U.S. Department of Health and Human Services NTP National Toxicology Program

NTP Monograph

Health Effects 

of Low-Level Lead

June 2012
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NTP MONOGRAPH ON HEALTH EFFECTS OF LOW-LEVEL LEAD

June 13, 2012

U.S. Department of Health and Human Services 

Office of Health Assessment and Translation

Division of the National Toxicology Program

National Institute of Environmental Health Sciences

National Institutes of Health

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
ii NTP Monograph on Health Effects of Low-Level Lead

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NTP Monograph on Health Effects of Low-Level Lead iii

Contents

TABLE OF CONTENTS

List of Tables............................................................................................................................................ vi

List of Figures ........................................................................................................................................ viii

Contributors ........................................................................................................................................... ix

Peer Review of the Draft NTP Monograph ................................................................................................ x

Abbreviations.......................................................................................................................................... xi

Abstract................................................................................................................................................. xiii

1.0 Executive Summary......................................................................................................................... xv

1.1 Introduction .....................................................................................................................................xv

1.2 Methods...........................................................................................................................................xv

1.2.1 Key Questions...................................................................................................................... xv

1.2.2 Approach to Develop Health Effects Conclusions ...............................................................xv

1.2.3 Appendices of Studies Considered ..................................................................................... xvi

1.2.4 Authoritative Sources and Peer Review ............................................................................. xvi

1.3 What Does It Mean to Refer to Blood Pb Levels <10 μg/dL? ..........................................................xvi

1.4 Health Effects Evidence................................................................................................................. xviii

1.4.1 NTP Conclusions............................................................................................................... xviii

1.4.2 Neurological Effects.......................................................................................................... xviii

1.4.3 Immune Effects................................................................................................................... xxi

1.4.4 Cardiovascular Effects........................................................................................................ xxii

1.4.5 Renal Effects...................................................................................................................... xxii

1.4.6 Reproduction and Developmental Effects........................................................................ xxiii

1.5 Future Research ............................................................................................................................ xxiv

2.0 Methods...........................................................................................................................................1

2.1 Key Questions.................................................................................................................................... 1

2.2 Approach to Develop Health Effects Conclusions ............................................................................. 1

2.3 Appendices of Studies Considered.................................................................................................... 2

2.4 Authoritative Sources Considered .................................................................................................... 3

2.4.1 U.S. EPA 2006 Air Quality Criteria Document (AQCD) for Lead ............................................ 3

2.4.2 ATSDR 2007 Toxicological Profile for Lead............................................................................ 3

2.4.3 CDC Lead Panel Documents.................................................................................................. 3

2.4.4 Technical Advisors ................................................................................................................ 4

2.5 Literature Search Strategy................................................................................................................. 4

2.6 Peer-Review Process......................................................................................................................... 4

3.0 Exposure...........................................................................................................................................7

3.1 What Does It Mean to Refer to Blood Pb <10 μg/dL? ...................................................................... 7

3.2 Biomarkers of Pb Exposure ............................................................................................................... 8

3.3 Sources of Pb................................................................................................................................... 12

3.4 Modifiers of Pb Exposure ................................................................................................................ 16

3.5 Summary......................................................................................................................................... 18
iv NTP Monograph on Health Effects of Low-Level Lead

Contents

4.0 Neurological Effects.........................................................................................................................19

4.1 Conclusions..................................................................................................................................... 19

4.2 How Conclusions Were Reached.................................................................................................... 19

4.2.1 Principal Measures of Neurological Effects ........................................................................ 20

4.2.2 Principal Conclusions from the 2006 EPA and 2007 ATSDR Pb Documents........................ 21

4.3 Evidence for Pb-Related Effects on Neurological Outcomes........................................................... 22

4.3.1 Cognitive Function.............................................................................................................. 22

4.3.2 Behavior ............................................................................................................................. 31

4.3.3 Neurodegeneration ............................................................................................................ 38

4.3.4 Sensory Organs................................................................................................................... 40

4.4 Conclusions..................................................................................................................................... 42

5.0 Immune Effects...............................................................................................................................45

5.1 Conclusions..................................................................................................................................... 45

5.2 How Conclusions Were Reached..................................................................................................... 45

5.2.1 Principal Measures of Immune Effects............................................................................... 46

5.2.2 Principal Conclusions from the 2006 EPA and 2007 ATSDR Pb Documents........................ 46

5.3 Evidence for Pb-Related Immune Effects........................................................................................ 47

5.3.1 Increased Serum IgE and Allergic Sensitization .................................................................. 47

5.3.2 IgG, IgM, IgA, and Antibody Response ............................................................................... 52

5.3.3 T Lymphocytes (T-cells)....................................................................................................... 53

5.3.4 Monocyte/Macrophages.................................................................................................... 55

5.3.5 Neutrophils......................................................................................................................... 55

5.4 Susceptible Populations or Life Stages............................................................................................ 56

5.5 Pb Exposure Measurements ........................................................................................................... 57

5.6 Delayed-Type Hypersensitivity (DTH) and Pb-Related Immune Effects in Animal Studies ............. 57

5.7 Conclusions..................................................................................................................................... 58

6.0 Cardiovascular Effects .....................................................................................................................61

6.1 Conclusions..................................................................................................................................... 61

6.2 How Conclusions Were Reached .................................................................................................... 61

6.2.1 Principal Measures of Cardiovascular Effects..................................................................... 62

6.2.2 Principal Conclusions from the 2006 EPA and 2007 ATSDR Pb Documents........................ 63

6.3 Evidence for Pb-related Effects on Cardiovascular Outcomes......................................................... 63

6.3.1 Blood Pressure (BP) and Hypertension .............................................................................. 63

6.3.2 Heart Rate Variability.......................................................................................................... 68

6.3.3 Electrocardiogram Abnormalities....................................................................................... 70

6.3.4 Clinical Cardiovascular Disease........................................................................................... 70

6.3.5 Cardiovascular Mortality .................................................................................................... 72

6.4 Susceptible Populations and Modifiers of Pb Exposure .................................................................. 72

6.5 Conclusions..................................................................................................................................... 74

7.0 Renal Effects ...................................................................................................................................77

7.1 Conclusions..................................................................................................................................... 77

7.2 How Conclusions Were Reached..................................................................................................... 77

7.2.1 Principal Measures of Kidney Effects.................................................................................. 78

7.2.2 Principal Conclusions from the 2006 EPA and 2007 ATSDR Pb Documents........................ 78

7.3 Evidence for Pb-related Effects on Kidney Function........................................................................ 80

7.3.1 Kidney Effects in Adults ...................................................................................................... 80

7.3.2 Occupational Exposures..................................................................................................... 84
NTP Monograph on Health Effects of Low-Level Lead v

Contents

7.4 Susceptible Populations or Life Stages............................................................................................ 84

7.4.1 Children .............................................................................................................................. 84

7.4.2 Hypertensives, Diabetics, and Kidney Disease Patients...................................................... 87

7.5 Conclusions..................................................................................................................................... 87

8.0 Reproductive/Developmental Effects..............................................................................................89

8.1 Conclusions..................................................................................................................................... 89

8.2 How Conclusions Were Reached..................................................................................................... 90

8.2.1 Principal Measures of Reproductive and Developmental Effects....................................... 90

8.2.2 Principal Conclusions from 2006 EPA and 2007 ATSDR Pb Documents.............................. 90

8.3 Evidence for Pb-Related Effects on Reproductive and Developmental Outcomes.......................... 91

8.3.1 Delayed Puberty ................................................................................................................. 91

8.3.2 Postnatal Growth................................................................................................................ 94

8.3.3 Sperm ................................................................................................................................. 98

8.3.4 Fertility/Delayed Conception Time .................................................................................. 104

8.3.5 Spontaneous Abortion...................................................................................................... 107

8.3.6 Stillbirth............................................................................................................................ 109

8.3.7 Fetal Growth and Lower Birth Weight.............................................................................. 109

8.3.8 Preterm Birth and Gestational Age................................................................................... 112

8.3.9 Endocrine Effects.............................................................................................................. 114

8.3.10 Congenital Malformations................................................................................................ 116

8.4 Conclusions................................................................................................................................... 117

9.0 References.................................................................................................................................... 119

9.1 Executive Summary....................................................................................................................... 119

9.2 Methods........................................................................................................................................ 119

9.3 Exposure........................................................................................................................................ 120

9.4 Neurological Effects....................................................................................................................... 125

9.5 Immune Effects ............................................................................................................................. 131

9.6 Cardiovascular Effects ................................................................................................................... 135

9.7 Renal Effects.................................................................................................................................. 138

9.8 Reproductive/Developmental Effects............................................................................................ 140

Appendices (not in printed copy. PDF files included on CD) Appenidx Page

Appendix A: Human Studies of Neurological Effects of Lead

Considered in Developing Conclusions.......................................................................................1

Appendix B: Human Studies of Immune Effects of Lead

Considered in Developing Conclusions...................................................................................115

Appendix C: Human Studies of Cardiovascular Effects of Lead

Considered in Developing Conclusions...................................................................................145

Appendix D: Human Studies of Renal Effects of Lead

Considered in Developing Conclusions...................................................................................191

Appendix E: Human Studies Appendices of Reproductive and Developmental Effects of Lead

Considered in Developing Conclusions...................................................................................207
vi NTP Monograph on Health Effects of Low-Level Lead

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LIST OF TABLES

Table 1.1: NTP conclusions on health effects of low-level Pb by life stage............................................................xix

Table 1.2: NTP conclusions on health effects of low-level Pb by major health effect areas ..................................xx

Table 4.1: Major neurological effects considered .................................................................................................. 20

Table 4.2: Main conclusions for neurological effects in the 2006 EPA AQCD for Lead

and the 2007 ATSDR Toxicological Profile for Lead .............................................................................. 21

Table 4.3: NTP conclusions on neurological effects of low-level Pb ...................................................................... 43

Table 5.1: Major immune effects considered......................................................................................................... 46

Table 5.2: Main conclusions for immunological effects in the 2006 EPA AQCD for Lead

and the 2007 ATSDR Toxicological Profile for Lead............................................................................... 46

Table 5.3: Studies of serum IgE, sensitization, and eczema with low-level Pb

used to develop conclusions for children ............................................................................................. 48

Table 5.4: NTP conclusions on immune effects of low-level Pb............................................................................. 59

Table 6.1: Major Pb-related cardiovascular outcomes/effects.............................................................................. 62

Table 6.2: Main conclusions for cardiovascular effects in the 2006 EPA AQCD for Lead

and the 2007 ATSDR Toxicological Profile for Lead .............................................................................. 63

Table 6.3: Studies of the association between bone Pb and blood pressure and hypertension

used to develop conclusions................................................................................................................. 65

Table 6.4: Studies of Pb and blood pressure and hypertension during pregnancy

used to develop conclusions................................................................................................................. 67

Table 6.5: Studies of childhood Pb exposure and BP............................................................................................. 69

Table 6.6: Studies of Pb and clinical cardiovascular disease used to develop conclusions...................................71

Table 6.7: Studies of Pb and cardiovascular mortality used to develop conclusions............................................73

Table 6.8: Conclusions on cardiovascular effects of low-level Pb.......................................................................... 75

Table 7.2: Main conclusions for kidney effects in 2006 EPA AQCD for Lead

and the 2007 ATSDR Toxicological Profile for Lead .............................................................................. 78

Table 7.1: Commonly used indicators of kidney function in the Pb literature references....................................79

Table 7.3: Studies of kidney outcomes in adults.................................................................................................... 81

Table 7.4: Studies of kidney outcomes in children................................................................................................. 85

Table 7.5: NTP conclusions on kidney effects of low-level Pb................................................................................ 88

LIST OF TABLES
NTP Monograph on Health Effects of Low-Level Lead vii

Contents

Table 8.1: Major reproductive/developmental effects considered ....................................................................... 91

Table 8.2: Main conclusions for reproductive/developmental effects in the 2006 EPA AQCD for Lead

and the 2007 ATSDR Toxicological Profile for Lead............................................................................... 91

Table 8.3: Studies of biomarkers of puberty associated with low-level Pb exposure

used to develop conclusions................................................................................................................. 92

Table 8.4: Studies of postnatal growth associated with low-level Pb exposure

used to develop conclusions................................................................................................................. 95

Table 8.5: Studies of sperm and semen parameters associated with low-level Pb exposure

used to develop conclusions................................................................................................................. 99

Table 8.6: NTP conclusions on reproductive and developmental effects of low-level Pb...................................118
viii NTP Monograph on Health Effects of Low-Level Lead

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LIST OF FIGURES

Figure 3.1: U.S. NHANES blood Pb levels for children and adults from 1976-2008............................................... 10

Figure 3.2: U.S. NHANES 1999-2002 blood Pb levels across ages and racial/ethnic groups.................................10

Figure 3.3: U.S. NHANES 1999-2008 blood Pb levels for all ages of males and females.......................................11

Figure 3.4: U.S. Pb air concentration from 1980-2009........................................................................................... 14

LIST OF FIGURES
NTP Monograph on Health Effects of Low-Level Lead ix

Contents

CONTRIBUTORS

Office of Health Assessment and Translation (OHAT),

Division of the National Toxicology Program (DNTP)

Conducted technical evaluation

Andrew A. Rooney, PhD (Project Lead)

Abee L. Boyles, PhD

Kyla Taylor, MS

Kembra L. Howdeshell, PhD

Vickie R. Walker

Michael D. Shelby, PhD

Kristina A. Thayer, PhD (Director, OHAT)

Office of Liaison, Policy and Review (OLPR), DNTP

Managed peer review and release of the Monograph

Mary Wolfe, PhD (Director, OLPR and Deputy Division Director for Policy)

Danica Andrews

Denise Lasko

Lori White, PhD

GLP Support Services

Provided support for development of appendix tables

Judy Stevens

Technical Advisors

Provided scientific input and reviewed a pre-public release draft of the Monograph

David Bellinger, PhD Professor, Department of Environmental Health, Harvard School of 

Public Health, Boston, MA

David Lawrence, PhD Chief, Laboratory of Clinical and Experimental Endocrinology and 

Immunology, Wadsworth Center, New York State Department of 

Health, Albany, NY

Barbara Materna, PhD, CIH Chief, Occupational Health Branch, California Department of Public 

Health, Richmond, CA

Ana Navas-Acien, MD, PhD Assistant Professor, Department of Environmental Health Sciences, 

Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Virginia Weaver, MD, MPH Associate Professor, Department of Environmental Health Sciences, 

Division of Occupational and Environmental Health, Johns Hopkins 

Bloomberg School of Public Health, Baltimore,MD

Elizabeth A. Whelan, PhD Chief, Industrywide Studies Branch, Division of Surveillance, Hazard 

Evaluations, and Field Studies, National Institute for Occupational 

Safety and Health, Cincinnati, OH
x	 NTP Monograph on Health Effects of Low-Level Lead

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PEER REVIEW OF THE DRAFT NTP 

MONOGRAPH

Peer review of the Draft NTP Monograph was conducted by an ad hoc expert panel at a public meeting

held November 17-18, 2011, at the National Institute

of Environmental Health Sciences, Research Triangle

Park, NC (see http://ntp.niehs.nih.gov/go/37090 for

materials, minutes, and panel recommendations

from the peer review meeting). The selection of

panel members and conduct of the peer review were

performed in accordance with the Federal Advisory

Committee Act and Federal policies and regulations.

The panel membersserved asindependentscientists,

not asrepresentatives of any institution, company, or

governmental agency. In this capacity, panel members had two major responsibilities in reviewing the

draft NTP Monograph: (1) to determine whether the

scientific information cited in the draft monograph

is technically correct, clearly stated, and objectively

presented and (2) to determine whether the scientific evidence presented in the draft monograph supports the NTP’s conclusions regarding health effects

of low-level lead (Pb).

The panel agreed with the draft NTP overall conclusions on cardiovascular, renal, and immune health

effects associated with blood Pb levels <10 μg/dL. The

panel recommended changing the draft summary

conclusion for neurological effects in children and for

reproductive effects in adult women from sufficient

evidence of an association at blood Pb levels <10 ug/

dL to sufficient evidence of an association at blood Pb

levels <5 ug/dL. Comments from the peer reviewers

and written public comments received on the draft

monograph were considered during finalization of the

document. The NTP concurred with the expert panel

on all of its recommendations on the conclusions

regarding health effects of Pb in this final document.

Peer-Review Panel

Joel Pounds, PhD (chair) Scientist, Division of Biological Sciences, Pacific Northwest

National Laboratory, Richland, WA

Deborah Cory-Slechta, PhD Professor, Department of Environmental Medicine, University of

Rochester School of Medicine and Dentistry, Rochester, NY

Pam Factor-Litvak, PhD Associate Professor of Clinical Epidemiology, Mailman School of

Public Health, Columbia University, New York, NY

Eliseo Guallar, MD, DrPH Associate Professor, Department of Epidemiology, Welch Centerfor

Prevention, Johns Hopkins University Bloomberg School of Public

Health, Baltimore, MD

Bruce Lanphear, MD, MPH, TM Senior Scientist, Child and Family Research Institute, BC Children’s

Hospital, University of British Columbia, Vancouver, British

Columbia, Canada

Michael Pollard, PhD Associate Professor, W.M. Keck Autoimmune Disease Center,

Department of Molecular and Experimental Medicine, The Scripps

Research Institute, San Diego, CA

Stephen Rothenberg, PhD Senior Investigator, Center for Research in Population Health,

National Institute of Public Health, Ministry of Mexico, Cuernavaca,

Morelos, Mexico

Nostratola Vaziri, MD, MACP Chief, Division of Nephrology and Hypertension, University of California, Irvine Medical Center, Orange, CA

Richard Wedeen, MD Clinical Professor, Department of Environmental and Community

Medicine, UMDNJ-Robert Wood Johnson Medical School, New

Brunswick, NJ
NTP Monograph on Health Effects of Low-Level Lead xi

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ABBREVIATIONS

ABLES Adult Blood Lead Epidemiology and Surveillance

ACCLPP Advisory Committee on Childhood Lead Poisoning Prevention

ADHD attention deficit hyperactivity disorder

ALAD δ-aminolevulinic acid dehydratase

ALS amyotrophic lateral sclerosis

AQCD Air Quality Criteria Document

ATSDR Agency for Toxic Substances and Disease Registry

BAEP brainstem auditory evoked potential

BMI body mass index

BP blood pressure

CBCL Child Behavior Checklist

BTQ Boston Teacher Questionnaire

CDC Centers for Disease Control and Prevention

CI confidence interval

CKD chronic kidney disease

DBP diastolic blood pressure

DSM Diagnostic and Statistical Manual of Mental Disorders

DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th edition (1994)

DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (2000)

DTH delayed-type hypersensitivity

E2 estradiol-17β

EBE early biological effect marker

ECG electrocardiographic

EDTA ethylenediaminetetraacetic acid

eGFR estimated glomerular filtration rate

EPA Environmental Protection Agency, U.S.

ERG electroretinographic

ETS environmental tobacco smoke

FR fecundability ratio

FSH follicle-stimulating hormone

FSIQ full-scale IQ

GCI General Cognitive Index from the McCarthy Scales of Children’s Abilities

GFR glomerular filtration rate

HFE hemochromatosis

HR hazard ratio

HRV heart rate variability

IgA immunoglobulin A

IgE immunoglobulin E

IGF-1 insulin-like growth factor 1

IgG Immunoglobulin G

IgM immunoglobulin M

IQ intelligence quotient

IVF in vitro fertilization

KTEA Kaufman Test of Educational Achievement

LH leutinizing hormone

MDI Mental Developmental Index from the Bayley Scales of Infant Development

MMSE Mini-Mental State Examination
xii NTP Monograph on Health Effects of Low-Level Lead

Contents

NAG N-acetyl-β-D-glucosaminidase

NHANES National Health and Nutrition Examination Survey

NIEHS National Institute of Environmental Health Sciences

NO nitric oxide

NTP National Toxicology Program

Pb lead

O2

- superoxide

OR odds ratio

PBPK physiologically based pharmacokinetic

PFC plaque-forming cell

PIQ performance IQ

PRL prolactin

RBP retinol-binding protein

RR relative risk

SBP systolic blood pressure

SD standard deviation

SES socioeconomic status

SPT skin prick test

T testosterone

T3 triiodothryonine

T4 thyroxin

Th-1 type 1 helper T-cell

Th-2 type 2 helper T-cell

TNF-α tumor necrosis factor-α

TSH thyroid-stimulating hormone

VEP visual evoked potential

VDR vitamin D receptor

VIQ verbal IQ

WHILA Swedish Women’s Health in the Lund Area

WISC Wechsler Intelligence Scale for Children

WISC-III Wechsler Intelligence Scale for Children, 3rd edition (1991)

WISC-R Wechsler Intelligence Scale for Children, revised edition (1974)

WISC-IV Wechsler Intelligence Scale for Children, 4th edition (2003)

WPPSI-R Wechsler Preschool and Primary Scale of Intelligence

WRAT-R Wide Range Achievement Test-Revised

ZPP zinc protoporphyrin
NTP Monograph on Health Effects of Low-Level Lead xiii

Contents

ABSTRACT

Although reductions in lead (Pb) exposure for the U.S. 

population have resulted in lower blood Pb levels over 

time, epidemiological studies continue to provide evidence of health effects at lower and lower blood Pb 

levels. Low-level Pb was selected for evaluation by 

the National Toxicology Program (NTP) because of (1) 

the availability of a large number of epidemiological 

studies of Pb, (2) a nomination by the National Institute for Occupational Safety and Health for an assessment of Pb at lower levels of exposure, and (3) public 

concern for effects of Pb in children and adults. This 

evaluation summarizes the evidence in humans and 

presents conclusions on health effects in children and 

adults associated with low-level Pb exposure as indicated by less than 10 micrograms of Pb per deciliter 

of blood (<10 μg/dL). The assessment focuses on epidemiological evidence at blood Pb levels <10 μg/dL 

and <5 μg/dL because health effects at higher blood 

Pb levels are well established. The NTP evaluation 

was conducted through the Office of Health Assessment and Translation (OHAT, formerly the Center for 

the Evaluation of Risks to Human Reproduction) and 

completed in April of 2012.

The results of this evaluation are published in 

the NTP Monograph on Health Effects of Low-Level 

Lead. The document and appendices are available 

at http://ntp.niehs.nih.gov/go/evals. This document 

provides background on Pb exposure and includes 

a review of the primary epidemiological literature 

for evidence that low-level Pb is associated with 

neurological, immunological, cardiovascular, renal, 

and/or reproductive and developmental effects. The 

NTP Monograph presents specific conclusions for 

each health effect area. Overall, the NTP concludes 

that there is sufficient evidence that blood Pb levels 

<10 μg/dL and <5 μg/dL are associated with adverse 

health effects in children and adults.

This conclusion was based on a review of the primary epidemiological literature, scientific input from 

technical advisors that reviewed pre-public release 

drafts of each chapter summarizing the evidence for 

specific health effects associated with low-level Pb, 

public comments received during the course of the 

evaluation, and comments from an expert panel of

ad hoc reviewers during a public meeting to review 

the Draft NTP Monograph on November 17-18, 2011

(http://ntp.niehs.nih.gov/go/37090).
xiv NTP Monograph on Health Effects of Low-Level Lead

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Summary

Executive

NTP Monograph on Health Effects of Low-Level Lead xv

1.0 EXECUTIVE SUMMARY

1.1 Introduction

Lead (Pb) exposure remains a significant health concern despite policies and practices that have resulted 

in continued progress in reducing exposure and lowering blood Pb levels in the U.S. population. Pb is one 

of the most extensively studied environmental toxicants, with more than 28,900 publications on health 

effects and exposure in the peer-reviewed literature1.

While the toxicity associated with exposure to high 

levels of Pb was recognized by the ancient Greeks and 

Romans, the adverse health effects associated with 

low-level Pb exposure became widely recognized only 

in the second half of the 20th century. Over the past 

40 years, epidemiological studies, particularly in children, continue to provide evidence of health effects 

at lower and lower blood Pb levels. In response, the 

Centers for Disease Control and Prevention (CDC) has 

repeatedly lowered the concentration of Pb in blood 

that is considered “elevated” in children (from 30 μg/

dL to 25 μg/dL in 1985 and to the current level of 

10 μg/dL in 1991).

The purpose of this evaluation is to summarize 

the evidence in humans and to reach conclusions 

about whether health effects are associated with 

low-level Pb exposure as indicated by less than 10 

micrograms of Pb per deciliter of blood (<10 μg/

dL), with specific focus on the life stage (childhood, adulthood) associated with these health 

effects. This evaluation focuses on epidemiological evidence at blood Pb levels <10 μg/dL because 

health effects at higher blood Pb levels are well 

established such that the definition of an elevated 

blood Pb level is ≥10 μg/dL for both children and 

adults (ABLES 2009, CDC 2010a). Pb was nominated 

by the National Institute for Occupational Safety 

and Health for a National Toxicology Program (NTP) 

evaluation to assess the reproductive and developmental effects of Pb (see http://ntp.niehs.nih.gov/

mtg?date=20100510&meeting=BSC). The scope of 

the evaluation has been expanded from the original nomination to include an evaluation of health 

effects other than reproduction and development 

(e.g., cardiovascular effects in adults) in order to 

maximize the utility of the evaluation.

1 Based on an April 2012 PubMed search for keyword (MeSH) 

“lead” or “lead poisoning.”

1.2 Methods

The key questions and general approach for developing the conclusions on the health effects of low-level 

Pb are outlined below. Section 2.0 of this document 

contains additional details on the authoritative 

sources considered, the literature search strategy, 

and the peer-review process.

1.2.1 Key Questions

What is the evidence that adverse health effects are 

associated with blood Pb <10 μg/dL?

6 What reproductive, developmental, neurological, 

immune, cardiovascular, and renal health effects 

are associated with blood Pb levels <10 μg/dL?

6 What is the blood Pb level associated with a given 

health effect (i.e., <10 μg/dL or <5 μg/dL)?

6 At which life stages (childhood or adulthood) is 

the effect identified?

6 Are there data to evaluate the association 

between bone Pb and the health effect, and how 

does the association to this biomarker of Pb exposure compare to the association with blood Pb?

1.2.2 Approach to Develop Health Effects 

Conclusions

Conclusions in the NTP evaluation of Pb-related 

health effects in humans associated with low-level 

Pb were derived by evaluating the data from epidemiological studies with a focus on blood Pb levels 

<10 μg/dL. The evaluation includes a review of the 

primary epidemiological literature for evidence that 

low-level Pb is associated with neurological, immunological, cardiovascular, renal, and/or reproductive 

and developmental effects. These health effect areas 

were selected because there is a relatively large database of human studies in each area. The NTP considered four possible conclusions for specific health 

effects within each area:

Sufficient Evidence of an Association:

An association is observed between the exposure and health outcome in studies in which 

chance, bias, and confounding could be ruled 

out with reasonable confidence.

Limited Evidence of an Association:

An association is observed between the exposure and health outcome in studies in which 

chance, bias, and confounding could not be 

ruled out with reasonable confidence.
xvi NTP Monograph on Health Effects of Low-Level Lead

Executive

Summary

Inadequate Evidence of an Association:

The available studies are insufficient in quality, 

consistency, or statistical power to permit a 

conclusion regarding the presence or absence 

of an association between exposure and health 

outcome, or no data in humans are available.

Evidence of No Association:

Several adequate studies covering the full range 

of levels of exposure that humans are known 

to encounter (in this case limited to blood Pb 

levels <10 μg/dL) are mutually consistent in not 

showing an association between exposure to 

the agent and any studied endpoint.

The discussion of each health effect begins with a 

statement of the NTP’s conclusion regarding whether 

the specific effect is associated with a blood Pb level 

<10 μg/dL or <5 μg/dL and the age group (childhood 

or adulthood) in which it is or is not identified, as well 

as the timing of exposure associated with the effect 

(prenatal, childhood, concurrent) if available. Then 

key data and principal studies considered in developing the NTP’s conclusions are discussed in detail. 

General strengths and limitations of study designs 

were considered when developing conclusions, with 

prospective studies providing stronger evidence than 

cross-sectional or case-control studies. Each section 

concludes with a summary discussing each health 

effect, describing experimental animal data that 

relate to the human data, and stating the basis for 

the NTP conclusions.

For the purposes of this evaluation, “children” 

refers to individuals <18 years of age unless otherwise 

specified. In addition to the blood Pb level of <10 μg/dL, 

a lower effect level of <5 μg/dL was also selected 

because it is commonly used in epidemiological studies to categorize health effects data by exposure levels; 

therefore, data are often available to evaluate health 

effects for groups above and below this value as well.

1.2.3 Appendices of Studies Considered

The information to support the NTP’s conclusions for 

individual health effects is presented in each chapter. 

In addition, human studies of groups with low-level 

Pb exposure that were considered in developing the 

conclusions are also abstracted for further reference 

and included in separate appendices for neurological 

effects, immune effects, cardiovascular effects, renal 

effects, and reproductive and developmental effects.

1.2.4 Authoritative Sources and Peer 

Review

In this evaluation, the NTP made extensive use of 

recent government assessments of the health effects 

of Pb, especially the U.S. Environmental Protection 

Agency (EPA) 2006 Air Quality Criteria Document 

(AQCD) for Lead (U.S. EPA 2006 and a draft updated 

version, 2012), which has undergone extensive external public peer review. In addition to the EPA’s 2006 

AQCD for Lead, sources include the Agency for Toxic 

Substances and Disease Registry’s (ATSDR) 2007 Toxicological Profile for Lead (ATSDR 2007) and the CDC’s 

Advisory Committee on Childhood Lead Poisoning 

Prevention reports, such as the 2010 Guidelines for 

the Identification and Management of Lead Exposure 

in Pregnant and Lactating Women (CDC 2010b).

The NTP used independent subject matter 

experts as technical advisers to provide scientific 

input and to review pre-public release drafts of each 

chapter summarizing the evidence that health effects 

are associated with low-level Pb, the appendices, and 

Section 3.0 that provides background on Pb exposure 

(see Contributors for a list of technical advisers). Peer 

review of the draft document was conducted by an 

expert panel of ad hoc reviewers at a public meeting 

held November 17-18, 2011, in Research Triangle Park, 

NC (see Peer-Review of the Draft NTP Monograph for 

details). Comments from peer reviewers and written 

public comments received on the draft monograph 

were considered during finalization of the document. 

The NTP concurred with the expert panel on all of 

the conclusions regarding health effects of Pb in this 

final document.

1.3 What Does It Mean to Refer to Blood 

Pb Levels <10 μg/dL?

The overwhelming majority of human epidemiological studies with Pb exposure data measured Pb 

in whole blood, and this measure of exposure serves 

as the basis for the evaluation of Pb levels <10 μg/dL. 

An individual’s blood Pb level reflects an equilibrium 

between current environmental Pb exposure and 

the preexisting amount of Pb in the body, stored primarily in bone (Factor-Litvak et al. 1999, Brown et al.

2000, Chuang et al. 2001). In adults, bone and teeth 

store 90-95% of the total body burden of Pb, while in 

young children, bone Pb represents a smaller fraction 

(down to 70%) (Barry 1981, for review, see Barbosa et 

al. 2005, Hu et al. 2007). The body eliminates half of 
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NTP Monograph on Health Effects of Low-Level Lead xvii

the Pb in circulating blood (half-life) in approximately 

one month, while bone is a more stable repository for 

Pb and, therefore, bone Pb levels reflect cumulative 

exposure to Pb integrated over years or even decades 

(reviewed in Hu et al. 1998, Hu et al. 2007). The halflife of Pb in bone ranges from 10 to 30 years, depending on the rate of bone turnover, which in turn varies 

by type of bone and life stage (Rabinowitz 1991). In 

young children, continuous growth results in constant bone remodeling, and bone Pb is exchanged 

with blood Pb much more frequently than in adults 

(reviewed in Barbosa et al. 2005, Hu et al. 2007).

This evaluation focuses on the relationship 

between health effects and blood Pb levels because 

blood Pb is the most widely available measure of 

exposure, blood Pb reflects the equilibrium between 

current and past exposure, as described above, and 

numerous studies have reported an association 

between blood Pb levels and health outcomes. However, measuring Pb in one tissue at one point in time 

does not present a complete picture of either current 

or cumulative Pb exposure, and bone Pb reflects longterm stores of Pb in the body better than does blood 

Pb (reviewed in Barbosa et al. 2005, Hu et al. 2007); 

therefore, bone Pb data were also considered when 

available. Note that measuring bone Pb is expensive, 

requires specialized equipment that is not generally 

accessible, and requires study subjects to travel to 

the location of the measurement apparatus (K-x-ray 

fluorescence); thus, fewer Pb data are available for 

bone than for blood.

Before bans on Pb in paint, solder, and gasoline, 

environmental Pb levels in the United States were 

higher, so older adults accumulated more Pb as children than children do today. Average blood Pb levels 

in children 1-5 years of age have decreased 10-fold 

over the last 30 years, from 15.1 μg/dL in 1976-1980 

to 1.51 μg/dL in 2007-2008 (geometric means; CDC 

2007, 2011). This is clearly good news for current 

populations of children and represents a significant 

public health accomplishment. However, most U.S. 

adults who were born before 1980 had blood Pb 

levels >10 μg/dL during early childhood, so health 

effects in adults today may have been influenced 

by blood Pb levels >10 μg/dL that many individuals 

experienced earlier in life.

Keeping childhood blood Pb levels in mind, 

there are data on multiple health effects in adults 

for which studies report a significant relationship 

between concurrent blood Pb levels as adults and the 

health effect (e.g., elevated blood pressure, reduced 

kidney function, or decreases in specific measures 

of cognitive function). There is a considerable body 

of evidence that these health effects are associated 

with Pb exposure, and multiple studies report a significant association with concurrent blood Pb levels 

<10 μg/dL. Furthermore, the association with blood 

Pb is supported by the consistency of effects among 

epidemiological studies and biological coherence 

with animal data. It is well recognized that the role of 

early-life Pb exposure cannot be discriminated from 

the role of concurrent blood Pb without additional 

long-term studies. To eliminate the potential role of 

early-life blood Pb levels >10 μg/dL on health effects 

observed in adults with blood Pb levels <10 μg/dL, 

prospective studies (following a group over time) 

would be required in a group with blood Pb levels 

consistently <10 μg/dL from birth until measurement 

of the outcome of interest.

As described in Section 1.2.2, the NTP’s conclusions were derived by evaluating data from epidemiological studies with a focus on blood Pb levels 

<10 μg/dL. The evidence discussed for specific health 

outcomes within each chapter varies by study design 

and type of analyses used to examine the relationship of the health outcome with blood Pb across the 

hundreds of studies evaluated. In some cases, studies 

examined only groups with blood Pb levels <10 μg/dL, 

<5 μg/dL, or even lower, and the association of the 

health effect with the blood Pb level is clear. For 

example, Lanphear et al. (2000) reported that higher 

blood Pb levels were associated with lower academic 

performance in a cross-sectional study (examining 

one point in time) of 4,853 children 6-16 years of age 

from the NHANES III data set. When they analyzed 

only children with blood Pb <10 μg/dL (n=4,681) 

or <5 μg/dL (n=4,043), the association with blood 

Pb was still significant (p<0.001 for <10 μg/dL and 

<5 μg/dL). In other cases, studies reported a significant association between blood Pb and an effect in 

a group whose mean blood Pb level was <10 μg/dL 

(e.g., higher blood Pb levels were associated with 

higher blood pressure in 964 adults in the Baltimore 

Memory Study (Martin et al. 2006)). These analyses 

support an effect of a blood Pb level <10 μg/dL, but 

they do not exclude the possibility that individuals 

significantly above or below the mean blood Pb level 

are driving the effect, or that past exposure levels are 
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driving the effect. Finally, some studies compared 

effects between two groups with higher and lower 

blood Pb levels. For example, Naicker et al. (2010) 

compared the effect of a blood Pb level ≥5 μg/dL with 

a blood Pb level <5 μg/dL on developmental markers 

of puberty in 13-year-old girls in South Africa (n=682) 

and found that a blood Pb level ≥5 μg/dL was significantly associated with delayed breast development, 

pubic hair development, and age of menarche.

1.4 Health Effects Evidence

1.4.1 NTP Conclusions

The NTP concludes that there is sufficient evidence 

for adverse health effects in children and adults at 

blood Pb levels <10 μg/dL, and <5 μg/dL as well (see 

Table 1.1 for summary of effect by life stage at which 

the effect is identified). A major strength of the evidence supporting effects of low-level Pb comes from 

the consistency demonstrated by adverse effects 

associated with blood Pb <10 μg/dL across a wide 

range of health outcomes, across major physiological 

systems from reproductive to renal, among multiple 

groups, from studies using substantially different 

methods and techniques, and for health effects in 

both children and adults.

In children, there is sufficient evidence that blood 

Pb levels <5 μg/dL are associated with increased diagnosis of attention-related behavioral problems, greater 

incidence of problem behaviors, and decreased cognitive performance as indicated by (1) lower academic 

achievement, (2) decreased intelligence quotient (IQ), 

and (3) reductions in specific cognitive measures. 

There is also limited evidence that blood Pb <5 μg/dL

is associated with delayed puberty and decreased 

kidney function in children ≥12 years of age. There 

is sufficient evidence that blood Pb levels <10 μg/dL 

in children are associated with delayed puberty and 

reduced postnatal growth. There is limited evidence 

that blood Pb levels <10 μg/dL are associated with 

elevated serum immunoglobulin E (IgE), which is a 

principal mediator of hypersensitivity; consistent with 

this effect, there is limited evidence that blood Pb levels <10 μg/dL are associated with changes to an IgErelated health effect, allergy diagnosed by skin prick 

test to common allergens. There is inadequate evidence of an association between blood Pb <10 μg/dL

in children and other allergic diseases, such as eczema 

or asthma. There is also inadequate evidence of an 

association between blood Pb <10 μg/dL and cardiovascular effects in children of any age, or renal function in children <12 years of age.

In adults, there is sufficient evidence that blood 

Pb levels <5 μg/dL are associated with decreased 

renal function and that blood Pb levels <10 μg/dL are 

associated with increased blood pressure and hypertension. There is sufficient evidence that maternal 

blood Pb levels <5 μg/dL are associated with reduced 

fetal growth and limited evidence that maternal blood 

Pb levels <10 μg/dL are associated with increased 

spontaneous abortion and preterm birth. There is 

sufficient evidence that blood Pb levels <10 μg/dL, 

and limited evidence that blood Pb levels <5 μg/dL, 

are associated with essential tremor in adults. There 

is also limited evidence for an association between 

blood Pb <10 μg/dL and increased cardiovascularrelated mortality, decreased auditory function, the 

neurodegenerative disease amyotrophic lateral sclerosis (ALS), and decreases in specific measures of cognitive function in older adults. The NTP conclusions 

of associations between blood Pb levels <10 μg/dL

in adults and health effects cannot completely eliminate the potential contributing effects of early-life 

blood Pb levels, as discussed in Section 1.3.

Although the relationship between many health 

effects and bone Pb as a measure of exposure has 

not been examined, the data support the importance 

of cumulative Pb exposure on cardiovascular effects 

of Pb in adults, as well as neurocognitive decline 

in adults, because the association between Pb and 

these endpoints is more consistent for bone Pb than 

for blood Pb.

1.4.2 Neurological Effects

The NTP concludes that there is sufficient evidence 

that blood Pb levels <5 μg/dL are associated with 

adverse neurological effects in children and limited 

evidence that blood Pb levels <10 μg/dL are associated with adverse neurological effects in adults (see 

Table 1.2 for summary of effects).

Unlike the data set for most other health effect 

areas, there are a number of prospective studies of 

neurological effects that include measures of prenatal exposure (either maternal blood or umbilical cord 

blood Pb levels). These prospective studies provide 

limited evidence that prenatal exposure to blood 

Pb levels <5 μg/dL is associated with decreases in 

measures of general and specific cognitive function 
NTP Monograph on Health Effects of Low-Level Lead xix

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Table 1.1: NTP conclusions on health effects of low-level Pb by life stage

Life Stage Blood Pb Level NTP Conclusion Principal Health Effects Bone Pb Evidence

Children <5 μg/dL Sufficient Decreased academic achievement, IQ, and specific cognitive measures; increased incidence of attention-related 

behaviors and problem behaviors

Tibia and dentin Pb are associated with attentionrelated behaviors, problem behaviors, and cognition.

Limited Delayed puberty and decreased kidney function in children ≥12 years of age The one available study of bone Pb in children does not support an association with postnatal growth.

<10 μg/dL Sufficient Delayed puberty, reduced postnatal growth, decreased 

IQ, and decreased hearing

No data

Limited Increased hypersensitivity/allergy by skin prick test to 

allergens and increased IgE* (not a health outcome)

No data

Inadequate Any age – asthma, eczema, nonallergy immune function, 

cardiovascular effects; <12 years of age – renal function

No data

Adults <5 μg/dL Sufficient Decreased glomerular filtration rate; maternal blood Pb 

associated with reduced fetal growth

The one available study of bone Pb in the general population supports an association between bone Pb and decreased kidney function.Maternal bone Pb is associated with reduced fetal growth.

Limited Increased incidence of essential tremor No data

<10 μg/dL Sufficient Increased blood pressure, increased risk of hypertension, 

and increased incidence of essential tremor

The association between bone Pb and cardiovascular effects is more consistent than for blood Pb.

Limited Psychological effects, decreased cognitive function, decreased hearing, increased incidence of ALS, and increased 

cardiovascular-related mortality; maternal blood Pb associated with increased incidence of spontaneous abortion 

and preterm birth

The association between bone Pb and cognitive decline is more consistent than for blood Pb.

Inadequate Immune function, stillbirth, endocrine effects, birth defects, 

fertility or time to pregnancy**, sperm parameters**

No data

Abbreviations: ALS, amyotrophic lateral sclerosis; IgE, immunoglobulin E; IQ, intelligence quotient

*Increased serum IgE is associated with hypersensitivity; however, as described in Section 1.4.3, increased IgE does not equate to disease.

**The NTP concludes that there is inadequate evidence that blood Pb levels <10 μg/dL are associated with fertility, time to pregnancy, and sperm parameters; however, given 

the basis of the original nomination, the NTP evaluated the evidence that higher blood Pb levels (i.e., >10 μg/dL) are associated with reproductive and developmental effects, and those conclusions are discussed in Section 1.4.6 and presented in Table 1.2.
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Table 1.2: NTP conclusions on health effects of low-level Pb by major health effect areas

Health Area Population or Exposure Window NTP Conclusion Principal Health Effects Blood Pb Evidence Bone Pb Evidence

Neurological Prenatal Limited Decrease in measures of cognitive function Yes, <5 μg/dL No data

Limited Decreased IQ, increased incidence of attention-related and problem behaviors, decreased hearing Yes, <10 μg/dL No data

Children Sufficient Decreased academic achievement, IQ, and specific 

cognitive measures; increased incidence of attention-related and problem behaviors

Yes, <5 μg/dL Tibia and dentin Pb are associated with attention, behavior, 

and cognition.

Sufficient Decreased hearing Yes, <10 μg/dL No data

Adults Sufficient Increased incidence of essential tremor Yes, <10 μg/dL No data

Limited Psychiatric effects, decreased hearing, decreased 

cognitive function, increased incidence of ALS

Yes, <10 μg/dL The association between bone 

Pb and cognitive decline is more consistent than blood. Limited Increased incidence of essential tremor Yes, <5 μg/dL

Immune Children Limited Increased hypersensitivity/allergy by skin prick 

test to common allergens and IgE* (not a health outcome)

Yes, <10 μg/dL No data

Inadequate Asthma, eczema Unclear No data

Adults Inadequate  – Unclear No data

Cardiovascular Children Inadequate  – Unclear No data

Adults Sufficient Increased blood pressure and increased risk of 

hypertension

Yes, <10 μg/dL The association between bone 

Pb and cardiovascular effects is more consistent than blood. Limited Increased cardiovascular-related mortality and ECG 

abnormalities

Yes, <10 μg/dL

Renal Children <12 years old Inadequate  – Unclear No data

Children ≥12 years old Limited Decreased glomerular filtration rate Yes, <5 μg/dL No data

Adults Sufficient Decreased glomerular filtration rate Yes, <5 μg/dL Yes, one study

Reproductive and Developmental

Prenatal Limited Reduced postnatal growth Yes, <10 μg/dL No data

Children Sufficient Delayed puberty, reduced postnatal growth Yes, <10 μg/dL

One study does not support 

effects of bone Pb on growth. Limited Delayed puberty Yes, <5 μg/dL

Adults Women Sufficient Reduced fetal growth Yes, <5 μg/dL Maternal tibia Pb is associated

Limited Increase in spontaneous abortion and preterm 

birth

Yes, <10 μg/dL No data

Men Sufficient Adverse changes in sperm parameters and increased time to pregnancy Yes,≥15-20 μg/dL No data

Limited Decreased fertility Yes, ≥10 μg/dL No dataLimited Increased spontaneous abortion Yes, >31 μg/dL No data

Adults Inadequate Stillbirth, endocrine effects, birth defects Unclear No data

Abbreviations: ALS, amyotrophic lateral sclerosis; ECG, electrocardiography; IgE, immunoglobulin E; IQ, intelligence quotient.*Increased serum IgE is associated with hypersensitivity; however, as described in Section 1.4.3, increased IgE does not equate to disease.
NTP Monograph on Health Effects of Low-Level Lead xxi

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evaluated in children. There is also limited evidence 

that prenatal exposure to blood Pb levels <10 μg/dL is 

associated with decreased IQ, increased incidence of 

attention-related behaviors and antisocial behavior 

problems, and decreased hearing measured in children. However, conclusions about effects of prenatal Pb exposure for outcomes evaluated as children 

are complicated by the high degree of correlation 

between prenatal and childhood blood Pb levels and 

as described below, blood Pb levels during childhood 

are also associated with these effects.

In children, there is sufficient evidence that blood 

Pb levels <5 μg/dL are associated with decreases in 

broad based and specific indices of cognitive function and an increase in attention-related behavioral 

problems and antisocial behavioral problems. The 

association between blood Pb and decreased IQ has 

been demonstrated in multiple prospective studies of 

children with blood Pb levels <10 μg/dL, pooled analyses that reported effects with peak blood Pb levels 

<7.5 μg/dL (Lanphear et al. 2005), and multiple crosssectional studies that reported effects with mean blood 

Pb levels <5 μg/dL. Lower levels of academic achievement, as determined by class rank and achievement 

tests, have been reported in multiple prospective 

and cross-sectional studies of children with blood Pb 

<5 μg/dL. An association between blood Pb <5 μg/dL

and decreases in specific measures of cognitive function has been demonstrated in prospective and crosssectional studies using a wide range of tests to assess 

cognitive function. Increases in attention-related and 

problem behaviors are consistently reported in studies 

with mean blood Pb levels <5μg/dL. The NTP concludes 

that blood Pb is associated with attention-related 

behaviors rather than attention deficit hyperactivity 

disorder (ADHD) alone because (1) this broad term 

more accurately reflects the range of Pb-associated 

behavioral effects in the area of attention, of which 

ADHD is one example on the more severe end of the 

spectrum, and (2) determination of ADHD in children 

from available studies are not as precise as an ADHD 

diagnosis by trained clinicians using specific DSMIV-TR criteria. There is sufficient evidence that blood 

Pb levels <10 μg/dL in children are associated with 

decreased auditory acuity. Multiple cross-sectional 

studies reported hearing loss, as indicated by higher 

hearing thresholds and increased latency of brainstem 

auditory evoked potentials (BAEPs), in children with 

blood Pb levels <10 μg/dL.

In adults, there is limited evidence that blood Pb 

levels <10 μg/dL are associated with psychiatric outcomes (including anxiety and depression), decreased 

auditory function, ALS, and decreases in specific 

measures of cognitive function in older adults. There 

is sufficient evidence that blood Pb levels <10 μg/dL 

are associated with essential tremor in adults, and 

limited evidence for blood Pb levels <5 μg/dL. Associations with decreases in cognitive function in adults 

are more consistent for bone Pb than for blood Pb, 

suggesting a role for cumulative Pb exposure.

1.4.3 Immune Effects

The NTP concludes that there is limited evidence 

that blood Pb levels <10 μg/dL are associated with 

adverse immune effects in children and that there is 

inadequate evidence in adults (see Table 1.2).

In children, there is limited evidence that blood 

Pb levels <10 μg/dL are associated with changes to 

an immune-related health outcome such as allergy or 

increased hypersensitivity. There is also limited evidence that blood Pb levels <10 μg/dL are associated 

with elevated serum IgE levels. Five studies of groups 

with mean blood Pb levels of 10 μg/dL and below 

support the relationship between blood Pb and 

increased serum IgE. Two of these studies reported 

an association at blood Pb levels of ≥10 μg/dL rather 

than <10 μg/dL, and only one of the remaining studies 

adjusted for age, a particularly important confounder 

in analyses of IgE in children. Although increases in 

serum levels of total IgE are not definitive indicators 

of allergic disease, elevated levels of IgE are primary 

mediators of hypersensitivity associated with sensitization and allergic disease. Therefore, the studies 

demonstrating Pb-related increases in IgE suggest a 

link to hypersensitivity and support more definitive 

data such as a prospective study that found blood 

Pb levels <10 μg/dL were associated with increased 

hypersensitivity (or allergy by skin prick testing) in 

children. These data support the conclusion of limited 

evidence that increased hypersensitivity responses or 

allergy are associated with blood Pb levels <10 μg/dL 

in children; however, there is inadequate evidence of 

an association between blood Pb and other allergic 

diseases such as eczema or asthma.

There is inadequate evidence in adults to ad­dress the potential association between blood Pb

<10 μg/dL and IgE, allergy, eczema, or asthma. Few 

studies have investigated the relationship between 
xxii NTP Monograph on Health Effects of Low-Level Lead

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immune function and Pb in humans, and most studies 

reported general observational markers of immunity 

rather than function. There is inadequate evidence 

that blood Pb levels <10 μg/dL are associated with 

observational immune effects such as altered lymphocyte counts or serum levels of IgG, IgM, or IgA in 

the blood of children or adults, because few studies 

have examined the lower exposure level and the available data are inconsistent. There is also inadequate 

evidence that blood Pb levels <10 μg/dL are associated with changes in immune function other than 

hypersensitivity, because few studies have examined 

immune function at lower blood Pb levels.

Bone Pb levels may be particularly relevant for 

cells of the immune system and immune function. All 

of the white blood cells or leukocytes that develop 

after birth are derived from progenitor cells in the bone 

marrow. Unfortunately, very few studies of immune 

effects have measured exposure other than blood Pb; 

therefore, the relative importance of blood or bone Pb 

levels for immune effects of Pb is unknown.

1.4.4 Cardiovascular Effects

The NTP concludes that there is sufficient evidence 

that blood Pb levels <10 μg/dL in adults are associated with adverse effects on cardiovascular function 

and that there is inadequate evidence to evaluate 

cardiovascular effects in children (see Table 1.2 for 

summary of effects).

There is sufficient evidence of a bone Pb-related 

increase in the risk of hypertension and increases in 

blood pressure in adults. Two prospective studies and 

five cross-sectional studies support a significant association between bone Pb and blood pressure or hypertension in groups with blood Pb levels <10 μg/dL. Studies show less consistent associations between blood 

Pb and blood pressure or hypertension than for bone 

Pb; however, most of the recent studies with mean 

blood Pb levels <5 μg/dL found significant associations 

between concurrent blood Pb levels and increased 

blood pressure. There is sufficient evidence that blood 

Pb levels <10 μg/dL increase the risk of hypertension 

during pregnancy, supported by one prospective study 

and five cross-sectional studies with blood Pb levels 

during pregnancy <10 μg/dL. There is limited evidence 

of increased risk of cardiovascular mortality associated with blood Pb levels <10 μg/dL. An association 

between increased cardiovascular mortality and blood 

Pb is supported by three prospective studies (two of 

which used the same NHANES III sample) but is not 

supported by two other prospective studies. One of 

the studies that did not find an association with blood 

Pb (at a mean blood Pb level of 5.6 μg/dL) reported 

a significant association between bone Pb levels and 

increased cardiovascular mortality. There is limited evidence for Pb effects on other cardiovascular outcomes, 

including electrocardiography (ECG) abnormalities and 

clinical cardiovascular disease primarily due to lack of 

replication studies. Chronic Pb exposure appears to 

be more critical than current Pb exposure, as shown 

by more consistent associations between chronic 

cardiovascular effects and bone Pb than for blood Pb. 

Studies support an association with concurrent blood 

Pb levels; however, the potential effect of early-life 

blood Pb levels on cardiovascular outcomes in adults 

cannot be discriminated from the effect of concurrent 

blood Pb levels without additional prospective studies 

in a population for which blood Pb levels remain consistently below 10 μg/dL from birth until evaluation 

of the various cardiovascular outcomes as described 

in Section 1.3. There is inadequate evidence for Pb 

effects on heart rate variability, due to a lack of replicated studies.

There is inadequate evidence to assess whether 

children or menopausal women present a sensitive 

life stage for cardiovascular effects of Pb. No prospective studies have followed children with early-life Pb 

measures and evaluated cardiovascular health in 

adulthood. During periods of bone demineralization 

such as menopause and with osteoporosis, Pb stored 

in bone may enter the blood stream at a higher rate, 

increasing circulating Pb levels; for example, increased 

blood Pb levels have been demonstrated in women 

after menopause in several studies (e.g., Silbergeld et 

al. 1988, Symanski and Hertz-Picciotto 1995, Webber 

et al. 1995, Korrick et al. 2002). Too few studies have 

examined Pb-related cardiovascular health risks in 

postmenopausal women to enable conclusions.

Although hypertension can contribute to adverse 

renal effects, and kidney dysfunction can contribute 

to increased blood pressure, effects are considered 

separately in this evaluation because most studies 

examined one outcome or the other, rather than testing both systems comprehensively.

1.4.5 Renal Effects

The NTP concludes that there is sufficient evidence 

that blood Pb levels <5 μg/dL are associated with 
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NTP Monograph on Health Effects of Low-Level Lead xxiii

adverse renal effects in adults (see Table 1.2 for summary of effects). There is limited evidence that blood 

Pb levels <5 μg/dL are associated with adverse renal 

effects in children ≥12 years of age, and the current 

evidence is inadequate to conclude that blood Pb 

<10 μg/dL is associated with renal effects in children 

<12 years of age.

There is sufficient evidence that blood Pb levels <5 μg/dL are associated with adverse effects on 

kidney function in adults. Most of the 13 epidemiological studies of the general population reported 

blood Pb levels <10 μg/dL are associated with (1) 

increased risk of chronic kidney disease (CKD), and 

(2) decreases in the estimated glomerular filtration 

rate (eGFR) and creatinine clearance, markers of kidney function. The associations are typically stronger 

in studies of groups with hypertension or diabetes. 

Few studies have examined other markers of Pb 

exposure, such as bone Pb; therefore, it is unknown 

whether blood or bone Pb levels would be a better 

measure of exposure for kidney effects related to Pb. 

Epidemiological data from the general population 

support an association with concurrent blood Pb levels in adults; however, the potential effect of early-life 

blood Pb levels on kidney function in adults cannot 

be discriminated from the effect of concurrent blood 

Pb levels without additional prospective studies in a 

group for which blood Pb levels remain consistently 

below 10 μg/dL from birth until evaluation of kidney 

function as described in Section 1.3.

There is inadequate evidence to address the 

potential association between blood Pb levels 

<10 μg/dL in children <12 years of age and impaired 

kidney function, because results are inconsistent 

and available studies of kidney function in young 

children are less reliable in general because tests 

of kidney function lack clear predictive value in this 

age group. There is limited evidence that blood Pb 

levels <5 μg/dL are associated with adverse effects 

on kidney function in children ≥12 years of age. This 

conclusion is based on one study of NHANES data, 

which reported effects in children ≥12 years of age 

that are consistent with reduced eGFR reported in 

adults in several NHANES studies.

1.4.6 Reproduction and Developmental 

Effects

The NTP concludes that there is sufficient evidence 

that blood Pb levels <10 μg/dL are associated with 

adverse health effects on development in children 

and that blood Pb levels <5 μg/dL are associated 

with adverse health effects on reproduction in adult 

women (see Table 1.2 for summary of effects).

Because most data on reproductive effects come 

from studies of occupational exposure, many of the 

available studies are for blood Pb levels >10 μg/dL. 

For this reason, and because the original nomination 

focused on reproductive and developmental effects, 

the evaluation of health effects in this area includes 

higher blood Pb levels, unlike other sections of this 

document. Consideration of these higher blood Pb 

levels resulted in several conclusions for Pb-related 

reproductive effects in men but did not affect the 

conclusions for women or children.

Unlike the data for most other health effect areas, 

a number of prospective studies of developmental 

effects have included prenatal measures of exposure (either maternal blood or umbilical cord blood). 

These prospective studies provide limited evidence 

that prenatal exposure to blood Pb levels <10 μg/dL is 

associated with reduced postnatal growth in children. 

Conclusions about effects of prenatal Pb exposure in 

children are complicated because blood Pb levels 

<10 μg/dL during childhood are also associated with 

reduced postnatal growth, and prenatal Pb levels are 

highly correlated with childhood Pb levels.

In children, there is sufficient evidence that 

blood Pb levels <10 μg/dL are associated with delayed 

puberty and limited evidence for this effect at blood 

Pb levels <5 μg/dL. Nine studies reported that concurrent blood Pb levels <10 μg/dL in children are 

associated with delayed puberty. There is sufficient 

evidence that blood Pb levels <10 μg/dL are associated with decreased postnatal growth. Numerous 

cross-sectional studies, including studies with large 

sample sizes such as the NHANES data sets, reported 

that concurrent blood Pb <10 μg/dL in children is 

associated with reduced head circumference, height, 

or other indicators of growth.

In adults, there is sufficient evidence that maternal blood Pb levels <5 μg/dL are associated with 

reduced fetal growth or lower birth weight. Three 

prospective studies with maternal blood Pb data during pregnancy, a large retrospective study (examining 

medical history) of >43,000 mother-infant pairs with 

a mean maternal blood Pb level of 2.1 μg/dL, and 

several cross-sectional studies of Pb levels in maternal or cord blood at delivery support an association 
xxiv NTP Monograph on Health Effects of Low-Level Lead

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between higher blood Pb and reduced fetal growth 

at mean blood Pb levels from 1 to 10 μg/dL. Although 

maternal or paternal bone Pb data are not available 

in most studies of reproductive health outcomes, a 

set of studies of a single group reported that higher 

maternal bone Pb is related to lower fetal growth. 

There is also limited evidence that maternal blood Pb 

levels <10 μg/dL are associated with preterm birth and 

spontaneous abortion. Although several prospective 

studies reported an association between maternal 

blood Pb and preterm birth, the conclusion of limited 

evidence is due to inconsistent results and a retrospective study with a large cohort of >43,000 mother-infant 

pairs not finding an association between maternal 

blood Pb levels and preterm birth. The conclusion of 

limited evidence for an association with spontaneous 

abortion is based primarily on the strength of a single 

prospective nested case-control study in women, with 

additional support provided by occupational studies 

that reported an association with Pb exposure but 

lacked blood Pb measurements. In men, there is inadequate evidence that blood Pb levels <10 μg/dL are 

associated with effects on reproduction.

In men there is sufficient evidence that blood 

Pb levels ≥15 μg/dL are associated with adverse 

effects on sperm or semen and that blood Pb levels 

≥20 μg/dL are associated with delayed conception 

time. Decreases in sperm count, density, and concentration have been reported in multiple retrospective and cross-sectional occupational studies of men 

with mean blood Pb levels from 15 to 68 μg/dL. Four 

studies reported increased time to pregnancy in 

women whose male partners had blood Pb levels of 

20-40μg/dL. A single retrospective occupational study 

reported increased risk of infertility among men with 

blood Pb levels ≥10 μg/dL, and the consistency of this 

observation with other studies reporting effects on 

time to pregnancy at higher blood Pb levels supports 

a conclusion of limited evidence that blood Pb levels 

≥10 μg/dL in men are associated with other measures 

of reduced fertility. There is also limited evidence that 

paternal blood Pb levels >31 μg/dL are associated 

with spontaneous abortion, based primarily on the 

strength of a single retrospective nested case-control 

study in men, with additional support provided by 

occupational studies that reported an association 

with Pb exposure but lacked blood Pb measurements.

1.5 Future Research

There are robust data and sufficient evidence that 

blood Pb levels <10 μg/dL in children and adults are 

associated with adverse health effects across a wide 

range of health outcomes, as described above. Over 

time, epidemiological studies have provided data to 

support health effects at lower and lower blood Pb 

levels, particularly in children. Prospective studies in 

children better address the lower limits of Pb exposure associated with health effects because they focus 

on children whose blood Pb levels remain <10 μg/dL 

or <5 μg/dL with certainty throughout their lifetime. 

Studies of health effects in adults cannot eliminate the 

potential effects of early-life blood Pb levels on health 

effects observed as adults. This is particularly important 

in an evaluation of the health effects of blood Pb levels 

<10 μg/dL because older adults were likely to have had 

blood Pb levels >10 μg/dL as children (see discussion in

Section 1.3), compared with only 0.8% of children with 

confirmed blood Pb levels >10 μg/dL in 2008.

Clarification of the effects of early-life blood 

Pb levels relative to the effects of concurrent blood 

Pb levels remains a significant issue for evaluating 

Pb-related health effects in adults. Epidemiological 

data from adults support an association between 

concurrent blood Pb levels <5 μg/dL and decreased 

renal function and between concurrent blood Pb 

levels <10 μg/dL and increased blood pressure and 

hypertension. Future research should be directed 

at clarifying the extent to which early life exposure 

(e.g., blood Pb levels >10 μg/dL) contribute to health 

effects observed in adults. Long-term prospective 

studies in a group for which blood Pb levels remain 

consistently <10 μg/dL from birth until the outcome 

of interest is measured would take one step in this 

direction by eliminating the potential role of early-life 

blood Pb levels >10 μg/dL on health effects observed 

in adults with concurrent blood Pb levels <10 μg/dL.
Methods

NTP Monograph on Health Effects of Low-Level Lead 1

2.0 METHODS

The NTP’s conclusions on health effects of low-level Pb 

are based on evaluation of data from epidemiological 

studies with a focus on blood Pb levels <10 μg/dL. The

methodological approach began with a statement of 

the key questions addressed by this evaluation. The 

general approach for developing the NTP’s conclusions 

on evidence of an association between blood Pb levels 

<10 μg/dL and specific health effects is described below, 

along with the format and definitions used throughout 

the document. The structure of appendix tables summarizing the relevant literature for each health effect 

area is also described below. The NTP considered several recent government evaluations of the health effects 

of Pb as authoritative sources to supplement a review of 

the primary epidemiological literature, and these documents are briefly described in this section. The NTP also 

used independent subject matter experts as technical 

advisors to provide scientific input and to review prepublic release drafts of each chapter summarizing the 

evidence for health effects associated with low-level Pb, 

as well as the appendices and background exposure 

section. The literature search strategy and details of the 

peer-review process are also described below.

2.1 Key Questions

What is the evidence that adverse health effects are 

associated with blood Pb <10 μg/dL?

6 What reproductive, developmental, neurological, 

immune, cardiovascular, and renal health effects 

are associated with blood Pb levels <10 μg/dL?

6 What is the blood Pb level associated with a given 

health effect (i.e., <10 μg/dL or <5 μg/dL)?

6 At which life stages (childhood or adulthood) is 

the effect identified?

6 Are there data to evaluate the association between 

bone Pb and the health effect, and how does the 

association to this biomarker of Pb exposure compare to the association with blood Pb?

2.2 Approach to Develop Health Effects 

Conclusions

Conclusions in the NTP evaluation of Pb-related 

health effects in humans associated with low-level 

Pb were derived by evaluating the data from epidemiological studies with a focus on blood Pb levels 

<10 μg/dL. The evaluation includes a review of the 

primary epidemiological literature, and these studies 

formed the basis for the NTP conclusions. The quality of individual studies was considered in reaching 

health effects conclusions, including consideration of 

known confounders, appropriateness of the method 

of diagnosis, strength of the study design, and the 

sample size. General strengths and limitations of 

study designs were considered when developing conclusions, with prospective studies providing stronger 

evidence than cross-sectional or case-control studies. 

Consistency of effects across the body of evidence 

and important factors such as the number of studies, 

exposure levels, biological plausibility, and support 

from the animal literature were all assessed when 

developing the NTP conclusions.

Draft NTP conclusions were evaluated for consistency with health effect conclusions from recent 

government evaluations considered authoritative 

sources: the U.S. EPA 2006 Air Quality Criteria Document (AQCD) for Lead (U.S. EPA 2006) and the ATSDR 

2007 Toxicological Profile for Lead (ATSDR 2007) (see 

Section 2.4 for discussion). Technical advisors with 

relevant subject matter expertise served as another 

authoritative source (see Section 2.4.4 for details). 

Technical advisors were asked to critically evaluate 

every one of the NTP’s conclusions regarding the 

potential for adverse health effects to occur at blood 

Pb levels <10 μg/dL and to determine whether the science cited was technically correct, clearly stated, and 

supported the NTP’s conclusions in pre-public release 

drafts of each chapter addressing specific health effect 

areas. As described in Section 2.6 and Peer-Review 

of the Draft NTP Monograph, a draft version of the 

Monograph was released for public comment and peer 

review by an expert panel of ad hoc reviewers. Written 

public comments and comments from peer reviewers 

were considered during finalization of the document.

Studies were evaluated for evidence that lowlevel Pb is associated with neurological, immunological, cardiovascular, renal, and/or reproductive and 

developmental effects. These health effects areas 

were selected because there is a relatively large 

database of human studies in each area. The NTP considered four possible conclusions for specific health 

effects within each area.

Sufficient Evidence of an Association:

An association is observed between the exposure and health outcome in studies in which 

chance, bias, and confounding could be ruled 

out with reasonable confidence.
Methods

2 NTP Monograph on Health Effects of Low-Level Lead

Limited Evidence of an Association:

An association is observed between the exposure and health outcome in studies in which 

chance, bias, and confounding could not be 

ruled out with reasonable confidence.

Inadequate Evidence of an Association:

The available studies are insufficient in quality, 

consistency, or statistical power to permit a 

conclusion regarding the presence or absence 

of an association between exposure and health 

outcome, or no data in humans are available.

Evidence of No Association:

Several adequate studies covering the full range 

of levels of exposure that humans are known 

to encounter (in this case limited to blood Pb 

levels <10 μg/dL) are mutually consistent in not 

showing an association between exposure to 

the agent and any studied endpoint.

The discussion of each health effect begins 

with a statement of the NTP’s conclusion regarding 

whether the specific effect is associated with a blood 

Pb level <10 μg/dL or <5 μg/dL and the age group 

in which it is or is not identified (childhood or adulthood), as well as the timing of exposure associated 

with the effect (prenatal, childhood, concurrent) 

when available. Then key data and principal studies 

considered in developing the NTP’s conclusions are 

then discussed in detail. Each section concludes with 

a summary discussing each health effect, describing 

experimental animal data that relate to the human 

data, and stating the basis for the NTP’s conclusions.

For the purposes of this evaluation, “children” 

refers to individuals <18 years of age unless otherwise specified. In addition to the blood Pb level 

of <10 μg/dL, a lower effect level of <5 μg/dL was 

also selected because it is commonly used in epidemiological studies to categorize health effect data by 

exposure levels; therefore, data are often available to 

evaluate health effects for groups above and below 

this value as well. Findings described in the text as 

having an “association” or “significant association” 

reflect a statistically significant result with a p-value 

<0.05 unless otherwise indicated.

2.3 Appendices of Studies Considered

The information to support the NTP’s conclusions 

for individual health effects is presented in each 

chapter. Human studies from groups with low-level 

Pb exposure that were considered in developing the 

conclusions are also abstracted for further reference 

and are included in separate appendices for each 

health effect area.

Each appendix table includes the following column headings:

Description: study design, reference, and geographic location

Population: sample size, description, years of 

study, and percent male

Age: mean age and standard deviation of the 

subjects

Blood Pb: mean blood Pb level and standard 

deviation (in μg/dL)

Outcomes: health effects assessed

Statistical: methods used and cofactors included in 

analyses

Findings: summary of results (bolded if statistical 

significance tests had a p-value <0.05)

Observed Effect: conclusion (Effect/No Effect/

Equivocal) and description

Potential overlap of subjects in multiple publications from the same epidemiological study is 

indicated in the first column of each appendix. 

These studies were not considered as independent 

findings to be evaluated in developing the NTP’s 

conclusions.

The grouping of studies within each appendix 

table varied by health effects considered:

Appendix A. Neurological Effects: no grouping, 

meta-analyses shaded

Appendix B. Immune Effects: grouped by low 

(<15 μg/dL) and high (>15 μg/dL) exposure

Appendix C. Cardiovascular Effects: grouped by 

outcome, meta-analyses shaded

Appendix D. Renal Effects: no grouping

Appendix E. Reproductive and Developmental 

Effects: grouped by outcome

Within each grouping, studies are listed alphabetically by first author and then chronologically by 

publication date. For the appendix tables grouped 

by outcome, if a publication contained results that 

applied to more than one group, results specific to 

each outcome group were included.

The NTP’s conclusions are based on the evidence from human studies with blood Pb levels of 

<10 μg/dL and therefore the abstracted studies in 
Methods

NTP Monograph on Health Effects of Low-Level Lead 3

the appendices are mainly those with a mean blood 

Pb level of <10 μg/dL. However, studies with data 

reflecting mean exposure levels up to 15 μg/dL were 

also included so that effects at and around 10 μg/dL 

were not missed during the evaluation. Reproductive 

effects in studies with mean blood Pb levels >15 μg/dL 

were included in the evaluation because the data set 

of human studies on these effects associated with 

lower blood Pb levels is limited. For this reason, and 

because the original nomination focused on reproductive and developmental effects, the evaluation 

of health effects in this area includes higher blood 

Pb levels. The immunological effects database was 

adequate to make conclusions on several effects at 

blood Pb levels <10 μg/dL; however, because the 

NTP makes limited reference to studies in humans 

at higher blood Pb levels, Appendix B also includes 

human studies with higher blood Pb levels (i.e., 

>15 μg/dL).

2.4 Authoritative Sources Considered

Recent government evaluations of the health effects 

of Pb include the U.S. EPA 2006 AQCD for Lead (U.S. 

EPA 2006), the ATSDR 2007 Toxicological Profile for 

Lead (ATSDR 2007), and the CDC’s Advisory Committee on Childhood Lead Poisoning Prevention 

(ACCLPP) Reports, such as the 2010 Guidelines for 

the Identification and Management of Lead Exposure in Pregnant and Lactating Women (CDC 2010). 

The NTP made extensive use of these evaluations in 

its assessment, especially the EPA’s 2006 AQCD for 

Lead (U.S. EPA 2006) because it underwent extensive external public peer review. NTP considered the 

conclusions and data summaries from the EPA and 

ATSDR documents. In general, NTP concurred with 

the conclusions and agreed that the data support 

them. Differences between the NTP’s conclusions 

and the 2007 ATSDR Toxicological Profile for Lead 

(ATSDR 2007) and the EPA’s 2006 AQCD (U.S. EPA 

2006) are identified for specific endpoints in this 

document. The database of studies on health effects 

in humans is supported by an equally large body of 

experimental animal studies. In this document, the 

experimental animal data are considered when relevant to reaching conclusions primarily based on 

the human literature. The reader is referred to the 

U.S. EPA AQCD for Lead (U.S. EPA 2006) and ATSDR 

Toxicological Profile for Lead (ATSDR 2007) for more 

in-depth reviews of the animal data.

2.4.1 U.S. EPA 2006 Air Quality Criteria 

Document (AQCD) for Lead

The EPA’s AQCD is an exhaustive review and assessment (>1,200 pages with an additional 900 pages 

of tables and other annex material) of the scientific 

information related to human health and ecological 

effects associated with Pb in ambient air (U.S. EPA 

2006). The EPA’s AQCDs are published periodically 

(the latest draft document, released February of 2012, 

updates the review with literature published since 

the U.S. EPA 2006 AQCD for Lead (U.S. EPA 2006)) 

to provide key scientific assessment of evidence to 

support periodic review of the current Pb National 

Ambient Air Quality Standards. The 2006 EPA AQCD 

for Lead (U.S. EPA 2006) is an extensively reviewed 

document that was subject to public comment and 

review by the Clean Air Scientific Advisory Committee in a series of public meetings. Because EPA is in 

the process of revising the AQCD, the 2012 Integrated 

Science Assessment for Lead (U.S. EPA 2012) is available only as a draft at this time.

2.4.2 ATSDR 2007 Toxicological Profile for 

Lead

The 2007 Toxicological Profile for Lead (ATSDR 2007) 

is a comprehensive evaluation of the available toxicological and epidemiological data on Pb. The toxicological profile is organized around a public health 

statement summarizing the toxicological and adverse 

health effects for Pb. ATSDR’s peer-review process for 

their toxicological profiles includes release for public 

comment and a peer review by a panel of experts.

2.4.3 CDC Lead Panel Documents

CDC’s fifth revision of the statement on preventing Pb 

poisoning in young children includes a companion document developed by the ACCLPP that reviews the scientific evidence for adverse health effects in children at 

blood Pb levels <10 μg/dL. The committee concluded 

that the “overall weight of the evidence supports an 

inverse (negative) association between BLLs [blood 

lead levels] <10 μg/dL and the cognitive function in 

children” (CDC 2005). The report focuses primarily on 

cognitive function, but the committee also concluded 

that additional health effects (e.g., other neurological 

functions, stature, sexual maturation) were associated 

with blood Pb levels <10 μg/dL in children.

The ACCLPP has also prepared a draft report 

providing Guidelines for the Identification and 
4 NTP Monograph on Health Effects of Low-Level Lead

Methods

Management of Lead Exposure in Pregnant and 

Lactating Women (CDC 2010). The report provides 

“practical considerations regarding preventing lead 

exposure during pregnancy, assessment and blood 

lead testing during pregnancy, medical and environmental management to reduce fetal exposure, 

breastfeeding and follow-up of infants and children 

exposed to lead in utero.” The document summarizes the evidence from human studies through 2008 

for health effects of Pb in pregnant women and the 

developing child (concentrating on exposure during 

gestation and from breastfeeding) and provides guidance for clinicians.

2.4.4 Technical Advisors

The primary mechanism for obtaining scientific input 

during development of the draft NTP Monograph on 

Health Effects of Low-Level Pb was through technical 

advisors (see Contributors for list of technical advisors). Technical advisors with relevant subject matter 

expertise were asked to provide input on issues of scientific complexity, adequacy of the literature review, 

and overall presentation of a pre-public release version of the draft NTP monograph. These advisors 

critically evaluated each of the NTP’s health effects 

conclusions and the basis for those conclusions, as 

well as the appendices and the background exposure 

section. Individuals who served as technical advisors 

were screened for potential conflict of interest.

2.5 Literature Search Strategy

The 2006 EPA AQCD for Lead (U.S. EPA 2006) and 

the 2007 ATSDR Toxicological Profile for Lead (ATSDR 

2007) were screened for citations on health effects 

assessed at low-level Pb exposure. The NTP’s conclusions are based on the evidence from human 

studies with blood Pb levels of <10 μg/dL with data 

reflecting mean exposure levels up to 15 μg/dL also 

considered so that effects at and around 10 μg/dL

were not missed during the evaluation. Primary literature searches in MEDLINE®, Web of Science, Scopus, Embase, and TOXNET were conducted on March 

1-5, 2010, to identify relevant studies published 

subsequent to the 2006 EPA and 2007 ATSDR documents. Search terms included the following MeSH 

subject headings: lead or lead poisoning; “diseases 

category” or “anatomy category” for health effects; 

and humans[mh or Medical Subject Headings in 

MEDLINE] or epidemiology[sh or SubHeadings in 

MEDLINE] or epidemiologic studies[mh] or age 

groups[mh] for limiting to human studies.

Because of the heteronym nature of the term 

“lead,” text word searching used four approaches: 

(1) searched for “lead” in title; (2) used various combinations to focus on low-level exposure: “low lead” 

or “low blood lead” or “lower lead” or “lower blood 

lead” or “low level” or “low levels” or “lower level” or 

“lower levels” or “lead level” or “lead levels” or “low 

dose” or “lead induced” or “lead intake” or “blood 

lead”; (3) combined “lead” with heavy metals or cadmium or mercury or arsenic; and (4) when necessary, 

excluded “lead to” or “leads to” from search results. 

For databases that allowed proximity searching, “lead” 

and “low or lower” were required to be in the same 

sentence. This strategy would retrieve articles such 

as “low cadmium and lead levels” or “low blood and 

urine lead levels” or “lower concentrations of lead in 

the blood.” Text words used to retrieve human studies 

included human(s), resident(s), inhabitant(s), population, people, subject(s), patient(s), case(s), women, 

men, girls, boys, parent(s), mother(s), father(s), 

adult(s), child, children, childhood, adolescent(s), 

infant(s), toddler(s), newborn(s), occupation(al), 

work, workplace, worker(s), employee(s), laborer(s), 

and staff.

An updated search was performed September 

12-15, 2011, to identify any additional references 

published since the last search. Technical advisors 

who were involved in the review of the draft document (see below) were also asked to identify relevant 

studies. In addition, NTP published a Federal Register 

notice regarding the low-level Pb evaluation, inviting 

submission of information about recently published/

in-press studies that might be relevant for consideration in the evaluation (75 FR 51815).

2.6 Peer-Review Process

Peer review of the Draft NTP Monograph was conducted by an expert panel of ad hoc reviewers with 

relevant scientific background (i.e., expertise in Pb or 

metals related to reproductive and developmental 

toxicology, neurotoxicology, immunotoxicology, cardiovascular toxicology, renal toxicology, and exposure) 

at a public meeting held November 17-18, 2011 in 

Research Triangle Park, NC (see Peer Review of the 

Draft NTP Monograph for list of panel members). 

The selection of panel members and conduct of the 

peer review were performed in accordance with the 
Methods

NTP Monograph on Health Effects of Low-Level Lead 5

Federal Advisory Committee Act and Federal policies 

and regulations. The panel was charged to determine 

whether the science cited in the draft NTP Monograph 

on Low-Level Lead was technically correct, was clearly 

stated, and supported NTP’s conclusions regarding the 

potential for adverse health effects to occur at blood 

Pb levels <10 μg/dL. Public comments received as part 

of the NTP’s evaluation of health effects of low-level 

Pb, meeting minutes, and other materials from the 

peer-review meeting are available at http://ntp.niehs.

nih.gov/go/37090. Written public comments and comments from peer reviewers were considered during 

finalization of the document.
Methods

6 NTP Monograph on Health Effects of Low-Level Lead

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Exposure

NTP Monograph on Health Effects of Low-Level Lead 7

3.0 EXPOSURE

Studies of health effects of Pb in humans commonly 

use one of several biomarkers to reflect the level of Pb 

exposure in an individual. The overwhelming majority of studies measure whole-blood Pb because blood 

samples are routinely collected and stored in large 

epidemiological studies; furthermore, the methods 

for measuring Pb in whole blood are widespread and 

extensively validated. Bone Pb is more likely to reflect 

cumulative exposure but must be measured by specialized equipment and requires measurements to be 

made on subjects present at a research clinic. Measures of Pb in urine and hair have been used in some 

studies, but how well they reflect the body burden of 

Pb is less clear.

Pb is ubiquitous in the environment, but the level 

of exposure to Pb that individuals experience can vary 

and depends on many factors, including occupation, 

geography, and life stage. This chapter briefly discusses 

common routes of exposure to Pb and associated factors that may affect the risk of exposure.

The NTP made extensive use of recent government evaluations of Pb exposure and associated 

health effects in developing the current assessment. 

The EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and 

ATSDR’s Toxicological Profile for Lead (ATSDR 2007) 

both contain extensive review and discussion of Pb 

exposure, with the AQCD document particularly 

focusing on Pb in air. The NTP also used two CDC documents focused on particularly vulnerable groups: 

the 2010 Guidelines for the Identification and Management of Lead Exposure in Pregnant and Lactating 

Women and the 2005 Preventing Lead Poisoning in 

Young Children report (CDC 2005b, 2010). The EPA is 

in the process of revising the AQCD and has released 

an external review draft that also includes extensive 

discussion of Pb exposures (U.S. EPA 2012).

3.1 What Does It Mean to Refer to Blood 

Pb <10 μg/dL?

This evaluation focuses on the relationship between 

health effects and blood Pb levels <10 μg/dL because 

(1) whole-blood Pb is the most widely available measure of exposure, (2) blood Pb reflects an equilibrium 

between current environmental Pb exposures and Pb 

stored in bone from prior exposures, and (3) numerous studies have reported an association between 

blood Pb levels and health effects.

However, measuring Pb in one tissue at one 

point in time does not present a complete picture 

of either current or cumulative Pb exposure. Bone 

Pb is considered superior to blood Pb in reflecting 

the long-term stores of Pb in the body (e.g., Rabinowitz 1991, reviewed in Barbosa et al. 2005, Hu et 

al. 2007). When available, bone Pb data were also 

considered in this evaluation. However, measuring 

bone Pb is expensive and requires subjects to travel 

the location of the specialized measurement apparatus (K-x-ray fluorescence). A number of authors have 

hypothesized that blood Pb may provide a better 

measure of Pb exposure in children or other subjects 

with active bone remodeling (see reviews by Barbosa 

et al. 2005, Hu et al. 2007). However, few studies in 

children have examined the usefulness of bone Pb 

data as a measure of exposure in children to test this 

hypothesis, other than studies that reported Pb levels in shed deciduous teeth (baby teeth).

When data were available for multiple measures 

of exposure, the association between health effects 

and either blood Pb or bone Pb levels was evaluated 

in this document. While the vast majority of exposure 

data were in the form of blood Pb measurements, in 

some cases there was enough data to begin to compare the association between a given health effect for 

both blood Pb and bone Pb levels. For example, bone 

Pb in adults appears to be more consistent than blood 

Pb in its relationship to decreases in specific cognitive 

measures (specifically in older adults), hypertension, 

and other cardiovascular effects. Although the relative strength of the association between measures of 

exposure and the health outcome has not been widely 

examined, in some cases bone and blood Pb measurements are available in the same group or study and 

the data have been analyzed in a method that allows 

such a comparison. For example, multiple studies have 

reported that blood Pb levels were associated with 

decreased IQ in the Yugoslavia Prospective Study (see 

discussion in Section 4.3.1). Wasserman et al. (2003) 

demonstrated a stronger association between bone Pb 

and IQ than for blood in a subset analysis of 167 children with blood and bone Pb measurements. In fact, 

the association with tibia bone Pb remained significant 

in a statistical model that controlled for concurrent or 

average lifetime blood Pb levels.

Pb exposures in the United States have dramatically declined over the last 30 years after bans on Pb in 

paint, solder, and gasoline, representing a significant 
Exposure

8 NTP Monograph on Health Effects of Low-Level Lead

public health accomplishment and protection for 

current populations of children. However, children 

born in the United States in the 1970s had a mean 

blood Pb of 15 μg/dL during early childhood. Consequently, health effects in adults today may have been 

influenced by blood Pb levels >10 μg/dL that many 

individuals experienced earlier in life.

Keeping these childhood blood Pb levels in mind, 

there are data on multiple health effects in adults for 

which studies report a significant relationship with 

concurrent blood Pb levels (e.g., elevated blood 

pressure, reduced kidney function, or decreases in 

specific measures of cognitive function). There is a 

considerable body of evidence that these health 

effects are associated with Pb exposure, and multiple studies report a significant association with 

concurrent blood Pb levels <10 μg/dL. Furthermore 

the association with blood Pb is supported by the 

consistency of effects across epidemiological studies, 

as well as biological coherence with animal data. It is 

well recognized that the role of early-life Pb exposure 

cannot be discriminated from the role of concurrent 

blood Pb without additional long-term studies.

As described in Section 2.2, the NTP’s conclusions 

were derived by evaluating data from epidemiological studies with a focus on blood Pb levels <10 μg/dL. 

The evidence discussed for specific health outcomes 

within each chapter varies by study design and type 

of analyses used to examine the relationship of the 

health outcome with blood Pb across the hundreds of 

studies evaluated. In some cases, studies examined 

only groups with blood Pb levels <10 μg/dL, <5 μg/dL, 

or even lower, and the association of the health 

effect with the blood Pb level is clear. For example, 

Lanphear et al. (2000) reported that higher blood Pb 

was associated with lower academic performance in 

a cross-sectional study of 4,853 children ages 6-16 

from the NHANES III data set. When they analyzed 

only children with blood Pb <10 μg/dL (n=4,681) or 

<5 μg/dL (n=4,043), the association with blood Pb was 

still significant (p<0.001 for <10 μg/dL and <5 μg/dL). 

In other cases, studies reported a significant association between blood Pb and an effect in a group 

whose mean blood Pb level <10 μg/dL (e.g., higher 

blood Pb level was associated with higher blood 

pressure in a study of 964 adults in the Baltimore 

Memory Study (Martin et al. 2006)). These analyses 

support an effect of a blood Pb level <10 μg/dL, but 

they do not exclude the possibility that individuals 

significantly above or below the mean blood Pb level 

are driving the effect, or that past exposure levels are 

driving the effect. Finally, some studies compared 

effects between two groups with higher and lower 

blood Pb levels. For example, Naicker et al. (2010) 

compared the effect of a blood Pb level ≥5 μg/dL with 

a blood Pb level <5 μg/dL on developmental markers 

of puberty in 13-year-old girls in South Africa (n=682) 

and found that blood Pb ≥5 μg/dL was significantly 

associated with delayed breast development, pubic 

hair development, and age of menarche.

3.2 Biomarkers of Pb Exposure

The large majority of human epidemiological studies 

that report individual Pb exposure levels measured 

Pb in blood samples. This chapter discusses U.S. 

blood Pb levels and trends for age, gender, and race 

or ethnicity. Bone Pb has been measured in some 

studies and is considered to more accurately reflect 

cumulative body burden of Pb because of the longer half-life of Pb in bone than in blood (reviewed in 

Barbosa et al. 2005, Hu et al. 2007). Bone and blood 

Pb are currently the most useful tools for measuring 

the body burden of Pb, while measures of Pb in urine 

and hair are less commonly used and are of low utility 

(see Hu et al. 2007 for review).

While whole-blood Pb is the most readily available biomarker for Pb exposure (and is the basis for 

this evaluation of Pb levels <10 μg/dL), plasma Pb 

is the portion of blood Pb that is available to cross 

cell membranes and enter specific tissues of the 

body (Cavalleri et al. 1978). Plasma Pb represents 

<5% of the whole-blood Pb concentration, but the 

proportion of whole-blood Pb in plasma Pb can 

vary widely and can be influenced by bone Pb levels 

(e.g., Hernandez-Avila et al. 1998, and reviewed in 

Hu et al. 1998). Measuring plasma Pb is technically 

difficult, requires specialized equipment not widely 

available, and is not typically measured in research or 

clinical settings (CDC 2010). Variation in whole blood 

or plasma collection methods and Pb quantification 

techniques may limit comparability across studies, 

particularly when a method with a relatively high 

level of detection is used in a population with lower 

Pb exposures.

The National Health and Nutrition Examination 

Surveys (NHANES) include whole-blood Pb measurements on a cross section of the U.S. population. Specific outcomes in subgroups of the study are routinely 
Exposure

NTP Monograph on Health Effects of Low-Level Lead 9

published and are included in the chapters of this 

document covering specific health effects. General 

trends in blood Pb levels from NHANES data are presented in Figures 7.1, 7.2, and 7.3 (from Mahaffey et 

al. (1982), Brody, et al. (1994), and the CDC (2005a, 

2011b) including the updated tables for CDC (2009b)).

Blood Pb levels have decreased over the last 30 

years for all age groups (see Figure 3.1). The declining 

blood Pb levels follow declines in Pb exposure related 

to bans on leaded gasoline, paint, and use of solder in 

food cans and plumbing in the United States (see Section 3.3 Sources of Pb). Prior to the 1970’s blood Pb 

levels were not routinely measured for research purposes, but tooth Pb measurements estimate that peak 

exposure occurred around 1960 and this is supported 

by Pb levels in lake sediments (Robbins et al. 2010).

Unfortunately, the burden of Pb exposure is not 

uniformly low in all racial and ethnic subgroups (see 

Figure 3.2). Non-Hispanic blacks have higher blood 

Pb levels than do non-Hispanic whites across all ages, 

and being non-Hispanic black is a major risk factor 

for higher Pb levels in children (Jones et al. 2009). 

When comparing Pb levels for non-Hispanic blacks to 

those for non-Hispanic whites, almost every age and 

gender group among blacks had Pb levels statistically 

significantly higher in both 1991-1994 and 1999-2002 

(CDC 2005a). In a study of 249 children in Rochester, 

NY followed from age 6 to 24 months, black children 

had higher blood Pb levels even after accounting for 

exposure level and other modifying factors (Lanphear 

et al. 2002). Males also consistently have higher 

blood Pb levels than do females (see Figure 3.3), and 

this trend was observed in NHANES across most age 

groups and all racial/ethnic groups (CDC 2005a).

Given an accumulating body burden of Pb and 

higher past levels of Pb exposure, blood Pb levels are 

expected to go up with age; however, young children 

(ages 1-5 years) consistently have higher blood Pb 

levels than do older children, likely due to hand-tomouth behavior in this age group (see Figure 3.2). Several studies show a peak in children’s blood Pb levels 

around 24 months of age (CDC 2007b). Children are 

the focus of blood Pb screening and exposure reduction programs because of these higher levels and the 

established developmental impairments associated 

with Pb exposure (e.g., CDC’s Childhood Lead Poisoning Prevention Program see http://www.cdc.gov/

nceh/lead/about/program.htm) (CDC 2005b, Clark 

et al. 2011). Blood Pb levels in young children (1-5 

years of age) have decreased 10-fold over the last 30 

years (geometric means: for 1976-1980, 15.1 μg/dL; 

for 2007-2008, 1.51 μg/dL (CDC 2007b, 2011b)).

In 2008, only 0.8% of children had confirmed 

blood Pb levels >10 μg/dL, down from 7.6% in 1997 

(http://www.cdc.gov/nceh/lead/data/national.htm). 

However, blood Pb levels have remained consistently 

higher in non-Hispanic black children, which may be 

linked to a variety of factors contributing to higher 

Pb exposure, such as lower socioeconomic status, living in older, urban housing, or having lower calcium 

intake (see Figure 3.2; discussed further in Section 

3.3 Sources of Pb and Section 3.4 Modifiers of Pb 

Exposure) (Haley and Talbot 2004). Pb exposure in 

this critical developmental period can have immediate impacts on children’s health and contribute to a 

lifetime of exposure from Pb.

An individual’s blood Pb level reflects an equilibrium between current exogenous environmental Pb 

exposure and the internal (endogenous) body burden of Pb (Factor-Litvak et al. 1999, Brown et al. 2000, 

Chuang et al. 2001). The body quickly eliminates metals from circulating blood, while bone is a repository 

for Pb and more accurately reflects the cumulative 

dose of Pb integrated over years or even decades 

(reviewed in Hu et al. 1998, Barbosa et al. 2005, Hu 

et al. 2007). The half-life of Pb in blood is approximately 1 month, while the half-life in bone ranges 

from 10 to 30 years depending on the bone turnover 

rate, which varies by type of bone and life stage 

(Rabinowitz 1991). An estimated 45-70% of blood Pb 

comes from Pb released from endogenous tissue Pb 

stores, primarily in bone (Gulson et al. 1995).Toxicokinetic models often include other tissues within the 

model for blood because Pb levels rapidly equilibrate 

between tissues and blood (e.g., Rabinowitz 1991); 

however, data on turnover in other organs is limited.

The distribution of Pb in tissues changes with life 

stage. The distribution is also heterogeneous within 

bone. Bone and teeth store 90-95% of the total body 

burden of Pb in adults and from 70% to 95% of the 

total body burden in children (reviewed in Barbosa 

et al. 2005, Hu et al. 2007). Bone Pb was the source 

of between 40% and 70% of blood Pb in individuals 

undergoing hip or knee replacement surgery (Smith 

et al. 1996). Pregnancy, lactation, menopause, and 

osteoporosis are periods of bone demineralization, 

which may release Pb from bone stores and contribute to increased Pb exposure to other tissues, or to 
Exposure

10 NTP Monograph on Health Effects of Low-Level Lead

Figure 3.1: U.S. NHANES Blood Pb Levels for Children and Adults From 1976-2008

Years and ages are grouped based on available published data:

• 1976-1980 (Mahaffey et al. 1982)

• 1988-1991 (Brody et al. 1994)

• 1991-1994, 1999-2002 (CDC 2005a)

• 2003-2008 (CDC (2005a, 2011b))

0

4

8

12

16

Mean Blood Pb (μg/dL)

NHANES Years

1976-1980

1988-1991 1991-1994

1999-2002

2003-2008

2

6

10

14

Children, 1-5 years

Children, 6-19 years

Adults, 20 years

Figure 3.2: U.S. NHANES 1999-2002 Blood Pb Levels Across Ages and Racial/Ethnic Groups

Mean blood Pb level and 95% CIs for different ages of non-Hispanic whites (open circle),

non-Hispanic blacks (closed circle), and Mexican Americans (shaded circle) (CDC 2005a).

1.0 1.5 2.0 2.5 3.0

Blood Pb Levels

(Geometric Mean ± 95% CI)

J

J

J

J

J

J

J

J

J

J

J

J

1-5 years (1,610)

White, non-Hispanic

Black, non-Hispanic

Mexican American

6-19 years (6,283)

White, non-Hispanic

Black, non-Hispanic

Mexican American

20-59 years (5,876)

White, non-Hispanic

Black, non-Hispanic

Mexican American

 60 years (3,056)

White, non-Hispanic

Black, non-Hispanic

Mexican American

Age (N, all races) 

Race/Ethnicity
Exposure

NTP Monograph on Health Effects of Low-Level Lead 11

Pb exposure for a developing fetus from Pb released 

from maternal bone. This hypothesis has been supported by several authors (e.g., Manton et al. 2003, 

Hu et al. 2007). In addition, there are data to support 

higher blood Pb levels in some groups where demineralization is expected; for example, increased blood 

Pb levels have been demonstrated in postmenopausal 

women in several studies (e.g., Silbergeld et al. 1988, 

Symanski and Hertz-Picciotto 1995, Webber et al.

1995, Korrick et al. 2002). In young children, continuous growth results in constant bone remodeling, and 

bone Pb is likely to be exchanged with blood Pb much 

more frequently than in adults (reviewed in Barbosa 

et al. 2005, Hu et al. 2007). Additional factors that can 

increase risks to women and children are discussed 

further in the Section 3.4 Modifiers of Pb Exposure.

Bone Pb is typically measured by K-x-ray fluorescence (also called KXRF); however, few research 

institutions possess this technology and staff trained 

to use it. The most commonly used KXRF devices 

have a high detection limit (~10 μg/g bone mineral) 

and a wide error of measurement, so studies that 

use this method may underestimate the effect on 

health. Newer configurations of KXRF with a lower 

detection limit and less measurement error may 

improve these estimates, particularly in populations 

with lower exposure to Pb (Behinaein et al. 2011). A 

more portable x-ray fluorescence device for in vivo 

(within the body) bone Pb measures was developed 

using lower energy L-band x-rays which measure Pb 

concentration in the outermost layer of bone (Nie et 

al. 2011). Both of these methods are impacted by the 

thickness of skin over the measurement site which 

may be a concern in health effects related to obesity. Comparison of bone Pb levels between research 

groups is challenging without a common standard 

for calibration of instruments. Another modeling 

approach estimates bone Pb levels from blood Pb 

measures and covariates typically collected in epidemiological studies (Park et al. 2009). This approach 

could be used to estimate bone Pb in existing studies that do not have the ability to measure bone Pb 

directly. While blood Pb is by far the most common 

measure of exposure, it may not be as appropriate 

as bone Pb, particularly for studies of chronic health 

conditions (reviewed in Barbosa et al. 2005, Hu et al.

Figure 3.3: U.S. NHANES 1999-2008 Blood Pb Levels for All Ages of Males and Females

Mean blood Pb level and 95% CIs for men (closed squares) and women (open circles) (CDC 2011b).

1999-2000

Male

Female

2001-2002

Male

Female

2003-2004

Male

Female

2005-2006

Male

Female

2007-2008

Male

Female

N

3,913

4,057

4,339

4,606

4,132

4,241

4,092

4,315

4,147

4,119

1.00 1.25 1.50 1.75 2.00 2.25

Blood Pb Levels

(Geometric Mean ± 95% CI)

J

J

J

J

J

Years

Gender
Exposure

12 NTP Monograph on Health Effects of Low-Level Lead

2007). Physiologically based pharmacokinetic (PBPK) 

models have been created to combine current blood 

and bone Pb measures to estimate the Pb levels 

at the time of the exposure, allowing a more complete model of the individual’s lifetime Pb exposure 

(Leggett 1993, Coon et al. 2006).

Pb has also been measured in hair, urine, and 

other materials that are easier to obtain; but in 

general Pb levels fluctuate more rapidly in these 

materials than in bone. Hair collection is minimally 

invasive, and hair is easier to ship and store; however, there are no reliable standardized protocols for 

hair collection, and hair is subject to contamination 

from environmental sources of Pb (reviewed in Seidel 

et al. 2001, Harkins and Susten 2003, Barbosa et al.

2005). In 2001 an ATSDR expert panel concluded that 

there were too many unresolved scientific issues for 

hair to be a useful source for evaluating exposures to 

trace metals, including Pb (ATSDR 2001). Collection 

of urine is noninvasive, and urine has also been used 

to measure Pb; however, urine Pb levels vary rapidly 

and independently of blood Pb and require correction for creatinine levels and glomerular filtration 

rates to estimate plasma Pb levels at a specific collection time (reviewed in Barbosa et al. 2005, Hu et al.

2007). Fecal Pb levels reflect both excreted biliary Pb 

and unabsorbed ingested Pb but must be completely 

collected over several days to accurately reflect Pb 

exposures (reviewed in Barbosa et al. 2005).

In studies designed to examine reproductive 

effects, Pb levels in other tissue and fluids have been 

measured, including semen (e.g., Naha and Manna 

2007), ovarian follicles (e.g., Silberstein et al. 2006, 

Al-Saleh et al. 2008), and placenta (e.g., Odland et al.

2004, Llanos and Ronco 2009, Gundacker et al. 2010). 

Most studies report a single measure of exposure and 

do not directly compare the relationship between a 

health effect and different measures of Pb exposure 

(i.e., tissue Pb compared to blood Pb). Therefore, the 

usefulness of semen Pb, follicular Pb, or placental Pb 

as a measure of exposure rather than blood Pb is difficult to ascertain. At this time, blood Pb is a more 

widely available and is a well-established measure 

of exposure that is associated with multiple adverse 

health effects.

Unlike these fluctuating measures, teeth accumulate Pb like other bone, lose Pb at a slower rate 

than other bone, and for childhood exposure studies, 

primary teeth (baby teeth) are readily available when 

lost after 6 years of age (e.g., Manea-Krichten et al.

1991). In addition, the layers of the tooth provide a 

timeline of Pb exposure, including in utero (enamel) 

and early-childhood (primary tooth dentin) exposures, which may be separately measurable (by laser 

ablation/inductively coupled plasma/mass spectrometry) without removing the tooth (Uryu et al. 2003).

Some studies used indirect measures to estimate Pb exposure, although this is less common 

because whole-blood Pb measurement has become 

more widespread. Pb inhibits cytoplasmic enzyme 

δ-aminolevulinic acid dehydratase (ALAD), which is 

responsible for heme biosynthesis. Heme is a component of several iron-containing proteins including 

hemoglobin, the protein that transports oxygen in 

blood. ALAD can be measured in urine, blood, and 

plasma and is inversely related to Pb levels (reviewed 

in Barbosa et al. 2005). While not widely used, ALAD

levels in blood may be a better marker of long-term 

exposure than blood Pb measures, but urine ALAD

is not sensitive and so is not a good indicator at low 

Pb exposure levels (Alessio et al. 1981, Telisman et al.

1982). Pb can also impair heme formation by inhibiting ferrochelatase such that zinc is used in place of 

iron, increasing levels of zinc protoporphyrin (ZPP) 

(reviewed in Barbosa et al. 2005). ZPP levels in blood 

have been used as an indicator of Pb poisoning, but 

ZPP testing is not sensitive when blood Pb levels 

are <25 μg/dL (Wildt et al. 1987, Parsons et al. 1991, 

Labbe et al. 1999).

3.3 Sources of Pb

The primary routes of exposure in the general population are oral exposure to Pb from ingesting contaminated water and food or inhaling air and soil containing Pb. For an extensive discussion of environmental 

sources of Pb, see the EPA’s 2006 AQCD (U.S. EPA 2006). 

Hand-to-mouth behavior in young children increases 

their risk of exposure to Pb in dust, toys, and paint. 

Occupational exposures in Pb industries are often 

associated with elevated Pb levels in workers and can 

also contribute to Pb exposures in coworkers who 

do not work with Pb, or in family members exposed 

to dust brought into the home from the person who 

works with Pb (Hipkins et al. 2004).

Tap water once contributed to as much as 

10-20% of total Pb exposure in the United States 

before amendments to the Clean Water Act (U.S. EPA 

2006), and some older pipes, taps, and pre-1986 pipe 
Exposure

NTP Monograph on Health Effects of Low-Level Lead 13

solder still contain Pb. Source drinking water rarely 

contains Pb, and the Pb enters tap water through 

corrosion of Pb from pipes and plumbing fixtures. 

Corrosion creates exposure from Pb deposits even 

after previous sources of Pb have been removed from 

water lines, as well as actual Pb pipes or Pb solder. 

This corrosion can significantly increase the Pb content in drinking water after changes in water disinfection processes, particularly with use of chloramine 

(Miranda et al. 2007, Jean Brown et al. 2011). In a 

highly publicized incident, the District of Columbia’s 

water supply exceeded the 15 μg/L action level for 

Pb several times between 2000 and 2004 because of 

corrosion of Pb scales in service pipes after a switch 

to chloramine to reduce disinfection byproducts (U.S. 

EPA 2007). Monitoring in homes with Pb service lines 

in the district found a small increase in the incidence 

of blood Pb levels >5 μg/dL, but not over the 10 μg/dL 

CDC level of concern for children; however, further 

analysis showed that children in homes with Pb service lines were at risk for blood Pb levels >10 μg/dL 

even during periods when Pb levels in water were 

below the action level (CDC 2004, Jean Brown et al.

2011). In addition, the incidence of blood Pb levels 

>10 μg/dL was increased in infants less than 1.3 years 

of age during the DC drinking water event (Edwards 

et al. 2009). Infants may be at an increased risk from 

contaminated water if they drink infant formula 

made with tap water, because they typically consume 

6 oz/kg of formula daily, so infants may have higher 

exposure relative to body weight than do others in 

the same household (Bearer 1995).

Dietary Pb sources in the United States have 

been reduced through several changes in practice, 

such as removing Pb solder from cans and banning 

Pb-arsenate pesticides (Bolger et al. 1996), and current Pb levels in the U.S. food supply are low (CDC 

2010). Contaminated food, particularly if imported 

from other countries, can be a source of dietary Pb 

exposure. A study of pregnant women in Monterey, 

California, identified prepared grasshoppers sent 

from Oaxaca, Mexico, as a source of Pb poisoning 

(Handley et al. 2007), and tamarind candies imported 

from Mexico were linked to several cases of Pb poisoning in children (CDC 2002). Spices, herbs, nutritional 

supplements, and traditional medicines have been 

shown to contain or be contaminated with Pb as well 

(Ko 1998, CDC 1999, 2002, Buettner et al. 2009, Lin 

et al. 2010). Pottery with a Pb glaze can contaminate 

food if used for cooking or storage (CDC 2010). While 

high, acute exposures have been reported from Pb 

from pottery leaching into food (Matte et al. 1994), 

long-term use may cause a low, chronic exposure and 

raise the body burden of Pb (Hernandez Avila et al.

1991). Use of Pb-glazed ceramics was a major source 

of cumulative Pb exposure in a study of women in 

Mexico (Brown et al. 2000). Pb crystal glassware can 

release Pb into alcoholic beverages at levels above 

the EPA’s maximum allowable level for drinking water 

(Graziano and Blum 1991). In addition, approximately 

25% of home-distilled alcohol (moonshine) samples 

tested by the U.S. Bureau of Alcohol Tobacco and 

Firearms between 1995 and 2001 had Pb concentrations >400 μg/dL from the use of inappropriate materials in the distillation process (e.g., car radiators or 

welded metal parts). These concentrations are high 

enough to produce blood Pb levels >25 μg/dL if one 

liter was consumed (Morgan et al. 2004). Moonshine 

consumption has been associated with blood Pb levels >15 μg/dL and Pb-related deaths (Pegues et al.

1993, Kaufmann et al. 2003).

Inhaled Pb is another source of Pb exposure 

(U.S. EPA 2006). During the renovation of buildings 

built before 1978, dust from Pb paint can be inhaled, 

and residual contamination after a renovation with 

inadequate cleanup may continue to expose building occupants to Pb. The U.S. Department of Housing 

and Urban Development estimated that 40% of U.S. 

housing contains Pb paint, which presents a potential 

Pb hazard when it is disturbed or deteriorates (HUD 

2001). Leaded gasoline is another inhaled source of 

Pb in parts of Asia, Eastern Europe, the Middle East, 

and South America. In the United States, leaded gasoline was banned in 1996 after being phased out for 

more than 20 years, and average ambient air Pb levels fell 93% between 1980 and 2009 (Figure 3.4) (U.S. 

EPA 2006). While Pb paint and leaded gasoline are no 

longer major sources of Pb in the United States, Pb 

from these sources remains in soil and dust, as well 

as inside people’s bodies in bone and other organs as 

part of the body burden of Pb from earlier exposures 

to Pb paint and leaded gasoline (U.S. EPA 2006, Zota 

et al. 2011).

Smoking or exposure to passive smoke may lead 

to increased exposure to Pb in environmental tobacco 

smoke (ETS). Tobacco itself contains Pb, in part at 

least, from ambient air sources: the levels of Pb in 

mainstream smoke from Canadian-grown tobacco 
Exposure

14 NTP Monograph on Health Effects of Low-Level Lead

cigarettes decreased by 62% from 1968 to 1988 as 

ambient air Pb levels declined (Rickert and Kaiserman 

1994). Serum cotinine (a metabolite of nicotine that 

can be used as a biomarker of tobacco exposure) and 

postnatal exposure to ETS were significantly associated with blood Pb levels of children in NHANES III; 

these levels did not decrease with age, indicating inhalation was more likely than hand-to-mouth behavior 

in younger children (Lanphear et al. 2000, Mannino et 

al. 2003). In studies of outcomes causally linked to ETS 

exposure, such as neurodevelopment or cardiovascular disease, ETS may confound the observed associations of Pb and the health effect (CDC 2005a).

Contaminated soil also contributes to Pb exposure in humans if inhaled as dust or eaten. Ingested 

Pb from soil is 26% bioavailable when consumed on 

an empty stomach and 2.5% bioavailable after a meal 

(Maddaloni et al. 1998). Clay tablets sold in Mexico, 

Central America, and parts of Africa are eaten for religious reasons, health promotion, or simply taste and 

texture (CDC 2010). Children and people (particularly 

pregnant women) with pica, a disorder causing an 

urge to eat nonfood items, such as dirt or chalk, can 

also ingest Pb (Klitzman et al. 2002).

Children are most commonly exposed to Pb in 

paint, household dust, and soil – particularly if they 

reside in pre-1978, deteriorated housing – and can 

increase their risk of exposure by natural mouthing 

tendencies (Lanphear et al. 1998, U.S. EPA 2006). 

There are few direct data on Pb absorption from toys 

or other consumer products, but it is clear that Pb is 

absorbed from toys in some cases. Pb concentration in 

toys is mainly associated with use of Pb in paints, coloring agents, and plastic stabilizers in polyvinyl chloride 

(PVC) plastics (Godoi et al. 2009, Greenway and Gerstenberger 2010). A 4-year-old boy had an extremely 

high Pb level (123 μg/dL blood Pb) after swallowing 

a vending machine necklace pendant that contained 

39% Pb (VanArsdale et al. 2004), and similar products 

could cause lower Pb exposure levels if chewed but 

not swallowed. Publications have not been identified 

that provide quantitative measures of the differences 

in Pb absorption between Pb paint and Pb embedded 

in plastics as a coloring agent or stabilizer. However, 

Sanchez-Nazario et al. (2003) demonstrated that toy 

chewing, along with Pb levels in window sills and soil 

eating habits, were significant predictors of blood Pb 

levels in children. Toy chewing may be a route of dust 

ingestion as well as absorption of Pb from the toy. Children may be exposed to Pb in other consumer products, including plastic window blinds, Pb core candle 

wicks, or backpacks (Sanborn et al. 2002).

Figure 3.4: U.S. Pb Air Concentration From 1980-2009

U.S. Pb air concentration (μg/m3) from 1980-2009 based on annual maximum 

3-month average. National trend based on 20 sites. U.S. Environmental Protection 

Agency (http://www.epa.gov/air/airtrends/lead.html, accessed 1 August, 2011).

1980 1990 2000 2010

0

1

2

3

4

Pb Concentration (μg/m3)

Year

National Standard (---)

Current standard=0.15μg/m3 (as of October 2008)

The previous standard of 1.5μg/m3 (from 1978 to 2008) is not shown
Exposure

NTP Monograph on Health Effects of Low-Level Lead 15

Renovating, repairing, or painting a pre-1978 

building can release particles of Pb-based paint and is 

associated with increases in blood Pb levels in children 

and adults who live in the home (CDC 2009a, 2011a). 

Thorough cleaning after completion of remodeling 

is effective in removing most of the Pb dust from a 

renovated residence (Yiin et al. 2004). Proper maintenance of housing by people trained in lead-safe practices, focusing on residential complexes with previous 

cases of elevated blood Pb levels, can prevent future 

Pb exposures (CDC 2005b). Construction and painting 

also contribute to occupational Pb exposures (CDC 

2011a). Contractors engaged in renovation or remodeling must be certified through the EPA Lead-Safe 

Certification Program and use safe work practices to 

reduce Pb exposures to their clients, employees, and 

themselves. Additional certification at the state or 

Federal level is required for abatement to permanently 

eliminate Pb-based paint hazards from a home (http://

www.epa.gov/lead/pubs/traincert.htm).

Some hobbies or recreational activities are 

potential sources of Pb exposure (e.g., Sanborn et al.

2002). Hobbies include furniture refinishing, jewelry 

making, creating stained glass, print-making, enameling copper, casting bronze or lead figurines, leaded 

glass blowing, working with Pb solder on electronics, and using Pb-containing paints or pottery glazes 

(CDC 2010). Fishing and hunting can contribute to 

Pb exposure when making fishing weights, casting 

ammunition, or eating animals contaminated with Pb 

after ingesting Pb shot or fishing weights (CDC 2010, 

2011a). Air Pb levels in indoor firing ranges were significantly higher in ranges that used powder charges 

(660 μg/m3) than in those that used air guns (4.6 μg/

m3) or in archery ranges (0.11 μg/m3), and blood Pb 

levels were significantly higher for marksmen using 

powder charges during the indoor shooting season 

(Svensson et al. 1992). Pb exposures from these 

hobbies can be significant: a potter and her family 

experienced elevated Pb levels from Pb glazes used 

in a home studio (48 μg/dL for the potter, 54 μg/dL 

for her daughter, and 20 μg/dL for her husband), and 

a man whose hobbies included melting Pb weights to 

make figurines and shooting firearms at an indoor firing range had a blood Pb level of 39 μg/dL (Fischbein 

et al. 1992).

Occupational exposures to Pb occur in more 

than 100 industries where Pb or Pb-containing 

materials are used or disturbed by workers (CDC 

2010). Approximately 95% of all elevated blood Pb 

levels reported in adults in the United States are 

work-related (CDC 2011a). The prevalence rate of 

workers with blood Pb levels >25 μg/dL decreased 

by more than 50% from 1994 to 2009 (from 14 to 6.3 

per 100,000 adult workers), and in 2009 the Adult 

Blood Lead Epidemiology and Surveillance (ABLES) 

program lowered their definition for elevated blood 

Pb level from 25 to 10 μg/dL because of increased 

concern over health risks from lower blood Pb levels 

(ABLES 2009). The lowest blood Pb level required to 

be reported under state laws varies by state; however, 

of the 10 states that collected all test levels in 2004, 

32% of women with blood Pb >5 μg/dL reported 

occupational exposures, mostly in manufacturing 

(CDC 2007a). Occupational sources of Pb can also 

expose workers’ families because Pb dust travels 

home on clothes and in vehicles (Hipkins et al. 2004, 

CDC 2009c). Living near Pb mining, smelting, and 

manufacturing sites may expose the surrounding 

community to low Pb levels, particularly in countries 

without environmental regulations or monitoring 

programs (Benin et al. 1999). These groups have been 

the subject of many older studies of health effects 

associated with Pb exposure and continue to be a 

source of study subjects with higher exposure levels 

(e.g., a study of birth outcomes for women living near 

a Pb smelter plant with a damaged pollution-control 

device Berkowitz et al. 2006).

Because the focus of this evaluation is on blood 

Pb levels <10 μg/dL, studies with mean blood Pb 

levels >15 μg/dL were not included in this evaluation except as specified in Section 8.0 Reproductive/Developmental Effects (e.g., groups in studies 

by Kromhout et al. (1985) and Locket and Arbuckle 

(1987) had mean blood Pb levels ≥15 μg/dL and 

were not included in the evaluation of cardiovascular 

effects). Stratified analyses of only subjects with Pb 

levels above and below 10 μg/dL have indicated that 

associations with some health effects can be stronger 

at lower exposure levels (e.g., Pb-related intellectual 

deficits (Lanphear et al. 2005)). Excluded occupational studies were mostly older publications on 

workers with mean blood Pb levels >10 μg/dL or on 

workers without occupational monitoring programs. 

Even with the ABLES definition of elevated blood Pb 

as 10 μg/dL, Pb-exposed workers can have higher 

blood levels than the general population and a higher 

lifetime burden of Pb from long-term exposures.
Exposure

16 NTP Monograph on Health Effects of Low-Level Lead

3.4 Modifiers of Pb Exposure

Individual-level differences in exposure and biology 

affect the amount of Pb that reaches a target tissue 

to impact health. These differences may influence 

contact with environmental Pb, as well as Pb metabolism and remobilization of Pb stores. Modifiers 

of Pb exposure include age, life stage, gender, diet, 

socioeconomic status, immigrant status, and genetic 

variants. These factors are often correlated with one 

another as well.

Blood Pb levels increase with age from bone 

Pb stores that accumulate over time, as previously 

discussed in Section 3.2 Biomarkers of Pb Exposure. 

Before bans on Pb in paint, solder, and gasoline, environmental Pb levels in the United States were higher, 

so older adults accumulated more Pb as children than 

children do today. Several authors have suggested that 

the aging process contributes to Pb exposure as bone 

begins to deteriorate, particularly if coupled with osteoporosis (Silbergeld et al. 1988, Campbell and Auinger 

2007). The data supporting this hypothesis come from 

cross-sectional studies and therefore the studies are 

only able to infer the temporal sequence. A particular 

challenge comes in relating increased blood Pb levels 

to mobilization of Pb from bone stores due to osteoporosis, because animal studies have demonstrated 

that Pb exposure results in lower bone density or bone 

strength (Hamilton et al. 1994, Ronis et al. 2001) and 

support a causal effect of Pb on bone density, rather 

than the other way around. A study of adults in New 

York found that age was not a risk factor for higher 

blood Pb levels (≥10 μg/dL) (Gelberg and Fletcher 

2010); however, blood Pb levels <10 μg/dL were not 

reported. Recent NHANES data support an association 

between higher blood Pb levels and increased age in 

older children and adults with generally low blood 

Pb levels (well below 10 μg/dL; see Figure 3.2) (CDC 

2005a). Young children are an exception to this age 

trend and have higher blood Pb levels than do infants 

and older children (CDC 2007b).

Young children show marked increases in blood 

Pb levels after birth, with a peak around 2 years of 

age (Rothenberg et al. 1999b). Initially, maternal 

sources of Pb could contribute to a child’s exposure 

levels. Mothers’ blood Pb levels at delivery are highly 

correlated with umbilical cord blood Pb levels, with 

umbilical cord blood levels slightly lower (Graziano 

et al. 1990, Rothenberg et al. 1999b). The CDC concluded that in utero exposure risks to children are 

greatest if mothers had a significant past Pb exposure 

(CDC 2010). Maternal blood and milk Pb levels are 

correlated as well, but the efficiency of Pb transfer 

from blood to milk varies at low levels, and Koyashiki 

et al. (2010) concluded that there are no established 

health risks from breast milk. Current CDC guidelines 

are to continue breastfeeding up to high blood Pb 

levels (40 μg/dL blood Pb levels in the mother) (CDC 

2010). A study in mice showed that gestational and 

lactational Pb exposure from the mother increases 

Pb levels in the offspring, with declining blood Pb levels after weaning (Snyder et al. 2000). There is some 

evidence that Pb from dietary sources is more readily 

absorbed and retained in young children and infants 

than in adults (Ziegler et al. 1978). Young children 

are also exposed to environmental Pb because of 

normal mouthing behaviors, as discussed in Section 

3.3 Sources of Pb. A number of authors have hypothesized that blood Pb may provide a better measure of 

Pb exposure in children because of highly active bone 

remodeling (see reviews by Barbosa et al. 2005, Hu 

et al. 2007). However, other than studies that examined Pb levels in shed primary teeth, few studies in 

children have examined the usefulness of bone Pb 

data as a measure of exposure in children that might 

be associated with health effects of Pb.

On average, adult men have higher levels of 

Pb in blood and bone than do adult women, and 

men are much more likely to be exposed to occupational sources of Pb. However, women typically go 

through more stages of life where demineralization 

of bone may be associated with mobilization of bone 

stores Pb into circulating Pb. Therefore, a number of 

authors have supported the hypothesis that women 

are at risk from increased blood Pb levels mobilized 

from bone stores during pregnancy and menopause 

and due to osteoporosis (e.g., Silbergeld et al. 1988, 

Manton et al. 2003, Hu et al. 2007). Blood Pb levels 

in pregnant women are generally low in the United 

States (NHANES geometric mean <5 μg/dL) and 

do not vary by the age of the mother (Jones et al.

2010). Pregnancy-associated increases in blood Pb 

have been demonstrated in a number of case studies (e.g., Rothenberg et al. 1992, Shannon 2003), but 

the overall pattern of blood Pb throughout pregnancy 

appears to be complex (Hertz-Picciotto et al. 2000, 

Schell et al. 2000). Blood Pb levels follow a U-shaped 

curve during pregnancy, decreasing during weeks 

12-20 and then increasing linearly over the second 
Exposure

NTP Monograph on Health Effects of Low-Level Lead 17

half of pregnancy (Rothenberg et al. 1994). Overall 

blood Pb levels decrease during subsequent pregnancies, so the first pregnancies pose the most risk of 

Pb toxicity, particularly if the mother had significant 

past Pb exposures (Manton et al. 2003, CDC 2010). 

A number of studies have demonstrated increased 

blood Pb levels in postmenopausal women (e.g., 

Silbergeld et al. 1988, Symanski and Hertz-Picciotto 

1995, Webber et al. 1995, Korrick et al. 2002, Nash et 

al. 2004). Data from Symanski et al. (1995) also support a greater relative increase in blood Pb levels in 

postmenopausal women that have never been pregnant, supporting both increased mobilization of Pb 

associated with menopause as well as mobilization 

and clearing of body burdens of Pb during pregnancy. 

To a lesser extent, studies also support increased 

blood Pb levels associated with osteoporosis (e.g., 

Campbell and Auinger 2007), although as discussed 

above, studies in laboratory animals demonstrate 

that Pb exposure causes reduced bone density and 

therefore cause-and-effect is particularly difficult to 

establish between osteoporosis and blood Pb levels.

Nutritional deficiencies can be related to Pb levels. Deficiencies in calcium, iron, and zinc were associated with increased Pb levels at 6 months of age, and 

iron deficiency continued to be associated with Pb at 

12 months of age (Schell et al. 2004). Low iron intake 

may contribute by increasing Pb absorption in these 

infants, who had a mean 12-month blood Pb level of 

5.1 μg/dL (Schell et al. 2004). In older people, calcium 

deficiency can increase bone turnover and circulating 

Pb levels (CDC 2010). Pb absorption is higher when 

there is less food in the digestive tract, making dietary 

habits and gastric emptying rates another source of 

individual variation in the body burden of Pb (James 

et al. 1985, Maddaloni et al. 1998).

Low socioeconomic status (SES) is associated 

with higher blood Pb levels (e.g., Wibowo et al.

1986, Greene et al. 1992, Schnaas et al. 2004, Bellinger 2008). People with low SES may be exposed to 

a collection of risk factors, including living in older, 

deteriorated housing with Pb in paint, household 

dust, pipes, or urban air; consuming diets lower in 

nutrients and calories; playing with potentially contaminated inexpensive toys; working in jobs with 

occupational Pb exposure; and other environmental 

hazards (reviewed in Sexton 1997, Strike and Steptoe 2004). The best strategy for preventing new Pb 

exposures in housing is to remove the Pb paint and 

dust, but authors such as Wakefield et al. (2002) have 

noted that Pb abatement can cost over $10,000 per 

home, and they suggest that this cost may result in 

remediation of less than 0.1% of seriously dangerous homes per year. Care has to be taken during the 

remediation, and workers performing the job should 

receive special training, because as discussed earlier, 

general repair and renovation can be associated with 

increased Pb exposure and higher blood Pb levels 

in building occupants and workers performing the 

repairs (CDC 2009a, 2011a).

Many immigrants face SES-related exposure risks, 

but they may have additional risk factors as well. If 

their home country has relatively high Pb exposure 

levels, immigrants carry a larger body burden of Pb 

(CDC 2010). Exposure to leaded gasoline emissions, 

as estimated from time spent in Mexico City, was a 

major source of cumulative Pb exposure in a study 

of postpartum women in Mexico (Brown et al. 2000). 

In a study of pregnant women, a Pb-related increase 

in blood pressure was only seen in immigrants, predominantly from Latin America, even without markedly higher blood Pb levels than nonimmigrants 

(Rothenberg et al. 1999a). In some cultures, pica during pregnancy is common and accepted (CDC 2010). In 

a study of pregnant women in New York, pica was the 

most frequently reported source of Pb exposure (13 

women, 39% of those with levels >20 μg/dL) (Klitzman 

et al. 2002). Immigrant status could increase exposure 

to Pb contaminated products, including alternative 

remedies, imported cosmetics or food items, or Pbglazed pottery for cooking or food storage (CDC 2010). 

Women in the United States using herbal supplements 

had higher blood Pb levels, particularly in those using 

St. John’s wort or Ayurvedic or traditional Chinese 

medicinal herbs (Buettner et al. 2009).

Biological variation in Pb absorption and metabolism rates can be partially explained by genetic 

variation. The relationship between Pb exposure 

and a particular health effect may be modified by 

the presence of a single nucleotide polymorphism 

(i.e., variation in a single DNA nucleotide between 

individuals or groups) or by other genetic variations. 

When studying genetic risk factors in observational 

studies, selection for the study is independent of 

genotype, which remains unknown to the subject, so 

sources of bias that may confound other risk factors 

are minimized. If specific genetic variants are found 

to increase or decrease the association of Pb with a 
Exposure

18 NTP Monograph on Health Effects of Low-Level Lead

health effect, there is a stronger biological basis for 

that relationship, and the gene function may give an 

indication of the mechanism of action. Genes studied 

for variations in Pb metabolism include hemochromatosis (HFE) and aminolevulinate dehydratase 

(ALAD), and specific study details are presented in 

the appendices for each chapter.

Interactions between many of the previously 

discussed factors make it difficult to separate the 

increases in risk from each individual factor. While 

many measures taken to reduce Pb exposure have 

decreased blood Pb levels in the U.S. population, 

economically disadvantaged young children in older 

housing or pregnant immigrants using contaminated 

products are still at risk for significant Pb exposures.

3.5 Summary

While Pb can be measured in a variety of human tissues, whole-blood Pb is the most common measure 

used in both research and clinical settings. Blood Pb 

levels fluctuate and represent both current exposures 

from the environment and internal (endogenous) 

sources of Pb, primarily stored in bone. Bone Pb is 

a better measure of the cumulative body burden of 

Pb and therefore it is commonly hypothesized that 

bone Pb may show more consistent associations with 

long-term health effects. Pb continues to be used in 

industrial processes and in manufactured products 

in the United States and worldwide and is persistent 

in the environment. Humans are exposed to Pb via 

water, air, soil, food, and consumer products. Several 

Pb reduction efforts have significantly reduced exposure levels over the last 30 years, and blood Pb levels 

have dropped considerably in the United States. Pb 

exposure levels vary greatly by age, life stage, gender, 

and socioeconomic level; and even at low levels with 

blood Pb <10 μg/dL there are health risks. The other 

chapters of this document outline the evidence for 

specific health effects from blood Pb levels <10 μg/dL. 

A discussion of Pb exposures in potentially susceptible populations for specific health effects is included 

in individual chapters.
Neurological 

Effects

NTP Monograph on Health Effects of Low-Level Lead 19

4.0 NEUROLOGICAL EFFECTS

4.1 Conclusions

The NTP concludes that there is sufficient evidence 

that blood Pb levels <5 μg/dL are associated with 

adverse neurological effects in children and limited 

evidence that blood Pb levels <10 μg/dL are associated with adverse neurological effects in adults. A 

major strength of the evidence for effects of lowlevel Pb on neurological outcomes is the consistency 

of results for an adverse effect of blood Pb <10 μg/dL 

across multiple indices of neurological effects (e.g., 

cognition, behavior, and sensory function), through 

multiple groups, with a wide age range from early 

childhood to older adults, and from studies using 

substantially different methods and techniques.

Unlike the data set for most other health outcomes, there are a number of prospective studies 

of neurological effects include measures of prenatal 

exposure (either maternal blood or umbilical cord 

blood). These prospective studies provide limited 

evidence that prenatal exposure to blood Pb levels 

<5 μg/dL are associated with decreases in measures 

of general and specific cognitive function evaluated in 

children. There is also limited evidence that prenatal 

exposure to blood Pb levels <10 μg/dL are associated 

with decreased IQ, increased incidence of attentionrelated and antisocial behavior problems, and 

decreased hearing measured in children. Conclusions 

on effects of prenatal exposure for outcomes evaluated as children are complicated by the high degree 

of correlation in childhood blood Pb levels over time, 

and as described below, blood Pb levels during childhood are also associated with these outcomes.

In children, there is sufficient evidence that 

blood Pb levels <5 μg/dL are associated with broadbased and specific indices of reduced cognitive function and an increase in attention-related behavior 

diagnosis and antisocial problem behaviors. The 

association between blood Pb and decreased IQ has 

been demonstrated in multiple prospective studies of 

children with blood Pb levels <10 μg/dL, the pooled 

analyses that reported effects with peak blood Pb 

levels <7.5 μg/dL (Lanphear et al. 2005), and multiple 

cross-sectional studies that reported effects with 

mean blood Pb levels <5 μg/dL. Lower levels of academic achievement, as determined by class rank and 

achievement tests, have been reported in multiple 

prospective and cross-sectional studies of children 

with blood Pb <5 μg/dL. An association between 

blood Pb levels <5 μg/dL and decreases in specific 

measures of cognitive function have been demonstrated in prospective and cross-sectional studies 

using a wide range of tests for assessment. Increases 

in attention-related and problem behaviors are consistently reported in studies with mean blood Pb levels <5 μg/dL. There is sufficient evidence that blood 

Pb levels <10 μg/dL in children are associated with 

decreased auditory acuity. Multiple cross-sectional 

studies reported hearing loss, as indicated by higher 

hearing thresholds and increased latency of BAEPs, in 

children with blood Pb levels <10 μg/dL.

In adults, there is limited evidence that blood Pb 

levels <10 μg/dL are associated with psychiatric outcomes (including anxiety and depression), decreased 

auditory function, decreases in specific measures of 

cognitive function in older adults, and the neurodegenerative disease ALS. There is sufficient evidence 

that blood Pb levels <10 μg/dL are associated with 

essential tremor in adults, and limited evidence for 

blood Pb levels <5 μg/dL. As with other studies of 

health effects of Pb in adults, long-term prospective 

studies in a group for which blood Pb levels remained 

consistently below 10 μg/dL from birth until measurement of the outcome of interest would eliminate the 

potential role of early-life blood Pb levels >10 μg/dL 

on health effects observed in adults with concurrent 

blood Pb levels <10 μg/dL. There are more consistent associations between bone Pb and decreases in 

cognitive function in older adults than for blood Pb, 

suggesting a role for cumulative Pb exposure.

4.2 How Conclusions Were Reached

Conclusions in the NTP evaluation of Pb-related 

neurological effects in humans associated with lowlevel Pb are derived by evaluating the data from 

epidemiological studies with a focus on blood Pb 

levels <10 μg/dL. Data reflecting exposure levels up 

to 15 μg/dL were also considered so that effects at 

and around 10 μg/dL were not excluded from the 

evaluation.

There is a relatively large database of human 

studies for a wide range of neurological effects (see

Table 4.1) of low-level Pb and therefore, the document makes limited use of the data from laboratory 

animals to support the human evidence. Major endpoints considered as potential indicators of neurological effects of Pb are listed and briefly described 
Neurological 

Effects

20 NTP Monograph on Health Effects of Low-Level Lead

in Section 4.2.1. This document is not a review of 

neurotoxicity, and the reader is directed to published reviews for additional background. Key data 

and principal studies considered in developing the 

NTP conclusions are discussed in detail in Section 

4.3: Evidence for Pb-related Effects on Neurological 

Outcomes. The discussion of each neurological effect 

begins with a statement of the NTP’s conclusion that 

the specific effect is associated with a blood Pb level 

<10 μg/dL or <5 μg/dL and the age group in which 

it is identified (childhood or adulthood), as well as 

the timing of exposure associated with the effect 

(prenatal, childhood, or concurrent), when available. 

Although the information necessary to support the 

NTP’s conclusions is presented in Section 4.3, the 

complete data set of human studies considered for 

evaluation of neurological effects with low-level Pb is 

included in Appendix A: Neurological Effects, where 

individual studies are abstracted for further reference. The NTP made extensive use of recent government evaluations of health effects of Pb in the current 

assessment, and the relevant conclusions of the EPA’s 

2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 

Toxicological Profile for Lead (ATSDR 2007) are briefly 

described in Section 4.2.2 below.

4.2.1 Principal Measures of Neurological 

Effects

Table 4.1 lists a number of key neurological endpoints evaluated in epidemiological studies on the 

Table 4.1: Major neurological effects considered

Effect Description

Cognitive Function

Intelligence quotient 

(IQ)

Full-scale IQ (FSIQ), verbal IQ (VIQ), and performance IQ (PIQ) are evaluated with a variety 

of tests, e.g., the Wechsler Intelligence Scales for Children (WISC) or the Stanford-Binet 

Intelligence Scale. WISC is a normative measure for assessing intelligence in children, 

allowing cross-study comparison (e.g., Lanphear et al. 2005).

Academic achievement Academic performance is measured with a variety of tests, e.g., the Boston Teacher Questionnaire (BTQ), Wide Range Achievement Test-Revised (WRAT-R), and, more recently, 

end-of-grade testing and standard assessment tests.

General and specific 

cognitive abilities

Cognitive function is measured with numerous tests including general measures, e.g., the 

Mental Development Index (MDI) and the General Cognitive Index (GCI); or specific measures such as individual subsets of the WISC, e.g., Block Design or Digit Span.

Behavior and Psychiatric Outcomes

Behavior Numerous measures of behavioral outcome are evaluated with tests such as Behavioral 

Assessment System for Children.

Attention-related behavior outcomes, including attention deficit hyperactivity disorder 

(ADHD), are measured with a variety of evaluation tools, e.g., Conners’ ADHD/Diagnostic and Statistical Manual of Mental Disorders (DSM).

Conduct or problem behavior outcomes are measured with a variety of evaluation tools, 

e.g., Teacher Report Form-Delinquent Behavior or self-reported delinquent behavior.

Psychiatric outcomes Mood disorders are diagnosed with various tests, e.g., the Child Behavior Checklist (CBCL) 

or Brief Symptom Inventory.

Neurodegeneration

Various diseases Diagnoses of amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, essential tremor, or 

Parkinson’s disease.

Sensory Function

Audio Several measures of auditory function, e.g., higher hearing thresholds and altered brainstem auditory evoked potentials (BAEPs).

Vision Several measures of visual function, e.g., altered visual evoked potentials (VEPs) and electroretinographic (ERG) testing.
Neurological 

Effects

NTP Monograph on Health Effects of Low-Level Lead 21

effects of Pb exposure and identifies representative 

tests that have been used to evaluate major neurological effects of Pb. A list or review of the full range 

of tests and tools used to evaluate neurocognitive, 

neurobehavioral, psychiatric, and neurophysiological 

outcomes is beyond the scope of this evaluation. The 

data available to evaluate each of the major effects 

are discussed in separate subheadings under Section 

4.3 below.

4.2.2 Principal Conclusions from the 2006 

EPA and 2007 ATSDR Pb Documents

The EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and 

ATSDR’s Toxicological Profile for Lead (ATSDR 2007) 

both concluded that negative effects of Pb on neurocognitive ability and neurobehavioral outcomes 

in children are observed across numerous studies 

at blood Pb levels <10 μg/dL even after adjusting for 

confounding factors (see Table 4.2).

The Lanphear et al. (2005) pooled analysis is 

cited by both EPA and ATSDR as supporting evidence 

for a decline of up to 6 full-scale IQ (FSIQ) points for 

an increase in blood Pb from 1 to 10 μg/dL in children. The 2006 EPA AQCD for Lead (U.S. EPA 2006) 

and the 2005 CDC statement on Preventing Lead 

Poisoning in Young Children (CDC 2005) highlight 

the evidence for a supralinear dose-response relationship for some neurodevelopmental outcomes 

(particularly IQ) and a steeper dose-response curve 

at lower Pb levels <10 μg/dL. The EPA 2006 AQCD for 

Lead (U.S. EPA 2006) also identifies recent evidence 

that neurocognitive deficits associated with Pb exposure are in turn associated with decreased academic 

achievement and notes that negative effects of Pb 

on attention may contribute to underachievement or 

delinquent behavior in children. The EPA 2006 AQCD 

for Lead (U.S. EPA 2006) concludes that the negative 

impacts of Pb on neurocognition and behavior persist 

into young adulthood and that there is clear evidence 

that blood Pb levels in children of 5-10 μg/dL (and 

possibly lower) are associated with these adverse 

effects. In adults, both ATSDR and EPA noted that 

chronic occupational Pb exposure is associated with 

decreased nerve conduction velocity and postural 

balance abnormalities. The EPA 2006 AQCD for Lead 

(U.S. EPA 2006) identified ≥14 μg/dL blood Pb level 

as a possible threshold for these effects, as well as 

for visuomotor and memory impairment, and effects 

on the visual and auditory systems (prolonged visual 

evoked potentials (VEPs) and BAEPs). The EPA 2006 

AQCD for Lead (U.S. EPA 2006) characterized the 

evidence for impairments in cognitive performance 

associated with Pb levels in adults as mixed, although 

bone Pb (and therefore long-term cumulative exposure) was associated with decreased cognitive performance. The EPA 2006 AQCD for Lead (U.S. EPA 2006) 

stated that four studies reported that past occupational exposure to Pb increased the risk of developing ALS and motor neuron disease and two studies 

reported that essential tremor was associated with 

low blood Pb levels (a mean of 3 μg/dL). EPA is in 

the process of revising the AQCD for Lead, and the 

conclusions of the external draft (U.S. EPA 2012) are 

largely in line with the 2006 AQCD for Lead (U.S. EPA 

2006), plus additional review of the evidence for 

attention-related behaviors, including ADHD.

The NTP considered the conclusions and data 

summaries from the EPA’s 2006 AQCD for Lead (U.S. 

EPA 2006) and ATSDR’s Toxicological Profile for Lead 

(ATSDR 2007). In general, the NTP accepted the 

conclusions and agreed that the data support them. 

Differences from the ATSDR and EPA documents are 

identified for specific endpoints.

Table 4.2: Main conclusions for neurological 

effects in the 2006 EPA AQCD for Lead and the 

2007 ATSDR Toxicological Profile for Lead

“....effects on neurobehavior in children have been 

observed with remarkable consistency across 

numerous studies of various designs, populations, 

and developmental assessment protocols. The 

negative impacts of Pb on neurocognitive ability and 

other neurobehavioral outcomes persist in most 

recent studies even after adjustment for numerous 

confounding factors, including social class, quality 

of caregiving, and parental intelligence.” (U.S. EPA 

2006, pg 6-269)

“...the preponderance of the evidence indicates 

that lead exposure is associated with decrements 

in cognitive function. Meta-analyses conducted on 

cross-sectional studies or a combination of crosssectional and prospective studies suggest that 

an IQ decline of 1-5 points is associated with an 

increase in PbB [blood Pb level] of 10 μg/dL. Most 

importantly, no threshold for the effects of lead on 

IQ has been identified...” (ATSDR 2007, pg 25)
Neurological 

Effects

22 NTP Monograph on Health Effects of Low-Level Lead

4.3 Evidence for Pb-Related Effects on 

Neurological Outcomes

4.3.1 Cognitive Function

There is sufficient evidence that blood Pb levels 

<5 μg/dL are associated with decreased cognitive 

function in children. There are many tests and measures used to evaluate cognitive function and blood Pb 

levels are associated with decreases in broad-based 

measures in children such as academic achievement 

or FSIQ, as well as specific cognitive measures evaluated in all age groups from young children to older 

adults. No clear and specific pattern of Pb-related 

decreases in specific cognitive abilities has been identified, although decreased performance on individual 

domains for attention, executive function, language, 

learning and memory, and visual-spatial processing 

have been reported (U.S. EPA 2006, ATSDR 2007). 

Generally, the lack of clear differences in sensitivity 

and specificity for individual domains is attributed 

in part to difficulty discriminating focused effects 

because test performance covers multiple neurobehavioral processes (U.S. EPA 2006).

The discussion of cognitive function below is 

divided into three sections: (1) academic achievement – a practical and perhaps more objective measure of cognitive function in children that may relate 

to achievement in life through education-based 

achievement measures, (2) IQ in children, and (3) 

other general and specific measures of cognitive 

abilities in children and adults.

Academic Achievement

There is sufficient evidence that blood Pb levels 

<5 μg/dL are associated with decreases in various 

measures of academic achievement in children 6-18 

of age (see Appendix A: Neurological Effects for full 

list of studies). An inverse association between blood 

Pb level and performance in tests of academic performance, class rank, or end-of-grade testing has 

been reported in multiple prospective and crosssectional studies involving children with blood Pb 

levels from 2 to 10 μg/dL from populations in North 

America, Europe, and Africa. Studies demonstrated 

that early-childhood Pb levels in blood (9-36 months 

age) or tooth dentin (6-8 years of age) are associated 

with decreased academic achievement measured 

when children were from 10 to 18 years of age. Data 

from cross-sectional studies also support a negative 

effect of concurrent blood Pb levels (between 5 and 

10 μg/dL) on academic achievement. However, there 

is inadequate evidence that prenatal blood Pb levels 

<10 μg/dL are associated with academic achievement 

in children because of a lack of academic performance studies that include Pb exposure data from 

prenatal time points.

A number of studies have used academic achievement as an indicator of effects of Pb on cognitive function in children. Many of the earlier studies of academic 

achievement used tooth dentin Pb as the measure of 

Pb exposure and compared measures of educational 

attainment in children with earlier dentin or blood 

Pb levels. For example, higher tooth dentin Pb levels 

at 6-8 years of age were associated with: lower class 

standing in 132 children in Massachusetts at 18 years 

of age (Needleman et al. 1990); reading and spelling 

difficulties in 8-year-old girls (n=1923 boys and girls) 

assessed with the Boston Teacher Questionnaire (BTQ) 

(Leviton et al. 1993); and various measures of achievement assessed from 8 to 18 years of age in 1,265 children from the Christchurch Health and Development 

Study cohort, including number of school certificate 

passes and Burt Word Reading test assessed at 8, 12, 

and 18 years of age (Fergusson et al. 1988, 1993, 1997). 

Bellinger et al. (1992) reported that blood Pb levels 

(mean, 6.5 μg/dL) at 2 years of age, but not umbilical 

cord blood Pb or children’s blood Pb levels at 6, 12, 

18, or 57 months of age, were significantly associated 

with lower scores in the Kaufman Test of Educational 

Achievement (KTEA) in 148 children 10 years of age 

from the Boston area. In general, the data support a 

persistent negative effect on cognitive achievement 

that results in reduced educational attainment. However, at least one study reported that tooth dentin Pb 

levels were not associated with achievement: Rabinowitz et al. (1992) stated that tooth Pb levels were 

not associated with scores on the BTQ in a study of 493 

Taiwanese children.

More recent studies have demonstrated a negative effect of concurrent or early-childhood blood Pb 

levels on academic achievement at blood Pb levels 

<10 μg/dL and down to 2 μg/dL. In a cross-sectional 

study of 4,853 children 6-16 years of age from the 

NHANES III data set, Lanphear et al. (2000) demonstrated that concurrent blood Pb levels <5 μg/dL 

(geometric mean, 1.9 μg/dL) were associated with 

decreased achievement measured by the Wide 

Range Achievement Test-Revised (WRAT-R). As with
Neurological 

Effects

NTP Monograph on Health Effects of Low-Level Lead 23

other cross-sectional studies of Pb, an important 

limitation is that blood Pb during early childhood is 

likely to have been higher than blood Pb measured 

during the study; and therefore, blood Pb may have 

been >10 μg/dL at earlier time points for children 

in this study. In a cross-sectional analysis of 511 U.S. 

children between 6 and 10 years of age, concurrent 

blood Pb ≥5 μg/dL was associated with lower scores 

on the Wechsler Individual Achievement Test (Surkan 

et al. 2007). In a cross-sectional study of 533 girls in 

Saudi Arabia between 6 and 12 years of age, Al-Saleh 

et al. (2001) reported that class rank percentile was 

inversely associated with concurrent blood Pb levels 

(mean, 8 μg/dL). Wang et al. (2002) found a similar 

inverse relationship between concurrent blood Pb 

level (mean, 5.5 μg/dL) and class ranking of 934 Taiwanese children 9 years of age for individual subject 

areas (e.g., natural sciences and Chinese). Min et al.

(2009) reported that blood Pb <5 μg/dL measured 

at 4 years of age was significantly associated with 

decreased school reading scores (Woodcock-Johnson 

III Tests of Achievement) at 9 and 11 years of age in 

a subgroup analysis as part of a prospective study of 

278 inner-city children from Cleveland, OH. Chandramouli et al. (2009) demonstrated that educational 

performance on standard achievement tests at 7-8 

years of age was inversely associated with blood Pb 

levels ≥5 μg/dL measured at 30 months of age in a 

prospective study of 582 children in the United Kingdom. Surkan et al. (2007) reported that blood Pb of 

5-10 μg/dL was associated with decreased performance in the Wechsler Individual Achievement Test 

in a study of 6- to 11-year-old children in Maine and 

Massachusetts. Miranda et al. (2007) reported that 

blood Pb levels down to 2 μg/dL (collected as part of 

Pb screening programs when the children were <5 

years of age) were negatively related to test performance in both reading and mathematics in a study 

of 8,603 children in the fourth grade (9- and 10-yearolds) from four counties in North Carolina. In an 

expanded study of over 57,000 children in the fourth 

grade from across North Carolina, who were screened 

for blood Pb between 9 months and 3 years of age, 

Miranda et al. (2009) demonstrated a similar effect 

of blood Pb levels down to 2 μg/dL on end-of-grade 

reading scores compared to the reference group with 

blood Pb levels of 1 μg/dL.

No studies were located that evaluated maternal Pb levels and educational achievement; however, 

Bellinger et al. (1992) reported that umbilical cord 

blood Pb levels (29% of the study group had levels 

≥10 μg/dL) were not significantly associated with 

lower scores in the KTEA in 148 children 10 years of 

age from the Boston area.

Confounding variables were considered in all of 

the studies listed above to some degree, but the studies of Miranda et al. (2007, 2009), Chandramouli et al.

(2009), and Lanphear et al. (2000) included a large 

number of confounders, such as socioeconomic variables, sex, race/ethnicity, age of blood Pb measurement, parental education, and tobacco exposure, and 

demonstrated that the effects on achievement were 

independent of known confounders. The Miranda 

et al. (2009) study found evidence of differential 

effects in students with lower test scores, reporting 

that children with the lowest test scores had a larger 

adverse effect of blood Pb on lowering the test score. 

Lower SES and lower parental education also had 

a larger adverse effect on children with lower test 

scores, suggesting that Pb and other confounders all 

have a greater impact in individuals that already have 

lower levels of achievement. The studies of Surkan 

et al. (2007) and Bellinger et al. (1992) reported a 

negative effect of Pb on academic achievement while 

controlling for the child’s IQ, suggesting that IQ and 

academic performance may serve as somewhat independent measures of cognitive function.

Summary of Support for Conclusions

Animal data support a Pb-associated decrease in neurobehavioral tests of learning including fixed-interval 

operant conditioning at blood Pb levels ≥11 μg/dL 

(see U.S. EPA 2006 for recent reviews of the animal 

data, ATSDR 2007). The human data include multiple 

prospective and cross-sectional studies supporting a 

Pb-associated decrease in educational attainment at 

blood Pb levels from 2 to 10 μg/dL. The conclusion of 

sufficient evidence for decreased academic achievement in children 6-18 years of age with blood Pb levels 

<5 μg/dL measured in early childhood through 18 years 

of age is based on the consistency of effects on several 

measures of academic achievement in multiple studies. 

The Bellinger et al. (1992) study includes multiple blood 

Pb measurements and only found a negative effect of 

blood Pb measured at 2 years of age on later life academic performance. Multiple studies (e.g., Miranda 

et al. 2007, Chandramouli et al. 2009, Miranda et al.

2009) reported that early-childhood Pb exposure is 
Neurological 

Effects

24 NTP Monograph on Health Effects of Low-Level Lead

associated with later performance. However, clear evidence that early-childhood Pb exposure is associated 

with academic performance at later ages is complicated by the high degree of correlation in childhood 

blood Pb levels over time (e.g., see Dietrich et al. 1993a, 

Lanphear et al. 2005). Current evidence can be used to 

support the importance of both early-life exposure and 

current blood Pb levels. The conclusion of inadequate 

evidence that prenatal blood Pb levels <10 μg/dL are 

associated with academic achievement in children is 

based on the lack of studies of academic performance 

in children with Pb exposure data from prenatal time 

points. The NTP’s conclusions for sufficient evidence 

that decreased academic achievement in children 

6-18 years of age is associated with Pb levels <5 μg/dL

extends the conclusions from EPA’s 2006 AQCD for Lead 

(U.S. EPA 2006) and ATSDR’s 2007 Toxicological Profile 

for Lead (ATSDR 2007), which were limited to blood Pb 

levels <10 μg/dL; however, the EPA’s 2012 draft (U.S. 

EPA 2012) currently supports a lower blood Pb level.

IQ

There is sufficient evidence that blood Pb levels 

<5 μg/dL are associated with decreases in FSIQ, a 

global measure of cognitive ability in children 4-13 

years of age (see Appendix A: Neurological Effects for 

full list of studies). The NTP conclusion of sufficient 

evidence that blood Pb levels <5 μg/dL are associated with decreased IQ is based on several lines of 

evidence, including multiple cross-sectional studies 

of children reporting lower IQ associated with mean 

blood Pb levels <5μg/dL, pooled analyses demonstrating reduced IQ with peak blood Pb levels <7.5 μg/dL, 

and multiple prospective studies reporting decreased 

IQ at blood Pb levels <10 μg/dL. Multiple prospective 

studies demonstrated that blood Pb levels <10 μg/dL 

during early childhood are associated with decreased 

IQ measured in children 6-13 years of age from populations in North America, Australia, Europe, and Asia 

by a range of different tests to assess IQ. Many recent 

studies have used the Wechsler Intelligence Scales for 

Children (WISC) and have adopted similar protocols 

to assist in cross-study comparison and greater generalization of the findings. The most recently published 

pooled analysis of IQ data, Lanphear et al. (2005), 

took advantage of the similarity in study design of 

seven prospective studies and concluded that blood 

Pb levels <10 μg/dL in children (and specifically in 

children with maximal blood Pb levels <7.5 μg/dL) 

are associated with intellectual deficits. The pooled 

analysis of Lanphear et al. (2005) estimated that 3.9 

IQ points (95%CI:2.4,5.3) were lost with an increase in 

blood Pb from 2.4 μg/dL to 10 μg/dL. Data from crosssectional studies also support an association between 

concurrent blood Pb levels <5μg/dL and decreased IQ 

in children up to 13 years of age. The evidence is mixed 

for an association between maternal or umbilical cord 

blood Pb and decreased IQ in children evaluated at 

a later age. Therefore, there is limited evidence that 

prenatal blood Pb levels <10μg/dL are associated with 

decreased IQ in children. There is some evidence that 

the association between decreased IQ might be more 

consistent for bone Pb than for blood Pb, but those 

data come from a group known to have blood Pb levels 

>10 μg/dL during early childhood.

A number of prospective studies have reported 

an association between blood Pb <10 μg/dL and 

decreased IQ score in children from 4 to 13 years of 

age. The decrease in IQ has been reported in groups 

for whom the blood Pb level remained <10 μg/dL 

from birth to evaluation. For example, in a prospective 

study of 148 children with serial blood Pb measurements from birth through 10 years of age, Bellinger 

et al. (1992) (reanalyzed in Bellinger and Needleman 

2003) demonstrated that blood Pb levels at 2 years 

of age (mean, 6.5 μg/dL), but not other ages, were 

significantly associated with decreases in FSIQ and 

verbal IQ (VIQ) assessed by the WISC-R at 10 years 

of age in a cohort from the Brigham and Women’s 

Hospital; the association with performance IQ (PIQ) 

was not significant (p=0.091). Min et al. (2009) 

demonstrated that blood Pb measured at 4 years 

of age (mean, 7 μg/dL) was significantly associated 

with decreased FSIQ by the Wechsler Preschool and 

Primary Scale of Intelligence (WPPSI-R) at 4 years 

of age and with decreased FSIQ by the full WISC-IV 

at 9 and 11 years of age in a prospective study of 

278 inner-city children from Cleveland, OH. However, many of the early studies were in children that 

had blood Pb levels >10 μg/dL at some stage before 

they were given a test to evaluate IQ. For example, 

Baghurst et al. (1992) reported that blood Pb levels 

during early childhood up to 4 years of age (but not 

maternal blood Pb, umbilical cord blood Pb, or average through 7 years of age) were significantly associated with decreased FSIQ and VIQ scores evaluated 

by the WISC-R at 7 years of age in 494 children in Port 

Pirie, Australia; however, mean blood Pb levels in this
Neurological 

Effects

NTP Monograph on Health Effects of Low-Level Lead 25

cohort were >10 μg/dL after birth. A similar association between blood Pb and decreased FSIQ has been 

demonstrated in a number of prospective studies 

with cumulative mean blood Pb levels >10 μg/dL that 

evaluated IQ in children at 5-13 years of age (Dietrich 

et al. 1993b, Tong et al. 1996, Wasserman et al. 1997, 

Factor-Litvak et al. 1999, Canfield et al. 2003a, Wasserman et al. 2003, Jusko et al. 2008).

An association between concurrent blood Pb 

<10 μg/dL as well as <5 μg/dL and decreased IQ has 

been reported in multiple studies. For example, the 

two studies by Chiodo et al. (2004, 2007) evaluated 

a range of neurodevelopmental endpoints in 240 

and 500 African-American inner-city children 7-9 

years of age with mean concurrent blood Pb levels 

of 5.4 μg/dL; these levels were related to decreased 

FSIQ, PIQ, and VIQ, as well as behavioral endpoints 

evaluated with the WISC-III. When grouped by cutoff points of 10, 7.5, 5, and 3 μg/dL blood Pb, the 

study supported significant effects on IQ at blood Pb 

levels of ≥5 μg/dL, with some support for effects at 

≥3 μg/dL. In a cross-sectional study of 261 children 

8-11 years of age in Korea, Kim et al. (2009) reported 

that concurrent blood Pb (mean, 1.7 μg/dL) was significantly associated with reduced FSIQ and VIQ as 

measured by the Korean Educational Development 

Institute – Wechsler Intelligence Scales for Children 

test. This study represents the cohort with the lowest mean blood Pb level associated with decreased 

IQ; however, because the Kim et al. (2009) was crosssectional in nature, and did not follow the children 

from birth, it does not provide information to verify 

that blood Pb levels were <5 or <10 μg/dL from birth 

to the age at which the test was administered.

In a study of 253 children from the Cincinnati 

Lead Study, Dietrich et al. (1993b) reported that 

decreases in FSIQ and PIQ by WISC-R were significantly associated with concurrent blood Pb levels at 

6 years of age and blood Pb for the year before (down 

to age 3 for PIQ); however, IQ was not associated with 

maternal blood Pb, umbilical cord blood Pb, or blood 

Pb levels during early childhood. Hornung et al. (2009) 

analyzed the age of greatest susceptibility for blood 

Pb to contribute to lower IQ scores as evaluated with 

the WISC-R in a combined cohort from the Cincinnati and Rochester lead studies (n=397 total), with 

peak blood Pb mean of 13.6 μg/dL and concurrent 

blood Pb at 6 years of age = 6 μg/dL. At 6 years of age, 

blood Pb measured concurrently (β=-3.48; p<0.001) 

and the prior year (at age 5; β=-4.39; p<0.001) had 

the strongest effect on IQ, compared to blood Pb 

at earlier ages (e.g., age 1; β=-0.08;p=0.934). Note 

that peak childhood blood Pb in the Cincinnati and 

Rochester cohorts was >10 μg/dL; therefore, it is not 

clear that the observed decreases in IQ reported in 

Dietrich et al. (1993b) and Hornung et al. (2009) are 

strictly associated with a blood Pb level <10 μg/dL.

No clear evidence was located that maternal or 

umbilical cord blood Pb levels <10 μg/dL are associated with decreased IQ in children. Many studies, such 

as Baghurst et al. (1992), Bellinger et al. (1992), and 

Dietrich et al. (1993b) described earlier, did not find 

a significant association with prenatal blood Pb levels 

in groups for which prenatal blood Pb was <10 μg/dL. 

In a prospective study that examined the relationship 

between maternal blood Pb during early and late pregnancy and FSIQ in children as measured by the WISC-R, 

Schnaas et al. (2006) reported that maternal blood Pb 

levels at 28-36 weeks of pregnancy (mean, 7.8 μg/dL) 

were related to reduced IQ in children 6-10 years of 

age. However, as in other studies, the mean blood Pb 

in this cohort was >10 μg/dL during early childhood.

The evidence for a Pb-related decrease in IQ 

has been the subject of four key meta-analyses combining data across several studies (Needleman and 

Gatsonis 1990, Pocock et al. 1994, Schwartz 1994, 

Lanphear et al. 2005) and was extensively reviewed 

in the 2006 EPA AQCD for Lead (U.S. EPA 2006) and 

ATSDR Toxicological Profile for Lead (ATSDR 2007). 

These analyses provide strong support that blood 

Pb and tooth Pb are significantly associated with 

decreases in IQ in children; however, many of the 

cross-sectional and prospective studies included in 

these analyses are based on cohorts with blood Pb 

levels >10 μg/dL at some age between birth and age 

of IQ test. The Schwartz et al. (1994) and Lanphear 

et al. (2005) meta-analyses support effects at blood 

Pb levels <10 μg/dL (and with peak blood Pb levels 

<7.5 μg/dL), although these analyses face challenges 

of confounding and the different tests used to assess 

IQ across studies. However, the 2005 pooled analysis 

(Lanphear et al. 2005) reduced these confounders 

by pooling data from seven prospective studies that 

used similar test protocols (e.g., relying principally on 

the WISC) and included 1,333 children from several 

countries. The analyses supported an association 

between blood Pb levels <10 μg/dL and decreased 

IQ, and the authors concluded that blood Pb levels 
Neurological 

Effects

26 NTP Monograph on Health Effects of Low-Level Lead

<10 μg/dL (and specifically <7.5 μg/dL) in children are 

associated with intellectual deficits. Lanphear et al.

(2005) reported significant decreases in IQ in analyses restricted to children with a maximum blood Pb 

level <10 μg/dL. The authors also attempted to characterize the shape of the dose-response between 

blood Pb and IQ (addressed further in the following 

discussion).

Although some earlier studies of Pb and cognitive 

function did not include adjustment for maternal IQ or 

other confounders, these studies were also generally 

in children with blood Pb levels >10μg/dL. More recent 

studies of the relationship between blood Pb and IQ 

in children with blood Pb levels <10 μg/dL considered 

a wide range of potential confounders. For example, 

the Lanphear et al. (2005) pooled analysis included 

maternal IQ, maternal education, score for the Home 

Observation for Measurement of the Environment (an 

assessment of the stimulation in the environment in 

which the child is raised), and birth weight in the final 

model; however, prenatal smoking, prenatal alcohol 

use, mother’s marital status, maternal age, the child’s 

sex, and birth order were also considered and did 

not to influence the analyses. Some studies have also 

considered the effects of co-exposure to other metals 

or toxicants. For example, Kim et al. (2009) demonstrated that children with higher levels of manganese 

in their blood had greater decreases in IQ for a given 

level of Pb; the results of this study suggest that coexposure to other metals should be considered in 

studies of cognitive effects of Pb.

In one example, the extensive data on potential covariates and the thorough characterization 

of exposure measurements based on serial blood 

Pb assessments over time allowed comparison of 

the strength of the association between Pb and 

decreased IQ for two measures of exposure: blood 

Pb and bone Pb. As part of the Yugoslavia Prospective 

Study, 290 children were assessed with the WISC-III at 

10-12 years of age, and 167 of these individuals had 

with tibia bone Pb measurements (Wasserman et al.

2003). Both bone Pb and average lifetime blood Pb 

levels were significantly associated with decreased 

FSIQ, PIQ, and VIQ. Bone and blood Pb measurements were highly correlated (concurrent Pb r=0.75; 

lifetime average Pb r=0.85; p<0.01) in children from 

Titova Mitrovica (a Pb smelter town with higher Pb 

exposure levels) but not in Pristina, the town with 

lower Pb exposure levels. Tibia Pb was a significant 

predictor of FSIQ or PIQ with or without adjustment 

for current or average lifetime blood Pb levels. In 

contrast, average or current blood Pb levels were 

not associated with IQ in models that included tibia 

Pb levels. Therefore, the authors concluded that the 

association with decreased IQ is stronger for bone 

Pb than for blood Pb (Wasserman et al. 2003). In is 

important to note two points in this analysis. First, 

blood Pb measurements were >10 μg/dL for most 

children in these groups. Second, this is one of the 

few studies in children that examined the usefulness 

of bone Pb data as a measure of exposure, although 

a number of studies have measured Pb levels in shed 

deciduous teeth.

Shape of the Dose-Response Curve

There is abundant discussion in the Pb literature on 

the shape of the dose-response curve in the lower 

range of exposure (i.e., at blood Pb levels <10 μg/dL) 

for neurodevelopmental effects of Pb. This discussion 

centers around several studies that have reported 

greater neurocognitive effects (principally on IQ 

and specific measures of cognitive function) of an 

incremental increase in blood Pb levels at lower 

concentrations compared to the effects for an incremental increase at higher blood Pb levels (Canfield 

et al. 2003a, Lanphear et al. 2005, Rothenberg and 

Rothenberg 2005, Kordas et al. 2006). This indicates a 

steeper slope (greater effect per unit increase) in the 

dose-response curve at lower blood Pb levels. The 

2006 EPA AQCD for Lead (U.S. EPA 2006) discusses 

this issue extensively and reviews the evidence that 

the dose-response curve has a steeper slope at lower 

blood Pb levels. The 2005 CDC (CDC 2005) review of 

the epidemiological evidence for neurological effects 

in children also noted that there was evidence for a 

steeper slope in the dose-response curve at lower 

blood Pb levels. Evaluation of the shape of the doseresponse curve is beyond the scope of the current 

evaluation.

Summary of Support for Conclusions

Animal data support a Pb-associated decrease in neurobehavioral tests of learning (including fixed interval 

operant conditioning) at blood Pb levels ≥11 μg/dL

(see U.S. EPA 2006 for recent reviews of the animal 

data, ATSDR 2007). The human data include several 

meta-analyses and prospective and cross-sectional 

studies that support an association between blood 
Neurological 

Effects

NTP Monograph on Health Effects of Low-Level Lead 27

Pb levels <10 μg/dL and lower FSIQ scores in children 4-13 years of age. The conclusion of sufficient 

evidence that decreases in IQ scores in children are 

associated with blood Pb levels <10 μg/dL measured 

in early childhood or in concurrent blood Pb samples 

is based on consistent evidence for decreased IQ 

across multiple studies and in well-accepted pooled 

analyses (e.g., Lanphear et al. 2005). Multiple studies (e.g., Baghurst et al. 1992, Bellinger et al. 1992, 

Min et al. 2009) reported that early-childhood (2-4 

years of age) Pb exposure is associated with IQ score 

in children at later ages. Clear evidence that earlychildhood exposure is associated with decreased IQ 

at later ages is complicated by the high degree of correlation in childhood blood Pb levels over time (e.g., 

see Dietrich et al. 1993a, Lanphear et al. 2005). The 

conclusion of limited evidence that prenatal blood Pb 

levels <10 μg/dL are associated with decreased IQ in 

children is based on mixed evidence for an association with maternal or umbilical cord blood Pb. The 

NTP’s conclusions for sufficient evidence that blood 

Pb levels <10 μg/dL are associated with decreased 

IQ in children 4-13 years of age is consistent with the 

conclusions from EPA’s 2006 AQCD for Lead (U.S. EPA 

2006) and ATSDR’s 2007 Toxicological Profile for Lead 

(ATSDR 2007).

Other General and Specific Measures of 

Cognitive Function

There is sufficient evidence that blood Pb levels 

<5 μg/dL are associated with decreases in various 

general and specific measures of cognitive function in children from 3 months to 16 years of age 

(see Appendix A: Neurological Effects for full list of 

studies). An association between increased blood 

Pb level and decreases in specific cognitive abilities 

has been demonstrated in prospective and crosssectional studies using a wide range of tests to assess 

cognitive function. Although Pb-related decreases 

have been reported in multiple cognitive measures, 

including individual domains for attention, executive function, language, learning and memory, and 

visual-spatial processing, the lack of a clear pattern of 

effects has contributed to difficulty in distinguishing 

specific, focused effects, because test performance 

covers multiple neurobehavioral processes (U.S. EPA 

2006, ATSDR 2007). Although relatively few studies 

have examined the potential effects of Pb in adults 

without occupational exposure, a number of studies 

have reported Pb-associated decreases in specific 

measures of cognitive function in groups of older 

adults, such as the Normative Aging Study. Several 

of these studies reported an association between 

concurrent blood Pb levels <10 μg/dL and decreased 

performance in the Mini-Mental State Examination 

(MMSE) and other cognitive measures. Six studies 

also demonstrated that bone Pb levels were associated with decreased cognitive performance. However, other studies did not find an association with 

concurrent blood Pb levels. There is limited evidence 

that blood Pb levels <10 μg/dL are associated with 

decreases in specific measures of cognitive function 

in older adults, because of the mixed results for an 

association with blood Pb and the more consistent 

support for an association with bone Pb.

There are a large number of tests used to evaluate cognitive function, with tests specific for subjects 

of different ages and designed to explore different 

cognitive domains (see Appendix A: Neurological 

Effects under outcomes measured for tests used in 

individual studies). Two of the more common tests 

that demonstrated effects of Pb in younger subjects 

measure general cognitive function: the Mental 

Developmental Index (MDI) from the Bayley Scales of 

Infant Development and the overall General Cognitive 

Index (GCI) from the McCarthy Scales of Children’s 

Abilities and individual measures. Data on older children evaluated with the WISC were discussed earlier 

in the context of Pb-related decreases of IQ, which 

is also a general measure of cognitive function; however, the WISC also includes more specific subsets, 

such as Block Design and Digit Span, and multiple 

studies reported decreases in scores on WISC subsets 

at blood Pb levels <5 μg/dL (lower than the 10 μg/dL 

blood Pb levels generally associated with effects on 

FSIQ). Multiple tests are used to evaluate cognitive 

function in adults, including the MMSE.

An association between increased blood Pb 

level and decreased MDI score was demonstrated 

in multiple studies at blood Pb levels from <2 to 

10 μg/dL. Maternal blood Pb levels <10 μg/dL and

umbilical cord blood Pb levels <5 μg/dL have been 

reported to be associated with decreased cognitive 

performance in children up to 3 years of age by the 

MDI. Recent studies (Gomaa et al. 2002, Al-Saleh et 

al. 2009, Jedrychowski et al. 2009a, Jedrychowski et 

al. 2009b, Pilsner et al. 2010) reported effects in children with blood Pb levels that remained consistently 
Neurological 

Effects

28 NTP Monograph on Health Effects of Low-Level Lead

below 10 μg/dL; however, early-childhood blood Pb 

increased to levels >10 μg/dL for some of the groups 

examined. Two recent studies reported that concurrent blood Pb levels <10 μg/dL are associated with 

decreased MDI scores, but there is less evidence that 

concurrent blood Pb is associated with MDI than 

there is for an association with measures of prenatal 

Pb exposure.

The overwhelming majority of prospective 

studies found that prenatal exposure determined 

by either umbilical cord or maternal blood Pb levels 

<10 μg/dL were associated with decreased MDI in children through 3 years of age. Significantly lower MDI 

scores in children tested at 3-36 months of age were 

associated with prenatal exposure based on umbilical 

cord blood Pb at the following levels: ≥1 μg/dL in children evaluated at 24 and 36 months of age in a study 

of 457 children in Poland (effects significant for boys 

and girls combined, but likely driven by boys (Jedrychowski et al. 2009a, Jedrychowski et al. 2009b)); 

2.7 μg/dL with MDI evaluated in 6-month-old children in Saudi Arabia (n=119) (Al-Saleh et al. 2009); 

6.4 μg/dL with MDI evaluated in 3-month-old children from the Cincinnati Lead Study (n=266) (Dietrich 

et al. 1987); 6.6 μg/dL with MDI evaluated in children 

6, 12, 18, and 24 months of age from Brigham and 

Women’s Hospital (n=182-249) (Bellinger et al. 1984, 

Bellinger et al. 1986, Bellinger et al. 1987); 6.7 μg/dL 

with MDI evaluated in 24-month-old children from 

Mexico City (n=197) (Gomaa et al. 2002, Pilsner et al.

2010); and 9.2 μg/dL evaluated at 3, 6, and 12 months 

of age in a study of 133 children in China (Shen et al.

1998). Although most of the studies demonstrated a 

Pb-associated decrease in MDI, Cooney et al. (1989a) 

reported that umbilical cord and maternal blood Pb 

levels (mean, 8-9 μg/dL) in participants in the Sydney 

Lead Study (n=215-274) were not related to change 

in MDI tested at 6, 12, 24, or 36 months of age.

Several prospective studies reported an association between maternal blood Pb and decreased 

MDI, with no relationship to umbilical cord blood 

or a less consistent relationship (e.g., Dietrich et al.

1987, Ernhart et al. 1987, 1988, 1990, Hu et al. 2006). 

Hu et al. (2006) examined maternal blood Pb during 

the first, second, and third trimester of pregnancy 

and found that first-trimester blood Pb level (mean, 

7 μg/dL) was associated with lower MDI in children 

at 24 months of age in a study of 146 mother-infant 

pairs from Mexico City; however, the association with 

umbilical cord blood Pb or maternal Pb during other 

time periods was not significant. Dietrich et al. (1987, 

1990) reported that maternal blood Pb sampled during pregnancy (mean, 8 μg/dL) was associated with 

decreased MDI tested at 3, 6, and 24 months of age 

in children from the Cincinnati Lead Study and that 

umbilical cord blood was only associated with MDI 

evaluated at 3 months of age. Ernhart et al. (1987) 

reported that decreased MDI evaluated at 6 months 

of age was associated with maternal blood Pb at delivery (mean, 6.5 μg/dL) in children from the Cleveland 

Lead Study; however, neither umbilical cord blood Pb 

or maternal Pb was associated with MDI evaluated 

at later time points (1-3 years of age). It is important 

to note that the blood Pb of infants from both the 

Cincinnati and Cleveland lead studies increased after 

birth and that childhood blood Pb levels for these 

groups were >10 μg/dL (mean, 16-17 μg/dL at 2 years 

of age), therefore, the lack of association with prenatal Pb levels may be influenced by the high childhood blood Pb levels. A follow-up study by Ernhart et 

al. (1988) did not find an association with MDI and 

early-childhood blood Pb or concurrent blood Pb 

levels; however, as noted above, the blood Pb levels 

in this cohort was >10 μg/dL. In contrast, Bellinger et 

al. (1990) found that postnatal blood Pb was associated with a change in cognitive performance from 24 

months of age (evaluated by the MDI) to 57 months 

of age (evaluated by the GCI) in a study of a group 

with a similar age range.

Few studies have examined the relationship 

between MDI and measures of exposure other 

than blood Pb. Gomma et al. (2002) reported that 

maternal patellar (knee cap) Pb level was significantly 

associated with a decrease in MDI scores evaluated 

in children at 24 months of age in a study of 197 

mother-infant pairs in Mexico City.

Several studies have also demonstrated that 

concurrent blood Pb levels <10 μg/dL were associated 

with lower MDI scores in children from 6 to 36 months 

of age. For example, Solon et al. (2008) reported that 

concurrent blood Pb (mean, 7.1 μg/dL) was associated 

with decreased MDI in children from 6 to 36 months 

of age. Similar results (Pb-related decrease in MDI) 

were reported in children evaluated at 24 months of 

age in Mexico City (Tellez-Rojo et al. 2006) with mean 

concurrent blood Pb level of 4.9 μg/dL.

Similar to the data supporting a negative effect of 

blood Pb on MDI scores, findings from several studies 
Neurological 

Effects

NTP Monograph on Health Effects of Low-Level Lead 29

support an association with decreased performance 

on the GCI in children. In a study of 170 children from 

the Brigham and Women’s Hospital, Bellinger et al.

(1991) reported that GCI scores and the McCarthy 

subscale score for perceptual performance evaluated 

at 57 months of age were inversely associated with 

blood Pb levels in the children at 24 months (mean, 

6.4 μg/dL) but not at other ages. Similarly, Schnaas 

et al. (2000) reported that blood Pb levels from 24 

to 36 months of age were associated with decreased 

performance on the GCI, but effects at earlier ages or 

later ages up to 56 months were not significant, in a 

study of 112 children from the Mexico City Prospective Study. Blood Pb was consistently below 10 μg/dL 

in the cohorts from both the Bellinger et al. (1991) 

and Schnaas et al. (2000) studies. It is also important 

to note that some studies did not find a significant 

association between blood Pb and performance on 

the GCI; for example, maternal blood Pb (9 μg/dL),

umbilical cord Pb (8 μg/dL), or current blood Pb 

were not associated with performance on the GCI in 

a study of 207 children from the Sydney Lead Study 

evaluated at 48 months of age (Cooney et al. 1989b).

Multiples studies have reported that concurrent 

and early-childhood blood Pb levels <10 μg/dL are 

associated with decreases in specific indices of cognitive function in children from 4 to 16 years of age. 

Examples include studies demonstrating decreased 

performance on subsets of the WISC. In a cross-sectional study of 384 children in Germany, Walkowiak 

et al. (1998) reported that concurrent blood Pb 

(mean, 4.7 μg/dL) in 6-year-olds was associated 

with decreased vocabulary scores evaluated as part 

of the German version of the WISC. In a large crosssectional study of children 6-16 years of age from the 

NHANES III data set, Lanphear et al. (2000) and Krieg 

et al. (2010) demonstrated that concurrent blood Pb 

levels <10 μg/dL (geometric mean, 1.9 μg/dL) were 

associated with decrements in the Block Design and 

Digit Span subsets of the WISC-R. In subgroup analysis, Min et al. (2009) reported that blood Pb <5 μg/dL

measured at 4 years of age was significantly associated with decreased performance by the WPPSI-R at 

4 years of age and with perceptual reasoning scores 

of the WISC at 9 years of age in a prospective study of 

278 inner-city children from Cleveland, OH. Chiodo et 

al. (2004, 2007) evaluated a range of neurocognitive 

effects in inner-city African American children 7-9 years 

of age (n=243 and 506, respectively) with concurrent 

blood Pb levels <10 μg/dL (mean 5.4 μg/dL; blood Pb 

levels were related to decreased performance in multiple tests, including the Block Design and Digit Span 

subsets of the WISC and various tests of executive 

function, memory, and attention. When grouped by 

cutoff points of 10, 7.5, 5, and 3 μg/dL blood Pb, the 

studies found significant effects on some tests at levels 

of ≥3 μg/dL (e.g., Block Design).

Most studies of the effects of Pb on cognitive 

function in adults involved occupationally exposed 

individuals with blood Pb levels >10 μg/dL, and fewer 

studies have been reported in adults from the general population. A number of studies in older adults 

reported a decrease in cognitive function associated 

with Pb, with more consistent evidence for an association with bone Pb than for concurrent blood Pb 

levels. Payton et al. (1998) reported that concurrent 

blood Pb (mean, 5.5 μg/dL) levels in 141 older men 

(mean age, 67 years) from the Normative Aging Study 

were associated with decreases in specific measures 

of cognitive function from a battery of tests administered, including slower pattern comparison speed, 

vocabulary, word list memory, constructional praxis, 

and the Boston Naming Test. Tibia Pb level (but not 

patellar Pb) was associated with decreased performance in a test of spatial ability. In a study of 736 

older men (mean age, 69 years) also from the Normative Aging Study, Wright et al. (2003) reported that 

blood Pb (mean, 4.5 μg/dL), patellar Pb, and tibia 

Pb were all associated with decreased performance 

on the MMSE. Muldoon et al. (1996) evaluated cognitive performance with the MMSE and Wechsler 

Adult Intelligence Scale-Revised for 530 older women 

(mean age, 71 years) either from rural residents in 

Pennsylvania or from urban dwellers in Baltimore. 

Blood Pb (mean, 4.8 μg/dL) was associated with 

decreased performance on the Trail Making Test (for 

blood Pb >8 μg/dL, OR=2.60 (95% CI: 1.04, 6.49); for 

blood Pb 4-7 μg/dL, OR=2.05 (95% CI: 1.05, 4.02); 

relative to referents with blood Pb ≤3 μg/dL) and the 

Digit Symbol Substitution test (for blood Pb >8 μg/dL, 

OR=3.73 (95% CI: 1.57, 8.84); for blood Pb 4-7 μg/dL, 

OR=2.03 (95% CI: 1.06, 3.88); relative to referents with 

blood Pb ≤3 μg/dL), but only in the rural population 

and not the urban population (Muldoon et al. 1996).

There are also several studies that reported 

an association between bone Pb and decreased 

performance but did not find an association with 

blood Pb levels. Shih et al. (2006) reported a lack 
Neurological 

Effects

30 NTP Monograph on Health Effects of Low-Level Lead

of an association between current blood Pb (mean, 

3.5 μg/dL) and cognitive function in a study of 985 

older adults in the Baltimore Memory Study (mean 

age, 60 years). However, tibia Pb levels were significantly associated with lower scores in all seven 

domains of the cognitive test battery (Shih et al.

2006). Weuve et al. (2009), reported that tibia Pb levels were associated with reduced cognitive function 

by the Telephone Interview for Cognitive Status in a 

study of 587 older women (mean age, 61 years) from 

the Nurses Health Study; blood Pb and patellar Pb 

levels were not significantly related to the test score. 

Two studies did not find an association with blood Pb 

levels and did not collect bone Pb data: Nordberg et 

al. (2000) did not find an association between blood 

Pb level (mean, 3.7 μg/dL) and performance on the 

MMSE in a study of 762 older adults (mean age, 88 

years) in Sweden; Gao et al. (2008) reported that 

concurrent blood Pb (mean, 3.9 μg/dL) was not significantly related with cognitive function in as study 

of 188 people (mean age, 69 years) from rural China 

assessed with a test battery that included the Community Screening Interview for Dementia.

Several studies have reported a greater effect on 

changes in cognitive function over time, rather than 

a single cross-sectional examination. Weisskopf et al.

(2004) tested cognitive function in 466 men (mean 

age, 67 years) from the Normative Aging Study over 

several years and reported that higher patella Pb was 

associated with a greater decline in performance on 

the MMSE over a 3.5-year period between retesting; they found no association with blood Pb (mean, 

4 μg/dL), and the association with tibia Pb level was 

weaker. In an expanded study of the same group covering 1,089 men, Weisskopf et al. (2007) reported 

similar results, stating that there was little association between blood or bone Pb levels and cognitive 

test scores on a cross-sectional basis; however, patellar and tibia Pb levels were associated with decline 

in performance on a range of cognitive functions, 

particularly visuospatial and visuomotor subscales. 

Bandeen-Roche (2009) reported that tibia Pb was 

associated with decreased hand-eye coordination 

over time in a study of 964 older adults from the Baltimore Memory Study (59 years of age at baseline), 

but not with other measures of cognitive function in 

a battery of 20 standardized tests.

Fewer studies have examined cognitive performance in younger adults with low blood Pb levels. In 

a series of studies from Krieg et al. in 4,937 adults 

20-59 years of age from the NHANES III data set, 

blood Pb levels <10 μg/dL in adults were not associated with performance on neurobehavioral tests. 

Krieg et al. (2005, 2009, 2009, 2010) did not find a 

significant relationship between blood Pb (mean, 

3.3 μg/dL) and neurobehavioral tests for simple 

reaction time, symbol-digit substitution, and serial 

digit learning. In a portion of the study that included 

both children and adults from the same NHANES data 

set, Krieg et al. (2010) demonstrated that vitamin D 

receptor (VDR) genotype did affect the relationship 

between blood Pb and performance on the WISC-R 

Digit Span and WRAT-R math scores; however, they 

found no clear pattern in terms of the effect of VDR 

genotype on the relationship between blood Pb and 

cognitive function.

Most of the recent studies of the relationship 

between blood Pb and specific measures of cognitive 

function considered a range of potential confounders, 

such as age, sex, education, and race/ethnicity. Some 

studies have also examined potential physical, genetic, 

and psychological confounders. In a study of 47 health 

adults 55-67 years of age in Rochester, NY, van Wijngaarden et al. (2009) found that higher tibia and calcaneus (heel bone) Pb levels were significantly correlated with measures of memory impairment; however, 

the relationship with bone Pb was not significant after 

adjusting for hypertension. Several studies of cognitive 

function in children and adults have also investigated 

the potential modifying effect of gene polymorphisms 

(e.g., ALAD, HFE, APOE, and VDR genotypes) and other 

factors (Weuve et al. 2006, Rajan et al. 2008, Glass et 

al. 2009, Krieg et al. 2010). In particular, Wang et al.

(2007) demonstrated a significant effect of HFE polymorphism on the rate of decline in MMSE score in 358 

participants from the Normative Aging Study. Krieg et 

al. (2010) and Rajan et al. (2008) reported that there 

was no clear pattern of ALAD or VDR genes modifying 

the relationship of Pb and cognitive function. Glass 

et al. (2009) found that tibia Pb was associated with 

impaired executive function and that there was a significant interaction with neighborhood psychosocial 

hazards in a study of 1,001 older adults (mean age, 59 

years) from the Baltimore Memory Study. Surkan et 

al. (2008) reported that higher maternal self-esteem 

attenuated the Pb-associated decrease in MDI score 

in a study of 309 children 2 years of age from Mexico 

City. Peters et al. (2010) reported that blood Pb (mean, 
Neurological 

Effects

NTP Monograph on Health Effects of Low-Level Lead 31

5 μg/dL) was significantly associated with decreased 

cognition as measured by the MMSE, but that bone 

Pb and stress were modifiers of the association with 

Pb in a study of 811 older men (mean age, 68 years) in 

Normative Aging Study.

Summary of Support for Conclusions

Animal data support a Pb-associated decrease in 

neurobehavioral tests of learning (including fixed 

interval operant conditioning) at blood Pb levels 

≥11 μg/dL and mixed evidence for effects on memory 

(see U.S. EPA 2006 for recent reviews of the animal 

data, ATSDR 2007). The human data include multiple 

prospective and cross-sectional studies supporting a 

Pb-associated decrease in specific measures of cognitive function in children at blood Pb levels from 1 

to 10 μg/dL. The conclusion of sufficient evidence for 

decreases in specific measures of cognitive function 

in children 3 months to 16 years of age with blood Pb 

levels <5 μg/dL measured in concurrent blood or in 

early childhood is based on the consistency of effects 

on multiple measures of cognitive function in multiple studies. Multiple studies (e.g., Min et al. 2009) 

reported that early-childhood Pb exposure is associated with decreases in cognitive function observed 

at later ages. However, as discussed for IQ, clear 

evidence that early-childhood or prenatal Pb exposure is associated with decreases in specific indices 

of cognitive function at later ages is complicated by 

the high degree of correlation in childhood blood Pb 

levels over time (e.g., see Dietrich et al. 1993a, Lanphear et al. 2005). Multiple studies (e.g., Bellinger 

et al. 1984, Al-Saleh et al. 2009, Jedrychowski et al.

2009a) also reported that levels of Pb in umbilical 

cord blood are associated with decreases in cognitive function observed at later ages by cognitive tests 

such as the MDI. The conclusion of limited evidence 

that prenatal blood Pb levels <5 μg/dL are associated 

decreases in specific measures of cognitive function 

in children is based on strong consistent support for 

an association between umbilical cord blood and MDI 

scores, and the mixed evidence for maternal blood 

Pb and MDI or other measures of cognitive function in children. The conclusion of limited evidence 

that blood Pb levels <10 μg/dL are associated with 

decreases in specific measures of cognitive function 

in older adults is based on the mixed evidence that 

concurrent blood Pb levels <10 μg/dL are associated 

with reduced cognitive function and the consistent 

support that bone Pb is associated with decreases 

in specific measures of cognitive function or with 

change in these measures through time in older 

adults. The EPA’s 2006 AQCD for Lead (U.S. EPA 

2006) suggests that cumulative exposure to Pb may 

be critical in contributing to neurocognitive deficits 

in adults because of the significant associations with 

bone Pb; EPA also highlights the mixed evidence for 

an association with blood Pb. As with other studies of 

health effects of Pb in adults, prospective studies in 

a group for which the data demonstrated that blood 

Pb levels remained consistently below 10 μg/dL from 

birth until measurement of the outcome of interest 

would eliminate the potential role of early-life blood 

Pb levels above 10 μg/dL on health effects observed 

in adults with concurrent blood Pb levels <10 μg/dL. 

The NTP’s conclusion of sufficient evidence that blood 

Pb levels <5 μg/dL are associated with decreases in 

general and specific measures of cognitive function 

in children 3 months to 16 years of age extends the 

conclusions from EPA’s 2006 AQCD for Lead (U.S. EPA 

2006) and ATSDR’s 2007 Toxicological Profile for Lead 

(ATSDR 2007), which were limited to blood Pb levels 

<10 μg/dL; however, the EPA’s 2012 draft (U.S. EPA 

2012) currently supports a lower blood Pb level.

4.3.2 Behavior

Attention-Related Behaviors

There is sufficient evidence that blood Pb levels 

<5 μg/dL are associated with attention-related behavioral problems in children 3-18 years of age (see 

Appendix A: Neurological Effects for full list of studies). This conclusion is for an association with attention-related behaviors, rather than ADHD alone, for 

two reasons: (1) “attention-related behaviors” is an 

inclusive expression that more accurately reflects the 

data supporting a range of Pb-associated behavioral 

effects in the area of attention, of which ADHD is one 

example on the more severe end of the spectrum of 

effects; and (2) in the available studies, designations 

of “ADHD” in children generally lack the strength of an 

ADHD diagnosis by trained clinicians using DSM-IV-TR

criteria. Most of the studies that demonstrated a significant association between Pb and attention-related 

behaviors are studies that report behavioral testing 

and concurrent blood Pb levels. Increased diagnosis 

of ADHD and attention-related behaviors (e.g., inattention and hyperactivity) are consistently reported 
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32 NTP Monograph on Health Effects of Low-Level Lead

in studies with mean blood Pb levels <5 μg/dL and 

in several studies at blood Pb levels <2 μg/dL. The 

diagnostic criteria for attention-related behaviors can 

include multiple categories of behavioral deficits in 

addition to inattention, hyperactivity, and the overall diagnosis of ADHD (Aguiar et al. 2010). A review 

of individual behavioral domains, such as response 

inhibition, flexibility, and planning aspects, was published by Eubig et al. (2010); however, data on those 

individual domains will not be covered here because 

a sufficient number of studies examine overall ADHD 

diagnosis, inattention, and hyperactivity to develop 

more general conclusions on the overall classification of attention-related behaviors. There is limited 

evidence that prenatal blood Pb levels <10 μg/dL are 

associated with attention-related behaviors in childhood. Several prospective studies reported that Pb 

exposure determined from maternal blood during 

pregnancy, umbilical cord blood, or early-childhood 

blood (up to 30 months) or from tooth dentin levels 

(6-8 years of age) is associated with inattention or 

hyperactivity as children or young adults1 (7-20 years 

of age); however, early-childhood blood Pb levels in 

some of these individuals were >10 μg/dL; therefore, 

the effect may not be strictly associated with blood 

Pb levels <10 μg/dL.

A clear majority of recent cross-sectional studies 

(more than 10 publications since 2000) demonstrate 

an association between current blood Pb at mean 

levels from 1 to 11 μg/dL and attention-related 

behavioral problems, ADHD, or other indicators of 

decreased attention or increased hypersensitivity in 

children from 3 to 18 years of age. Multiple studies 

reported an association with blood Pb of ≤5 μg/dL. 

In a case-control study of 1,260 children 4-12 years 

of age in China (n=630 ADHD cases and 630 matched 

controls), Wang et al. (2008) reported a significant 

association between concurrent blood Pb levels 

>5 μg/dL and ADHD determined from a structured 

diagnostic interview. An increase in attention-related 

behavioral problems, particularly inattention, was 

observed on the teachers’ and parents’ ratings using 

a German questionnaire version of the Conners’ 

Rating Scale (namely the Fremdbeurteilungsbogenfür Auf-merksamkeits-Hyperaktivitäts-Störung 

(FBB-ADHS)) and German-KITAP (Testbatterie zur 

1 Note: children are defined as <18 years of age in this document; therefore, 18- to 20-year-olds in the study are considered adults.

Aufmerksamkeitsprüfung fü Kinder) test battery in a 

study of 83 children 8-12 years of age in Romania with 

concurrent mean blood Pb levels 3-5 μg/dL (Nicolescu 

et al. 2010). Two studies by Chiodo et al. (2004, 2007) 

evaluated a range of neurodevelopmental measures 

in inner-city African American children 7-9 years of 

age (n=243 and 506, respectively) with concurrent 

blood Pb levels (mean, 5.4 μg/dL); blood Pb levels 

were related to higher ADHD and inattention scores 

on the Barkley-DuPaul Scale, greater hyperactivity 

on the PROBS-14 Problem Behavior Scale, and poor 

attention on the Achenbach Child Behavior Checklist 

Teacher Report Form. When they grouped the children by cutoff points of 10, 7.5, 5, and 3 μg/dL blood 

Pb, the two studies supported significant effects on 

inattention at blood Pb levels of ≥3 μg/dL.

Two publications that evaluated ADHD in children from the NHANES (1999-2002) data set (Braun 

et al. 2006, Froehlich et al. 2009) reported an association between concurrent blood Pb levels of 1-2 μg/dL 

and ADHD. Braun et al. (2006) reported a significant 

increase in the odds ratio ((OR=4.1 (95% CI: 1.2, 14.0; 

p=0.001)) for ADHD among children 4-15 years of age 

with blood Pb levels >2 μg/dL compared to referents 

with blood Pb 0.8 μg/dL (n=4,704 participants); 

the determination of ADHD was based on parental reported previous diagnosis or use of stimulant 

medication. In children 8-15 years of age from the 

same NHANES data set (n=2,588), Froehlich et al.

(2009) found that children with concurrent blood Pb 

>1.3 μg/dL (the third tertile of Pb exposure) had a significantly greater odds ratio (OR=2.3 (95% CI: 1.5, 3.8; 

p=0.001)) and children with blood Pb ≥0.9 to 1.3 μg/dL

had an OR=1.7 (95% CI: 0.97, 2.9; p=0.06) of ADHD 

compared to referents (the first tertile of Pb exposure) with 0.8 μg/dL blood Pb; the determination of 

ADHD was based the Diagnostic Interview Schedule 

for Children.

Several other cross-sectional studies support 

an association between concurrent blood Pb levels 

of ≤2 μg/dL and attention-related behaviors, ADHD, 

or symptoms of inattention and or hyperactivity. In a 

cross-sectional study of 639 children 8-11 years of age 

in Korea, Cho et al. (2010) reported a significant association between blood Pb levels (mean, 1.9 μg/dL)

and ADHD ratings in the inattention, hyperactivity, and total scores using the teacher evaluation of 

the Korean version of the ADHD rating scale. Higher 

concurrent blood Pb level (mean, 1.8 μg/dL) was 
Neurological 

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NTP Monograph on Health Effects of Low-Level Lead 33

associated with increased score on the Korean version of the abbreviated Conners’ scale for ADHD in a 

study of 1,778 children 7 years of age in South Korea 

in the Children’s Health and Environment Research 

Study (Ha et al. 2009). In a pair of studies of 236 

children, Nigg et al. (2008, 2010) reported that concurrent blood Pb levels were significantly higher in 

ADHD-combined type children 6-17 years of age than 

in controls, and that blood Pb levels (mean, 1 μg/dL) 

were significantly correlated with aspects of ADHD 

diagnosis by two experienced clinicians, including 

hyperactivity, oppositional behaviors, ADHD index, 

and attention problems evaluated with the Conners’ 

ADHD Rating Scale, revised. Nigg et al. (2008, 2010) 

found that measures of hyperactivity-impulsivity 

were more consistently associated with blood Pb 

measurements than were inattention symptoms.

However, the consistent association with hyperactivity over inattention observed by Nigg et al. (2008, 

2010) is not universal, and several other studies 

have found an association with blood Pb and ADHD 

or measures of inattention. Kim et al. (2010) found 

increased inattention and hyperactivity symptoms on 

the teacher-completed Korean version of the ADHD 

Rating Scale in children with blood Pb ≥2.2 μg/dL

compared to referents with lower blood Pb levels in a 

study of 275 South Korean children 8-10 years of age. 

Roy et al. (2009) reported an increase in the ADHD 

index (β=0.17; p=0.05), and ratings on the DSM-IV

inattentive scale (β=0.24; p=0.01), but not ratings 

on the DSM-IV hyperactive scale (β=0.17; p=0.13) 

by the Connors’ ADHD/Diagnostic and Statistical 

Manual of Mental Disorders (4th edition (DMS-IV)) 

scales, in 3- to 7-year-old children in India with concurrent mean blood Pb of 11 μg/dL; increased anxiety and social problems were also noted. Inattention 

and hyperactivity in 11-year-olds evaluated by the 

Rutter Parent and Teacher Behavior Questionnaires 

were also correlated with blood Pb (mean, 11 μg/dL) 

in a cross-sectional study of 579 children from the 

Dunedin Multidisciplinary Health and Development 

Study in New Zealand (Silva et al. 1988). Canfield et al.

(2003b) reported that blood Pb at 4 years of age was 

associated with decreased focused attention by the 

Shape School Task at 4-5 years of age in 172 children 

in Rochester, NY.

The relationship between concurrent blood Pb 

levels and attention-related behaviors is supported by 

multiple studies, but there are also data supporting a 

role for early-life prenatal or early-childhood Pb exposure and attention-related behaviors in older children. 

In a prospective study with Pb exposure measures 

spanning prenatal and early childhood to 6 years of 

age, Ris et al. (2004) reported that attention in 15- to 

17-year-old children by the Continuous Performance 

Test-Conners’ Version was inversely associated with 

maternal blood Pb during the first or second trimester 

of pregnancy (mean, 8.9 μg/dL), average childhood 

blood Pb <5 years of age, and blood Pb at 6.5 years 

of age in a study of 195 children from the Cincinnati 

Lead Study); however, blood Pb levels during early 

childhood were above 10 μg/dL in this cohort (Dietrich et al. 1993a, Wright et al. 2008), so it is not clear 

that this is strictly associated with blood Pb levels 

<10 μg/dL. Chandramouli et al. (2009) found that 

attention in 7- and 8-year-olds in the United Kingdom, 

as assessed with the Test of Everyday Attention for 

Children, was not significantly related to blood Pb 

(mean, 4.2 μg/dL) at 30 months of age (n=582), but 

there was a greater odds for teacher-rated hyperactivity (OR=2.82 (95% CI: 1.08, 7.35)) in children with 

blood Pb >10 μg/dL. Cord blood Pb (mean, 6.8 μg/dL)

and tooth dentin Pb were associated with inflexible 

behavior in 8-year-olds in the Task domain of the 

BTQ, but there was no relationship with hyperactivity, in their study of 1,923 children in Boston (Leviton 

et al. 1993). Fergusson (1993) reported a significant 

association between tooth dentin Pb of shed primary 

teeth (6-8 years of age) and measures of inattention and restlessness at 12-13 years of age by the 

Rutter and Conners parental and teacher questionnaires in a study of 1,265 children from the Christchurch Health and Development Study cohort. In a 

similar study of 79 young adults2 19-20 years of age, 

Bellinger et al. (1994a) reported that both dentin Pb 

levels in shed teeth (6-8 years of age) and tibia Pb 

levels were significantly associated with specific measures of attention. 

Summary of Support for Conclusions

Animal data support a Pb-associated reduced performance on neurobehavioral tasks (including increased 

distractibility), with effects observed down to approximately 10 μg/dL (e.g., deficits in waiting behavior in 

rats Brockel and Cory-Slechta 1998, U.S. EPA 2006 for 

2 Note: children are defined as <18 years of age in this document; therefore, 19- and 20-year-olds in the study are considered adults.
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34 NTP Monograph on Health Effects of Low-Level Lead

recent reviews of the animal data, see ATSDR 2007). 

In general the animal data are unlikely to represent 

thresholds because the lowest levels of effect have yet 

to be studied. The human data supporting a Pb-associated increase in attention-related behaviors such as 

ADHD, inattention, and hyperactivity include multiple 

cross-sectional studies of children from 3 to 18 years of 

age with blood Pb levels of 1-11 μg/dL. The conclusion 

of sufficient evidence for a positive association with 

attention-related behaviors in children at blood Pb 

levels <5 μg/dL is based on the consistency of effects 

in these studies and supports effects down to and 

below 2 μg/dL blood Pb. This conclusion is for an association with attention-related behaviors rather than 

ADHD alone for two reasons. First, “attention-related 

behaviors” is a more inclusive term that more accurately reflects the support for a range of Pb-associated 

behavioral changes in the area of attention, of which 

ADHD is one example on the more severe end of the 

spectrum of effects. Second, diagnostic criteria in the 

available studies, with the exception of the two Nigg et 

al. (2008, 2010) reports, are based largely on the parent reporting a physician’s diagnosis, untrained teacher 

evaluations, or that the child is taking ADHD medication; therefore, they lack the additional strength that 

would be provided by studies that incorporate diagnostic evaluations by trained clinicians or physicians to 

identify ADHD using DSM-IV-TR criteria. Recent studies found effects on attention-related behaviors after 

controlling for a large number of confounders, such 

as socioeconomic variables, sex, race/ethnicity, age 

of blood Pb measurement, parental education, and 

tobacco exposure. Several studies reported that blood 

Pb levels were significantly associated with ADHD even 

after controlling for potential mediating effects of child 

IQ (e.g., Nigg et al. 2008, Nigg et al. 2010). Although 

several studies reported an association between concurrent blood Pb and attention-related behaviors in 

children up to 15 or 17 years of age (Braun et al. 2006, 

Nigg et al. 2008, Froehlich et al. 2009, Nigg et al. 2010), 

or between bone Pb measured as children and attention evaluated as young adults 19 and 20 years of age 

(Bellinger et al. 1994a), no studies were located that 

examined the relationship between blood Pb levels in 

adults and ADHD or attention-related behaviors. There 

is inadequate evidence to evaluate the potential association between blood Pb <10 μg/dL and effects on 

attention-related behaviors in adults. The conclusion of 

limited evidence for an association between blood Pb 

levels and attention-related behaviors in children with 

prenatal Pb exposure at blood Pb levels <10 μg/dL is 

based on the evidence for an association with prenatal 

blood Pb <10 μg/dL that may include childhood exposure >10μg/dL, with support from the concurrent blood 

Pb data and a number of bone Pb studies reporting 

an association with attention-related behaviors such 

as inattention or hyperactivity. Existing data support 

the importance of current Pb exposure for attentionrelated behaviors but does not allow a clear distinction 

between the role of early-life Pb exposure and current 

exposure. The NTP’s conclusions for sufficient evidence 

that attention-related behaviors in children 3-18 years 

of age are associated with Pb levels <5 μg/dL are stronger than the limited relationship with behavioral features of ADHD outlined in the EPA’s 2006 AQCD for Lead 

(U.S. EPA 2006) and ATSDR’s 2007 Toxicological Profile 

for Lead (ATSDR 2007); however, given the growth of 

the database in recent years, the EPA’s 2012 draft (U.S. 

EPA 2012) currently supports an association with ADHD 

and biological plausibility supported by Pb-associated 

increases in attention-related behaviors.

Problem Behaviors

The discussion of problem behaviors below is divided 

into two sections: (1) delinquent, criminal, or antisocial behavior; and (2) psychiatric outcomes. Most 

of the studies of Pb effects on problem behaviors 

focused on studies of conduct problems or criminal 

behavior. Recent studies of mood disorders or psychiatric outcomes such as anxiety and depression have 

also reported an association with blood Pb levels.

Delinquent, Criminal, or Antisocial Behaviors

There is sufficient evidence that blood Pb levels 

<5 μg/dL are associated with antisocial behavioral 

problems or actual criminal behavior in children from 

6 to 15 years of age (see Appendix A: Neurological 

Effects for full list of studies). Recent studies, including 

studies with large sample sizes such as the NHANES 

data sets, have reported effects down to blood Pb levels <1 μg/dL, and a number of cross-sectional studies 

demonstrated an association between concurrent 

blood Pb at and below 10 μg/dL and antisocial problem behaviors. Multiple studies reported that bone Pb 

and tooth dentin Pb are related to antisocial behavior 

problems. There is limited evidence that prenatal 

blood Pb levels <10 μg/dL are associated behavioral 

problems in childhood. A number of prospective 
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Effects

NTP Monograph on Health Effects of Low-Level Lead 35

studies have reported a significant association 

between prenatal blood Pb <10 μg/dL and delinquent 

behavior or criminal arrests as children; however, 

childhood blood Pb levels in some of these individuals are >10 μg/dL; therefore, the effect may not be 

strictly associated with blood Pb levels <10 μg/dL. 

Several studies have also reported that umbilical cord 

blood Pb was not associated with antisocial problem 

behaviors in children. Although several studies have 

reported an association between prenatal Pb levels 

<10 μg/dL and criminal arrests in young adults3 up 

to 24 years of age, no studies of antisocial behavioral 

problems were located with Pb levels in adults. There 

is inadequate evidence to evaluate the potential association between blood Pb <10 μg/dL and effects on 

behavior problems in adults.

Braun et al. (2008) reported a significant increase 

in the odds ratio (OR=7.24 (95% CI: 1.1, 49.5)) for conduct disorder among children 8-15 years of age with 

blood Pb levels ≥0.8 μg/dL compared to referents 

with blood Pb ≤0.7 μg/dL (conduct disorder measured 

using criteria described in DSM-IV; n= 3,081 from the 

NHANES 2001-2004 data set). This study extended 

the findings from earlier cross-sectional studies that 

found associations between current blood Pb at and 

above 10 μg/dL and behavioral problems or criminal 

behavior in children from 6 to 13 years of age (i.e., 

mean blood Pb 10-15 μg/dL in Yule et al. 1984, Silva 

et al. 1988, Thomson et al. 1989, Burns et al. 1999). 

For example, in a cross-sectional study of 11-year-old 

children (n=579) in New Zealand, blood Pb (mean, 

11 μg/dL) was significantly correlated with behavioral problems evaluated with the Rutter Parent and 

Teacher Behavior Questionnaires (Silva et al. 1988). 

Burns et al. (1999) reported that increased behavioral problem scores by the Child Behavior Checklist 

(CBCL) were associated with lifetime average blood 

Pb (geometric mean, 14 μg/dL) in a study of 322 children 11-13 years of age from the birth cohort in Port 

Pirie, Australia.

Several prospective studies support an effect of 

Pb exposure on antisocial problem behaviors using 

Pb exposure determined by blood Pb or bone Pb 

(Bellinger et al. 1994b, Dietrich et al. 2001, Wasserman et al. 2001, Chen et al. 2007). Results of 

some studies support a stronger or more consistent 

3 Note: children are defined as <18 years of age in this document; therefore, 19- to 24-year-olds in these studies are 

considered adults.

relationship between bone Pb or concurrent blood 

Pb and behavioral outcomes than for prenatal or 

early-childhood blood Pb. For example, Bellinger 

et al. (1994b) reported that problem behaviors in 

8-year-old children in Boston (n=1,782 judged by the 

Teacher Report Form of the Child Behavior Profile) 

were significantly associated with tooth dentin Pb 

levels; however, there was no association with umbilical cord blood Pb levels (mean, 7 μg/dL). Behavioral 

measures in a study of 7-year-old children (n=780) 

demonstrated an association with concurrent blood 

Pb (mean, 8 μg/dL) for both indirect effects on behavior symptoms mediated through IQ and direct effects 

on school problems and behavioral symptoms index 

evaluated with the Behavioral Assessment System 

for Children (Chen et al. 2007); however, there was 

no association with earlier blood Pb levels that were 

significantly above 10 μg/dL at 2 years of age (mean, 

26 μg/dL) or 5 years of age (mean, 12 μg/dL).

In contrast, other prospective studies support 

an association with prenatal or early-childhood 

exposure with problem behaviors at a later age. 

Dietrich et al. (2001) found significant associations 

between maternal blood Pb (mean, 8.9 μg/dL) and 

childhood blood Pb measures ≤7 years of age with 

self-report of delinquent behavior in children from 

the Cincinnati Lead Study evaluated at 15-17 years 

of age (concurrent mean, 3 μg/dL); however, as in 

the study by Chen et al. (2007), blood Pb levels during early childhood were above 10 μg/dL, so it is not 

clear that this is strictly associated with blood Pb 

levels <10 μg/dL. Similar results were reported for 

umbilical cord blood and concurrent blood Pb and 

behavior problems in 3-year-olds from the Yugoslavia 

Prospective Study; however, blood Pb levels (means 

of 5.5 μg/dL in Pristina and 22 μg/dL in Mitrovica) 

in many children in this study were also >10 μg/dL 

(Wasserman et al. 1998). Chandramouli et al. (2009) 

found that the odds ratio for antisocial behaviors 

(OR=2.90 (95% CI: 1.05, 8.03)) in 7- and 8-year-olds 

(n=582) in the United Kingdom assessed by the Antisocial Behavior Interview was significantly elevated 

with blood Pb >10 μg/dL at 30 months of age. Two 

studies have also reported an association with prenatal or childhood blood Pb levels and antisocial 

behavior problems as young adults4. Higher rates 

4 Note: children are defined as <18 years of age in this document; therefore, 19- to 24-year-olds in the following studies are considered adults.
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36 NTP Monograph on Health Effects of Low-Level Lead

for total criminal arrests in 19- to 24-year-olds for 

a 5 μg/dL increase in blood Pb were significantly 

associated with higher maternal blood Pb during the 

first or early second trimester of pregnancy (mean, 

8.3 μg/dL; relative risk (RR)=1.4 (95% CI: 1.07, 1.85)) 

as well as blood Pb at 6 years of age (mean, 8.3 μg/dL; 

RR=1.27 (95% CI: 1.03, 1.57)) in a study of 250 young 

adults from the Cincinnati Lead Study (Wright et al.

2008). Hornung et al. (2009) reported that blood 

Pb at 6 years of age was more strongly related to 

adult criminal arrests (age was not reported) than 

was blood Pb at 2 years of age in a similar analysis 

reported for the combined cohort from the Cincinnati and Rochester lead studies, with a peak blood 

Pb mean of 13.6 μg/dL and concurrent blood Pb at 6 

years of age of 6 μg/dL; there was a strong correlation between the ratio of blood Pb at 6 years to blood 

Pb 2 years and criminal arrests (β=1.21; p<0.001).

Several studies support an association between 

higher bone Pb, tooth dentin Pb, or hair Pb and antisocial problem behaviors but did not provide blood 

Pb measurements for comparison. Bone Pb levels 

were associated with antisocial behavior, including delinquency and aggression, in a study of 212 

boys tested by the CBCL at 7 and 11 years of age 

(Needleman et al. 1996). Needleman et al. (2002) 

found that tibia bone Pb in 12- to 18-year-olds was 

associated with an increased odds ratio for delinquent behavior that resulted in a court appearance 

(OR=3.7 (95% CI: 1.3, 10.5)) in a case-control study of 

194 delinquent and 146 nondelinquent youths from 

the same high schools in Pennsylvania. Fergusson et 

al. (2008) reported a significant association between 

tooth dentin Pb of shed primary teeth (6-8 years of 

age) and officially reported crime at 21 years of age in 

a study of 1,265 young adults from the Christchurch 

Health and Development Study cohort.

A meta-analysis of 19 studies of Pb exposure 

and conduct problems in children 3-18 years of age 

reported a significant overall correlation (r=0.19; 

p<0.001) or medium effect size across the 19 studies 

evaluated, consisting of 8,561 total children (Marcus 

et al. 2010). Although conduct problems were more 

common in boys than in girls, the percentage of boys 

in the study did not appear to attenuate the relationship with Pb, nor did adjustment for other confounders such as age, socioeconomic status, parental IQ, 

or home environment. Marcus et al. (2010) note 

that effects were similar whether Pb exposure was 

measured by blood Pb, by bone Pb measured in 

tooth dentin, or by bone Pb measured with K-x-ray 

analysis; however, a larger effect of hair Pb was found 

in three studies from the same laboratory (Marlowe 

and Errera 1982, Marlowe et al. 1985, Marlowe and 

Bliss 1993) that used hair as the measure of exposure. 

Marcus et al. (2010) cannot explain why the hair Pb 

data displayed a stronger relationship and noted that 

multiple studies have determined that hair Pb is less 

accurate than blood Pb measurements for determining Pb exposure (e.g., ATSDR 2001)(see discussion in 

Section in Section 3.2 Biomarkers of Pb Exposure). 

This suggests that the Marlowe et al. studies contain 

a bias or other population factor that may explain the 

stronger relationship in these studies.

Summary of Support for Conclusions

Animal data support a Pb-associated neurobehavioral deficits (including reduced ability to inhibit 

inappropriate responding) at blood Pb levels close to 

levels reported in human studies (i.e., approximately 

10 μg/dL) (see U.S. EPA 2006 for recent reviews of 

the animal data, ATSDR 2007). The human data from 

multiple prospective and cross-sectional studies support a Pb-associated increase in antisocial problem 

behaviors or criminal behavior in children from 6 to 

15 years of age with concurrent blood Pb levels of 

<1-15 μg/dL. The conclusion of sufficient evidence 

for a positive association with behavior problems in 

children at blood Pb levels <5 μg/dL is based on the 

consistency of effects in these studies and the Braun 

et al. (2008) study from the NHANES 2001-2004 data 

set that reported conduct disorder at blood Pb levels 

≥0.8 μg/dL blood Pb. Most of the recent studies in the 

database include a large number of confounders, such 

as socioeconomic variables, sex, race/ethnicity, age 

of blood Pb measurement, parental education, and 

tobacco exposure. Several studies reported that blood 

Pb levels were significantly associated with antisocial 

behavioral problems even after controlling for child 

IQ through model adjustments or by path analysis 

(Silva et al. 1988, Burns et al. 1999, Chen et al. 2007). 

Although the Wright et al. (2008) study reported that 

criminal arrests in young adults 19-24 years of age 

were associated with prenatal and childhood blood Pb 

levels, and the Fergusson et al. (2008) study found an 

association between reported crimes in 21-year-olds 

and dentin Pb of shed primary teeth at 6-8 years of 

age, no studies of antisocial behavioral problems were 
Neurological 

Effects

NTP Monograph on Health Effects of Low-Level Lead 37

located that used Pb levels in adults. There is inadequate evidence to evaluate the potential association 

between blood Pb <10 μg/dL and effects on behavior 

problems in adults. The conclusion of limited evidence 

for a positive association between prenatal Pb exposure to blood Pb <10 μg/dL and behavioral problems 

in children is based on the mixed results of studies 

with prenatal exposure data. The NTP’s conclusion of 

sufficient evidence that antisocial behavior problems 

in children are associated with Pb levels <5 μg/dL is 

stronger than the discussion of Pb effects on mood 

and behavior that may extend into increased risk for 

delinquent behavior described in the EPA’s 2006 AQCD 

for Lead (U.S. EPA 2006) and ATSDR’s 2007 Toxicological Profile for Lead (ATSDR 2007); however, given the 

growth of the database in recent years, the EPA’s 2012 

draft (U.S. EPA 2012) currently supports an association 

with problem behavior.

Psychiatric Outcomes, Including Anxiety and 

Depression

There is inadequate evidence to evaluate the potential association between blood Pb <10 μg/dL and 

anxiety- or depression-related psychiatric outcomes 

in children (see Appendix A: Neurological Effects for 

full list of studies). There is limited evidence that 

blood Pb <10 μg/dL in adults is associated with psychiatric symptoms that include anxiety and depression. Although relatively few studies of children or 

adults with low blood Pb levels address these mood 

symptoms, the available data in adults are from several large cross-sectional studies (n=526-1,987) and 

support an effect of concurrent blood Pb or bone Pb 

on these psychiatric outcomes.

Most studies of behavior in children that have 

identified an association with Pb exposure have been 

in the area of attention-related behaviors or conduct 

problems. However, several studies have reported an 

association between blood Pb at and above 10 μg/dL 

and anxiety- or depression-related behaviors in children. Wasserman et al. (1998) reported that umbilical cord blood Pb (means of 5.5 μg/dL in Pristina and 

22 μg/dL in Mitrovica) and concurrent blood Pb levels 

in 3-year-olds were associated with somatic problems, anxious-depressed and withdrawn behavior by 

the CBCL in a study of 293 children from the Yugoslavia Prospective Study; however, many children in this 

study had blood Pb levels above 10 μg/dL, so these 

effects may not be associated with blood Pb levels 

<10 μg/dL. Roy et al. (2009) reported increased anxiety and social problems evaluated by teachers using 

the Conners’ Teacher Rating Scales in 3- to 7-year-old 

children in India with concurrent mean blood Pb of 

11 μg/dL. In a small study of 42 children 3-5 years of 

age with a mean blood Pb of 2 μg/dL, higher blood 

Pb was associated with lower teacher ratings of social 

confidence and sociability in girls but not to measures 

of anxiety or aggression in boys or girls (Hubbs-Tait et 

al. 2007).

Several studies have demonstrated an association between concurrent blood Pb <10 μg/dL in

adults and psychiatric symptoms, including anxiety, 

depression, and panic disorder. However, these 

studies do not include cohorts in which it has been 

demonstrated that blood Pb levels were consistently 

below 10 μg/dL from birth to behavioral assessment. 

Bouchard et al. (2009) reported a significant increase 

in the odds ratio for diagnoses of major depression 

disorder (OR=2.32 (95% CI: 1.13, 4.75)) and panic 

disorder (OR=4.94 (95% CI: 1.32, 18.48)) at concurrent blood Pb levels of ≥2.11 μg/dL in a study of 1987 

adults 20-39 years of age from the NHANES 1999-

2004 data set; a diagnosis of generalized anxiety 

disorder was not associated with blood Pb levels in 

this study. In a study of 526 men in the Normative 

Aging Study (mean age, 67 years), blood Pb (mean, 

6.3 μg/dL), tibia Pb (mean, 22 μg/g), and patella Pb 

(mean, 32 μg/g) were significantly associated with 

combined measure of mood, including elevated 

anxiety, depression, and phobic anxiety (Rhodes et 

al. 2003). In a further study of 744 men from the 

Normative Aging Study, an interquartile increase in 

tibia bone Pb (14 μg/g) or patella Pb (20 μg/g) was 

associated with increased risk of psychiatric symptoms of somatization and increased global severity 

index (Rajan et al. 2007).

Summary of Support for Conclusions

There are some examples of Pb-associated increases 

in depression-related outcomes in rats and mice at 

blood Pb levels down to 17 μg/dL (e.g., Dyatlov and 

Lawrence 2002, U.S. EPA 2006 for recent reviews of 

the animal data, see ATSDR 2007). The data set of 

human studies to evaluate the association with psychiatric outcomes is relatively small both for children 

and for adults; however, several studies in adults 

support an effect of concurrent blood Pb <10 μg/dL 

or bone Pb. The conclusion of inadequate evidence 
Neurological 

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38 NTP Monograph on Health Effects of Low-Level Lead

to evaluate the potential association between blood 

Pb <10 μg/dL in children and anxiety- or depressionrelated psychiatric outcomes is based on the lack of 

studies at blood Pb levels <10 μg/dL. The conclusion 

of limited evidence that concurrent adult blood Pb 

levels <10 μg/dL are associated with psychiatric symptoms including anxiety and depression is based on the 

small number of studies supporting an effect (one at 

blood Pb <10 μg/dL and one at blood Pb <5 μg/dL) 

and because two of the three studies are from a single 

cohort, the Normative Aging Study. As with other studies of health effects of Pb in adults, prospective studies in a group for which blood Pb levels remained consistently below 10 μg/dL from birth until assessment 

of anxiety, depression, or other psychiatric outcomes 

would eliminate the potential role of early-life blood 

Pb levels above 10 μg/dL on health effects observed 

in adults with concurrent blood Pb levels <10 μg/dL. 

The 2007 ATSDR Toxicological Profile for Lead (ATSDR 

2007) and 2006 EPA AQCD for Lead (U.S. EPA 2006) 

discuss evidence that effects of Pb may extend into 

increased risk for antisocial and delinquent behavior. 

The 2006 EPA AQCD for Lead (U.S. EPA 2006) does not 

have specific conclusions on the potential association 

between Pb exposure and anxiety. The 2007 ATSDR 

Toxicological Profile for Lead (ATSDR 2007) highlights 

the evidence for neurobehavioral effects in older 

adults at blood Pb levels >4 μg/dL.

4.3.3 Neurodegeneration

Amyotrophic Lateral Sclerosis (ALS)

There is limited evidence that blood Pb levels 

<10 μg/dL are associated with increased risk for ALS. 

A number of case-control studies have reported a 

significant association between blood Pb and ALS 

diagnosis, with most of the studies coming from two 

patient groups (see Appendix A: Neurological Effects 

for full list of studies). The data present limited evidence because of issues with potential reverse causality, because an association between ALS and bone 

turnover might lead to higher Pb levels among ALS 

patients, and issues with bias because a reported 

increased survival time in ALS patients relative to 

control patients might also lead to higher Pb levels.

In a small case-control study of 19 ALS patients 

and 39 controls (mean age, 64-66 years), mean blood 

Pb was not significantly different (p=0.38) between 

ALS patients (12.7 μg/dL) and controls (10.8 μg/dL)

(Vinceti et al. 1997). The relative risk of ALS was significantly associated with blood Pb (continuous measure: OR=1.9 (95% CI: 1.4, 2.6); categorical variable, 

3-4 μg/dL: OR=14.3 (95% CI: 3, 69)), but the association with bone Pb was not significant, in a case-control 

study of 109 ALS patients and 256 matched controls in 

New England (Kamel et al. 2002). The study reported 

that cases had greater odds of having a job with Pb 

exposure (OR=1.9 (95% CI: 1.1, 3.3)) compared to controls, and odds ratio for having ALS was significantly 

associated with lifetime days of Pb exposure greater 

than 2,000 hours (OR=2.3 (95% CI: 1.1, 4.9)). The significant association with lifetime exposure is interesting because bone Pb was not significantly associated 

with ALS in the study, and bone Pb is considered a 

better measure of cumulative exposure. The issue of 

reverse causality (the possibility that increased blood 

Pb is related to greater bone Pb mobilization from the 

reduced physical activity in ALS patients) was examined in a separate case-control study of 184 ALS cases 

and 194 controls among U.S. veterans (Fang et al.

2010). Fang et al. (2010) reported that blood Pb was 

significantly higher among the ALS patients (mean, 

2.4 μg/dL) than among controls (1.8 μg/dL). The odds 

ratio for having ALS was significantly associated with 

blood Pb (OR=2.6 (95% CI: 1.9, 3.7) for a doubling of 

blood Pb). The study examined the potential influence 

of measures of bone turnover and genetic factors 

and reported a significant interaction between blood 

Pb–ALS and plasma biomarkers for bone turnover 

(procollagen type-1 amino-terminal peptide (PINP)) 

and resorption (C-terminal telopeptides of type 1 

collagen (CTX)), but not the K59N polymorphism in 

the ALAD gene (Fang et al. 2010). However, adjusting 

the model to account for differences in biomarkers 

of bone turnover did alter the association between 

blood Pb and ALS to a large degree. The authors state 

that reverse causality is unlikely because the Pb-ALS 

association persisted after adjusting for biomarkers of Pb mobilization from bone, but that reverse 

causality cannot be entirely ruled out because of the 

cross-sectional nature of the data.

In further study of the population in New England, Kamel et al. (2003, 2005) reported that the 

ALAD gene was associated with altered bone Pb levels, 

but not with blood Pb, and the effect on ALS was not 

significant. In a second, follow-up study, Kamel et al.

(2008) demonstrated that tibia bone Pb was significantly associated with greater survival time between 
Neurological 

Effects

NTP Monograph on Health Effects of Low-Level Lead 39

diagnosis and death (HR=0.3 (95% CI: 0.1, 0.7)), 

while the association between greater survival time 

and patella Pb (HR=0.5 (95% CI: 0.2, 1.0)) or blood 

Pb (HR=0.9 (95% CI: 0.8, 1.0)) had only borderline 

significance. The association of bone and blood Pb 

with greater survival time in ALS patients relative 

to control patients introduces the possibility of bias, 

because the case groups in these case-controls studies may be individuals with longer survival time, and 

higher Pb levels may be related to a longer period of 

exposure or more time for Pb to be released from 

bone stores.

Summary of Support for Conclusions

Several recent animal studies have demonstrated 

findings similar to the human data supporting a 

relationship between Pb and ALS. For example, Barbeito et al. (2010) reported that blood Pb levels of 

27 μg/dL were associated with increased survival time 

in a mouse model of severe ALS, analogous to the 

longer survival time in ALS patients with higher blood 

Pb levels observed by Kamel et al. (2008). The NTP 

concluded that there is limited evidence that blood 

Pb levels <10 μg/dL are associated with diagnosis of 

ALS because the case-control studies that reported an 

association with blood Pb have potential issues with 

reverse causality and bias due to a reported increased 

survival time in ALS patients relative to control patients, 

both of which might also lead to higher Pb levels in ALS 

patients. The data from Fang et al. (2010) addressed 

some of the reverse causality issues by controlling for 

factors associated with bone turnover. As with other 

studies of health effects of Pb in adults, studies that 

demonstrate an association between ALS and blood Pb 

in a group for which blood Pb levels remained consistently below 10 μg/dL from birth until diagnosis of ALS 

would eliminate the potential role of early-life blood 

Pb levels above 10 μg/dL on health effects observed in 

adults with concurrent blood Pb levels <10 μg/dL. The 

NTP’s conclusions for limited evidence that blood Pb 

levels <10 μg/dL are associated with diagnosis of ALS 

is consistent with the four studies highlighted in EPA’s 

2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 2007 

Toxicological Profile for Lead (ATSDR 2007).

Alzheimer’s Disease

There is inadequate evidence to evaluate the potential association between blood Pb <10 μg/dL and 

Alzheimer’s disease because no studies examining 

Alzheimer’s disease in groups with blood Pb levels 

<10 μg/dL were located. Although the ATSDR’s 2007 

Toxicological Profile for Lead (ATSDR 2007) and EPA’s 

2006 AQCD for Lead (U.S. EPA 2006) have similar conclusions on the lack of epidemiological evidence for 

an association between Pb and Alzheimer’s disease, 

the EPA’s 2006 AQCD for Lead (U.S. EPA 2006) highlights the evidence from studies of laboratory animals that early-life exposure to Pb is associated with 

Alzheimer-like pathologies at later ages. In particular, 

exposure of rats (Basha et al. 2005) and monkeys 

(Zawia and Basha 2005) to Pb during development 

was associated with overexpression of the amyloid 

precursor protein associated with Alzheimer’s disease; however, Pb exposure in adult animals did not 

result in increased amyloid deposits in the brain. It 

should also be noted that laboratory animal data 

have not demonstrated dementia in existing models.

Essential Tremor

There is sufficient evidence that blood Pb levels 

<10 μg/dL and limited evidence that blood Pb levels 

<5 μg/dL in adults are associated with increased risk 

for diagnosis of essential tremor, a type of involuntary tremor. A number of case-control studies have 

reported a significant association between blood Pb 

and essential tremor diagnosis, with most of the studies coming from New York and similar results reported 

for a population in Turkey (see Appendix A: Neurological Effects for full list of studies). The data present 

consistent evidence for an association between blood 

Pb and essential tremor from two distinct groups in different countries, but reflect a total sample size of only 

approximately 300 cases of essential tremor.

Louis et al. (2003) reported that blood Pb was significantly higher in essential tremor patients (3.3μg/dL) 

than in controls (2.7 μg/dL) in a case-control study of 

100 essential tremor cases (mean age, 66 years) and 

143 matched controls (mean age, 71 years) from New 

York. Blood Pb was significantly associated with an 

increased odds ratio for essential tremor diagnosis 

OR=1.21 (95% CI: 1, 1.39). Louis et al. (2005, 2011) 

also examined the interaction between blood Pb and 

other modifying factors such as ALAD genetic polymorphisms and exposure to harmane (a β-carboline 

alkaloid compound associated with essential tremor) 

in this New York cohort. The odds of essential tremor 

were significantly, and to a large degree, elevated in 

individuals with the ALAD-2 allele and higher blood Pb 
Neurological 

Effects

40 NTP Monograph on Health Effects of Low-Level Lead

(OR=80 (95% CI: 3, 2096)) in a case-control study of 

63 essential tremor cases and 101 matched controls 

(Louis et al. 2005). In a further case-control study of 

106 essential tremor cases and 151 controls, Louis et 

al. (2011) found that essential tremor score was highest in individuals with higher concentrations of both 

Pb and harmane; they concluded that there was an 

additive effect of Pb and harmane on essential tremor 

severity. Louis collaborated with researchers in Turkey 

to examine essential tremor and Pb in Turkey, a population distinct from the New York-based group in earlier 

publications. In a case-control study in 105 essential 

tremor patients and 105 controls from Turkey, Dogu 

et al. (2007) reported that blood Pb (mean, 3.2 μg/dL

in cases and 1.6 μg/dL in controls) was associated with 

a significantly greater odds ratio for essential tremor 

diagnosis (OR=4.19 (2.59,6.78)).

Summary of Support for Conclusions

Animal data support Pb-associated neurological 

effects, including tremor, at higher Pb exposure levels (e.g., Booze et al. 1983, see U.S. EPA 2006, ATSDR 

2007 for recent reviews of the animal data). The NTP 

concluded that there is sufficient evidence that blood 

Pb levels <10 μg/dL and limited evidence that blood 

Pb levels <5 μg/dL are associated with diagnosis of 

essential tremor. The data are considered to provide 

sufficient evidence because the case-control studies 

that reported an association with blood Pb are from 

two distinct, widely separated groups which report 

the same pattern of effects. Given that the two 

studies represent a small total number of essential 

tremor patients (sample size of about 300), a conclusion of limited evidence at the lower blood Pb 

level <5 μg/dL is supported. As with other studies 

of health effects of Pb in adults, prospective studies 

in a group for which blood Pb levels remained consistently below 10 μg/dL from birth until diagnosis 

of essential tremor would eliminate the potential 

role of early-life blood Pb levels >10 μg/dL on health 

effects observed in adults with concurrent blood Pb 

levels <10 μg/dL. The NTP’s conclusions for sufficient 

evidence that blood Pb levels <10 μg/dL and limited 

evidence that blood Pb levels <5 μg/dL are associated 

with diagnosis of essential tremor is consistent with 

the blood Pb level of 3 μg/dL highlighted in the two 

studies listed in EPA’s 2006 AQCD for Lead (U.S. EPA 

2006) and ATSDR’s 2007 Toxicological Profile for Lead 

(ATSDR 2007).

Parkinson’s Disease

There is inadequate evidence to evaluate the potential association between blood Pb <10 μg/dL and 

Parkinson’s disease, because few studies examining 

this association were located, and no studies were 

identified in groups with blood Pb levels <10 μg/dL. 

Two studies were found that reported a significant 

association between lifetime Pb or bone Pb and incidence of Parkinson’s disease. In a case-control study 

of 121 Parkinson’s disease patients and 414 controls 

in Michigan, Coon et al. (2006) reported that the 

odds ratio of a diagnosis of Parkinson’s disease was 

increased for whole-body lifetime Pb exposure (blood 

and bone combined, by a physiologically based pharmacokinetic model) and was significantly elevated in 

the top fourth (highest quartile) of Pb measurements 

(OR=2.27 (95% CI: 1.13, 4.55)), but there was no association with bone Pb alone. Weisskopf et al. (2010) 

reported that the odds ratio for Parkinson’s disease 

was increased (OR=3.21 (95% CI: 1.17, 8.83)) for highest quartile of tibia Pb compared to the lowest quartile in a case-control study of 330 Parkinson’s disease 

patients and 308 controls in Boston.

4.3.4 Sensory Organs

Auditory

There is sufficient evidence that blood Pb levels 

<10 μg/dL in children are associated with decreased 

hearing (decreased auditory acuity). Cross-sectional 

studies reported a Pb-related increase in hearing 

thresholds and an increase in latency of BAEPs in children and young adults5 4-19 years of age, and altered 

BAEPs in newborns (see Appendix A: Neurological 

Effects for full list of studies). Hearing loss indicated by 

higher hearing thresholds have been demonstrated at 

blood Pb levels <10 μg/dL, and increased BAEP latency 

has been reported at slightly higher blood Pb levels 

(<10 μg/dL). There is limited evidence that prenatal 

blood Pb levels <10 μg/dL are associated with auditory 

effects because few studies have addressed low-level 

Pb exposure during this developmental period. There 

is also limited evidence that blood Pb levels <10 μg/dL

in adults are associated with decreased auditory acuity 

due to the limited number of studies with blood Pb 

data <10 μg/dL and auditory effects in adults.

5 Note: children are defined as <18 years of age in this document; therefore, 18- and 19-year-olds in the study are considered adults.
Neurological 

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NTP Monograph on Health Effects of Low-Level Lead 41

In a cross-sectional study of 4,519 children and 

young adults 4-19 years of age from the NHANES II 

data set, Schwartz and Otto (1987) reported a significant association between blood Pb level and hearing 

loss as determined by an increase in hearing thresholds for pure-tone frequencies from 500 to 4,000 Hz. 

In a second study using the same measures of hearing, 

Schwartz and Otto (1991) found that mean hearing 

thresholds were significantly increased in association 

with blood Pb levels in a large cross-sectional study 

of 3,545 children and young adults 6-19 years of age 

from the Hispanic Health and Nutrition Examination 

Survey. Hearing loss was observed at blood Pb levels 

≥8 μg/dL, and a 2-decibel hearing loss at all frequencies 

was reported with an increase in blood Pb from 6 to 

18μg/dL (Schwartz and Otto 1991). Similar results were 

observed in a study of 155 Polish children 4-14 years of 

age, with hearing loss demonstrated by increased hearing thresholds at blood Pb levels <10 μg/dL (median 

blood Pb, 7.2 μg/dL); there were also increased latencies of peak I BAEPs that were significant for blood Pb 

levels >10 μg/dL compared to children with blood Pb 

<4.6 μg/dL (Osman et al. 1999). Increased latencies of 

BAEP waves I-IV have also been reported at higher blood 

Pb levels (10 μg/dL) in adults and children (reviewed in 

Otto and Fox 1993), and in two studies of children with 

higher mean blood Pb that included some subjects 

with blood Pb levels <10 μg/dL (Otto et al. 1985, Robinson et al. 1985). An effect of prenatal exposure is supported by data from the Rothenberg et al. (1994, 2000) 

studies demonstrating that the latency and interpeak 

interval of BAEPs were significantly altered in infants 

(n=30 born to mothers with pregnancy Pb levels of 2.5-

35 μg/dL) and 5- and 6-year-olds (n=100) born to mothers with mean blood Pb levels of 8 μg/dL. Dietrich et 

al. (1992) reported that performance on the screening 

test for auditory processing disorders at 5 years of age 

was inversely affected in a study of 259 children from 

the Cincinnati Lead Study with mean prenatal blood 

Pb 8 μg/dL, and infant blood Pb of 5 μg/dL; however, 

mean blood Pb levels from 1 to 5 years of age ranged 

from 10 to 17 μg/dL, so effects may not be associated 

with blood Pb levels <10 μg/dL.

Four studies in adults addressed individuals with 

lower blood Pb levels. Forst et al. (1997) reported that 

blood Pb level (mean, 5 μg/dL; range, 1-18 μg/dL) was 

associated with an elevated hearing threshold at 4,000 

Hz, but not at other frequencies, examined in a study 

of 183 workers. Hwang et al. (2009) found that hearing 

thresholds were significantly increased in a study of 

259 steel plant workers in Taiwan at blood Pb levels 

≥7 μg/dL (mean blood Pb, 5 μg/dL) for frequencies 

from 3,000 to 8,000 Hz but not for lower frequencies. 

In a case-control study of 121 adult cases referred 

for hearing testing with geometric mean blood Pb 

10.7 μg/dL and 173 workers with normal hearing 

(mean blood Pb, 4 μg/dL), blood Pb was significantly 

associated with higher hearing thresholds (Chuang et 

al. 2007). In a cross-sectional analysis of 448 men in the 

Normative Aging Study (mean age, 65 years at time of 

bone Pb measurement), tibia Pb (mean, 23 μg/g) and 

patella Pb (mean, 33 μg/g) were significantly associated with hearing loss indicated by higher hearing 

thresholds at 2,000-8,000 Hz and pure-tone averages 

(Park et al. 2010). Although blood Pb and the potential 

relationship between blood Pb and hearing were not 

examined in the Park et al. (2010) study, other studies 

reported mean concurrent blood Pb levels in members 

of this cohort as <10 μg/dL (Rajan et al. 2007). Additional support for effects in adults is provided by the 

large cross-sectional studies of individuals from 4 to 19 

years of age (Schwartz and Otto 1987, 1991) described 

earlier; these studies included young adults in the age 

range of the group studied (i.e., individuals 18 and 19 

years of age are considered adults).

Summary of Support for Conclusions

Animal data support a Pb-associated effect on auditory acuity determined by an increase in the latency 

of BAEPs at blood Pb levels higher than the level 

observed in human studies (i.e., 33-100 μg/dL) (see 

U.S. EPA 2006 for recent reviews of the animal data, 

ATSDR 2007). The human data from several cross-sectional and prospective studies support a Pb-associated 

decrease in auditory acuity and increase in latency of 

BAEPs in children with blood Pb levels <10 μg/dL. The

conclusion of sufficient evidence for decreased auditory acuity at concurrent blood Pb levels <10 μg/dL in

children is based on the consistency of effects between 

hearing loss as determined by increased hearing 

thresholds and increased latency of BAEPs. In adults, 

the conclusion of limited evidence for similar effects 

at concurrent blood Pb levels <10 μg/dL is based on 

the small number of studies supporting an effect 

(two at blood Pb <10 μg/dL with total n <450), the 

two Schwartz and Otto (1987, 1991) cross-sectional 

studies that included adults 18 and 19 years of age in 

studies primarily focused on children, and supporting 
Neurological 

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42 NTP Monograph on Health Effects of Low-Level Lead

evidence from occupational studies at higher blood 

Pb levels (e.g., Bleecker et al. 2003) plus additional 

supporting evidence of an effect of Pb from bone Pb 

data in a group of elderly men. As with other studies of 

health effects of Pb in adults, prospective studies in a 

group for which blood Pb levels remained consistently 

below 10 μg/dL from birth until measurement of auditory acuity would eliminate the potential role of earlylife blood Pb levels above 10 μg/dL on auditory effects 

observed in adults with concurrent blood Pb levels 

<10 μg/dL. The conclusion of limited evidence that 

prenatal exposure to blood Pb <10 μg/dL is associated 

with auditory effects is based on the two Rothenberg 

et al. (1994, 2000) studies and the Dietrich et al. (1992) 

study that demonstrated an effect of maternal exposure but provided data only on 100 individuals with 

blood Pb <10 μg/dL that remained <10 μg/dL until 

auditory function was tested. The NTP’s conclusion for 

sufficient evidence that blood Pb levels <10 μg/dL are 

associated with decreased auditory acuity in children 

is in line with the supportive evidence of a relationship 

with auditory processing decrements outlined in EPA’s 

2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 2007 

Toxicological Profile for Lead (ATSDR 2007).

Visual

There is inadequate evidence to evaluate the potential association between blood Pb <10 μg/dL and

effects on vision in children or adults. Multiple studies reported an inverse relationship between blood 

Pb levels ≤10 μg/dL and visual-motor performance 

evaluated with tests such as the Beery Developmental Test (e.g., Wasserman et al. 2000, Al-Saleh et al.

2001, Chiodo et al. 2004); however, few epidemiological studies addressed the effects of low-level Pb 

exposure on visual function. Only three studies were 

located that examined the impact of blood Pb levels 

<10 μg/dL and retinal or visual function. Maternal 

blood Pb at 12 weeks of pregnancy (mean, 8.5 μg/dL) 

in 45 participants of the Mexico City Prospective 

Study was associated with altered retinal function in 

7- to 10-year-old children, as indicated by changes in 

electroretinographic (ERG) testing results (Rothenberg et al. 2002). In a study of 100-200 children in 

Artic Quebec at 5 and 11 years of age, Boucher et 

al. (2009) demonstrated that umbilical cord blood 

Pb (mean, 5 μg/dL) was significantly associated with 

changes in visual brain signals (event-related potential P3b wave amplitude) at 5 years but not at 11 years 

of age. Altmann et al. (1998) reported that blood Pb 

levels (mean, 4 μg/dL) in 6-year-old children (n= 384) 

in Germany were associated with altered visual function as determined by changes in interpeak latency 

of VEPs. Animal data include evidence for retinal and 

visual cortical structural and functional abnormalities in rats and nonhuman primates at 11-300 μg/dL 

(reviewed in Otto and Fox 1993, U.S. EPA 2006, ATSDR 

2007, Fox and Boyles 2007). Recent studies in rats 

support the limited data in humans, and rats exposed 

to Pb also displayed significant changes in ERG testing 

results (Fox et al. 2008). The NTP concludes that there 

is inadequate evidence to evaluate the potential association between blood Pb <10 μg/dL and effects on 

vision because of the general lack of human data on 

retinal or visual function in individuals with blood Pb 

levels <10 μg/dL. Increased latency in VEPs has been 

demonstrated in studies of adults with higher blood 

Pb levels (e.g., 60 down to 17 μg/dL in Abbate et 

al. 1995). The report of a potential lower threshold 

of 14 μg/dL for postural sway in adults with higher 

occupational Pb exposure (Iwata et al. 2005) provides some support for an effect on the auditory and 

visual systems, because postural sway requires the 

integration of visual and vestibular input along with 

peripheral sensory input and motor output. The NTP’s 

conclusions for inadequate evidence that blood Pb 

levels <10 μg/dL are associated with effects on vision 

in humans are in line with the supportive evidence of 

a relationship with auditory processing decrements 

outlined in the EPA’s 2006 AQCD for Lead (U.S. EPA 

2006) and ATSDR’s 2007 Toxicological Profile for Lead 

(ATSDR 2007) and identification of a potential threshold of 14-20 μg/dL for effects including VEPs in adults.

4.4 Conclusions

The NTP concludes there is sufficient evidence that 

blood Pb levels <5 μg/dL are associated with neurological effects in children and limited evidence 

that blood Pb levels <10 μg/dL are associated with 

adverse neurological effects in adults (see Table 4.3: 

NTP conclusions on neurological effects of low-level 

Pb for complete list of conclusions). A major strength 

of the evidence for effects of low-level Pb on neurological outcomes is in the consistency of results for an 

adverse effect of blood Pb <10 μg/dL across multiple

indices of neurological effects (e.g., cognition, behavior, and sensory function), through multiple groups, 

with a wide age range from early childhood to older 
Neurological 

Effects

NTP Monograph on Health Effects of Low-Level Lead 43

adults, and from studies using substantially different 

methods and techniques. In some studies, blood Pb 

levels of 2 μg/dL are associated with effects in children (e.g., academic achievement in Miranda et al.

2007, ADHD in Cho et al. 2010). In children, there is 

sufficient evidence that blood Pb levels <5 μg/dL are 

associated with various indices of reduced cognitive 

function, increased incidence of attention-related 

behavior diagnosis, and increased behavioral problems, and there is sufficient evidence that blood Pb 

levels of 10 μg/dL are associated with decreased auditory function. In adults, there is sufficient evidence 

that blood Pb levels <10 μg/dL and limited evidence 

that blood Pb levels <5 μg/dL are associated with 

essential tremor. There is also limited evidence that 

blood Pb levels <10 μg/dL in adults are associated 

with psychiatric outcomes, including anxiety and 

depression, as well as decreases in auditory function, 

decreases in specific measures of cognitive function in 

older adults, and the neurodegenerative disease ALS. 

There are more consistent associations between bone 

Pb and decreases in cognitive function in older adults 

than for blood Pb, suggesting a role for cumulative Pb 

exposure in Pb-related cognitive decline.

Table 4.3: NTP conclusions on neurological effects of low-level Pb

Health Effect

Population 

or Exposure 

Window

NTP 

Conclusion

Blood Pb 

Evidence Bone Pb Evidence

Cognitive

Function

Academic 

achievement

Prenatal Inadequate No studies located Not studied

Children Sufficient Yes, <5 μg/dL Yes, tooth dentin Pb

IQ Prenatal Limited Yes, <10 μg/dL Not studied

Children Sufficient Yes, <5 μg/dL Yes, tibia and tooth dentin Pb

Other general and 

specific measures

Prenatal Limited Yes, <5 μg/dL Not studied

Children Sufficient Yes, <5 μg/dL Yes, tibia and tooth dentin Pb

Older adults Limited Yes, <10 μg/dL Yes, tibia and patella Pb

Behavior Attention-related 

behaviors

Prenatal Limited Yes, <10 μg/dL Not studied

Children Sufficient Yes, <5 μg/dL Yes, tibia and tooth dentin Pb

Adults Inadequate No studies located Not studied

Behavioral 

problems

Prenatal Limited Yes, <10 μg/dL Not studied

Children Sufficient Yes, <5 μg/dL Yes, tooth dentin Pb, bone, hair

Adults Inadequate No studies located Not studied

Psychological 

Effects

Depression, 

anxiety, other

Prenatal Inadequate No studies located Not studied

Children Inadequate Unclear, some 

data >10 μg/dL

Not studied

Adults Limited Yes, <10 μg/dL Tibia and patella Pb

NeurodegenerationALS Adults Limited Yes, <10 μg/dL Yes, tibia and patella

Alzheimer’s disease Adults Inadequate No studies 

<10 μg/dL located

Not studied

Essential tremor Adults Sufficient Yes, <10 μg/dL Not studied

Limited Yes, <5 μg/dL Not studied

Parkinson’s disease Adults Inadequate No studies 

<10 μg/dL located

Yes, tibia and PBPK 

(cumulative)

Sensory

Function

Auditory Prenatal Limited Yes, <10 μg/dL Not studied

Children Sufficient Yes, <10 μg/dL Not studied

Adults Limited Yes, <10 μg/dL Yes, tibia and patella

Visual Prenatal Inadequate Yes, <10 μg/dL Not studied

Children Inadequate Yes, <10 μg/dL Not studied

Adults Inadequate No studies 

<10 μg/dL located

Not studied

Abbreviation: ALS, amyotrophic lateral sclerosis; PBPK, physiologically based pharmacokinetic.
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44 NTP Monograph on Health Effects of Low-Level Lead

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Immune 

Effects

NTP Monograph on Health Effects of Low-Level Lead 45

5.0 IMMUNE EFFECTS

5.1 Conclusions

The NTP concludes that there is limited evidence 

that blood Pb levels <10 μg/dL are associated with 

adverse immune effects in children and that there is 

inadequate evidence in adults.

In children, there is limited evidence that blood 

Pb levels <10 μg/dL are associated with increased 

hypersensitivity responses and allergic sensitization 

diagnosed by skin prick testing to common allergens. 

Five studies with mean blood Pb levels of 10 μg/dL 

and below support the relationship between blood 

Pb and increased serum IgE (see Table 5.3). Two 

of these studies report an association at blood Pb 

levels of 10 μg/dL or above, rather than <10 μg/dL 

(Lutz et al. 1999, Sun et al. 2003). Only one of the 

remaining studies, Karmaus et al. (2005), considers 

age as a co-factor in the analyses of IgE (Karmaus 

et al. 2005, Hon et al. 2009, Hon et al. 2010, Hon 

2011). Given these limitations, and particularly the 

known age-dependent ranges for IgE, these studies 

provide the basis for the conclusion of limited evidence that blood Pb levels <10 μg/dL are associated 

with elevated serum IgE in children up to 17 years 

of age. Although increases in serum levels of total 

IgE do not equate to disease, elevated levels of IgE 

are the primary mediators of type I hypersensitivity 

associated with allergic sensitization, and the data 

demonstrating Pb-related increases in IgE support 

an association with hypersensitivity. Further support 

of an association between blood Pb levels <10 μg/dL 

and hypersensitivity is provided by a prospective 

study on Pb-related increased allergic sensitization 

demonstrated by positive response to skin prick testing to common allergens. Together these data support the conclusion of limited evidence that blood Pb 

levels <10 μg/dL are associated with increased hypersensitivity. However, there is inadequate evidence of 

an association between blood Pb and other allergic 

diseases such as eczema or asthma.

There is inadequate evidence in adults to address 

the potential association between blood Pb <10 μg/dL 

and IgE, allergy, eczema, or asthma. Few studies have 

investigated the relationship between immune function and Pb in adults or children, and most studies 

report general observational markers of immunity 

rather than function. There is inadequate evidence 

that blood Pb levels <10 μg/dL are associated with 

observational immune endpoints such as altered lymphocyte counts or serum levels of IgG, IgM, or IgA in 

the blood of children or adults because of a general 

lack of studies at the lower dose and inconsistency 

in available data. There is inadequate evidence that 

blood Pb levels <10 μg/dL are associated with changes 

in immune function other than hypersensitivity, 

because there are few studies of Pb and immune function in humans, particularly at lower blood Pb levels. 

Very few studies examine markers of exposure other 

than blood Pb levels, and therefore it is unknown if 

blood or bone Pb levels would be more consistently 

associated with immune effects.

5.2 How Conclusions Were Reached

Conclusions in the NTP’s evaluation of Pb-related 

immunological effects in humans associated with 

low-level Pb are derived by evaluating the data from 

epidemiological studies with a focus on blood Pb 

levels <10 μg/dL. Although there is a large database of 

immune studies of Pb in laboratory animals, the database of human studies is somewhat limited, particularly at blood Pb levels <10 μg/dL. The NTP’s conclusions are based on the evidence from human studies 

with blood Pb levels of <10 μg/dL, with data reflecting 

exposure levels up to 15 μg/dL also considered so that 

effects at and around 10μg/dL were not excluded from 

the evaluation. Given the limited database of human 

studies available to evaluate immune effects associated with blood Pb levels <10 μg/dL, a discussion of 

immune effects associated with higher blood Pb levels 

is also included in the evaluation. The discussion below 

also assesses the biological plausibility and support for 

Pb-associated immune effects provided by the database of studies in laboratory animals. Major endpoints 

considered as potential indicators of effects of Pb on 

the immune system are listed and briefly described 

in Section 5.2.1. This document is not a review of the 

immune system or immunotoxicity, and the reader 

is directed to published reviews for additional background. Key data and principal studies considered in 

developing the NTP’s conclusions are discussed in 

detail in Section 5.3 Evidence for Pb-related Immune 

Effects. The discussion of each immune effect begins 

with a statement of the NTP’s conclusion that the specific effect is associated with a blood Pb level <10μg/dL 

or <5 μg/dL and the age group in which it is identified 

(childhood or adulthood), as well as the timing of exposure associated with the effect (prenatal, childhood, 
Immune 

Effects

46 NTP Monograph on Health Effects of Low-Level Lead

concurrent) when available. Although the information necessary to support the NTP’s conclusions is 

presented in Section 5.3, the complete data set of 

human studies considered for evaluation of immune 

effects with low-level Pb is included in Appendix B: 

Immune Effects, and individual studies are abstracted 

for further reference. The NTP made extensive use of 

recent government evaluations of health effects of Pb 

in the current assessment, and the relevant conclusions of the EPA’s 2006 AQCD for Lead (U.S. EPA 2006) 

and ATSDR’s Toxicological Profile for Lead (ATSDR 

2007) are briefly described in Section 5.2.2.

5.2.1 Principal Measures of Immune Effects

Table 5.1 lists a number of key immune endpoints 

potentially evaluated in epidemiological studies. A 

distinction is made between observational markers, 

which generally have less predictive value for immunotoxicity, and markers of immune function, which 

are considered better indicators of potential adverse 

immune effects. Functional assays can be performed 

in humans, including specific antibody response to 

vaccination, delayed-type hypersensitivity (DTH) 

response, phagocytic activity of neutrophils and 

macrophages, and oxidative burst of neutrophils and 

macrophages (Tryphonas 2001). However, human 

epidemiological data are much more likely to be 

restricted to observational data, such as circulating 

immunoglobulin levels, lymphocyte counts, and cytokine levels. The data available to evaluate each of the 

major effects are discussed in separate subheadings 

under Section 5.3 below.

5.2.2 Principal Conclusions from the 2006 

EPA and 2007 ATSDR Pb Documents

The EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s Toxicological Profile for Lead (ATSDR 2007) both 

list a number of immune parameters (see Table 5.2 for 

principal conclusions and original documents for complete conclusions) that have been reported as altered in 

populations exposed to Pb, including increased serum 

IgE levels, altered T-cell and B-cell numbers, changes 

in macrophage and neutrophil activation, suppressed 

neutrophil chemotaxis, and phagocytosis.

Table 5.1: Major immune effects considered

Effect Description

Observational

Immunoglobulin (Ig)

or antibodies

Serum IgE, IgM, IgG; IgA, and IgD (A and D not routinely measured)

Immunophenotyping White blood cell differential (T-cells, B-cells, NK-cells, monocytes/macrophages, etc.)

Functional

Antibody response Production of Ig to challenge:

Hypersensitivity evaluated with antigen-specific IgE and skin prick test (SPT)

Suppression commonly evaluated by specific IgM or IgG after T-cell antigen challenge

Delayed-type hypersensitivity (DTH) response

Type 1 helper T cells and macrophage-dependent DTH response to antigen challenge

Neutrophils Peripheral blood mononuclear leukocyte phagocytosis, respiratory burst, migration

Monocyte/macrophages Phagocytosis, respiratory burst (monocytes circulate and mature into tissue macrophages)

Allergy, asthma, eczema, etc. Clinical manifestation of hypersensitivity

Table 5.2: Main conclusions for immunological 

effects in the 2006 EPA AQCD for Lead and the 

2007 ATSDR Toxicological Profile for Lead

“...effects include changes in serum immunoglobulin levels; perturbation of peripheral lymphocyte phenotype 

profiles, including decreases in peripheral blood T-cell 

abundance and changes in T-cell to B-cell abundance 

ratios; suppression of lymphocyte activation; and suppression of neutrophil chemotaxis and phagocytosis. 

Studies of biomarkers of humoral immunity in children 

have consistently found significant associations between 

increasing blood Pb concentrations and serum IgE levels 

at blood Pb levels <10 μg/dL.” (U.S. EPA 2006, pg 6-272)

“Altered immune parameters have been described in 

lead workers with PbB [blood Pb level] in the range of 

30-70 μg/dL. Reported effects included changes in some 

T-cell subpopulations, response to T-cell mitogens, and 

reduced chemotaxis of polymorphonuclear leukocytes. 

Several studies of children reported significant associations between PbB and increases in serum IgE levels...” 

(ATSDR 2007, pg 22)
Immune 

Effects

NTP Monograph on Health Effects of Low-Level Lead 47

The 2006 EPA AQCD for Lead (U.S. EPA 2006) 

states that studies have consistently found consistent 

evidence of increased serum IgE levels in children at 

blood Pb <10 μg/dL but that results from studies in 

adults are mixed. The 2006 EPA AQCD for Lead (U.S. 

EPA 2006) also states that the principal functional 

immune changes associated with Pb exposure are 

(1) increases in type 2 helper T-cell (Th-2)-associated 

production of IgE; (2) suppressed type 1 helper T-cell 

(Th-1) responses (i.e., DTH); (3) shifting the balance 

of Th-1/Th-2 cytokines toward a Th-2 response; and 

(4) stimulating macrophages into a hyper-inflammatory state. The EPA notes that functional changes had 

not been rigorously evaluated in human studies at 

the time of the 2006 AQCD for Lead (U.S. EPA 2006), 

and that the available epidemiological studies rely 

primarily on observational data detailing circulating 

immunoglobulin levels and lymphocyte counts. The 

EPA is in the process of revising the AQCD, and the 

conclusions of the external draft (U.S. EPA 2012) are 

largely in line with the 2006 AQCD for Lead.

The NTP considered the conclusions and data 

summaries from the EPA’s 2006 AQCD for Lead (U.S. 

EPA 2006) and ATSDR’s Toxicological Profile for Lead 

(ATSDR 2007). In general, the NTP concurred with the 

conclusions and agreed that the data support them. 

Differences from the ATSDR and EPA documents are 

identified for specific endpoints in the document.

5.3 Evidence for Pb-Related Immune Effects

5.3.1 Increased Serum IgE and Allergic 

Sensitization

There is limited evidence that blood Pb levels <10μg/dL 

are associated with increased serum IgE in children up 

to 17 years of age (Table 5.3 and Appendix B: Immune 

Effects). Elevated serum IgE was reported with Pb 

exposure in five cross-sectional studies involving children from multiple groups in North America, Europe, 

and China. An association between increased blood 

Pb and increased IgE has been observed in children at 

mean blood Pb values from 1.9 to 14 μg/dL and subjects ranging from 1 month to 17 years of age. Three 

of the five available studies (Karmaus et al. 2005, 

Hon et al. 2009, Hon et al. 2010, Hon 2011) report 

an association between blood Pb levels <10 μg/dL 

and increased serum IgE, but only one of the studies (Karmaus et al. 2005) reports an association with 

blood Pb levels <10 μg/dL in an analyses that adjusted 

for age, an important confounder when considering IgE levels, particularly in children. The database 

for potential association between blood Pb and IgE 

in children is restricted to cross-sectional studies 

and therefore the data only inform the association 

between current blood Pb and current IgE. The influence of prenatal Pb exposure on IgE was the subject of 

a single study (Annesi-Maesano et al. 2003) that demonstrated an association between increased IgE and 

increased infant hair Pb levels but provided equivocal 

data on the association between maternal blood Pb 

and infant IgE at birth. Although increases in serum 

levels of total IgE do not equate to disease, elevated 

IgE is the primary mediator of type I hypersensitivity associated with allergic sensitization and allergic 

diseases such as asthma (Beeh et al. 2000, Ahmad Al 

Obaidi et al. 2008). The data supporting Pb-related 

increases in IgE, together with a prospective study on 

allergic sensitization (diagnosed by skin prick testing), 

provide limited evidence that blood Pb <10 μg/dL is 

associated with increased hypersensitivity responses 

in children. However, there is inadequate evidence 

of an association between blood Pb and eczema or 

asthma in children because the results of the few 

available studies are generally negative for asthma 

and because the eczema data come from a pair of 

studies of a single group of children from a dermatology clinic. There are fewer studies of the association 

between low level Pb (blood <10 μg/dL) and hypersensitivity in adults than for children, and available 

data that address IgE and related endpoints are mixed. 

There is inadequate evidence in adults to address the 

potential association between blood Pb <10 μg/dL 

and IgE, allergy, eczema, or asthma.

Increased serum IgE was reported in five crosssectional studies of children from 1 month to 17 

years of age and mean blood Pb from 1.9 to 14 μg/dL 

(Lutz et al. 1999, Sun et al. 2003, Karmaus et al. 2005, 

Hon et al. 2009, Hon et al. 2010, Hon 2011). Higher 

serum IgE correlated (r=0.22; p=0.0004) with higher 

blood Pb levels in a study of 279 children in Missouri 

9 months to 6 years of age (Lutz et al. 1999). Lutz 

et al. (1999) stated that 64% of the children in their 

study had blood Pb <10 μg/dL; however, the authors 

do not report mean blood Pb levels and therefore the 

data may reflect an effect of blood Pb levels above 

10 μg/dL. Serum IgE was also correlated with blood 

Pb levels (r=0.48; p=0.002) in children with blood 

Pb levels ≥10 μg/dL in a subsample of 72 children 
48 NTP Monograph on Health Effects of Low-Level Leadii

Immune 

Effects

Table 5.3: Studies of serum IgE, sensitization, and eczema with low-level Pb used to develop conclusions for children

Relevance to 

Conclusions

Study

Description

Study

Design Key Immunological Findings Reference

Increased IgE

Effect 374 newborns in Paris

Study A: 1985Study B: 1991-1992

Crosssectional Increased serum IgE in umbilical cord blood was associated with infant hair levels of Pb. IgE was also associated with maternal blood Pb in study B (Pb=6 μg/dL) not in study 

A (Pb=13 μg/dL) or with infant blood in either study.

Annesi-Maesano (2003)

Effect 331 children 7-10 years 

old in Germany

Crosssectional Increased serum IgE was associated with current blood Pb (mean Pb, 2.7 μg/dL). Karmaus (2005)

Equivocal 318 children 0.5 -7 years 

old in Egypt

Crosssectional Serum IgE differed by blood Pb (mean Pb, 9.2 μg/dL). However, authors report that IgE is not correlated with blood Pb. Hegazy (2011)

Effect 279 children 0.75 - 6 

years old in Missouri

Crosssectional Increased serum IgE was associated with current blood Pb (mean not reported, 64% had blood Pb <10 μg/dL). Lutz (1999)

Effect 72 children aged 3-6 in 

China of 217 in study

Crosssectional Increased serum IgE was correlated with blood Pb in children with Pb ≥10 μg/dL. Increased serum IgE in girls with blood Pb≥10 μg/dL relative to Pb <10 μg/dL; not boys. Sun (2003)

Hong Kong Eczema Patients Crosssectional Increased serum IgE was positively correlated with blood Pb (mean Pb, 1.9 μg/dL) in children with eczema (age > 1 month; mean age, 10 years). Hon (2010, 2011); may over- lap with Hon (2009) Effect 110 children age ≤17

Effect 58 children age 10 Crosssectional Increased serum IgE was positively correlated with blood Pb (mean Pb, 1.9 μg/dL) in children with eczema (age > 1 month; authors state average age of 10 years). Hon (2009) Also for eczema

Effect 2,470 children aged 5 -14 

in Germany

Ecological Odds ratios for increase in specific IgE to common allergens were elevated in children 

from a polluted area in Germany that had higher Pb dustfall; no blood Pb data.

Heinrich (1999)Also for sensitivity & eczema

Evidence of Enhanced Sensitization Based On Skin Prick Test (SPT)

Effect 224 children 5 years old 

in Poland

Prospective Frequency of atopy (positive SPT) associated with cord Pb (mean, 1.2 μg/dL) and maternal 

blood Pb (mean, 1.6 μg/dL); not current Pb. Risk ratio for SPT/atopy related to cord Pb; 

authors state that prenatal Pb may enhance sensitization to aeroallergens.

Jedrychowski (2011)

Effect 2,470 children aged 5 -14 

in Germany

Ecological Odds ratio for sensitization (positive SPT) or allergy (doctor diagnosis) was elevated in 

children from a polluted area in Germany that had higher Pb dustfall; no blood Pb data.

Heinrich (1999)Also for IgE & eczema.

Eczema And Atopic Dermatitis

No effect 1,768 children born in 

Boston 1979 -1981

Retrospective Relative risk of eczema in childhood (age not reported) did not differ for children with umbilical cord blood Pb >10 μg/dL compared to rest of the population. Rabinowitz (1990)

Hong Kong Eczema Patients Crosssectional Atopic dermatitis severity, eczema severity score, and children’s dermatology life quality index were positively correlated with blood Pb (mean, 1.9 μg/dL). Hon (2010, 2011); may over- lap with Hon (2009) Effect 110 children age ≤17

Effect 58 children age 10 Crosssectional Atopic dermatitis severity, eczema severity score, and children’s dermatology life qual- ity index were positively correlated with blood Pb (mean, 1.9 μg/dL; mean age, 10). Hon (2009) Also for IgE

Effect 2,470 children aged 5 -14 

in Germany

Ecological Odds ratio for eczema was elevated in children from a polluted area in Germany that 

also had higher Pb dustfall; no blood Pb data.

Heinrich (1999)Also for IgE & sensitivity

Epidemiological studies of low-level Pb exposure, immunoglobulin E (IgE), sensitization, and eczema are listed by decreasing cohort size and grouped together for overlapping study groups. Blood Pb levels up to 15 μg/dL were included so that effects at and around 10 μg/dL were not excluded from the evaluation.
Immune 

Effects

NTP Monograph on Health Effects of Low-Level Lead 49

with a mean blood Pb level of 14 μg/dL from a larger 

study of 217 children 3-6 years of age with overall 

mean blood Pb of 9.5 μg/dL in China (Sun et al. 2003). 

Although the Lutz et al. (1999) and Sun et al. (2003) 

studies report an effect of blood Pb at levels near 

10 μg/dL, additional studies demonstrate increased 

IgE at mean blood Pb levels in the range of 2 μg/dL. 

Higher serum IgE was correlated with higher blood 

Pb (mean, 1.9 μg/dL) in 110 children with eczema 

in which the age ranged from 1 month to 17 years 

for the participants recruited from a dermatology 

clinic in Hong Kong (Hon et al. 2009, Hon et al. 2010, 

Hon 2011). Karmaus et al. (2005) reported increased 

serum IgE in a study of 331 children 7-10 years of 

age in Germany at blood Pb levels >2.8 μg/dL, the 

median for the group. The studies by Lutz et al.

(1999), Sun et al. (2003), and Karmaus et al. (2005) 

include adjustments for age and sex in their analyses 

of the relationship between blood Pb and IgE. These 

are important considerations because of the strong 

age- and sex-related effects on serum IgE: higher IgE 

levels are observed in boys, and increased IgE levels 

are expected with increasing age up to puberty, with 

slowly decreasing levels observed thereafter (Lindberg and Arroyave 1986, Blackwell et al. 2011).

There is some evidence that in children the 

association of IgE with blood Pb may exhibit a nonmonotonic (or bi-phasic) dose response: increased 

IgE levels are reported at the lower end of blood Pb 

levels, from 2 to 20 μg/dL, but decreasing serum IgE 

levels occur at higher blood Pb levels (i.e., >20 μg/dL). 

Nonmonotonic dose responses are thought to reflect 

multiple mechanisms of toxicant action that affect a 

given endpoint (including immune effects) differently 

at different doses (Welshons et al. 2003). For example, 

Narita et al. (2007) described stimulation of IgEmediated release of allergic mediators from human 

mast cells with surface-bound IgE in response to toxicants, including Aroclor 1242; a nonmonotonic dose 

response was reported for IgE-mediated release of 

β-hexosaminidase, with lower doses resulting in activation of this key step in allergic reactions and higher 

doses having no effect. Blood Pb levels >20 μg/dL (23-

42 μg/dL determined graphically from Wagnerova et al.

1986) were associated with decreased IgE in a study of 

11-year-old children in Czechoslovakia in which both 

the exposed and reference group had blood Pb levels >10 μg/dL (Wagnerova et al. 1986). In the Lutz et 

al. (1999) study described earlier, serum IgE differed 

significantly (p<0.05 Kruskal-Wallis) by blood Pb levels 

stratified by CDC blood Pb classification levels (I=<10, 

IIA=10-14, IIB=15-19, and III=20-44 μg/dL); however, 

IgE was not increased in the group with blood Pb levels >20 μg/dL (IgE=52, 74, 210, and 64 IU/mL at blood 

Pb <10, 10-14, 15-19, and 20-44 μg/dL, respectively). 

In a similar analysis of 318 children in Egypt under 

8 years of age, serum IgE also differed significantly 

(p=0.001 Kruskal-Wallis) by blood Pb levels stratified 

by CDC blood Pb classification levels (IA=<5, IB=5-9, 

IIA=10-14, IIB=15-19, III=20-44, IV=and 45-69 μg/dL); 

however, the correlation between blood Pb and IgE 

was not significant (p=0.12) for the overall group, 

which had a mean blood Pb of 9.2 μg/dL (Hegazy et al.

2011). The reason for the lack of a significant correlation with blood Pb in the Hegazy et al. (2011) study is 

not clear, but it may relate to differential effects of Pb 

at low and high blood Pb levels.

Prospective studies are not available to examine the relationship between blood Pb and serum 

IgE at later time points in children. However, in a 

study of newborns in Paris, Annesi-Maesano et al.

(2003) demonstrated an association between higher 

umbilical cord IgE and higher infant hair Pb (p<0.001). 

Maternal blood Pb and infant blood Pb were not 

correlated to umbilical cord IgE levels, although the 

authors report that the association between maternal blood Pb and umbilical cord IgE was at borderline 

significance (p<0.1) (Annesi-Maesano et al. 2003). As 

discussed in Section 3.2, hair Pb has been examined 

in a number of studies because collection is easy and 

minimally invasive; however, an ATSDR expert panel 

concluded that widespread use is not recommended 

because of unresolved scientific issues in collection 

and analysis (ATSDR 2001).

As discussed above, elevated levels of total IgE 

are associated with allergic sensitization and allergic 

disease such as asthma (Beeh et al. 2000, KotaniemiSyrjanen et al. 2002, Ahmad Al Obaidi et al. 2008, 

Donohue et al. 2008). However, there is limited evidence that blood Pb levels <10 μg/dL are associated 

with increased incidence of allergic sensitization in 

children. This conclusion is based two lines of evidence: (1) a prospective study reporting a significant 

association between maternal or umbilical cord blood 

Pb <10 μg/dL and greater incidence of sensitization to 

common allergens in children, and (2) data supporting Pb-associated increases in serum IgE in children. 

In a prospective study of the children of 224 women 
Immune 

Effects

50 NTP Monograph on Health Effects of Low-Level Lead

in Poland recruited in the second trimester of pregnancy, allergic sensitization or atopy was determined 

by skin prick test to common allergens administered 

when the children were 5 years of age (Jedrychowski 

et al. 2011). Frequency of sensitization was significantly associated with maternal blood Pb (p=0.006; 

mean Pb, 1.6 μg/dL) and with umbilical cord blood Pb 

(p=0.001; mean Pb, 1.2 μg/dL), but not with current 

blood Pb levels in the 5-year-olds (p=0.43; mean Pb, 

2.0 μg/dL). In an analysis of the relative risk, umbilical 

cord blood Pb in the Jedrychowski et al. (2011) study 

was associated with an increased relative risk (RR=2.28 

(95% CI: 1.1, 4.6)) of atopy as indicated by at least one 

positive skin prick test. The 224 individuals included in 

the statistical analysis all had umbilical cord blood Pb 

levels <2.5 μg/dL, because the authors state that outliers above the 95th percentile were removed before 

analysis. The effect of the removal of individuals with 

higher blood Pb levels is unknown. No other studies 

were located that reported blood Pb and sensitization; 

however, an ecological study supports the association 

between higher Pb exposure and higher sensitization in 

children (Heinrich et al. 1999). The odds ratio for positive skin prick test (OR=1.38 (95% CI: 1.02, 1.86)) and 

increased specific IgE (OR=1.75 (95% CI: 1.31, 2.33)) 

to common allergens were also elevated in children 

from an area in Germany with higher Pb dustfall and 

Pb emissions. The study examined 2,470 children 5-14 

years of age; it lacked blood Pb data but compared 

children from areas with high Pb dustfall to children 

in the reference group living in a low-Pb-dustfall area 

(Heinrich et al. 1999).

There are few studies of eczema or atopic dermatitis in children, and the evidence of an association 

with blood Pb is restricted to a single group of 110 

children at a dermatology clinic, which may represent 

a sensitive subpopulation. In two overlapping studies 

of 110 patients with eczema from a Hong Kong pediatric dermatology clinic, blood Pb was significantly 

associated with atopic dermatitis severity, eczema 

severity score, children’s dermatology life quality 

index, and eosinophil count (Hon et al. 2009, Hon et al.

2010, Hon 2011). The association between blood Pb 

and clinical diagnosis for severity among the eczema 

patients is supported by the objective measure of a Pbrelated increase in eosinophil count (r=0.27; p=0.001). 

The Hon et al. (2009, 2010, 2011) studies report an 

association between blood Pb and multiple clinical 

parameters rating severity of symptoms of atopic 

dermatitis, but not the incidence of eczema. Blood 

Pb levels did not differ between 110 eczema patients 

and 41 patients at the dermatology clinic with other 

skin conditions that did not have eczema (p=0.160); 

however, the study did not have a nonatopic reference group. The Heinrich et al. (1999) ecological 

study described earlier also reported an increased 

odds ratio for eczema (OR=1.52 (95% CI: 1.03, 2.24))

among children living in the area with higher Pb 

dustfall. However, a retrospective study of 1,768 children born in Boston between 1979 and 1981, which 

determined relative risk of eczema in childhood with 

umbilical cord blood Pb levels, did not find a difference between children with umbilical cord blood 

Pb levels above and below 10 μg/dL (Rabinowitz et 

al. 1990). This study differs from the two Hon et al.

(2009, 2010) studies in the timing of the Pb exposure 

measurement and in the reporting of incidence rather 

than severity of eczema. The Rabinowitz et al. (1990) 

study compared umbilical cord blood Pb to incidence 

of eczema years later (exact timing not reported) and 

addressed incidence (present vs. not present) rather 

than severity of eczema.

Although four retrospective studies examined 

the potential relationship between Pb exposure 

and asthma in children, the results are primarily 

negative, and only one of the four studies reported 

an association between asthma and blood Pb. 

Blood Pb levels >10 μg/dL were associated with an 

increased odds ratio for doctor diagnosis of asthma 

(OR=7.5 (95% CI: 1.3, 42.9)) in a study of 356 children 

<13 years of age in the STELLAR database in Michigan (Pugh Smith and Nriagu 2011). The analysis in 

Pugh Smith et al. (2011) was thoroughly adjusted 

for risk factors associated with asthma or confounders related to Pb exposure, such as age, gender, and 

exposure to passive smoke, cats, dogs, cockroaches, 

and other factors known to contribute to asthma. A 

retrospective study of 4,634 children in managed 

care in Michigan did not find an association between 

blood Pb at 1-3 years of age and incidence of asthma 

based on insurance records or dispensed medication 

in an analysis adjusted for income, birth weight, and 

sex (Joseph et al. 2005). A retrospective study of 1,768 

children born in Boston between 1979 and 1981 that 

determined relative risk of asthma in childhood with 

umbilical cord blood Pb levels did not find a difference 

between children with umbilical cord blood Pb levels 

above and below 10 μg/dL in an analysis that did not 
Immune 

Effects

NTP Monograph on Health Effects of Low-Level Lead 51

include adjustment for confounders (Rabinowitz et al.

1990). Myers et al. (2002) reported that the incidence 

of asthma based on medical records did not differ 

between 151 patients in Chicago with high blood Pb 

levels (≥25 μg/dL) and a reference group with blood 

Pb <5 μg/dL. The Myers et al. (2002) tested for effects 

of high blood levels and did not report any adjustments for confounders.

The data from Sun et al. (2003) in girls and 

Pizent et al. (2008) in women suggest that Pb exposure may have a stronger effect on IgE in females. 

The results also indicate that analyses of Pb and IgE 

should consider sex as a potential confounder, which 

is not unexpected because sex differences in serum 

IgE are apparent early in childhood (Blackwell et al.

2011, Hunninghake et al. 2011), and other toxicantinduced or exacerbated hypersensitivity reactions 

have a gender bias (Corsini and Kimber 2007). All of 

the studies of IgE adjust for age, except the Hon et al.

(Hon et al. 2009, Hon et al. 2010, 2011) set of studies. Therefore, as noted above, only the Karmaus et 

al. (2005) study reports an association with blood Pb 

levels <10 μg/dL in an analyses that adjusted for age. 

This represents a limitation in the data set because 

there are well-established age-dependent changes 

in serum IgE: increased IgE levels are expected with 

increasing age up to puberty, and slowly decreasing levels are observed thereafter (Blackwell et al.

2011). Smoking or exposure to passive smoke has 

also been associated with IgE. The effects of smoke 

exposure may be two-fold, as exposure may increase 

IgE directly or it may lead to increased exposure to 

Pb because of the Pb content in tobacco smoke. In 

a study of 318 children in Egypt under 8 years of 

age, Hegazy et al. (2011) reported a significant correlation (r=0.133; p<0.05) between blood Pb and 

parental tobacco smoking. The analysis of IgE in the 

Karmaus et al. (2005) study was particularly thorough 

in its consideration and adjustment for confounders, 

including gender, age, number of infections in the last 

12 months, exposure to passive smoke, and exposure 

to other toxicants including DDE (a metabolite of DDT 

that is also associated with increased IgE).

In adults, the results are mixed for an association 

between blood Pb and IgE or sensitization-related 

endpoints, but there are only three relevant studies 

in adults with blood Pb levels <10 μg/dL: a study of 

523 office workers in Korea (Min et al. 2008), a study 

of 216 office workers in Croatia (Pizent et al. 2008), 

and a study of 94 Italians without occupational exposure to Pb (Boscolo et al. 1999, Boscolo et al. 2000). 

There was no correlation between blood Pb levels 

and serum IgE in men or women in the Boscolo et al.

(1999, 2000) publications. Serum IgE was correlated 

to blood Pb levels in the women office workers in the 

Pizent et al. (2008) study, but not in the men. The 

Pizent et al. (2008) study also examined functional 

endpoints (sensitization to allergens by positive skin 

prick test and nonspecific bronchial reactivity by histamine challenge) as well as the observational data on 

serum IgE. Although blood Pb (range, 0.56-7 μg/dL) 

was associated with increased IgE in women, there 

was no effect of blood Pb on sensitization or bronchial reactivity. In men, blood Pb (range, 1-7 μg/dL)

was not associated with serum IgE, and blood Pb was 

associated with decreased hypersensitivity responses, 

including decrease in sensitization to allergens and 

decrease in nonspecific bronchial reactivity (Pizent et 

al. 2008). In contrast, Min et al. (2008) reported a significant association between higher blood Pb (mean, 

3 μg/dL) and higher nonspecific bronchial reactivity 

(by methacholine bronco-provocation test) in both 

male and female office workers. Two additional studies of IgE in adults support an association with Pb at 

higher blood Pb levels. Higher serum IgE was correlated with higher blood Pb levels in two studies: a 

study of 47 Pb refinery workers in Osaka with mean 

blood Pb 50 μg/dL (Horiguchi et al. 1992) and a study 

of 606 Pb battery workers in Korea with mean blood 

Pb 23 μg/dL in which IgE was elevated in workers 

with blood Pb >30 μg/dL compared with workers with 

blood Pb <30μg/dL (Heo et al. 2004). Collectively, only 

four studies report data on blood Pb and IgE in adults. 

The two high-exposure studies (mean blood Pb levels, 

23 and 50 μg/dL) suggest there may be an association 

between IgE and blood Pb ≥30 μg/dL (Horiguchi et al.

1992, Heo et al. 2004); the two studies with blood Pb 

levels <10 μg/dL are negative for effects in men and 

report mixed results in women (Boscolo et al. 1999, 

Boscolo et al. 2000, Pizent et al. 2008). An increase in 

symptoms of asthma and rhinitis was also reported in 

male industrial workers in the United Arab Emirates 

with extremely high blood Pb levels (mean, 78 μg/dL) 

relative to referents that also had high blood Pb levels 

(20 μg/dL) (Bener et al. 2001). In adults with blood Pb 

levels <10 μg/dL, the data for asthma or respiratory 

symptoms are conflicting, with one study reporting 

increased bronchial responsiveness (Min et al. 2008) 
Immune 

Effects

52 NTP Monograph on Health Effects of Low-Level Lead

and one study reporting decreased bronchial responsiveness or no effect of Pb (Pizent et al. 2008). The 

data for sensitization with blood Pb are negative, with 

no effect in female office workers and reduced sensitization with increasing blood Pb in males, although 

data are from a single study (Pizent et al. 2008).

Summary of Support for Conclusions

Animal data support an increase in IgE in adult mice 

at high Pb levels (50 μg injected subcutaneously three 

times per week for 3 weeks) and associated with developmental Pb exposure at levels that include blood Pb 

<10 μg/dL (2-20 μg/dL in mice and 40 μg/dL in rats; 

see U.S. EPA 2006 for recent reviews of the animal 

data, ATSDR 2007). Prenatal or postnatal exposure 

to Pb at low, environmentally relevant levels in mice 

have been associated with increased IgE at later time 

points. Plasma IgE levels were significantly increased 

in neonatal BALB/c mice with blood Pb levels from 

2 to 20 μg/dL at 2 weeks of age in mice that were 

the offspring of mothers exposed to Pb in drinking 

water during gestation alone, during lactation alone, 

or during both periods (unexposed neonate blood Pb 

was approximately 3 μg/dL and maternal blood Pb 

not reported Snyder et al. 2000). A number of studies 

in mice also support Pb-associated skewing of T-cell 

response toward a type 2 helper T-cell (Th-2) response, 

which is associated with allergy and increased IgE production, versus a type 1 helper T-cell (Th-1) response, 

which is associated with host resistance and delayedtype hypersensitivity (reviewed in Dietert and 

Piepenbrink 2006, U.S. EPA 2006). The human data 

supporting a Pb-associated increase in serum IgE in 

children are restricted to cross-sectional studies. The 

determination of causation from cross-sectional studies has the inherent limitation of making conclusions 

based on current blood Pb measurements and lacking 

information on cumulative Pb or Pb exposure at earlier time points. The demonstration that infant hair Pb 

in newborns was associated with umbilical cord IgE 

levels from the Annesi-Maesano et al. (2003) study 

suggests that Pb exposure at earlier time points is 

associated with IgE in children, but prospective studies are lacking. The most relevant time for measuring 

exposure relative to IgE may include both earlier time 

points relating to mechanisms of Th-2 skewing (Parronchi et al. 2000) or current blood Pb directly related 

to secretion of IgE because IgE in serum has a half-life 

of less than 2 days. Five cross-sectional studies report 

a correlation between blood Pb (mean levels from 2 

to 14 μg/dL) and serum IgE in children up to 17 years 

of age. Elevated levels of serum IgE were reported 

in children with increasing blood Pb across multiple 

studies from different populations in analyses that 

adjusted or controlled for age, sex, and in some cases 

smoking and exposure to other contaminants known 

to effect serum IgE. However, only the Karmaus et al.

(2005) study reports an association at blood Pb levels 

<10 μg/dL in analyses that adjusted for age; therefore, the NTP concluded there is limited evidence 

that blood Pb <10 μg/dL is associated with elevated 

serum IgE in children. The conclusion of limited evidence for increased hypersensitivity responses at 

blood Pb <10 μg/dL in children is supported by the 

evidence for Pb-related increases in IgE together with 

the Jedrychowski et al. (2011) prospective study on 

allergic sensitization (diagnosed by skin prick testing). There are some data supporting an association 

between blood Pb <10 μg/dL and eczema or asthma 

in children; however, the conclusion of inadequate 

evidence is because the eczema studies with blood 

Pb are from a single patient group and represent 110 

total children, and the data supporting an association with asthma are restricted to a single study. For 

adults, there are only three studies of IgE or sensitization-related effects of people with blood Pb levels 

<10 μg/dL. There is inadequate evidence in adults to 

address the potential association between blood Pb 

<10 μg/dL and IgE, allergy, eczema, or asthma. The 

NTP’s conclusions for limited evidence for increased 

serum IgE in children at blood Pb levels <10 μg/dL are 

in line with other agencies, although the conclusions 

of a consistent association from the 2006 EPA AQCD 

for Lead (U.S. EPA 2006) and significant associations 

in ATSDR’s Toxicological Profile for Lead (ATSDR 2007) 

suggest slightly stronger conclusions by these agencies that may reflect the data from studies with blood 

Pb levels above 10 μg/dL.

5.3.2 IgG, IgM, IgA, and Antibody Response

There is inadequate evidence that blood Pb levels 

<10 μg/dL are associated with serum levels of IgG, 

IgM, or IgA in the blood of children or adults (see 

Appendix B: Immune Effects). Studies that examined serum immunoglobulins found no evidence 

of a consistent change, either increase or decrease, 

associated with blood Pb below or above 10 μg/dL. 

There is inadequate evidence that blood Pb at any 
Immune 

Effects

NTP Monograph on Health Effects of Low-Level Lead 53

level is associated with changes to the IgM- or IgGspecific functional antibody response. Two studies 

were located that evaluated an antibody response 

in humans in conjunction with blood Pb levels, and 

both reported that there was no effect of blood Pb 

level on the antibody response. There was no effect of 

blood Pb levels on the anti-rubella IgG antibody titer 

to a previous antigen (Rubella vaccine) in 279 children 

in Missouri from 9 months to 6 years of age (mean 

not reported, 65% had blood Pb <10 μg/dL Lutz et al.

1999), and there was no difference in tetanus toxoidspecific antibodies between children with very high 

blood Pb levels (45 μg/dL) and high blood Pb levels 

(23 μg/dL) (Reigart and Graber 1976). The few studies 

that examined serum immunoglobulin levels (other 

than serum IgE discussed in the previous section) 

in children or adults with blood Pb levels <10 μg/dL

report inconsistent results. Serum levels of IgG were 

correlated (r=0.31; p=0.002) with blood Pb levels 

(mean, <2 μg/dL), but IgM was not related to blood 

Pb in a study of umbilical cord blood from 101 newborns in Quebec (Belles-Isles et al. 2002). There was 

no effect of blood Pb level (mean, 3 μg/dL) on serum 

IgG, IgM, or IgA in a study of 331 children 7-10 years 

of age in Germany (Karmaus et al. 2005). Serum IgG, 

IgM, and IgA were increased in children with blood Pb 

≥15 μg/dL compared to children with Pb <5 μg/dL in 

children <3 years of age at mean blood Pb level of 

7 μg/dL; immunoglobulin levels were not related to 

blood Pb in children >3 years of age or in adults (Sarasua et al. 2000). In contrast, serum IgG and IgM were 

decreased in children in China 3-6 years of age with 

blood Pb >10 μg/dL from a sample of 72 children 3-6 

years of age in China with mean blood Pb of 9.5 μg/dL 

(Sun et al. 2003). Blood Pb was not correlated with 

serum IgA, IgM, or IgG in a study of atopic and nonallergic men in Italy without occupational exposure to 

Pb (mean Pb, 11 μg/dL; (n=34 Boscolo et al. 1999).

Summary of Support for Conclusions

Animal data are mixed for an effect of Pb on the antibody response and most studies do not report serum 

immunoglobulin levels (see U.S. EPA 2006 for recent 

reviews of the animal data, ATSDR 2007). Studies in 

mice report no effect, suppression, or stimulation of 

the T dependent antibody response (plaque-forming 

cell (PFC) assay to sheep red blood cell challenge) at 

blood Pb levels of 25-130 μg/dL (Blakley and Archer 

1981, Mudzinski et al. 1986), while suppression of the 

PFC response was observed in rats at 29μg/dL (Luster et 

al. 1978). The conclusion of inadequate evidence that 

blood Pb levels <10 μg/dL are associated with serum 

levels of IgG, IgM or IgA or functional antibody response 

in children or adults is based on the inconsistent results 

for serum IgG, IgM, and IgA and the general lack of 

human studies on Pb and the antibody response. The 

2006 EPA AQCD for Lead (U.S. EPA 2006) and the 2007 

ATSDR Toxicological Profile for Lead (ATSDR 2007) do 

not make strong conclusions on the antibody response 

or serum immunoglobulins; however, the NTP’s conclusions for inadequate evidence for an association 

between blood Pb levels <10μg/dL and serum IgG, IgM, 

IgA, or the antibody response are consistent with the 

evidence presented in these documents.

5.3.3 T Lymphocytes (T-cells)

There is inadequate evidence that blood Pb levels 

<10 μg/dL are associated with altered T lymphocyte 

(T-cell) numbers or percentages in the blood of children or adults (see Appendix B: Immune Effects). The 

results of studies at lower blood Pb levels (<10 μg/dL) 

are inconsistent; however, there are a number of 

occupational studies that report decreased absolute 

numbers or percentages of T-cells or T-cell populations or subsets (particularly CD4+ T-helper cells), and 

some include a corresponding increase in B-cells at 

blood Pb <15 or <30 μg/dL. An association between 

higher blood Pb and higher numbers of naive T-cells 

(CD45RA+ or CD45RO-; cells not yet programmed for 

a specific immune response) is reported in several 

studies at low (<10 μg/dL) and high blood Pb levels.

The results of studies in children and adults with 

blood Pb levels <10 μg/dL are inconsistent for a potential relationship between blood Pb and T-cell numbers. 

In a study of 70 children 3-6 years of age in China, the 

percentage of T-cells was unchanged, the percentage 

of CD4+ T-cells was decreased, and the percentage 

of CD8+ T-cells was increased in children with blood 

Pb levels >10 μg/dL compared to children <10 μg/dL

(Zhao et al. 2004, Li et al. 2005). In contrast, Sarasua 

et al. (2000) reported decreased percentage of T-cells, 

no change in CD4+ or CD8+ T-cells, and increased 

percentage of B-cells in children under 3 years of 

age at mean blood Pb level of 7 μg/dL. Lymphocyte 

populations were not related to blood Pb levels in 

children >3 years of age or in adults (Sarasua et al.

2000). Four additional studies in children reported 

no effect of blood Pb on lymphocyte populations at 
Immune 

Effects

54 NTP Monograph on Health Effects of Low-Level Lead

mean blood Pb levels ranging from <2 μg/dL to 9 μg/dL

in 318 children <8 years of age in Egypt (Hegazy et al.

2011), in 279 children from 9 months to 6 years of 

age in Missouri (Lutz et al. 1999), in 331 children 7-10 

years of age in Germany (Karmaus et al. 2005), or in 

101 newborns in Quebec (Belles-Isles et al. 2002). In 

adults with blood Pb levels <10 μg/dL, the results of 

studies that examined the relationship between blood 

Pb and lymphocyte populations are mixed. Higher 

blood Pb was correlated with higher numbers of CD4+ 

T-cells in atopic and nonallergic men (n=34 Boscolo et 

al. 1999) and with higher numbers of CD8+ T-cells in 

nonallergic women, but not in atopics, in Italy without 

occupational exposure to Pb (mean Pb, 5-11 μg/dL; 

n=60)(n=60 Boscolo et al. 2000) . Increased blood Pb 

was also correlated with increased numbers of CD4/

CD45RO- naive CD4 T-cells in both nonallergic men 

and women, but not in atopics (Boscolo et al. 1999, 

Boscolo et al. 2000). Naive CD4/CD45RA+ CD4 T-cells 

were also increased in three-wheel drivers in India 

(mean, Pb=7 μg/dL; n=26) compared to a reference 

group (mean Pb, 5 μg/dL; n=59), but CD4+ T-cells were 

decreased (Mishra et al. 2010).

For higher blood Pb levels (i.e., >15 μg/dL), a 

number of occupational studies report altered Tor B-cells concentrations. In general, the absolute 

numbers or percentages of T-cell subsets (particularly CD4+ T-helper cells) are decreased and there 

is a corresponding increase in B-cells. No clear and 

consistent cell group is related to Pb levels, although 

several studies have shown an association between 

higher blood Pb and greater numbers of naive T-cells. 

The numbers and percentages of T-cells and CD4+ 

T-cells were decreased in firearms instructors in the 

United States (mean Pb, 15 (n=36) and 31 μg/dL 

(n=15)) (Fischbein et al. 1993). The number of CD4 

T-cells was reduced in 25 Pb battery workers in Turkey with very high mean blood Pb levels of 75 μg/dL 

(Undeger et al. 1996, Basaran and Undeger 2000). In 

a separate study of Pb battery workers with very high 

mean blood Pb of 132 μg/dL (n=33 in India), Mishra 

et al. (2010) reported that the percentage of CD4+ 

T-cells were decreased and percentages of CD45RA+ 

(naive) T-cells were increased. In contrast, Pinkerton 

et al. (1998) reported no effect on CD4+ T-cells, that 

higher B-cell counts were associated with higher Pb 

exposure, and that lower CD4/CD45RA+ naive CD4 

T-cell counts were correlated with higher cumulative 

Pb exposure in a study of U.S. Pb smelter workers 

(median Pb, 39 μg/dL; n=145). Several studies have 

reported that CD4+ T-cells were not related to blood 

Pb but found either decreases in CD8+ T-cells (GarciaLeston et al. 2011) and decreased CD8+ T-cells along 

with decreased B-cells (Kuo et al. 2001), or increased 

percentages of CD8+ T-cells (Sata et al. 1998).

The issue of reverse causality is also possible 

because Pb in whole blood is largely contained in 

the circulating blood cells, although this is generally attributed to the red blood cells, not to the 

white blood cells or leukocytes (lymphocytes are a 

subpopulation of leukocytes). Choi and Kim (2005) 

reported that boys with higher blood Pb levels had 

higher counts for leukocytes, and these counts correlated significantly with blood Pb levels (mean, 

3 μg/dL; r=0.39; p<0.05) in a study of 251 adolescents 

13-15 years of age in South Korea; the authors did not 

report data for lymphocytes or for specific lymphocyte subsets (e.g., T-cells). Higher blood Pb levels in 

these individuals may cause higher leukocyte counts, 

or higher circulating leukocyte counts may lead to 

higher measurements of blood Pb if the leukocytes 

contain substantial amounts of Pb.

Summary of Support for Conclusions

Animal data support a Pb-associated effect on T-cell 

maturation, and particularly a shift toward the type 

2 helper T-cell (Th-2) phenotype, which is associated 

with allergy and increased IgE production, versus a 

type 1 helper T-cell (Th-1) response, which is associated with host resistance and DTH response (reviewed 

in Dietert and Piepenbrink 2006, U.S. EPA 2006). 

Some animal data support Pb-associated decreases 

in T-cell populations (e.g., decreased thymic CD4 and 

CD8 T-cells with Pb exposure and Listeria infection 

in BALB/c mice at blood Pb <25 μg/dL Dyatlov and 

Lawrence 2002); however, decreased T-cell populations with Pb exposure are not widely reported in the 

experimental animal literature. White blood cell differentials with enumeration of lymphocyte subsets 

(T-cells, B-cells, CD4 and CD8 T-cells) are among the 

most common immune assays used in human studies, in part because of the relative ease of the assay 

and ability to obtain data from a small blood sample. 

Values typically have a large degree of variation that 

is influenced by sex, race, age, and methodological 

differences in obtaining and processing the samples. 

It is worth noting that lymphocyte subset analysis 

does not evaluate immune function, although it is 
Immune 

Effects

NTP Monograph on Health Effects of Low-Level Lead 55

an accepted part of a tiered screening approach to 

the evaluation of potential immunotoxicity of a given 

chemical (Luster et al. 1992). Differential white blood 

cell counts are not particularly sensitive indicators of 

immunotoxicity, and statistically significant effects 

associated with exposure often fall within normal 

ranges for the population. Pb-associated changes in 

T-cell counts or percentages at lower exposure levels 

are relatively small and may be without a functional 

impact on the immune response of individuals. However, on a population level, a small change in cell 

numbers or percentages may be adverse. A good 

example is the demonstration that increased mortality risk is associated with small decreases in CD4 and 

total white blood cell counts in a study of people ≥85 

years of age (Izaks et al. 2003).

Although no clear or consistent cell population relates to Pb levels, changes in T-cell populations are reported in a wide range of human studies. Decreased T-cells or CD4 T-cells (particularly at 

blood Pb >15 μg/dL) and increased naive T-cells may 

be a biological signal of Pb exposure in humans. The 

NTP’s conclusion of inadequate evidence that blood 

Pb levels <10 μg/dL are associated with altered 

T-cell abundance in the blood of children or adults 

is based on the lack of a clear pattern of results in 

studies with lower blood Pb levels. Changes in T-cell 

populations do not equate to a functional immune 

outcome, although they may be relevant to changes 

in the DTH response. Although a large body of data 

from animals demonstrates clear and consistent Pbassociated suppression of the DTH response in mice, 

rats, goats, and chickens (see discussion of the animal 

data on DTH below and Dietert and Piepenbrink 2006 

for review, U.S. EPA 2006), no studies of Pb and the 

DTH response were located in humans. The EPA 2006 

AQCD for Lead (U.S. EPA 2006) and 2007 ATSDR Toxicological Profile for Lead (ATSDR 2007) both include 

changes in T-cell subpopulations as characteristic 

immune effects identified with Pb exposure at higher 

levels (e.g., 30-70 μg/dL in ATSDR).

5.3.4 Monocyte/Macrophages

There is inadequate evidence that blood Pb levels 

<10 μg/dL are associated with changes in macrophage 

function. The human data on macrophage function are 

limited to a single study of 65 children 6-11 years of age 

in Mexico living near a Pb smelter (mean blood Pb levels 

of 21 and 30μg/dL) compared to children with blood Pb 

levels of 7μg/dL (Pineda-Zavaleta et al. 2004). The study 

investigated nitric oxide (NO) and increased superoxide 

(O2

–) production by macrophages. At appropriate levels, 

both NO and O2

– are involved in destruction of bacteria 

by macrophages and other cells. Decreased macrophage NO and increased O2

– production after indirect 

(phytohemagglutinin) stimulation through lymphocytes as well as direct (interferon-γ/lipopolysaccharide) 

stimulation of the macrophages were observed in cell 

cultures from the Pb-exposed boys but not from Pbexposed girls. Animal data provide strong support for 

decreased NO and increased O2- or reactive oxygen 

intermediate production by macrophages after in vivo 

or in vitro exposure to Pb but generally lack blood Pb 

data (see U.S. EPA 2006 for recent reviews of the animal data, ATSDR 2007). Production of the proinflammatory cytokine (tumor necrosis factor-α (TNF-α)) by 

macrophages is also associated with Pb exposure, and 

the animal data suggest that production of TNF-α by 

macrophages is linked to increased sensitivity to bacteria-derived endotoxin (see U.S. EPA 2006 for recent 

reviews of the animal data). In vitro studies of human 

macrophages and other mononuclear cells in blood 

demonstrated increased production of TNF-α with Pb 

exposure (Villanueva et al. 2000) in the presence of lipopolysaccharide plus Pb (Guo et al. 1996). However, low 

levels of Pb were associated with suppression of TNF-α 

release in human mononuclear cells from blood in the 

presence of heat-killed Salmonella enteritidis (Hemdan et al. 2005). The 2006 EPA AQCD for Lead (U.S. EPA 

2006) identifies stimulation of a hyper-inflammatory 

state in macrophages as one of the principal immune 

effects of Pb; however, it notes that there is a general 

lack of human epidemiological data in this area.

5.3.5 Neutrophils

There is inadequate evidence that blood Pb levels 

<10 μg/dL are associated with changes in neutrophil 

function. There are limited human data on the potential association between Pb exposure and neutrophils, and the studies are restricted to occupationally 

exposed individuals with mean blood Pb levels that 

are >30 μg/dL (see Appendix B: Immune Effects). 

Several studies report that movement of neutrophils 

toward their targets (chemotaxis) may be reduced 

in Pb workers at high blood Pb levels (Governa et al.

1988, Queiroz et al. 1993) or after in vitro exposure to 

Pb (Governa et al. 1987). There is also evidence that 

lytic activity of Candida may be reduced (Queiroz et al.
Immune 

Effects

56 NTP Monograph on Health Effects of Low-Level Lead

1994) but phagocytic activity is relatively unaffected 

in Pb workers (Guillard and Lauwerys 1989, Queiroz 

et al. 1994). There are few animal data on neutrophil 

function, and in humans there is a complete lack of 

data with lower blood Pb levels. Additional studies of 

neutrophil function are required to clarify the potential relationship to blood Pb in adults and children. The 

2006 EPA AQCD for Lead (U.S. EPA 2006) and the 2007 

ATSDR Toxicological Profile for Lead (ATSDR 2007) 

identify changes in neutrophil chemotaxis as a consistent finding with Pb exposure; however, the studies do 

not include blood Pb levels <10 μg/dL.

5.4 Susceptible Populations or Life 

Stages

Segments of the population that are may be more 

susceptible to health effects of Pb are discussed more 

extensively in Section 3.0 Exposure. A significant body 

of literature supports the developmental period as a 

susceptible window for immunotoxicity, with immune 

effects of developmental toxicant exposures occurring 

at lower doses and adverse effects may be more persistent than similar exposures in adults (Luebke et al.

2006, Dietert 2008). As described above, the database 

of immune studies of Pb in humans provides limited 

evidence that blood Pb levels <10 μg/dL are associated 

with increased hypersensitivity responses and allergic 

sensitization diagnosed by skin prick testing in children; 

however, there is inadequate evidence to assess these 

effects in adults. Children may represent a sensitive life 

stage for the effects of Pb on IgE and IgE-related effects, 

but there is not enough data on these endpoints in adults 

with low blood Pb levels to make this determination.

There are some established age-related differences in immunity including a general decline in 

IgE and allergic symptoms with increasing age that 

is more pronounced in the elderly (Mediaty and 

Neuber 2005). However, there is some evidence that 

the apparent age-related decrease in hypersensitivity may be associated with more than age-related 

decline, and the difference may reflect an increase 

in IgE and sensitization rates in recent cohorts (Jarvis 

et al. 2005). In either case, childhood and prenatal 

exposure periods are potentially susceptible life 

stages because of the elevated background level of 

IgE and IgE-mediated hypersensitivity. In addition, 

young children have higher levels of Pb exposure 

related to early hand-to-mouth behaviors. Therefore, 

children may experience higher levels of Pb during a 

life stage that is already characterized by elevated IgE.

There are also gender-related differences in 

immune function, with many studies reporting higher 

total IgE levels in boys and men than in girls or women 

(e.g., see Raby et al. 2007). A recent meta-analysis 

of over 550 studies reported that boys make up 64% 

of children age 18 or younger with allergies but that 

women make up 65% of adults above the age of 18 

with allergies (Kelly and Gangur 2009). The Pb epidemiological data include two studies that report significant effect of gender on the effects of Pb on IgE. Sun et 

al. (2003) reported that increased IgE was statistically 

significantly correlated with blood Pb in girls in China 

with blood Pb ≥10 μg/dL 3-6 years of age but that the 

effect was not significant in boys. Similarly, Pizent et al.

(2008) reported that serum IgE was correlated to blood 

Pb levels in female office workers in Croatia, but not 

in the males. These data suggest that females may be 

more susceptible to the effects of Pb on IgE and allergy. 

Alternatively, the higher basal IgE levels in males may 

make it more difficult to detect the effects of Pb.

The risk factors for hypersensitivity and allergies 

include age and sex discussed above, but evidence 

suggests that heredity is by far the most important 

factor (De Swert 1999). This may manifest as a difference by race; for example, Joseph et al. (2005) 

reported that African American children were at 

statistically significantly greater risk of asthma compared to Caucasians, regardless of blood Pb level. The 

general or background allergic status of mothers or of 

children may be relevant to the effects of Pb on IgE 

and hypersensitivity. Annesi-Maesano et al. (2003) 

reported that the association between infant hair Pb 

levels and umbilical cord blood IgE were affected by 

the allergic status of the mothers. In analyses dividing mothers by history of IgE-mediated allergic status 

(either allergic, as indicated by asthma, allergic rhinitis, or eczema, or nonallergic), the study reported 

that infant hair Pb was statistically significantly associated with increased IgE in children born to nonallergic mothers (r=0.21; p<0.01), but the relationship 

was not significant for children born to allergic mothers (r=0.12; p>0.05). The authors suggest that family 

history of allergy (in other words, atopy) may overshadow the effect of Pb on IgE in children. It is unclear 

from these data whether this reflects genetic factors 

predisposing the children to allergy (e.g., Raby et 

al. 2007, Hunninghake et al. 2008, Hunninghake et 

al. 2011) or whether prenatal exposure to cytokines, 
Immune 

Effects

NTP Monograph on Health Effects of Low-Level Lead 57

histamine, or other factors are important. In the 

one prospective study available, Jedrychowski et al.

(2011) controlled for maternal allergic history (or 

atopy) in the analysis that demonstrated a statistically 

significant association between higher umbilical cord 

blood Pb and atopic status as indicated by a positive 

skin prick test to at least one common allergen in the 

children at 5 years of age. Furthermore, adjustment 

for maternal atopy, as well as child’s gender, parity, 

maternal age, maternal education, and environmental tobacco, had very little effect on the relative risk 

(before adjustment: RR=2.20 (95% CI: 1.17, 4.16); 

after adjustment: R=2.28 (95% CI: 1.12, 4.62)). The 

association with maternal blood Pb also had a relatively small effect, but it did change the results from 

statistically significant to borderline (before adjustment: RR=1.81 (95% CI: 1.10, 3.00); after adjustment: 

R=1.72 (95%CI: 0.98, 3.00)) (Jedrychowski et al. 2011).

5.5 Pb Exposure Measurements

The following brief discussion outlines several Pb 

exposure issues that are directly relevant to immune 

effects of Pb. An expanded discussion is included in 

a separate section of this document (see Section 3.0 

Exposure). No studies of immune effects in humans 

were located that used a measure of exposure other 

than blood Pb and hair Pb. However, it is important 

to note that blood Pb is only one measure of exposure, and it reflects only a portion of the Pb that is 

present in a given subject. The half-life of Pb in blood 

is approximately 35 days and therefore blood Pb is 

considered a good indicator of recent exposure. Most 

of the Pb is stored in bones (approximately 90% in 

adults, 80% in adolescents, and 66% in children under 

5 years of age), and Pb from past environmental 

exposure is released into the blood, contributing to 

a chronic internal source of exposure (Leggett 1993).

The higher levels of Pb in bone may be particularly relevant for cells of the immune system and 

immune function. All of the white blood cells or 

leukocytes that develop postnatally are derived from 

progenitor cells in the bone marrow in a process 

termed hematopoiesis. Elevated Pb concentrations 

in bone are therefore of direct concern for the development of immune cells, and future studies should 

more closely consider the potential relationship 

between bone Pb levels and immune effects. Mechanistic studies in animals support the importance of Pb 

exposure on the development and differentiation of 

leukocytes. For example, Gao et al. (2007) reported 

that Pb modified bone-marrow-derived dendritic 

cells to promote Th-2 phenotype and immune 

responses associated with allergy and increased IgE 

production. The location of Pb within blood is also 

of particular relevance to immune function. The Pb 

in blood is mainly contained in cells, primarily in red 

blood cells, with less than 1% in serum. As discussed 

in Section 5.3.3 T lymphocytes (T-cells) above, Choi 

and Kim (2005) reported that blood Pb concentrations (mean, 3 μg/dL) were 2 fold higher in boys 

with higher leukocyte counts, and leukocyte counts 

correlated significantly with blood Pb levels (r=0.39; 

p<0.05), in a study of 251 adolescents 13-15 years of 

age in South Korea. The issue of reverse causality is 

suggested: higher blood Pb levels in these individuals 

may cause higher leukocyte counts, or higher circulating leukocyte counts may result in elevated blood Pb 

concentrations if the leukocytes contain substantial 

amounts of Pb in the boys in this study.

5.6 Delayed-Type Hypersensitivity (DTH) 

and Pb-Related Immune Effects in 

Animal Studies

There is a large body of laboratory animal data on 

immune effects of Pb. The effects in animal models support the human data, as discussed above 

for increased IgE, with evidence to support a 

Th-2-related mechanism and proinflammatory shift 

in macrophage function. However, the major effect 

on immune function associated with Pb exposure 

appears to be suppression of the delayed-type 

hypersensitivity (DTH) response. Animal data provide 

strong and consistent support for Pb-associated suppression of DTH response (see U.S. EPA 2006, ATSDR 

2007 for recent reviews of the animal data). The 

DTH response depends on priming and expansion 

of antigen-specific T-cells that are Th-1 dependent 

and therefore the Pb-associated suppression of Th-1 

responses is consistent with the Pb-associated suppression of DTH. The DTH response is a functional 

immune endpoint that is widely accepted as an indicator of cell-mediated function (Luster et al. 1992, 

U.S. EPA 1998). Although DTH response can be evaluated as a measure of immune response in humans 

(e.g., Vukmanovic-Stejic et al. 2006), no studies were 

located that evaluate the relationship between blood 

Pb and DTH in humans. Studies on the DTH response 

in humans with low blood Pb levels are recommended 
Immune 

Effects

58 NTP Monograph on Health Effects of Low-Level Lead

because of the lack of data in humans and the clear 

and consistent Pb-related suppression of the DTH 

response in mice, rats, goats, and chickens.

Exposure to Pb is associated with suppression of 

the DTH response in mice, rats, goats, and chickens, 

and following both acute and subchronic exposures 

of up to 16 weeks. Although blood Pb levels are not 

available in all studies, decreased DTH response has 

been reported at blood Pb levels from 29 to 87 μg/dL. 

Wistar rats that were the offspring of dams exposed 

from premating to weaning, and continued to receive 

25 or 50 ppm Pb acetate in drinking water until 

tested, had suppressed DTH at blood Pb level of 29 

and 52 μg/dL (Faith et al. 1979). Adult BALB/c mice 

exposed to 32, 128, 512, or 2048 ppm Pb acetate in 

drinking water for 3 weeks had blood Pb levels of 9, 49, 

87, and 169 μg/dL, and the blood Pb level correlated 

with suppressed DTH response (McCabe et al. 1999). 

Although McCabe et al. (1999) report that the DTH 

response in the mice with 87 μg/dL blood Pb level was 

statistically suppressed, it is not clear from the paper 

if blood Pb 9 μg/dL (a more environmentally relevant 

level) was associated with suppressed DTH response. 

In a study of maternal exposure of Fisher 344 rats to 

250 ppm Pb acetate, maternal blood Pb levels were as 

high as 66 μg/dL; however, there was no effect of Pb 

exposure in the dams 8 weeks after parturition and 

the Pb exposure was stopped (Chen et al. 2004). In 

contrast, the offspring with blood Pb levels between 

6 and 8 μg/dL measured 4 weeks after the dams 

were last exposed had significantly suppressed DTH 

response. The developmental nature of this study and 

the early removal of Pb exposure to the dams suggest 

that the DTH effect of Pb has a clear developmental 

component. No experimental animal data report a 

blood Pb level associated with a “no effect” level, and 

therefore the lower blood Pb range associated with 

effects is unknown, even in laboratory animals.

5.7 Conclusions

The NTP concludes that there is limited evidence that 

blood Pb levels <10 μg/dL are associated with adverse 

immune effects in children and inadequate evidence 

in adults (see Table 5.4 for complete list of immune 

effects conclusions). In children, there is limited evidence that blood Pb levels <10 μg/dL are associated 

with increased hypersensitivity responses and allergic 

sensitization diagnosed by skin prick testing to common allergens. There is also limited evidence that blood 

Pb levels <10μg/dL are associated with elevated serum 

IgE levels. The data supporting Pb-related increases 

in IgE, together with a prospective study on allergic 

sensitization, provide limited evidence that blood Pb 

<10 μg/dL is associated with increased hypersensitivity 

responses in children. In some studies blood Pb levels 

≤2 μg/dL are associated with increased serum IgE (e.g., 

Karmaus et al. 2005, Hon et al. 2010) or increased sensitization to common allergens indicated by positive 

skin prick test (e.g., Jedrychowski et al. 2011). There is 

inadequate evidence of an association between blood 

Pb and eczema or asthma in children and inadequate 

evidence in adults to address the potential association 

between blood Pb <10 μg/dL and IgE, allergy, eczema, 

or asthma. There is inadequate evidence that blood 

Pb levels <10 μg/dL are associated with observational 

data such as altered lymphocyte counts or serum levels 

of IgG, IgM, or IgA in the blood of children or adults 

because of a general lack of studies at the lower dose 

and inconsistency in available data. There is inadequate 

evidence that blood Pb levels <10 μg/dL are associated with changes in immune function other than 

hypersensitivity because there are few studies of Pb 

and immune function in humans, particularly at lower 

blood Pb levels. Very few studies examine markers of 

exposure other than blood Pb levels, and therefore it is 

unknown if blood or bone Pb levels would be a better 

measure of exposure for Pb-related immune effects.
Immune 

Effects

NTP Monograph on Health Effects of Low-Level Lead 59

Table 5.4: NTP conclusions on immune effects of low-level Pb

Health Effect

Population 

or Exposure 

Window

NTP 

Conclusion

Blood Pb

Evidence

Bone Pb 

Evidence

Increased serum 

immunoglobulin E (IgE)

Prenatal Inadequate Unclear Hair Pb 

data

Children Limited Yes, <10 μg/dL No data

Adults Inadequate Unclear No data

Increased hypersensitivity and 

allergy (e.g., positive skin prick 

test)

Prenatal Limited Maternal and umbilical cord <10 μg/dL No data

Children Limited Yes, <10 μg/dL No data

Adults Inadequate Unclear No data

Asthma, eczema, etc. Prenatal Inadequate Unclear No data

Children Inadequate Unclear No data

Adults Inadequate Unclear No data

Altered serum IgG, IgM Prenatal Inadequate No data No data

Children Inadequate Unclear No data

Adults Inadequate Unclear No data

Altered antibody response Prenatal Inadequate No data No data

Children Inadequate No data No data

Adults Inadequate No data No data

Immunophenotyping

(e.g., T-cells, B-cells)

Prenatal Inadequate No data No data

Children Inadequate Unclear No data

Adults Inadequate Unclear; >15μg/dL data suggest changes 

in T-cells or T-cell subpopulations

No data

Monocyte/macrophage 

function

Prenatal Inadequate No data No data

Children Inadequate Unclear (one study) No data

Adults Inadequate No data No data

Neutrophil function Prenatal Inadequate No data No data

Children Inadequate No data No data

Adults Inadequate Unclear; >30 μg/dL data suggest 

changes in chemotaxis and lytic 

activity

No data

Delayed-type hypersensitivity 

(DTH) response

Prenatal Inadequate No data No data

Children Inadequate No data No data

Adults Inadequate No data No data
Immune 

Effects

60 NTP Monograph on Health Effects of Low-Level Lead

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Cardiovascular

Effects

NTP Monograph on Health Effects of Low-Level Lead 61

6.0 CARDIOVASCULAR EFFECTS

6.1 Conclusions

NTP concludes that there is sufficient evidence that 

blood Pb levels <10 μg/dL in adults are associated 

with adverse effects on cardiovascular function.

There is sufficient evidence of a bone-Pbrelated increase in blood pressure (BP) and the risk 

of hypertension. Two prospective studies and five 

cross-sectional studies found a statistically significant association between bone Pb and increased BP 

or hypertension. These studies were in populations 

or samples with blood Pb levels <10 μg/dL, and most 

of them had mean levels <5 μg/dL. Blood Pb was less 

consistently associated with BP and hypertension in 

adults. Studies of groups with mean blood Pb levels 

<5 μg/dL (often more recent studies) have found significant associations between concurrent blood Pb 

and higher BP. The NTP recognizes that an individual 

with blood levels <10 μg/dL during adulthood may 

have had higher blood Pb levels earlier in life, and the 

role of early-life Pb exposure cannot be discriminated 

from the role of concurrent blood Pb.

There is sufficient evidence that blood Pb levels <10 μg/dL are associated with an increased risk 

of hypertension during pregnancy. One prospective 

study and five cross-sectional studies supported an 

association, all with mean blood Pb levels <10 μg/dL. 

There is limited evidence of increased risk of cardiovascular-related mortality associated with blood Pb 

levels <10 μg/dL based on three prospective studies 

that report an association with blood Pb, and two 

prospective studies that did not support an association with blood Pb at mean levels of 11.5 μg/dL 

and 5.6 μg/dL. There is also limited evidence for Pb 

effects on ECG abnormalities and cardiovascular disease including cerebrovascular disease and peripheral arterial disease, because there are few replicated 

studies of blood Pb effects.

There is inadequate evidence to assess whether 

children present a sensitive life stage for cardiovascular effects of Pb. No prospective studies have 

followed children with early-life Pb measures with 

determination of cardiovascular health after childhood, and the few studies of blood Pb and BP during 

childhood had inconsistent results. There is some 

evidence that menopause is associated with higher 

blood Pb levels, associated with mobilization of bone 

stores of Pb, and this could put women at greater risk 

of Pb-related cardiovascular effects. However, there 

are few studies and inadequate evidence to assess 

cardiovascular effects of Pb in menopausal women. 

One cross-sectional study (mean blood Pb) found a 

stronger statistically significant association between 

blood Pb and hypertension in postmenopausal 

women (Nash et al. 2003), but two smaller studies 

found no association (Pizent et al. 2001, Al-Saleh et 

al. 2005). There is inadequate evidence for Pb effects 

on heart rate variability or specific types of cardiovascular disease; due to few replicated studies.

Chronic Pb exposure appears to be more critical 

than current Pb exposure, as indicated by more consistent associations with bone Pb than with blood Pb 

for chronic cardiovascular effects such as hypertension and mortality from cardiovascular causes. The 

data are inadequate to evaluate prenatal or childhood Pb exposure with health effects at later stages 

of development or in adulthood.

Although the cardiovascular and renal systems 

are intimately linked, effects are considered separately in this evaluation because studies generally 

reported individual effects rather than testing both 

systems comprehensively. Nevertheless, it is recognized that kidney dysfunction can contribute to 

increased BP and that hypertension can contribute to 

adverse renal effects. The EPA’s 2006 AQCD for Lead 

(U.S. EPA 2006) and ATSDR’s Toxicological Profile for 

Lead (ATSDR 2007) both conclude that cardiovascular 

and renal effects of Pb may share biological mechanisms. As discussed in Section 6.4, multiple studies 

suggest that individuals with decreased renal function are a susceptible population for adverse cardiovascular effects of Pb.

6.2 How Conclusions Were Reached

Conclusions in the NTP evaluation of Pb-related 

cardiovascular effects in humans associated with 

low-level Pb were derived by evaluating the data 

from epidemiological studies with a focus on blood 

Pb levels <10 μg/dL. The NTP’s conclusions are based 

on the evidence from human studies with blood Pb 

levels of <10 μg/dL, with data reflecting exposure 

levels up to 15 μg/dL. This section of the evaluation 

focuses primarily on the human data for cardiovascular effects of Pb because there is a relatively large 

database of human studies for these endpoints. 

Major endpoints considered as potential indicators 

of effects of Pb on cardiovascular functions are listed 
Cardiovascular

Effects

62 NTP Monograph on Health Effects of Low-Level Lead

and briefly described in Section 6.2.1. This document 

is not a review of the cardiovascular system or toxicity, 

and the reader is directed to published reviews for 

additional background. Key data and principal studies 

considered in developing the NTP conclusions are discussed in detail in Section 6.3 Evidence for Pb-related 

Effects on Cardiovascular Outcomes. The discussion 

of each cardiovascular effect begins with a statement of the NTP conclusion of whether the specific 

effect is associated with a blood Pb level <10 μg/dL 

or <5 μg/dL and the age group in which it is identified 

(childhood or adulthood). Most studies are prospective or cross-sectional within a life stage (childhood or 

adulthood exposure and outcome) unless otherwise 

indicated. The discussion also highlights the extent 

to which experimental animal data support the 

association between Pb exposure and cardiovascular 

effects. Although the information necessary to support the NTP conclusions is presented in Section 6.3, 

the complete data set of human studies with data on 

cardiovascular endpoints from Pb-exposed groups is 

included in Appendix C: Cardiovascular Effects, and 

individual studies are abstracted for further reference. The NTP made extensive use of recent government evaluations of health effects of Pb in the current 

assessment, and the relevant conclusions of the EPA’s 

2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 

Toxicological Profile for Lead (ATSDR 2007) are briefly 

described in Section 6.2.2 below.

6.2.1 Principal Measures of Cardiovascular 

Effects

Table 6.1 lists a number of key cardiovascular endpoints commonly evaluated in epidemiological studies (as defined by the American Heart Association 

Cardiac Glossary (http://www.heart.org/HEARTORG/

Conditions/HeartAttack/HeartAttackToolsResources/

Cardiac-Glossary_UCM_303945_Article.jsp) or studies of pulse pressure and heart rate variability cited 

below). Blood pressure (BP) is the most widely measured cardiovascular effect in studies of Pb exposure 

and is evaluated as a continuous measure (range, in 

mmHg) or as categories (dichotomized as hypertension vs. no hypertension). High BP increases the risk 

of myocardial infarction and stroke, and BP control 

is one of the primary strategies to prevent the development of cardiovascular disease, with evidence of 

efficacy in patients without prior heart disease (Law 

et al. 2009). Pulse pressure is the difference between 

systolic and diastolic blood pressure (SBP and DBP), 

Table 6.1: Major Pb-related cardiovascular outcomes/effects

Cardiovascular Effect Description

Blood pressure (BP) The force exerted by the heart against the walls of the arteries (measured in millimeters of 

mercury (mmHg)), with a maximum during the pumping phase of the heartbeat (systolic, 

SBP) and a minimum when the heart muscle relaxes between beats (diastolic, DBP).

Hypertension Medical term for high blood pressure (currently, SBP ≥140 or DBP ≥90) compared to an optimal BP of <120/80 mmHg. BPs of 120-139/80-89 mmHg are considered prehypertension.

Pulse pressure The difference between SBP and DBP; a marker of arterial stiffness.

Heart rate variability Changes in the interval between heart beats. Decreased variability is a marker of abnormal 

autonomic nervous system functioning.

Electrocardiographic (ECG) 

conduction abnormalities

Changes in the typical pattern of electrical activity of the heart, including the P wave (atrial 

activity), QRS wave (ventricle activity), and T wave (return to resting state).

Peripheral artery disease Narrowing of arteries carrying blood to the arms and legs, caused by atherosclerosis.

Coronary heart disease Narrowing of the arteries that supply blood and oxygen to the heart muscle, caused by atherosclerosis, and which can result in a myocardial infarction (also called ischemic heart disease).

Myocardial infarction Medical term for a heart attack: damage to heart muscle resulting from a blocked blood 

supply.

Stroke Death or injury to brain cells when a blood clot blocks an artery in or leading to the brain 

(ischemic) or when a blood vessel ruptures (hemorrhagic).

Cardiovascular mortality Death attributed to heart or circulatory causes.

American Heart Association Cardiac Glossary: (http://www.heart.org/HEARTORG/Conditions/HeartAttack/

HeartAttackToolsResources/Cardiac-Glossary_UCM_303945_Article.jsp)
Cardiovascular

Effects

NTP Monograph on Health Effects of Low-Level Lead 63

and increases reflect arterial stiffness, a critical cardiovascular risk factor (Lakatta and Levy 2003). Heart rate 

variability is an indicator of cardiac autonomic function, with decreased variability being associated with 

risk of heart disease and mortality, and with clinical 

relevance in relation to Pb exposure (Park et al. 2006).

Electrocardiographic (ECG) conduction abnormalities have also been investigated in relation to 

Pb exposure. Major clinical cardiovascular effects 

that have been associated with Pb exposure include 

peripheral artery disease, coronary heart disease 

(ischemic heart disease), and stroke (cerebrovascular disease). Cardiovascular disease mortality has also 

been related to Pb exposure.

The data available to evaluate each of the major 

effects are discussed in separate subheadings under 

Section 6.3 Evidence for Pb-related Effects on Cardiovascular Outcomes below.

6.2.2 Principal Conclusions from the 2006 

EPA and 2007 ATSDR Pb Documents

The EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and 

ATSDR’s Toxicological Profile for Lead (ATSDR 2007) 

both concluded that epidemiological studies support a relationship between higher Pb exposure 

and decreases in cardiovascular health, including 

increased SBP and DBP, higher incidence of hypertension, and increased incidence of cardiovascular 

disease and cardiovascular-related mortality (see 

Table 6.2 for principal conclusions; see the original 

documents for complete conclusions). The association between elevated blood Pb and increased 

BP (SBP and DBP) is supported by a large body of 

literature, including cross-sectional (e.g., NHANES), 

prospective cohort (e.g., Boston Normative Aging 

Study), and occupational studies, as well as several 

meta-analyses (Staessen et al. 1994, Schwartz 1995, 

Nawrot et al. 2002). The EPA (U.S. EPA 2006) and 

ATSDR (ATSDR 2007) both stated that the data support an increase of approximately 1.0 mmHg in SBP 

and 0.6 mmHg in DBP for every doubling of the blood 

Pb level. Both agencies concluded that cumulative 

past Pb exposure, reflected in bone Pb levels, may be 

as important as, if not a more important than, current 

exposure as indicated by blood Pb level in the contribution to Pb-related increases in BP. Every 10 μg/g 

increase in bone Pb was associated with an odds ratio 

for hypertension of 1.28 to 1.86 over a bone Pb range 

of <1.0 μg/g to 96 μg/g (U.S. EPA 2006). ATSDR also 

highlighted the potential mechanistic link between 

cardiovascular and renal effects of Pb.

The NTP considered the conclusions and data 

summaries from the EPA’s 2006 AQCD for Lead (U.S. 

EPA 2006) and ATSDR’s Toxicological Profile for Lead 

(ATSDR 2007). In general, the NTP accepted the 

conclusions and agreed that the data support them. 

Differences from the ATSDR and EPA documents are 

identified for specific endpoints. The focus of EPA’s 

document did not clearly discriminate effects below 

and above 10 μg/dL. Most of the studies of the 

quantitative relationship between blood Pb and SBP 

report mean blood Pb levels <10 μg/dL (e.g., table 

6-2 in U.S. EPA 2006). However, the conclusion on the 

increase in BP associated with a doubling of blood 

Pb did not specify whether this doubling occurred at 

blood Pb levels <10 μg/dL. Some studies considered 

by the EPA, particularly those conducted before 1990 

or in occupational settings, had more than 90% of 

their subjects with blood Pb >10 μg/dL (Kromhout et 

al. 1985, Lockett and Arbuckle 1987, Gartside 1988). 

Such studies were not considered for the NTP conclusions on Pb effects at levels <10 μg/dL.

6.3 Evidence for Pb-related Effects on 

Cardiovascular Outcomes

6.3.1 Blood Pressure (BP) and Hypertension

There is sufficient evidence that blood Pb levels 

<10 μg/dL are associated with increases in BP and 

risk of hypertension (see the Blood Pressure (BP) and 

Hypertension section of Appendix C: Cardiovascular 

Effects). BP is the most widely studied cardiovascular 

Table 6.2: Main conclusions for cardiovascular 

effects in the 2006 EPA AQCD for Lead and the 

2007 ATSDR Toxicological Profile for Lead

“Epidemiologic studies support the relationship 

between increased lead exposure and increased deleterious cardiovascular outcomes, including increased 

blood pressure and increased incidence of hypertension. ... The evidence for an association of Pb with cardiovascular morbidity and mortality is limited but supportive.” (U.S. EPA 2006, pg 6-271)

“Population studies suggest that there is a significant 

association between bone-lead levels and elevated 

blood pressure. Blood lead levels (PbBs) also have been 

associated with small elevations in blood pressure.“ 

(ATSDR 2007, pg 21)
Cardiovascular

Effects

64 NTP Monograph on Health Effects of Low-Level Lead

measure in studies of Pb, because it is routinely and 

easily measured. An association between higher Pb 

levels and higher BP is most consistent in studies of 

bone Pb (see Table 6.3). Women are at particular risk: 

there is sufficient evidence that blood Pb <10 μg/dL 

increases the risk of hypertension during pregnancy. 

Adults with concurrent blood Pb levels <10 μg/dL may 

have had higher Pb levels in the past, so the role of 

current blood Pb cannot be separated from an effect 

of early-life Pb exposure.

There is inadequate evidence for Pb effects on BP 

or hypertension in children. The size of the increase 

in BP that is detected is relatively small (1-2 mmHg). 

It is well established, however, that small increases 

in BP levels at the population level can have a substantial public health impact by increasing the risk 

of hypertension and incident cardiovascular disease 

(Whelton et al. 2002).

Despite some inconsistency across human studies, meta-analyses conclude that Pb exposure is associated with increased BP levels (Nawrot et al. 2002, 

Navas-Acien et al. 2008). Meta-analyses can account 

for the relative contributions of each study and multiple publications on overlapping data sets. Several 

recent meta-analyses support a small increase in 

BP from both blood (Nawrot et al. 2002) and bone 

Pb (Navas-Acien et al. 2008). Small but significantly 

increased risks of hypertension were found with tibia 

Pb (for a 10 μg/g increase: OR=1.04 (95% CI: 1.01, 

1.07)), and nonsignificant increases for patella Pb (for 

a 10 μg/g increase: OR=1.04 (95% CI: 0.96, 1.12) and 

blood Pb (for a 5 μg/dL increase: OR=1.02 (95% CI: 

0.93, 1.13)) (Navas-Acien et al. 2008). Neither metaanalysis focused on low-level Pb exposure; for example, of the 10 studies included in the Navas-Acien et al.

(2008) meta-analysis, two had mean blood Pb levels 

over 30 μg/dL, while the other eight were <10 μg/dL.

Bone Pb: Long-term exposure to Pb is often reflected 

in bone Pb levels, and several studies reported a significant association of BP with bone Pb but not with 

blood Pb (Cheng et al. 2001, Gerr et al. 2002, Rothenberg et al. 2002). However, bone Pb must be measured during specialized clinic visits and has not been 

as widely studied. Table 6.3 summarizes the bone Pb 

literature for BP and hypertension listed by study 

type and decreasing study size, grouped together 

for overlapping or shared study groups. Most crosssectional studies found an association with bone Pb 

and hypertension in the general population (Hu et 

al. 1996, Rothenberg et al. 2002, Elmarsafawy et al.

2006, Martin et al. 2006). One cross-sectional study 

did not find bone Pb to significantly increase the risk 

of hypertension, while blood Pb was significantly 

associated (Schwartz and Stewart 2000).

Blood Pb: Studies of blood Pb and BP do not consistently support an association as compared to studies 

of bone Pb and BP (see Blood Pressure (BP) and Hypertension section of Appendix C: Cardiovascular Effects). 

One prospective study supports a modest increase in 

SBP with both blood and bone Pb (Glenn et al. 2003), 

while three publications from two prospective studies 

failed to show an association with SBP or DBP (Grandjean et al. 1989, Moller and Kristensen 1992, Staessen 

et al. 1996). The prospective studies that did not find 

a significant association were in groups with higher 

mean blood Pb levels (between 10 and 15 μg/dL at 

baseline in Møller and Kristensen (1992) and Staessen 

et al. (1996)) than in the supportive study (4.6 μg/dL in 

Glenn et al. (2003)). The Glostrup Population Study, 

which did not support an association, was also larger 

than the supportive cohort (1,052 subjects in Møller 

and Kristensen (1992) vs. 496 in Glenn et al. (2003)). 

Thus, the studies that do not support an association 

between blood Pb levels and increased BP are not 

necessarily underpowered or include less exposed 

groups compared to the supportive studies. Twentynine publications of cross-sectional analyses with 

mean blood Pb levels <15 μg/dL support a small 

increase in SBP or DBP, while 17 did not support a 

relationship (some studies had multiple publications, 

so not all results are independent; see Blood Pressure 

(BP) and Hypertension section of Appendix C: Cardiovascular Effects for a complete list of studies considered). Analysis of NHANES 1999-2006 restricted to 

subjects with blood Pb <10 μg/dL (n=16,222) found 

a significant association with increased SBP and DBP 

(Scinicariello et al. 2011).

Three prospective studies failed to find an 

association between blood Pb and hypertension 

(Grandjean et al. 1989, Staessen et al. 1996, Cheng 

et al. 2001), although one of them did find an association with bone Pb (Cheng et al. 2001). Blood Pb 

was associated with increased prevalence of hypertension in 10 cross-sectional studies, but one study 

found no association (Kim et al. 2008). Black men 

had a significantly increased risk of hypertension 
NTP Monograph on Health Effects of Low-Level Lead 65

Cardiovascular

Effects

Table 6.3: Studies of the association between bone Pb and blood pressure and hypertension used to develop conclusions

Relevance 

to 

Conclusions

Study Description Study Design Key Cardiovascular Findings Reference

Effect 496 former Pb workers, USA Prospective In men with past occupational Pb exposure (mean blood Pb, 4.6 μg/dL), 

blood and tibia Pb were associated with annual increases in SBP, but not DBP, over 3 years of follow-up.

Glenn (2003)

Normative Aging Study, USA

Effect 474 men Prospective Bone Pb was correlated with increased SBP at baseline and an increased 

risk of hypertension 3-6 years later, while blood Pb was not associated.

Cheng (2001)

619 men Cross-sectional A positive association between pulse pressure and bone Pb in a group of 

older men was modified by genetic variations in the HFE gene.

Zhang (2010)

593 men Cross-sectional In a group of older men, tibia Pb was positively association with pulse pressure, but not blood Pb, which was positively correlated with DBP. Perlstein (2007)590 men Cross-sectional Bone and blood Pb levels were higher in hypertensives (mean blood Pb, 

<7 μg/dL), and tibia Pb independently increased the risk of hypertension.

Hu (1996)

471 men Cross-sectional The relationship between blood Pb, tibia Pb, or patella Pb and hypertension 

or BP may be modified by dietary calcium intake in a group of men with low Pb levels.

Elmarsafawy (2006)

No effect 750 older men (513 with 

hypertension)

Case-control Bone Pb in the patella and tibia was not associated with risk of hypertension in these older men with low blood Pb levels (mean, 6.3 μg/dL). Peters (2007)

Effect 667 third-trimester or postpartum women, USA Cross-sectional Calcaneus bone Pb measured postpartum was associated with increased BP and hypertension during the third trimester (mean blood Pb, 2.3 μg/dL 

postpartum).

Rothenberg (2002)

Effect 964 adults, Baltimore Memory Study, USA Cross-sectional In these older adults, blood Pb (mean, 3.5 μg/dL) was associated with BP, while bone Pb was associated with risk of hypertension. Martin (2006)

Effect 543 former Pb workers, USA Cross-sectional In men with prior occupational exposure, blood Pb was associated with 

increased BP and an increased risk of hypertension, but not tibia or DMSA chelatable Pb.

Schwartz (2000)

Effect 508 young adults, half lived 

near Pb as children, USA

Cross-sectional In young adults, some with childhood Pb exposure, SBP and DBP were significantly increased in those with the highest bone Pb levels (>10 μg/g, 

blood Pb 3.15 μg/dL).

Gerr (2002)

Effect 284 women (89 with hypertension), Nurses’ Health Study Case-control Patella Pb was associated with an increased risk of hypertension in these middle-age women without occupational exposures (mean, 3 μg/dL), but 

tibia and blood Pb were not significantly associated.

Korrick (1999)

Epidemiological studies of bone Pb exposure and blood pressure and hypertension are listed by study type and decreasing study size, grouped together for overlapping or shared study groups.Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; DMSA, dimercaptosuccinic acid, used in the treatment of Pb poisoning; SBP, systolic blood pressure.
Cardiovascular

Effects

66 NTP Monograph on Health Effects of Low-Level Lead

(adjusted prevalence OR=2.69 (95% CI: 1.08, 6.72) 

for 90th (≥3.50 μg/dL) vs. 10th (≤0.70 μg/dL) percentile) when restricted to 1,767 subjects with blood Pb 

<10 μg/dL from NHANES 1999-2006 (Scinicariello et 

al. 2011). Case-control studies of hypertension were 

also inconsistent: supporting blood Pb (Bakhtiarian 

et al. 2006), not supporting blood Pb while supporting bone Pb (Korrick et al. 1999), and not supporting either blood Pb (Al-Saleh et al. 2005) or bone Pb 

(Peters et al. 2007).

Pulse Pressure: Higher pulse pressure (the difference between SBP and DBP) is a marker of arterial 

stiffness, and there was no association with blood 

Pb in the Normative Aging, but tibia Pb above the 

median was associated with an increase of 4 mmHg 

in pulse pressure (Perlstein et al. 2007, Zhang et al.

2010). In Mexican-American male NHANES subjects 

with blood Pb <10 μg/dL (n=1925), there was a significant 1.4 mmHg increase in pulse pressure per unit 

increase in the natural log of blood Pb (Scinicariello 

et al. 2011).

Differential Impacts: Blood Pb and bone Pb may 

reflect variable cardiovascular effects of Pb with acute 

effects on transient measures, such as BP, and chronic 

effects on clinical disease, such as hypertension – the 

more permanent state of elevated BP (Navas-Acien et 

al. 2008). Martin et al. (2006) proposed this hypothesis when they reported a significant association 

between blood Pb and BP as well as between bone 

Pb and hypertension. A prediction model for bone Pb 

based on the Normative Aging Study was developed 

by Park et al. (2009b). When it was applied to data 

from NHANES III, they found relatively more significant associations between estimated bone Pb and 

hypertension (Park et al. 2009b). This data should be 

considered cautiously because it was developed with 

a new method for modeling exposure. However, it 

should be noted that the model-building Normative 

Aging Study population only included older men, and 

factors such as age, menopause, and past pregnancies are associated with the mobilization of bone Pb 

(Symanski and Hertz-Picciotto 1995).

Modifiers: Blood pressure itself is a transient measure 

influenced by important cofactors that may modify an 

association with Pb (see Section 6.4 Susceptible Populations and Modifiers of Pb Exposure). The increase 

in BP that is supported by the data is 1-2 mmHg per 

doubling of blood Pb, and on a population basis the 

impact is likely to be larger in susceptible populations 

such as pregnant women or individuals with a particular metabolic gene variant.

Pregnancy puts women at greater risk of hypertension, which can contribute to preeclampsia and 

other complications. The mobilization of bone Pb 

during pregnancy (Gulson et al. 1997, Rothenberg et 

al. 2000) (see further discussion in Section 3.4 Modifiers of Pb Exposure) may contribute to the more 

consistent association of Pb exposure with hypertension and the greater magnitude of the change 

in BP during pregnancy (see Table 6.4). The change 

(increase) in blood Pb levels during pregnancy was 

associated with hypertension during pregnancy in 

a prospective study (Sowers et al. 2002); similarly, 

maternal blood Pb levels during pregnancy were 

associated with hypertension in cross-sectional studies (Rabinowitz et al. 1987, Yazbeck et al. 2009) and 

a case-control study (Vigeh et al. 2004). One study 

did not find an association between umbilical cord 

blood Pb and hypertension in the mother but did find 

a significant association with maternal SBP and DBP 

before delivery (Wells et al. 2011). All of these studies 

had mean blood Pb levels <10 μg/dL, and two of the 

supportive studies were had mean Pb levels <2 μg/dL 

(Sowers et al. 2002, Yazbeck et al. 2009). Additional 

studies in pregnant women support an association 

between higher blood Pb and higher BP (Rothenberg 

et al. 1999, Magri et al. 2003) and between higher 

bone Pb and higher BP (Rothenberg et al. 2002).

Women experiencing menopause may be 

at an increased risk due to mobilization of bone 

Pb stores that may be associated with periods of 

demineralization; increased blood Pb levels have 

been demonstrated in postmenopausal women in 

several studies (e.g., Silbergeld et al. 1988, Symanski and Hertz-Picciotto 1995, Webber et al. 1995, 

Korrick et al. 2002). In NHANES III, among women 

40-59 years of age untreated for hypertension, the 

association between blood Pb and hypertension was 

stronger in postmenopausal women, with statistically significant odds ratios for systolic hypertension 

(quartile 2 (blood Pb 2.1-3.0 μg/dL): OR=3.0 (95% CI: 

1.3, 6.9) quartile 3 (blood Pb 3.1-4.6 μg/dL): OR=2.7 

(95% CI 1.2-6.2) compared to quartile 1 (blood Pb 

0.5-2.0 μg/dL) (Nash et al. 2003)). The odds ratios 

for systolic hypertension in premenopausal women 
Cardiovascular

Effects

NTP Monograph on Health Effects of Low-Level Lead 67 Table 6.4: Studies of Pb and blood pressure and hypertension during pregnancy used to develop conclusions Relevance to Conclusions Study Description Study Design Key Cardiovascular Findings Reference Effect 705 pregnant women, USA Prospective Change in blood Pb concentration during pregnancy (mean, 1.2 μg/dL) was associated with hypertension in pregnancy, including the serious complications of preeclampsia and toxemia. Sowers (2002) Effect 3,851 women at birth of child, USA Cross-sectional There was an increase in women’s BP during labor with increased umbilical cord blood Pb, as well as an increased risk of pregnancy hypertension from low Pb levels (6.3

μg/dL), but not preeclampsia.

Rabinowitz (1987)

Pregnant Women, Los Angeles, USA

Effect 1,627 pregnant women Cross-sectional In the third trimester of pregnancy, increased blood Pb was associated 

with increased BP only in immigrant women, primarily Latina (mean 

blood Pb, 2.3

μg/dL).

Rothenberg (1999)

667 third trimester or postpartum women

Cross-sectional Postpartum calcaneus bone Pb was associated with increased BP and 

hypertension during the third trimester (mean blood Pb, 2.3

μg/dL 

postpartum).

Rothenberg (2002)

Effect 971 pregnant women, EDEN Study, 

France

Cross-sectional Blood Pb levels in the second trimester (mean, 1.9 μg/dL) were correlated with BP before and after 36 weeks gestation and increased the 

risk of pregnancy induced hypertension, particularly in parous women.

Yazbeck (2009)

Effect 285 pregnant women, Baltimore 

THREE Study, USA

Cross-sectional Umbilical cord blood Pb of the child was associated with increased 

BP in the mother during labor and delivery (Q4 ≥ 0.96 μg/dL vs. Q1 ≤ 0.46 μg/dL), but not with other BP-related pregnancy conditions.

Wells (2011)

Effect 143 third trimester primigravid 

women, Malta

Cross-sectional Blood Pb during the third trimester was higher in pregnant women 

with hypertension during pregnancy (mean, 9.6 vs. 5.8

μg/dL) and 

correlated with SBP and DBP in all pregnant women.

Magri (2003)

Effect 110 pregnant women, half with 

gestational hypertension, Iran

Case-control Blood Pb at delivery was higher in women with hypertension during 

pregnancy (5.7 vs. 4.8

μg/dL), but Pb levels did not correlate with BP 

in the hypertensive women.

Vigeh (2004)

Epidemiological studies of Pb exposure and blood pressure and hypertension during pregnancy are listed by study type and decreasing size, grouped together for overlapping or shared study groups.Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; EDEN, Etude des Déterminants pré et post natals du développement et de la santé de Enfant; SBP, systolic blood pressure; Q1, first quartile; Q4, fourth quartile; THREE, Tracking Health Responses to Environmental Exposures.
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68 NTP Monograph on Health Effects of Low-Level Lead

were around 1.5 and were not statistically significant. 

Other, smaller studies found no association between 

blood Pb and BP or hypertension in postmenopausal 

women (Pizent et al. 2001, Al-Saleh et al. 2005).

Children are at greater risk of Pb exposure due 

to early hand-to-mouth behaviors (see further discussion in Section 3.0 Exposure). Few studies evaluating the effects of Pb on BP have been conducted 

in children (see Table 6.5). Young adults with childhood Pb exposure had higher bone Pb and 3-4 mmHg 

higher SBP and DBP (>10 μg/dL vs. <1 μg/g, p<0.05) 

(Gerr et al. 2002). In the Oswego Children’s Study, 

umbilical cord blood Pb levels were associated with 

BP at 9.5 years of age, and early-childhood blood Pb 

(mean age, 2.6 years) was associated with increased 

BP in response to acute stress tasks at 9.5 years of 

age – particularly in children with low socioeconomic 

status (Gump et al. 2005, Gump et al. 2007). Other 

studies of blood Pb in children did not find an effect 

on BP (Factor-Litvak et al. 1996, Factor-Litvak et al.

1999, Chen et al. 2006). The adult origin of disease 

from childhood Pb exposure has not been sufficiently 

studied to inform a conclusion on cardiovascular risks 

from early or chronic Pb exposure.

While most of the literature supports a role for 

Pb in risk of hypertension, the definition of hypertension is not consistent across studies. The current 

standard is ≥140 mmHg SBP and/or ≥90 mmHg DBP, 

but several studies used a higher (Grandjean et al.

1989, Apostoli et al. 1990, Bakhtiarian et al. 2006, 

Elmarsafawy et al. 2006), lower (Al-Saleh et al. 2005), 

or “borderline” (140-159 mmHg SBP and/or 91-94 

mmHg DBP) (Staessen et al. 1996) definition of hypertension. Studies also differed by how subjects taking 

anti-hypertensive medication were included, with 

one study excluding these subjects from analyses of 

BP (Scinicariello et al. 2010) and several considering 

subjects hypertensive based only on medication use 

(Hu et al. 1996, Staessen et al. 1996, Nash et al. 2003, 

Al-Saleh et al. 2005, Muntner et al. 2005, Martin et al.

2006, Scinicariello et al. 2010).

Summary of Support for Conclusions on BP 

and Hypertension

Animal studies provide strong evidence for low-level 

Pb elevating BP in humans and contributing to the 

onset of hypertension, even after the exposure to Pb 

has stopped (U.S. EPA 2006 pg 5-103, ATSDR 2007 pg 

28). In rats, blood Pb levels as low as 2.15μg/dL showed 

significant increases in both SBP and DBP compared to 

unexposed rats, while exposures resulting in blood Pb 

levels >29 μg/dL did not show further increases in BP 

(Tsao et al. 2000). Many in vivo and in vitro studies support oxidative stress as the mechanism by which Pb contributes to the pathogenesis of hypertension (see U.S. 

EPA 2006 for further review of animal and mechanistic 

studies). Experimental animals do not show consistent 

dose-dependent increases in risk of hypertension: low, 

but not high, levels cause hypertension in some models (U.S. EPA 2006 pg 5-124). This nonmonotonic (or 

bi-phasic) relationship could partially explain inconsistency observed in human studies, where studies with 

mean blood Pb levels <5 μg/dL were generally more 

supportive of a relationship with BP and hypertension 

(see Blood Pressure (BP) and Hypertension section of 

Appendix C: Cardiovascular Effects).

The conclusion of sufficient evidence for a Pbrelated increase in BP and risk of hypertension is based 

on a large body of literature in humans, with significant 

associations that are more consistently found with 

bone Pb as a measure of exposure than with blood Pb. 

There is a small but sufficient literature supporting Pbrelated increases in hypertension during pregnancy, 

while there is inadequate evidence for Pb effects on 

BP or hypertension in children. The NTP’s conclusions 

for sufficient evidence for BP and hypertension at 

blood Pb levels <10 μg/dL expand the conclusions of 

EPA’s 2006 AQCD for Pb (U.S. EPA 2006) and ATSDR’s 

Toxicological Profile for Lead (ATSDR 2007).

6.3.2 Heart Rate Variability

There is inadequate evidence to evaluate a potential 

association between Pb exposure and heart rate variability (HRV). HRV reflects sympathetic (low frequency 

only) and parasympathetic (high and low frequency) 

autonomic nervous system function, with decreases 

in variability indicating abnormal autonomic function 

(Park et al. 2006). The literature contained only four 

publications of Pb and HRV with mean blood Pb levels 

<10 μg/dL, and the results were not consistent (Jhun 

et al. 2005, Park et al. 2006, Park et al. 2008, Gump et 

al. 2011). In the Oswego Children’s Study, concurrent 

blood Pb in children 9-11 years of age (median blood 

Pb, 0.94 μg/dL) was significantly associated with 

impaired autonomic response to acute stress tasks as 

evaluated by HRV (Gump et al. 2011). In adults there 

was an indication that Pb may modify the effect of 

other metals (Jhun et al. 2005) or air pollution (Park 
Cardiovascular

Effects

NTP Monograph on Health Effects of Low-Level Lead 69 Table 6.5: Studies of childhood Pb exposure and BP Relevance to Conclusions Study Description Study Design Key Cardiovascular Findings Reference Oswego Children’s Study, USA Effect 122 children Prospective Cord blood Pb levels (mean, 3 μg/dL) were associated with increased SBP at 9.5 years old, while childhood Pb levels (mean, 4.6 μg/dL at 2.6 years old) were associated with an increased DBP, decreased stroke vol- ume, and increased total peripheral resistance response to acute stress. Gump (2005) 122 children Prospective Family socioeconomic status interacted with blood Pb to increase BP and may interact with blood Pb to increase total peripheral resistance response to acute stress tasks in these children with low blood Pb (mean, 4.6 μg/dL at 2.6 years old). Gump (2007) 140 children, 9-11 years old Cross-sectional Concurrent blood Pb (median, 0.94 μg/dL) was not associated with BP or BP responses to acute stress in these children, but blood Pb was associated with measures of impaired cardiac function in response to acute stress tasks. Gump (2011) No effect 780 children with moderately high Pb, half treated with suc- cimer, USA Cross-sectional In these children with Pb exposure (20-44 μg/dL), there was no associa- tion between blood Pb and BP, including after 5 years of follow-up when mean blood levels were 8 μg/dL. Chelation of Pb with succimer had no effect on BP. Chen (2006) Effect 508 young adults, half lived near Pb as children, USA Cross-sectional In young adults, some of whom had childhood Pb exposure, SBP and DBP was significantly increased in those with the highest bone Pb levels (>10 μg/g, blood Pb 3.15 μg/dL). Gerr (2002) No effect 144 children in the town unex- posed to Pb; Pristina, Kosovo Cross-sectional For the children residing in the town without Pb exposure, the small positive correlation of blood Pb with BP was not statistically significant. Factor-Litvak (1996) Epidemiological studies of childhood Pb exposure and blood pressure and hypertension are listed by study type and decreasing size, grouped together for overlapping or shared study groups. Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure.
Cardiovascular

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70 NTP Monograph on Health Effects of Low-Level Lead

et al. 2008) on HRV. The EPA’s 2006 AQCD for Lead 

(U.S. EPA 2006) mentions HRV as a possible intermediary between Pb exposure and cardiovascular 

mortality, and HRV is not considered in the ATSDR’s 

Toxicological Profile for Lead (ATSDR 2007).

6.3.3 Electrocardiogram Abnormalities

There is limited evidence for Pb effects on electrocardiogram (ECG) abnormalities. The Normative Aging 

Study supports a role for bone Pb and ECG abnormalities at the time of Pb measurement and 8 years later 

for QT and JT/ST prolongation and intraventricular or 

atrioventricular conduction defects (Cheng et al. 1998, 

Eum et al. 2011). Polymorphisms in iron metabolism 

genes (HFE, TFC2, HMEX-1) may modify these relationships (Park et al. 2009a). The Oswego Children’s Study 

found that early-childhood blood Pb and concurrent 

blood Pb were associated with decreased stroke 

volume and increased total peripheral resistance in 

response to acute stress tasks at 9.5 years of age, especially in subjects with lower socioeconomic status who 

had higher blood Pb (overall mean, 4.6 μg/dL at age 

2.6) (Gump et al. 2005, Gump et al. 2007, Gump et 

al. 2011). The studies of ECG abnormalities by Cheng 

et al. (1998) and Gump et al. (2005) were included in 

the EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and the 

ATSDR’s Toxicological Profile for Lead (ATSDR 2007), 

but no conclusions were reached.

6.3.4 Clinical Cardiovascular Disease

There is limited evidence that blood Pb levels <5 μg/dL 

are associated with clinical cardiovascular disease 

(see Table 6.6 and Clinical Cardiovascular Disease section of Appendix C: Cardiovascular Effects). A positive 

association has been reported between blood Pb level 

and several related cardiovascular diseases, including peripheral arterial disease and coronary artery 

disease, as well as blood flow measures indicative of 

atherosclerotic vascular resistance.

For cardiovascular disease in general, particularly conditions exacerbated by increases in BP, there 

was an increased risk from Pb exposure. In large 

studies that found a relationship between Pb and BP, 

Pb was also associated with an increased incidence 

of coronary artery disease (Normative Aging Study: 

(Jain et al. 2007)) and prevalence of peripheral artery 

disease (NHANES: (Navas-Acien et al. 2004, Muntner 

et al. 2005, Guallar et al. 2006)), while in the Glostrup 

Population Study there was no association between 

Pb and BP or cardiovascular disease (Moller and Kristensen 1992).

In prospective analyses, the Normative Aging 

Study reported an increased risk of coronary heart 

disease (myocardial infarction or angina) with blood 

Pb (log blood Pb adjusted HR=1.45 (95% CI: 1.01, 2.06), 

p=0.05) and bone Pb (log patella Pb, adjusted HR=2.64 

(95% CI: 1.09, 6.37), p=0.05) (Jain et al. 2007). The prospective Glostrup Population Study in Denmark with a 

mean blood Pb at baseline of 11.6 μg/dL failed to find 

an increased risk of coronary heart disease or cardiovascular disease (Moller and Kristensen 1992).

A large cross-sectional study in Korea with low 

blood Pb (geometric mean, 6μg/dL) found no increased 

risk for coronary heart disease or cerebral vascular 

disease (Kim et al. 2008). Two cross-sectional studies 

with mean blood Pb levels >10 μg/dL do support a 

relationship between blood Pb and coronary heart disease and stroke (Pocock et al. 1988, Schwartz 1991). In 

cross-sectional studies of peripheral artery disease, risk 

increased with blood Pb in NHANES 1999-2002 studies 

with very low Pb levels (mean, 1.6-2.1 μg/dL) (NavasAcien et al. 2004, Muntner et al. 2005, Guallar et al.

2006), independent of an unadjusted association with 

homocysteine level and accounting for renal function 

(Guallar et al. 2006).

Several studies used vascular measures as indicators of arterial function in the absence of physiciandiagnosed disease, but there was inadequate information to form a conclusion because each was only 

studied for an association with Pb exposure in one 

group. In a study of Japanese ceramics workers, blood 

Pb (mean, 13 μg/dL) was associated with decreased 

finger blood flow in response to a postural change, 

consistent with an atherosclerotic effect, but four 

other measures of cardiac function were not associated (Ishida et al. 1996). In a study of bus drivers 

with low blood Pb levels (mean, 6 μg/dL), mean aging 

index of second derivative finger photoplethysmogram waveform (SDPTG-AI) was increased with blood 

Pb, indicating lower central and peripheral arterial 

function (Kaewboonchoo et al. 2010). In otherwise 

healthy young women with very low blood levels 

(mean not reported, but almost all subjects <1 μg/dL), 

intima-media thickness of the common and carotid 

arteries was increased with blood Pb, while there was 

no association with increases in eight other metals 

tested (Zeller et al. 2010). The associations of blood 

Pb with these tests of cardiovascular functions have 
Cardiovascular

Effects

NTP Monograph on Health Effects of Low-Level Lead 71 Table 6.6: Studies of Pb and clinical cardiovascular disease used to develop conclusions Relevance to Conclusions Study Description Study Design Key Cardiovascular Findings Reference No effect 1,052 adults, >40 years old, Glostrup Population Study, Denmark Prospective After 14 years of follow-up, blood Pb levels dropped, but there was no association with coronary heart disease or cardiovascular disease (fatal and nonfatal cases) in adults with 11.5 μg/dL mean blood Pb at baseline 40 years of age in 1976. Møller (1992) Effect 837 men, NAS, USA Prospective Blood and patella bone Pb were associated with an increased risk of coronary heart disease later in life in these older men with low blood Pb levels (mean, 6.3 μg/dL). Jain (2007) No effect 13,043 Pb workers, SHSP, South Korea Cross-sectional Pb workers showed no increased risk of coronary heart disease or cerebral vascular disease at low levels of exposure (5-10

μg/dL vs. <5

μg/dL).

Kim (2008)

NHANES (≥ 1999)

Effect 9,961 adults, 1999-2002 Cross-sectional Peripheral artery disease prevalence and risk increased with increasing 

quartiles of blood Pb (highest ≥2.47

μg/dL) in these adults from the general 

population.

Muntner (2005)

4,447 adults, > 40 years old, 1999-2002

Cross-sectional Blood Pb was associated with peripheral artery disease in these older adults 

with low levels (mean, 1.95 μg/dL) after adjustment, including renal function.

Guallar (2006)

2,125 adults, > 40 years old, 1999-2000

Cross-sectional These older subjects with peripheral artery disease had higher blood Pb, the 

risk of peripheral artery disease increased with increasing Pb (highest quartile: >2.9

μg/dL).

Navas-Acien (2004)

Effect 420 male bus drivers, 

Bangkok, Thailand

Cross-sectional Aging index of second derivative finger photoplethysmogram waveform

(SDPTG-AI), an assessment of arterial properties, is correlated with blood Pb in male bus drivers (mean, 6.3 μg/dL) and may be an independent cardiovascular 

risk factor.

Kaewboonchoo (2010)

Effect 197 women, ARFYS, 

Austria

Cross-sectional Intima-media thickness of the common and carotid arteries was increased at 

very low levels of Pb (highest tertile = >0.82 μg/dL).

Zeller (2010)

Effect 128 ceramic painters, 

Japan

Cross-sectional Increases in blood Pb were associated with decreases in postural changes in 

finger blood flow volume consistent with an atherosclerotic effect, although most of the subjects had Pb levels >10 μg/dL and other cardiac function tests were not associated.

Ishida (1996)

Effect 130 myocardial infarction patients, 61 controls, Pakistan Case-control Patients admitted for myocardial infarction had higher hair Pb levels, increas- ing for second and third myocardial infarction, and survival of third myocardial infarction decreased with higher hair Pb. Afridi (2010)

Epidemiological studies of Pb exposure and cardiovascular morbidities are listed by study type and decreasing size, grouped together for overlapping or shared study groups.Abbreviations: ARFYFS, Atherosclerosis Risk Factors in Young Females Study NAS, Normative Aging Study (Boston area, began in 1963 by the Veterans Administration); NHANES, National Health and Nutrition Examination Survey; SHSP, Special Health Surveillance Program.
Cardiovascular

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72 NTP Monograph on Health Effects of Low-Level Lead

not been replicated, but they suggest a role for Pb in 

early hallmarks of impaired cardiovascular function 

without a diagnosis of clinical cardiovascular disease.

Summary of Support for Conclusions on 

Clinical Cardiovascular Disease

The EPA’s 2006 AQCD presents a small animal literature supporting an atherogenic effect of chronic Pb 

exposure, as well as impacts on vascular tissue and 

smooth muscle cells (see U.S. EPA 2006 for further 

review of these studies). They reported effects of Pb 

as conducive to thrombosis, hyperlipidemia, arteriosclerosis, and vascular remodeling. The human 

data are consistent with these findings but diverse in 

scope, hampering the ability to form conclusions on 

specific cardiovascular disease endpoints.

The NTP’s conclusion of limited evidence for 

clinical cardiovascular disease is based on a heterogeneous group of related cardiovascular outcomes in 

studies that mostly found significant effects associated with blood Pb <5 μg/dL.

6.3.5 Cardiovascular Mortality

There is limited evidence that blood Pb levels 

<10 μg/dL are associated with increased mortality 

from cardiovascular causes (see Table 6.7 and Cardiovascular Mortality section of Appendix C: Cardiovascular Effects). A association between increased 

cardiovascular mortality and increased blood Pb was 

supported by three prospective studies but was not 

supported by two prospective studies, one of which 

reported a significant association with bone Pb. One 

of the supportive studies had a mean blood Pb level 

above 10 μg/dL (12.64 μg/dL) (Moller and Kristensen 

1992), and one reported mean blood Pb levels of 

2.58 μg/dL (Menke et al. 2006).

Large studies that found associations between 

Pb and BP also indicated an increased risk of mortality from cardiovascular causes. In NHANES III, after 

12 years of follow-up using the National Death Index, 

there was increased mortality associated with baseline blood Pb levels (Menke et al. 2006, Schober et 

al. 2006). In the Normative Aging Study, bone Pb, 

but not blood Pb at mean Pb level of 5.6 μg/dL, was 

associated with BP and cardiovascular mortality 

(Weisskopf et al. 2009). In the Glostrup Population 

Study, there was no association between blood Pb 

and BP, cardiovascular disease, or total mortality after 

14 years of follow-up (Moller and Kristensen 1992). 

While Pb levels were not associated with incidence 

of myocardial infarction, subjects who died of a third 

myocardial infarction had significantly higher hair Pb 

levels (Afridi et al. 2010).

Summary of Support for Conclusions on 

Cardiovascular Mortality

Mortality from cardiovascular causes is not addressed 

in the EPA’s 2006 AQCD summary of the animal data. 

The conclusion of limited evidence for Pb in cardiovascular mortality is based on consideration of the 

three studies (two of which used the same NHANES 

III sample) with a significant effect of blood Pb and 

the two studies that did not find an association with 

blood Pb levels. The NTP’s conclusions for limited evidence for cardiovascular mortality at blood Pb levels 

<10 μg/dL expands upon the conclusion from ATSDR’s 

Toxicological Profile (ATSDR 2007) on increased cerebrovascular mortality.

6.4 Susceptible Populations and Modifiers 

of Pb Exposure

Segments of the population that are more susceptible 

to health effects of Pb are discussed more extensively in Section 3.0 Exposure. It is unknown whether 

chronic exposure and other cardiovascular risk factors 

can modify the relationship between Pb and BP, putting some portions of the population at greater risk of 

cardiovascular disease. These other factors may also 

impair the ability to detect an association of Pb with 

BP in some general population studies, even those 

with higher Pb levels. This concept was proposed by 

Orssaud et al. (1985): “The increase in blood lead concentration parallels the increase in blood pressure until 

some limit value, so that such a trend is apparent only 

when other factors (such as age) do not competitively 

increase blood pressure by greater amounts..

Susceptible Populations: Pb exposure may disproportionately affect populations with preexisting conditions that can be exacerbated by a small increase 

in BP (see Section 7.0 Renal Effects). A prospective 

study of dialysis patients found significantly increased 

cardiovascular mortality over 18 months of follow-up 

for the middle range of Pb levels (second tertile, 8.5-

12.6 μg/dL: HR=3.7 (95% CI: 2.1, 6.5)) and high levels 

of Pb (third tertile, >12.6 μg/dL: HR=9.7 (95% CI: 2.1, 

23.3)) compared to the low Pb range (first tertile, 

<8.5 μg/dL) (Lin et al. 2011).
Cardiovascular

Effects

NTP Monograph on Health Effects of Low-Level Lead 73 Table 6.7: Studies of Pb and cardiovascular mortality used to develop conclusions Relevance to Conclusions Study Description Study Design Key Cardiovascular Findings Reference NHANES III Effect 13,946 adults Prospective Mortality was increased with higher Pb levels for death from all causes, cardiovascular disease, myocardial infarction, and stroke – but not can- cer – for these adults from the general population with low blood Pb levels (geometric mean=2.58 μg/dL) and up to 12 years of follow-up. Menke (2006) 9,757 adults, >40 years old Prospective In this cohort of older NHANES III participants followed for up to 12 years, blood Pb was associated with higher mortality from all causes, cardiovas- cular disease, and cancer, at blood Pb levels of 5-10 μg/dL. Schober (2006) No effect 1,052 adults, 14-year follow-up, Glostrup Population Study, Denmark Prospective In adults with 11.5 μg/dL mean blood Pb at 40 years old, there was no association with all-cause mortality after 14 years of follow-up, while there were reductions in blood Pb levels over this time. Møller (1992) Effect 927 dialysis patients, 18 months of follow-up, Taiwan Prospective In these hemodialysis patients, baseline blood Pb >12.64 μg/dL (median, 16.4 μg/dL) was associated with higher all-cause, cardiovascular cause, and infection cause mortality over 18 months of follow-up. Lin (2011) Effect 860 men in NAS with bone Pb, 1,235 with blood Pb (1994) and follow-up (2007) Prospective Bone Pb >35 μg/g increased the risk of mortality from all causes and from cardiovascular causes, but not cancer mortality. Blood Pb was not associ- ated with mortality (highest >6 μg/dL). Weisskopf (2009) Epidemiological studies of Pb exposure and cardiovascular mortality are listed by decreasing size, grouped together for overlapping or shared study groups. Abbreviations: NAS, Normative Aging Study (Boston area, began in 1963 by the Veterans Administration); NHANES, National Health and Nutrition Examination Survey.
Cardiovascular

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74 NTP Monograph on Health Effects of Low-Level Lead

As discussed in Section 6.3.1 Blood Pressure 

(BP) and Hypertension, pregnant women, menopausal women, and children may be at greater risk of 

Pb related increases in BP (see further discussion in 

Section 3.4 Modifiers of Pb Exposure). The evidence 

for an effect of Pb on BP in children is limited, but 

blood Pb at 2 years of age was also associated with 

ECG abnormalities at 9.5 years of age, particularly in 

subjects with lower socioeconomic status (Gump et 

al. 2005, Gump et al. 2007).

Modifiers: Age is associated with higher BP and 

increased risk of cardiovascular disease, and Pb levels 

are also strongly correlated with age (Den Hond et 

al. 2002). It is unclear if this is an effect of higher Pb 

exposures in earlier eras in this group, or if the elderly 

are more susceptible to cardiovascular effects of Pb 

(see further discussion in Section 3.4 Modifiers of 

Pb Exposure). Many studies adjusted for age in their 

analyses, while others did analyses within specific 

age groups (stratified analyses). One study of subjects over age 75 years of age found no association 

between blood Pb and BP (Nordberg et al. 2000).

Gender and ethnicity are also correlated with Pb 

exposure and cardiovascular risk and are frequently 

adjusted for in analyses. Many general population 

studies found higher blood Pb, higher BP, and more 

hypertension in non-Caucasian groups (Rothenberg 

et al. 1999, Den Hond et al. 2002, Scinicariello et al.

2010). Men generally have higher blood Pb and BP 

than do women (Staessen et al. 1990, Hense et al.

1993, 1994, Chu et al. 1999, Den Hond et al. 2002). 

Many occupational studies only included male subjects, even in those with low occupational Pb exposure (mean Pb levels, <10 μg/dL) (Orssaud et al. 1985, 

Sharp et al. 1990, Schuhmacher et al. 1994, Wolf et 

al. 1995, Sirivarasai et al. 2004, Kaewboonchoo et al.

2007), while only the Nurses’ Health Study focused on 

female workers (Korrick et al. 1999). Numerous other 

studies included gender in their adjustment factors.

Genetic variation is an important biological factor that can characterize a susceptible population 

and modify the relationship between an exposure 

and disease via altered absorption or metabolism. 

Unlike other relevant cofactors such as gender and 

age group, genotype is almost always blinded from 

subjects and investigators and so is less likely to bias 

exposure or ascertainment. In the three studies that 

included genetic variants in evaluation of Pb and 

cardiovascular effects, the genotyped polymorphisms 

were not independent risk factors for increased pulse 

pressure, hypertension, or QT prolongation, but carriers of genetic variants had stronger associations 

between Pb and effects (Park et al. 2009a, Scinicariello et al. 2010, Zhang et al. 2010). These genetic 

modifications of the effect of Pb on cardiovascular 

outcomes have not been sufficiently studied to judge 

their reproducibility. However, if genetic variants can 

modify the impact of Pb exposure, it supports a biological basis for associations between Pb and effects 

beyond what might spuriously arise by unmeasured 

confounding factors.

Dietary factors may also modify the relationship between Pb and BP. People who drank alcohol 

had higher blood Pb and stronger associations 

between Pb and BP (Hense et al. 1994, Menditto 

et al. 1994, Pizent et al. 2001). Among black male 

bus drivers, infrequent caffeine users had a stronger 

positive relationship between blood Pb and BP than 

did habitual users (Sharp et al. 1990). There is some 

indication from the literature that there is an interaction between Pb and calcium intake (Dolenc et al.

1993), with low calcium related with higher blood Pb 

(Pizent et al. 2001) and a higher risk of hypertension 

(Elmarsafawy et al. 2006). However, a 12-week calcium supplement intervention had no effect on blood 

Pb, indicating that any effect of calcium on BP is not 

via interaction with Pb (Morris et al. 1990).

6.5 Conclusions

The NTP concludes that there is sufficient evidence 

for a small, but detectable, increase in BP associated with Pb exposure in groups with mean blood Pb 

levels <10 μg/dL (see Table 6.8 for complete list of 

cardiovascular effects conclusions). There is sufficient 

evidence for an increase in BP and hypertension during pregnancy at levels <10 μg/dL. There is limited 

evidence for increased mortality from cardiovascular 

causes from Pb levels <10 μg/dL. There is limited evidence of an increase in early markers of impaired cardiac function (ECG abnormalities) and cardiovascular 

disease in general. There is inadequate evidence to 

evaluate Pb effects at levels <10 μg/dL on heart rate 

variability, specific cardiovascular morbidities, or any 

cardiovascular effects in children. There is inadequate 

evidence to evaluate Pb effects at levels <10 μg/dL 

on hypertension or other cardiovascular diseases in 

menopausal women.
Cardiovascular

Effects

NTP Monograph on Health Effects of Low-Level Lead 75

Bone Pb reflects chronic Pb exposure and is more 

consistently associated with increased BP, hypertension, 

cardiovascular disease, and mortality. Not all human 

studies conducted at low levels of exposure support 

these associations. The animal data strongly support 

a causative relationship, even at low levels relevant 

to human exposure (e.g., BP increases in rats with 

blood Pb as low as 2.15 μg/dL Tsao et al. 2000). The 

observed heterogeneity across the human literature 

may be partially explained by variation in biologically 

susceptible groups with other Pb-related risk factors for 

cardiovascular disease, such as age, alcohol, caffeine, or 

calcium intake, or genetic polymorphisms in metabolic 

genes. Menopausal women and children may also be 

at increased risk of cardiovascular effects from Pb exposure, but they have been inadequately studied.

Table 6.8: Conclusions on cardiovascular effects of low-level Pb

Health Effect Population Conclusion Blood Pb Evidence Bone Pb 

Evidence

Blood pressure and hypertension Adults Sufficient Yes, <10 μg/dL Yes

Children Inadequate Unclear Yes (one study)

Pregnant women Sufficient Yes, <10 μg/dL Not studied

Menopausal women Inadequate Unclear Not studied

Heart rate variability Adults Inadequate Unclear Yes (one study)

Electrocardiogram abnormalities Men Limited No Yes (one study)

Children Limited Yes, <5 μg/dL (one study) Not studied

Clinical cardiovascular disease 

(general)

Adults Limited Yes, <5 μg/dL Yes (one study)

Clinical cardiovascular disease 

(specific)

Adults Inadequate Unclear Yes (one study)

Cardiovascular mortality Adults Limited Yes, <10 μg/dL Yes (one study)
Cardiovascular

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Effects

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NTP Monograph on Health Effects of Low-Level Lead 77

7.0 RENAL EFFECTS

7.1 Conclusions

The NTP concludes that there is sufficient evidence 

that blood Pb levels <5 μg/dL in adults are associated 

with adverse effects on kidney function adults. With 

few exceptions, epidemiological studies of the general population reported associations between blood 

Pb levels <10 μg/dL and (1) increased risk of chronic 

kidney disease (CKD) and (2) decreased estimated 

glomerular filtration rate (eGFR) and creatinine 

clearance. The associations are typically stronger in 

people with hypertension or diabetes (Muntner et al.

2003, Tsaih et al. 2004). The NTP recognizes that an 

individual with blood levels <10 μg/dL during adulthood may have had higher blood Pb levels earlier 

in life, and the role of early-life Pb exposure cannot 

be discriminated from the role of concurrent blood 

Pb. Comparatively few studies examined markers of 

exposure other than blood Pb levels; therefore, it is 

unknown if blood or bone Pb levels are more consistently associated with kidney effects.

The data are inadequate to evaluate whether 

prenatal exposure to Pb is associated with impaired 

kidney function later in life. No studies were identified that evaluated prenatal blood Pb and kidney 

function in children or adults. Relatively few studies 

have assessed kidney measures in children in association with low-level Pb exposure. The findings from 

these studies are less consistent than are studies in 

adults. Most of these studies also use kidney biomarkers, whose prognostic value for renal function is 

less clear compared to GFR measures and biomarkers, such as microalbuminuria, commonly measured 

in the adult studies. Thus, there is currently inadequate evidence to conclude that blood Pb <10 μg/dL 

is associated with impaired kidney function in children <12 years old. In contrast, there is limited evidence that blood Pb levels <5 μg/dL are associated 

with adverse effects on kidney function in children 

≥12 years old. A recent study of children and young 

adults 12-20 years of age in NHANES 1988-1994 with 

mean blood Pb of 1.5 μg/dL reported a reduction in 

eGFR rate per doubling of blood Pb (Fadrowski et al.

2010). The reduction in GFR demonstrated in Fadrowski et al. (2010) is consistent with results from 

adults within NHANES and supports adverse effects 

on kidney function in children age 12 and over at 

blood Pb <5 μg/dL.

Although the cardiovascular and renal systems 

are intimately linked, effects are considered separately in this evaluation because studies generally 

reported individual effects rather than testing both 

systems comprehensively. Nevertheless, it is recognized that hypertension can contribute to adverse 

renal effects and that kidney dysfunction can contribute to increased blood pressure (BP) and hypertension. Cardiovascular and renal effects of Pb may 

share the same biological mechanisms (U.S. EPA 

2006, ATSDR 2007). As discussed in Section 7.4.2, 

the human literature supports a strong association 

between BP and renal effects of Pb, and multiple 

studies suggest that people with hypertension are 

a susceptible population for adverse renal effects of 

Pb. This interrelationship of effects is also supported 

in animal models; for example, Pb exposure accelerates chronic renal disease by raising BP in male rats 

(Roncal et al. 2007).

7.2 How Conclusions Were Reached

Conclusions in the NTP evaluation of Pb-related 

kidney effects in humans associated with low-level 

Pb are derived from epidemiological studies with a 

focus on blood Pb levels <10 μg/dL. For this evaluation we did not consider studies with mean blood 

Pb >15 μg/dL, because in those studies, the subjects 

with Pb <10 μg/dL are often used as the reference 

group and are not appropriate for evaluating lowlevel Pb effects. This evaluation focuses on the 

human data for kidney effects of Pb because there is 

a relatively large database of human studies for these 

effects; therefore, the document makes only limited 

use of the data from laboratory animals to support 

the human evidence. Major endpoints considered as 

potential indicators of kidney effects of Pb are listed 

and briefly described in Section 7.2.1. This document 

is not a review of kidney toxicity, and the reader is 

directed to published reviews for additional background. Key data and principal studies considered 

in developing the NTP’s conclusions are discussed in 

detail in Section 7.3 Evidence for Pb-related Effects 

on Kidney Function. The discussion of each kidney 

effect begins with a statement of the NTP conclusion 

whether the specific effect is associated with a blood 

Pb level <10 μg/dL or <5 μg/dL and the age group 

in which it is identified (childhood, or adulthood), 

as well as the timing of exposure associated with 

the effect (prenatal, childhood, concurrent) when 
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78 NTP Monograph on Health Effects of Low-Level Lead

available. Although the information necessary to support the NTP’s conclusions is presented in Section 7.3, 

the complete data set of human studies considered 

for evaluation of kidney effects of low-level Pb is 

included in Appendix D: Renal Effects, and individual 

studies are abstracted for further reference. The NTP 

made extensive use of recent government evaluations of health effects of Pb in the current assessment, 

and the relevant conclusions of the EPA’s 2006 AQCD 

for Lead (U.S. EPA 2006) and ATSDR’s Toxicological 

Profile for Lead (ATSDR 2007) are briefly described in 

Section 7.2.2 below.

7.2.1 Principal Measures of Kidney Effects

Table 7.1 lists a number of kidney endpoints commonly evaluated in epidemiological studies. The most 

clinically accepted measure of kidney function is glomerular filtration rate (GFR), which is the flow rate of 

filtered fluid through the kidney. The gold standard 

method of determining GFR is through the use of 

radionuclide or radiocontrast markers, which is both 

costly and time consuming. GFR can be approximated 

by creatinine clearance, which compares creatinine 

levels in blood and urine to calculate the volume of 

blood plasma cleared per milliliter of creatinine per 

unit time. Direct measurement of creatinine clearance 

requires 24-hour urine collection. There are also a 

number of equations for estimating GFR or creatinine 

clearance based on serum biomarkers (e.g., creatinine, cystatin C) and consideration of other variables 

such as age, sex, race, or weight. Historically, serum 

creatinine has been used most often, although serum 

cystatin C is increasingly being used as an alternative 

or complementary approach to serum creatinine for 

estimating GFR.

GFR is notoriously insensitive (Levey et al. 1999), 

and “early biological effect markers” (EBEs), such as 

N-acetyl-β-D-glucosaminidase (NAG), are thought to 

be more sensitive because they areoften elevated 

when GFR measures are not abnormal. However, the 

validity and reliability of EBEs for long-term prognostic value are unclear. The epidemiological studies in 

children more often assess EBEs for kidney rather 

than eGFR or creatinine clearance. It should also be 

noted that the list of biomarkers of EBEs presented 

in Table 7.1 is not comprehensive and reflects those 

most commonly reported in the Pb epidemiological 

studies. Other biomarkers of kidney function continue to be assessed within kidney epidemiology 

research, especially for acute kidney injury, with 

recent attention focusing on urinary proteins such 

as neutrophil gelatinase-associated lipocalin, kidney 

injury molecule-1, and liver-type fatty acid binding 

protein (Devarajan 2010, Tesch 2010).

7.2.2 Principal Conclusions from the 2006 

EPA and 2007 ATSDR Pb Documents

The EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and 

ATSDR’s Toxicological Profile for Lead (ATSDR 2007) 

both concluded that epidemiologic studies support 

a relationship between Pb exposure kidney effects at 

lower blood Pb levels (Table 7.2).

The EPA states that most studies in general adult 

and patient populations published between 1986 

and 2006 indicate that Pb, at much lower doses than 

those causing Pb nephropathy, acts as a cofactor 

with other more established renal risks to increase 

the risk for renal dysfunction. Other explanations, 

such as residual confounding or reverse causality, are 

not likely to account for the observed associations 

between Pb dose and kidney dysfunction. It should 

Table 7.2: Main conclusions for kidney effects 

in 2006 EPA AQCD for Lead and the 2007 ATSDR 

Toxicological Profile for Lead

“General population studies are the most important 

advance in this regard. These studies provide strong 

evidence that renal effects occur at much lower blood 

Pb levels than previously recognized. These effects are 

clinically relevant in U.S. subpopulations who continue 

to have higher Pb exposure than the general population. At levels of exposure in the general U.S. population 

overall, Pb combined with other risk factors, such as diabetes, hypertension, or chronic renal insufficiency from 

non-Pb related causes, can result in clinically relevant 

effects. Notably, the size of such susceptible populations 

is increasing in the US due to obesity...The threshold for 

Pb-related nephrotoxicity cannot be determined based 

on current data. However, associations with clinically 

relevant renal outcomes have been observed in populations with mean blood Pb levels as low as 2.2 μg/dL.”

(U.S. EPA 2006, pg 6-113)

“The overall dose-effect pattern suggests an increasing 

severity of nephrotoxicity associated with increasing PbB 

[blood Pb level], with effects on glomerular filtration evident at PbBs below 20 μg/dL, enzymuria and proteinuria 

becoming evident above 30 μg/dL, and severe deficits in 

function and pathological changes occurring in association 

with PbBs exceeding 50 μg/dL.” (ATSDR 2007, pg 79)
NTP Monograph on Health Effects of Low-Level Lead 79

Effects

Renal

Table 7.1: Commonly used indicators of kidney function in the Pb literature references

Kidney 

Endpoint Measurement Description Indication of Impaired Kidney Function

Clinical Indicators of Impaired Kidney FunctionGlomerular filtration rate (GFR)

Serum creatinine (most common) Breakdown product of creatine phosphate in muscles; commonly used measure of GFR (considered less precise than 

cystatin C); can be influenced by non-kidney function variables that affect muscle mass (gender, age, race, weight, diet)

↑ serum concentration

Serum cystatin C A cysteine protease inhibitor protein used as an alternative to 

serum creatinine or complementary measure to estimate GFR

↑ serum concentration

eGFR (estimated GFR, based on equations) Modification of Diet in Kidney Disease (MDRD) Study: Clinical standard of estimated GFR based on creatinine but underestimates at levels in normal range

CKD-Epidemiology Collaboration (CKD-EPI): More recent way 

to estimate GFR based on creatinine; better accuracy in normal range than MDRD

↓ eGFR

Creatinine clearance (based on timed urine collections)

Cockcroft-Gault: Oldest, estimates creatinine clearance ↓ creatinine clearance

Blood urea nitrogen Measures the amount of nitrogen in blood in the form of urea

(a waste product of protein digestion)

↑ serum concentration

125I-iothalamate, iohexol, and other radioisotopes Radioactive markers used to measure GFR by timed sequential 

blood samples or imaging (invasive and time consuming)

↓ urinary clearance

Indicators of Early Biological Effect Markers (EBEs)Function β2-microblobulin (only validated EBE marker) ↑ urine concentration

Total protein, albumin, low- to intermediatemolecular-weight proteins (e.g., retinol-binding protein (RBP)), Clara cell protein, transferrin)

↑ urine concentration

Biochemical or histological alteration

Biochemical: Urinary eicosanoids, (e.g., prostaglandin E2 (PGE2), prostaglandin F2 alpha, 6-keto-pros- taglandin F1 alpha (6-keto-PGF), and thromboxane B2 (TXB2)), fibronectin Varies/not necessarily known1 (e.g., ↓ urine PGE2, 6-keto- PGF; ↑ TXB2)

Histological: Brush border antigen, fibronectin (glomerular fibrosis)

Cytotoxicity N-acetyl-β-D-glucosaminidase (NAG) Lysosomal enzyme involved in the breakdown of glycoproteins ↑ activityOther

Urate/uric acid Urate is a salt derived from uric acid; can build up in the body 

when uric acid is not adequately metabolized, e.g., in cases of gout

↑ urine concentration

1(Cardenas et al. 1993, Rose and Post 2011).
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80 NTP Monograph on Health Effects of Low-Level Lead

be noted that the EPA is in the process of revising the 

AQCD, and the conclusions of the external draft (U.S. 

EPA 2012) are largely in line with the 2006 AQCD plus 

additional review of the evidence for reduced kidney 

function at low blood Pb.

The NTP considered the conclusions and data 

summaries from the EPA’s 2006 AQCD for Lead (U.S. 

EPA 2006) and ATSDR’s Toxicological Profile for Lead 

(ATSDR 2007). In general, the NTP concurred with the 

conclusions and agreed that the data support them.

7.3 Evidence for Pb-related Effects on 

Kidney Function

7.3.1 Kidney Effects in Adults

There is sufficient evidence available for an association 

between current blood Pb levels <5 μg/dL in adults, 

measured at the time of the study, and reduced kidney function in general populations (Table 7.3, see 

also Appendix A: Neurological Effects). Associations 

between low-level blood Pb and impaired kidney 

function have been reported in studies assessing 

participants in NHANES (Muntner et al. 2003, Muntner et al. 2005, Navas-Acien et al. 2009), the Normative Aging Study (Payton et al. 1994, Kim et al. 1996, 

Tsaih et al. 2004), the Swedish Women’s Health in the 

Lund Area (WHILA) study (Akesson et al. 2005), and 

native and nonnative residents in rural Taiwan (Lai et 

al. 2008). The blood Pb levels associated with kidney 

effects in these studies were ≤10 μg/dL and <5 μg/dL 

in the NHANES and WHILA studies.

There is no apparent threshold for kidney 

effects. Significant increases in risk of CKD based on 

an eGFR <60 mL/min/1.73 m2 have been reported in 

NHANES for blood Pb levels of >1.63 μg/dL (adjusted 

OR=1.89 (95% CI: 1.09, 3.30) (Muntner et al. 2005)) 

and >2.4 μg/dL (adjusted OR=1.56 (95% CI: 1.17, 

2.08) (Navas-Acien et al. 2009)). Similarly, blood 

Pb levels of ≤5 μg/dL in the WHILA study (median, 

2.2 μg/dL; 5th to 95th percentile, 1.1-4.6 μg/dL) 

were significantly associated with reduced eGFR 

(adjusted β=-0.2 (95% CI: -0.32, -0.09) (Akesson et 

al. 2005)). No significant associations with blood Pb 

and either serum creatinine or creatinine clearance 

were observed in a study of 709 men in the Normative Aging Study (β coefficients not reported) (Wu et 

al. 2003); however, this study did report a significant 

association between higher patella Pb and lower 

creatinine clearance. Higher blood Pb levels were 

associated with lower creat­inine clearance in WHILA 

participants (adjusted β=-0.18 (95% CI: -0.3, -0.06)).

The EPA’s 2006 AQCD for Lead (U.S. EPA 2006) considered the clinical significance of these findings. An 

increase in blood Pb reported in Akesson et al. (2005) 

of 3.5 μg/dL from the 5th percentile (1.1 μg/dL) to the 

95th percentile (4.6 μg/dL) had the same effect on 

glomerular filtration as an increase in age of 4.7 years 

or 7 kg/m2 in body mass index (BMI) (U.S. EPA 2006). 

A 10-fold increase from 1 to 10 μg/dL would result 

in a 16.2 mL/min decrease in estimated creatinine 

clearance (U.S. EPA 2006). As discussed below under 

Section 7.4 Susceptible Populations or Life Stages, 

the impacts of Pb on kidney function in people with 

diabetes, hypertension, or CKD from non-Pb related 

causes are expected to be higher (U.S. EPA 2006).

Many of the studies that support an association 

between blood Pb and kidney outcomes included 

statistical adjustments for factors such as age and 

sex, with studies based on the Normative Aging Study, 

NHANES, WHILA, and rural Taiwanese groups including 

additional variables for smoking status and/or alcohol 

consumption. The significant associations remaining 

after adjustment suggest that these factors were not 

sufficient to account for the observed associations 

between blood Pb and kidney outcomes (Payton et al.

1994, Kim et al. 1996, Muntner et al. 2003, Tsaih et al.

2004, Akesson et al. 2005, Muntner et al. 2005, Lai et 

al. 2008, Navas-Acien et al. 2009). Most of these studies also included blood pressure (BP) or hypertension 

status as an adjustment factor, which is expected to 

underestimate the association between Pb exposure 

and kidney effects (i.e., bias towards the null) given 

the positive relationship that exists between Pb and BP 

in the general population (U.S. EPA 2006). The studies 

that were considered equivocal or not supportive of 

an association typically assessed kidney effect by measurement of serum creatinine and did not consider the 

impact of potential or modifying variables at all (de 

Burbure et al. 2003) or to the same extent as the studies cited above that assessed GFR or creatinine clearance (Pocock et al. 1984, Staessen et al. 1990, Mortada 

et al. 2004). An additional limitation to interpretation 

of the nonsupportive findings of de Burbure et al.

(2003) is that the average blood Pb levels between 

the “exposed” and reference groups were quite similar and actually higher in men in the reference group 

than in men considered exposed based on living near 

a smelter for ≥8 years (average blood Pb in referents: 
Effects

Renal

Table 7.3: Studies of kidney outcomes in adults

Relevance 

to 

Conclusions

Study Description Study Design Key Kidney Findings Reference

Normative Aging Study, USAEffect Men 43-90 years old; n=744 Cross-sectional Creatinine clearance (natural log (Ln)) was inversely associated with Ln 

blood Pb (adjusted β (SE) =-0.0403 (0.0198) μg/dL; p=0.0426). Average blood Pb, 8.1 μg/dL (range, <5 to 26 μg/dL).

Payton (1994)

Effect Men 34-88 years old; n=459 Prospective Blood Pb ≤10 μg/dL positively associated with concurrent serum creatinine (β  (SE) = 0.060 (0.019); p=0.002), but not with a change in serum 

creatinine (β  (SE) = 0.039 (0.025); p=0.13).

Kim (1996)

Effect Men average age of 66 years 

followed for 6 years; n=448

Prospective Significant association with change in serum creatinine with baseline 

blood Pb in diabetics (adjusted β (SE) = 0.076 (0.023); p<0.05) but not nondiabetics (adjusted β (SE) = 0.006 (0.005); p=not significant). Average baseline blood Pb, 6.5 μg/dL

Tsaih (2004)

Cadmibel, BelgiumEffect Adults 20-88 years old participating in the Cadmibel study; 

n=1,981

Cross-sectional 10-fold increase in blood Pb associated with reduction in creatinine clearance of 10 mL/min (female) to 13 mL/min (male); adjusted OR (95% CI)

for 10-fold increase in blood Pb and impaired kidney function = 3.76 (1.37, 10.4). Average (range) blood Pb of 11.4 (2.3, 72.5) μg/dL in males and 7.5 (1.7, 60.3) μg/dL in females.

Staessen (1992)

NHANES, USAEffect Adults >20 years old included in 

NHANES 1988-1994; n=15,211 total; 4,813 hypertensives

Cross-sectional Increased risk in hypertensives (but not normotensives) for elevated 

serum creatinine (Q2 (2.5-3.8μg/dL) vs. Q1 (0.7-2.4); adjusted OR (95%CI) =1.47 (1.03, 2.10)) and CKD (Q3 (3.9-5.9 μg/dL) vs. Q1 (0.7-2.4); adjusted OR (95% CI) = 1.85 (1.32, 2.59)).

Munter (2003)

Effect Adults ≥20 years of age included 

in NHANES 1999-2006; n=14,778

Cross-sectional Risk of having a reduced GFR (defined at <60 mL/minute/1.73 m2) was 

higher for blood Pb of >2.4μg/dL vs. ≤1.1μg/dL (adjusted OR=1.56 (95% CI: 1.17, 2.08); ptrend <0.001); significant trend for albuminuria (ptrend ≤0.001).

Navas-Acien (2009)

Effect Adults 18-75 years old from 

NHANES 1999-2002; n=9,961

Cross-sectional Increased risk for CKD (GFR <60 mL/min) associated with blood Pb of 

>1.63

μg/dL (Q3 (1.63-2.47

μg/dL) vs. Q1 (<1.06

μg/dL); adjusted OR 

(95% CI) = 1.89 (1.09, 3.30)).

Muntner (2005)

PatientsEffect CKD Taiwanese patients 25-82 

years old followed for 4 years; n=121

Prospective 1 μg/dL higher blood Pb at baseline associated with a 4.0 mL/min/1.73 

m2 reduction in eGFR over 4 years. Average (range) blood Pb, 4.2 μg/dL (1-13.4 μg/dL).

Yu (2004)

Effect Chronic renal insufficiency 

patients 25-80 years old followed for 2 years; n=202

Prospective Baseline chelatable Pb was significantly associated with risk for achieving an 

increase in serum creatinine to 1.5 times baseline (HR (95% CI) = 1.00 (1.00,1.01)). Average (range) blood Pb at baseline, 5.3(0.6-16.1)

μg/dL; 31 patients 

on chelation therapy during months 24-51 had better GFR outcomes.

Lin (2003)

NTP Monograph on Health Effects of Low-Level Lead 81
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82NTP Monograph on Health Effects of Low-Level Lead

Table 7.3: Studies of kidney outcomes in adults (continued)

Relevance 

to 

Conclusions

Study Description Study Design Key Kidney Findings Reference

Effect CKD patients 30-80 years old followed for 2 years Prospective Baseline chelatable Pb was significantly associated with risk for achieving an increase in serum creatinine to 1.5 times baseline (HR (95%CI) = 1.03 (1.00, 

1.07)). Average (range) blood Pb at baseline, 2.9 (0.8-10.3) μg/dL; 16 patients on chelation therapy during months 24-51 had better GFR outcomes.

Lin (2006a)

Effect Diabetes patients 33-79 years 

old followed for 1 year

Prospective Baseline chelatable Pb was significantly associated with risk for achieving an increase in serum creatinine to 1.5 times baseline (HR (95%

CI) = 1.01 (1.01, 1.02)). Average (range) blood Pb at baseline, 6.5 (1.9-19.1) μg/dL; 15 patients on 3-month chelation therapy during months 13-24 had better GFR outcomes.

Lin (2006b)

OtherEffect Adult women from WHILA study 

in Sweden; n=820

Cross-sectional Inverse association with GFR (β (95% CI) = -0.20 (-0.32, -0.09)) and creatinine clearance (β (95% CI) = -0.18 (-0.30, -0.06)). Mean (5-95% percentiles) 

blood Pb, 2.2 (1.1, 4.6)μg/dL. No association with NAG or α1-microglobulin.

Akesson (2005)

Effect Adult native and nonnative rural 

Taiwanese; n=2565

Cross-sectional Increased risk of serum creatinine >1.2 mg/dL for blood Pb >7.5 versus 

≤ 7.5 μg/dL (adjusted OR=1.92 (95% CI: 1.18, 3.10)).

Lai (2008)

No effect Adults 18-51 years old living 

near two smelters in France; n=300 and 300 age/gendermatched referents

Cross-sectional No difference in any kidney parameters in adults living in reference area 

(average blood Pb: males, 7.1 μg/dL; females, 4.2 μg/dL) and polluted area (average blood Pb: males, 6.8μg/dL; females: 5.3μg/dL) (serum creatinine, total protein, albumin, transferrin, β2-microblobulin, RBP, brush border 

antigen, and NAG).

de Burbure (2003)

Equivocal Men 40-59 years old participating in the Regional Heart Study 

in England; n=7,364

Cross-sectional Blood Pb associated with log-transformed serum urate (β=0.06) and 

serum urea (β=-0.05); no association with serum creatinine. Blood Pb levels ranged from <12.4 to 37.3 μg/dL (authors considered the magnitude of the changes to be small and unlikely to be of biological importance)

Pocock (1984)

Equivocal Adult London civil servants in 

England 37-58 years old; n=531

Cross-sectional In males, significant correlation between serum creatinine and log 

blood Pb (r=0.10, p=0.04). In females, no correlation with serum creatinine and log blood Pb (r=0.03, p=not significant).

Staessen (1990)

No effect Men 25-38 years old in Egypt; 

n=35 smokers, 33 nonsmokers

Cross-sectional No significant correlations were found between Pb and markers of kidney damage in smokers (14.4 μg/dL) or nonsmokers (10.2 μg/dL). Mortada (2004)

Epidemiological studies of blood Pb exposure and kidney function are listed by study are listed by study type and decreasing study size, grouped together for overlapping or shared study groups.Abbreviations: CI, confidence interval; CKD, chronic kidney disease; GFR, glomerular filtration rate; HR, hazard ratio; NAG, N-acetyl-β-D-glucosaminidase; NHANES, National Health and Nutrition Examination Survey; OR, odds ratio; Q1, first quartile; Q2, second quartile; Q3, third quartile; RBP, retinol-binding protein; SE, standard error; WHILA, Women’s Health in the Lund Area.
Effects

Renal

NTP Monograph on Health Effects of Low-Level Lead 83

males, 7.1 μg/dL; females, 4.2 μg/dL; vs. “exposed”: 

males, 6.8 μg/dL; females, 5.3 μg/dL).

Most of the studies summarized in Table 7.3, 

were cited in the EPA’s 2006 AQCD for Lead (U.S. EPA 

2006) and considered in relation to potential reverse 

causality, which would occur if impaired kidney excretion leads to less efficient elimination of Pb, and thus 

higher estimates of internal Pb exposure, resulting in 

a bias towards detecting associations between Pb and 

impaired kidney function. The EPA did not consider 

potential reverse causality to be sufficient to explain 

the associations between Pb and kidney outcomes 

(U.S. EPA 2006). There are three lines of evidence that 

argue against reverse causality as an explanation linking higher blood Pb levels and reduced kidney function: (1) there is no experimental evidence supporting 

reverse causality; (2) there is evidence against reverse 

causality; and (3) there is no evidence that renal 

failure changes blood Pb concentrations. Evidence 

against reverse causality is found in (1) direct bone 

biopsies, (2) EDTA (ethylenediaminetetraacetic acid) 

chelation tests, and (3) blood Pb measurement performed in subjects without renal failure, with renal 

failure of known non-Pb etiology, and with chronic Pb 

nephropathy, indicating that renal failure per se does 

not increase bone Pb stores or blood Pb and does not 

mobilizable Pb (Van de Vyver et al. 1988). The absence 

of excessive Pb retention caused by renal failure is further supported by the finding that EDTA mobilizable 

Pb in patients with Pb-associated renal failure is the 

same as in subjects without renal failure (Emmerson 

1973, Batuman et al. 1983). Additional data against 

reverse causality comes from the longitudinal study 

by Yu et al. (2004) of CKD patients in Taiwan, where 

both baseline blood and EDTA-chelatable Pb levels 

predicted kidney function decline over 4 years. Also, 

two publications from the Normative Aging Study 

report associations between blood Pb and serum 

creatinine across the entire range of serum creatinine 

(Kim et al. 1996, Tsaih et al. 2004), including at levels 

in the normal range where reverse causality would 

not be occurring. Other evidence considered in the 

EPA’s 2006 AQCD for Lead (U.S. EPA 2006), cited as an 

April 12, 2006, personal communication from Agneta 

Ǻkesson to Virginia Weaver, is that higher urine Pb 

was associated with lower estimated creatinine clearance in Swedish women in the WHILA study. Urinary 

excretion of Pb should decrease as kidney function 

declines.

Summary of Support for Conclusions

Data from animal studies provide strong support 

for an association of Pb-associated kidney toxicity, 

including histopathological changes and decreased 

glomerular filtration rate (GFR), with chronic exposure that results in high blood Pb levels (>40μg/dL 

in rats; seeU.S. EPA 2006 for recent reviews of the 

animal data, ATSDR 2007). Rodent studies also support hyperfiltration, or increased GFR as part of an 

early phase of kidney injury (e.g., Khalil-Manesh et 

al. 1992b). Many in vivo and in vitro studies support oxidative stress as the mechanism by which Pb 

contributes to the pathogenesis of kidney disease 

(see U.S. EPA 2006 for further review of animal and 

mechanistic studies). Although animal data support 

a role for oxidative stress and a potential role for 

metallothionein in kidney effects associated with Pb 

exposure, the animal studies are generally at higher 

Pb exposure levels (20-60 μg/dL) than the blood Pb 

levels associated with decreased GFR in humans 

(<10 μg/dL). The human data include multiple studies 

that reported an association between blood Pb levels 

<10 μg/dL and increased risk of CKD, as well as inverse 

associations with GFR and creatinine clearance in 

the general population and even stronger evidence 

in people with hypertension or diabetes. A number 

of studies reported effects at blood Pb levels in the 

2-3 μg/dL range (e.g., Akesson et al. 2005, Muntner et 

al. 2005, Navas-Acien et al. 2009). Collectively, these 

data provide sufficient evidence that blood Pb levels 

<5 μg/dL are associated with adverse effects on kidney function in adults. The NTP recognizes that blood 

levels measured during adulthood in this range do not 

preclude the possibility that an individual might have 

had past exposure to higher blood levels. Although 

several studies of groups with high occupational Pb 

exposure have demonstrated an association between 

elevated bone Pb levels and serum creatinine (e.g., 

Weaver et al. 2003, Weaver et al. 2005, Weaver et al.

2009), few studies of groups with low blood Pb levels 

have included bone Pb or other measures of exposure. Currently, the only data on bone Pb and kidney 

effects in the general population are from Tsaih et al.

(2004) on men followed up in the Normative Aging 

Study for 6 years. In this study, baseline tibia Pb, but 

not patella Pb, was significantly associated in diabetics with baseline serum creatinine, follow-up serum 

creatinine, and changes in serum creatinine. Tibia Pb 

was also associated with a change in serum creatinine 
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84 NTP Monograph on Health Effects of Low-Level Lead

in men with hypertension. No significant associations 

were reported in nondiabetics or normotensives. The 

associations were stronger for tibia Pb than for blood 

Pb, measured either at baseline or follow-up.

7.3.2 Occupational Exposures

Assessment of kidney effects at higher blood Pb, 

such as those experienced in occupational cohorts, is 

beyond the scope of this evaluation but is addressed 

in the EPA’s 2006 AQCD for Lead (U.S. EPA 2006), with 

an expanded discussion in EPA’s current external 

review draft document (U.S. EPA 2012). Historically, 

research in occupational settings where Pb levels 

are higher (≥30 μg/dL) has been less consistent than 

findings from general population studies (U.S. EPA 

2006). For example, several of these studies reported 

inverse associations, including higher Pb dose with 

lower blood urea nitrogen, serum creatinine, and/

or higher creatinine clearance. These seemingly 

paradoxical effects compared to findings at lower Pb 

exposure levels may indicate different mechanisms 

of Pb-mediated kidney toxicity in different subgroups, 

namely, Pb-related hyperfiltration (U.S. EPA 2006), a 

condition where a sustained increase in the kidney 

filtration rate can lead to kidney damage over time. 

However, studies published since the EPA’s 2006 AQCD 

Lead document (U.S. EPA 2006) more consistently 

report worse kidney outcomes in exposed workers 

(Alinovi et al. 2005, Garcon et al. 2007, Lin and TaiYi 2007, Patil et al. 2007, Khan et al. 2008, Sun et al.

2008). These more recent studies in workers at higher 

exposure levels also lessen a previous concern that 

the kidney effects reported in the general populations 

are due to reverse causality, because no effects were 

observed in workers at higher exposure levels.

7.4 Susceptible Populations or Life Stages

7.4.1 Children

There is inadequate evidence available to address 

the potential association between low-level blood 

Pb in children <12 years of age and impaired kidney 

function, but limited evidence that blood Pb levels 

<5 μg/dL are associated with adverse effects on kidney function in children ≥12 years of age. Relatively 

few studies have addressed kidney function or serum 

creatinine in children compared to adults; more often 

early biological effect markers (EBEs) are reported 

(Table 7.4; see also Appendix A: Neurological Effects). 

How well EBEs predict impaired kidney function is 

not well established, even in adults (U.S. EPA 2006). 

However, Fadrowski et al. (2010) analyzed data 

from 769 children and young adults 12-20 years of 

age in NHANES 1988-1994 and reported a reduced 

mean decrease in eGFR (based on cystatin C) of 2.9 

mL/min/1.73 m2 (95% CI: -0.7, -5.0) per doubling 

of blood Pb in the fully adjusted model. When the 

data were analyzed based on categories of Pb exposure, the mean difference in eGFR was significantly 

reduced for the highest group (quartile 4, >2.9 μg/dL) 

compared to the lowest group (quartile 1, <1 μg/dL), 

with a mean decrease in eGFR of 6.6 mL/min/1.73 m2

(95% CI: 0.7, 12.6), and the trend of greater decreases 

with higher Pb levels was significant across exposure 

categories (p-trend=0.009). This cross-sectional study 

presents the strongest indication to date for an association between low-level Pb and impaired kidney 

function in children and is restricted to children ≥12 

years of age. It is unknown from the analysis reported 

in Fadrowski et al. (2010) whether or not the effect is 

driven by the older children in the study (i.e., whether 

decreased eGFR in children ≥17 years of age was 

responsible for the significant decline in the entire 

group from 12 to 20 years of age). The conclusion of 

limited evidence that blood Pb levels <5 μg/dL are 

associated with adverse effects on kidney function in 

children ≥12 years of age is based mainly on the Fadrowski et al. (2010) study, with support provided by 

the consistency of the data with effects observed at 

similar levels in adults. These findings are also consistent with reduced eGFR reported in adults (Muntner 

et al. 2003, Akesson et al. 2005, Muntner et al. 2005, 

Navas-Acien et al. 2009). This conclusion is supported 

by the increased serum levels of cystatin C reported in 

children in Belgium (Staessen et al. 2001), a measure 

that is becoming more widely accepted and used.

The existing literature does not permit a determination on relative sensitivity in children and adults. 

One challenge in interpreting the data for kidney 

effects in children is the potential for renal complications to be asymptomatic and may not become 

detectable until many years after exposure. This 

relatively slow response to Pb is supported by the 

animal data in which male rats exposed to Pb-acetate 

in drinking water did not display decreased GFR until 

6 or 12 months of exposure (e.g., Khalil-Manesh et 

al. 1992a, Khalil-Manesh et al. 1992b, Khalil-Manesh 

et al. 1993). Young children with an age less than the 
Effects

Renal

NTP Monograph on Health Effects of Low-Level Lead 85 Table 7.4: Studies of kidney outcomes in children Relevance to Conclusions Study Description Study Design Key Kidney Findings Reference Effect 769 children and young adults age 12-20 in NHANES 1988-1994 Cross- sectional Reduced GFR associated with blood Pb of >2.9 μg/dL versus <1 μg/dL (β (95% CI) = -6.6 (-0.7, -12.6)) Fadrowski (2010) Effect Children age 17 living near indus- trial areas in Belgium; n=100 Pb exposed and 100 referents Cross- sectional Increased levels of serum cystatin C and β2-microblobulin in children with higher blood Pb (mean, 2.7 μg/dL) compared to referents (mean, 1.5 μg/dL) Staessen (2001) Effect Children 1-6 years old of workers in Pakistani Pb plants; n=123 Pb exposed and 123 referents Cross- sectional Increased levels of serum creatinine and urea in Pb-exposed children compared to controls (median Pb, 8.1 and 6.7

μg/dL, respectively; p≤0.01 for both measures in unadjusted analyses)

Khan (2010)

Equivocal Children 12-15 years old in Czech 

Republic living near two smelters: area 1, n=91; area 2, n=53; reference site, n=51

Crosssectional Increased levels of urinary levels of β2-microblobulin, Clara cell protein, and NAG in children living in area 1 (mean blood Pb: males, 10.9 μg/dL; females, 

9.44 μg/dL) compared to referents (mean blood Pb: males, 8.7 μg/dL; females, 8.39 μg/dL), but not area 2, where blood Pb levels were highest mean blood Pb: males, 14.9 μg/dL; females, 12.9 μg/dL); increased levels of RBP in children living in both smelter areas. Significant correlation between urinary excretion and 

blood Pb in total group (partial r2=0.046, regression coefficient=0.302, p=0.005)

Bernard (1995)

Equivocal Children 10 years old in Poland living near Pb-producing factories; 

n=62 exposed and 50 referents

Crosssectional Altered urinary biomarkers (transferrin, 6-keto-PGF1α, NAG B, β2-microblobulin, Clara cell protein, EGF, PGE2) between 62 exposed (mean blood Pb, 13.3

μg/dL) 

and 50 control (mean blood Pb=3.9 μg/dL) children. No difference in serum creatinine or serum Clara cell protein; no difference in other urine biomarkers (e.g., fibronectin, NAG, α1-microglobulin, RBP, total protein, and albumin laminin)

Fels (1998)

No effect Children 8.5-12.3 years old in 

France living near two smelters; n=200 exposed and 200 matched referents

Crosssectional No difference in any kidney parameters in children living in reference (mean blood Pb: males, 3.4

μg/dL; females, 2.7

μg/dL) and polluted areas (mean 

blood Pb: males, 4.2 μg/dL; females, 3.7 μg/dL) (total protein, albumin, transferrin, β2-microblobulin, RBP, brush border antigen, and NAG)

de Burbure (2003)

No effect because of direction of effect

Children 8.5-12.3 years old in Europe living near two smelters; n=364 exposed and 352 matched referents

Crosssectional Inverse relationship (regression coefficients) with blood Pb and serum creati- nine (-0.026, p=0.007), serum cystatin C (-0.056, p=0.02), and β2-microblobulin 

(-0.095, p=0.01) in children living near smelters (mean Pb: males, 4.2; females, 

3.6 μg/dL) compared to controls (mean Pb: males, 3.4; females, 2.8 μg/dL)

de Burbure (2006)

Abbreviations: CI, confidence interval; EGF, epidermal growth factor; GFR, glomerular filtration rate; NAG, N-acetyl-β-D-glucosaminidase; NHANES, National Health and Nutrition Examination Survey; PGE2, prostaglandin E2; PGF1α, prostaglandin F1α; RBP, retinol-binding protein.
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86 NTP Monograph on Health Effects of Low-Level Lead

latent period of clinically detectable kidney disease 

would not be expected to show Pb-related kidney 

effects. In addition, glomerular hyperfiltration during 

early stages of Pb nephropathy (as has been observed 

in rats after 3 months of exposure (Khalil-Manesh et 

al. 1992b)) would also mask the effect of Pb exposure 

on kidney function in young children (see also discussion of de Burbure et al. 2006 below). The lack of clear 

evidence of adverse effects of blood Pb on children 

<12 years of age does not exclude the potential role 

of Pb exposure on development of Pb-related kidney 

effects later in life.

The studies of serum creatinine and other blood 

or urine biomarkers present less indication of an 

effect of Pb on kidney function in children (Table 

7.4). De Burbure et al. (2006) reported an association between higher blood Pb and lower serum 

creatinine (adjusted regression coefficient=-0.026, 

p=0.007); however, the opposite direction of effect, 

an increase in serum creatinine, would be considered 

to indicate decreased kidney function. Alternatively, 

the de Burbure et al. (2006) finding may be consistent with hyperfiltration. The data in children may be 

inconsistent because of a lack of reliable measures 

in children, differential effects by age (hyperfiltration 

vs. decreased clearance), or other factors. An earlier 

study found no difference in mean serum creatinine 

between 62 exposed (mean blood Pb, 13.3 μg/dL) 

and 50 control (mean blood Pb, 3.9 μg/dL) Polish 

children (Fels et al. 1998). Khan et al. (2010) reported 

a correlation of blood Pb levels with serum creatinine 

(r=0.13; p=0.05) in a study in 1- to 6-year-old children of workers in Pakistani Pb smelters and battery 

recycling plants; blood Pb, serum creatinine, and 

urea were higher in the children of workers (n=123 

exposed) compared to controls (n=123; medians=8.1 

and 6.7 μg/dL; 56 and 52 μmol/L; and 4.5 and 4.3 

mmol/L, respectively; p≤ 0.01 for all in unadjusted 

analyses). Two studies assessed associations between 

blood Pb and serum cystatin C and reported opposite findings (Staessen et al. 2001, de Burbure et al.

2006). Staessen et al. (2001) measured higher levels 

of serum cystatin C in 17-year-old Belgian children 

living in a chemical industrial region (mean blood Pb, 

2.7 μg/dL) compared to the reference group (mean 

blood Pb, 1.5 μg/dL). de Burbure et al. (2006) found 

an inverse association with blood Pb in 300-600 European children 8.5-12.3 years of age (adjusted regression coefficient=-0.056, p=0.02). The same pattern of 

opposite direction was observed for β2-microblobulin 

in these two studies. Findings on urine biomarkers are 

also inconsistent and difficult to interpret (Bernard 

et al. 1995, Fels et al. 1998, de Burbure et al. 2003)

(Table 7.4). For example, Bernard et al. (1995) found 

higher urinary levels of β2-microblobulin, Clara cell 

protein, and N-acetyl-β-D-glucosaminidase (NAG) in 

children living in one “polluted” region compared to 

children living the reference area, but not in another 

“polluted” region where average blood Pb levels 

were the highest. The levels of blood Pb in the comparison groups are another factor to consider when 

interpreting the studies in children. No differences in 

kidney parameters were observed in de Burbure et 

al. (2003) (Table 7.4). Although the average blood Pb 

levels between the “exposed” and reference groups 

were quite similar in this study (mean blood Pb in 200 

referents: males, 3.4 μg/dL; females, 2.7 μg/dL; vs. 

200 children considered exposed: males, 4.2 μg/dL; 

females, 3.7 μg/dL), no associations were observed 

when stepwise multiple regression analysis was conducted on the whole group of children as well.

Several studies have assessed the impact of 

higher Pb exposures during childhood on kidney 

measures, but these studies do not necessarily provide additional clarity (Inglis et al. 1978, Moel and 

Sachs 1992, Verberk et al. 1996, Coria et al. 2009). 

No nephrotoxicity was reported in a group of 77 

individuals in rural Chile who were assessed 10 years 

after being exposed to Pb-contaminated flour as children in 1996 and subsequently treated with EDTA (Pb 

levels measured in 1996 ranged from 37 to 87 μg/

dL) (Coria et al. 2009). Similarly, Moel et al. (1992) 

did not detect any significant differences between 

previously Pb-poisoned children and their siblings 

for serum creatinine, uric acid, and β2-microblobulin, 

fractional excretion of β2-microblobulin, urinary 

protein:creatinine ratio, and tubular reabsorption 

of phosphate. The study compared 62 patients at a 

Chicago Pb clinic, who were diagnosed and received 

chelation treatment between 1966 and 1972 for initial blood Pb levels >100 μg/dL, to 19 age-matched 

siblings whose initial blood Pb levels were <40 μg/dL. 

Kidney pathology was documented in certain adult 

survivors of untreated childhood Pb poisoning in 

Queensland before its removal from paint (Inglis et al.

1978). It is unclear whether differences in outcomes 

between those studies can be attributed to use of 

EDTA in Coria et al. (2009) and Moel et al. (1992); 
Effects

Renal

NTP Monograph on Health Effects of Low-Level Lead 87

an elevated risk of low IQ was reported in that study. 

An impact on IQ but not on the kidney in that study 

may also suggest the kidney is less susceptible than 

the neurological system. Hu et al. (1991) reported 

elevated creatinine clearance rates in 21 survivors 

of childhood poisoning in Boston from 1930 to 1942 

compared to controls matched for age, sex, race, and 

neighborhood (1.88 versus 1.48 mL/s per 1.73 m2). 

There were no differences in serum creatinine levels 

between subjects and controls. The creatinine clearance finding is opposite results reported in adults 

in the general population discussed above but is 

consistent with the suggestion that Pb may induce 

kidney hyperfiltration in certain subpopulations. 

Verberk et al. (1996) looked at a number of kidney 

biomarkers in 151 children 3-6 years of age living near 

a Pb smelter in Baia Mare, Romania. The average Pb 

levels in the subgroups (based on proximity to the 

smelter) ranged from 34.2 to 43.8 μg/dL (Verberk et 

al. 1996). An increase in NAG per 100 μg/dL blood Pb 

was reported, but there were no associations with 

albumin, α1-microglobulin, retinol-binding protein, or 

alanine aminopeptidase.

7.4.2 Hypertensives, Diabetics, and Kidney 

Disease Patients

The impacts of Pb on kidney function in susceptible 

populations, such as people with diabetes, hypertensions, or CKD, are expected to be higher (U.S. EPA 

2006). This pattern is apparent in several studies that 

conducted subgroup analyses of NHANES data and the 

Normative Aging Study and found that associations 

were stronger in NHANES participants with hypertension (Muntner et al. 2003) or men in the Normative 

Aging Study with diabetes (Tsaih et al. 2004).

Follow-up studies in people with renal disease 

or type II diabetes also indicate worse disease progression (kidney function decline) in association with 

higher baseline blood Pb levels (Lin et al. 2003, Yu 

et al. 2004, Lin et al. 2006a, Lin et al. 2006b, U.S. 

EPA 2006, Weaver and Jaar 2010, U.S. EPA 2012). 

Although most of the patient studies are relatively 

small in size (ranging from 87 to 202 subjects), they 

are longitudinal in design, with follow-up ranging 

from 1.1 to 3.87 years. They provide additional support for kidney effects at low-levels of blood Pb and 

also support the conclusion that reverse causality is 

not likely to account for the effects of Pb on kidney 

function at low levels. In the study with the longest 

period of follow-up, 4 years, a 1 μg/dl higher blood Pb 

at baseline in patients with chronic renal insufficiency 

was associated with a 4.0 mL/min/1.73 m2 reduction 

in eGFR (Yu et al. 2004). The average blood Pb level in 

the sample of 121 patients was 4.2 μg/dL. In order to 

be eligible, patients were required to have baseline 

EDTA-chelatable Pb below a level thought to indicate 

risk for Pb-related kidney toxicity. Across these studies, the decline in eGFR per 1 SD increase in Pb dose 

at baseline per year ranged from 0.16 (Lin et al. 2003) 

to 3.87 4.0 mL/min/1.73 m2 (Lin et al. 2006b). The 

magnitude of decline in eGFR in the study with the 

lowest baseline blood Pb (2.9 μg/dL) was 1.1 per 1 

SD increase in Pb dose at baseline per year (Lin et 

al. 2006b). A collection of Taiwanese patient studies 

included intervention arms with chelation therapy 

(Lin et al. 2003, Lin et al. 2006a, Lin et al. 2006b, Lin 

and Tai-Yi 2007); these studies show less kidney function decline in patients undergoing chelation therapy 

compared to those receiving the placebo. However, 

interpreting these studies is complex because of difficulty in separating outcomes that may be due to a 

direct beneficial effect of the chelating agent, such as 

via anti-oxidation, from outcomes due to Pb removal. 

In addition, they involve small number of patients, 

and the findings should be repeated in larger populations in multiple centers.

Thus, Pb-associated reduced kidney function in 

healthy individuals may not necessarily result in CKD, 

although Pb may be a risk factor for CKD in susceptible patient populations (e.g., people with kidney 

disease, diabetes, or obesity), in older populations, or 

when combined with exposure to other compounds 

known to cause kidney damage (e.g., cadmium, mercury, arsenic, zinc) (U.S. EPA 2006).

7.5 Conclusions

The NTP concludes that there is sufficient evidence 

that blood Pb levels <5 μg/dL are associated with 

adverse effects on kidney function in adults (see Table 

7.5 for complete list of kidney effects conclusions). 

With few exceptions, epidemiological studies of the 

general population reported associations between 

blood Pb levels <10 μg/dL and (1) increased risk of 

CKD and (2) decreased kidney function as measured 

by GFR and creatinine clearance. The NTP recognizes 

that blood levels in this range measured during adulthood do not preclude the possibility that an individual might have had past exposure to higher blood 
Renal

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88 NTP Monograph on Health Effects of Low-Level Lead

levels. As with other studies of health effects of Pb in 

adults, prospective studies in a group for which blood 

Pb levels remained consistently below 10 μg/dL from 

birth until measurement would eliminate the potential role of early-life blood Pb levels above 10 μg/dL 

on health effects observed in adults with concurrent 

blood Pb levels <10 μg/dL. The associations are typically stronger in people with hypertension or diabetes (Muntner et al. 2003, Tsaih et al. 2004). The NTP 

also concludes that there is limited evidence that 

blood Pb levels <5 μg/dL are associated with adverse 

effects on kidney function in children ≥12 years of age 

based on the recent cross-sectional data from the 

NHANES data set published by Fadrowski et al. (2010) 

and the consistency of effects with observations in 

adults. There is inadequate evidence that blood Pb 

levels <10 μg/dL are associated with kidney function 

in children <12 years of age because of inconsistent 

results and studies lacking clear predictive measures 

of kidney function in children. The lack of consistent 

predictive measures of kidney function in children 

makes studying the effects of Pb on this life stage 

difficult. The NTP’s conclusions of sufficient evidence 

that blood Pb levels <5 μg/dL are associated with 

adverse effects on kidney function in adults and limited evidence in children ≥12 years of age, extend the 

conclusions of the 2007 ATSDR Toxicological Profile 

for Lead (ATSDR 2007) and 2006 EPA AQCD for Lead 

(U.S. EPA 2006) from adults to children age 12 and 

older based on recent data.

Table 7.5: NTP conclusions on kidney effects of low-level Pb

Health Effect Population NTP 

Conclusions

Blood Pb 

Evidence

Bone Pb 

Evidence

Increased chronic kidney disease 

(CKD) and decreased glomerular 

filtration rate (GFR)

Adults Sufficient Yes, <5 μg/dL Not studied

Children ≥12 years old Limited Yes, <5 μg/dL Not studied

Children <12 years old Inadequate Unclear Not studied
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 89

8.0 REPRODUCTIVE/

DEVELOPMENTAL EFFECTS

8.1 Conclusions

The NTP concludes there is sufficient evidence 

that blood Pb levels <10 μg/dL are associated with 

adverse health effects on development in children 

and that blood Pb levels <5 μg/dL are associated 

with adverse health effects on reproduction in adult 

women.

Because the database of human studies on most 

reproductive endpoints is limited to occupational 

exposure studies, many of the available studies are 

for blood Pb levels >10 μg/dL. Given this fact and the 

focus of the original nomination on reproductive and 

developmental effects, higher blood Pb levels were 

included in the evaluation of these health effects, 

unlike other sections of this document. Consideration of blood Pb levels >10 μg/dL resulted in several 

conclusions for Pb-related reproductive effects in 

men but did not affect the conclusions for women 

or children.

Unlike the data set for most other health effects, 

a number of prospective studies of developmental 

effects include prenatal measures of exposure (either 

maternal blood or umbilical cord blood). Maternal 

blood Pb <10 μg/dL is associated with decreased 

head circumference in children through 4 years of 

age, providing evidence that prenatal exposure is 

associated with reduced postnatal growth in children. Conclusions on effects of prenatal exposure for 

outcomes evaluated as children are complicated by 

the high degree of correlation in childhood blood Pb 

levels over time, and as described below, concurrent 

blood Pb levels <10 μg/dL in children are also associated with reduced postnatal growth.

Children

In children, there is sufficient evidence that blood Pb 

levels <10 μg/dL are associated with delayed puberty 

in both boys and girls. Nine studies with mean blood 

Pb levels <10 μg/dL support the relationship between 

Pb and delayed puberty (see Table 8.3); although 

several studies report effects on puberty at blood Pb 

levels <5 μg/dL, there is also evidence indicating no 

effect of blood Pb <5 μg/dL. Therefore, there is limited evidence that delayed puberty is associated with 

blood Pb levels <5 μg/dL. There is sufficient evidence 

that decreased postnatal growth is associated with 

blood Pb levels <10 μg/dL in children. Epidemiological studies consistently report an inverse relationship 

between blood Pb levels <10 μg/dL and postnatal 

growth (see Table 8.4). Developmental effects on neurological, immunological, renal, and cardiovascular 

systems are not covered in this section because they 

are reviewed in individual chapters.

Women

In adult women, there is sufficient evidence that 

maternal blood Pb levels <5 μg/dL are associated with 

reduced fetal growth or lower birth weight. The association between maternal Pb exposure and reduced fetal 

growth is supported by several prospective studies with 

maternal blood Pb data during pregnancy, a large retrospective cohort of over 43,000 mother-infant pairs that 

reports a mean maternal blood Pb level of 2.1 μg/dL, 

and a number of cross-sectional studies with maternal 

or umbilical cord blood Pb at delivery. Although maternal or paternal bone Pb data are not available in studies 

of most reproductive health outcomes, a set of studies 

from a single group reported that maternal bone Pb is 

associated with lower birth weight, birth length, and 

head circumference. There is limited evidence that 

maternal blood Pb levels <10μg/dL are associated with 

spontaneous abortion and preterm birth or reduced 

gestational age. Although a number of prospective 

studies with maternal blood Pb levels during pregnancy 

and cross-sectional studies with umbilical cord blood 

Pb levels at delivery reported an association between 

prenatal blood Pb levels <10 μg/dL and preterm birth, 

the conclusion of limited evidence is based on the 

inconsistent results and because a retrospective study 

with a large cohort of over 43,000 mother-infant pairs 

did not find an association between maternal blood 

Pb levels and preterm birth. The conclusion of limited 

evidence for an association with spontaneous abortion 

in women is based principally on the Borja-Aburto et al.

(1999) study, which has the strength of its prospective 

nested case-control design, with additional support 

provided by occupational studies that reported an 

association with Pb exposure but lack blood Pb measurements. There is inadequate evidence for other 

reproductive and effects of Pb associated with blood 

Pb levels <10 μg/dL in women.

Men

In adult men, there is inadequate evidence that 

blood Pb levels <10 μg/dL are associated with 
Reproductive 

Effects

90 NTP Monograph on Health Effects of Low-Level Lead

effects on reproduction. There is sufficient evidence 

that blood Pb levels ≥15 μg/dL are associated with 

adverse effects on sperm or semen in men, and 

inadequate evidence for adverse effects on sperm 

at lower blood Pb levels. Decreased sperm count, 

density, and/or concentration has been reported 

in multiple retrospective and cross-sectional occupational studies of men with mean blood Pb levels 

from 15-68 μg/dL (see Table 8.5). There is sufficient 

evidence that paternal blood Pb levels ≥20 μg/dL are 

associated with delayed conception time and limited 

evidence that blood Pb levels ≥10 μg/dL in men are 

associated with other measures of reduced fertility. 

Four studies reported increased time to pregnancy 

in women whose male partners had blood Pb levels 

of 20-40 μg/dL. A single retrospective occupational 

study reported increased risk of infertility among 

men with blood Pb levels ≥10 μg/dL, and the continuity of these data with effects on time to pregnancy 

supports a conclusion of limited evidence that blood 

Pb levels ≥10 μg/dL in men are associated with other 

measures of reduced fertility. There is limited evidence that paternal blood Pb >31 μg/dL is associated 

with spontaneous abortion. The conclusion of limited 

evidence that spontaneous abortion is associated 

with paternal exposure is based mainly on the retrospective nested case-control study by Lindbohm et 

al. (1991a) in men, with additional support provided 

by occupational studies that reported an association 

with Pb exposure but lack blood Pb measurements.

8.2 How Conclusions Were Reached

Conclusions in the NTP’s evaluation of Pb-related 

reproductive and developmental effects in humans 

associated with low-level Pb are derived by evaluating the data from epidemiological studies with a 

focus on blood Pb levels <10 μg/dL. Because the 

database of human studies on most reproductive 

endpoints is limited to occupational exposure studies, many of the available studies are for blood Pb 

levels >10 μg/dL. Unlike other sections of this document, reproductive effects of these higher blood Pb 

levels were included in the evaluation because the 

data set of human studies on potential reproductive 

effects associated with lower blood Pb levels is limited. Major endpoints considered as potential indicators of effects of Pb on reproduction and development are listed and briefly described in Section 8.2.1. 

This document is not a review of the reproductive 

system or reproductive and developmental toxicity, 

and the reader is directed to published reviews for 

additional background. Key data and principal studies considered in developing the NTP conclusions are 

discussed in detail in Section 8.3 Evidence for Pbrelated Effects on Reproductive and Developmental 

Outcomes. The discussion of each effect begins with 

a statement of the NTP’s conclusion that the specific 

effect is associated with a blood Pb level <10 μg/dL 

or <5 μg/dL and the age group in which it is identified 

(childhood or adulthood), as well as the timing of 

exposure associated with the effect (prenatal, childhood, concurrent) when available. The discussion 

also highlights the extent to which experimental 

animal data support the association between Pb 

exposure and reproductive effects. Although the 

information necessary to support the NTP conclusions is presented in Section 8.3, the complete data 

set of human studies considered for evaluation of 

reproductive and developmental effects with lowlevel Pb is included in Appendix E: Reproductive 

and Developmental Effects, and individual studies 

are abstracted for further reference. The NTP made 

extensive use of recent government evaluations of 

health effects of Pb in the current assessment, and 

the relevant conclusions of the EPA’s 2006 AQCD for 

Lead (U.S. EPA 2006) and ATSDR’s 2007 Toxicological 

Profile for Lead (ATSDR 2007) are briefly described in 

Section 8.2.2 below.

8.2.1 Principal Measures of Reproductive 

and Developmental Effects

Table 8.1 lists a number of key reproductive and 

developmental endpoints commonly evaluated in 

epidemiological studies. The data available to evaluate each of the major effects are discussed in separate subheadings under Section 8.3 Evidence for Pbrelated Effects on Reproductive and Developmental 

Outcomes below.

8.2.2 Principal Conclusions from 2006 EPA 

and 2007 ATSDR Pb Documents

The EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and 

ATSDR’s 2007 Toxicological Profile for Lead (ATSDR 

2007) both concluded that there is evidence for 

reproductive effects in males at high blood Pb levels 

(30-40 μg/dL in ATSDR, 2007 and 45 μg/dL in U.S. EPA, 

2006) and suggest that more research is needed to 

determine if effects occur at lower blood Pb levels 
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 91

(see Table 8.2 for principal conclusions and original 

documents for complete conclusions). Although the 

2006 EPA AQCD for Lead (U.S. EPA 2006) cited the 

Borja-Aburto et al. study (1999) as a well-conducted 

prospective case-control study supporting a significant relationship between maternal blood Pb level 

at 10 μg/dL to 12 μg/dL and spontaneous abortion, 

the EPA concluded that, collectively, there is little evidence to support an association between maternal or 

paternal Pb exposure and incidence of spontaneous 

abortion. The 2006 EPA AQCD for Lead (U.S. EPA 2006) 

concluded that the data are inadequate to evaluate 

reproductive effects in females, and studies of developmental effects suggest at most a small association 

between Pb exposure and preterm birth, congenital 

abnormalities, birth weight, or fetal growth. The EPA 

is in the process of revising the AQCD, and the conclusions of the external draft (U.S. EPA 2012) are largely 

in line with the 2006 AQCD for Lead (U.S. EPA 2006), 

plus additional review of the evidence for delayed 

pubertal onset.

The NTP considered the conclusions and data 

summaries from the EPA’s 2006 AQCD for Lead (U.S. 

EPA 2006) and ATSDR’s 2007 Toxicological Profile for 

Lead (ATSDR 2007). In general, the NTP concurred 

with the conclusions and agreed that the data support them. Differences from the ATSDR and EPA 

documents are identified for specific endpoints in 

this document.

8.3 Evidence for Pb-Related Effects on 

Reproductive and Developmental 

Outcomes

8.3.1 Delayed Puberty

There is sufficient evidence that blood Pb levels 

<10 μg/dL are associated with a delay in sexual maturation or puberty onset in children 8-17 years of age 

(see Table 8.3 and the Puberty section of Appendix E: 

Reproductive and Developmental Effects). An inverse 

association between blood Pb level and markers of 

sexual maturation has been reported in eight crosssectional studies and a single prospective study involving children with blood Pb levels from 10 to <1 μg/dL 

from seven different populations in North America, 

Europe, and Africa. Pb-related developmental delay 

in a several biological markers of puberty (e.g., age 

Table 8.1: Major reproductive/developmental effects considered

Effect Description

Delayed puberty Delay in measures of puberty (e.g., Tanner staging of genitalia, pubic hair, and breast development)

Postnatal growth Slower growth (as indicated by height, head circumference, etc., for age)

Sperm parameters Numerous sperm or semen measures (sperm count, motility, morphology, etc.)

Conception Greater time to pregnancy or lower fecundity

Pregnancy loss Spontaneous abortion (fetal loss <20 weeks gestation), stillbirth (fetal loss ≥20 weeks)

Gestation length Shorter length of gestation (as a continuous measure), preterm birth (<37 weeks)

Fetal growth Lower birth weight, often adjusted for gestational age

Birth defects Congenital malformations

Table 8.2: Main conclusions for reproductive/

developmental effects in the 2006 EPA AQCD for 

Lead and the 2007 ATSDR Toxicological Profile 

for Lead

“The epidemiologic evidence suggests small associations 

between exposure to Pb and male reproductive outcomes, including perturbed semen quality and increased 

time to pregnancy. These associations appear at blood Pb 

levels >45 μg/dL, as most studies have only considered 

exposure in the occupational setting. There are no adequate data to evaluate associations between Pb exposure 

and female fertility.” (U.S. EPA 2006, pg 6-271)

“Studies of children also have shown associations 

between PbB [blood Pb level] and growth, delayed 

sexual maturation in girls, and decreased erythropoietin 

production. Some studies of humans occupationally or 

environmentally exposed to Pb have observed associations between PbB and abortion and preterm delivery 

in women and alterations in sperm and decreased fertility in men. On the other hand, there are several studies that found no significant association between Pb 

exposure and these end points. At least for the effects in 

males, the threshold PbB appears to be in the range of 

30-40 μg/dL.” (ATSDR 2007, pg 23)
Reproductive 

Effects

92NTP Monograph on Health Effects of Low-Level Lead

Table 8.3: Studies of biomarkers of puberty associated with low-level Pb exposure used to develop conclusions

Relevance 

to 

Conclusions

Study 

Description

Study 

Design Key Reproductive/Developmental Findings Reference

Chapaevsk, Russia

Effect Boys 11-12; n=481 Prospective Delayed puberty onset in boys with blood Pb ≥5 μg/dL. Puberty measures differed 

by testicular volume and Tanner genital and pubic hair staging.

Williams (2010) (same population as Hauser)

Boys 8-9; n=489 Crosssectional Delayed puberty onset in boys with blood Pb ≥5 μg/dL. Puberty determined by Tan- ner genital staging and testicular volume; effects not significant for pubic hair staging. Hauser (2008)

NHANES III

Effect Girls 8-16 years of 

age; n=1,235

Crosssectional Delayed puberty onset in girls with blood Pb ≥2 μg/dL compared to those with blood Pb <2 μg/dL. Puberty differed by Tanner pubic hair developmental stage and 

age at menarche; no effect on developmental stage of breasts.

Wu (2003)(population overlap with Gollenberg, Selevan)

Girls 8-11 years old; n=705

Crosssectional Girls with higher blood Pb (blood Pb ≥5 μg/dL compared with those <1 μg/dL) had lower likelihood of having inhibin B levels >35 pg/mL, a level the authors report to 

be associated with puberty and development of pubic hair and breasts.

Gollenberg (2010)

Girls 8-16 years old; n=600-805 per race/ethnicity

Crosssectional Delayed puberty onset in African American girls (age at menarche, Tanner breast and pubic hair developmental stage) and Mexican American girls (breast and pubic 

hair stage) at blood Pb >3 μg/dL compared to blood Pb <1 μg/dL; not in non-Hispanic whites.

Selevan (2003)

Effect Girls 13 years old in 

South Africa; n=682-712, by endpoint

Crosssectional Delayed puberty onset (determined by Tanner pubic hair and breast developmen- tal stage and age at menarche) in girls with blood Pb ≥5 μg/dL, and significant 

association with blood Pb by trend analysis across for stage or age at menarche.

Naicker (2010)

Effect Children aged 17 in 

Belgium; n=100 Pb and 100 referent

Crosssectional Testicular volume was lower in boys living in areas with higher blood Pb (1.8- 2.7 μg/dL) compared to referents (1.5 μg/dL). Genital and breast stage did not 

differ consistently and significantly between referent and exposed; comparison by blood Pb not reported.

Staessen (2001)

Effect Girls aged 10-17 in 

Akwesasne Mohawk Nation; n=138

Crosssectional Delayed puberty onset (age at menarche) in girls with blood Pb above mean (≥0.49 μg/dL) and a predicted delay in age at menarche of 10 months with blood 

Pb above median (1.2 μg/dL).

Denham (2005)

No effect Girls 9 years old in 

New York; n=139

Crosssectional Blood Pb had no effect on puberty onset in girls (by breast and pubic hair stage) with median blood Pb level of 2 μg/dL. Wolff (2008)

Effect Children 10-13 years 

old in Egypt; n=41

Crosssectional Delayed puberty onset in boys and girls with blood Pb ≥10 μg/dL. Puberty mea- sures differed for testes size, Tanner pubic hair and penile stage in boys, and Tanner developmental stage of breasts in girls, but not pubic hair in girls. Tomoum (2010)

Epidemiological studies of Pb exposure and puberty are listed by decreasing cohort size and grouped together for overlapping or shared study groups.

Abbreviations: NHANES: National Health and Nutrition Examination Survey.
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 93

at menarche and Tanner developmental staging of 

breasts) have been reported in cross-sectional studies of girls, although there is no single measure that 

is consistently associated with blood Pb levels in all 

analyses. For boys, a Pb-related decrease in testicular 

volume was observed in all four publications, suggesting that testicular volume may be a reliable indicator 

of the effects of Pb on puberty in boys. The reported 

delay in sexual maturation with increasing blood Pb 

was significant across multiple studies, in various 

endpoints, and from different groups in analyses that 

adjusted for factors known to effect puberty such as 

race, BMI, and socioeconomic status. A conclusion of 

limited evidence that delayed puberty is associated 

with blood Pb levels <5 μg/dL is based on the four 

studies (three in girls and one in boys) that report 

delay in markers of puberty associated with blood Pb 

levels <5 μg/dL and the lack of association with blood 

Pb among girls in the Wolff et al. (2008) study with a 

median blood Pb level of 2 μg/dL.

Three cross-sectional studies using the NHANES 

III data set reported delayed puberty onset in girls. 

Wu et al. (2003) reported delayed Tanner pubic hair 

stage and age at menarche in girls 8-16 years of age 

with blood Pb levels ≥2 μg/dL, with no effect on 

developmental stage of breasts. In a separate analysis divided by race and ethnicity, Selevan et al. (2003) 

reported an association between blood Pb >3 μg/dL 

and delayed puberty onset in African American and 

Mexican American girls as determined by Tanner 

pubic hair and breast stages. Age at menarche was 

also delayed at blood Pb levels >3 μg/dL in African 

American girls; however, there was no Pb-related 

effect on puberty in non-Hispanic whites. Gollenberg 

et al. (2010) reported that girls with blood Pb levels 

≥5 μg/dL were less likely to have levels of inhibin 

B of >35 pg/mL, a level that the authors suggest is 

associated with pubic hair and breast development. 

A similar delay in puberty onset indicated by age at 

menarche was reported in 13-year-old girls in South 

Africa (Naicker et al. 2010) and 10- to 17-year-old 

girls from the Mohawk Nation (Denham et al. 2005). 

Naicker et al. (2010) also found an association with 

blood Pb ≥5 μg/dL and delays pubic hair and breast 

development stage. In contrast, Tomoum et al. (2010) 

reported decreased Tanner breast developmental 

stage and no effect on pubic hair in girls 10-13 years 

of age with blood Pb>10 μg/dL in Egypt. Staessen et 

al. (2001) reported significant (p=0.04) differences in 

breast development in 17-year-old girls among three 

groups: two study groups with blood Pb levels of 1.8 

and 2.7 μg/dL and a reference group with blood Pb 

of 1.5 μg/dL. However, a direct comparison of breast 

stage by blood Pb levels was not reported, and the 

delay in breast stage was significant only when 

comparing the study group with mean blood Pb of 

1.8 μg/dL to the reference group. One of the eight 

studies reporting data on girls did not detect a delay 

in any marker of puberty onset associated with blood 

Pb; mean blood Pb was 2 μg/dL in the 9-year-old girls 

from New York in that study (Wolff et al. 2008).

All four of the studies addressing boys report 

Pb-associated decreases in testicular volume or Tanner genital or pubic hair staging (Staessen et al. 2001, 

Hauser et al. 2008, Tomoum et al. 2010, Williams et 

al. 2010). In a paired cross-sectional and follow-up 

prospective study, blood Pb ≥5 μg/dL was associated 

with delayed puberty that was significant by Tanner 

genital staging (p<0.05) and reduced testicular volume (p≤0.05) in Russian boys when they were 8-9 

years of age and again at 11-12 years of age (Hauser 

et al. 2008, Williams et al. 2010). Testicular volume 

was significantly lower in 17-year-old boys living in 

areas with higher blood levels (1.8-2.7 μg/dL) compared to a reference group (1.5 μg/dL), although the 

authors do not include a direct comparison of testicular volume by blood Pb levels (Staessen et al. 2001). 

Blood Pb ≥10 μg/dL was associated with decreased 

testes size and developmental delay in Tanner pubic 

hair and penile stages in 10- to 13-year-old boys in 

Egypt (Tomoum et al. 2010).

Summary of Support for Conclusions

Animal data supports a Pb-associated developmental 

delay in sexual maturation, indicated by biomarkers of 

puberty such as reduced prostate weight and delay in 

vaginal opening, at high blood Pb levels in some studies 

(i.e., 40 to >300 μg/dL) in Fisher and Sprague Dawley 

rats and at blood Pb levels similar to the human studies (i.e., 3-13 μg/dL) in Swiss mice (see U.S. EPA 2006 

for recent reviews of the animal data, ATSDR 2007). 

The mouse data from Iavicoli et al. (2004) are interesting because the exposure that resulted in blood Pb 

from 3 to 13 μg/dL is associated with delayed puberty 

in female mice similar to the human data, whereas 

blood Pb <3 μg/dL was associated with accelerated 

time to puberty in mice, which suggests the possibility of a different mechanism of action in mice at 
Reproductive 

Effects

94 NTP Monograph on Health Effects of Low-Level Lead

blood Pb levels <3 μg/dL. The human data supporting Pb-associated delay in puberty include the one 

prospective study in boys discussed above, with the 

rest being cross-sectional studies. The determination 

of causation from cross-sectional studies has a serious limitation because cross-sectional studies rely on 

concurrent blood Pb measurements and provide no 

information on cumulative Pb or Pb exposure at earlier 

time points that may be critical for sexual maturation. 

However, the consistency of effects across studies, 

among multiple groups, and in multiple measures of 

puberty in both males and females lends weight to the 

evidence for developmental delay in puberty at blood 

Pb concentrations from 10 to <1 μg/dL. The conclusion of sufficient evidence for developmental delay 

in puberty in children at blood Pb levels <10 μg/dL 

is based on the prospective study and eight crosssectional studies that report effects above the mean 

blood Pb level (0.49 μg/dL to 5 μg/dL) of the group 

under study. A lower effect level and the conclusion 

of limited evidence for delayed puberty at blood Pb 

<5μg/dL is supported by two of the studies (Selevan et 

al. 2003, Wu et al. 2003) that use the NHANES III data 

to examine puberty onset in girls from 8-16 years of 

age, the Denham et al. (2005) study of 10- to 17-yearold girls in the Mohawk Nation, and the Staessen et al.

(2003) study reporting lower testicular volume in boys. 

The Tomoum et al. (2010) study provides additional 

support but reported delay in measures of puberty 

in boys and girls at blood Pb levels ≥10 μg/dL. The

NTP’s conclusions for sufficient evidence for delay in 

sexual maturation in boys and girls at blood Pb levels 

<10 μg/dL and limited evidence at blood Pb <5 μg/dL 

expands the conclusion from ATSDR’s 2007 Toxicological Profile for Lead (ATSDR 2007), which was limited 

to girls at blood Pb levels <10 μg/dL; the EPA’s 2006 

AQCD for Lead (U.S. EPA 2006) did not present specific 

conclusions on sexual maturation.

8.3.2 Postnatal Growth

There is limited evidence that maternal Pb <10 μg/dL 

is associated with decreased head circumference in 

children up to 4 years of age and sufficient evidence 

that concurrent blood Pb <10 μg/dL in children is 

associated with decreased postnatal growth. Prospective studies in two groups (Rothenberg et al. 1993, 

Rothenberg et al. 1999, Schell et al. 2009) report an 

inverse association between maternal blood Pb and 

head circumference, and one study reports the lack of 

an association between maternal blood Pb and height 

or weight through 10 years of age (Lamb et al. 2008). 

The data from prospective studies (see Table 8.4 and 

Postnatal Growth section of Appendix E: Reproductive and Developmental Effects) in two groups support an association between higher blood Pb levels in 

children and lower subsequent growth (Greene and 

Ernhart 1991, Rothenberg et al. 1993, Rothenberg et 

al. 1999). Numerous cross-sectional studies report an 

association between higher blood Pb in children and 

smaller head circumference, height, or other indicators of growth (e.g., weight, chest circumference, etc.). 

The clear majority of cross-sectional studies, including studies with large numbers of subjects, such as 

the NHANES data sets, demonstrate an association 

between higher concurrent blood Pb (means from 2 to 

15 μg/dL) and lower height or other indicators of postnatal growth in children from 1 to 16 years of age. This 

strong evidence for an association between growth 

and concurrent blood Pb is based on exposure data 

that is largely outside the relevant time window – the 

relevant timing of Pb exposure to effect growth is during or before the growth that results in differences 

in height. Therefore, the conclusion of sufficient evidence that blood Pb <10μg/dL in children is associated 

with decreased growth is based on the combination 

of strong support from the cross-sectional studies and 

the additional support from the three prospective 

studies that evaluate blood Pb levels in children on 

subsequent growth rather than current height.

Several prospective studies support an inverse 

association between maternal Pb <10 μg/dL and 

postnatal growth as indicated by head circumference, but the relationship is less clear for height. 

Higher maternal blood Pb at 36 weeks of gestation 

was associated with smaller head circumference 

up to 4 years of age in children in the Mexico City 

Prospective Study (Rothenberg et al. 1993, Rothenberg et al. 1999). Schell et al. (2009) also report an 

effect of maternal blood Pb on head circumference, 

but not on height or weight, in 6- to 12-month-olds 

in Albany, NY. Maternal blood Pb was not related 

to height or weight in children from 1 to 10 years 

of age in the Yugoslavia Prospective Study (Lamb et 

al. 2008). Data from the Cincinnati Pb study support 

a combined effect of maternal blood Pb as well as 

concurrent blood Pb levels in the children; height at 

15 months was decreased only in children with blood 

Pb >3.4 μg/dL that also experienced maternal blood 
Reproductive 

Effects

Table 8.4: Studies of postnatal growth associated with low-level Pb exposure used to develop conclusions

Relevance 

to 

Conclusions

Study 

Description

Study 

Design Key Reproductive/Developmental Findings Reference

Cincinnati Pb StudyEffect Children 15 months 

of age; n= 260

Prospective Concurrent blood Pb (>3.4μg/dL) in children was inversely associated with growth 

rate (length) at 15 months of age in children of mothers with Pb >7.7 μg/dL.

Shukla (1989) (same study 

population as Shukla, 1991)

Children ≤33 months of age; n=235

Prospective Current blood Pb was inversely associated with length at 33 months of age in 

children with higher blood Pb (>10.8 μg/dL) from 3 to 15 months of age.

Shukla (1991)

Albany Pregnancy Infancy Pb StudyEffect Children 0.5-1 years 

old; n=211

Prospective Maternal blood Pb (≥3 μg/dL) was inversely associated with infant head circumference at 6 and 12 months, but not with length or weight. Schell (2009)

Cleveland Pb StudyEffect Children <5 years; n= 

151-185 per sample

Prospective Blood Pb at 6 months of age (10 μg/dL) was related to subsequent head circumference (p=0.05) and marginally related to subsequent length (p=0.06) and 

weight (p=0.08); blood Pb at 1-4 years old was not related to weight, length, head circumference at 4 years old.

Greene (1991)

Mexico City Prospective StudyEffect Children 0.5-1 years; 

n=50-111 per sample

Prospective Maternal blood Pb at 36 weeks (median, <10 μg/dL) was inversely associated 

with infant head circumference at 6 and 18 months. Infant blood Pb (1 year) was inversely associated with head circumference at 36 months.

Rothenberg (1993)(same study population as Rothenberg, 1999)

Children 0.5-4 year; n =119-199 per sample

Prospective Maternal (36 weeks) and infant (1 year) blood Pb (median, <10μg/dL) were inversely 

associated with infant head circumference at later ages, up to 4 years of age.

Rothenberg (1999)

Yugoslavia Prospective StudyNo effect Children birth, 1, 4, 6, 

and 10 years; n=309

Prospective Maternal blood Pb was not correlated to height or weight in children from 1 

to 10 years of age.

Lamb (2008)

Effect Children at 4 years of 

age; n=156-175

Crosssectional Concurrent blood Pb (<15 μg/dL) was inversely associated with height in Pristina, but blood Pb (20-40 μg/dL) was not related to height in Titova-Mitrovica, a Pb 

smelter town.

Factor-Litvak (1999)

NHANES IIIEffect Children 1-7 years 

old; n=4,391

Crosssectional Concurrent blood Pb (mean, 3.6 μg/dL) was inversely associated with height and head circumference but not with weight. Ballew (1999) (same study population as Selevan)

Girls 8-16 years of age; n=600-805 per race/ethnicity

Crosssectional Concurrent blood Pb ≥3 μg/dL was associated with decreased height compared to individuals with a blood Pb of 1 μg/dL but not with weight. Selevan (2003)

NHANES IIEffect Children 0.5-7 years 

of age; n=2695

Crosssectional Concurrent blood Pb (range, 5-35 μg/dL) was inversely associated with height, weight, and chest circumference. Schwartz (1986) (same study population as Frisancho)

Mexican-Americans age 5-12; n=1,454

Crosssectional Concurrent blood Pb (mean: boys, 10.6 μg/dL; girls, 9.3 μg/dL) was inversely associated with height. Frisancho (1991)

NTP Monograph on Health Effects of Low-Level Lead 95
Reproductive 

Effects

96 NTP Monograph on Health Effects of Low-Level Lead Table 8.4: Studies of postnatal growth associated with low-level Pb exposure used to develop conclusions (continued) Relevance to Conclusions Study Description Study Design Key Reproductive/Developmental Findings Reference Effect Children aged 7-15 in Poland; n=899 Cross- sectional Concurrent blood Pb (mean, 7.7 μg/dL) was inversely associated with height, leg length, arm length in both, trunk length in boys, weight in girls; not weight in boys, trunk in girls. Ignasiak (2006) Effect Children aged 2-12 in Dallas; n=764 (1980s: n=404; 2002: n=390) Cross- sectional Concurrent blood Pb was inversely associated with height, weight, and head circumference. The height-Pb relationship was not statistically different between children in 1980s (mean=24.8 μg/dL) or 2002 (mean= 1.8 μg/dL). Little (2009) Effect Children 7 years old in Mexico n=602 Cross- sectional Concurrent blood Pb (11.5 μg/dL) was inversely associated with height and positively associated with head circumference. Kordas (2004) Effect Children aged 6-9 in Greece; n=522 Cross- sectional Concurrent blood Pb (mean, 12.3 μg/dL) was inversely associated with height, head circumference, and chest circumference. Kafourou (1997) Effect Boys 8-9 in Russia; n=489 Cross- sectional Concurrent blood Pb (median, 3 μg/dL) was inversely related to height but not with weight or BMI. Hauser (2008) Effect Children 11-13 years old in Italy; n=418 Cross- sectional Concurrent blood Pb inversely associated with height, weight in 13-year-old boys (mean, 8.5 μg/dL) and height in 12-year-old girls (mean, 7 μg/dL), not children of other ages. Vivoli (1993) Effect 12-month-old infants in Mexico City; n=329 Prospective & cross-sectional Infant blood Pb (6.8 μg/dL) at 1 month and maternal bone Pb (tibia 10.1 μg/g) were inversely related to infant weight and/or weight gain through 12 months of age. Sanin (2001) No effect Children 6-9 years old in Malaysia; n=268 Cross-sectional Concurrent blood Pb (mean, 3.75 μg/dL) was not correlated to height, weight, or arm circumference for age. Zailina (2008) Effect Children aged 7 and 20 in USA; n=236 Prospective & cross-sectional Dentin Pb level of teeth lost before age 7 was inversely associated with BMI at age 7 and BMI at age 20, not weight or height. No association between growth & bone Pb at age 20 Kim (1995) Effect Children 1-10 years old in Dallas; n=139 Cross- sectional Concurrent blood Pb was inversely associated with height, weight, and head circumference. Little (1990) Effect Children 5-13 years old in Korea; n=108 Cross- sectional Concurrent blood Pb (mean, 2.4 μg/dL) was inversely associated with height and arm length but not with weight or BMI. Min (2008) No effect Children 10-13 years old in Egypt; n=41 Cross- sectional Mean height and weight did not differ as a percentage of median for age and sex for individual above and below blood Pb of 10 μg/dL in children with mean Pb of 9.46 μg/dL. Tomoum (2010) Effect Children age 18-36 mo in Omaha; n=21 Cross- sectional Concurrent blood Pb (mean, 6.4 μg/dL) was inversely associated with head circumference. Stanek (1998) Epidemiological studies of Pb exposure and growth are listed by decreasing cohort size and grouped together for overlapping or shared study groups. Abbreviations: BMI, body mass index; NHANES, National Health and Nutrition Examination Survey.
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 97

Pb >7.7 μg/dL (Shukla et al. 1989). A subsequent 

study supported the combined effect of blood Pb at 

3-15 months of age and concurrent blood Pb level for 

height at 33 months (Shukla et al. 1991). In children 

from the Mexico City Prospective Study, infant blood 

Pb at 1 year of age was inversely associated with head 

circumference up to 4 years of age (Rothenberg et al.

1993, Rothenberg et al. 1999). Greene et al. (1991) 

reported that blood Pb in children at 6 months of age 

was related to subsequent growth at borderline statistical significance for head circumference (p=0.05), 

length (p=0.06), and weight (p=0.08) in children in 

the Cleveland Lead Study (n=151-185 per sample).

The clear majority of cross-sectional studies support an inverse association between concurrent blood 

Pb (with mean levels of 2-15 μg/dL and higher) and 

height. Additional measures of growth such as head 

circumference, arm or leg length, and weight were 

also related to blood Pb in some studies, but these 

endpoints were less widely reported, and weight is 

less consistently associated with blood Pb. Data from 

NHANES II support an inverse association between 

concurrent blood Pb from 5 to 35 μg/dL and height, 

weight, and chest circumference (Schwartz et al. 1986, 

Frisancho and Ryan 1991). The inverse relationship 

between height (but not weight) and blood Pb was 

further supported by studies using data from NHANES 

III on children 1-7 years of age with mean blood Pb 

of 4 μg/dL (Ballew et al. 1999) and in girls 8-16 years 

of age with blood Pb ≥3 μg/dL (Selevan et al. 2003) 

compared to girls with blood Pb of 1 μg/dL. Other 

large cross-sectional studies have reported a similar 

inverse relationship between blood Pb and markers 

of growth: height and leg and arm length in Polish 

children 7-15 years of age (8 μg/dL mean blood Pb 

and n=899) (Ignasiak et al. 2006); height, weight, and 

head circumference in Children 2-12 years of age in 

Dallas (25 μg/dL mean blood Pb and n=764; 2 μg/dL 

mean blood Pb and n=390) (Little et al. 2009); height 

in 7-year-olds in Mexico (12 μg/dL mean blood Pb; 

n=602) (Kordas et al. 2004); height, head circumference, and chest circumference in children 6-9 years of 

age in Greece (12 μg/dL mean blood Pb; n=522) (Kafourou et al. 1997); and height in boys 8 and 9 years 

of age in Russia (3 μg/dL median blood Pb; n=489) 

(Hauser et al. 2008). None of the studies that support 

an effect level <5 μg/dL controlled for parental height, 

which may relate to the cross-sectional nature of the 

studies. However, parental height is considered in 

prospective studies as well as a few cross-sectional 

analyses that support an association with blood Pb 

levels <10 μg/dL (Shukla et al. 1989, Greene and Ernhart 1991, Shukla et al. 1991, Vivoli et al. 1993, Kafourou et al. 1997, Sanin et al. 2001, Schell et al. 2009).

There are also a number of smaller cross-sectional studies with sample sizes ranging from 330 to 

21 that support an association between lower height 

and higher concurrent blood Pb levels (see Table 8.4

and Postnatal Growth section of Appendix E: Reproductive and Developmental Effects). The data are not 

completely consistent, because Zailina et al. (2008) 

did not find a correlation between blood Pb in a study 

of 269 children in Malaysia in the relative height for 

age, and Tomoum et al. (2010) did not find a difference between individuals above and below 10 μg/dL 

in a study of 41 children 12 years of age in Egypt in 

the mean height as a percentage of median height. 

Although the finding of an association in a study with 

a small sample size suggests a larger magnitude of 

effect, it is less informative when studies with a small 

sample size such as the data from Egypt, fail to find 

an effect. In the Yugoslavia Prospective Study, higher 

blood Pb in 4-year-olds was associated with lower 

height in Pristina at blood Pb levels <15 μg/dL, but 

blood Pb levels from 20 to 40 μg/dL in Titova-Mitrovica (a Pb smelter town) were not associated with 

height (Factor-Litvak et al. 1999). Although Vivoli et al.

(1993) reported an association between higher blood 

Pb and lower height in girls from 11 to 13 years of age, 

12-year-old girls, and 13-year-old boys, the association was not significant for all age groups (i.e., not for 

all boys combined, 11-year-old boys, 11-year-old girls, 

12-year-old boys, or 13-year-old girls).

Few studies of growth include measures of 

exposure other than blood Pb data. Kim et al. (1995) 

reported an association between higher dentin Pb 

levels in teeth lost before 7 years of age and lower 

BMI at 20 years of age; however, neither dentin Pb at 

7 years of age nor concurrent bone at 20 years of age 

was related to height or weight in the 20-year-olds. 

Sanin et al. (2001) reported an association between 

either maternal bone Pb or infant blood Pb and lower 

weight and less weight gain through 12 months of 

age, but the study did not report data on height.

Summary of Support for Conclusions

Animal data support a decrease in postnatal growth 

rate associated with prenatal and developmental Pb 
Reproductive 

Effects

98 NTP Monograph on Health Effects of Low-Level Lead

exposure at high blood Pb levels in some studies (i.e., 

40-100μg/dL Sprague Dawley rats; see U.S. EPA 2006 

for recent reviews of the animal data, ATSDR 2007). 

The human data include multiple prospective studies and numerous cross-sectional studies. The three 

available prospective studies support an association 

between maternal blood Pb and smaller head circumference from 1 to 4 years of age (Rothenberg et al. 1993, 

Rothenberg et al. 1999, Schell et al. 2009). The three 

available prospective studies addressing the potential 

association between maternal blood Pb and height 

or weight do not support an association (Lamb et al.

2008, Schell et al. 2009), although maternal Pb may be 

a contributing factor along with infant blood Pb levels (Shukla et al. 1989). The prospective studies that 

investigated the relationship between early-life blood 

Pb levels in children and measures of growth support 

a relationship between higher Pb and lower growth. 

The two Rothenberg et al. (1993, 1999) publications 

from the Mexico City Prospective Study reported an 

association between higher blood Pb in infants at 1 

year of age and smaller head circumference up to 4 

years of age, and Greene et al. (1991) reported that 

blood Pb in 1-year-old children was related to subsequent head circumference (p=0.05), length (p=0.06), 

and weight (p=0.08) in children in the Cleveland Lead 

Study. The strength of the evidence comes from the 

number of cross-sectional studies, including large 

numbers of subjects, such as the NHANES data sets, 

that report an inverse association between concurrent blood Pb (mean, 2-15 μg/dL) in children from 

1 to 16 years of age and height or other indicators 

of postnatal growth. However, cross-sectional studies have considerable limitations because they only 

provide concurrent blood Pb measurements and lack 

data on cumulative Pb or Pb exposure at earlier time 

points that may be critical for growth. The consistency 

of effects across studies, among multiple populations 

in both males and females, lends weight to the evidence that decreased growth indicated by reduced 

height (and, to a lesser extent, other measures) is 

associated with blood Pb. The conclusion of sufficient 

evidence that blood Pb levels <10 μg/dL in children 

are associated with decreased growth is based on 

the combination of strong support from the crosssectional studies and the additional support from the 

four prospective studies that evaluate blood Pb levels 

in children on subsequent growth. Although several 

studies report an association down to blood Pb levels 

<5 μg/dL, these studies do not adequately control for 

parental height, which is a known important predictor 

for postnatal growth, so there is inadequate data to 

evaluate an association with blood Pb levels <5 μg/dL. 

Data from the Cincinnati Lead Study suggest that 

growth may depend on a combination of gestational 

and early-childhood exposure, so effects may only be 

observed in children of mothers with elevated blood 

Pb that subsequently experienced elevated blood Pb 

levels in early childhood. The conclusion of limited 

evidence that maternal blood Pb <10 μg/dL is associated with decreased head circumference in children 

up to 4 years of age is based on three studies from two 

groups. The NTP’s conclusions on an inverse association between blood Pb and growth are in line with the 

2007 ATSDR Toxicological Profile for Lead, although 

ATSDR does not specifically identify an effect level for 

growth, and the EPA’s 2006 AQCD for Lead (U.S. EPA 

2006) reviews the animal data in greater detail than 

the epidemiological data relating to growth.

8.3.3 Sperm

There is sufficient evidence that blood Pb ≥15 μg/dL is 

associated with adverse effects on sperm or semen in 

adult men, and inadequate evidence for adverse effects 

on sperm at blood Pb levels <15 μg/dL. Although there 

is no single measure of adverse effects that is consistently associated with elevated blood Pb, occupational 

studies report effects that include lower sperm numbers, decreased motility, reduced semen volume, and 

an increased percentage with abnormal morphology. 

Decreased sperm count, density, and/or concentration have been reported in multiple retrospective 

and cross-sectional studies of men with occupational 

exposure to Pb at mean blood Pb levels from 15 to 

68 μg/dL (Table 8.5 and Sperm section of Appendix E: 

Reproductive and Developmental Effects). Among men 

recruited from infertility or in vitro fertilization (IVF) 

clinics, decreased sperm concentrations and increases 

in the percentage of abnormal sperm are associated 

with blood Pb levels from 1 to 15 μg/dL in several studies (Chia et al. 1992, Telisman et al. 2007, Meeker et al.

2008). Men recruited from infertility clinics may represent a susceptible subpopulation, and even within this 

group the evidence is not consistent, because several 

studies did not find adverse sperm effects at blood Pb 

levels <15 μg/dL (mean, 7-10 μg/dL) (Xu et al. 1993, 

Mendiola et al. 2011). The conclusion of inadequate 

evidence that blood Pb levels <15 μg/dL are associated 
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 99 Table 8.5: Studies of sperm and semen parameters associated with low-level Pb exposure used to develop conclusions Relevance to Conclusions Study Description Study Design Key Reproductive/Developmental Findings Reference Smelter Employees, British Columbia Effect Male employees; n=119 Retrospective Blood Pb levels (>40 μg/dL) were associated with decreased sperm concentra- tion, but not with motility or morphology. Alexander (1996b) Male employees; n=81 of 119 original Retrospective Blood Pb levels (mean, 22.8 μg/dL) were associated with decreased sperm count and concentration, but not with motility or morphology. Alexander (1998) Effect Male Pb workers in Europe; n=486 Cross-sectional Blood Pb (>50 μg/dL) was associated with lower sperm count and density, but not with volume, density ≤20 million/mL, or chromatin in Pb workers (n=306; mean blood Pb, 31 μg/dL) and 197 referents (mean blood Pb, 4.4). The authors suggest a threshold of 44 μg/dL blood Pb for association with sperm concentration. Bonde (2002) Effect Men at clinic in Croatia; n=240 Cross-sectional Blood Pb (median, 4.9 μg/dL) was associated with increased percentages of pathological sperm, wide sperm, round sperm, but not with sperm count, den- sity, viability, motility, or other measures, in men at fertility clinic or donors for artificial insemination. Telisman (2007) No effect Men at infertility clinic in China; n=221 Cross-sectional Blood Pb (mean, 8 μg/dL) and semen plasma Pb (mean, 1.27 μg/dL) were not cor- related with sperm density, motility, viability, morphology, or semen volume in men screened for infertility. Xu (1993) Effect Men at fertility clinic in Michigan; n=219 Cross-sectional Blood Pb (median, 1.5 μg/dL) was associated with a greater odds ratio for below- reference sperm concentration but not with count, volume, motility, or morphol- ogy, for men at an infertility clinic. Meeker (2008) Effect Male Pb workers and referents; n= 200 Cross-sectional Men with Pb exposure (blood Pb ≥41μg/dL; n=100) showed reduced sperm motility and semen volume and increased abnormal morphology compared to technicians (n=50) and referents (n=50). Lancranjan (1975) No effect Men at fertility clinic in Germany; n=190 Case-control Blood Pb not reported; grouped by sperm concentration, motility, and percent normal morphology, there were no differences in semen Pb among 172 infertile men and 18 referents. Jockenhovel (1990) No effect Men at fertility clinic in Finland; n=188 Cross-sectional Blood Pb not reported; sperm density, motility, and morphology did not differ by semen Pb above and below 0.2 μg/dL. Saaranen (1987) Effect Male smelter workers in Belgium; n=159 Cross-sectional Sperm concentration was significantly reduced in Pb workers (mean blood Pb, 31 μg/dL; n=68) compared to hospital staff (referents; median, 3.4 μg/dL; n=91). Mahmoud (2005) Effect Male Pb workers in Croatia; n=146 Cross-sectional Blood Pb levels were associated with decreased sperm count (blood Pb ≥~25

μg/dL), decreased sperm density, increased abnormal head morphology, 

and other parameters in Pb workers (mean blood Pb, 39 μg/dL; n=98) and referents (mean, 11 μg/dL; n=51).

Telisman (2000)
100

NTP Monograph on Health Effects of Low-Level Lead

Reproductive 

Effects

Table 8.5: Studies of sperm and semen parameters associated with low-level Pb exposure used to develop conclusions (continued)

Relevance to 

Conclusions Study Description Study Design Key Reproductive/Developmental Findings Reference

Effect Male Pb workers in 

India; n=130

Cross-sectional Occupational exposure (mean blood Pb, 48 μg/dL (n=30) and 77 μg/dL (n=50)) 

was associated with decreased sperm count, density, motility, semen volume, increased abnormal morphology, and other sperm changes compared to referents (mean blood Pb, 14 μg/dL; n=50)

Naha (2006)

Effect Male battery workers in 

India; n=120

Cross-sectional Occupational Pb exposure (blood Pb ≥~14 μg/dL; n=80) was associated with 

decreased sperm count, density, motility, semen volume, increased abnormal morphology, and other sperm changes compared to referents (blood Pb 7 μg/dL; n=40).

Naha (2005)

Effect Male Pb workers in 

Italy; n=120

Cross-sectional Blood Pb levels were associated with decreased sperm count in 39 employees of 

a Pb battery plant (mean Pb, 61 μg/dL) and 81 workers at a cement plant (mean, 18 μg/dL).

Assennato(1986, 1987)

Effect Male paint workers in 

India; n=100

Cross-sectional Occupational Pb exposure (mean blood Pb, ≥50 μg/dL; n=50) was associated with 

decreased sperm count, motility, semen volume, and increased abnormal morphology and DNA hyploidy, compared to non-occupationally exposed workers (n=50).

Naha (2007)

No effect Male battery workers in 

England; n=97

Cross-sectional Sperm count, density, and motilitywere notassociated with blood (mean Pb, 53μg/dL) 

or semen Pb (mean Pb, 9.6 μg/dL). Percent of normal sperm was reduced at p=0.06.

Robins (1997)

Effect Men in IVF clinic in New 

York; n=96

Cross-sectional Blood Pb not reported; semen plasma Pb (mean, 40 μg/dL) was associated with 

decrease in sperm motility, concentration, morphology, other sperm measures, and decreased IVF fertilization.

Benoff (2003a)

Effect Male battery workers in 

Taiwan; n=80

Cross-sectional Blood Pb levels (mean, 40 μg/dL) were associated with increased percent abnormal 

sperm and sperm head morphology, and DNA denaturation, but not with sperm 

count, semen volume, or motility.

Hsu (2009)

Effect Male battery workers in 

Argentina; n=68

Cross-sectional Male Pb battery workers with blood Pb ≥49 μg/dL (n=38) show reduced sperm 

motility and semen volume and increased abnormal morphology compared to referents (n=30).

Lerda (1992)

Blood Pb:

No effect;

Semen Pb: 

Effect

Men living near a smelter in Mexico; n=68

Cross-sectional Blood Pb (mean, 9 μg/dL) was not associated with sperm parameters. Sperm Pb 

(0.05 ng/106 cells) was associated with decreased sperm concentration, morphology, viability, motility; semen Pb (mean, 0.2 μg/dL) was associated with decreased 

volume and increased nuclear chromatin condensation.

Hernandez-Ochoa (2005)

Blood Pb:

No effect;

Semen Pb: 

Effect

Men at fertility clinic in Spain; n=60

Cross-sectional Sperm motility, concentration, and morphology did not differ by blood Pb (mean, 

9.8 μg/dL) for men at infertility clinic (n=30) and referents (n=30); motility was inversely related to semen Pb (3.0 μg/dL).

Mendiola (2011)

Effect Male metal workers in 

Poland; n=63

Cross-sectional Percent motile sperm was decreased in workers with high blood Pb (>40 μg/dL; 

n=29; mean Pb, 53 μg/dL) compared to workers with low Pb (<40 μg/dL; n=20) or referents (mean, 8 μg/dL; n=14); semen volume, sperm count, and morphology did not differ.

Kasperczyk (2008)
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 101 Table 8.5: Studies of sperm and semen parameters associated with low-level Pb exposure used to develop conclusions (continued) Relevance to Conclusions Study Description Study Design Key Reproductive/Developmental Findings Reference No effect Men in China; n=56 Cross-sectional Blood Pb not reported; semen plasma Pb (mean, 0.78 μg/dL) was not correlated with sperm count, density, motility, morphology, or viability; semen Pb was asso- ciated with 8-OHdG in men (n=56; group characteristics not reported). Xu (2003) Equivocal Men at infertility clinic in Europe; n=47 Cross-sectional Blood Pb not reported; authors state inverse correlation between Pb and flagel- lum ball, and that no correlation was detected between pathological changes and elements. Slivkova (2009) Effect Men in andrology clinic in China; n=35 Cross-sectional Blood Pb was elevated (mean, 7.2 μg/dL) in men with <40% sperm motility com- pared to men with >40% sperm motility (mean blood Pb, 5.1 μg/dL) . Chia (1992) No effect Men in Germany; n=22 Cross-sectional Blood Pb not reported; Pb in semen (0.98 μg/dL) and semen plasma (0.77 μg/dL) was not correlated to sperm density, count, motility, or morphology in men with no occupational Pb exposure. Noack-Fuller (1993) No effect Men in Connecticut; n=21 Cross-sectional No correlation between semen Pb (mean, 5.9 μg/dL) and sperm count, density, or semen protein in medical students and technicians; unclear if blood Pb (13.1

μg/dL) 

effect on sperm examined.

Plechaty (1977)

Effect Male Pb workers in India; 

n=20

Cross-sectional Men with occupational Pb exposure (average blood Pb, 42.5 μg/dL; n=10) had 

lower sperm count, decreased percent motile sperm, and increased percent abnormal sperm compared to referents (n=10).

Chowdhury (1986)

Effect Male battery workers in 

Netherlands; n=19

Cross-sectional Decrease in blood Pb (median, 42-19 μg/dL) was associated with improved 

number of motile sperm and penetration in men undergoing treatment to lower blood Pb.

Viskum (1999)

Equivocal Men with high Pb and 

referents; n=19

Cross-sectional Men with chronic high occupational Pb exposure (mean blood Pb, 39 μg/dL; n=10) 

did not differ from referents (Pb=16μg/dL; n=9) in sperm volume, motility, or percent 

abnormal; two men with highest Pb demonstrated peritubular fibrosis, oligospermia, and Sertoli cell vacuolization.

Braunstein (1978)

Effect Male semen donors in 

New York; n=15

Cross-sectional Blood Pb not reported; semen plasma Pb was associated with sperm motility, premature acrosome loss, and fertilization rate in IVF but not with sperm 

concentration.

Benoff (2003b)

Effect Men with Pb toxicity in 

Connecticut; n=7

Case-series Two of 7 men with occupational Pb intoxication had no sperm; 2 had reduced 

sperm count; 4 of the 5 with sperm had reduced sperm motility.

Cullen (1984)

Effect A firearms instructor in 

New York

Case Report A case report of increases in sperm density and total sperm count and decreases in 

abnormal morphology in parallel with decreasing blood Pb with chelation therapy in a 41-year-old.

Fisher-Fischbein (1987)

Epidemiological studies of Pb exposure and sperm effects listed by decreasing cohort size and grouped together for overlapping or shared study groupsAbbreviations: 8-OHdG, 8-hydroxydeoxyguanosine; IVF, in vitro fertilization.
Reproductive 

Effects

102 NTP Monograph on Health Effects of Low-Level Lead

with adverse effects on sperm is based on the limited 

number of studies with evidence of effects at these 

lower blood Pb levels, the lack of consistency in the 

sperm data from men attending infertility or IVF clinics, and the uncertainty in using this patient group to 

extrapolate to other groups. There are few studies of 

the relationship between sperm and blood Pb in the 

general population.

Twelve occupational studies report adverse 

effects on sperm at blood Pb levels of 15-50 μg/dL 

using mean blood Pb levels of occupationally exposed 

men or blood Pb levels of workers categorized by 

blood Pb levels. Lower sperm counts or concentration are associated with the following blood Pb concentrations: approximately 15 μg/dL (estimated from 

graphs presented) in Naha et al. (2005); 20 μg/dL 

in De Rosa et al. (2003); approximately 25 μg/dL 

(estimated from graphs presented) in Telisman et al.

(2000); 31 μg/dL in Mahmoud et al. (2005); ≥40 μg/dL 

in Alexander et al. (1996b); ≥44 μg/dL in Bonde et al.

(2002); 48 μg/dL in Naha et al. (2006); and 50 μg/dL in 

Naha et al. (2007). Sperm motility is reduced at blood 

Pb levels of 20 μg/dL in De Rosa et al. (2003); 41 μg/dL 

blood Pb in Lancranjan et al. (1975); 49 μg/dL blood 

Pb in Lerda (1992); 53 μg/dL blood Pb in Kasperczyk 

et al. (2008); and 15 μg/dL, 48 μg/dL, and 50 μg/dL 

in three studies already listed above for decreased 

sperm count (Naha et al. 2005, Naha and Chowdhury 

2006, Naha and Manna 2007). Five of the studies support effects in men with mean blood Pb levels from 

15 to 31 μg/dL. Hsu et al. (2009) reported a threshold 

for increased abnormal sperm morphology at blood 

Pb levels ≥45 μg/dL in Pb battery workers, relative 

to workers with blood Pb <25 μg/dL. However, the 

extent of DNA denaturation per cell was significantly 

increased at lower blood Pb levels, among workers 

in both the mid-Pb group (25-45 μg/dL) and high-Pb 

group (>45 μg/dL) workers (Hsu et al. 2009). A similar 

threshold of approximately 25μg/dL was associated 

with decreased sperm count relative to workers with 

blood Pb <10 μg/dL in a study of 146 industrial workers in which Pb was dichotomized into six groups 

(n=25 per group) with mean blood Pb levels of <10, 

12, 25, 35, 42, and 58 μg/dL (estimated from Figure 4 

in Telisman et al. (2000)). Naha et al. (2005) reported 

effects on sperm in Pb workers with mean blood Pb 

of approximately 15 μg/dL (estimated from data presented in a graph; n=10 per group) compared to workers with mean blood Pb of 7 μg/dL. The Pb workers 

in the Naha et al. (2005) study had the lowest mean 

blood Pb level (15 μg/dL compared to 48-50 μg/dL) 

in a series of papers from the same group (Naha et al.

2005, Naha and Chowdhury 2006, Naha and Manna 

2007) that consistently report effects on sperm count, 

motility, semen volume, and abnormal morphology 

in all Pb-exposed groups working in paint and battery 

factories compared to a reference group not working in the factory. A cross-sectional study of 68 Pb 

smelter workers reported reduced sperm concentration in the Pb workers (mean blood Pb, 31 μg/dL)

compared to 91 hospital personnel (mean blood 

Pb, 3.4 μg/dL) (Mahmoud et al. 2005). De Rosa et 

al. (2003) reported lower sperm motility, viability, 

penetration, and velocity in 85 tollgate workers with 

mean blood Pb of 20 μg/dL compared to referents 

with mean blood Pb of 7 μg/dL, and linear regression for sperm count was also significant. The occupational studies of Naha et al. (2005), Telisman et al.

(2000), Mahmoud et al. (2005), De Rosa et al. (2003) 

and Hsu et al. (2009) report adverse sperm effects 

down to blood Pb levels of 15-31 μg/dL.

A closer examination of the reference groups in 

the above studies adds to evidence for a threshold 

closer to 20 μg/dL for adverse effects on sperm than 

a threshold of 40 μg/dL; however, the data are not 

consistent. Of the seven studies that report the higher 

threshold, five rely on internal reference groups with 

blood Pb levels >10 μg/dL (Lerda 1992, Alexander et al.

1996b, Naha and Chowdhury 2006, Naha and Manna 

2007) or fail to report blood Pb levels in the reference 

group (Lancranjan et al. 1975), so these studies have 

limited ability to detect effects in the lower concentration range. Among the six studies with a reference 

group <10 μg/dL, four reported effects on sperm at 

mean blood Pb levels from 15 to 31 μg/dL: ~15 μg/dL

in Naha et al. (2005), 20 μg/dL in De Rosa et al. (2003), 

~25 μg/dL in Telisman et al. (2000), and 31 μg/dL in 

Mahmoud et al. (2005). The other two studies (Bonde 

et al. 2002, Kasperczyk et al. 2008) report effects in 

men with blood Pb levels >40 μg/dL and not in men 

with blood Pb <40 μg/dL. While adjustment for potential confounders is not described in several of the studies, the studies of Telisman et al. (2000), Mahmoud et 

al. (2005), and Bonde (2002) are all adjusted for factors known to effect sperm count or function, such as 

age and period of abstinence, so a lack of adjustment 

does not explain the difference in the effect levels 

identified in the studies.
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 103

In addition to the occupational Pb exposure 

studies, there are a number of studies of individuals attending infertility or IVF clinics. Three of these 

studies reported an association between blood Pb 

levels <10 μg/dL and several sperm parameters, 

whereas two studies with similar blood Pb levels 

did not. In a cross-sectional study of 240 Croatian 

men that combined men at an infertility clinic with 

men donating for artificial insemination, blood Pb 

in the range of 1.1-14.9 μg/dL was associated with 

increasing percentage of pathologic sperm and wide 

sperm, with no effect on motility, viability, count, or 

other measures (Telisman et al. 2007). In a study 

of 219 men attending infertility clinics in Michigan, 

blood Pb was marginally (p-trend=0.07) related to 

sperm concentration below reference (<20 mil./mL) 

(Meeker et al. 2008). The odds ratio for low sperm 

concentration compared to the reference was significant for individuals in the second and third quartile 

compared to the first quartile: (second quartile, 1.1-

1.5 μg/dL: OR=0.89 (95% CI: 0.27, 2.89); third quartile, 

1.5-2.0 μg/dL: OR=3.94 (95% CI: 1.15, 13.6); fourth 

quartile, >2.0 μg/dL: OR=2.48 (95% CI: 0.59, 10.4) 

(Meeker et al. 2008). Chia et al. (1992) reported 

significantly elevated blood Pb (mean, 7.2 (SD: 6.2) 

μg/dL vs. 5.1 (SD: 2.4) μg/dL; p=0.0034) in men with 

<40% sperm motility among 35 men attending an 

andrology clinic in Singapore. The other two studies 

that report blood Pb and sperm parameters for men 

attending infertility clinics in China (n=221 at mean 

blood Pb of 8 μg/dL) and Spain (n=60 at mean blood 

Pb of 10 μg/dL) did not find an association between 

blood Pb and effects on sperm (Xu et al. 1993, Mendiola et al. 2011); however, Mendiola et al. (2011) 

reported an association between semen Pb levels 

and increased percentage of immotile sperm.

There are few studies of sperm effects associated with blood Pb levels in the general population 

that were not patients at infertility clinics, and the 

available studies do not support an effect of blood 

Pb on sperm. Hernandez-Ochoa et al. (2005) and 

Plechaty et al. (1977) did not detect a significant association between blood Pb (means, 9 and 13 μg/dL, 

respectively) and sperm parameters, but the studies 

are relatively small, with fewer than 89 men sampled 

from the two studies combined. It is also worth noting that two Pb-treatment studies support the inverse 

association between high blood Pb levels and sperm 

parameters. Motility, penetration, and morphology 

were all improved in 19 Danish Pb-workers treated 

for high Pb levels in association with lowering blood 

Pb from a median of 42 μg/dL to 19.9 μg/dL (Viskum 

et al. 1999). Similar results were observed in a casereport of a firearms instructor with blood Pb levels 

that were reduced from 88 to 30 μg/dL (Fisher-Fischbein et al. 1987).

In studies that report semen Pb levels, the results 

are inconsistent on whether semen Pb levels are associated with sperm parameters or whether semen Pb 

is a better measure of exposure than blood Pb for 

effects of Pb on sperm. Five reported sperm effects 

associated with semen Pb (Benoff et al. 2003a, Benoff 

et al. 2003b, Hernandez-Ochoa et al. 2005, Slivkova 

et al. 2009, Mendiola et al. 2011), and six did not 

find an association (Plechaty et al. 1977, Saaranen et 

al. 1987, Jockenhovel et al. 1990, Noack-Fuller et al.

1993, Robins et al. 1997, Xu et al. 2003). Several studies (e.g., Saaranen et al. 1987, Jockenhovel et al. 1990, 

Noack-Fuller et al. 1993, Benoff et al. 2003a, Benoff et 

al. 2003b, Xu et al. 2003, Slivkova et al. 2009) report 

only semen or sperm Pb, so the usefulness of semen 

Pb cannot be compared to blood or bone Pb as a 

potential biomarker of Pb exposure related to sperm 

parameters. In studies that report both blood and 

semen Pb, there is some support that both measures 

of exposure are equally good indicators of Pb exposure, because as several studies report sperm effects 

associated with both blood and semen Pb (Telisman 

et al. 2000, Naha et al. 2005, Naha and Chowdhury 

2006, Naha and Manna 2007) or a lack of an association that is consistent with both blood and semen Pb 

(Xu et al. 1993, Robins et al. 1997). Other studies have 

reported a significant association of sperm parameters 

with semen Pb (and not blood Pb) (Hernandez-Ochoa 

et al. 2005, Mendiola et al. 2011) or blood Pb (and 

not semen Pb) (Assennato et al. 1986, Kasperczyk et 

al. 2008). In a study of 81 employees of the Cominco 

smelter in British Columbia, semen and blood Pb levels 

were associated with decreased sperm concentration; 

however, after adjustment for ejaculate volume, blood 

Pb remained significant and semen Pb levels were no 

longer significantly related to sperm concentration 

(Alexander et al. 1998).

Summary of Support for Conclusions

Animal data support adverse effects of Pb exposure on 

sperm and semen, including decreased sperm count, 

reduced sperm motility, and increased morphological 
Reproductive 

Effects

104 NTP Monograph on Health Effects of Low-Level Lead

abnormalities, in sperm in some studies (see U.S. EPA 

2006 for recent reviews of the animal data, ATSDR 

2007). Although the animal data generally support 

adverse effects of Pb on sperm, effects may be associated with high doses (40-75 μg/dL in rats), and the 

animal data display differences in sensitivity to sperm 

effects by species and strain (effects observed down 

to 16-24 μg/dL in rabbits), differences that are likely 

to be exacerbated by variation in route and duration 

of exposure, age at initial exposure, and chemical 

form of Pb used in the experiment. The human data 

include 12 studies of men with occupational exposure that report effects on sperm or semen at blood 

Pb levels from 15 to 50 μg/dL. This is supported by 

six studies reporting effects on time to pregnancy 

or fertility at similar Pb levels (10-46 μg/dL) in men 

described in Section 8.3.4 Fertility/Delayed Conception Time below. The conclusion of sufficient evidence that blood Pb levels ≥15 μg/dL are associated 

with adverse effects on sperm or semen is based on 

these studies and specifically the five studies that 

report effects on sperm at blood Pb levels from 15 

to 31 μg/dL. Although occupational studies support 

adverse sperm effects down to 15 μg/dL, the lower 

threshold of blood Pb level associated with these 

effects is unclear.

Several studies of men recruited from IVF or 

infertility clinics report effects at blood Pb levels 

<10 μg/dL. However, men recruited from infertility 

clinics may represent a susceptible subpopulation, 

and even within this group, the evidence is not 

consistent. One challenge in determining the lower 

limit is that much of the data come from occupational studies in which the mean blood Pb level is 

30-40 μg/dL. Also, as discussed above, there are few 

studies of effects in the general population, and many 

studies have a low ability to detect effects associated 

with lower blood Pb levels, because occupational 

studies generally do not include many men with 

lower blood Pb levels (i.e., blood Pb <10 μg/dL). A 

number of older studies of sperm or semen parameters (e.g., Lancranjan et al. 1975, Lerda 1992) do 

not adjust for confounding factors such as period of 

abstinence, age, and smoking. In addition, no human 

data were located that examine effects of early or 

developmental exposure on sperm parameters as 

adults. The NTP’s conclusion of sufficient evidence 

that blood Pb levels ≥15 μg/dL are associated with 

adverse effects on sperm or semen extends the 

conclusions of the 2007 ATSDR Toxicological Profile 

for Lead (ATSDR 2007) and 2006 EPA AQCD for Lead 

(U.S. EPA 2006) down to 15 μg/dL blood Pb from the 

range of 30-45 μg/dL suggested by the 2006 EPA and 

2007 ATSDR documents.

8.3.4 Fertility/Delayed Conception Time

There is sufficient evidence that paternal blood Pb 

levels ≥20 μg/dL are associated with delayed conception time and limited evidence that blood Pb levels 

≥10 μg/dL in men are associated with other measures 

of reduced fertility. Four studies reported increased 

time to pregnancy or decreased odds of conception 

over a given time (fecundability) in men with blood Pb 

levels from 20 to 40 μg/dL, and a fifth study reported 

decreased odds ratio for probability of live birth in Pb 

workers with mean blood Pb of 46 μg/dL (see Fertility /Delayed Conception Time section of Appendix E: 

Reproductive and Developmental Effects). A lower 

effect level of 10 μg/dL is supported by a single large 

(n=4,146) retrospective occupational study that 

reported increased odds of infertility among men 

with blood Pb ≥10 μg/dL (Sallmen et al. 2000b), providing limited evidence for effects on fertility at blood 

Pb levels down to 10 μg/dL in men. The database of 

studies that examined male Pb exposure and fertility 

also includes several occupational studies that did 

not observe a significant relationship between blood 

Pb levels in men and fertility or time to pregnancy. 

There is inadequate evidence that blood Pb levels of 

≤10 μg/dL in women are associated with decreased 

fertility or greater time to pregnancy because few 

studies address these effects, and all of them report 

that maternal blood Pb levels are not associated 

with time to pregnancy. There is one prospective 

study of time to pregnancy for women in the general 

population with blood Pb levels <10 μg/dL, and this 

study found no effect on time to pregnancy. Several 

studies of couples attending IVF or infertility clinics 

report an association between blood Pb levels from 1 

to 30 μg/dL and a decrease in some measure of fertility (e.g., fertilization or embryo quality); additional 

studies are required to confirm this relationship. The 

best studies of fertility and delayed conception time 

include exposure measurements in both partners, 

but these data are often not collected. Women and 

men recruited from infertility or IVF clinics may represent a susceptible subpopulation, and the effects 

observed in this patient population should be applied 
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 105

with caution to the general population. There are not 

enough studies of fertility with Pb exposure data for 

women in the general population or even with occupational exposure to evaluate the potential relationship between Pb exposure and fertility in women.

Six occupational studies in five groups report 

decreased fertility or greater time to pregnancy for 

men at blood Pb levels of 10-46 μg/dL, and four other 

studies report no association at similar blood Pb levels. In a cross-sectional study of 85 tollgate workers 

with blood Pb levels of 20 μg/dL compared to 85 referents with blood Pb of 7 μg/dL, De Rosa et al. (2003) 

reported a significant increase from 8 to 15 months 

in time to pregnancy. Male workers (n=133) in a Pb 

battery plant in Taiwan had delayed time to pregnancy and reduced odds of conception over a given 

time compared to referents (fecundability ratio (FR)) 

at blood Pb levels ≥30 μg/dL (blood Pb 30-39 μg/dL: 

FR=0.52 (95% CI: 0.35, 0.77); blood Pb ≥40 μg/dL: 

FR=0.40 (95% CI: 0.27, 0.59); (Shiau et al. 2004). In 

retrospective occupational exposure studies of men 

monitored for Pb exposure by the Finnish Institute of 

Occupational Health, Sallmen et al. (2000a) reported 

the decreased FR relative to the reference group 

(FR=0.57 (95% CI: 0.34-0.91)) among men (n=502) 

with blood Pb ≥31 μg/dL in analyses that included 

only full-term pregnancies. Apostoli et al. (2000) 

reported a significant delay in time to pregnancy for 

men with blood Pb ≥40 μg/dL (p=0.012) in a study 

of 251 men working at a Pb-related factory in Italy; 

however, the time to pregnancy was not reduced 

at lower blood Pb levels, and FR analysis suggests a 

shorter time to pregnancy at lower blood Pb levels. In 

a cross-sectional study of 365 male Pb battery plant 

workers with mean blood Pb of 46 μg/dL, the odds 

ratio for probability of live birth was decreased compared to workers with mean blood Pb of 10 μg/dL

(OR=0.65 (95% CI: 0.43, 0.98)) or relative to preexposure (OR=0.43 (95% CI: 0.25, 0.73)) (Gennart et 

al. 1992b). The five studies described above support 

greater time to pregnancy or reduced fertility in men 

at blood Pb levels of 20 μg/dL, 30 μg/dL, 31 μg/dL, 

40 μg/dL, and 46 μg/dL, and a large retrospective 

study reported increased odds ratio of infertility at 

even lower blood Pb levels, down to 10 μg/dL. In 

a retrospective studies of men monitored for Pb 

exposure by the Finnish Institute of Occupational 

Health, Sallmen et al. (2000b) reported increased 

odds of infertility (RR=1.27 (95% CI: 1.08, 1.51)) and 

decreased success ratio (SR=0.86 (95% CI: 0.77, 0.97) 

for pregnancy among wives of male workers (n=4,146) 

with blood Pb ≥10 μg/dL. Male Pb workers reporting 

to the New York State Heavy Metals Registry with 

more than 5 years of Pb work had a reduced fertility rate relative to bus drivers or Pb workers with <5 

years of occupational exposure; however, blood Pb 

levels alone were not related to fertility (Lin et al.

1996). There are also four retrospective studies that 

report no association between time to pregnancy or 

odds ratio for fertility in men occupational exposed 

to Pb. Paternal Pb was not associated with standardized fertility ratio in 376 male Pb battery workers 

compared to preemployment group or workers with 

blood Pb <25 μg/dL (Selevan et al. 1984). Odds ratios 

for reduced fertility did not differ between 1,349 

Danish Pb workers with a mean blood Pb of 36 μg/dL 

compared to 9,596 referents (without blood Pb data) 

(Bonde and Kolstad 1997). The odds ratios for infertility did not differ between 229 Pb workers categorized 

by blood Pb into three groups of <40, 40-60, and 

>60 μg/dL and 125 reference employees classified as 

nonexposed (Coste et al. 1991). Time to pregnancy 

was not increased in 638 Pb-exposed male workers 

(mean Pb, 29-37 μg/dL) compared to external referents (n=236) or an internal control group (n=230) 

(Joffe et al. 2003).

Few studies have investigated the potential relationship between Pb exposure and fertility or time 

to pregnancy in women. There is one prospective 

study of time to pregnancy for women in the general 

population, Bloom et al. (2011a), which reported 

that blood Pb levels (mean, 1.5 μg/dL) were not 

associated with time to pregnancy in a study of 80 

women in New York. Sallman et al. (1995) did not 

detect a relationship between odds of conception 

and maternal occupational blood Pb levels in a retrospective study of 121 women in which exposure was 

estimated based on work descriptions and limited 

biological measurements.

Several fertility studies report measures of exposure other than blood Pb levels. Three case-control 

studies of infertile men and two studies of men 

undergoing IVF examined semen Pb levels and did 

not report blood Pb data, so the usefulness of semen 

Pb cannot be compared to blood or bone Pb as a 

potential biomarker of Pb exposure related to sperm 

parameters. Semen Pb was higher in infertile men in 

two of the studies (Saaranen et al. 1987, Jockenhovel 
Reproductive 

Effects

106 NTP Monograph on Health Effects of Low-Level Lead

et al. 1990), but not in a third study (Umeyama et 

al. 1986). Benoff et al. (2003a, 2003b) reported an 

inverse correlation between semen plasma Pb and 

IVF rate in two studies at IVF/ artificial insemination 

clinics in studies that did not include blood Pb values. 

Of the two studies reporting follicular Pb levels, one 

reported an association with fertility and one did not. 

In a study of 619 women undergoing IVF in Saudi Arabia, follicular Pb levels were not related to fertilization 

or pregnancy outcome, although blood Pb was associated with decreased OR for fertilization (Al-Saleh et 

al. 2008a). In a small study (n=9 women) that did not 

report blood Pb, follicular Pb was significantly higher 

from IVF patients that did not get pregnant than from 

women that did get pregnant (Silberstein et al. 2006).

Several studies of couples attending IVF or infertility clinics report an association between blood Pb 

levels and a decrease in some measure of fertility (e.g., 

fertilization or embryo quality). Results from studies 

of men or women reporting to IVF or infertility clinics should be interpreted with caution because they 

may represent a sensitive subpopulation. In a study 

of couples undergoing IVF in California, increased 

blood Pb levels in the women (n=24; mean blood Pb, 

0.83 μg/dL) were associated with a decreased OR for 

higher embryo cell numbers (a measure of embryo 

quality) (OR=0.25 (95% CI: 0.07, 0.86)), or a 75% 

reduction in embryo quality for each 1 μg/dL increase 

in maternal blood Pb (Bloom et al. 2010, Bloom et al.

2011b). Increased blood Pb levels in the men (n=15; 

mean blood Pb, 1.5μg/dL) were also associated with a 

decreased OR for higher embryo cell numbers (OR=0.

58 (95% CI: 0.37, 0.91)), or a 42% reduction in embryo 

quality for each 1 μg/dL increase in paternal blood Pb. 

There are only two case-control studies of infertile 

patients with blood Pb levels: one comparing infertile 

men to fertile controls and one comparing infertile 

women to fertile controls. Blood Pb (36.8 μg/dL (SD: 

12) vs. 23.2 μg/dL (SD: 5.6)) and semen Pb were higher 

in infertile men at a fertility clinic than in controls in 

a case-control study that examined Pb and smoking 

(Kiziler et al. 2007). Self-reported Pb exposure did not 

differ between infertile men recruited from infertility 

clinics and fertile men from prenatal clinics (Gracia et 

al. 2005). In a case-control study of women recruited 

at an infertility clinic (n=64) and controls from a 

postpartum clinic (n=83) in Taiwan, blood Pb levels 

>2 μg/dL were associated with an increased OR for 

infertility (OR=2.94 (95% CI: 1.18, 7.34)) (Chang et al.

2006). In a study of 619 women undergoing IVF, mean 

blood Pb levels were significantly higher in women 

that failed to achieve fertilization (4.1 (SD: 3.7) μg/dL)

than in women in which the IVF produced fertilized 

eggs (3.26 (SD: 2) μg/dL); however, blood Pb was not 

related to pregnancy outcome (Al-Saleh et al. 2008a).

Summary of Support for Conclusions

Animal data support adverse effects of Pb on fertility in several studies at high blood Pb concentrations 

(>60μg/dL; see U.S. EPA 2006 for recent reviews of 

the animal data, ATSDR 2007). Effects in male rodents 

exposed to Pb before mating include increased time 

to birth in mice and decreased pregnancy rate in mice 

or rats (Gandley et al. 1999, Pace et al. 2005). Female 

mice exposed to Pb during pregnancy exhibited 

smaller litter size in several studies (e.g., Pinon-Lataillade et al. 1995). The human data include six studies of men with occupational exposure that report 

increased time to pregnancy or reduced fertility at 

blood Pb levels from 10 to 46 μg/dL. The conclusion 

of sufficient evidence that blood Pb levels ≥20 μg/dL 

are associated with delayed conception time is based 

on four studies reporting increased time to pregnancy 

with blood Pb levels of 20-40 μg/dL in men. This is 

supported by numerous studies reporting adverse 

effects on sperm at similar Pb levels (15-50 μg/dL) in 

men described earlier. Although some studies do not 

support an association between paternal blood Pb 

levels and time to pregnancy or fertility, the database 

(including the sperm data) provides sufficient evidence for delayed conception time at blood Pb levels 

≥20 μg/dL in men. The conclusion of limited evidence 

that blood Pb levels ≥10 μg/dL in men are associated with decreased fertility is based on the above 

data with the addition of a single large retrospective 

occupational study that reported increased odds of 

infertility among men with blood Pb levels ≥10 μg/dL 

(Sallmen et al. 2000b). In the human data, few studies 

examined fertility or time to pregnancy with Pb exposure data in women, and both studies that examined 

time to pregnancy reported that maternal blood Pb 

was not related to time to pregnancy. The conclusion 

of inadequate evidence that blood ≤Pb 10 μg/dL in 

women are associated with increased time to pregnancy or reduced fertility is based on the limited 

number of studies addressing these endpoints, and 

the lack of a significant association with blood Pb 

reported in some studies on time to pregnancy. The 
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 107

conclusion of inadequate evidence for effects on 

fertility in women is consistent with the 2007 ATSDR 

Toxicological Profile for Lead (ATSDR 2007) and EPA’s 

2006 AQCD for Lead; however, for men, the 2006 EPA 

AQCD for Lead (U.S. EPA 2006) states that epidemiological studies suggest a small association between 

blood Pb levels >45 μg/dL in men and increased time 

to pregnancy. The NTP conclusions of sufficient evidence for effects of blood Pb levels ≥20 μg/dL in men 

on time to pregnancy and limited evidence that blood 

Pb levels ≥10 μg/dL are associated with reduced fertility are consistent with the conclusions of an effect 

of Pb in the 2006 EPA and 2007 ATSDR Lead documents, but the NTP outlines the support for a lower 

effect level (i.e., 20 μg/dL rather than 30-45 μg/dL).

While adjustment for potential confounders is not 

described in several of the studies, the studies of 

Shiau et al. (2004), Sallmen et al. (2000a), and Apostoli (2000) adjusted for factors known to effect fertility, 

such as maternal age and previous abortion, and all 

three studies demonstrated an effect of paternal Pb 

on time to pregnancy. Therefore, a lack of consideration of confounders does not explain the difference 

between studies that identified an effect of paternal 

Pb and studies such as Joffe et al. (2003) that did not 

observe an association between blood Pb in men and 

time to pregnancy.

8.3.5 Spontaneous Abortion

There is limited evidence that maternal blood Pb 

<10 μg/dL is associated with spontaneous abortion. 

In an extensive review, Hertz-Picciotto et al. (2000) 

concluded that there is consistent evidence from 

case series and epidemiologic studies in the 19th 

and early 20th century that Pb exposure at high levels appears to play a role in spontaneous abortion, 

but the older studies cited lack blood Pb or other 

biological monitoring data, so it is unclear what 

blood Pb level the data would support. Although >20 

studies published since the 1970s address maternal 

or paternal Pb exposure and spontaneous abortion 

(see Spontaneous Abortion section of Appendix E: 

Reproductive and Developmental Effects), many lack 

biological monitoring data. Four of the five retrospective studies that determine exposure by employment 

or residence report an association between maternal 

Pb exposure and spontaneous abortion (Nordstrom 

et al. 1978, 1979, Driscoll 1998, Tang and Zhu 2003). 

Of the studies with blood Pb data, two studies report 

an association between maternal Pb levels and spontaneous abortion. One case-control study and one 

nested case-control study found an effect of maternal 

blood Pb or plasma Pb <10 μg/dL and increased risk 

of spontaneous abortion (Borja-Aburto et al. 1999, 

Yin et al. 2008). A number of studies have reported 

no association between maternal blood Pb levels 

above or below 10 μg/dL and spontaneous abortion. 

The conclusion of limited evidence that maternal 

blood Pb <10 μg/dL is associated with spontaneous 

abortion is based principally on the Borja-Aburto et 

al. (1999) study, which has the strength of the prospective nested case-control design, and additional 

supporting evidence provided by the Yin et al. (2008) 

data, as well as the occupational studies without 

blood Pb measurements. There is limited evidence 

that paternal blood Pb >31 μg/dL is associated 

with spontaneous abortion. A positive association 

between paternal blood Pb >31 μg/dL was reported 

in one occupational study (Lindbohm et al. 1991a, 

Lindbohm et al. 1991b) and two retrospective studies that determined exposure by employment but 

lack blood Pb data (Beckman and Nordstrom 1982, 

Al-Hakkak et al. 1986). Two other studies have 

reported no association at similar blood Pb levels 

(i.e., >25μg/dL Selevan et al. 1984, Alexander et 

al. 1996a)). The conclusion of limited evidence that 

paternal blood Pb >31 is associated with spontaneous abortion is based mainly on the retrospective 

nested case-control study by Lindbohm et al. (1991a, 

1991b), with support from the occupational studies 

without blood Pb measurements.

The principal evidence supporting an association 

between maternal blood Pb levels and spontaneous abortion relies primarily on the Borja-Aburto et 

al. (1999) prospective nested case-control study of 

women in Mexico. The study reported evidence for 

a dose response (p-trend=0.03) and significant ORs 

for spontaneous abortion (ORs of 2.3, 5.4, and 12.2) 

with maternal blood Pb during the first trimester of 

pregnancy of 5-9, 10-14 and ≥15 μg/dL compared 

to <5.0 μg/dL in the reference group (Borja-Aburto 

et al. 1999). The analysis highlighted the careful 

matching of the timing of exposure measurements 

in the 35 cases with controls and was adjusted for a 

range of potential confounders, including age, smoking, alcohol consumption, and physical activity. Four 

retrospective studies support an association between 

maternal Pb exposure and spontaneous abortion; 
Reproductive 

Effects

108 NTP Monograph on Health Effects of Low-Level Lead

however, no blood Pb data were included, and exposure was determined by employment or residence 

(Nordstrom et al. 1978, 1979, Driscoll 1998, Tang and 

Zhu 2003). Additional support is provided by a casecontrol study that reported plasma Pb levels with no 

blood Pb data; maternal plasma Pb (5.3 μg/dL in the 

40 case women compared to 4.5 μg/dL in the 40 controls) was significantly higher in women with anembryonic pregnancy (i.e., a pregnancy that appears 

normal in early stages, with the embryo that is visible by ultrasound never developing (Yin et al. 2008)). 

However, the study reports high levels of plasma 

Pb suggesting either very high blood Pb levels or a 

potential problem in study performance or reporting. 

Several studies with mean blood Pb levels from 4 to 

16 μg/dL reported no association between maternal 

blood Pb levels and spontaneous abortion. Maternal 

blood Pb during the first trimester was not associated 

with spontaneous abortion at mean blood Pb levels of 

4 μg/dL in a recent prospective study of 351 women 

in Iran (Vigeh et al. 2010). A prospective study of 

women residing in a Pb-smelting community reported 

that maternal blood Pb was not statistically different 

between cases of spontaneous abortion (11.3 μg/dL) 

and controls (10.8 μg/dL) (McMichael et al. 1986). 

Two retrospective studies that compared recalled 

pregnancy outcomes and concurrent blood Pb levels 

(means of 6 μg/dL in Lamadrid-Figueroa et al. (2007) 

and 16 μg/dL in Murphy et al. (1990)) reported that 

concurrent blood Pb in women was not associated 

with previous history of spontaneous abortion.

The principal evidence supporting an association between paternal blood Pb levels and spontaneous abortion relies on three studies that report an 

association with paternal Pb exposure. In a retrospective analysis of blood Pb measurements in men occupationally exposed to Pb restricted to within 1 year 

of the spermatogenesis period relevant to a given 

pregnancy, paternal blood Pb >31 μg/dL was associated with higher odds ratio of spontaneous abortion 

(OR=3.8 (95% CI: 1.2, 12)) compared to men with 

blood Pb <21 μg/dL (Lindbohm et al. 1991b). Two retrospective studies of men with occupational exposure 

to Pb also reported an association between paternal 

Pb exposure and spontaneous abortion; however, 

exposure was determined by employment, and the 

studies lack blood Pb data (Beckman and Nordstrom 

1982, Al-Hakkak et al. 1986). Two additional occupational studies that include blood Pb levels did not 

detect an association between spontaneous abortion 

and paternal blood Pb from 25 to >60 μg/dL (Selevan 

et al. 1984, Alexander et al. 1996a).

In analyses of other biomarkers of Pb exposure, 

Figueroa et al. (2007) found that women with higher 

ratio of Pb in plasma to Pb in blood had a greater 

incidence rate for previous abortion (incidence rate 

ratio=1.18; p=0.02 for 1 SD increase); however, when 

examined individually, neither blood, plasma, tibia, 

nor patella Pb levels were related to spontaneous 

abortions. In a case-control study that also reported 

plasma Pb levels, maternal plasma Pb (5.3 μg/dL in 

the 40 case women compared to 4.5 μg/dL in the 

40 controls) was significantly higher in women with 

anembryonic pregnancy (Yin et al. 2008); however, 

the study does not report Pb levels in whole blood, 

reports high levels of plasma Pb suggesting either 

very high blood Pb levels or a potential problem in 

study performance or reporting, and ratios of Pb in 

plasma to Pb in whole blood vary widely (from 0.27% 

to 0.70%), so it is unclear how plasma Pb data relates 

to the blood Pb data described above (HernandezAvila et al. 1998). Placental Pb was significantly higher 

in women that had a previous miscarriage (Gundacker 

et al. 2010).

Summary of Support for Conclusions

Animal data were not located that support an association between Pb and spontaneous abortion, although 

prenatal exposure to Pb has been associated with 

decreased litter sizes, decreased pup survival, and 

increased embryonic resorption at very high blood 

Pb levels (>200μg/dL in mice and rats; see U.S. EPA 

2006 for recent reviews of the animal data, ATSDR 

2007). As described above, there are few human 

studies with blood Pb data that evaluate the potential association with spontaneous abortion. The conclusions that there is limited evidence that maternal 

blood Pb <10 μg/dL and paternal blood Pb >31 μg/dL 

are associated with spontaneous abortion are based 

primarily on two key studies: the Borja-Aburto et al.

(1999) prospective nested case-control study and 

Lindbohm et al. (1991a) retrospective nested casecontrol study. Additional support for the association 

is provided by several studies that determine exposure by occupation or residence rather than by blood 

Pb data. In addition, some studies with blood Pb data 

did not find an association between maternal or 

paternal blood Pb levels and spontaneous abortion. 
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 109

The inconsistency of the results contributes to the 

determination of limited evidence. Although not all 

studies considered confounders, a lack of adjustment for confounders does not appear to explain 

the lack of consistency, because studies that both 

supportive for Pb effects on spontaneous abortion 

(e.g., Borja-Aburto et al. 1999) and studies that are 

not supportive for effects of Pb (e.g., data from Vigeh 

et al. 2010) included adjustments for maternal age, 

smoking, and other factors. The 2007 ATSDR Toxicological Profile for Lead (ATSDR 2007) and 2006 EPA 

AQCD for Lead (U.S. EPA 2006) both highlight the lack 

of consistency of the data on spontaneous abortion; 

however, the Borja-Aburto et al. (1999) study is highlighted as a well-conducted prospective case-control 

study supporting a significant relationship between 

maternal blood Pb and spontaneous abortion.

8.3.6 Stillbirth

There is inadequate evidence to evaluate the potential association between blood Pb at any level and 

incidence of stillbirth. Few studies investigate the 

potential association between Pb exposure and 

stillbirth, and only a handful have blood Pb or other 

biological monitoring data (see Stillbirth section 

of Appendix E: Reproductive and Developmental 

Effects). Of the studies with blood Pb data, none of 

the studies support an association between maternal or paternal blood Pb and stillbirth. For example, a 

prospective study of women residing in a Pb-smelting 

community reported that maternal blood Pb levels 

were not significantly different between cases of stillbirth (10.3 μg/dL during pregnancy and 7.2 μg/dL at 

delivery) and controls (9.9 μg/dL during pregnancy 

and 10.4 μg/dL at delivery) (McMichael et al. 1986). 

In a retrospective study that compared recalled pregnancy outcome and concurrent blood Pb levels (means 

of 16 μg/dL in the residents in a Pb-smelter community and 5.1 μg/dL in referents), Murphy et al. (1990) 

reported that concurrent blood Pb was not associated 

with previous history of stillbirth (OR=1.0 (95% CI: 0.6,

1.5)). There are some examples of Pb-associated 

increases in stillbirth in animal literature at very high 

doses (e.g., >200μg/dL in Sprague-Dawley rats; see 

U.S. EPA 2006 for recent reviews of the animal data, 

ATSDR 2007). The data set available to evaluate this 

association is small and includes a single prospective 

study. The 2007 ATSDR Toxicological Profile for Lead 

(ATSDR 2007) and 2006 EPA AQCD for Lead (U.S. EPA 

2006) do not have specific conclusions on the potential association between Pb exposure and stillbirth.

8.3.7 Fetal Growth and Lower Birth Weight

There are several measures of reduced prenatal 

growth or intrauterine growth restriction: small for 

gestational age (babies with birth weight below the 

10th percentile for a given gestational age), lower birth 

weight (evaluated as a continuous variable), low birth 

weight (<2,500 g after at least 37 weeks of gestation), 

and low birth weight adjusted for gestation length. For 

this evaluation, any indication of reduced fetal growth 

is included below.

There is sufficient evidence that maternal blood 

Pb levels <5 μg/dL are associated with reduced fetal 

growth and lower birth weight. The association 

between maternal Pb exposure and reduced fetal 

growth is supported by a number of prospective 

studies with maternal blood Pb data during pregnancy (Dietrich et al. 1987, Bornschein et al. 1989, 

Jelliffe-Pawlowski et al. 2006, Gundacker et al. 2010), 

a large retrospective cohort study of over 43,000 

mother-infant pairs with mean maternal blood Pb 

level of 2.1 μg/dL (Zhu et al. 2010), and a number 

of cross-sectional studies with maternal or umbilical cord blood Pb at delivery (Bellinger et al. 1991, 

Neuspiel et al. 1994, Odland et al. 1999, Osman et 

al. 2000, Srivastava et al. 2001, Chen et al. 2006, 

Zentner et al. 2006, Al-Saleh et al. 2008b) (see Fetal 

Growth and Lower Birth Weight section of Appendix 

E: Reproductive and Developmental Effects). There 

is also one prospective study (Sowers et al. 2002) 

and several cross-sectional studies that report no 

association between maternal blood Pb and reduced 

fetal growth at blood Pb levels <10 μg/dL and similar results at higher blood Pb levels. Although the 

results are not entirely consistent across studies, the 

supporting evidence outlined above with maternal 

or umbilical cord blood Pb levels <10 μg/dL from 

multiple prospective, retrospective, and crosssectional studies provides sufficient evidence at 

maternal blood Pb levels <10 μg/dL are associated 

with reduced fetal growth and lower birth weight. 

The large retrospective study of 43,288 motherinfant pairs from the New York State Heavy Metals 

Registry contributes substantially to the conclusions, 

because the study reported a significant association 

between maternal blood Pb (mean, 2.1 μg/dL) and 

lower birth weight in such a large cohort from a study 
Reproductive 

Effects

110 NTP Monograph on Health Effects of Low-Level Lead

that included adjustment for multiple potential confounders (Zhu et al. 2010). The evidence supporting an effect of maternal Pb exposure on reduced 

fetal growth is further strengthened by a number of 

studies from a population in Mexico demonstrating 

that maternal bone Pb is associated with lower birth 

weight, birth length, and head circumference. These 

studies provide limited evidence that maternal bone 

Pb levels >15.1 μg/g (tibia Pb) are associated with 

reduced fetal growth. Unfortunately, the evidence to 

evaluate the potential association between maternal 

bone Pb and low birth weight is restricted to a single 

group. All five of the studies that include maternal 

bone Pb measurements report a significant association between increased maternal bone Pb levels and 

lower fetal growth, but they are all studies of women 

attending one of three hospitals in Mexico City from 

1994 to 1995. There is inadequate evidence that 

paternal blood Pb at any level is associated with 

reduced fetal growth, because few studies of birth 

weight or related endpoints have included paternal 

Pb exposure data, and the available studies do not 

support an association with blood Pb in men.

Most prospective or retrospective studies that 

evaluated the association between maternal blood 

Pb levels of ≤10 μg/dL during pregnancy with measures of fetal growth found an inverse association 

(i.e., higher Pb levels were related to reduced fetal 

growth), although one study did not find an effect 

of blood Pb. Maternal blood Pb (mean, 2.5 μg/dL) at 

34-38 weeks of gestation (n=53) in women at General 

Hospital in Vienna was associated with lower birth 

weight (Gundacker et al. 2010). Maternal blood Pb 

levels (mean, 7.5 μg/dL) of 861 women from the 

Cincinnati Lead Study at 16-28 weeks of gestation 

(from the second trimester into the start of the third 

trimester) were associated with decreased birth 

weight (Bornschein et al. 1989). This result was also 

supported in a smaller analysis: higher maternal 

blood Pb levels (mean, 8.3 μg/dL) sampled at the 

first prenatal visit in women (n=185) from the Cincinnati Lead Study were correlated with lower birth 

weight (Dietrich et al. 1987). Maternal blood Pb 

≥10 μg/dL during pregnancy in women in the California Pb surveillance program (n=262) was associated 

with a greater odds ratio for small for gestational age 

(OR=4.2 (95% CI: 1.3, 13.9)); however, the association was not significant when analyzed for low birth 

weight (OR=3.6 (95% CI: 0.3, 40)) (Jelliffe-Pawlowski 

et al. 2006). Maternal blood Pb (mean, 2.1 μg/dL) 

during pregnancy or at birth was associated with 

lower birth weight in a large retrospective study of 

43,288 mother-infant pairs from the New York State 

Heavy Metals Registry (Zhu et al. 2010). The large retrospective study of over 43,000 mother-infant pairs 

from Zhu et al. (2010) contributes substantially to the 

conclusions because the study reported a significant 

association between a maternal blood Pb level well 

below 10 μg/dL and lower birth weight in very large 

cohort from a study that included adjustment for 

multiple potential confounders, including maternal 

age, race, parity, smoking, drug abuse, infant sex, 

and participation in financial assistance as a measure 

of socioeconomic status (Zhu et al. 2010). Maternal 

blood Pb (mean, 1.1 μg/dL) sampled at 12, 20, and 

28 weeks of gestation, and the change in blood Pb 

levels over pregnancy in 705 women in Camden, NJ, 

were not associated with low birth weight or small for 

gestational age (Sowers et al. 2002). Other than the 

clear difference in the sample size for the Zhu et al.

study (2010), there is no obvious difference in blood 

Pb levels, or in statistical adjustments, between the 

five studies that support an effect of maternal blood 

Pb levels <10 μg/dL and the one that does not.

Additional studies that sampled maternal or 

umbilical cord blood Pb at delivery also reported an 

association between blood Pb levels of ≤10 μg/dL 

and measures of fetal growth. Studies of cohorts with 

higher mean blood Pb levels (i.e., >10 μg/dL) are not 

described below because the discussion focuses on 

the evidence at blood Pb levels <10 μg/dL. However, 

as with the prospective studies described above, 

the results are not consistent across all studies. The 

principal studies with maternal blood Pb levels at 

delivery are listed below. The data on umbilical cord 

blood and blood Pb and higher mean blood Pb levels 

(i.e., >10 μg/dL) are not detailed below because they 

present similar results, but all studies are included 

in the Fetal Growth and Lower Birth Weight section 

of Appendix E: Reproductive and Developmental 

Effects. Mean maternal blood Pb levels at delivery of 

2-13 μg/dL were associated with lower birth weight 

in mother-infant pairs from a case-control study of 30 

births with intrauterine growth restriction (referred 

to as intrauterine growth retardation by the authors) 

and 24 normal births in India (Srivastava et al. 2001); 

a combined population from Russia and Norway 

(n=262) (Odland et al. 1999); and a Pb surveillance 
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 111

program in Taiwan (n=72 low-birth-weight infants 

of 1,611 births) (Chen et al. 2006). Mean maternal 

blood Pb levels at delivery of 6-10 μg/dL were not 

associated with birth weight, birth length, or head 

circumference in mother-infant pairs from women 

in Cleveland (n=185) (Ernhart et al. 1986); Karachi 

(n=73) (Rahman and Hakeem 2003); or Mexico City 

(n=272-533) (Cantonwine et al. 2010b).

Few studies of fetal growth include paternal 

blood Pb levels, and the available evidence provides 

little support for an association with blood Pb in 

men. Paternal occupational exposure estimated by 

job category was associated with low birth weight 

and small for gestational age in a study of 742 births 

in the Baltimore-Washington Infant Study (Min et al.

1996). In two other studies that classified exposure 

by paternal job category, paternal occupation Pb 

exposure was not associated with low birth weight 

in a study of members of the printers’ unions in Oslo, 

Norway (n=6,251 births) (Kristensen et al. 1993) 

or occupational exposure in Norway with possible 

paternal Pb exposure (n=35,930 births, although 

maternal Pb exposure was associated with low birth 

weight) (Irgens et al. 1998). Paternal blood Pb (mean, 

13 μg/dL) was not associated with small for gestational age or low birth weight in data from a Pb surveillance program in Taiwan (n=72 low-birth-weight 

infants of 1,611 births) (Chen et al. 2006). Low birth 

weight was associated with maternal blood Pb levels 

in the Chen et al. (2006) study and occupational Pb 

exposure in the Irgens et al. (1998) study. Paternal 

blood Pb was not associated with birth weight or 

small for gestational age; however, blood Pb levels 

>25 μg/dL for more than 5 years was associated with 

increased relative risk of low birth weight in a study 

of workers (n=747) reporting to the New York State 

Heavy Metals Registry compared to a reference group 

of bus drivers (Lin et al. 1998).

A number of studies of fetal growth include measures of exposure other than blood Pb data. Data from 

several studies suggest that maternal bone Pb may 

be more consistently associated with reduced fetal 

growth compared to blood Pb; however, the data are 

restricted to a single population. In a series of studies of women from one of three hospitals in Mexico 

City, higher maternal bone Pb measurements, but 

not maternal blood Pb levels, were associated with 

lower measures of fetal growth (Gonzalez-Cossio 

et al. 1997, Hernandez-Avila et al. 2002, Kordas et 

al. 2009, Cantonwine et al. 2010b). Higher maternal 

tibia Pb (mean, 9.8 μg/g) was associated with lower 

birth weight at levels >15.1 μg/g (Gonzalez-Cossio et 

al. 1997) and shorter birth length at levels >16.6 μg/g 

(Hernandez-Avila et al. 2002). Higher maternal patellar Pb (mean, 14 μg/dL) was associated with smaller 

head circumference at levels >24.7 μg/g (Hernandez-Avila et al. 2002). In further study the authors 

reported that the H62D genotype may enhance the 

adverse effect of Pb (Cantonwine et al. 2010b), and 

folate may decrease the adverse effect of Pb (Kordas 

et al. 2009). In a study of 100 mother-infant pairs in 

France, maternal and infant hair Pb levels were not 

associated with small for gestational age (Huel et al.

1981).

Several studies have investigated the association 

between placental Pb levels and fetal growth. Two 

studies (n=53 and n=79, respectively) reported a 

relationship between higher placental Pb and lower 

birth weight, shorter length, and/or smaller head 

circumference (Ward et al. 1990, Gundacker et al.

2010). Two case-control studies reported higher 

placental Pb levels in births with fetal growth restriction (n=20) (Llanos and Ronco 2009) or intrauterine 

growth restriction (referred to as intrauterine growth 

retardation by the authors) (n=50) (Richter et al.

1999). Three studies reported a lack of an association 

between placental Pb and birth weight: 161 women 

from the Yugoslavia Prospective Study (Loiacono et al.

1992); 262 women constituting a combined population from Russia and Norway (Odland et al. 2004); 

and 126 births at the Birmingham Maternal Hospital 

(Wibberley et al. 1977). It is difficult to determine of 

usefulness of placental Pb as a measure of exposure 

rather than blood Pb for low birth weight because 

most studies do not report exposure data for both 

measures, and the results are inconsistent. In the one 

study that did include both placental Pb and maternal blood Pb levels (Gundacker et al. 2010), low birth 

weight was associated with both maternal blood Pb 

levels and placental Pb, as described above.

Summary of Support for Conclusions

Animal data support an association between Pb 

and lower birth weight at high blood Pb levels (54-

300μg/dL in squirrel monkeys, mice, and rats; see 

U.S. EPA 2006 for recent reviews of the animal data, 

ATSDR 2007). As described above, a number of epidemiological studies report effects of Pb on fetal growth 
Reproductive 

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112 NTP Monograph on Health Effects of Low-Level Lead

or birth weight. The conclusion of sufficient evidence 

that maternal blood Pb <10 μg/dL is associated with 

reduced fetal growth is based on four prospective 

studies with maternal blood Pb during pregnancy, a 

large retrospective cohort study, and a number of 

cross-sectional studies with maternal or umbilical 

cord blood Pb at delivery. Although the results are not 

entirely consistent across studies, and some studies 

report that prenatal blood Pb levels <10 μg/dL are not 

associated, the supporting studies provide sufficient 

evidence that maternal blood Pb levels <10 μg/dL are 

associated with reduced fetal growth. In particular, 

the large retrospective study of 43,288 mother-infant 

pairs from the New York State Heavy Metals Registry 

contributes substantially to the conclusion of sufficient evidence because it is based on such a large 

cohort with a low mean blood Pb level (2.1 μg/dL),

and the analyses adjust for multiple potential confounders, including maternal age, race, parity, smoking, drug abuse, infant sex, and participation in financial assistance as a measure of socioeconomic status 

(Zhu et al. 2010). Additional support is provided by 

a number of cross-sectional studies with maternal 

or umbilical cord blood Pb <10 μg/dL at delivery, as 

well as a group of studies from a single group that 

demonstrate a relationship between higher maternal 

bone Pb and lower fetal growth. The conclusion of 

inadequate evidence that paternal blood Pb at any 

level is associated with fetal growth is based on a 

small number of studies and general lack of observed 

effect. The NTP conclusion of sufficient evidence 

for effects of maternal blood Pb <10 μg/dL on fetal 

growth is stronger than the 2007 ATSDR Toxicological 

Profile for Lead (ATSDR 2007) and the 2006 EPA AQCD 

for Lead (U.S. EPA 2006), in which the evidence was 

characterized as inconsistent. The NTP conclusion of 

inadequate evidence for effects of parental blood Pb 

on fetal growth is consistent with the 2007 ATSDR 

Toxicological Profile for Lead (ATSDR 2007) and the 

2006 EPA AQCD for Lead (U.S. EPA 2006).

8.3.8 Preterm Birth and Gestational Age

There is limited evidence that maternal blood Pb 

levels <10 μg/dL are associated with preterm birth 

or reduced gestational age, because of inconsistent 

results in studies with low blood Pb levels. Increasing 

maternal blood Pb levels during pregnancy were associated with preterm birth or reduced gestational age 

in two prospective studies (Cantonwine et al. 2010a, 

Vigeh et al. 2011) and five cross-sectional studies 

(Satin et al. 1991, Fagher et al. 1993, Odland et al.

1999, Torres-Sanchez et al. 1999, Patel and Prabhu 

2009) with exposure data from maternal or umbilical 

cord blood Pb at delivery with mean blood Pb levels 

<10 μg/dL (see the Preterm section of Appendix E: 

Reproductive and Developmental Effects). However, 

a number of cross-sectional studies and several prospective studies (e.g., Bornschein et al. 1989, Sowers 

et al. 2002) report no association between maternal 

blood Pb and preterm birth at the same blood Pb 

levels. In addition, the large retrospective study of 

43,288 mother-infant pairs from the New York State 

Heavy Metals Registry did not find an association 

between maternal blood Pb (mean, 2.1 μg/dL) and 

preterm birth (Zhu et al. 2010). There is inadequate 

evidence that paternal blood Pb at any level is associated with preterm birth, because of the small number of studies and general lack of observed effects in 

studies that report blood Pb levels in men.

Studies that compare maternal blood Pb levels 

during pregnancy with preterm births report mixed 

results; four studies found an association between 

blood Pb (mean, 4-10 μg/dL) and preterm birth or 

decreased gestational age, and three did not find an 

effect of blood Pb (mean, 1-23 μg/dL). The data are 

also inconsistent when examined by maternal Pb levels from a specific trimester. Higher maternal blood 

levels (mean, 6-7 μg/dL) in the first and second trimester, but not the third trimester, were associated 

with decreases in gestational age in a prospective 

study of 327 women in Mexico City (Cantonwine et 

al. 2010a). Higher maternal blood levels in the first 

trimester was associated with preterm birth and with 

decreases in gestational age in a prospective study 

of 348 women with mean blood of 4 μg/dL in Iran 

(Vigeh et al. 2011). Maternal blood Pb ≥10 μg/dL was 

associated with preterm birth in a study of women in 

the California Pb surveillance program (n=262); however, in contrast to the data from Mexico City and Iran, 

the effect was significant during the second and third 

trimesters, but not during the first trimester (JelliffePawlowski et al. 2006). Higher maternal blood Pb 

levels (mean, 8.3 μg/dL) sampled at the first prenatal visit in women (n=185) from the Cincinnati Lead 

Study were correlated with decreases in gestational 

age (Dietrich et al. 1987); the results were reported 

as part of an analysis of neurological data, and the 

study group was a subset of women evaluated in a 
Reproductive 

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NTP Monograph on Health Effects of Low-Level Lead 113

later study that did not find a significant association 

(Bornschein et al. 1989). Maternal blood Pb levels 

(mean, 7.5 μg/dL) at 16-28 weeks (second trimester 

into start of third trimester) of gestation were not 

associated with gestational age (Bornschein et al.

1989). Maternal blood Pb (mean, 1.1 μg/dL) sampled 

at 12 weeks (first trimester), 20 weeks (second trimester), and 28 weeks (third trimester) of gestation 

in 705 women in Camden, NJ, was not associated 

with preterm birth (Sowers et al. 2002). Maternal 

blood Pb levels at mid-pregnancy (second trimester, 

mean=20 μg/dL) and delivery (mean, 23 μg/dL) were 

not associated with preterm birth in women from the 

Yugoslavia Prospective Study (n=907) (Factor-Litvak 

et al. 1991). Excluding the Dietrich et al. (1987) study, 

three prospective or retrospective studies support 

an association between maternal blood Pb from 4 

to 10 μg/dL during pregnancy and preterm birth (Jelliffe-Pawlowski et al. 2006, Cantonwine et al. 2010a, 

Vigeh et al. 2011), and three studies do not support 

an association with maternal blood Pb (Bornschein 

et al. 1989, Factor-Litvak et al. 1991, Sowers et al.

2002). The studies that do not support a relationship 

with Pb exposure are older, but all of these studies 

considered and adjusted for potential confounders, 

including maternal age, smoking, and other factors. 

The studies that do not support a relationship with 

Pb exposure also have larger sample sizes (n= 705-

907) than the studies that support an effect of Pb 

(n=262-348).

Additional studies that sampled maternal or 

umbilical cord blood Pb at delivery also reported 

inconsistent results for these indicators of Pb exposure 

and preterm birth. Mean Pb levels from 1 to 15 μg/dL

in maternal blood or umbilical cord blood at delivery 

were associated with preterm birth or reduced gestational age in mother-infant pairs from studies in several locations: five cities in California (n=723) (Satin et 

al. 1991); the Port Pirie, Australia, birth cohort study 

(n=721) (McMichael et al. 1986); Rolla and Columbia, 

MO (n=502) (Fahim et al. 1976); Mexico City (n=620) 

(Torres-Sanchez et al. 1999); a combined population from Russia and Norway (n=262) (Odland et al.

1999); Glasgow (n=236) (Moore et al. 1982); a hospital in India (n=205) (Patel and Prabhu 2009); and a 

small combined population from Poland and Sweden 

(gestational age) (n=17 preterm and n=13 controls)

(Fagher et al. 1993). Mean Pb levels from 2 to 30 μg/dL

in maternal blood at delivery or umbilical cord blood 

were not associated with preterm delivery or reduced 

gestational age in mother-infant pairs from the New 

York State Heavy Metals Registry (n=43,288) (Zhu et al.

2010); the Brigham and Women’s Hospital (n=3,503) 

(Bellinger et al. 1991); Louisville, KY, General Hospital (n=635) (Angell and Lavery 1982); Memphis 

(n=102) (Jones et al. 2010); or New York City (n=100) 

(Rajegowda et al. 1972). The database of studies that 

determined exposure from maternal or umbilical 

cord blood Pb at delivery includes a number of studies that do not report appropriate adjustments (e.g., 

Fahim et al. 1976), but there are also positive (e.g., 

Torres-Sanchez et al. 1999) and negative studies (e.g., 

Zhu et al. 2010) for the effects of Pb that adjusted for 

potential confounders, including maternal age, parity, 

and smoking.

Few studies address the relationship between 

paternal blood Pb and preterm births, and the available data do not support a relationship between blood 

Pb in men and preterm birth. In a study of over 3,000 

births to male workers in the New York State Heavy 

Metals Registry, Lin et al. (1998) reported that parental blood Pb >25 μg/dL did not affect the relative risk 

of preterm births (RR=0.89 (95% CI: 0.64, 1.26)) compared to a reference group of bus drivers; however, 

continued blood Pb >25 μg/dL for more than 5 years 

was associated with increased relative risk of preterm 

births (RR=3.03 (95% CI: 1.35, 6.77)) compared to 

workers that did not consistently report a blood Pb 

level >25 μg/dL. In a similar worker surveillance program in China, paternal blood Pb (mean, 14 μg/dL)

was not associated with preterm birth (Chen et al.

2006). Paternal Pb exposure determined by paternal 

job category was also not associated with preterm 

birth in studies of members of the printers’ unions 

in Oslo, Norway (n=6,251 births) (Kristensen et al.

1993) or births from the National Natality Survey and 

Fetal Mortality Survey in the United States (Savitz 

et al. 1989). Occupational exposure in Norway with 

possible paternal Pb exposure (n=35,930 births) was 

associated with longer-term births, and maternal Pb 

exposure was associated with preterm birth (Irgens 

et al. 1998).

Several studies also address other measures of 

exposure such as hair or placental Pb levels. Huel et 

al. (1981) reported higher hair Pb levels in mothers 

and offspring from preterm births than from normal births. Two studies reported higher placental 

Pb levels in preterm birth (or combined analysis of 
Reproductive 

Effects

114 NTP Monograph on Health Effects of Low-Level Lead

preterm births and births with premature rupture 

of membranes) than in births with normal delivery 

(Ward et al. 1990, Falcón et al. 2003). However, four 

other cross-sectional studies did not find a significant 

relationship between placental tissue Pb concentrations and preterm births (Fahim et al. 1976, Ward et 

al. 1987, Baghurst et al. 1991, Loiacono et al. 1992). 

Cantonwine (2010a) did not find a significant association between maternal plasma Pb and preterm 

birth, although the relationship was significant with 

maternal blood Pb levels.

Summary of Support for Conclusions

Animal data were not located that support an effect 

of Pb on preterm delivery, although potentially 

related endpoints such as pup survival and birth 

weight were adversely affected at high blood Pb levels (54-300μg/dL in squirrel monkeys, mice, and rats; 

see U.S. EPA 2006 for recent reviews of the animal 

data, ATSDR 2007). As described above, the human 

data are not consistent for an effect of Pb on preterm birth. Although a number of prospective studies 

with maternal blood Pb levels during pregnancy and 

cross-sectional studies with umbilical cord blood Pb 

levels at delivery reported an association between 

prenatal blood Pb levels <10 μg/dL and preterm birth, 

the conclusion of limited evidence is based on the 

inconsistent results and because a large retrospective 

study did not find an association between maternal 

blood Pb levels and preterm birth. In particular, the 

large retrospective study of the New York State Heavy 

Metals Registry included 43,288 mother-infant pairs 

and did not find an association between maternal 

blood Pb (mean, 2.1 μg/dL) and preterm birth (Zhu et 

al. 2010). The conclusion of inadequate evidence that 

paternal blood Pb at any level is associated with preterm birth or reduced gestational age is based on a 

small number of studies and general lack of observed 

effect. Of the five studies located that address paternal exposure and preterm birth, three report no effect, 

one reports a Pb-associated increase in gestational 

age, and one reports an association with persistently 

elevated paternal Pb (>25 μg/dL for 5 years) and preterm birth. The NTP conclusion of limited evidence 

for effects of maternal or umbilical cord blood Pb 

<10 μg/dL on preterm birth is in line with the 2007 

ATSDR Toxicological Profile for Lead (ATSDR 2007) and 

the 2006 EPA AQCD for Lead (U.S. EPA 2006), in which 

the evidence was characterized as inconsistent.

8.3.9 Endocrine Effects

There is inadequate evidence to evaluate the 

potential association between blood Pb and major 

endocrine or changes in hormone levels, because of 

inconsistency of effects across available studies (see 

Endocrine section of Appendix E: Reproductive and 

Developmental Effects). The data are inconsistent 

for the effects of Pb on luteinizing hormone (LH), 

follicle-stimulating hormone (FSH), testosterone (T), 

and other hormones, including estradiol-17β (E2), 

prolactin (PRL), thyroid-stimulating hormone (TSH), 

thyroxin (T4), triiodothryonine (T3), parathyroid hormone, inhibin B, and insulin-like growth factor 1 (IGF1). There are inadequate studies of endocrine effects 

in general to determine if the lack of consistency in 

the data reflects variation in the potential interaction 

with Pb or whether it is due to well-known hormonal 

variation and cyclicality on a daily, monthly, and seasonal basis.

In studies that examined the relationship between 

blood Pb and LH or FSH, the results are inconsistent. 

Blood Pb levels (mean, 30-69 μg/dL) were not associated with serum levels of LH or FSH in a number of 

studies of men with occupational Pb exposure (Assennato et al. 1986, Ng et al. 1991, Gennart et al. 1992a, 

Alexander et al. 1996b, Telisman et al. 2000, Mahmoud 

et al. 2005, Naha and Manna 2007, Hsieh et al. 2009) 

and not at lower blood Pb levels (mean, 3-10 μg/dL) 

in men or women recruited at infertility clinics (Chang 

et al. 2006, Meeker et al. 2010, Mendiola et al. 2011) 

or men without occupational Pb exposure (Telisman 

et al. 2007). Basal levels of LH and FSH did not differ 

between Pb workers and a reference group; however, 

gonadotropin-releasing hormone-stimulated FSH was 

decreased in Pb workers with median blood Pb levels 

of 31 μg/dL (Erfurth et al. 2001). In a study of 23 Pb 

workers serum (mean, 60-73 μg/dL), LH was increased 

compared to a reference group (mean, 17 μg/dL) 

(Rodamilans et al. 1988). Several studies have reported 

that FSH was increased (Cullen et al. 1984, McGregor 

and Mason 1990, McGregor and Mason 1991, De 

Rosa et al. 2003) or decreased (Gustafson et al. 1989) 

in men at blood Pb levels of 20-45 μg/dL compared 

to a reference group. Results of a study by Krieg et al.

(2007) of women from NHANES III suggest that the 

effect of Pb on FSH and LH is modified by reproductive 

status (e.g., menopausal status) or external hormones. 

FSH was increased with increasing blood Pb in women 

from NHANES III (mean blood Pb, 2.8 μg/dL) but 
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 115

decreased with increasing blood Pb in women taking 

birth control pills (Krieg 2007). LH was increased with 

increasing blood Pb in postmenopausal women from 

NHANES III, and LH was not associated with blood Pb 

in other women (Krieg 2007).

The data are inconsistent for the effects of Pb on T, 

thyroid hormones (TSH, T4, and T3), and for other hormones, including E2 and PRL. Blood Pb levels (mean, 

30-69 μg/dL) were not associated with serum T levels 

in a number of studies of men with occupational Pb 

exposure (Assennato et al. 1986, Ng et al. 1991, Gennart et al. 1992a, Alexander et al. 1996b, Mahmoud et 

al. 2005, Naha and Manna 2007, Hsieh et al. 2009). 

Several studies have reported lower basal or stimulated T with occupational exposure in the same blood 

Pb range (Braunstein et al. 1978, Rodamilans et al.

1988, Telisman et al. 2000). At lower blood Pb levels 

(<10 μg/dL), exposure was associated with increased 

serum T in a study of 240 men without occupational 

Pb exposure (Telisman et al. 2007) and in 219 men 

recruited from infertility clinics, but not after adjustment for exposure to other metals (Meeker et al.

2010). However, Mendiola et al. (2011) did not find 

an association between blood Pb (mean, 10 μg/dL) 

and serum T in 60 men recruited at an infertility clinic. 

Occupational Pb exposure in men at mean blood Pb 

levels 30-40 μg/dL were not associated with E2 in one 

study (Mahmoud et al. 2005) but was associated with 

decreased E2 in another study (Telisman et al. 2000). 

At blood Pb levels <10 μg/dL, Pb was associated 

with increased E2 in a case-control study of women 

recruited at an infertility clinic (n=64) and controls 

from a postpartum clinic (n=83) in Taiwan (Chang et 

al. 2006). Also, at blood Pb levels <10 μg/dL, E2 was 

increased and PRL was decreased in association with 

Pb in men without occupational Pb exposure (Telisman et al. 2007). In men with occupational exposure 

to Pb and mean Pb levels from 30 to 60 μg/dL, blood 

Pb was not associated with PRL or did not differ from 

a reference group (Assennato et al. 1986, Roses et 

al. 1989, Ng et al. 1991, Telisman et al. 2000). Serum 

TSH was elevated in Pb gas station workers with blood 

Pb mean of 51 μg/dL compared to a reference group 

(Singh et al. 2000). In contrast, higher blood Pb levels 

were related to lower TSH in women, but not in men, 

among people in Quebec that regularly eat freshwater fish; T3 and T4 were not associated with Pb levels 

<10 μg/dL (Abdelouahab et al. 2008). Serum levels of 

TSH, T3, or T4 did not differ between men with high 

occupational Pb (mean, 51 μg/dL) and a reference 

group (21 μg/dL) (Gennart et al. 1992a); in male Pb 

workers with mean blood Pb of 31 μg/dL (Erfurth et 

al. 2001); in male Pb workers with mean blood Pb 

of 24 μg/dL (Schumacher et al. 1998); in a study of 

24 newborns with mean blood Pb levels of 6 μg/dL

(Iijima et al. 2007); or in 68 children <8 years of age 

with range of blood Pb from 2 to 77 μg/dL (Siegel et al.

1989). Two studies of men with occupational Pb exposure (mean Pb level, 42-51 μg/dL) reported opposite 

results: T4 and free T4 were higher in 75 Pb workers 

than in 68 matched controls (Lopez et al. 2000); lower 

T4 and free T4 were associated with higher blood Pb 

in a study of 54 workers at a brass foundry (Robins 

et al. 1983). In 309 mother-children pairs from the 

Yugoslavia Prospective Study, higher maternal T4 was 

associated with lower blood Pb in women from a Pbsmelting town (median blood Pb, 20 μg/dL) but not in 

a reference town (median blood Pb, 6 μg/dL) (Lamb 

et al. 2008). Cumulative Pb exposure was associated 

with increased serum inhibin B levels in two studies 

of male Pb workers (n=181 (Hsieh et al. 2009); n=68 

(Mahmoud et al. 2005)).

There are few studies of Pb and hormone levels in children. Two available studies suggest that 

Pb may decrease LH and FSH. In a study of 41 children 10-13 years of age in Egypt, boys and girls with 

blood Pb >10 μg/dL had lower FSH and LH; boys had 

lower serum T, but there was no effect of Pb on E2 

(Tomoum et al. 2010). Similarly, Vivoli et al. (1993) 

reported decreased LH and FSH in boys with blood 

Pb ≥10 μg/dL in a study of 418 children in Italy; T 

and E2 were not related to blood Pb levels. Girls 6-11 

years of age in NHANES III with blood Pb ≥1 μg/dL

had lower levels of inhibin B (Gollenberg et al. 2010).

Summary of Support for Conclusions

Animal data support an association between Pb exposure and altered hormones, particularly decreased 

LH, FSH, and E2 in females, at high blood Pb levels 

(30-300μg/dL in Cynomolgus monkeys and rats; see 

U.S. EPA 2006 for recent reviews of the animal data, 

ATSDR 2007). Rodent data also support an effect of Pb 

testosterone in some studies; however, even within 

the animal literature, increase, decrease, and lack 

of effect are all reported. Animal data also support 

decreased IGF-1, LH, and E2 as potential mechanisms 

for the Pb-associated delay in puberty. Animal data 

also support an effect of developmental Pb exposure 
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116 NTP Monograph on Health Effects of Low-Level Lead

on the hypothalamic-pituitary-adrenal axis and 

changes in the stress response or basal corticosteroids. 

The human data on potential associations between 

Pb and LH, FSH, and T are inconsistent, and for other 

hormones the data are inconsistent as well as limited 

in nature. Therefore, the NTP determined there was 

inadequate evidence to conclude that blood Pb was 

associated with specific hormone changes. The conclusion of inadequate evidence for endocrine effects 

of Pb in humans is in line with the discussion of the 

general inconsistencies in the human database with 

the ATSDR and EPA; however, the 2006 EPA AQCD 

for Lead (U.S. EPA 2006) states that the toxicological 

data (animal data) support Pb as an endocrine disruptor in males and females at various points along 

the hypothalamic-pituitary-gonadal axis. Additional 

data, particularly data from prospective studies with 

appropriate consideration and control for timing in 

the reproductive cycle, age, and other factors, are 

required to clarify the potential relationship between 

blood Pb and endocrine parameters.

8.3.10 Congenital Malformations

There is inadequate evidence to evaluate the potential 

association between blood Pb and congenital malformations. Few studies investigate the potential association between Pb exposure and malformations, and 

even fewer have blood Pb or other biological monitoring data (see the Congenital Malformations section of Appendix E: Reproductive and Developmental 

Effects). Of the studies with blood Pb data, only one 

supports an association between blood Pb levels and 

congenital malformations: in a retrospective analysis, 

Needleman et al. (1984) found a higher relative risk 

of minor congenital anomaly with higher all umbilical 

cord blood Pb levels (6.3 μg/dL: RR=1.87 9 (1.4, 2.4); 

15 μg/dL: RR=2.39 (1.7,3.4); 24 μg/dL: RR=2.73 (1.8, 

4.2)). There are few other published studies; most 

lack blood Pb data or other biomarkers, and exposure 

is based on job categories or indirect measures. For 

example, residence in the ceramic district in Italy, an 

area known for higher Pb exposure levels, was associated with increased relative risk of congenital malformations (RR=1.48 (95% CI: 1.15, 1.89)), including 

hydrocephalus, oral clefts, cleft lip, and malformations 

of the ear, heart, cardiovascular system, musculoskeletal system, and integument (Vinceti et al. 2001).

Several occupational studies investigated 

the relationship between paternal blood Pb and 

congenital malformations, and the available evidence 

is inconsistent. Blood Pb levels determined from 

monitoring data for 929 employees of the Cominco 

smelter in British Columbia were not associated with 

odds ratio for still births and birth defects combined 

(Alexander et al. 1996a). Paternal occupational Pb 

exposure was not associated with congenital malformations in a study of 764 workers at a copper smelter 

that compared rates of malformations between pregnancies after employment to pregnancies that took 

place before occupational Pb exposure (Beckman 

and Nordstrom 1982). Estimated paternal blood Pb 

levels based on job categories were associated with 

an increased odds ratio for congenital malformations 

(OR=3.2 (95% CI: 1.0, 10.2)) when evaluated along 

with paternal smoking (Sallmen et al. 1992).

A number of studies have examined the potential association between Pb exposure and neural tube 

defects. The evidence that Pb exposure is associated 

with neural tube defects is inconsistent, and both 

studies that include blood Pb data do not support an 

association with Pb exposure: umbilical cord blood Pb 

at birth in a case-control study of mother-infant pairs 

in Turkey (Zeyrek et al. 2009), and maternal blood Pb 

taken 5-6 weeks after birth in Mexican-Americans living near the Texas-Mexico border (Brender et al. 2002, 

2006). Dawson et al. (1999) reported higher Pb levels 

in amniotic fluid of neural tube defect cases (n=11) 

than in controls (n=29). In a study that looked for serious birth defects among births in Norway with possible parental occupational Pb exposure by job classification, Irgens et al. (1998) reported that maternal 

Pb exposure (of n=1,803 exposed births) was associated with a greater odds ratio for neural tube defects 

(OR=2.87 (95% CI: 1.05, 6.38)) but not paternal exposure (n=35,930 exposed births). Bound et al. (1997) 

reported a significant association between risk of 

neural tube defects in a case-control study that determined Pb exposure by residence in a district in the 

United Kingdom known to have higher drinking water 

levels of Pb. Drinking water levels of Pb or residence 

near a hazardous waste site with known Pb were not 

associated with neural tube defects or anencephalus 

in several case-control studies (Elwood and Coldman 

1981, Croen et al. 1997, Macdonell et al. 2000).

Several studies have examined the potential 

association between Pb exposure and cardiovascular 

defects. The evidence that Pb exposure is associated 

with cardiovascular defects is inconsistent, comes 
Reproductive 

Effects

NTP Monograph on Health Effects of Low-Level Lead 117

from few studies, and lacks good exposure data. The 

study of residents in the Pb-associated ceramic district in Italy described above reported increased relative risk of prevalence of specific heart malformations 

(RR=2.47 (95% CI: 1.57, 3.70)) and general cardiovascular malformations (RR=2.59 (95% CI: 1.68, 3.82)) 

(Vinceti et al. 2001). Drinking water levels of Pb and 

residence near a hazardous waste site with known Pb 

were not associated with congenital heart disease or 

cardiovascular anomalies in several case-control studies (Zierler et al. 1988, Aschengrau et al. 1993, Croen 

et al. 1997). A case-control study of 54 children with 

total anomalous pulmonary venous return (TAPVR) 

and 522 matched controls in the Baltimore-Washington Infant Study reported significant odds ratio for 

paternal Pb exposure (OR=1.83 (95% CI: 1.00, 3.42) 

(Jackson et al. 2004)).

Several studies have also examined the potential association between Pb exposure and cleft lip or 

cleft palate. The evidence that Pb exposure is associated with oral clefts comes from few studies, all of 

which lack biological exposure data. The study of 

residents in the Pb-associated ceramic district in Italy 

described above reported increased relative risk of 

oral clefts (RR=2.28 (95% CI: 1.16, 4.07)) and cleft lip 

(RR=2.43 (95% CI: 1.13, 4.62)) (Vinceti et al. 2001). A 

case-control study of 100 mothers of babies with oral 

clefts and 751 controls reported increased odds ratio 

of oral clefts (OR=4.0 (95% CI: 1.3, 12.2)) (Lorente et al.

2000). Paternal Pb exposure by job category among 

6,251 births to male members of printers’ unions 

in Oslo, Norway, was associated with an increased 

standardized morbidity ratio for cleft lip in boys 

(SMR=4.1 (95% CI: 1.8, 8.1)) (Kristensen et al. 1993).

Summary of Support for Conclusions

Limited animal data support an effect of Pb on congenital malformations, mainly tail defects and general external malformations in NOS rats, although 

increased fetal mortality was reported in some studies 

at high blood Pb levels (54-300μg/dL in squirrel monkeys and mice; seeU.S. EPA 2006 for recent reviews 

of the animal data, ATSDR 2007). In the human data, 

there are few studies of congenital malformations 

with parental Pb exposure data. Although studies 

have reported general effects on congenital malformations, and specific effects on neural tube defects, 

cardiovascular defects, and oral clefts, the results are 

inconsistent and the studies generally lack biological 

exposure data. The NTP determination that there is 

inadequate evidence to conclude parental blood Pb 

levels are associated with congenital malformations 

is consistent with the 2007 ATSDR Toxicological Profile for Lead (ATSDR 2007) and the 2006 EPA AQCD for 

Lead (U.S. EPA 2006).

8.4 Conclusions

The NTP concludes there is sufficient evidence that 

blood Pb levels <10 μg/dL are associated with adverse 

effects on development in children and that blood Pb 

levels <5 μg/dL are associated with adverse effects 

on reproduction in adult women (see Table 8.6 for 

complete list of reproductive and developmental 

effects conclusions). In some studies blood Pb levels 

≤2 μg/dL are associated with adverse effects (e.g., Wu 

et al. 2003, Denham et al. 2005 for delayed onset of 

puberty), and the ability to discriminate effects at the 

lower dose may depend on the availability of a reference group with lower blood Pb levels or the precision of blood Pb measurements. In children, there 

is sufficient evidence that blood Pb levels <10 μg/dL

are associated with delayed puberty and decreased 

postnatal growth and limited evidence that delayed 

puberty is associated with blood Pb levels <5 μg/dL. 

In adults, there is sufficient evidence that maternal 

blood Pb levels <5 μg/dL are associated with reduced 

fetal growth and limited evidence that maternal blood 

Pb levels <10 μg/dL are associated with spontaneous 

abortion and preterm birth. In men there is sufficient 

evidence that blood Pb levels ≥15 μg/dL are associated with adverse effects on sperm or semen and that 

blood Pb levels ≥20 are associated with delayed conception time. There is limited evidvence that blood 

Pb levels ≥10 μg/dL in men are associated with other 

measures of reduced fertility and that blood Pb levels 

>31 μg/dL are associated with spontaneous abortion.
Reproductive 

Effects

118 NTP Monograph on Health Effects of Low-Level Lead

Table 8.6: NTP conclusions on reproductive and developmental effects of low-level Pb

Health Effect Population or 

Exposure Window

NTP 

Conclusion

Blood Pb 

Evidence Bone Pb Evidence

Delayed puberty Prenatal Inadequate No data No data

Children Sufficient Yes, <10 μg/dL No data

Limited Yes, <5 μg/dL

Postnatal growth Prenatal Limited Yes, <10 μg/dL One study

Children Sufficient Yes, <10 μg/dL One study available, no 

evidence of an association

Sperm parameters Children Inadequate No data No data

Men Sufficient Yes, ≥15 μg/dL No data

Fertility / delayed 

conception time

Men: time to conception Sufficient Yes, ≥20 μg/dL No data

Men: fertility Limited Yes, ≥10 μg/dL 

(one study)

No data

Women Inadequate Unclear No data

Spontaneous abortion Men Limited Yes, >31 μg/dL No data

Women Limited Yes, <10 μg/dL No data

Stillbirth Adults Inadequate Unclear No data

Reduced fetal growth 

and lower birth weight

Men Inadequate Unclear No data

Women Sufficient Yes, <5 μg/dL Yes, tibia

Preterm birth and 

gestational age

Men Inadequate Unclear No data

Women Limited Yes, <10 μg/dL No data

Endocrine effects Adults Inadequate Unclear One study

Birth defects Adults Inadequate Unclear No data
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9.0 REFERENCES

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9.7 Renal Effects

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Cardenas A, Roels H, Bernard AM, Barbon R, Buchet JP, 

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