; Vigeh et al. 2011), many studies show no associations 

between PbB and these outcomes. In general, most studies are limited by small sample sizes, although, as 

discussed below, some studies were of larger populations. The basis for differences in study outcomes in 

not readily apparent, although several factors may contribute, including low samples size, timing of 

evaluations in menstrual and life cycles, and inclusion of study participants identified from fertility 

clinics. Results are summarized in Table 2-38, with study details provided in the Supporting Document 

for Epidemiological Studies for Lead Table 12.
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Table 2-38. Summary of Epidemiological Studies Evaluating Effects on the Female Reproductive System at 

Mean Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Effects on serum hormone levels

Chang et al. 2006

Case control study; n=147

Mean: 3.55 Estradiol β coefficient pg/mL per μg/dL (SE): 1.18 

(0.60); p=0.049*

Chen et al. 2016

Cross-sectional study; 

n=1,571 postmenopausal women

Median: 4.1

• Q1: <2.7 (n=558)

• Q2: 2.7–4.09 

(n=572)

• Q3: 4.1–5.98

(n=585)

• Q4: >5.98 (n=571)

FSH β coefficients (SE) 

• Q3: 0.047 (0.015); p<0.01*

• Q4: 0.046 (0.016); p<0.01*

LH β coefficients (SE), Q4: 0.037 (0.016); 

p<0.05*

Estradiol β coefficients (SE), Q4: -0.021 (0.020)

Testosterone β coefficients (SE), Q4: -0.016 (0.020)

Sex hormone binding globulin β coefficients (SE), Q4: 0.048 (0.016);

p<0.01*

Jackson et al. 2011

Longitudinal cohort study; n=252

Mean: 0.87 FSH β coefficient (IU/L per μg/dL): -2.5 (-11.2, 7.0)

LH β coefficient (mg/L per μg/dL): 2.5 (-12.3, 19.9)

Estradiol β coefficient (pg/mL per μg/dL): 4.9 (-5.0, 15.9)

Progesterone β coefficient (ng/mL per μg/dL): 4.6 (-12.2, 

24.6)

Krieg 2007

Cross-sectional study; n=3,375

Gmean: 2.2 FSH • Slope pre-menopausal (IU/L per μg/dL): 

8.3 (2.2); 95% CI 3.8, 12.7; p=0.0006*

• Slope post-menopausal (IU/L per μg/dL): 

22.2 (4.3); 95% CI 13.5, 30.8; p=0.0000*

• Slope both ovaries removed (IU/L per 

μg/dL): 32.6 (11.2); 95% CI 10.1, 55.1; 

p=0.0054*

LH • Slope pre-menopausal (IU/L per μg/dL): 1.7 

(1.2); 95% CI -0.6, 4.1; p=0.1486

• Slope post-menopausal (IU/L per μg/dL): 

6.2 (1.6); 95% C: 3.0, 9.5; p=0.0003*
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Table 2-38. Summary of Epidemiological Studies Evaluating Effects on the Female Reproductive System at 

Mean Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

• Slope both ovaries removed (IU/L per 

μg/dL): 10.0 (4.4); 95% CI 1.1, 18.9; 

p=0.0279*

Pollack et al. 2011

Longitudinal cohort study; n=252

Mean: 0.93 Estradiol β coefficient (pg/mL per μg/dL): 0.03 (-0.05, 

0.11)

FSH β coefficient (mIU/mL per μg/dL): -0.01 (-0.07, 

0.06)

LH β coefficient (ng/mL per μg/dL): 0.02 (-0.06, 

0.10)

Progesterone β coefficient (ng/mL per μg/dL): 0.06 (-0.04, 

0.17)

Fertility

Bloom et al. 2010

Longitudinal cohort study; n=15

Mean: 0.82 Oocyte fertilization (in vitro) RR: 1.09 (0.72, 1.65). 

Bloom et al. 2011

Longitudinal cohort study; n=80

Mean: 1.54 Achieving pregnancy over 

12 menstrual cycles

β coefficient (probability of pregnancy per 

μg/dL): -0.031 (95% CI -1.066, 1.004); p=0.954

Chang et al. 2006

Case control study; n=147

Mean:

• All: 3.12

• Controls: 2.78

• Cases: 3.55

Infertility OR for PbB >2.5 versus ≤2.5 μg/dL: 2.94 

(95% CI 1.18, 7.34); p=0.021*

Pregnancy outcome

Bloom et al. 2015

Case control study; n=235

Mean: 0.71

Tertiles (mean):

• T1: not reported

• T2: 0.55

• T3: 0.73

Duration of gestation Regression coefficient gestational age per 

μg/dL) T3: 0.14 (-0.81, 1.09)
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Table 2-38. Summary of Epidemiological Studies Evaluating Effects on the Female Reproductive System at 

Mean Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Garcia-Esquinas et al. 2014

Birth cohort study; n=100

Gmean: 1.83 Duration of gestation Mean difference in gestational age (weeks) per 

2-fold increase in PbB: 0.02 (95% CI -0.44, 

0.47)

Gundacker et al. 2010

Cross-sectional study; n=30

Median PbB: 2.5

Median Pb (placenta): 

25.8 μg/kg

Spontaneous abortion Placenta Pb concentration in women with a 

history of miscarriage was higher (n=8; 

p=0.039) than in women with no history of 

miscarriage (n=22)*

Lamadrid-Figueroa et al. 2007

Cross-sectional study; n=207

Mean PbB: 6.24 (4.48)

Mean plasma Pb: 0.014 

Mean plasma/blood Pb 

ratio: 0.22% 

(tertile values not 

reported)

Spontaneous abortion IRR PbB: 0.93; p=0.56

IRR Plasma Pb: 1.12; p=0.22

Plasma/blood Pb ratio: 1.18; p=0.02*

IRR for T2 plasma/blood Pb ratio: 1.161; 

p=0.612

IRR for T3 plasma/blood Pb ratio: 1.903; 

p=0.015*

Li et al. 2017b

Birth cohort study; n=3,125

Mean (range): 1.5 (0.02-

5.46)

Stratified:

• Low: <1.18

• Medium: 1.18–1.70

• High: ≥1.71

Preterm birth • OR Medium PbB: 2.33 (1.49, 3.65); 

p<0.001*

• OR High PbB: 3.09 (2.01, 4.76); p<0.001*

Perkins et al. 2014

Birth cohort; n=949

Estimated mean PbB: 0.4

Mean RBC: 1.22 μg/dL

Quartile RBC (μg/dL): 

• Q1: 0.65

• Q2: 0.96

• Q3: 1.27

• Q4: 2.02

Duration of gestation β coefficient Q4 gestational age (weeks) per 

μg/dL: -0.17 (-0.51, 0.16)

Rabito et al. 2014

Birth cohort; n=98

Second trimester mean: 

0.42

Third trimester mean: 

0.45 

Preterm birth OR second trimester: 1.66 (1.23, 2.23); 

p<0.01*

OR third trimester: 1.24 (1.01, 1.52); p=0.04*
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Table 2-38. Summary of Epidemiological Studies Evaluating Effects on the Female Reproductive System at 

Mean Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study populationb PbB (μg/dL) Outcome evaluated Resultc

Taylor et al. 2013, 2015

Longitudinal cohort study; n=3,870

Mean: 3.67

Median: 3.42

Preterm birth OR for PbB ≥5.0: 2.0 (1.35, 3.00); p=0.001*

Vigeh et al. 2010

Longitudinal cohort study; n=351

Mean: 3.8 Spontaneous abortion OR (log PbB): 0.331 (0.011, 10.096); p=0.53

Vigeh et al. 2011

Longitudinal cohort study; n=44 women 

with preterm birth; n=304 women with 

term birth

Mean:

• Term birth: 3.72

• Preterm birth: 4.52

Preterm birth OR: 1.41 (1.08, 1.84)*

Yin et al. 2008

Case-control study; n=80

Control (term birth): 4.5

Spontaneous abortion: 

5.3

Spontaneous abortion PbB was higher in cases of anembryonic 

pregnancy during gestational weeks 8–13 

compared to controls with term births 

(p=0.03).*

Zhu et al. 2010

Retrospective cohort; n=43,288 motherinfant pairs (n=3,519 preterm birth; 

n=39,769 term birth)

PbB

Mean: 2.1

Quartiles:

• Q1: ≤1.0

• Q2: 1.1–2.0

• Q3: 2.1–3.0

• Q4: 3.1–9.9

Preterm birth Adjusted ORs did not show an increased risk of 

preterm birth for any quartile. Q4: 1.04 (0.89, 

1.22)

aSee the Supporting Document for Epidemiological Studies for Lead, Table 12 for more detailed descriptions of studies. bParticipants had no known occupational exposure to Pb.

cAsterisk and bold indicate association with PB; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

CI = confidence interval; FSH = follicle-stimulating hormone; Gmean = geometric mean; IRR = incidence rate ratio; LH = luteinizing hormone; OR = odds ratio; 

Pb = lead; PbPl = Pb concentration in placenta (μg/kg); RBC = red blood cell; RR = relative risk; SE = standard error
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Serum hormone levels and estrus cycle. Results of epidemiological studies on associations between PbB 

≤10 μg/dL and serum hormone levels show conflicting results (Table 2-38). The strongest evidence 

showing that chronic Pb exposure alters serum hormone levels is from a large cross-sectional study (mean 

PbB: 2.2 μg/dL) participating in the NHANES III study (Krieg 2007). Serum levels of FSH (IU/L) 

increased with PbB in both pre-menopausal and post-menopausal women. Serum levels of LH increased 

with PbB in post-menopausal women, but not pre-menopausal women. The lowest PbBs associated with 

a significant increase in FSH in pre- and post-menopausal women were 4.1 μg/dL and 2.4 μg/dL, 

respectively. The lowest PbB associated with a significant increase in FSH in post-menopausal women 

was 2.8 μg/dL (slope±SE 8.6±3.3; 95% CI 2.1, 15.2; p=0.0109). Increases in serum FSH and LH were 

also observed in women who had total ovariectomy, indicating that increased hormone levels may be 

related to effects on the hypothalamus or pituitary (Krieg 2007). A large cross-sectional study of 

postmenopausal Chinese women also found that elevated serum hormones levels were positively 

associated with PbB. Increased FSH was observed in the two highest PbB quartiles (4.1–5.9 and 

>5.9 μg/dL), with LH increased in the highest quartile (Chen et al. 2016). SHBG was also increased in 

the highest quartile. No associations were observed between Pb and serum levels of FSH, LH, estradiol, 

or progesterone or menstrual cycle length in a smaller study of pre-menopausal women with a mean PbB 

of 0.87 μg/dL (Jackson et al. 2011). In this same study population, when PbB was examined by tertiles, 

increased serum progesterone levels were observed in the second PbB tertile (0.73–1.10 μg/dL) compared 

to the lowest tertile (0.30–0.72 μg/dL), but no effects were observed in the highest PbB tertile (1.11–

6.20 μg/dL) compared to the lowest (Pollack et al. 2011). In this study population, no association was 

observed between PbB and anovulation. In a case-control study of women attending a fertility clinic, a 

significant association was observed between PbB and serum estradiol concentrations (Chang et al. 2006).

Fertility. Little epidemiological information is available on the effects of PbB ≤10 μg/dL on female 

fertility. A prospective cohort study with a mean Pb of 1.5 μg/dL showed no effect on achieving 

pregnancy over 12 menstrual cycles (Bloom et al. 2011). A case-control study of women from a fertility 

clinic showed a 2.9-fold risk of infertility for PbB >2.5 μg/dL compared to PbB ≤2.5 μg/dL (Chang et al. 

2006). In a study of women undergoing in vitro fertilization, no association was observed between PbB 

and oocyte fertilization; however, only 15 women were included in this study. Available epidemiological 

studies on the effects of PbB ≤10 μg/dL on fertility are limited due to small numbers of participants and 

study populations of women undergoing fertility treatment; thus, data are not sufficient to determine if 

fertility in women is affected at PbB ≤10 μg/dL. 
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Spontaneous abortion. Few epidemiological studies have evaluated associations between PbB ≤10 μg/dL 

and spontaneous abortion (Table 2-38). Although studies provide some evidence suggesting associations 

between PbB ≤10 μg/dL or plasma/blood Pb ratio and spontaneous abortion, results are inconsistent. In a 

case-control study, PbB was significantly higher in cases of spontaneous abortion (PbB 5.3 μg/dL; 

p=0.03) during weeks 8–13, compared to women with term birth (PbB 4.5 μg/dL) (Yin et al. 2008). A 

cross-sectional study reported that the risk of miscarriage per 1 SD increase of plasma/blood Pb ratio 

[mean plasma/blood Pb ratio±SD (%): 0.22±0.14] was associated with an 18% greater incidence of 

spontaneous abortion, although the association between risk of spontaneous abortion and PbB (mean 

6.24) was not significant (Lamadrid-Figueroa et al. 2007). In contrast, results of a longitudinal cohort 

study showed no association between PbB and spontaneous abortion during gestational weeks 13–19 

(Vigeh et al. 2010).

Preterm birth. Several studies have evaluated associations between PbB ≤10 μg/dL and preterm birth 

(<37 weeks of gestation), including three studies of larger study populations (n=705–3,870) (Li et al. 

2017b; Perkins et al. 2014; Taylor et al. 2015). Results of these studies are mixed (Table 2-38). The 

strongest evidence showing that chronic Pb exposure is associated with preterm birth is from two large, 

cohort studies (Li et al. 2017b; Taylor et al. 2013, 2015). Taylor et al. (2013, 2015) reported that when 

stratified into groups of PbB <5 and ≥5.0 μg/dL, there was a 2-fold increase in the risk of preterm birth 

for PbB ≥5.0 μg/dL compared to PbB <5 μg/dL. In the PbB ≥5.0 μg/dL group, the maximum PbB was 

19.14 μg/dL, although very few PbBs were >10 μg/dL; however, the group mean PbB was not reported. 

In a large cohort study, the risk of preterm birth was increased in women with PbBs of 1.18–1.70 and 

1.71–5.46 μg/dL, relative to women with PbBs of 0.02–1.18 μg/dL (Li et al. 2017b). The risk of preterm 

birth also was increased in a longitudinal cohort study (Vigeh et al. 2011). Mean PbB in women with 

preterm birth was significantly higher than in women with term birth (preterm PbB: 4.52 μg/dL; term 

birth PbB: 3.72 μg/dL). A cohort study showed increased odds of preterm birth associated with PbB 

measured in the 2nd (mean: 0.42 μg/dL) and 3rd (mean: 0.45 μg/dL) trimesters (Rabito et al. 2014). ORs 

for risks of preterm birth were 1.66 (p<0.01) and 1.24 (p=0.04) for 2nd and 3rd trimester PbB, respectively. 

Other studies reported no associations between PbB and preterm birth at mean PbB of 0.71–5.70 μg/dL 

(Bloom et al. 2015; Perkins et al. 2014; Zhu et al. 2010), including a large retrospective cohort study (Zhu 

et al. 2010) and a large case-control study (Perkins et al. 2014).

Age at menopause. A few studies had evaluated associations between Pb exposure and age at menopause 

(Eum et al. 2014; Popovic et al. 2005). Eum et al. (2014) found an inverse association between tibia Pb 

and age at onset of natural menopause (e.g., non-surgical) in a population of 434 participants in the 
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Nurses Health Study cohort. In the highest tibia Pb tertile, the age at onset of menopause was 1.21 years 

earlier than controls. However, no associations were observed between PbB (mean PbB: <5 μg/dL) or 

patella Pb. In a study of 108 former smelters (mean PbB: 2.73 μg/dL), the age at onset of combined 

natural and surgical menopause was earlier by 7 years (p=0.001) compared to controls (n=99; 

PbB: 1.25 μg/dL) (Popovic et al. 2005). No difference was observed between the age at onset and natural 

menopause between the exposed and control groups.

Mechanisms of Action. General mechanisms of toxicity of Pb (reviewed in Section 2.21) are likely 

involved in the development of toxicity to male and female reproductive systems. Oxidative stress 

through ROS is a plausible mechanism for reproductive effects, as is the disruption of calcium 

homeostasis. Mechanisms for alterations in circulating hormone levels have been not been established. 

However, EPA (2014c) and NRC (2012) noted several possible mechanisms that may be involved in 

alterations of serum hormones, including direct inhibition of LH secretion; reduced expression of 

steroidogenic acute regulatory protein (a protein required in maintaining gonadotropin-stimulated 

steroidogenesis); altered release of pituitary hormones due to interference with cation-dependent second 

messenger systems; and altered binding of hormones to receptors. Pb is distributed to, and has been 

measured in, semen, spermatozoa, the fetus, umbilical cord blood, placenta, and follicular fluid (see 

Section 3.1.2, Toxicokinetics, Distribution), providing a toxicokinetic mechanism for direct effects to 

reproductive tissues. 

2.18 DEVELOPMENTAL

This section discusses developmental effects of Pb other than neurodevelopmental defects. 

Neurodevelopmental effects are discussed in Section 2.16 (Neurological Effects). The term 

“developmental” used in the discussion that follows refers to effects other than neurodevelopmental.

Overview. Numerous epidemiological studies have evaluated developmental effects (birth outcomes, 

birth defect, neural tube defects, decreased anthropometric measures in children, and delayed puberty) 

associated with Pb exposure, with the database for developmental effects dominated by environmental 

exposure studies with PbB ≤10 μg/dL. In general, studies provide mixed evidence for effects on birth 

outcomes (e.g., infant size) and anthropometric measures in children, but more consistent evidence for 

delayed puberty. Although studies provide evidence of associations between PbB and developmental 

outcomes, results are inconsistent, and several studies, including prospective studies, with PbB ≤10 μg/dL 

show no associations with developmental outcomes.
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The following developmental effects have been associated with PbB:

• ≤10 μg/dL:

o Effects on birth outcomes (decreased birth weight, head circumference, and crown-heel 

length); results are mixed when compared across studies.

o Decreased anthropometric measures in children (weight, height, head circumference, trunk 

length, leg length, arm length, BMI); results are mixed when compared across studies.

o Delayed puberty in females (breast development, pubic hair development, onset of 

menarche); corroborated in multiple studies.

o Delayed puberty in males (testicular volume, genitalia development, pubic hair 

development); a few studies with equivocal results.

• >10 μg/dL (based on few studies):

o Effects on birth outcomes (low birth weight).

o Decreased anthropometric measures in children (decreased weight, height, head 

circumference, chest circumference).

o Delayed puberty in females (breast development).

o Delayed puberty in males (decreased testicular size, delayed pubic hair development, delayed 

penile development).

Measures of Exposure. Most studies evaluating developmental effects used maternal PbB and/or cord, 

infant, or child PbB as the biomarker for exposure. In some studies, Pb concentrations in red blood cells 

(Perkins et al. 2014), maternal bone (Afeiche et al. 2011; Cantonwine et al. 2010; Hernandez-Avila et al. 

2002; Kordas et al. 2009), or hair (Sanín et al. 2001; Sanna and Vallascas 2011) were used as biomarkers.

Confounding Factors and Effect Modifiers. Numerous complicating factors may add uncertainty in the 

interpretation of studies examining associations between PbB and developmental effects. These factors 

include nutrition during pregnancy, prenatal care, adequate nutrition during infancy and childhood, SES, 

intercurrent diseases, alcohol consumption, smoking status, and potential exposure to other chemicals. 

Failure to account for these factors may attenuate or strengthen the apparent associations between Pb 

exposure and the outcome, depending on the direction of the effect of the variable on the outcome.

Characterization of Effects. As noted above, most epidemiological studies evaluated developmental 

effects at PbB ≤10 μg/dL, with few studies of PbB >10 μg/dL. Studies of PbB ≤10 μg/dL are discussed 
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in detail in the section below. General trends for studies showing a relationship between PbB ≤10–

50 μg/dL and developmental effects are shown in Table 2-39. Effects on birth outcomes, including 

decreased birth weight, head circumference, and crown-heel length have been observed at maternal PbBs 

of ≤10–50 μg/dL. Decreased anthropometric measures in infants and children, including decreased 

weight, height, head circumference, trunk length, leg length, arm length, and BMI, have been observed 

over the PbB range of ≤10–30 μg/dL. Delayed onset of puberty in males and females was observed over 

the PbB range of ≤10–30 μg/dL. Very little data are available regarding in utero exposure to Pb and birth 

defects. Two studies that examined neural tube defects did not find associations with Pb exposure at 

mean blood levels over for PbB means ranging from 2.4 to 24 μg/dL (Brender et al. 2006; Zeyrek et al. 

2009). As discussed below, although epidemiological studies demonstrate developmental effects of Pb, 

results across studies are inconsistent, with several studies reporting no association between PbB and 

developmental effects. For example, results of effects on birth outcomes in study populations with 

maternal PbB ≤10 μg/dL are equivocal (see Tables 2-40 and 2-41). For studies with maternal PbB 

>10 μg/dL, equivocal results also were observed for associations between PbB and birth weight and 

length (Factor-Litvak et al. 1991; Hernandez-Avila et al. 2002; McMichael et al. 1986; Murphy et al. 

1990). Dose-dependence has not been firmly established within the relatively narrow range of PbB 

(≤10 μg/dL) in most studies.

Table 2-39. Overview of Developmental Effects Associated with Chronic 

Exposure to Lead (Pb)

Mean blood lead 

concentration (PbB) 

(μg/dL)

Effects associated with Pb 

exposure References

≤10 Effects on birth outcome (decreased 

birth weight, crown-heel length, head 

circumference)

Bornschein et al. 1989; González -

Cossío et al. 1997; Nishioka et al. 

2014; Odland et al. 1999; Taylor et al. 

2013, 2015; Wang et al. 2017b, 2017b; 

Xie et al. 2013; Zhu et al. 2010

Minor congenital anomalies Needleman et al. 1984

Decreased anthropometric measures 

in children (decreased weight, height, 

head circumference, waist 

circumference, trunk length, leg 

length, arm length, body mass index, 

body fat)

Afeiche et al. 2011; Alvarez-Ortega et 

al. 2019; Dallaire et al. 2014; Deierlein 

et al. 2019; Hauser et al. 2008; Hong et 

al. 2014; Ignasiak et al. 2006; Little et 

al. 2009; Min et al. 2008b; OliveroVerbel et al. 2007; Raihan et al. 2018; 

Schell et al. 2009; Yang et al. 2013a

Delayed puberty in females (breast 

development, pubic hair development, 

onset of menarche)

Denham et al. 2005; Den Hond et al. 

2011; Gollenberg et al. 2010; Naicker 

et al. 2010; Selevan et al. 2003; Wu et 

al. 2003b
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Table 2-39. Overview of Developmental Effects Associated with Chronic 

Exposure to Lead (Pb)

Mean blood lead 

concentration (PbB) 

(μg/dL)

Effects associated with Pb 

exposure References

Delayed puberty in males (testicular 

volume, genitalia development, pubic 

hair development)

Hauser et al. 2008; Williams et al. 

2010, 2019

>10–30 Effects on birth outcome (decreased 

birth weight)

Chen et al. 2006; Hernandez-Avila et 

al. 2002

Decreased anthropometric measures 

in children (decreased weight, height, 

head circumference, chest 

circumference)

Frisancho and Ryan 1991; Kerr et al. 

2019; Tomoum et al. 2010

Delayed puberty in females (breast 

development)

Liu et al. 2019b; Tomoum et al. 2010

Delayed puberty in males (decreased 

testicular size, delayed pubic hair 

development; delayed penile 

development)

Tomoum et al. 2010

>30–50 Effects on birth outcome (low birth 

weight)

Jelliffe-Pawlowski et al. 2006 

Table 2-40. Effects on Birth Outcomes at Blood Lead Concentration (PbB) 

≤10 μg/dL

Reference (population size)

Birth outcome

Birth weight

Height or 

C-H length SGA

Head 

circumference

Al-Saleh et al. 2014 (n=1,577) 0a 0 0 0

Bloom et al. 2015 (n=235) 0a 0 − 0

Bornschein et al. 1989 (n=202) ↓a ↓ − 0

Garcia-Esquinas et al. 2014 (n=97) 0a 0 − −

González-Cossío et al. 1997 (n=272) 0b − − −

Kim et al. 2017b (n=280) 0b ↑ (M), 0 (F) − 0

Nishioka et al. 2014 (n=386) ↓b − − −

Odland et al. 1999 (n=50) ↓a,b − − −

Perkins et al. 2014 (n=949) 0a,b 0 − 0

Rabito et al. 2014 (n=98) 0a − − −

Rodosthenous et al. 2017 (n=946) − − 0 −

Taylor et al. 2015 (n=4,285) ↓b ↓ − ↓

Thomas et al. 2015 (n=1,835) − − 0 −

Wang et al. 2017b ↓ 0 ↓ 0

Wang et al. 2017c ↑ (M), 0 (F) 0 (F) − 0
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Table 2-40. Effects on Birth Outcomes at Blood Lead Concentration (PbB) 

≤10 μg/dL

Reference (population size)

Birth outcome

Birth weight

Height or 

C-H length SGA

Head 

circumference

Xie et al. 2013 (n=252) ↓b 0 − 0

Zhu et al. 2010 (n=43,288) ↓b − 0 −

aBirth weight not adjusted for gestational age

bBirth weight adjusted for gestational age

↓ = decrease in outcome measure; ↑ = increase in outcome measure; 0 = no effect on outcome measure; − = not 

assessed; C-H = crown-heel; F = female; M = male; SGA = small for gestational age
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Table 2-41. Summary of Epidemiological Studies Evaluating Birth Outcomes Effects of Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Al-Saleh et al. 2014

Cross-sectional study; 

n=1578 mother-infant pairs

Maternal PbB mean: 2.897 Birth weight OR: 1.107 (0.797, 1.538); p=0.545

Birth height OR: 1.299 (0.945, 1.786); p=0.107

Crown-heel length OR: 1.061 (0.795, 1.415); p=0.689

SGA OR: 1.168 (0.837, 1.631); p=0.362

Head circumference OR: 1.007 (0.724,1.400); p=0.968

Apgar OR: 1.027 (0.787, 1.341); p=0.842

Bloom et al. 2015

Case-control study; 

n=235 mother-infant pairs

Maternal PbB mean: 0.71

Tertiles: 

• T1: <0.55 (reference)

• T2: 0.55–<0.73

• T3: 0.73–2.23

Birth weight Linear regression coefficient (g per μg/dL) 

T3: -34.85 (-97.76, 128.06); p-trend=0.202

Birth length Linear regression coefficient (cm per μg/dL) T3: 

0.14 (-0.81, 1.09); p-trend:0.671

Head circumference Linear regression coefficient (cm per μg/dL) 

T3: -0.33 (-1.07, 0.41); p-trend: 0.132

Bornschein et al. 1989

Prospective study;

n=202 mother-infant pairs

PbB:

Mean (SD): 7.5 

Birth weight Regression coefficient (g per ln μg/dL) for all 

births: -114; p<0.001*.

Regression coefficient (g per ln μg/dL) with 

significant interaction with maternal age 

(p=0.0073)*:

maternal age 18 years: -58*

maternal age 30 years: -601*

Birth length Regression coefficient (cm per ln μg/dL): -2.5; 

p=0.019*

Head circumference Regression coefficient (cm per ln PbB μg/dL): 0.0 

p=0.97
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Table 2-41. Summary of Epidemiological Studies Evaluating Birth Outcomes Effects of Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Garcia-Esquinas et al. 2014

Birth cohort study; 

n=100 mother-infant pairs

Maternal PbB Gmean: 1.83 Birth weight Adjusted mean difference in grams for a 2-fold 

increase in PbB (μg/L): 62.4 (-73.1, 197.8)

Birth length Adjusted mean difference in cm for a 2-fold 

increase in PbB (μg/L): 0.17 (-0.56, 0.91)

Abdominal diameter Adjusted mean difference in cm for a 2-fold 

increase in PbB (μg/d): 0.31 (-0.52, 1.15)

Cephalic diameter Adjusted mean difference in cm for a 2-fold 

increase in PbB (μg/L): 0.15 (-0.21, 0.51)

González-Cossío et al. 1997

Birth cohort study; 

n=272 mother-infant pairs 

PbB:

• Maternal

o Mean (SD): 8.9 (4.1)

o Quartiles: 

 Q1: ≤5.8

 Q2: 5.9–8.0

 Q3: 8.1–11.0

 Q4: ≥11.1

• Umbilical cord

o Mean (SD): 7.1 (3.5)

o Quartiles

 Q1: ≤4.6

 Q2: 4.7–6.1

 Q3: 6.2–8.5

 Q4: ≥8.6

Birth weight Regression coefficient:

• Maternal PbB for Q4: -98.30 (59.55); p=0.100

• Umbilical cord PbB for Q4: -41.74 (64.04); 

p=0.514
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Table 2-41. Summary of Epidemiological Studies Evaluating Birth Outcomes Effects of Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Kim et al. 2017b

Prospective longitudinal study; 

n=280 mother-infant pairs

PbB:

Umbilical cord, mean (SE)

• All: 1.31 (0.06)

• Boys: 1.39 (0.09)

• Girls: 1.21 (0.07)

Birth weight Regression coefficient:

• Boys: 0.010 (-0.014, 0.034); p=0.403

• Girls: 0.001 (-0.025, 0.027); p=0.950

Birth length Regression coefficient:

• Boys: 0.017 (0.003, 0.031); p=0.019*

• Girls: 0.007 (-0.010, 0.025); p=0.410

Head circumference Regression coefficient:

• Boys: 0.010 (-0.001, 0.022); p=0.083

• Girls: -0.007 (-0.016, 0.002); p=0.148

Ponderal index Regression coefficient:

• Boys: -0.055 (-0.103, -0.006); p=0.027*

• Girls: -0.009 (-0.062, 0.045); p=0.748

Nishioka et al. 2014

Cohort study; 

n=386 mother-infant pairs

Maternal PbB mean at 

gestational weeks:

• 12 weeks: 0.98 

• 25 weeks: 0.92 

• 36 weeks: 0.99 

Birth weight Regression coefficient based on log μg/dL: 

• Infant males: -0.151 (p<0.05)*

• Infant females: -0.098 (p>0.05)

Odland et al. 1999

Cohort study;

n=262 mother-infant pairs

Maternal, mean (range); 

p-values compare Russian and 

Norwegian cohorts

• Russian cohort: 2.9 (0.83–

13.5) 

• Norwegian cohort: 2.3 (0.41–

3.9); p<0.001

Birth weight Regression coefficient, combined Russian and 

Norwegian cohorts [g per μmol/L (g per 

20.7 μg/dL)]:

-1,068 (95% CI -2,134, -2); p<0.05*
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Table 2-41. Summary of Epidemiological Studies Evaluating Birth Outcomes Effects of Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Perkins et al. 2014

Birth cohort study;

n=829 mother-infant pairs

Maternal RBC Pb concentration 

(μg/dL) mean: 1.22

Quartiles for RBC Pb; mean:

• Q1: 0.65 

• Q2: 0.96

• Q3: 1.27

• Q4: 2.02

Estimated maternal PbB mean: 

0.4

Birth weight Linear regression β coefficient for RBC (μg/dL) 

Q4: -47

(-128, 35); p-trend: 0.27

Birth length Linear regression β coefficient for RBC (μg/dL) 

Q4: -0.15 (-0.54, 0.23); p-trend: 0.37

Head circumference Linear regression β coefficient for RBC (μg/dL) 

Q4: -0.08 (-0.33, 0.16); p-trend: 0.56

Rabito et al. 2014

Birth cohort study; 

n=98 mother-infant pairs

Maternal 2nd trimester PbB mean: 

0.42

Maternal 3rd trimester PbB mean: 

0.45

Birth weight Linear regression β coefficient, g per μg/dL 

maternal:

• 2nd trimester: -43.21 (-88.6, 2.18); p=0.06

• 3rd trimester: β not reported; p=0.68

• Delivery: β not reported; p=0.83

Rodosthenous et al. 2017

Prospective cohort study; 

n=944 mother-infant pairs

Maternal 2nd trimester PbB: 3.7

• Quartiles:

o Q1: <1.93

o Q2: 1.93–2.79

o Q3: 2.80–4.53

o Q4: >4.53

Birthweight-forgestational age z-score

• Linear regression β for a doubling for 

PbB: -0.06 (-0.13, 0.003); p=0.06

SGA Logistic regression OR Q4: 1.62 (0.99–2.65)

Taylor et al. 2013, 2015

Longitudinal cohort study; 

n=4,285 mother-infant pairs

Maternal PbB mean: 3.67

Population stratified by PbB <5.0 

and ≥5.0

Birth weight β coefficient (g per 

μg/dL): -13.23 (-23.75, -2.70); p=0.014*

Head circumference β coefficient (cm per 

μg/dL): -0.04 (-0.07, -0.06)e; p=0.021*

Crown-heel length β coefficient (cm per 

μg/dL): -0.05 (-0.10, -0.00); p=0.034*
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Table 2-41. Summary of Epidemiological Studies Evaluating Birth Outcomes Effects of Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Thomas et al. 2015

Prospective cohort; 

n=1,835 mother-infant pairs

Maternal PbB median: 0.59

Tertiles:

• T1: <0.52

• T2: 0.52–1.04

• T3: >1.04–4.04

SGA Adjusted RR for T3 (95% CI): 1.19 (0.65, 2.18)

Wang et al. 2017b

Prospective cohort study; 

n=3,125 mother-infant pairs

Maternal serum Pb mean: 1.50

Tertiles:

• T1: <1.18

• T2: 1.18–1.70

• T3: ≥1.71

Birth weight Regression coefficient β: -2.74 (-5.17, -0.31); 

p=0.03*

Birth length Regression coefficient β: -0.013 (-0.026, 0.001); 

p=0.06

Head circumference Regression coefficient β: -0.008 (-0.019, 0.004); 

p=0.18

Chest circumference Regression coefficient β: -0.008 (-0.018, 0.002); 

p=0.13

SGA • OR T2: 1.45 (1.04, 2.02); p=0.03*

• OR T3: 1.69 (1.22, 2.34); p=0.002*

Wang et al. 2017c

Cross-sectional study; 

n=1,009 mother-infant pairs

PbB:

Cord PbB, Gmean (95% CI)

All: 4.07 (3.98, 4.17)

Infant boys: 4.07 (3.89, 4.17)

Infant girls: 4.17 (3.98, 4.36)

Birth weight Regression coefficient β (95%), per 1-unit 

increase in log10-transformed PbB: 

• All: 60.78 (-66.30, 187.85); p=0.35

• Boys: 182.32 (15.24. 349.39); p=0.03*

• Girls: -96.06 (-289.23, 97.10); p=0.33

Birth length Regression coefficient β (95%), per 1-unit 

increase in log10-transformed PbB:

• All: 0.32 (-0.18, 0.82); p=0.21

• Boys: not reported

• Girls: 0.30 (-0.46, 1.05); p=0.44
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Table 2-41. Summary of Epidemiological Studies Evaluating Birth Outcomes Effects of Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Head circumference Regression coefficient β (95%), per 1-unit 

increase in log10-transformed PbB: 

• All: -0.36 (-0.78, 0.06); p=0.09

• Boys: -0.50 (-1.09, 0.09); p=0.10

• Girls: -0.32 (-0.91, 0.27); p=0.29

Ponderal index Regression coefficient β (95%), per 1-unit 

increase in log10-transformed PbB: 

• All: -0.01(-0.10, 0.09); p=0.94

• Boys: 0.10 (-0.03, 0.23); p=0.12

• Girls: -0.17 (-0.31, -0.02); p=0.02*

Xie et al. 2013

Birth cohort study; 

n=252 mother-infant pairs

Maternal PbB mean: 3.53 Birth weight β coefficient (g per square root μg/dL): -148.99 

(-286.33, -11.66); p=0.03*

Birth length β coefficient (cm per square root 

μg/dL): -0.46 (-1.25, 0.34); p=0.26

Head circumference β coefficients (cm per square root 

μg/dL): -0.37 (-0.78, 0.19); p=0.24
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Table 2-41. Summary of Epidemiological Studies Evaluating Birth Outcomes Effects of Mean Blood Lead 

Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Zhu et al. 2010

Retrospective cohort study; 

n=43,288 mother-infant pairs

Maternal PbB mean: 2.1 Birth weight β coefficient g per μg/dL (95% CI): 

0: reference

1: -27.4 (-17.1, -37.8)*

2: -38.8 (-24.1, -53.4)*

3: -47.5 (-29.6, -65.4)*

4: -54.8 (-34.2, -75.5)*

5: -61.3 (-38.2, -84.4)*

6: -67.2 (-41.8, -92.5)*

7: -72.5 (-45.2, -99.9)*

8: -77.6 (-48.3, -106.8)*

9: -82.3 (-51.2, -113.3)*

10: -86.7 (-54.0, -119.4)*

SGA Adjusted OR for Q4: 1.07 (0.93, 1.23)

aSee the Supporting Document for Epidemiological Studies for Lead, Table 13 for more detailed descriptions of studies. bParticipants had no known occupational exposure to Pb.

cValues are for maternal PbB, unless otherwise specified. dAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

eValues are reported; the value for the β coefficient is outside of the 95% CI.

CI = confidence interval; Gmean = geometric mean; OR = odds ratio; Pb = lead; RBC = red blood cell; RR = relative risk; SD = standard deviation; SE = standard 

error; SGA = small for gestational age
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Effect at Blood Pb Levels ≤10 μg/dL. Epidemiology studies have reported developmental effects, 

including birth outcomes, birth defects, anthropometric measures in children, and delayed onset of 

puberty, at mean PbB ≤10 μg/dL. Study details are provided in Supporting Document for 

Epidemiological Studies for Lead, Table 13. Results of studies on associations between PbB and adverse 

effects on birth outcomes and anthropometric measures are mixed when compared across studies. 

Delayed onset of puberty in females has been corroborated in several studies. Fewer studies are available 

regarding effects of Pb on onset of puberty in males, with equivocal results. Exposure to Pb has not been 

shown to cause birth defects in humans. Neural tube defects have not been associated with Pb exposure 

and findings of a single study showing minor anomalies have not been corroborated. 

Birth outcomes. An overview of results of studies that evaluated associations between Pb exposure and 

birth outcomes (infant weight, height or crown-heel length, small for gestation age [SGA], head 

circumference, and ponderal index) at maternal PbB ≤10 μg/dL is shown in Table 2-40, with more 

detailed results in Table 2-41. Studies include two prospective studies (Bornschein et al. 1989; Thomas et 

al. 2015), several studies of large populations (n=829–43,288) (Al-Saleh et al. 2014; Perkins et al. 2014; 

Rodosthenouse et al. 2017; Taylor et al. 2015; Thomas et al. 2015; Wang et al. 2017b, 2017b; Zhu et al. 

2010), and cohort and case-control studies of smaller (n=98–386) populations (Bloom et al. 2015; GarciaEsquinas et al. 2014; González-Cossío et al. 1997; Kim et al. 2017b; Nishioka et al. 2014; Rabito et al. 

2014). As shown in Table 2-41, results of most studies show either decreases or no change in birth 

outcomes. Some positive associations between PbB and birth outcomes have been reported. A large 

cross-sectional study (n=1,009) reported a positive association between umbilical cord PbB (mean: 

4.07 g/dL) and birth weight in male infants, but no change for female infants (PbB mean: 4.17 μg/dL) 

(Wang et al. 2017c). A longitudinal study showed a positive association between umbilical cord PbB in 

infant boys (mean: 1.39 μg/dL) and birth length, but an inverse association for ponderal index (calculated 

relationship between body mass and height); no associations were observed for infant girls (PbB mean: 

1.21 μg/dL) (Kim et al. 2017b). In a small (n=202) prospective study, Bornschein et al. (1989) reported 

associations between maternal PbB (mean 7.5 μg/dL) and decreased birth weight and length. The size of 

the effect of PbB varied with maternal age (p<0.007), with a 58 g per lnPbB decrease for pregnancies at 

age 18 years and a 601 g decrease per ln PbB (μg/dL) for pregnancies at age 30 years. In the complete 

birth cohort from this study, which included mothers who declined participation in the infant follow-up 

(n=861), the decline in birth weight was -114 g per ln PbB. Results of the largest cohort study, a 

retrospective study of >43,000 participants (mean PbB: 2.1 μg/dL), showed an inverse association 

between PbB and birth weight (Zhu et al. 2010). The best fitting model was a linear change in birth 

weight with square root of PbB (Figure 2-7). The model predicts a 34 g decrease in birth weight for an 
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increase in PbB from 1 to 5 μg/dL and a 59 g decrease for an increase in PbB from 1 to 10 μg/dL 

(adjusted for confounders). 

Figure 2-7. Relationship Between Blood Lead Concentration (PbB) and Birth 

Weight at PbB ≤10 μg/dL

Source: Zhu et al. 2010

Results of a longitudinal cohort study of 4,285 mother-infant pairs (maternal PbB mean: 2.1 μg/dL; range 

0.42–19.14) showed inverse associations between birth weight, crown-heel length, and head 

circumference for participants with PbB ≥5 μg/dL compared to PbB <5 μg/dL (Taylor et al. 2015). A 

prospective cohort study of 3,125 mother infant pairs observed an inverse association between maternal 

serum Pb (mean: 1.50 μg/dL) and birth weight and SGA (Wang et al. 2017b). Other smaller cohort 

studies also showed associations between maternal PbB ≤10 μg/dL and decreased birth weight (Nisioka et 

al. 2014; Odland et al. 1999). In contrast, other studies, including a prospective study and cohort studies 

of large populations, did not find associations between PbB and birth outcome measures. A prospective 

study of 1,835 mother-infant pairs did not find an association between PbB and SGA, with PbB data 

stratified by tertiles (range for highest tertile: 1.04–4.04 μg/dL) (Thomas et al. 2015). Similarly, no 

associations between maternal PbB and decreased birth weight, length, or head circumference were 
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observed in a cohort study of 829 participants (estimated PbB mean of 0.4 μg/dL) (Perkins et al. 2014), or 

in a cross-sectional study of 1,578 participants (Al-Saleh et al. 2014). Smaller cohort studies also report 

no associations between PbB and adverse birth outcome measures (Bloom et al. 2015; Garcia-Esquinas et 

al. 2014; González-Cossío et al. 1997; Rabito et al. 2014). Equivocal findings for birth outcomes in 

studies examining effects at maternal PbB ≤10 μg/dL are not surprising, given that prospective studies at 

maternal PbB >10 μg/dL also have reported conflicting results for adverse effects on birth outcomes 

(Factor-Litvak et al. 1991; Hernandez-Avila et al. 2002; McMichael et al. 1986; Murphy et al. 1990). For 

example, two prospective studies found no associations between PbB and birth weight in birth cohorts 

that had mean maternal PbBs >10 μg/dL (Factor-Litvak et al. 1991; McMichael et al. 1986). 

Birth defects. Few studies have evaluated associations between in utero exposure to Pb and birth defects. 

Details of studies evaluating PbB ≤10 μg/dL are provided in the Supporting Document for 

Epidemiological Studies for Lead, Table 13. No association was observed between PbB and neural tube 

defects in a case-control study (n=409) with mean maternal PbB of 2.5 μg/dL (Brender et al. 2006). 

Other epidemiological studies that have reported associations between Pb in exposure media (e.g., water, 

soil) and neural tube defects are limited by the lack of PbB measurement (Bound et al. 1997; Huang et al. 

2011; Irgens et al. 1998). An early cross-sectional study of birth outcomes examined associations 

between PbB and congenital anomalies using hospital records on 5,183 deliveries in Boston, 

Massachusetts (Needleman et al. 1984). The RR of an anomaly increased with increasing cord PbB; the 

RR (relative to PbB 0.7 μg/dL) was 1.87 (95% CI 1.44, 2.42) for PbB of 6.3 μg/dL and increased to 

2.39 (95% CI 1.66, 3.43) at 15 μg/dL and 2.73 (95% CI 1.80, 4.16) at 24 μg/dL. The anomalies were 

considered to be minor (hemangiomas, lymphangiomas, hydrocele, minor skin anomalies, undescended 

testicle) and no specific anomaly was associated with PbB. Limitations of this study are that it was a 

cross-sectional study of a convenience sample with outcomes obtained from hospital records. 

Associations between PbB and congenital anomalies have not been corroborated. A case-control study of 

97 cases and 201 controls did not find an increased risk for congenital heart defects (Liu et al. 2018a). 

For the highest umbilical cord PbB tertile (≥0.826 μg/dL), the OR (95% CI) for congenital heart defects 

was 1.67 (0.88, 3.17).

Anthropometric measures in children. An overview of results of studies evaluating associations between 

Pb exposure and growth of infants and children (aged 0.5–15 years) at maternal and/or offspring PbB 

≤10 μg/dL is shown in Table 2-42, with more detailed results in Table 2-43. Studies include five 

prospective studies (Dallaire et al. 2014; Deierlein et al. 2019; Lamb et al. 2008 Kim et al. 2017b; 

Renzetti et al. 2017), cross-sectional studies of large (n=899–1,050) populations (Afeiche et al. 2011; 
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Hong et al. 2014; Ignasiak et al. 2006), and several smaller (n=108–729) cohort and cross-sectional 

studies (Alvarez-Ortega et al. 2019; Hauser et al. 2008; Little et al. 2009; Min et al. 2008b; OliveroVerbel et al. 2007; Raihan et al. 2018; Schell et al. 2009; Yang et al. 2013a). Most studies report inverse

associations between Pb exposure and height, with mixed results for weight and BMI (Table 2-42). In a 

prospective longitudinal study of girls (n=692; mean PbB: 1.16 μg/dL), height, BMI, waist circumference,

and percent body fat were decreased in participants with PbB ≥1 μg/dL, compared to participants with 

PbB <1 μg/dL; decreases were observed at yearly assessments at ages 7–14 years (Deierlein et al. 2019). 

The Renzetti et al. (2017) prospective study (n=513 mothers) reported inverse associations between 

3rd pregnancy trimester maternal PbB (mean: 3.1 μg/dL) and weight-for-age and height-for-age, but no 

associations for BMI or percentage body fat. No associations were observed between 2nd trimester PbB or 

cord PbB. In contrast, a prospective study of 280 children (18–27 months) observed positive associations 

between umbilical cord PbB (mean: 1.31 μg/dL) and weight and BMI, but not height; no associations 

were observed at 18 or 27 months (Kim et al. 2017b). A small (n=290) prospective study showed an 

association between cord PbB (mean 4.8 μg/dL) and small decreases in height and head circumference, 

but not for weight or BMI (Dallaire et al. 2014). Similarly, Lamb et al. (2008) did not find an association 

between maternal PbB and height or BMI at maternal PbB means of 5.60–20.56 μg/dL (means for 

different geographic locations). In contrast, results of large case-control studies showed inverse

associations between maternal bone Pb and weight (Afeiche et al. 2011), maternal PbB and weight and 

height (Hong et al. 2014), and child PbB and several growth measures, including weight, height, and BMI 

(Ignasiak et al. 2006). The largest inverse association for decreased weight was observed for maternal 

bone Pb in females assessed at 2–5 years of age; the mean PbB in children was 3.8 μg/dL (Afeiche et al. 

2011). At the 5-year assessment, body weight in females was decreased by approximately 172 g for each 

1-SD increase in maternal bone Pb. Smaller case-control and cohort studies reported consistent inverse

associations between PbB and height, with equivocal findings for weight, and no associations for BMI. 

Table 2-42. Overview of Decreased Anthropometric Measures in Children at 

Blood Lead Concentration (PbB) ≤10 μg/dL

Reference

Age at time of 

assessment (years)

Anthropometric measurements

Weight Height BMI

Afeiche et al. 2011 1–5 ↓ (F); 0 (M) − −

Alvarez-Ortega et al. 2019 5–16 ↓ (F); 0 (M) ↓ (F); 0 (M) ↓ (F); 0 (M)

5–11 0 0 0

12–16 ↓ ↓ ↓

Dallaire et al. 2014 8–14 0 ↓ 0

Deierlein et al. 2019 7–14 ↓ ↓ ↓
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Table 2-42. Overview of Decreased Anthropometric Measures in Children at 

Blood Lead Concentration (PbB) ≤10 μg/dL

Reference

Age at time of 

assessment (years)

Anthropometric measurements

Weight Height BMI

Hauser et al. 2008 8–9 0 ↓ 0

Hong et al. 2014 0.5–2 ↓ ↓ −

Ignasiak et al. 2006 7–15 ↓ (F); 0 (M) ↓ (F); 0 (M) ↓

Kim et al. 2017b 2.25 0 0 0

Lamb et al. 2008 1–10 0 0 0 

Little et al. 2009 2–12 ↓ − −

Min et al. 2008b 5–13 0 ↓ −

Olivero-Verbel et al. 2007 5–9 0 ↓ −

Raihan et al. 2018 <2 ↓a ↓a 0

Renzetti et al. 2017 4–6 ↓ ↓ −

Schell et al. 2009 0.5−1 0 ↓ −

Yang et al. 2013a 3–9 ↓ ↓ 0

aAssessments were underweight (defined as weight-for-age z-score <-2) and “stunting” (defined as length-for-age 

z-score <-2).

↓ = decrease in outcome measure; 0 = no effect on outcome measure; − = not assessed; BMI = body mass index; 

F = females; M = males

Delayed puberty. Results of studies that evaluated associations between Pb exposure and sexual 

maturation in boys and girls at child PbB ≤10 μg/dL are summarized in Table 2-44. In girls, delayed 

onset of puberty, as measured by breast development, pubic hair development, and attainment of 

menarche, has been corroborated in multiple cross-sectional studies (Den Hond et al. 2011; Denham et al. 

2005; Gollenberg et al. 2010; Naicker et al. 2010; Selevan et al. 2003; Wu et al. 2003b). Mean PbB in 

these studies ranged from 0.49 to 4.9 μg/dL. Delays in the predicted attainment of menarche ranged from 

3.6 to 10.6 months (Denham et al. 2005; Selevan et al. 2003). Fewer studies examining associations 

between Pb exposure and sexual maturation in boys at child PbB ≤10 μg/dL are available. Results of 

these studies are equivocal. Delayed sexual maturation (time to onset to puberty and sexual maturity), 

measured by genitalia development, testicular volume, and pubic hair development, was observed in three 

cross-sectional studies of the same study population of 481–489 boys; the median child PbB was 3 μg/dL 

at the time of study enrollment (Hauser et al. 2008; Williams et al. 2010, 2019). However, no association 

between PbB and the onset of puberty was observed in a cross-sectional study of 887 boys with a median 

PbB of 2.5 μg/dL (Den Hond et al. 2011).
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Table 2-43. Summary of Epidemiological Studies Evaluating Anthropometric Measurements in Infants and 

Children with Mean Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Afeiche et al. 2011

Cross-sectional study; 

n=999 mother-child pairs

• Child PbB mean: 3.8

• Maternal bone Pb (patella) 

mean (μg/g): 10.4

Weight (females) Associations between a 1-SD increase in 

maternal bone Pb (μg/g) and child weight (g) for 

children aged:

• 12 months: -70.9 (-147.9, 6.0)

• 24 months: -96.1 (-170.4, -21.8)*

• 36 months: -121.3 (-200.0, -42.6)*

• 48 months: -146.4 (-235.5, -57.4)*

• 60 months: -171.6 (-275.2, -68.0)*

Weight (males) Associations between a 1-SD increase in 

maternal bone Pb (μg/g) and child weight (g) for 

children aged:

• 12 months: 29.4 (-42.1, 100.8)

• 24 months: 27.8 (-43.5, 99.1)

• 36 months: 7.9 (-67.3, 83.1)

• 48 months: -13.6 (-97.9, 70.8)

• 60 months: -35.0 (-132.4, 62.3)

Alvarez-Ortega et al. 2019

Cross-sectional study; 

n=554 children (ages 5–16 years) 

Mean (SE): 3.5 (0.2)

Median: 1.9

Range: 0.1–50.1

Weight Spearman correlations:

• All participants: -0.152; p<0.001*

• Females: -0.226; p<0.001*

• Males: -0.056; p=0.380

• Age 5–11 years: -0.069; p=0.010*

• Age 12–16 years: -0.385; p<0.001*

Height Spearman correlations:

• All participants: -0.101; p=0.019*

• Females: -0.153; p=0.009*

• Males: -0.037; p=0.567

• Age 5–11 years: -0.137; p=0.418

• Age 12–16 years: -0.206; p=0.009*
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Table 2-43. Summary of Epidemiological Studies Evaluating Anthropometric Measurements in Infants and 

Children with Mean Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

BMI Spearman correlations:

• All participants: -0.172; p<0.001*

• Females: -0.273; p<0.001*

• Males: -0.040; p=0.536

• Age 5–11 years: -0.056; p=0.295

• Age 12–16 years: -0.384; p<0.001*

Dallaire et al. 2014

Prospective cohort study;

n=290 children (aged 8–14 years)

• Cord PbB mean: 4.8 

• Child PbB mean: 2.7 

Height β coefficients (cm per μg/dL cord): -1.57; 

p=0.004*

Head circumference β coefficients (cm per μg/dL cord): -0.005; 

p=0.04*

Weight β coefficients (kg per μg/dL cord): β not reported; 

p=0.70

BMI β coefficients (kg/m2 per μg/dL cord): 0.07; 

p=0.23

Deierlein et al. 2019

Prospective longitudinal study; 

n=of 683 girls (enrolled at ages 6–

8 years)

• Mean (SD): 1.16 (0.67)

• Range: 0.18–5.40

Height Predicted mean differences (cm) for PbB 

≥1 μg/dL compared to <1 μg/dL: 

• Age 7: -2.0 (-3.0, -1.0); p<0.001*

• Age 14: -1.5 (-2.5, -0.4): p=0.01*

BMI Predicted mean differences (kg/m2) for PbB ≥1 

μg/dL compared to <1 μg/dL: 

• Age 7: -0.7 (-1.2, -0.2); p=0.005*

• Age 14: -0.8 (-1.5, -0.02); p=0.05*

Waist circumference Predicted mean differences (cm) for PbB 

≥1 μg/dL compared to <1 μg/dL: 

• Age 7: -2.2 (-3.8, -0.6); p=0.01*

• Age 14: -2.9 (-4.8, -0.9); p=0.005*

Body fat Predicted mean differences (%) for PbB 

≥1 μg/dL compared to <1 μg/dL: 

• Age 7: -1.8 (-3.2, -0.4); p=0.01*

• Age 14: -1.7 (-3.1, -0.4); p=0.01*
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Table 2-43. Summary of Epidemiological Studies Evaluating Anthropometric Measurements in Infants and 

Children with Mean Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Hauser et al. 2008

Cross-sectional study

n=489 children (aged 8–9 years)

Child PbB, mean: 3 Height Regression coefficient (cm per 

μg/dL): -1.439 (-2.25, -0.63); p<0.001*

Weight Regression coefficient (kg per 

μg/dL): -0.761 (-1.54, 0.02); p=0.067

BMI Regression coefficient (kg/m2 per 

μg/dL): -0.107 (-0.44, 0.23); p=0.53

Hong et al. 2014

Cross-sectional study;

n=1,150 infants (aged 6–

24 months)

Maternal PbB mean: 1.25 Weight Weight z score: -0.28 (-0.48, -0.09); p<0.05*

Height Height z score: -0.28 (-0.49, -0.06); p<0.05*

Ignasiak et al. 2006

Cross-section study;

n=899 children (aged 7–15 years)

Child PbB mean: 7.7 Weight • Slope boys(kg per log10 μg/dL): 4.00 (2.45); 

p=0.10

• Slope girls (kg per log10

μg/dL): -6.59 (2.09); p=0.001*

Height • Slope boys (cm per log10 μg/dL): -6.26 (1.40); 

p=0.002

• Slope girls (cm per log10

μg/dL): -5.54 (2.05); p=0.007*

BMI • Slope boys (kg/m2 per log10

μg/dL): -0.39 (0.82); p=NS

• Slope girls (kg/m2 per log 

μg/dL): -1.86 (0.75); p=0.01*

Trunk length • Slope boys (cm per log10

μg/dL): -2.21 (0.97); p=0.02* 

• Slope girls (cm per log μg/dL): -1.47 (1.00); 

p=NS
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Table 2-43. Summary of Epidemiological Studies Evaluating Anthropometric Measurements in Infants and 

Children with Mean Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Leg length • Slope boys (cm per log10

μg/dL): -4.05 (1.27); p=0.002*

• Slope girls (cm per log10

μg/dL): -4.08 (1.27) p=0.0001*

Arm length • Slope boys (cm per μg/dL): -3.20 (0.97); 

p=0.0001*

• Slope girls (cm per log10

μg/dL): -2.61 (0.98); p=0.008*

Trunk-length ratio • Slope boys (per log10 μg/dL): 0.71 (0.34): 

p=0.04*

• Slope girls (per log10 μg/dL): 1.03 (0.34); 

p=0.003*

Lamb et al. 2008

Population-based prospective 

cohort; n=309 children (aged 1–10) 

years

Maternal PbB mean for 

towns of:

• Pristina: 5.60

• Mitrovica: 20.56 

Height/BMI Pristina (β coefficients per log μg/dL):

• Age 1 year: -0.61 (-2.24, 1.03)

• Age 10 years: -0.09 (-3.69, 3.52)

Mitrovica (β coefficients per log μg/dL):

• Age 1 year: -0.30 (-2.55, 1.96)

• Age 10 years: -2.87 (-6.21, 0.47)

Little et al. 2009

Cross-sectional study;

n=360 children (aged 2–12 years)

Child PbB mean

• 1980 cohort: 23.6 

• 2002 cohort: 1.6 

• Pooled cohort PbB mean 

not reported

Height β coefficient (cm per10 μg/dL PbB decrease): 

2.1 (1.9, 2.3); p<0.0001*

Weight β coefficient (kg per 10 μg/dL PbB decrease): 

1.9 (1.7, 2.1); p<0.0001*

BMI β coefficient (kg/m2 per 10 μg/dL PbB 

decrease): 0.5 (0.4, 0.7); p<0.0001*
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Table 2-43. Summary of Epidemiological Studies Evaluating Anthropometric Measurements in Infants and 

Children with Mean Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Kim et al. 2017b

Prospective longitudinal study; 

n=280 children (18–27 months)

Umbilical cord, mean: 1.31

• All: 1.31 (0.06)

• Boys: 1.39 (0.09)

• Girls: 1.21 (0.07)

Weight Regression coefficient β:

• 18 months: 0.897 (-0.171, 1.965); p=0.092

• 24 months: 0.717 (0.195, 1.239); p=0.009* 

• 27 months: 0.316 (-0.345, 0.977); p=0.333 

Height Regression coefficient β:

• 18 months: 0.909 (-0.222, 2.040); p=0.101

• 24 months: 0.138 (-0.530, 0.806); p=0.675

• 27 months: 0.354 (-0.497, 1.205); p=0.394

BMI Regression coefficient β:

• 18 months: 0.157 (-1.266, 1.580) p=0.806

• 24 months: 0.695 (0.077, 1.313); p=0.029*

• 27 months: 0.409 (-0.398, 1.216); p=0.300

Min et al. 2008b

Cross-sectional study;

n=108 children (aged 5–13 years)

Child PbB mean: 2.4 Height Regression coefficient cm per μg/dL 

(SE): -1.449 (0.639); p=0.026*

Weight Regression coefficient kg per μg/dL 

(SE): -0.646 (0.718); 0.370

BMI Regression coefficient kg/m2 per μg/dL 

(SE): -0.006 (0.272); p=0.982

Arm length Regression coefficient cm per μg/dL 

(SE): -1.804 (0.702); p=0.012*

Olivero-Verbel et al. 2007 

Cross-sectional study;

n=189 children (aged 5–9 years)

Child PbB mean: 5.53 Height Correlation coefficient: -0.224; p=0.002*

Weight Correlation coefficient: -0.126; p=0.087

Raihan et al. 2018

Cross-sectional study; 

n=729 children (<2 years of age)

Mean (SD): 8.25 (3.64)

95% CI: 7.98, 8.51

“Normal” PbB: <5

“Elevated” PbB: ≥5

Stuntinge OR for PbB ≥5 μg/dL (compared to PbB 

<5 μg/dL): 1.78 (1.07, 2.99); p=0.028*

Wastinge OR for PbB ≥5 μg/dL (compared to PbB 

<5 μg/dL): 1.18 (0.64, 2.19); p=0.581

Underweighte OR for PbB ≥5 μg/dL (compared to PbB 

<5 μg/dL): 1.63 (1.02, 2.61); p=0.043*
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Table 2-43. Summary of Epidemiological Studies Evaluating Anthropometric Measurements in Infants and 

Children with Mean Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Renzetti et al. 2017

Prospective study; n=513 mothers 

(children assessed at ages 4–

6 years)

Maternal PbB (Gmean)

• 2nd trimester: 3.0 (0.8–17.8)

• 3rd trimester: 3.1 (0.3–28.3)

• At delivery: 3.5 (0.7–21.9)

• Umbilical cord: 2.8 (0.4–18.5)

BMI z-score β coefficient for:

• 2nd trimester: 0.04 (-0.07, 0.15); p=0.51

• 3rd trimester: -0.01 (-0.12, 0.10); p=0.81

• At delivery: -0.03 (-0.08, 0.14); p=0.58

• Cord PbB: 0.05 (-0.08, 0.17); p=0.46

Percentage body fat β coefficient for:

• 2nd trimester: -0.13 (-0.75, 0.49); p=0.68

• 3rd trimester: -0.21 (-0.82, 0.41); p=0.52

• At delivery: -0.12 (-0.74, 0.50); p=0.70

• Cord PbB: 0.31 (-0.37, 0.99); p=0.37

Weight-for-age z-score β coefficient for:

• 2nd trimester: -0.02 (-0.13, 0.09); p=0.68

• 3rd trimester: -0.11 (-0.22, -0.003); p=0.04*

• At delivery: -0.03 (-0.13, 0.08); p=0.58

• Cord PbB: -0.03 (-0.15, 0.09); p=0.64

Height-for-age z-score β coefficient for:

• 2nd trimester: -0.04 (-0.13, 0.04); p=0.32

• 3rd trimester: -0.10 (-0.19, -0.01); p=0.03*

• At delivery: -0.04 (-0.13, 0.05); p=0.39

• Cord PbB: -0.04 (-0.14, 0.06); p=0.39

Schell et al. 2009

Longitudinal cohort study;

n=244 children (aged 3–

12 months)

Maternal PbB mean: 2.8 Length Regression coefficients (SE):

• 6 months (cm per log μg/dL): 

0.149 (0.076); p=0.05*

• 12 months (cm per log μg/dL): 0.073 (0.083); 

p=0.38

Weight-for-age Regression coefficients (SE):

• 6 months (kg per μg/dL): 0.013 (0.098); 

p=0.89

• 12 months (kg per μg/dL): 0.124 (0.107); 

p=0.25
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Table 2-43. Summary of Epidemiological Studies Evaluating Anthropometric Measurements in Infants and 

Children with Mean Blood Lead Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Weight for length Regression coefficients (SE):

• 6 months(per μg/dL): -0.158 (0.111); p=0.16

• 12 months (per μg/dL): 0.084 (0.111); p=0.45

Head circumference Regression coefficients (SE):

• 6 months (cm per μg/dL): -0.242 (0.094); 

p=0.01*

• 12 months (cm per μg/dL): -0.220 (0.109); 

p=0.05*

Upper arm 

circumference

Regression coefficients (SE):

• 12 months (cm per μg/dL):-0.132 (0.114); 

p=0.25

Yang et al. 2013a

Cross sectional study;

n=246 children (aged 3–8 years)

Child PbB mean: 7.30 Height β coefficient(cm per μg/dL): -0.10; p=0.02*

Weight β coefficient (kg per μg/dL): -0.14; p=0.01*

BMI β coefficient (kg/m2 per μg/dL): -0.08;p=0.24

aSee the Supporting Document for Epidemiological Studies for Lead, Table 13 for more detailed descriptions of studies. bParticipants had no known occupational exposure to Pb.

cValues are for maternal PbB, unless otherwise specified. dAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table. eStunting (defined as length-for-age z score <-2), wasting (defined as weight-for-length z-score <-2), and underweight (defined as weight-for-age z-score <-2)

BMI = body mass index; CI = confidence interval; Gmean = geometric mean; NS = not statistically significant; OR = odds ratio; Pb = lead; SD = standard 

deviation; SE = standard error
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Table 2-44. Summary of Epidemiological Studies Evaluating the Onset of Puberty in Children with Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Onset of puberty in females

Den Hond et al. 2011

Cross-sectional study; n=792 girls 

(aged 14–15 years)

Median: 1.81 Pubic hair development OR: 0.65 (0.45, 0.93); p=0.020*

Denham et al. 2005

Cross-sectional study; n=138 girls 

(aged 10–16.9 years)

Mean: 0.49 Attainment of menarche β coefficient (SE) predicting likelihood of 

attaining menarche (per ln 

μg/dL): -1.29 (0.494); p=0.01*

Gollenberg et al. 2010 

Cross-sectional study; n=705 girls 

(aged 6–11 years)

Median: 2.5

Tertiles

• T1: <1.0

• T2: 1–4.99

• T3: ≥5.00

Inhibin B pubertal 

cutoff value

OR for exceeding pubertal cutoff value:

• T2 (OR): 0.38 (0.12, 1.15)*

• T3 (OR): 0.26 (0.11, 0.60)*

Naicker et al. 2010

Cross-sectional, longitudinal 

study; n=682 girls (aged 13 years)

Mean: 4.9 Breast development Trend analysis over ages 8–16 years: 

p<0.001*

Pubic hair development Trend analysis over ages 8–16 years: 

p<0.001*

Attainment of menarche Trend analysis over ages 8–16 years: 

p<0.001*
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Table 2-44. Summary of Epidemiological Studies Evaluating the Onset of Puberty in Children with Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Selevan et al. 2003

Cross-sectional study; 

n=2,186 girls (aged 8–18 years)

Gmean

• NHW: 1.4

• NHAA: 2.1

• MA: 1.7

Breast development • NHW OR: 0.82 (0.47, 1.42)

• NHAA OR: 0.64 (0.42, 0.97); p<0.05*

• MA OR: 0.76 (0.63, 0.91); p<0.05*

Pubic hair development • NHW OR: 0.75 (0.37, 1.51)

• NHAA OR: 0.62 (0.41, 0.96); P<0.05

• MA OR: 0.70 (0.54, 0.91); p<0.05

Age of menarche • NHW HR: 0.74 (0.55, 1.002)

• NHAA HR: 0.78 (0.63, 0.98); p<0.05 (age at 

menarche delayed 3.6 months)*

• MA HR: 0.90 (0.73, 1.11)

Wolff et al. 2008

Cross-sectional study; n=192 girls 

(aged 9 years)

Median: 2.4 Breast development PR for breast stage ≥2 versus stage 1: 

1.01 (0.79,1.30)

Pubic hair development PR for pubic hair stage ≥2 versus stage 1: 

1.25 (0.83, 1.88)

Wu et al. 2003b

Cross-sectional study; 

n=1,706 girls (aged 8–16 years)

Mean: 2.5 

Tertiles:

• T1: 0.7–2.0 (reference)

• T2: 2.1–4.9

• T3: 5.0–21.7

Breast development • OR for T2: 1.51 (0.90, 2.53)

• OR for T3: 1.20 (0.51, 2.85)

Pubic hair development • OR for T2: 0.48 (0.25, 0.92)*

• OR for T3: 0.27 (0.08, 0.93)*

Attainment of menarche • OR for T2: 0.42 (0.18, 0.97)*

• OR for T3: 0.19 (0.08, 0.43)*
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Table 2-44. Summary of Epidemiological Studies Evaluating the Onset of Puberty in Children with Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Onset of puberty in males

Den Hond et al. 2011

Cross-sectional study; n=887 boys 

(aged 12–15 years)

Median: 2.50 Onset of puberty No association between PbB and the onset of 

puberty (specific data not reported)

Hauser et al. 2008

Cross-sectional study; 

n=489 peripubertal boys (aged 8–

9 years)

Median: 3 Genitalia development OR for having entered genitalia stage G2 for 

PbB ≥5 compared to PbB <5: 0.57 (0.34, 

0.95); p=0.03*

Williams et al. 2010 

Longitudinal cohort; 

n=489 peripubertal boys (aged 8–

9 years)

Median: 3 Testicular volume HR for testicular volume <3 mL for PbB 

≥5 μg/dL compared to PbB <5 μg/dL: 

0.73 (0.55, 0.97); p=0.03*

Genitalia stage HR for having entered genitalia stage G2 for 

PbB ≥5 μg/dL compared to PbB <5 μg/dL: 

0.76 (0.59, 0.98); p=0.04*

Pubic hair stage HR for having entered pubic hair stage G2 for 

PbB ≥5 μg/dL compared to PbB <5 μg/dL: 

0.69 (0.44, 1.07); p=0.10
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Table 2-44. Summary of Epidemiological Studies Evaluating the Onset of Puberty in Children with Mean Blood 

Lead Concentration (PbB) ≤10 μg/dLa

Reference and study 

populationb PbB (μg/dL)c Outcome evaluated Resultd

Williams et al. 2019

Longitudinal cohort; n=481 boys 

(enrolled at ages 8–9 years) 

Median: 3 Onset of puberty Difference in age (shift in mean age in 

months) (95% CI) for PbB ≥5 μg/dL compared 

to PbB, based on:

• Genitalia: 8.40 (3.70, 13.10); p<0.001*

• Pubic hair: 8.12(3.46, 12.78); p<0.001*

• Testicular volume: 7.68 (3.46, 11.90);

p<0.001*

Onset of sexual 

maturity

Difference in age (shift in mean age in 

months) (95% CI) for PbB ≥5 μg/dL compared 

to PbB, based on:

• Genitalia: 4.20 (0.56, 7.84); p=0.024*

• Pubic hair: 4.23 (-0.31, 8.77); p=0.068

• Testicular volume: 5.14 (1.70, 8.58);

p=0.003*

aSee the Supporting Document for Epidemiological Studies for Lead, Table 13 for more detailed descriptions of studies. bParticipants had no known occupational exposure to Pb.

cValues are for maternal PbB, unless otherwise specified.

dAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table

CI = confidence interval; Gmean = geometric mean; HR = hazard ratio; MA = Mexican Americans; NHW = Non-Hispanic whites; NHAA = Non-Hispanic African 

Americans; OR = odds ratio; Pb = lead; PR = prevalence ratio; SE = standard error
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Associations Between Bone Pb and Birth Outcome and Postnatal Growth. Studies evaluating 

associations between maternal bone Pb and birth outcome (birth weight and length, head circumference) 

and postnatal growth (infant and child weight gain) are summarized in Table 2-45. Studies were 

conducted in mother-infant/child pairs residing in Mexico City. Maternal tibia Pb was inversely 

associated with birth weight (Cantonwine et al. 2010; González-Cossío; Kordas et al. 2009), birth length 

(Hernandez-Avila et al. 2002), and head circumference (Hernandez-Avila et al. 2002; Kordas et al. 2009). 

Maternal patella Pb was associated with decreased head circumference (Hernandez-Avila et al. 2002), but 

not birth weight (Afeiche et al. 2011; González-Cossío) or birth length (Hernandez-Avila et al. 2002). 

Infant weight gain measured at 1 month of age was inversely associated with maternal patella Pb, but not 

maternal tibia Pb (Sanin et al. 2001); no associations between maternal tibia or patella Pb were observed 

from birth to 12 months of age (Afeiche et al. 2011). Maternal patella Pb was inversely associated with 

weight gain in girls, but not boys, at 5 years of age; however, no associations were observed for maternal 

tibia Pb for boys or girls. In contrast, no associations were observed in a prospective study examining the 

relationships between maternal patella or tibia Pb (measured 1 month postpartum) and BMI, percent body 

fat, weight-for-age score, or height-for-age score in children ages 4–6 years (Renzetti et al. 2017). Taken 

together, results of these studies provide evidence that long-term maternal Pb exposure is inversely

associated with infant size and post-natal growth.

Table 2-45. Associations Between Maternal Bone Pb and Birth Outcome and 

Postnatal Growth

Reference Populationa

Effect

Birth 

weight

Birth 

length

Head 

circumference

Infant weight 

gain

Child 

weight 

gain 

Afeiche et al. 

2011

Mother-infant pairs 

(522 boys; 477 girls)

0 T (M, F)

0 P (M, F)

– – 0 T (M, F)b

0 P (M, F)b

0 T (M, F)

0 P (M)

↓ P (F)c

Cantonwine et 

al. 2010

538 mother-infant 

pairs

↓ T – – – –

GonzalezCossio et al. 

1997

272 mother-infant 

pairs

↓ T

0 P

– – – –

HernandezAvila et al. 

2002

223 mother-infant 

pairs

– ↓ T

0 P

↓ T

↓ P

– –

Kordas et al. 

2009

474 mother-infant 

pairs

↓ T 0 T ↓ T – –
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Table 2-45. Associations Between Maternal Bone Pb and Birth Outcome and 

Postnatal Growth

Reference Populationa

Effect

Birth 

weight

Birth 

length

Head 

circumference

Infant weight 

gain

Child 

weight 

gain 

Renzetti et al. 

2017

424 (P) and 430 (T) 

mother-child pairs 

– – – – 0 Td

0 Pd

Sanin et al. 

2001

329 mother-infant 

pairs

– – – 0 Te

↓ Pe

–

aFrom Mexico City.

bMeasured from birth to 12 months of age.

cMeasured at 5 years of age.

dMeasured at 4–6 years; assessments included BMI, percentage body fat, weight-for-age, and height-for-age. No 

associations between maternal Pb and any of the assessments were observed.

eMeasured at 1 month of age.

↓ = inverse association; 0 = no association; – = not reported; F = female; M = male; P = patella; Pb = lead; T = tibia

Mechanisms of Action. General mechanisms of toxicity of Pb (reviewed in Section 2.21) are likely 

involved in adverse development effects. EPA (2014c) specifically noted that delayed puberty may result 

from alterations in pulsatile release of sex hormones and that insulin-like growth factor 1 (IGF-1) may 

play a role in this effect. Pb is distributed to the fetus and has been measured in umbilical cord blood, 

placenta, and follicular fluid (See Section 3.1.2, Toxicokinetics, Distribution), providing a toxicokinetic 

mechanism for direct exposure of the fetus.

2.19 CANCER

Overview. Numerous epidemiological studies have investigated associations between Pb exposure and 

cancer. Studies include exposure of workers and general populations, with many studies reporting PbB. 

In most studies, mean PbBs in these studies are <10 μg/dL. Although studies provide limited evidence of 

carcinogenicity of Pb in humans, results are inconsistent and interpretation may be limited due to 

confounding factors.

Many studies of occupational cohorts and cancer risks do not report PbB data. These studies have 

reported associations between occupational exposure to Pb and cancer, including overall cancer mortality 

and cancers of the lung, brain, stomach, kidney, and bladder. However, results are inconsistent and 

interpretation may be limited due to confounding factors.
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The following cancers have been associated with PbB: 

• ≤10 μg/dL:

o Increased risk of all cancer; evaluated in multiple studies with mixed results.

o Increased risk of lung cancer; evaluated in multiple studies with mixed results.

• >10 μg/dL:

o Increased risk of all cancer; evaluated in multiple studies with mixed results.

o Increased risk of respiratory tract cancers (bronchus, trachea, lung); evaluated in multiple 

studies with mixed results.

o Increased risk of stomach cancer; evaluated in multiple studies with mixed results.

o Increased risk of intestinal cancer.

o Increased risk of cancer of the larynx.

o Increased risk of glioma.

Carcinogenicity Classifications of Pb and Pb Compounds. IARC has classified inorganic Pb 

compounds as probably carcinogenic to humans (Group 2A) based on sufficient evidence in animals and 

limited evidence in humans; evidence for organic Pb compounds was considered to be inadequate in 

humans and animals (IARC 2006). The National Toxicology Program 14th Report on Carcinogens 

classified Pb and Pb compounds as reasonably anticipated to be human carcinogens (NTP 2016). As the 

basis of the Group 2A classification for inorganic Pb compounds, IARC (2006) cited multiple animal 

studies showing kidney cancer following chronic oral and parenteral exposure (Azar et al. 1973; Balo et 

al. 1965; Fears et al. 1989; Kasprzak et al. 1985; Koller et al. 1985; Van Esch and Kroes 1969; Zawirska 

1981; Zollinger 1953), renal tubular adenoma in offspring of mice exposed during gestation and lactation 

(Waalkes et al. 1995), and brain gliomas following oral exposure of rats (Zawirska 1981; Zawirska and 

Medras 1972). For epidemiological studies of occupational cohorts, IARC (2006) noted limited evidence 

of carcinogenicity of the lung, stomach, kidney, and brain/nervous system, although studies yielded 

inconsistent results, and interpretation of results was compromised due to potential confounding factors 

(e.g., smoking, occupational exposure to other carcinogens such as arsenic).

Confounding Factors and Effect Modifiers. Numerous factors can influence results of epidemiological 

studies evaluating associations between Pb exposure and cancer, including smoking status, family history 

of cancer, and co-exposure to other carcinogens. Failure to account for these factors may attenuate or 

strengthen the apparent associations between Pb exposure and the outcome, depending on the direction of 
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2. HEALTH EFFECTS

the effect of the variable on the outcome. For example, many occupational studies include smelters where 

exposure to arsenic and other carcinogenic metals (e.g., cadmium) can be correlated with exposure to Pb. 

Exposures to Pb occur throughout the lifetime and a cross-sectional evaluation of PbB may not 

adequately represent the exposure history of the individual.

Measures of Exposure. Numerous studies evaluating cancer in general populations and Pb-exposed 

workers report PbB as a measure of exposure. A few studies measured exposure by bone Pb 

concentrations, cumulative blood Pb index, or cumulative exposure (Bhatti et al. 2009; Englyst et al. 

2001; Ionescu et al. 2007; Rajaraman et al. 2006); however, these studies did not report PbB.

Characterization of Effects. Numerous epidemiological studies have assessed associations between PbB 

and cancer. Studies of general populations and workers are briefly summarized in Table 2-46. Studies of 

general populations include large cross-sectional studies (n=5,482–13,946) of NHANES participants 

(Cheung et al. 2013; Jemal et al. 2002; Menke et al. 2013; Schober et al. 2006). Mean PbBs in most 

studies are <10 μg/dL, although in some studies that stratify by PbB, the highest exposure categories are 

>10 μg/dL (Jemal et al. 2002; Kelly et al. 2013; Schober et al. 2006). Results of two studies with PbB 

<10 μg/dL show increased risks of all cancer and of lung cancer (Cheung et al. 2013; Schober et al. 

2006), although other studies show no increases in cancer risk (Jemal et al. 2002; Khalil et al. 2009; Kelly 

et al. 2013; Menke et al. 2013; Santibanez et al. 2008; Wiesskopf et al. 2009). Results of occupational 

exposure studies are mixed and do not establish a pattern of effects of exposure-response relationships. 

PbBs in these studies generally are >40 μg/dL. Studies have reported associations between PbB and all 

cancers (Anttila et al. 1995; Lundstrom et al. 1997; Lustberg and Silbergeld 2002; McElvenny et al. 2015; 

Wong and Harris et al. 2000), cancers of the bronchus, trachea, and lung (Anttila et al. 1995; Barry and 

Steenland 2019; Chowdhury et al. 2014; Kim et al. 2015; Lundstrom et al. 1997; McElvenny et al. 2015; 

Steenland and Boffetta 2000; Steenland et al. 2017, 2019), cancer of the larynx (Barry and Steenland 

2019; Chowdhury et al. 2014; Steenland et al. 2019), esophageal cancer (Steenland et al. 2019), stomach 

cancer (Cooper et al. 1985; Steenland and Boffetta 2000; Steenland et al. 2017, 2019; Wong and Harris et 

al. 2000), intestinal or rectal cancer (Kim et al. 2015; Steenland et al. 2019), bladder cancer (Steenland et 

al. 2017), and gliomas (Anttila et al. 1996).

Many studies of occupational cohorts with high exposure to Pb and cancer risks do not report PbB data 

(Bertazzi and Zocchetti 1980; Bhatti et al. 2009; Cocco et al. 1994, 1997, 1998a, 1998b, 1999a, 1999b; 

Davies 1984a, 1984b; Dingwall-Fordyce and Lane 1963; Fayerweather et al. 1997; Hu et al. 1999; Jones 

et al. 2007; Kauppinen et al. 1992; Lin et al. 2009; McElroy et al. 2008; Michaels et al. 1991; Pan et al. 
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Table 2-46. Summary of Epidemiological Studies Evaluating Cancer Endpoints and Blood Lead Concentration 

(PbB)

Reference and study population PbB (μg/dL) Cancer outcomes Effectsa

General population

Cheung et al. 2013

Cross-sectional study; n=3,482 (NHANES III)

Mean (SE): 4.44 (0.14) All cancer OR: 1.071 (1.036, 1.106)*

Lung cancer OR: 1.090 (1.054, 1.127)*

Jemal et al. 2002

Cross-sectional study; n=3,592 (NHANES II, 

age 6 months–74 years)

Quartiles:

• Q1: ≤9.8

• Q2: 9.9–12.9

• Q3: 13.0–16.9

• Q4: ≥17.0

All cancer Adjusted RR Q4: 1.50 (0.75, 3.01) 

Khalil et al. 2009

Prospective cohort study; n=532 women 

(age 65–87 years)

Mean: 5.3

<8 (n=453)

≥8 (n=79)

All cancer Adjusted HR PbB ≥8 (versus <8): 1.64 

(0.73, 3.71)

Kelly et al. 2013

Nested case-control study; n=194 cases 

NHL; 76 cases MM; and 270 controls (mean 

age 53.08 years)

Mean (range)

• Males: 6.18 (1.54, 67.2)

• Females: 5.27 (1.1, 40.1)

Quartiles

• Q1: 1.5423–3.986

• Q2: 3.9504–5.8763

• Q3: 5.8832–8.7218

• Q4: 8.7531–40.0843

NHL OR Q4: 0.93 (0.43, 2.02)

p-trend=0.849

MM OR Q4: 1.63 (0.45, 5.94)

p-trend=0.533

Menke et al. 2006

Cross-sectional study; n=13,946 (NHANES 

1988–1994; mean age 44.4 years)

Mean: 2.58

Tertiles: 

• T1: <1.93

• T2: 1.94–3.62

• T3: ≥3.62

All cancer Adjusted OR 

• T2: 0.72 (0.46, 1.12); p-trend=0.130

• T3: 1.10 (0.82, 1.47); p-trend=0.101

Santibanez et al. 2008

Case-control study; n=185 esophageal 

cancer patients; 285 controls (age 30–

80 years)

Low: ≤4.9

High: >4.9

Esophageal Adjusted OR 

• Low: 0.79 (0.43, 1.46)

• High: 1.69 (0.57, 5.03)
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2. HEALTH EFFECTS

Table 2-46. Summary of Epidemiological Studies Evaluating Cancer Endpoints and Blood Lead Concentration 

(PbB)

Reference and study population PbB (μg/dL) Cancer outcomes Effectsa

Schober et al. 2006

Cross-sectional study; n=9,757 (NHANES III; 

age ≥40 years)

Tertiles

• T1: <5 (mean 2.6)

• T2: 5–9 (mean 6.3)

• T3: >10 (mean 11.8)

All cancer Adjusted RR 

• T2: 1.44 (1.12, 1.86)*

• T3: 1.69 (1.14, 2.52)*

• p-trend<0.01*

Weisskopf et al. 2009

Prospective study; n=868 men (Normative 

Aging Study; age 21–80 years)

Mean (SD): 5.6 (3.4)

Tertiles:

• T1: <4

• T2: 4–6

• T3: >6

All cancer Adjusted HR T3: 0.48 (0.25–0.91)*; 

p-trend=0.02

Workers

Anttila et al. 1995

Cross-sectional study; n=20,700 workers 

(age 30–74 years)

Tertiles:

• T1: 0–18.6

• T2: 20.7–39.4

• T3: 41.1–161.6

All cancer SMR T2: 1.4 (1.1, 1.8)*

SMR T3: 1.2 (0.9, 1.8)

Lung, trachea SMR T2: 2.0 (1.2, 3.2)*

SMR T3: 1.5 (0.8, 2.1)

Anttila et al. 1996

Cross-sectional study; n=20,741 workers 

(age 18–74 years)

Tertiles:

• T1: 2.1–14.5

• T2: 16.6–26.9

• T3: 29.0–89.1

All nervous system 

cancers

Adjusted OR T3: 2.2 (0.7, 6.6)

p-trend=0.17

Glioma Adjusted OR T3: 11 (1.0, 626)*

p-trend: 0.037
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Table 2-46. Summary of Epidemiological Studies Evaluating Cancer Endpoints and Blood Lead Concentration 

(PbB)

Reference and study population PbB (μg/dL) Cancer outcomes Effectsa

Barry and Steenland 2019

Retrospective study; n=58,368 male workers 

(follow-up of Chowdhury et al. 2014)

Quartiles

• Q1: 0–<5

• Q2: 5–<25

• Q3: 25–<40

• Q4: ≥40

Colon HR Q4: 1.19 (0.54, 2.61)

Esophagus HR Q4: 0.97 (0.43, 2.20)

Kidney HR Q4: 0.92 (0.32, 2.58)

Liver HR Q4: 1.53 (0.79, 2.99)

Lung HR Q2: 1.61 (1.04, 2.48)*

HR Q3: 2.03 (1.34, 3.10)*

HR Q4: 2.92 (1.91, 4.46)*

p-trend: <0.01*

Stomach HR Q4: 0.64 (0.22, 1.82)

Tertiles:

• T1: 0–<25

• T2: 25–<40

• T4: ≥40

Brain HR Q4: 1.49 (0.71, 3.12)

Bladder HR Q4: 1.71 (0.83, 3.55)

Larynx HR Q4: 3.42 (1.29, 9.09)*

Non-Hodgkin’s lymphoma HR Q4: 1.60 (0.85, 3.01)

Pancreas HR Q4: 1.15 (0.72, 1.85)

Rectal HR Q4: 2.06 (0.87, 4.84)

Chowdhury et al. 2014

Survey study/cross-sectional study; 

n=58,368 male workers (mean age 

38.9 years)

Quartiles

• Q1: 0–<5

• Q2: 5–<25

• Q3: 25–<40

• Q4: ≥40

Lung SMR Q4: 1.20 (1.03, 1.39)*

Brain SMR Q4: 0.83 (0.41, 1.49)

Kidney SMR Q4: 0.72 (0.33, 1.37)

Stomach SMR Q4: 0.92 (0.44, 1.69)

Esophagus SMR Q4: 0.65 (0.32, 1.16)

Larynx SMR Q4: 2.11 (1.05, 3.77)*

Bladder SMR Q4: 0.70 (0.28, 1.45)

Cooper et al. 1985

Cohort study; n=4,519 battery workers; 

2,300 smelters

Mean

• Battery (n=1,326): 62.7

• Smelters (n=537): 79.7

All cancer Battery PMR: 1.06 (0.96, 1.16)

Smelters PMR: 1.02 (0.87, 1.19)

Stomach Battery PMR: 1.54 (1.11, 2.15)*

Smelters PMR: 1.03 (0.75, 1.42)

Large intestine Battery PMR: 0.98 (0.69, 1.40)

Smelters PMR: 1.19 (0.62, 2.28)
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Table 2-46. Summary of Epidemiological Studies Evaluating Cancer Endpoints and Blood Lead Concentration 

(PbB)

Reference and study population PbB (μg/dL) Cancer outcomes Effectsa

Larynx Battery PMR: 1.19 (0.54, 2.65)

Smelters PMR (95% CI): 1.06 (0.27, 

4.21)

Bronchus, trachea, lung Battery PMR: 1.16 (0.97, 1.39)

Smelters PMR: 1.13 (0.84, 1.51)

Brain and other CNS Battery PMR: 1.09 (0.55, 2.18)

Smelters PMR: 0.97 (0.32, 3.01)

Kim et al. 2015

Cross-sectional study; n=81,067 inorganic 

Pb workers (54,788 males; 26,279 females; 

age 20–≤50 years)

Mean (SD)

• Males: 8.8 (8.5)

• Females 5.8 (5.4)

Tertiles:

• T1: <10

• T2: 10–20

• T3: >20

All cancer Males: RR T3: 0.95 (0.56, 1.61)

Females RR T3: 1.68 (0.40, 7.13)

Stomach Males: RR T3: 0.80 (0.23, 2.71)

Females RR T2: 1.82 (0.20, 16.36)

Females T3: no cases 

Colo-rectal Males: RR T3: 1.86 (0.35, 9.79)

Females RR T2: 13.42 (1.21, 149.4)*; 

p<0.05

Females T3: no cases

Liver Males: RR T3: 1.72 (0.72, 4.14)

Females T2 RR: 0.83 (0.10, 6.56)

Females T3: no cases

Bronchus, lung Males: RR T3: 0.46 (0.10, 2.01)

Females RR T2: 10.45 (1.74, 62.93)*; 

p<0.05

Females RR T3: 12.68 (1.69, 147.86)*; 

p<0.05

Lundstrom et al. 1997

Cross-sectional study; n=3979 workers

Mean:

• In 1950: 62.2

• In 1987: 33.2

All cancer SMR: 1.2 (1.0, 1.5)*

Lung SMR: 2.8 (2.0, 3.8)*

Lundstrom et al. 2006

Nested case-referent study; 3,979 smelter 

workers

Peak:

Cases (n=40): 49.7

Referents (n=114): 55.9

Lung OR: 0.93 (0.60, 1.44)
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Table 2-46. Summary of Epidemiological Studies Evaluating Cancer Endpoints and Blood Lead Concentration 

(PbB)

Reference and study population PbB (μg/dL) Cancer outcomes Effectsa

Lustberg and Silbergeld 2002

Cross-sectional study; n=4,292; age 30–

74 years (NHANES II)

Tertiles:

• T1 (n=818): <10

• T2 (n=2,735): 10–19

• T3 (n=637): 20–29

All cancer (rate ratio) RR T2: 1.46 (0.87, 2.48)

RR T3: 1.68 (1.02, 2.78)*

McElvenny et al. 2015

Cohort study; n=9,122 workers; mean age 

29.2 years

Mean (SD): 44.3 (22.7)

Range: 2.3–321.5

All cancer SMR: 1.13 (1.07, 1.20)*

Esophagus SMR: 1.05 (0.78, 13.8)

Stomach SMR: 1.11 (0.86, 1.43)

Colon SMR: 0.98 (0.77, 1.26)

Kidney SMR: 1.30 (0.91, 1.86)

Bladder SMR: 0.95 (0.67, 1.35)

Bronchus, trachea, lung SMR: 1.42 (1.29, 1.57)*

Brain SMR: 0.92 (0.61, 1.38)

Selevan et al. 1985

Retrospective cohort study; n=1,987 male 

workers

Mean: 56.3 All cancer SMR: 0.95 (0.78, 1.14)

Digestive organs SMR: 0.77 (0.52, 1.10)

Respiratory system SMR: 1.11 (0.80, 1.51)

Kidney SMR: 2.04 (0.75, 4.44)

Bladder SMR: 1.44 (0.53, 3.14)

Steenland and Boffetta 2000

Meta-analysis; data from eight studies on Pb 

workers; n=36,027 workers

Range of study means: 26–80 Lung RR: 1.14 (1.04, 1.25)*

Stomach RR: 1.34 (1.14, 1.57)*

Brain RR: 1.06 (0.81, 1.40)

Steenland et al. 1992

Cohort study (same cohort as Selevan et al. 

1985); n=1,990 male smelter workers

Mean: 56.3 All Cancer SMR: 0.98 (0.84, 1.12)

Colon SMR: 0.48 (0.22, 0.90)

Lung SMR: 1.18 (0.92, 1.48)

Kidney SMR: 1.93 (0.88, 3.67)
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Table 2-46. Summary of Epidemiological Studies Evaluating Cancer Endpoints and Blood Lead Concentration 

(PbB)

Reference and study population PbB (μg/dL) Cancer outcomes Effectsa

Steenland et al. 2017

Cohort study; n=88,000 Pb workers 

Median: 26 Bladder (>40 μg/dL) HR: 1.86 (1.04, 3.33)*

Kidney (>40 μg/dL) HR: 1.21 (0.74, 1.97)

Larynx (>40 μg/dL) HR: 2.69 (1.07, 6.76)*

Lung (20–<30 μg/dL) HR: 1.39 (1.19, 1.64)*

Stomach (20–<40 μg/dL) HR: 1.62 (1.13, 2.32)*

Steenland et al. 2019

Cohort study; n=29,874 Pb workers

Median: 29 Brain (>40 μg/dL) HR: 1.71 (0.94, 3.12)

Bladder (>40 μg/dL) HR: 1.24 (0.87, 1,75)

Esophagus (30–39 μg/dL) HR: 2.00 (1.08, 3.71)*

Kidney (>40 μg/dL) HR: 1.00 (0.66, 1.51)

Larynx (>40 μg/dL) HR: 1.92 (0.94, 3.91)

Lung (20–29 μg/dL) HR: 1.39 (1.17, 1.65)*

Rectum (>40 μg/dL) HR: 1.49 (1.03, 2.17)*

Stomach (20–29 μg/dL) HR: 1.55 (1.10, 2.18)*

Wong and Harris et al. 2000

Cohort study; n=4,519 battery workers; 

2,300 smelters (same cohort as Cooper et 

al. 1985)

Mean:

• All workers: 64.0

• Battery workers: 62.7

• Smelters: 79.7

All cancer SMR: 1.045 (1.012, 1.080)*

Stomach SMR: 1.474 (1.125, 1.898)*

Large intestine SMR: 0.994 (0.789, 1.235)

Bronchus, trachea, lung SMR: 1.164 (1.039, 1.299)

Kidney SMR: 0.636 (0.339, 1.087)

CNS SMR: 0.748 (0.419, 1.234)

aAsterisk and bold indicate association with Pb; unless otherwise specified, values in parenthesis are 95% CIs; p-values <0.05 unless otherwise noted in the 

table.

CI = confidence interval; CNS = central nervous system; HR = hazard ratio; MM = multiple myeloma; NHANES = National Health and Nutrition Examination 

Survey; NHL = non-Hodgkin’s lymphoma; OR = odds ratio; Pb = lead; PMR = proportionate mortality ratio; RR = rate ratio or relative ratio; SD = standard 

deviation; SE = standard error; SMR = standard mortality ratio
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2011; Partanen et al. 1991; Pesch et al. 2000; Rajaraman et al. 2006; Risch et al. 1988; Rousseau et al. 

2007; Sankila et al. 1990; Sheffet et al. 1982; Siemiatycki 1991; Sweeney et al. 1986; van Wijngaarden 

and Dosemeci 2006; Wingren and Englander 1990). Although results of these studies are mixed and 

interpretation may be limited due to confounding factors, associations have been reported between 

occupational exposure to Pb and cancer, including overall cancer mortality and cancers of the lung, brain, 

stomach, kidney, and bladder. 

Mechanisms of Action. Numerous mechanisms for Pb-induced carcinogenicity have been proposed 

(EPA 2014c); however, it is likely that a combination of mechanisms, rather than a single mechanism, is 

involved. Although Pb is considered to be only weakly mutagenic, it has been shown to produce DNA 

damage (single and double strand breaks), sister chromatid exchanges (SCEs), chromosome aberrations, 

micronuclei (MN) formation, and cytogenetic damage. Epigenetic mechanisms (e.g., changes in gene 

expression in the absence of changes to DNA), post-translational alterations to protein structure, and 

immune modulation of tumorigenesis in response to Pb-induced ROS oxidative damage and inflammation 

have also been proposed as possible mechanisms involved in Pb-induced carcinogenesis.

2.20 GENOTOXICITY

The genotoxicity of Pb has been studied in Pb workers and the general population, in in vivo animal 

models, and in vitro cultures of microorganisms and mammalian cells. For the following discussions, 

data from epidemiological studies on genotoxicity were obtained from the primary literature. Information 

on in vitro studies and in vivo animal studies was taken from comprehensive reviews of Pb genotoxicity 

(EPA 2014c; Garcia-Leston et al. 2010; IARC 2006; NTP 2003). 

Epidemiological Studies

Overview. Epidemiological studies have examined genotoxic effects associated with Pb exposure in 

adults (general populations and workers) and children. Most studies were conducted in small populations 

of workers. Numerous studies with PbB ≥10 μg/dL report associations for exposure to Pb and genotoxic 

endpoints (gene mutation, DNA damage, SCE, MN formation, and DNA methylation), although some 

inverse associations have been reported. Few epidemiology studies have evaluated genotoxicity at PbB 

≤10 μg/dL.
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The following genotoxic effects have been associated with PbB: 

• ≤10 μg/dL:

o Gene mutation.

o DNA damage; evaluated in a few studies with mixed results.

o DNA methylation; positive results, corroborated in a few studies.

• >10 μg/dL:

o DNA damage; corroborated in numerous studies.

o Decreased telomere length.

o Chromosomal aberrations; evaluated in numerous studies with mainly positive results.

o Sister chromatid exchange; evaluated in numerous studies with mainly positive results.

o Micronuclei formation; evaluated in numerous studies with mainly positive results.

o DNA methylation.

Measures of Exposure. Studies evaluating the association between genotoxic effects and Pb exposure 

typically evaluate exposure by measurement of PbB.

Confounding Factors and Effect Modifiers. Most epidemiological studies evaluating genotoxic effects 

were conducted in worker populations. Therefore, potential co-exposure to other genotoxic compounds 

(such as arsenic) could occur, complicating interpretation of results. In addition, many studies were 

conducted in small populations (n<100). Variable outcomes of genotoxicity studies in human populations 

may derive from the influence of experimental variables that may act as confounders, such as duration 

and route of Pb exposure, cell culturing time following the exposure, smoking habits, and simultaneous 

exposure to other toxic agents that could act by modifying the genotoxic response of the cells to Pb

exposure and similarly, modifying the results of the studies (García-Lestón et al. 2010).

Characterization of Effects. General trends for studies demonstrating associations between PbB and 

genotoxic effects are shown in Table 2-47. Additional study details are provided in the Supporting 

Document for Epidemiological Studies for Lead, Table 14. Although few studies have evaluated 

genotoxic effects at PbB ≤10 μg/dL (see discussion below), numerous studies in adult workers with mean 

PbBs ranging from 20 to >50 μg/dL provide evidence of increased DNA damage, chromosomal 

aberrations, SCEs, and MN. One study reported decreased telomere length in workers (Pawlas et al. 

2016). A few studies in workers reported negative findings for chromosomal aberrations (Anwar and 

Kamal 1988; Bulsma and DeFrance 1976; Mäki-Paakkanen et al. 1981; Schwanitz et al. 1975) and SCEs 
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(Grandjean et al. 1983; Mäki-Paakkanen et al. 1981); however, positive results for these endpoints were 

reported in other studies at similar PbBs.

Table 2-47. Overview of Epidemiology Studies Evaluating Genotoxicity 

Associated with Chronic Exposure to Lead (Pb)

Mean PbB 

(μg/dL)

Effects associated with Pb 

exposure References

≤10 Gene mutation Van Larebeke et al. 2004

DNA damage/repair Akram et al. 2019; Jasso-Pineda et al. 2012; 

Decreased telomere length Pawlas et al. 2015

MN Mielzynska et al. 2006; Wu et al. 2017

DNA methylation Hanna et al. 2012; Li et al. 2016b; Pilsner et al. 2009

>10–30 DNA damage/repair Chinde et al. 2014; Danadevi et al. 2003; Dobrakowski et al. 

2017; Jannuzzi and Alpertunga 2016; Kašuba et al. 2012; 

Kayaalti et al. 2015b; Méndez-Gómez et al. 2008; Shaik and 

Jamil 2009

Chromosomal aberrations Pinto et al. 2000

SCE Anwar and Kamal 1988; Pinto et al. 2000

MN Chinde et al. 2014; Khan et al. 2010b; Kašuba et al. 

2012;Nordenson et al. 1978; Pinto et al. 2000

>30–50 DNA damage/repair Dobrakowski et al. 2017; Fracasso et al. 2002; Grover et al. 

2010; Pawlas et al. 2017

Decreased telomere length Pawlas et al. 2016

Chromosomal aberrations Forni et al. 1976; Grover et al. 2010; Schwanitz et al. 1970

SCE Duydu et al. 2001, 2005; Wiwanitkit et al. 2008; Wu et al. 

2002

MN Grover et al. 2010; Hamurcu et al. 2001; Minozzo et al. 2004

DNA methylation Devoz et al. 2017

>50 DNA damage/repair de Restrepo et al. 2000

Chromosomal aberrations Al-Hakkak et al. 1986; Forni et al. 1976; Huang et al. 1988; 

Nordenson et al. 1978; Schwanitz et al. 1970

SCE Huang et al. 1988

MN Shaik and Jamil 2009; Singh et al. 2013; Vaglenov et al. 

1998, 2001

DNA = deoxyribonucleic acid; MN = micronuclei; PbB = blood lead concentration; SCE = sister chromatid exchange

Results of genotoxicity studies conducted in small populations of children (n=12–103) are inconsistent; 

for study details, see the Supporting Document for Epidemiological Studies for Lead, Table 14. Mixed 

results were observed for studies on DNA damage, with positive associations at mean PbBs of 7.3 and 

28.5 μg/dL (Méndez-Gómez et al. 2008; Jasso-Pineda et al. 2012) and no associations at a mean PbB of 

19.5 μg/dL (Méndez-Gómez et al. 2008). No associations were observed for chromosome aberrations at 
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a PbB range of 12–33 μg/dL (Bauchinger et al. 1977) and for SCE at mean PbBs of 7.69 and 62.7 μg/dL 

(Dalpra et al. 1983; Mielzynska et al. 2006). MN formation was positively associated with a mean PbB 

of 7.69 μg/dL (Mielzynska et al. 2006), and altered DNA methylation was found in newborns at mean 

umbilical cord PbB of 6.6 μg/dL (Pilsner et al. 2009) and mean prenatal maternal RBC Pb of 1.2 μg/dL 

(Wu et al. 2017).

Effect at Blood Pb Levels ≤10 μg/dL. Results of studies evaluating genotoxic effects of PbB ≤10 μg/dL 

are summarized in Table 2-48, with study details provided in the Supporting Document for 

Epidemiological Studies for Lead, Table 14. Few studies have evaluated genotoxicity at PbB ≤10 μg/dL. 

Some endpoints were only evaluated in a single study; therefore, it is difficult to draw conclusions. With 

the exception of a large study conducted in NHANES participants (Zota et al. 2015), genotoxic effects 

were evaluated in small study populations (n=12–103). Gene mutations were observed in a single study 

of Finnish women at a PbB range of 1.6–5.2 μg/dL (Van Larebeke et al. 2004). Results of studies on 

DNA damage are mixed, with no associations in adult workers at PbB means of 2.1–4.4 μg/dL (Al 

Bakheet et al. 2013; Hengstler et al. 2003), and positive associations in a small study of children with a 

mean PbB of 7.3 μg/dL (Jasso-Pineda et al. 2012). No effect on telomere length was observed in a large 

NHANES study of adults with a mean PbB of 1.67 μg/dL (Zota et al. 2015). No associations were 

observed for SCE in a single study in workers with a mean PbB of 9.3 μg/dL and for MN in children with 

a mean PbB of 7.69 μg/dL (Mielzyńska et al. 2006; Wu et al. 2002). Studies on DNA methylation 

showed positive associations in adult women undergoing in vitro fertilization (median PbB 2.88 μg/dL), 

in children (mean PbB: 1.36 μg/dL), and in newborns (mean umbilical cord PbB 6.6 μg/dL or prenatal 

maternal RBC Pb 1.2 μg/dL) (Hanna et al. 2012; Li et al. 2016b; Pilsner et al. 2009; Wu et al. 2017).

In Vivo Animal Models and In Vitro Cultures of Mammalian Cells and Microorganisms. Numerous 

studies have investigated the genotoxicity of Pb using in vivo animal models and cultured mammalian 

cells and microorganisms. Rather than reviewing these numerous studies, an overview of findings is 

summarized below. This information was taken from the following reviews: EPA 2006, 2014c; IARC 

2006; NTP 2016.

In vivo studies in animals. DNA damage has been observed in several in vivo exposure studies in rodents. 

DNA damage (single strand breaks), as measured in comet assays, was observed in various organ 

systems, bone marrow, leukocytes, and spermatozoa of mice and rats following repeated inhalation or 

oral exposures to Pb or Pb acetate. Many of these studies administered Pb by parenteral routes 

(intravenous, intraperitoneal). Narayana and Al-Bader (2011) and Narayana and Raghupathy (2012) did 
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Table 2-48. Results of Genotoxicity Studies at Blood Lead Concentration (PbB) ≤10 μg/dL

PbB or range 

(μg/dL) Population (n)

Gene 

mutation

DNA 

damage

Telomere 

length SCE MN

DNA 

methylation Reference

1.6–5.2 Women (99) ↑ NA NA NA NA NA Van Larebeke et al. 2004

2.1 Men (40) NA 0 NA NA NA NA Al Bakheet et al. 2013

3.28 Children (99) NA NA ↓ NA NA NA Pawlas et al. 2015

4.4 Workers (78) NA 0 NA NA NA NA Hengstler et al. 2003

7.3 Children (12) NA ↑ NA NA NA NA Jasso-Pineda et al. 2012

1.67 Adults (6,796)a NA NA 0 NA NA NA Zota et al. 2015

9.3 Workers (34) NA NA NA 0 NA NA Wu et al. 2002

7.69 Children NA NA NA NA 0 NA Mielzyńska et al. 2006

>0.73 Women (43) NA NA NA NA NA ↓ Hanna et al. 2012

1.45 Adults (78)b NA NA NA NA NA ↓ Li et al. 2016b

6.6c Newborns (103) NA NA NA NA NA ↑↓ Pilsner et al. 2009

8 Workers (100) NA ↑ NA NA NA NA Akram et al. 2019

1.2d Newborns (268) NA NA NA NA ↓ Wu et al. 2017

aNHANES participants.

bProspective study; genotoxicity assessed in adults and evaluated against PbB obtained during childhood (birth–78 months). cUmbilical cord PbB.

dMaternal RBC lead at gestation week 28. 

↑ = increase observed for specific effect; ↓ = decrease observed for specific effect; ↑↓ = decreased DNA methylations at some differentially methylated regions, 

and increased DNA methylation at other regions; 0 = no effect observed; DNA = deoxyribonucleic acid; MN = micronuclei; NA = not assessed; 

NHANES = National Health and Nutrition Examination Survey; RBC = red blood cell; SCE = sister chromatid exchange
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not find DNA damage in rats that received oral doses of lead nitrate at levels that produced necrotic 

changes in the liver. Global hypomethylation in hepatic DNA of rats was observed following single 

intravenous injection of Pb nitrate; hypomethylation was associated with an increase in cell proliferation. 

Exposure to Pb compounds is correlated with increased DNA synthesis and cell proliferation in the 

mammalian liver following intravenous injection. Numerous studies have assessed Pb compounds for 

chromosomal damage. Chromosomal aberrations were observed in bone marrow cells and spermatocytes 

of mice and rats following single or repeated exposure (intraperitoneal, gavage, dietary); however, the 

increase in aberrations did not consistently demonstrate dose-dependence. 

Exposure to Pb compounds has been associated with SCEs in bone marrow of mice and rats following 

intravenous exposure. Studies assessing Pb compounds for MN formation in bone marrow erythrocytes 

of rats and mice were positive for multiple exposure routes (gavage, drinking water, intraperitoneal). 

In vitro studies in human cell lines. In vitro studies in human cells lines have yielded mixed results. Pb 

acetate was weakly mutagenic in keratinocytes in the presence of 6-thioguanine, but not mutagenic in 

human foreskin, fibroblasts, or lung carcinoma cells. Results of assays assessing Pb compounds for DNA 

damage in human cell cultures were inconsistent. Double or single DNA strand breaks have been 

observed in peripheral blood lymphocytes, endothelial cells, hTERT-immortalized human skin 

fibroblasts, and HepG2 cells, but not in HeLa cells. DNA-protein crosslinks were observed in lymphoma 

cells exposed to 100 μM Pb acetate, although cross-links were not observed for Pb nitrate at 

concentrations up to 10,000 μM. Studies investigating SCEs and MN formation in human lymphocytes 

were positive following exposure to Pb nitrate and Pb chloride; however, no SCEs were observed in 

human lung cells or primary lymphocytes exposed to Pb. Interpretation of in vitro studies is challenging 

because concentrations used in these studies typically are very high and are not relevant to environmental 

or occupational exposures. As discussed in Section 3.1.2 (Toxicokinetics, Distribution), >99% of Pb in 

blood is bound to erythrocytes, leaving <1% available in plasma. Thus, plasma levels of Pb are far lower 

(at least two orders of magnitude) than the concentrations examined in in vitro studies in human cell lines. 

This leads to the introduction of considerable bias when interpreting study results (Bannon and Williams 

2017).

In vitro studies in prokaryotic and mammalian cells. Mutagenicity tests of Pb compounds in prokaryotic 

organisms have mostly yielded negative results. Studies assessed gene mutation and DNA damage in 

Salmonella typhimurium, Escherichia coli, and Bacillus subtilis and gene conversion and mitotic 

recombination in Saccharomyces cerevisiae in the presence or absence of metabolic activation. The only 
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Pb compound that yielded positive results for gene mutation in S. typhimurium and E. coli was Pb 

bromide. Results of in vitro studies in mammalian cells for Pb compounds are mixed. Mutagenicity 

assays (hypoxanthine phosphorybosyl transferase [HPRT] and glutamate pyruvate transaminase [gpt] 

assays) were mutagenic in Chinese hamster ovary (CHO) and CHV79 cells at higher concentrations 

(>100 μM) and negative at lower concentrations (<100 μM). Pb chloride was the only Pb compound that 

was consistently mutagenic (gpt assay) in CHO cells at low concentrations (0.1–1.1 μM; equivalent to 

2.3–23 μg/dL). Comet assays assessing Pb acetate for DNA damage (single strand breaks) in 

undifferentiated PC12 cells and mouse bone marrow mesenchymal stem cells were positive. 

Concentration-dependent increases in DNA-protein crosslinks were observed in hepatoma cells exposed 

to Pb nitrate, although Pb acetate did not induce single or double DNA strand breaks or DNA crosslinks 

in CHV79 cells. Exposure to Pb nitrate or Pb glutamate did not induce chromosomal aberrations in CHO 

cells. Assays assessing Pb compounds for SCEs in CHV79 cells were negative when fewer cells per 

concentrations were utilized (25–30 cells), but were positive when the number of cells per concentration 

was increased (100 cells). Conflicting results were reported for MN formation in Chinese hamster cells. 

Mechanisms of Action. Several mechanisms of action are likely involved in the genotoxic effects of Pb 

(EPA 2014c; IARC 2006; NTP 2016). Studies in occupationally exposed populations have found 

significant correlations between DNA breaks, decreased glutathione levels in the lymphocytes, and 

increased production of ROS, which may indicate oxidative stress as a possible mechanism for this 

response. The production of ROS after Pb exposure is a multi-pathway process, which results from 

oxidation of ALA, membrane and lipid oxidation, NAD(P)H oxidase activation, and antioxidant enzyme 

depletion. Disruption of functional metal ions that form enzymes (superoxide dismutase [SOD], catalase 

[CAT], and glutathione peroxidase [GPx]) may occur as part of this process.

2.21 GENERAL CELLULAR MECHANISMS OF ACTION

2.21.1 Perturbation of Ion Homeostasis

Pb exerts many of its adverse effects by perturbing ion homeostasis. This perturbation occurs when Pb

displaces other metal ions such as iron, calcium, zinc, magnesium, selenium, and manganese, interfering 

with the critical biological processes mediated by the ions themselves or by enzymes and proteins that 

require these ions (reviewed by EPA 2014c; Flora et al. 2012). Among the biological processes that Pb

has been shown to affect via its impact on ion homeostasis are: calcium homeostasis; transportation of 
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ions across cell membranes; cellular energetics; and the functioning of numerous proteins involved in cell 

signaling, growth and differentiation, gene expression, energy metabolism, and biosynthetic pathways.

Calcium Homeostasis. Many of Pb’s adverse effects can be traced back to its ability to displace calcium, 

leading to perturbations of numerous calcium-dependent cellular functions, including energy metabolism, 

apoptosis, cellular motility, signal transduction, and hormonal regulation (reviewed by EPA 2014c). In 

addition, intracellular migration of Pb has been shown in several cell lines (HEK293, HeLa, and PC12) to 

occur via calcium channels; higher Pb permeation correlated with lower calcium concentrations, 

suggesting that Pb competed with calcium for the channel binding sites. 

Ion Transport. Pb has been shown to disrupt the transportation of critical cations across the cell 

membrane by decreasing the activity of ATPases (including Na+/K+-, Ca2+, and Mg2+-ATPases; 

reviewed by EPA 2014c). Pb-induced inhibition of ATPase activities has been shown in the kidneys, 

livers, erythrocytes, and brain synaptosomes of rats exposed to Pb in drinking water; in testes of rat pups 

exposed during lactation and postweaning; in primary cerebellar granule neuronal cultures of rat pups 

exposed pre- and postnatally; in rabbit kidney membranes and sarcoplasmic reticulum exposed in vitro; 

and in human erythrocyte ghosts. Furthermore, blood or hair Pb levels were inversely correlated with 

ATPase activities in erythrocytes in several human epidemiological studies. 

In addition to ATPases, Pb’s action on ion transport includes competitive inhibition of voltage-gated 

calcium channels (reviewed by EPA 2014c). A number of in vitro studies have demonstrated inhibition 

of calcium transport via voltage gated channels in cultured neurons and neuroblastoma cells, bovine 

adrenal chromaffin cells, and human embryonic kidney cells. Inhibition of calcium transportation via 

voltage-gated channels can disrupt release of neurotransmitters, and impaired neurotransmitter release 

has, in fact, been shown with Pb exposure at low in vitro levels. In addition to inhibiting calciumdependent neurotransmitter release, Pb may mimic calcium, thereby increasing neurotransmitter release in 

some circumstances. For example, Pb exposure in vitro has been shown to induce the spontaneous 

release of norepinephrine from bovine adrenal chromaffin cells and increase the release of catecholamine 

from PC12 cells. It has been suggested that Pb may trigger spontaneous neurotransmitter release via 

activation of calcium/calmodulin-dependent protein kinase II-dependent phosphorylation of synapsin I, or 

by directly activating synaptotagmin I (a calcium-sensing protein that regulates neurotransmitter release). 

Intracellular migration of Pb has been shown to occur via calcium channels; higher Pb permeation in 

several cell lines (HEK293, HeLa, and PC12) correlated with lower calcium concentrations, suggesting 

that Pb competed with calcium for the channel binding sites. 
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Pb also disrupts the activity of calcium-dependent potassium channels, as shown by increased efflux of 

potassium from inverted erythrocyte vesicles, and alterations in potassium channel activation in 

erythrocytes exposed to Pb (reviewed by EPA 2014c). The nature of the effect on potassium channels is 

dose-dependent; at low Pb concentrations (<10 μM), potassium channels are activated, while inhibition of 

the channels is seen at higher Pb concentrations. As with calcium channels, alterations in potassium 

channel activity may also disrupt neurotransmitter release. In rats exposed to Pb in utero and postnatally, 

potassium-stimulated release of hippocampal GABA was decreased at low exposure levels, but enhanced 

GABA release was observed at higher exposures (in the absence of calcium). 

Cellular Energetics. Evidence indicating that Pb exposure perturbs mitochondrial function and cellular 

energy metabolism is abundant (as reviewed by EPA 2014c). In rats exposed to Pb via diet or drinking 

water, renal tubular and epididymal mitochondria exhibited swelling, rupture of the outer membrane, 

distorted cristae or loss of cristae, vacuolization, inclusion bodies, and fusion with nearby mitochondria. 

As discussed further in Section 2.21.6, Apoptosis, Pb exposure has been shown to open the mitochondrial 

transmembrane pore, initiating the apoptotic caspase cascade. Evidence for Pb’s effect on energy 

metabolism includes decreased ATP levels and/or adenylate energy charge (AEC) (along with increased 

ADP, AMP, and/or adenosine levels) in forebrain synaptosomes from rats exposed via drinking water, in 

cerebellar granule neuronal cultures from rats exposed by drinking water, in PC-12 cells exposed in vitro, 

and in isolated mitochondria exposed in vitro. In osteoblasts exposed in vitro, Pb inhibited both coupled 

and uncoupled respiratory oxygen use in mitochondria. Pb has been proposed to behave as a classic 

chemical uncoupler of respiration, abolishing the proton gradient necessary for oxidative phosphorylation. 

In the muscles of rats exposed to Pb in drinking water, decreased activities of the enzymes of complex I 

and IV of the respiratory chain were observed. However, in forebrain synaptosomes from rats exposed to 

Pb in vivo, oxidative phosphorylation was not inhibited, despite the fact that ATP levels were decreased. 

Pb may affect cellular energetics via perturbation of the glycolysis pathway. Decreased glycolysis was 

observed in osteoblasts and erythrocytes exposed to Pb in vitro (reviewed by EPA 2014c). However, 

increased levels of glycolytic enzymes were noted in workers with higher blood Pb levels, when 

compared with workers with lower blood Pb, suggesting that Pb may activate anaerobic glycolysis. 

Depletion of cellular nucleotide pools required for ATP synthesis has also been observed after Pb

exposure of human erythrocytes in vitro and in rats exposed via drinking water (reviewed by EPA 2014c). 

This effect may be mediated by Pb-induced inhibition of enzymes involved in nucleotide biosynthesis in 
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erythrocytes, including adenine phosphoribosyltransferase (see Impaired Protein Function below) and 

NAD synthetase (which depends on magnesium for activity). In support of the latter mechanism, in 

humans exposed to Pb, PbB levels were inversely correlated with NAD synthetase activity.

Impaired Protein Function. Pb impairs the functions of numerous proteins, with concomitant effects on 

signaling, growth and differentiation, gene expression, energy metabolism, and biosynthetic pathways. 

The mechanisms by which Pb alters protein activity are by displacing metal cofactors or binding to 

sulfhydryl groups (reviewed by EPA 2014c). Table 2-49 shows proteins known to be bound to or 

otherwise altered by Pb, along with their functions and brief summaries of the evidence for Pb-induced 

alterations. As the table suggests, Pb-induced alterations in proteins may play a role in its adverse effects 

on the neurological, hematological, cardiovascular, and skeletal systems. 

Through its displacement of calcium, Pb perturbs the function of several calcium-dependent proteins, 

including protein kinase C, calmodulin, osteocalcin, the mitochondrial transmembrane pore, and 

NAD(P)H oxidase (reviewed by EPA 2014c). The protein kinase C family of enzymes is important to 

cell signaling, growth, and differentiation. Pb exposure has been shown to activate PKC in a number of 

cell types tested in vitro (see table), and to decrease its activity in mouse macrophages and rat brain 

cortex. Pb stimulates calmodulin activity, as shown by increased activity of several calmodulindependent enzymes, and increased binding of calmodulin to brain membranes. In experiments testing the 

affinity of metal cations to bind calmodulin, Pb was more potent than mercury, cadmium, iron, and even 

calcium. Pb binding to calmodulin has been postulated as a mechanism for its stimulatory effect on 

Ca2+/Mg2+ ATPase. Calmodulin plays an essential role in maintaining calcium homeostasis and 

regulating calcium-dependent cell signaling important to structural integrity, gene expression, and 

maintaining membrane potential (reviewed by EPA 2014c). 

Skeletal effects of Pb may be mediated in part by Pb’s interference with another calcium-dependent 

protein: osteocalcin (reviewed by EPA 2014c). The binding of Pb to osteocalcin is much stronger than 

binding of calcium, and Pb binding alters the structure of osteocalcin. The conformational change in 

osteocalcin induced by Pb has been postulated as the mechanism by which Pb exposure diminishes the 

adsorption of osteocalcin to hydroxyapatite.
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Table 2-49. Effects of Lead (Pb) on Function of Various Proteins

Protein General function Effect of Pb; summary of evidence

Calcium-dependent proteins

Calcium binding proteins 

(CABPs I and II)

Regulation of calcium 

signaling, especially in 

neuronal cells

No data

-Ca2+ displacement shown in vitro.

Ca2+-dependent K+

channel 

Ion transport; activation of 

channels regulates neuron 

firing and neurotransmitter 

release

Activates or inhibits channel

-Pb promoted efflux of K+ from inverted red blood cell vesicles.

-Pb induced activation of K+ channel in erythrocytes at low Pb concentrations and 

inhibited activity at high concentrations.

Calmodulin Cell signaling, including 

structural integrity, gene 

expression, and maintenance 

of membrane potential

Amplifies calmodulin activity

-Pb activated calmodulin-dependent phosphodiesterase and cyclic nucleotide 

phosphodiesterase activities.

-Pb stimulated brain membrane phosphorylation. 

-Pb increased binding of calmodulin to brain membranes. 

Mitochondrial 

transmembrane pore 

(MTMP)

Triggers mitochondrial 

apoptosis cascade when open

Opens MTMP, triggering apoptosis 

-Pb increased mitochondria-regulated apoptotic indicators (cytochrome c, caspases) 

in rat retinal rod cells and hepatic oval cells in vitro.

NAD(P)H oxidase Inflammatory mediator; triggers 

oxidative burst (via production 

of superoxide) in response to 

infection

Increases activity, leading to ROS generation

-Pb increased protein levels of glycosylated subunit of NAD(P)H oxidase in brain, 

heart, and renal cortex of rats exposed via drinking water and in human coronary 

artery endothelial cells in vitro.

Osteocalcin Bone resorption, osteoclast 

differentiation, and bone 

growth

Alters binding of osteocalcin to hydroxyapatite

-Pb exposure has been shown to both increase and decrease binding of osteocalcin 

to hydroxyapatite.

Parvalbumin Unclear; may buffer Ca2+

levels; expressed at high levels 

in interneurons

No data

-Ca2+ displacement shown in vitro.

Phospholipase A2 Hydrolyze fatty acids from 

membrane phospholipids; 

released fatty acids are 

metabolized to bioactive lipid 

mediators

No data

-Ca2+ displacement shown in vitro.
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Table 2-49. Effects of Lead (Pb) on Function of Various Proteins

Protein General function Effect of Pb; summary of evidence

Protein kinase C (PKC) Cell signaling, especially 

growth and differentiation

Increases or decreases activity

-Pb shown to activate PKC in vitro in bovine adrenal chromaffin cells, rat brain 

microvessels, human erythrocytes, and rabbit mesenteric arteries.

-Pb decreased PKC activity in mouse macrophages and rat brain cortex. 

Synaptotagmin I Ca2+ sensor regulating 

neurotransmitter release

No data

-Ca2+ displacement shown in vitro.

Troponin C Ca2+ sensor regulating muscle 

contraction

No data

-Ca2+ displacement shown in vitro.

Heme-dependent proteins

Catalase Antioxidant; scavenger of 

hydrogen peroxide

Increases or decreases activity

-Pb shown to increase activity in some studies and decrease activity in others, 

possibly due to differences in species, exposure duration, dose, or other study design 

variations.

Guanylate cyclase Catalyzes synthesis of cGMP, 

which stimulates 

vasorelaxation in vascular 

tissues 

Impairs production of cGMP

-Pb reduced cGMP in plasma and urine of rats exposed by drinking water.

-Pb decreased protein levels of soluble guanylate cyclase in vascular tissue.

Hemoglobin Oxygen transportation Impairs heme production needed for synthesis of hemoglobin

-Pb binding to hemoglobin demonstrated in human blood.

Magnesium-dependent proteins

Adenine and 

hypoxanthine/guanine 

phosphoribosyltransferases 

Recycling of nucleotides Inhibits activity

-Pb inhibited phosphoribosyltransferase activities in erythrocytes of rats exposed via 

drinking water and in human erythrocytes in vitro. 

NAD synthetase (Mg) Nucleotide biosynthesis Decreases activity

-Blood Pb was inversely correlated with NAD synthetase activity in humans.

Pyrimidine 5'-nucleotidase Dephosphorylates pyrimidine 

nucleotides in erythrocytes, 

preserving purine nucleotides 

(e.g., ATP, ADP) necessary for 

energy

Alters protein conformation and amino acid positioning at active site, possibly by 

occupying active site

-Pb binding and protein conformation changes observed in vitro.

-Pyrimidine nucleotide accumulation in erythrocytes is seen in Pb poisoning.
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Table 2-49. Effects of Lead (Pb) on Function of Various Proteins

Protein General function Effect of Pb; summary of evidence

Zinc-dependent proteins 

δ-ALA (δ-ALAD or 

porphobilinogen synthase)

Heme biosynthesis (converts 

δ-ALA to porphobilinogen)

Depletes δ-ALAD, preventing heme biosynthesis and leading to accumulation of 

δ-ALA. 

- δ-ALAD shown to be major binding target of Pb in erythrocytes. 

GATA zinc finger proteins Activation/suppression of DNA 

transcription

Decreases ability of GATA proteins to bind to DNA and regulate transcription

-Pb binding to cysteine residues and displacement of Zn from GATA proteins 

observed in vitro. 

-Pb-bound GATA proteins exhibited reduced DNA binding.

Transcription factors 

TFIIIA, Sp1, and Erg-1

Activation/suppression of DNA 

transcription

Decreases ability of TFIIIA, Sp1, and Erg-1 to bind to DNA and regulate transcription

-Pb exposure caused dissociation of TFIIIA-DNA adducts.

-Pb exposure altered DNA binding profile of Sp-1 and Erg-1 in rat pups exposed via 

lactation, leading to changes in gene expression.

Proteins altered by lead interaction with other cations or sulfhydryl groups

ATPases (Ca2+-, Mg2+-, 

and Na+/K+-) 

Ion transport Decreases activity

-Pb decreased ATPase activities in brain, kidneys, liver, testes, and erythrocytes 

(cells or tissues).

cGMP phosphodiesterase 

(Zn, Mg)

Hydrolysis of cGMP Inhibits activity

-Decreased activity observed in homogenized bovine retinas exposed to Pb in vitro.

Ferrochelatase (Fe) Heme biosynthesis; 

incorporates Fe2+ into 

protoporphyrin IX to form heme

Inhibits insertion of Fe into protoporphyrin ring, leading to substitution by Zn 

-Zn-protoporphyrin levels correlated with blood Pb levels in humans.

Glutathione peroxidase 

and glutathione 

S-transferase (Se) 

Antioxidants Reduces uptake of Se and depletes cellular GSH and protein thiols, resulting in 

altered GST and GPx enzyme activities

-Decreased activity, often with compensatory upregulation of the enzymes, seen in 

Pb-exposed animals and humans.
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Table 2-49. Effects of Lead (Pb) on Function of Various Proteins

Protein General function Effect of Pb; summary of evidence

Metallothionein (Zn, Cu) Trace element homeostasis; 

free radical scavenging

Sequestered by metallothionein, providing protective effect

-Pb toxicity is seen at lower blood Pb levels in humans with low expression of 

metallothionein or low Pb binding to metallothionein.

-Pb induced production of metallothionein in mice exposed via intraperitoneal or 

intravenous injection and in rats exposed via intraperitoneal injection, but not in rats 

exposed via drinking water.

-Presence of zinc metallothionein reduced effect of Pb on membrane integrity in 

hepatocytes exposed in vitro.

-Pb nephrotoxicity and preneoplastic and neoplastic lesions in the testes, bladder, 

and kidneys were more severe or seen at increased incidences in metallothionein-null 

mice compared with wild-type.

Superoxide dismutase Antioxidant; catalyzes 

conversion of superoxide to 

hydrogen peroxide; inhibits 

oxidative inactivation of nitric 

oxide

Increased or decreased activity

-Pb shown to increase activity in several studies and decrease activity in others, 

possibly due to differences in species, exposure duration, dose, or other study design 

variations.

Thymosin β-4 Actin regulation; exerts 

angiogenic, anti-inflammatory, 

and cardioprotective effects on 

the heart

No data

-Pb binding observed in vitro.

ADP = adenosine diphosphate; δ-ALA = aminolevulinic acid; δ-ALAD = aminolevulinic acid dehydratase; ATP = adenosine triphosphate; ATPase = family of 

phosphatase enzymes that breakdown ATP and ADP; cGMP = cyclic guanosine monophosphate; DNA = deoxyribonucleic acid; Erg-1 = early growth response 

protein 1; GST = glutathione S-transferase; GSH = glutathione; GPx = glutathione peroxidase; NAD = nicotinamide adenine dinucleotide; NAD(P)H = the reduced 

form of nicotinamide adenine dinucleotide phosphate; ROS = reactive oxygen species; Sp1 = Transcription factor specificity protein 1; TFIIIA = transcription 

factor IIIA

Sources: EPA 2014c; Ahamed and Siddiqui 2007; Flora et al. 2012; Gonick 2011
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Other calcium-dependent proteins bound to or impaired by Pb include parvalbumin, phospholipase A2, 

synaptotagmin I (see Ion Transport above), troponin C, the mitochondrial transmembrane pore (see 

Section 2.21.6, Apoptosis), and NAD(P)H oxidase (see Section 2.21.3, Oxidative Stress) (reviewed by 

EPA 2014c).

Pb also displaces zinc in a number of critical proteins, including ALAD, GATA proteins, and several 

zinc-binding transcription factors (TFIIIA, Sp1, and Erg-1) (reviewed by EPA 2014c). Section 2.8 

provides a detailed discussion of Pb’s effects on ALAD and heme biosynthesis. Binding of Pb to zincbinding domains in GATA proteins and transcription factors inhibits their binding to DNA and impairs 

their ability to regulate gene expression (see Section 2.21.5, Epigenetic Effects, below for further detail).

Through competitive inhibition of magnesium-dependent proteins, Pb also affects the activities of adenine 

and hypoxanthine/guanine phosphoribosyltransferases, cyclic guanosine monophosphate (cGMP) 

phosphodiesterase, and pyrimidine 5’-nucleotidase (reviewed by EPA 2014c). In erythrocytes, adenine 

phosphoribosyltransferase catalyzes the synthesis of nucleotides via the adenine salvage pathway; Pb

exposure has been shown to decrease nucleotide pools in human erythrocytes in vitro and in erythrocytes 

from rats exposed via drinking water. Inhibition of cGMP phosphodiesterase, a magnesium-dependent 

enzyme regulating cGMP signaling in smooth muscle contraction and relaxation, has been observed in 

homogenized bovine retinas cultured with Pb. Pb inhibits magnesium binding in pyrimidine 

5’-nucleotidase, inhibiting its activity by changing its active site conformation. Pyrimidine 

5’-nucleotidase occurs at high levels in erythrocytes, where it dephosphorylates pyrimidine nucleotides 

while leaving purine nucleotides (used as an energy source in erythrocytes, as they lack mitochondria), 

intact. Basophilic stippling of erythrocytes, a common feature of Pb poisoning, is also seen in individuals 

with inherited pyrimidine-5’-nucleotidase deficiency (Rees et al. 2003), providing supporting evidence 

that Pb inactivates the enzyme. 

2.21.2 Protein Binding/Sequestration

A number of low molecular-weight proteins, including metallothionein, have been shown to bind 

(through thiol residues) to Pb, forming inclusion bodies in the kidney, liver, lung, and glial cells 

(reviewed by EPA 2014c; Gonick 2011). In the case of metallothionein, the effect of the binding is to 

sequester Pb, protecting the exposed cells and tissues. The strongest evidence for the protective effect of 

metallothionein comes from studies of metallothionein-null mice, which exhibit more severe Pb-induced 

renal toxicity, as well as increased incidences of neoplastic and nonneoplastic lesions in the testes, 
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bladder, and kidneys, compared with wild-type mice. Supporting this finding is the observation that 

higher blood Pb levels, as well as more pronounced Pb-induced effects on systolic blood pressure and 

kidney function, were observed in exposed workers with a metallothionein mutation (compared with 

those exhibiting a normal metallothionein genotype). Metallothionein levels have been shown to be 

induced by Pb exposure in mice and in rats pretreated with zinc. 

In erythrocytes, the major Pb-binding protein is ALAD; hemoglobin also binds Pb (reviewed by EPA 

2014c; Gonick 2011). In exposed humans, polymorphisms in the ALAD gene that increase the 

Pb-binding capacity of its protein product (e.g., ALAD-2) were observed to decrease blood Pb levels and 

biomarkers for Pb toxicity, including plasma levulinic acid, zinc protoporphyrin, cortical bone Pb levels, 

and dimercaptosuccinic acid-chelatable Pb levels. Other proteins that bind Pb in erythrocytes include 

pyrimidine 5’-nucleotidase and acyl-coenzyme A binding protein. 

In rat kidneys, inclusion bodies consisting of Pb-bound proteins have been observed in a number of 

studies (reviewed by EPA 2014c; Gonick 2011). These inclusion bodies are initially observed in the 

cytosol, but appear to translocate to the nucleus, as they disappear concomitantly with the appearance of 

intranuclear inclusion bodies. The primary Pb-bound protein in the kidney (a 32 kDa protein with an 

isoelectric point of 6.3, named p32/6.3) has not been identified, but has been shown to be enriched in the 

brain and is highly conserved across species (rats, mice, dogs, chickens, and humans). Studies in rats 

exposed by food or drinking water showed that p32/6.3 is not found in the kidneys of untreated rats but 

rather is induced by Pb exposure. Other Pb-binding proteins identified in the kidneys of rats or humans

include acyl-CoA binding protein and thymosin β-4 (the latter is involved in actin regulation).

2.21.3 Oxidative Stress

Pb exposure has resulted in oxidative damage in several tissues in humans and rats, including the brain, 

kidneys, reproductive organs, heart, and erythrocytes (reviewed by EPA 2014c; Ahamed and Siddiqui 

2007). Oxidative damage may play a role in Pb-induced toxicity in these tissues, including neurological 

effects, hypertension and other cardiovascular effects, and diminished fertility. Pb induces oxidative 

stress through several mechanisms, including increased production of ROS via inhibition of heme 

biosynthesis and activation of NAD(P)H oxidase; stimulation of lipid peroxidation and alteration of lipids 

enhancing their susceptibility to lipid peroxidation; and inactivation and/or depletion of antioxidant 

enzymes. Through the increased production of ROS, which sequesters nitric oxide, Pb exposure also 

leads to perturbation of nitric oxide signaling that is critical to vasodilation. 
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Exposure to Pb triggers increased production of ROS via its effects on heme biosynthesis. In 

erythrocytes, Pb has been shown to bind to δ-ALAD as well as to inhibit its activity by interfering with 

the zinc ions the enzyme requires for heme biosynthesis; in fact, inhibition of δ-ALAD activity is 

inversely correlated with PbB levels in humans (reviewed by EPA 2014c; Ahamed and Siddiqui 2007). 

δ-ALAD catalyzes the conversion of δ-ALA to porphobilinogen; thus, its inhibition results in 

accumulation of δ-ALA in blood and in urine. In these environments, δ-ALA undergoes autoxidation, 

yielding superoxide and hydroxyl radicals, as well as hydrogen peroxide and an ALA radical. In addition, 

through subsequent reduction of ferricytochrome c and transfer of electrons from oxyhemoglobin, 

methemoglobin, and ferric and ferrous iron complexes, oxidized δ-ALA also produces ROS. 

Pb may also increase intracellular ROS by upregulating expression of NAD(P)H oxidase, an enzyme that 

produces superoxide anion via reaction of NAD(P)H and molecular oxygen, but data are limited 

(reviewed by EPA 2014c). Increased protein expression of the glycosylated subunit of NAD(P)H oxidase 

was observed in tissues of rats exposed to Pb in drinking water, and in human endothelial cells in vitro. 

ROS produced via Pb effects on δ-ALA and/or NAD(P)H oxidase can damage membrane lipids through 

peroxidation. In addition, however, Pb has been shown to catalyze ferrous ion-initiated lipid peroxidation 

(reviewed by EPA 2014c). Furthermore, there is evidence that Pb exerts effects on membrane lipids that 

render them more vulnerable to peroxidation (reviewed by EPA 2014c; Ahamed and Siddiqui 2007). For 

example, Pb has been shown to alter the composition of fatty acids in chicks exposed by drinking water, 

such that a higher fraction of longer fatty acids (such as arachidonic acid) and lower fraction of shorter 

fatty acids (compared with controls) were observed. Oxidative potential of fatty acids is correlated with 

both length and desaturation (i.e., the number of double bonds; the hydrogen on a double bond is easier to 

remove). It has been proposed that Pb may stimulate both elongation and desaturation of fatty acids, 

increasing their susceptibility to peroxidation. Alterations in lipid composition may also affect membrane 

permeability and functions, including the activity of membrane-associated enzymes, solute transport 

functions, endo- and exocytosis, and signal transduction. 

Increased circulating ROS (specifically, superoxide anion) can inactivate nitric oxide, an endogenously 

produced molecule that plays an important role in vasodilation (reviewed by EPA 2014c). Depletion of 

nitric oxide has been observed in animals exposed to Pb, as well as in human and animal immune cells 

treated in vitro. In addition, nitric oxide depletion is believed to be the mechanism behind Pb-induced 

upregulation of nitric oxide synthases seen in vascular tissues after Pb exposure. Nitric oxide depletion 
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occurs when it reacts with superoxide anion to form the highly reactive peroxynitrite anion, which itself 

damages DNA and proteins. Levels of nitrotyrosine, which results from peroxynitrite-induced nitration 

of tyrosine residues in proteins, were increased in plasma and other tissues after in vivo exposure to Pb. 

In vascular tissues, nitric oxide induces vasorelaxation via cGMP signaling (reviewed by EPA 2014c). 

Exposure of rats to Pb in drinking water for 1–3 months markedly reduced cGMP levels in both blood 

and urine. Synthesis of cGMP is catalyzed by soluble guanylate cyclase, a heme-dependent enzyme. Pb

exposure has been shown to reduce protein levels of soluble guanylate cyclase in vascular tissues; 

alleviation of this effect by antioxidant treatment (ascorbic acid) demonstrated that this finding was 

mediated, at least in part, by increased oxidative stress. 

In human epidemiological studies, the ratio of oxidized glutathione (glutathione disulfide or GSSG) to 

reduced glutathione (GSH), a measure of oxidative stress, was positively correlated with blood Pb levels 

(reviewed by EPA 2014c; Ahamed and Siddiqui 2007; Flora et al. 2012). The effects of Pb on oxidative 

stress levels may occur through depletion of antioxidant levels in addition to stimulation of ROS, as 

oxidative stress occurs when the antioxidant capacity of the body is exceeded. Pb forms covalent bonds 

with sulfhydryl groups in antioxidant enzymes such as GSH, glutathione reductase (GR), and glutathione 

S-transferase (GST) (reviewed by EPA 2014c; Ahamed and Siddiqui 2007; Flora et al. 2012). In humans, 

animals, and in vitro studies, decreased GSH in blood and organs has been associated with Pb exposure. 

After long-term exposure to Pb, increased GSH levels, attributed to compensatory upregulation of GSH 

biosynthesis, have been reported. Like GSH, GR (which reduces GSSG back to GSH) and GST also have 

disulfides at their active site that could be bound by Pb. Studies examining GR and GST activity after Pb

exposure used varying study designs and showed both increases and decreases; it is not clear whether the 

differences in results reflect species, strain, dose, or duration differences. 

Pb’s capacity to compete with cations and its interference with heme biosynthesis have also been 

suggested as potential mechanisms for its ability to alter levels of SOD, CAT, GPx, and GST (reviewed 

by EPA 2014c; Flora et al. 2012; Ahamed and Siddiqui 2007). SOD forms require copper, zinc, or 

manganese, cations that Pb may displace, while catalase is a heme-dependent enzyme. Several studies in 

humans and animals have shown alterations in SOD and CAT activity, with some evidence for a 

nonlinear dose-response relationship. EPA (2014c) suggested that increased SOD and CAT may occur at 

low doses as a result of ROS generation by Pb, while at higher doses, Pb may inactivate the enzymes. Pb

exposure also alters activities of GPx and GST, potentially by reducing the uptake of selenium (required 

by GPx) and/or disrupting protein thiols (necessary for GST function). Decreased GPx and GST 
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activities have been observed, along with compensatory upregulation of these enzymes, in Pb-exposed 

humans and animals. 

2.21.4 Inflammation

Increasing oxidative stress through ROS generation and depletion of antioxidant enzymes may be one 

mechanism by which Pb induces an inflammatory response (reviewed by EPA 2014c). Inflammation, 

considered a hallmark of Pb exposure (EPA 2014c), may also be triggered by pro-inflammatory signaling 

and cytokine production. Inflammation has been seen after Pb exposure in many different cell types, as 

well as in the kidneys of rats exposed to Pb in drinking water.

Oxidative stress is known to activate the pro-inflammatory nuclear transcription factor kappa B (NFκB).

In the rat kidney, Pb-induced inflammation was accompanied by activation of NFκB as well as 

lymphocyte and macrophage infiltration (reviewed by EPA 2014c). Pb has been shown to stimulate the

expression of pro-inflammatory signal mediators including NFκB, activator protein-1 (AP-1), and c-Jun, 

and to stimulate phosphorylation of the Erk/MAPK pathway. In addition, exposure to Pb is associated 

with increased production of prostaglandins, which also mediate pro-inflammatory messaging. Increases 

in arachidonic acid production, leading to increases in prostaglandins E2 and F2 and thromboxane levels, 

have been seen in Pb-exposed workers as well as in animals and in cultured cells systems exposed to Pb. 

In vascular smooth muscle cells, Pb has been shown to activate phospholipase A2, which may explain its 

ability to stimulate the release of arachidonic acid. 

In both human epidemiological and laboratory animal studies, Pb exposure has been demonstrated to 

increase cytokine production (reviewed by EPA 2014c). In these studies, a fairly consistent picture of 

decreasing Th-1 cytokines and increasing Th-2 cytokines has emerged. EPA (2014c) outlined three 

modes by which Pb influences cytokine production: (1) direct action on macrophages to increase proinflammatory cytokines such as TNF-α and interleukin 6 (IL-6); (2) skew the ratio of IL-12 to IL-10, 

leading to suppression of Th-1 cell responses and stimulation of Th-2 cell responses; and (3) during 

acquired immune response occurring after Pb exposure, production of cytokines by Th-1 lymphocytes is 

suppressed, and Th-2 cytokines are increased. The net result of these changes is consistent with the proinflammatory picture seen with Pb exposure. 

Human epidemiological studies have provided evidence that Pb exposure skews immune responses 

toward Th-2 pro-inflammatory responses (reviewed by EPA 2014c). Higher blood Pb levels in children 
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were associated with increased serum levels of Il-4 (which induces differentiation of Th0 cells to the Th-2 

phenotype) and lower levels of interferon gamma (IFN-γ). In adult students in Korea, higher blood Pb

levels were positively associated with increased TNF-α and IL-6; a 1 μg/dL increase in blood Pb was 

associated with a 23% increase in log TNF-α and a 26% increase in IL-6. Finally, in occupationallyexposed workers, higher blood Pb levels were associated with increases in IL-2, IL-10, IL-6, TNF-α, and 

granulocyte colony stimulating factor (G-CSF), and, in one study, lower levels of Th-1 cytokines IL-1β 

and IFN-γ. Similar effects were seen in mice exposed to Pb in feed; blood levels of Th-1 cytokines (IL-2 

and IFN-γ) were decreased at low dietary doses, while increases in IL-4 were seen as the Pb dose 

increased. Based on these data, EPA (2014c) suggested that the immune system response to Pb may 

exhibit nonlinearities at low doses. In rats exposed to Pb via intraperitoneal injection, increased levels of 

TNF-α were seen in the hippocampus, and increased IL-6 was noted in the forebrain. In vitro data have 

also shown alterations in cytokine production after exposure to Pb. 

2.21.5 Epigenetic Effects

In a small number of studies, Pb has been shown to induce epigenetic effects, including perturbations in 

DNA methylation as well as alterations in mitogenesis (reviewed by EPA 2014c; Bakulski et al. 2012). 

In human studies, maternal blood Pb was correlated with decreased DNA methylation of Alu 

retrotransposable elements in umbilical cord blood, and bone Pb levels were correlated with decreased 

DNA methylation of LINE-1 retrotransposons in elderly men, while higher blood Pb was associated with 

increased methylation of p16 tumor suppressor gene promoters in occupationally exposed individuals. 

Other evidence for effects of Pb on DNA methylation include a study in primates in which the activity of 

DNA methyltransferase 1 was decreased by early life Pb exposure, and in vitro data showing decreased 

global DNA methylation in rat pheochromocytoma cells. Hypomethylation of DNA has been shown to 

trigger changes in gene expression that may lead to alterations in tissue differentiation. 

Pb exposure also induces effects on mitogenesis, including both increases in cell proliferation and 

decreases in some systems (reviewed by EPA 2014c). Increased cell proliferation and/or DNA synthesis 

have been reported in workers exposed to Pb, in hepatocytes of rats exposed by intravenous injection of 

Pb nitrate, and in mouse lung after exposure to Pb acetate via inhalation. In in vitro studies, results were 

mixed: in some cases cell proliferation was decreased, as Pb exposure resulted in cell cycle arrest. 

Effects of Pb exposure on gene expression have been demonstrated in several studies (reviewed by EPA 

2014c). Although the exact mechanisms by which Pb alters gene expression have not been elucidated, Pb

is known to interfere with GATA proteins and several transcription factors (TFIIIA, Sp1, and Erg-1) 
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through its interaction with zinc-binding domains, reducing the ability of these proteins to bind to DNA 

and exert their transcriptional regulation functions. In vivo and in vitro studies have shown that Pb alters 

the transcription of genes for metabolic enzymes including GST-P and GST-Ya, CYPs 1A1 and 1A2, and 

NAD(P)H:quinone oxidoreductase, as well as genes involved in the pentose phosphate pathway and 

amino acid metabolism. 

2.21.6 Apoptosis

As discussed earlier, Pb is capable of opening the mitochondrial transmembrane pore (MTMP, the first 

step in the mitochondrial apoptosis cascade), possibly by displacing calcium on the matrix side of the 

pore (reviewed by EPA 2014c). Evidence for this effect includes observations of mitochondrial swelling 

and decreased membrane potential in rat primary cerebellar granule neuronal cultures, astroglia, proximal 

tubule cells, and retinal rod photoreceptor cells. In addition, release of cytochrome c and activation of 

caspases 3 and 9 were observed in rat retinal rod cells and hepatic oval cells exposed to Pb in vitro. In 

lymphocytes of Pb-exposed humans, increased apoptosis, karyorrhexis, and karyolysis (early indicators of 

apoptosis) were observed. Other tissues have also exhibited increased apoptosis after Pb exposure, 

including liver, fibroblasts, and alveolar macrophages.
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CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, 

BIOMARKERS, CHEMICAL INTERACTIONS

3.1 TOXICOKINETICS 

Overview. The toxicokinetics of Pb in humans has been extensively studied and several models have 

been published that simulate the absorption and complex distribution and elimination of Pb from blood, 

soft tissues, and bone.

• Absorption:

o Respiratory tract: Inorganic Pb in submicron size particles can be almost completely 

absorbed through the respiratory tract, whereas larger particles may be moved after 

deposition in the respiratory tract by mucociliary clearance toward the oropharynx and 

swallowed. 

o Gastrointestinal tract: The fraction of ingested Pb absorbed from the gastrointestinal tract 

depends on many factors, including age, diet, nutrition, and physiological characteristics 

of Pb in the medium ingested. 

o Children can absorb 40–50% of an oral dose of water-soluble Pb compared to 3–10% for 

adults.

o Gastrointestinal absorption of inorganic Pb occurs primarily in the duodenum by 

saturable mechanisms.

o Dermal: Inorganic Pb can be absorbed following inhalation, oral, and dermal exposure, 

but the latter route is much less efficient than the former two, with the exception of handto-mouth behavior. Studies in animals have shown that organic Pb is absorbed through 

the skin. 

• Distribution: 

o The distribution of Pb in the body is route-independent and, in adults, approximately 94% 

of the total body burden of Pb is in the bones compared to approximately 73% in 

children. 

o Pb in blood is primarily in red blood cells. Conditions such as pregnancy, lactation, 

menopause, and osteoporosis increase bone resorption and consequently also increase Pb 

in blood. 
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o Pb can be transferred from the mother to the fetus and also from the mother to infants via 

maternal milk. 

• Metabolism:

o Metabolism of inorganic Pb consists of formation of complexes with a variety of protein 

and nonprotein ligands. 

o Organic Pb compounds are actively metabolized in the liver by oxidative dealkylation by 

P-450 enzymes. 

• Excretion:

o Pb is excreted primarily in urine and feces regardless of the route of exposure. Minor 

routes of excretion include sweat, saliva, hair, nails, breast milk, and seminal fluid. 

o Elimination of Pb is multiphasic, reflecting pools of Pb in the body that have varying 

retention times. The apparent elimination half-time in blood varies with age and 

exposure history and ranges from 1 week to 2 years. Elimination of Pb from bone occurs 

with an apparent half-time of 1–2 decades. 

• Toxicokinetics models: 

o Several models of Pb pharmacokinetics have been proposed to characterize such 

parameters as intercompartmental Pb exchange rates, retention of Pb in various tissues, 

and relative rates of distribution among the tissue groups. 

o Some models are currently being used or are being considered for broad application in Pb 

risk assessment.

3.1.1 Absorption 

Inhalation Exposure 

Inorganic Pb. Inorganic Pb 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 versus mouth breathing), airway geometry, and air-stream velocity within 

the respiratory tract (James et al. 1994). Absorption of deposited Pb is influenced by particle size and 

solubility as well as the pattern of regional deposition within the respiratory tract. Larger particles 
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(>2.5 μm) that are deposited in the ciliated airways (nasopharyngeal and tracheobronchial regions) can be 

transferred by mucociliary transport into the esophagus and swallowed. Smaller particles (2.5 to <1 μm), 

which can be deposited in the alveolar region, can be absorbed after extracellular dissolution or ingestion 

by phagocytic cells (Bailey and Roy 1994).

Deposition in, 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 Pb-bearing particles having mass median aerodynamic 

diameters (MMADs) below 1 μm and, therefore, deposition of the inhaled Pb 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 Pb to the gastrointestinal tract is likely to have been only a minor component 

of particle clearance (Hursh et al. 1969). Approximately 25% of inhaled Pb chloride or Pb hydroxide 

(MMAD 0.26 and 0.24 μm, respectively) was deposited in the respiratory tract in adult subjects who 

inhaled an inorganic Pb aerosol through a standard respiratory mouthpiece for 5 minutes (Morrow et al. 

1980). Approximately 95% of deposited inorganic Pb that was inhaled as submicron particles was 

absorbed (Hursh et al. 1969; Wells et al. 1975). Rates of clearance from the respiratory tract of inorganic 

Pb inhaled as submicron particles of Pb oxide, or Pb nitrate, were described with half-times (t1/2) 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. Absorption half-times have been estimated in adults who inhaled aerosols of Pb and 

bismuth isotopes generated from decay of 220Rn or 222Rn (Butterweck et al. 2002; Marsh and Birchall 

1999). The absorption half-time was approximately 10 hours in subjects who inhaled aerosols having an 

activity median particle diameter of approximately 160 nm (range 50–500 nm), and approximately 

68 minutes for aerosols having diameters of approximately 0.3–3 nm.

Rates and amounts of absorption of inhaled Pb particles >2.5 μm will be determined, primarily by rates of 

transport to and absorption from the gastrointestinal tract. Absorption of Pb from the gastrointestinal tract 

varies with the chemical form ingested, age, meal status (e.g., fed versus fasted), and nutritional factors 

(see Section 3.1.1 Oral Exposure).

Organic Pb. Clinical studies of subjects who inhaled tetraethyl or tetramethyl Pb found that 60–80% of 

the Pb deposited in the respiratory tract was absorbed (Heard et al. 1979). Following a single exposure to 

vapors of radioactive (203Pb) tetraethyl Pb (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 
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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% was associated with 

kidney, and the remaining burden was widely distributed throughout the body (determined by external 

gamma counting), suggesting near complete absorption of the Pb that was not exhaled. In a similar 

experiment conducted with (203Pb) tetramethyl Pb, 51% of the inhaled 203Pb dose was initially deposited 

in the respiratory tract, of which approximately 40% was exhaled in 48 hours. The distribution of 203Pb 

1 hour after the exposure was similar to that observed following exposure to tetraethyl Pb.

The relatively rapid and near complete absorption of tetraalkyl Pb 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).

Oral Exposure 

Inorganic Pb. The extent and rate of gastrointestinal absorption of ingested inorganic Pb are influenced 

by physiology (e.g., age, fasting, nutritional calcium and iron status, pregnancy), physicochemical 

characteristics of the medium ingested (e.g., particle size, mineralogy, solubility, and Pb species) and the 

ingested Pb dose. 

Mechanisms of Absorption. Gastrointestinal absorption of inorganic Pb 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 Pb (Pb+2) and/or inorganic or organic complexes of Pb. In vitro studies of Pb 

speciation in simulated human intestinal chyme indicate that the concentration of ionized Pb is negligible 

at Pb concentrations below 10-3 M (207 mg/L) and that Pb phosphate and bile acid complexes are the 

dominant forms when inorganic Pb salts (e.g., Pb nitrate) are added to chyme (Oomen et al. 2003a). 

However, these complexes may be sufficiently labile to provide ionized Pb for transport across cell 

membranes (Oomen et al. 2003b). Saturable mechanisms of absorption have been inferred from 

measurements of net flux kinetics of Pb in in situ perfused mouse intestine, in situ ligated chicken 

intestine, and 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 
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intracellular binding proteins for Ca2+ (Bronner et al. 1986; Fleming et al. 1998b; Gross and Kumar 1990; 

Teichmann and Stremmel 1990).

Effect of Age. Gastrointestinal absorption of water-soluble Pb 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 Pb is absorbed (Alexander et al. 1974; Ziegler et 

al. 1978). In adults, estimates of absorption of ingested water-soluble Pb compounds (e.g., Pb chloride, 

Pb nitrate, Pb 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 Pb absorption between childhood 

and adulthood ages are very limited. While no absorption studies have been conducted on subjects in this 

age range, the kinetics of the change in stable isotope signatures of blood Pb in mothers and their 

children, as both come into equilibrium with a novel environmental Pb isotope profile, suggest that 

children ages 6–11 years and their mothers may absorb a similar percentage of ingested Pb (Gulson et al. 

1997b).

Studies in experimental animals provide additional evidence for an age-dependency of gastrointestinal 

absorption of Pb. Absorption of Pb, administered as Pb acetate (6.37 mg Pb/kg, 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 Pb from 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 (enzymes, 

transporters, gastric pH) of the gastrointestinal tract (Weis and LaVelle 1991). 

Effect of Fasting. The presence of food in the gastrointestinal tract decreases absorption of water-soluble 

Pb (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 Pb 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 Pb 

when Pb is ingested with a meal; in particular, the presence of calcium and phosphate in a meal will 

depress the absorption of ingested Pb (Blake and Mann 1983; Blake et al. 1983; Heard and Chamberlain 
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1982). Suppression of absorption by meals may explain the observation of lower PbB in children (age 3–

5 years) who ate breakfast compared to children who went without breakfast, after controlling for 

nutritional variables (Liu et al. 2011).

Effect of Nutrition. Pb absorption in children is affected by nutritional iron status. Children who are iron 

deficient have higher PbBs than similarly exposed children who are iron replete, which would suggest 

that iron deficiency may result in higher absorption of Pb or, possibly, other changes in Pb biokinetics 

that would contribute to higher PbBs (Mahaffey and Annest 1986; Marcus and Schwartz 1987). Genetic 

variation in genes involved in iron metabolism appear to affect PbBs; however, it is not certain if these 

associations are caused by changes in Pb absorption. These include variants in the hemochromatosis 

(HFE) and transferrin genes, which have been associated with higher PbBs in children (Hopkins et al. 

2008), and with lower PbBs and bone Pb levels in elderly men (Wright et al. 2004).

Evidence for the effect for iron deficiency on Pb absorption has been provided from animal studies. In 

rats, iron deficiency increases the gastrointestinal absorption of Pb, possibly by enhancing binding of Pb 

to iron binding proteins in the intestine (Bannon et al. 2003; Barton et al. 1978b; Morrison and Quaterman 

1987). Interactions between iron and Pb appear to involve either intracellular transfer or basolateral 

transfer mechanisms. Iron (FeCl2) added to the mucosal fluid of the everted rat duodenal sac decreases 

serosal transfer, but not mucosal uptake of Pb (Barton 1984). When mRNA for DMT1, a mucosal 

membrane carrier for iron (which also transports other divalent metal cations), 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 Pb uptake by Caco 2 cells, indicating that Pb 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 Pb absorption are associated with transfer of Pb from cell to blood 

rather than with mucosal transfer. Similar mechanisms may contribute to Pb-iron and Pb-calcium 

absorption interactions in humans, and possibly interactions between Pb and other divalent cations such 

as cadmium, copper, magnesium, and zinc. 

Dietary calcium intake affects Pb absorption. An inverse relationship has been observed between dietary 

calcium intake and PbBs in children, suggesting that children who are calcium-deficient may absorb more 

Pb than calcium-replete children (Elias et al. 2007; Mahaffey et al. 1986; Schell et al. 2004; Ziegler et al. 

1978). An effect of calcium on Pb absorption is also evident in adults. In experimental studies of adults, 

absorption of a single dose of Pb (100–300 μg Pb chloride) was lower when the Pb was ingested together 
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with calcium carbonate (0.2–1 g calcium carbonate) than when the Pb 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). 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 Pb from the 

gastrointestinal tract is enhanced by dietary calcium depletion or administration of cholecalciferol 

(Mykkänen and Wasserman 1981, 1982). This "cholecalciferol-dependent" component of Pb absorption 

appears to involve a stimulation of the serosal transfer of Pb from the epithelium, not stimulation of 

mucosal uptake of Pb (Mykkänen and Wasserman 1981, 1982). This is similar to the effects of 

cholecalciferol on calcium absorption (Bronner et al. 1986; Fullmer and Rosen 1990).

In a study of young children (ages 6–12 months), PbBs increased in association with lower dietary Zn 

levels (Schell et al. 2004); however, it is not certain if these associations were caused by changes in Pb 

absorption.

Effect of Pregnancy. Absorption of Pb may increase during pregnancy. Although there is no direct 

evidence for this in humans, an increase in Pb absorption may contribute, along with other mechanisms 

(e.g., increased mobilization of bone Pb), to the increase in PbBs that has been observed during the latter 

half of pregnancy (see Section 3.1.2, Pb Distribution during Pregnancy and Maternal-Fetal-Infant 

Transfer).

Effect of Dose. Pb absorption in humans may be a capacity-limited process, in which case, the 

percentage of ingested Pb that is absorbed may decrease with increasing rate of Pb intake. Studies, to 

date, do not provide a firm basis for discerning if the gastrointestinal absorption of Pb is limited by dose. 

Numerous observations of nonlinear relationships between PbB and Pb intake in humans provide support 

for the existence of a saturable absorption mechanism or some other capacity-limited process in the 

distribution of Pb in humans (Pocock et al. 1983; Sherlock and Quinn 1986; Sherlock et al. 1984) (see 

Section 3.1.2, Pb in Blood and Pb in Plasma for discussion of saturable uptake of Pb in red blood cells). 

However, in immature swine that received oral doses of Pb in soil, Pb dose-blood Pb relationships were 

curvilinear, whereas dose-tissue Pb relationships for bone, kidney, and liver were linear. The same 

pattern (nonlinearity for PbB and linearity for tissues) was observed in swine administered Pb acetate 

intravenously (Casteel et al. 1997, 2006). These results suggest that the nonlinearity in the Pb dose-blood 

Pb relationship may derive from an effect of Pb dose on some aspect of the biokinetics of Pb other than 

absorption. In fasted rats, absorption was estimated at 42 and 2% following single oral administration of 
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1 and 100 mg Pb/kg, respectively, as Pb 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 

(Aungst and Fung 1981; Barton 1984; Flanagan et al. 1979; Mykkänen and Wasserman 1981) suggests 

that the intake-uptake relationship for Pb is likely to be nonlinear; 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 Pb in diets 

containing metallic Pb particles that were ≤250 μm in diameter (Barltrop and Meek 1979). Tissue Pb 

concentration was a 2.3-fold higher when rats ingested an acute dose (37.5 mg Pb/kg) of Pb 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 Pb-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 (Davis et al. 

1994). Similarly, Healy et al. (1982) found that the solubility of Pb 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 Pb from the gastrointestinal tract involves absorptive transport of 

soluble Pb species (e.g., Pb2+) across the gastrointestinal tract epithelium. In order for Pb to be absorbed 

from soil, it must first be made bioaccessible in the gastrointestinal tract. The process of rendering soil Pb 

bioaccessible may involve: (1) physical and/or chemical digestion of the soil particles to expose Pb 

deposits to gastrointestinal tract fluids; (2) transfer of Pb minerals from exposed surfaces on soil particles 

to the aqueous environment of the gastrointestinal tract; and (3) chemical transformation of Pb minerals to 

soluble Pb species (e.g., Pb2+) that are substrates for absorptive transport. Although absorptive transport 

of Pb occurs predominantly, if not solely, in the upper small intestine, bioaccessibility processes 

occurring in the stomach appear to be major determinants of Pb absorption.

Adult subjects who ingested soil (particle size <250 μm) collected from the Bunker Hill National 

Priorities List (NPL) site absorbed 26% of the resulting 250 μg/70 kg body weight Pb dose when the soil 

was ingested in the fasted state, and 2.5% when the same soil Pb dose was ingested with a meal 

(Maddaloni et al. 1998). The value reported for fasted subjects (26%) was approximately half that 

reported for soluble Pb ingested by fasting adults, or approximately 60% (Blake et al. 1983; Heard and 

Chamberlain 1983; James et al. 1985; Rabinowitz et al. 1980). Measurements of the absorption of soil Pb 

in infants or children have not been reported. 
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Absorption of Pb from ingested soils and surface dust has been studied more extensively in animals 

(Bannon et al. 2009; Barltrop and Meek 1979; Bradham et al. 2016, 2019; Brown et al. 2004; Casteel et 

al. 1997, 2006; Freeman et al. 1992, 1994, 1996; Healy et al. 1982; Hettiearachchi et al. 2003; Juhasz et 

al. 2009; Ryan et al. 2004; Weis and Lavelle 1991). These studies have shown that absorption of soil Pb 

varies depending upon the Pb mineralogy and physical characteristics of the Pb in the soil 

(e.g., encapsulated or exposed, particle size). Studies conducted in swine and other animal models have 

provided estimates of relative bioavailability (RBA) of Pb in soils collected from sites impacted by a 

variety of sources of Pb contamination including ore and ore processing, shooting of Pb munitions, and 

Pb-based paint (Bannon et al. 2009; Barltrop and Meek 1979; Bradham et al. 2016, 2019; Brown et al. 

2004; Casteel et al. 1997, 2006; Freeman et al. 1992, 1994, 1996; Healy et al. 1982; Hettiearachchi et al. 

2003; Juhasz et al. 2009; Ryan et al. 2004; Weis and Lavelle 1991). RBA is the ratio of the absolute 

bioavailability (or absorption fraction) of Pb in soil to that of a water-soluble reference (Pb acetate). RBA 

has been measured in animal models using various approaches, including measurement of blood and 

tissue Pb in animals following dosing with soil or Pb acetate. RBA estimates from these studies ranged 

from 1 to 100% (mean 60%, n=33, calculated by ATSDR). RBAs for soils (sieved to <250 μm) from 

firing ranges where the predominant form of Pb was Pb carbonate were approximately 100% (Bannon et 

al. 2009). A soil amended with NIST paint standard (a mixture of Pb carbonate and Pb oxide) had an 

RBA of 92%. Smelter slag and soils in which the dominant source of Pb was smelter slag had relatively 

low RBA (14–40%). Galena (lead sulfide) in soil also had relatively low RBA (1–6%). 

Casteel et al. (2006) estimated Pb RBA of 19 soils in swine and categorized the RBA according to Pb 

mineral associations. Electron microprobe analyses of Pb-bearing grains in the various soils 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 Pb was present in a wide range of different mineral associations (phases), 

including various oxides, sulfides, sulfates, and phosphates. These variations in size and mineral content 

of the Pb-bearing grains are the suspected cause of variations in the gastrointestinal absorption of Pb from 

different samples of soil. Based on these very limited data, the RBA of Pb mineral phases were rankordered (Table 3-1).
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Table 3-1. Ranking of Relative Bioavailability of Lead (Pb) Mineral Phases in Soila

Low bioavailability 

(RBA<0.25)

Medium bioavailability 

(RBA=0.25–0.75)

High bioavailability 

(RBA>0.75)

Angelsite

Fe(M) oxide

Fe(M) sulfate

Galena

Pb(M) oxide

Pb oxide

Pb phosphate

Cerussite

Mn(M) oxide

aEstimates are based on studies of immature swine.

Fe = iron; M = metal; Mn = manganese; RBA = relative bioavailability (compared to Pb acetate)

Source: Casteel et al. 2006

Several studies have shown that elevating the phosphate concentration of soil can decrease soil Pb RBA 

(Brown et al. 2004; Hettiarachichi et al. 2003; Ryan et al. 2004). The mechanism for the effect is thought 

to be the formation of a relatively insoluble form of Pb in soil, pyromorphite, which has a low RBA 

(Scheckel et al. 2013).

Bioaccessibility in Soil and its Relationship to Relative Bioavailability. Empirical evidence supporting 

the importance of gastric bioaccessibility in Pb absorption comes from studies of relationships between 

extractability of Pb from soil measured in vitro and Pb RBA measured in animals. In vitro extractability 

of Pb from soil (in vitro bioaccessibility, IVBA) strongly correlates with RBA measured swine assays 

when the extraction is performed at gastric pH (r2

=0.92, n=18; Drexler and Brattin 2007). 

Bioaccessibility estimates obtained from IVBA assays are sensitive to assay conditions such as pH, 

liquid:soil ratios, inclusion or absence of food material, and differences in methods used to separate 

dissolved and particle-bound Pb (e.g., centrifugation versus filtration); as a result, different assays can 

yield different results when applied to the same soils or surface dusts (Dong et al. 2016; Juhasz et al. 

2011; Lu et al. 2011; Roussel et al. 2010; Saikat et al. 2007; Smith et al. 2011; Van de Wiele et al. 2007). 

For this reason, application of IVBA assays for predicting RBA must be supported by demonstration of a 

strong correlation between IVBA and RBA (Drexler and Brattin 2007). Even in the absence of validation 

of RBA predictions, IVBA assays may be useful for predicting relative differences in RBA between soils. 

For example, the relative change in Pb RBA resulting from treatment of soils with phosphate amendments 

was predicted from IVBA measurements even though the IVBA assay performed poorly at predicting the 

actual RBA of the soils (Juhasz et al. 2016). Bioaccessibility measured with IVBA assays has been 

shown to increase with decreasing particle size (varied from <2,000 to <50 μm) (Juhasz et al. 2011) and 

increase with increasing soil acidity and organic matter content (Jin et al. 2005).
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Dermal Exposure 

Inorganic Pb. Dermal absorption of inorganic Pb 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 Pb in humans, and the quantitative significance of the dermal 

absorption pathway as a contributor to Pb body burden in humans remains an uncertainty. Pb was 

detected in the upper layers of the stratum corneum of Pb-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 

Pb. Following skin application of 203Pb-labeled Pb 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. Pb also appears to be absorbed across human skin when applied to the skin as Pb nitrate; 

however, quantitative estimates of absorption have not been reported. Pb (4.4 mg, as Pb 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 Pb was quantified in the cover material and rinse (Stauber et al. 1994). The amount of Pb recovered 

from the cover material and rinse was 3.1 mg (70% of the applied dose). Based 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 Pb (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). Pb concentrations in sweat collected from the right arm 

increased 4-fold following the application of Pb to the left arm, indicating that some Pb had been 

absorbed (amounts of sweat collected or total Pb recovered in sweat were not reported; Stauber et al. 

1994). 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 (Stauber et al. 1994). This study also reported that absorption 

of Pb could not be detected from measurements of Pb in sweat following dermal exposure to Pb as Pb 

carbonate.

Information on relative dermal permeability of inorganic and organic Pb salts of Pb comes from studies of 

in vitro preparations of excised skin; the rank ordering of penetration rates through excised human skin 
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was: Pb nuolate (Pb linoleic and oleic acid complex) > Pb naphthanate > Pb acetate > Pb oxide 

(nondetectable) (Bress and Bidanset 1991).

Studies conducted in animals provide additional evidence that dermal absorption of inorganic Pb is 

substantially lower than absorption from the inhalation or oral route. In a comparative study of dermal 

absorption of inorganic and organic salts of Pb conducted in rats, approximately 100 mg of Pb was 

applied in an occluded patch to the shaved backs of rats. Based on urinary Pb measurements made prior 

to and for 12 days following exposure, Pb compounds could be ranked according to the relative amounts 

absorbed (i.e., percent of dose recovered in urine; calculated by ATSDR): Pb naphthalene (0.17%), Pb 

nitrate (0.03%), Pb stearate (0.006%), Pb sulfate (0.006%), Pb oxide (0.005%), and metal Pb powder 

(0.002%). This rank order (i.e., Pb naphthalene > Pb oxide) is consistent with a rank ordering of 

penetration rates of inorganic and organic Pb salts through excised skin from humans and guinea pigs: Pb 

nuolate (Pb linoleic and oleic acid complex) > Pb naphthanate > Pb acetate > Pb oxide (nondetectable) 

(Bress and Bidanset 1991). The estimates for percent of dose excreted underestimate actual absorption as 

these estimates do not account for the Pb retained in bone and other tissues.

Following application of Pb acetate to the shaved clipped skin of rats, the concentration of Pb in the 

kidneys was found to be higher relative to controls, suggesting that absorption of Pb had occurred (Laug 

and Kunze 1948). This study also observed that dermal absorption of Pb from Pb arsenate was 

significantly less than from Pb acetate, and that mechanical injury to the skin significantly increased the 

dermal penetration of Pb.

Organic Pb. Relative to inorganic Pb and organic Pb salts, tetraalkyl Pb 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 Pb, which was allowed to spread uniformly over an 

area of 25 cm2 on the abdominal skin of rabbits, resulted in 10.6 mg of Pb in the carcass at 0.5 hours and 

4.41 mg at 6 hours (Kehoe and Thamann 1931). Tetraethyl Pb was reported to be absorbed by the skin of 

rats to a much greater extent than Pb acetate, Pb oleate, and Pb arsenate (Laug and Kunze 1948). 

Evidence for higher dermal permeability of organic Pb compounds compared to inorganic organic salts of 

Pb also comes from in vitro studies conducted with excised skin. The rank order of absorption rates 

through excised skin from humans and guinea pigs was as follows: tetrabutyl Pb > Pb nuolate (Pb 

linoleic and oleic acid complex) > Pb naphthanate > Pb acetate > Pb oxide (nondetectable) (Bress and 

Bidanset 1991).
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3.1.2 Distribution 

Inorganic Pb. Absorbed inorganic Pb 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 

Pb (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 Pb in the 

body. Most of the available information about the distribution of Pb 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). A more recent autopsy study 

found lower Pb concentrations in autopsies performed during the period 2004–2013 (Mari et al. 2014). In 

general, these studies indicate that the distribution of Pb appears to be similar in children and adults, 

although a larger fraction of the Pb body burden of adults resides in bone. Several models of Pb 

pharmacokinetics have been proposed to characterize such parameters as intercompartmental Pb 

exchange rates, retention of Pb in various tissues, and relative rates of distribution among the tissue 

groups (see Section 3.1.5 for further discussion of models).

Pb in Blood. Concentrations of Pb in blood vary considerably with age, physiology/life stage (e.g., 

pregnancy, lactation, menopause), and numerous factors that affect exposure to Pb. PbBs in various 

demographic strata of the U.S. population are periodically estimated from the NHANES. Based on data 

from NHANES (2015–2016, CDC 2018a), the geometric mean PbB of U.S. adults, age ≥20 years, was 

0.920 μg/dL (95% CI 0.862, 0.982). The geometric mean PbB of U.S. children, age 1–5 years, was 

0.758 (95% CI 0.675, 0.850). PbBs in the United States have decreased considerably in the last several 

decades as a result of removal of Pb from gasoline and restrictions placed on the use of Pb in residential 

paints (Brody et al. 1994; CDC 2011, 2018a; Pirkle et al. 1994, 1998; Schwartz and Pitcher 1989). While 

historically, the geometric mean PbB in U.S. children has been higher than that of the adult population, 

recent estimates indicate that geometric means in children have fallen below that of adults. 

Pb in Red Blood Cells. Pb 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). 

Although the mechanisms by which Pb 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 Pb 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. 
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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). Pb and 

calcium may also share a permeability pathway, which may be a Ca2+-channel (Calderon-Salinas et al. 

1999). Pb is transferred out of the erythrocyte by an active transport pathway, most likely a (Ca2+, Mg2+)-

ATPase (Simons 1988).

Pb in erythrocytes binds to several intracellular proteins. ALAD is the primary binding ligand for Pb in 

erythrocytes (Bergdahl et al. 1997a, 1998; Sakai et al. 1982; Xie et al. 1998). Pb binding to ALAD is 

saturable; the binding capacity has been estimated to be approximately 85 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 Pb-binding proteins have been identified in 

erythrocytes, 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 Pb-binding proteins identified in erythrocytes, 

ALAD has the strongest affinity for Pb (Bergdahl et al. 1998) and appears to dominate the ligand 

distribution of Pb (35–84% of total erythrocyte Pb) at blood Pb levels below 40 μg/dL (Bergdahl et al. 

1996, 1998; Sakai et al. 1982). The decrease in hematocrit that occurs in early infancy (51% at birth to 

35% at 6 months) may decrease the total binding capacity of blood and PbBs over the first postnatal 

6 months (Simon et al. 2007).

Pb binds to and inhibits the activity of ALAD (Gercken and Barnes 1991; Gibbs et al. 1985; Jaffe et al. 

2000; Sakai et al. 1982, 1983). Binding of zinc is essential for ALAD activity, and Pb inhibits activity of 

ALAD by displacing zinc (Jaffe et al. 2000). Synthesis of ALAD appears to be induced in response to 

inhibition of ALAD and, therefore, in response to binding of Pb 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 Pb; (2) inhibition by protoporphyrin, secondary to accumulation of protoporphyrin as a 

result of Pb inhibition of ferrochelatase; and (3) accumulation of ALA (a substrate of ASAD), 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, Scinicariello et al. 2007). Numerous 

studies have examined the relationship between ALAD genotype and PbBs and the results of these studies 

are mixed with some studies finding higher PbBs in association with the ALAD 2 allele and other studies 

finding no associations or lower PbBs associated with the ALAD 2 allele (see Section 3.2). One possible 
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mechanism by which ALAD polymorphism could affect PbBs is by allelic variation in Pb binding to 

ALAD (Bergdahl et al. 1997b). However, competitive displacement studies with recombinant human 

ALAD 1 and ALAD 2 did not indicate differences in affinity for Pb relative to zinc (Jaffe et al. 2000).

Pb in Blood Plasma. Pb binds to several constituents in plasma and it has been proposed that Pb in 

plasma exists in four states: loosely bound to serum albumin or other proteins with relatively low affinity 

for Pb, 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 Pb (i.e., 

Pb2+) in plasma represents an extremely small percentage of total plasma Pb. The concentration of Pb2+ in 

fresh serum, as measured by an ion-selective Pb electrode, was reported to be 1/5,000 of the total serum 

Pb (Al-Modhefer et al. 1991). Approximately 40–75% of Pb 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 1980). Pb 

also binds to transferrins and γ-globulins (Guo et al. 2014; Ong and Lee 1980). Pb 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 Pb-binding ligands in serum may include 

citrate, cysteamine, ergothioneine, glutathione, histidine, and oxylate (Al-Modhefer et al. 1991).

Saturable binding to red blood cell proteins contributes to curvature to the blood Pb-plasma Pb 

relationship with an increase in the plasma/blood Pb ratio with increasing PbB (Barbosa et al. 2006a; 

Bergdahl et al. 1997b, 1998, 1999; DeSilva 1981; Jin et al. 2008; Kang et al. 2009; Manton et al. 2001; 

Rentschler et al. 2012; Smith et al. 2002; Tian et al. 2013). The curvature becomes evident at PbBs well 

above 10 μg/dL. As binding sites for Pb in red blood cells become saturated, a larger fraction of the 

blood Pb is available in plasma to distribute to brain and other Pb-responsive tissues. This contributes to 

a curvature in the relationship between Pb intake and PbB, with the blood Pb/intake slope decreasing with 

increasing Pb intake, which has been observed in children (Sherlock and Quinn 1986) and immature 

swine (Casteel et al. 2006). Saturable binding of Pb to red blood cell proteins also contributes to a 

curvilinear relationship between blood Pb and urinary Pb, whereas the relationship between plasma Pb 

concentration and urine Pb is linear (Bergdahl et al. 1997b).

Pb in Bone. In human adults, approximately >90% of the total body burden of Pb is found in the bones. 

Based on analyses of post-mortem tissues, bone accounted for 94% of the total Pb body burden of adults 

and 73% of the body burden in children (Barry 1975). Pb concentrations in bone increase with age, 

indicative of a relatively slow turnover of Pb in adult bone (Barry 1975, 1981; Gross et al. 1975; 

Schroeder and Tipton 1968; Wilker et al. 2011). A portion of Pb in bone readily exchanges with the 
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plasma Pb pool and, as a result, bone Pb is a reservoir for replenishment of Pb eliminated from blood by 

excretion (Alessio 1988; Behinaein et al. 2012, 2014; Chettle et al. 1991; Hryhorczuk et al. 1985; Nie et 

al. 2005; Nilsson et al. 1991; Rabinowitz et al. 1976). Pb in adult bone can serve to maintain blood Pb 

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 Pb 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).

Pb forms highly stable complexes with phosphate and can replace calcium in the calcium-phosphate salt, 

hydroxyapatite, which comprises the primary crystalline matrix of bone (Bres et al. 1986; Lloyd et al. 

1975; Meirer et al. 2011; Miyake 1986; Verbeeck et al. 1981). As a result, Pb 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 (Aufderheide and Wittmers 1992; O'Flaherty 1991b, 1993). 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 Pb 

accumulation will occur predominantly in trabecular bone during childhood, and in both cortical and 

trabecular bone in adulthood (Aufderheide and Wittmers 1992). The association of Pb uptake and release 

from bone with the normal physiological processes of bone formation and resorption renders Pb 

biokinetics sensitive to these processes. Physiological states (e.g., pregnancy, menopause, advanced age) 

or disease-related states (e.g., osteoporosis, prolonged immobilization) that are associated with increased 

bone resorption will tend to promote the release of Pb from bone, which, in turn, may contribute to an 

increase in the concentration of Pb in blood (Berkowtiz et al. 2004; Bonithon-Kopp et al. 1985; Garrido 

Latorre et al. 2003; Hernandez-Avila et al. 2000; Jackson et al. 2010; Markowitz and Weinberger 1990;

Mendola et al. 2013; Nash et al. 2004; Nie et al. 2009; Popovic et al. 2005; Silbergeld et al. 1988; 

Symanski and Hertz-Picciotto 1995; Thompson et al. 1985).

Two physiological compartments appear to exist for Pb in cortical and trabecular bone, to varying 

degrees. In one compartment, bone Pb is essentially inert, having an elimination half-time of several 

decades. A labile compartment exists as well that allows for maintenance of an equilibrium of Pb 

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 Pb into mineralizing bone, bone Pb is also 

recycled to other tissue compartments or excreted in accordance with a high bone resorption rate 

(O'Flaherty 1995a). Thus, most of the Pb 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 Pb levels among adults (Barry 1975; Gross et al. 1975; Schroeder and Tipton 1968). 
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Bone Pb burdens in adults are slowly lost by diffusion (heteroionic exchange) as well as by resorption 

(O'Flaherty 1995a, 1995b). An XRF study of tibia Pb concentrations in individuals >10 years old showed 

a gradual increase in bone Pb after age 20 (Kosnett et al. 1994). In 60–70-year-old men, the total bone Pb 

burden may be ≥200 mg, while children <16 years old have been shown to have a total bone Pb burden of 

8 mg (Barry 1975). However, in some bones (i.e., mid femur and pelvic bone), the increase in Pb content 

plateaus at middle age and then decreases at higher ages; the decrease with age was more pronounced in 

females (Drasch et al. 1987). Osteoporosis and release of Pb from resorbed bone to blood may contribute 

to decreasing bone Pb content in females (Gulson et al. 2002). 

Evidence for the exchange of bone Pb and soft tissue Pb stores comes from analyses of stable Pb isotope 

signatures of Pb in bone and blood. A comparison of blood and bone Pb stable isotope signatures in five 

adults indicated that bone Pb stores contributed to approximately 40–70% of the Pb in blood (Smith et al. 

1996). During pregnancy, the mobilization of bone Pb increases, as the bone is resorbed to produce the 

fetal skeleton. Analysis for kinetics of changes in the stable isotope signatures of blood Pb in pregnant 

women as they came into equilibrium with a novel environmental Pb isotope signature indicated that 10–

88% of the Pb in blood may derive from the mobilization of bone Pb store and approximately 80% of 

cord blood may be contributed from maternal bone Pb (Gulson 2000; Gulson et al. 1997b, 1999c, 2003). 

The mobilization of bone Pb during pregnancy may contribute, along with other mechanisms (e.g., 

increased absorption), to the increase in Pb concentration that has been observed during the later stages of 

pregnancy (Gulson et al. 1997b, 2016; 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 Pb 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 Pb to the fetus has been provided from stable Pb isotope studies in 

Cynomolgus monkeys (Macaca fascicularis) that were dosed with Pb having a different stable isotope 

ratio than the Pb to which the monkeys were exposed at an earlier age; approximately 7–39% of the 

maternal Pb 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 Pb to 

blood; these include lactation, osteoporosis, and severe weight loss. Analysis of kinetics of changes in the 

stable isotope signatures of blood Pb in postpartum women as they came into equilibrium with a novel 

environmental Pb isotope signature indicated that the release of maternal bone Pb to blood appears to 

accelerate during lactation (Gulson et al. 2002, 2003, 2004). This is consistent with declines in patella 
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bone Pb (measured by XRF) during lactation without calcium supplementation (Hernandez-Avila et al. 

1996). Similar approaches have detected increased release of bone Pb 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; Garrido Latorre et al. 2003; Hernandez-Avila et al. 2000; 

Korrick et al. 2002; Nash et al. 2004; Popovic et al. 2005; Symanski and Hertz-Picciotto 1995). In a 

prospective study of women who were scheduled to undergo bilateral oophorectomy for benign 

conditions, blood and tibia bone Pb (measured by XRF and adjusted for bone mineral density) did not 

change 6–18 months post-surgery, regardless of whether patients were given estrogen replacement 

therapy (Berkowitz et al. 2004). Severe weight loss (28% of BMI in 6 months) in women, which 

increased bone turnover, increased PbB (Riedt et al. 2009).

Pb in Soft Tissues. Several studies have compared soft tissue concentrations of Pb 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. A more recent autopsy study 

found lower Pb concentrations in autopsies performed during the period 2004–2013 (Mari et al. 2014). 

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 

<5 μg/dL (CDC 2018a). Levels in other soft tissues also appear to have decreased substantially since 

these studies were reported (Barregård et al. 1999; Mari et al. 2014). For example, average Pb 

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). An analysis of kidney biopsy samples collected in Sweden found 

that the mean level of Pb in kidney cortex among subjects not occupationally exposed to Pb was 

0.18 μg/g (maximum, 0.56 μg/g) (Barregård et al. 1999). Mari et al. (2014) reported a value of 0.18 μg/g 

for mean kidney Pb concentration in 20 autopsies performed in Spain. In spite of the downward trends in 

soft tissue Pb levels, the autopsy studies provide a basis for describing the relative soft tissue distribution 

of Pb in adults and children. Most of the Pb in soft tissue is in liver. Relative amounts of Pb in soft 

tissues as reported by Schroeder and Tipton (1968), expressed as percent of total soft tissue Pb, 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. 1986, 1995b; Gross et al. 1975; Mari 

et al. 2014; Oldereid et al. 1993). The relative distribution of Pb in soft tissues, in males and females, 
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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; 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 Pb in bone, which accumulates Pb 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 Pb in soft tissue, relative to bone.

Mechanisms by which Pb 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 Pb transfer and suggest that Pb can interact with transport mechanisms for 

calcium and iron (see Section 3.1.1). Pb can enter cells through voltage-gated 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 embryonic kidney, and 

bovine brain capillary endothelial cells (Kerper and Hinkle 1997a, 1997b). Anion exchangers may also 

participate in Pb 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 Pb across the renal tubular epithelium. In Madin-Darby canine kidney cells (MDCK), Pb 

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 Pb into MDCK cells was 

both time and temperature dependent. Overexpression of DMT1 in the human embryonic kidney 

fibroblast cells (HEK293) resulted in increased Pb 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 Pb.

Pb in other soft tissues such as kidney, liver, and brain exists predominantly bound to protein. High 

affinity cytosolic Pb binding proteins have been identified in rat kidney and brain (DuVal and Fowler 

1989; Gonick et al. 2011). The Pb binding proteins 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 hyaline droplet nephropathy produced by certain hydrocarbons (EPA 1991; 

Swenberg et al. 1989); however, there is no evidence that Pb induces male-specific nephropathy or 

hyaline droplet nephropathy. The precise role for Pb binding proteins in the toxicokinetics and toxicity of 

Pb has not been firmly established; however, it has been proposed that binding proteins may serve as a 

cytosolic Pb "receptor" that, when transported into the nucleus, binds to chromatin and modulates gene 
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expression (Fowler and DuVal 1991; Mistry et al. 1985, 1986). Other high-affinity Pb 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). Pb 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 Pb 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, Pb will more readily displace zinc 

from metallothionein than cadmium (Goering and Fowler 1987; Nielson et al. 1985; Waalkes et al. 1984).

Pb Distribution during Pregnancy and Maternal-Fetal-Infant Transfer. PbBs tend to be lower in 

pregnant women compared to non-pregnant women of similar age, BMI, iron status, and smoking status 

(Jain 2013a; Liu et al. 2013). This difference may reflect increased elimination of Pb from the maternal 

system (Jain 2013b). Maternal PbB changes during and following pregnancy. A U-shaped temporal 

pattern has been observed in which maternal PbBs decrease during the second trimester and increase 

during the third trimester and postpartum period (Gulson et al. 2004, 1997b, 2016; Hertz-Picciotto et al. 

2000; Lagerkvist et al. 1996; Lamadrid-Figueroa et al. 2006; Rothenberg et al. 1994). Several factors 

appear to contribute to these changes. During the second trimester, increased plasma volume contributes 

to hemodilution of maternal blood Pb and a lowering in the PbB (Hytten 1985). During the third 

trimester, growth of the fetal skeleton accelerates, which results in increased mobilization of calcium and 

Pb from the maternal skeleton, increasing maternal PbB (Gulson et al. 1998b, 2003). Postpartum 

calcium demand increases further during lactation and breastfeeding, which promotes further 

mobilization of calcium and Pb from bone and sustains or increases maternal PbBs (Gulson et al. 1998b; 

Hansen 2011; Tellez-Rojo et al. 2002). Increased demand for calcium in the third trimester and 

postpartum (to supply calcium for breast milk) is also evident from studies of the effects of dietary 

calcium supplementation during pregnancy. Calcium supplementation of the maternal diet decreased or 

delayed the onset of the increase in maternal PbB during the third trimester and postpartum period and 

delayed mobilization of maternal bone Pb in the third trimester (Ettinger et al. 2009; Gulson et al. 2004, 

2016; Manton et al. 2003). The increase in PbB associated with late pregnancy was greater in older 

women who had a longer history of Pb exposure and, presumably, higher bone Pb levels (Miranda et al. 

2010). Pb has been detected in follicular fluid at concentrations similar to that in blood plasma 

(Silberstein et al. 2006).

A portion of the maternal Pb burden is transferred to the placenta and fetus during pregnancy (EstebanVasaloo et al. 2012; Franklin et al. 1997; Gulson et al. 2003, 2016; Irwinda et al. 2019; Kayaalti et al. 
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2016; Kazi et al. 2014; O’Flaherty 1998; Reddy et al. 2014). Measurements of stable Pb isotope ratios in 

pregnant women and cord blood, as they came into equilibrium with a novel environmental Pb isotope 

signature, indicated that approximately 80% of Pb in fetal cord blood appears to derive from maternal 

bone stores (Gulson et al. 1997b, 1999c, 2000, 2003, 2016). Stable isotope studies have also 

demonstrated transfer of Pb from the maternal skeleton to fetus in nonhuman primates (Franklin et al. 

1997; O'Flaherty 1998). Transplacental transfer of Pb may be facilitated by an increase in the 

plasma/PbB ratio during pregnancy (Lamadrid-Figueroa et al. 2006; Montenegro et al. 2008).

Fetal and maternal PbBs and placental Pb concentrations are correlated (Amaral et al. 2010; Baeyens et 

al. 2014; Baranowska-Boisiacka et al. 2016; Carbone et al. 1998; Chen et al. 2014; Goyer 1990; Graziano 

et al. 1990; Gulson et al. 2016; Kayaalti et al. 2015b; Kazi et al. 2014; Kim et al. 2015; Kordas et al. 

2009; Patel and Prabhu 2009; Reddy et al. 2014). Estimates of the maternal/fetal PbB ratio, based on 

cord blood Pb measurements at the time of delivery, range from 0.7 to 1.0 at mean maternal PbBs ranging 

from 1 to 9 μg/dL. In one of the larger studies of fetal PbB, maternal and cord PbB were measured at 

delivery in 888 mother-infant pairs; the cord/maternal ratio was relatively constant, 0.93, over a blood Pb 

range of approximately 3–40 μg/dL (Graziano et al. 1990). An analysis of data from 159 mother-infant 

pairs revealed that higher blood pressure and alcohol consumption late in pregnancy were associated with 

higher concentrations of Pb in cord blood relative to maternal blood, while higher hemoglobin and sickle 

cell trait were associated with lower cord blood Pb relative to maternal blood Pb (Harville et al. 2005). 

No associations were found for calcium intake, physical activity, or smoking. Placental Pb concentrations 

were found to correlate with ALAD polymorphisms, with higher concentrations observed in association 

with ALAD2 (Kayaalti et al. 2015b).

Maternal Pb is transferred to infants during breastfeeding. Stable Pb isotope dilution studies suggested 

that Pb in breast milk can contribute substantially to the isotope profile of infant blood (approximately 

40–80%; Gulson et al. 1998b). Numerous studies have reported Pb concentrations in maternal blood and 

breast milk. In general, these studies indicate that Pb concentrations in breast milk are correlated with Pb 

concentrations in maternal blood or plasma. Milk/maternal concentration ratios are <0.1, although values 

of 0.9 have been reported (Baranowska-Boisiacka et al. 2016; Counter et al. 2014; Ettinger et al. 2006, 

2014; Gulson et al. 1998a; Koyashiki et al. 2010). Ettinger et al. (2004, 2006) assessed factors 

influencing breast milk Pb 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 Pb (mean 0.9–1.4 μg/dL; range 0.2–8 μg/dL) than 

bone Pb, and that tibia Pb (mean 9.5 μg/g; range <1–76.5 μg/dL) was a stronger predictor of breast milk 

Pb than patella bone Pb (mean 14.6 μg/dL; range <1–67.2 μg/dL). Dietary intake of polyunsaturated fatty 
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acids (PUFA) may decrease transfer of Pb from bone to breast milk (Arora et al. 2008). Pb 

concentrations in maternal blood and breast milk have been shown to correlate with PbBs in breastfeeding 

infants (Ettinger et al. 2014; Farhat et al. 2013). Breast milk Pb concentrations explained 37% of the 

variation in infant blood Pb of breastfeeding infants (Ettinger et al. 2014).

Organic Pb. Information on the distribution of Pb in humans following exposures to organic Pb is 

extremely limited. One hour following 1–2-minute inhalation exposures to 203Pb tetraethyl or tetramethyl 

Pb (1 mg/m3

), approximately 50% of the 203Pb body burden was associated with liver and 5% was 

associated 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 Pb) or 10 hours (tetraethyl Pb) after the exposure, followed by a phase of gradual 

increase in PbB that lasted for up to 500 hours after the exposure. Radioactive Pb 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 Pb from the respiratory tract, followed by a 

redistribution of de-alkylated Pb compounds (see Section 3.1.3 for further discussion of alkyl Pb 

metabolism). 

In a man and woman who accidentally inhaled a solvent containing 31% tetraethyl Pb (17.6% Pb by 

weight), Pb 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 Pb (38% Pb w/w); Pb concentration was highest in the liver followed by kidney, pancreas, 

brain, and heart (Bolanowska et al. 1967).

3.1.3 Metabolism 

Inorganic Pb. Metabolism of inorganic Pb consists of formation of complexes with a variety of protein 

and nonprotein ligands (see Section 3.1.2 for further discussion). Major extracellular ligands include 

albumen and nonprotein sulfhydryls. The major intracellular ligand in red blood cells is ALAD. Pb also 

forms complexes with proteins in the cell nucleus and cytosol.

Organic Pb. Alkyl Pb compounds are actively metabolized in the liver by oxidative dealkylation 

catalyzed by cytochrome P-450. Relatively few studies that address the metabolism of alkyl Pb 

compounds in humans have been reported. Studies of workers who were exposed to tetraethyl Pb have 

shown that tetraethyl Pb is excreted in the urine as diethyl Pb, ethyl Pb, and inorganic Pb (Turlakiewicz 
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and Chmielnicka 1985; Vural and Duydu 1995; Zhang et al. 1994). Trialkyl Pb 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 Pb/m3 of 203Pb-labeled 

tetraethyl and tetramethyl Pb, respectively, Pb was cleared from the 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 Pb. The 

subsequent rise in blood radioactivity, however, probably represents water-soluble inorganic Pb and 

trialkyl and dialkyl Pb compounds that were formed from the metabolic conversion of the volatile parent 

compounds (Heard et al. 1979).

3.1.4 Excretion 

Independent of the route of exposure, absorbed Pb is excreted primarily in urine and feces; sweat, saliva, 

hair and nails, breast milk, and seminal fluids are minor routes of excretion (Chamberlain et al. 1978; 

Griffin et al. 1975; Hernandez-Ochoa et al. 2005; Hursh and Suomela 1968; Hursh et al. 1969; Kehoe 

1987; Rabinowitz et al. 1976; Sears et al. 2012; Stauber et al. 1994). Fecal excretion accounts for 

approximately one-third of total excretion of absorbed Pb (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 Pb particles (Chamberlain et al. 1978; Hursh et al. 1969). Contributors to fecal excretion may 

include secretion into the bile, gastric fluid, and saliva (Rabinowitz et al. 1976). Biliary excretion of Pb 

has been observed in the dog, rat, and rabbit (Klaassen and Shoeman 1974; O'Flaherty 1993).

Mechanisms by which inorganic Pb is excreted in urine have not been fully characterized. Such studies 

have been hampered by the difficulties associated with measuring ultrafilterable Pb in plasma and thereby 

in measuring the GFR of Pb. 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). Urinary 

Pb excretion is strongly correlated with the GFR of Pb (Araki et al. 1986) and plasma Pb concentration 

(Bergdahl et al. 1997b; Rentschler et al. 2012) (i.e., urinary excretion is proportional to GFR x plasma Pb 

concentration). Estimates of plasma-to-urine clearance of Pb range from 13 to 22 L/day, with a mean of 

18 L/day (Araki et al. 1986; Manton and Cook 1984; Manton and Malloy 1983; Chamberlain et al. 1978). 

The rate of urinary excretion of Pb was less than the GFR of ultrafilterable Pb, suggesting renal tubular 

reabsorption of Pb from the glomerular filtrate (Araki et al. 1986, 1990). Measurement of the renal 
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clearance of ultrafilterable Pb in plasma indicates that in dogs, Pb undergoes glomerular filtration and net 

tubular reabsorption (Araki et al. 1986, 1990; Vander et al. 1977; Victery et al. 1979). Net tubular 

secretion of Pb has been demonstrated in dogs made alkalotic by infusions of bicarbonate (Victery et al. 

1979). Renal clearance of blood Pb increases with increasing PbBs >25 μg/dL (Chamberlain 1983). The 

mechanism for this has not been elucidated and could involve a shift in the distribution of Pb in blood 

towards a fraction having a higher GFR (e.g., lower molecular weight complex), a capacity-limited 

mechanism in the tubular reabsorption of Pb, or the effects of Pb-induced nephrotoxicity on Pb 

reabsorption. Renal clearance of blood Pb has been estimated in approximately 7,600 subjects who 

participated in the NHANES 2009–2016 (Diamond et al. 2019). Blood Pb concentrations ranged from 

0.05 to 34 μg/dL, with medians of 0.54 μg/dL in adolescents (12–<20 years old) and 1.08 μg/dL in adults 

(≥20 years old). The median blood Pb clearance was 0.043 L/day in adolescents and 0.040 L/day in 

adults. Blood Pb clearance was approximately 3% of GFR, estimated from creatinine clearance.

Excretion and Routes of Exposure

Inhalation Exposure

Inorganic Pb. Inorganic Pb 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 Pb-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 3.1.1).

Organic Pb. Pb derived from inhaled tetraethyl and tetramethyl Pb 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 Pb, 51% of the inhaled 203Pb dose was initially deposited in the 

respiratory tract, of which approximately 40% was exhaled in 48 hours. Pb that was not exhaled was 

excreted in urine and feces. Fecal/urinary excretion ratios were 1.8 following exposure to tetraethyl Pb 

and 1.0 following exposure to tetramethyl Pb (Heard et al. 1979). Occupational monitoring studies of 

workers who were exposed to tetraethyl Pb have shown that tetraethyl Pb is excreted in the urine as 
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diethyl Pb, ethyl Pb, and inorganic Pb (Turlakiewicz and Chmielnicka 1985; Vural and Duydu 1995; 

Zhang et al. 1994).

Oral Exposure

Inorganic Pb. Much of the available information on the excretion of ingested Pb 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 Pb 

intake and excretion. Total Pb 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 Pb in saliva, gastric secretions, bile, and pancreatic secretions (samples collected from 

three subjects by intubation), gastrointestinal secretion of Pb 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 Pb excretion accounted for approximately 5% of the ingested dose (Kehoe 1987). 

Elimination of Pb is multiphasic, reflecting pools of Pb in the body that have varying retention times. 

Elimination from blood and soft tissues is faster than bone (Nilsson et al. 1991; Rabinowitz et al. 1976). 

As a result, after an abrupt decrease in exposure, PbB declines at an apparent rate that reflects excretion of 

Pb from blood and replenishment of Pb in blood from bone stores. The elimination half-time of Pb in 

blood in retired Pb workers was tri-exponential, with approximately 22% of elimination occurring at a 

half-time of 34 days (95% CI: 29, 41), 28% at a half-time of 1.2 years (95% CI: 0.85, 1.8), and 50% at a 

half-time of 13 years (95% CI: 10, 18) (Nilsson et al. 1991). The corresponding mono-exponential halftime for finger bone (XRF) in these same subjects was 16 years (85% CL 12, 23). Apparent elimination 

half-times for blood Pb in children also vary considerably, dependent in part on age and exposure history 

of the child that establishes levels of Pb in bone (Manton et al. 2000; Specht et al. 2018). Manton et al. 

(2000) estimated apparent elimination half-times for PbB in children (ages 2–3 years at time of exposure) 

that ranged from 8 to 38 months. However, these estimates reflect both excretion of Pb from blood as 

well as transfer of Pb from bone to blood; the latter would tend to increase the apparent blood elimination 

half-time. Specht et al. (2018) estimated blood Pb elimination half-times for Pb transferred from bone to 

blood (estimated with XRF measurements and biokinetics modeling). Estimated blood Pb half-times 

were 6.9±4 (SD) days in children 1–3 years old and 19.3±14.1 days in children >3 years old (Specht et al. 

2018). 
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Dermal Exposure. Inorganic Pb is excreted in sweat and urine following dermal exposure to Pb nitrate or 

Pb acetate (Moore et al. 1980; Stauber et al. 1994).

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

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 endpoints. 

Early Pb 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 Pb isotope tracers and Pb balance data in five healthy adult males. The 

Rabinowitz model included 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 Pb 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. The model predicted pseudo-first-order half-times for Pb of 

approximately 25, 28, and 104 days in the central, shallow tissue, and deep compartments, respectively. 

The slow kinetics of the deep tissue compartment led to the prediction that it would contain most of the 

Pb burden after lengthy exposures (e.g., years), consistent with Pb measurements made in human autopsy 

samples (see Section 3.1.2 Distribution). Note that this model did not simulate the distribution of Pb 

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.
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Marcus (1985b) reanalyzed the data from stable isotope tracer studies of Rabinowitz et al. (1976) and 

derived an expanded multicompartment kinetic model for Pb that 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 Pb disposition in bone included explicit simulation 

of diffusion of Pb within the bone volume of the osteon and exchange with blood at the canaliculus 

(Marcus 1985a). The bone diffusion model was based on Pb kinetics data from studies conducted in 

dogs. Marcus (1985c) also introduced nonlinear kinetics of exchange of Pb between plasma and 

erythrocytes. The blood model included four blood subcompartments: diffusible Pb in plasma, proteinbound Pb in plasma, a "shallow" erythrocyte pool, and a "deep" erythrocyte pool. This model predicted 

the curvilinear relationship between plasma and PbBs observed in humans (see Section 3.1.2 Distribution 

for further discussion of plasma-erythrocyte Pb concentrations).

Additional information on Pb biokinetics, bone mineral metabolism, and Pb exposures has led to further 

refinements and expansions of these earlier modeling efforts. Four pharmacokinetic models, in particular, 

are currently being used or are being considered for broad application in Pb risk assessment: (1) the 

O'Flaherty Model, which simulates Pb kinetics from birth through adulthood (O'Flaherty 1993, 1995a); 

(2) the EPA Integrated Exposure Uptake BioKinetic (IEUBK) Model for Lead in Children developed by 

EPA (1994a, 1994b); (3) the Leggett Model, which simulates Pb kinetics from birth through adulthood 

(Leggett 1993); and (4) the EPA All Ages Lead Model (AALM, EPA 2014a). The AALM is currently 

under review by EPA; a version of the model is available at https://cfpub.epa.gov/ncea/risk/

recordisplay.cfm?deid=343670 (January 10, 2020). The structure and parameterization of the O'Flaherty 

Model is distinct from both the IEUBK Model and Leggett Model. The AALM is an update of the 

O’Flaherty and Leggett models, extended to include a multi-media exposure model. 

The IEUBK Model simulates multimedia exposures, uptake, and kinetics of Pb in children ages 0–7 years 

for predicting pseudo-steady state relationships between Pb exposure and PbB; the model is not intended 

for use in predicting short-term kinetics of blood Pb or Pb concentrations in tissues other than whole 

blood. The O'Flaherty Model, Leggett Model, and AALM are lifetime models, and include parameters 

that simulate uptake and kinetics of Pb during infancy, childhood, adolescence, and adulthood. Pb 

exposure (e.g., residence-specific environmental Pb concentrations, childhood activity patterns) is not 

readily described by current versions of the O’Flaherty and Leggett models. The IEUBK Model and 

AALM include parameters for simulating exposures and uptake to estimate average daily uptake of Pb 
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(μg/day) among populations potentially exposed via soil and dust ingestion, air inhalation, tap water 

ingestion, diet, and miscellaneous (other) intakes. All four models have been calibrated, to varying 

degrees, against empirical physiological data on animals and humans, and data on PbBs in individuals 

and/or populations (Beck et al. 2001; Bowers and Mattuck 2001; Cal EPA 2013; EPA 1994a, 1994c, 

2014a, 2014b, 2016; Griffin et al. 1999; Hogan et al. 1998; Leggett 1993; Li et al. 2016a; MacMillan et 

al. 2015; O'Flaherty 1993, 1995a, 1998, 2000; Pounds and Leggett 1998; White et al. 1998; Von Lindern 

et al. 2003, 2016). 

The focus on relying on PbBs for model evaluation and calibration derives from several concerns. The 

empirical basis for a relationship between low levels of Pb exposure and behavioral dysfunction largely 

consists of prospective epidemiological studies relating various indices of dysfunction with PbB (see 

Section 3.3). In this context, PbB has been related to health effects of Pb, and this is the main reason that 

the focus of interest in the models has been on estimating PbBs. Also, the most available data with which 

to calibrate and validate the models have been data relating exposure and/or Pb intake to blood 

concentration. Thus, there is greater confidence in the validity of the models for estimating blood 

concentrations, rather than Pb levels in other physiologic compartments. Although the principal adverse 

health effects of Pb have been related to concentrations of Pb in blood, other biomarkers of Pb exposure, 

such as bone Pb concentrations, are also of value in assessing associations between Pb exposure and 

health; hence, there is a need for models that predict concentrations of Pb in tissues other than blood (see 

Section 3.3). 

The following four 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); (3) the 

Leggett Model (Leggett 1993); and (4) AALM (EPA 2014a).

3.1.5.1 O'Flaherty Model

The O'Flaherty Model simulates Pb exposure, uptake, and disposition in humans, from birth through 

adulthood (O'Flaherty 1993, 1995a). Figure 3-1 shows a conceptualized representation of the O'Flaherty 

Model, including the movement of Pb 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 PbBs 
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Figure 3-1. Compartments and Pathways of Lead (Pb) Exchange in the O’Flaherty 

Model*

*Schematic model for Pb kinetics in which Pb 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

Respiratory tract

Blood plasma

Well-perfused tissues

Poorly-perfused tissues

Cortical bone

Trabecular bone

Liver

Kidney

Urine

Air

Diet, Dust, 

Paint, Soil, 

Water

Feces

Gastrointestinal tract

Elimination pools of

the body

Intake from environmental

Media (μg/lead/year)

Body compartment
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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 Pb in the human body.

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 Pb in tissues. Other physiologic 

functions (e.g., bone formation) are linked to body weight, age, or both. 

Pb 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 Pb 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 Pb kinetics in bone. The model simulates an age-related transition 

from immature bone, in which bone turnover (formation and resorption) rates are relatively high, to 

mature bone, in which turnover 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 Pb uptake and loss is dominated by bone formation and 

loss, a region of slow kinetics in mature cortical bone is also simulated, in which Pb 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 Pb 

uptake and release from bone. Exchanges of Pb between blood plasma and soft tissues (e.g., kidney and 

liver) are represented as flow-limited processes. The model simulates saturable binding of Pb in 

erythrocytes; this replicates the curvilinear relationship between plasma and erythrocyte Pb 

concentrations observed in humans (see Section 3.1.2). 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 

GFR. Biliary and urinary excretory rates are proportioned as 70 and 30% of the total plasma clearance, 

respectively. 

The O'Flaherty Model simulates Pb intake from inhalation and ingestion. Inhalation rates are agedependent. Absorption of inhaled Pb is simulated as a fraction (0.5) of the amount inhaled, and is 
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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 Pb 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 Pb ingested in dust or soil.

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 Pb binding capacity (Beck et al. 2001). This extension of the model can be used to predict the 

probability that children exposed to Pb in environmental media will have PbBs exceeding a health-based 

reference value (e.g., 5 μg/dL). 

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).

The O'Flaherty Model was initially calibrated to predict blood, bone, and tissue Pb 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. Comparisons of 

predicted and observed PbB in children and adults are reported in O'Flaherty (1993, 1995a). MacMillan 

et al. (2015) evaluated performance of the model for predicting population blood and bone Pb levels in a 

convenience sample of 263 individuals (age range 1–83 years) who experienced low chronic exposure. 

Based on this evaluation, model performance for predicting general trends in population PbBs and 

cortical bone Pb concentrations was improved by revising parameters that determine binding of Pb in red 

blood cells. Revisions included decreasing the maximum and affinity constants (BIND and KBIND, 

respectively) and increasing clearance of Pb from blood to bone by increasing the permeability constant 

for Pb diffusion across the canaliculi-bone interface from canaliculi to bone (P0).
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3.1.5.2 EPA IEUBK Model

The EPA IEUBK Model for Lead in Children simulates Pb exposure, uptake, and disposition in human 

children from birth to age 7 years (EPA 1994a, 1994b, 2002a; White et al. 1998). Figure 3-2 shows a 

conceptualized representation of the IEUBK Model. The model has four major submodels: (1) exposure 

model, in which average daily intakes of Pb (μg/day) are calculated for each inputted exposure 

concentration (or rates) of Pb in air, diet, dust, soil, and water; (2) uptake model, which converts 

environmental media-specific Pb intake rates calculated from the exposure model into a media-specific 

time-averaged uptake rate (μg/day) of Pb to the central compartment (blood plasma); (3) biokinetic 

model, which simulates the transfer of absorbed Pb between blood and other body tissues, elimination of 

Pb from the body (via urine, feces, skin, hair, and nails), and predicts an average PbB for the exposure 

time period of interest; and (4) blood Pb probability model, which applies a log-normal distribution (using 

geometric mean and geometric standard deviation for parameters) to predict probabilities for the 

occurrence of a specified given PbB in a population of similarly exposed children.

Exposure Model. The exposure model simulates intake of Pb (μg/day) for inputted exposures to Pb 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 Pb to soil-derived 

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 Pb absorption for the gastrointestinal tract as the sum of 

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 Pb absorption, an approach that is in accord with limited available data in humans and 

animals that suggest a capacity limitation to Pb absorption (see Section 3.2.1). One of the parameters for 

the capacity-limited absorption process (that represents that maximum rate of absorption) is agedependent. The above representation gives rise to a decrease in the fractional absorption of ingested Pb as 

a function of total Pb intake as well as an age-dependence of fractional Pb absorption. Absorption 
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Figure 3-2. Structure of the IEUBK Model for Lead (Pb) in Children*

*Schematic for integrated Pb exposure-kinetics model in which simulated multi-media exposures are linked to 

simulations of lead uptake (i.e., absorption into the plasma-extracellular fluid), tissue distribution, and excretion). 

Sources: EPA 1994a, 1994b

Gastrointestinal tract Respiratory 

tract

Diet

Elimination pools of

the body

Intake from environmental

Media (μg/lead/day)

Air Water Dust Soil Other

Exposure Component

Gastrointestinal tract Respiratory

tract

Uptake Component

Plasma extra-cellular fluid

Feces

Red blood 

cells

Biokinetic Component

Plasma extra-cellular fluid Feces

Trabecular 

bone

Cortical 

bone Kidney Other soft 

tissues Liver

Urine

Skin,

hair,

nails

Body compartment

Body compartment or 

elimination pool required in 

more than one component
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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 Pb in food or 

drinking water that is absorbed is 0.5 and decreases to approximately 0.11 (intake, >5,000 μg/day). For 

Pb 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 Pb 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 Pb 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. Pb deposited in the alveolar 

region is assumed to be completely absorbed from the respiratory tract, whereas Pb deposited in the 

nasopharyngeal and tracheobronchial regions (30–80% of the Pb 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 (urine, feces, lumped pool representing skin, hair, and nails). 

The body compartments include plasma and extracellular fluid (central compartment), red blood cells, 

kidney, liver, trabecular bone, cortical bone, and other soft tissue (EPA 1994a). The model simulates 

growth of the body and tissues, compartment volumes, and Pb masses and concentrations in each 

compartment. PbB at birth (neonatal) is assumed to be 0.85 of the maternal blood Pb. Neonatal Pb 

masses and concentrations are assigned to other compartments based on a weighted distribution of the 

neonatal PbB. 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 Pb into erythrocytes is simulated, with a maximum erythrocyte Pb concentration of 

12 μg/dL. Excretory routes simulated include urine, from the central compartment; bile-feces, from the 

liver; and a lumped excretory pathway representing losses from skin, hair and nail, from the other soft 

tissue compartment.

Blood Pb 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 tendency 

estimate of PbB for children who might experience the inputted exposures. However, within a group of 
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similarly exposed children, PbBs 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 PbB for which the geometric mean is given by 

the central tendency PbB 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 PbB within a population of similarly exposed children. The model can be iterated for varying 

exposure concentrations (e.g., a series of increasing soil Pb concentrations) to predict the media 

concentration that would be associated with a probability of 0.05 for the occurrence of a PbB 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 alternative to the blood Pb probability model for 

incorporating, explicitly, estimates of variability (and uncertainty in variability) in exposure and 

absorption into predictions of an expected probability distribution of PbBs. More recently, Zartarian et al. 

(2017) provided an analysis coupling the IEUBK model with EPA’s Stochastic Human Exposure and 

Dose Simulation (SHEDS)-Multimedia Model that considered general U.S. childhood exposures 

probabilistically and assessed primary sources of Pb exposure across the distribution of PbB.

Performance of the IEUBK Model has been evaluated for predicting observed PbBs in children (Hogan et 

al. 1998; Li et al. 2016a; Von Lindern et al. 2003, 2016). The largest evaluation utilized longitudinal 

exposure and blood Pb data for approximately 2,200 children who resided near a former smelter in 

northern Idaho (Bunker Hill site) during a 14-year period of remediation activities (Von Lindern et al. 

2003, 2016). The observed annual blood Pb geometric means ranged from 2.5 to 10.6 μg/dL. The model 

predicted the time course of the observed PbBs as the remediation progressed when the gastrointestinal 

absorption fraction was calibrated to agree with blood Pb observations (Von Lindern et al. 2003). A 

similar outcome was obtained in a subsequent analysis in which the gastrointestinal absorption fraction 

was adjusted to agree with site measurements of soil Pb RBA, and soil and dust ingestion rates were 

calibrated to the blood Pb observations (Von Lindern et al. 2016). The mean difference between 

predicted and observed annual geometric mean PbBs (predicted - observed) was -0.31 μg/dL 

(range: -1.07, 1.93) and the mean relative percent difference was -8.4% (range: -23–21%). Applications 

of the IEUBK Model to the Bunker Hill site were reviewed by the National Research Council (NRC 

2005). Hogan et al. (1998) evaluated the IEUBK Model performance based on residential exposure and 

blood data for approximately 478 children who resided near three Pb mining and smelting sites. The 

observed geometric means for the three sites ranged from 5.2 to 6.8 μg/dL. The IEUBK Model 

predictions agreed reasonably well with observations for children whose exposures were predominantly 
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from their residence (e.g., who spent no more than 10 hours/week away from home). The mean 

difference between predicted and observed site geometric mean PbBs (predicted-observed) was 

0.03 μg/dL (range -0.6–0.7) and the mean relative percent difference was -0.4% (range -12–10%). The 

predicted geometric mean PbBs were within 0.7 μg/dL of the observed geometric means at each site. The 

prediction of the percentage of children expected to have PbBs exceeding 10 μg/dL were within 4% of the 

observed percentage at each site. Li et al. (2016a) compared predictions of PbB to observations in a 

cohort of 760 children in Central China. The observed residence area geometric means ranged from 5 to 

14 μg/dL. When exposure parameters were set to the study population (e.g., exposure media Pb 

concentration and intakes), predicted and observed PbBs were not significantly different. The mean 

difference between predicted and observed geometric mean PbBs for 21 residence areas (predictedobserved) was 0.55 μg/dL (range -2.0–3.2) and the mean relative percent difference was 3.5% (range -32–

28%). These evaluations provide support for the validity of the IEUBK Model for estimating PbBs in 

children at sites where their exposures can be adequately characterized. Similar empirical comparisons of 

the IEUBK Model have shown that agreement between model predictions and observed PbBs at specific

locations is influenced by numerous factors, including the extent to which the exposure and blood Pb 

measurements are adequately matched, and site-specific factors (e.g., soil characteristics, behavior 

patterns, bioavailability) that may affect Pb intake or uptake in children (Bowers and Mattuck 2001; Von 

Lindern et al. 2003, 2016). 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). 

3.1.5.3 Leggett Model

The Leggett Model simulates Pb intake, absorption, and disposition in humans, from birth through 

adulthood (Leggett 1993). Figure 3-3 shows a conceptualized representation of the model, including the 

movement of Pb 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, Pb exposure estimates are incorporated into the model as age-specific 

point estimates of average daily intake (μg/day) from inhalation and ingestion. A description of the 

model and its potential application to risk assessment are provided below.
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Figure 3-3. Compartments and Pathways of Lead (Pb) Exchange in the Leggett 

Model*

*Schematic model for Pb kinetics in which Pb distribution is represented by exchanges between the central plasmaextracellular fluid and tissue compartments. Bone is represented as having surface (which rapidly exchanges with 

plasma-extracellular fluid) and volume compartments; the latter simulates slow exchange with the surface and slow 

return of Pb to the plasma-extracellular fluid from bone resorption. 

GI = gastrointestinal; RBC = red blood cell; RT = respiratory

Source: Leggett 1993

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

RT Tract

GI Tract

Other 

Kidney 

Tissue

Urinary 

Path

Kidneys

Bladder 

Contents

Urine

Feces

Losses in 

Hair, Nails, 

Skin

Sweat

Bound 

Plasma

Brain

Liver 2

Liver 1

Liver

Diffusible 

Plasma

ExtraVascular

RBC

Tenacious 

Turnover

Rapid 

Turnover

Intermediate 

Turnover

Other Soft Tissues

Tenacious 

Turnover

Rapid 

Turnover

Intermediate 

Turnover

Other Soft Tissues

Cortical 

Surface

Trabecular 

Surface

Cortical Volume

NonExchange Exchange

Trabecular Volume

NonExchange Exchange

Skeleton

RT Tract

GI Tract

Other 

Kidney 

Tissue

Urinary 

Path

Kidneys

Other 

Kidney 

Tissue

Urinary 

Path

Kidneys

Bladder 

Contents

Urine

Feces

Losses in 

Hair, Nails, 

Skin

Sweat

Bound 

Plasma
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The Leggett Model includes a central compartment, 15 peripheral body compartments, and 4 elimination 

pools (urine, feces, sweat, and lumped pool representing skin, hair, and nails), as illustrated in Figure 3-3. 

Transport of Pb from blood plasma to tissues is assumed to follow first-order kinetics. Transfer rate 

constants vary with age and PbB. 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 cells observed in humans (see Section 3.1.2). The model simulates blood volume as an agedependent function, which allows simulation of plasma and PbBs. Pb 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 Pb 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 

Pb 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 Pb (Leggett 1993). The Leggett Model simulates agedependent bone physiology using a model structure developed for application to the alkaline earth 

elements, but parameterized using data specific to Pb where possible. The model simulates both rapid 

exchange of Pb 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 Pb with the blood plasma, and bone volume, within which are

exchangeable and nonexchangeable pools. Pb 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 Pb 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 Pb from 

plasma and a relatively short removal half-time (days) for transfers to plasma and to the small intestine by 

biliary secretion, and a second compartment simulates a more gradual transfer to plasma of approximately 

10% of Pb uptake in liver. The kidney is simulated as two compartments: one that exchanges slowly with 
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blood plasma and accounts for Pb accumulation in kidney tissue, and a second compartment that receives 

Pb from blood plasma and rapidly transfers Pb 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 Pb 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 Pb is 

deposited and absorbed with half-times of 1, 3, 10, and 48 hours. Four percent of the inhaled Pb 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 

Pb-bearing 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 3.1.1). Absorption of ingested Pb is 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.

Output from the Leggett Model has been compared with data in children and adult subjects exposed to Pb 

in order to calibrate model parameters (Leggett et al. 1993; Pounds and Leggett 1998). Nie et al. (2005) 

evaluated performance of the Leggett Model for predicting bone Pb concentrations in 539 Pb workers. 

The data included periodic monitoring of PbBs and XRF bone Pb measurements made in 1994 and 1999. 

Pb intakes of each individual were calibrated to agree with measured PbBs. The Leggett Model 

underpredicted observed cortical bone Pb concentrations by a factor of 3–4, and underpredicted trabecular 

bone Pb concentration by a factor of 12–18. EPA (2014a) evaluated performance of the Leggett Model 

for predicting PbBs in children and blood and bone Pb concentrations in adults. The evaluation of 

predictions for children used data on PbBs reported in the NHANES for the years 2007–2008, and 

required making assumptions about Pb exposures in this population. The Leggett Model overpredicted 

observed PbBs in children 1–7 years of age by a factor of 2–3. Cal EPA (2013) evaluated the Leggett 

Model for predicting PbBs in smelter workers whose occupational exposures were interrupted during a 

workers strike. Pre-hire background Pb intakes and pre-strike intakes were calibrated to agree with 

measured PbBs and the predicted rate of decline in blood Pb that occurred during the strike period was 

compared to observations. Cal EPA (2013) reported “the average difference between the measured and 

predicted post-strike BLL was unacceptably large and indicated significant under-prediction of BLLs”. 
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The average difference was >4 μg/dL in a cohort that had a mean post-strike PbB of 31 μg/dL (no further 

details were provided). Performance was substantially improved when various parameters were 

calibrated to the observations. These included parameters that control transfers between plasma and bone 

and red blood cell saturation (see Cal EPA [2013] for details of parameter value changes). The mean 

difference between predicted and observed annual geometric mean PbBs (predicted-observed) was -0.9 

μg/dL (range -26–32) and the mean relative percent difference was -8.8% (range: -55–320%). Cal EPA 

(2013) reported several other evaluations of their recalibrated model, including observed and predicted 

relationships between plasma and whole PbBs in adults, and predicted distribution of Pb in bone and soft 

tissues compared to estimates from human autopsy studies.

3.1.5.4 EPA All Ages Lead Model (AALM)

The AALM simulates blood and tissue Pb masses (μg) and concentrations (μg/g) resulting from 

exposures to Pb in air, drinking water, surface dust (e.g., indoor dust, soil dust), food, or miscellaneous Pb 

ingestion pathways. The AALM exposure module allows the user to simulate multi-pathway exposures 

that are constant or that vary in time increments as small as 1 day and that occur at any age from birth to 

90 years. The user can select to run a systemic biokinetics simulation based on either the Leggett 

(AALM-LG) or O’Flaherty (AALM-OF) biokinetics models. Parameters in both systemic models were 

re-calibrated with observations of blood, bone, and soft tissue Pb concentrations in children and adults 

(EPA 2014a). The version of the AALM described in EPA (2014a) was implemented in Advanced 

Continuous Simulation Language (acslX, ver. 3.1.4.2). The ICRP Human Respiratory Tract Model 

(HRTM) deposition and absorption parameters are used in both the AALM-LG and AALM-OF, which 

allows simulation of inhaled Pb particles of specified size ranges and absorption kinetics (ICRP 1994). 

The gastrointestinal tract model includes age-dependent absorption fractions and parameters for RBA of 

Pb from all ingestion pathways.

The structures of the two systemic biokinetics models in AALM-OF and AALM-LG are based on the 

O’Flaherty and Leggett models, respectively, with the following modifications. Growth parameters from 

the O’Flaherty Model are used in both models to simulate age-dependent body weight tissue weights. 

This provides a means for calculating tissue concentrations as the Pb mass (μg) divided by the tissue 

weight (g). Concentrations of Pb in bone wet weight are converted to concentration per g bone mineral 

by dividing the wet weight concentration by the ash fraction of bone. This conversion provides a means 

for comparing model predictions of bone Pb concentration with bone XRF data, which is typically 

reported in units of Pb per g bone mineral. Parameters for RBA of Pb in each intake medium include the 
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gastrointestinal tract model. This provides a means for independently adjusting the absorption fraction 

for each of the intake pathways (including respiratory tract-to-gastrointestinal tract) and maintains mass 

balance for fecal excretion of unabsorbed Pb. Inhalation, deposition, mucociliary clearance, and 

absorptive clearance of airborne Pb is simulated with a simplified implementation of the ICRP HRTM. 

The AALM systemic biokinetic models were recalibrated from the original Leggett and O’Flaherty 

Models (EPA 2014b). The sequential recalibration utilized several sources of data on blood and bone Pb 

concentrations in humans. Parameters that control the uptake and retention of Pb in red blood cells were 

recalibrated using paired data on whole blood and plasma Pb concentrations in children and adults 

(Bergdahl et al. 1997c, 1998, 1999; Hernández-Avila et al. 1998; Manton et al. 2001; Schütz et al. 1996; 

Smith et al. 2002). Parameters that control plasma-to-urine clearance were recalibrated based on 

clearance estimates from studies that measured paired plasma concentration and urinary Pb excretion in 

adults (Araki et al. 1986; Chamberlain et al. 1978; Manton and Cook 1984; Manton and Malloy 1983). 

Autopsy data from children and adults were used to evaluate parameters that control the relationship 

between of tissue Pb concentrations and bone Pb concentrations (Barry 1975). The relationship between 

bone and plasma Pb concentrations was evaluated with paired data for plasma Pb concentration and XRF 

bone Pb in adults (Cake et al. 1996; Hernández-Avila et al. 1998). The long-term rate elimination of Pb 

from blood and bone was evaluated with data on blood and XRF bone Pb in retired Pb workers (Nilsson 

et al. 1991).

The calibrated AALM was evaluated with data on PbBs measured in infants (Ryu et al. 1983; Sherlock 

and Quinn 1986) or adults (Rabinowitz et al. 1976) who consumed known quantities of Pb. In the Ryu et 

al. (1983) study, PbBs were monitored in formula-fed infants who were fed measured quantiles of 

formula. PbBs predicted from the AALM-LG were within 1 SD of the group means and the r2 for 

predictions was 0.85. Predictions from the AALM-OF were uniformly higher than observations and the 

r

2 for predictions was 0.76. Sherlock and Quinn (1986) measured PbB in infants at age 13 weeks and 

estimated dietary intake of Pb for each infant based on Pb measurements made in duplicate diet samples 

collected daily during week 13. The observed dose-blood Pb relationship was predicted with r2 values of 

0.95 for AALM-LG and 0.98 for AALM-OF. Rabinowitz et al. (1976) conducted a pharmacokinetics 

study in which four adults ingested daily doses of [207Pb] nitrate for periods up to 124 days. 

Concentrations of 207Pb in blood, urine, and feces were then monitored during and following cessation of 

exposure, and data on daily intakes and blood concentrations for each subject were reported. Absorption 

fractions for Pb were estimated for each individual based on mass balance in feces. AALM-LG 
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predictions are closer to the observations; r2 values ranged from 0.92 to 0.98 for four subjects in the study. 

The AALM-OF predicted a slower accrual and decline of blood Pb, and lower peak PbBs (r2 <0.25).

3.1.5.5 Model Comparisons

The O’Flaherty, IEUBK, and Leggett Model differ considerably in the way each represents tissues, 

exchanges of Pb between tissues, and Pb exposure. The AALM includes biokinetics models based on, 

but updated from, the O’Flaherty and Leggett models.

Figure 3-4 compares the PbBs predicted by each model for a hypothetical child who ingests 100 μg 

Pb/day in soil for a period of 1 year beginning at the age of 2 years (e.g., equivalent to ingestion of 100 μg 

soil/day at a soil Pb concentration of 1,000 mg Pb/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 five models predict 

an increase in PbB towards a quasi-steady state during the exposure period, followed by a decline towards 

the pre-exposure baseline PbB with an apparent half-time of approximately 1 month. Predicted PbBs at 

the end of the 12-month soil exposure period were 10, 23, 5.9, 9.4, and 10.4 μg/dL for the IEUBK Model, 

Leggett Model, O’Flaherty Model, AALM-LG, and AALM-OF, respectively. Differences in the 

magnitude of the predicted impact of the soil exposure on PbB reflect differences in assumptions about Pb 

biokinetics and cannot be attributed solely to different assumptions about Pb bioavailability. 

Bioavailability assumptions in the 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 Pb at low intakes); Leggett 

Model, 30%; and AALM-LG and AALM-OF 34% (38% at age 2 years and decreasing to 30% at age 

3 years). 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 3-5. Predicted PbBs at the end of the 12-month soil 

exposure period were 8.4, 3.3, 4.0, and 4.8 μg/dL for the Leggett Model, O’Flaherty Model, AALM-LG, 

and AALM-OF, respectively. All four 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 Pb 

bioavailability in adults (i.e., O’Flaherty, 8%; Leggett, 15%; AALM-LG and AALM-OF, 8%).
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Figure 3-4. Blood Lead Concentrations (PbBs) in Children Predicted by the 

IEUBK, Leggett, and O’Flaherty Models and AALM* 

*The simulations are of a hypothetical child who has a PbB of 2 μg/dL at age 2 years, and then experiences a 1-year 

exposure to 100 μg Pb/day. The 100 μg/day exposure was simulated as an exposure to lead in soil in the IEUBK 

Model. Default bioavailability assumptions were applied in all three models. 

Figure 3-5. Blood Lead Concentrations (PbBs) in Adults Predicted by the Leggett 

and O’Flaherty Models and AALM* 

*The simulations are of a hypothetical adult who has a PbB of 2 μg/dL at age 25 years, and then experiences a 

1-year exposure to 100 μg Pb/day. Default bioavailability assumptions were applied in all three models. 

0

5

10

15

20

25

0 1 2 3 4 5 6 7

Blood Lead (ug/dL)

Age (year)

Base

IEUBK Model

Leggett Model

O'Flaherty Model

AALM-LG

AALM-OF

0

2

4

6

8

10

21 22 23 24 25 26 27 28 29 30

Blood Lead (μg/dL)

Age (year)

Leggett Model

O'Flaherty Model

AALM-LG

AALM-OF
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3.1.5.6 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. 1997; Bowers et al. 1994; Carlisle 

and Wade 1992; EPA 2017d; Maddaloni et al. 2005; Stern 1994, 1996). In slope factor models, Pb 

biokinetics is represented with a simple linear relationship between the PbB and either Pb uptake 

(biokinetic slope factor, BSF) or Pb intake (intake slope factor, ISF). The models take the general 

mathematical forms:

where E is an expression for exposure (e.g., soil intake x soil Pb concentration) and AF is the absorption 

fraction for Pb in the specific exposure medium of interest. Intake slope factors are based on ingested Pb, 

rather than absorbed Pb and, therefore, integrate both absorption and biokinetics into a single slope factor, 

whereas models that utilize a biokinetic slope factor (BSF) to account for absorption in the relationship 

include an absorption parameter. Slope factors used in various models are presented in Table 3-2. Of the 

various models presented in Table 3-2, the Bowers et al. (1994) and EPA (2017b) models implement 

BSFs. The slope factors used in both models (approximately 0.4 μg/dL per μg Pb/day) are similar to 

BSFs predicted from the O’Flaherty Model (0.65 μg/dL per μg Pb uptake/day) and Leggett Model 

(0.43 μg/dL per μg Pb uptake/day) for simulations of adult exposures (Maddaloni et al. 2005).

Table 3-2. Comparison of Slope Factors in Selected Slope Factor Models

Model Receptor

Slope factor Absorption 

Intake route Intake Biokinetics fraction

Bowers et al. 1994 Adult Ingestion of soil/dust ND 0.375 0.08

Carlisle and Wade 

1992

Child Ingestion of soil/dust

Ingestion of water

0.07

0.04

ND ND

Carlisle and Wade 

1992

Adult Ingestion of soil/dust

Ingestion of water

0.018

0.04

ND ND

Cal EPA 2017 Child Ingestion of soil/dust

Inhalation of 

respirable dust

Dermal contact

ND

0.192

0.0001

0.16

ND

ND

0.44

ND

ND

EPA 2017d; 

Maddaloni et al. 

2005

Adult Ingestion of soil/dust ND 0.4 0.12

PbB = E ⋅ ISF

PbB = E ⋅ AF ⋅ BSF
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Table 3-2. Comparison of Slope Factors in Selected Slope Factor Models

Model Receptor

Slope factor Absorption 

Intake route Intake Biokinetics fraction

Stern 1994 Child Ingestion of soil/dust T (0.056, 0.16, 0.18) ND ND

Stern 1996 Adult Ingestion of soil dust U (0.014, 0.034) ND ND

ND = no data; T = triangular probability distribution function (PDF); U = uniform PDF

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans. 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. Children may be more or less susceptible than adults to health 

effects from exposure to hazardous substances and the relationship may change with developmental age. 

This section also discusses unusually susceptible populations. A susceptible population may exhibit 

different or enhanced responses to certain chemicals than most persons exposed to the same level of these 

chemicals in the environment. Factors involved with increased susceptibility may include genetic 

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters can reduce detoxification or excretion or compromise organ function. 

Populations at greater exposure risk to unusually high exposure levels to Pb are discussed in Section 5.7, 

Populations with Potentially High Exposures.

Age. Children and the elderly are likely to have increased susceptibility to Pb compared to non-elderly 

adults. As reviewed in Section 3.1.2 (Distribution), Pb crosses the placenta and is distributed to the fetus; 

neonates are also exposed to Pb in breast milk. Epidemiological studies show that umbilical cord PbB 

(reflective of neonatal PbB) and PbB in infants are associated with adverse health outcomes during 

childhood, including decrements in neurological function (reviewed in Chapter 2). Results of a few 

studies that have followed children to early adulthood show an association between child PbB and 

behavioral and neuroanatomical changes in adults, suggesting a possible role of exposures in childhood to 

adult outcomes. Children are likely to be more susceptible than adults to Pb for the following reasons: 

(1) it is generally accepted that developing systems are more susceptible than mature systems; 

(2) absorption of Pb is higher in children compared to adults (see Section 3.1.1, Absorption); and 
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(3) children exhibit behaviors that increase ingestion of Pb surface dusts (e.g., hand-to-mouth activity, 

pica behavior [the compulsive, habitual consumption of nonfood items]), proximity of breathing zone to 

entrained surface dust). 

Regarding the elderly, it is well-established that physiological functions (e.g., renal, neurological, 

cardiovascular) decline with age. Thus, populations with age-related compromises in physiological 

function would be anticipated to be more susceptible to Pb than younger populations. Furthermore, 

because aging is associated with bone loss, Pb is mobilized into blood, resulting in potential increases in 

PbB.

Sex. As reviewed in Chapter 2, some epidemiological studies examined health outcomes in populations 

stratified by sex. However, studies have not demonstrated clear sex-related susceptibilities to Pb-induced 

toxicity for any health effect outcome. In women, pregnancy, lactation, and post-menopausal status may 

increase bone demineralization, mobilizing bone Pb into the blood and potentially redistributing Pb to 

other tissues. 

Nutritional Status. As discussed in Sections 3.1 (Toxicokinetics) and 3.4 (Interactions with other 

Chemicals), dietary calcium and nutritional status of iron and zinc can affect absorption of Pb, potentially 

leading to alterations in PbB and health effects. See Sections 3.1 and 3.4 for additional details. 

Pre-existing Conditions, Diseases, and Exposure to Other Substances. Because health effects 

associated with Pb are observed in every organ system, it is assumed that any condition or disease that 

compromises physiological functions could cause increased susceptibility to Pb. Examples of underlying 

conditions include diseases of the kidney (e.g., glomerular nephritis), neurological system (e.g., autism), 

hematological system (e.g., anemia, thalassemia), and cardiovascular system (e.g., hypertension, cardiac 

conduction disorders). Similarly, increased susceptibility to Pb would be anticipated due to use of 

alcohol, tobacco, or any other substance that causes deficits in physiological function. 

Genetic Polymorphisms. Numerous genetic polymorphisms that may alter susceptibility to Pb through 

altered toxicokinetics (i.e., absorption, distribution, and retention of Pb) or toxicodynamics (e.g., effects) 

have been identified. The most well-studied polymorphisms are δ-ALAD and the VDR. Several other 

polymorphisms that may alter susceptibility to Pb have been identified, although little data are available. 

In addition to the references listed below, information also was obtained from a recent review by Broberg 

et al. 2015.
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ALAD. As reviewed in Section 2.8 (Heath Effects, Hematological), Pb binds to and inhibits δ-ALAD, 

causing decreased hemoglobin formation, measurable decreases in blood hemoglobin concentration, and 

anemia. δ-ALAD is the major binding site for Pb in the blood (see Section 3.1.2). As such, 

polymorphisms of ALAD have the potential to alter Pb toxicokinetics, and thereby alter health effects. 

Many studies have evaluated the potential effects of ALAD polymorphisms on Pb distribution and 

toxicity. Information reviewed below was obtained from the following publications: Åkesson et al. 

(2000); Alexander et al. (1998b); Astrin et al. (1987); Battistuzzi et al. (1981); Bellinger et al. (1994); 

Bergdahl et al. (1997a, 1997b); Chia et al. (2005); Chiu et al. (2013); Fang et al. (2010); Fleming et al. 

(1998a); Gao et al. (2010); Hsieh et al. (2000); Hu et al. (2001); Huo et al. (2014); Jaffe et al. (2000, 

2001); Kim et al. (2004); Krieg et al. (2009); Lee et al. (2001); Mitra et al. (2017); Ong et al. (1990); 

Pagliuca et al. (1990); Pawlas et al. (2012); Petrucci et al. (1982); Sakai et al. (2000); Schwartz (1995); 

Schwartz et al. (1995, 1997a, 1997b, 2000a, 2000b); Scinicariello et al. (2007, 2010); Shen et al. (2001); 

Sithisarankul et al. (1997); Smith (1995); Suzen et al. (2003); Szymanska-Chaowska et al. (2015); Tasmin 

et al. (2015); Warrington et al. (2015); Weaver et al. (2008); Wetmur et al. (1991a, 1991b); Wu et al. 

(2003a); and Zheng et al. (2011).

The ALAD gene encodes for the heme metabolism enzyme δ-ALAD. 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). 

The ALAD 2,2 genotype is rare, and is found in 1% of Caucasians; in contrast, the ALAD 1,1 and ALAD 

1,2 genotypes occur in 80 and 19%, respectively, of Caucasians. The ALAD 2,2 genotype occurs in <1% 

of Asian and African populations. A study using NHANES III data (1988–1994) reported that 15.6% of 

non-Hispanic whites, 2.6% non-Hispanic blacks, and 8.8% Mexican Americans carried the ALAD-2 

allele (Scinicariello et al. 2010). The ALAD-2 protein has a higher binding affinity than the ALAD-1 

protein for Pb. Due to this higher binding affinity, it has been proposed that ALAD-2 sequesters Pb in 

erythrocytes, limiting distribution of Pb to other tissues. Numerous studies have shown that ALAD-2 

carriers have higher PbB than ALAD-1 carriers. Although it has been demonstrated that ALAD genotype 

affects the toxicokinetics of Pb, the association between adverse effects of Pb and ALAD genotype have 

not been definitively established.

VDR. Several studies have evaluated the potential effects of VDR polymorphisms on Pb uptake and 

distribution. Information reviewed below was obtained from the following publications: Ames et al. 

(1999); Cooper and Umbach (1996); Gundacker et al. (2009, 2010); Haynes et al. (2003); Krieg et al. 

(2010); Mitra et al. (2017); Morrison et al. (1992); Onalaja and Claudio (2000); Rezende et al. (2008); 
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Schwartz et al. (2000a, 2000b); Szymanska-Chaowska et al. (2015); Theppeang et al. (2004); and Weaver 

et al. (2003b).

The VDR is located in the nucleus of intestinal, renal, and bone cells. It is involved in maintaining 

calcium and phosphate homeostasis and regulating bone metabolism. Binding of vitamin D3 (the active 

form of vitamin D) to the VDR activates genes that encode for various calcium-binding proteins involved 

in intestinal absorption and accumulation of calcium in bone. The VDR regulates the production of 

calcium-binding proteins, and accounts for up to 75% of the total genetic effect on bone density. Because 

Pb can replace and mimic calcium, the VDR plays a critical role in the accumulation of Pb in bone. The 

VDR has several polymorphic forms that are defined based on restriction enzyme digestion; these include 

FokI with three genotypes (FF, Ff, and ff) and BsmI with three genotypes (BB, Bb, bb). The FF genotype 

has been associated with higher PbB and increased bone mineral density and calcium uptake. The BB 

genotype has been associated with higher PbB and bone Pb. However, the role of VDR polymorphisms 

in the Pb uptake into bone remains to be fully elucidated.

Hemochromatosis gene (HFE). Information on HFE polymorphisms was taken from the following 

publications: Åkesson et al. (2000); Barton et al. (1994); Fan et al. (2014); Hopkins et al. (2008); Mitra et 

al. (2017); Onalaja and Claudio (2000); Park et al. (2009a); Wang et al. (2007); Wright et al. (2004); and 

Zhang et al. (2010). 

Hemochromatosis is an autosomal, recessive disease characterized by the excessive accumulation of iron 

in the body. In individuals with hemochromatosis, excess iron accumulates in various organs of the body

and causes damage to the liver and compromises cardiovascular function. Hemochromatosis is caused by 

mutations of the HFE gene, which result in defects to the HFE protein. In individuals with normal HFE, 

HFE binds to transferrin, decreasing the gastrointestinal absorption of iron; however, in individuals with 

hemochromatosis, the HFE protein is not functional, leading to an increased accumulation of iron. The 

absorption of Pb is linked to iron status such that Pb absorption increases when iron is limited. HFE 

polymorphisms have been shown to enhance Pb-induced cognitive impairment (Wang et al. 2007) and the 

HFE H63D polymorphism appears to enhance positive associations between bone Pb and pulse pressure 

(Zhang et al. 2010). However, the influence of HFE variants on absorption and health effects of Pb is still 

being defined. 

Other polymorphisms. Several other polymorphisms have been examined to evaluate potential alterations 

in susceptibility to adverse effects of Pb; however, little data are available. These include:
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• Apoprotein E (APOE). APOE is an intracellular transporter of cholesterol and fatty acids that is 

synthesized by astrocytes in the brain and plays a key role in the structure of cell membranes and 

myelin. There are three alleles of the APOE gene: E2, E3, and E4. It has been proposed that 

APOE gene variants may alter susceptibility to Pb-induced changes in neurodevelopment and 

neurological deficits (Stewart et al. 2002; Wright et al. 2003a).

• Dopamine receptor D4 (DRD4), Dopamine Receptor D2 (DRD2), and Dopamine Transporter 

(DAT1). Pb is associated with alterations in the dopaminergic system, which is involved in 

cognition and behavior. Thus, polymorphisms of DRD4, DRD2, and DAT1 may alter 

susceptibility to Pb-induced neurocognitive impairment (Froehlich et al. 2007; Kordas et al. 2011; 

Roy et al. 2011).

• N-Methyl-D-aspartate receptors (NMDAR subunits GRIN2A and GRIN2B). NMDARs mediate 

excitatory actions of glutamate in the central nervous system, which affect learning and memory. 

Polymorphisms in GRIN2A and GRIN2B have been shown to be interacting factors with PbB in 

association between PbB and cognitive performance in children (Rooney et al. 2018).

• Glutathione S-transferase mu 1 (GSTM1). Glutathione is an intracellular scavenger of oxidants 

and electrophiles. It is encoded by the polymorphic gene GSTM1. Genetic alterations causing a 

decrease in functional glutathione could result in increased oxidative damage or inflammation 

(Kim et al. 2007).

• Endothelial nitric oxide synthase (eNOS). Nitric oxide, an endogenous signaling molecule 

involved in vasodilation, is produced by a family of nitric oxide synthase enzymes, including 

eNOS. Polymorphisms of eNOS could increase susceptibility to Pb (Barbosa et al. 2006b).

• Metallothionein (MT). MT binds to and sequesters Pb. It has been proposed that polymorphisms 

of MT (MT1 and MT2) may affect binding of Pb to MT and lead to an increased PbB (Chen et al. 

2010; Fernandes et al. 2016; Mitra et al. 2017; Yang et al. 2013b).

• Peptide transporter 2 (PEPT2). Polymorphisms of PEPT2 have been associated with increased 

PbB in children (Sobin et al. 2009).

• Tumor necrosis factor-alpha (TNF-α): TNF-α is a cell signaling protein involved in the 

development of inflammation. Genetic variants in TNF-α have the potential to alter susceptibility 

to Pb (Kim et al. 2007).
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3.3 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as biomarkers of exposure, biomarkers of effect, and biomarkers of susceptibility 

(NAS/NRC 1989).

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. Biomarkers of 

exposure to Pb are discussed in Section 3.3.1. The National Report on Human Exposure to 

Environmental Chemicals provides an ongoing assessment of the exposure of a generalizable sample of 

the U.S. population to environmental chemicals using biomonitoring (see 

http://www.cdc.gov/exposurereport/). If available, biomonitoring data for Pb from this report are 

discussed in Section 5.6, General Population Exposure. 

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 effect caused 

by Pb are discussed in Section 3.3.2.

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 3.2, Children and Other Populations that are Unusually Susceptible.
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3.3.1 Biomarkers of Exposure

Biomarkers of exposure in practical use today are measurements of total Pb levels in body fluids or 

tissues, such as blood, bone, or urine. Tetraalkyl Pb compounds may also be measured in the breath. Of 

these, PbB is the most widely used and is considered to be the most reliable biomarker for general clinical 

use and public health surveillance. Currently, PbB measurement is the screening test of choice to identify 

children with elevated PbBs (CDC 2012d). Venous sampling of blood is preferable to finger prick 

sampling, which has a considerable risk of surface Pb contamination from the finger if proper finger 

cleaning is not carried out. In children, PbBs greater than the blood lead reference value identify highrisk childhood populations and geographic areas most in need of primary prevention (CDC 2012d). In 

2012, the blood lead reference value was defined as 5 μg/dL (CDC 2012d). Based on an analyses of 

NHANES data, geometric mean PbB decreased in the United States population during the period 2009–

2014 (Tsoi et al. 2016) and the percentage of children (<6 years of age) in the United States who had PbB 

≥5 μg/dL in the survey period 2014–2015 decreased compared to the survey period 2009–2010 

(Baertkein and Yendell 2017; McClure et al. 2016). 

PbB. Measurement of PbB is the most widely used biomarker of Pb exposure. CDC considers PbB to be 

elevated in children when it exceeds a reference value defined as the 97.5th percentile for the U.S. 

population. The blood lead reference value was set at 5 μg/dL in 2012, based on data from NHANES 

2007–2008 and 2009–2010, is 5 μg/dL (CDC 2012d). Elevated PbB (e.g., >5 μg/dL) is an indication of 

excessive exposure in infants and children. The biological exposure index (BEI) for Pb in blood of 

exposed workers is 20 μg/dL (ACGIH 2018). The BEI also notes to advise “female workers of childbearing age about the risk of delivering a child with a PbB over the current CDC reference value.” The 

Occupational Safety and Health Administration’s (OSHA) permissible exposure limit (PEL) for Pb

(50 μg/m3 air, 8-hour time-weighted average [TWA]) was established to keep a majority of worker PbBs 

below 40 μg/dL (OSHA 2016a). The National Institute for Occupational Safety and Health (NIOSH) 

recommended exposure limit (REL) for workers (50 μg/m3 air, 8-hour TWA) is established to ensure that 

the PbB does not exceed 60 μg/dL (NIOSH 2016b).

The extensive use of PbB as a dose metric reflects mainly the greater feasibility of incorporating PbB 

measurements into clinical or epidemiological studies, compared to other potential dose indicators, such 

as Pb in kidney, plasma, or bone. PbB measurements have several limitations as measures of total Pb 

body burden. Blood comprises <2% of the total Pb burden; most of the Pb burden resides in bone (Barry 

1975). Pb is eliminated from blood more rapidly than from bone (Behinaein et al. 2014; Brito et al. 2005; 
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Chamberlain et al. 1978; Griffin et al. 1975; Manton et al. 2001; Nie et al. 2005; Nilsson et al. 1991; 

Rabinowitz et al. 1976; Rentschler et al. 2012); therefore, the Pb concentration 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 Pb in bone (Graziano 1994; Lyngbye et al. 1990). Slow release of Pb 

from bone can contribute to blood Pb levels long after external exposure has ceased (Fleming et al. 1997; 

Inskip et al. 1996; Kehoe 1987; McNeill et al. 2000; O'Flaherty et al. 1982; Smith et al. 1996). The 

relationship between Pb 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). Pb intakePbB relationships also vary with age as a result of age-dependency of gastrointestinal absorption of Pb, 

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., days to 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 

total Pb body burden. A single PbB determination cannot distinguish between lower-level intermediate or 

chronic exposure and higher-level 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 

(CBLI) may provide a means for accounting for some of these factors and thereby provide a better 

measure of long-term exposure (Armstrong et al. 1992; Behinaein et al. 2014; Chuang et al. 2000; 

Fleming et al. 1997; Gerhardsson et al. 1993; Healey et al. 2008; Hu et al. 2007; McNeill et al. 2000; Nie 

et al. 2011a; Roels et al. 1995). The correlation observed between CBLI and tibia bone Pb concentrations 

provides supporting evidence for this (Hu et al. 2007). 

Bone and Tooth Pb Measurements. The development of noninvasive XRF techniques for measuring Pb 

concentrations in bone has enabled the exploration of bone Pb as a biomarker of Pb exposure in children 

and in adults (Behinaein et al. 2011; Chettle et al. 2003; Hu et al. 2007; Ji et al. 2014; Nie et al. 2011b; 

Specht et al. 2016; Todd et al. 2000). Pb in bone is considered a biomarker of cumulative exposure to Pb 

because Pb accumulates in bone over the lifetime and most of the Pb body burden resides in bone. Pb is 

not distributed uniformly in bone. Pb 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 both cortical 

and trabecular bone. This suggests that Pb 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 Pb in trabecular bone, 

whereas XRF measurements of midtibia, phalanx, or ulna primarily reflect primarily Pb in cortical bone. 

Pb levels in cortical bone may be a better indicator of long-term cumulative exposure than Pb in 
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trabecular bone, possibly because Pb in trabecular bone may exchange more actively with Pb in blood 

than does cortical bone. This is consistent with estimates of a longer elimination half-time of Pb in 

cortical bone, compared to trabecular bone (Behinaein et al. 2014; Borjesson et al. 1997; Brito et al. 2005; 

Nie et al. 2005; Nilsson et al. 1991; Schutz et al. 1987). Longitudinal studies that have repeatedly 

measured bone Pb (by XRF) over many years have shown more rapid declines in trabecular bone 

compared to cortical bone (Kim et al. 1997; Wilker et al. 2011). Estimates of cortical bone Pb 

elimination half-times (5–50 years) show a dependence on Pb burden, with longer half-times in people 

who have higher total body burdens (estimated from CBLI) and bone Pb burdens (Behinaein et al. 2014; 

Brito et al. 2005; Nie et al. 2005). Further evidence that cortical bone Pb 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 Pb measurements have been compared to PbB. Pb levels in trabecular 

bone (in adults) correlate more highly with contemporary PbB than do levels of Pb in cortical bone 

(Erkkila et al. 1992; Hernandez-Avila et al. 1996; Hu et al. 1996b, 1998; Watanabe et al. 1994). Cortical 

bone Pb measurements correlate well with time-integrated PbB measurements, which would be expected 

to be a better reflection of cumulative exposure than contemporary PbB measurements (Behinaein et al. 

2012; Borjesson et al. 1997; Hu et al. 2007; Roels et al. 1994). Bone Pb 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 Pb 

may be stronger after adolescence (Hoppin et al. 1997). These observations are consistent with cortical 

bone reflecting cumulative exposures over the lifetime. 

Standard methods for bone Pb XRF measurements have not been universally accepted, in part, because 

the technology continues to be improved, and this needs to be considered in comparisons of 

measurements reported by different laboratories and at different times in development of the methodology 

used. Historically, two XRF methods have seen the most use in bone Pb epidemiology: K-shell and 

L-shell methods. The K-shell method is the more widely used, although, improvements in L-shell 

technology continue to be reported (Nie et al. 2011a). One study reported a correlation of 0.65 between 

bone Pb measurements made with a portable L-shell device and a K-shell method (Nie et al. 2011a). In 

general, recent advances in K-shell technology have yielded higher sensitivities (approximately 3 μg/g 

tibia mineral; Behinaein et al. 2011) than L-shell technology (approximately 8 μg/g tibia bone mineral; 

Nie et al. 2011a). Precision of K-shell XRF bone Pb measurements have been extensively discussed (Aro 

et al. 2000; Behinaein et al. 2014; Todd et al. 2000, 2001, 2002). Methodological factors can contribute 

substantially to observed variability in bone Pb measurements in populations (Behinaein et al. 2014). 

These factors include bone Pb target, radioactive source, measurement time, and data reduction methods 

(e.g., approach to handling negative values). Measurement uncertainty also appears to contribute by 
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biological factors, such as BMI and bone mineral content (Behinaein et al. 2014; Berkowitz et al. 2004; 

Hu et al. 2007; Theppeang et al. 2008). The association between BMI and measurement uncertainty may 

reflect the effect attenuation of the XRF signal by tissue overlaying the target bone site (Behinaein et al. 

2014). Bone mineral can be a factor because XRF measures bone Pb fluorescence in relation to 

fluorescence from bone calcium and the result is expressed in units of μg Pb per g bone mineral. As a 

result, variability in bone mineral content can contribute to variability in measured bone Pb. Typically, 

potential associations between bone density and bone Pb concentration are not evaluated in epidemiologic 

studies (Berkowitz et al. 2004; Hu et al. 2007; Theppeang et al. 2008). An important consequence of 

expressing bone Pb measures relative to bone mineral content is that lower bone mineral density is 

associated with greater measurement uncertainty in bone Pb. This uncertainty can have important 

implications for studies in older women for whom low bone mineral density is more common than in 

other populations including men and younger adults.

Tooth Pb has been considered a potential biomarker for measuring long-term exposure to Pb (e.g., years) 

because Pb that accumulates in tooth dentin and enamel appears to be retained until the tooth is shed or 

extracted (Costa de Almeida et al. 2007; Ericson 2001; Fosse et al. 1995; Gomes et al. 2004; Gulson and 

Wilson 1994: Gulson et al. 1996; Omar et al. 2001; Rabinowitz 1995; Rabinowitz et al. 1989, 1993; 

Robbins et al. 2010; Steenhout and Pourtois 1987; Tvinnereim et al. 1997). Formation of enamel and 

primary dentin of deciduous teeth begins in utero and is complete prior to the time children begin to 

crawl. Formation of secondary dentin begins after completion of the tooth root and continues through 

childhood until the tooth is lost, or otherwise loses vitality. Pb in shed deciduous teeth is not uniformly 

distributed. Differences in Pb levels and stable isotope signatures of the enamel and dentin suggest that 

Pb uptake occurs differentially in enamel and dentin (Gulson 1996; Gulson and Wilson 1994). Pb in 

enamel is thought to reflect primarily Pb exposure that occurs in utero and early infancy, prior to tooth 

eruption. Dentin appears to continue to accumulate Pb after eruption of the tooth; therefore, dentin Pb 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). The technique of laser ablation-inductively 

coupled plasma-mass spectrometry (LA-ICP-MS) allows measurement of Pb levels in regions of dentin 

formed at various times during deciduous tooth formation in utero and after birth (Arora et al. 2014; 

Shepherd et al. 2016). Accumulation of Pb in dentin of permanent teeth may continue for the life of the 

tooth (Steenhout 1982; Steenhout and Pourtois 1981). Because enamel is in direct contact with the 

external environment, enamel Pb levels may be more influenced than dentin Pb by external Pb levels and 

tooth wear (Purchase and Fergusson 1986). 
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An analysis of eight cross-sectional and/or prospective studies that reported tooth Pb and PbBs of the 

same children found considerable consistency among the studies (Rabinowitz 1995). The mean tooth Pb 

levels ranged from <3 to >12 μg/g. Dentin Pb was found to be predictive of Pb in tibia, patella, and mean 

bone Pb in 32 of 63 subjects at follow-up of ≤13 years (Kim et al. 1996b). The authors estimated that a 

10 μg/g increase in dentin Pb levels in childhood was predictive of a 1 μg/g increase in tibia Pb levels, a 

5 μg/g in patella Pb levels, and a 3 μg/g increase in mean bone Pb among the young adults. Arora et al. 

(2014) found that Pb levels in primary (prenatal) dentin were more strongly correlated with PbBs at birth 

(correlation coefficient, r=0.69, n=27), whereas Pb levels in secondary (postnatal) dentin were more 

strongly correlated with CBLI (r=0.38, n=75). Shepherd et al. (2016) combined LA-ICP-MS with 

histological determinations of dentin age to reconstruct the history of incorporation of environmental Pb 

from various sources. 

Plasma Pb Concentration. The concentration of Pb in plasma (e.g., approximately 0.04 μg/dL at PbB of 

10 μg/dL) is extremely difficult to measure accurately because levels in plasma are near the quantitation 

limits of most analytical techniques (Bergdahl and Skerfving 1997; Bergdahl et al. 1997a) and because

hemolysis that occurs with typical analytical practices can contribute to substantial measurement error 

(Bergdahl et al. 1998, 2006; Cavalleri et al. 1978; Smith et al. 1998a). ICP-MS offers sensitivity 

sufficient for measurements of Pb in plasma (Schütz et al. 1996). The technique has been applied to 

assessing Pb exposures in adults (Barbosa et al. 2006a; Cake et al. 1996; Hernandez-Avila et al. 1998; 

Manton et al. 2001; Smith et al. 2002; Tellez-Rojo et al. 2004; Tian et al. 2013). A direct comparison of 

Pb concentrations in plasma and serum yielded similar results (Bergdahl et al. 2006); however, the 

interchangeability of plasma and serum Pb measurements for biomonitoring of Pb 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 Pb. Measurements of urinary Pb levels have been used to assess Pb exposure (e.g., Chiang et al. 

2008; Fels et al. 1998; Fukui et al. 1999; Gerhardsson et al. 1992; Lilis et al. 1968; Lin et al. 2001; Mendy 

et al. 2012; Mortada et al. 2001; Navas-Acien et al. 2005; Rentschler et al. 2012; Roels et al. 1994; Sun et 

al. 2008b). However, like PbB, urinary Pb excretion mainly reflects recent exposure and thus shares 

many of the same limitations for assessing Pb body burden or long-term exposure (Sakai 2000; Skerfving 

1988). Although collection of urine is noninvasive, urine Pb levels exhibit variability with PbB, and 

interpretation of urine Pb levels requires estimates of GFR and measurement of urine volume (NTP 

2012). A significant, but relatively weak correlation between urinary Pb levels (μg/g creatinine) and 

individual Pb intakes (μg/day) was observed in a study of 10–12-year-old children (β: 0.053, R=0.320, 
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p=0.02, N=57; Chiang et al. 2008). In this study, urine sampling and measurements used to estimate 

intake were separated by as long as 6 months for some children, which may have contributed to the 

relatively weak correlation. 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 Pb exposures or kidney 

disease (Lilis et al. 1968; Wedeen et al. 1975). Urinary Pb 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). However, the relationship between plasma Pb and urinary Pb (μg Pb/g creatinine) 

was linear in a small group of children (Rentschler et al. 2012). The linear relationship between plasma 

and urinary Pb may reflect the importance of plasma Pb in determining the rate of glomerular filtration 

and renal tubular transport of Pb (see Section 3.1.4). Urinary diethyl Pb has been proposed as a 

qualitative marker of exposure to tetraethyl Pb (Turlakiewicz and Chmielnicka 1985; Vural and Duydu 

1995; Zhang et al. 1994).

The measurement of Pb excreted in urine following an injection (intravenous or intramuscular) of the 

chelating agent, calcium disodium EDTA (EDTA provocation), or oral dosing with dimercaptosuccinic 

acid (DMSA) has been used to detect elevated body burden of Pb in adults (Biagini et al. 1977; Lee et al. 

2009; Lilis et al. 1968; Lin et al. 2003, 2006a, 2006b; Schwartz et al. 2000a, 2000c; Wedeen 1992; 

Wedeen et al. 1975)and children (Chisolm et al. 1976; Markowitz and Rosen 1981). However, the 

American College of Medical Toxicology (ACMT 2010) position statement on post-chelator challenge 

urinary metal testing states that “post-challenge urinary metal testing has not been scientifically validated, 

has no demonstrated benefit, and may be harmful when applied in the assessment and treatment of 

patients in whom there is concern for metal poisoning.” The assay is not a substitute for PbB 

measurements in the clinical setting. Note that children whose PbBs are ≥45 μg/dL should not receive a 

provocative chelation test; they should be immediately referred for appropriate chelation therapy (CDC 

2002a, 2012e). For additional information on recommended actions based on PbB level in children and 

adults, see Section 3.5 (Methods for Reducing Toxic Effects). 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 

Pb in drinking water increased levels of Pb 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 Pb (Wedeen 1992) is largely being supplanted by more direct, noninvasive 

procedures for measuring Pb in bone. DMSA is a Pb chelating agent that can be administered orally. 
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DMSA-chelatable Pb has been used as marker of Pb body burden in adults (Schwartz et al. 1997b, 2000a, 

2000c; Scinicariello et al. 2007; Weaver et al. 2003a, 2003b).

Pb in Saliva and Sweat. Pb is excreted in human saliva and sweat (Genuis et al. 2011; Lilley et al. 1988; 

Omokhodion and Crockford 1991; Rabinowitz et al. 1976; Stauber and Florence 1988; Sears et al. 2012; 

Stauber et al. 1994). Sweat has not been widely adopted for monitoring Pb exposures. Lilley et al. 

(1988) found that Pb concentrations in sweat were elevated in Pb workers; however, sweat and PbBs were 

poorly correlated. This may reflect excretion of Pb in or on the skin that had not been absorbed into 

blood. Studies conducted in rats have found relatively strong correlations between Pb concentrations in 

plasma and saliva (e.g., r2

>0.9), compared to blood Pb and saliva; therefore, saliva may serve as a better 

predictor of plasma Pb than PbB (Timchalk et al. 2006). However, studies of saliva Pb conducted in 

humans have had mixed results, with some studies showing relatively strong correlations between 

salivary Pb concentration and PbB (Brodeur et al. 1983; Omokhodion and Crockford 1991; P'an 1981), 

and other studies showing weak or inconsistent relationships (Barbosa et al. 2006c; Costa de Almeida et 

al. 2009, 2010, 2011; Nriagu et al. 2006). Variable outcomes from these studies may reflect differences 

in PbBs, exposure history and/or dental health (i.e., transfer of Pb between dentin and saliva), and 

methods used for determining Pb in saliva. Other complicating factors reported in the literature include 

uncontrolled variation in salivary flow rates (Barbosa et al. 2005; Esteban and Castano 2009) and 

potential blood contamination of saliva (Koh and Koh 2007).

Hair and Nail Pb. Pb 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 Pb body burden 

(Gerhardsson et al. 1995b; Wilhelm et al. 1989). The method is subject to error from contamination of 

the surface with environmental Pb 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; Rodrigues et al. 2008). 

Nevertheless, levels of Pb in hair were positively correlated with children’s classroom attention deficit 

behavior in a study (Tuthill 1996). Pb in hair was correlated with liver and kidney Pb in a study of 

deceased smelter workers (Gerhardsson et al. 1995b). Correlations between maternal and infant hair Pb 

concentrations have been observed (Kordas et al. 2010). Although hair Pb measurements have been used 

in some epidemiologic studies (Bao et al. 2009; Huel et al. 2008; Marcus et al. 2010; Shah et al. 2011), an 

empirical basis for interpreting hair Pb measurements in terms of body burden or exposure has not been 

firmly established. Nail Pb has also been utilized as a marker of Pb exposure, although nails may be 

contaminated with Pb from external sources (Barbosa et al. 2005; Gerhardsson et al. 1995b).
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Semen Pb. Pb concentrations in semen have been explored as an internal exposure biomarker for adverse 

effects of Pb on the testes (Hernandez-Ochoa et al. 2005; Kasperczyk et al. 2015; Slivkova et al. 2009; 

Taha et al. 2013; Wu et al. 2012). Correlations between concentrations of Pb in semen and blood have 

been reported and vary in strength across studies (Alexander et al. 1998a, 1998b; Farias et al. 2005; 

Hernandez-Ochoa et al. 2005; Mendiola et al. 2011; Telisman et al. 2000). This variation may relate, in 

part, to analytical challenges in the measurement of the relatively low concentrations of Pb 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 Pb concentration in a group of 160 men (age range 19–

48 years) who were not exposed to Pb occupationally was 2.66 μg/L (range 0.08–19.42) and was 

significantly correlated with PbB (mean 10.8 μg/dL, range 4.5–40.2) and tibia bone Pb (mean 14.51 μg/g, 

range not-detected–44.71 μg/g). 

Stable Pb Isotopes. Analysis of the relative abundance of stable isotopes of Pb 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 Pb (204Pb, 206Pb, 207Pb, and 

208Pb) in Pb ores vary with the age of the ore (which determines the extent to which the parent isotopes 

have undergone radioactive decay to stable Pb). Humans have Pb isotope abundance profiles that reflect 

the profiles of Pb deposits to which they have been exposed. Pb isotope studies can be used to exclude

sources of Pb contributing to exposure. Similarly, if exposure abruptly changes to a Pb 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 Pb 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 Pb exposures have been reported (Angle et al. 1995; 

Graziano et al. 1996; Gulson and Wilson 1994; Gulson et al. 1996, 1997b, 1999c, 2016; Manton 1977, 

1998).

Effect Biomarkers Used to Assess Exposure to Pb. Certain physiological changes that are associated

with Pb exposure have been used as biomarkers of exposure (see Section 3.3.2). These include 

measurements of biomarkers of impaired heme biosynthesis (blood zinc protoporphyrin, urinary 

coproporphyrin, erythrocyte ALAD activity, serum ALA). These types of measurements have largely 

been supplanted with measurement of PbB for the purpose of assessing Pb exposure due to the higher 

sensitivity of PbB measurements in quantifying lower level Pb exposures. 
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3.3.2 Biomarkers of Effect

Certain effects of Pb have been used in diagnosing Pb poisoning to support measurements of PbB; 

however, none of these diagnostic aids are considered preferable to measurement of PbB. 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 system 

dysfunction, kidney dysfunction, liver dysfunction, and hematopoietic dysfunction (ATSDR 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. Pb in soil and water was found to be higher in comparison areas than in the target areas, 

but Pb in house dust and in interior paint was higher in the target areas. PbB correlated with Pb in soil 

and dust, but not with Pb 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 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. 

Pb inhibits heme biosynthesis, which is necessary for production of red blood cells. Hematologic tests 

such as hemoglobin concentration may suggest toxicity, but this is not specific for Pb (Bernard and 

Becker 1988). However, inhibition of ferrochelatase in the heme pathway causes accumulation of 

protoporphyrin in erythrocytes (CDC 1985). Most protoporphyrin in erythrocytes (about 90%) exists as 

zinc-protoporphyrin (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) free erythrocyte 

protoporphyrin (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 Pb 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). Pb toxicity is generally considered to be present 

when a PbB ≥10 μg/dL is associated with an EP level ≥35 μg/dL (CDC 1991; Somashekaraiah et al. 
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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 EP 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 blood lead 

reference value was set at 5 μg/dL in 2012, relying on EP measures would result in many false negative 

cases. Some have estimated that relying only on ZPP screening to predict future Pb toxicity would miss 

approximately three cases with toxic PbBs 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 Pb 

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 

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 Pb is the observation of basophilic stippling and 

premature erythrocyte hemolysis (Paglia et al. 1975, 1977). Pb 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 Pb poisoning, it is relatively insensitive to lesser 

degrees of Pb toxicity (CDC 1985). The activity of adenine dinucleotide synthetase (NADS) in 
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

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).

Reduction in the serum 1,25-dihydroxyvitamin D concentration has been reported as an indicator of 

increased Pb absorption or Pb concentrations in the blood (Rosen et al. 1980). Pb 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-dihydroxyvitamin 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 Pb 

exposure and several diseases can influence this measurement. 

One of the most sensitive systems affected by Pb 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 than adults. 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 Pb 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 Pb 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 Pb exposure.

Functional deficits associated with Pb-induced nephrotoxicity increase in severity with increasing PbB. 

Effects include decreased glomerular filtration, enzymuria and proteinuria, and impaired transport 

function. 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 Pb-induced nephrotoxicity. A characteristic histologic feature of Pb 

nephrotoxicity is the formation of intranuclear inclusion bodies in the renal proximal tubule (Choie and 

Richter 1972; Goyer et al. 1970a, 1970b).
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3.4 INTERACTIONS WITH OTHER CHEMICALS

Interactions between Pb and other chemicals can be classified into two categories: interactions with 

contaminants that are commonly found together with Pb at hazardous waste sites, and interactions with 

essential elements (ATSDR 2004a, 2004b, 2006; EPA 2014c).

Interactions with Other Contaminants. Several metals and metalloids frequently are found together with 

Pb at hazardous waste sites, including arsenic (As), cadmium (Cd), manganese (Mn), zinc (Zn), copper 

(Cu), and inorganic mercury (Hg). ATSDR (2004a, 2004b, 2006) has conducted assessments to predict 

interactions of these chemicals with Pb; conclusions are presented in Table 3-3. For each co-contaminant, 

interactions were classified as less than additive (indicating an antagonistic effect with Pb), additive 

(indicating no effect of combined exposure), or greater than additive (indicating a synergistic effect with 

Pb). Greater-than-additive effects were observed for neurological effects for As and Cd, male 

reproductive effects for Cd, and renal effects for Hg. Interactions for other metals were either less than 

additive or additive for cardiovascular (Cd, Zn), developmental (Zn), hematological (As, Cd, Mn, Zn, 

Cu), immunological (Cd), neurological effects (Zn), renal (As, Cd, Mn, Zn, Cu), and male reproductive 

(Zn) effects. Other metals that may interact with Pb include selenium and chromium(VI) (Nordberg et al. 

2015). Observed interactions of metals and metalloids with Pb could be the results of alterations to Pb 

toxicokinetics, toxicodynamics, or a combination of both.

Table 3-3. Influence of Other Metals and Metalloids on Lead (Pb) Toxicity

Organ system

Metal

Arsenica Cadmiuma Manganeseb Zincb Copperb

Inorganic 

mercuryc

Cardiovascular – < or 0 – < – –

Developmental – – – < – –

Hematological < or 0 < or 0 0 < or 0 < –

Immunological – < – – – –

Neurological > > – < or 0 < –

Renal 0 < or 0 0 < – >

Male reproductive – > – < – –

aATSDR 2004a.

bATSDR 2004b.

cATSDR 2006.

< = less than additive; 0 = additive (no effect); > = greater than additive; – = not assessed 
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Interactions with Essential Elements. In physiological systems, Pb mimics divalent cations (calcium, 

iron, zinc). Substitution of Pb for essential elements in membrane transport systems is the mechanism by 

which Pb is absorbed from the intestine and crosses cell membranes throughout the body. Thus, 

numerous interactions between Pb and essential elements have been observed, including the following 

(additional details on these finding are provided in Section 3.1, Toxicokinetics):

• Dietary calcium intake appears to affect Pb absorption. An inverse relationship has been 

observed between dietary calcium intake and PbBs in children (Elias et al. 2007; Mahaffey et al. 

1986; Schell et al. 2004; Ziegler et al. 1978).

• Nutritional iron status may affect Pb absorption in children. Higher PbBs have been observed in 

iron-deficient children compared to children who are iron replete. This observation suggests that 

iron deficiency may result in higher absorption of Pb or, possibly, other changes in Pb biokinetics 

that would contribute to higher PbBs (Mahaffey and Annest 1986; Marcus and Schwartz 1987). 

• In young children (ages 6–12 months), PbB increased in association with lower dietary Zn levels 

(Schell et al. 2004). It is not clear, however, if these associations were caused by changes in Pb 

absorption.

3.5 METHODS FOR REDUCING TOXIC EFFECTS

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to Pb. 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 Pb. When specific exposures have 

occurred, poison control centers, medical toxicologists, or other clinicians with expertise and experience 

treating and managing Pb-exposed adults and/or children should be consulted. The following resources 

provide specific information about treatment and management of patients following exposure to Pb:

AAP. 2005. Lead exposure in children: Prevention, detection, and management. Pediatrics 

116(4):1036-1046. 10.1542/peds.2005-1947.

AAP. 2016. Council on Environmental Health. Prevention of childhood lead toxicity. Pediatrics 

38(1):e20161493

ATSDR. 2017. Case studies in environmental medicine (CSEM). Lead toxicity. 

https://www.atsdr.cdc.gov/csem/lead/docs/csem-lead_toxicity_508.pdf. August 30, 2018.

Calello DP, Henretig FM. 2014. Lead. In: Goldfrank's toxicologic emergencies. Tenth ed. New York, 

NY: McGraw-Hill, 1219-1234.

Holland MG, Cawthon D. 2016. ACOEM Position Statement. Workplace lead exposure. J Occup 

Environ Med 58(12):e371-e374.
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

Leikin JB, Paloucek FP. 2008. Lead. In: Poisoning and toxicology handbook. Fourth ed. Boca Raton, 

FL: CRC Press, 807-811.

CDC. 2002a. Managing elevated blood levels among young children. Recommendations from the 

Advisory Committee on Childhood Lead Poisoning. Centers for Disease Control and Prevention. 

https://www.cdc.gov/nceh/lead/casemanagement/managingEBLLs.pdf. July 18, 2018.

Kosnett MJ. 2001. Lead. In: Ford M, Delaney KA, Ling L, et al., eds. Clinical toxicology. St. Louis: 

WB Saunders, 723-736.

Kosnett MJ. 2005. Lead. In: Brent J, Wallace KL, Burkhart KK, et al., eds. Critical care toxicology. 

Philadelphia, PA: Elsevier Mosby, 821-836.

PEHSU. 2013. Recommendations on medical management of childhood lead exposure and poisoning. 

Pediatric Environmental Health Specialty Units. 

Additional publicly available clinical resources for the health care professional can be found in 

Appendix D.

3.5.1 Reducing Absorption Following Exposure 

No treatment modalities to reduce Pb absorption have been developed. Therefore, the most important 

intervention is to identify and remove the source of exposure (AAP 2005, 2016; ATSDR 2017; CDC 

2012e). Pb absorption from the gastrointestinal tract is influenced by nutrition, especially calcium, iron, 

and vitamin C (AAP 2005; CDC 2012e). It is recommended that a child's diet contain ample amounts of 

iron and calcium to reduce the likelihood of increased absorption of Pb and that children eat regular meals 

since more Pb is absorbed on an empty stomach (AAP 2005; CDC 2002a, 2012e). 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 Pb following acute exposure include the following 

(AAP 2016; ATSDR 2017; Calello and Henretig 2014; Kosnett et al. 2007):

• remove the individual from the source of exposure;

• mitigate source of exposure;

• if suspected that elevated PbB is due to ingestion of a foreign object (e.g., Pb paint chips, toys or 

jewelry containing Pb, Pb ammunition), radiographic imaging is suggested; 

• if elevated PbB is due to ingestion of a foreign object, decontamination of the bowel (surgical or 

gastric lavage) is indicated; and

• ensure that diet is adequate in calcium, iron, and vitamin C.
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For children, specific recommended actions based on PbB levels are summarized in Table 3-4. CDC 

considers PbB to be elevated in children when it exceeds a reference value defined as the 97.5th percentile 

for the U.S. population. In 2012, CDC adopted a blood lead reference value, based on data from 

NHANES 2007–2008 and 2009–2010, of 5 μg/dL (CDC 2016). 

Table 3-4. Recommended Actions Based on Child Blood Lead Level (PbB)

PbB (μg/dL) Recommended actions 

<Reference valuea • Routine assessment of nutritional and developmental milestones

• Education on common sources of Pb exposure

• Follow-up PbB monitoring

5-19 • Follow recommendations for <Reference value

• Nutritional counseling for calcium and iron intake

20-44 • Complete history and physical examination with neurodevelopmental 

assessment

• Environmental assessment of home and lead hazard reduction

• Follow-up PbB monitoring

• Assess iron status, hemoglobin, and hematocrit

• Abdominal x-ray and bowel decontamination if indicated

≥45 and ≤69 • Follow recommendations for 45–69 μg/dL

• Complete neurological examination

• Consider oral chelation therapy with consultation with a medical 

toxicologist or pediatric environmental health expert or unit

• Consider hospitalization if cannot assure mitigation of Pb source

≥70 • Hospitalize

• Initiate chelation therapy with consultation with a medical toxicologist or 

pediatric environmental health expert or unit

• Follow recommendations for ≥45 and ≤69 μg/dL

• Environmental investigation of the home and lead hazard reduction; child 

receiving chelation therapy should not return to home until lead hazard 

remediation is completed

a5 μg/dL (CDC 2012d).

Source: CDC 2012f

For occupational exposures, OSHA and NIOSH have developed recommendations to reduce Pb exposure 

through procedures and surveillance. In 1987, NIOSH created the Adult Blood Lead Epidemiology and 

Surveillance (ABLES) program to monitor adult PbBs through coordinated efforts with state agencies 

(NIOSH 2017a). This program was designed to decrease the rate of adults with PbBs ≥10 μg/dL as a 

result of work-related Pb exposure. In 2015, NIOSH designated PbB of 5 μg/dL as the PbB reference 

value and defined elevated PbB as PbB ≥5 μg/dL (NIOSH 2017a). Several federal and state agencies 

work together to reduce the rate of elevated PbBs among workers. The OSHA (1995) mandated rule on 
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Pb provides recommendations to reduce occupational Pb exposure for general industry, shipyard 

employment, and construction through use of respirators, protective clothing, routine biological 

monitoring of PbB and zinc protoporphyrin, and medical assessments for workers with elevated PbB. 

More recently, Holland and Cawthon (2016) suggested the actions based on PbB levels, with a baseline 

PbB <5 μg/dL (Table 3-5).

Table 3-5. Recommended Actions for Workers Based on Blood Lead Level (PbB)

PbB (μg/dL) Recommended actions 

All workers • PbB monitoring at initial employment

• Monitor PbB every 6 months after initial employment monitoring

• PbB goal is <5 μg/dL for pregnant workers

≥5–9 • Increase monitoring if indicated

• Recommend removal for pregnant workers or workers who are trying to become 

pregnant; return to work may be considered if two consecutive PbB measurements 

are <5 μg/dL

• Continue PbB monitoring as noted above

10–19 • Monitor PbB every 2 months until two consecutive PbB measurements are 

<10 μg/dL

• Mandatory medical removal for pregnant workers or workers who are trying to 

become pregnant; return to work may be considered if two consecutive PbB 

measurements are <5 μg/dL

• Continue PbB monitoring as noted above

• Evaluate exposure, controls, and work practices

≥20 • Remove from work if repeat PbB measurement in 4 weeks is ≥20 μg/dL or if single 

PbB measurement is ≥30 μg/dL

• Monitor PbB monthly; return to work after two consecutive monthly PbB 

measurements are <15 μg/dL

• Continue PbB monitoring as noted above 

• Evaluate exposure, controls, and work practices

≥30 • Removed from exposure immediately

• Monitor PbB monthly; return to work after two consecutive monthly PbB 

measurements are <15 μg/dL

• Continue PbB monitoring as noted above 

• Evaluate exposure, controls, and work practices

Source: Holland and Cawthon (2016)

3.5.2 Reducing Body Burden 

Pb 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 Pb is found in bones, 

respectively. Pb 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).
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Currently available methods to obviate the toxic effects of Pb are based on their ability to reduce the body 

burden of Pb by chelation. All of the chelating agents bind inorganic Pb, enhance its excretion, and 

facilitate the transfer of Pb from soft tissues to the circulation where it can be excreted. Since the success 

of chelation therapy depends on excretion of chelated Pb via the kidney, caution should be used when 

treating a patient with renal failure. For all cases where chelation therapy is considered or implemented, 

medical providers should consult with a medical toxicologist or an expert in the medical management of 

Pb toxicity (CDC 2002a, 2012e). Chelation treatment should be administered in conjunction with 

meticulous supportive therapy (Calello and Henretig 2014). Most of the information below regarding 

chelators was obtained from Calello and Henretig (2014) and Kosnett (2005, 2007).

Several pharmacological substances are available for chelation therapy for Pb intoxication. Chelating 

agents currently in use are dimercaprol (British Anti-Lewisite, or BAL), CaNa2-EDTA (or EDTA), and 

2,3-dimercaptosuccinic acid (DMSA; Succimer®). Dosages and administration protocols for these agents 

vary with patient age, PbB level, and symptom types and severity. Specific treatment protocols should be 

developed in consultation with clinical experts in the management of Pb toxicity for the most current 

chelation therapy procedures for children and adults (CDC 2002a, 2012e). 

Dimercaprol (BAL). The mechanism of action of BAL is through formation of stable chelate-metal 

compounds intra- and extracellularly. BAL is administered parenterally. The onset of action for BAL is 

30 minutes. BAL increases fecal excretion of Pb as chelated Pb is excreted predominantly in bile within 

4–6 hours; BAL also increases urinary excretion of chelated Pb. A number of adverse reactions have 

been associated with BAL, including nausea, vomiting, hypertension, tachycardia, headache, increased 

secretions, anxiety, abdominal pain, and fever. 

CaNa2-EDTA (or EDTA). EDTA works by forming a stable metal-chelate complex that is excreted by 

the kidney. It increases renal excretion of Pb 20–50 times. EDTA is administered parenterally. 

Numerous adverse effects have been described due to treatment with EDTA including rash, fever, fatigue, 

thirst, myalgias, chills, and cardiac dysrhythmias. 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.
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2,3-Dimercaptosuccinic acid (DMSA; Succimer®). The mechanism of action of DMSA is similar to 

BAL. DMSA is administered orally. DMSA has been shown to be as effective as EDTA in increasing 

the urinary excretion of Pb. 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 calcium, iron, magnesium, and copper. 
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CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION

4.1 CHEMICAL IDENTITY

Pb is a naturally occurring element with an abundance of 0.0016% in the earth’s crust (Davidson et al. 

2014). It is a member of Group 14 (IVA) of the periodic table. Natural Pb is a mixture of four stable 

isotopes: 204Pb (1.4%), 206Pb (24.1%), 207Pb (22.1%), and 208Pb (52.4%). The Pb isotopes 206Pb, 207Pb, and 

208Pb are the stable decay product of the naturally occurring decay series of uranium, actinium, and 

thorium, respectively (Haynes 2014).

Pb is found in concentrated and easily accessible Pb ore deposits that are widely distributed throughout 

the world (King et al. 2014). 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 Pb and 

several of its compounds are provided in Table 4-1.

Table 4-1. Chemical Identity of Lead and Compounds

Characteristic Lead Lead(II) acetate Lead(II) azide Lead(II) bromide

Synonym(s) and 

registered trade 

name(s)

C.I. 77575; C.I. 

Pigment metal 4; 

Glover; Lead flake; 

Lead S2; Omaha; 

Omaha & Grant; SI; 

SOa

Acetic acid 

lead(2+) salt (2:1); 

neutral lead 

acetate; plumbous 

acetate; normal 

lead acetate; sugar 

of lead; salt of 

Saturnb

Lead azideb Lead bromide 

(PbBr2); plumbous 

bromideb

Chemical formula Pbb Pb(CH3CO2)2b Pb(N3)2b PbBr2b

Chemical structure Not applicable Not applicable Not applicable Not applicable

CAS Registry 

Number

7439-92-1b 301-04-2b 13424-46-9b 10031-22-8b
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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-1. Chemical Identity of Lead and Compounds

Characteristic Lead(II) chloride Lead(II) chromate

Lead(II) 

tetrafluoroboratec Lead(II) iodide

Synonym(s) and 

registered trade 

name(s)

Lead chloride 

(PbCl2); Lead(2+) 

chloride; Plumbous 

chlorideb

Chromic acid 

(H2CrO4 lead(2+) 

salt (1:1); Chrome 

yellow; Cologne 

yellow; King’s 

yellow; Leipzig 

yellow; Paris 

yellow; C.I. 

Pigment Yellow 34; 

lead chromium 

oxide (PbCrO4); 

plumbous 

chromate; C.I. 

77600b

Tetrafluoro 

borate(1-) 

Lead(2+)a

Lead iodide (PbI2); 

Plumbous iodideb

Chemical formula PbCl2b PbCrO4b Pb(BF4)2a PbI2b

Chemical structure Not applicable Not applicable Not applicable Not applicable

CAS Registry 

Number

7758-95-4b 7758-97-6b 13814-96-5a 10101-63-0b
LEAD 347

4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-1. Chemical Identity of Lead and Compounds

Characteristic

Lead molybdenum 

chromate Lead(II) nitrate Lead(II) oxide Lead(II,II,IV) oxide

Synonym(s) and 

registered trade 

name(s)

Chromic acid, lead 

and molybdenum salt; 

chromic acid lead salt 

with lead molybdate; 

C.I. Pigment Red 104; 

Lead chromate, 

Molybdenum-Lead 

chromate; 

Molybdenum Orangea

Nitric acid 

lead(2+) salt (2:1); 

Plumbous nitrateb

C.I. 77577; C.I. 

Pigment Yellow 46; 

Lead oxide; Lead 

oxide yellow; Lead 

protoxide; Litharge; 

Litharge Yellow 

L-28; Massicot; 

Massicotite; 

Plumbous oxide; 

Yellow lead ochera

Lead tetraoxide; 

Lead tetroxide; Lead 

oxide red; C.I. 

Pigment Red 105; 

C.I. 77578; Gold 

satinobre; Lead 

orthoplumbate; Lead 

oxide (3:4); Mineral 

Orange; Mineral Red; 

Paris Red; Saturn 

Red; Minium; 

Plumboplumbic 

oxide; Red Lead; 

Red Lead oxide; 

Trilead tetraoxided,e

Chemical formula No data Pb(NO3)2b PbOa Pb3O4e

Chemical structure Not applicable Not applicable Not applicable

CAS Registry 

Number

12709-98-7a 10099-74-8b 1317-36-8a 1314-41-6d

Pb

O

Pb

O

O

Pb

O

Pb

O O

Pb

O O

Pb
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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-1. Chemical Identity of Lead and Compounds

Characteristic Lead(II) phosphate Lead(II) styphnate Lead(II) sulfate

Synonym(s) and 

registered trade 

name(s)

C.I. 77622; Lead 

orthophosphate; Lead 

phosphate (3:2); 

Lead(2+) phosphate; 

normal lead 

orthophosphate; 

Phosphoric acid, 

lead(2+) salt (2:3); 

Plumbous phosphate; 

Trilead phosphatea

Lead trinitroresorcinatef Anglesite; C.I. 77630; 

C.I. Pigment White 3; 

Fast White; 

Freemans White 

Lead; Lead bottoms; 

Milk white; Mulhouse 

White; Sulfuric acid, 

lead(2+) salt (1:1)a

Chemical formula Pb3(PO4)2a Pb(C6HN3O8)2f PbSO4b

Chemical structure Not applicable Not applicable Not applicable

CAS Registry 

Number

7446-27-7a 15245-44-0f 7446-14-2b

Characteristic Lead(II) sulfide Tetraethyl lead Lead(II) carbonate

Synonym(s) and 

registered trade 

name(s)

C.I. 77640; Galena; 

Natural lead sulfide; 

Plumbous sulfidea

Tetraethylplumbane; Lead tetraethyl; 

TELb

Carbonic acid, 

lead(2+) salt (1:1); 

Cerussite; Dibasic 

lead carbonate; 

Lead(2+) carbonate; 

White leada

Chemical formula PbSa Pb(C2H5)4a PbCO3a

Chemical structure Not applicable Pb Not applicable

CAS Registry 

Number

1314-87-0a 78-00-2b 598-63-0a

aLewis 2012.

bO’Neil et al. 2013.

cStable only in aqueous solution (Haynes 2014). dNLM 2020. eHaynes 2014.

f

Boileau et al. 2012.

CAS = Chemical Abstracts Services

4.2 PHYSICAL AND CHEMICAL PROPERTIES

Pb, a blueish-white metal with bright luster, is very soft, highly malleable, ductile, a poor conductor of 

electricity, and is very resistant to corrosion (Haynes 2014). A clean Pb surface will not be attacked by 

dry air; however, in moist air, the surface will react and become coated with a layer of lead(II) oxide 

(PbO). This coating may be hydrated and combine with carbon dioxide to form lead(II) carbonate 

(PbCO3) (Carr et al. 2004). This protective coating of insoluble Pb compounds slows or halts corrosion 

of the underlying metal. Pb is rarely found in its metallic form in nature and commonly occurs as a 
LEAD 349

4. CHEMICAL AND PHYSICAL INFORMATION

mineral with sulfur or oxygen. The most important Pb mineral is galena (PbS). Other common 

Pb-containing minerals include anglesite (PbSO4), cerussite (PbCO3), and minium (Pb3O4) (Carr et al. 

2004; Davidson et al. 2014; Haynes 2014).

Pb can exist in the 0 oxidation state in metallic Pb and in compounds as the +2 or +4 oxidation states. In 

the environment, Pb is primarily found in the +2 state in inorganic compounds. The chemistry of 

inorganic Pb compounds is generally similar to that of the Group 2(II) or alkaline earth metals. There are 

three common oxides of Pb: lead(II) oxide (PbO); lead(II,IV) oxide or lead tetroxide (Pb3O4); and 

lead(IV) oxide or lead dioxide (PbO2). The +4 state is only formed under strongly oxidizing conditions. 

Inorganic Pb(+4) compounds are relatively unstable and would not be expected to be found under 

ordinary environmental conditions. Pb is amphoteric, meaning that it can react with acids and bases. In 

acid, Pb forms Pb(+2) (plumbous) and Pb(+4) (plumbic) salts and in basic solution, it forms plumbites 

(PbO2

2-

) and plumbates (Pb(OH)6

2-

) (Carr et al. 2004). In organolead compounds, Pb is typically in the 

tetravalent (+4) oxidation state (Carr et al. 2004; Haynes 2014).

Data on the physical and chemical properties of Pb and several of its compounds are provided in 

Table 4-2.
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4. CHEMICAL AND PHYSICAL INFORMATION

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

Property Lead Lead(II) acetate Lead(II) azide Lead(II) bromide

Molecular weight 207.2a 325.3b 291.24a 367.0b

Color Bluish-white, 

silvery, gray metala

White crystalsb Needles or white 

powder a

White orthorhombic 

crystalsb

Physical state Solid Solid Solid Solid

Melting point 327.4°Ca 280°Cb Decomposes at 

190°Cc

371°Cb 

Boiling point 1,740°Ca Decomposesb No data 892°Cb

Density 11.34 g/cm3 at 

20°Ca

3.25 g/cm3b 4.17 g/cm3 at 

20°Cc

6.69 g/cm3b

Odor No data Slightly acetic odor 

(trihydrate)a

No data No data

Odor threshold:

Water No data No data No data No data

Air No data No data No data No data

Solubility:

Water Insolubled 443,000 mg/L at 

20°Cb

230 mg/L at 18°Ca 9,750 mg/L at 25°Cb

Acids Soluble in dilute 

nitric acidd; reacts 

with sulfuric acida

Soluble in acide Freely soluble in 

acetic acida

No data

Bases No data Soluble in alkalie No data No data

Organic solvents Soluble in glycerin; 

slightly soluble in 

alcohole

Slightly soluble in 

alcohol; freely 

soluble in glycerold

No data Insoluble in 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 1.77 mmHg at 

1,000°Ca

No data No data 0.0075 mmHg at 374°Cb

Henry’s law 

constant

No data No data No data No data

Autoignition 

temperature

No data No data No data No data

Flashpoint No data No data No data No data

Flammability limits No data No data No data No data

Conversion factors Not relevantf Not relevantf Not relevantf Not relevantf

Explosive limits No data No data Explodes at 

350°Ca

No data

Valence state 0 +2 +2 +2
LEAD 351

4. CHEMICAL AND PHYSICAL INFORMATION

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

Property Lead(II) chloride Lead(II) chromate

Lead(II) 

tetrafluoroborate Lead iodide

Molecular weight 278.1g 323.19a 380.8b 461.05g

Color White, orthorhombic 

needlesg

Yellow or orangeyellow powderaNo data Yellow 

hexagonal 

crystalsg

Physical state Solid Solid Stable only in 

aqueous solutionb

Solid

Melting point 501°Cg 844°Ca No data 402°Cg

Boiling point 950°Cg No data No data 954°Cg

Density 5.85 g/cm3g 6.12 g/cm3b No data 6.16 g/cm3g

Odor No data No data No data No data

Odor threshold No data No data No data No data

Solubility:

Water 9,900 mg/L at 20°Cg 0.2 mg/La Solubleb 630 mg/L at 

20°Cg

Acids Slightly soluble in 

dilute hydrochloric 

acidg

Soluble in dilute 

nitric acid; insoluble 

in acetic acida

No data No data

Bases Slightly soluble in 

dilute ammoniag

No data No data No data

Organic solvents Insoluble in alcoholg No data No data Insoluble in 

alcoholg

Partition coefficients:

Log Kow No data No data No data No data

Log Koc No data No data No data No data

Vapor pressure 7.5 mmHg at 637°Cb No data No data 0.75 mmHg at 

470°Cb

Henry’s law 

constant

No data No data No data No data

Autoignition 

temperature

No data No data No data No data

Flashpoint No data No data No data No data

Flammability limits No data No data No data No data

Conversion factors Not relevantf Not relevantf Not relevantf Not relevantf

Explosive limits No data No data No data No data

Valence state +2 +2 +2 +2
LEAD 352

4. CHEMICAL AND PHYSICAL INFORMATION

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

Property

Lead molybdenum 

chromate Lead(II) nitrate Lead(II) oxide Lead(II,II,IV) oxide

Molecular weight No data 331.23g 223.21g 685.57e

Color No data Cubic or monoclinic 

colorless crystalsg

Reddish-yellow; 

yellow (above 

489°C)g

Bright red heavy 

powdera; red 

tetrahedral crystalsb

Physical state No data Solid Solid Solid

Melting point No data Begins to 

decompose above 

205°Cg

897°C (begins to 

sublime before 

melting)g

830°Cb; 500°Ce

Boiling point No data No data Decomposes at 

1,472°Cg

Decomposes between 

500-530°Cd

Density No data 4.53 g/cm3g 9.53 g/cm3

(Litharge)g; 

9.6 

g/cm3 (Massicot)g

8.92 g/cm3b; 

9.1 g/cm3e

Odor No data No data No data No data

Odor threshold: No data No data No data No data

Solubility:

Water No data 56:5 g/100 mL at 

20°Cg

50.4 mg/L at 25°C 

(Litharge)g; 

106.5 mg/L at 

25°C (Massicot)g

Insoluble in waterd

Acid No data Insoluble in 

concentrated nitric 

acida

Solubleg Dissolves in acetic 

acid or hot 

hydrochloric acidb,g

Base No data Soluble in alkali and 

ammoniag

Solubleg No data

Organic solvents No data 87.7 mg/L (43% 

aqueous ethanol) at 

22°Cg

Insoluble in 

alcohola

Insoluble in alcoholg

Partition coefficients:

Log Kow No data No data No data No data

Log Koc No data No data No data No data

Vapor pressure No data No data 0.0075 mmHg at 

724°Cb

No data

Henry’s law 

constant

No data No data No data No data

Autoignition 

temperature

No data No data No data No data

Flashpoint No data No data No data No data

Flammability limits No data No data No data No data

Conversion factors Not relevantf Not relevantf Not relevantf Not relevantf

Explosive limits No data No data No data No data

Valence state +2 +2 +2 +2, +2, +4
LEAD 353

4. CHEMICAL AND PHYSICAL INFORMATION

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

Property Lead(II) phosphate Lead(II) styphnate Lead(II) sulfate

Molecular weight 811.54a 450.29h 303.25g

Color White powdera Monoclinic orange-yellow 

crystal (monohydrate)b

White, heavy, crystalline 

powdera

Physical state Solid Solid Solid

Melting point 1,014°Ca No data 1,170°Cg

Boiling point No data No data No data

Density 6.9 g/cm3a 3.1 g/cm3 (monohydrate); 

2.9 g/cm3 (anhydrous)b

6.2 g/cm3g 

Odor No data No data No data

Odor threshold: No data No data No data

Solubility:

Water Insolubleb Insolubleb 42.5 mg/L at 25°Cg

Acid Soluble in nitric acida No data Soluble in concentrated acidsg

Base Soluble in fixed alkali 

hydroxidesa

No data Soluble in alkaliesg

Organic solvents Insoluble in alcohola No data Insoluble in alcohola

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 

constant

No data No data No data

Autoignition 

temperature

No data No data No data

Flashpoint No data No data No data

Flammability limits No data No data No data

Conversion factors Not relevantf Not relevantf Not relevantf

Explosive limits No data Detonates at 260°Cb No data

Valence state +2 +2 +2
LEAD 354

4. CHEMICAL AND PHYSICAL INFORMATION

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

Property Lead(II) sulfide Tetraethyl lead Lead(II) carbonate

Molecular weight 239.25g 323.45a 267.22g

Color Metallic black cubic 

crystalsg

Colorlessa Colorless rhombic crystalsg

Physical state Solid Liquida Solid

Melting point 1,114°Cd No data 315°C (decomposes)g

Boiling point Sublimes at 1,281°Cd 200 °C; 227.7°C (with 

decomposition)a

No data

Density 7.57–7.59 g/cm3g 1.653 g/cm3a 6.6 g/cm3g

Odor No data No data No data

Odor threshold: No data No data No data

Solubility:

Water 124.4 mg/L 20°Cg 0.29 mg/Li 1.1 mg/L at 20°Cg

Acid Soluble in nitric acidg No data Solubleg

Base Insoluble in alkaliesd No data Soluble in alkalies; insoluble in 

ammoniag

Organic solvents Insoluble in alcohola Soluble in benzene, 

petroleum ether, gasoline; 

slightly soluble in alcohola

Insoluble in alcoholg

Partition coefficients:

Log Kow No data 4.15j No data

Log Koc No data No data No data

Vapor pressure 0.0075 mmHg at 

705°Cb

0.26 mmHg at 25°Cj No data

Henry’s law 

constant

No data No data No data

Autoignition 

temperature

No data No data No data

Flashpoint No data 200°F (93°C) (closed cup)k No data

Flammability limits No data Lower flammable limit: 

1.8% by volumek

No data

Conversion factors Not relevantf No data Not relevantf

Explosive limits No data No data No data

Valence state +2 +4 +2

aO’Neil et al. 2013.

bHaynes 2014.

cAkhavan 2004. dLarrañaga et al. 2016. 

eJacob 2012.

f

Since these compounds exist in the atmosphere in the particulate state, their concentrations are expressed as 

μg/m3 only.

gCarr et al. 2004.

hMolecular weight calculated from atomic weights. i

Feldhake and Stevens 1963.

j

Wang et al. 1996.

kNFPA 2002.
LEAD 355

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

Pb and Pb compounds have been identified in at least 1,287 and 46 sites, respectively, of the 1,867 

hazardous waste sites that have been proposed for inclusion on the EPA National Priorities List (NPL) 

(ATSDR 2019). However, the number of sites evaluated for Pb is not known. The number of sites in 

each state is shown in Figures 5-1 and 5-2, respectively. Of these 1,287 sites for Pb, 1,273 are located 

within the United States, 2 are located in the Virgin Islands, 2 are located in Guam, and 10 are located in 

Puerto Rico (not shown). All the sites for Pb compounds are only in the United States.

Figure 5-1. Number of NPL Sites with Lead Contamination
LEAD 356

5. POTENTIAL FOR HUMAN EXPOSURE

Figure 5-2. Number of NPL Sites with Lead Compound Contamination

• Pb is an element found in concentrated and easily accessible Pb ore deposits that are widely 

distributed throughout the world. 

• The general population may be exposed to Pb in ambient air, foods, drinking water, soil, and dust. 

For adults, exposure to levels of Pb beyond background are usually associated with occupational 

exposures. 

• For children, exposure to high levels of Pb are associated with living in areas contaminated by Pb 

(e.g., soil or indoor dust in older homes with Pb paint). Exposure usually occurs by hand-tomouth activities. 

• As an element, Pb does not degrade. However, particulate matter contaminated with Pb can 

move through air, water, and soil. 

• Atmospheric deposition is the largest source of Pb found in soils. Pb 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 Pb. 

• Pb adsorbs strongly to most soils, which limits the rate of leaching of Pb from soil. Soil acidity 

(pH) is the most important factor affecting solubility, mobility, and phytoavailability of Pb in soil. 
LEAD 357

5. POTENTIAL FOR HUMAN EXPOSURE

Other conditions that increase Pb mobility in soils are reducing conditions (low redox potential; 

for example, anoxia) and high chloride content.

Pb is dispersed throughout the environment primarily as the result of anthropogenic activities. In the air, 

Pb is in the form of particles and is removed by rain or gravitational settling. The solubility of Pb 

compounds in water is a function of pH, ionic strength, and the presence of humic material. Solubility is 

highest in acidic water. Soil and sediment are an important sink for Pb. Because Pb is strongly adsorbed 

to soil, very little is transported through runoff to surface water or leached to groundwater except under 

acidic conditions. Anthropogenic sources of Pb include the mining and smelting of ore, manufacture and 

use of Pb-containing products, combustion of coal and oil, and waste incineration. Many anthropogenic 

sources of Pb, most notably leaded gasoline, Pb-based paint, Pb solder in food cans, Pb-arsenate 

pesticides, and shot and sinkers, have been eliminated or are regulated. Pb compounds released to the 

environment may be transformed to other Pb compounds; however, Pb is an element and cannot be 

destroyed or degraded. Because Pb does not degrade over time, deposits of Pb in the environment by 

current and former uses leave their legacy as higher concentrations of Pb in the environment. These 

deposits can continue to be a source for potential Pb exposure (e.g., soil particles containing Pb also may 

be resuspended and redeposited). Plants and animals may bioconcentrate Pb, but Pb is not biomagnified 

in the aquatic or terrestrial food chain.

The general population may be exposed to Pb in ambient air, foods, drinking water, soil, and dust. 

Segments of the general population at highest risk of health effects from Pb exposure are preschool-age 

children and pregnant women and their fetuses. Other segments of the general population with an 

increased exposure include individuals living near sites where Pb was produced or disposed. Some of the 

more important Pb exposures have occurred as a result of living in urban environments, particularly in 

areas near stationary emission sources (e.g., smelters); renovation of homes containing Pb-based paint; 

pica (the compulsive, habitual consumption of nonfood items); contact with interior Pb paint dust; 

occupational exposure; and secondary occupational exposure (e.g., families of workers in Pb industries). 

Higher exposures may also occur to residents living in close proximity to NPL sites that contain elevated 

levels of Pb. 

The primary source of Pb 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 Pb emissions. The United States gradually phased out the use of Pb alkyls in gasoline, and 

by 1990, auto emissions accounted for only 33% of the annual Pb emissions (EPA 1996b). Use of Pb 
LEAD 358

5. POTENTIAL FOR HUMAN EXPOSURE

additives in most motor fuels was totally banned after December 31, 1995 (EPA 1996a). The ban went 

into effect on February 2, 1996. The ban did not include off-road vehicles, including aircraft, racing cars, 

farm equipment, and marine engines. Pb additives are still used in fuels for piston driven airplane engines 

and it continues to be commercially available for other off-road uses. Atmospheric deposition is the 

largest source of Pb found in soils. Pb 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 Pb. Pb 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. The speciation of Pb in these media varies widely depending upon such factors as temperature, pH, 

and the presence of humic materials. Pb is largely associated with suspended solids and sediments in 

aquatic systems, and it occurs in relatively immobile forms in soil.

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

5.2.1 Production

The most important mineable Pb ore is galena (PbS), which is commonly associated with other minerals, 

typically zinc ores. Anglesite (PbSO4) and cerussite (PbCO3), formed by the weathering of galena, are 

two other important Pb minerals. Pb is processed from ore to refined metal in four steps: ore dressing; 

smelting; drossing; and refining. Ore dressing involves crushing, grinding, and beneficiation 

(concentration) (King et al. 2014). 

Since 1998, U.S. production of Pb has shifted to the domestic secondary Pb industry (USGS 2014). Since 

2014, primary Pb metal has not been produced in the United States (USGS 2016). The Doe Run 

Resources Corporation operated the last domestic primary Pb smelter-refinery facility in the United States 

at Herculaneum, Missouri and it was closed at the end of 2013. Pb-acid batteries are the dominant source 

of recoverable Pb scrap, accounting for nearly 100% of all secondary Pb (USGS 2016, 2019). 

Domestic mines produced 368,000 metric tons of recoverable Pb in 2014, a more than 11% increase from 

2013. Nearly all of the secondary Pb produced in 2014 was by 7 companies operating 12 plants in 

Alabama, California, Florida, Indiana, Minnesota, Missouri, New York, Pennsylvania, Tennessee, and 

Texas (USGS 2016). Secondary (recycled) Pb, derived from mainly scrapped Pb-acid batteries, 

accounted for all of the domestic refined Pb production in 2014. Due to plant closings, U.S. production 
LEAD 359

5. POTENTIAL FOR HUMAN EXPOSURE

of secondary refined Pb decreased in 2014 by 11% to 1.02 metric tons, from 1.5 metric tons in 2013 

(USGS 2016). 

World mine production of Pb was 4.91 million metric tons in 2014, a decrease of 9% from 2013. The 

United States accounted for approximately 8% of global mine production in 2014. The United States 

ranked third in global mine production behind China and Australia, which accounted for 49 and 15%, 

respectively. World production of refined Pb (primary and secondary) was 10.6 million metric tons in 

2014. China produced about 45% of global refined Pb in 2014 with the United States as the second 

leading world producer of refined Pb, accounting for 10% (USGS 2016). In 2017 and 2018 worldwide 

mine production of Pb was reported as 4.58 and 4.40 million metric tons, respectively (USGS 2019). As 

in previous years, China was the dominant producer accounting for nearly half of the world production. 

Manufacturers and importers of Pb metal and selected Pb compounds are listed in Table 5-1. These data 

are from EPA’s Chemical Data Access Tool (now called Chemical Data Reporting [CDR]), which 

provides information on chemicals submitted to the EPA under the Toxic Substance Control Act that are 

manufactured or imported into the United States. Manufacturing volumes for more recent years are not 

available in the CDR as most manufacturers have withheld these data as confidential business 

information; however, as in previous years, the U.S. Geological Survey (USGS) reported total Pb mined 

in the United States in its Minerals Commodity summaries and these data for 2015–2018 are provided in 

Table 5-2. According to the USGS, five Pb mines located in the state of Missouri along with five mines 

in Alaska, Idaho, and the state of Washington accounted for all domestic Pb mine production (USGS 

2019).

Table 5-1. U.S. Manufacturers of Lead Metal and Selected Lead Compounds

Company Location

Domestic 

manufacturing 

(pounds/year)

Lead

5n Plus Inc. Fairfield, Connecticut 36,671

Colfin Specialty Steel Corp. New Brighton, Pennsylvania 2,552

Compliance Administrators & Project Services Inc. Bloomington, California 848,008

Concorde/Interspace Battery West Covina, California 348,998

Doe Run Co. Herculaneum, Missouri 280,000,000

East Penn Manufacturing Co. Inc. Lyon Station, Pennsylvania 194,537,569

Exide Technologies Bristol, Tennessee 150,000
LEAD 360

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-1. U.S. Manufacturers of Lead Metal and Selected Lead Compounds

Company Location

Domestic 

manufacturing 

(pounds/year)

Columbus, Georgia 4,200,000

Forest City, Missouri 84,000,000

Fort Smith, Arkansas 3,600,000

Frisco, Texas 140,000,000

Kansas City, Kansas 9,100,000

Los Angeles, California 230,000,000

Manchester, Iowa 16,000,000

Muncie, Indiana 160,000,000

Reading, Pennsylvania 130,000,000

Salina, Kansas 990,000

Gopher Resource Eagan, Minnesota 310,000,000

Tampa, Florida 38,000,000

Horsehead Holding Corp. Chicago, Illinois 2,444,492

Palmerton, Pennsylvania 3,867,016

Rockwood, Tennessee 1,872,054

Snelling, South Carolina 2,012,236

Johnson Controls Canby, Oregon 36,832,250

Geneva, Illinois 47,025,828

Holland, Ohio 82,721,150

Kernersville, North Carolina 204,679,893

Middletown, Delaware 86,732,852

Tampa, Florida 3,069,380

Yuma, Arizona 359,977,380

Johnson Controls Distribution Center Saint Joseph, Missouri 2,550,177

St. Joseph, Missouri 266,151,342

Renco Group Inc. Boss, Missouri 310,000,000

Sanders Lead Co., Inc. Troy, Alabama 471,954,520

Stemar Investments Inc. Butler, Pennsylvania 40,506

Yuasa Battery Inc. Laureldale, Pennsylvania 1,492,754 

Lead(II) nitrate

American Pacific Corp. Cedar City, Utah 42,500

Lead(II) oxide

C&D Technologies Inc. Attica, Indiana 18,657,255

Leola, Pennsylvania 1,348,311

Milwaukee, Wisconsin 48,491,557

Crown Battery Manufacturing Co. Fremont, Ohio 25,600,000
LEAD 361

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-1. U.S. Manufacturers of Lead Metal and Selected Lead Compounds

Company Location

Domestic 

manufacturing 

(pounds/year)

Fiamm Energy LLC Waynesboro, Georgia 4,700,000

Hammond Group Inc. Hammond, Indiana 3,585,529

Pottstown, Pennsylvania 8,287,521

Renco Group Inc. Boss, Missouri 7,700,000

Steel Dust Recycling Millport, Alabama 2,000,000

Superior Battery Manufacturing Russell Springs, Kentucky 16,866,793

Trojan Battery Co. Lithonia, Georgia 38,540,700

Santa Fe Springs, California 35,241,500

Lead(II) styphnate

Alliant Techsystems Inc. Lewiston, Idaho 78,767

Alliant Techsystems Operations LLC Independence, Missouri 43,489

Lead(II) sulfate

Crown Battery Manufacturing Co. Fremont, Ohio 768,000

East Penn Manufacturing Co., Inc. Corydon, Iowa 17,006,710

Lyon Station, Pennsylvania 220,436,420

Johnson Controls Canby, Oregon 6,098,880

Geneva, Illinois 11,340,306

Holland, Ohio 10,714,048

Middletown, Delaware 5,749,910

Tampa, Florida 5,506,240

Yuma, Arizona 86,756

Johnson Controls Distribution Center Saint Joseph, Missouri 306,021

St. Joseph, Missouri 29,577,055

Palos Verdes Bldg Corp. Augusta, Georgia 6,904,629

Superior Battery Manufacturing Russell Springs, Kentucky 22,905,105

Trojan Battery Co. Lithonia, Georgia 58,127,100

Santa Fe Springs, California 53,083,500

Lead(II) chloride

Horsehead Holding Corp. Monaca, Pennsylvania 1,891,700

Palmerton, Pennsylvania 11,484,955

Source: EPA 2014d
LEAD 362

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Table 5-2. U.S. Lead Production 2015–2018

Production volumes in metric tons

2015 2016 2017 2018

Mine, lead in concentrates 370,000 346,000 310,000 260,000

Secondary refinery, old scrap 1,050,000 986,000 1,130,000 1,300,000

Source: USGS 2019

Tables 5-3 (Pb) and 5-4 (Pb compounds) list the facilities in each state that manufacture or process Pb or 

Pb compounds, the intended use, and the range of maximum amounts of Pb that are stored on site. The 

data listed in Tables 5-3 and 5-4 are derived from the Toxics Release Inventory (TRI) (TRI18 2020). The 

data presented in Table 5-3 are for Pb metal and the data from Table 5-4 are for all Pb compounds. 

Facilities with ≥10 full-time employees in certain TRI-covered industry sectors (e.g., manufacturing) 

must submit data on releases and other waste management for TRI-listed chemicals (Pb and Pb 

compounds are TRI listed). Therefore, there are sources for Pb and Pb compounds not contained in the 

TRI database. In comparing TRI data with that of previous years, it is important to note that starting in 

2001, the threshold for reporting Pb and all Pb compounds was reduced to 100 pounds, except for Pb

contained in a stainless steel, brass, or bronze alloy. Previously, reporting was only required of facilities 

that manufactured or processed >25,000 pounds annually or that used >10,000 pounds annually. 

Beginning in 1998, additional industries were required to report, including metal mining, coal mining, 

electrical utilities, and Resource Conservation and Recovery Act (RCRA)/Solvent Recovery. Table 5-3

lists the producers of primary Pb metal and selected Pb compounds. Companies listed are those 

producing Pb compounds in commercial quantities >5,000 pounds or $10,000 in value annually. 

Table 5-4 shows the U.S. production volumes for Pb for 2010 through 2013. During this time, the 

primary Pb production declined, while secondary Pb production was relatively constant.

Table 5-3. Facilities that Produce, Process, or Use Lead

Statea

Number of 

facilities

Minimum 

amount on site 

in poundsb

Maximum 

amount on site 

in poundsb Activities and usesc

AK 4 100 99,999 12

AL 105 0 999,999,999 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

AR 67 0 49,999,999 1, 2, 5, 6, 7, 8, 9, 11, 12, 13, 14

AZ 52 0 9,999,999 1, 3, 5, 7, 8, 9, 10, 11, 12, 14

CA 188 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

CO 33 0 99,999 1, 5, 6, 7, 8, 10, 11, 12, 14
LEAD 363

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Table 5-3. Facilities that Produce, Process, or Use Lead

Statea

Number of 

facilities

Minimum 

amount on site 

in poundsb

Maximum 

amount on site 

in poundsb Activities and usesc

CT 42 0 99,999 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

DC 6 0 9,999 1, 7, 8, 11, 12, 13, 14

DE 6 0 99,999 7, 12, 14

FL 223 0 999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

GA 108 0 999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

GU 1 0 99 1, 5

HI 2 0 99,999 8, 12

IA 114 0 9,999,999 1, 2, 5, 6, 7, 8, 9, 11, 12, 13, 14

ID 27 0 49,999,999 1, 2, 3, 5, 8, 9, 11, 12, 13, 14

IL 228 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14

IN 161 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

KS 70 0 9,999,999 1, 3, 5, 7, 8, 9, 10, 12, 13, 14

KY 79 0 999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

LA 46 0 999,999 1, 2, 3, 5, 8, 9, 10, 11, 12, 13, 14

MA 55 0 999,999 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

MD 35 0 99,999 1, 5, 7, 8, 9, 10, 11, 12, 14

ME 20 0 99,999 1, 2, 3, 4, 5, 8, 9, 11, 12, 13, 14

MI 148 0 999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14

MN 123 0 99,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

MO 92 0 9,999,999 1, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

MS 62 0 999,999 1, 5, 7, 8, 9, 10, 12, 14

MT 15 0 99,999 1, 2, 5, 11, 12, 13, 14

NC 162 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 13, 14

ND 14 0 9,999 1, 5, 8, 9, 12, 14

NE 62 0 999,999 1, 2, 3, 5, 7, 8, 9, 11, 12, 13, 14

NH 30 0 99,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 14

NJ 43 0 99,999 1, 2, 5, 7, 8, 9, 11, 12, 13, 14

NM 17 0 999,999 1, 5, 6, 8, 9, 10, 11, 12, 14

NV 28 0 999,999 1, 2, 4, 5, 8, 9, 12, 13, 14

NY 140 0 999,999 1, 2, 3, 5, 7, 8, 9, 10, 11, 12, 13, 14

OH 237 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

OK 54 0 999,999 1, 2, 3, 5, 7, 8, 11, 12, 14

OR 48 0 9,999,999 1, 2, 3, 5, 7, 8, 10, 11, 12, 13, 14

PA 182 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

PR 5 100 9,999 2, 3, 8, 9, 12

RI 15 0 999,999 1, 5, 7, 8, 9, 10, 11, 12, 13, 14

SC 81 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14

SD 14 0 99,999 1, 2, 5, 7, 8, 9, 13, 14
LEAD 364

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-3. Facilities that Produce, Process, or Use Lead

Statea

Number of 

facilities

Minimum 

amount on site 

in poundsb

Maximum 

amount on site 

in poundsb Activities and usesc

TN 110 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

TX 326 0 49,999,999 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

UT 50 0 999,999 1, 5, 6, 8, 9, 10, 11, 12, 13, 14

VA 98 0 999,999 1, 2, 3, 5, 7, 8, 9, 10, 11, 12, 13, 14

VI 3 0 99 7, 9, 14

VT 11 0 99,999 1, 2, 3, 5, 8, 11, 12, 13, 14

WA 57 0 999,999 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 13, 14

WI 165 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

WV 31 0 999,999 1, 2, 5, 8, 9, 10, 11, 12, 13, 14

WY 12 0 99,999 1, 5, 6, 8, 9, 10, 11, 12, 13, 14

aPost office state abbreviations used. bAmounts on site reported by facilities in each state.

cActivities/Uses:

1. Produce

2. Import

3. Used Processing

4. Sale/Distribution

5. Byproduct

6. Reactant

7. Formulation Component

8. Article Component

9. Repackaging

10. Chemical Processing Aid

11. Manufacture Aid

12. Ancillary

13. Manufacture Impurity

14. Process Impurity

Source: TRI18 2020 (Data are from 2018)

Table 5-4. Facilities that Produce, Process, or Use Lead Compounds

Statea

Number of 

facilities

Minimum 

amount on site 

in poundsb

Maximum 

amount on site 

in poundsb Activities and usesc

AK 16 0 499,999,999 1, 5, 9, 12, 13, 14

AL 130 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

AR 68 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

AZ 65 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14

CA 315 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

CO 76 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 13, 14

CT 39 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

DC 1 100 999 14

DE 5 100 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 12, 13, 14

FL 150 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 13, 14

GA 108 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14

GU 3 0 99 1, 5, 7, 9, 12, 13, 14

HI 14 0 99,999 1, 2, 5, 7, 9, 12, 13, 14

IA 66 0 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14
LEAD 365

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-4. Facilities that Produce, Process, or Use Lead Compounds

Statea

Number of 

facilities

Minimum 

amount on site 

in poundsb

Maximum 

amount on site 

in poundsb Activities and usesc

ID 31 0 9,999,999 1, 2, 3, 4, 5, 7, 8, 11, 12, 13, 14

IL 166 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

IN 151 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

KS 40 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

KY 64 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

LA 85 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

MA 53 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

MD 35 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14

ME 13 0 999,999 1, 2, 4, 5, 8, 9, 12, 13, 14

MI 102 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

MN 50 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

MO 74 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14

MP 1 0 99 1, 5, 12, 13, 14

MS 50 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14

MT 20 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 12, 13, 14

NC 149 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

ND 20 0 99,999 1, 2, 3, 4, 5, 7, 8, 9, 12, 13, 14

NE 24 0 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14

NH 14 0 999,999 1, 2, 5, 7, 8, 9, 11, 12, 14

NJ 55 0 999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14

NM 18 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 13, 14

NV 51 0 49,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

NY 82 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

OH 175 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

OK 81 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

OR 55 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

PA 195 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

PR 11 0 99,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 14

RI 19 0 99,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14

SC 101 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14

SD 11 0 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14

TN 89 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14

TX 330 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

UT 41 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

VA 84 0 49,999,999 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

VI 2 0 99 1, 5, 12, 0

VT 5 0 9,999 7, 8, 14

WA 76 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14
LEAD 366

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-4. Facilities that Produce, Process, or Use Lead Compounds

Statea

Number of 

facilities

Minimum 

amount on site 

in poundsb

Maximum 

amount on site 

in poundsb Activities and usesc

WI 100 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

WV 44 0 49,999,999 1, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14

WY 16 0 999,999 1, 2, 3, 4, 5, 8, 9, 12, 13, 14

aPost office state abbreviations used.

bAmounts on site reported by facilities in each state. cActivities/Uses:

1. Produce

2. Import

3. Used Processing

4. Sale/Distribution

5. Byproduct

6. Reactant

7. Formulation Component

8. Article Component

9. Repackaging

10. Chemical Processing Aid

11. Manufacture Aid

12. Ancillary

13. Manufacture Impurity

14. Process Impurity

Source: TRI18 2020 (Data are from 2018)

5.2.2 Import/Export

In 2014, 1,080 and 593,000 metric tons of Pb as base bullion and pigs and bars, respectively, were 

imported into the United States. Imports have increased since 2010 when 602 and 271,000 metric tons of 

Pb as base bullion and pigs and bars, respectively, were imported. In 2014, 65,100 metric tons, Pb 

content of Pb pigments and compounds were imported in the United States (USGS 2016). In 2015, 2016, 

2017, and 2018 imports of Pb refined metal (unwrought) were reported as 521,000, 533,000, 658,000, and 

580,000 metric tons, respectively (USGS 2019). 

Exports of Pb in ore and concentrates and Pb materials, excluding scrap were 299,000 and 83,500 metric 

tons, respectively, in 2010 as compared to 365,000 and 61,300 metric tons, respectively, in 2014. In 2013 

and 2014, 34,900 and 36,400 metric tons of Pb scrap were exported, respectively (USGS 2016). Total 

exports of Pb (Pb in concentrates and refined metal, unwrought gross weight) were reported as 406,000, 

384,000, 293,000, and 324,000 metric tons in 2015, 2016, 2017, and 2018, respectively (USGS 2019). 

5.2.3 Use

Pb may be used in the form of metal, either pure or alloyed with other metals, or as chemical compounds. 

The main uses of Pb and its compounds are in Pb-acid batteries, with most other applications using Pb 

alloys. The commercial importance of Pb is based on its physical properties, including its low melting 
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5. POTENTIAL FOR HUMAN EXPOSURE

point, ease of casting, high density, softness, malleability, low strength, ease of fabrication, acid 

resistance, electrochemical reaction with sulfuric acid, and chemical stability in air, water, and soil (King 

et al. 2014). 

In the United States in 2014, Pb was consumed by over 70 companies to manufacture products such as 

ammunition; building-construction materials; covering for power and communication cable; Pb-acid 

storage batteries; Pb oxides for ceramics, chemicals, glass, and pigments; Pb sheet; and solder for 

construction, electronic components and accessories, metal containers, and motor vehicles (USGS 2016). 

In 2018, it was estimated that the Pb-acid battery industry accounted for >85% of the domestic 

consumption of Pb in the United States (USGS 2019). Pb-acid batteries were primarily used as startinglighting-ignition (SLI) batteries for automobiles and trucks and as industrial-type batteries for standby 

power for computer and telecommunications networks and for motive power. Global consumption of

refined Pb was 11.71 million metric tons in 2018, (USGS 2019).

Prior to the EPA beginning to regulate the Pb content in gasoline during the early 1970s, approximately 

250,000 tons of organic Pb (e.g., tetraethyl Pb) were added to gasoline on an annual basis in the United 

States (Giddings 1973). These Pb-based “anti-knock” additives increased the octane rating of the 

gasoline and, as a result, increased engine efficiency (Giddings 1973). In 1971, the average Pb content 

for a gallon of gasoline purchased in the United States was 2.2 g/gallon (Giddings 1973). After 

determining that Pb additives would impair the performance of emission control systems installed on 

motor vehicles, and that Pb 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 Pb 

in gasoline over time. By 1988, the phase-down program had reduced the total Pb usage in gasoline to 

<1% of the amount of Pb 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 

Pb or Pb additives as fuel in most 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 Pb up to 0.05 g/gallon (EPA 1996a). The definition still allowed trace amounts of Pb, but expressly 

prohibited the use of any Pb additive in the production of unleaded gasoline. The term “lead additive” 

was defined to include pure Pb as well as Pb 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 Pb or Pb additives (EPA 1996a). Gasoline produced with Pb additives 

continues to be made and marketed for use as fuels in aircraft, race cars, and non-road engines such as 
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5. POTENTIAL FOR HUMAN EXPOSURE

farm equipment engines and marine engines to the extent allowed by law (EPA 1996a), but tetraethyl Pb 

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 2020a).

Table 5-5 lists the uses of the specific Pb compounds identified in Chapter 4.

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

Compound Uses

Lead(II) acetate Dyeing of textiles, waterproofing, varnishes, lead driers, chrome pigments, 

gold cyanidation process, insecticide, anti-fouling paints, analytical reagent, 

hair dye

Lead(II) azide Primary detonating compound for high explosives, firing of Pb-based 

ammunition

Lead(II) bromide Photopolymerization catalyst, inorganic filler in fire-retardant plastics, 

general purpose welding flux

Lead(II) carbonate Polymerization catalyst, component of high pressure lubricating greases, 

coating on vinyl chloride polymers

Lead(II) chloride Preparation of lead salts, lead chromate pigments, analytical reagent

Lead(II) chromate Pigment in industrial paints, rubber, plastics, ceramic coatings; organic 

analysis

Lead(II) tetrafluoroborate Salt for electroplating lead; can be mixed with stannous fluoborate to 

electroplate any composition of tin and lead as an alloy

Lead(II) iodide Bronzing, printing, photography, cloud seeding

Lead molybdenum chromate Analytical chemistry, pigments

Lead(II) 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(II) oxide 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), acidresisting compositions, match-head compositions, other lead compounds, 

rubber accelerator

Lead(II) phosphate Stabilizing agent in plastics 

Lead(II) styphnate Primary explosive, firing of Pb-based ammunition

Lead(II) sulfate Storage batteries, paints, ceramics, pigments, electrical and other vinyl 

compounds requiring high heat stability

Lead(II) 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; Carr et al. 2004; Davidson et al. 2014 

Pb arsenate, basic Pb arsenate, and Pb arsenite were formerly used as herbicides, insecticides, or 

rodenticides. Until the 1960s, they were widely used to control pests in fruit orchards, especially apple 
LEAD 369

5. POTENTIAL FOR HUMAN EXPOSURE

orchards (EPA 2002c; PAN Pesticides Database 2004; Peryea 1998; Wisconsin DHS 2002). All 

insecticidal use of Pb arsenate was officially banned on August 1, 1988. However, all registrations for its 

insecticidal use had lapsed before that time. 

5.2.4 Disposal

Secondary (recycled) Pb, derived mainly from scrapped Pb-acid batteries, accounted for 100% of refined 

Pb production in the United States in 2014. Almost all of the Pb recycled in 2014 was recovered by 

7 companies operating 12 plants in Alabama, California, Florida, Indiana, Minnesota, Missouri, New

York, Pennsylvania, Tennessee, and Texas (USGS 2016). More than 99% of all battery Pb is recycled 

and new batteries contain between 60 and 80% recycled Pb and plastic, respectively (BCI 2019). Scrap 

Pb is also recovered from dross, dust, residue, and sludge generated by smelting of metals, Pb pipe and 

sheet, printing materials, sheaths from power and telephone cable, and vehicle wheel weights (USGS 

2014). 

Disposal of wastes containing Pb or Pb compounds is controlled by several federal regulations (see 

Chapter 7). Pb 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 1988). Pb-containing waste products include storage batteries, 

ammunition waste, ordnance, sheet Pb, solder, pipes, traps, and other metal products; solid waste and 

tailings from Pb mining; items covered with Pb-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 

Pb-containing products (EPA 1982a).

In the United States., federal laws require, used nickel cadmium (Ni-Cd) and lead (Pb) batteries to be 

managed as Universal Waste and recycled or disposed of in accordance under Title 40 Parts 266 and 273 

of the Code of Federal Regulations (EPA 2020b). The Mercury-Containing and Rechargeable Battery 

Management Act (the Battery Act) of 1996 removed certain barriers to the recycling of batteries including 

small, sealed lead acid (SSLA) batteries (EPA 2002b). The intent was to provide the efficient and costeffective collection and recycling or proper disposal of batteries to keep them out of the waste stream. 

The Act established uniform national labeling requirements, mandated that batteries under the Act be 

“easily removable” from consumer products where possible, made the Universal Waste Rule effective in 

all 50 states for the collection, storage, and transportation of batteries covered by the Battery Act, and 
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5. POTENTIAL FOR HUMAN EXPOSURE

required EPA to establish a public education program on battery recycling and the proper handling and 

disposal of used batteries (EPA 1997a).

According to data from the TRI, total disposal of Pb and Pb compounds varied during the period of 2005–

2015 from 387 million pounds in 2009 to 832 million pounds in 2013, with an overall increase of 20% 

during this time period. The metal mining sector contributes most to the disposal of Pb and Pb 

compounds, with metal mines reporting 85% of total Pb and Pb compound releases in 2015.

5.3 RELEASES TO THE ENVIRONMENT

Facilities with ≥10 full-time employees in certain industry sectors (e.g., manufacturing) covered by the 

TRI (e.g., manufacturing) must submit data to TRI on releases and other waste management for TRIlisted chemicals (Pb and Pb compounds are TRI listed). Therefore, TRI data do not reflect all sources of 

Pb releases (EPA 2005a). TRI-covered facilities are required to report information to the TRI only if they 

employ the equivalent of ≥10 full-time employees; if their facility is included in Standard Industrial 

Classification (SIC) Codes 10 (except 1011, 1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4931 (limited to facilities that combust coal and/or oil for the purpose of generating 

electricity for distribution in commerce), 4939 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4953 (limited to facilities regulated under 

RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited S.C. section 6921 et 

seq.), 5169, 5171, and 7389 (limited to facilities primarily engaged in solvents recovery services on a 

contract or fee basis); and if their facility produces, imports, or processes >25,000 pounds of any TRI 

chemical or otherwise uses >10,000 pounds of a TRI chemical in a calendar year (EPA 2005a). 

Starting in 2001, the threshold to trigger reporting of Pb in most Pb compounds was reduced to 

100 pounds. The higher threshold still applies to Pb contained in stainless steel, brass, or bronze alloys. 

The threshold for Pb is determined using the weight of the metal, whereas the threshold for Pb 

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 

industries required to report were enlarged to include other industrial sectors, such as metal mining, coal 

mining, electrical utilities, and hazardous waste treatment (EPA 2001). 
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5. POTENTIAL FOR HUMAN EXPOSURE

Pb is a naturally-occurring element that is typically found combined in various minerals. It occurs in the 

Earth’s crust primarily as the mineral galena (PbS), and to a lesser extent as anglesite (PbSO4) and 

cerussite (PbCO3) (Carr et al. 2004; Davidson et al. 2014; Haynes 2014). Pb 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 Pb concentrations in some ores and fuels 

are: copper ores, 11,000 ppm; Pb 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 2001). 

Leaded gasoline remains commercially available for off-road uses, including aircraft, racing cars, farm 

equipment, and marine engines. Currently, the largest contributor to atmospheric Pb emissions in the 

United States is piston-engine aircraft emissions (EPA 2016c). Industrial sources of Pb can result from 

the mining and smelting of Pb ores, as well as other ores in which Pb is a byproduct or contaminant. Fuel 

combustion also contributes to releases of Pb to the environment. As a result of these processes, Pb may 

be released to land, water, and air. Many of the anthropogenic sources of Pb have been eliminated or 

phased out because of Pb’s persistence, bioaccumulative nature, and toxicity. These include Pb-based 

paint in 1978, Pb-containing pesticides in 1988, and Pb in gasoline for use in on-road vehicles in 1996. In 

early 2017, the use of Pb ammunition and Pb sinkers was banned on most federal lands; however, this ban 

was temporarily halted soon after. Because Pb does not degrade and remains in the environment long 

after its release, these former uses continue to be a potential source for Pb exposure. 

5.3.1 Air

According to the TRI, in 2018, a total of 57,240 pounds of Pb were released to air from 4,064 reporting 

facilities (TRI18 2020). In addition, a total of 343,142 pounds of Pb compounds were released to air from 

3,789 reporting facilities (TRI18 2020). Tables 5-6 and 5-7 list amounts of Pb and Pb compounds 

released from these facilities grouped by state, respectively.
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Table 5-6. Releases to the Environment from Facilities that Produce, Process, or 

Use Leada

Reported amounts released in pounds per yearb

Statec RFd Aire Waterf UIg Landh Otheri

Total release

On-sitej Off-sitek

On- and 

off-site

AK 4 1 0 0 22,766 0 22,167 600 22,767 

AL 105 2,944 1,133 11 1,481,278 7,384 1,483,641 9,109 1,492,750 

AR 66 2,318 107 0 176,475 730 177,674 1,955 179,629 

AZ 52 103 129 0 42,201 331 40,794 1,970 42,765 

CA 179 662 1,313 0 585,305 58,212 572,870 72,623 645,493 

CO 34 296 20 0 108,291 51 108,414 244 108,658 

CT 42 52 541 0 2 5,360 62 5,893 5,955 

DC 6 1 2 0 6,493 1,000 6,464 1,031 7,495 

DE 6 9 3 89 7,852 0 7,864 89 7,954 

FL 221 693 89 1 98,375 15,249 84,880 29,527 114,408 

GA 107 3,397 1,000 0 18,503 8,671 20,456 11,114 31,571 

GU 1 28 0 0 0 0 0 0 28 

HI 2 0 0 0 10,359 0 10,358 1 10,359 

IA 114 10,241 80 849 6,205 12,559 14,396 15,538 29,934 

ID 27 268 45 0 367,560 29,707 367,635 29,945 397,579 

IL 228 3,147 2,286 27 649,364 43,310 613,450 84,683 698,133 

IN 160 1,056 272 22 454,088 557,867 7,434 1,005,871 1,013,305 

KS 70 536 26 0 24,749 729 13,856 12,183 26,039 

KY 79 891 509 0 32,991 5,941 30,618 9,715 40,333 

LA 45 511 967 13 22,715 462 22,763 1,905 24,669 

MA 55 70 10,245 28 36,566 3,555 15,467 34,998 50,465 

MD 34 25 59 0 13,986 86 13,467 689 14,156 

ME 20 3 23 0 219 123 39 329 368 

MI 147 2,095 396 11 41,090 5,359 19,114 29,837 48,951 

MN 123 1,199 232 5 4,017 624 1,971 4,106 6,077 

MO 92 483 225 1 20,478 729 12,844 9,072 21,915 

MS 62 1,102 35 1 63,143 1,327 63,240 2,368 65,608 

MT 13 16 2 0 36,873 0 36,872 20 36,892 

NC 162 567 708 248 122,679 1,295 16,540 108,957 125,497 

ND 13 1 229 0 6,038 7 6,130 144 6,275 

NE 61 4,505 1,379 0 79,160 9,063 83,397 10,709 94,107 

NH 29 17 6 0 726 26,933 743 26,939 27,682 

NJ 42 198 27 17 3,286 4,976 1,419 7,086 8,505 

NM 16 12 0 0 6,472 61 5,582 963 6,545 

NV 27 502 1 1 2,554,095 150 2,554,538 210 2,554,748 
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Table 5-6. Releases to the Environment from Facilities that Produce, Process, or 

Use Leada

Reported amounts released in pounds per yearb

Statec RFd Aire Waterf UIg Landh Otheri

Total release

On-sitej Off-sitek

On- and 

off-site

NY 140 499 89 0 21,001 9,770 14,560 16,799 31,359 

OH 236 4,321 540 232 68,683 33,151 34,929 71,997 106,926 

OK 54 451 11 14 81,644 3,422 81,961 3,581 85,542 

OR 48 77 45 0 1,495,571 742 1,494,474 1,961 1,496,435 

PA 183 6,456 1,908 425 167,238 486,904 12,164 650,767 662,931 

PR 4 4 0 0 3,777 47 3,780 48 3,828 

RI 14 10 1 0 3 5,086 10 5,091 5,101 

SC 80 517 212 0 43,446 947 35,803 9,319 45,123 

SD 14 100 0 0 0 25 100 25 126 

TN 109 756 222 1 33,156 8,866 21,918 21,083 43,001 

TX 325 1,223 1,027 2,833 468,642 45,651 468,737 50,638 519,376 

UT 49 835 24 0 95,346 80 89,493 6,793 96,286 

VA 93 1,176 574 17 184,110 26,197 83,245 128,828 212,074 

VI 3 2 0 0 31 0 24 8 32 

VT 11 1 6 0 16,304 397 16,289 419 16,708 

WA 54 115 184 0 382,285 212,687 371,196 224,075 595,272 

WI 163 1,921 638 0 35,520 13,924 5,242 46,762 52,004 

WV 30 410 190 52 144,313 38 144,201 803 145,004 

WY 10 416 1 0 47,579 1 47,733 263 47,996 

Total 4,064 57,240 27,764 4,901 10,393,047 1,649,785 9,363,048 2,769,688 12,132,737 

aThe 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.

bData in TRI are maximum amounts released by each facility. cPost office state abbreviations are used.

dNumber of reporting facilities.

eThe 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).

gClass I wells, Class II-V wells, and underground injection. hResource Conservation and Recovery Act (RCRA) subtitle C landfills; other onsite 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. kTotal amount of chemical transferred off0site, including to POTWs.

RF = reporting facilities; UI = underground injection

Source: TRI18 2020 (Data are from 2018)
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Table 5-7. Releases to the Environment from Facilities that Produce, Process, or 

Use Lead Compoundsa

Reported amounts released in pounds per yearb

Statec RFd Aire Waterf UIg Landh Otheri

Total release

On-sitej Off-sitek

On- and 

off-site

AK 15 19,345 139 0 499,679,935 1,006 499,696,960 3,465 499,700,425 

AL 130 6,801 4,859 0 1,254,651 4,503 1,167,133 103,682 1,270,814 

AR 67 5,268 1,098 0 481,839 53,191 239,131 302,264 541,396 

AZ 64 64,290 103 0 27,547,626 7,110 27,600,302 18,827 27,619,128 

CA 305 5,816 435 0 2,656,973 27,145 1,127,596 1,562,773 2,690,369 

CO 76 2,931 244 1 10,195,005 239 10,180,490 17,930 10,198,420 

CT 39 445 565 0 32,116 14,510 708 46,929 47,637 

DC 1 0 0 0 24 0 24 0 24 

DE 5 127 17 0 489 1,070 599 1,103 1,703 

FL 150 5,429 1,691 1 972,024 2,470 946,498 35,116 981,615 

GA 107 6,011 4,228 0 573,267 242 361,887 221,860 583,747 

GU 3 30 0 0 1,510 0 1,540 0 1,540 

HI 14 2,406 35 18 57,605 4 57,568 2,501 60,068 

IA 66 3,101 568 4 98,007 47,899 35,369 114,209 149,578 

ID 31 1,337 105 0 587,617 1,071 588,601 1,529 590,130 

IL 163 10,458 3,316 158 1,044,749 382,696 219,957 1,221,420 1,441,377 

IN 147 26,832 60,668 86 3,554,799 1,702,496 1,345,912 3,998,968 5,344,880 

KS 40 2,171 126 35 33,471 7,290 31,594 11,499 43,092 

KY 64 15,233 719 272 758,794 116,393 739,954 151,456 891,411 

LA 82 8,193 8,065 303 694,825 3,582 504,890 210,078 714,968 

MA 53 888 357 0 20,874 2,919 2,655 22,382 25,037 

MD 35 209 203 0 4,611 55,261 1,443 58,842 60,285 

ME 13 750 510 0 23,485 8,099 4,729 28,116 32,844 

MI 100 4,220 979 13 2,091,026 18,914 1,514,558 600,594 2,115,152 

MN 50 2,961 291 0 980,965 2,228 97,635 888,810 986,445 

MO 73 12,990 1,919 206 18,739,390 243,396 18,118,610 879,290 18,997,900 

MP 1 2 0 0 1 0 3 0 3 

MS 50 2,260 1,770 197,869 261,610 3,066 235,034 231,540 466,575 

MT 20 3,438 20 4,503 6,091,825 581 6,092,803 7,565 6,100,367 

NC 145 10,843 973 0 728,520 35,993 551,282 225,047 776,329 

ND 19 4,103 19 0 90,847 5,984 76,746 24,207 100,953 

NE 24 1,473 125 0 50,473 529 46,977 5,623 52,600 

NH 14 20 23 0 1,509 6,243 94 7,702 7,796 

NJ 54 871 12,266 0 410,073 234,474 62,349 595,336 657,685 

NM 17 902 283 1 2,978,296 31,276 2,893,375 117,383 3,010,758 

NV 49 9,161 1 0 49,276,056 40 49,282,572 2,685 49,285,258 

NY 82 2,294 1,167 0 209,644 26,579 132,597 107,087 239,684 
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Table 5-7. Releases to the Environment from Facilities that Produce, Process, or 

Use Lead Compoundsa

Reported amounts released in pounds per yearb

Statec RFd Aire Waterf UIg Landh Otheri

Total release

On-sitej Off-sitek

On- and 

off-site

OH 175 9,346 17,583 5,952 1,483,307 263,386 1,093,350 686,224 1,779,574 

OK 80 11,075 378 58 307,485 945 307,785 12,157 319,941 

OR 55 1,591 2,127 0 5,176 1,827 6,272 4,449 10,721 

PA 195 13,623 15,874 0 3,488,454 229,953 3,176,873 571,031 3,747,904 

PR 11 759 13 0 236 1,300 772 1,536 2,308 

RI 19 23 15 0 1,018 124 24 1,155 1,179 

SC 100 4,198 1,783 0 459,973 38,536 101,830 402,660 504,490 

SD 11 149 0 0 1,757,845 9 1,757,955 48 1,758,003 

TN 89 4,151 2,653 184 3,375,608 11,693 2,953,656 440,633 3,394,289 

TX 323 14,625 2,732 2,309 1,365,901 3,582 1,170,161 218,988 1,389,149 

UT 40 17,378 657 0 185,430,965 41,774 185,290,906 199,868 185,490,774 

VA 82 10,922 8,300 0 201,670 12,410 206,084 27,217 233,301 

VI 2 13 0 0 0 0 13 0 13 

VT 5 10 0 0 117 0 10 117 127 

WA 76 4,205 843 0 2,976,519 10,118 2,925,078 66,607 2,991,685 

WI 98 3,448 1,598 0 279,692 27,606 74,486 237,858 312,344 

WV 44 3,235 920 0 362,089 1,142 240,520 126,866 367,385 

WY 16 783 2 0 79,050 284 67,659 12,461 80,119 

Total 3,789 343,142 163,361 211,975 833,759,635 3,693,189 823,333,608 14,837,694 838,171,302 

aThe 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.

bData in TRI are maximum amounts released by each facility.

cPost office state abbreviations are used.

dNumber of reporting facilities.

eThe 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).

gClass I wells, Class II–V wells, and underground injection. hResource Conservation and Recovery Act (RCRA) subtitle C landfills; other onsite landfills, land treatment, surface 

impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other offsite 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.

kTotal amount of chemical transferred offsite, including to POTWs.

RF = reporting facilities; UI = underground injection

Source: TRI18 2020 (Data are from 2018)
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The decrease in national Pb emissions between 1970 to 2011 is estimated to be 99.6% (220,000 tons), 

which is mostly attributed to the elimination of leaded gasoline for on-road vehicles. Since 2000, nonroad 

engines and metals industrial processing have accounted for most of the anthropogenic Pb emissions in 

the United States (EPA 2015). Based on data from the National Emissions Inventory (NEI 2014), the 

following sectors contribute the largest portions of total Pb emissions in the United States: mobile-aircraft 

(63%), industrial processes–not elsewhere classified (6.8%), industrial processes–ferrous metals (6.8%), 

fuel combustion–electric generation–coal (5.5%), and industrial processes–non-ferrous metals (4.1%) 

(EPA 2016c). Historical trends of Pb emissions in the United States are provided in Table 5-8 (EPA 

2015).

Table 5-8. Historic Levels of Lead Emissions to the Atmosphere 

in the United States (in Thousand Metric Tons)

1970 1975 1980 1985 1990 1995 1999 2002 2005 2008 2011

On-road vehicles 172 130.2 60.5 18.1 2.17 2.05 1 0 0 0 0

Metals industrial 

processing

24.22 9.923 3.03 2.1 0.5 0.49 0.96 0.4 0.3 0.16 0.14

Fuel combustion 10.62 10.35 4.3 0.52 0.42 0.02 0 0.39 0.14 0.12 0.09

Nonroad engines 9.737 6.13 4.2 0.92 0.78 0.54 0.55 0.45 0.66 0.56 0.49

Other sources 4.331 3.053 2.12 1.31 1.11 0.83 0.84 0.43 0.25 0.11 0.1

Source: EPA 2015

According to the data from the NEI, the largest portions of total Pb emissions are in the U.S. mobileaircraft sector. Murphy et al. (2008) studied weekly patterns of metals and other aerosol components 

using data collected from 2000 to 2006 at Interagency Monitoring of Protected Visual Environments 

(IMPROVE) sites, and these data suggested that Pb concentrations were impacted by piston aircraft 

emissions. 

As indicated in Table 5-6, by the early 2000s, transportation (i.e., automotive) emissions were no longer 

the dominant source of Pb emitted to the atmosphere. When such emissions were prevalent, >90% (mass 

basis) of automotive Pb emissions from leaded gasoline were in the form of inorganic particulate matter 

(e.g., Pb bromochloride [PbBrCl]) and <10% (mass basis) were in the form of organolead vapors (e.g., Pb 

alkyls). In 1984, the average Pb content of gasoline was 0.44 g Pb/gallon (EPA 1986b); however, as of 

January 1986, the allowable Pb content of leaded gasoline dropped to 0.1 g Pb/gallon (EPA 1985d). 

Between January and June of 1990, the actual average Pb concentration in leaded gasoline was 0.085 g 

Pb/gallon, indicating consumption of approximately 230,000 kg of Pb for the production of 2.74 billion 
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gallons of leaded gasoline. In the early 1980s, EPA allowed up to 0.05 g of Pb in a gallon of unleaded 

gasoline (EPA 1982b). 

According to data from TRI, on-site air releases of Pb and Pb compounds varied over the same period 

from 431,311 pounds in 2014 to 1,037,265 pounds in 2006, with an overall decrease of 40%. In 2018, 

91,028 pounds of Pb and Pb compounds were released to air. The electric utility and primary metals 

industry sectors contributed to this overall decrease; both sectors have decreased air Pb and Pb 

compounds releases by approximately 70% from 2005 to 2015. The primary metal sector, which includes 

iron and steel manufacturers and smelting operations, contributes the greatest quantity of Pb and Pb 

compounds to air releases (EPA 2017a, 2017b). 

While Pb levels in paints for interior use have been restricted since the 1950s, older houses and furniture 

may still be covered with leaded paint. Releases from Pb-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 Pb 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 Pb as an anti-knock additive was also a 

major contributor. Tetraalkyl Pb vapors are photoreactive, and their presence in local atmospheres is 

transitory. Halogenated Pb compounds are formed during combustion by reaction of the tetraalkyl Pb 

compounds with halogenated Pb scavenger compounds. These halogenated Pb compounds ultimately 

give rise to Pb oxides and carbonates in the environment (EPA 1985b). Tetraalkyl Pb compounds once 

contributed 5–10% of the total particulate Pb 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).

5.3.2 Water

According to the TRI, in 2018, a total of 27,764 pounds of Pb were released to water from 4,064 reporting 

facilities (TRI18 2020). In addition, a total of 163,361 pounds of Pb compounds were released to water 

from 3,789 reporting facilities (TRI18 2020). Tables 5-6 and 5-7 list amounts of Pb and Pb compounds 

released from these facilities grouped by state, respectively.
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The following industry sectors accounted for the majority of release of Pb to surface water in 2018: 

chemicals (14%); paper (12%); primary metals (10%); transportation equipment (5%); and fabricated 

metals (2%). The following industry sectors accounted for the majority of release of Pb compounds to 

surface water in 2018: paper (20%); electric utilities (8%); primary metals (8%); metal mining (3%)

(TRI18 2020). The trends in discharges of Pb and Pb compounds to surface water from 2001 to 2018 are 

presented in Table 5-9. 

Table 5-9. U.S. Surface Water Discharges of Lead and Lead Compounds 

(Pounds/Year)

Year Lead Lead compounds

2001 45,871 97,479

2002 20,694 92,366

2003 21,314 109,299

2004 14,564 107,386

2005 15,883 100,778

2006 22,985 86,772

2007 16,745 82,815

2008 11,404 153,681

2009 9,886 73,683

2010 7,263 72,556

2011 7,086 77,568

2012 7,307 60,656

2013 6,327 76,053

2014 8,836 79,344

2015 5,264 70,981

2016 9,507 119,566

2017 11,901 100,552

2018 9,943 105,473

Source: EPA 2017c; TRI18 2020

Data reported by Environment and Climate Change Canada (2016) show that other industries, which 

include the iron and steel industry, oil and gas industry, and cement and concrete industry, contributed 

136.9 tonnes of the total Pb released to water in 2014. This release includes 134.1 tonnes of Pb that were 

released when a dam securing a tailings pond from the Mount Polley mine in central British Columbia 

breached on August 4, 2014, spilling mining waste into Polley Lake and surrounding waters. Waste, 

pulp, paper, and paperboard industry, and non-ferrous smelting and refining were the next largest 

contributors (Table 5-10). In 2013, Pb releases to water were similar for other industries and waste. 
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Table 5-10. Canada Surface Water Discharges of Lead and Lead Compounds 

(Tonnes)

Year

Other

industries Waste

Pulp, paper, and 

paperboard industry

Non-ferrous smelting 

and refining Other sources

2003 4.38 15.49 2.55 1.74 0.18

2004 3.97 11.53 2.84 2.26 0.26

2005 6.11 9.47 3.29 1.82 0.58

2006 5 9.9 2.35 1.65 0.24

2007 3.63 6.42 2.37 1.64 0.19

2008 4.76 11.58 2.42 2.04 0.16

2009 3.39 8.49 2.25 2.13 0.19

2010 3.21 11.97 2.12 1.45 0.14

2011 3.65 8.97 2.91 1.5 0.16

2012 4.66 4.69 2.8 1.75 0.12

2013 4.17 4.66 2.42 1.48 0.13

2014 136.92 5.11 1.85 1.77 0.13

Source: Environment and Climate Change Canada (2016) 

Urban runoff and atmospheric deposition are significant indirect sources of Pb found in the aquatic 

environment. Pb reaching surface waters is sorbed to suspended solids and sediments (EPA 1982a; EPA 

2006, 2014c).

Pb is released into surface water from Pb shot and Pb sinkers. A study of a shooting range in 

Southwestern Virginia found that the dissolved Pb 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 Pb 

concentration was 0.5 ppb. In 1991, the U.S. Fish and Wildlife Service banned the use of Pb shot when 

hunting waterfowl, such as geese or ducks, in order to avoid releasing Pb directly to surface water.

5.3.3 Soil

According to the TRI, in 2018, a total of 10,393,047 pounds of Pb were released to the land, both on-site 

and off-site, by 4,064 reporting facilities (TRI18 2020). Table 5-6 lists amounts of Pb released from these 

facilities grouped by state. In addition, a total of 833,759,635 pounds of Pb compounds were released to 

land, both on-site and off-site, by 3,789 reporting facilities (TRI18 2020). Table 5-7 lists amounts of Pb 

compounds released from these facilities grouped by state. In addition, 27,764 and 211,975 pounds of Pb 

and Pb compounds, respectively, were injected underground. 
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Pb-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 Pb, and Pb released to air and water ultimately is deposited 

in soil or sediment. For example, Pb 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. Road dust contributes to Pb in soil. Pb concentrations were higher in surface soils within 

1,000 m of roadways (134 kg/ha) as compared to outside the 1,000-m region (38.7 kg/ha) (Yesilonis et al. 

2008). Wheel weights can contribute to releases of Pb along roadways. Aucott and Caldarelli (2012) 

estimated that approximately 12 tons of Pb as wheel weights are deposited on New Jersey roadways; 

however, they estimated that only a small amount enters the environment as small particulate from 

grinding. Root (2000) also estimated a rate of Pb deposition in Albuquerque, New Mexico as 50–

70 kg/km/year. However, use of Pb wheel weights are on the decline due to legislation, voluntary phaseout, and new wheel technology (Aucott and Caldarelli 2012). 

5.3.4 Paint

Although the sale of residential Pb-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 Pb 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 1986b). Pb concentrations of 1–5 mg/cm2 have been found in chips 

of Pb-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 Pb (EPA 1986b). An estimated 40–50% of 

occupied housing in the United States may contain Pb-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 Pb-based paint in housing. The EPA subsequently sponsored a comprehensive technical report 

on the HUD-sponsored survey to provide estimates of the extent of Pb-based paint in housing. In the 

EPA report, a home is considered to have Pb-based paint if the measured Pb 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 Pb-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 Pb-based paint in 
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their interiors. By contrast, approximately 86% (±8%) of all pre-1980 public housing family units have 

Pb-based paint somewhere in the building (EPA 1995b).

Damaged Pb-based paint is associated with excessive dust Pb levels. Approximately 14 million homes 

(19% of pre-1980 housing) have >5 square feet of damaged Pb-based paint, and nearly half (47%) of 

those homes have excessive dust Pb levels (EPA 1995b).

In the Cincinnati prospective Pb study of public and private low- and moderate-income housing, the Pb 

concentration ranges were: painted interior walls, 0.1–35 mg/cm2

; interior home surface dust, 0.04–

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 Pb 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 Pb-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 Pb 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; median, 90th percentile, and 

maximum Pb concentrations in 31 study houses were 35, 126, and 257 mg/g, respectively (Mielke et al. 

2001). Pb 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 

Pb would have been released to the environment. Disturbance of older structures containing Pb-based 

paints is now a significant contributor to total Pb releases.

The authors of a report of findings from NHANES III, conducted in 1988–1991, commented that of the 

multiple sources of exposure, Pb-based paint is the principal high-dose source of Pb. 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 Pb-based paints in homes can 

produce significant amounts of Pb dust, which can be inhaled or ingested (CDC 1997a).
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5.4 ENVIRONMENTAL FATE

The atmosphere is the main environmental transport media for Pb that is deposited onto surface water and 

soils (EPA 2006, 2014c). Upon release to the atmosphere, Pb particles are dispersed and ultimately 

removed from the atmosphere by wet or dry deposition. Pb deposition is typically greatest closer to Pb 

emission sources. An important factor in determining the atmospheric transport of Pb is particle size 

distribution. Large particles settle out of the atmosphere more rapidly and are deposited relatively close 

to emission sources and smaller particles may be transported much farther distances. After deposition, 

particles may be resuspended and redeposited. The cycling of Pb in aquatic environments is governed by 

chemical, biological, and mechanical processes. The exchange between sediment and surface water will 

be affected by pH, ionic strength, formation of organic complexes with Pb ions, and oxidation-reduction 

potential of the environment (EPA 2006, 2014c).

5.4.1 Transport and Partitioning

Transport and partitioning of Pb in the environment is an interplay of various processes (EPA 2014c). 

Global atmospheric deposition of Pb peaked in the 1970s and has declined since then; however, these 

deposits are still in the environment and can be transported and partitioned between environmental 

compartments. Past and current releases of Pb to the air result in the deposition of Pb on land and in 

surface water. While soil is a repository for Pb, it is not a passive repository, and resuspension of Pb 

contaminated soil-derived dust particulates can contribute to Pb exposure (Laidlaw and Filippelli 2008; 

Laidlaw et al. 2012). Pb in soil can be washed off surfaces into waters, and within water, it can partition 

between water and sediments (EPA 2006, 2014c). 

Air. EPA (2006) summarized that the major pathway for the transport of Pb in the environment is the 

atmosphere and that airborne Pb tends to be in the form of submicron aerosols, which can travel large 

distances. After release to the atmosphere, Pb particles are dispersed and ultimately removed from the 

atmosphere by wet or dry deposition. Dry deposition was the major removal process for Pb in coarse 

particulate matter and wet deposition was the most important removal process for fine particulate matter. 

Soil-bound Pb and contaminated road dust can be resuspended and can be a significant source of airborne 

Pb in areas near major sources of Pb emissions (EPA 2006, 2014c). 

In the atmosphere, non-organic compounds of Pb exist primarily in the particulate form. The median 

particle distribution for Pb emissions from smelters is 1.5 μm, with 86% of the particle sizes under 10 μm 
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(Corrin and Natusch 1977). The smallest Pb-containing particulate matter (<1 μm) is associated with 

high-temperature combustion processes. Upon release to the atmosphere, Pb particles are dispersed and 

ultimately removed from the atmosphere by wet or dry deposition. Approximately 40–70% of the 

deposition of Pb is by wet fallout; 20–60% of particulate Pb once emitted from automobiles is deposited 

near the source. An important factor in determining the atmospheric transport of Pb is particle size 

distribution. Large particles, particularly those with aerodynamic diameters of >2 μm, settle out of the 

atmosphere more 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 away from the emission source. 

The amount of Pb scavenged from the atmosphere by wet deposition varies widely; wet deposition can 

account for 40–70% of Pb 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 Pb, making it the lowest value among 

seven trace metals studied (iron, aluminum, manganese, copper, zinc, cadmium); this indicates that Pb 

(which initially exists as fine particles in the atmosphere) is removed from the atmosphere by wet 

deposition relatively inefficiently. 

While Pb particles from automobile emissions are quite relatively small (<0.1 μm in diameter), they may 

coagulate to form larger particulates (Chamberlain et al. 1979). Pb has been found in sediment cores of 

lakes in Ontario and Quebec, Canada far from any point sources of Pb releases, suggesting that longrange atmospheric transport was occurring (Evans and Rigler 1985). Sabin and Schiff (2008) reported 

that median dry deposition fluxes along a coastal transect in southern California ranged from 0.52 to 

14 μg/m2

-day in 2006. Pb fluxes ranged from 20 to 330 μg/m2-day in 1975. Osterberg et al. (2008) 

reported elevated concentrations of Pb in a 1970–1998 ice core from the summit of Mt. Logan, Canada, 

and indicated that elevated levels correspond to increased industrial activity in Asia over the same time 

period. Mean Pb concentrations in the 1970–1998 portion were 68.9 ng/L, more than 10-fold above the 

natural background (5.6 ng/L). 

Pb in soil in urban areas of older cities may be a source of airborne Pb (Laidlaw and Filippelli 2008). 

Studies of the Pb species found in airborne particulate matter collected in El Paso, Texas found that Pbhumate was the dominant form of Pb in air samples. Pb-humate, a stable, sorbed complex formed in the 

humus fraction of Pb contaminated soil, is the major Pb species in soils in El Paso (Pingitore et al. 2009). 

In a review, Cho et al. (2011) noted that, over the past 40 years, lead-bound air particulates have shifted to 
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larger air particulate sizes as concentrations of Pb in urban areas have decreased. They note that this shift 

has occurred as the use of leaded gasoline was phased-out and that industrial emissions and resuspension 

of road dust became more important sources of Pb. In addition to soil-derived dust, re-entrainment of 

dusts near highways and deteriorating Pb-based paint from elevated steel structures can contribute to 

airborne Pb (Sabin et al. 2006; Weiss et al. 2006). Studies suggest that there is long-range transport of Pb 

bound to particulate matter from industrial emissions. Dust samples from surface glaciers and in dust 

traps in remote areas on the west coast of New Zealand’s South Island were identified as being both 

Australian and New Zealand in origin. Samples were enriched in metals, including Pb, and the degree of 

metal enrichment indicted that they were transported from eastern Australia (Marx et al. 2008). 

Water. The amount of soluble Pb in surface waters depends upon the pH and the ionic strength of the 

water. Equilibrium calculations show that at pH >5.4, the total solubility of Pb 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 Pb 

concentration in solution through the formation of Pb sulfate. Above pH 5.4, the Pb carbonates, 

PbCO3 and Pb2(OH)2CO3, limit the amount of soluble Pb. The carbonate concentration is in turn 

dependent upon the partial pressure of carbon dioxide, pH, and temperature (EPA 1986b).

A significant fraction of Pb carried by river water is expected to be in an undissolved form, which can 

consist of colloidal particles or larger undissolved particles of Pb carbonate, Pb oxide, Pb hydroxide, or 

other Pb compounds incorporated in other components of surface particulate matter from runoff. Pb 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. 

Sediment and Soil. EPA (2006, 2014c) reviewed and summarized the factors affecting the behavior 

of Pb in soil. While Pb is relatively immobile in soil and has a long retention time in most soils, it has 

some capacity to leach through the soil column and potentially contaminate groundwater. Pb sorbs 

strongly to soil components and is only weakly soluble in pore water, making the leaching of Pb in soil a 

slower process as compared to other contaminants. Various soil conditions and characteristics affect the 

sorbing capacity of the soil and the solubility of contaminants including hydraulic conductivity of the 

soils, composition of the soil solution, organic matter, clay mineral content of the soil, pH, and microbial 

activity (EPA 2006). In soil, Pb can be partitioned between the soil water, precipitate forms, secondary 

iron and manganese oxides, carbonates, organic matter, sulfides, or the surfaces of clay, humus, or silicate 

particles. Pb adsorbed to the surfaces of colloid soil particles (e.g., organic matter, clay, oxides, and 

carbonates) are the most labile fraction. High chloride content in soil also enhances Pb solubility. At low 
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pH, metal species bound to carbonates, hydroxides, and other soil components are more likely to dissolve 

into solution, increasing rates of Pb migration through the soil. EPA (2014c) reported that soil pH is the 

most important factor affecting solubility, mobility, and phytoavailability of Pb in soil; however, reducing 

conditions (e.g., anoxia) in soil also increase Pb mobility. In addition, dissolved organic matter is more 

important than iron oxyhydroxides in Pb mobility in soil. 

The fate of Pb in soil is affected by the adsorption at mineral interfaces, precipitation of sparingly soluble 

solid forms of the compound, and 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, presence of inorganic colloids and iron oxides, cation exchange capacity 

(CEC), and amount of Pb in soil (Getz et al. 1977; Reddy et al. 1995). Soil samples were extracted from 

the Powder River Basin in Wyoming to determine the relative distribution and speciation of Pb and other 

metals in acidic environments (Reddy et al. 1995). At near neutral pH, organic carbon-Pb complexes 

were the predominant species in the soil water extracts. At low pH, dissolved Pb in ionic form (Pb2+) and 

ion pairs (e.g., PbSO4) were the predominant species. It was concluded that the mobility of Pb will 

increase in environments having low pH due to the enhanced solubility of Pb under acidic conditions. 

The accumulation of Pb in most soils is primarily a function of the rate of deposition from the 

atmosphere. Most Pb is retained strongly in soil, and very little is transported through runoff to surface 

water or leached to groundwater except under acidic conditions (EPA 1986b; Getz et al. 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). Although sorption to organic 

matter in soil limits the rate and extent of leaching, Pb may enter surface waters as a result of erosion of 

Pb-containing soil particulates. Pb bromochloride, the primary form of Pb emitted from motor vehicles, 

which once burned leaded gasoline in the presence of organohalogen scavenger compounds, is converted 

to the less-soluble Pb sulfate either by reactions in the atmosphere or by reactions at the soil surface, thus 

limiting its mobility in soil. It has been determined that Pb 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). Pb 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 Pb is retained in the upper 2–5 cm of undisturbed soil. Inorganic Pb 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). In soil with high organic matter content and a pH of 6–8, Pb 

may form insoluble organic Pb complexes; if the soil has less organic matter at the same pH, hydrous Pb 
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oxide complexes may form or Pb may precipitate out with carbonate or phosphate ions. At a pH of 4–6, 

the organic Pb complexes become soluble and leach out or may be taken up by plants (EPA 1986b). 

Entrainment or suspension of soil particles in moving air is another route of Pb transport (EPA 1982c). 

This process may be important in contributing to the atmospheric burden of Pb around some Pb smelting 

facilities and NPL sites that contain elevated levels of Pb in soil. 

The downward movement of elemental Pb and inorganic Pb compounds from soil to groundwater by 

leaching is very slow under most natural conditions except for highly acidic situations (Getz et al. 1977). 

The conditions that induce leaching are the presence of Pb 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 Pb, and a decrease in the pH of the leaching solution (e.g., acid rain) (Getz et al. 1977). Favorable 

conditions for leaching may be present in some soils near Pb smelting and NPL sites. Tetraalkyl Pb 

compounds, such as tetraethyl Pb, 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 Pb compounds are first degraded to their respective 

ionic trialkyl Pb species and are eventually mineralized to inorganic Pb (Pb2+) by biological and chemical 

degradation processes (Ou et al. 1995). 

In a study of Pb migration in forest soils in Vermont, Miller and Friedland (1994) used Pb deposition time 

series and measurements of organic soil horizon Pb content made in 1966, 1980, and 1990 to compute 

dynamic response times for Pb storage in several types of soil. The authors concluded that maximum Pb 

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 Pb 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 Pb transit times through mineral soil horizons, the pulse of Pb 

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 Pb migration in forest soils is slowed 

considerably due to a decrease in solubility when Pb moves from the soil surface horizon to streams. 

Their results suggest that Pb is effectively trapped in the subsurface soil horizons, which may greatly 

reduce its release to streams.

Lewis et al. (2010) studied the distribution, chemical speciation, and mobility of Pb and antimony from 

small arms ammunition in a coarse-grained surface sand and reported that the transport of Pb was small in 
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this soil type. Ninety-three percent of the mass of the bullets was found in the top 30 cm of the sand. Pb 

was mostly associated with the following grain sizes in decreasing order >5.0 mm (~3.3 g/kg), 1.2–

5.0 mm (~1.5 g/kg), and <0.06 mm (~0.25 m/kg). In the 0.06–0.6 mm fractions, Pb concentrations were 

just above background levels (0.0004 g/kg). Declining concentrations with depth has also been observed 

in clay/loam shooting range soils (Vantelon et al. 2005). Pb in the fine fraction (<2 mm) shooting range 

soils also showed a depth distribution, with the highest concentrations in the top 10 cm (Cao et al. 2003a, 

2003b; Hui et al. 2002; Lin et al. 1995; Perroy et al. 2014; Selonen et al. 2012). In a study of various 

contaminant levels in soil at a major training facility used for testing military tanks and munitions, Pb 

concentrations in the 0–15 cm soil depth ranged from 249.2 to 1,963.7 mg/kg (Berthelot et al. 2008).

Flooding events can change the spatial distribution of Pb in soil and sediments (EPA 2014c). Zahran et 

al. (2010) and Presley et al. (2010) reported variations in Pb concentrations in soil samples from 

schoolyards in New Orleans, Louisiana before and after Hurricanes Katrina and Rita in 2005, with some 

sites increasing and others decreasing in Pb concentrations. Forty-six census tracts in New Orleans were 

sampled before and after Hurricanes Katrina and Rita; 29 of these showed a decline in Pb concentrations, 

with 6 samples >400 mg/kg. Prior to these hurricanes, 15 of 46 samples had Pb concentrations 

>400 mg/kg. Across the tracts, the average median Pb concentration decreased from 328.5 to 

203.33 mg/kg (Zahran et al. 2010). Presley et al. (2010) reported similar trends. Of the 17 schoolyard 

sites that were sampled, 7 sites had concentrations exceeding Pb concentrations of 400 mg/kg in June 

2005, and in January 2006, Pb concentrations at 3 sites exceeded this concentration. The geometric mean 

concentration of the sites decreased from 290.0 to 207.4 mg/kg; however, at two sites, Pb concentrations 

increased from 804.0 to 1,740.0 mg/kg and from 1,090.0 to 2,500.0 mg/kg. During a 4-day storm event, 

2,400 tonnes of suspended particulate matter were transported in a historical mining, ore processing, and 

smelting region in the Czech Republic that contained various metals including 2,954 kg of Pb (Žak et al. 

2009).

Other Media. Plants and animals may bioconcentrate Pb, but biomagnification is not expected. In 

general, the highest Pb concentrations are found in aquatic and terrestrial organisms with habitats near Pb 

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 (Pb from spent shot or sinkers); and urban and industrialized areas. Pb 

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 Pb in 

soil to plants is limited because of the strong adsorption of Pb to soil organic matter, bioavailability 
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increases with increased soil organic matter content and with decreased soil pH (more acidic). Plants 

grown in Pb-contaminated soils were shown to accumulate low levels of Pb 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 Pb levels (27–

4,580 mg/kg). Samples were harvested and washed with either water or detergents and analyzed for Pb 

content. Only one fruiting vegetable among 52 samples contained Pb levels greater than the detection 

limit of 10 μg/g in the edible portion. However, 39% of the leafy vegetables and herbs had Pb levels 

>10 μg/g in the edible shoot portion following washing of the vegetables with detergent and water 

(Finster et al. 2004).

Pb 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 Pb 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 Pb 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 Pb 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 Pb) 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 Pb nitrate (from 100 to 

1,000 mg/kg) was also studied (Nwosu et al. 1995). Results indicated that the mean uptake of Pb by 

lettuce increased as the concentration of Pb rose in the soil mixture. However, the uptake was low and 

this finding is inconsistent with other reports. Pb was not bioaccumulated by either plant regardless of 

soil Pb concentrations. The response of kidney bean growth to the concentration and chemical form of Pb 

in soils obtained near a zinc smelter in Japan has been studied (Xian 1989). It was found that the amount 

of Pb in the total plant (approximately 35–80 μg) correlated strongly with the concentration of Pb 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 Pb in the soil.

Uptake of Pb in animals may occur as a result of inhalation of contaminated ambient air or ingestion of 

contaminated plants. However, Pb is not biomagnified in aquatic or terrestrial food chains. Older 

organisms tend to contain the greatest body burdens of Pb. In aquatic organisms, Pb concentrations are 
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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 Pb for a period of 

30 days showed significant accumulation of Pb in the blood and tissues. The Pb accumulation in tissues 

was found to increase with Pb in water up to a concentration of 5 mg/L (μg/mL); at concentrations of 

10 and 20 mg/L, the Pb accumulation in the tissues, although indicating an increase, was not proportional 

to the Pb 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 

Senenastrum capricornutum), and rainbow trout (726 for Salmo gairdneri). However, most median BCF 

values for aquatic biota were significantly lower: 42 for fish, 536 for oysters, 500 for insects, 725 for 

algae, and 2,570 for mussels (Eisler 1988). Pb is toxic to all aquatic biota, and organisms higher up in the 

food chain may experience Pb poisoning as a result of eating Pb-contaminated food. Organolead 

compounds, such as trialkyl and tetraalkyl Pb 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 Pb. Tetraalkyl Pb 

compounds are more toxic than trialkyl Pb 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 Pb from solidified media and soil, has been reported (Vesper et al. 1996). The rate of uptake of 

Pb nitrate by CHL004 was very rapid initially and then decreased greatly.

5.4.2 Transformation and Degradation

As an element, Pb cannot be degraded in the environment, but may undergo various precipitation or 

ligand exchange reactions. Pb will typically be found in compounds with oxygen and sulfur, and may 

undergo oxidation-reduction reactions under different environmental conditions. Under most 

environmental conditions, Pb will most likely exist in its Pb(II) oxidation state. Pb can be complexed by 

various ligands present in the environment (e.g., fulvic and humic acids). Despite forming complexes 

with organic matter, it is unlikely that it would be incorporated into organic compounds under 

environmental conditions. Transformations of Pb compounds that occur during their movement through 

the environment will be between various inorganic compounds. 

Air. According to EPA (2014c), Pb accumulated on airborne mineral dusts can be transformed into 

different compounds during transport. It was also noted that Pb can accumulate on coarse particulate 
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matter during transport in air and undergo chemical transformations. For example, Pb sulfate (PbSO4), 

one of the main components of Pb-containing aerosols from coal combustion, can react with calcite 

(CaCO3) in particulate matter to form various Pb carbonate compounds on the calcite surface. Another 

study included in the discussion noted that Pb levels in the PM10 fraction from dust storms collected in 

Israel were enriched with Pb at levels higher than those found in their source in the Sahara desert, 

suggesting that the dust samples accumulated Pb during transit between the Sahara desert and Israel (EPA 

2014c).

Before the ban on sales of leaded gasoline, Pb particles were emitted to the atmosphere from automobile 

exhaust as Pb 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 Pb carbonates, 

oxycarbonates, and oxides were produced. These Pb oxides are subject to further weathering to form 

additional carbonates and sulfates (Olson and Skogerboe 1975). Pb particles are emitted from mines and 

smelters primarily in the form of elemental Pb and Pb-sulfur compounds, PbSO4, PbO·PbSO4, and PbS 

(Corrin and Natusch 1977; EPA 1986b; Spear et al. 1998). The Pb emitted from the combustion of waste 

oil was found to be in the form of PbCl2, PbO, and elemental Pb (Pb0

) (Nerin et al. 1999). In the 

atmosphere, Pb exists primarily in the form of PbSO4 and PbCO3 (EPA 1986b). 

While Pb is no longer added to gasoline for on-road use, the inorganic Pb degradation products of these 

organolead compounds may still be present in the environment. Based on the vapor pressure of tetraethyl 

Pb (0.26 mmHg at 25 °C) and tetramethyl Pb (26.0 mmHg 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 

decompose rapidly to trialkyl and dialkyl Pb compounds, and eventually to inorganic Pb oxides by a 

combination of direct photolysis, reaction with hydroxyl radicals, and reaction with ozone. The half-life 

of tetraethyl Pb in reactions with hydroxyl radicals during summer is approximately 5.7 hours, based on a 

rate constant of 6.8x10-11 cm3

/molecule-second (Nielsen et al. 1991). The half-life for tetramethyl Pb is 

about 65 hours, based on a rate constant of 5.9x10-12 cm3

/molecule-second. 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). 

Water. The fate of Pb in water will be determined by the conditions of the water, including acidity 

(pH), ionic strength, oxidation-reduction potential, flow rate, and amount and composition of suspended 

materials (EPA 2014c). The pH of water is an important factor in determining the fate of Pb in water. At 
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neutral to more basic pH, Pb will tend to be complexed, precipitated, or sorbed to suspended sediments in 

water (EPA 2014c). Pb will form compounds of low solubility with the major anions found in natural 

waters. The maximum solubility of Pb in hard water is about 30 μg/L at pH>5.4 and the maximum 

solubility of Pb 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 Pb. Hydroxide, carbonate, sulfide, and, more rarely, 

sulfate may act as solubility controls in precipitating Pb from water. At pH<5.4, the formation of Pb 

sulfate limits the concentration of soluble Pb in water, while at pH>5.4, the formation of Pb carbonates 

limits the amount of soluble Pb (EPA 1979). The relatively volatile organolead compound, tetramethyl 

Pb, may form as a result of biological alkylation of organic and inorganic Pb compounds by 

microorganisms in anaerobic lake sediments; however, if the water over the sediments is aerobic, 

volatilization of tetramethyl Pb from the sediments is not considered to be important because the 

tetramethyl Pb will be oxidized (EPA 1979).

The speciation of Pb was found to differ in fresh water and seawater. In fresh water, Pb 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 Pb concentrations in rivers at the 

500 μg/L solubility limit (EPA 1979). Pb chloride and Pb carbonate are the primary compounds formed 

in seawater (Long and Angino 1977). The speciation of Pb in water is also dependent on the presence of 

other ligands in water. Pb 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). Pb-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 Pb complexed to Fe-Mn oxides, which is due to the 

content of these oxides in seawater (Elbaz-Poulichet et al. 1984). Sorption of Pb to polar particulate 

matter in fresh water and estuarine environments is an important process for the removal of Pb from these 

surface waters. The adsorption of Pb to organic matter, clay, and mineral surfaces, and coprecipitation 

and/or sorption by hydrous iron and manganese oxides increases with increasing pH (EPA 1979).

Sediment and Soil. Pb in its naturally-occurring mineral forms is a component of many soils in the 

United States. The speciation of Pb 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 Pb content, whereas in roadside dust, 

PbSO4, elemental Pb, 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 Pb in the form of 
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PbSO4, subsequent extractions revealed that the Pb sulfate was rapidly transformed to other Pb 

compounds in the soil (Chaney et al. 1988). 

Nearly all forms of Pb that are released to soil from anthropogenic sources, such as elemental Pb, 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 Pb 

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 Pb 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 1986b). Only a small fraction (0.1–1%) of Pb 

appears to remain water-soluble in soil (Khan and Frankland 1983). The solubility of Pb 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 Pb solubility in soil are observed. These 

changes in Pb solubility appear to correlate with the pH-dependent adsorption and dissolution of Fe-Mn 

oxyhydroxides. In addition to pH, other factors that influence Pb solubility in soil are total Pb 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).

Large particles of elemental Pb (e.g., shot and bullet fragments) degrade from weathering processes (Cao 

et al. 2003a, 2003b). Weathering includes physical transformation of larger particles to smaller particles 

(particle dissolution), as well as oxidation of the particle surface (coating) to PbO2, with subsequent 

further oxidation to carbonates, phosphates, and sulfates (Cao et al. 2003a, 2003b; Hardison et al. 2004; 

Hashimoto 2013; Lewis et al. 2010; Lin et al. 1995; Rooney et al. 2007; Vantenlon et al. 2005). Particle 

dissolution rates for shotgun pellets in soils have been estimated to range from 1 to 20 mg/g pellet/year, 

depending on soil type, precipitation, and vegetation cover (Jorgenson and Willems 1987; Takamatsu et 

al. 2010). 

Since the ban on the use of leaded gasoline, atmospheric Pb 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 Pb are converted into water-soluble Pb 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 Pb was shown to degrade 

sequentially to monoionic triethyl Pb, diionic diethyl Pb, and eventually Pb+2 (Ou et al. 1994). 

Experiments were conducted using non-sterilized and autoclaved soil samples. The presence of 
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monoionic triethyl Pb and diionic diethyl Pb was generally lower in the autoclaved samples, suggesting 

that both abiotic and biotic mechanisms are responsible for the degradation of tetraethyl Pb. At the end of

a 28-day incubation period, no tetraethyl Pb was present in the soil; however, there were significant 

quantities of monoionic triethyl Pb and diionic diethyl Pb, which suggest that the degradation products 

are more persistent than the original species. Although tetraethyl and tetramethyl Pb are not expected to 

leach significantly through soil, their more water-soluble metabolites may be subject to leaching (EPA 

1985a). 

Pb 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). Uptake of Pb 

into plant tissue appears to involve a combination of uptake from the leaf surface and uptake from roots, 

with the relative contribution of each pathway dependent on species and soil characteristics (Angelova et 

al. 2010; Bindler et al. 2008; Chrastny et al. 2010; Cui et al. 2007; Guyette et al. 1991; Hu and Ding 

2009; Nwosu et al. 1995). Pb taken up by the root systems remains largely associated with root tissues 

(Comino et al. 2011; Businelli et al. 2011; Deng et al. 2004; Mellem et al. 2009; Murray et al. 2009; Nan 

and Cheng 2001; Sonmez et al. 2008; Wang et al. 2011). Translocation from roots to stem and leaf tissue 

has been shown to occur in some species (Peralta-Videa et al. 2009; Shaheen and Tsadilas 2009; Tamura 

et al. 2005; Wang et al. 2006; Zaprjanova et al. 2010). Eventually, the Pb will be returned to soil when 

these plants decay unless they are harvested (to possibly enter the food chain) or removed.

5.5 LEVELS IN THE ENVIRONMENT

Reliable evaluation of the potential for human exposure to Pb depends, in part, on the reliability of 

supporting analytical data from environmental samples and biological specimens. Concentrations of Pb 

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 Pb levels monitored or estimated in the environment, it 

should also be noted that the amount of chemical identified analytically is not necessarily equivalent to 

the amount that is bioavailable.

Table 5-11 shows the lowest limit of detections that are achieved by analytical analysis in environmental 

media. An overview summary of the range of concentrations detected in environmental media is 

presented in Table 5-12.
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Table 5-11. Lowest Limit of Detection Based on Standardsa

Media Detection limit Reference

Air 1.5 ng/cm2 (XRF) EPA, 1999, Method IO-3.3

2.6 μg/sample NIOSH 2017b, Method 7082

6 μg/sample NIOSH 1998, Method 7702

0.02 μg/sample NIOSH 1994c, Method 7105

0.05 μg/sample NIOSH 2016a, Method 7701

0.062 μg/filter NIOSH 2003c, Method 7300

0.062 μg/filter NIOSH 2003a, Method 7301

0.023 μg/mL NIOSH 2003b, Method 7303

0.6 μg/sample NIOSH 2014a, Method 7302

1 μg/sample NIOSH 2014b, Method 7304

0.062 μg/sample NIOSH 2015, Method 7306

0.03 μg/mL OSHA 2002, Method ID-121

2.1 μg/sample OSHA 2002, Method ID-125G

Drinking 

water

1.1 μg/L (ICP-AES)

0.02 μg/L (ICP-MS)

EPA 2003 Method 200.5

EPA 1994f Method 200.8

Surface water 

and 

groundwater

0.07 μg/L EPA 1997b

2.4 μg/L (GFAA)

0.28 μg/L (GFAA with preconcentration)

0.07 μg/L (ICP-MS)

EPA 1997b

0.05 μg/L (ICP-MS)

60 μg/L (ICP-OES)

USGS 1989

1 μg/L (GFAA)

1.1 μg/L (AVICP-AES)

USGS 1993

10 μg/L (ICP)

100 μg/L (total recoverable, FLAA)

1 μg/L (whole water recoverable, GFAA)

0.5 μg/L (dissolved in water by GFAA)

100μg/L (suspended recoverable, FLAA)

100 μg/L (dissolved, FLAA)

USGS 1989

0.6 μg/L (ICP-MS)

0.7 μg/L (GFAA)

10 μg/L (ICP-AES)

EPA 1994d

Soil/sediment 0.15 μg/g (ICP-MS)

0.2 μg/g (XRF)

0.2 μg/g (GF-AAS)

NOAA 1998

10 μg/g (FLAA) USGS 1989
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Table 5-11. Lowest Limit of Detection Based on Standardsa

Media Detection limit Reference

Wipes 0.042 μg/wipe NIOSH 2003d, Method 9102

0.02 μg/cm2 for 100-cm2 area (FLAA or 

ICP); 

0.001 μg/cm2 for 100-cm2 area (GF-AAS)

NIOSH 1996a, Method 9100

Range: 5–15 μg/wipe sample NIOSH 2003e, Method 9105

aDetection limits based on using appropriate preparation and analytics. These limits may not be possible in all 

situations.

AES = atomic emission spectroscopy; AVICP = axially viewed inductively coupled plasma; FLAA = flame atomic 

absorption; GFAA = graphite furnace atomic absorption; GF-AAS = graphite furnace-atomic absorption 

spectrometer; GRAV = gravimetry; ICP = inductively coupled plasma; MS = mass spectrometry; OES = optical 

emission spectrometry; Pb = lead; XRF = x-ray fluorescence

Table 5-12. Lead Levels in Water, Soil, and Air of National Priorities List (NPL) 

Sites

Medium Mediana

Geometric 

meana

Geometric 

standard 

deviationa

Number of 

quantitative 

measurements NPL sites

Water (ppb) 75 118 13.8 1,452 659

Soil (ppb) 1,110,000 885,000 19.7 1,453 661

Air (ppbv) 0.194 0.286 32.3 85 51

aConcentrations found in ATSDR site documents from 1981 to 2019 for 1,867 NPL sites (ATSDR 2019). Maximum 

concentrations were abstracted for types of environmental media for which exposure is likely. Pathways do not 

necessarily involve exposure or levels of concern.

5.5.1 Air

Four national monitoring networks collect data on Pb concentrations in ambient air to report to the Air 

Quality System (AQS). State and local agencies carry out monitoring at state and local monitoring 

stations (SLAMS). These data are primarily used to evaluate compliance with the National Ambient Air 

Quality Standard (NAAQS) for Pb. Pb levels are also monitored in the Chemical Speciation Network 

(CSN), Interagency Monitoring of Protected Visual Environments (IMPROVE), and National Air Toxics 

Trends Station (NATTS) networks. Pb concentrations in air are measured in three particulate matter 

(PM) size fractions: total suspended particles (TSP), PM10, and PM2.5. The CSN and IMPROVE 

networks monitor Pb in PM2.5 and the NATTS network monitors Pb in PM10. These networks are 

designed to meet different objectives than those of the Pb NAAQS monitoring network (EPA 2006, 

2014c). EPA (2014c) analyzed data from these monitoring systems and presented data summaries for 
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source-oriented (defined as near point sources and exceeded a defined emission threshold) and nonsource-oriented Pb monitors across the United States for 2008–2010 (EPA 2014c). Maximum 3-month 

daily average Pb concentrations were calculated for non-source-oriented Pb-TSP monitors for 47 counties 

across the United States (1.5% of U.S. counties) and for source-oriented Pb-TSP monitors for 50 counties 

across the United States (1.6% of U.S. counties) during the period 2008–2010. Summaries of these 

analyses are presented in Table 5-13.

Table 5-13. Summary Data for Lead Monitors Across the United States, 2008–

2010 (μg/m3)

Mean Median 95th% 99th% Maximum

Monthly (source-oriented) 0.20 0.063 0.86 1.6 4.4

Monthly (nonsource-oriented) 0.012 0.010 0.040 0.052 0.14

Source: EPA 2014c

Pb levels have been declining in the ambient air of the United States for several decades and according to 

the EPA, there has been approximately a 94% decrease since 2000 (EPA 2018a). Figure 5-3 shows the 

annual maximum 3-month average Pb level in the United States based upon data at 24 monitoring sites.

Figure 5-3. Annual Maximum 3-Month Average Representing the National Trend

Source: EPA 2018a
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Data compiled from the EPA AQS database from 2015 to 2018 were used to calculate the percentile 

distribution of arithmetic mean 3-month averages at locations across the United States. These data are 

summarized in Table 5-14.

Table 5-14. Percentile Distribution of Mean Lead (TSP) Concentrations (μg/m3) 

Measured in Ambient Air at Locations Across the United States

Year

Percentile

25th 50th 75th 95th Maximum

2015 0.0036 0.0090 0.0216 0.0753 0.1942

2016 0.0038 0.0093 0.0220 0.0782 0.1466

2017 0.0039 0.0080 0.0190 0.0756 0.2087

2018 0.0035 0.0090 0.0313 0.1248 0.5574

TSP = total suspended particles

Source: EPA 2018b

Pb in indoor air is related to Pb in housedust, and predominant sources are outdoor air and degraded 

Pb-based paint (EPA 2006). Smoking can also contribute to higher concentrations of Pb in indoor air. Pb 

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 SD) and median concentrations of Pb 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 Pb concentration in outdoor air was 8.84 ng/m3 (Clayton 

et al. 2002). Pb 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 Pb 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 Pb 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 Pb were correlated with dilapidated and suburban homes. Dixon et al. (2009) analyzed 

children’s exposures to residential dust Pb using data from the NHANES survey and associated 

demographics as well as smoking status to exposure levels. Children who resided in homes in which 

smoking occurred indoors had significantly (p=0.015) higher PbB levels than children who lived in 

homes of nonsmokers. 
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In another analysis of the NHEXAS EPA Region V data, Pellizzari et al. (1999) looked at potential 

differences in Pb 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) Pb 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 were also not significantly different (p=0.266). When the age of the home was 

considered in the analysis, it was found that Pb 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 Pb concentrations measured in 

indoor air in homes built before 1940 were not significantly different from mean (±1 SD) Pb 

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.

5.5.2 Water

Pb has been monitored in surface water, groundwater, and drinking water throughout the United States 

and other countries. The concentration of Pb in surface water is highly variable depending upon sources 

of pollution, Pb content of sediments, and characteristics of the system (pH, temperature, etc.). Pb 

concentrations in surface water are generally higher in urban areas than in rural areas (EPA 1982c), and 

Pb measured in natural or “pristine” surface waters may be due to anthropogenic input. Western Airborne 

Contaminants Assessment Project (WACAP) data collected at five U.S. National Parks showed median 

Pb levels in surface waters ranging from 0.006 to 0.075 μg/L (EPA 2014c). The median Pb level in 

natural river water was 5 μg/L, with a range of 0.6–120 μg/L; however, lower Pb levels are to be expected 

after leaded gasoline was banned in 1985, which resulted in decreased rates of atmospheric deposition 

(Bowen et al. 1966; King et al. 2014). The National Academies of Science reported Pb concentration 

levels in surface water and groundwater (EPA 1986b). The mean Pb concentration level in surface water 

was 4 μg/L with a range from below the detection limit to 890 μg/L (EPA 2014c); concentrations 

>100 μg/L were observed near sources of urban runoff or industrial discharge. Mean levels of Pb in 

surface water measured at 50,000 surface water stations throughout the United States were 3.9 μg/L 

(based on 39,490 occurrences) (Eckel and Jacob 1988). Using the EPA Storage and Retrieval (STORET) 

database, from January 1, 2005 to May 16, 2005, Pb 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 2005b). Pb was not detected above the detection limits in 224 other surface water samples obtained 
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from various locations in Utah and Iowa over the sampling period (EPA 2005b). Pb content in 

groundwater is driven largely by the surrounding bedrock geochemistry; Pb concentrations are generally 

low in groundwater and natural springs ranging from below the detection limit to 100 μg/L (EPA 2014c). 

A USGS study of groundwater in the United States from 2000 to 2016 concluded that <1% of measured 

Pb concentrations are >15 μg/L, but when high levels are detected, they are typically associated with 

geographic locations where the Pb solubility potentials (the amount of Pb that could dissolve before a Pb 

mineral precipitates out of solution) are naturally high (Jurgens et al. 2019). Pb levels in seawater are 

typically in the range of 0.001–0.036 μg/L in the open ocean and about 0.050–0.30 μg/L in coastal waters 

influenced by anthropogenic activity (Angel et al. 2016).

Urban storm water runoff is an important source of Pb entering receiving waterways. Sources of Pb in 

runoff can be contributed to substantial direct atmospheric deposition, as well as indirect release from 

building materials, soil, and road dust, and industrial discharge. Pb 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. 

Soto-Jiménez and Flegal (2009) evaluated the sources of Pb pollution in the Gulf of California, northwest 

Mexico by sampling urban and rural areas for Pb levels and isotope ratios. Urban street dust (157 μg/g), 

agricultural soils (29.0 μg/g), and surface estuary sediments (35.6 μg/g) were all higher than natural 

bedrock (16.0 μg/g). Isotopic ratios in rural and soil runoff samples were comparable to natural Pb 

containing bedrock. Pb concentrations in the suspended particulate matter were measured in sewage 

effluent (132 μg/g), agricultural effluent (29.3 μg/g), river runoff (7.3 μg/g), and estuary water 

(68.3 μg/g). Urban, street dust, and sewage showed contributions from automotive emissions from past 

leaded gasoline combustion. 

Pb in drinking water can derive from source water contamination as described above, but the more 

common source of Pb in drinking water is from internal corrosion of water distribution system piping and 

plumbing. Internal corrosion of Pb service lines, Pb-based pipe solder, brass meters and plumbing 

fixtures, and dissolution of existing protective scales contribute directly to Pb levels in drinking water. 

The Lead and Copper Rule (LCR) was promulgated in 1991 with the purpose of protecting public health 

by minimizing Pb and copper levels in drinking water, primarily by reducing water corrosivity (EPA 

2004). The LCR established a Pb action level (AL) of 15 μg/L and a maximum contaminant level goal 

(MCLG) of zero. The Pb action level is based on feasibility of public water systems to control corrosion 

in their distribution systems and is not a health benchmark for Pb in drinking water. The Pb action level 

is exceeded if the concentration of the 90th percentile first draw tap sample (collected after a minimum 
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stagnation period of 6 hours from high risk sites) exceeds 15 μg/L (EPA 2016a). If the Pb AL is 

exceeded, the LCR can require public water systems to take steps to minimize the risk of Pb exposure that 

may include source water monitoring/treatment, public education, water quality monitoring, 

implementing corrosion control treatment, and Pb service line replacement. In October 2019, EPA 

proposed significant changes to the LCR (EPA 2019a). These changes include: (1) identify areas most in 

need of remediation of Pb service lines; (2) establish a trigger level of 10 μg/L for requiring corrosion 

control in drinking water systems that do not currently treat for corrosion; (3) require water system to 

replace Pb service lines; (4) increase sampling reliability by prohibiting pre-stagnation flushing and other 

methods; (5) require systems to notify customers of action level exceedance within 24 hours; and 

(6) protect children in schools by expanding testing at drinking water outlets. 

Analyses done in support of the short-term revisions to the LCR at the beginning of the 21st century 

suggest that in 2003, <2% of public water systems serving >3,300 people exceeded the Pb action level of 

15 μg/L (EPA 2007a). Additionally, a 2004 study conducted by the EPA on LCR compliance monitoring 

for public water systems serving >3,300 people indicated that <4% of those systems exceeded the Pb 

action level (Hill 2011). It is important to note that states were not required until 2002 to report 

90th percentile Pb concentrations to the EPA unless those samples exceeded the Pb AL; therefore, it is 

difficult to accurately compare differences between tap water Pb levels prior to LCR implementation and 

immediately following LCR implementation with current nationwide Pb concentration levels (Hill 2011). 

Nevertheless, the EPA evaluated water sample data from 166 large public water systems (systems serving 

>50,000 people) that exceeded the Pb AL in 1992 and 1993 (Hill 2011). Of the large systems that 

exceeded the Pb AL in 1992–1993, only 15 of those systems continued to exceed the Pb AL between 

2000 and 2004, and their associated average 90th percentile Pb concentration levels significantly 

decreased from 32 to 8.2 μg/L.

The amount of Pb contained in pipes and plumbing fittings has been strictly regulated since 1986. 

Section 1417 of the Safe Drinking Water Act (SDWA) was amended to ban the use of service lines, pipe 

fittings, pipe solder, and fixtures that are not “Pb free” (not more than 0.2% Pb for pipe solder and flux, 

and not more than 8% Pb for pipe fittings and service lines) and are connected to a public water system 

and intended to provide water for human consumption. The 1996 Amendment broadened this ban by 

limiting the amount of leaching of Pb from new plumbing, and an industry standard was established. In 

2011, the Reduction of Lead in Drinking Water Act amended Section 1417, revising the existing SDWA 

definition of “Pb free” and getting rid of the leaching certification requirement. Implemented in 2014, the 
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act reduced the allowable level of Pb by “not more than a weighted average of 0.25 percent Pb when used 

with respect to the wetted surfaces of pipes, pipe fittings, plumbing fittings and fixtures.”

According to EPA's National Public Water Systems Compliance Report for calendar year 2013 (EPA 

2013), 73% of public water systems in the United States, serving approximately 77% of the population, 

had no significant reported violations of any type. Significant violations include all violations of healthbased standards, including violations of the maximum contaminant levels, treatment technique 

requirements, and significant monitoring and reporting requirements. In 2013, 7% of public water 

systems had no reported violations of health-based standards, and 5% of all health-based standard 

violations were LCR violations.

In the spring of 2014, the source of drinking water in the city of Flint, Michigan was switched from 

treated water obtained from Lake Huron to the Flint River. However, the treated water from the Flint 

River was more corrosive and did not contain corrosion inhibitors, which resulted in Pb leaching from the 

city’s aging service lines. Sampling data conducted in August of 2015 showed that the 90th percentile 

concentration of Pb in first-draw drinking water was 26.8 μg/L for 268 samples of tap water, which far 

exceeded the EPA AL of 15 μg/L (Pieper et al. 2018). In response to the high Pb levels in Flint drinking 

water, the city reconnected to the DWSD in October of 2015. By August of 2017, the 90th percentile 

concentration of Pb in first-draw tap water was 7.9 μg/L (Pieper et al. 2018). 

5.5.3 Sediment and Soil

Pb is a naturally occurring metal found in the earth's crust at about 15–20 mg/kg (Goyer 2001). However, 

the concentration of Pb in the top layers of soil varies widely due to deposition and accumulation of 

atmospheric particulates from anthropogenic sources. The concentration of soil Pb generally decreases as 

distance from contaminating sources increases. The estimated Pb 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 1986b). Soil adjacent to a smelter in Missouri had Pb levels in excess 

of 60,000 μg/g (Palmer and Kucera 1980). Soils adjacent to houses with exterior Pb-based paints have 

reported Pb levels >10,000 μg/g (EPA 1986b). As a result of Pb reactions with the soil, extractable Pb 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 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 Pb concentrations of >840 μg/g in New 
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Orleans and 265 μg/g in Minneapolis. In contrast, the small towns of Natchitoches, Louisiana, and 

Rochester, Minnesota had soil Pb concentrations of <50 and 58 μg/g, respectively. These data suggest 

that Pb-contaminated soil is a major source of Pb exposure in urban areas (Mielke 1993). As would be 

expected, soils in elementary school properties were also found to have the same pattern of Pb levels as 

the soils in the surrounding residences. Pb concentrations in soils collected from inner-city schools in 

New Orleans were higher (median 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).

The former use of Pb in paints, particularly in older structures, is also a source of Pb in soil and within 

homes. Mielke and Gonzales (2008) reported median Pb concentrations of 76,603 mg/kg (464–

317,151 mg/kg) and 416 mg/kg (24–63,313 mg/kg) for exterior and interior paints, respectively, in 

40 paint chip samples collected from homes in metropolitan New Orleans. The authors noted that the age 

of the house is often used as a surrogate for the amount of Pb in paints; the mid-1920s being the peak use 

of leaded paint with declines until 1978. Demolition and renovation of buildings where leaded paint was 

used can result in transport of Pb to soil surrounding the building as well as indoor dust that contains Pb. 

Pb concentrations were measured in residential transects through Lubbock, Texas. Pb concentrations 

through the city showed a trend of decreasing Pb concentrations with increasing distance from the city 

center, which also paralleled a decrease in the property age. The highest Pb concentrations in the city 

center were 90.0–174.0 mg/kg, with a median of 35.4 mg/kg, and decreased out to the farther part of the 

residential transect to 6.0–9.0 mg/kg. The highest concentrations outside city development were 

4.9 mg/kg (Brown et al. 2008). 

Studies conducted in Maryland and Minnesota indicate that within large, light-industrial, urban settings 

such as Baltimore, the highest soil Pb levels generally occur near inner-city areas, especially where high 

traffic flows have long prevailed (Mielke et al. 1983, 1984, 1989) and that the amount of Pb in the soil is 

correlated with the size of the city (Mielke 1991). In 1981, soil Pb 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 Pb content of gasoline had been significantly reduced, found that 

median soil Pb levels taken from the foundations of homes, in yards, and adjacent to the street were 700, 

210, and 160 μg/g, respectively; median soil Pb 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 Pb levels were elevated in soil samples taken from the 
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foundations of homes, but that Pb 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 Pb 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 Pb-based paint. Elevated soil Pb concentrations were found in larger urban areas, 

with 27, 26, 32, and 42% of the soil samples exceeding 300 μg/g Pb 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 Pb levels 

>150 μg/g. It has been suggested that the higher Pb levels associated with soils taken from around 

painted homes in the inner city are the result of greater atmospheric Pb content, resulting from the burning 

of leaded gasoline in cars and the washdown of building surfaces to which the small Pb particles adhere 

by rain (Mielke et al. 1989). A state-wide Minnesota study concluded that exterior Pb-based paint was 

the major source of contamination in severely contaminated soils located near the foundations of private 

residences and that aerosol Pb accounted for virtually all of the contamination found in soils removed 

from the influence of Pb-based paint. Contamination due to Pb-based paint was found to be “highly 

concentrated over a limited area, while contamination due to aerosol Pb was found to be less 

concentrated, but more widespread” (Schmitt et al. 1988).

Pb 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 Pb loading (μg m-2

) from kitchens, living rooms, and two children’s 

bedrooms were 151 (5th–95th percentile range: 22, 674), 936 (86, 10,190), and 8,560 (818, 313,000) 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.

5.5.4 Paint

Weathering and deterioration of Pb-based paint can contribute to the Pb content of dust and soil (Clark et 

al. 2004; Hunt et al. 1993; Jaeger et al. 1998; Lucas et al. 2014; Marcus and Elias 1995). A soil Pb study 
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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). Pb-based 

paint, removed from surfaces by burning (gas torch or hot air gun), scraping, or sanding have been found 

to result, at least temporarily, in higher levels of exposure for families residing in these homes. A 2006 

survey of U.S. housing stock estimated that 35% of 106 million housing units contained Pb-based paint 

and that approximately 20% of houses contained deteriorating Pb-based paint (HUD 2011).

5.5.5 Other Media

Pb has been detected in a variety of foods and spices (Lin et al. 2010). Pb 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 1986b). The ban on leaded gasoline as well as the use 

of welded (non-soldered) food cans during the 1980s are largely responsible for the decreases in levels of 

Pb in the U.S. diet beginning in the 1980s (FDA 2006). The FDA analyzed samples of foods commonly 

eaten by toddlers and infants for Pb and noted that levels of Pb in infant and toddler foods, on average, are 

relatively low (FDA 2016a). These results are summarized in Table 5-15. Selected data from the 2006–

2011 FDA Total Diet Study Market Baskets are presented in Table 5-16 (FDA 2016b). Mean Pb levels in 

dairy products (e.g., milk, cheese, ice cream, cream, yogurt) were generally low or below the detection 

limit. The dairy product category with the highest Pb level was for low-fat fruit-flavored yogurt, with a 

mean concentration of 0.002 mg/kg for 24 analyses. Mean concentrations of Pb in fruits and vegetable 

were also generally low, with the highest concentrations in raisins (0.005 mg/kg), spinach (0.004 mg/kg), 

and lettuce (0.004 mg/kg). Mean concentration of Pb in baby foods ranged from not detected to 

0.013 mg/kg. The highest levels reported were found in sweet potatoes (0.013 mg/kg), arrowroot cookies 

(0.012 mg/kg), grape juice (0.011 mg/kg), teething biscuits (0.008 mg/kg), and apple-cherry juice 

(0.008 mg/kg). Based on a multimedia Pb exposure modeling analysis for children 1–5 years old, below 

the 70th percentile of PbB in the general U.S. population, dietary intake was a major background exposure 

pathway (Zartarian et al. 2017)

Table 5-15. Lead Levels in Foods Commonly Eaten by Toddlers and Infants

Product category Averagea (range) (μg/kg) Number of samples

Cereal, infant/toddler (rice) 15.6 (5.0–82.0) 76

Cereal, infant/toddler (multigrain) 7.2 (6.0–8.0) 6

Cereal, infant/toddler (non-rice) 4.8 (0.4–17.0) 30
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Table 5-15. Lead Levels in Foods Commonly Eaten by Toddlers and Infants

Product category Averagea (range) (μg/kg) Number of samples

Applesb 3.3 10

Cereal, oat ring 7.8 (3.3–16.4) 30

Grapes 3.7 (3.3–7.6) 10

Juice, grape 5.6 (0.3–41.3) 30

Juice boxes and pouches 3.3 (0.3–17.0) 40

Peanut butter 5.3 (3.3–45.2) 29

Quinoa 22.2 (0.4–98.0) 30

Raisins 18.1 (1.8–151) 23

Stage 2 toddler foods 5.2 (1.0–22.2) 35

Teething biscuits 12.0 (2.0–131) 27

Toddler puffs 19.1 (3.3-–91.0) 31

aThe average concentration reported for each product category was calculated using all values. For those samples 

with results below the detection limit, half of the detection limit was used to calculate the average.

bAll of the apple samples were below the limit of detection. 

Source: FDA 2016a

Table 5-16. Selected Mean Lead Concentrations in Food from the FDA Total Diet 

Study

Food Mean (range) (mg/kg)a

Number of

analyses

Number 

<LOD

LOD

(mg/kg)

Syrup, chocolate 0.016 (0–0.027) 24 1 0.007

Apricots, canned in heavy/light syrup 0.015 (0–0.036) 24 1 0.007

Baby food, sweet potatoes 0.013 (0–0.034) 24 5 0.007

Peach, canned in light/medium syrup 0.013 (0–0.038) 24 2 0.007

Candy bar, milk chocolate, plain 0.013 (0–0.027) 24 5 0.01

Baby food, arrowroot cookies 0.012 (0–0.031) 24 9 0.01

Sweet potatoes, canned 0.012 (0–0.018) 24 2 0.007

Shrimp, boiled 0.012 (0–0.18) 24 18 0.01

Baby food, juice, grape 0.011 (0–0.02) 24 1 0.004

Fruit cocktail, canned in light syrup 0.011 (0–0.025) 24 4 0.007

Brownie 0.01 (0–0.032) 24 5 0.007

aNote: 1 mg/kg = 1,000 μg/kg.

FDA = U.S. Food and Drug Administration; LOD = limit of detection

Source: FDA 2016b
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The U.S. Fish and Wildlife Service reported the concentrations of metals in a total of 315 composite 

samples of whole fish sampled from 109 stations nationwide from late 1994 to early 1995. For Pb, 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 Pb was significantly lower than in the 1980–1981 survey. 

Pb 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 Pb in the aquatic environment 

(Schmitt and Brumbaugh 1990).

In order to reduce Pb exposure from consumption of Pb-contaminated fish and shellfish, consumption 

advisories are issued by states recommending that individuals restrict their consumption of specific fish 

and shellfish species from certain water bodies where Pb 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 1995a). These two groups within the general population consume larger 

quantities of fish and shellfish than the general population and frequently fish the same water bodies 

routinely. Because of this, these populations are at greater risk of exposure to Pb and other chemical 

contaminants if the waters they fish are contaminated. In 2007, eight advisories restricting the 

consumption of Pb-contaminated fish and shellfish were in effect in five states (Hawaii, Idaho, 

Washington, Kansas, and Missouri) and one territory (American Samoa) (EPA 2007b).

Elevated levels of Pb in the blood of cattle grazing near a Pb smelter have been reported, although no 

implications regarding Pb in beef were made. The mean Pb 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 Pb 

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 Pb in muscle of acutely sick cows that were slaughtered ranged 

from 0.23 to 0.5 mg/kg (wet weight basis). Normal Pb levels in bovine meat from Swedish farms are 

<0.005 mg/kg. For eight cows that were less exposed, levels of Pb in milk taken 2 weeks after the 

exposure were 0.08±0.04 mg/kg. The highest Pb level found in the milk of eight cows studied for 

18 weeks was 0.22 mg/kg. Pb in most milk samples decreased to values <0.03 mg/kg 6 weeks after 
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exposure. Two affected cows delivered a calf at 35 and 38 weeks after the exposure. There was a high 

Pb level in the blood of the cows at the time of delivery, which suggests mobilization of Pb in connection 

with the latter stages of gestation and delivery. Pb levels in colostrum were increased as compared to 

mature milk samples taken 18 weeks after exposure. The concentration of Pb in milk produced after 

delivery decreased rapidly with time and was almost down to the limit of detection in mature milk. 

In a survey, 324 multivitamin-mineral products were analyzed for Pb content (Mindak et al. 2008). 

Estimates of Pb exposure from these products were derived for four groups summarized in Table 5-17. 

The overall median value for Pb exposure was 0.576 μg/day. Five samples would have provided 

exposures that exceeded 4 μg/day. The authors reported that the estimates of Pb exposures were below 

the provisional total tolerable intake levels for the four population groups (Mindak et al. 2008). Twentyone elements, including Pb, were analyzed in various botanical and dietary supplements; Pb 

concentrations ranged from not detected to 4.21 μg/g. None of the products analyzed would result in a 

maximum exposure that exceeds a tolerable level of exposure (Avula et al. 2010).

Table 5-17. Estimated Median and Maximum Lead Exposures

Population group Median (μg/day) Maximum (μg/day)

Young children (0–6 years) 0.123 2.88

Older children (7+ years) 0.356 1.78

Pregnant or lactating women 0.845 8.97

Adult women 0.842 4.92

Source: Adapted with permission from Mindak et al. (2008), American Chemical Society.

Many non-Western folk remedies used to treat diarrhea or other ailments may contain substantial amounts 

of Pb. Examples of these include: Alarcon, Ghasard, Alkohl, Greta, Azarcon, Liga, Bali Goli, 

Pay-loo-ah, Coral, and Rueda. In addition, an adult case of Pb poisoning was attributed to an Asian 

remedy for menstrual cramps known as Koo Sar. The pills contained Pb at levels as high as 12 ppm 

(CDC 1998). The source of the Pb was thought to be in the red dye used to color the pills. Pb 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 Pb in excess of 300 mg when 

taken according to labeling instructions. Pb poisoning has been caused by ingestion of a Chinese herbal 

medicine to which metallic Pb 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 
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and nonstandardized formulations (CDC 2004b). CDC (1998, 2002b) reported cases of elevated PbBs in 

children after consuming candy from Mexico or using various folk remedies. Elevated PbBs were 

reported in two 7-year-old children in Rhode Island. A sample of litargirio, which was used as an 

antiperspirant/deodorant, found in the home contained 79% Pb (CDC 2005). 

During 2011–2012, six cases of Pb poisoning were associated with the use of 10 oral Ayurvedic 

medications made in India. Pb concentrations in these medications were as high as 2.4%. Blood Pb 

levels of these women ranged from 16 to 64 μg/dL (CDC 2012c). In 2004–2012, the New York City 

Department of Health and Mental Hygiene identified 22 oral medications, supplements, or remedies 

containing high levels of heavy metals, including Pb (Table 5-18). 

Table 5-18. Lead Content in Ayurvedic Medications and Other Health Remedies

Product

Country where 

manufactured

Country where 

purchased

Lead content 

(ppm)

Calabash Chalk (Nzu) Unknown United States 6.6

Emperor’s Tea Pill (concentrated) China United States 5,400

Garbha Chintamani Ras (Vrihat) (Swarna Yukt) India India 120

Garbha Dharak Yog India India 110

Garbhapal Ras India India 22,000

Garbhapal Ras India United States 15,000

Hepatico Extract (concentrated) China United States 5,900

Jambrulin India United States 243,000

Kankayan Bati (Gulma) India United States 12

Lakshmivilash Ras (Nardiya) India United States 260

Laxmana Louh India India 180

Maha Sudarshan India United States 41

Mahashakti Rasayan India India 9,400

Mahayogaraj Guggulu (enriched with silver) India United States 47,000

Ovarin India India 24,000

Pigmento India India 7.3

Pregnita India India 12,000

Sorin India India 46,707

Tierra Santa Mexico United States 13

Vasant Kusumakar Ras (with Gold and Pearl) India India 29

Vatvidhwansan Ras India United States 20,000

Vita Breath United States United States 1,100

Source: CDC 2012c
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A study was conducted in an urban neighborhood in Chicago in order to gauge the levels of Pb in an array 

of fruits, vegetables, and herbs (Finster et al. 2004). The soil Pb concentrations where the plants were 

sampled varied from 27 to 4,580 ppm (median 800 ppm, geometric mean 639 ppm). Detectable Pb levels 

in the edible fruit, 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 Pb in the edible portion. However, 

12 of the 31 leafy vegetables and herbs sampled contained Pb in the edible shoot part of the plant (range, 

11–60 ppm). The Pb concentrations in the four samples of root vegetables ranged from 10 to 21 ppm. 

No significant correlation was found between the Pb concentrations in the edible portion of plant and the 

soil Pb level.

Pb may leach from Pb crystal decanters and glasses into the liquids they contain. Port wine that contained 

an initial concentration of 89 μg/L Pb was stored for 4 months in crystal decanters containing up to 32% 

Pb oxide. At the end of 4 months, Pb concentrations in the port were 5,331, 3,061, and 2,162 μg/L in 

decanters containing 32, 32, and 24% Pb oxide, respectively. Pb was also found to elute from Pb crystal 

wine glasses within minutes. Mean Pb 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).

Hair dyes and some cosmetics may contain Pb compounds (Cohen and Roe 1991). Hair dyes formulated 

with Pb acetate may have Pb concentrations 3–10 times the allowable concentration in paint. Measured 

Pb concentrations of 2,300–6,000 μg of Pb/gram of product have been reported (Mielke et al. 1997). Pb 

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 Pb on each hand following application 

have been reported (Mielke et al. 1997). In addition to transfer of Pb to the hand-to-mouth pathway of the 

person applying the product, Pb can be 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 that it 

is applied to and the hands applying it. Objects coming into contact with hair dyed with a Pb-containing 

product also become contaminated. A dry hand passed through dry hair dyed with a Pb-containing 

product in cream form was been shown to pick up about 786 μg of Pb. A dry hand passed through dry 

hair dyed using foam or liquid Pb-containing hair dye products picked up less Pb: 69 μg/hand for foam 

products and 73 μg/hand for liquid products (Mielke et al. 1997). An elevated PbB (12 μg/dL) in an 

infant was observed after the use of tiro, a Nigerian eye cosmetic applied to the infant’s eyes (CDC 

2012a). Elevated PbBs (27.0 and 33.5 μg/dL) were reported in two young children in New Mexico after 

the use of kajal, a cosmetic imported from Afghanistan, that was applied to the children’s eyelids. The 
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kajal was reported to contain 54% Pb (CDC 2013). Sindoor, a cosmetic and cultural/religious powder 

used in Hindu cultures, has been found to contain very high amounts of Pb (Lin et al. 2010).

Cases of Pb poisoning have been related to less common sources of exposure. Illicit "moonshine" 

whiskey made in stills composed of Pb-soldered parts (e.g., truck radiators) may contain high levels of 

Pb. Detectable levels of Pb 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 Pb levels >300 μg/dL. The median and maximum levels were 

44.0 and 53,200 μg/dL, respectively (Parramore et al. 2001). 

Firing of Pb ammunition may result in exposure to Pb aerosols and dusts generated during gun or rifle 

discharge at levels up to 1,000 μg/m3 (EPA 1985c), from Pb pellets ingested by or imbedded in animals 

that are used as food sources, and from Pb pellets or fragments imbedded in humans from shooting 

incidents (see Appendix C, Ingestion of Lead Debris). Exposures to airborne Pb dust from firearm 

discharge in indoor shooting ranges has been shown to result in increases in PbBs 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 well-ventilated indoor firing ranges lessen the 

impact of airborne Pb on blood Pb levels (Gulson et al. 2002).

A Pb poisoning hazard for young children exists in imported vinyl miniblinds that had Pb added to 

stabilize the plastic. Over time, the plastic deteriorates to produce Pb 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 Pb. As a consequence, vinyl miniblinds should now be Pb-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 Pb or with alternative window 

coverings.

Inexpensive metallic jewelry items specifically intended for children and teenagers have been shown to 

contain varying levels of Pb (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 Pb 

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 Pb for all 311 assays was 30.6%. Of the 
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311 samples tested, 169 contained at least 3% Pb by weight in at least one portion of the jewelry piece 

and 123 of the samples were found to contain >50% Pb by weight (Maas et al. 2005). In addition, 

62 pieces of the purchased jewelry were tested for surface levels of Pb 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 Pb 

content. Mean Pb levels in the wipes ranged from 0.06 to 541.97 μg. The authors characterized the 

potential Pb exposure from these dermal transfer experiments as either low exposure (<1 μg of Pb 

transferred to the laboratory wipe), moderate exposure (1–10 μg of Pb transferred to the laboratory wipe), 

high exposure (10–50 μg of Pb transferred to the laboratory wipe), and very high exposure (>50 μg of Pb 

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). 

5.6 GENERAL POPULATION EXPOSURE

Measurements of Pb in blood, urine, and tissues (postmortem) have been used to assess exposures of 

individuals to Pb. Table 5-19 shows the lowest limit of detections that are achieved by analytical analysis 

of blood, urine and tissues.

Table 5-19. Lowest Limit of Detection Based on Standardsa

Media Detection limit Reference

Whole blood/urine/tissue 0.05 μg Pb/g blood or mL urine NIOSH 1994b, Method 8003

1 μg/100 g blood; 0.2 μg/g tissue NIOSH 1994a, Method 8005

Animal tissue 0.1 μg/g (ICP-MS or GFAA) NOAA 1998

aDetection limits based on using appropriate preparation and analytics. These limits may not be possible in all 

situations.

GFAA = graphite furnace atomic absorption; ICP-MS = inductively coupled plasma-mass spectrometry

Prior to the 1980s, aerolized Pb emissions from the use of leaded gasoline was the main source of Pb 

exposure for the general U.S. population. Aerolized Pb can be either inhaled or ingested after deposition 

on surfaces and food crops. Adult Pb exposures tend to be limited to occupational or recreational sources. 

For children, the primary source of Pb exposure is from surface dusts (on the ground or entrained) that 

contain Pb from a variety of sources including deteriorated Pb-based paint (Bornschein et al. 1986; CDC 

2009; Dixon et al. 2009; Egeghy et al. 2005; EPA 1996c; Garavan et al. 2008; Gulson et al. 2009; 
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Lanphear and Roghmann 1997; Lanphear et al. 1998a; Lewin et al. 1999; Malcoe et al. 2002; Mielke et 

al. 2007; Succop et al. 1998; Von Lindern et al. 2003, 2016; Zahran et al. 2013). Young children are 

particularly vulnerable to Pb exposure because of hand-to-mouth activity, which contributes to ingestion 

of Pb in surface dusts. Pb in the fine particle fraction of surface dusts (<150 μm) readily adheres to the 

skin surface, from which it can be inadvertently ingested from hand-to-mouth activity (Choate et al. 

2006a, 2006b; Clausing et al. 1987; Davis and Mirick 2006; Davis et al. 1990; Siciliano et al. 2009; 

Yamamoto et al. 2006). Several studies have attempted to quantify soil and dust ingestion in children 

(Chien et al. 2017; Ozkaynak et al. 2011; Sedman et al. 1994; Stanek et al. 2012; Von Lindern et al. 2016; 

Wilson et al. 2013) and adults (Calabrese et al. 1990; Doyle et al. 2012; Irvine et al. 2014; Stanek et al. 

1997). 

Although air Pb can be a direct pathway of exposure in children, it can also be an indirect pathway from 

its effect on Pb concentration in surface dusts (Brunekreef 1984; Hayes et al. 1994; Hilts 2003; 

Rabinowitz et al. 1985; Schnaas et al. 2004; Schwartz and Pitcher 1989; Tripathi et al. 2001). Secondhand smoke may also contribute to increased Pb exposure (Apostolou et al. 2012; Mannino et al. 2003; 

Richter et al. 2013). Dietary sources of Pb can originate from direct or indirect transfer of atmospheric Pb 

emissions to secondary media such as water, food crops, game, and fish. Pb in the maternal system can 

also be transferred to the fetus during gestation and to the nursing infant (EPA 2014c). 

Several studies provided data on Pb levels in food, with which dietary intakes of Pb for the general 

population in the United States have been estimated (FDA 2016a, 2016b). An analysis of individual food 

intakes and PbB from NHANES (2006–2008) estimated that diet explained approximately 2.9% of the 

variations of PbB in children and 1.6% in adults (Davis et al. 2014). A randomized survey of 

250 individuals (adults and children) from the Midwest United States conducted over the period 1995–

1997 estimated average dietary Pb intake to be approximately 10 μg/day (Clayton et al. 1999). The EPA 

has estimated mean dietary Pb intakes in children ages 6–84 months to be approximately 2 μg/day (EPA 

2014c). The ban on the use of welded (non-soldered) food cans during the 1980s has resulted in a 

decrease in Pb exposure from foods (FDA 2006). In recent surveys, the mean Pb levels in dairy products 

(e.g., milk, cheese, ice cream, cream, yogurt) were generally low or below the detection limit. Mean 

concentrations of Pb in fruits and vegetables were also generally low. Mean concentration of Pb in baby 

foods ranged from not detected to 0.013 mg/kg. Possible sources of Pb in food samples include 

introduction during processing or preparation with drinking water contaminated with Pb, deposition of Pb

onto raw materials for each food, and Pb exposure in livestock that produce dairy or meat ingredients 

(EPA 2014c). Pb has also been reported in home-prepared reconstituted infant formula. Although, at one 
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time, use of Pb solder in formula containers contributed to PbB from formula consumption (Ryu et al. 

1983), this practice was phased out after 1970 in the United States and subsequently banned (FDA 1995). 

However, tap water remains a potential source of Pb in home-prepared formula at locations where tap 

water Pb concentrations are elevated. In a study conducted in the Boston area in 1997, 2 of 40 samples of 

home-prepared formula had Pb 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. Pb-containing ceramic ware used in food preparation has also been associated with childhood Pb 

exposure in children of Hispanic ethnicity in San Diego County, California. One study (Gersberg et al. 

1997) used the IEUBK Model to determine that dietary Pb exposure from beans prepared in Mexican 

ceramic bean pots may account for a major fraction of blood Pb burden in children whose families use 

such ceramic ware.

The main source of Pb in drinking water is from the corrosion of Pb service lines, which are pipes 

constructed of pure Pb that connect the water distribution main to a building’s internal plumbing. Other 

common sources of Pb in drinking water are exposed leaded solder or corroded fixtures containing Pb 

(EPA 2016a). While Pb was restricted to no more than 8% in plumbing materials in 1986, older homes 

and neighborhoods may still contain Pb service lines, Pb connections, Pb solder, or other Pb-based 

plumbing materials that may contaminate drinking water during its delivery from its source to homes. 

Corrosion of these older plumbing materials can result in leaching of Pb into drinking water (CDC 2012b; 

Hanna-Attisha et al. 2016). Flint, Michigan is an example of how a water system with Pb sources in 

drinking water infrastructure resulted in elevated Pb levels in drinking water. For decades, the drinking 

water for the City of Flint was purchased from the Detroit Water and Sewer Department (DWSD). This 

water had optimized corrosion control and was treated with orthophosphate, a corrosion inhibitor that 

reduces Pb solubility and leaching from leaded plumbing materials by the formation of protective scales 

on the pipe’s interior surface. When the water source was changed to the Flint River in 2014, corrosion 

control was not implemented, which allowed Pb to leach into the drinking water (EPA 2017e). Pb 

concentration in first-draw tap water tends to be higher than after the plumbing system has been flushed, 

although with Pb service lines, it is possible to see higher Pb concentrations in flushed water, if flushing 

is sufficient to draw stagnant water from the service line to the tap. Gulson et al. (1997a) measured Pb 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 1991 LCR was implemented to protect 

public health by minimizing Pb and copper levels in drinking water, by primarily reducing water 

corrosivity (EPA 2010). The rule set a Pb action level of 15 μg/L based on 90th percentile levels of tap 
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water samples. The LCR established tap sampling monitoring requirements for public water systems. 

One-liter samples are taken at the tap where water has stood in the pipes for at least 6 hours (first-draw) in 

homes and buildings that are considered high-risk of Pb and copper contamination, and the number of 

samples are based on the system size. Pb action level exceedances can trigger a number of steps that a 

water system can take to reduce Pb exposure. These requirements include implementing a corrosion 

control treatment program, monitoring and/or treating source water, public education, and Pb service line 

replacement (EPA 2004). As discussed in Section 5.5.2, EPA has proposed major changes in the LCR as 

of October 2019. 

Other less common sources of Pb exposure also exist. Exposure may also result from engaging in 

hobbies that use Pb (e.g., leaded solder is used in making stained glass, molten Pb used in casting, leaded 

glazes and frits are used in making pottery, and Pb compounds as coloring agents in glassblowing) (Grabo 

1997). The use of inadequately glazed or heavily worn earthenware vessels for food storage and cooking 

may result in Pb exposure (CDC 1985; EPA 1986b). Various folk remedies and Ayurvedic medication 

(CDC 1998, 2004b, 2012c; Garvey et al. 2001; Wu et al. 1996) and some cosmetics (Mielke et al. 1997) 

may also be sources of Pb exposure. 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 (Parramore 

et al. 2001). Exposure to infants and children can occur from mouthing of leaded jewelry and toys 

containing Pb or painted with leaded paint (CDC 2018c).

Plastic food wrappers may be printed with pigments that contain Pb chromates. Plastic wrappers used for 

14 different national brands of bread collected in New Jersey contained a mean concentration of 26 mg of 

Pb 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 Pb leaching from the paint into the stored food (Weisel et al. 1991). 

Blood Pb levels measured as a part of the NHANES revealed that between 1976 and 1991, the mean PbBs 

of the U.S. population aged 1–74 years old 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 Pb from gasoline and the removal of Pb from soldered cans 

(Pirkle et al. 1994). Data from the Fourth National Report on Human Exposure to Environmental 

Chemical are summarized in Tables 5-20 and 5-21, which provide geometric means of Pb levels in the 

blood and urine in segments of the U.S. population. 
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Table 5-20. Geometric Mean Blood Lead Levels (μg/dL) and the 95th

Percentile Confidence Interval, by Race/Ethnicity, Sex, and Age for 

the Years for 2011–2016

Survey years Geometric mean (95% confidence interval) Sample size

Total 11–12 0.973 (0.916–1.04) 7,920

13–14 0.858 (0.813–0.906) 5,215

15–16 0.820 (0.772–0.872) 4,988

Age group

1–5 years 11–12 0.970 (0.877–1.07) 713

13–14 0.782 (0.705–0.869) 818

15–16 0.758 (0.675–0.850 790

6–11 years 11–12 0.681 (0.623–0.744) 1,048

13–14 0.567 (0.529–0.607) 1,075

15–16 0.571 (0.523–0.623) 565

12–19 years 11–12 0.554 (0.511–0.601) 1,129

13–14 0.506 (0.464–0.551) 627

15–16 0.467 (0.433–0.504 1,023

20 years and older 11–12 1.09 (1.03–1.16) 5,030

13–14 0.967 (0.921–1.02) 2,695

15–16 0.920 (0.862–0.982) 2,610

Gender

Males 11–12 1.13 (1.06–1.21) 3,968

13–14 0.994 (0.919–1.08) 2,587

15–16 1.13 (1.06–1.21) 3,968

Females 11–12 0.842 (0.796–0.890) 3,952

13–14 0.746 (0.715–0.777) 2,628

15–16 0.735 (0.679–0.795) 2,500

Race/ethnicity

Mexican Americans 11–12 0.838 (0.767–0.916) 1,077

13–14 0.746 (0.685–0.813) 969

15–16 0.704 (0.659–0.759) 994

Non-Hispanic blacks 11–12 0.998 (0.947–1.05) 2,195

13–14 0.871 (0.787–0.963) 1,119

15–16 0.856 (0.763–0.962 1,070

Non-Hispanic whites 11–12 0.993 (0.914–1.08) 2,493

13–14 0.882 (0.820–0.950) 1,848

15–16 0.835 (0.774–0.900) 1,511

All Hispanics 11–12 0.855 (0.793–0.922) 1,931

13–14 0.742 (0.695–0.793) 1,481

15–16 0.703 (0.658–0.750) 1,664

Asians 11–12 1.15 (1.06–1.24) 1,005

13–14 1.01 (0.923–1.11) 510
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Table 5-20. Geometric Mean Blood Lead Levels (μg/dL) and the 95th

Percentile Confidence Interval, by Race/Ethnicity, Sex, and Age for 

the Years for 2011–2016

Survey years Geometric mean (95% confidence interval) Sample size

15–16 1.07 (0.976–1.18) 479

Source: CDC 2018a 

Table 5-21. Geometric Mean Urine Lead Levels (μg/dL) and the 95th Percentile 

Confidence Interval, by Race/Ethnicity, Sex, and Age

Survey years Geometric mean (95% confidence interval) Sample size

Total 11–12 0.360 (0.328–0.396) 2,504

13–14 0.277 (0.257–0.298) 2,664

15–16 3,061

Age group

3–5 years 15–16 0.257 (0.225–0.292) 486

6–11 years 11–12 0.346 (0.292–0.410) 399

13–14 0.222 (0.192–0.258) 402

15–16 0.346 (0.292–0.410) 399

12–19 years 11–12 0.259 (0.219–0.305) 390

13–14 0.201 (0.166–0.245) 451

15–16 0.196 (0.183–0.211) 402

20 years and older 11–12 0.381 (0.348–0.416) 1,715

13–14 0.297 (0.280–0.315) 1,811

15–16 0.304 (0.276–0.334) 1,794

Gender 

Males 11–12 0.414 (0.367–0.466) 1,262

13–14 0.315 (0.295–0.337) 1,318

15–16 0.313 (0.285–0.343) 1,524

Females 11–12 0.316 (0.282–0.355) 1,242

13–14 0.245 (0.222–0.269) 1,346

15–16 0.259 (0.233–0.288) 1,537

Race/ethnicity 

Mexican Americans 11–12 0.372 (0.320–0.431) 317

13–14 0.277 (0.240–0.319) 453

15–16 0.259 (0.233–0.288) 585

Non-Hispanic 

blacks

11–12 0.431 (0.385–0.483) 669

13–14 0.371 (0.320–0.429) 581

0.340 (0.298–0.388) 671

Non-Hispanic 

whites

11–12 0.346 (0.311–0.385) 820

13–14 0.267 (0.245–0.290) 985

15–16 0.275 (0.247–0.305) 924

All Hispanics 11–12 0.372 (0.327–0.423) 573
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Table 5-21. Geometric Mean Urine Lead Levels (μg/dL) and the 95th Percentile 

Confidence Interval, by Race/Ethnicity, Sex, and Age

Survey years Geometric mean (95% confidence interval) Sample size

13–14 0.270 (0.239–0.305) 701

15–16 0.284 (0.258–0.312) 982

Asians 11–12 0.383 (0.341–0.429) 353

13–14 0.257 (0.230–0.287) 292

15–16 0.292 (0.264–0.324) 332

Source: CDC 2019

The Adult Blood Lead Epidemiology and Surveillance (ABLES) program tracks adult (aged ≥16 years) 

cases with elevated PbBs from workplace exposure. In 2016, 26 states submitted PbB data on 

18,093 adults with PbBs ≥10 μg/dL. PbBs ≥10 μg/dL declined from 26.6 adults per 100,000 employed in 

2010 to 15.8 per 100,000 employed in 2016 (results for data submitted as of December 2018). In 2016, 

among adults with known exposures, 90.3% had occupational exposure. The majority of these adults 

were employed in manufacturing, construction, mining, and services. Table 5-22 presents industries 

within each sector with the most workers with occupational exposures resulting in PbB ≥25 μg/dL during 

2010–2016 (NIOSH 2017a). 

Table 5-22. Industries by Sector with Most Workers having Blood Lead 

Concentrations (PbBs) ≥25 μg/dL, 2010–2016

NORA Sector Industry NAICS Code

Manufacturing Storage battery manufacturing (33591)

Nonferrous metal (except copper and aluminum) rolling, drawing, 

extruding, and alloying (33149)

Alumina and aluminum production and processing (33131)

Nonferrous metal foundries (33152)

Nonferrous metal (except aluminum) smelting and refining (33141)

Other basic inorganic chemical manufacturing (32518)

Motor vehicle electrical and electronic equipment manufacturing (33632)

Construction Painting and wall covering contractors (23832)

Highway, street, and bridge construction (23731)

Residential building construction (23611)

Plumbing, heating, and air-conditioning contractors (23822)

Site preparation contractors (23891)

Commercial and institutional building construction (23622)

Services (except public safety) All other amusement and recreation industries (71399)

Remediation services (56291)
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Table 5-22. Industries by Sector with Most Workers having Blood Lead 

Concentrations (PbBs) ≥25 μg/dL, 2010–2016

NORA Sector Industry NAICS Code

Automotive mechanical and electrical repair and maintenance (81111)

Other services (except public safety industries) (71394)

Mining Copper, nickel, lead, and zinc mining (21223)

NAICS = North American Industry Classification System; NORA = National Occupational Research Agenda

Source: NIOSH 2017a

Raymond and Brown (2015a, 2015b, 2017) and analyzed the 2007–2012 and 2009–2014 datasets from 

the Childhood Blood Lead Surveillance (CBLS) system. In 2007, a total of 38 states identified and 

reported 37,289 children (<6 years) with PbB ≥10 μg/dL. In 2012, a total of 30 jurisdictions identified 

and reported approximately 138,000 children (<6 years) with PbB ≥5 μg/dL. In 2012, federal funding 

ended and several states lost their state-wide Pb poisoning prevention programs and in 2013, the number 

of states reporting data declined, as did the number of children reported to the CDC with PbB ≥5 μg/dL. 

In October 2013, federal funding resumed and in 2013, 27 states, the District of Columbia, and New York 

City reported data. In 2014, 30 states, the District of Columbia, and New York City reported data. 

Table 5-23 summarizes the number and rate per 100,000 children aged <5 years with blood Pb levels 5–

9 μg/dL reported in the 2010–2014 CBLS system. PbBs ≥10 μg/dL continue to be more prevalent among 

children with known risk factors, such as minority race or ethnicity, urban residence, residing in homes 

built prior to the 1950s, and low family income (CDC 2009). 

Table 5-23. Number and Rate per 100,000 Children Aged <5 Years with Blood 

Lead Levels 5–9 μg/dL in the Childhood Blood Lead Surveillance System, 

United States, 2010–2014

Year

<1 Year 1–4 Years

Number Rate Number Rate

2010a 18,598 448.48 137,887 805.62

2011b 13,981 352.69 130,838 810.56

2012c 7,876 199.74 95,854 596.58

2013d 5,494 138.26 57,293 360.46

2014e 5,904 148.51 70,680 444.49

a37 jurisdictions reporting. 

b36 jurisdictions reporting.

c30 jurisdictions reporting.

d29 jurisdictions reporting. 

e32 jurisdictions reporting. 
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Table 5-23. Number and Rate per 100,000 Children Aged <5 Years with Blood 

Lead Levels 5–9 μg/dL in the Childhood Blood Lead Surveillance System, 

United States, 2010–2014

Year

<1 Year 1–4 Years

Number Rate Number Rate

Source: Raymond and Brown 2017

Various studies suggest that ingestion of game hunted with Pb shot is associated with increased PbBs. 

Johansen et al. (2006) collected blood samples from 50 men in Nuuk, Greenland to study the relationship 

between the consumption of birds hunted with Pb shot and PbBs. Men who regularly ate hunted birds 

killed with Pb shot had mean PbB ranging from 6.2 μg/dL in the group eating 0.1–5 bird equivalents per 

month to 12.8 μg/dL in those eating >30 bird equivalents per month. In addition, levels were highest in 

mid-winter when consumption of hunted birds was highest. Those who did not consume hunted birds had 

a mean PbB of 1.5 μg/dL. These results are consistent with earlier surveys of Arctic hunting 

communities. A 1992 survey of 492 Inuit adults from the Arctic region of Quebec, Canada showed that 

consumption of waterfowl, along with age and smoking, were associated with elevated PbB (Dewailly et 

al. 2001). The geometric mean PbB was 0.42 μmol/L (8.7 μg/dL), with a range of 0.04–2.28 μmol/L 

(0.8–47 μg/dL). In a cohort of Inuit newborns from northern Quebec, where the population consumed 

game killed with Pb shot, the geometric umbilical cord PbB was 3.9 μg/dL (range 0.2–27 μg/dL); 7% of 

Inuit newborns had cord PbBs >10 μg/dL as compared to 0.16% of the non-Inuit population in southern 

Quebec (Lévesque et al. 2003).

Second-hand smoke may also contribute to increased Pb exposure (Apostolou et al. 2012; Mannino et al. 

2003; Richter et al. 2013). Pb is a component of tobacco and tobacco smoke, and smokers often have 

higher Pb 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). Recent Pb urine concentrations for 

the U.S. adult population from the NHANES by smoking status are presented in Table 5-24.
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Table 5-24. Geometric Mean Urine Lead Levels (μg/dL) and the 95th Percentile 

Confidence Interval by Smoking Status

Survey years

Geometric mean (95% 

confidence interval) Sample size

Cigarette smokers

Total 11–12 2.36 (1.71–4.62) 876

13–14 1.51 (1.30–1.91) 957

Age group

20–49 years 11–12 1.78 (1.41–3.07) 522

18–49 years 13–14 1.34 (1.13–1.92) 583

50 years and older 11–12 3.35 (1.62–6.83) 354

13–14 1.72 (1.40–2.03) 374

Gender

Males 11–12 3.07 (1.73–5.03) 527

13–14 1.91 (1.48–2.14) 512

Females 11–12 1.58 (1.14–3.45) 349

13–14 1.30 (1.12–1.41) 445

Nonsmokersa

Total 11–12 1.38 (1.25–1.58) 1,343

13–14 1.16 (0.950–1.51) 1,487

Age group

20–49 years 11–12 1.26 (1.02–1.38) 671

18–49 years 13–14 0.880 (0.720–1.04) 778

50 years and older 11–12 1.63 (1.29–2.16) 672

13–14 1.48 (1.12–2.52) 709

Gender

Males 11–12 1.61 (1.18–2.13) 635

13–14 1.51 (1.04–2.68) 663

Females 11–12 1.32 (1.06–1.38) 708

13–14 0.238 (0.219–0.258) 824

aCigarette nonsmokers who used other tobacco products were excluded.

Source: CDC 2018a

Studies have been conducted to determine exposure of firearm instructors to Pb at outdoor firing ranges 

when either nonjacketed (pure Pb) 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 Pb 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

. PbBs of the instructors did not exceed 

the OSHA Pb standard’s medical removal level of 2.4 μmol/L (60 μg/dL) in either case (OSHA 2016a). 
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When shooters fired conventional Pb bullets, their mean exposures to airborne Pb were 128 μg/m3 in the 

personal breathing zone and 68 μg/m3 in the general area. When totally copper-jacketed Pb 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 Pb 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 Pb exposures among FBI and Drug 

Enforcement Agency (DEA) firing range personnel (NIOSH 1996b). Sixty-one personal breathing-zone 

and 30 area samples for airborne Pb 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 higher (p<0.0005) dust-Pb concentrations when 

compared to nonstudent dormitories (dust-Pb concentration range of 116–546 μg/g with a geometric 

mean of 214 μg/g in the student's rooms versus a dust-Pb 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 Pb.

The American Academy of Pediatrics (AAP) (1998, 2005) concluded that although monitoring data 

demonstrate a decline in PbBs, Pb remains a common, preventable, environmental health threat. Most Pb 

poisoning in children is the result of dust and chips from deteriorating Pb paint on interior surfaces (AAP 

2005, 2016; ATSDR 2017). The AAP supported the CDC guidelines endorsing universal screening in 

certain areas and targeted screening for children at high risk (CDC 1997b, 2005). Many children continue 

to be at risk for ingestion of Pb-based paint and of soil and dust contaminated through the deterioration of 

Pb-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 Pb-contaminated soil, and that the most 

likely source was Pb-based paint rather than Pb from automotive exhaust (Ter Haar and Aronow 1974). 

However, more recent studies have shown that children with the highest PbBs live in areas with high 

traffic flow where Pb 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, 2008, 2010). The CDC concluded that a 
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common source of Pb exposure for children who have elevated PbB is Pb-based paint that has 

deteriorated into paint chips and Pb dusts (CDC 1997b, 2012d).

Pb can readily cross the placenta; therefore, exposure of women to Pb during pregnancy results in uptake 

by the fetus. Furthermore, since the physiological stress of pregnancy may result in mobilization of Pb 

from maternal bone, fetal uptake of Pb can occur from a mother who was exposed to Pb before 

pregnancy, even if no Pb exposure occurs during pregnancy. Maternal Pb can also be transferred to 

breastfeeding infants. 

Malcoe et al. (2002) assessed Pb sources and their effect on blood Pb 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 years. There were no ethnic differences in the 

results. However, poor children were especially vulnerable. Regression analysis showed that mean floor 

dust Pb loading >10.1 μg/ft2 and yard soil Pb >165.3 mg/kg were independently associated with blood Pb 

levels ≥10 μg/dL.

The Pb 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 1989a). For children who engage in pica behavior 

(the compulsive, habitual consumption of nonfood items), the ingestion rate of soil can be as high as 

5 g/day. Although ingestion of Pb-containing paint may lead to elevated PbBs in young children, a major 

source of elevated PbBs (>10 μg/dL) in children is often contaminated household dust and subsequent 

hand contamination and repetitive mouthing (Bornschein et al. 1986; Charney et al. 1980; Dixon et al. 

2009; Lanphear and Roghmann 1997; Lanphear et al. 1998a; Succop et al. 1998). Weathering of 

Pb-based paint can contribute to the Pb content of dust and soil. Pb 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, PbBs were not correlated with indoor air or tap water Pb levels, nor the size of 

nearby roadways. Indoor dust Pb levels and soil Pb 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 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 
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increase, at least temporarily, a child's exposure to Pb 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, Pb dust, and 

blood Pb 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 Pb concentrations were observed in 

children where regular dust control methods had been used to reduce indoor levels of Pb (Rhoads et al. 

1999). EPA (2014c) summarized concentrations of Pb in house dust in the United Stated from 2006 to 

2011; these data are presented in Table 5-25.

PbB samples from 1,473 children <5 years old were analyzed prior to and after the change in drinking 

water source in the city of Flint, Michigan (Hanna-Attisha et al. 2016). Prior to the change, 2.4% of the 

children had PbB levels exceeding 5 μg/dL (n=736). Following the change in water source, 4.9% of 

children’s PbB levels exceeded 5 μg/dL for samples obtained from January 1 to September 15, 2015 

(n=737). The study also found that in areas where ≥25% of the drinking water samples exceeded 

15 μg/L, the percentage of children with PbB levels >5 μg/dL increased from 4.0 to 10.6%. Gomez et al. 

(2018) analyzed PbB levels for children <5 years old in Flint, Michigan over an 11-year time span from 

2006 to 2016. The percentage of children with PbB levels >5.0 μg/dL declined from 11.8% in 2006 to 

3.2% by 2016. The study authors noted an uptick in the geometric mean PbB level during the height of 

the Flint water crisis from 1.19±0.02 to 1.30±0.02 μg/dL in 2014–2015, but it declined to 

1.15±0.02 μg/dL in 2016 after the water source was switched back to the DWSD. The authors concluded 

that while there was a slight increase in PbB levels during the time at which the source of drinking water 

was changed for residents of Flint, the overall trend for the 11-year time span was decreasing PbB levels 

with a nearly 73% reduction in the percentage of children having levels >5 μg/dL. A second study 

analyzed PbB levels for females aged 12–50 years prior to (April 25, 2012–October 15, 2013), during 

(April 25, 2014–October 15, 2015), and immediately after (April 25, 2016–October 15, 2017) the Flint 

water crisis (Gomez et al. 2019). The authors found that blood levels did not increase for females of 

child-bearing age residing in Flint during the period when the water supply was changed from the DWSD 

to the Flint River. The geometric means reported were 0.69 μg/dL (April 25, 2012–October 15, 2013), 

0.65 μg/dL (April 25, 2014–October 15, 2015), and 0.55 μg/dL, (April 25, 2016–October 15, 2017). 
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Table 5-25. Measurements of Lead in Indoor Dust in the United States from 2006 

to 2011

Location Sample site Value reported

New York City, New York Glass plate next to open 

window of academic 

building 

Median weekly dust loading: 52 μg/m2

Eureka, Utah near Eureka Mills 

Superfund Site 

Indoor home site (not 

specified) 

Dust concentrations, range: 160–

2,000 mg/kg

Denver, Colorado, near 

Vasquez Blvd and I-70 

Superfund Site 

Indoor home site (not 

specified) 

Dust concentrations, range: 11–660 mg/kg

East Helena, Montana, near 

East Helena Superfund Site 

Indoor home site (not 

specified) 

Dust concentrations, range: 68–

1,000 mg/kg

Syracuse, New York Floor Dust concentrations, range: 209–

1,770 mg/kg

United States (nationwide) Smooth floor Median dust loading: 1.7 μg/m2

Average dust loading: 4.4 μg/m2

Rough floor Median dust loading: 5.6 μg/m2

Average dust loading: 16 μg/m2

Smooth windowsill Median dust loading: 2.5 μg/m2

Average dust loading: 190 μg/m2

Rough windowsill Median dust loading: 55 μg/m2

Average dust loading: 480 μg/m2

Milwaukee, Wisconsin Central perimeter Average dust concentration: 107 μg/m2

Entry Average dust concentration: 140 μg/m2

Window Average dust concentration: 151 μg/m2

Rural towns, Idaho Vacuum Dust concentration

Median: 120 mg/kg

Maximum: 830 mg/kg

Floor Median dust concentration: 95 mg/kg

Maximum dust concentration: 1,300 mg/kg

Bunker Hill, Idaho Superfund 

Site

Vacuum Median dust concentration: 470 mg/kg

Maximum dust concentration: 2,000 mg/kg

Floor Median dust concentration: 290 mg/kg

Maximum dust concentration: 4,600 mg/kg

Source: EPA 2014c

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 Pb 

loading in homes (carpets, uncarpeted floors, window sills, and troughs), African-American 

race/ethnicity, foundation perimeter soil Pb levels, ingestion of soil or dirt, Pb content and condition of 

interior painted surfaces, and first-flush kitchen drinking water Pb levels (Lanphear et al. 1996a, 1996b). 

Differences in housing conditions and exposures to Pb-containing house dust appear to contribute to the 
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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. Interior Pb exposures were 

more significant for African American children and exterior Pb exposures were more significant for white 

children (Lanphear et al. 1996a, 1996b). Mouthing behaviors are an important mechanism of Pb 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 

owner-occupied 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 Pb concentrations in household dust, 

tap water, foundation perimeter soil, and interior house paint has been used to predict the effect of 

changing concentrations of Pb in environmental media on children's PbBs. An increase in dust Pb 

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 tap water Pb 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 Pb 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 Pb dust was found to be a more potent contaminant of children's hands than indoor dust at 

daycare centers in New Orleans; boys, in general, had higher hand Pb levels than girls. The conclusions 

were based on Pb analysis of hand wipe samples taken before and after children played outdoors at four 

different daycare 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 Pb 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 Pb 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 Pb 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 Pb reduction of 1,856 ppm resulted in a 
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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 Pb in the child’s environment, under certain conditions, 

the abatement of that soil will result in a reduction in exposure and consequently, PbB level. 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 Pb exposure.

Authors of a study of PbBs in children in Toronto, Canada, before and after abatement of 

Pb-contaminated 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, 

household, lifestyle, neighborhood, and environmental factors relating to study participants (Langlois et 

al. 1996).

Seasonal variations in PbBs in children have been observed in a number of studies (Gulson et al. 2008; 

Haley and Talbot 2004; Havlena et al. 2009; Kemp et al. 2007; Johnson and Bretsch 2002; Johnson et al. 

1996; Laidlaw et al. 2005; Yiin et al. 2000). These studies suggest a general trend of increasing PbB 

during late summer and early fall. In addition to seasonal patterns in behavior (e.g., outdoor activities), 

seasonal patterns in weather (humidity and wind velocity) that promote re-entrainment and transport of 

dust Pb may contribute to the observed seasonal patterns in PbB (Laidlaw et al. 2005, 2012). 

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 Pb. 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 of soil/day (LaGoy 

1987; Mielke et al. 1989). If the soil contains 100 μg/g of Pb, an average child may be exposed to 5 μg 

Pb/day from this source alone (Mielke et al. 1989), and a pica child may be exposed to >100 times that 

amount.
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Improper removal of Pb from housing known to contain Pb-based paint can significantly increase Pb 

levels in dust, thus causing Pb toxicity in children living in the home during the Pb-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 1997a).

Workers occupationally exposed to Pb can carry Pb home on clothing, bodies, or tools (take home 

exposure). 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 Pb (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 Pb in workplace air at an electronic components plant (61–1,700 μg 

Pb/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 to 1994, children aged 1–5 years (n=139) of workers whose occupation 

resulted in Pb 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). However, improved industrial hygiene procedures are likely to 

have decreased worker take-home exposures. Exposures of Pb 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 Pb smelting, battery manufacturing and recycling, radiator repair, electrical 

components manufacturing, pottery and ceramics, and stained glass making (NIOSH 1995). Children of 

Pb-exposed construction workers may also be at increased risk (Whelan et al. 1997).

Children may be exposed to Pb 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 

Pb-containing materials include casting, stained glass, pottery, painting, glassblowing, and screenprinting. 

Activities involving use of Pb-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 close proximity. Maas et al. 

(2005) indicated that high levels of Pb are prevalent in inexpensive cosmetic jewelry that is sold to the 

general public at retail stores. 
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5. POTENTIAL FOR HUMAN EXPOSURE

Accidental or intentional ingestion of folk remedies (e.g., Chinese herbal medicines and Ayurvedic 

medicines containing Pb) or use of the Pb containing eye cosmetic tiro in children (discussed in 

Section 5.5.5) represents another source for potential Pb-poisoning in children. Sindoor, a cosmetic and 

cultural/religious powder used in Hindu cultures, has been found to contain very high amounts of Pb (Lin 

et al. 2010). Hair dyes formulated with Pb acetate represent a potential source for Pb-poisoning both by 

accidental ingestion and by hand-to-mouth activity following contact with Pb-contaminated surfaces, 

including dyed hair of adults (Mielke et al. 1997).

Children may be exposed to Pb 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 years 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). 

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

In addition to workers exposed to Pb in the workplace and family members of workers exposed via take 

home exposure, other population groups are at risk for potential exposure to high levels of Pb. These 

include populations residing in older housing or buildings that contain deteriorating leaded paint or that 

have galvanized pipes, Pb service lines, or scales that contain Pb within a distribution public water 

system; in high-traffic areas with legacies from leaded gasoline; near sites where Pb was produced or 

disposed; or near one of the NPL hazardous waste sites where Pb has been detected in some 

environmental media (ATSDR 2017b; EPA 2014c, 2016a). Since Pb is often detected in tobacco and 

tobacco smoke, persons who use chewing tobacco or smoke or are exposed to second-hand smoke, may 

have higher PbB levels than persons that do not use these products (Apostolou et al. 2012; Bonanno et al. 

2001; Richter et al. 2013). Recent studies have also found e-cigarettes to be a potential source of Pb 

exposure (Olmedo et al. 2018). Other Pb sources that can contribute to elevated exposures to individual 

children or adults include mouthing or ingestion of toys containing Pb and consumption of candy and folk 

remedies and illicitly manufactured drugs that contain Pb (CDC 2002b, 2018c).

General population exposure is most likely to occur through the ingestion of food and water contaminated 

with Pb. Based on a multimedia Pb exposure modeling analysis for children 1–5 years old at upper 
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percentiles of PbB in the U.S. population, soil and dust ingestion are dominant exposure pathways, but for 

lower percentiles, other age groups (e.g., younger children), or specific local U.S. locations, the main 

exposure source/pathway could be different (Zartarian et al. 2017). However, some individuals and 

families may be exposed to additional sources of Pb in their homes. This is particularly true of older 

homes that may contain Pb-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 Pb) can be exposed to 

such excessive levels that Pb poisoning may occur (Chisolm 1986; Fischbein et al. 1981; Rabinowitz et 

al. 1985). Special populations at risk of high exposure to tetraethyl Pb include workers at hazardous 

waste sites and those involved in the manufacture and dispensing of tetraethyl Pb (Bress and Bidanset 

1991). 
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CHAPTER 6. 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 Pb 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 adverse health effects (and techniques for developing methods to determine 

such health effects) of Pb.

Data needs are defined as substance-specific informational needs that, if met, would reduce the 

uncertainties of human health risk 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. 

6.1 INFORMATION ON HEALTH EFFECTS

Studies evaluating the health effects of exposure of humans Pb that are discussed in Chapter 2 are 

summarized in Figure 2-1. The purpose of this figure is to illustrate the information concerning the health 

effects of Pb. The number of human studies included in the profile for each endpoint is indicated 

regardless of whether an effect was found. 

The health effects of Pb have been extensively studied in humans, including numerous studies in children. 

Due to the extent of the database in humans, a comprehensive review of the complete epidemiological 

database is not feasible. Epidemiological studies included in Chapter 2 were selected to identify the 

major lines of evidence regarding health effects in humans. Because the database of epidemiological 

studies is so large, animal studies were not included in the profile. Due to the increasing awareness that 

low-level environmental exposure resulting in blood Pb concentrations (PbB) <10 μg/dL is associated 

with adverse effects, particularly in children, the primary objective of current research is focused on 

health effects associated with PbB ≤10 μg/dL. Additional details on studies with PbB ≤10 μg/dL, 

including statistical analyses and assessment of confounding factors, are provided in the Supporting 

Document for Epidemiological Studies for Lead.

Health effects of Pb in humans are not defined in terms of route or duration of exposure. Epidemiological 

studies on Pb toxicity rely on internal exposure metrics (e.g., PbB), rather than measurements of external 
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6. ADEQUACY OF THE DATABASE

exposures (e.g., concentration of Pb in water or air) or ingested dose. Furthermore, once absorbed into 

the body, the health effects of Pb are the same, regardless of the route of exposure. Environmental 

exposure to Pb occurs continuously over a lifetime and Pb can be retained in the body for decades; 

therefore, health effects of Pb in humans are considered to be associated with chronic exposure, rather 

than to shorter exposures.

6.2 IDENTIFICATION OF DATA NEEDS

A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs 

Related to Toxicological Profiles (ATSDR 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.

Increased awareness of the potential adverse consequences of low environmental exposures to Pb has led 

to changes in U.S. public health policy, with a focus on lowering PbB levels to well below 10 μg/dL 

(CDC 2012d; EPA 2016b). In 2012, the CDC concluded that the 97.5th percentile of the U.S. PbB 

distribution (based on NHANES data) should be considered a reference value for identifying children 

who have “elevated” PbB (CDC 2012d). At that time, the 97.5th percentile was approximately 5 μg/dL. 

Therefore, additional epidemiological studies for all health outcomes are needed. The objective of these 

additional studies would be to define the low end of the dose-response curve (e.g., at PbB ≤5 μg/dL) and

to identify threshold levels for health outcomes.

MRLs. Epidemiological studies have identified health effects of Pb in all organ systems. However, 

exposure thresholds for effects have not been identified, and it is not possible to determine from the 

epidemiological data which organ system are the most sensitive (i.e., primary) targets for Pb toxicity. 

Because clear thresholds for these effects have not been identified, MRLs for Pb have not been derived. 

Additional epidemiological studies would provide more data to further characterize effects; however, as 

PbBs continue to decline and effects are observed at the lowest PbB examined, identification of control 

groups has become increasingly difficult. Thus, it is not anticipated that additional epidemiological 

studies would identify threshold values for Pb-induced toxicity endpoints. 

Health Effects. As noted above, epidemiological studies have identified health effects of Pb in every 

organ system at the lowest PbB evaluated. Additional prospective studies on all health outcomes would 

provide important information to further characterize the effects of Pb and evaluate potential implications 
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6. ADEQUACY OF THE DATABASE

for long-term effects. However, as noted above, it is not anticipated that additional epidemiological 

studies would identify threshold values for health effects.

Epidemiology and Human Dosimetry Studies. Several models of the Pb exposure-biokinetics 

toxicokinetics in humans have been developed and used in dosimetry studies. Additional studies would 

be helpful for addressing major uncertainties in these models, including: (1) absence of calibration data 

for the kinetics of Pb in blood and bone in children in association with exposures that have been 

quantified with high certainty; (2) absence of calibration data on bone Pb concentrations in adolescents 

and adults in association with exposures that have been quantified with high certainty; (3) absence of data 

on the absolute bioavailability of ingested Pb in older children and adolescents; (4) incomplete 

understanding of Pb kinetics during periods of changing bone metabolism, including adolescence, 

pregnancy, and menopause; and (5) incomplete understanding of inter- and intra-individual variability in 

model parameter values in humans. In addition, there is a need for studies that can evaluate or validate 

model predictions of concentrations of Pb in blood and other tissues in populations in which PbBs are 

typical of the U.S. population (≤5 μg/dL).

Biomarkers of Exposure and Effect. Measurement of blood Pb concentration is the most widely 

used biomarker of Pb exposure and is used to identity children who have elevated exposures. 

Measurement of bone Pb by XRF has been used to estimate Pb body burden in adults, which is a more 

accurate biomarker of long-term exposure than PbB. Additional studies that could improve and evaluate 

the validity of non-invasive biomarkers (e.g., hair, saliva, sweat, deciduous teeth, urine) for quantifying 

exposure would be helpful for population monitoring of Pb exposures and for epidemiology of Pb health 

effects.

Absorption, Distribution, Metabolism, and Excretion. Studies of Pb absorption are limited to 

studies in infants and adults. No data are available on the absorption of Pb in older children and 

adolescents. Additional studies of Pb absorption in this age category would be useful for improving 

exposure-biokinetic models. 

A variety of factors are known to influence the absorption of ingested Pb, including the chemical form of 

the ingested Pb, the presence of food in the gastrointestinal tract, diet, and nutritional status with respect 

to calcium, vitamin D, and iron; 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 

Pb is absorbed in the gastrointestinal tract, and studies aimed at elucidating such mechanisms would be 
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6. ADEQUACY OF THE DATABASE

helpful for developing PBPK models that accurately simulate relationships between Pb exposure and Pb 

in blood and other target and biomarker tissue.

The quantitative significance of the dermal absorption pathway as a contributor to Pb body burden 

remains an uncertainty. Few studies are available on Pb absorption after dermal exposure of inorganic Pb 

compounds in humans. Children may experience extensive dermal contact with Pb 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 Pb compounds from both aqueous media and from 

soil would be helpful for improving PBPK models, in particular, studies that enable measurements to be 

extrapolated to children.

Comparative Toxicokinetics. Animal models (e.g., swine, mouse) have been used extensively as a 

model for assessing relative bioavailability of Pb in ingested soil in humans and for evaluating in vitro

approaches to assessing bioaccessibility of Pb. However, no studies are available in which the absolute or 

relative bioavailability of ingested Pb has been quantitatively compared in animal models and humans. 

Such studies would be useful for validating both the in vivo swine model and the in vitro bioaccessibility 

model.

Children’s Susceptibility. Children are likely to have increased susceptibility to Pb compared to 

adults for several reasons: increased susceptibility of developing physiological systems compared to 

mature systems; increased absorption of Pb in children compared to adults; and common childhood 

behaviors (e.g., hand-to-mouth activity, pica behavior [the compulsive, habitual consumption of nonfood 

items], proximity of breathing zone to entrained surface dust). In addition, several other factors may 

affect children’s susceptibility to Pb, including (but not limited to) family socio-economic status, parent 

education, parent alcohol, tobacco, and drug use, allergen exposure, and family history of disease, 

although these factors may not be unique to children. Additional studies evaluating these factors would 

provide an increased understanding of relative contributions of these factors to child PbB and associated 

health effects.

Physical and Chemical Properties. No data needs were identified regarding physical and chemical 

properties of Pb.
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6. ADEQUACY OF THE DATABASE

Production, Import/Export, Use, Release, and Disposal. Continued monitoring of Pb 

production, import/export, use, release, and disposal would be helpful for identifying sources of potential 

human exposure. In particular, additional data on releases of Pb from leaded gasoline used in pistondriven engines would be helpful for determining potential contributions of this source to human exposure. 

Industrial wastes, as well as consumer products, containing Pb are disposed of in municipal and 

hazardous waste landfills. Current information on the amounts being disposed would be helpful for 

evaluating potential for exposures to Pb from these sources.

Environmental Fate. Additional information on the atmospheric transformations of organic and 

inorganic Pb compounds would be helpful for identifying Pb compounds to which humans are most likely 

to be exposed by inhalation. Additional data regarding the chemical speciation and the transformation 

pathways of Pb in soils and water with varying properties such as pH, oxygen content, and salinity would 

be helpful for improved understanding of the environmental fate of Pb in soils and water.

Bioavailability from Environmental Media. Studies conducted in animal models show that oral 

RBA of soil Pb varies depending upon the Pb mineralogy and physical characteristics of the Pb in the 

soil. There is only one published study that assessed the bioavailability of Pb in humans (adults) who 

ingested hazardous waste site soil. Additional studies of this type would provide an improved basis for 

estimating Pb uptake in people who are exposed to Pb in soil. No studies have measured oral RBA of 

surface dusts. Since this is an important exposure pathway, especially in urban environments, studies of 

oral Pb RBA of surface dusts collected from various types of indoor and outdoor surfaces, including those 

impacted by paint Pb, would be helpful.

Recent interest in the use of soil-amending agents (e.g., phosphate) to reduce soil Pb bioavailability, 

would be served by additional studies directed at developing methods for monitoring the magnitude and 

persistence of the effect of amending agents on Pb bioavailability and for predicting the magnitude of the 

effect for improved design of amending projects.

Food Chain Bioaccumulation. No data needs were identified regarding food chain bioaccumulation. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of Pb in 

contaminated media at hazardous waste sites are needed so that the information obtained on levels of Pb 

in the environment can be used in combination with the known body burden of Pb to assess the potential 

risk of adverse health effects in populations living in the vicinity of hazardous waste sites. Continued 
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6. ADEQUACY OF THE DATABASE

monitoring of Pb levels in air, drinking water, and diet (e.g., food and bottled water) would be helpful for 

evaluating potential for exposures to Pb from these sources. Continued testing of consumer products 

would be helpful for identifying potential localized sources of human exposure (e.g., ceramics, cosmetics, 

jewelry, toys).

Exposure Levels in Humans. Continued updating of national (e.g., NHANES) and regional surveys 

of Pb biomarkers (e.g., PbB) would be helpful for assessing temporal and demographic trends in Pb 

exposure in the U.S. population as well as for evaluating associations between Pb exposure and health

metrics (e.g., those included in the NHANES), and for evaluating models that relate exposure to PbB.

Exposures of Children. Since an important variable in estimating Pb intakes from measurements of 

surface dust Pb levels is the rate of surface dust ingestion, improved estimates of soil ingestion would 

increase confidence in predictions of Pb intakes associated with exposures to Pb in surface dusts. In some 

contexts, exposure to surface dust Pb is measured in terms of Pb loading (μg/Pb/cm2 of surface area 

available for contact); however, Pb loading measurements do not provide a direct way of estimating Pb 

ingestion without corresponding estimates of dust loading and surface dust ingestion rates. Improved 

methods for translating measurements of Pb loading into estimates of surface dust Pb concentration or 

surface dust Pb intake would be helpful for improving models for predicting exposure-Pb relationships in 

children.

6.3 ONGOING STUDIES

Ongoing studies on Pb are outlined in Table 6-1. Note that the studies listed below are funded by the 

National Institute of Health (NIH) and do not include ongoing studies that are funded by other sources. 

Table 6-1. Ongoing Studies on Lead (Pb)

Investigator Affiliation Research description Sponsor

Bhattacharya, A University of 

Cincinnati

Epidemiological study evaluating the effects of 

childhood Pb exposure on bone and musculature in 

African-American women

NIEHS

Kordas, K State University 

of New York at 

Buffalo

Epidemiological study on the interaction between 

metals and neurobehavioral outcomes in children 

and adolescents

NIEHS

Lamas, G Mt. Sinai Medical 

Center

Investigation effects of chelation-reduced PbB on 

myocardial infarction

NCCIH
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6. ADEQUACY OF THE DATABASE

Table 6-1. Ongoing Studies on Lead (Pb)

Investigator Affiliation Research description Sponsor

Lu, Q Harvard School of 

Public Health

Study in children to evaluate SPP1 upregulation as 

a critical mechanism linking Pb exposure with 

neural stem cell function and neurodevelopment in 

children

NIEHS

Papautsky, I University of 

Illinois at Chicago

Longitudinal study to evaluate the relationship 

between PbB and functional gait and static and 

dynamic balance in an adolescent cohort

NIEHS

Reuben, A Duke University Longitudinal birth cohort study of neuroimaging 

data to determine whether childhood Pb exposure 

relates to degenerative alterations in neural 

structure or function by late midlife

NIEHS

Upson, K Michigan State 

University

Prospective cohort study to evaluate the 

association between PbB and uterine fibroid tumors

NINR

Wang, G Johns Hopkins 

University

Prospective birth cohort study to evaluate the 

relationship between PbB and placental pathology 

and cardiometabolic outcomes in childhood

NIEHS

Weuve, J Boston University 

Medical Campus

Pilot study to evaluate XRF energy-dispersed X-ray 

fluorescence measurement of Pb in bone and 

toenails

NIEHS

NCCIH = National Center for Complementary and Integrative Health; NIEHS = National Institute of Environmental 

Health Sciences; NINR = National Institute of Nursing Research; PbB = blood lead concentration; SSP1 = secreted 

phosphoprotein 1; XRF = X-ray fluorescence

Source: NIH Reporter 2020 (https://projectreporter.nih.gov/reporter.cfm)
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CHAPTER 7. REGULATIONS AND GUIDELINES

Pertinent international and national regulations, advisories, and guidelines regarding lead in air, water, 

and other media are summarized in Table 7-1. This table is not an exhaustive list, and current regulations 

should be verified by the appropriate regulatory agency.

ATSDR develops MRLs, which are substance-specific guidelines intended to serve as screening levels by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. See Section 1.3 and Appendix A for detailed information on 

the MRLs for Pb. As discussed in Appendix A, no MRLs were derived for Pb.

Table 7-1. Regulations and Guidelines Applicable to Lead (Pb)

Agency Description Information Reference

Air

EPA RfC Not evaluated IRIS 2002, 2004

EPA NAAQS 0.15 μg/m3 a EPA 2019b

WHO Air quality guidelines Not listed WHO 2010

Water & Food

EPA Drinking water standards and health 

advisories 

No data EPA 2018c

National primary drinking water 

regulations for inorganic lead

EPA 2009

MCL or TT TTb

Action level 0.015 mg/L

Public health goal zero 

Lead and copper rule proposal EPA 2019a

Trigger level (proposed) 10 μg/Lc

RfD 

Tetraethyl lead 1x10-7 mg/kg/day IRIS 2002

WHO Drinking water quality guidelines WHO 2017

Provisional guideline value, lead 0.01 mg/L (10 μg/L)d

FDA Substances Added to Foode Not listed FDA 2019a

Allowable level of lead in bottled water 0.005 mg/L FDA 2019b
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7. REGULATIONS AND GUIDELINES

Table 7-1. Regulations and Guidelines Applicable to Lead (Pb)

Agency Description Information Reference

Cancer

HHS Carcinogenicity classification NTP 2016

Lead and lead compounds Reasonably anticipated to 

be human carcinogens

EPA Carcinogenicity classification IRIS 2004

Lead and compounds (inorganic) B2f

IARC Carcinogenicity classification

Lead Group 2Bg IARC 1987, 2019

Lead compounds, inorganic Group 2Ah IARC 2006, 2019

Lead compounds, organic Group 3i IARC 2006, 2019

Occupational

OSHA PEL (8-hour TWA) for general industry

Lead (elemental, inorganic and 

organic soaps)

50 μg/m3 OSHA 2019a

Tetraethyl lead and tetramethyl lead 0.075 mg/m3 j OSHA 2019b

PEL (8-hour TWA) for construction 

and shipyards

Lead (elemental, inorganic and 

organic soaps)

50 μg/m3 OSHA 2019c, 2019a

Tetraethyl lead 0.1 mg/m3 j OSHA 2019d, 2019e

Tetramethyl lead 0.15 mg/m3 j OSHA 2019d, 2019f

Action level (8-hour TWA) for general 

industry, construction

Lead (elemental, inorganic and 

organic soaps)

30 μg/m3 OSHA 2019a, 2019c

Medical removal protection for general 

industry

OSHA 2019a

Temporary removal blood lead level ≥60 μg/100 g

Return to work blood lead level <40 μg/100 g

Medical removal protection for 

construction and shipyards

OSHA 2019c

Temporary removal blood lead level ≥50 μg/dL

Return to work blood lead level <40 μg/dL

NIOSH REL (8-hour TWA)

Lead and compounds (as Pb) 0.05 mg/m3 NIOSH 2019a

Tetraethyl lead (as Pb) and 

tetramethyl lead (as Pb)

0.075 mg/m3 j NIOSH 2019b, 2019c

IDLH

Lead and compounds (as Pb) 100 mg/m3 NIOSH 2019a

Tetraethyl lead (as Pb) and 

tetramethyl lead (as Pb)

40 mg/m3 NIOSH 2019b, 2019c
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7. REGULATIONS AND GUIDELINES

Table 7-1. Regulations and Guidelines Applicable to Lead (Pb)

Agency Description Information Reference

Emergency Criteria

EPA AEGLs-air No data EPA 2018c

DOE PACs-airk DOE 2018a

Lead

PAC-1 0.15 mg/m3

PAC-2 120 mg/m3

PAC-3 700 mg/m3

Tetraethyl lead

PAC-1 0.3 mg/m3

PAC-2 4 mg/m3

PAC-3 40 mg/m3

Tetramethyl lead

PAC-1 0.45 mg/m3

PAC-2 4 mg/m3

PAC-3 40 mg/m3

Lead acetate

PAC-1 5 mg/m3

PAC-2 55 mg/m3

PAC-3 330 mg/m3

Lead carbonate

PAC-1 0.19 mg/m3

PAC-2 24 mg/m3

PAC-3 900 mg/m3

Lead dioxide and lead sulfide

PAC-1 0.17 mg/m3

PAC-2 140 mg/m3

PAC-3 810 mg/m3

Lead tetroxide

PAC-1 0.17 mg/m3

PAC-2 130 mg/m3

PAC-3 770 mg/m3

Lead sulfide

PAC-1 0.17 mg/m3

PAC-2 140 mg/m3

PAC-3 810 mg/m3

Lead oxide

PAC-1 0.16 mg/m3

PAC-2 130 mg/m3

PAC-3 750 mg/m3
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7. REGULATIONS AND GUIDELINES

Table 7-1. Regulations and Guidelines Applicable to Lead (Pb)

Agency Description Information Reference

Lead sulfate

PAC-1 0.22 mg/m3

PAC-2 170 mg/m3

PAC-3 1,000 mg/m3

Lead phosphate

PAC-1 0.2 mg/m3

PAC-2 150 mg/m3

PAC-3 910 mg/m3

Lead chloride

PAC-1 0.2 mg/m3

PAC-2 160 mg/m3

PAC-3 940 mg/m3

Lead chromate

PAC-1 0.036 mg/m3

PAC-2 16 mg/m3

PAC-3 97 mg/m3

Lead bromide

PAC-1 0.27 mg/m3

PAC-2 200 mg/m3

PAC-3 1,200 mg/m3

Lead nitrate

PAC-1 0.24 mg/m3

PAC-2 180 mg/m3

PAC-3 1,100 mg/m3

Lead iodide

PAC-1 0.33 mg/m3

PAC-2 270 mg/m3

PAC-3 1,600 mg/m3

Lead fluoroborate

PAC-1 0.28 mg/m3

PAC-2 220 mg/m3

PAC-3 1,300 mg/m3

Miscellaneous Federal Guidance

CDC PbB reference value 5 μg/dL CDC 2012d, 2012e

EPA Dust-lead hazard standards

Floors

Window sills

10 μg/ft2

100 μg/ft2

EPA 2019c
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7. REGULATIONS AND GUIDELINES

Table 7-1. Regulations and Guidelines Applicable to Lead (Pb)

Agency Description Information Reference

EPA Soil screening level 400 ppm EPA 1994e, 1998;

2016d

HUD Dust lead hazard action levels

Floors

Window sills

Dust lead clearance action levels

Interior floors

Porch floors

Window sills

Window troughs

≥10 μg/ft2

≥100 μg/ft2

<10 μg/ft2

<40 μg/ft2

<100 μg/ft2

<100 μg/ft2

HUD 2017

aNot-to-exceed air Pb concentration of 0.15 μg/m3 in total suspended solids for a 3-month rolling average, 

evaluated over a 3-year period (i.e., the 3-month rolling average cannot exceed 0.15 μg/m3 over a 3-year period). bIf >10% of tap water samples exceed the action level, a water system must take additional steps to 

control the corrosiveness of its water. 

cExceedance would trigger additional planning, monitoring, and treatment requirements, which vary depending on 

the characteristics of the water system.

dThe guideline value is designated as provisional on the basis of treatment performance and analytical achievability 

because it is extremely difficult to achieve a lower concentration by central conditioning, such as phosphate dosing. eThe Substances Added to Food inventory replaces EAFUS and contains the following types of ingredients: food 

and color additives listed in FDA regulations, flavoring substances evaluated by FEMA or JECFA, GRAS 

substances listed in FDA regulations, substances approved for specific uses in food prior to September 6, 1958, 

substances that are listed in FDA regulations as prohibited in food, delisted color additives, and some substances 

"no longer FEMA GRAS." f

Group B2: probable human carcinogen.

gGroup 2B: possibly carcinogenic to humans.

hGroup 2A: probably carcinogenic to humans.

i

Group 3: not classifiable as to carcinogenicity to humans.

j

Skin designation. kDefinitions of PAC terminology are available from U.S. Department of Energy (DOE 2018b).

AEGL = acute exposure guideline levels; CDC = Centers for Disease Control and Prevention; DOE = Department of 

Energy; EAFUS = Everything Added to Food in the United States; EPA = Environmental Protection Agency; 

FDA = Food and Drug Administration; FEMA = Flavor and Extract Manufacturers Association of the United States; 

GRAS = generally recognized as safe; HHS = Department of Health and Human Services; HUD = Housing and 

Urban Development; IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or 

health concentration; IRIS = Integrated Risk Information System; JECFA = Joint FAO/WHO Expert Committee on 

Food Additives; MCL = maximum contaminant level; NAAQS = National Ambient Air Quality Standard; 

NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; 

OSHA = Occupational Safety and Health Administration; PAC = Protective Action Criteria; PbB = blood lead 

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LEAD A-1

APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS

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 route and duration of exposure. MRLs are based on 

noncancer health effects only; cancer effects are not considered. 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 NOAEL/uncertainty factor approach. They are 

below levels that might cause adverse health effects in the people most sensitive to such chemicalinduced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and chronic 

(≥365 days) 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 substance-induced endpoint 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 

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.
LEAD A-2

APPENDIX A

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Human Health Sciences, 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 MRLs. 

For additional information regarding MRLs, please contact the Division of Toxicology and Human 

Health Sciences, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, Mailstop 

S102-1, Atlanta, Georgia 30329-4027.

The literature evaluating the health effects of Pb is enormous, and includes an extensive database in 

humans, including children. Effects are diverse and exposure to Pb is associated with toxicity to every 

organ system. For the most studied endpoints (neurological, renal, cardiovascular, hematological, 

immunological, reproductive, and developmental), effects occur at the lowest PbBs studied (≤5 μg/dL). 

Exposure thresholds for effects on specific organ systems have not been identified (i.e., no safe level has 

been identified). Cognitive deficits in children occurring at the lowest PbBs (≤5 μg/dL) are the best 

substantiated effects. However, because the lowest PbBs are associated with serious adverse effects (e.g., 

declining cognitive function in children), MRLs for Pb have not been derived.
LEAD B-1

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR LEAD

The objective of the toxicological profile is to evaluate the potential for human exposure and the potential 

health hazards associated with inhalation, oral, or dermal/ocular exposure to Pb. 

B.1 LITERATURE SEARCH AND SCREEN 

A literature search and screen were conducted to identify studies examining health effects, toxicokinetics, 

mechanisms of action, susceptible populations, biomarkers, chemical interactions, physical and chemical 

properties, production, use, environmental fate, environmental releases, and environmental and biological 

monitoring data for Pb. ATSDR primarily focused on peer-reviewed articles without publication date or 

language restrictions. Non-peer-reviewed studies that were considered relevant to the assessment of the 

health effects of Pb have undergone peer review by at least three ATSDR-selected experts who have been 

screened for conflict of interest. The inclusion criteria used to identify relevant studies examining the 

health effects of Pb are presented in Table B-1.

Table B-1. Inclusion Criteria for the Literature Search and Screen

Health Effects

Species

Human

Laboratory mammals

Route of exposure

Inhalation

Oral

Dermal (or ocular)

Parenteral (these studies will be considered supporting data)

Health outcome

Death

Systemic effects

Body weight effects 

Respiratory effects

Cardiovascular effects

Gastrointestinal effects

Hematological effects

Musculoskeletal effects

Hepatic effects

Renal effects

Dermal effects

Ocular effects

Endocrine effects

Immunological effects

Neurological effects

Reproductive effects

Developmental effects

Other noncancer effects
LEAD B-2

APPENDIX B

Table B-1. Inclusion Criteria for the Literature Search and Screen

Cancer

Toxicokinetics

Absorption

Distribution

Metabolism

Excretion

PBPK models

Biomarkers

Biomarkers of exposure

Biomarkers of effect

Interactions with other chemicals

Potential for human exposure

Releases to the environment

Air

Water

Soil

Environmental fate

Transport and partitioning

Transformation and degradation

Environmental monitoring

Air

Water

Sediment and soil

Other media

Biomonitoring

General populations

Occupation populations

B.1.1 Literature Search

The current literature search was intended to update the draft toxicological profile for Pb released for 

public comment in 2019; thus, the literature search was restricted to studies published between February 

2015 and September 2019. The following main databases were searched in September 2019:

• PubMed 

• National Library of Medicine’s TOXLINE

• Scientific and Technical Information Network’s TOXCENTER

The search strategy used the chemical names, Chemical Abstracts Service (CAS) numbers, 

synonyms, Medical Subject Headings (MeSH) headings, and keywords for Pb. The query strings 

used for the literature search are presented in Table B-2. 

The search was augmented by searching the Toxic Substances Control Act Test Submissions (TSCATS), 

NTP website, and National Institute of Health Research Portfolio Online Reporting Tools Expenditures 
LEAD B-3

APPENDIX B

and Results (NIH RePORTER) databases using the queries presented in Table B-3. Additional databases 

were searched in the creation of various tables and figures, such as the TRI Explorer, the Substance 

Priority List (SPL) resource page, and other items as needed. Regulations applicable to Pb were 

identified by searching international and U.S. agency websites and documents.

Review articles were identified and used for the purpose of providing background information and 

identifying additional references. ATSDR also identified reports from the grey literature, which included 

unpublished research reports, technical reports from government agencies, conference proceedings and 

abstracts, and theses and dissertations. 

Table B-2. Database Query Strings 

Database

search date Query string

PubMed

09/2019 ((((10031-22-8[rn] OR 10099-74-8[rn] OR 10101-63-0[rn] OR 11119-70-3[rn] OR 12709-

98-7[rn] OR 1309-60-0[rn] OR 1314-41-6[rn] OR 1314-87-0[rn] OR 1317-36-8[rn] [ 13424-

46-9[rn] OR 13814-96-5[rn] OR 15245-44-0[rn] OR 16040-38-3[rn] OR 39377-56-5[rn] OR 

598-63-0[rn] OR 7439-92-1[rn] OR 7446-14-2[rn] OR 7446-27-7[rn] OR 7758-95-4[rn] OR 

7758-97-6[rn] OR 78-00-2[rn] OR 301-04-2[rn] ) AND ((("Lead/toxicity"[mh] OR 

"Lead/adverse effects"[mh] OR "Lead/poisoning"[mh] OR "Lead/pharmacokinetics"[mh]) 

OR ("Lead"[mh] AND ("environmental exposure"[mh] OR ci[sh])) OR ("Lead"[mh] AND 

toxicokinetics[mh:noexp]) OR ("Lead/blood"[mh] OR "Lead/cerebrospinal fluid"[mh] OR 

"Lead/urine"[mh]) OR ("Lead"[mh] AND ("endocrine system"[mh] OR "hormones, hormone 

substitutes, and hormone antagonists"[mh] OR "endocrine disruptors"[mh])) OR 

("Lead"[mh] AND ("computational biology"[mh] OR "medical informatics"[mh] OR 

genomics[mh] OR genome[mh] OR proteomics[mh] OR proteome[mh] OR 

metabolomics[mh] OR metabolome[mh] OR genes[mh] OR "gene expression"[mh] OR 

phenotype[mh] OR genetics[mh] OR genotype[mh] OR transcriptome[mh] OR ("systems 

biology"[mh] AND ("environmental exposure"[mh] OR "epidemiological monitoring"[mh] OR 

analysis[sh])) OR "transcription, genetic "[mh] OR "reverse transcription"[mh] OR 

"transcriptional activation"[mh] OR "transcription factors"[mh] OR ("biosynthesis"[sh] AND 

(RNA[mh] OR DNA[mh])) OR "RNA, messenger"[mh] OR "RNA, transfer"[mh] OR "peptide 

biosynthesis"[mh] OR "protein biosynthesis"[mh] OR "reverse transcriptase polymerase 

chain reaction"[mh] OR "base sequence"[mh] OR "trans-activators"[mh] OR "gene 

expression profiling"[mh])) OR ("Lead/antagonists and inhibitors"[mh]) OR 

("Lead/metabolism"[mh] AND ("humans"[mh] OR "animals"[mh])) OR ("Lead"[majr] AND 

cancer[sb]) OR ("Lead/pharmacology"[majr])) AND (2016/02/01 : 3000[mhda] OR 

2016/02/01 : 3000[crdt] OR 2016/02/01 : 3000[edat] OR 2015/02/01 : 3000[dp]))) OR 

("lead poisoning"[mh] AND (2016/02/01 : 3000[mhda] OR 2016/02/01 : 3000[crdt] OR 

2016/02/01 : 3000[edat] OR 2015/02/01 : 3000[dp])) OR ((("Tetraethyl Lead/toxicity"[mh] 

OR "Tetraethyl Lead/adverse effects"[mh] OR "Tetraethyl Lead/poisoning"[mh] OR 

"Tetraethyl Lead/pharmacokinetics"[mh]) OR ("Tetraethyl Lead"[mh] AND ("environmental 

exposure"[mh] OR ci[sh])) OR ("Tetraethyl Lead"[mh] AND toxicokinetics[mh:noexp]) OR 

("Tetraethyl Lead/blood"[mh] OR "Tetraethyl Lead/cerebrospinal fluid"[mh] OR "Tetraethyl 

Lead/urine"[mh]) OR ("Tetraethyl Lead"[mh] AND ("endocrine system"[mh] OR "hormones, 

hormone substitutes, and hormone antagonists"[mh] OR "endocrine disruptors"[mh])) OR 

("Tetraethyl Lead"[mh] AND ("computational biology"[mh] OR "medical informatics"[mh] 

OR genomics[mh] OR genome[mh] OR proteomics[mh] OR proteome[mh] OR 

metabolomics[mh] OR metabolome[mh] OR genes[mh] OR "gene expression"[mh] OR 

phenotype[mh] OR genetics[mh] OR genotype[mh] OR transcriptome[mh] OR ("systems 

biology"[mh] AND ("environmental exposure"[mh] OR "epidemiological monitoring"[mh] OR 

analysis[sh])) OR "transcription, genetic "[mh] OR "reverse transcription"[mh] OR 
LEAD B-4

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

"transcriptional activation"[mh] OR "transcription factors"[mh] OR ("biosynthesis"[sh] AND 

(RNA[mh] OR DNA[mh])) OR "RNA, messenger"[mh] OR "RNA, transfer"[mh] OR "peptide 

biosynthesis"[mh] OR "protein biosynthesis"[mh] OR "reverse transcriptase polymerase 

chain reaction"[mh] OR "base sequence"[mh] OR "trans-activators"[mh] OR "gene 

expression profiling"[mh])) OR ("Tetraethyl Lead/antagonists and inhibitors"[mh]) OR 

("Tetraethyl Lead/metabolism"[mh] AND ("humans"[mh] OR "animals"[mh])) OR 

("Tetraethyl Lead"[majr] AND cancer[sb]) OR ("Tetraethyl Lead/pharmacology"[majr])) 

AND (2016/02/01 : 3000[mhda] OR 2016/02/01 : 3000[crdt] OR 2016/02/01 : 3000[edat] 

OR 2015/02/01 : 3000[dp])) OR ((301-04-2[rn] AND (("Organometallic 

Compounds/toxicity"[mh] OR "Organometallic Compounds/adverse effects"[mh] OR 

"Organometallic Compounds/poisoning"[mh] OR "Organometallic 

Compounds/pharmacokinetics"[mh]) OR ("Organometallic Compounds"[mh] AND 

("environmental exposure"[mh] OR ci[sh])) OR ("Organometallic Compounds"[mh] AND 

toxicokinetics[mh:noexp]) OR ("Organometallic Compounds/blood"[mh] OR 

"Organometallic Compounds/cerebrospinal fluid"[mh] OR "Organometallic 

Compounds/urine"[mh]) OR ("Organometallic Compounds"[mh] AND ("endocrine 

system"[mh] OR "hormones, hormone substitutes, and hormone antagonists"[mh] OR 

"endocrine disruptors"[mh])) OR ("Organometallic Compounds"[mh] AND ("computational 

biology"[mh] OR "medical informatics"[mh] OR genomics[mh] OR genome[mh] OR 

proteomics[mh] OR proteome[mh] OR metabolomics[mh] OR metabolome[mh] OR 

genes[mh] OR "gene expression"[mh] OR phenotype[mh] OR genetics[mh] OR 

genotype[mh] OR transcriptome[mh] OR ("systems biology"[mh] AND ("environmental 

exposure"[mh] OR "epidemiological monitoring"[mh] OR analysis[sh])) OR "transcription,

genetic "[mh] OR "reverse transcription"[mh] OR "transcriptional activation"[mh] OR 

"transcription factors"[mh] OR ("biosynthesis"[sh] AND (RNA[mh] OR DNA[mh])) OR "RNA, 

messenger"[mh] OR "RNA, transfer"[mh] OR "peptide biosynthesis"[mh] OR "protein 

biosynthesis"[mh] OR "reverse transcriptase polymerase chain reaction"[mh] OR "base 

sequence"[mh] OR "trans-activators"[mh] OR "gene expression profiling"[mh])) OR 

("Organometallic Compounds/antagonists and inhibitors"[mh]) OR ("Organometallic 

Compounds/metabolism"[mh] AND ("humans"[mh] OR "animals"[mh])) OR 

("Organometallic Compounds"[majr] AND cancer[sb]) OR ("Organometallic 

Compounds/pharmacology"[majr]))) AND (2016/02/01 : 3000[mhda] OR 2016/02/01 : 

3000[crdt] OR 2016/02/01 : 3000[edat] OR 2015/02/01 : 3000[dp])) OR ((("1,3-

Benzenediol, 2,4,6-trinitro-, lead(2+) salt"[tw] OR "Borate(1-), tetrafluoro-, lead (2+)"[tw] OR 

"Borate(1-), tetrafluoro-, lead(2+)"[tw] OR "Chromic acid lead salt with lead molybdate"[tw] 

OR "Chromic acid, lead and molybdenum salt"[tw] OR "Chromium lead molybdenum 

oxide"[tw] OR "Lead (II) iodide"[tw] OR "Lead 2,4,6-trinitro-m-phenylene dioxide"[tw] OR 

"Lead bis(tetrafluoroborate)"[tw] OR "Lead borofluoride"[tw] OR "Lead boron fluoride"[tw] 

OR "Lead Brown"[tw] OR "Lead chromate molybdate"[tw] OR "lead diiodide"[tw] OR "Lead 

dioxide"[tw] OR "Lead fluoborate"[tw] OR "Lead fluoroborate"[tw] OR "Lead iodide"[tw] OR 

"Lead molybdate chromate"[tw] OR "Lead molybdenum chromate"[tw] OR "Lead oxide"[tw] 

OR "Lead peroxide"[tw] OR "Lead styphnate"[tw] OR "Lead superoxide"[tw] OR "Lead 

tetrafluoroborate"[tw] OR "Lead tricinate"[tw] OR "Lead trinitroresorcinate"[tw] OR "Lead(II) 

iodide"[tw] OR "Lead(II) styphnate"[tw] OR "Lead(II) tetrafluoroborate"[tw] OR "Lead(IV) 

oxide"[tw] OR "Lead-molybdenum chromate"[tw] OR "Molybdenum-lead chromate"[tw] OR 

"Plumbic oxide"[tw] OR "Plumbous iodide"[tw] OR "Plumbum jodatum"[tw] OR "Resorcinol, 

2,4,6-trinitro-, lead(2+) salt"[tw] OR "Thiolead A"[tw] OR "Tricinat"[tw]) AND (to[sh] OR 

po[sh] OR ae[sh] OR pk[sh] OR ai[sh] OR ci[sh] OR bl[sh] OR cf[sh] OR ur[sh] OR 

"pharmacology"[sh:noexp] OR "environmental exposure"[mh] OR "endocrine system"[mh] 

OR "hormones, hormone substitutes, and hormone antagonists"[mh] OR "endocrine 
LEAD B-5

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

disruptors"[mh] OR "Computational biology"[mh] OR "Medical Informatics"[mh] OR 

Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR Proteome[mh] OR 

Metabolomics[mh] OR Metabolome[mh] OR Genes[mh] OR "Gene expression"[mh] OR 

Phenotype[mh] OR genetics[mh] OR genotype[mh] OR Transcriptome[mh] OR ("Systems 

Biology"[mh] AND ("Environmental Exposure"[mh] OR "Epidemiological Monitoring"[mh] 

OR analysis[sh])) OR "Transcription, Genetic "[mh] OR "Reverse transcription"[mh] OR 

"Transcriptional activation"[mh] OR "Transcription factors"[mh] OR ("biosynthesis"[sh] AND 

(RNA[mh] OR DNA[mh])) OR "RNA, Messenger"[mh] OR "RNA, Transfer"[mh] OR 

"peptide biosynthesis"[mh] OR "protein biosynthesis"[mh] OR "Reverse Transcriptase 

Polymerase Chain Reaction"[mh] OR "Base Sequence"[mh] OR "Trans-activators"[mh] OR 

"Gene Expression Profiling"[mh] OR cancer[sb] OR (me[sh] AND ("humans"[mh] OR 

"animals"[mh])))) AND (2016/02/01 : 3000[mhda] OR 2016/02/01 : 3000[crdt] OR 

2016/02/01 : 3000[edat] OR 2015/02/01 : 3000[dp])) OR (("Plumbism"[tw] OR 

"saturnism"[tw] OR "colica pictorum"[tw] OR "Devon colic"[tw] OR "painter's colic"[tw]) NOT 

"lead poisoning"[mh]) OR ((("1,3-Benzenediol, 2,4,6-trinitro-, lead(2+) salt (1:1)"[tw] OR 

"Acetic acid lead(2+) salt"[tw] OR "Acetic acid, lead salt"[tw] OR "Acetic acid, lead(2 +) 

salt"[tw] OR "Acetic acid, lead(2+) salt"[tw] OR "Anglislite"[tw] OR "Azarcon"[tw] OR 

"Borate(1-), tetrafluoro-, lead (2+)"[tw] OR "Borate(1-), tetrafluoro-, lead(2+) (2:1)"[tw] OR 

"C.I. Pigment Metal 4"[tw] OR "C.I. Pigment Yellow 46"[tw] OR "CARBONIC ACID, LEAD 

SALT (1:1)"[tw] OR "Carbonic acid, lead salt (2+) (1:1) "[tw] OR "Carbonic acid, lead(2+) 

salt"[tw] OR "Cerussete"[tw] OR "Cerussite"[tw] OR "Chrome Orange"[tw] OR "Chrome 

Yellow"[tw] OR "Chromic acid (H2CrO4), lead(2+) salt (1:1)"[tw] OR "Chromic acid lead 

salt "[tw] OR "CHROMIC ACID, LEAD (2+) SALT (1:1)"[tw] OR "Chromic Acid, Lead (II) 

Salt (1:1)"[tw] OR "Chromic acid, lead and molybdenum salt"[tw] OR "Chromic acid, lead 

salt"[tw] OR "Chromic acid, lead(2+) salt (1:1)"[tw] OR "Chromium lead molybdenum 

oxide"[tw] OR "Chromium lead oxide"[tw] OR "CI pigment metal 4"[tw] OR "CI Pigment 

Yellow 46"[tw] OR "Collodial lead phosphate"[tw] OR "Dibasic lead acetate"[tw] OR 

"Dibasic lead carbonate"[tw] OR "Dibasic lead sulfate"[tw] OR "Entan"[tw] OR "Fast 

White"[tw] OR "Flowsperse R 12"[tw] OR "Freemans White Lead"[tw] OR "Galena"[tw] OR 

"Glover"[tw] OR "Gold Satinobre"[tw] OR "Heuconin 5"[tw] OR "Lead (II) carbonate"[tw] OR 

"Lead (II) chloride"[tw] OR "Lead (II) chromate"[tw] OR "Lead (II) iodide"[tw] OR "Lead (II) 

nitrate"[tw] OR "Lead (II) oxide"[tw] OR "Lead (II) sulfate"[tw] OR "Lead (II) sulfide"[tw] OR 

"Lead (II, IV) oxide"[tw] OR "Lead (IV) oxide "[tw] OR "Lead 2,4,6-trinitro-m-phenylene 

dioxide"[tw] OR "Lead acetate"[tw] OR "Lead azide"[tw] OR "Lead 

bis(tetrafluoroborate)"[tw] OR "Lead borofluoride"[tw] OR "Lead boron fluoride"[tw] OR 

"Lead Bottoms"[tw] OR "Lead bromide"[tw] OR "Lead brown"[tw] OR "Lead carbonate"[tw] 

OR "Lead chloride"[tw] OR "Lead chromate"[tw] OR "Lead chromate(VI)"[tw] OR "Lead 

chromium oxide (PbCrO4)"[tw] OR "Lead di(acetate)"[tw] OR "Lead diacetate"[tw] OR 

"Lead diazide"[tw] OR "Lead dibasic acetate"[tw] OR "Lead dibromide"[tw] OR "Lead 

dichloride"[tw] OR "Lead diiodide"[tw] OR "Lead dinitrate"[tw] OR "Lead dioxide"[tw] OR 

"Lead element"[tw] OR "Lead flake"[tw] OR "Lead fluoborate"[tw] OR "Lead 

fluoroborate"[tw] OR "Lead iodide"[tw] OR "Lead metal"[tw] OR "Lead molybdate 

chromate"[tw] OR "Lead molybdenum chromate"[tw] OR "Lead monooxide"[tw] OR "Lead 

monosulfate"[tw] OR "Lead monosulfide"[tw] OR "Lead monoxide"[tw] OR "Lead 

nitrate"[tw] OR "Lead orthophosphate"[tw] OR "Lead orthoplumbate"[tw] OR "Lead 

oxide"[tw] OR "Lead peroxide"[tw] OR "Lead phosphate"[tw] OR "Lead protoxide"[tw] OR 

"Lead S 2"[tw] OR "Lead S2"[tw] OR "Lead styphnate"[tw] OR "Lead sulfate"[tw] OR "Lead 

sulfide"[tw] OR "Lead sulphate"[tw] OR "Lead sulphide"[tw] OR "Lead superoxide"[tw] OR 

"Lead tetraethide"[tw] OR "Lead tetraethyl"[tw] OR "Lead tetrafluoroborate"[tw] OR "Lead 

tetraoxide"[tw] OR "Lead tetroxide"[tw] OR "Lead tricinate"[tw] OR "Lead 
LEAD B-6

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

trinitroresorcinate"[tw] OR "Lead(+2) sulfate"[tw] OR "Lead(2+) acetate"[tw] OR "Lead(2+) 

azide"[tw] OR "Lead(2+) bis(nitrate)"[tw] OR "Lead(2+) bromide"[tw] OR "Lead(2+) 

carbonate"[tw] OR "Lead(2+) chloride"[tw] OR "Lead(2+) nitrate"[tw] OR "Lead(2+) 

oxide"[tw] OR "Lead(2+) phosphate"[tw] OR "Lead(2+) phosphate (Pb3(PO4)2)"[tw] OR 

"Lead(2+) salt carbamic acid (1:1) "[tw] OR "Lead(2+) sulfate"[tw] OR "Lead(2+) 

sulfide"[tw] OR "Lead(II) acetate"[tw] OR "Lead(II) azide"[tw] OR "Lead(II) bromide"[tw] OR 

"Lead(II) carbonate"[tw] OR "Lead(II) chloride"[tw] OR "Lead(II) chromate"[tw] OR "Lead(II) 

dinitrate"[tw] OR "Lead(II) iodide"[tw] OR "Lead(II) nitrate"[tw] OR "Lead(II) oxide"[tw] OR 

"Lead(II) phosphate"[tw] OR "Lead(II) phosphate (3:2)"[tw] OR "Lead(II) styphnate"[tw] OR 

"Lead(II) sulfate"[tw] OR "Lead(II) sulfide"[tw] OR "Lead(II) tetrafluoroborate"[tw] OR 

"Lead(IV) oxide"[tw] OR "Lead, elemental"[tw] OR "Lead, inorganic"[tw] OR "Lead, 

tetraethyl"[tw] OR "Lead, tetraethyl-"[tw] OR "Lead-molybdenum chromate"[tw] OR 

"Litharge"[tw] OR "Massicot"[tw] OR "Massicotite"[tw] OR "Mennige"[tw] OR "Milk 

White"[tw] OR "mine orange"[tw] OR "Mineral Orange"[tw] OR "Mineral red"[tw] OR "minio 

anaranjado"[tw] OR "Minium"[tw] OR "Molybdenum-lead chromate"[tw] OR "Mulhouse 

White"[tw] OR "Nitric acid lead(2+) salt"[tw] OR "Nitric acid, lead(2+) salt"[tw] OR "Orange 

lead"[tw] OR "Orangemennige"[tw] OR "Paris Red"[tw] OR "PbSO4"[tw] OR "Perlex paste 

500"[tw] OR "Perlex paste 600A"[tw] OR "Phoenicochroite"[tw] OR "Phosphoric acid, lead 

salt"[tw] OR "Phosphoric acid, lead(2+) salt (2:3)"[tw] OR "Pigment Red 105"[tw] OR 

"Pigment White 3"[tw] OR "Pigment Yellow 34"[tw] OR "Pigment Yellow 46"[tw] OR 

"Plumbane"[tw] OR "Plumbi"[tw] OR "Plumbic oxide"[tw] OR "Plumboplumbic oxide"[tw] 

OR "Plumbous"[tw] OR "Plumbum"[tw] OR "Red lead"[tw] OR "Resorcinol, 2,4,6-trinitro-, 

lead(2+) salt (1:1)"[tw] OR "Rough lead bullion"[tw] OR "Royal Yellow 6000"[tw] OR "Salt of 

saturn"[tw] OR "Sandix"[tw] OR "Saturn red"[tw] OR "Sugar of lead"[tw] OR "Sulfuric acid, 

lead(2+) salt"[tw] OR "Tetra Ethylene Lead"[tw] OR "Tetra(methylethyl)lead"[tw] OR 

"Tetraethyl lead"[tw] OR "Tetraethyl plumbane"[tw] OR "Tetraethyllead"[tw] OR 

"Tetraethyllead, liquid"[tw] OR "tetraethylplomb"[tw] OR "Tetraethylplombane"[tw] OR 

"Tetraethylplumbane"[tw] OR "tetraetilplomo"[tw] OR "Thiolead A"[tw] OR "Tricinat"[tw] OR 

"Trilead bis(orthophosphate)"[tw] OR "Trilead phosphate"[tw] OR "Trilead tetraoxide"[tw] 

OR "Trilead tetroxide"[tw] OR "Unichem PBA"[tw] OR "Yellow lead ocher"[tw]) NOT 

medline[sb]) AND (2016/02/01 : 3000[crdt] OR 2016/02/01 : 3000[edat] OR 2015/02/01 : 

3000[dp])))) OR (((("Lead"[ti] NOT "lead to"[ti]) OR "Pb"[ti] OR "PbS"[ti] OR "PbO"[ti]) NOT 

medline[sb]) AND (2016/02/01 : 3000[crdt] OR 2016/02/01 : 3000[edat] OR 2015/02/01 : 

3000[dp]))

Toxline

09/2019 Date limit: 2015 to present:

(10031-22-8[rn] OR 10099-74-8[rn] OR 10101-63-0[rn] OR 11119-70-3[rn] OR 12709-98-

7[rn] OR 1309-60-0[rn] OR 1314-41-6[rn] OR 1314-87-0[rn] OR 1317-36-8[rn] OR 13424-

46-9[rn] OR 13814-96-5[rn] OR 15245-44-0[rn] OR 16040-38-3[rn] OR 39377-56-5[rn] OR 

598-63-0[rn] OR 7439-92-1[rn] OR 7446-14-2[rn] OR 7446-27-7[rn] OR 7758-95-4[rn] OR 

7758-97-6[rn] OR 78-00-2[rn]) AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR 

DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP [org] OR HMTC [org] OR IPA [org] 

OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] 

OR PPBIB [org] )

("1,3-Benzenediol, 2,4,6-trinitro-, lead(2+) salt (1:1)" OR "Acetic acid lead(2+) salt" OR 

"Acetic acid, lead salt" OR "Acetic acid, lead(2 +) salt" OR "Acetic acid, lead(2+) salt" OR 

"Anglislite" OR "Azarcon" OR "Borate(1-), tetrafluoro-, lead (2+)" OR "Borate(1-), 

tetrafluoro-, lead(2+) (2:1)" OR "C.I. Pigment Metal 4" OR "C.I. Pigment Yellow 46" OR 

"CARBONIC ACID, LEAD SALT (1:1)" OR "Carbonic acid, lead salt (2+) (1:1)") AND ( 

ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM 
LEAD B-7

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

[org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] 

OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

("Carbonic acid, lead(2+) salt" OR "Cerussete" OR "Cerussite" OR "Chrome Orange" OR 

"Chrome Yellow" OR "Chromic acid (H2CrO4), lead(2+) salt (1:1)" OR "Chromic acid lead 

salt " OR "CHROMIC ACID, LEAD (2+) SALT (1:1)" OR "Chromic Acid, Lead (II) Salt (1:1)" 

OR "Chromic acid, lead and molybdenum salt" OR "Chromic acid, lead salt" OR "Chromic 

acid, lead(2+) salt (1:1)" OR "Chromium lead molybdenum oxide") AND ( ANEUPL [org] 

OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP 

[org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] 

OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

("Chromium lead oxide" OR "CI pigment metal 4" OR "CI Pigment Yellow 46" OR "Collodial 

lead phosphate" OR "Dibasic lead acetate" OR "Dibasic lead carbonate" OR "Dibasic lead 

sulfate" OR "Entan" OR "Fast White" OR "Flowsperse R 12" OR "Freemans White Lead" 

OR "Galena" OR "Glover" OR "Gold Satinobre" OR "Heuconin 5" OR "Lead (II) carbonate" 

OR "Lead (II) chloride" OR "Lead (II) chromate" OR "Lead (II) iodide" OR "Lead (II) nitrate" 

OR "Lead (II) oxide" OR "Lead (II) sulfate" OR "Lead (II) sulfide") AND ( ANEUPL [org] OR 

BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP 

[org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] 

OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

("Lead (II,IV) oxide" OR "Lead (IV) oxide " OR "Lead 2,4,6-trinitro-m-phenylene dioxide" 

OR "Lead acetate" OR "Lead azide" OR "Lead bis(tetrafluoroborate)" OR "Lead 

borofluoride" OR "Lead boron fluoride" OR "Lead Bottoms" OR "Lead bromide" OR "Lead 

brown" OR "Lead carbonate" OR "Lead chloride" OR "Lead chromate" OR "Lead 

chromate(VI)" OR "Lead chromium oxide (PbCrO4)" OR "Lead di(acetate)") AND ( 

ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM 

[org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] 

OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

("Lead diacetate" OR "Lead diazide" OR "Lead dibasic acetate" OR "Lead dibromide" OR 

"Lead dichloride" OR "Lead diiodide" OR "Lead dinitrate" OR "Lead dioxide" OR "Lead 

element" OR "Lead flake" OR "Lead fluoborate" OR "Lead fluoroborate" OR "Lead iodide" 

OR "Lead metal" OR "Lead molybdate chromate" OR "Lead molybdenum chromate" OR 

"Lead monooxide" OR "Lead monosulfate" OR "Lead monosulfide") AND ( ANEUPL [org] 

OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP 

[org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] 

OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

("Lead monoxide" OR "Lead nitrate" OR "Lead orthophosphate" OR "Lead orthoplumbate" 

OR "Lead oxide" OR "Lead peroxide" OR "Lead phosphate" OR "Lead protoxide" OR 

"Lead S 2" OR "Lead S2" OR "Lead styphnate" OR "Lead sulfate" OR "Lead sulfide" OR 

"Lead sulphate" OR "Lead sulphide" OR "Lead superoxide" OR "Lead tetraethide" OR 

"Lead tetraethyl" OR "Lead tetrafluoroborate" OR "Lead tetraoxide") AND ( ANEUPL [org] 

OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP 

[org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] 

OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

("Lead tetroxide" OR "Lead tricinate" OR "Lead trinitroresorcinate" OR "Lead(+2) sulfate" 

OR "Lead(2+) acetate" OR "Lead(2+) azide" OR "Lead(2+) bis(nitrate)" OR "Lead(2+) 

bromide" OR "Lead(2+) carbonate" OR "Lead(2+) chloride" OR "Lead(2+) nitrate" OR 

"Lead(2+) oxide" OR "Lead(2+) phosphate" OR "Lead(2+) phosphate (Pb3(PO4)2)" OR 

"Lead(2+) salt carbamic acid (1:1) " OR "Lead(2+) sulfate") AND ( ANEUPL [org] OR 

BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP 
LEAD B-8

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

[org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] 

OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

("Lead(2+) sulfide" OR "Lead(II) acetate" OR "Lead(II) azide" OR "Lead(II) bromide" OR 

"Lead(II) carbonate" OR "Lead(II) chloride" OR "Lead(II) chromate" OR "Lead(II) dinitrate" 

OR "Lead(II) iodide" OR "Lead(II) nitrate" OR "Lead(II) oxide" OR "Lead(II) phosphate" OR 

"Lead(II) phosphate (3:2)" OR "Lead(II) styphnate" OR "Lead(II) sulfate" OR "Lead(II) 

sulfide" OR "Lead(II) tetrafluoroborate" OR "Lead(IV) oxide") AND ( ANEUPL [org] OR 

BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP 

[org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] 

OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

("Lead, elemental" OR "Lead, inorganic" OR "Lead, tetraethyl" OR "Lead, tetraethyl-" OR 

"Lead-molybdenum chromate" OR "Litharge" OR "Massicot" OR "Massicotite" OR 

"Mennige" OR "Milk White" OR "mine orange" OR "Mineral Orange" OR "Mineral red" OR 

"minio anaranjado" OR "Minium" OR "Molybdenum-lead chromate" OR "Mulhouse White" 

OR "Nitric acid lead(2+) salt" OR "Nitric acid, lead(2+) salt") AND ( ANEUPL [org] OR 

BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP 

[org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] 

OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

("Orange lead" OR "Orangemennige" OR "Paris Red" OR "PbSO4" OR "Perlex paste 500" 

OR "Perlex paste 600A" OR "Phoenicochroite" OR "Phosphoric acid, lead salt" OR 

"Phosphoric acid, lead(2+) salt (2:3)" OR "Pigment Red 105" OR "Pigment White 3" OR 

"Pigment Yellow 34" OR "Pigment Yellow 46" OR "Plumbane" OR "Plumbi" OR "Plumbic 

oxide" OR "Plumboplumbic oxide" OR "Plumbous" OR "Plumbum") AND ( ANEUPL [org] 

OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP 

[org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] 

OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

("Red lead" OR "Resorcinol, 2,4,6-trinitro-, lead(2+) salt (1:1)" OR "Rough lead bullion" OR 

"Royal Yellow 6000" OR "Salt of saturn" OR "Sandix" OR "Saturn red" OR "Sugar of lead" 

OR "Sulfuric acid, lead(2+) salt" OR "Tetra Ethylene Lead" OR "Tetra(methylethyl)lead" 

OR "Tetraethyl lead" OR "Tetraethyl plumbane" OR "Tetraethyllead" OR "Tetraethyllead, 

liquid" OR "tetraethylplomb") AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR 

DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP [org] OR HMTC [org] OR IPA [org] 

OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] 

OR PPBIB [org] )

("Tetraethylplombane" OR "Tetraethylplumbane" OR "tetraetilplomo" OR "Thiolead A" OR 

"Tricinat" OR "Trilead bis(orthophosphate)" OR "Trilead phosphate" OR "Trilead tetraoxide" 

OR "Trilead tetroxide" OR "Unichem PBA" OR "Yellow lead ocher") AND ( ANEUPL [org] 

OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP 

[org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] 

OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

Term searched as exact words:

"lead" AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] 

OR EPIDEM [org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR 

MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )

Date limit: 2013 to present:

"Plumbism" OR "saturnism" OR "colica pictorum" OR "Devon colic" OR "painter's colic"

Toxcenter

09/2019 L1 8918 SEA 10031-22-8 OR 10099-74-8 OR 10101-63-0 OR 11119-70-3 OR 
LEAD B-9

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

 12709-98-7 OR 1309-60-0 OR 1314-41-6 OR 1314-87-0 OR 1317-36-8 

 OR 13424-46-9 

L2 239150 SEA 13814-96-5 OR 15245-44-0 OR 16040-38-3 OR 301-04-2 OR 

 39377-56-5 OR 598-63-0 OR 7439-92-1 OR 7446-14-2 OR 7446-27-7 

 OR 7758-95-4 OR 7758-97-6 OR 78-00-2 

L3 244612 SEA L1 OR L2 

L4 244408 SEA L3 NOT TSCATS/FS 

L5 225905 SEA L4 NOT PATENT/DT 

L6 26519 SEA L5 AND ED>=20160201 

 ACT TOXQUERY/Q

 ---------

L7 QUE (CHRONIC OR IMMUNOTOX? OR NEUROTOX? OR TOXICOKIN? OR 

 BIOMARKER? OR NEUROLOG?) 

L8 QUE (PHARMACOKIN? OR SUBCHRONIC OR PBPK OR EPIDEMIOLOGY/ST,CT,

 IT) 

L9 QUE (ACUTE OR SUBACUTE OR LD50# OR LD(W)50 OR LC50# OR 

 LC(W)50) 

L10 QUE (TOXICITY OR ADVERSE OR POISONING)/ST,CT,IT 

L11 QUE (INHAL? OR PULMON? OR NASAL? OR LUNG? OR RESPIR?) 

L12 QUE ((OCCUPATION? OR WORKPLACE? OR WORKER?) AND EXPOS?) 

L13 QUE (ORAL OR ORALLY OR INGEST? OR GAVAGE? OR DIET OR DIETS OR 

 DIETARY OR DRINKING(W)WATER?) 

L14 QUE (MAXIMUM AND CONCENTRATION? AND (ALLOWABLE OR PERMISSIBLE))

L15 QUE (ABORT? OR ABNORMALIT? OR EMBRYO? OR CLEFT? OR FETUS?) 

L16 QUE (FOETUS? OR FETAL? OR FOETAL? OR FERTIL? OR MALFORM? OR 

 OVUM?) 

L17 QUE (OVA OR OVARY OR PLACENTA? OR PREGNAN? OR PRENATAL?) 

L18 QUE (PERINATAL? OR POSTNATAL? OR REPRODUC? OR STERIL? OR 

 TERATOGEN?) 

L19 QUE (SPERM OR SPERMAC? OR SPERMAG? OR SPERMATI? OR SPERMAS? OR 

 SPERMATOB? OR SPERMATOC? OR SPERMATOG?) 

L20 QUE (SPERMATOI? OR SPERMATOL? OR SPERMATOR? OR SPERMATOX? OR 

 SPERMATOZ? OR SPERMATU? OR SPERMI? OR SPERMO?) 

L21 QUE (NEONAT? OR NEWBORN? OR DEVELOPMENT OR DEVELOPMENTAL?) 

L22 QUE (ENDOCRIN? AND DISRUPT?) 

L23 QUE (ZYGOTE? OR CHILD OR CHILDREN OR ADOLESCEN? OR INFANT?) 

L24 QUE (WEAN? OR OFFSPRING OR AGE(W)FACTOR?) 

L25 QUE (DERMAL? OR DERMIS OR SKIN OR EPIDERM? OR CUTANEOUS?) 

L26 QUE (CARCINOG? OR COCARCINOG? OR CANCER? OR PRECANCER? OR 

 NEOPLAS?) 

L27 QUE (TUMOR? OR TUMOUR? OR ONCOGEN? OR LYMPHOMA? OR CARCINOM?) 

L28 QUE (GENETOX? OR GENOTOX? OR MUTAGEN? OR GENETIC(W)TOXIC?) 

L29 QUE (NEPHROTOX? OR HEPATOTOX?) 

L30 QUE (ENDOCRIN? OR ESTROGEN? OR ANDROGEN? OR HORMON?) 

L31 QUE (OCCUPATION? OR WORKER? OR WORKPLACE? OR EPIDEM?) 

L32 QUE L7 OR L8 OR L9 OR L10 OR L11 OR L12 OR L13 OR L14 OR L15 

 OR L16 OR L17 OR L18 OR L19 OR L20 OR L21 OR L22 OR L23 OR L24 

 OR L25 OR L26 OR L27 OR L28 OR L29 OR L30 OR L31

L33 QUE (RAT OR RATS OR MOUSE OR MICE OR GUINEA(W)PIG? OR MURIDAE 

 OR DOG OR DOGS OR RABBIT? OR HAMSTER? OR PIG OR PIGS OR SWINE 

 OR PORCINE OR MONKEY? OR MACAQUE?) 

L34 QUE (MARMOSET? OR FERRET? OR GERBIL? OR RODENT? OR LAGOMORPHA 

 OR BABOON? OR CANINE OR CAT OR CATS OR FELINE OR MURINE) 

L35 QUE L32 OR L33 OR L34 

L36 QUE (HUMAN OR HUMANS OR HOMINIDAE OR MAMMALS OR MAMMAL? OR 
LEAD B-10

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

 PRIMATES OR PRIMATE?) 

L37 QUE L35 OR L36 

 ---------

L38 14067 SEA L6 AND L37 

L39 2663 SEA L38 AND MEDLINE/FS 

L40 4980 SEA L38 AND BIOSIS/FS 

L41 6411 SEA L38 AND CAPLUS/FS 

L42 13 SEA L38 NOT (L39 OR L40 OR L41) 

L43 11438 DUP REM L39 L40 L42 L41 (2629 DUPLICATES REMOVED)

 ANSWERS '1-11438' FROM FILE TOXCENTER

L*** DEL 2663 S L38 AND MEDLINE/FS

L*** DEL 2663 S L38 AND MEDLINE/FS

L44 2663 SEA L43 

L*** DEL 4980 S L38 AND BIOSIS/FS

L*** DEL 4980 S L38 AND BIOSIS/FS

L45 3952 SEA L43 

L*** DEL 6411 S L38 AND CAPLUS/FS

L*** DEL 6411 S L38 AND CAPLUS/FS

L46 4810 SEA L43 

L*** DEL 13 S L38 NOT (L39 OR L40 OR L41)

L*** DEL 13 S L38 NOT (L39 OR L40 OR L41)

L47 13 SEA L43 

L48 8775 SEA (L44 OR L45 OR L46 OR L47) NOT MEDLINE/FS 

 SAVE TEMP L48 LEAD/A

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

TSCATS via 

ChemView

09/2019 Compounds searched: 10031-22-8; 10099-74-8; 10101-63-0; 11119-70-3; 

12709-98-7; 1309-60-0; 1314-41-6; 1314-87-0; 1317-36-8; 13424-46-9; 13814-

96-5; 15245-44-0; 16040-38-3; 301-04-2; 39377-56-5; 598-63-0; 7439-92-1; 

7446-14-2; 7446-27-7; 7758-95-4; 7758-97-6; 78-00-2

NTP

09/2019 NTP Site Search (http://ntpsearch.niehs.nih.gov/home), date limit 2015 to 

present:

"10031-22-8" "10099-74-8" "10101-63-0" "11119-70-3" 

"12709-98-7" "1309-60-0" "1314-41-6" "1314-87-0" 

"1317-36-8" "13424-46-9" "13814-96-5" "15245-44-0" 

"16040-38-3" "301-04-2" "39377-56-5" "598-63-0" 

"7439-92-1" "7446-14-2" "7446-27-7" "7758-95-4" 

"7758-97-6" "78-00-2"

Limited to content types reports & publications; systematic reviews; ROC 

profiles, reviews, or candidates; or testing status, date limit 2015 to present:

"lead"

Regulations.gov

10/2019 Compounds searched: 10031-22-8; 10099-74-8; 10101-63-0; 11119-70-3; 

12709-98-7; 1309-60-0; 1314-41-6; 1314-87-0; 1317-36-8; 13424-46-9; 13814-
LEAD B-11

APPENDIX B

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

96-5; 15245-44-0; 16040-38-3; 301-04-2; 39377-56-5; 598-63-0; 7439-92-1; 

7446-14-2; 7446-27-7; 7758-95-4; 7758-97-6; 78-00-2

NIH RePORTER

01/2020 Search in: Projects AdminIC: All, Fiscal Year: Active Projects Text Search 

(Advanced):

"1,3-Benzenediol, 2,4,6-trinitro-, lead" OR "Acetic acid lead " OR "Acetic acid, 

lead salt" OR "Acetic acid, lead " OR "Acetic acid, lead " OR "Anglislite" OR 

"Azarcon" OR "Borate(1-), tetrafluoro-, lead" OR "Borate(1-), tetrafluoro-, lead" 

OR "C.I. Pigment Metal 4" OR "C.I. Pigment Yellow 46" OR "CARBONIC ACID, 

LEAD SALT" OR "Carbonic acid, lead salt" OR "Carbonic acid, lead" OR 

"Cerussete" OR "Cerussite" OR "Chrome Orange" OR "Chrome Yellow" OR 

"Chromic acid (H2CrO4), lead" OR "Chromic acid lead salt " OR "CHROMIC 

ACID, LEAD" OR "Chromic Acid, Lead (II) Salt" OR "Chromic acid, lead and 

molybdenum salt" OR "Chromic acid, lead salt" OR "Chromic acid, lead" OR 

"Chromium lead molybdenum oxide" OR "Chromium lead oxide" OR "CI 

pigment metal 4" OR "CI Pigment Yellow 46" OR "Collodial lead phosphate" OR 

"Dibasic lead acetate" OR "Dibasic lead carbonate" OR "Dibasic lead sulfate" 

OR "Entan" OR "Fast White" OR "Flowsperse R 12" OR "Freemans White 

Lead" OR "Galena" OR "Glover" OR "Gold Satinobre" OR "Heuconin 5" OR 

"Lead (II) carbonate" OR "Lead (II) chloride" OR "Lead (II) chromate" OR "Lead 

(II) iodide" OR "Lead (II) nitrate" OR "Lead (II) oxide" OR "Lead (II) sulfate" OR 

"Lead (II) sulfide" OR "Lead (II, IV) oxide" OR "Lead (IV) oxide " OR "Lead 

2,4,6-trinitro-m-phenylene dioxide" OR "Lead acetate" OR "Lead azide" OR 

"Lead bis(tetrafluoroborate)" OR "Lead borofluoride" OR "Lead boron fluoride" 

OR "Lead Bottoms" OR "Lead bromide" OR "Lead brown" OR "Lead carbonate" 

OR "Lead chloride" OR "Lead chromate" OR "Lead chromate(VI)" OR "Lead 

chromium oxide (PbCrO4)" OR "Lead di(acetate)" OR "Lead diacetate" OR 

"Lead diazide" OR "Lead dibasic acetate" OR "Lead dibromide" OR "Lead 

dichloride" OR "Lead diiodide" OR "Lead dinitrate" OR "Lead dioxide" OR "Lead 

element" OR "Lead flake" OR "Lead fluoborate" OR "Lead fluoroborate" OR 

"Lead iodide" OR "Lead metal" OR "Lead molybdate chromate" OR "Lead 

molybdenum chromate" OR "Lead monooxide" OR "Lead monosulfate" OR 

"Lead monosulfide" OR "Lead monoxide" OR "Lead nitrate" OR "Lead 

orthophosphate" OR "Lead orthoplumbate" OR "Lead oxide" OR "Lead 

peroxide" OR "Lead phosphate" OR "Lead protoxide" OR "Lead S 2" OR "Lead 

S2" OR "Lead styphnate" OR "Lead sulfate" OR "Lead sulfide" OR "Lead 

sulphate" OR "Lead sulphide" OR "Lead superoxide" OR "Lead tetraethide" OR 

"Lead tetraethyl"

"Lead tetrafluoroborate" OR "Lead tetraoxide" OR "Lead tetroxide" OR "Lead 

tricinate" OR "Lead trinitroresorcinate" OR "Lead(II) acetate" OR "Lead(II) 

azide" OR "Lead(II) bromide" OR "Lead(II) carbonate" OR "Lead(II) chloride" 

OR "Lead(II) chromate" OR "Lead(II) dinitrate" OR "Lead(II) iodide" OR

"Lead(II) nitrate" OR "Lead(II) oxide" OR "Lead(II) phosphate" OR "Lead(II) 

phosphate" OR "Lead(II) styphnate" OR "Lead(II) sulfate" OR "Lead(II) sulfide" 

OR "Lead(II) tetrafluoroborate" OR "Lead(IV) oxide" OR "Lead, elemental" OR 

"Lead, inorganic" OR "Lead, tetraethyl" OR "Lead, tetraethyl-" OR "Leadmolybdenum chromate" OR "Litharge" OR "Massicot" OR "Massicotite" OR 

"Mennige" OR "Milk White" OR "mine orange" OR "Mineral Orange" OR 

"Mineral red" OR "minio anaranjado" OR "Minium" OR "Molybdenum-lead 

chromate" OR "Mulhouse White" OR "Nitric acid lead" OR "Nitric acid, lead" OR 

"Orange lead" OR "Orangemennige" OR "Paris Red" OR "PbSO4" OR "Perlex 
LEAD B-12

APPENDIX B

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

paste 500" OR "Perlex paste 600A" OR "Phoenicochroite" OR "Phosphoric 

acid, lead salt" OR "Phosphoric acid, lead" OR "Pigment Red 105" OR "Pigment 

White 3" OR "Pigment Yellow 34" OR "Pigment Yellow 46" OR "Plumbane" OR 

"Plumbi" OR "Plumbic oxide" OR "Plumboplumbic oxide" OR "Plumbous" OR 

"Plumbum" OR "Red lead" OR "Resorcinol, 2,4,6-trinitro-, lead" OR "Rough 

lead bullion" OR "Royal Yellow 6000" OR "Salt of saturn" OR "Sandix" OR 

"Saturn red" OR "Sugar of lead" OR "Sulfuric acid, lead" OR "Tetra Ethylene 

Lead" OR "Tetra(methylethyl)lead" OR "Tetraethyl lead" OR "Tetraethyl 

plumbane" OR "Tetraethyllead" OR "Tetraethyllead, liquid" OR 

"tetraethylplomb" OR "Tetraethylplombane" OR "Tetraethylplumbane" OR 

"tetraetilplomo" OR "Thiolead A" OR "Tricinat" OR "Trilead bis(orthophosphate)" 

OR "Trilead phosphate" OR "Trilead tetraoxide" OR "Trilead tetroxide" OR 

"Unichem PBA" OR "Yellow lead ocher" OR "Lead(2) sulfate" OR "Lead(2) 

acetate" OR "Lead(2) azide" OR "Lead(2) bis(nitrate)" OR "Lead(2) bromide" 

OR "Lead(2) carbonate" OR "Lead(2) chloride" OR "Lead(2) nitrate" OR 

"Lead(2) oxide" OR "Lead(2) phosphate" OR "Lead(2) phosphate (Pb3(PO4)2)" 

OR "Lead(2) salt carbamic acid" OR "Lead(2) sulfate" OR "Lead(2) sulfide"

"lead poisoning" OR "Plumbism" OR "saturnism" OR "colica pictorum" OR 

"Devon colic" OR "painter's colic"

"blood lead"

Search in: Projects Limit to: Project Title, AdminIC: All, Fiscal Year: Active 

Projects Text Search (Advanced): 

"lead" not ("lead academic" or "lead optimization")

Other Identified throughout the assessment process

The 2019 results were: 

• Number of records identified from PubMed, TOXLINE, and TOXCENTER (after duplicate 

removal): 15,240

• Number of records identified from other strategies: 107

• Total number of records to undergo literature screening: 15,347

B.1.2 Literature Screening 

A two-step process was used to screen the literature search to identify relevant studies on Pb: 

• Title and abstract screen

• Full text screen

Title and Abstract Screen. Within the reference library, titles and abstracts were screened manually for 

relevance. Studies that were considered relevant (see Table B-1 for inclusion criteria) were moved to the 

second step of the literature screening process. Studies were excluded when the title and abstract clearly 

indicated that the study was not relevant to the toxicological profile. 

• Number of titles and abstracts screened: 388

• Number of studies considered relevant and moved to the next step: 388
LEAD B-13

APPENDIX B

Full Text Screen. The second step in the literature screening process was a full text review of individual 

studies considered relevant in the title and abstract screen step. Each study was reviewed to determine 

whether it was relevant for inclusion in the toxicological profile. 

• Number of studies undergoing full text review: 388 

• Number of studies cited in the pre-public draft of the toxicological profile: 1,589 

• Total number of studies cited in the profile: 1,803 

A summary of the results of the literature search and screening is presented in Figure B-1. 

Figure B-1. September 2019 Literature Search Results and Screen for Lead (Pb)
LEAD C-1

APPENDIX C. INGESTION OF LEAD DEBRIS

The main focus of this ATSDR Toxicological Profile for Lead is on health effects of chronic low-level 

environmental exposures. The profile also provides information on the clinical presentation of acute Pb 

toxicity, which occurs when large amounts of Pb are ingested. In children, this often occurs through 

ingestion of paint chips containing Pb, Pb-contaminated soils, or other non-solid forms of Pb. Ingestion 

of solid forms of Pb (Pb debris) is a unique exposure scenario in which there is accidental or purposeful 

ingestion of visible debris containing Pb. This exposure may be acute (debris is expelled or removed 

from the body soon after ingestion) or chronic (Pb debris is retained within the body, leading to continued 

elevation in PbB). There are several sources of Pb debris, including Pb shot or other debris found at 

firing or artillery ranges, or Pb shot found in wild game meats. The information presented below reviews 

toxicokinetics and adverse health effects of ingested Pb debris. Information regarding the chemistry, fate, 

and transport of Pb debris is reviewed in Chapter 5. It should also be noted that in addition to ingestion of 

Pb debris, retained Pb shot or shrapnel, especially in military personnel, could contribute to elevated PbB 

(Gerhardsson et al. 2002; McQuirter et al. 2004); this possibility should be considered in individuals as 

appropriate.

Overview. No controlled studies in humans have evaluated bioavailability or toxicity of ingested Pb 

debris (e.g., Pb shot and other Pb-containing debris from artillery or shooting ranges). Available 

information is anecdotal, obtained from case reports. Thus, data are not sufficient to determine the 

bioavailability of ingested Pb debris or to develop dose-response relationships for toxicity. Case reports 

of acute exposures from ingestion of Pb debris are summarized in Table C-1; these reports demonstrate 

the following:

• PbB rises rapidly (within hours to a few days) following ingestion of Pb debris.

• The clinical presentation of toxicity following ingestion of Pb debris is the same as that observed 

for acute Pb poisoning from ingestion of other forms of Pb (see Section 2.2).

• Severity of toxicity of ingested Pb debris will depend upon how much Pb is absorbed 

(e.g., toxicity is related to PbB; see Section 2.2). 

• The onset of toxicity can be rapid (within hours to a few days).

• Following removal of Pb debris from the body, PbBs decrease; however, applying clinical 

protocols for chelation therapy results in a more rapid decrease in PbB.

• Ingested Pb debris can be retained in the appendix of some individuals and continue to contribute 

to elevated PbB.
LEAD C-2

APPENDIX C

Table C-1. Selected Case Studies of Ingestion of Solid Lead (Pb) Debris or Pb Retained in Gunshot Wounds

Reference and exposure

Blood lead concentration (PbB) 

(μg/dL) Effects Treatment

Banner et al. 2012

A 15-year-old boy ingested a “handful” of 

Pb shot. He was admitted to the hospital 

for treatment 14 days after exposure.

• Post-ingestion

o 8 days: 54

o 14 days: 41

• Post-treatment (2 weeks): <5

• Most Pb was located in the 

appendix (14 days postingestion)

• Abdominal pain

• Elevated free erythrocyte 

protoporphyrin

• Whole bowel irrigation

• Appendectomy

• Chelation

CDC 2006

A 4-year-old boy with previously diagnosed 

microcephaly and mental delays ingested 

a metallic charm containing Pb. Time from 

exposure to first medical visit was not 

reported.

At death: 180 • Charm was retained in the 

stomach (was not removed)

• Intractable vomiting

• Cerebral edema

• Seizures

• Death

Supportive therapy

Clifton et al. 2002

A 21-month-old girl ingested Pb BB pellets. 

She was taken to the hospital 

approximately 6 hours post-ingestion.

• Pre-ingestion (routine): 12

• Post-ingestion (6 hours): 47

• Post-removal of pellets: 25

• Post-treatment (10 days): 16

• Hyperactivity

• No signs of neurological or 

gastrointestinal toxicity

• Bowel irrigation

• Colonoscopy for 

removal of pellets

• Chelation

Cox and Pesola 2005

A 73-year-old woman ingested Pb shot in 

game over decades.

Not reported • Pb shot accumulated in the 

appendix

• No information on adverse 

health effects was reported

Not reported

Durlach et al. 1986

A 30-year-old man ingested Pb shot in 

game regularly over an unspecified period 

of time.

• At initial examination: 67.4

• Post-treatment 

o 10 days: 52.2

o 13 days: 24.5

o 1 month: 36.8

o 1.5 months: 31.6

• Pb shot accumulated in the 

appendix

• Acute abdominal pain

• Bowel irritation

• Chelation

• Appendectomy
LEAD C-3

APPENDIX C

Table C-1. Selected Case Studies of Ingestion of Solid Lead (Pb) Debris or Pb Retained in Gunshot Wounds

Reference and exposure

Blood lead concentration (PbB) 

(μg/dL) Effects Treatment

Fergusson et al. 1997

A 4-year-old girl ingested a Pb fishing 

sinker. She was evaluated in the 

emergency room within 1 hour of 

ingestion.

• Day of ingestion: 4

• Day after ingestion: 16

No signs of toxicity observed Endoscopy

Gerhardsson et al. 2002

A man in his “late 40s” had retained Pb 

shot following a gunshot wound to the 

shoulder. Reconstructive surgery occurred 

54 days post-accident. Some, but not all, 

of the Pb shot was removed during 

surgery.

Approximate (data presented 

graphically), time after accident:

• 25 days: 28

• 50 days: 41

• 54 days (day of surgery): 55

• ~60 days: 31

• 75 days: 48

• 200 days: 36

• 375 days: 30

• No signs of toxicity observed

• Not all of the Pb shot could be 

removed during surgery

Surgical removal of Pb 

pellets

Guillard et al. 2006

A 2-year-old boy ingested toy money made 

from pure metallic Pb.

Time post-ingestion

• 1 day: 31.3

• 8 days: 61.1

• 1 month: 30.0

• 4 months: 24.9

• 10 months: 9.9

• Development of microcytic 

anemia and increased blood 

zinc protoporphyrin

• No signs of toxicity observed

• Removal of object 

• Chelation (8 days 

post-ingestion)

Gustavsson and Gerhardsson 2005

A 45-year-old woman with elevated PbB 

was found to have Pb shot in her intestine 

from ingestion of game. The Pb shot was 

spontaneously eliminated. Time from 

ingestion was estimated to be sometime 

between 1993 and 2001.

Time of assessment:

• January 2002: 55.0

• April 2003 (2 months postelimination): 34.5

• November 2003: 7.2

• Malaise and fatigue

• “Diffuse gastrointestinal 

symptoms”

No treatment (object was 

spontaneously eliminated)
LEAD C-4

APPENDIX C

Table C-1. Selected Case Studies of Ingestion of Solid Lead (Pb) Debris or Pb Retained in Gunshot Wounds

Reference and exposure

Blood lead concentration (PbB) 

(μg/dL) Effects Treatment

Hatten et al. 2013

• Case 1: A 15-year-old boy ingested 

rifle cartridges approximately 1 month 

prior to evaluation.

• Case 2: A 65-year-old woman 

ingested several handfuls of bullets.

Case 1

• Initial assessment: 146

• 19 days post-treatment: 53

• 3 months post-treatment: 38

Case 1

• Decreased activity level

• Vomiting, diarrhea, anorexia

• Hyperactive patellar and 

brachioradialis reflexes 

Case 1

• Cartridges removed 

by endoscopy

• Chelation

Case 2: Days after ingestion

• Day 1: 9.7

• Day 2: 25.7

• Day 3: 40.5

• Day 60: 17.2

Case 2

• No signs of toxicity were 

observed

Case 2

• Endoscopy

Larsen and Blanton 2000

A 9-year-old boy ingested Pb shot in 

game; the Pb shot was retained in the 

appendix.

Not reported • Abdominal pain and anorexia Appendectomy

Lyons and Filston 1994

A 4-year-old boy ingested Pb shot, which 

was lodged in his appendix. 

• Peak (time of assessment not 

reported): 23

• Prior to surgery (1.5 months after 

ingestion): 12

• Abdominal discomfort, nausea, 

vomiting, diarrhea 

• Headache

Appendectomy

Madsen et al. 1988

Seven patients with Pb shot retained in the 

appendix.

Range: 4.6–18.2 Not reported Not reported

McKinney and McKinney 2000

A 5.5-year-old girl ingested several Pb 

pellets.

Time after ingestion

• 13 hours: 57

• 36 hours: 79

After treatment: 

• 14 days: 14.3

• 6 months: 25

• Vomiting and abdominal pain

• Decreased blood hemoglobin 

and hematocrit

• “Mild” speech and language 

delays noted post-treatment

• Whole bowel irrigation

• Chelation
LEAD C-5

APPENDIX C

Table C-1. Selected Case Studies of Ingestion of Solid Lead (Pb) Debris or Pb Retained in Gunshot Wounds

Reference and exposure

Blood lead concentration (PbB) 

(μg/dL) Effects Treatment

McNutt et al. 2001

A 45-year-old male ingested 206 Pb 

bullets. Medical evaluation occurred 

5 days after ingestion. Bullets were 

spontaneously eliminated over 4–47 days 

after first medical evaluation.

Time after ingestion:

• 5 days: 391

• 10 days: 171

• 25 days: 41

• 6 weeks: 24

• Abdominal pain and 

gastrointestinal bleeding

• Anemia

Chelation started at initial 

medical visit

McQuirter et al. 2004

Subjects (n=451) 1-year following gunshot 

wound with retained bullets.

• PbB at time after injury: 1.9

• % with PbB ≥10 (days after injury)

o 0 days: 2.1

o 3 days: 7.6

o 18 days: 25.1

o 3 months: 38.1

o 6 months: 28.5 

o 12 months: 15.8

Not reported Not reported

CDC 2004a

A 4-year-old boy ingested a Pb medallion.

• 2–3 weeks after ingestion: 123

• After treatment: 57

• Abdominal pain, vomiting, 

diarrhea

• Normocytic anemia, elevated 

protoporphyrin

• Endoscopy

• Chelation

Mowad et al. 1998

An 8-year-old boy ingested several Pb 

fishing sinkers. Medical assessment was 

within 1 days of ingestion.

Time after ingestion:

• 1 day: 53

• 6 days: 45 (start of chelation)

• 1 month: 3

No signs of toxicity observed • Bowel irrigation

• Colonoscopy

• Chelation

Rosenberg and Haynes 2019

A 3-year-old ingested Pb pellets.

Time after ingestion:

• 7 days: 27

• Post-surgical removal: 14

Not reported Laproscopic removal of 

pellets
LEAD C-6

APPENDIX C

Table C-1. Selected Case Studies of Ingestion of Solid Lead (Pb) Debris or Pb Retained in Gunshot Wounds

Reference and exposure

Blood lead concentration (PbB) 

(μg/dL) Effects Treatment

Rozier and Liebelt 2019

A 2-year-old boy, a 10-year-old boy, and a 

16-year old girl ingested Pb pellets.

2-year-old boy, PbB measurement:

• Day 0: 65

• 5 days post-chelation: 25.2

10-year-old boy, PbB measurement:

• 3 days post-ingestion: 70

• 7 months post-chelation: 9.5

16-year old girl, PbB measurement:

• 9 days post-ingestion: 53

• 13 days post-treatment: 3

• 5 weeks post-treatment: 13

2-year-old boy: asymptomatic

10-year-old boy: not reported

16-year old girl: 

• abdominal pain

• shortness of breath

2-year-old boy

• Bowel irrigation

• Chelation

10-year-old boy

• Bowel irrigation

• Chelation

16-year old girl

• Bowel irrigation

• Chelation

• Colonoscopy

Treble and Thompson 2002

A 2.5-year-old girl ingested Pb pellets.

Time after ingestion

• 1.5 hours: 56

• 29 hours: 35

• 94 hours: 35

No signs of toxicity observed Laxatives

Zardawi and Siriweera 2013

An 8-year-old boy ingested Pb pellets in 

game over a 2-year period.

Elevated PbB (17.4–27.4) over 

2 years

Pellets observed in appendix

Hyperactivity • Bowel irrigation

• Appendectomy
LEAD C-7

APPENDIX C

Confounding Factors. There are several uncertainties from case reports on ingestion of Pb debris. 

Therefore, it is not possible to determine dose, bioavailability, or accurate plasma-time concentration 

curves. Uncertainties include:

• Baseline PbB data are rarely available. Thus, it is difficult to determine the contribution of 

ingested Pb debris to measured PbB following ingestion.

• Time from ingestion of Pb debris to first clinical evaluation and PbB assessment is often 

unknown.

• No quantitative data on the dose of Pb ingested in debris are reported.

• No quantitative data on fecal excretion of ingested Pb are reported.

• Information on the chemical composition of Pb debris often is not reported.

• No information on potential differences in the bioavailability of different types of Pb debris is 

available

Bioavailability of Pb Debris. No quantitative estimates on the bioavailability of Pb debris in humans are 

available. Several case reports show increased PbB following ingestion of Pb debris, demonstrating that 

ingested Pb is absorbed (CDC 2006; Clifton et al. 2002; Durlach et al. 1986; Fergusson et al. 1997; 

Greensher et al. 1974; Guillard et al. 2006; Hatten et al. 2013; McKinney and McKinney 2000; McNutt et 

al. 2001; CDC 2004a; Mowad et al. 1998; Treble and Thompson 2002); see Table C-1 for details. 

However, due to lack of information on ingested dose, quantitative estimates of absorption cannot be 

determined. No information on bioavailability of Pb debris in animals was identified. Lead debris 

retained within the body will continue to contribute to elevated PbB until it is removed from the body, 

either spontaneously or by medical intervention (Banner et al. 2012; Clifton et al. 2002; Durlach et al. 

1986; Gerhardsson et al. 2002; Guillard et al. 2006; McQuirter et al. 2004).

Lead debris must become bioaccessible (i.e., soluble) in the gastrointestinal tract in order for it to be 

absorbed. It is likely that processes thought to contribute to rendering ingested soil Pb bioaccessible also 

are important in rendering ingested Pb debris bioaccessible (see Section 3.1.1). IVBA assays that 

measure extractable Pb have not been evaluated for predicting bioavailability or RBA of ingested Pb 

debris, although one study found that IVBA measured at gastric pH predicted the relatively high in vivo

RBA (100%) of firing range soils (Bannon et al. 2009; see Section 3.1.1).
LEAD C-8

APPENDIX C

Although dose-PbB relationships and bioavailability cannot be reliably established from the published 

case history of Pb debris ingestion, it is possible to use exposure-biokinetics models to reconstruct the 

time course of PbB expected for a given acute dose of soluble Pb and, from this, estimate the relative 

bioavailability of Pb from ingested Pb shot that would result in a given peak PbB. This scenario assumes 

that Pb debris is not retained in the body. The AALM-LG (EPA 2014a) can simulate the internal 

biokinetics of Pb associated with daily doses of Pb. This model predicts that a child 30 months of age 

who has a baseline PbB of 1 μg/dL would experience a 10 μg/dL increase in PbB in response to ingestion 

of approximately 1 mg of soluble Pb (Figure C-1). The peak PbB would occur during the day of

ingestion and PbB would return to approximately 120% of baseline in approximately 35 days following 

the dose. If this prediction is extrapolated to the ingestion of Pb shot or other debris, the 1 mg dose of 

soluble Pb could occur in association with a dose of 100 mg of debris having an RBA of 1%, or 1 g of 

debris having an RBA of 0.1% (see Section 3.1.5.4 EPA All Ages Lead Model [AALM] for more 

information). Figure C-1 also shows the predicted PbB pattern for six repeated, weekly events in which 

the child ingested 1 mg of soluble PbB. This would result in periodic increases in PbB, with the 

maximum following each exposure event increasing until a pseudo-steady-state PbB was reached at

approximately 14.5 μg/dL (13.5 μg/dL above baseline). The PbB would return to approximately 120% of 

baseline in approximately 570 days after the last exposure event. This longer time to baseline following 

multiple exposures reflects the accrual of Pb in bone with multiple dosing and the relatively slow transfer 

of Pb from bone to blood after exposure ceases (see Section 3.1).

Ingestion of soil from firing ranges may also contribute to PbB. A study in juvenile swine of eight soils 

(sieved to <250 μm) from small arms firing ranges showed a relative bioavailability range of 77–140%, 

with a mean of 108 % (SD or SE [not specified]: 18%). Soil from this site largely consisted of highly 

bioavailable Pb carbonate. However, this study did not provide information on bioavailability of Pb 

debris.
LEAD C-9

APPENDIX C

Figure C-1. PbB Predicted from AALM-LG for a 0.9 mg Dose of Soluble Pb 

Ingested by a Child 30 Months of Age

Retention of Pb Debris in the Appendix. Case reports show that Pb debris can be retained within the 

appendix (Banner et al. 2012; Cox and Pesola 2005; Durlach et al. 1986; Larsen and Blanton 2000; Lyons 

and Filston 1994; Madsen et al. 1988; Reddy 1985; Zardawi and Siriweera 2013); see Table C-1 for 

details. For this to occur, the appendix must be oriented with respect to the cecum in such a way to 

allow objects to pass through the appendiceal-cecal orifice; approximately 45% of the population 

have appendices with this orientation. However, approximately 65% of the population have 

appendices that might hinder foreign body access into the appendiceal lumen due to atypical anatomic 

position, adhesions, or kinks (Klingler et al. 1998). In addition to orientation of the appendix, the 

physical size and shape of the debris likely contribute to retention. Although it is not possible to 

determine the incidence of Pb debris lodged in the gastrointestinal tract or the appendix because not all 

cases of ingestion of Pb debris are reported in the published literature, approximately 45% of the 

population is predisposed to retention of Pb debris on orientation of the appendix. 

Toxicity of Ingested Pb Debris. Regardless of the source of Pb (e.g., ingested Pb debris, Pb paint, Pbcontaminated soil, occupational exposure), once Pb is absorbed into the body, toxicity will be related to 

PbB; thus, bioavailability and duration of elevated PbB, rather than the form of Pb ingested, will 

determine adverse health outcomes. If ingested Pb debris is not retained by the body, toxicity of PbB 

0

2

4

6

8

10

12

14

16

980 1000 1020 1040 1060 1080 1100 1120

PbB (μg/dL)

Age (day)

Multiple Exposure Event

Single Exposure Events

Baseline
LEAD C-10

APPENDIX C

would be consistent with that described for acute Pb toxicity. A summary of peak PbBs and associated 

toxicity following exposure of ingested Pb debris is shown in Table C-2. Severity of toxicity increases 

with PbB. At PbB ≤47 μg/dL, the only adverse health effect observed was a single report of headache at 

a PbB of 12 μg/dL. With increased PbB, effects were observed in several organ systems and severity of 

effects increased. At a PbB range of 54–146 μg/dL, abdominal colic, vomiting, hematological effects, 

and neurological effects were observed, and at a PbB of 180 μg/dL, severe effects (seizure and cerebral 

edema) leading to death were observed. In most cases, the onset of toxicity occurs within hours or days 

of ingestion. If PbB remains elevated, either due to inadequate medical intervention or Pb that is retained 

within the body (i.e., appendix, gastrointestinal tract, etc.) adverse health effects associated with 

chronically elevated PbB would be expected to occur (see Chapter 2, Health Effects). As reviewed in 

Chapter 2, PbBs ≤10 μg/dL are associated with adverse health effects to numerous organ systems, 

including developmental and neurological effects, with severity exhibiting dose-dependence. Given the 

many factors that can affect development of Pb-induced toxicity, case reports of individuals cannot 

provide generalizations of exposure-response relationships. 

Table C-2. Peak Blood Lead Concentration (PbB) and Acute Toxicity Associated 

with Ingestion of Lead (Pb) Debris

Peak PbB (μg/dL)a Effects associated with Pb exposure References

12–16 No effects observed Fergusson et al. 1997

Headache Lyons and Filston 1994

40.5–47 No effects observed Clifton et al. 2002; Hatten et al. 2013

54–61 No effects observed Mowad et al. 1998; Treble and 

Thompson 2002

Abdominal colic Banner et al. 2012

Hematological effectsb

79 Abdominal colic and vomiting McKinney and McKinney 2000

Hematological effectsc

Neurological effectsd

123 Abdominal colic, vomiting, diarrhea

Hematological effectse

CDC 2004a

146 Vomiting Hatten et al. 2013

Neurological signsf

180 Vomiting CDC 2006

Seizures

Cerebral edema

Death
LEAD C-11

APPENDIX C

Table C-2. Peak Blood Lead Concentration (PbB) and Acute Toxicity Associated 

with Ingestion of Lead (Pb) Debris

Peak PbB (μg/dL)a Effects associated with Pb exposure References

391 Abdominal colic, gastrointestinal bleeding McNutt et al. 2001

Anemia

aPeak blood Pb reported.

bElevated free erythrocyte protoporphyrin or microcytic anemia and increased blood zinc protoporphyrin.

cDecreased blood hemoglobin and hematocrit. d“Mild” speech and language delays.

eNormocytic anemia, elevated protoporphyrin

f

Decreased activity level and hyperactive patellar and brachioradialis reflexes.

REFERENCES

Banner B, Schaeffer S, Badillo RB, et al. 2012. Multiple lead appendoliths following ingestion of lead 

shot: Time course and removal by laporoscopic appendectomy. Clin Toxicol 50(4):266-267. 

http://doi.org/10.3109/15563650.2012.658473. 

Bannon DI, Drexler JW, Fent GM, et al. 2009. Evaluation of small arms range soils for metal 

contamination and lead bioavailability. Environ Sci Technol 43(24):9071-9076. 

http://doi.org/10.1021/es901834h. 

CDC. 2004a. Brief report: Lead poisoning from ingestion of a toy necklace- Oregon, 2003. Centers for 

Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 53(23):509-511. 

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5323a5.htm. 

CDC. 2006. Death of a child after ingestion of a metallic charm -- Minnesota, 2006. MMWR Morb 

Mortal Wkly Rep 55(12):340-341. https://www.cdc.gov/mmwr/pdf/wk/mm5512.pdf. May 23, 

2017. 

Clifton JC, Sigg T, Burda AM, et al. 2002. Acute pediatric lead poisoning: Combined whole bowel 

irrigation, succimer therapy, and endoscopic removal of ingested lead pellets. Pediatr Emerg Care 

18(3):200-202. http://doi.org/10.1097/01.pec.0000019226.25165.86. 

Cox WM, Pesola GR. 2005. Buckshot ingestion. N Engl J Med 353(26):e23. 

Durlach V, Lisovoski F, Gross A, et al. 1986. Appendicectomy in an unusual case of lead poisoning. 

Lancet 1(8482):687-688. 

EPA. 2014a. Development and evaluation of the all ages lead model (AALM). U.S. Environmental 

Protection Agency. 

Fergusson J, Malecky G, Simpson E. 1997. Lead foreign body ingestion in children. J Paediatr Child 

Health 33:542-544. 

Gerhardsson L, Dahlin L, Knebel R, et al. 2002. Blood lead concentration after a shotgun accident. 

Environ Health Perspect 110:115-117. 

Greensher J, Mofenson HC, Balakrishnan C, et al. 1974. Leading poisoning from ingestion of lead shot. 

Pediatrics 54(5):641-643. 

Guillard O, Flamen P, Fauconneau B. 2006. A case of acute lead poisoning in a 2-year-old child. Br J 

Clin Pharmacol 62(2):247-247. http://doi.org/10.1111/j.1365-2125.2006.02603.x. 

Gustavsson P, Gerhardsson L. 2005. Intoxication from an accidentally ingested lead shot retained in the 

gastrointestinal tract. Environ Health Perspect 113:491-493. 

Hatten BW, Bueso A, Craven P, et al. 2013. Lead toxicity and endoscopic removal of ingested firearm 

cartridges. Clin Toxicol (Phila) 51(5):448-450. http://doi.org/10.3109/15563650.2013.792114. 

Klingler PJ, Seelig MH, DeVault KR, et al. 1998. Ingested foreign bodies within the appendix: A 100-

year review of the literature. Dig Dis 16(5):308-314. 
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APPENDIX C

Larsen AR, Blanton RH. 2000. Appendicitis due to bird shot ingestion: A case study. Am Surg 

66(6):589-591. 

Lyons JD, Filston HC. 1994. Lead intoxication from a pellet entrapped in the appendix of a child: 

Treatment considerations. J Pediatr Surg 29(12):1618-1620. 

Madsen HH, Skjodt T, Jorgensen PJ, et al. 1988. Blood lead levels in patients with lead shot retained in 

the appendix. Acta Radiol 29(6):745-746. http://doi.org/10.1080/02841858809171977. 

McNutt TK, Chambers-Emerson J, Dethlefsen M, et al. 2001. Bite the bullet: Lead poisoning after 

ingestion of 206 lead bullets. Vet Hum Toxicol 43(5):288-289. 

McQuirter JL, Rothenberg SJ, Dinkins GA, et al. 2004. Change in blood lead concentration up to 1 year 

after a gunshot wound with a retained bullet. Am J Epidemiol 159(7):683-692. 

http://doi.org/10.1093/aje/kwh074. 

Mowad E, Haddad I, Gemmel DJ. 1998. Management of lead poisoning from ingested fishing sinkers. 

Arch Pediatr Adolesc Med 152(5):485-488. 

Reddy ER. 1985. Retained lead shot in the appendix. J Can Assoc Radiol 36(1):47-48. 

Rosenberg A, Haynes J. 2019. Management of ingested lead pellets with elevated blood lead levels in a 

pediatric patient. J Pediatr Gastroenterol Nutr 69(6):e159-e160. 

http://doi.org/10.1097/mpg.0000000000002438. 

Rozier B, Liebelt E. 2019. Lead pellet ingestion in 3 children: Another source for lead toxicity. Pediatr 

Emerg Care 35(5):385-388. http://doi.org/10.1097/pec.0000000000001469. 

Treble RG, Thompson TS. 2002. Elevated blood lead levels resulting from the ingestion of air rifle 

pellets. J Anal Toxicol 26:370-373. 

Zardawi I, Siriweera E. 2013. Images in clinical medicine. Pellets in the appendix. N Engl J Med 

369(6):e7. http://doi.org/10.1056/NEJMicm1214754. 
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APPENDIX D. 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 may find the following information helpful for fast 

answers to often-asked questions.

Primary Chapters/Sections of Interest

Chapter 1: Relevance to Public Health: The Relevance to Public Health Section provides an overview 

of exposure and health effects and evaluates, interprets, and assesses the significance of toxicity 

data to human health. A table listing minimal risk levels (MRLs) is also included in this chapter.

Chapter 2: Health Effects: Specific health effects identified in both human and animal studies are 

reported by type of health effect (e.g., death, hepatic, renal, immune, reproductive), route of 

exposure (e.g., inhalation, oral, dermal), and length of exposure (e.g., acute, intermediate, and 

chronic). 

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

setting. 

Pediatrics: 

Section 3.2 Children and Other Populations that are Unusually Susceptible

Section 3.3 Biomarkers of Exposure and Effect

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) 

Internet: http://www.atsdr.cdc.gov

The following additional materials are available online:

Case Studies in Environmental Medicine are self-instructional publications designed to increase primary 

health care providers’ knowledge of a hazardous substance in the environment and to aid in the 

evaluation of potentially exposed patients (see https://www.atsdr.cdc.gov/csem/csem.html). 

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 (see https://www.atsdr.cdc.gov/MHMI/index.asp). 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 (ToxFAQsTM) provide answers to frequently asked questions about toxic substances (see 

https://www.atsdr.cdc.gov/toxfaqs/Index.asp).
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APPENDIX D

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 • Web Page: 

https://www.cdc.gov/nceh/.

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, 395 E Street, S.W., Suite 9200, 

Patriots Plaza Building, Washington, DC 20201 • Phone: 202-245-0625 or 1-800-CDC-INFO 

(800-232-4636) • Web Page: https://www.cdc.gov/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 • Web Page: 

https://www.niehs.nih.gov/.

Clinical Resources (Publicly Available Information)

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 • Web Page: 

http://www.acoem.org/.

The American College of Medical Toxicology (ACMT) is a nonprofit association of physicians with 

recognized expertise in medical toxicology. Contact: ACMT, 10645 North Tatum Boulevard, 

Suite 200-111, Phoenix AZ 85028 • Phone: 844-226-8333 • FAX: 844-226-8333 • Web Page: 

http://www.acmt.net.

The Pediatric Environmental Health Specialty Units (PEHSUs) is an interconnected system of specialists 

who respond to questions from public health professionals, clinicians, policy makers, and the 

public about the impact of environmental factors on the health of children and reproductive-aged 

adults. Contact information for regional centers can be found at http://pehsu.net/findhelp.html.

The American Association of Poison Control Centers (AAPCC) provide support on the prevention and 

treatment of poison exposures. Contact: AAPCC, 515 King Street, Suite 510, Alexandria VA 

22314 • Phone: 701-894-1858 • Poison Help Line: 1-800-222-1222 • Web Page: 

http://www.aapcc.org/.
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APPENDIX E. GLOSSARY

Absorption—The process by which a substance crosses biological membranes and enters systemic 

circulation. Absorption can also refer to 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, 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) or Benchmark Concentration (BMC)—is the dose/concentration 

corresponding to a specific response level estimate using a statistical dose-response model applied to 

either experimental toxicology or epidemiology data. For example, a BMD10 would be the dose

corresponding to a 10% benchmark response (BMR). The BMD is determined by modeling the doseresponse curve in the region of the dose-response relationship where biologically observable data are 

feasible. The BMDL or BMCL is the 95% lower confidence limit on the BMD or BMC. 

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—Indicators signaling events in biologic systems or samples, typically classified as markers 

of exposure, effect, and susceptibility.

Cancer Effect Level (CEL)—The lowest dose of a 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-control study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without the outcome.

Case Report—A report that describes a single individual with a particular disease or exposure. These 

reports may suggest some potential topics for scientific research, but are not actual research studies.

Case Series—Reports that describe the experience of a small number of individuals with the same 

disease or exposure. These reports may suggest potential topics for scientific research, but are not actual 

research studies.
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APPENDIX E

Ceiling Value—A concentration that must not be exceeded.

Chronic Exposure—Exposure to a chemical for ≥365 days, as specified in the Toxicological Profiles.

Clastogen—A substance that causes breaks in chromosomes resulting in addition, deletion, or 

rearrangement of parts of the chromosome.

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, and who are disease-free at start of follow-up. Often, at 

least one exposed group is compared to one unexposed group, while in other cohorts, exposure is a 

continuous variable and analyses are directed towards analyzing an exposure-response coefficient.

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 a specific point in time.

Data Needs—Substance-specific informational needs that, if met, would reduce the uncertainties of 

human health risk 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 response or amount of the response.

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 

effect occurs. Effects include malformations and variations, altered growth, and in utero death.

Epidemiology—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. 

Excretion—The process by which metabolic waste products are removed from the body.

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.

Health Advisory—An estimate of acceptable drinking water levels for a chemical substance derived by 

EPA and 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.

Immediately Dangerous to Life or Health (IDLH)—A condition that poses a threat of life or health, or 

conditions that pose an immediate threat of severe exposure to contaminants that are likely to have 

adverse cumulative or delayed effects on health.
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APPENDIX E

Immunotoxicity—Adverse effect on the functioning of the immune system that may result from 

exposure to chemical substances. 

Incidence—The ratio of new cases 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.

Metabolism—Process in which chemical substances are biotransformed in the body that could result in 

less toxic and/or readily excreted compounds or produce a biologically active intermediate.

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.
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APPENDIX E

Morbidity—The state of being diseased; the morbidity rate is the incidence or prevalence of a disease in 

a specific population.

Mortality—Death; the mortality rate is a measure of the number of deaths in a population during a 

specified interval of time.

Mutagen—A substance that causes mutations, which are changes 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 

hazardous substance.

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. Although effects may be produced at this dose, 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 odds ratio that is greater than 1 is considered to indicate greater risk of 

disease in the exposed group compared to the unexposed group.

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

regulatory limit on the amount or concentration of a substance not to be exceeded in workplace air 

averaged over any 8-hour work 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 (insects or other organisms harmful to cultivated plants or animals).

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 

endpoints. 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. 
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APPENDIX E

Physiologically Based Pharmacokinetic (PBPK) Model—A type of physiologically based doseresponse model that is 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, including 

tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates, and possibly 

membrane permeabilities. The models also utilize biochemical information, such as blood:air 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 a group is followed over time and the pertinent 

observations are made on events occurring after the start of the study. 

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 RfC is expressed in units of mg/m3 or ppm.

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily oral exposure of the human population to a potential hazard that is likely to be without risk of 

deleterious noncancer health effects during a lifetime. The oral RfD is expressed in units of mg/kg/day. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). RQs are 

(1) ≥1 pound 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 hazardous substance. 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 hazardous 

substance.

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, existing health 

condition, or an inborn or inherited characteristic that is associated with an increased occurrence of 

disease or other health-related event or condition.
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APPENDIX E

Risk Ratio/Relative Risk—The ratio of the risk among persons with specific risk factors compared to the 

risk among persons without risk factors. A risk ratio that is greater than 1 indicates greater risk of disease 

in the exposed group compared to the unexposed group.

Short-Term Exposure Limit (STEL)—A STEL is a 15-minute TWA exposure that should not be 

exceeded at any time during a workday. 

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 it is believed that nearly all workers may be repeatedly 

exposed, day after day, for a working lifetime without adverse effect. The TLV may be expressed as a 

Time-Weighted Average (TLV-TWA), as a Short-Term Exposure Limit (TLV-STEL), or as a ceiling 

limit (TLV-C).

Time-Weighted Average (TWA)—An average exposure within a given time period. 

Toxicokinetic—The absorption, distribution, metabolism, and elimination of toxic compounds in the 

living organism.

Toxics Release Inventory (TRI)—The TRI is an EPA program that tracks toxic chemical releases and 

pollution prevention activities reported by industrial and federal facilities. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL),

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 substance that is foreign to the biological system.
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APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS

AAPCC American Association of Poison Control Centers

ACGIH American Conference of Governmental Industrial Hygienists

ACOEM American College of Occupational and Environmental Medicine

ACMT American College of Medical Toxicology

ADI acceptable daily intake

ADME absorption, distribution, metabolism, and excretion

AEGL Acute Exposure Guideline Level

AIC Akaike’s information criterion 

AIHA American Industrial Hygiene Association 

ALT alanine aminotransferase

AOEC Association of Occupational and Environmental Clinics

AP alkaline phosphatase

AST aspartate aminotransferase

atm atmosphere

ATSDR Agency for Toxic Substances and Disease Registry

AWQC Ambient Water Quality Criteria

BCF bioconcentration factor

BMD/C benchmark dose or benchmark concentration

BMDX dose that produces a X% change in response rate of an adverse effect

BMDLX 95% lower confidence limit on the BMDX

BMDS Benchmark Dose Software 

BMR benchmark response

BUN blood urea nitrogen 

C centigrade

CAA Clean Air Act

CAS Chemical Abstract Services

CDC Centers for Disease Control and Prevention

CEL cancer effect level

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act

CFR Code of Federal Regulations

Ci curie

CI confidence interval

cm centimeter

CPSC Consumer Products Safety Commission

CWA Clean Water Act

DNA deoxyribonucleic acid

DOD Department of Defense

DOE Department of Energy

DWEL drinking water exposure level

EAFUS Everything Added to Food in the United States

ECG/EKG electrocardiogram

EEG electroencephalogram

EPA Environmental Protection Agency

ERPG emergency response planning guidelines 

F Fahrenheit

F1 first-filial generation

FDA Food and Drug Administration

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FR Federal Register
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APPENDIX F

FSH follicle stimulating hormone

g gram

GC gas chromatography

gd gestational day

GGT γ-glutamyl transferase 

GRAS generally recognized as safe

HEC human equivalent concentration 

HED human equivalent dose 

HHS Department of Health and Human Services 

HPLC high-performance liquid chromatography

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer

IDLH immediately dangerous to life and health

IRIS Integrated Risk Information System 

Kd adsorption ratio

kg kilogram

kkg kilokilogram; 1 kilokilogram is equivalent to 1,000 kilograms and 1 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 Level of Significant Exposure

LT50 lethal time, 50% kill

m meter

mCi millicurie

MCL maximum contaminant level

MCLG maximum contaminant level goal

MF modifying factor

mg milligram

mL milliliter

mm millimeter

mmHg millimeters of mercury

mmol millimole

MRL Minimal Risk Level

MS mass spectrometry

MSHA Mine Safety and Health Administration

Mt metric ton

NAAQS National Ambient Air Quality Standard

NAS National Academy of Science

NCEH National Center for Environmental Health

ND not detected

ng nanogram

NHANES National Health and Nutrition Examination Survey

NIEHS National Institute of Environmental Health Sciences
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APPENDIX F

NIOSH National Institute for Occupational Safety and Health

NLM National Library of Medicine

nm nanometer

nmol nanomole

NOAEL no-observed-adverse-effect level

NPL National Priorities List

NR not reported

NRC National Research Council

NS not specified

NTP National Toxicology Program

OR odds ratio

OSHA Occupational Safety and Health Administration

PAC Protective Action Criteria

PAH polycyclic aromatic hydrocarbon

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PEHSU Pediatric Environmental Health Specialty Unit

PEL permissible exposure limit

PEL-C permissible exposure limit-ceiling value

pg picogram

PND postnatal day

POD point of departure

ppb parts per billion

ppbv parts per billion by volume

ppm parts per million

ppt parts per trillion

REL recommended exposure level/limit

REL-C recommended exposure level-ceiling value

RfC reference concentration

RfD reference dose

RNA ribonucleic acid

SARA Superfund Amendments and Reauthorization Act

SCE sister chromatid exchange

SD standard deviation

SE standard error

SGOT serum glutamic oxaloacetic transaminase (same as aspartate aminotransferase or AST)

SGPT serum glutamic pyruvic transaminase (same as alanine aminotransferase or ALT)

SIC standard industrial classification

SMR standardized mortality ratio

sRBC sheep red blood cell

STEL short term exposure limit

TLV threshold limit value

TLV-C threshold limit value-ceiling value

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

USNRC U.S. Nuclear Regulatory Commission
LEAD

F-4

APPENDIX F

VOC volatile organic compound

WBC white blood cell

WHO World Health Organization > 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