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

NTP Monograph
Health Effects
of Low-Level Lead

June 2012

THIS PAGE LEFT INTENTIONALLY BLANKU.S. Department of Health and Human Services

NTP MONOGRAPH ON HEALTH EFFECTS OF LOW-LEVEL LEAD
June 13, 2012

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THIS PAGE LEFT INTENTIONALLY BLANKii

NTP Monograph on Health Effects of Low-Level Lead

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

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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...................................................................................................... 84iv

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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

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LIST OF TABLESTABLES
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 Leadand 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 Leadand 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 Leadand 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 Leadand 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................................................................................. 88vi

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Table 8.1: Major reproductive/developmental effects considered........................................................................ 91
Table 8.2: Main conclusions for repro­ductive/developmental effects in the 2006 EPA AQCD for Leadand 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

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LIST OF FIGURESFIGURES
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

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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 MonographMary 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 MonographDavid 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

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PEER REVIEW OF THE DRAFT NTPMONOGRAPH
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 Instituteof Environmental Health Sciences, Research Triangle
Park, NC (see http://ntp.niehs.nih.gov/go/37090 formaterials, minutes, and panel recommendations
from the peer review meeting). The selection ofpanel members and conduct of the peer review were
performed in accordance with the Federal Advisory
Committee Act and Federal policies and regulations.
The panel members served as independent scientists,
not as representatives of any institution, company, or
governmental agency. In this capacity, panel members had two major responsibilities in reviewing thedraft NTP Monograph: (1) to determine whether thescientific information cited in the draft monographis 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 effectsof low-level lead (Pb).
The panel agreed with the draft NTP overall conclusions on cardiovascular, renal, and immune healtheffects 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 sufficientevidence of an association at blood Pb levels <10 ug/
dL to sufficient evidence of an association at blood Pblevels <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 ofRochester 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 Center for
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

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NTP Monograph on Health Effects of Low-Level Lead

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ABBREVIATIONSABLESACCLPP
ADHD
ALAD
ALS
AQCD
ATSDR
BAEP
BMI
BP
CBCL
BTQ
CDC
CI
CKD
DBP
DSM
DSM-IVDSM-IV-TR
DTH
E2
EBE
ECG
EDTA
eGFR
EPA
ERG
ETS
FR
FSH
FSIQ
GCI
GFR
HFE
HR
HRV
IgA
IgE
IGF-1
IgG
IgM
IQ
IVF
KTEA
LH
MDI
MMSE

Adult Blood Lead Epidemiology and Surveillance
Advisory Committee on Childhood Lead Poisoning Prevention
attention deficit hyperactivity disorderδ-aminolevulinic acid dehydrataseamyotrophic lateral sclerosis
Air Quality Criteria Document
Agency for Toxic Substances and Disease Registrybrainstem auditory evoked potential
body mass index
blood pressureChild Behavior Checklist
Boston Teacher Questionnaire
Centers for Disease Control and Prevention
confidence interval
chronic kidney disease
diastolic blood pressure
Diagnostic and Statistical Manual of Mental Disorders
Diagnostic and Statistical Manual of Mental Disorders, 4th edition (1994)
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (2000)
delayed-type hypersensitivity
estradiol-17β
early biological effect marker
electrocardiographic
ethylenediaminetetraacetic acidestimated glomerular filtration rate
Environmental Protection Agency, U.S.
electroretinographic
environmental tobacco smoke
fecundability ratio
follicle-stimulating hormone
full-scale IQ
General Cognitive Index from the McCarthy Scales of Children’s Abilities
glomerular filtration rate
hemochromatosis
hazard ratio
heart rate variability
immunoglobulin A
immunoglobulin E
insulin-like growth factor 1
Immunoglobulin G
immunoglobulin M
intelligence quotientin vitro fertilization
Kaufman Test of Educational Achievement
leutinizing hormone
Mental Developmental Index from the Bayley Scales of Infant Development
Mini-Mental State Examination

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NAG
NHANES
NIEHS
NO
NTP
Pb
O2OR
PBPK
PFC
PIQ
PRL
RBP
RR
SBP
SD
SES
SPT
T
T3
T4
Th-1
Th-2
TNF-α
TSH
VEP
VDR
VIQ
WHILA
WISC
WISC-III
WISC-R
WISC-IVWPPSI-R
WRAT-R
ZPP

xii

N-acetyl-β-D-glucosaminidase
National Health and Nutrition Examination Survey
National Institute of Environmental Health Sciences
nitric oxide
National Toxicology Program
leadsuperoxide
odds ratio
physiologically based pharmacokinetic
plaque-forming cell
performance IQ
prolactin
retinol-binding protein
relative risk
systolic blood pressure
standard deviationsocioeconomic statusskin prick test
testosterone
triiodothryonine
thyroxin
type 1 helper T-cell
type 2 helper T-celltumor necrosis factor-α
thyroid-stimulating hormone
visual evoked potential
vitamin D receptor
verbal IQ
Swedish Women’s Health in the Lund Area
Wechsler Intelligence Scale for Children
Wechsler Intelligence Scale for Children, 3rd edition (1991)
Wechsler Intelligence Scale for Children, revised edition (1974)
Wechsler Intelligence Scale for Children, 4th edition (2003)
Wechsler Preschool and Primary Scale of Intelligence
Wide Range Achievement Test-Revised
zinc protoporphyrin

NTP Monograph on Health Effects of Low-Level Lead

Contents

ABSTRACT
Although reductions in lead (Pb) exposure for the U.S.
population have resulted in lower blood Pb levels overtime, epidemiological studies continue to provide evidence of health effects at lower and lower blood Pblevels. Low-level Pb was selected for evaluation by
the National Toxicology Program (NTP) because of (1)the availability of a large number of epidemiologicalstudies 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) publicconcern for effects of Pb in children and adults. Thisevaluation summarizes the evidence in humans andpresents conclusions on health effects in children andadults associated with low-level Pb exposure as indicated by less than 10 micrograms of Pb per deciliterof 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) andcompleted in April of 2012.

NTP Monograph on Health Effects of Low-Level Lead

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 literaturefor evidence that low-level Pb is associated withneurological, immunological, cardiovascular, renal,
and/or reproductive and developmental effects. The
NTP Monograph presents specific conclusions foreach 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 fromtechnical advisors that reviewed pre-public releasedrafts of each chapter summarizing the evidence for
specific health effects associated with low-level Pb,
public comments received during the course of theevaluation, and comments from an expert panel ofad hoc reviewers during a public meeting to review
the Draft NTP Monograph on November 17-18, 2011(http://ntp.niehs.nih.gov/go/37090).

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NTP Monograph on Health Effects of Low-Level Lead

1.0 EXECUTIVE SUMMARY

1.2 Methods“lead” or “lead poisoning.”

NTP Monograph on Health Effects of Low-Level Leadxv

Executive
Summary

The key questions and general approach for developing the conclusions on the health effects of low-level
Lead (Pb) exposure remains a significant health con- Pb are outlined below. Section 2.0 of this document
cern despite policies and practices that have resulted contains additional details on the authoritativein continued progress in reducing exposure and low- sources considered, the literature search strategy,
ering blood Pb levels in the U.S. population. Pb is one and the peer-review process.
of the most extensively studied environmental toxicants, with more than 28,900 publications on health 1.2.1 Key Questions
effects and exposure in the peer-reviewed literature1. What is the evidence that adverse health effects are
While the toxicity associated with exposure to high associated with blood Pb <10 µg/dL?
levels of Pb was recognized by the ancient Greeks and66 What reproductive, developmental, neurological,
Romans, the adverse health effects associated withimmune, cardiovascular, and renal health effects
low-level Pb exposure became widely recognized only
are associated with blood Pb levels <10 µg/dL?
in the second half of the 20th century. Over the past
66 What is the blood Pb level associated with a given
40 years, epidemiological studies, particularly in chilhealth effect (i.e., <10 µg/dL or <5 µg/dL)?
dren, continue to provide evidence of health effects
66 At which life stages (childhood or adulthood) isthe effect identified?
at lower and lower blood Pb levels. In response, theCenters for Disease Control and Prevention (CDC) has
66 Are there data to evaluate the association
repeatedly lowered the concentration of Pb in blood
between bone Pb and the health effect, and howthat is considered “elevated” in children (from 30 µg/
does the association to this biomarker of Pb expodL to 25 µg/dL in 1985 and to the current level ofsure compare to the association with blood Pb?
10 µg/dL in 1991).
The purpose of this evaluation is to summarize 1.2.2 Approach to Develop Health Effects
Conclusions
the evidence in humans and to reach conclusions
about whether health effects are associated with Conclusions in the NTP evaluation of Pb-related
low-level Pb exposure as indicated by less than 10 health effects in humans associated with low-level
micrograms of Pb per deciliter of blood (<10 µg/ Pb were derived by evaluating the data from epidedL), with specific focus on the life stage (child- miological studies with a focus on blood Pb levels
hood, adulthood) associated with these health <10 µg/dL. The evaluation includes a review of theeffects. This evaluation focuses on epidemiologi- primary epidemiological literature for evidence thatcal evidence at blood Pb levels <10 μg/dL because low-level Pb is associated with neurological, immuhealth effects at higher blood Pb levels are well nological, cardiovascular, renal, and/or reproductive
established such that the definition of an elevated and developmental effects. These health effect areas
blood Pb level is ≥10 µg/dL for both children and were selected because there is a relatively large dataadults (ABLES 2009, CDC 2010a). Pb was nominated base of human studies in each area. The NTP conby the National Institute for Occupational Safety sidered four possible conclusions for specific healthand Health for a National Toxicology Program (NTP) effects within each area:
evaluation to assess the reproductive and developSufficient Evidence of an Association:
mental effects of Pb (see http://ntp.niehs.nih.gov/
An association is observed between the exposure and health outcome in studies in which
mtg?date=20100510&meeting=BSC). The scope ofthe evaluation has been expanded from the origichance, bias, and confounding could be ruledout with reasonable confidence.
nal nomination to include an evaluation of healtheffects other than reproduction and development
Limited Evidence of an Association:(e.g., cardiovascular effects in adults) in order to
An association is observed between the expomaximize the utility of the evaluation.
sure and health outcome in studies in whichchance, bias, and confounding could not be
ruled out with reasonable confidence.
1 Based on an April 2012 PubMed search for keyword (MeSH)

1.1 Introduction

Executive
Summary

Inadequate Evidence of an Association:
The available studies are insufficient in quality,
consistency, or statistical power to permit aconclusion regarding the presence or absenceof an association between exposure and healthoutcome, or no data in humans are available.
Evidence of No Association:
Several adequate studies covering the full rangeof levels of exposure that humans are known
to encounter (in this case limited to blood Pblevels <10 µg/dL) are mutually consistent in notshowing an association between exposure to
the agent and any studied endpoint.

1.2.4 Authoritative Sources and Peer
Review

In this evaluation, the NTP made extensive use ofrecent government assessments of the health effectsof 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 discussion of each health effect begins with a the Identification and Management of Lead Exposurestatement of the NTP’s conclusion regarding whether in Pregnant and Lactating Women (CDC 2010b).
the specific effect is associated with a blood Pb level
The NTP used independent subject matter<10 µg/dL or <5 µg/dL and the age group (childhood experts as technical advisers to provide scientificor adulthood) in which it is or is not identified, as well input and to review pre-public release drafts of eachas the timing of exposure associated with the effect chapter summarizing the evidence that health effects(prenatal, childhood, concurrent) if available. Then are associated with low-level Pb, the appendices, andkey data and principal studies considered in devel- Section 3.0 that provides background on Pb exposure
oping the NTP’s conclusions are discussed in detail. (see Contributors for a list of technical advisers). Peer
General strengths and limitations of study designs review of the draft document was conducted by anwere considered when developing conclusions, with expert panel of ad hoc reviewers at a public meeting
prospective studies providing stronger evidence than held November 17-18, 2011, in Research Triangle Park,
cross-sectional or case-control studies. Each section NC (see Peer-Review of the Draft NTP Monograph forconcludes with a summary discussing each health details). Comments from peer reviewers and written
effect, describing experimental animal data that public comments received on the draft monographrelate to the human data, and stating the basis for were considered during finalization of the document.
The NTP concurred with the expert panel on all of
the NTP conclusions.
For the purposes of this evaluation, “children” the conclusions regarding health effects of Pb in thisrefers to individuals <18 years of age unless otherwise final document.
specified. In addition to the blood Pb level of <10 µg/dL,
a lower effect level of <5 µg/dL was also selected 1.3 What Does It Mean to Refer to Bloodbecause it is commonly used in epidemiological studPb Levels <10 µg/dL?
ies to categorize health effects data by exposure levels; The overwhelming majority of human epidemiotherefore, data are often available to evaluate health logical studies with Pb exposure data measured Pb
effects for groups above and below this value as well. in whole blood, and this measure of exposure serves
as the basis for the evaluation of Pb levels <10 µg/dL.
1.2.3 Appendices of Studies Considered
An individual’s blood Pb level reflects an equilibrium
The information to support the NTP’s conclusions for between current environmental Pb exposure andindividual health effects is presented in each chapter. the preexisting amount of Pb in the body, stored priIn addition, human studies of groups with low-level marily in bone (Factor-Litvak et al. 1999, Brown et al.
Pb exposure that were considered in developing the 2000, Chuang et al. 2001). In adults, bone and teeth
conclusions are also abstracted for further reference store 90-95% of the total body burden of Pb, while inand included in separate appendices for neurological young children, bone Pb represents a smaller fraction
effects, immune effects, cardiovascular effects, renal (down to 70%) (Barry 1981, for review, see Barbosa eteffects, and reproductive and developmental effects. al. 2005, Hu et al. 2007). The body eliminates half ofxvi

NTP Monograph on Health Effects of Low-Level LeadNTP Monograph on Health Effects of Low-Level Leadbetween concurrent blood Pb levels as adults and thehealth effect (e.g., elevated blood pressure, reduced
kidney function, or decreases in specific measuresof cognitive function). There is a considerable bodyof evidence that these health effects are associatedwith 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 coherencewith animal data. It is well recognized that the role ofearly-life Pb exposure cannot be discriminated fromthe role of concurrent blood Pb without additional
long-term studies. To eliminate the potential role ofearly-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 measurementof 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 healthoutcomes within each chapter varies by study design
and type of analyses used to examine the relationship of the health outcome with blood Pb across thehundreds 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 thehealth 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 ina group whose mean blood Pb level was <10 µg/dL(e.g., higher blood Pb levels were associated withhigher 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, butthey do not exclude the possibility that individuals
significantly above or below the mean blood Pb levelare driving the effect, or that past exposure levels are
xvii

Executive
Summary

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 relationshipbetween 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, andnumerous 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 whenavailable. Note that measuring bone Pb is expensive,
requires specialized equipment that is not generally
accessible, and requires study subjects to travel tothe location of the measurement apparatus (K-x-ray
fluorescence); thus, fewer Pb data are available forbone than for blood.
Before bans on Pb in paint, solder, and gasoline,
environmental Pb levels in the United States werehigher, 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-foldover 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 Pblevels >10 µg/dL during early childhood, so healtheffects in adults today may have been influencedby 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Executive
Summary

driving the effect. Finally, some studies comparedeffects 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 witha 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 atblood Pb levels <10 µg/dL, and <5 µg/dL as well (seeTable 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 fromthe consistency demonstrated by adverse effects
associated with blood Pb <10 µg/dL across a wide
range of health outcomes, across major physiologicalsystems from reproductive to renal, among multiple
groups, from studies using substantially different
methods and techniques, and for health effects inboth 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. Thereis sufficient evidence that blood Pb levels <10 µg/dL
in children are associated with delayed puberty andreduced postnatal growth. There is limited evidence
that blood Pb levels <10 µg/dL are associated withelevated serum immunoglobulin E (IgE), which is aprincipal mediator of hypersensitivity; consistent withthis 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 eczemaor asthma. There is also inadequate evidence of anxviii

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 areassociated 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 issufficient 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. Thereis also limited evidence for an association between
blood Pb <10 µg/dL and increased cardiovascularrelated mortality, decreased auditory function, theneurodegenerative disease amyotrophic lateral sclerosis (ALS), and decreases in specific measures of cognitive function in older adults. The NTP conclusionsof 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 healtheffects and bone Pb as a measure of exposure has
not been examined, the data support the importanceof cumulative Pb exposure on cardio­vascular effectsof Pb in adults, as well as neuro­cognitive decline
in adults, because the association between Pb andthese endpoints is more consistent for bone Pb thanfor blood Pb.

1.4.2 Neurological Effects

The NTP concludes that there is sufficient evidence
that blood Pb levels <5 µg/dL are associated withadverse neurological effects in children and limited
evidence that blood Pb levels <10 µg/dL are associated with adverse neurological effects in adults (seeTable 1.2 for summary of effects).
Unlike the data set for most other health effectareas, there are a number of prospective studies ofneurological 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 inmeasures of general and specific cognitive function
NTP Monograph on Health Effects of Low-Level Lead

<10 µg/dL<5 µg/dL<10 µg/dL<5 µg/dL

Blood Pb
Level

Increased blood pressure, increased risk of hypertension,and increased incidence of essential tremor
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 abortionand preterm birth
Immune function, stillbirth, endocrine effects, birth defects,
fertility or time to pregnancy**, sperm parameters**

Sufficient

Inadequate

LimitedIncreased incidence of essential tremor

Decreased academic achievement, IQ, and specific cognitive measures; increased incidence of attention-related
behaviors and problem behaviors
Delayed puberty and decreased kidney function in children ≥12 years of age
Delayed puberty, reduced postnatal growth, decreased
IQ, and decreased hearing
Increased hypersensitivity/allergy by skin prick test toallergens and increased IgE* (not a health outcome)Any age – asthma, eczema, nonallergy immune function,
cardiovascular effects; <12 years of age – renal function
Decreased glomerular filtration rate; maternal blood Pb
associated with reduced fetal growth

Principal Health Effects

LimitedSufficient

Inadequate

LimitedSufficient

LimitedSufficient

NTP
Conclusion

No data

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

The one available study of bone Pb in the general population supports an association between bone Pb anddecreased kidney function.
Maternal bone Pb is associated with reduced fetal
growth.
No data

No data

No data

The one available study of bone Pb in children does notsupport an association with postnatal growth.
No data

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

Bone Pb Evidence

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.

AdultsChildrenLife Stage

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

Executive
Summary

NTP Monograph on Health Effects of Low-Level Lead

xix

xx

NTP Monograph on Health Effects of Low-Level Lead
Sufficient
LimitedLimitedInadequate

Men

Adults

Women

Inadequate
LimitedSufficient
LimitedSufficient
LimitedSufficient
LimitedBlood Pb
Evidence

Decrease in measures of cognitive function
Yes, <5 µg/dL
Decreased IQ, increased incidence of attention-re­ Yes, <10 µg/dL
lated and problem behaviors, decreased hearing
Decreased academic achievement, IQ, and specific Yes, <5 µg/dL
cognitive measures; increased incidence of attention-related and problem behaviors
Decreased hearing
Yes, <10 µg/dL
Increased incidence of essential tremor
Yes, <10 µg/dL
Psychiatric effects, decreased hearing, decreased Yes, <10 µg/dL
cognitive function, increased incidence of ALS
Increased incidence of essential tremor
Yes, <5 µg/dL
Increased hypersensitivity/allergy by skin prick Yes, <10 µg/dL
test to common allergens and IgE* (not a healthoutcome)Asthma, eczema
Unclear–Unclear–UnclearIncreased blood pressure and increased risk of Yes, <10 µg/dL
hypertension
Increased cardiovascular-related mortality and ECG Yes, <10 µg/dL
abnormalities–
UnclearDecreased glomerular filtration rate
Yes, <5 µg/dL
Decreased glomerular filtration rate
Yes, <5 µg/dL
Reduced postnatal growthYes, <10 µg/dL
Yes, <10 µg/dL
Delayed puberty, reduced postnatal growth
Delayed puberty
Yes, <5 µg/dL
Reduced fetal growthYes, <5 µg/dL
Increase in spontaneous abortion and preterm Yes, <10 µg/dL
birth
Adverse changes in sperm parameters and in-­ Yes,≥15-20 µg/dL
creased time to pregnancy
Yes, ≥10 µg/dL
Decreased fertility
Increased spontaneous abortion
Yes, >31 µg/dL
Stillbirth, endocrine effects, birth defects
Unclear

Principal Health Effects

Bone Pb
Evidence

No data
No data
No data

No data

Maternal tibia Pb is associatedNo data

No data
No dataYes, one study
No data
One study does not support
effects of bone Pb on growth.

No data
No data
No data
The association between bone
Pb and cardiovascular effects ismore consistent than blood.

No data

Tibia and dentin Pb are associated with attention, behavior,and cognition.
No data
No data
The association between bone
Pb and cognitive decline is moreconsistent than blood.

No data
No dataAbbreviations: 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.

AdultsChildren <12 years oldChildren ≥12 years old
AdultsReproductive and Prenatal
Developmental
Children

Renal

AdultsChildren
AdultsCardiovascular

LimitedInadequate
Inadequate
Inadequate
SufficientSufficientSufficient
LimitedAdultsLimitedLimitedSufficientChildrenChildrenLimitedLimitedNTP
Conclusion

Prenatal

Population or
Exposure Window

ImmuneNeurological

Health Area

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

Executive
Summary

NTP Monograph on Health Effects of Low-Level Lead

In adults, there is limited evidence that blood Pblevels <10 µg/dL are associated with psychiatric outcomes (including anxiety and depression), decreased
auditory function, ALS, and decreases in specificmeasures of cognitive function in older adults. Thereis sufficient evidence that blood Pb levels <10 µg/dL
are associated with essential tremor in adults, andlimited 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 withadverse immune effects in children and that there isinadequate evidence in adults (see Table 1.2).
In children, there is limited evidence that blood
Pb levels <10 µg/dL are associated with changes toan immune-related health outcome such as allergy or
increased hypersensitivity. There is also limited evidence that blood Pb levels <10 µg/dL are associatedwith 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 andincreased 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 confounderin analyses of IgE in children. Although increases inserum levels of total IgE are not definitive indicatorsof 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 alink 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) inchildren. These data support the conclusion of limited
evidence that increased hypersensitivity responses orallergy are associated with blood Pb levels <10 µg/dL
in children; however, there is inadequate evidence ofan 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
xxi

Executive
Summary

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 ofattention-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 andas 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 inbroad 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 ofchildren 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 andproblem behaviors are consistently reported in studies
with mean blood Pb levels <5 µg/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-associatedbehavioral effects in the area of attention, of which
ADHD is one example on the more severe end of thespectrum, 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 withdecreased 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 withblood Pb levels <10 µg/dL.

Executive
Summaryimmune 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 withobservational 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 thanhypersensitivity, because few studies have examined
immune function at lower blood Pb levels.
Bone Pb levels may be particularly relevant forcells of the immune system and immune function. Allof the white blood cells or leukocytes that develop
after birth are derived from progenitor cells in the bonemarrow. 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

which used the same NHANES III sample) but is notsupported 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 andincreased cardiovascular mortality. There is limited evidence for Pb effects on other cardiovascular outcomes,
including electrocardiography (ECG) abnormalities andclinical cardiovascular disease primarily due to lack ofreplication studies. Chronic Pb exposure appears to
be more critical than current Pb exposure, as shownby 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 evaluationof the various cardiovascular outcomes as describedin 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 inadulthood. During periods of bone demineralizationsuch 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 etal. 1988, Symanski and Hertz-Picciotto 1995, Webber
et al. 1995, Korrick et al. 2002). Too few studies haveexamined Pb-related cardiovascular health risks inpostmenopausal women to enable conclusions.
Although hypertension can contribute to adverse
renal effects, and kidney dysfunction can contributeto increased blood pressure, effects are consideredseparately in this evaluation because most studies
examined one outcome or the other, rather than testing both systems comprehensively.

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NTP Monograph on Health Effects of Low-Level Lead

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 forsummary of effects).
There is sufficient evidence of a bone Pb-related
increase in the risk of hypertension and increases inblood pressure in adults. Two prospective studies andfive 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 bonePb; 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 1.4.5 Renal Effects
between increased cardiovascular mortality and blood The NTP concludes that there is sufficient evidence
Pb is supported by three prospective studies (two of that blood Pb levels <5 µg/dL are associated with

The NTP concludes that there is sufficient evidence
that blood Pb levels <10 µg/dL are associated withadverse health effects on development in children
and that blood Pb levels <5 µg/dL are associatedwith adverse health effects on reproduction in adultwomen (see Table 1.2 for summary of effects).
Because most data on reproductive effects comefrom studies of occupational exposure, many of theavailable 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 thisdocument. Consideration of these higher blood Pblevels resulted in several conclusions for Pb-related
reproductive effects in men but did not affect theconclusions 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 inchildren are complicated because blood Pb levels<10 µg/dL during childhood are also associated with
reduced postnatal growth, and prenatal Pb levels arehighly correlated with childhood Pb levels.
In children, there is sufficient evidence thatblood 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 areassociated with delayed puberty. There is sufficientevidence 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 isassociated 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 witha mean maternal blood Pb level of 2.1 µg/dL, andseveral cross-sectional studies of Pb levels in maternal or cord blood at delivery support an association

NTP Monograph on Health Effects of Low-Level Leadxxiii

1.4.6 Reproduction and Developmental
Effects

Executive
Summary

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 bettermeasure 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 agroup 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 thepotential association between blood Pb levels<10 µg/dL in children <12 years of age and impaired
kidney function, because results are inconsistentand available studies of kidney function in young
children are less reliable in general because testsof kidney function lack clear predictive value in thisage group. There is limited evidence that blood Pblevels <5 µg/dL are associated with adverse effects
on kidney function in children ≥12 years of age. Thisconclusion 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.

Executive
Summary

between higher blood Pb and reduced fetal growthat mean blood Pb levels from 1 to 10 µg/dL. Althoughmaternal 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 Pblevels <10 µg/dL are associated with preterm birth andspontaneous 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 oflimited evidence for an association with spontaneousabortion is based primarily on the strength of a single
prospective nested case-control study in women, withadditional support provided by occupational studies
that reported an association with Pb exposure butlacked blood Pb measurements. In men, there is inadequate evidence that blood Pb levels <10 µg/dL areassociated 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. Fourstudies reported increased time to pregnancy inwomen whose male partners had blood Pb levels of
20-40 µg/dL. A single retrospective occupational study
reported increased risk of infertility among men withblood Pb levels ≥10 µg/dL, and the consistency of thisobservation with other studies reporting effects ontime 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 measuresof reduced fertility. There is also limited evidence thatpaternal blood Pb levels >31 µg/dL are associatedwith spontaneous abortion, based primarily on thestrength of a single retrospective nested case-control
study in men, with additional support provided byoccupational studies that reported an association
with Pb exposure but lacked blood Pb measurements.
There are robust data and sufficient evidence thatblood Pb levels <10 µg/dL in children and adults areassociated with adverse health effects across a wide
range of health outcomes, as described above. Overtime, epidemiological studies have provided data to
support health effects at lower and lower blood Pblevels, particularly in children. Prospective studies inchildren 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 thepotential effects of early-life blood Pb levels on healtheffects observed as adults. This is particularly importantin 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 withconfirmed 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 Pblevels <10 µg/dL and increased blood pressure andhypertension. Future research should be directed
at clarifying the extent to which early life exposure(e.g., blood Pb levels >10 µg/dL) contribute to healtheffects observed in adults. Long-term prospective
studies in a group for which blood Pb levels remain
consistently <10 µg/dL from birth until the outcomeof interest is measured would take one step in thisdirection by eliminating the potential role of early-life
blood Pb levels >10 µg/dL on health effects observedin adults with concurrent blood Pb levels <10 µg/dL.

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NTP Monograph on Health Effects of Low-Level Lead

1.5 Future Research2.0 METHODS

2.1 Key Questions

What is the evidence that adverse health effects areassociated with blood Pb <10 µg/dL?
66 What reproductive, developmental, neurological,
immune, cardiovascular, and renal health effects
are associated with blood Pb levels <10 µg/dL?
66 What is the blood Pb level associated with a given
health effect (i.e., <10 µg/dL or <5 µg/dL)?
66 At which life stages (childhood or adulthood) isthe effect identified?
66 Are there data to evaluate the association be­tweenbone Pb and the health effect, and how does theassociation 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
NTP Monograph on Health Effects of Low-Level Lead

1

Methods

The NTP’s conclusions on health effects of low-level Pb
are based on evaluation of data from epidemiologicalstudies 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 effectarea is also described below. The NTP considered several recent government evaluations of the health effectsof Pb as authoritative sources to supplement a review ofthe primary epidemiological literature, and these documents are briefly described in this section. The NTP also
used independent subject matter experts as technicaladvisors to provide scientific input and to review prepublic release drafts of each chapter summarizing theevidence for health effects associated with low-level Pb,
as well as the appendices and background exposure
section. The literature search strategy and details of thepeer-review process are also described below.

formed the basis for the NTP conclusions. The quality of individual studies was considered in reachinghealth effects conclusions, including consideration of
known confounders, appropriateness of the methodof diagnosis, strength of the study design, and thesample size. General strengths and limitations ofstudy 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 whendeveloping 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 ATSDR2007 Toxicological Profile for Lead (ATSDR 2007) (seeSection 2.4 for discussion). Technical advisors with
relevant subject matter expertise served as anotherauthoritative source (see Section 2.4.4 for details).
Technical advisors were asked to critically evaluate
every one of the NTP’s conclusions regarding thepotential 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, andsupported the NTP’s conclusions in pre-public releasedrafts of each chapter addressing specific health effectareas. As described in Section 2.6 and Peer-Reviewof the Draft NTP Monograph, a draft version of theMonograph 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 anddevelopmental 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 healtheffects within each area.
Sufficient Evidence of an Association:
An association is observed between the exposure and health outcome in studies in whichchance, bias, and confounding could be ruledout with reasonable confidence.

Methods

Limited Evidence of an Association:
An association is observed between the exposure and health outcome in studies in whichchance, 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 aconclusion regarding the presence or absenceof an association between exposure and healthoutcome, or no data in humans are available.
Evidence of No Association:
Several adequate studies covering the full rangeof levels of exposure that humans are known
to encounter (in this case limited to blood Pblevels <10 µg/dL) are mutually consistent in notshowing 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 regardingwhether the specific effect is associated with a blood
Pb level <10 µg/dL or <5 µg/dL and the age groupin which it is or is not identified (childhood or adulthood), as well as the timing of exposure associatedwith the effect (prenatal, childhood, concurrent)
when available. Then key data and principal studies
considered in developing the NTP’s conclusions arethen discussed in detail. Each section concludes witha summary discussing each health effect, describing
experimental animal data that relate to the humandata, 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 levelof <10 µg/dL, a lower effect level of <5 µg/dL wasalso selected because it is commonly used in epidemiological studies to categorize health effect data by
exposure levels; therefore, data are often available toevaluate 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.

Pb exposure that were considered in developing theconclusions are also abstracted for further reference
and are included in separate appendices for eachhealth effect area.
Each appendix table includes the following column headings:
Description: study design, reference, and geographic location
Population: sample size, description, years ofstudy, and percent male
Age: mean age and standard deviation of thesubjects
Blood Pb: mean blood Pb level and standard
deviation (in µg/dL)
Outcomes: health effects assessed
Statistical: methods used and cofactors in­clud­ed inanalysesFindings: summary of results (bolded if statisticalsignificance 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 isindicated in the first column of each appendix.
These studies were not considered as independentfindings 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 byoutcome, meta-analyses shaded
Appendix D. Renal Effects: no grouping
Appendix E. Reproductive and Developmental
Effects: grouped by outcome

The information to support the NTP’s conclusions
for individual health effects is presented in eachchapter. Human studies from groups with low-levelWithin each grouping, studies are listed alphabetically by first author and then chrono­logic­ally by
publication date. For the appendix tables groupedby outcome, if a publication contained results thatapplied to more than one group, results specific toeach 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

2

NTP Monograph on Health Effects of Low-Level Lead

2.3 Appendices of Studies Considered2.4 Authoritative Sources Considered

Recent government evaluations of the health effectsof Pb include the U.S. EPA 2006 AQCD for Lead (U.S.
EPA 2006), the ATSDR 2007 Toxicological Profile forLead (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 theconclusions and data summaries from the EPA and
ATSDR documents. In general, NTP concurred withthe 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 thisdocument. The database of studies on health effects
in humans is supported by an equally large body ofexperimental animal studies. In this document, theexperimental 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 morein-depth reviews of the animal data.
NTP Monograph on Health Effects of Low-Level Lead

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 pagesof tables and other annex material) of the scientificinformation related to human health and ecologicaleffects 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 tosupport 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 andreview 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 healthstatement summarizing the toxicological and adverse
health effects for Pb. ATSDR’s peer-review process fortheir toxicological profiles includes release for publiccomment 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 atblood Pb levels <10 µg/dL. The committee concluded
that the “overall weight of the evidence supports aninverse (negative) association between BLLs [bloodlead levels] <10 µg/dL and the cognitive function inchildren” (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 associatedwith blood Pb levels <10 µg/dL in children.
The ACCLPP has also prepared a draft reportproviding Guidelines for the Identification and3

Methods

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 werealso 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 setof human studies on these effects associated withlower blood Pb levels is limited. For this reason, andbecause the original nomination focused on reproductive and developmental effects, the evaluationof health effects in this area includes higher blood
Pb levels. The immunological effects database wasadequate to make conclusions on several effects atblood 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).

Methods

Management of Lead Exposure in Pregnant and MEDLINE] or epidemiologic studies[mh] or age
Lactating Women (CDC 2010). The report provides groups[mh] for limiting to human studies.
“practical considerations regarding preventing lead
Because of the heteronym nature of the term
exposure during pregnancy, assessment and blood “lead,” text word searching used four approaches:lead testing during pregnancy, medical and envi- (1) searched for “lead” in title; (2) used various comronmental management to reduce fetal exposure, binations to focus on low-level exposure: “low lead”
breastfeeding and follow-up of infants and children or “low blood lead” or “lower lead” or “lower blood
exposed to lead in utero.” The document summa- lead” or “low level” or “low levels” or “lower level” orrizes the evidence from human studies through 2008 “lower levels” or “lead level” or “lead levels” or “lowfor health effects of Pb in pregnant women and the dose” or “lead induced” or “lead intake” or “blood
developing child (concentrating on exposure during lead”; (3) combined “lead” with heavy metals or cadgestation and from breastfeeding) and provides guid- mium or mercury or arsenic; and (4) when necessary,ance for clinicians.
excluded “lead to” or “leads to” from search results.
For databases that allowed proximity searching, “lead”
2.4.4 Technical Advisorsand “low or lower” were required to be in the same
The primary mechanism for obtaining scientific input sentence. This strategy would retrieve articles suchduring development of the draft NTP Monograph on as “low cadmium and lead levels” or “low blood and
Health Effects of Low-Level Pb was through technical urine lead levels” or “lower concentrations of lead in
advisors (see Contributors for list of technical advi- the blood.” Text words used to retrieve human studiessors). Technical advisors with relevant subject matter included human(s), resident(s), inhabitant(s), populaexpertise were asked to provide input on issues of sci- tion, people, subject(s), patient(s), case(s), women,
entific complexity, adequacy of the literature review, men, girls, boys, parent(s), mother(s), father(s),and overall presentation of a pre-public release ver- adult(s), child, children, childhood, adolescent(s),sion of the draft NTP monograph. These advisors infant(s), toddler(s), newborn(s), occupation(al),critically evaluated each of the NTP’s health effects work, workplace, worker(s), employee(s), laborer(s),conclusions and the basis for those conclusions, as and staff.
well as the appendices and the background exposure
An updated search was performed September
section. Individuals who served as technical advisors 12-15, 2011, to identify any additional referenceswere screened for potential conflict of interest.
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
2.5 Literature Search Strategy
The 2006 EPA AQCD for Lead (U.S. EPA 2006) and studies. In addition, NTP published a Federal Registerthe 2007 ATSDR Toxicological Profile for Lead (ATSDR notice regarding the low-level Pb evaluation, inviting2007) were screened for citations on health effects submission of information about recently published/assessed at low-level Pb exposure. The NTP’s con- in-press studies that might be relevant for considerclusions are based on the evidence from human ation in the evaluation (75 FR 51815).
studies with blood Pb levels of <10 µg/dL with data
reflecting mean exposure levels up to 15 µg/dL also 2.6 Peer-Review Process
considered so that effects at and around 10 µg/dL Peer review of the Draft NTP Monograph was conwere not missed during the evaluation. Primary lit- ducted by an expert panel of ad hoc reviewers witherature searches in MEDLINE®, Web of Science, Sco- relevant scientific background (i.e., expertise in Pb orpus, Embase, and TOXNET were conducted on March metals related to reproductive and developmental
1-5, 2010, to identify relevant studies published toxicology, neurotoxicology, immunotoxicology, carsubsequent to the 2006 EPA and 2007 ATSDR docu- diovascular toxicology, renal toxicology, and exposure)ments. Search terms included the following MeSH at a public meeting held November 17-18, 2011 in
subject headings: lead or lead poisoning; “diseases Research Triangle Park, NC (see Peer Review of thecategory” or “anatomy category” for health effects; Draft NTP Monograph for list of panel members).
and humans[mh or Medical Subject Headings in The selection of panel members and conduct of the
MEDLINE] or epidemiology[sh or SubHeadings in peer review were performed in accordance with the4

NTP Monograph on Health Effects of Low-Level LeadNTP Monograph on Health Effects of Low-Level Lead

Methods

Federal Advisory Committee Act and Federal policies
and regulations. The panel was charged to determine
whether the science cited in the draft NTP Monographon Low-Level Lead was technically correct, was clearlystated, and supported NTP’s conclusions regarding thepotential for adverse health effects to occur at blood
Pb levels <10 µg/dL. Public comments received as partof the NTP’s evaluation of health effects of low-level
Pb, meeting minutes, and other materials from thepeer-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.

5

Methods

THIS PAGE LEFT INTENTIONALLY BLANK6NTP Monograph on Health Effects of Low-Level Lead

3.0 EXPOSURE

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.
NTP Monograph on Health Effects of Low-Level Lead

7

ExposureStudies of health effects of Pb in humans commonlyuse 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 andextensively validated. Bone Pb is more likely to reflect
cumulative exposure but must be measured by specialized equipment and requires measurements to bemade on subjects present at a research clinic. Measures of Pb in urine and hair have been used in somestudies, but how well they reflect the body burden of
Pb is less clear.
Pb is ubiquitous in the environment, but the levelof exposure to Pb that individuals experience can varyand 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 associatedhealth 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 inYoung Children report (CDC 2005b, 2010). The EPA isin 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).

However, measuring Pb in one tissue at one
point in time does not present a complete pictureof either current or cumulative Pb exposure. BonePb 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 etal. 2007). When available, bone Pb data were also
considered in this evaluation. However, measuringbone 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 bettermeasure 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 inchildren have examined the usefulness of bone Pb
data as a measure of exposure in children to test thishypothesis, other than studies that reported Pb levels in shed deciduous teeth (baby teeth).
When data were available for multiple measuresof exposure, the association between health effects
and either blood Pb or bone Pb levels was evaluatedin this document. While the vast majority of exposure
data were in the form of blood Pb measurements, insome 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 andthe data have been analyzed in a method that allows
such a comparison. For example, multiple studies havereported that blood Pb levels were associated withdecreased IQ in the Yugoslavia Prospective Study (seediscussion 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 inpaint, solder, and gasoline, representing a significant

Exposuresignificantly above or below the mean blood Pb levelare driving the effect, or that past exposure levels are
driving the effect. Finally, some studies comparedeffects 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 witha 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.

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 forwhich studies report a significant relationship withconcurrent blood Pb levels (e.g., elevated bloodpressure, reduced kidney function, or decreases in
specific measures of cognitive function). There is aconsiderable body of evidence that these healtheffects are associated with Pb exposure, and multiple studies report a significant association withconcurrent blood Pb levels <10 µg/dL. Furthermore
the association with blood Pb is supported by theconsistency 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 typeof analyses used to examine the relationship of thehealth outcome with blood Pb across the hundreds ofstudies 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 healtheffect with the blood Pb level is clear. For example,
Lanphear et al. (2000) reported that higher blood Pb
was associated with lower academic performance ina 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 wasstill 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 groupwhose mean blood Pb level <10 µg/dL (e.g., higher
blood Pb level was associated with higher bloodpressure 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, butthey do not exclude the possibility that individuals

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 raceor ethnicity. Bone Pb has been measured in somestudies 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 forthis evaluation of Pb levels <10 µg/dL), plasma Pb
is the portion of blood Pb that is available to crosscell 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 canvary 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 technicallydifficult, requires specialized equipment not widely
available, and is not typically measured in research or
clinical settings (CDC 2010). Variation in whole bloodor plasma collection methods and Pb quantification
techniques may limit comparability across studies,particularly when a method with a relatively highlevel 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

8

NTP Monograph on Health Effects of Low-Level Lead

3.2 Biomarkers of Pb Exposure

NTP Monograph on Health Effects of Low-Level Leadyears 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 belinked 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 inthis 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 turnoverrate, 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 themodel 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 withinbone. Bone and teeth store 90-95% of the total bodyburden of Pb in adults and from 70% to 95% of thetotal body burden in children (reviewed in Barbosa
et al. 2005, Hu et al. 2007). Bone Pb was the sourceof between 40% and 70% of blood Pb in individuals
undergoing hip or knee replacement surgery (Smithet al. 1996). Pregnancy, lactation, menopause, andosteoporosis are periods of bone demineralization,
which may release Pb from bone stores and contribute to increased Pb exposure to other tissues, or to
9

Exposure

published and are included in the chapters of thisdocument covering specific health effects. Generaltrends in blood Pb levels from NHANES data are presented in Figures 7.1, 7.2, and 7.3 (from Mahaffey etal. (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 infood cans and plumbing in the United States (see Section 3.3 Sources of Pb). Prior to the 1970’s blood Pblevels 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 (seeFigure 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 tothose for non-Hispanic whites, almost every age andgender group among blacks had Pb levels statisticallysignificantly 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), andthis trend was observed in NHANES across most age
groups and all racial/ethnic groups (CDC 2005a).
Given an accumulating body burden of Pb andhigher 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 Pblevels 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 theestablished developmental impairments associatedwith 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

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

Mean Blood Pb (µg/dL)

16

12
10
8
6
4
2
0

ExposureChildren, 1- 5 years
Children, 6 -19 years
Adults, 20 years

14

1999-2002
1991-1994

1976 -1980
1988 -1991

2003-2008

NHANES Years

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))

Figure 3.2: U.S. NHANES 1999-2002 Blood Pb Levels Across Ages and Racial/Ethnic Groups
Age (N, all races)
Race/Ethnicity

J

J

J
J
J

6-19 years (6,283)
White, non-Hispanic
Black, non-Hispanic
Mexican AmericanJ

1-5 years (1,610)
White, non-Hispanic
Black, non-Hispanic
Mexican AmericanJ

20-59 years (5,876)
White, non-Hispanic
Black, non-Hispanic
Mexican AmericanJJJ

60 years (3,056)
White, non-Hispanic
Black, non-Hispanic
Mexican American

J

J

1.0

1.5

2.0

2.5

3.0

Blood Pb Levels(Geometric Mean ± 95% CI)

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).

10

NTP Monograph on Health Effects of Low-Level Lead

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

2005-2006
Male
Female

4,092
4,315

2007-2008
Male
Female

4,147
4,119

Exposure

4,132
4,241

J

2003-2004
Male
Female

J

4,339
4,606

J

2001-2002
Male
Female

J

N
3,913
4,057

J

Years
Gender1999-2000
Male
Female

1.00

1.25

1.50

1.75

2.00

2.25

Blood Pb Levels(Geometric Mean ± 95% CI)

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

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, andbone 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 canincrease 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
NTP Monograph on Health Effects of Low-Level Leadhealth. 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 etal. 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 researchgroups is challenging without a common standard
for calibration of instruments. Another modelingapproach 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 healthconditions (reviewed in Barbosa et al. 2005, Hu et al.
11

Exposure2007). Physiologically based pharmacokinetic (PBPK)
models have been created to combine current bloodand 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, andother materials that are easier to obtain; but ingeneral Pb levels fluctuate more rapidly in thesematerials than in bone. Hair collection is minimallyinvasive, and hair is easier to ship and store; however, there are no reliable standardized protocols forhair collection, and hair is subject to contaminationfrom 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 forhair to be a useful source for evaluating exposures totrace metals, including Pb (ATSDR 2001). Collectionof 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 beenmeasured, 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 anddo not directly compare the relationship between ahealth effect and different measures of Pb exposure(i.e., tissue Pb compared to blood Pb). Therefore, theusefulness 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 measureof 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 whenlost after 6 years of age (e.g., Manea-Krichten et al.
1991). In addition, the layers of the tooth provide atimeline 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 inblood. ALAD can be measured in urine, blood, andplasma 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 ofiron, 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).

12

NTP Monograph on Health Effects of Low-Level Lead

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 canalso 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

NTP Monograph on Health Effects of Low-Level Leadfood if used for cooking or storage (CDC 2010). Whilehigh, acute exposures have been reported from Pbfrom pottery leaching into food (Matte et al. 1994),
long-term use may cause a low, chronic exposure andraise the body burden of Pb (Hernandez Avila et al.
1991). Use of Pb-glazed ceramics was a major sourceof cumulative Pb exposure in a study of women in
Mexico (Brown et al. 2000). Pb crystal glassware canrelease 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 andFirearms 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 highenough 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 withinadequate 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 (HUD2001). 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 nolonger major sources of Pb in the United States, Pbfrom these sources remains in soil and dust, as wellas inside people’s bodies in bone and other organs aspart 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 leadto increased exposure to Pb in environmental tobaccosmoke (ETS). Tobacco itself contains Pb, in part at
least, from ambient air sources: the levels of Pb in
mainstream smoke from Canadian-grown tobacco
13

Exposure

solder still contain Pb. Source drinking water rarely
contains Pb, and the Pb enters tap water throughcorrosion of Pb from pipes and plumbing fixtures.
Corrosion creates exposure from Pb deposits evenafter previous sources of Pb have been removed fromwater 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 ahighly 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 incidenceof 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 yearsof age during the DC drinking water event (Edwards
et al. 2009). Infants may be at an increased risk fromcontaminated 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 inthe same household (Bearer 1995).
Dietary Pb sources in the United States havebeen reduced through several changes in practice,such as removing Pb solder from cans and banningPb-arsenate pesticides (Bolger et al. 1996), and current Pb levels in the U.S. food supply are low (CDC2010). 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 sentfrom 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 beenshown to contain or be contaminated with Pb as well
(Ko 1998, CDC 1999, 2002, Buettner et al. 2009, Linet al. 2010). Pottery with a Pb glaze can contaminate

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

Exposure

Pb Concentration (µg/m 3)

4

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

3

2

1

0
1980

1990

2000

2010

Year
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).

cigarettes decreased by 62% from 1968 to 1988 as
ambient air Pb levels declined (Rickert and Kaiserman1994). Serum cotinine (a metabolite of nicotine thatcan be used as a biomarker of tobacco exposure) andpostnatal 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 etal. 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 onan 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 andtexture (CDC 2010). Children and people (particularly
pregnant women) with pica, a disorder causing anurge to eat nonfood items, such as dirt or chalk, canalso ingest Pb (Klitzman et al. 2002).
Children are most commonly exposed to Pb inpaint, household dust, and soil – particularly if they

reside in pre-1978, deteriorated housing – and canincrease their risk of exposure by natural mouthingtendencies (Lanphear et al. 1998, U.S. EPA 2006).
There are few direct data on Pb absorption from toysor other consumer products, but it is clear that Pb isabsorbed from toys in some cases. Pb concentration intoys 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 differencesin Pb absorption between Pb paint and Pb embeddedin 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 Pblevels 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).

14

NTP Monograph on Health Effects of Low-Level LeadNTP Monograph on Health Effects of Low-Level Lead2010). Approximately 95% of all elevated blood Pblevels reported in adults in the United States are
work-related (CDC 2011a). The prevalence rate ofworkers with blood Pb levels >25 µg/dL decreasedby 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 tobe 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, andmanufacturing 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 asource of study subjects with higher exposure levels(e.g., a study of birth outcomes for women living neara 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 Pblevels >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 andwere not included in the evaluation of cardiovasculareffects). Stratified analyses of only subjects with Pb
levels above and below 10 µg/dL have indicated thatassociations 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.
15

Exposure

Renovating, repairing, or painting a pre-1978
building can release particles of Pb-based paint and isassociated with increases in blood Pb levels in children
and adults who live in the home (CDC 2009a, 2011a).
Thorough cleaning after completion of remodelingis effective in removing most of the Pb dust from arenovated 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-SafeCertification Program and use safe work practices toreduce Pb exposures to their clients, employees, andthemselves. Additional certification at the state orFederal 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 arepotential 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 toPb 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 Pblevels were significantly higher for marksmen using
powder charges during the indoor shooting season(Svensson et al. 1992). Pb exposures from thesehobbies 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), anda man whose hobbies included melting Pb weights tomake 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 morethan 100 industries where Pb or Pb-containing
materials are used or disturbed by workers (CDC

Exposure

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. Modifiersof 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 thanchildren do today. Several authors have suggested thatthe 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 fromcross-sectional studies and therefore the studies are
only able to infer the temporal sequence. A particularchallenge 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 bonestrength (Hamilton et al. 1994, Ronis et al. 2001) andsupport 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 notreported. Recent NHANES data support an association
between higher blood Pb levels and increased age inolder 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 ofage (Rothenberg et al. 1999b). Initially, maternalsources of Pb could contribute to a child’s exposurelevels. Mothers’ blood Pb levels at delivery are highly
correlated with umbilical cord blood Pb levels, withumbilical 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 arecorrelated as well, but the efficiency of Pb transferfrom blood to milk varies at low levels, and Koyashiki
et al. (2010) concluded that there are no establishedhealth risks from breast milk. Current CDC guidelines
are to continue breastfeeding up to high blood Pblevels (40 µg/dL blood Pb levels in the mother) (CDC2010). A study in mice showed that gestational andlactational Pb exposure from the mother increases
Pb levels in the offspring, with declining blood Pb levels after weaning (Snyder et al. 2000). There is someevidence 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 inchildren 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, andmen are much more likely to be exposed to occupational sources of Pb. However, women typically go
through more stages of life where demineralizationof bone may be associated with mobilization of bonestores Pb into circulating Pb. Therefore, a number ofauthors have supported the hypothesis that womenare 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 UnitedStates (NHANES geometric mean <5 µg/dL) anddo 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

16

NTP Monograph on Health Effects of Low-Level LeadNTP Monograph on Health Effects of Low-Level Leaddust, but authors such as Wakefield et al. (2002) havenoted 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 theremediation, and workers performing the job should
receive special training, because as discussed earlier,general repair and renovation can be associated withincreased Pb exposure and higher blood Pb levels
in building occupants and workers performing therepairs (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 exposurelevels, immigrants carry a larger body burden of Pb(CDC 2010). Exposure to leaded gasoline emissions,as estimated from time spent in Mexico City, was amajor source of cumulative Pb exposure in a studyof postpartum women in Mexico (Brown et al. 2000).
In a study of pregnant women, a Pb-related increasein 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). Ina study of pregnant women in New York, pica was themost frequently reported source of Pb exposure (13women, 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 exposureand 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 ofgenotype, which remains unknown to the subject, so
sources of bias that may confound other risk factors
are minimized. If specific genetic variants are foundto increase or decrease the association of Pb with a17

Exposure

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 etal. 2004). Data from Symanski et al. (1995) also support a greater relative increase in blood Pb levels inpostmenopausal women that have never been pregnant, supporting both increased mobilization of Pb
associated with menopause as well as mobilizationand 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 demonstratethat Pb exposure causes reduced bone density andtherefore cause-and-effect is particularly difficult toestablish 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, andiron 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 ofindividual variation in the body burden of Pb (Jameset al. 1985, Maddaloni et al. 1998).
Low socioeconomic status (SES) is associatedwith 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 toa collection of risk factors, including living in older,
deteriorated housing with Pb in paint, household
dust, pipes, or urban air; consuming diets lower innutrients and calories; playing with potentially contaminated inexpensive toys; working in jobs withoccupational 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Exposure

health effect, there is a stronger biological basis forthat 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 theincreases in risk from each individual factor. While
many measures taken to reduce Pb exposure havedecreased blood Pb levels in the U.S. population,
economically disadvantaged young children in older
housing or pregnant immigrants using contaminatedproducts are still at risk for significant Pb exposures.

from the environment and internal (endogenous)
sources of Pb, primarily stored in bone. Bone Pb isa better measure of the cumulative body burden of
Pb and therefore it is commonly hypothesized thatbone Pb may show more consistent associations withlong-term health effects. Pb continues to be used inindustrial processes and in manufactured productsin the United States and worldwide and is persistentin 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 withblood Pb <10 µg/dL there are health risks. The other3.5 Summary
chapters of this document outline the evidence for
While Pb can be measured in a variety of human tis- specific health effects from blood Pb levels <10 µg/dL.
sues, whole-blood Pb is the most common measure A discussion of Pb exposures in potentially suscepused in both research and clinical settings. Blood Pb tible populations for specific health effects is included
levels fluctuate and represent both current exposures in individual chapters.

18

NTP Monograph on Health Effects of Low-Level Lead

4.0 NEUROLOGICAL EFFECTS
4.1 Conclusions

NTP Monograph on Health Effects of Low-Level Lead

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 fromepidemiological studies with a focus on blood Pblevels <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 theevaluation.
There is a relatively large database of humanstudies for a wide range of neurological effects (seeTable 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
19

Neurological
Effects

The NTP concludes that there is sufficient evidence
that blood Pb levels <5 µg/dL are associated withadverse 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 consistencyof results for an adverse effect of blood Pb <10 µg/dL
across multiple indices of neurological effects (e.g.,
cognition, behavior, and sensory function), throughmultiple groups, with a wide age range from earlychildhood 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 studiesof 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 measuresof general and specific cognitive function evaluated inchildren. There is also limited evidence that prenatal
exposure to blood Pb levels <10 µg/dL are associatedwith decreased IQ, increased incidence of attentionrelated and antisocial behavior problems, anddecreased hearing measured in children. Conclusions
on effects of prenatal exposure for outcomes evaluated as children are complicated by the high degreeof 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 thatblood 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 ofchildren with blood Pb levels <10 µg/dL, the pooled
analyses that reported effects with peak blood Pblevels <7.5 µg/dL (Lanphear et al. 2005), and multiple
cross-sectional studies that reported effects withmean blood Pb levels <5 µg/dL. Lower levels of academic achievement, as determined by class rank andachievement 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 specificmeasures 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 withdecreased auditory acuity. Multiple cross-sectional
studies reported hearing loss, as indicated by higher
hearing thresholds and increased latency of BAEPs, inchildren with blood Pb levels <10 µg/dL.
In adults, there is limited evidence that blood Pblevels <10 µg/dL are associated with psychiatric outcomes (including anxiety and depression), decreased
auditory function, decreases in specific measures ofcognitive function in older adults, and the neurodegenerative disease ALS. There is sufficient evidence
that blood Pb levels <10 µg/dL are associated withessential tremor in adults, and limited evidence forblood Pb levels <5 µg/dL. As with other studies ofhealth 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 thepotential 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 incognitive function in older adults than for blood Pb,
suggesting a role for cumulative Pb exposure.

in Section 4.2.1. This document is not a review ofneurotoxicity, and the reader is directed to published reviews for additional background. Key dataand 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 effectbegins with a statement of the NTP’s conclusion thatthe 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, thecomplete data set of human studies considered forevaluation of neurological effects with low-level Pb isincluded in Appendix A: Neurological Effects, whereindividual 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

Neurological
Effects

Table 4.1: Major neurological effects considered
EffectDescription

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-BinetIntelligence 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 specificcognitive abilities

Cognitive function is measured with numerous tests including general measures, e.g., theMental 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

Neurodegeneration
Various diseases

Mood disorders are diagnosed with various tests, e.g., the Child Behavior Checklist (CBCL)
or Brief Symptom Inventory.
Diagnoses of amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, essential tremor, orParkinson’s disease.

Sensory Function
Audio

Several measures of auditory function, e.g., higher hearing thresholds and altered brainstem auditory evoked potentials (BAEPs).

VisionSeveral measures of visual function, e.g., altered visual evoked potentials (VEPs) and electro­
retinographic (ERG) testing.

20

NTP Monograph on Health Effects of Low-Level Lead

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 rangeof tests and tools used to evaluate neurocognitive,
neurobehavioral, psychiatric, and neurophysiologicaloutcomes 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.

NTP Monograph on Health Effects of Low-Level Lead

21

Neurological
Effects

and the 2005 CDC statement on Preventing Lead
Poisoning in Young Children (CDC 2005) highlightthe 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
4.2.2 Principal Conclusions from the 2006 on attention may contribute to underachievement or
EPA and 2007 ATSDR Pb Documents
delinquent behavior in children. The EPA 2006 AQCD
The EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and for Lead (U.S. EPA 2006) concludes that the negative
ATSDR’s Toxicological Profile for Lead (ATSDR 2007) impacts of Pb on neurocognition and behavior persist
both concluded that negative effects of Pb on neu- into young adulthood and that there is clear evidence
rocognitive ability and neurobehavioral outcomes that blood Pb levels in children of 5-10 µg/dL (andin children are observed across numerous studies possibly lower) are associated with these adverseat blood Pb levels <10 µg/dL even after adjusting for effects. In adults, both ATSDR and EPA noted thatchronic occupational Pb exposure is associated with
confounding factors (see Table 4.2).
decreased nerve conduction velocity and posturalbalanceabnormalities. The EPA 2006 AQCD for Lead
Table 4.2: Main conclusions for neurological
(U.S.
EPA
2006) identified ≥14 µg/dL blood Pb level
effects in the 2006 EPA AQCD for Lead and theasapossiblethreshold for these effects, as well as2007 ATSDR Toxicological Profile for Leadfor visuomotor and memory impairment, and effects“….effects on neurobehavior in children have beenon the visual and auditory systems (prolonged visualobserved with remarkable consistency acrossevoked potentials (VEPs) and BAEPs). The EPA 2006
numerous studies of various designs, populations,
AQCD for Lead (U.S. EPA 2006) characterized theand developmental assessment protocols. The
evidence for impairments in cognitive performancenegative impacts of Pb on neurocognitive ability andassociated with Pb levels in adults as mixed, althoughother neurobehavioral outcomes persist in mostbone Pb (and therefore long-term cumulative exporecent studies even after adjustment for numeroussure) was associated with decreased cognitive perforconfounding factors, including social class, quality
mance. The EPA 2006 AQCD for Lead (U.S. EPA 2006)of caregiving, and parental intelligence.” (U.S. EPA
stated that four studies reported that past occupa2006, pg 6-269)
tional exposure to Pb increased the risk of developing ALS and motor neuron disease and two studies“…the preponderance of the evidence indicates
reported that essential tremor was associated withthat lead exposure is associated with decrements
low blood Pb levels (a mean of 3 µg/dL). EPA is inin cognitive function. Meta-analyses conducted on
theprocess of revising the AQCD for Lead, and thecross-sectional studies or a combination of crossconclusionsof the external draft (U.S. EPA 2012) are
sectional and prospective studies suggest thatlargely in line with the 2006 AQCD for Lead (U.S. EPA
an IQ decline of 1-5 points is associated with an2006),
plus additional review of the evidence forincrease in PbB [blood Pb level] of 10 µg/dL. Most
attention-related
behaviors, including ADHD.
importantly, no threshold for the effects of lead on
The
NTP
considered
the conclusions and data
IQ has been identified…” (ATSDR 2007, pg 25)
summaries from the EPA’s 2006 AQCD for Lead (U.S.
The Lanphear et al. (2005) pooled analysis is EPA 2006) and ATSDR’s Toxicological Profile for Leadcited by both EPA and ATSDR as supporting evidence (ATSDR 2007). In general, the NTP accepted thefor a decline of up to 6 full-scale IQ (FSIQ) points for conclusions and agreed that the data support them.
an increase in blood Pb from 1 to 10 µg/dL in chil- Differences from the ATSDR and EPA documents aredren. The 2006 EPA AQCD for Lead (U.S. EPA 2006) identified for specific endpoints.

4.3 Evidence for Pb-Related Effects on
Neurological Outcomes

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 fulllist 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 Pblevels 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 monthsage) or tooth dentin (6-8 years of age) are associatedwith 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 and10 µg/dL) on academic achievement. However, there
is inadequate evidence that prenatal blood Pb levels<10 µg/dL are associated with academic achievementin children because of a lack of academic performance studies that include Pb exposure data fromprenatal 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 classstanding in 132 children in Massachusetts at 18 yearsof age (Needleman et al. 1990); reading and spellingdifficulties 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 umbilicalcord blood Pb or children’s blood Pb levels at 6, 12,
18, or 57 months of age, were significantly associatedwith 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 apersistent negative effect on cognitive achievementthat 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 Pblevels 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 withdecreased achievement measured by the Wide
Range Achievement Test-Revised (WRAT-R). As with22

NTP Monograph on Health Effects of Low-Level Lead

Neurological
Effects

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 Pblevels 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 attributedin part to difficulty discriminating focused effects
because test performance covers multiple neurobehavioral processes (U.S. EPA 2006).
The discussion of cognitive function below isdivided 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-basedachievement measures, (2) IQ in children, and (3)other general and specific measures of cognitive
abilities in children and adults.

Academic Achievement

NTP Monograph on Health Effects of Low-Level Lead

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 withlower scores in the KTEA in 148 children 10 years ofage 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, anddemonstrated that the effects on achievement wereindependent of known confounders. The Miranda
et al. (2009) study found evidence of differential
effects in students with lower test scores, reportingthat 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 hada larger adverse effect on children with lower testscores, suggesting that Pb and other confounders all
have a greater impact in individuals that already havelower levels of achievement. The studies of Surkan
et al. (2007) and Bellinger et al. (1992) reported anegative effect of Pb on academic achievement while
controlling for the child’s IQ, suggesting that IQ andacademic 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 atblood 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 yearsof 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 ofblood 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 is23

Neurological
Effectsother cross-sectional studies of Pb, an important
limitation is that blood Pb during early childhood islikely to have been higher than blood Pb measured
during the study; and therefore, blood Pb may havebeen >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 scoreson 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 wasinversely associated with concurrent blood Pb levels(mean, 8 µg/dL). Wang et al. (2002) found a similar
inverse relationship between concurrent blood Pblevel (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 withdecreased school reading scores (Woodcock-Johnson
III Tests of Achievement) at 9 and 11 years of age ina 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 Pblevels ≥5 µg/dL measured at 30 months of age in aprospective 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 andMassachusetts. Miranda et al. (2007) reported thatblood Pb levels down to 2 µg/dL (collected as part ofPb screening programs when the children were <5years of age) were negatively related to test performance in both reading and mathematics in a studyof 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 effectof blood Pb levels down to 2 µg/dL on end-of-grade
reading scores compared to the reference group withblood Pb levels of 1 µg/dL.
No studies were located that evaluated maternal Pb levels and educational achievement; however,Neurological
Effects

associated with later performance. However, clear evidence that early-childhood Pb exposure is associatedwith 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 tosupport the importance of both early-life exposure andcurrent blood Pb levels. The conclusion of inadequate
evidence that prenatal blood Pb levels <10 µg/dL areassociated with academic achievement in children isbased on the lack of studies of academic performancein 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 Pblevels <10 µg/dL; however, the EPA’s 2012 draft (U.S.
EPA 2012) currently supports a lower blood Pb level.
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 forfull list of studies). The NTP conclusion of sufficientevidence that blood Pb levels <5 µg/dL are associated with decreased IQ is based on several lines ofevidence, including multiple cross-sectional studies
of children reporting lower IQ associated with mean
blood Pb levels <5 µg/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 forChildren (WISC) and have adopted similar protocols
to assist in cross-study comparison and greater generalization of the findings. The most recently publishedpooled analysis of IQ data, Lanphear et al. (2005),
took advantage of the similarity in study design ofseven prospective studies and concluded that blood
Pb levels <10 µg/dL in children (and specifically inchildren 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 inblood Pb from 2.4 µg/dL to 10 µg/dL. Data from crosssectional studies also support an association between
concurrent blood Pb levels <5 µg/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 thatprenatal blood Pb levels <10 µg/dL are associated withdecreased IQ in children. There is some evidence thatthe association between decreased IQ might be moreconsistent for bone Pb than for blood Pb, but thosedata 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 anddecreased IQ score in children from 4 to 13 years ofage. 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 yearsof age (mean, 6.5 µg/dL), but not other ages, weresignificantly associated with decreases in FSIQ andverbal IQ (VIQ) assessed by the WISC-R at 10 yearsof 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 yearsof age (mean, 7 µg/dL) was significantly associatedwith decreased FSIQ by the Wechsler Preschool andPrimary Scale of Intelligence (WPPSI-R) at 4 yearsof 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 notmaternal blood Pb, umbilical cord blood Pb, or average through 7 years of age) were significantly associated with decreased FSIQ and VIQ scores evaluatedby the WISC-R at 7 years of age in 494 children in Port
Pirie, Australia; however, mean blood Pb levels in this24

NTP Monograph on Health Effects of Low-Level Lead

IQ

NTP Monograph on Health Effects of Low-Level Leadand 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). Notethat peak childhood blood Pb in the Cincinnati andRochester cohorts was >10 µg/dL; therefore, it is notclear that the observed decreases in IQ reported in
Dietrich et al. (1993b) and Hornung et al. (2009) arestrictly associated with a blood Pb level <10 µg/dL.
No clear evidence was located that maternal orumbilical cord blood Pb levels <10 µg/dL are associated with decreased IQ in children. Many studies, suchas Baghurst et al. (1992), Bellinger et al. (1992), andDietrich et al. (1993b) described earlier, did not finda 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 relationshipbetween 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 Pblevels at 28-36 weeks of pregnancy (mean, 7.8 µg/dL)
were related to reduced IQ in children 6-10 years ofage. 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 andGatsonis 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 withdecreases in IQ in children; however, many of thecross-sectional and prospective studies included inthese analyses are based on cohorts with blood Pblevels >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 thatused 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
25

Neurological
Effects

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, thetwo studies by Chiodo et al. (2004, 2007) evaluateda range of neurodevelopmental endpoints in 240
and 500 African-American inner-city children 7-9
years of age with mean concurrent blood Pb levelsof 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, thestudy supported significant effects on IQ at blood Pblevels 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 (downto age 3 for PIQ); however, IQ was not associated withmaternal 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), withpeak 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)

Neurological
Effects<10 µg/dL (and specifically <7.5 µg/dL) in children areassociated with intellectual deficits. Lanphear et al.
(2005) reported significant decreases in IQ in analyses restricted to children with a maximum blood Pblevel <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 orother confounders, these studies were also generally
in children with blood Pb levels >10 µg/dL. More recent
studies of the relationship between blood Pb and IQ
in children with blood Pb levels <10 µg/dL considereda 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 (anassessment of the stimulation in the environment inwhich the child is raised), and birth weight in the final
model; however, prenatal smoking, prenatal alcoholuse, 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 manganesein 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 instudies of cognitive effects of Pb.
In one example, the extensive data on potential covariates and the thorough characterizationof exposure measurements based on serial blood
Pb assessments over time allowed comparison of
the strength of the association between Pb anddecreased 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 Pblevels 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 withlower Pb exposure levels. Tibia Pb was a significant
26

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 theassociation with decreased IQ is stronger for bone
Pb than for blood Pb (Wasserman et al. 2003). In isimportant to note two points in this analysis. First,
blood Pb measurements were >10 µg/dL for mostchildren in these groups. Second, this is one of the
few studies in children that examined the usefulnessof bone Pb data as a measure of exposure, althougha 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 anincremental 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 andRothenberg 2005, Kordas et al. 2006). This indicates asteeper slope (greater effect per unit increase) in thedose-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 thatthe dose-response curve has a steeper slope at lower
blood Pb levels. The 2005 CDC (CDC 2005) review ofthe epidemiological evidence for neurological effects
in children also noted that there was evidence for asteeper 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
NTP Monograph on Health Effects of Low-Level Lead

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, andvisual-spatial processing, the lack of a clear pattern ofeffects has contributed to difficulty in distinguishingspecific, focused effects, because test performancecovers 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
NTP Monograph on Health Effects of Low-Level Lead

have reported Pb-associated decreases in specificmeasures of cognitive function in groups of older
adults, such as the Normative Aging Study. Severalof 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 withconcurrent blood Pb levels. There is limited evidence
that blood Pb levels <10 µg/dL are associated withdecreases 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 subjectsof different ages and designed to explore different
cognitive domains (see Appendix A: Neurological
Effects under outcomes measured for tests used inindividual 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 ofInfant 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, whichis 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 Pblevel and decreased MDI score was demonstrated
in multiple studies at blood Pb levels from <2 to10 µg/dL. Maternal blood Pb levels <10 µg/dL andumbilical cord blood Pb levels <5 µg/dL have beenreported 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 etal. 2009, Jedrychowski et al. 2009a, Jedrychowski etal. 2009b, Pilsner et al. 2010) reported effects in children with blood Pb levels that remained consistently
27

Neurological
Effects

Pb levels <10 µg/dL and lower FSIQ scores in children 4-13 years of age. The conclusion of sufficientevidence that decreases in IQ scores in children areassociated 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 scorein 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 Pblevels <10 µg/dL are associated with decreased IQ inchildren 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 theconclusions from EPA’s 2006 AQCD for Lead (U.S. EPA
2006) and ATSDR’s 2007 Toxicological Profile for Lead
(ATSDR 2007).

Neurological
Effects

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 withdecreased MDI scores, but there is less evidence that
concurrent blood Pb is associated with MDI thanthere is for an association with measures of prenatal
Pb exposure.
The overwhelming majority of prospective
studies found that prenatal exposure determinedby 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 wereassociated with prenatal exposure based on umbilicalcord blood Pb at the following levels: ≥1 µg/dL in children evaluated at 24 and 36 months of age in a studyof 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 monthsof 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 Pblevels (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 withumbilical cord blood Pb or maternal Pb during othertime periods was not significant. Dietrich et al. (1987,
1990) reported that maternal blood Pb sampled during pregnancy (mean, 8 µg/dL) was associated withdecreased MDI tested at 3, 6, and 24 months of age
in children from the Cincinnati Lead Study and thatumbilical cord blood was only associated with MDI
evaluated at 3 months of age. Ernhart et al. (1987)
reported that decreased MDI evaluated at 6 monthsof 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 evaluatedat later time points (1-3 years of age). It is important
to note that the blood Pb of infants from both theCincinnati and Cleveland lead studies increased after
birth and that childhood blood Pb levels for thesegroups were >10 µg/dL (mean, 16-17 µg/dL at 2 yearsof 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 etal. (1988) did not find an association with MDI andearly-childhood blood Pb or concurrent blood Pblevels; however, as noted above, the blood Pb levelsin this cohort was >10 µg/dL. In contrast, Bellinger etal. (1990) found that postnatal blood Pb was associated with a change in cognitive performance from 24months of age (evaluated by the MDI) to 57 monthsof age (evaluated by the GCI) in a study of a groupwith a similar age range.
Few studies have examined the relationshipbetween MDI and measures of exposure otherthan blood Pb. Gomma et al. (2002) reported thatmaternal patellar (knee cap) Pb level was significantly
associated with a decrease in MDI scores evaluatedin 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 associatedwith lower MDI scores in children from 6 to 36 monthsof age. For example, Solon et al. (2008) reported that
concurrent blood Pb (mean, 7.1 µg/dL) was associatedwith decreased MDI in children from 6 to 36 monthsof age. Similar results (Pb-related decrease in MDI)
were reported in children evaluated at 24 months ofage 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 ofblood Pb on MDI scores, findings from several studies

28

NTP Monograph on Health Effects of Low-Level LeadNTP Monograph on Health Effects of Low-Level Leadblood Pb levels <10 µg/dL (mean 5.4 µg/dL; blood Pblevels were related to decreased performance in multiple tests, including the Block Design and Digit Spansubsets of the WISC and various tests of executivefunction, memory, and attention. When grouped by
cutoff points of 10, 7.5, 5, and 3 µg/dL blood Pb, thestudies found significant effects on some tests at levelsof ≥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 fewerstudies have been reported in adults from the general population. A number of studies in older adults
reported a decrease in cognitive function associatedwith Pb, with more consistent evidence for an association with bone Pb than for concurrent blood Pblevels. 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 measuresof 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 notpatellar 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 thatblood Pb (mean, 4.5 µg/dL), patellar Pb, and tibia
Pb were all associated with decreased performanceon 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 withdecreased performance on the Trail Making Test (forblood Pb >8 µg/dL, OR=2.60 (95% CI: 1.04, 6.49); forblood Pb 4-7 µg/dL, OR=2.05 (95% CI: 1.05, 4.02);
relative to referents with blood Pb ≤3 µg/dL) and theDigit 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 withblood Pb ≤3 µg/dL), but only in the rural populationand 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 withblood Pb levels. Shih et al. (2006) reported a lack29

Neurological
Effects

support an association with decreased performanceon the GCI in children. In a study of 170 children fromthe Brigham and Women’s Hospital, Bellinger et al.
(1991) reported that GCI scores and the McCarthy
subscale score for perceptual performance evaluatedat 57 months of age were inversely associated withblood 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 orlater ages up to 56 months were not significant, in astudy 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 ina study of 207 children from the Sydney Lead Studyevaluated at 48 months of age (Cooney et al. 1989b).
Multiples studies have reported that concurrent
and early-childhood blood Pb levels <10 µg/dL areassociated 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 associatedwith decreased vocabulary scores evaluated as partof 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 Pblevels <10 µg/dL (geometric mean, 1.9 µg/dL) wereassociated 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 scoresof the WISC at 9 years of age in a prospective study of
278 inner-city children from Cleveland, OH. Chiodo etal. (2004, 2007) evaluated a range of neurocognitiveeffects in inner-city African American children 7-9 yearsof age (n=243 and 506, respectively) with concurrent

Neurological
Effectsof 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 (meanage, 60 years). However, tibia Pb levels were significantly associated with lower scores in all sevendomains 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 astudy of 587 older women (mean age, 61 years) fromthe 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 Pblevels and did not collect bone Pb data: Nordberg etal. (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 studyof 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 onchanges in cognitive function over time, rather thana single cross-sectional examination. Weisskopf et al.
(2004) tested cognitive function in 466 men (meanage, 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 ina 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 asignificant 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 dataset, Krieg et al. (2010) demonstrated that vitamin D
receptor (VDR) genotype did affect the relationshipbetween blood Pb and performance on the WISC-R
Digit Span and WRAT-R math scores; however, theyfound no clear pattern in terms of the effect of VDRgenotype on the relationship between blood Pb andcognitive function.
Most of the recent studies of the relationshipbetween blood Pb and specific measures of cognitive
function considered a range of potential confounders,such as age, sex, education, and race/ethnicity. Somestudies have also examined potential physical, genetic,
and psychological confounders. In a study of 47 healthadults 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 investigatedthe potential modifying effect of gene polymorphisms(e.g., ALAD, HFE, APOE, and VDR genotypes) and otherfactors (Weuve et al. 2006, Rajan et al. 2008, Glass etal. 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 etal. (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. Glasset 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 etal. (2008) reported that higher maternal self-esteem
attenuated the Pb-associated decrease in MDI scorein a study of 309 children 2 years of age from Mexico
City. Peters et al. (2010) reported that blood Pb (mean,

30

NTP Monograph on Health Effects of Low-Level Lead

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.

NTP Monograph on Health Effects of Low-Level Lead

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 (seeAppendix 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 thedata 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 ofeffects; and (2) in the available studies, designationsof “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 diagnosisof ADHD and attention-related behaviors (e.g., inattention and hyperactivity) are consistently reported
31

Neurological
Effects

Summary of Support for Conclusions
Animal data support a Pb-associated decrease inneurobehavioral tests of learning (including fixedinterval 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 fordecreases in specific measures of cognitive function
in children 3 months to 16 years of age with blood Pblevels <5 µg/dL measured in concurrent blood or inearly 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 observedat later ages. However, as discussed for IQ, clear
evidence that early-childhood or prenatal Pb exposure is associated with decreases in specific indicesof cognitive function at later ages is complicated by
the high degree of correlation in childhood blood Pblevels 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 umbilicalcord 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 associateddecreases in specific measures of cognitive function
in children is based on strong consistent support foran association between umbilical cord blood and MDIscores, 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 withdecreases in specific measures of cognitive function
in older adults is based on the mixed evidence that
concurrent blood Pb levels <10 µg/dL are associatedwith reduced cognitive function and the consistent

support that bone Pb is associated with decreases
in specific measures of cognitive function or withchange 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 withbone Pb; EPA also highlights the mixed evidence foran association with blood Pb. As with other studies ofhealth effects of Pb in adults, prospective studies ina group for which the data demonstrated that blood
Pb levels remained consistently below 10 µg/dL frombirth 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 observedin 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 ingeneral and specific measures of cognitive function
in children 3 months to 16 years of age extends theconclusions 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.

Neurological
Effects

in studies with mean blood Pb levels <5 µg/dL andin several studies at blood Pb levels <2 µg/dL. The
diagnostic criteria for attention-related behaviors can
include multiple categories of behavioral deficits inaddition 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 thoseindividual domains will not be covered here becausea 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 areassociated 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 adults 1 (7-20 yearsof age); however, early-childhood blood Pb levels insome 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 meanlevels from 1 to 11 µg/dL and attention-related
behavioral problems, ADHD, or other indicators ofdecreased attention or increased hypersensitivity inchildren 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 yearsof 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, wasobserved on the teachers’ and parents’ ratings usinga German questionnaire version of the Conners’
Rating Scale (namely the Fremdbeurteilungsbogenfür Auf-merksamkeits-Hyperaktivitäts-Störung
(FBB-ADHS)) and German-KITAP (Testbatterie zur

Aufmerksamkeitsprüfung fü Kinder) test battery in astudy of 83 children 8-12 years of age in Romania withconcurrent 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 measuresin inner-city African American children 7-9 years ofage (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 scoreson 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 (Braunet 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 thesame 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 levelsof ≤2 µg/dL and attention-related behaviors, ADHD,or symptoms of inattention and or hyperactivity. In across-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
1 Note: children are defined as <18 years of age in this docuthe
Korean version of the ADHD rating scale. Higher
ment; therefore, 18- to 20-year-olds in the study are conconcurrent blood Pb level (mean, 1.8 µg/dL) was
sidered adults.

32

NTP Monograph on Health Effects of Low-Level LeadNTP Monograph on Health Effects of Low-Level Leadrole for early-life prenatal or early-childhood Pb exposure and attention-related behaviors in older children.
In a prospective study with Pb exposure measuresspanning prenatal and early childhood to 6 years ofage, Ris et al. (2004) reported that attention in 15- to
17-year-old children by the Continuous Performance
Test-Conners’ Version was inversely associated withmaternal blood Pb during the first or second trimesterof pregnancy (mean, 8.9 µg/dL), average childhood
blood Pb <5 years of age, and blood Pb at 6.5 yearsof age in a study of 195 children from the Cincinnati
Lead Study); however, blood Pb levels during earlychildhood were above 10 µg/dL in this cohort (Dietrich et al. 1993a, Wright et al. 2008), so it is not clearthat 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 forChildren, was not significantly related to blood Pb(mean, 4.2 µg/dL) at 30 months of age (n=582), butthere was a greater odds for teacher-rated hyperactivity (OR=2.82 (95% CI: 1.08, 7.35)) in children withblood 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 asimilar 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 Pblevels 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 inrats Brockel and Cory-Slechta 1998, U.S. EPA 2006 for
2 Note: children are defined as <18 years of age in this docu-

ment; therefore, 19- and 20-year-olds in the study are considered adults.

33

Neurological
Effects

associated with increased score on the Korean version of the abbreviated Conners’ scale for ADHD in astudy 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 thanin 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) foundincreased 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 astudy 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 theDunedin 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 wasassociated with decreased focused attention by the
Shape School Task at 4-5 years of age in 172 childrenin Rochester, NY.
The relationship between concurrent blood Pblevels and attention-related behaviors is supported bymultiple studies, but there are also data supporting a

Neurological
Effects

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 ofage with blood Pb levels of 1-11 µg/dL. The conclusionof sufficient evidence for a positive association withattention-related behaviors in children at blood Pblevels <5 µg/dL is based on the consistency of effects
in these studies and supports effects down to andbelow 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-associatedbehavioral changes in the area of attention, of which
ADHD is one example on the more severe end of thespectrum of effects. Second, diagnostic criteria in theavailable studies, with the exception of the two Nigg etal. (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 thatwould 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, suchas socioeconomic variables, sex, race/ethnicity, ageof blood Pb measurement, parental education, andtobacco exposure. Several studies reported that blood
Pb levels were significantly associated with ADHD evenafter controlling for potential mediating effects of child
IQ (e.g., Nigg et al. 2008, Nigg et al. 2010). Althoughseveral studies reported an association between concurrent blood Pb and attention-related behaviors inchildren 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 thatexamined the relationship between blood Pb levels in
adults and ADHD or attention-related behaviors. Thereis inadequate evidence to evaluate the potential association between blood Pb <10 µg/dL and effects on
attention-related behaviors in adults. The conclusion oflimited evidence for an association between blood Pblevels and attention-related behaviors in children withprenatal Pb exposure at blood Pb levels <10 µg/dL isbased on the evidence for an association with prenatal
blood Pb <10 µg/dL that may include childhood exposure >10 µg/dL, with support from the concurrent blood
Pb data and a number of bone Pb studies reporting
an association with attention-related behaviors suchas 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 yearsof 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 ofthe 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-associatedincreases in attention-related behaviors.

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

34

NTP Monograph on Health Effects of Low-Level Lead

Problem Behaviors

The discussion of problem behaviors below is divided
into two sections: (1) delinquent, criminal, or antisocial behavior; and (2) psychiatric outcomes. Mostof 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 havealso reported an association with blood Pb levels.

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 wasno association with earlier blood Pb levels that weresignificantly 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) andchildhood blood Pb measures ≤7 years of age with
self-report of delinquent behavior in children fromthe Cincinnati Lead Study evaluated at 15-17 yearsof 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 notclear that this is strictly associated with blood Pblevels <10 µg/dL. Similar results were reported forumbilical cord blood and concurrent blood Pb andbehavior problems in 3-year-olds from the Yugoslavia
Prospective Study; however, blood Pb levels (meansof 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 elevatedwith blood Pb >10 µg/dL at 30 months of age. Twostudies have also reported an association with prenatal or childhood blood Pb levels and antisocial
behavior problems as young adults4. Higher rates

3 Note: children are defined as <18 years of age in this docu-

4 Note: children are defined as <18 years of age in this docu-

ment; therefore, 19- to 24-year-olds in these studies are
considered adults.

NTP Monograph on Health Effects of Low-Level Lead

ment; therefore, 19- to 24-year-olds in the following studies are considered adults.

35

Neurological
Effectsstudies 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 bestrictly 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 havereported 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. Thereis 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 increasein the odds ratio (OR=7.24 (95% CI: 1.1, 49.5)) for conduct disorder among children 8-15 years of age withblood 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 thatfound associations between current blood Pb at andabove 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 andTeacher 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 ofsome studies support a stronger or more consistentNeurological
Effects

for total criminal arrests in 19- to 24-year-olds fora 5 µg/dL increase in blood Pb were significantly
associated with higher maternal blood Pb during thefirst 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 toadult 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 fromthe same high schools in Pennsylvania. Fergusson etal. (2008) reported a significant association between
tooth dentin Pb of shed primary teeth (6-8 years ofage) and officially reported crime at 21 years of age ina study of 1,265 young adults from the Christchurch
Health and Development Study cohort.
A meta-analysis of 19 studies of Pb exposureand 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 morecommon in boys than in girls, the percentage of boysin 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) notethat effects were similar whether Pb exposure wasmeasured 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 foundin three studies from the same laboratory (Marlowe
and Errera 1982, Marlowe et al. 1985, Marlowe andBliss 1993) that used hair as the measure of exposure.
Marcus et al. (2010) cannot explain why the hair Pbdata displayed a stronger relationship and noted thatmultiple studies have determined that hair Pb is lessaccurate 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 containa bias or other population factor that may explain thestronger 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 tolevels 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 frommultiple 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 inchildren at blood Pb levels <5 µg/dL is based on theconsistency of effects in these studies and the Braunet 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, suchas socioeconomic variables, sex, race/ethnicity, ageof blood Pb measurement, parental education, andtobacco 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 thatcriminal arrests in young adults 19-24 years of age
were associated with prenatal and childhood blood Pblevels, 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 ofage, no studies of antisocial behavioral problems were36

NTP Monograph on Health Effects of Low-Level Lead

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 isstronger than the discussion of Pb effects on moodand behavior that may extend into increased risk fordelinquent 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 thegrowth of the database in recent years, the EPA’s 2012draft (U.S. EPA 2012) currently supports an association
with problem behavior.

NTP Monograph on Health Effects of Low-Level Lead

Summary of Support for Conclusions
There are some examples of Pb-associated increases
in depression-related outcomes in rats and mice atblood Pb levels down to 17 µg/dL (e.g., Dyatlov andLawrence 2002, U.S. EPA 2006 for recent reviews of
the animal data, see ATSDR 2007). The data set ofhuman 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
37

Neurological
Effects

Psychiatric Outcomes, Including Anxiety andDepression
There is inadequate evidence to evaluate the potential association between blood Pb <10 µg/dL andanxiety- or depression-related psychiatric outcomesin children (see Appendix A: Neurological Effects forfull list of studies). There is limited evidence thatblood 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) andsupport an effect of concurrent blood Pb or bone Pb
on these psychiatric outcomes.
Most studies of behavior in children that haveidentified an association with Pb exposure have beenin 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 and22 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 thisstudy had blood Pb levels above 10 µg/dL, so theseeffects 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 ofage 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 measuresof anxiety or aggression in boys or girls (Hubbs-Tait etal. 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, thesestudies 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 increasein 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 19992004 data set; a diagnosis of generalized anxiety
disorder was not associated with blood Pb levels inthis 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 withcombined measure of mood, including elevatedanxiety, depression, and phobic anxiety (Rhodes etal. 2003). In a further study of 744 men from theNormative Aging Study, an interquartile increase intibia 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).

Neurological
Effects(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 greaterthan 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 associatedwith ALS in the study, and bone Pb is considered abetter measure of cumulative exposure. The issue ofreverse causality (the possibility that increased blood
Pb is related to greater bone Pb mobilization from thereduced 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 wassignificantly 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 withblood Pb (OR=2.6 (95% CI: 1.9, 3.7) for a doubling ofblood Pb). The study examined the potential influenceof measures of bone turnover and genetic factors
and reported a significant interaction between blood
4.3.3 Neurodegeneration
Pb –ALS and plasma biomarkers for bone turnover(procollagen type-1 amino-terminal peptide (PINP))
Amyotrophic Lateral Sclerosis (ALS)
and resorption (C-terminal telopeptides of type 1
There is limited evidence that blood Pb levels collagen (CTX)), but not the K59N polymorphism in<10 µg/dL are associated with increased risk for ALS. the ALAD gene (Fang et al. 2010). However, adjusting
A number of case-control studies have reported a the model to account for differences in biomarkers
significant association between blood Pb and ALS of bone turnover did alter the association between
diagnosis, with most of the studies coming from two blood Pb and ALS to a large degree. The authors statepatient groups (see Appendix A: Neurological Effects that reverse causality is unlikely because the Pb-ALS
for full list of studies). The data present limited evi- association persisted after adjusting for biomarkdence because of issues with potential reverse cau- ers of Pb mobilization from bone, but that reverse
sality, because an association between ALS and bone causality cannot be entirely ruled out because of theturnover might lead to higher Pb levels among ALS cross-sectional nature of the data.
In further study of the population in New Engpatients, and issues with bias because a reported
increased survival time in ALS patients relative to land, Kamel et al. (2003, 2005) reported that the
ALAD gene was associated with altered bone Pb levels,
control patients might also lead to higher Pb levels.
In a small case-control study of 19 ALS patients but not with blood Pb, and the effect on ALS was notand 39 controls (mean age, 64-66 years), mean blood significant. In a second, follow-up study, Kamel et al.
Pb was not significantly different (p=0.38) between (2008) demonstrated that tibia bone Pb was signifiALS patients (12.7 µg/dL) and controls (10.8 µg/dL) cantly associated with greater survival time between
to evaluate the potential association between blood
Pb <10 µg/dL in children and anxiety- or depressionrelated psychiatric outcomes is based on the lack ofstudies at blood Pb levels <10 µg/dL. The conclusionof limited evidence that concurrent adult blood Pblevels <10 µg/dL are associated with psychiatric symptoms including anxiety and depression is based on thesmall number of studies supporting an effect (one atblood 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 assessmentof anxiety, depression, or other psychiatric outcomes
would eliminate the potential role of early-life blood
Pb levels above 10 µg/dL on health effects observedin 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 nothave 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.

38

NTP Monograph on Health Effects of Low-Level Lead

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 foran 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
Summary of Support for Conclusions
precursor protein associated with Alzheimer’s disSeveral recent animal studies have demonstrated ease; however, Pb exposure in adult animals did not
findings similar to the human data supporting a result in increased amyloid deposits in the brain. It
relationship between Pb and ALS. For example, Bar- should also be noted that laboratory animal data
beito et al. (2010) reported that blood Pb levels of have not demonstrated dementia in existing models.
27 µg/dL were associated with increased survival timein a mouse model of severe ALS, analogous to the Essential Tremor
longer survival time in ALS patients with higher blood There is sufficient evidence that blood Pb levels
Pb levels observed by Kamel et al. (2008). The NTP <10 µg/dL and limited evidence that blood Pb levels
concluded that there is limited evidence that blood <5 µg/dL in adults are associated with increased risk
Pb levels <10 µg/dL are associated with diagnosis of for diagnosis of essential tremor, a type of involunALS because the case-control studies that reported an tary tremor. A number of case-control studies haveassociation with blood Pb have potential issues with reported a significant association between blood Pb
reverse causality and bias due to a reported increased and essential tremor diagnosis, with most of the studsurvival time in ALS patients relative to control patients, ies coming from New York and similar results reported
both of which might also lead to higher Pb levels in ALS for a population in Turkey (see Appendix A: Neuropatients. The data from Fang et al. (2010) addressed logical Effects for full list of studies). The data present
some of the reverse causality issues by controlling for consistent evidence for an association between blood
factors associated with bone turnover. As with other Pb and essential tremor from two distinct groups in difstudies of health effects of Pb in adults, studies that ferent countries, but reflect a total sample size of only
demonstrate an association between ALS and blood Pb approximately 300 cases of essential tremor.
in a group for which blood Pb levels remained consisLouis et al. (2003) reported that blood Pb was sigtently below 10 µg/dL from birth until diagnosis of ALS nificantly higher in essential tremor patients (3.3 µg/dL)
would eliminate the potential role of early-life blood than in controls (2.7 µg/dL) in a case-control study of
Pb levels above 10 µg/dL on health effects observed in 100 essential tremor cases (mean age, 66 years) andadults with concurrent blood Pb levels <10 µg/dL. The 143 matched controls (mean age, 71 years) from New
NTP’s conclusions for limited evidence that blood Pb York. Blood Pb was significantly associated with anlevels <10 µg/dL are associated with diagnosis of ALS increased odds ratio for essential tremor diagnosis
is consistent with the four studies highlighted in EPA’s OR=1.21 (95% CI: 1, 1.39). Louis et al. (2005, 2011)
2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 2007 also examined the interaction between blood Pb andToxicological Profile for Lead (ATSDR 2007).
other modifying factors such as ALAD genetic polymorphisms and exposure to harmane (a β-carboline
Alzheimer’s Diseasealkaloid compound associated with essential tremor)
There is inadequate evidence to evaluate the poten- in this New York cohort. The odds of essential tremor
tial association between blood Pb <10 µg/dL and were significantly, and to a large degree, elevated in
Alzheimer’s disease because no studies examining individuals with the ALAD-2 allele and higher blood Pb
diagnosis and death (HR=0.3 (95% CI: 0.1, 0.7)),
while the association between greater survival timeand 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, andhigher Pb levels may be related to a longer period of
exposure or more time for Pb to be released frombone stores.

39

Neurological
Effects

NTP Monograph on Health Effects of Low-Level Lead

Neurological
Effects(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 etal. (2011) found that essential tremor score was highest in individuals with higher concentrations of both
Pb and harmane; they concluded that there was anadditive 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 witha significantly greater odds ratio for essential tremor
diagnosis (OR=4.19 (2.59,6.78)).

Parkinson’s Disease40

NTP Monograph on Health Effects of Low-Level Lead

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 wereidentified 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 studyof 121 Parkinson’s disease patients and 414 controlsin Michigan, Coon et al. (2006) reported that theodds ratio of a diagnosis of Parkinson’s disease wasincreased for whole-body lifetime Pb exposure (bloodand 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
Summary of Support for Conclusions
Animal data support Pb-associated neurological was increased (OR=3.21 (95% CI: 1.17, 8.83)) for higheffects, including tremor, at higher Pb exposure lev- est quartile of tibia Pb compared to the lowest quarels (e.g., Booze et al. 1983, see U.S. EPA 2006, ATSDR tile in a case-control study of 330 Parkinson’s disease2007 for recent reviews of the animal data). The NTP patients and 308 controls in Boston.
concluded that there is sufficient evidence that blood
Pb levels <10 µg/dL and limited evidence that blood 4.3.4 Sensory Organs
Pb levels <5 µg/dL are associated with diagnosis ofessential tremor. The data are considered to provide Auditory
sufficient evidence because the case-control studies There is sufficient evidence that blood Pb levels
that reported an association with blood Pb are from <10 µg/dL in children are associated with decreased
two distinct, widely separated groups which report hearing (decreased auditory acuity). Cross-sectional
the same pattern of effects. Given that the two studies reported a Pb-related increase in hearing
studies represent a small total number of essential thresholds and an increase in latency of BAEPs in chiltremor patients (sample size of about 300), a con- dren and young adults5 4-19 years of age, and alteredclusion of limited evidence at the lower blood Pb BAEPs in newborns (see Appendix A: Neurologicallevel <5 µg/dL is supported. As with other studies Effects for full list of studies). Hearing loss indicated byof health effects of Pb in adults, prospective studies higher hearing thresholds have been demonstrated at
in a group for which blood Pb levels remained con- blood Pb levels <10 µg/dL, and increased BAEP latency
sistently below 10 µg/dL from birth until diagnosis has been reported at slightly higher blood Pb levelsof essential tremor would eliminate the potential (<10 µg/dL). There is limited evidence that prenatalrole of early-life blood Pb levels >10 µg/dL on health blood Pb levels <10 µg/dL are associated with auditory
effects observed in adults with concurrent blood Pb effects because few studies have addressed low-level
levels <10 µg/dL. The NTP’s conclusions for sufficient Pb exposure during this developmental period. Thereevidence that blood Pb levels <10 µg/dL and limited is also limited evidence that blood Pb levels <10 µg/dL
evidence that blood Pb levels <5 µg/dL are associated in adults are associated with decreased auditory acuitywith diagnosis of essential tremor is consistent with due to the limited number of studies with blood Pb
the blood Pb level of 3 µg/dL highlighted in the two data <10 µg/dL and auditory effects in adults.
studies listed in EPA’s 2006 AQCD for Lead (U.S. EPA
5 Note: children are defined as <18 years of age in this docu2006) and ATSDR’s 2007 Toxicological Profile for Lead
ment; therefore, 18- and 19-year-olds in the study are con(ATSDR 2007).
sidered adults.

NTP Monograph on Health Effects of Low-Level Leadthresholds 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 etal. 2007). In a cross-sectional analysis of 448 men in theNormative Aging Study (mean age, 65 years at time ofbone Pb measurement), tibia Pb (mean, 23 µg/g) andpatella 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 notexamined in the Park et al. (2010) study, other studies
reported mean concurrent blood Pb levels in membersof this cohort as <10 µg/dL (Rajan et al. 2007). Additional support for effects in adults is provided by thelarge cross-sectional studies of individuals from 4 to 19
years of age (Schwartz and Otto 1987, 1991) describedearlier; 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 latencyof BAEPs at blood Pb levels higher than the level
observed in human studies (i.e., 33-100 µg/dL) (seeU.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-associateddecrease 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 inchildren 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), thetwo Schwartz and Otto (1987, 1991) cross-sectional
studies that included adults 18 and 19 years of age instudies primarily focused on children, and supporting41

Neurological
Effects

In a cross-sectional study of 4,519 children andyoung 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 studyof 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 to18 µg/dL (Schwartz and Otto 1991). Similar results wereobserved in a study of 155 Polish children 4-14 years ofage, with hearing loss demonstrated by increased hearing thresholds at blood Pb levels <10 µg/dL (medianblood Pb, 7.2 µg/dL); there were also increased latencies of peak I BAEPs that were significant for blood Pblevels >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 withhigher 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 interpeakinterval of BAEPs were significantly altered in infants(n=30 born to mothers with pregnancy Pb levels of 2.535 µg/dL) and 5- and 6-year-olds (n=100) born to mothers with mean blood Pb levels of 8 µg/dL. Dietrich etal. (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 fromthe 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 associatedwith blood Pb levels <10 µg/dL.
Four studies in adults addressed individuals withlower blood Pb levels. Forst et al. (1997) reported thatblood 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 studyof 183 workers. Hwang et al. (2009) found that hearingNeurological
Effects

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 ofhealth effects of Pb in adults, prospective studies in agroup 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 thatprenatal exposure to blood Pb <10 µg/dL is associatedwith 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 withblood Pb <10 µg/dL that remained <10 µg/dL until
auditory function was tested. The NTP’s conclusion forsufficient evidence that blood Pb levels <10 µg/dL areassociated with decreased auditory acuity in children
is in line with the supportive evidence of a relationshipwith 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).

Visualof age. Altmann et al. (1998) reported that blood Pblevels (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 latencyof VEPs. Animal data include evidence for retinal andvisual 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 Pblevels <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 etal. 1995). The report of a potential lower thresholdof 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 andvisual systems, because postural sway requires theintegration of visual and vestibular input along with
peripheral sensory input and motor output. The NTP’s
conclusions for inadequate evidence that blood Pblevels <10 µg/dL are associated with effects on visionin humans are in line with the supportive evidence ofa 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.

There is inadequate evidence to evaluate the potential association between blood Pb <10 µg/dL andeffects 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 werelocated 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 inelectroretino­graphic (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 etal. (2009) demonstrated that umbilical cord blood
Pb (mean, 5 µg/dL) was significantly associated withchanges in visual brain signals (event-related potential P3b wave amplitude) at 5 years but not at 11 years

The NTP concludes there is sufficient evidence thatblood Pb levels <5 µg/dL are associated with neurological effects in children and limited evidence
that blood Pb levels <10 µg/dL are associated withadverse neurological effects in adults (see Table 4.3:
NTP conclusions on neurological effects of low-level
Pb for complete list of conclusions). A major strengthof the evidence for effects of low-level Pb on neurological outcomes is in the consistency of results for anadverse 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

42

NTP Monograph on Health Effects of Low-Level Lead

4.4 Conclusions

adults, and from studies using substantially different
methods and techniques. In some studies, blood Pblevels 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 issufficient evidence that blood Pb levels <5 µg/dL areassociated 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 Pblevels 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 withessential tremor. There is also limited evidence thatblood Pb levels <10 µg/dL in adults are associatedwith psychiatric outcomes, including anxiety anddepression, as well as decreases in auditory function,
decreases in specific measures of cognitive function inolder 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 EffectAcademicachievement
IQ
Other general andspecific measures
Behavior

Attention-related
behaviors
Behavioral
problems

Psychological Depression,anxiety, other
Effects

PrenatalChildren
PrenatalChildren
PrenatalChildrenOlder adults
PrenatalChildren
AdultsPrenatalChildren
AdultsPrenatalChildrenInadequate
Sufficient
LimitedSufficient
LimitedSufficient
LimitedLimitedSufficient
Inadequate
LimitedSufficient
Inadequate
Inadequate
Inadequate

Adults
Neuro­
ALS
Adultsdegeneration Alzheimer’s disease Adults

LimitedLimitedInadequate

Essential tremor

Sufficient
LimitedInadequate

AdultsParkinson’s disease Adults
Sensory
Function

Auditory

VisualPrenatalChildren
AdultsPrenatalChildren
AdultsLimitedSufficient
LimitedInadequate
Inadequate
Inadequate

Blood Pb
Evidence
No studies locatedYes, <5 µg/dL
Yes, <10 µg/dL
Yes, <5 µg/dL
Yes, <5 µg/dL
Yes, <5 µg/dL
Yes, <10 µg/dL
Yes, <10 µg/dL
Yes, <5 µg/dL
No studies locatedYes, <10 µg/dL
Yes, <5 µg/dL
No studies locatedNo studies locatedUnclear, somedata >10 µg/dL
Yes, <10 µg/dL
Yes, <10 µg/dL
No studies<10 µg/dL locatedYes, <10 µg/dL
Yes, <5 µg/dL
No studies<10 µg/dL locatedYes, <10 µg/dL
Yes, <10 µg/dL
Yes, <10 µg/dL
Yes, <10 µg/dL
Yes, <10 µg/dL
No studies<10 µg/dL locatedBone Pb Evidence
Not studied
Yes, tooth dentin Pb
Not studied
Yes, tibia and tooth dentin Pb
Not studied
Yes, tibia and tooth dentin Pb
Yes, tibia and patella Pb
Not studied
Yes, tibia and tooth dentin Pb
Not studied
Not studied
Yes, tooth dentin Pb, bone, hair
Not studied
Not studied
Not studied
Tibia and patella Pb
Yes, tibia and patella
Not studied
Not studied
Not studied
Yes, tibia and PBPK
(cumulative)
Not studied
Not studied
Yes, tibia and patella
Not studied
Not studied
Not studied

Abbreviation: ALS, amyotrophic lateral sclerosis; PBPK, physiologically based pharmacokinetic.

NTP Monograph on Health Effects of Low-Level Lead

43

Neurological
Effects

Cognitive
Function

Population
NTP
or Exposure Conclusion
Window

Neurological
Effects

THIS PAGE LEFT INTENTIONALLY BLANK44

NTP Monograph on Health Effects of Low-Level Lead

5.0 IMMUNE EFFECTS

NTP Monograph on Health Effects of Low-Level Lead

45

ImmuneEffects

observational immune endpoints such as altered lymphocyte counts or serum levels of IgG, IgM, or IgA in
5.1 Conclusions
the blood of children or adults because of a general
The NTP concludes that there is limited evidence lack of studies at the lower dose and inconsistency
that blood Pb levels <10 µg/dL are associated with in available data. There is inadequate evidence thatadverse immune effects in children and that there is blood Pb levels <10 µg/dL are associated with changes
in immune function other than hypersensitivity,
inadequate evidence in adults.
In children, there is limited evidence that blood because there are few studies of Pb and immune funcPb levels <10 µg/dL are associated with increased tion in humans, particularly at lower blood Pb levels.
hypersensitivity responses and allergic sensitization Very few studies examine markers of exposure otherdiagnosed by skin prick testing to common allergens. than blood Pb levels, and therefore it is unknown if
Five studies with mean blood Pb levels of 10 µg/dL blood or bone Pb levels would be more consistently
and below support the relationship between blood associated with immune effects.
Pb and increased serum IgE (see Table 5.3). Twoof these studies report an association at blood Pb 5.2 How Conclusions Were Reachedlevels of 10 µg/dL or above, rather than <10 µg/dL Conclusions in the NTP’s evaluation of Pb-related(Lutz et al. 1999, Sun et al. 2003). Only one of the immunological effects in humans associated withremaining studies, Karmaus et al. (2005), considers low-level Pb are derived by evaluating the data fromage as a co-factor in the analyses of IgE (Karmaus epidemiological studies with a focus on blood Pb
et al. 2005, Hon et al. 2009, Hon et al. 2010, Hon levels <10 µg/dL. Although there is a large database of2011). Given these limitations, and particularly the immune studies of Pb in laboratory animals, the dataknown age-dependent ranges for IgE, these studies base of human studies is somewhat limited, particuprovide the basis for the conclusion of limited evi- larly at blood Pb levels <10 µg/dL. The NTP’s concludence that blood Pb levels <10 µg/dL are associated sions are based on the evidence from human studies
with elevated serum IgE in children up to 17 years with blood Pb levels of <10 µg/dL, with data reflectingof age. Although increases in serum levels of total exposure levels up to 15 µg/dL also considered so thatIgE do not equate to disease, elevated levels of IgE effects at and around 10 µg/dL were not excluded fromare the primary mediators of type I hypersensitivity the evaluation. Given the limited database of humanassociated with allergic sensitization, and the data studies available to evaluate immune effects associdemonstrating Pb-related increases in IgE support ated with blood Pb levels <10 µg/dL, a discussion ofan association with hypersensitivity. Further support immune effects associated with higher blood Pb levelsof an association between blood Pb levels <10 µg/dL is also included in the evaluation. The discussion below
and hypersensitivity is provided by a prospective also assesses the biological plausibility and support forstudy on Pb-related increased allergic sensitization Pb-associated immune effects provided by the datademonstrated by positive response to skin prick test- base of studies in laboratory animals. Major endpoints
ing to common allergens. Together these data sup- considered as potential indicators of effects of Pb on
port the conclusion of limited evidence that blood Pb the immune system are listed and briefly described
levels <10 µg/dL are associated with increased hyper- in Section 5.2.1. This document is not a review of thesensitivity. However, there is inadequate evidence of immune system or immunotoxicity, and the reader
an association between blood Pb and other allergic is directed to published reviews for additional background. Key data and principal studies considered indiseases such as eczema or asthma.
There is inadequate evidence in adults to address developing the NTP’s conclusions are discussed in
the potential association between blood Pb <10 µg/dL detail in Section 5.3 Evidence for Pb-related Immune
and IgE, allergy, eczema, or asthma. Few studies have Effects. The discussion of each immune effect begins
investigated the relationship between immune func- with a statement of the NTP’s conclusion that the spetion and Pb in adults or children, and most studies cific effect is associated with a blood Pb level <10 µg/dL
report general observational markers of immunity or <5 µg/dL and the age group in which it is identified
rather than function. There is inadequate evidence (childhood or adulthood), as well as the timing of expothat blood Pb levels <10 µg/dL are associated with sure associated with the effect (prenatal, childhood,Table 5.1: Major immune effects considered
EffectObservational
Immunoglobulin (Ig)or antibodies
Immunophenotyping

Functional
Antibody response

Description

Serum IgE, IgM, IgG; IgA, and IgD (A and D not routinely measured)White blood cell differential (T-cells, B-cells, NK-cells, monocytes/macrophages, etc.)
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 hyper­
sensitivity (DTH) response
NeutrophilsType 1 helper T cells and macrophage-dependent DTH response to antigen challenge

Monocyte/macrophages

Phagocytosis, respiratory burst (monocytes circulate and mature into tissue macrophages)

Peripheral blood mononuclear leukocyte phagocytosis, respiratory burst, migration

ImmuneEffects

Allergy, asthma, eczema, etc. Clinical manifestation of hypersensitivity

concurrent) when available. Although the information necessary to support the NTP’s conclusions ispresented in Section 5.3, the complete data set ofhuman 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 ofrecent 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 performedin humans, including specific antibody response tovaccination, delayed-type hypersensitivity (DTH)
response, phagocytic activity of neutrophils andmacrophages, and oxidative burst of neutrophils andmacrophages (Tryphonas 2001). However, humanepidemiological 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.
46

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) bothlist a number of immune parameters (see Table 5.2 forprincipal 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 5.2: Main conclusions for immunologicaleffects in the 2006 EPA AQCD for Lead and the2007 ATSDR Toxicological Profile for Lead“…effects include changes in serum immunoglobulin levels; perturbation of peripheral lymphocyte phenotype
profiles, including decreases in peripheral blood T-cellabundance 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 inlead workers with PbB [blood Pb level] in the range of
30-70 µg/dL. Reported effects included changes in someT-cell subpopulations, response to T-cell mitogens, andreduced chemotaxis of polymorphonuclear leukocytes.
Several studies of children reported significant associations between PbB and increases in serum IgE levels…”(ATSDR 2007, pg 22)

NTP Monograph on Health Effects of Low-Level Lead

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 <10 µg/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 atmean blood Pb values from 1.9 to 14 µg/dL and subjects ranging from 1 month to 17 years of age. Threeof the five available studies (Karmaus et al. 2005,
Hon et al. 2009, Hon et al. 2010, Hon 2011) reportan 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 withblood Pb levels <10 µg/dL in an analyses that adjusted
NTP Monograph on Health Effects of Low-Level Leadfor age, an important confounder when considering IgE levels, particularly in children. The databasefor 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 ofa single study (Annesi-Maesano et al. 2003) that demonstrated an association between increased IgE andincreased 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, elevatedIgE 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 onallergic 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 evidenceof 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 ofstudies 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 thepotential 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 theirstudy had blood Pb <10 µg/dL; however, the authors
do not report mean blood Pb levels and therefore thedata 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
47

ImmuneEffects

The 2006 EPA AQCD for Lead (U.S. EPA 2006)
states that studies have consistently found consistentevidence of increased serum IgE levels in children atblood Pb <10 µg/dL but that results from studies inadults 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)-associatedproduction of IgE; (2) suppressed type 1 helper T-cell(Th-1) responses (i.e., DTH); (3) shifting the balanceof 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 theconclusions of the external draft (U.S. EPA 2012) arelargely in line with the 2006 AQCD for Lead.
The NTP considered the conclusions and datasummaries 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 theconclusions and agreed that the data support them.
Differences from the ATSDR and EPA documents are
identified for specific endpoints in the document.

48

NTP Monograph on Health Effects of Low-Level Leadii

Crosssectional
Crosssectional
Crosssectional

331 children 7-10 years
old in Germany
318 children 0.5 -7 years
old in Egypt

279 children 0.75 - 6years old in Missouri

72 children aged 3-6 in CrossChina of 217 in study
sectional

EffectEffectEffectCrosssectional

58 children age 10

2,470 children aged 5 -14 Ecologicalin Germany

EffectEffectOdds ratios for increase in specific IgE to common allergens were elevated in children Heinrich (1999)
from a polluted area in Germany that had higher Pb dustfall; no blood Pb data.
Also for sensitivity & eczema

Increased serum IgE was positively correlated with blood Pb (mean Pb, 1.9 µg/dL) in Hon (2009)
children with eczema (age > 1 month; authors state average age of 10 years).
Also for eczema

Increased serum IgE was positively correlated with blood Pb (mean Pb, 1.9 µg/dL) in Hon (2010, 2011); may overchildren with eczema (age > 1 month; mean age, 10 years).
lap with Hon (2009)

Increased serum IgE was correlated with blood Pb in children with Pb ≥10 µg/dL. Sun (2003)
Increased serum IgE in girls with blood Pb≥10 µg/dL relative to Pb <10 µg/dL; not boys.

Serum IgE differed by blood Pb (mean Pb, 9.2 µg/dL). However, authors report that IgE Hegazy (2011)is not correlated with blood Pb.
Increased serum IgE was associated with current blood Pb (mean not reported, 64% Lutz (1999)
had blood Pb <10 µg/dL).

Increased serum IgE in umbilical cord blood was associated with infant hair levels of Pb. Annesi-Maesano (2003)
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.
Increased serum IgE was associated with current blood Pb (mean Pb, 2.7 µg/dL).
Karmaus (2005)

Reference

Crosssectional

58 children age 10

2,470 children aged 5 -14 Ecologicalin Germany

EffectEffectOdds ratio for eczema was elevated in children from a polluted area in Germany that Heinrich (1999)
also had higher Pb dustfall; no blood Pb data.
Also for IgE & sensitivity

Atopic dermatitis severity, eczema severity score, and children’s dermatology life qual- Hon (2009)ity index were positively correlated with blood Pb (mean, 1.9 µg/dL; mean age, 10). Also for IgE

Atopic dermatitis severity, eczema severity score, and children’s dermatology life Hon (2010, 2011); may overquality index were positively correlated with blood Pb (mean, 1.9 µg/dL).
lap with Hon (2009)

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.

Crosssectional

110 children age ≤17

EffectHong Kong Eczema Patients

Evidence of Enhanced Sensitization Based On Skin Prick Test (SPT)
224 children 5 years old Prospective Frequency of atopy (positive SPT) associated with cord Pb (mean, 1.2 µg/dL) and maternal Jedrychowski (2011)
Effectin Poland
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.
2,470 children aged 5 -14 Ecological
Odds ratio for sensitization (positive SPT) or allergy (doctor diagnosis) was elevated in Heinrich (1999)
Effectin Germany
children from a polluted area in Germany that had higher Pb dustfall; no blood Pb data. Also for IgE & eczema.
Eczema And Atopic Dermatitis
1,768 children born in Retro­
Relative risk of eczema in childhood (age not reported) did not differ for children with Rabinowitz (1990)
No effect
Boston 1979 -1981
spective
umbilical cord blood Pb >10 µg/dL compared to rest of the population.

Crosssectional

110 children age ≤17

EffectHong Kong Eczema Patients

Equivocal

Crosssectional

374 newborns in Paris
Study A: 1985
Study B: 1991-1992

EffectTable 5.3: Studies of serum IgE, sensitization, and eczema with low-level Pb used to develop conclusions for children
Relevance to
Study
Study
Key Immunological Findings
Conclusions
Description
DesignIncreased IgE

ImmuneEffects

NTP Monograph on Health Effects of Low-Level Leadsignificantly (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 astudy 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 notcorrelated to umbilical cord IgE levels, although theauthors 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 examinedin a number of studies because collection is easy andminimally 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 associatedwith increased incidence of allergic sensitization inchildren. 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 tocommon 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
49

ImmuneEffects

with a mean blood Pb level of 14 µg/dL from a larger
study of 217 children 3-6 years of age with overallmean 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 ofage in Germany at blood Pb levels >2.8 µg/dL, themedian 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 analysesof the relationship between blood Pb and IgE. These
are important considerations because of the strong
age- and sex-related effects on serum IgE: higher IgElevels are observed in boys, and increased IgE levels
are expected with increasing age up to puberty, withslowly decreasing levels observed thereafter (Lindberg and Arroyave 1986, Blackwell et al. 2011).
There is some evidence that in children theassociation 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 Pblevels, from 2 to 20 µg/dL, but decreasing serum IgElevels occur at higher blood Pb levels (i.e., >20 µg/dL).
Nonmonotonic dose responses are thought to re­flectmultiple mechanisms of toxicant action that affect agiven 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 humanmast cells with surface-bound IgE in response to toxicants, including Aroclor 1242; a nonmonotonic dose
response was reported for IgE-mediated release ofβ-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 (2342 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 boththe exposed and reference group had blood Pb levels >10 µg/dL (Wagnerova et al. 1986). In the Lutz etal. (1999) study described earlier, serum IgE differedImmuneEffectsin Poland recruited in the second trimester of pregnancy, allergic sensitization or atopy was determinedby skin prick test to common allergens administeredwhen 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, umbilicalcord 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 Pblevels <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 withhigher 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 inchildren (Heinrich et al. 1999). The odds ratio for positive skin prick test (OR=1.38 (95% CI: 1.02, 1.86)) andincreased 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 andPb emissions. The study examined 2,470 children 5-14
years of age; it lacked blood Pb data but comparedchildren 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 studiesof 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 anassociation between blood Pb and multiple clinicalparameters rating severity of symptoms of atopic

dermatitis, but not the incidence of eczema. Blood
Pb levels did not differ between 110 eczema patientsand 41 patients at the dermatology clinic with otherskin conditions that did not have eczema (p=0.160);
however, the study did not have a nonatopic reference group. The Heinrich et al. (1999) ecologicalstudy 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 withumbilical cord blood Pb levels, did not find a difference between children with umbilical cord blood
Pb levels above and below 10 µg/dL (Rabinowitz etal. 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 incidenceof eczema years later (exact timing not reported) andaddressed incidence (present vs. not present) rather
than severity of eczema.
Although four retrospective studies examined
the potential relationship between Pb exposureand 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 anincreased 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, andexposure 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 medicationin an analysis adjusted for income, birth weight, andsex (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 withumbilical 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

50

NTP Monograph on Health Effects of Low-Level LeadNTP Monograph on Health Effects of Low-Level Leadand 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 skinprick 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 anddecrease in nonspecific bronchial reactivity (Pizent etal. 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 bothmale and female office workers. Two additional studies of IgE in adults support an association with Pb athigher blood Pb levels. Higher serum IgE was correlated with higher blood Pb levels in two studies: astudy of 47 Pb refinery workers in Osaka with mean
blood Pb 50 µg/dL (Horiguchi et al. 1992) and a studyof 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 withblood Pb <30 µg/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 Pblevels <10 µg/dL are negative for effects in men andreport 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 inmale 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 Pblevels <10 µg/dL, the data for asthma or respiratory
symptoms are conflicting, with one study reporting
increased bronchial responsiveness (Min et al. 2008)
51

ImmuneEffects

include adjustment for confounders (Rabinowitz et al.
1990). Myers et al. (2002) reported that the incidenceof asthma based on medical records did not differ
between 151 patients in Chicago with high blood Pblevels (≥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 andPizent 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 IgEshould 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 etal. (2005) study reports an association with blood Pblevels <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 withincreasing 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 ofage, Hegazy et al. (2011) reported a significant correlation (r=0.133; p<0.05) between blood Pb andparental tobacco smoking. The analysis of IgE in the
Karmaus et al. (2005) study was particularly thoroughin 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 studyof 216 office workers in Croatia (Pizent et al. 2008),

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, withno effect in female office workers and reduced sensitization with increasing blood Pb in males, althoughdata are from a single study (Pizent et al. 2008).

ImmuneEffects

Summary of Support for Conclusions

Animal data support an increase in IgE in adult miceat high Pb levels (50 µg injected subcutaneously threetimes 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 andPiepenbrink 2006, U.S. EPA 2006). The human data
supporting a Pb-associated increase in serum IgE inchildren 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 IgElevels 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 measuringexposure 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-lifeof less than 2 days. Five cross-sectional studies report52

a correlation between blood Pb (mean levels from 2
to 14 µg/dL) and serum IgE in children up to 17 yearsof 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 elevatedserum IgE in children. The conclusion of limited evidence for increased hypersensitivity responses atblood Pb <10 µg/dL in children is supported by theevidence for Pb-related increases in IgE together with
the Jedrychowski et al. (2011) prospective study onallergic 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 toaddress 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 conclusionsof a consistent association from the 2006 EPA AQCD
for Lead (U.S. EPA 2006) and significant associationsin 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 (seeAppendix B: Immune Effects). Studies that examined serum immunoglobulins found no evidenceof 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
NTP Monograph on Health Effects of Low-Level Lead

PFC response was observed in rats at 29 µg/dL (Luster etal. 1978). The conclusion of inadequate evidence thatblood 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 ofhuman 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 responseor serum immunoglobulins; however, the NTP’s conclusions for inadequate evidence for an association
between blood Pb levels <10 µg/dL and serum IgG, IgM,
IgA, or the antibody response are consistent with theevidence 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 ofoccupational studies that report decreased absolute
numbers or percentages of T-cells or T-cell populations or subsets (particularly CD4+ T-helper cells), andsome include a corresponding increase in B-cells atblood 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 fora 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 withblood 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, thepercentage 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
Summary of Support for Conclusions
Pb levels >10 µg/dL compared to children <10 µg/dL
Animal data are mixed for an effect of Pb on the anti- (Zhao et al. 2004, Li et al. 2005). In contrast, Sarasua
body response and most studies do not report serum et al. (2000) reported decreased percentage of T-cells,
immunoglobulin levels (see U.S. EPA 2006 for recent no change in CD4+ or CD8+ T-cells, and increased
reviews of the animal data, ATSDR 2007). Studies in percentage of B-cells in children under 3 years ofmice report no effect, suppression, or stimulation of age at mean blood Pb level of 7 µg/dL. Lymphocyte
the T dependent antibody response (plaque-forming populations were not related to blood Pb levels incell (PFC) assay to sheep red blood cell challenge) at children >3 years of age or in adults (Sarasua et al.
blood Pb levels of 25-130 µg/dL (Blakley and Archer 2000). Four additional studies in children reported
1981, Mudzinski et al. 1986), while suppression of the no effect of blood Pb on lymphocyte populations at
NTP Monograph on Health Effects of Low-Level Lead

53

ImmuneEffects

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, andboth reported that there was no effect of blood Pblevel on the antibody response. There was no effect ofblood 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 (meannot 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 highblood 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 (otherthan 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 werecorrelated (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 wasno effect of blood Pb level (mean, 3 µg/dL) on serum
IgG, IgM, or IgA in a study of 331 children 7-10 yearsof 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 inchildren <3 years of age at mean blood Pb level of
7 µg/dL; immunoglobulin levels were not related toblood Pb in children >3 years of age or in adults (Sarasua et al. 2000). In contrast, serum IgG and IgM weredecreased in children in China 3-6 years of age withblood 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 withserum IgA, IgM, or IgG in a study of atopic and nonallergic men in Italy without occupational exposure toPb (mean Pb, 11 µg/dL; (n=34 Boscolo et al. 1999).

ImmuneEffects

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 ofage 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 ofstudies 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 etal. 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 referencegroup (mean Pb, 5 µg/dL; n=59), but CD4+ T-cells weredecreased (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 andconsistent cell group is related to Pb levels, althoughseveral 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). Ina separate study of Pb battery workers with very highmean 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, thathigher 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 havereported 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 alongwith 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 thewhite 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 notreport data for lymphocytes or for specific lymphocyte subsets (e.g., T-cells). Higher blood Pb levels inthese individuals may cause higher leukocyte counts,
or higher circulating leukocyte counts may lead tohigher measurements of blood Pb if the leukocytes
contain substantial amounts of Pb.

54

NTP Monograph on Health Effects of Low-Level Lead

Summary of Support for Conclusions

Animal data support a Pb-associated effect on T-cellmaturation, and particularly a shift toward the type2 helper T-cell (Th-2) phenotype, which is associatedwith 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 infectionin BALB/c mice at blood Pb <25 µg/dL Dyatlov andLawrence 2002); however, decreased T-cell populations with Pb exposure are not widely reported in theexperimental animal literature. White blood cell differentials with enumeration of lymphocyte subsets(T-cells, B-cells, CD4 and CD8 T-cells) are among themost 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 thatis influenced by sex, race, age, and methodologicaldifferences in obtaining and processing the samples.
It is worth noting that lymphocyte subset analysis
does not evaluate immune function, although it islevels of 7 µg/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 Pbdata (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, andthe animal data suggest that production of TNF-α bymacrophages 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 humanmacrophages and other mononuclear cells in blooddemonstrated increased production of TNF-α with Pb
exposure (Villanueva et al. 2000) in the presence of lipopolysaccharide plus Pb (Guo et al. 1996). However, lowlevels of Pb were associated with suppression of TNF-α
release in human mononuclear cells from blood in thepresence 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 generallack 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 macrophagefunction. The human data on macrophage function arelimited to a single study of 65 children 6-11 years of age
in Mexico living near a Pb smelter (mean blood Pb levelsof 21 and 30 µg/dL) compared to children with blood Pb

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 thatare >30 µg/dL (see Appendix B: Immune Effects).
Several studies report that movement of neutrophils
toward their targets (chemotaxis) may be reducedin 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 thatlytic activity of Candida may be reduced (Queiroz et al.

NTP Monograph on Health Effects of Low-Level Lead

55

5.3.4 Monocyte/Macrophages

ImmuneEffects

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 inT-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 cellnumbers or percentages may be adverse. A good
example is the demonstration that increased mortality risk is associated with small decreases in CD4 andtotal 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 atblood 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 alteredT-cell abundance in the blood of children or adults
is based on the lack of a clear pattern of results instudies 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 datafrom 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 theDTH 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).

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 bodyof literature supports the developmental period as asusceptible 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 databaseof immune studies of Pb in humans provides limited
evidence that blood Pb levels <10 µg/dL are associatedwith increased hypersensitivity responses and allergic
sensitization diagnosed by skin prick testing in children;
however, there is inadequate evidence to assess theseeffects 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 thatis more pronounced in the elderly (Mediaty and
Neuber 2005). However, there is some evidence thatthe apparent age-related decrease in hypersensitivity may be associated with more than age-related
decline, and the difference may reflect an increasein 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 alife 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-analysisof over 550 studies reported that boys make up 64%
of children age 18 or younger with allergies but thatwomen 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 etal. (2003) reported that increased IgE was statisticallysignificantly correlated with blood Pb in girls in China
with blood Pb ≥10 µg/dL 3-6 years of age but that theeffect 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 notin 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 importantfactor (De Swert 1999). This may manifest as a difference by race; for example, Joseph et al. (2005)
reported that African American children were atstatistically significantly greater risk of asthma compared to Caucasians, regardless of blood Pb level. The
general or background allergic status of mothers or ofchildren may be relevant to the effects of Pb on IgE
and hypersensitivity. Annesi-Maesano et al. (2003)
reported that the association between infant hair Pblevels 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 relationshipwas 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 etal. 2007, Hunninghake et al. 2008, Hunninghake etal. 2011) or whether prenatal exposure to cytokines,

56

NTP Monograph on Health Effects of Low-Level Lead

1994) but phagocytic activity is relatively unaffectedin 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 ofdata with lower blood Pb levels. Additional studies ofneutrophil 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.

ImmuneEffects

5.4 Susceptible Populations or Life
Stageshistamine, or other factors are important. In the
one prospective study available, Jedrychowski et al.
(2011) controlled for maternal allergic history (oratopy) in the analysis that demonstrated a statisticallysignificant 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 thechildren 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 fromstatistically 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

NTP Monograph on Health Effects of Low-Level Lead

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 effecton 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, ATSDR2007 for recent reviews of the animal data). The
DTH response depends on priming and expansionof antigen-specific T-cells that are Th-1 dependentand 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 werelocated 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
57

ImmuneEffects

The following brief discussion outlines several Pb
exposure issues that are directly relevant to immune
effects of Pb. An expanded discussion is included ina 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 otherthan 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 ispresent in a given subject. The half-life of Pb in blood
is approximately 35 days and therefore blood Pb isconsidered a good indicator of recent exposure. Mostof 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 toa chronic internal source of exposure (Leggett 1993).
The higher levels of Pb in bone may be particularly relevant for cells of the immune system andimmune function. All of the white blood cells or
leukocytes that develop postnatally are derived fromprogenitor cells in the bone marrow in a processtermed 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 relationshipbetween bone Pb levels and immune effects. Mechanistic studies in animals support the importance of Pb
exposure on the development and differentiation ofleukocytes. 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 IgEproduction. The location of Pb within blood is alsoof 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, Choiand 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 ofage in South Korea. The issue of reverse causality issuggested: 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.

ImmuneEffects

5.7 Conclusions

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 exposuresof up to 16 weeks. Although blood Pb levels are notavailable 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 exposedfrom 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 indrinking water for 3 weeks had blood Pb levels of 9, 49,
87, and 169 µg/dL, and the blood Pb level correlatedwith 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 ashigh 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 andthe early removal of Pb exposure to the dams suggestthat 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, andtherefore the lower blood Pb range associated witheffects is unknown, even in laboratory animals.

The NTP concludes that there is limited evidence thatblood 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 associatedwith increased hypersensitivity responses and allergic
sensitization diagnosed by skin prick testing to common allergens. There is also limited evidence that blood
Pb levels <10 µg/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 isinadequate 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 levelsof IgG, IgM, or IgA in the blood of children or adults
because of a general lack of studies at the lower doseand inconsistency in available data. There is inadequate
evidence that blood Pb levels <10 µg/dL are associated with changes in immune function other thanhypersensitivity 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 isunknown if blood or bone Pb levels would be a bettermeasure of exposure for Pb-related immune effects.

58

NTP Monograph on Health Effects of Low-Level Lead

Table 5.4: NTP conclusions on immune effects of low-level Pb
Health Effect
Increased serum
immunoglobulin E (IgE)

Increased hypersensitivity andallergy (e.g., positive skin prick
test)
Asthma, eczema, etc.

Altered serum IgG, IgM

Altered antibody response

Immunophenotyping(e.g., T-cells, B-cells)

Neutrophil function

Delayed-type hypersensitivity(DTH) response

NTP
Conclusion

Prenatal

Inadequate

Children
AdultsPrenatalChildren
AdultsPrenatalChildren
AdultsPrenatalChildren
AdultsPrenatalChildren
AdultsPrenatalChildren
AdultsLimitedInadequate
LimitedLimitedInadequate
Inadequate
Inadequate
Inadequate
Inadequate
Inadequate
Inadequate
Inadequate
Inadequate
Inadequate
Inadequate
Inadequate
Inadequate

PrenatalChildren
AdultsPrenatalChildren
AdultsInadequate
Inadequate
Inadequate
Inadequate
Inadequate
Inadequate

PrenatalChildren
AdultsInadequate
Inadequate
Inadequate

NTP Monograph on Health Effects of Low-Level LeadBlood Pb
Evidence

Bone Pb
Evidence

UnclearHair Pb
data
Yes, <10 µg/dL
No data
UnclearNo data
Maternal and umbilical cord <10 µg/dL No data
Yes, <10 µg/dL
No data
UnclearNo data
UnclearNo data
UnclearNo data
UnclearNo data
No data
No data
UnclearNo data
UnclearNo data
No data
No data
No data
No data
No data
No data
No data
No data
UnclearNo data
Unclear; >15 µg/dL data suggest changes No data
in T-cells or T-cell subpopulations
No data
No data
Unclear (one study)
No data
No data
No data
No data
No data
No data
No data
Unclear; >30 µg/dL data suggest
No datachanges in chemotaxis and lytic
activity
No data
No data
No data
No data
No data
No dataImmuneEffects

Monocyte/macrophagefunction

Population
or Exposure
Window

59

ImmuneEffects

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NTP Monograph on Health Effects of Low-Level Lead

6.0 CARDIOVASCULAR EFFECTS
6.1 Conclusions

NTP Monograph on Health Effects of Low-Level Lead

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 datafrom epidemiological studies with a focus on blood
Pb levels <10 µg/dL. The NTP’s conclusions are basedon the evidence from human studies with blood Pblevels of <10 µg/dL, with data reflecting exposurelevels 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 indicatorsof effects of Pb on cardiovascular functions are listed
61

Cardiovascular
Effects

NTP concludes that there is sufficient evidence thatblood Pb levels <10 µg/dL in adults are associatedwith adverse effects on cardiovascular function.
There is sufficient evidence of a bone-Pbrelated increase in blood pressure (BP) and the riskof hypertension. Two prospective studies and fivecross-sectional studies found a statistically significant association between bone Pb and increased BPor hypertension. These studies were in populations
or samples with blood Pb levels <10 µg/dL, and mostof them had mean levels <5 µg/dL. Blood Pb was lessconsistently 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 individualwith blood levels <10 µg/dL during adulthood may
have had higher blood Pb levels earlier in life, and therole of early-life Pb exposure cannot be discriminatedfrom the role of concurrent blood Pb.
There is sufficient evidence that blood Pb levels <10 µg/dL are associated with an increased riskof 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 Pblevels <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 replicatedstudies 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 havefollowed children with early-life Pb measures withdetermination of cardiovascular health after childhood, and the few studies of blood Pb and BP duringchildhood had inconsistent results. There is someevidence that menopause is associated with higher
blood Pb levels, associated with mobilization of bonestores of Pb, and this could put women at greater riskof 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 astronger 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 etal. 2005). There is inadequate evidence for Pb effects
on heart rate variability or specific types of cardio­
vascular disease; due to few replicated studies.
Chronic Pb exposure appears to be more criticalthan 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 stagesof 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 toincreased BP and that hypertension can contribute toadverse renal effects. The EPA’s 2006 AQCD for Lead
(U.S. EPA 2006) and ATSDR’s Toxicological Profile forLead (ATSDR 2007) both conclude that cardiovascularand 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.

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 discussionof each cardiovascular effect begins with a statement of the NTP conclusion of whether the specificeffect 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 theassociation between Pb exposure and cardiovasculareffects. 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 isincluded in Appendix C: Cardiovascular Effects, andindividual 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, inmmHg) or as categories (dichotomized as hypertension vs. no hypertension). High BP increases the riskof myocardial infarction and stroke, and BP control
is one of the primary strategies to prevent the development of cardiovascular disease, with evidence ofefficacy in patients without prior heart disease (Lawet 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
Effects

Cardiovascular EffectDescription

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) Changes in the typical pattern of electrical activity of the heart, including the P wave (atrial
conduction abnormalities
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.

StrokeDeath 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)

62

NTP Monograph on Health Effects of Low-Level Lead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 rangeof <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
6.2.2 Principal Conclusions from the 2006
summaries from the EPA’s 2006 AQCD for Lead (U.S.
EPA and 2007 ATSDR Pb Documents
EPA 2006) and ATSDR’s Toxicological Profile for Lead
The EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and (ATSDR 2007). In general, the NTP accepted the
ATSDR’s Toxicological Profile for Lead (ATSDR 2007) conclusions and agreed that the data support them.
both concluded that epidemiological studies sup- Differences from the ATSDR and EPA documents areport a relationship between higher Pb exposure identified for specific endpoints. The focus of EPA’sand decreases in cardiovascular health, including document did not clearly discriminate effects below
increased SBP and DBP, higher incidence of hyper- and above 10 µg/dL. Most of the studies of thetension, and increased incidence of cardiovascular quantitative relationship between blood Pb and SBP
disease and cardiovascular-related mortality (see report mean blood Pb levels <10 µg/dL (e.g., table
Table 6.2 for principal conclusions; see the original 6-2 in U.S. EPA 2006). However, the conclusion on the
documents for complete conclusions). The asso- increase in BP associated with a doubling of blood
ciation between elevated blood Pb and increased Pb did not specify whether this doubling occurred at
BP (SBP and DBP) is supported by a large body of blood Pb levels <10 µg/dL. Some studies consideredby the EPA, particularly those conducted before 1990
orin occupational settings, had more than 90% of
Table 6.2: Main conclusions for cardiovascular
theirsubjects with blood Pb >10 µg/dL (Kromhout eteffects in the 2006 EPA AQCD for Lead and theal. 1985, Lockett and Arbuckle 1987, Gartside 1988).
2007 ATSDR Toxicological Profile for Lead
Such studies were not considered for the NTP conclu“Epidemiologic studies support the relationshipsions on Pb effects at levels <10 µg/dL.
and increases reflect arterial stiffness, a critical cardiovascular risk factor (Lakatta and Levy 2003). Heart ratevariability is an indicator of cardiac autonomic function, with decreased variability being associated withrisk of heart disease and mortality, and with clinicalrelevance 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.

6.3 Evidence for Pb-related Effects on
Cardiovascular Outcomes
6.3.1 Blood Pressure (BP) and Hypertension“Population studies suggest that there is a significant
association between bone-lead levels and elevatedblood pressure. Blood lead levels (PbBs) also have been
associated with small elevations in blood pressure.“(ATSDR 2007, pg 21)

There is sufficient evidence that blood Pb levels<10 µg/dL are associated with increases in BP andrisk of hypertension (see the Blood Pressure (BP) andHypertension section of Appendix C: Cardiovascular
Effects). BP is the most widely studied cardiovascular

NTP Monograph on Health Effects of Low-Level Lead

63

Cardiovascular
Effects

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)

Cardiovascular
Effects

measure in studies of Pb, because it is routinely andeasily measured. An association between higher Pblevels and higher BP is most consistent in studies ofbone 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 ofcurrent blood Pb cannot be separated from an effectof early-life Pb exposure.
There is inadequate evidence for Pb effects on BPor 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 riskof 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 accountfor 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 (fora 10 µg/g increase: OR=1.04 (95% CI: 0.96, 1.12) andblood 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.

and hypertension in the general population (Hu etal. 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 riskof hypertension, while blood Pb was significantly
associated (Schwartz and Stewart 2000).

Bone Pb: Long-term exposure to Pb is often reflectedin bone Pb levels, and several studies reported a significant association of BP with bone Pb but not withblood 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

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 finda significant association were in groups with higher
mean blood Pb levels (between 10 and 15 µg/dL atbaseline 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 notnecessarily underpowered or include less exposedgroups compared to the supportive studies. Twentynine publications of cross-sectional analyses withmean 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 tosubjects with blood Pb <10 µg/dL (n=16,222) founda 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, Chenget 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

64

NTP Monograph on Health Effects of Low-Level Lead

65

Epidemiological studies of bone Pb exposure and blood pressure and hypertension are listed by study type and decreasing study size, grouped together for overlappingor 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.

EffectEffectCross-sectional In men with prior occupational exposure, blood Pb was associated with Schwartz (2000)
increased BP and an increased risk of hypertension, but not tibia or DMSA
chelatable Pb.
508 young adults, half lived Cross-sectional In young adults, some with childhood Pb exposure, SBP and DBP were sig- Gerr (2002)
near Pb as children, USA
nificantly increased in those with the highest bone Pb levels (>10 µg/g,
blood Pb 3.15 µg/dL).
284 women (89 with hyper- Case-control
Patella Pb was associated with an increased risk of hypertension in these Korrick (1999)
tension), Nurses’ Health Study
middle-age women without occupational exposures (mean, 3 µg/dL), buttibia and blood Pb were not significantly associated.

543 former Pb workers, USA

EffectEffect

667 third-trimester or post- Cross-sectional Calcaneus bone Pb measured postpartum was associated with increased Rothenberg (2002)
partum women, USA
BP and hypertension during the third trimester (mean blood Pb, 2.3 µg/dL
postpartum).
964 adults, Baltimore Mem- Cross-sectional In these older adults, blood Pb (mean, 3.5 µg/dL) was associated with BP, Martin (2006)
ory Study, USA
while bone Pb was associated with risk of hypertension.

EffectBone Pb in the patella and tibia was not associated with risk of hyperten- Peters (2007)
sion in these older men with low blood Pb levels (mean, 6.3 µg/dL).

750 older men (513 with Case-control
hypertension)

Elmarsafawy (2006)

Hu (1996)

Perlstein (2007)

Zhang (2010)

Cheng (2001)

No effect

471 men

590 men593 men

619 men

Reference

In men with past occupational Pb exposure (mean blood Pb, 4.6 µg/dL), Glenn (2003)
blood and tibia Pb were associated with annual increases in SBP, but not
DBP, over 3 years of follow-up.

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.
Cross-sectional A positive association between pulse pressure and bone Pb in a group ofolder men was modified by genetic variations in the HFE gene.
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.
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.
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 withlow Pb levels.

Prospective

496 former Pb workers, USA Prospective

Normative Aging Study, USA
Effect474 men

EffectTable 6.3: Studies of the association between bone Pb and blood pressure and hypertension used to develop conclusions
Relevance
Study
toStudy Description
Key Cardiovascular Findings
DesignConclusions

Cardiovascular
Effects

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 werealso 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).

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 theimpact 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 andother complications. The mobilization of bone Pb
during pregnancy (Gulson et al. 1997, Rothenberg etal. 2000) (see further discussion in Section 3.4 Modifiers of Pb Exposure) may contribute to the moreconsistent 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 ina prospective study (Sowers et al. 2002); similarly,
maternal blood Pb levels during pregnancy wereassociated with hypertension in cross-sectional studies (Rabinowitz et al. 1987, Yazbeck et al. 2009) anda 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 finda 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 beat an increased risk due to mobilization of bone
Pb stores that may be associated with periods ofdemineralization; increased blood Pb levels havebeen demonstrated in postmenopausal women inseveral 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, theassociation between blood Pb and hypertension wasstronger 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 women66

NTP Monograph on Health Effects of Low-Level Lead

Cardiovascular
Effects

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 themedian 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 (Scinicarielloet al. 2011).
Differential Impacts: Blood Pb and bone Pb may
reflect variable cardiovascular effects of Pb with acuteeffects on transient measures, such as BP, and chronic
effects on clinical disease, such as hypertension – themore permanent state of elevated BP (Navas-Acien etal. 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 datafrom NHANES III, they found relatively more significant associations between estimated bone Pb andhypertension (Park et al. 2009b). This data should beconsidered cautiously because it was developed witha new method for modeling exposure. However, it
should be noted that the model-building Normative
Aging Study population only included older men, andfactors such as age, menopause, and past pregnancies are associated with the mobilization of bone Pb(Symanski and Hertz-Picciotto 1995).

971 pregnant women, EDEN Study, Cross-sectional Blood Pb levels in the second trimester (mean, 1.9 µg/dL) were cor- Yazbeck (2009)
Francerelated with BP before and after 36 weeks gestation and increased therisk of pregnancy induced hypertension, particularly in parous women.
285 pregnant women, Baltimore Cross-sectional Umbilical cord blood Pb of the child was associated with increased Wells (2011)
THREE Study, USA
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.
143 third trimester primi­gravid
Cross-sectional Blood Pb during the third trimester was higher in pregnant women Magri (2003)
women, Malta
with hypertension during pregnancy (mean, 9.6 vs. 5.8 µg/dL) andcorrelated with SBP and DBP in all pregnant women.
110 pregnant women, half with Case-control
Blood Pb at delivery was higher in women with hypertension during Vigeh (2004)
gestational hyper­tension, Iranpregnancy (5.7 vs. 4.8 µg/dL), but Pb levels did not correlate with BP
in the hypertensive women.

Epidemiological studies of Pb exposure and blood pressure and hypertension during pregnancy are listed by study type and decreasing size, grouped together foroverlapping 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, systolicblood pressure; Q1, first quartile; Q4, fourth quartile; THREE, Tracking Health Responses to Environmental Exposures.

EffectEffectEffectEffect

667 third trimester or postpartum Cross-sectional Postpartum calcaneus bone Pb was associated with increased BP and Rothenberg (2002)
hyper­tension during the third trimester (mean blood Pb, 2.3 µg/dL
women
postpartum).

Cross-sectional In the third trimester of pregnancy, increased blood Pb was associated Rothenberg (1999)
with increased BP only in immigrant women, primarily Latina (meanblood Pb, 2.3 µg/dL).

Prospective

Reference

Change in blood Pb concentration during pregnancy (mean, 1.2 µg/dL) Sowers (2002)
was associated with hypertension in pregnancy, including the serious
complications of preeclampsia and toxemia.
3,851 women at birth of child, USA Cross-sectional There was an increase in women’s BP during labor with increased Rabinowitz (1987)
umbilical cord blood Pb, as well as an increased risk of pregnancy
hypertension from low Pb levels (6.3 µg/dL), but not preeclampsia.

705 pregnant women, USA

Pregnant Women, Los Angeles, USA
Effect
1,627 pregnant women

EffectEffectTable 6.4: Studies of Pb and blood pressure and hypertension during pregnancy used to develop conclusions
Relevance
Study
toStudy Description
Key Cardiovascular Findings
DesignConclusions

Cardiovascular
Effects

NTP Monograph on Health Effects of Low-Level Lead

67

Cardiovascular
Effects

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 conductedin 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 ofage – 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 effecton 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 91-94mmHg 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 ofBP (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).

significant increases in both SBP and DBP compared to
unexposed rats, while exposures resulting in blood Pblevels >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 consistentdose-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 (orbi-phasic) relationship could partially explain inconsistency observed in human studies, where studies withmean blood Pb levels <5 µg/dL were generally more
supportive of a relationship with BP and hypertension(see Blood Pressure (BP) and Hypertension section ofAppendix C: Cardiovascular Effects).
The conclusion of sufficient evidence for a Pbrelated increase in BP and risk of hypertension is basedon a large body of literature in humans, with significant
associations that are more consistently found withbone 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 atblood 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

Animal studies provide strong evidence for low-level
Pb elevating BP in humans and contributing to theonset 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 2.15 µg/dL showed

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 (Jhunet 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 asevaluated by HRV (Gump et al. 2011). In adults there
was an indication that Pb may modify the effect ofother metals (Jhun et al. 2005) or air pollution (Park68

NTP Monograph on Health Effects of Low-Level Lead

Summary of Support for Conclusions on BP
and Hypertension

Cord blood Pb levels (mean, 3 µg/dL) were associated with increased Gump (2005)
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 volume, and increased total peripheral resistance response to acute stress.
Prospective
Family socioeconomic status interacted with blood Pb to increase BP Gump (2007)
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).
Cross-sectional Concurrent blood Pb (median, 0.94 µg/dL) was not associated with BP Gump (2011)or BP responses to acute stress in these children, but blood Pb was
associated with measures of impaired cardiac function in response toacute stress tasks.

Prospective

Reference

780 children with moderately Cross-sectional In these children with Pb exposure (20-44 µg/dL), there was no associa- Chen (2006)
high Pb, half treated with suction between blood Pb and BP, including after 5 years of follow-up whencimer, USA
mean blood levels were 8 µg/dL. Chelation of Pb with succimer had noeffect on BP.
508 young adults, half lived Cross-sectional In young adults, some of whom had childhood Pb exposure, SBP and Gerr (2002)
near Pb as children, USA
DBP was significantly increased in those with the highest bone Pb levels(>10 µg/g, blood Pb 3.15 µg/dL).
144 children in the town unex- Cross-sectional For the children residing in the town without Pb exposure, the small Factor-Litvak (1996)
posed to Pb; Pristina, Kosovo
positive correlation of blood Pb with BP was not statistically significant.

140 children, 9-11 years old

122 children

122 children

Key Cardiovascular Findings

Epidemiological studies of childhood Pb exposure and blood pressure and hypertension are listed by study type and decreasing size, grouped together for overlappingor shared study groups.
Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure.

No effect

EffectNo effect

EffectTable 6.5: Studies of childhood Pb exposure and BP
Relevance to
Study
Study Description
Conclusions
DesignOswego Children’s Study, USA

Cardiovascular
Effects

NTP Monograph on Health Effects of Low-Level Lead69

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 cardiovascularmortality, and HRV is not considered in the ATSDR’s
Toxicological Profile for Lead (ATSDR 2007).

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 leveland several related cardiovascular diseases, including peripheral arterial disease and coronary arterydisease, as well as blood flow measures indicative ofatherosclerotic 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 incidenceof coronary artery disease (Normative Aging Study:(Jain et al. 2007)) and prevalence of peripheral arterydisease (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 heartdisease (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 amean blood Pb at baseline of 11.6 µg/dL failed to findan 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, 6 µg/dL) found no increased
risk for coronary heart disease or cerebral vasculardisease (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, riskincreased 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 withhomocysteine 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 fourother 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 wasno association with increases in eight other metals
tested (Zeller et al. 2010). The associations of blood
Pb with these tests of cardiovascular functions have70

NTP Monograph on Health Effects of Low-Level Lead

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 strokevolume 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 Chenget 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.

Cardiovascular
Effects

6.3.4 Clinical Cardiovascular Disease

71

13,043 Pb workers,
SHSP, South Korea

No effect

Prospective

Blood and patella bone Pb were associated with an increased risk of coronary Jain (2007)
heart disease later in life in these older men with low blood Pb levels (mean,
6.3 µg/dL).
Cross-sectional Pb workers showed no increased risk of coronary heart disease or cerebral Kim (2008)
vascular disease at low levels of exposure (5-10 µg/dL vs. <5 µg/dL).

After 14 years of follow-up, blood Pb levels dropped, but there was no association Møller (1992)
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.

Reference

128 ceramic painters, Cross-sectional Increases in blood Pb were associated with decreases in postural changes in Ishida (1996)Japan
finger blood flow volume consistent with an atherosclerotic effect, althoughmost of the subjects had Pb levels >10 µg/dL and other cardiac function tests
were not associated.
130 myocardial infarc- Case-control
Patients admitted for myocardial infarction had higher hair Pb levels, increas- Afridi (2010)tion patients, 61 coning for second and third myocardial infarction, and survival of third myocardial
trols, Pakistan
infarction decreased with higher hair Pb.

420 male bus drivers, Cross-sectional Aging index of second derivative finger photoplethysmogram waveform Kaewboonchoo
Bangkok, Thailand(SDPTG-AI), an assessment of arterial properties, is correlated with blood Pb in (2010)
male bus drivers (mean, 6.3 µg/dL) and may be an independent cardiovascularrisk factor.
197 women, ARFYS,
Cross-sectional Intima-media thickness of the common and carotid arteries was increased at Zeller (2010)
Austriavery low levels of Pb (highest tertile = >0.82 µg/dL).

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.

EffectEffectEffectEffectNHANES (≥ 1999)
9,961 adults, 1999-2002 Cross-sectional Peripheral artery disease prevalence and risk increased with increasing Muntner (2005)
Effectquartiles of blood Pb (highest ≥2.47 µg/dL) in these adults from the general
population.
4,447 adults, > 40 years Cross-sectional Blood Pb was associated with peripheral artery disease in these older adults Guallar (2006)
old, 1999-2002
with low levels (mean, 1.95 µg/dL) after adjustment, including renal function.
2,125 adults, > 40 years Cross-sectional These older subjects with peripheral artery disease had higher blood Pb, the Navas-Acien (2004)
old, 1999-2000
risk of peripheral artery disease increased with increasing Pb (highest quartile:>2.9 µg/dL).

837 men, NAS, USA

1,052 adults, >40 years Prospective
old, Glostrup Population
Study, Denmark

EffectNo effect

Table 6.6: Studies of Pb and clinical cardiovascular disease used to develop conclusions
Relevance to
Study
Study Description
Key Cardiovascular Findings
Conclusions
DesignCardiovascular
Effects

NTP Monograph on Health Effects of Low-Level Leadnot been replicated, but they suggest a role for Pb in While Pb levels were not associated with incidence
early hallmarks of impaired cardiovascular function of myocardial infarction, subjects who died of a third
without a diagnosis of clinical cardiovascular disease. myocardial infarction had significantly higher hair Pblevels (Afridi et al. 2010).

Summary of Support for Conclusions on
Clinical Cardiovascular Disease

Summary of Support for Conclusions on
The EPA’s 2006 AQCD presents a small animal litera- Cardiovascular Mortality
ture supporting an atherogenic effect of chronic Pb
exposure, as well as impacts on vascular tissue andsmooth 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 humandata are consistent with these findings but diverse inscope, hampering the ability to form conclusions on
specific cardiovascular disease endpoints.
The NTP’s conclusion of limited evidence forclinical cardiovascular disease is based on a heterogeneous group of related cardiovascular outcomes instudies that mostly found significant effects associated with blood Pb <5 µg/dL.

Cardiovascular
Effects

6.3.5 Cardiovascular Mortality

Mortality from cardiovascular causes is not addressedin 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 thethree studies (two of which used the same NHANES
III sample) with a significant effect of blood Pb andthe two studies that did not find an association withblood 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 Modifiersof Pb Exposure

Segments of the population that are more susceptible
There is limited evidence that blood Pb levels to health effects of Pb are discussed more exten<10 µg/dL are associated with increased mortality sively in Section 3.0 Exposure. It is unknown whether
from cardiovascular causes (see Table 6.7 and Car- chronic exposure and other cardiovascular risk factors
diovascular Mortality section of Appendix C: Cardio- can modify the relationship between Pb and BP, putvascular Effects). A association between increased ting some portions of the population at greater risk ofcardiovascular mortality and increased blood Pb was cardiovascular disease. These other factors may also
supported by three prospective studies but was not impair the ability to detect an association of Pb withsupported by two prospective studies, one of which BP in some general population studies, even thosereported a significant association with bone Pb. One with higher Pb levels. This concept was proposed byof the supportive studies had a mean blood Pb level Orssaud et al. (1985): “The increase in blood lead conabove 10 µg/dL (12.64 µg/dL) (Moller and Kristensen centration parallels the increase in blood pressure until
1992), and one reported mean blood Pb levels of some limit value, so that such a trend is apparent only
2.58 µg/dL (Menke et al. 2006).
when other factors (such as age) do not competitively
Large studies that found associations between increase blood pressure by greater amounts..
Pb and BP also indicated an increased risk of mortality from cardiovascular causes. In NHANES III, after Susceptible Populations: Pb exposure may dispro12 years of follow-up using the National Death Index, portionately affect populations with preexisting conthere was increased mortality associated with base- ditions that can be exacerbated by a small increaseline blood Pb levels (Menke et al. 2006, Schober et in BP (see Section 7.0 Renal Effects). A prospective
al. 2006). In the Normative Aging Study, bone Pb, study of dialysis patients found significantly increased
but not blood Pb at mean Pb level of 5.6 µg/dL, was cardiovascular mortality over 18 months of follow-up
associated with BP and cardiovascular mortality for the middle range of Pb levels (second tertile, 8.5(Weisskopf et al. 2009). In the Glostrup Population 12.6 µg/dL: HR=3.7 (95% CI: 2.1, 6.5)) and high levels
Study, there was no association between blood Pb of Pb (third tertile, >12.6 µg/dL: HR=9.7 (95% CI: 2.1,
and BP, cardio­vascular disease, or total mortality after 23.3)) compared to the low Pb range (first tertile,
14 years of follow-up (Moller and Kristensen 1992). <8.5 µg/dL) (Lin et al. 2011).
72

NTP Monograph on Health Effects of Low-Level Lead

860 men in NAS with bone Pb, Prospective
1,235 with blood Pb (1994) andfollow-up (2007)

EffectIn these hemodialysis patients, baseline blood Pb >12.64 µg/dL (median, Lin (2011)16.4 µg/dL) was associated with higher all-cause, cardiovascular cause, andinfection cause mortality over 18 months of follow-up.
Bone Pb >35 µg/g increased the risk of mortality from all causes and from Weisskopf (2009)cardio­vascular causes, but not cancer mortality. Blood Pb was not associated with mortality (highest >6 µg/dL).

In adults with 11.5 µg/dL mean blood Pb at 40 years old, there was no Møller (1992)
association with all-cause mortality after 14 years of follow-up, while there
were reductions in blood Pb levels over this time.

Mortality was increased with higher Pb levels for death from all causes, Menke (2006)
cardio­vascular disease, myocardial infarction, and stroke – but not cancer – 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.
In this cohort of older NHANES III participants followed for up to 12 years, Schober (2006)
blood Pb was associated with higher mortality from all causes, cardiovascular disease, and cancer, at blood Pb levels of 5-10 µg/dL.

Reference

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.

927 dialysis patients, 18 months Prospectiveof follow-up, Taiwan

EffectProspective

9,757 adults, >40 years old

1,052 adults, 14-year follow-up, Prospective
Glostrup Population Study,
Denmark

Prospective

13,946 adults

No effect

EffectTable 6.7: Studies of Pb and cardiovascular mortality used to develop conclusions
Relevance to
Study
Study Description
Key Cardiovascular Findings
Conclusions
DesignNHANES III

Cardiovascular
Effects

NTP Monograph on Health Effects of Low-Level Lead

73

Cardiovascular
Effects

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, butblood Pb at 2 years of age was also associated with
ECG abnormalities at 9.5 years of age, particularly insubjects with lower socioeconomic status (Gump et
al. 2005, Gump et al. 2007).

cardiovascular effects, the genotyped polymorphisms
were not independent risk factors for increased pulsepressure, 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 cardiovascularoutcomes have not been sufficiently studied to judge
their reproducibility. However, if genetic variants canmodify the impact of Pb exposure, it supports a biological basis for associations between Pb and effects
Modifiers: Age is associated with higher BP and beyond what might spuriously arise by unmeasured
increased risk of cardiovascular disease, and Pb levels confounding factors.
are also strongly correlated with age (Den Hond et
Dietary factors may also modify the relational. 2002). It is unclear if this is an effect of higher Pb ship between Pb and BP. People who drank alcohol
exposures in earlier eras in this group, or if the elderly had higher blood Pb and stronger associations
are more susceptible to cardiovascular effects of Pb between Pb and BP (Hense et al. 1994, Menditto(see further discussion in Section 3.4 Modifiers of et al. 1994, Pizent et al. 2001). Among black male
Pb Exposure). Many studies adjusted for age in their bus drivers, infrequent caffeine users had a stronger
analyses, while others did analyses within specific positive relationship between blood Pb and BP thanage groups (stratified analyses). One study of sub- did habitual users (Sharp et al. 1990). There is somejects over age 75 years of age found no association indication from the literature that there is an interbetween blood Pb and BP (Nordberg et al. 2000).
action between Pb and calcium intake (Dolenc et al.
Gender and ethnicity are also correlated with Pb 1993), with low calcium related with higher blood Pb
exposure and cardiovascular risk and are frequently (Pizent et al. 2001) and a higher risk of hypertension
adjusted for in analyses. Many general population (Elmarsafawy et al. 2006). However, a 12-week calstudies found higher blood Pb, higher BP, and more cium supplement intervention had no effect on blood
hypertension in non-Caucasian groups (Rothenberg Pb, indicating that any effect of calcium on BP is not
et al. 1999, Den Hond et al. 2002, Scinicariello et al. via interaction with Pb (Morris et al. 1990).
2010). Men generally have higher blood Pb and BP
than do women (Staessen et al. 1990, Hense et al. 6.5 Conclusions
1993, 1994, Chu et al. 1999, Den Hond et al. 2002). The NTP concludes that there is sufficient evidence
Many occupational studies only included male sub- for a small, but detectable, increase in BP associjects, even in those with low occupational Pb expo- ated with Pb exposure in groups with mean blood Pbsure (mean Pb levels, <10 µg/dL) (Orssaud et al. 1985, levels <10 µg/dL (see Table 6.8 for complete list of
Sharp et al. 1990, Schuhmacher et al. 1994, Wolf et cardiovascular effects conclusions). There is sufficiental. 1995, Sirivarasai et al. 2004, Kaewboonchoo et al. evidence for an increase in BP and hypertension dur2007), while only the Nurses’ Health Study focused on ing pregnancy at levels <10 µg/dL. There is limited
female workers (Korrick et al. 1999). Numerous other evidence for increased mortality from cardiovascularstudies included gender in their adjustment factors.
causes from Pb levels <10 µg/dL. There is limited eviGenetic variation is an important biological fac- dence of an increase in early markers of impaired cartor that can characterize a susceptible population diac function (ECG abnormalities) and cardiovascularand modify the relationship between an exposure disease in general. There is inadequate evidence toand disease via altered absorption or metabolism. evaluate Pb effects at levels <10 µg/dL on heart rate
Unlike other relevant cofactors such as gender and variability, specific cardiovascular morbidities, or any
age group, genotype is almost always blinded from cardiovascular effects in children. There is inadequate
subjects and investigators and so is less likely to bias evidence to evaluate Pb effects at levels <10 µg/dL
exposure or ascertainment. In the three studies that on hypertension or other cardiovascular diseases inincluded genetic variants in evaluation of Pb and menopausal women.
74

NTP Monograph on Health Effects of Low-Level Lead

Bone Pb reflects chronic Pb exposure and is moreconsistently associated with increased BP, hypertension,
cardiovascular disease, and mortality. Not all humanstudies 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 withblood 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 biologicallysusceptible 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 beat 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 EffectPopulation

Conclusion

Blood Pb Evidence

Bone Pb
Evidence

SufficientYes, <10 µg/dL

YesChildrenInadequate

UnclearYes (one study)

Pregnant women

SufficientYes, <10 µg/dL

Not studied

Menopausal women Inadequate

UnclearNot studied

Inadequate

UnclearYes (one study)

LimitedNo

Yes (one study)

ChildrenLimitedYes, <5 µg/dL (one study) Not studied

Clinical cardiovascular disease(general)

AdultsLimitedYes, <5 µg/dL

Yes (one study)

Clinical cardiovascular disease(specific)

AdultsInadequate

UnclearYes (one study)

Cardiovascular mortality

AdultsLimitedYes, <10 µg/dL

Yes (one study)

Blood pressure and hypertension Adults

Heart rate variability

AdultsElectrocardiogram abnormalities Men

Cardiovascular
Effects

NTP Monograph on Health Effects of Low-Level Lead

75

Cardiovascular
Effects

THIS PAGE LEFT INTENTIONALLY BLANK76

NTP Monograph on Health Effects of Low-Level Lead

7.0 RENAL EFFECTS

NTP Monograph on Health Effects of Low-Level Lead

77

Renal
Effects

Although the cardiovascular and renal systems
are intimately linked, effects are considered sepa7.1 Conclusions
rately in this evaluation because studies generally
The NTP concludes that there is sufficient evidence reported individual effects rather than testing boththat blood Pb levels <5 µg/dL in adults are associated systems comprehensively. Nevertheless, it is recogwith adverse effects on kidney function adults. With nized that hypertension can contribute to adverse
few exceptions, epidemiological studies of the gen- renal effects and that kidney dysfunction can coneral population reported associations between blood tribute to increased blood pressure (BP) and hyperPb levels <10 µg/dL and (1) increased risk of chronic tension. Cardiovascular and renal effects of Pb may
kidney disease (CKD) and (2) decreased estimated share the same biological mechanisms (U.S. EPA
glomerular filtration rate (eGFR) and creatinine 2006, ATSDR 2007). As discussed in Section 7.4.2,
clearance. The associations are typically stronger in the human literature supports a strong association
people with hypertension or diabetes (Muntner et al. between BP and renal effects of Pb, and multiple
2003, Tsaih et al. 2004). The NTP recognizes that an studies suggest that people with hypertension are
individual with blood levels <10 µg/dL during adult- a susceptible population for adverse renal effects ofhood may have had higher blood Pb levels earlier Pb. This interrelationship of effects is also supported
in life, and the role of early-life Pb exposure cannot in animal models; for example, Pb exposure accelerbe discriminated from the role of concurrent blood ates chronic renal disease by raising BP in male rats
Pb. Comparatively few studies examined markers of (Roncal et al. 2007).
exposure other than blood Pb levels; therefore, it isunknown if blood or bone Pb levels are more consis- 7.2 How Conclusions Were Reachedtently associated with kidney effects.
Conclusions in the NTP evaluation of Pb-related
The data are inadequate to evaluate whether kidney effects in humans associated with low-level
prenatal exposure to Pb is associated with impaired Pb are derived from epidemiological studies with akidney function later in life. No studies were iden- focus on blood Pb levels <10 µg/dL. For this evalutified that evaluated prenatal blood Pb and kidney ation we did not consider studies with mean blood
function in children or adults. Relatively few studies Pb >15 µg/dL, because in those studies, the subjects
have assessed kidney measures in children in asso- with Pb <10 µg/dL are often used as the reference
ciation with low-level Pb exposure. The findings from group and are not appropriate for evaluating lowthese studies are less consistent than are studies in level Pb effects. This evaluation focuses on theadults. Most of these studies also use kidney bio- human data for kidney effects of Pb because there ismarkers, whose prognostic value for renal function is a relatively large database of human studies for theseless clear compared to GFR measures and biomark- effects; therefore, the document makes only limited
ers, such as microalbuminuria, commonly measured use of the data from laboratory animals to support
in the adult studies. Thus, there is currently inade- the human evidence. Major endpoints considered as
quate evidence to conclude that blood Pb <10 µg/dL potential indicators of kidney effects of Pb are listed
is associated with impaired kidney function in chil- and briefly described in Section 7.2.1. This document
dren <12 years old. In contrast, there is limited evi- is not a review of kidney toxicity, and the reader isdence that blood Pb levels <5 µg/dL are associated directed to published reviews for additional backwith adverse effects on kidney function in children ground. Key data and principal studies considered≥12 years old. A recent study of children and young in developing the NTP’s conclusions are discussed in
adults 12-20 years of age in NHANES 1988-1994 with detail in Section 7.3 Evidence for Pb-related Effects
mean blood Pb of 1.5 µg/dL reported a reduction in on Kidney Function. The discussion of each kidney
eGFR rate per doubling of blood Pb (Fadrowski et al. effect begins with a statement of the NTP conclusion
2010). The reduction in GFR demonstrated in Fad- whether the specific effect is associated with a bloodrowski et al. (2010) is consistent with results from Pb level <10 µg/dL or <5 µg/dL and the age group
adults within NHANES and supports adverse effects in which it is identified (childhood, or adulthood),on kidney function in children age 12 and over at as well as the timing of exposure associated withblood Pb <5 µg/dL.
the effect (prenatal, childhood, concurrent) when

RenalEffects

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 isincluded 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.

research, especially for acute kidney injury, withrecent attention focusing on urinary proteins suchas 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 atlower blood Pb levels (Table 7.2).
7.2.1 Principal Measures of Kidney Effects
The EPA states that most studies in general adult
Table 7.1 lists a number of kidney endpoints com- and patient populations published between 1986
monly evaluated in epidemiological studies. The most and 2006 indicate that Pb, at much lower doses thanclinically accepted measure of kidney function is glo- those causing Pb nephropathy, acts as a cofactor
merular filtration rate (GFR), which is the flow rate of with other more established renal risks to increase
filtered fluid through the kidney. The gold standard the risk for renal dysfunction. Other explanations,
method of determining GFR is through the use of such as residual confounding or reverse causality, areradionuclide or radiocontrast markers, which is both not likely to account for the observed associations
costly and time consuming. GFR can be approximated between Pb dose and kidney dysfunction. It shouldby creatinine clearance, which compares creatininelevels in blood and urine to calculate the volume of
Table 7.2: Main conclusions for kidney effects
blood plasma cleared per milliliter of creatinine perin 2006 EPA AQCD for Lead and the 2007 ATSDR
unit time. Direct measurement of creatinine clearance
Toxicological Profile for Leadrequires 24-hour urine collection. There are also a
number of equations for estimating GFR or creatinine “General population studies are the most importantclearance based on serum biomarkers (e.g., creati- advance in this regard. These studies provide strong
nine, cystatin C) and consideration of other variables evidence that renal effects occur at much lower blood
Pb levels than previously recognized. These effects are
such as age, sex, race, or weight. Historically, serum clinically relevant in U.S. subpopulations who continue
creatinine has been used most often, although serum to have higher Pb exposure than the general populacystatin C is increasingly being used as an alternative tion. At levels of exposure in the general U.S. populationor complementary approach to serum creatinine for overall, Pb combined with other risk factors, such as diabetes, hyper­tension, or chronic renal insufficiency fromestimating GFR.
GFR is notoriously insensitive (Levey et al. 1999), non-Pb related causes, can result in clinically relevant
effects. Notably, the size of such susceptible populationsand “early biological effect markers” (EBEs), such as
is increasing in the US due to obesity…The threshold for
N-acetyl-β-D-glucosaminidase (NAG), are thought to Pb-related nephro­toxicity cannot be determined based
be more sensitive because they areoften elevated on current data. However, associations with clinicallywhen GFR measures are not abnormal. However, the relevant renal outcomes have been observed in populavalidity and reliability of EBEs for long-term prognos- tions with mean blood Pb levels as low as 2.2 µg/dL.”
tic value are unclear. The epidemiological studies in (U.S. EPA 2006, pg 6-113)
children more often assess EBEs for kidney rather “The overall dose-effect pattern suggests an increasing
than eGFR or creatinine clearance. It should also be severity of nephrotoxicity associated with increasing PbB
noted that the list of biomarkers of EBEs presented [blood Pb level], with effects on glomerular filtration eviin Table 7.1 is not comprehensive and reflects those dent at PbBs below 20 µg/dL, enzymuria and proteinuria
most commonly reported in the Pb epidemiological becoming evident above 30 µg/dL, and severe deficits instudies. Other biomarkers of kidney function con- function and pathological changes occurring in association
with PbBs exceeding 50 µg/dL.” (ATSDR 2007, pg 79)
tinue to be assessed within kidney epidemiology
78

NTP Monograph on Health Effects of Low-Level Lead

79

Breakdown product of creatine phosphate in muscles; commonly used measure of GFR (considered less precise thancystatin C); can be influenced by non-kidney function variables
that affect muscle mass (gender, age, race, weight, diet)A cysteine protease inhibitor protein used as an alternative toserum creatinine or complementary measure to estimate GFR
Modification of Diet in Kidney Disease (MDRD) Study: Clinical standard of estimated GFR based on creatinine but under­
estimates 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
Cockcroft-Gault: Oldest, estimates creatinine clearance

1(Cardenas et al. 1993, Rose and Post 2011).

Urate/uric acid

Urate is a salt derived from uric acid; can build up in the bodywhen uric acid is not adequately metabolized, e.g., in casesof gout

Total protein, albumin, low- to intermediatemolecular-weight proteins (e.g., retinol-binding
protein (RBP)), Clara cell protein, transferrin)
Biochemical
Biochemical: Urinary eicosanoids, (e.g., prostaor histological glandin E2 (PGE2), prostaglandin F2 alpha, 6-keto-prosalteration
taglandin F1 alpha (6-keto-PGF), and thromboxane B2(TXB2)), fibronectin
Histological: Brush border antigen, fibronectin(glomerular fibrosis)
Cytotoxicity
N-acetyl-β-D-glucosaminidase (NAG)
Lysosomal enzyme involved in the breakdown of glycoproteinsOther↓ creatinine clearance↓ eGFR↑ serum concentration↑ serum concentration

Indication of Impaired
Kidney Function↑ urine concentration↑ activity

Varies/not necessarily known1(e.g., ↓ urine PGE2, 6-ketoPGF; ↑ TXB2)↑ urine concentration↑ urine concentration

Measures the amount of nitrogen in blood in the form of urea ↑ serum concentration(a waste product of protein digestion)
125I-iothalamate, iohexol, and other radioisotopes Radioactive markers used to measure GFR by timed sequential ↓ urinary clearance
blood samples or imaging (invasive and time consuming)

Creatinine clearance (based on timed urine
collections)
Blood urea nitrogen

eGFR (estimated GFR, based on equations)

Serum cystatin C

Serum creatinine (most common)

Indicators of Early Biological Effect Markers (EBEs)
Function
β2-microblobulin (only validated EBE marker)

Glomerular
filtration rate
(GFR)

Table 7.1: Commonly used indicators of kidney function in the Pb literature references
KidneyMeasurement
Description
Endpoint
Clinical Indicators of Impaired Kidney Function

Renal
Effects

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 datasummaries 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 theconclusions and agreed that the data support them.

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, seealso 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), andnative and nonnative residents in rural Taiwan (Lai etal. 2008). The blood Pb levels associated with kidneyeffects in these studies were ≤10 µg/dL and <5 µg/dL
in the NHANES and WHILA studies.
There is no apparent threshold for kidneyeffects. Significant increases in risk of CKD based onan 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 etal. 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 wereassociated 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 the95th percentile (4.6 µg/dL) had the same effect onglomerular 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 resultin 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 withdiabetes, hypertension, or CKD from non-Pb relatedcauses 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 andsex, 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 notsufficient 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 etal. 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 tounderestimate the association between Pb exposureand 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 ofan association typically assessed kidney effect by measurement of serum creatinine and did not consider the
impact of potential or modifying variables at all (deBurbure 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 interpretationof 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 groupthan in men considered exposed based on living neara smelter for ≥8 years (average blood Pb in referents:

80

NTP Monograph on Health Effects of Low-Level Lead

7.3 Evidence for Pb-related Effects on
Kidney Function

Renal
Effects

7.3.1 Kidney Effects in Adults

81

Reference

Cross-sectional Creatinine clearance (natural log (Ln)) was inversely associated with Ln Payton (1994)
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).
Men 34-88 years old; n=459
Prospective
Blood Pb ≤10 µg/dL positively associated with concurrent serum creati- Kim (1996)
nine (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).
Men average age of 66 years Prospective
Significant association with change in serum creatinine with baseline Tsaih (2004)
blood Pb in diabetics (adjusted β (SE) = 0.076 (0.023); p<0.05) but not
followed for 6 years; n=448
nondiabetics (adjusted β (SE) = 0.006 (0.005); p=not significant). Average baseline blood Pb, 6.5 µg/dL

Men 43-90 years old; n=744

Key Kidney Findings

EffectPatients
Effect1 µg/dL higher blood Pb at baseline associated with a 4.0 mL/min/1.73 Yu (2004)
m2 reduction in eGFR over 4 years. Average (range) blood Pb, 4.2 µg/dL(1-13.4 µg/dL).
Baseline chelatable Pb was significantly associated with risk for achieving an Lin (2003)
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 patientson chelation therapy during months 24-51 had better GFR outcomes.

CKD Taiwanese patients 25-82 Prospective
years old followed for 4 years;
n=121

Chronic renal insufficiency Prospective
patients 25-80 years old followed for 2 years; n=202

Cadmibel, Belgium
EffectAdults 20-88 years old partici- Cross-sectional 10-fold increase in blood Pb associated with reduction in creatinine clear- Staessen (1992)
ance of 10 mL/min (female) to 13 mL/min (male); adjusted OR (95% CI)
pating in the Cadmibel study;for 10-fold increase in blood Pb and impaired kidney function = 3.76 (1.37,
n=1,98110.4). 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.
NHANES, USA
EffectAdults >20 years old included in Cross-sectional Increased risk in hypertensives (but not normotensives) for elevated Munter (2003)
serum creatinine (Q2 (2.5-3.8 µg/dL) vs. Q1 (0.7-2.4); adjusted OR (95% CI)
NHANES 1988-1994; n=15,211=1.47 (1.03, 2.10)) and CKD (Q3 (3.9-5.9 µg/dL) vs. Q1 (0.7-2.4); adjusted
total; 4,813 hypertensives
OR (95% CI) = 1.85 (1.32, 2.59)).
EffectAdults ≥20 years of age included Cross-sectional Risk of having a reduced GFR (defined at <60 mL/minute/1.73 m2) was Navas-Acien (2009)higher for blood Pb of >2.4 µg/dL vs. ≤1.1 µg/dL (adjusted OR=1.56 (95% CI:
in NHANES 1999-2006; n=14,778
1.17, 2.08); ptrend <0.001); significant trend for albuminuria (ptrend ≤0.001).
EffectAdults 18-75 years old from Cross-sectional Increased risk for CKD (GFR <60 mL/min) associated with blood Pb of Muntner (2005)>1.63 µg/dL (Q3 (1.63-2.47 µg/dL) vs. Q1 (<1.06 µg/dL); adjusted OR
NHANES 1999-2002; n=9,961(95% CI) = 1.89 (1.09, 3.30)).

EffectEffectEffectTable 7.3: Studies of kidney outcomes in adults
RelevancetoStudy Description
Study Design
Conclusions
Normative Aging Study, USA

Renal
Effects

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82

NTP Monograph on Health Effects of Low-Level Lead

Reference

Adults 18-51 years old living 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
near two smelters in France;(average blood Pb: males, 6.8 µg/dL; females: 5.3 µg/dL) (serum creatinine,
n=300 and 300 age/gendertotal protein, albumin, transferrin, β2-microblobulin, RBP, brush bordermatched referents
antigen, and NAG).
Men 40-59 years old participat- Cross-sectional Blood Pb associated with log-transformed serum urate (β=0.06) andserum urea (β=-0.05); no association with serum creatinine. Blood Pb leving in the Regional Heart Studyels ranged from <12.4 to 37.3 µg/dL (authors considered the magnitude
in England; n=7,364
of the changes to be small and unlikely to be of biological importance)
Adult London civil servants in 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 creatiEngland 37-58 years old; n=531
nine and log blood Pb (r=0.03, p=not significant).
Men 25-38 years old in Egypt; 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).
n=35 smokers, 33 nonsmokers

Mortada (2004)

Staessen (1990)

Pocock (1984)de Burbure (2003)

Adult women from WHILA study Cross-sectional Inverse association with GFR (β (95% CI) = -0.20 (-0.32, -0.09)) and creati- Akesson (2005)
nine clearance (β (95% CI) = -0.18 (-0.30, -0.06)). Mean (5-95% percentiles)
in Sweden; n=820
blood Pb, 2.2 (1.1, 4.6) µg/dL. No association with NAG or α1-microglobulin.
Adult native and nonnative rural Cross-sectional Increased risk of serum creatinine >1.2 mg/dL for blood Pb >7.5 versus Lai (2008)≤ 7.5 µg/dL (adjusted OR=1.92 (95% CI: 1.18, 3.10)).
Taiwanese; n=2565

Baseline chelatable Pb was significantly associated with risk for achieving an Lin (2006a)
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.
Baseline chelatable Pb was significantly associated with risk for achiev- Lin (2006b)
ing 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 (1.919.1) µg/dL; 15 patients on 3-month chelation therapy during months
13-24 had better GFR outcomes.

Key Kidney Findings

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 overlappingor 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.

No effect

Equivocal

Equivocal

No effect

EffectOther
EffectDiabetes patients 33-79 years Prospective
old followed for 1 year

EffectStudy Design

CKD patients 30-80 years old fol- Prospective
lowed for 2 years

Study Description

EffectRelevancetoConclusions

Table 7.3: Studies of kidney outcomes in adults (continued)

Renal
Effects

NTP Monograph on Health Effects of Low-Level Lead

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 theanimal data, ATSDR 2007). Rodent studies also support hyperfiltration, or increased GFR as part of anearly phase of kidney injury (e.g., Khalil-Manesh etal. 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 andmechanistic studies). Although animal data support
a role for oxidative stress and a potential role formetallothionein in kidney effects associated with Pb
exposure, the animal studies are generally at higher
Pb exposure levels (20-60 µg/dL) than the blood Pblevels 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 inthe general population and even stronger evidence
in people with hypertension or diabetes. A numberof 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, thesedata provide sufficient evidence that blood Pb levels<5 µg/dL are associated with adverse effects on kidney function in adults. The NTP recognizes that bloodlevels measured during adulthood in this range do notpreclude the possibility that an individual might have
had past exposure to higher blood levels. Althoughseveral 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 kidneyeffects 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
83

Renal
Effects

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 ina bias towards detecting associations between Pb andimpaired 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 thatargue 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 bonebiopsies, (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 notmobilizable Pb (Van de Vyver et al. 1988). The absenceof 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 thesame 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 levelsin 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.

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.

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 datafrom 769 children and young adults 12-20 years ofage 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 doublingof blood Pb in the fully adjusted model. When thedata 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 ≥12years of age. It is unknown from the analysis reported
in Fadrowski et al. (2010) whether or not the effect isdriven 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 oflimited evidence that blood Pb levels <5 µg/dL areassociated with adverse effects on kidney function inchildren ≥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 atsimilar 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 supportedby the increased serum levels of cystatin C reported inchildren in Belgium (Staessen et al. 2001), a measurethat 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 kidneyeffects 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 etal. 1992a, Khalil-Manesh et al. 1992b, Khalil-Manesh
et al. 1993). Young children with an age less than the84

NTP Monograph on Health Effects of Low-Level Lead

7.3.2 Occupational Exposures

Assessment of kidney effects at higher blood Pb,
such as those experienced in occupational cohorts, isbeyond the scope of this evaluation but is addressedin the EPA’s 2006 AQCD for Lead (U.S. EPA 2006), withan 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 thanfindings from general population studies (U.S. EPA
2006). For example, several of these studies reported
inverse associations, including higher Pb dose withlower 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 mechanismsof 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 thatthe kidney effects reported in the general populations
are due to reverse causality, because no effects wereobserved in workers at higher exposure levels.

Renal
Effects

7.4 Susceptible Populations or Life Stages
7.4.1 Children

Children 8.5-12.3 years old in CrossEurope living near two smelters; sectional
n=364 exposed and 352 matchedreferents

Equivocal

No effect
because of
direction ofeffectAbbreviations: CI, confidence interval; EGF, epidermal growth factor; GFR, glomerular filtration rate; NAG, N-acetyl-β-D-glucosaminidase; NHANES, National Health andNutrition Examination Survey; PGE2, prostaglandin E2; PGF1α, prostaglandin F1α; RBP, retinol-binding protein.

Inverse relationship (regression coefficients) with blood Pb and serum creati- de Burbure (2006)
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)

Increased levels of urinary levels of β2-microblobulin, Clara cell protein, and Bernard (1995)
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 andblood Pb in total group (partial r2=0.046, regression coefficient=0.302, p=0.005)
Children 10 years old in Poland liv- CrossAltered urinary biomarkers (transferrin, 6-keto-PGF1α, NAG B, β2-microblobulin, Fels (1998)
ing near Pb-producing factories; sectional Clara cell protein, EGF, PGE2) between 62 exposed (mean blood Pb, 13.3 µg/dL)
n=62 exposed and 50 referents
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)Children 8.5-12.3 years old in CrossNo difference in any kidney parameters in children living in reference (mean de Burbure (2003)
France living near two smelters; sectional blood Pb: males, 3.4 µg/dL; females, 2.7 µg/dL) and polluted areas (meanblood Pb: males, 4.2 µg/dL; females, 3.7 µg/dL) (total protein, albumin, transn=200 exposed and 200 matched
ferrin, β2 -microblobulin, RBP, brush border antigen, and NAG)
referents

Equivocal

No effect

Children 1-6 years old of workers CrossIncreased levels of serum creatinine and urea in Pb-exposed children compared Khan (2010)
in Pakistani Pb plants; n=123 Pb sectional to controls (median Pb, 8.1 and 6.7 µg/dL, respectively; p≤0.01 for both meaexposed and 123 referents
sures in unadjusted analyses)

EffectChildren 12-15 years old in Czech CrossRepublic living near two smelters: sectional
area 1, n=91; area 2, n=53; reference site, n=51

Children age 17 living near indus- CrossIncreased levels of serum cystatin C and β2-microblobulin in children with Staessen (2001)
trial areas in Belgium; n=100 Pb sectional higher blood Pb (mean, 2.7 µg/dL) compared to referents (mean, 1.5 µg/dL)
exposed and 100 referents

EffectReference

769 children and young adults age CrossReduced GFR associated with blood Pb of >2.9 µg/dL versus <1 µg/dL (β (95% CI) Fadrowski (2010)12-20 in NHANES 1988-1994
sectional = -6.6 (-0.7, -12.6))

Key Kidney Findings

EffectTable 7.4: Studies of kidney outcomes in children
Relevance to
Study
Study Description
Conclusions
DesignRenal
Effects

NTP Monograph on Health Effects of Low-Level Lead

85

RenalEffects

latent period of clinically detectable kidney disease opposite direction was observed for β2-microblobulin
would not be expected to show Pb-related kidney in these two studies. Findings on urine biomarkers are
effects. In addition, glomerular hyperfiltration during also inconsistent and difficult to interpret (Bernard
early stages of Pb nephropathy (as has been observed et al. 1995, Fels et al. 1998, de Burbure et al. 2003)
in rats after 3 months of exposure (Khalil-Manesh et (Table 7.4). For example, Bernard et al. (1995) foundal. 1992b)) would also mask the effect of Pb exposure higher urinary levels of β2-microblobulin, Clara cellon kidney function in young children (see also discus- protein, and N-acetyl-β-D-glucosaminidase (NAG) insion of de Burbure et al. 2006 below). The lack of clear children living in one “polluted” region compared toevidence of adverse effects of blood Pb on children children living the reference area, but not in another<12 years of age does not exclude the potential role “polluted” region where average blood Pb levelsof Pb exposure on development of Pb-related kidney were the highest. The levels of blood Pb in the comeffects later in life.
parison groups are another factor to consider when
The studies of serum creatinine and other blood interpreting the studies in children. No differences inor urine biomarkers present less indication of an kidney parameters were observed in de Burbure eteffect of Pb on kidney function in children (Table al. (2003) (Table 7.4). Although the average blood Pb
7.4). De Burbure et al. (2006) reported an asso- levels between the “exposed” and reference groups
ciation between higher blood Pb and lower serum were quite similar in this study (mean blood Pb in 200
creatinine (adjusted regression coefficient=-0.026, referents: males, 3.4 µg/dL; females, 2.7 µg/dL; vs.
p=0.007); however, the opposite direction of effect, 200 children considered exposed: males, 4.2 µg/dL;
an increase in serum creatinine, would be considered females, 3.7 µg/dL), no associations were observed
to indicate decreased kidney function. Alternatively, when stepwise multiple regression analysis was conthe de Burbure et al. (2006) finding may be consis- ducted on the whole group of children as well.
tent with hyperfiltration. The data in children may be
Several studies have assessed the impact ofinconsistent because of a lack of reliable measures higher Pb exposures during childhood on kidney
in children, differential effects by age (hyperfiltration measures, but these studies do not necessarily provs. decreased clearance), or other factors. An earlier vide additional clarity (Inglis et al. 1978, Moel andstudy found no difference in mean serum creatinine Sachs 1992, Verberk et al. 1996, Coria et al. 2009).
between 62 exposed (mean blood Pb, 13.3 µg/dL) No nephrotoxicity was reported in a group of 77
and 50 control (mean blood Pb, 3.9 µg/dL) Polish individuals in rural Chile who were assessed 10 years
children (Fels et al. 1998). Khan et al. (2010) reported after being exposed to Pb-contaminated flour as chila correlation of blood Pb levels with serum creatinine dren in 1996 and subsequently treated with EDTA (Pb(r=0.13; p=0.05) in a study in 1- to 6-year-old chil- levels measured in 1996 ranged from 37 to 87 µg/
dren of workers in Pakistani Pb smelters and battery dL) (Coria et al. 2009). Similarly, Moel et al. (1992)
recycling plants; blood Pb, serum creatinine, and did not detect any significant differences between
urea were higher in the children of workers (n=123 previously Pb-poisoned children and their siblings
exposed) compared to controls (n=123; medians=8.1 for serum creatinine, uric acid, and β2-microblobulin,
and 6.7 µg/dL; 56 and 52 µmol/L; and 4.5 and 4.3 fractional excretion of β2-microblobulin, urinary
mmol/L, respectively; p≤ 0.01 for all in unadjusted protein:creatinine ratio, and tubular reabsorption
analyses). Two studies assessed associations between of phosphate. The study compared 62 patients at a
blood Pb and serum cystatin C and reported oppo- Chicago Pb clinic, who were diagnosed and received
site findings (Staessen et al. 2001, de Burbure et al. chelation treatment between 1966 and 1972 for ini2006). Staessen et al. (2001) measured higher levels tial blood Pb levels >100 µg/dL, to 19 age-matchedof serum cystatin C in 17-year-old Belgian children siblings whose initial blood Pb levels were <40 µg/dL.
living in a chemical industrial region (mean blood Pb, Kidney pathology was documented in certain adult2.7 µg/dL) compared to the reference group (mean survivors of untreated childhood Pb poisoning inblood Pb, 1.5 µg/dL). de Burbure et al. (2006) found Queensland before its removal from paint (Inglis et al.
an inverse association with blood Pb in 300-600 Euro- 1978). It is unclear whether differences in outcomespean children 8.5-12.3 years of age (adjusted regres- between those studies can be attributed to use ofsion coefficient=-0.056, p=0.02). The same pattern of EDTA in Coria et al. (2009) and Moel et al. (1992);
86

NTP Monograph on Health Effects of Low-Level Lead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 survivorsof childhood poisoning in Boston from 1930 to 1942
compared to controls matched for age, sex, race, andneighborhood (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 isconsistent 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 neara Pb smelter in Baia Mare, Romania. The average Pb
levels in the subgroups (based on proximity to thesmelter) 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.

NTP Monograph on Health Effects of Low-Level Lead

87

Renal
Effects

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 reductionin eGFR (Yu et al. 2004). The average blood Pb level inthe sample of 121 patients was 4.2 µg/dL. In order tobe 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 doseat 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 thelowest baseline blood Pb (2.9 µg/dL) was 1.1 per 1
SD increase in Pb dose at baseline per year (Lin etal. 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, Linand 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.
7.4.2 Hypertensives, Diabetics, and Kidney In addition, they involve small number of patients,
Disease Patientsand the findings should be repeated in larger populaThe impacts of Pb on kidney function in susceptible tions in multiple centers.
Thus, Pb-associated reduced kidney function in
populations, such as people with diabetes, hypertensions, or CKD, are expected to be higher (U.S. EPA healthy individuals may not necessarily result in CKD,
2006). This pattern is apparent in several studies that although Pb may be a risk factor for CKD in suscepconducted subgroup analyses of NHANES data and the tible patient populations (e.g., people with kidney
Normative Aging Study and found that associations disease, diabetes, or obesity), in older populations, orwere stronger in NHANES participants with hyperten- when combined with exposure to other compounds
sion (Muntner et al. 2003) or men in the Normative known to cause kidney damage (e.g., cadmium, mercury, arsenic, zinc) (U.S. EPA 2006).
Aging Study with diabetes (Tsaih et al. 2004).
Follow-up studies in people with renal diseaseor type II diabetes also indicate worse disease pro- 7.5 Conclusions
gression (kidney function decline) in association with The NTP concludes that there is sufficient evidence
higher baseline blood Pb levels (Lin et al. 2003, Yu that blood Pb levels <5 µg/dL are associated withet al. 2004, Lin et al. 2006a, Lin et al. 2006b, U.S. adverse effects on kidney function in adults (see TableEPA 2006, Weaver and Jaar 2010, U.S. EPA 2012). 7.5 for complete list of kidney effects conclusions).
Although most of the patient studies are relatively With few exceptions, epidemiological studies of thesmall in size (ranging from 87 to 202 subjects), they general population reported associations between
are longitudinal in design, with follow-up ranging blood Pb levels <10 µg/dL and (1) increased risk offrom 1.1 to 3.87 years. They provide additional sup- CKD and (2) decreased kidney function as measured
port for kidney effects at low-levels of blood Pb and by GFR and creatinine clearance. The NTP recognizes
also support the conclusion that reverse causality is that blood levels in this range measured during adultnot likely to account for the effects of Pb on kidney hood do not preclude the possibility that an indifunction at low levels. In the study with the longest vidual might have had past exposure to higher blood

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 frombirth 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 thatblood 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 inadults. There is inadequate evidence that blood Pblevels <10 µg/dL are associated with kidney function
in children <12 years of age because of inconsistent
results and studies lacking clear predictive measuresof kidney function in children. The lack of consistentpredictive 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 withadverse effects on kidney function in adults and limited evidence in children ≥12 years of age, extend theconclusions 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 andolder based on recent data.

Table 7.5: NTP conclusions on kidney effects of low-level Pb
Health EffectPopulation

NTP
Conclusions

Blood Pb
Evidence

Bone Pb
Evidence

SufficientYes, <5 µg/dL

Not studied

LimitedYes, <5 µg/dL

Not studied

Inadequate

UnclearNot studied

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NTP Monograph on Health Effects of Low-Level Lead

Renal
Effects

Increased chronic kidney disease Adults(CKD) and decreased glomerular Children ≥12 years old
filtration rate (GFR)
Children <12 years old8.0 REPRODUCTIVE/
DEVELOPMENTAL EFFECTS
8.1 Conclusions

The NTP concludes there is sufficient evidence
that blood Pb levels <10 µg/dL are associated withadverse health effects on development in children
and that blood Pb levels <5 µg/dL are associatedwith adverse health effects on reproduction in adultwomen.
Because the database of human studies on most
reproductive endpoints is limited to occupational
exposure studies, many of the available studies arefor blood Pb levels >10 µg/dL. Given this fact and thefocus of the original nomination on reproductive anddevelopmental 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 inmen but did not affect the conclusions for womenor children.
Unlike the data set for most other health effects,
a number of prospective studies of developmental
effects include prenatal measures of exposure (eithermaternal blood or umbilical cord blood). Maternal
blood Pb <10 µg/dL is associated with decreased
head circumference in children through 4 years ofage, providing evidence that prenatal exposure isassociated with reduced postnatal growth in children. Conclusions on effects of prenatal exposure foroutcomes evaluated as children are complicated by
the high degree of correlation in childhood blood Pblevels over time, and as described below, concurrent
blood Pb levels <10 µg/dL in children are also associated with reduced postnatal growth.

Childrenblood Pb levels <10 µg/dL in children. Epidemiological studies consistently report an inverse relationshipbetween blood Pb levels <10 µg/dL and postnatal
growth (see Table 8.4). Developmental effects on neurological, immunological, renal, and cardiovascularsystems are not covered in this section because they
are reviewed in individual chapters.

Women

In children, there is sufficient evidence that blood Pblevels <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); althoughseveral studies report effects on puberty at blood Pblevels <5 µg/dL, there is also evidence indicating noeffect of blood Pb <5 µg/dL. Therefore, there is limited evidence that delayed puberty is associated with Men
blood Pb levels <5 µg/dL. There is sufficient evidence In adult men, there is inadequate evidence thatthat decreased postnatal growth is associated with blood Pb levels <10 µg/dL are associated withNTP Monograph on Health Effects of Low-Level Lead

89

Reproductive
Effects

In adult women, there is sufficient evidence thatmaternal 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 withmaternal blood Pb data during pregnancy, a large retrospective cohort of over 43,000 mother-infant pairs thatreports 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, andhead circumference. There is limited evidence thatmaternal blood Pb levels <10 µg/dL are associated withspontaneous 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 theinconsistent 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 otherreproductive and effects of Pb associated with blood
Pb levels <10 µg/dL in women.

effects on reproduction. There is sufficient evidence
that blood Pb levels ≥15 µg/dL are associated withadverse effects on sperm or semen in men, andinadequate 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 sufficientevidence that paternal blood Pb levels ≥20 µg/dL areassociated with delayed conception time and limited
evidence that blood Pb levels ≥10 µg/dL in men areassociated with other measures of reduced fertility.
Four studies reported increased time to pregnancy
in women whose male partners had blood Pb levelsof 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 othermeasures of reduced fertility. There is limited evidence that paternal blood Pb >31 µg/dL is associatedwith spontaneous abortion. The conclusion of limited
evidence that spontaneous abortion is associatedwith paternal exposure is based mainly on the retrospective nested case-control study by Lindbohm etal. (1991a) in men, with additional support provided
by occupational studies that reported an association
with Pb exposure but lack blood Pb measurements.

Reproductive
Effects

8.2 How Conclusions Were Reachedsystem 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 witha statement of the NTP’s conclusion that the specificeffect 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 theinformation 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: Reproductiveand Developmental Effects, and individual studies
are abstracted for further reference. The NTP madeextensive use of recent government evaluations ofhealth effects of Pb in the current assessment, andthe 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 Reproductiveand Developmental Effects

Table 8.1 lists a number of key reproductive anddevelopmental endpoints commonly evaluated inepidemiological 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.

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 afocus on blood Pb levels <10 µg/dL. Because thedatabase of human studies on most reproductive
endpoints is limited to occupational exposure studies, many of the available studies are for blood Pblevels >10 µg/dL. Unlike other sections of this document, reproductive effects of these higher blood Pblevels were included in the evaluation because thedata 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

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 forreproductive 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 todetermine if effects occur at lower blood Pb levels

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NTP Monograph on Health Effects of Low-Level Lead

8.2.2 Principal Conclusions from 2006 EPA
and 2007 ATSDR Pb Documents

Table 8.1: Major reproductive/developmental effects considered
EffectDescription
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(see Table 8.2 for principal conclusions and original
documents for complete conclusions). Although the2006 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 levelat 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 spontaneousabortion. The 2006 EPA AQCD for Lead (U.S. EPA 2006)
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 Pblevels >45 µg/dL, as most studies have only considered
exposure in the occupational setting. There are no adequate data to evaluate associations between Pb exposureand female fertility.” (U.S. EPA 2006, pg 6-271)

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, congenitalabnormalities, 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 datasummaries from the EPA’s 2006 AQCD for Lead (U.S.
EPA 2006) and ATSDR’s 2007 Toxicological Profile forLead (ATSDR 2007). In general, the NTP concurredwith the conclusions and agreed that the data support them. Differences from the ATSDR and EPA
documents are identified for specific endpoints inthis document.

8.3 Evidence for Pb-Related Effects on
Reproductive and Developmental
Outcomes
8.3.1 Delayed Puberty

NTP Monograph on Health Effects of Low-Level Lead

91

Reproductive
Effects“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 inmales, the threshold PbB appears to be in the range of
30-40 µg/dL.” (ATSDR 2007, pg 23)

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

92

NTP Monograph on Health Effects of Low-Level Lead

Children 10-13 years Crosssectional
old in Egypt; n=41

Girls aged 10-17 in CrossAkwesasne Mohawk sectional
Nation; n=138
Girls 9 years old in Crosssectional
New York; n=139

Girls 13 years old in CrossSouth Africa; n=682- sectional
712, by endpoint
Children aged 17 in CrossBelgium; n=100 Pb sectionaland 100 referent

Delayed puberty onset in boys and girls with blood Pb ≥10 µg/dL. Puberty mea- Tomoum (2010)
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.

Blood Pb had no effect on puberty onset in girls (by breast and pubic hair stage) Wolff (2008)
with median blood Pb level of 2 µg/dL.

Testicular volume was lower in boys living in areas with higher blood Pb (1.8- Staessen (2001)
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; comparisonby blood Pb not reported.
Delayed puberty onset (age at menarche) in girls with blood Pb above mean Denham (2005)(≥0.49 µg/dL) and a predicted delay in age at menarche of 10 months with blood
Pb above median (1.2 µg/dL).

Delayed puberty onset (determined by Tanner pubic hair and breast developmen- Naicker (2010)
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.

Girls with higher blood Pb (blood Pb ≥5 µg/dL compared with those <1 µg/dL) had Gollenberg (2010)
lower likelihood of having inhibin B levels >35 pg/mL, a level the authors report tobe associated with puberty and development of pubic hair and breasts.
Delayed puberty onset in African American girls (age at menarche, Tanner breast Selevan (2003)
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.

Girls 8-11 years old; Crosssectional
n=705

Girls 8-16 years old; Crossn=600-805 per race/ sectional
ethnicity

Delayed puberty onset in girls with blood Pb ≥2 µg/dL compared to those with Wu (2003)
blood Pb <2 µg/dL. Puberty differed by Tanner pubic hair developmental stage and (population overlap withage at menarche; no effect on developmental stage of breasts.
Gollenberg, Selevan)

Delayed puberty onset in boys with blood Pb ≥5 µg/dL. Puberty determined by Tan- Hauser (2008)
ner genital staging and testicular volume; effects not significant for pubic hair staging.

Girls 8-16 years of Crosssectional
age; n=1,235

Crosssectional

Prospective Delayed puberty onset in boys with blood Pb ≥5 µg/dL. Puberty measures differed Williams (2010) (sameby testicular volume and Tanner genital and pubic hair staging.
population as Hauser)

Reference

Abbreviations: NHANES: National Health and Nutrition Examination Survey.

Epidemiological studies of Pb exposure and puberty are listed by decreasing cohort size and grouped together for overlapping or shared study groups.

EffectNo effect

EffectEffectEffectNHANES III
EffectBoys 8-9; n=489

Chapaevsk, Russia
EffectBoys 11-12; n=481

Table 8.3: Studies of biomarkers of puberty associated with low-level Pb exposure used to develop conclusions
Relevance
Study
Study
to
Key Reproductive/Developmental Findings
Description
DesignConclusions

Reproductive
Effects

NTP Monograph on Health Effects of Low-Level Leadbreast development in 17-year-old girls among threegroups: two study groups with blood Pb levels of 1.8
and 2.7 µg/dL and a reference group with blood Pbof 1.5 µg/dL. However, a direct comparison of breaststage by blood Pb levels was not reported, and thedelay in breast stage was significant only whencomparing the study group with mean blood Pb of
1.8 µg/dL to the reference group. One of the eightstudies 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 etal. 2010). In a paired cross-sectional and follow-up
prospective study, blood Pb ≥5 µg/dL was associatedwith 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 inareas with higher blood levels (1.8-2.7 µg/dL) compared to a reference group (1.5 µg/dL), although theauthors 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 ofpuberty such as reduced prostate weight and delay invaginal 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 Pbfrom 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
93

Reproductive
Effects

at menarche and Tanner developmental staging ofbreasts) have been reported in cross-sectional studies of girls, although there is no single measure thatis consistently associated with blood Pb levels in all
analyses. For boys, a Pb-related decrease in testicularvolume was observed in all four publications, suggesting that testicular volume may be a reliable indicatorof 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 oflimited evidence that delayed puberty is associatedwith blood Pb levels <5 µg/dL is based on the fourstudies (three in girls and one in boys) that reportdelay in markers of puberty associated with blood Pblevels <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 hairstage 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 Tannerpubic hair and breast stages. Age at menarche wasalso 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 withblood 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 yearsof age with blood Pb>10 µg/dL in Egypt. Staessen etal. (2001) reported significant (p=0.04) differences inan association between maternal blood Pb and heightor weight through 10 years of age (Lamb et al. 2008).
The data from prospective studies (see Table 8.4 andPostnatal Growth section of Appendix E: Reproductive and Developmental Effects) in two groups support an association between higher blood Pb levels inchildren and lower subsequent growth (Greene andErnhart 1991, Rothenberg et al. 1993, Rothenberg etal. 1999). Numerous cross-sectional studies report anassociation between higher blood Pb in children andsmaller 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 to15 µg/dL) and lower height or other indicators of postnatal growth in children from 1 to 16 years of age. Thisstrong evidence for an association between growthand concurrent blood Pb is based on exposure datathat is largely outside the relevant time window – therelevant timing of Pb exposure to effect growth is during or before the growth that results in differencesin height. Therefore, the conclusion of sufficient evidence that blood Pb <10 µg/dL in children is associatedwith decreased growth is based on the combinationof strong support from the cross-sectional studies andthe 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 andpostnatal 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
8.3.2 Postnatal Growtheffect of maternal blood Pb on head circumference,
There is limited evidence that maternal Pb <10 µg/dL but not on height or weight, in 6- to 12-month-olds
is associated with decreased head circumference in in Albany, NY. Maternal blood Pb was not relatedchildren up to 4 years of age and sufficient evidence to height or weight in children from 1 to 10 years
that concurrent blood Pb <10 µg/dL in children is of age in the Yugoslavia Prospective Study (Lamb etassociated with decreased postnatal growth. Pro- al. 2008). Data from the Cincinnati Pb study support
spective studies in two groups (Rothenberg et al. 1993, a combined effect of maternal blood Pb as well as
Rothenberg et al. 1999, Schell et al. 2009) report an concurrent blood Pb levels in the children; height atinverse association between maternal blood Pb and 15 months was decreased only in children with blood
head circumference, and one study reports the lack of Pb >3.4 µg/dL that also experienced maternal blood

Reproductive
Effects

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 therest being cross-sectional studies. The determinationof 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 ofpuberty in both males and females lends weight to theevidence 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 conclusionof limited evidence for delayed puberty at blood Pb<5 µg/dL is supported by two of the studies (Selevan etal. 2003, Wu et al. 2003) that use the NHANES III data
to examine puberty onset in girls from 8-16 years ofage, 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 insexual 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 specificconclusions on sexual maturation.

94

NTP Monograph on Health Effects of Low-Level Lead

95

NHANES II
EffectNHANES III
EffectEffectCrosssectional
Crosssectional

Crosssectional

Girls 8-16 years ofage; n=600-805 perrace/ethnicity

Children 0.5-7 yearsof age; n=2695
Mexican-Americans
age 5-12; n=1,454

Crosssectional

Children 1-7 years
old; n=4,391

Children at 4 years of Crossage; n=156-175
sectional

Yugoslavia Prospective Study
No effect
Children birth, 1, 4, 6, Prospective
and 10 years; n=309

Children 0.5-4 year; n Prospective=119-199 per sample

Mexico City Prospective Study
EffectChildren 0.5-1 years; Prospective
n=50-111 per sample

Cincinnati Pb Study
EffectChildren 15 months Prospectiveof age; n= 260Children ≤33 months Prospectiveof age; n=235
Albany Pregnancy Infancy Pb Study
EffectChildren 0.5-1 years Prospective
old; n=211
Cleveland Pb Study
EffectChildren <5 years; n= Prospective
151-185 per sample

Reference

Concurrent blood Pb (range, 5-35 µg/dL) was inversely associated with height, Schwartz (1986) (same study
weight, and chest circumference.
population as Frisancho)
Concurrent blood Pb (mean: boys, 10.6 µg/dL; girls, 9.3 µg/dL) was inversely Frisancho (1991)
associated with height.

Concurrent blood Pb ≥3 µg/dL was associated with decreased height compared Selevan
to individuals with a blood Pb of 1 µg/dL but not with weight.
(2003)

Concurrent blood Pb (mean, 3.6 µg/dL) was inversely associated with height Ballew (1999) (same study
and head circumference but not with weight.
population as Selevan)

Concurrent blood Pb (<15 µg/dL) was inversely associated with height in Pristina, Factor-Litvak (1999)
but blood Pb (20-40 µg/dL) was not related to height in Titova-Mitrovica, a Pb
smelter town.

Maternal blood Pb was not correlated to height or weight in children from 1 Lamb (2008)
to 10 years of age.

Maternal (36 weeks) and infant (1 year) blood Pb (median, <10 µg/dL) were inversely Rothenberg (1999)
associated with infant head circumference at later ages, up to 4 years of age.

Maternal blood Pb at 36 weeks (median, <10 µg/dL) was inversely associated Rothenberg (1993)
with infant head circumference at 6 and 18 months. Infant blood Pb (1 year) (same study population as
was inversely associated with head circumference at 36 months.
Rothenberg, 1999)

Blood Pb at 6 months of age (10 µg/dL) was related to subsequent head cir- Greene (1991)
cumference (p=0.05) and marginally related to subsequent length (p=0.06) andweight (p=0.08); blood Pb at 1-4 years old was not related to weight, length, headcircumference at 4 years old.

Maternal blood Pb (≥3 µg/dL) was inversely associated with infant head cir- Schell (2009)
cumference at 6 and 12 months, but not with length or weight.

Current blood Pb was inversely associated with length at 33 months of age in Shukla (1991)
children with higher blood Pb (>10.8 µg/dL) from 3 to 15 months of age.

Concurrent blood Pb (>3.4 µg/dL) in children was inversely associated with growth Shukla (1989) (same study
rate (length) at 15 months of age in children of mothers with Pb >7.7 µg/dL.
population as Shukla, 1991)

Table 8.4: Studies of postnatal growth associated with low-level Pb exposure used to develop conclusions
Relevance
Study
Study
to
Key Reproductive/Developmental Findings
Description
DesignConclusions

Reproductive
Effects

NTP Monograph on Health Effects of Low-Level Lead

96

NTP Monograph on Health Effects of Low-Level Lead

Study
DesignKey Reproductive/Developmental FindingsChildren aged 7-15 in CrossPoland; n=899
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.
Concurrent blood Pb was inversely associated with height, weight, and headChildren aged 2-12 in Crosscircumference. The height-Pb relationship was not statistically different between
Dallas; n=764 (1980s: sectionalchildren in 1980s (mean=24.8 µg/dL) or 2002 (mean= 1.8 µg/dL).
n=404; 2002: n=390)
Concurrent blood Pb (11.5 µg/dL) was inversely associated with height andChildren 7 years old Crosspositively associated with head circumference.
in Mexico n=602
sectional
Concurrent blood Pb (mean, 12.3 µg/dL) was inversely associated with height,
Children aged 6-9 in Crosshead circumference, and chest circumference.
Greece; n=522
sectional
Concurrent blood Pb (median, 3 µg/dL) was inversely related to height but not
Boys 8-9 in Russia;
Crosswith weight or BMI.
n=489
sectional
Concurrent blood Pb inversely associated with height, weight in 13-year-old boys
Children 11-13 years Cross(mean, 8.5 µg/dL) and height in 12-year-old girls (mean, 7 µg/dL), not children ofold in Italy; n=418
sectional
other ages.
Infantblood Pb (6.8 µg/dL) at 1 month and maternal bone Pb (tibia 10.1 µg/g)
12-month-old infants Prospective &in Mexico City; n=329 cross-sectional were inversely related to infant weight and/or weight gain through 12 monthsof age.
Children 6-9 years old Cross-sectional Concurrent blood Pb (mean, 3.75 µg/dL) was not correlated to height, weight,
or arm circumference for age.
in Malaysia; n=268
Children aged 7 and Prospective & Dentin Pb level of teeth lost before age 7 was inversely associated with BMI at age
20 in USA; n=236
cross-sectional 7 and BMI at age 20, not weight or height. No association between growth & bonePb at age 20
Concurrent blood Pb was inversely associated with height, weight, and headChildren 1-10 years Crosscircumference.
old in Dallas; n=139 sectional
Concurrent blood Pb (mean, 2.4 µg/dL) was inversely associated with heightChildren 5-13 years Crossand arm length but not with weight or BMI.
old in Korea; n=108 sectional
Mean height and weight did not differ as a percentage of median for age and sex
Children 10-13 years Crossfor individual above and below blood Pb of 10 µg/dL in children with mean Pb of
old in Egypt; n=41
sectional
9.46 µg/dL.
Concurrent blood Pb (mean, 6.4 µg/dL) was inversely associated with headChildren age 18-36 Crosscircumference.
mo in Omaha; n=21 sectional

Study
Description

Stanek (1998)

Tomoum (2010)

Min (2008)

Little (1990)

Kim (1995)

Zailina (2008)

Sanin (2001)

Vivoli (1993)

Hauser (2008)

Kafourou (1997)

Kordas (2004)

Little (2009)

Ignasiak (2006)

Reference

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.

EffectNo effect

EffectEffectEffectNo effect

EffectEffectEffectEffectEffectEffectEffectRelevance toConclusions

Table 8.4: Studies of postnatal growth associated with low-level Pb exposure used to develop conclusions (continued)

Reproductive
Effects

NTP Monograph on Health Effects of Low-Level Leadprospective studies as well as a few cross-sectional
analyses that support an association with blood Pblevels <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 heightand higher concurrent blood Pb levels (see Table 8.4
and Postnatal Growth section of Appendix E: Reproductive and Developmental Effects). The data are notcompletely consistent, because Zailina et al. (2008)
did not find a correlation between blood Pb in a studyof 269 children in Malaysia in the relative height forage, 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 witha small sample size suggests a larger magnitude ofeffect, it is less informative when studies with a small
sample size such as the data from Egypt, fail to findan 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, butblood Pb levels from 20 to 40 µg/dL in Titova-Mitrovica (a Pb smelter town) were not associated withheight (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 ofage, but the study did not report data on height.

Summary of Support for Conclusions

Animal data support a decrease in postnatal growthrate associated with prenatal and developmental Pb
97

Reproductive
Effects

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 forheight 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 headcircumference 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) andheight. Additional measures of growth such as headcircumference, arm or leg length, and weight werealso related to blood Pb in some studies, but these
endpoints were less widely reported, and weight isless consistently associated with blood Pb. Data fromNHANES 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 relationshipbetween height (but not weight) and blood Pb was
further supported by studies using data from NHANESIII on children 1-7 years of age with mean blood Pbof 4 µg/dL (Ballew et al. 1999) and in girls 8-16 yearsof 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 Polishchildren 7-15 years of age (8 µg/dL mean blood Pb
and n=899) (Ignasiak et al. 2006); height, weight, andhead 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); heightin 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 ofage in Greece (12 µg/dL mean blood Pb; n=522) (Kafourou et al. 1997); and height in boys 8 and 9 yearsof 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 thestudies. However, parental height is considered inReproductive
Effects

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 threeavailable 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 threeavailable prospective studies addressing the potential
association between maternal blood Pb and heightor 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 thatinvestigated 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 thatblood 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 thenumber 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 indicatorsof postnatal growth. However, cross-sectional studies have considerable limitations because they only
provide concurrent blood Pb measurements and lackdata on cumulative Pb or Pb exposure at earlier time
points that may be critical for growth. The consistencyof effects across studies, among multiple populations
in both males and females, lends weight to the evidence that decreased growth indicated by reducedheight (and, to a lesser extent, other measures) is
associated with blood Pb. The conclusion of sufficientevidence 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 thefour 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 forparental height, which is a known important predictor
for postnatal growth, so there is inadequate data toevaluate an association with blood Pb levels <5 µg/dL.
Data from the Cincinnati Lead Study suggest thatgrowth may depend on a combination of gestationaland early-childhood exposure, so effects may only beobserved in children of mothers with elevated blood
Pb that subsequently experienced elevated blood Pblevels 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 twogroups. The NTP’s conclusions on an inverse association between blood Pb and growth are in line with the2007 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 thanthe epidemiological data relating to growth.

98

NTP Monograph on Health Effects of Low-Level Lead

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, andan 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 to68 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 associatedwith 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 thisgroup the evidence is not consistent, because several
studies did not find adverse sperm effects at blood Pblevels <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Effect

EffectNo effect

No effect

EffectEffectNo effect

EffectEffectEffectSaaranen (1987)

Jockenhovel (1990)

Lancranjan (1975)

Meeker (2008)

Xu (1993)

Telisman (2007)

Male Pb workers in
Croatia; n=146

Cross-sectional Blood Pb levels were associated with decreased sperm count (blood Pb Telisman (2000)≥~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).

Male smelter workers in Cross-sectional Sperm concentration was significantly reduced in Pb workers (mean blood Pb, Mahmoud (2005)
Belgium; n=159
31 µg/dL; n=68) compared to hospital staff (referents; median, 3.4 µg/dL; n=91).

Male Pb workers in
Europe; n=486

Bonde (2002)

Blood Pb levels (mean, 22.8 µg/dL) were associated with decreased sperm count Alexander (1998)
and concentration, but not with motility or morphology.

Male employees; n=81 Retrospectiveof 119 original

Cross-sectional Blood Pb (>50 µg/dL) was associated with lower sperm count and density, but notwith 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.
Men at clinic in Croatia; Cross-sectional Blood Pb (median, 4.9 µg/dL) was associated with increased percentages ofn=240
pathological sperm, wide sperm, round sperm, but not with sperm count, density, viability, motility, or other measures, in men at fertility clinic or donors for
artificial insemination.
Men at infertility clinic in Cross-sectional Blood Pb (mean, 8 µg/dL) and semen plasma Pb (mean, 1.27 µg/dL) were not corChina; n=221
related with sperm density, motility, viability, morphology, or semen volume in men
screened for infertility.
Men at fertility clinic in Cross-sectional Blood Pb (median, 1.5 µg/dL) was associated with a greater odds ratio for belowMichigan; n=219
reference sperm concentration but not with count, volume, motility, or morphology, for men at an infertility clinic.
Male Pb workers and Cross-sectional Men with Pb exposure (blood Pb ≥41 µg/dL; n=100) showed reduced sperm motility
referents; n= 200
and semen volume and increased abnormal morphology compared to technicians(n=50) and referents (n=50).
Men at fertility clinic in Case-control
Blood Pb not reported; grouped by sperm concentration, motility, and percent
Germany; n=190
normal morphology, there were no differences in semen Pb among 172 infertile
men and 18 referents.
Men at fertility clinic in Cross-sectional Blood Pb not reported; sperm density, motility, and morphology did not differ by
Finland; n=188
semen Pb above and below 0.2 µg/dL.

Blood Pb levels (>40 µg/dL) were associated with decreased sperm concentra- Alexander (1996b)
tion, but not with motility or morphology.

Reference

Retrospective

Male employees;
n=119

Table 8.5: Studies of sperm and semen parameters associated with low-level Pb exposure used to develop conclusions
Relevance to Study Description
Study
Key Reproductive/Developmental Findings
Conclusions
DesignSmelter Employees, British Columbia

Reproductive
Effects

NTP Monograph on Health Effects of Low-Level Lead

99

100

NTP Monograph on Health Effects of Low-Level Lead

Study
DesignKey Reproductive/Developmental Findings

Male metal workers in Cross-sectional Percent motile sperm was decreased in workers with high blood Pb (>40 µg/dL; Kasperczyk (2008)
Poland; n=63
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.

EffectHernandez-Ochoa(2005)

Lerda (1992)

Hsu (2009)

Benoff (2003a)

Robins (1997)

Naha (2007)

Assennato(1986, 1987)

Naha (2005)

Naha (2006)

Reference

Men at fertility clinic in Cross-sectional Sperm motility, concentration, and morphology did not differ by blood Pb (mean, Mendiola (2011)
Spain; n=60
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).

Men in IVF clinic in New Cross-sectional Blood Pb not reported; semen plasma Pb (mean, 40 µg/dL) was associated with
York; n=96
decrease in sperm motility, concentration, morphology, other sperm measures, anddecreased IVF fertilization.
Male battery workers in Cross-sectional Blood Pb levels (mean, 40 µg/dL) were associated with increased percent abnormal
Taiwan; n=80
sperm and sperm head morphology, and DNA denaturation, but not with sperm
count, semen volume, or motility.
Male battery workers in Cross-sectional Male Pb battery workers with blood Pb ≥49 µg/dL (n=38) show reduced sperm
Argentina; n=68
motility and semen volume and increased abnormal morphology compared toreferents (n=30).
Men living near a smelter Cross-sectional Blood Pb (mean, 9 µg/dL) was not associated with sperm parameters. Sperm Pb
in Mexico; n=68
(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.

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)
Male battery workers in Cross-sectional Occupational Pb exposure (blood Pb ≥~14 µg/dL; n=80) was associated with
India; n=120
decreased sperm count, density, motility, semen volume, increased abnormal morphology, and other sperm changes compared to referents (blood Pb 7 µg/dL; n=40).
Male Pb workers in Cross-sectional Blood Pb levels were associated with decreased sperm count in 39 employees of
Italy; n=120
a Pb battery plant (mean Pb, 61 µg/dL) and 81 workers at a cement plant (mean,
18 µg/dL).
Male paint workers in Cross-sectional Occupational Pb exposure (mean blood Pb, ≥50 µg/dL; n=50) was associated with
India; n=100
decreased sperm count, motility, semen volume, and increased abnormal morphology and DNA hyploidy, compared to non-occupationally exposed workers (n=50).
Male battery workers in Cross-sectional Sperm count, density, and motility were not associated with blood (mean Pb, 53 µg/dL)
England; n=97
or semen Pb (mean Pb, 9.6 µg/dL). Percent of normal sperm was reduced at p=0.06.

Male Pb workers inIndia; n=130

Study Description

Blood Pb:
No effect;
Semen Pb:
EffectBlood Pb:
No effect;
Semen Pb:
EffectEffectEffectEffectNo effect

EffectEffectEffectEffectRelevance toConclusions

Table 8.5: Studies of sperm and semen parameters associated with low-level Pb exposure used to develop conclusions (continued)

Reproductive
Effects

101

Reference

A firearms instructor in Case Report
New York

Cullen (1984)

Benoff (2003b)

Braunstein (1978)

Viskum (1999)

Chowdhury (1986)

Plechaty (1977)

Noack-Fuller (1993)

A case report of increases in sperm density and total sperm count and decreases in Fisher-Fischbein
abnormal morphology in parallel with decreasing blood Pb with chelation therapy (1987)
in a 41-year-old.

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 nooccupational Pb exposure.
Men in Connecticut;
Cross-sectional No correlation between semen Pb (mean, 5.9 µg/dL) and sperm count, density, or
n=21
semen protein in medical students and technicians; unclear if blood Pb (13.1 µg/dL)
effect on sperm examined.
Male Pb workers in India; Cross-sectional Men with occupational Pb exposure (average blood Pb, 42.5 µg/dL; n=10) had
n=20
lower sperm count, decreased percent motile sperm, and increased percent
abnormal sperm compared to referents (n=10).
Male battery workers in Cross-sectional Decrease in blood Pb (median, 42-19 µg/dL) was associated with improved
Netherlands; n=19
number of motile sperm and penetration in men undergoing treatment to lower
blood Pb.
Men with high Pb and Cross-sectional Men with chronic high occupational Pb exposure (mean blood Pb, 39 µg/dL; n=10)referents; n=19
did not differ from referents (Pb=16 µg/dL; n=9) in sperm volume, motility, or percent
abnormal; two men with highest Pb demonstrated peritubular fibrosis, oligospermia, and Sertoli cell vacuolization.
Male semen donors in Cross-sectional Blood Pb not reported; semen plasma Pb was associated with sperm motilNew York; n=15
ity, premature acrosome loss, and fertilization rate in IVF but not with sperm
concentration.
Men with Pb toxicity in Case-series
Two of 7 men with occupational Pb intoxication had no sperm; 2 had reduced
Connecticut; n=7
sperm count; 4 of the 5 with sperm had reduced sperm motility.

Epidemiological studies of Pb exposure and sperm effects listed by decreasing cohort size and grouped together for overlapping or shared study groups
Abbreviations: 8-OHdG, 8-hydroxydeoxyguanosine; IVF, in vitro fertilization.

EffectEffectEffectEquivocal

EffectEffectNo effect

EffectMen in Germany; n=22

Key Reproductive/Developmental Findings

No effect

Study
DesignEquivocal

Men in China; n=56

Study Description

Cross-sectional Blood Pb not reported; semen plasma Pb (mean, 0.78 µg/dL) was not correlated Xu (2003)
with sperm count, density, motility, morphology, or viability; semen Pb was associated with 8-OHdG in men (n=56; group characteristics not reported).
Men at infertility clinic in Cross-sectional Blood Pb not reported; authors state inverse correlation between Pb and flagel- Slivkova (2009)
Europe; n=47
lum ball, and that no correlation was detected between pathological changes
and elements.
Men in andrology clinic Cross-sectional Blood Pb was elevated (mean, 7.2 µg/dL) in men with <40% sperm motility com- Chia (1992)
in China; n=35
pared to men with >40% sperm motility (mean blood Pb, 5.1 µg/dL) .

No effect

Relevance toConclusions

Table 8.5: Studies of sperm and semen parameters associated with low-level Pb exposure used to develop conclusions (continued)

Reproductive
Effects

NTP Monograph on Health Effects of Low-Level Lead

Reproductive
Effects

with adverse effects on sperm is based on the limited in the Naha et al. (2005) study had the lowest mean
number of studies with evidence of effects at these blood Pb level (15 µg/dL compared to 48-50 µg/dL)
lower blood Pb levels, the lack of consistency in the in a series of papers from the same group (Naha et al.
sperm data from men attending infertility or IVF clin- 2005, Naha and Chowdhury 2006, Naha and Manna
ics, and the uncertainty in using this patient group to 2007) that consistently report effects on sperm count,
extrapolate to other groups. There are few studies of motility, semen volume, and abnormal morphology
the relationship between sperm and blood Pb in the in all Pb-exposed groups working in paint and battery
general population.
factories compared to a reference group not workTwelve occupational studies report adverse ing in the factory. A cross-sectional study of 68 Pb
effects on sperm at blood Pb levels of 15-50 µg/dL smelter workers reported reduced sperm concentrausing mean blood Pb levels of occupationally exposed tion in the Pb workers (mean blood Pb, 31 µg/dL)
men or blood Pb levels of workers categorized by compared to 91 hospital personnel (mean blood
blood Pb levels. Lower sperm counts or concentra- Pb, 3.4 µg/dL) (Mahmoud et al. 2005). De Rosa ettion are associated with the following blood Pb con- al. (2003) reported lower sperm motility, viability,
centrations: approximately 15 µg/dL (estimated from penetration, and velocity in 85 tollgate workers withgraphs presented) in Naha et al. (2005); 20 µg/dL mean blood Pb of 20 µg/dL compared to referents
in De Rosa et al. (2003); approximately 25 µg/dL with mean blood Pb of 7 µg/dL, and linear regres(estimated from graphs presented) in Telisman et al. sion for sperm count was also significant. The occu(2000); 31 µg/dL in Mahmoud et al. (2005); ≥40 µg/dL pational studies of Naha et al. (2005), Telisman et al.
in Alexander et al. (1996b); ≥44 µg/dL in Bonde et al. (2000), Mahmoud et al. (2005), De Rosa et al. (2003)(2002); 48 µg/dL in Naha et al. (2006); and 50 µg/dL in and Hsu et al. (2009) report adverse sperm effects
Naha et al. (2007). Sperm motility is reduced at blood down to blood Pb levels of 15-31 µg/dL.
Pb levels of 20 µg/dL in De Rosa et al. (2003); 41 µg/dL
A closer examination of the reference groups inblood Pb in Lancranjan et al. (1975); 49 µg/dL blood the above studies adds to evidence for a thresholdPb in Lerda (1992); 53 µg/dL blood Pb in Kasperczyk closer to 20 µg/dL for adverse effects on sperm thanet al. (2008); and 15 µg/dL, 48 µg/dL, and 50 µg/dL a threshold of 40 µg/dL; however, the data are notin three studies already listed above for decreased consistent. Of the seven studies that report the higher
sperm count (Naha et al. 2005, Naha and Chowdhury threshold, five rely on internal reference groups with
2006, Naha and Manna 2007). Five of the studies sup- blood Pb levels >10 µg/dL (Lerda 1992, Alexander et al.
port effects in men with mean blood Pb levels from 1996b, Naha and Chowdhury 2006, Naha and Manna
15 to 31 µg/dL. Hsu et al. (2009) reported a threshold 2007) or fail to report blood Pb levels in the reference
for increased abnormal sperm morphology at blood group (Lancranjan et al. 1975), so these studies have
Pb levels ≥45 µg/dL in Pb battery workers, relative limited ability to detect effects in the lower concento workers with blood Pb <25 µg/dL. However, the tration range. Among the six studies with a reference
extent of DNA denaturation per cell was significantly group <10 µg/dL, four reported effects on sperm atincreased at lower blood Pb levels, among workers mean blood Pb levels from 15 to 31 µg/dL: ~15 µg/dL
in both the mid-Pb group (25-45 µg/dL) and high-Pb in Naha et al. (2005), 20 µg/dL in De Rosa et al. (2003),
group (>45 µg/dL) workers (Hsu et al. 2009). A similar ~25 µg/dL in Telisman et al. (2000), and 31 µg/dL inthreshold of approximately 25µg/dL was associated Mahmoud et al. (2005). The other two studies (Bondewith decreased sperm count relative to workers with et al. 2002, Kasperczyk et al. 2008) report effects inblood Pb <10 µg/dL in a study of 146 industrial work- men with blood Pb levels >40 µg/dL and not in men
ers in which Pb was dichotomized into six groups with blood Pb <40 µg/dL. While adjustment for poten(n=25 per group) with mean blood Pb levels of <10, tial confounders is not described in several of the stud12, 25, 35, 42, and 58 µg/dL (estimated from Figure 4 ies, the studies of Telisman et al. (2000), Mahmoud etin Telisman et al. (2000)). Naha et al. (2005) reported al. (2005), and Bonde (2002) are all adjusted for faceffects on sperm in Pb workers with mean blood Pb tors known to effect sperm count or function, such asof approximately 15 µg/dL (estimated from data pre- age and period of abstinence, so a lack of adjustment
sented in a graph; n=10 per group) compared to work- does not explain the difference in the effect levels
ers with mean blood Pb of 7 µg/dL. The Pb workers identified in the studies.
102

NTP Monograph on Health Effects of Low-Level LeadNTP Monograph on Health Effects of Low-Level Leadwere all improved in 19 Danish Pb-workers treatedfor 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 etal. 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 apotential biomarker of Pb exposure related to sperm
parameters. In studies that report both blood andsemen Pb, there is some support that both measuresof 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 havereported a significant association of sperm parameterswith semen Pb (and not blood Pb) (Hernandez-Ochoa
et al. 2005, Mendiola et al. 2011) or blood Pb (andnot 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 nolonger 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
103

Reproductive
Effects

In addition to the occupational Pb exposurestudies, there are a number of studies of individuals attending infertility or IVF clinics. Three of thesestudies reported an association between blood Pblevels <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 withmen donating for artificial insemination, blood Pb
in the range of 1.1-14.9 µg/dL was associated withincreasing percentage of pathologic sperm and wide
sperm, with no effect on motility, viability, count, orother measures (Telisman et al. 2007). In a studyof 219 men attending infertility clinics in Michigan,
blood Pb was marginally (p-trend=0.07) related tosperm 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, 1.11.5 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 populationthat were not patients at infertility clinics, and theavailable 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 sampledfrom 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

Reproductive
Effects

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 therange of 30-45 µg/dL suggested by the 2006 EPA and2007 ATSDR documents.

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 theanimal 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 durationof 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 bysix 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 associatedwith adverse effects on sperm or semen is based onthese studies and specifically the five studies thatreport 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 theseeffects is unclear.
Several studies of men recruited from IVF orinfertility 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 notconsistent. One challenge in determining the lower
limit is that much of the data come from occupational studies in which the mean blood Pb level is30-40 µg/dL. Also, as discussed above, there are few
studies of effects in the general population, and manystudies have a low ability to detect effects associatedwith lower blood Pb levels, because occupational
studies generally do not include many men withlower 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 humandata were located that examine effects of early ordevelopmental exposure on sperm parameters asadults. The NTP’s conclusion of sufficient evidence
that blood Pb levels ≥15 µg/dL are associated withadverse effects on sperm or semen extends the

There is sufficient evidence that paternal blood Pblevels ≥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 measuresof reduced fertility. Four studies reported increased
time to pregnancy or decreased odds of conception
over a given time (fecundability) in men with blood Pblevels 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 thatreported 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 ofstudies 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 reportthat maternal blood Pb levels are not associatedwith 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 thisstudy 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 andmen recruited from infertility or IVF clinics may represent a susceptible subpopulation, and the effects
observed in this patient population should be applied104

NTP Monograph on Health Effects of Low-Level Lead

8.3.4 Fertility/Delayed Conception Time

NTP Monograph on Health Effects of Low-Level Leaddecreased 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 reportingto the New York State Heavy Metals Registry withmore than 5 years of Pb work had a reduced fertility rate relative to bus drivers or Pb workers with <5years of occupational exposure; however, blood Pblevels alone were not related to fertility (Lin et al.
1996). There are also four retrospective studies thatreport no association between time to pregnancy orodds 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 withblood 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 categorizedby 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 timeto 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 notassociated with time to pregnancy in a study of 80
women in New York. Sallman et al. (1995) did notdetect a relationship between odds of conception
and maternal occupational blood Pb levels in a retrospective study of 121 women in which exposure wasestimated 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 apotential 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
105

Reproductive
Effects

with caution to the general population. There are notenough 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 formen at blood Pb levels of 10-46 µg/dL, and four otherstudies 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 menmonitored for Pb exposure by the Finnish Institute ofOccupational 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 formen with blood Pb ≥40 µg/dL (p=0.012) in a studyof 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. Ina 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 etal. 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 ateven 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Reproductive
Effects

et al. 1990), but not in a third study (Umeyama etal. 1986). Benoff et al. (2003a, 2003b) reported aninverse 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 fertilizationor pregnancy outcome, although blood Pb was associated with decreased OR for fertilization (Al-Saleh etal. 2008a). In a small study (n=9 women) that did notreport blood Pb, follicular Pb was significantly higher
from IVF patients that did not get pregnant than fromwomen that did get pregnant (Silberstein et al. 2006).
Several studies of couples attending IVF or infertility clinics report an association between blood Pblevels and a decrease in some measure of fertility (e.g.,
fertilization or embryo quality). Results from studiesof men or women reporting to IVF or infertility clinics should be interpreted with caution because they
may represent a sensitive subpopulation. In a studyof 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 increasein maternal blood Pb (Bloom et al. 2010, Bloom et al.
2011b). Increased blood Pb levels in the men (n=15;
mean blood Pb, 1.5 µg/dL) were also associated with adecreased 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 ina 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 etal. 2005). In a case-control study of women recruitedat 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 womenthat 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).

106

NTP Monograph on Health Effects of Low-Level Lead

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 miceor 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 reportincreased time to pregnancy or reduced fertility at
blood Pb levels from 10 to 46 µg/dL. The conclusionof sufficient evidence that blood Pb levels ≥20 µg/dL
are associated with delayed conception time is basedon 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 notsupport an association between paternal blood Pblevels 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 ofinfertility 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 conclusionof 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, andthe lack of a significant association with blood Pbreported in some studies on time to pregnancy. The

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 timeto 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 effectof 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 notdescribed 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 notobserve an association between blood Pb in men andtime to pregnancy.

8.3.5 Spontaneous Abortion

NTP Monograph on Health Effects of Low-Level Lead

107

Reproductive
Effects

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 fromcase series and epidemiologic studies in the 19thand 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 otherbiological monitoring data, so it is unclear whatblood Pb level the data would support. Although >20
studies published since the 1970s address maternalor paternal Pb exposure and spontaneous abortion(see Spontaneous Abortion section of Appendix E:
Reproductive and Developmental Effects), many lackbiological 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 reportan 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 riskof 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 spontaneousabortion is based principally on the Borja-Aburto etal. (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 associatedwith 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 butlack blood Pb data (Beckman and Nordstrom 1982,
Al-Hakkak et al. 1986). Two other studies havereported no association at similar blood Pb levels(i.e., >25µg/dL Selevan et al. 1984, Alexander etal. 1996a)). The conclusion of limited evidence thatpaternal 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 etal. (1999) prospective nested case-control study ofwomen in Mexico. The study reported evidence fora 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 ofpregnancy of 5-9, 10-14 and ≥15 µg/dL comparedto <5.0 µg/dL in the reference group (Borja-Aburto
et al. 1999). The analysis highlighted the carefulmatching of the timing of exposure measurementsin the 35 cases with controls and was adjusted for arange 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

detect an association between spontaneous abortionand 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 spontaneousabortions. 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 instudy 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).

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 noblood 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 apotential problem in study performance or reporting.
Several studies with mean blood Pb levels from 4 to16 µg/dL reported no association between maternal
blood Pb levels and spontaneous abortion. Maternal
blood Pb during the first trimester was not associatedwith spontaneous abortion at mean blood Pb levels of
4 µg/dL in a recent prospective study of 351 womenin Iran (Vigeh et al. 2010). A prospective study ofwomen 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 associatedwith 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 anassociation with paternal Pb exposure. In a retrospective analysis of blood Pb measurements in men occupationally exposed to Pb restricted to within 1 yearof 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 withblood 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 thestudies lack blood Pb data (Beckman and Nordstrom
1982, Al-Hakkak et al. 1986). Two additional occupational studies that include blood Pb levels did not

Animal data were not located that support an association between Pb and spontaneous abortion, althoughprenatal exposure to Pb has been associated withdecreased litter sizes, decreased pup survival, andincreased 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 humanstudies 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.

108

NTP Monograph on Health Effects of Low-Level Lead

Summary of Support for Conclusions

The inconsistency of the results contributes to thedetermination 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 bothsupportive 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 lackof 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

NTP Monograph on Health Effects of Low-Level Lead

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 the10th percentile for a given gestational age), lower birthweight (evaluated as a continuous variable), low birthweight (<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 growthis 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 Pblevel of 2.1 µg/dL (Zhu et al. 2010), and a numberof 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 etal. 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). Thereis also one prospective study (Sowers et al. 2002)
and several cross-sectional studies that report noassociation between maternal blood Pb and reduced
fetal growth at blood Pb levels <10 µg/dL and similar results at higher blood Pb levels. Although theresults are not entirely consistent across studies, thesupporting evidence outlined above with maternal
or umbilical cord blood Pb levels <10 µg/dL frommultiple prospective, retrospective, and crosssectional studies provides sufficient evidence atmaternal blood Pb levels <10 µg/dL are associatedwith 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) andlower birth weight in such a large cohort from a study
109

Reproductive
Effects

There is inadequate evidence to evaluate the potential association between blood Pb at any level andincidence of stillbirth. Few studies investigate thepotential association between Pb exposure andstillbirth, and only a handful have blood Pb or otherbiological monitoring data (see Stillbirth sectionof 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, aprospective 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 atdelivery) 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 (meansof 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 associatedwith previous history of stillbirth (OR=1.0 (95% CI: 0.6,1.5)). There are some examples of Pb-associatedincreases in stillbirth in animal literature at very highdoses (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 thisassociation 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.

Reproductive
Effects

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 ofstudies from a population in Mexico demonstratingthat maternal bone Pb is associated with lower birthweight, birth length, and head circumference. Thesestudies provide limited evidence that maternal bone
Pb levels >15.1 µg/g (tibia Pb) are associated with
reduced fetal growth. Unfortunately, the evidence toevaluate the potential association between maternalbone Pb and low birth weight is restricted to a single
group. All five of the studies that include maternalbone Pb measurements report a significant association between increased maternal bone Pb levels andlower fetal growth, but they are all studies of womenattending one of three hospitals in Mexico City from1994 to 1995. There is inadequate evidence thatpaternal blood Pb at any level is associated with
reduced fetal growth, because few studies of birthweight or related endpoints have included paternal
Pb exposure data, and the available studies do notsupport 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 effectof 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 birthweight (Gundacker et al. 2010). Maternal blood Pblevels (mean, 7.5 µg/dL) of 861 women from theCincinnati Lead Study at 16-28 weeks of gestation(from the second trimester into the start of the third
trimester) were associated with decreased birthweight (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 thefirst prenatal visit in women (n=185) from the Cincinnati Lead Study were correlated with lower birthweight (Dietrich et al. 1987). Maternal blood Pb≥10 µg/dL during pregnancy in women in the California Pb surveillance program (n=262) was associatedwith 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 birthweight (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 withlower 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 theconclusions 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 maternalage, race, parity, smoking, drug abuse, infant sex,
and participation in financial assistance as a measureof socioeconomic status (Zhu et al. 2010). Maternal
blood Pb (mean, 1.1 µg/dL) sampled at 12, 20, and28 weeks of gestation, and the change in blood Pblevels 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 theclear 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 thefive studies that support an effect of maternal blood
Pb levels <10 µg/dL and the one that does not.
Additional studies that sampled maternal orumbilical 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 withhigher mean blood Pb levels (i.e., >10 µg/dL) are notdescribed 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 atdelivery 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 theypresent similar results, but all studies are includedin the Fetal Growth and Lower Birth Weight sectionof Appendix E: Reproductive and Developmental
Effects. Mean maternal blood Pb levels at delivery of
2-13 µg/dL were associated with lower birth weightin 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

110

NTP Monograph on Health Effects of Low-Level LeadNTP Monograph on Health Effects of Low-Level Leadal. 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 etal. 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 theadverse effect of Pb (Cantonwine et al. 2010b), andfolate may decrease the adverse effect of Pb (Kordas
et al. 2009). In a study of 100 mother-infant pairs inFrance, maternal and infant hair Pb levels were notassociated with small for gestational age (Huel et al.
1981).
Several studies have investigated the association
between placental Pb levels and fetal growth. Twostudies (n=53 and n=79, respectively) reported a
relationship between higher placental Pb and lower
birth weight, shorter length, and/or smaller headcircumference (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 womenfrom 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 ofusefulness 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 bothmeasures, 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 birthweight was associated with both maternal blood Pblevels 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 (54300µg/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 growth111

Reproductive
Effects

program in Taiwan (n=72 low-birth-weight infantsof 1,611 births) (Chen et al. 2006). Mean maternal
blood Pb levels at delivery of 6-10 µg/dL were notassociated with birth weight, birth length, or headcircumference in mother-infant pairs from womenin 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 inmen. Paternal occupational exposure estimated byjob category was associated with low birth weightand 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 weightin 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, althoughmaternal Pb exposure was associated with low birthweight) (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 birthweight was associated with maternal blood Pb levelsin 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 orsmall for gestational age; however, blood Pb levels>25 µg/dL for more than 5 years was associated withincreased relative risk of low birth weight in a studyof workers (n=747) reporting to the New York State
Heavy Metals Registry compared to a reference groupof bus drivers (Lin et al. 1998).
A number of studies of fetal growth include measures of exposure other than blood Pb data. Data fromseveral 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 withlower measures of fetal growth (Gonzalez-Cossio
et al. 1997, Hernandez-Avila et al. 2002, Kordas et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 umbilicalcord 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 Pblevels. 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) andpreterm 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 instudies 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 ordecreased gestational age, and three did not find an
effect of blood Pb (mean, 1-23 µg/dL). The data arealso inconsistent when examined by maternal Pb levels from a specific trimester. Higher maternal bloodlevels (mean, 6-7 µg/dL) in the first and second trimester, but not the third trimester, were associatedwith decreases in gestational age in a prospective
study of 327 women in Mexico City (Cantonwine etal. 2010a). Higher maternal blood levels in the firsttrimester was associated with preterm birth and withdecreases in gestational age in a prospective studyof 348 women with mean blood of 4 µg/dL in Iran(Vigeh et al. 2011). Maternal blood Pb ≥10 µg/dL wasassociated 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
8.3.8 Preterm Birth and Gestational Agetrimesters, but not during the first trimester (JelliffeThere is limited evidence that maternal blood Pb Pawlowski et al. 2006). Higher maternal blood Pblevels <10 µg/dL are associated with preterm birth levels (mean, 8.3 µg/dL) sampled at the first prenaor reduced gestational age, because of inconsistent tal visit in women (n=185) from the Cincinnati Lead
results in studies with low blood Pb levels. Increasing Study were correlated with decreases in gestational
maternal blood Pb levels during pregnancy were asso- age (Dietrich et al. 1987); the results were reported
ciated with preterm birth or reduced gestational age as part of an analysis of neurological data, and thein two prospective studies (Cantonwine et al. 2010a, study group was a subset of women evaluated in a

Reproductive
Effectsor 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, alarge retrospective cohort study, and a number ofcross-sectional studies with maternal or umbilicalcord blood Pb at delivery. Although the results are notentirely consistent across studies, and some studies
report that prenatal blood Pb levels <10 µg/dL are notassociated, the supporting studies provide sufficientevidence that maternal blood Pb levels <10 µg/dL areassociated 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 bya 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 maternalbone 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 asmall 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 wascharacterized 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 the2006 EPA AQCD for Lead (U.S. EPA 2006).

112

NTP Monograph on Health Effects of Low-Level LeadNTP Monograph on Health Effects of Low-Level Leadwere 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 umbilicalcord 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 forpotential 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 riskof 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 toworkers that did not consistently report a blood Pblevel >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 andFetal Mortality Survey in the United States (Savitz
et al. 1989). Occupational exposure in Norway withpossible 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 etal. (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
113

Reproductive
Effects

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 notassociated 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 gestationin 705 women in Camden, NJ, was not associatedwith 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 relationshipwith 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 withPb exposure also have larger sample sizes (n= 705907) than the studies that support an effect of Pb(n=262-348).
Additional studies that sampled maternal orumbilical 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 etal. 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 asmall 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

preterm births and births with premature ruptureof membranes) than in births with normal delivery(Ward et al. 1990, Falcón et al. 2003). However, fourother cross-sectional studies did not find a significant
relationship between placental tissue Pb concentrations and preterm births (Fahim et al. 1976, Ward etal. 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 withmaternal blood Pb levels.
Animal data were not located that support an effectof Pb on preterm delivery, although potentiallyrelated endpoints such as pup survival and birthweight 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 humandata are not consistent for an effect of Pb on preterm birth. Although a number of prospective studies
with maternal blood Pb levels during pregnancy andcross-sectional studies with umbilical cord blood Pblevels at delivery reported an association between
prenatal blood Pb levels <10 µg/dL and preterm birth,the conclusion of limited evidence is based on theinconsistent results and because a large retrospective
study did not find an association between maternal
blood Pb levels and preterm birth. In particular, thelarge 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 etal. 2010). The conclusion of inadequate evidence thatpaternal blood Pb at any level is associated with preterm birth or reduced gestational age is based on asmall 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 gestationalage, 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) andthe 2006 EPA AQCD for Lead (U.S. EPA 2006), in which
the evidence was characterized as inconsistent.
114

NTP Monograph on Health Effects of Low-Level Lead

Summary of Support for Conclusions

Reproductive
Effects

8.3.9 Endocrine Effects

There is inadequate evidence to evaluate thepotential association between blood Pb and major
endocrine or changes in hormone levels, because ofinconsistency of effects across available studies (seeEndocrine section of Appendix E: Reproductive andDevelopmental Effects). The data are inconsistentfor 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 inthe data reflects variation in the potential interaction
with Pb or whether it is due to well-known hormonalvariation 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 ofstudies 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 (Changet 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 wasdecreased in Pb workers with median blood Pb levelsof 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 theeffect 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 womenfrom NHANES III (mean blood Pb, 2.8 µg/dL) but

NTP Monograph on Health Effects of Low-Level Leadoccupational Pb (mean, 51 µg/dL) and a referencegroup (21 µg/dL) (Gennart et al. 1992a); in male Pb
workers with mean blood Pb of 31 µg/dL (Erfurth etal. 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 ina reference town (median blood Pb, 6 µg/dL) (Lambet al. 2008). Cumulative Pb exposure was associatedwith 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 thatPb may decrease LH and FSH. In a study of 41 children 10-13 years of age in Egypt, boys and girls withblood 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 bloodPb ≥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 lackof 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 dataalso support an effect of developmental Pb exposure
115

Reproductive
Effects

decreased with increasing blood Pb in women taking
birth control pills (Krieg 2007). LH was increased withincreasing blood Pb in postmenopausal women fromNHANES 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 etal. 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 findan 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 Pblevels 30-40 µg/dL were not associated with E2 in one
study (Mahmoud et al. 2005) but was associated withdecreased E2 in another study (Telisman et al. 2000).
At blood Pb levels <10 µg/dL, Pb was associatedwith 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 etal. 2006). Also, at blood Pb levels <10 µg/dL, E2 wasincreased 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 froma reference group (Assennato et al. 1986, Roses etal. 1989, Ng et al. 1991, Telisman et al. 2000). SerumTSH 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

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, andeven 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 andcongenital malformations: in a retrospective analysis,
Needleman et al. (1984) found a higher relative riskof minor congenital anomaly with higher all umbilicalcord 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; mostlack blood Pb data or other biomarkers, and exposureis 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)), includinghydrocephalus, oral clefts, cleft lip, and malformationsof the ear, heart, cardiovascular system, musculoskeletal system, and integument (Vinceti et al. 2001).
Several occupational studies investigated
the relationship between paternal blood Pb andcongenital malformations, and the available evidence
is inconsistent. Blood Pb levels determined frommonitoring data for 929 employees of the Cominco
smelter in British Columbia were not associated withodds 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 Pblevels based on job categories were associated withan increased odds ratio for congenital malformations(OR=3.2 (95% CI: 1.0, 10.2)) when evaluated alongwith 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 associatedwith neural tube defects is inconsistent, and bothstudies that include blood Pb data do not support anassociation 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 Pbtaken 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 ofneural 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 waterlevels of Pb. Drinking water levels of Pb or residence
near a hazardous waste site with known Pb were notassociated 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 associatedwith cardiovascular defects is inconsistent, comes116

NTP Monograph on Health Effects of Low-Level Leadon the hypothalamic-pituitary-adrenal axis andchanges in the stress response or basal corticosteroids.
The human data on potential associations between
Pb and LH, FSH, and T are inconsistent, and for otherhormones the data are inconsistent as well as limited
in nature. Therefore, the NTP determined there wasinadequate evidence to conclude that blood Pb was
associated with specific hormone changes. The conclusion of inadequate evidence for endocrine effectsof Pb in humans is in line with the discussion of thegeneral 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. Additionaldata, particularly data from prospective studies withappropriate consideration and control for timing in
the reproductive cycle, age, and other factors, arerequired to clarify the potential relationship between
blood Pb and endocrine parameters.

Reproductive
Effects

8.3.10 Congenital Malformations

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 andresidence 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 withtotal anomalous pulmonary venous return (TAPVR)
and 522 matched controls in the Baltimore-Washington Infant Study reported significant odds ratio forpaternal 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 orcleft palate. The evidence that Pb exposure is associated with oral clefts comes from few studies, all ofwhich lack biological exposure data. The study ofresidents in the Pb-associated ceramic district in Italy
described above reported increased relative risk oforal 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 ratioof 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

NTP Monograph on Health Effects of Low-Level Lead

8.4 Conclusions

The NTP concludes there is sufficient evidence thatblood Pb levels <10 µg/dL are associated with adverse
effects on development in children and that blood Pblevels <5 µg/dL are associated with adverse effects
on reproduction in adult women (see Table 8.6 forcomplete 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 ofpuberty), and the ability to discriminate effects at thelower 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 spontaneousabortion and preterm birth. In men there is sufficientevidence that blood Pb levels ≥15 µg/dL are associated with adverse effects on sperm or semen and thatblood 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 othermeasures of reduced fertility and that blood Pb levels>31 µg/dL are associated with spontaneous abortion.

117

Reproductive
Effects

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 reviewsof 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 areinconsistent and the studies generally lack biological
exposure data. The NTP determination that there isinadequate evidence to conclude parental blood Pblevels 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).

Table 8.6: NTP conclusions on reproductive and developmental effects of low-level Pb
Health EffectPopulation or
Exposure Window

PrenatalChildrenNo dataYes, <10 µg/dL
Yes, <5 µg/dL
Yes, <10 µg/dL
Yes, <10 µg/dL

Children
Men
Men: time to conception
Men: fertility

Inadequate
SufficientSufficient
Limited

Women
Men
Women
Adults
Men
Women
Men
Women
AdultsAdultsInadequate
LimitedLimitedInadequate
Inadequate
Sufficient
Inadequate
LimitedInadequate
Inadequate

No dataYes, ≥15 µg/dL
Yes, ≥20 µg/dL
Yes, ≥10 µg/dL(one study)
UnclearYes, >31 µg/dL
Yes, <10 µg/dL
UnclearUnclearYes, <5 µg/dL
UnclearYes, <10 µg/dL
UnclearUnclearPrenatalChildren

Postnatal growth

Sperm parameters

Spontaneous abortion
Stillbirth
Reduced fetal growthand lower birth weight
Preterm birth andgestational age

Bone Pb Evidence
No data
No data
One study
One study available, noevidence of an association
No data
No data
No data
No data
No data
No data
No data
No data
No dataYes, tibia
No data
No data
One study
No data

Reproductive
Effects

Endocrine effects
Birth defects

Blood Pb
Evidence

Inadequate
Sufficient
LimitedLimitedSufficient

Delayed puberty

Fertility / delayed
conception time

NTP
Conclusion

118

NTP Monograph on Health Effects of Low-Level Lead

9.0 REFERENCES
9.1 Executive Summary

NTP Monograph on Health Effects of Low-Level Lead

9.2 Methods

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