U.S. Department of Health and Human Services 

## National Toxicology Program 

# NTP

**NTP Monograph**

Health Effects of Low-Level Lead

June 2012THIS PAGE LEFT INTENTIONALLY BLANK

# NTP MONOGRAPH ON HEALTH EFFECTS OF LOW-LEVEL LEAD

June 13, 2012 U.S. D epartment of Health and Human Service s

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 SERVICESii N TP Monograph on Health Effects of Low-Level Lead THIS PAGE LEFT INTENTIONALLY BLANKNTP Monograph on Health Effects of Low-Level Lead iii 

## 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 Ex ecutive Summary

......................................................................................................................... xv 1.1 In troduction

..................................................................................................................................... xv 1.2 Me thods

........................................................................................................................................... xv 1.2.1 K ey Questions

...................................................................................................................... xv 1.2.2 Appr oach to Develop Health Effects Conclusions

............................................................... xv 1.2.3 Append ices of Studies Considered

..................................................................................... xvi 1.2.4 Authorit ative Sources and Peer Review

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

.......................................................... xvi 1.4 Health E ffects Evidence

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

............................................................................................................... xviii 1.4.2 Neur ological Effects

...... .................................................................................................... xviii 1.4.3 Immune E ffects

................................................................................................................... xxi 1.4.4 Car diovascular Effects

........................................................................................................ xxii 1.4.5 R enal Effects

...................................................................................................................... xxii 1.4.6 R eproduction and Developmental Effects

........................................................................ xxiii 1.5 Futur e Research

............................................................................................................................ xxiv

2.0 Me thods

........................................................................................................................................... 1 2.1 K ey Questions

.................................................................................................................................... 1 2.2 Appr oach to Develop Health Effects Conclusions

............................................................................. 1 2.3 Appendice s of Studies Considered

.................................................................................................... 2 2.4 Authorit ative Sources Considered

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

............................................ 3 2.4.2 A TSDR 2007 Toxicological Profile for Lead

............................................................................ 3 2.4.3 CDC Le ad Panel Documents

.................................................................................................. 3 2.4.4 T echnical Advisors

................................................................................................................ 4 2.5 Lit erature Search Strategy

................................................................................................................. 4 2.6 P eer-Review Process

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

3.0 Exposur e
........................................................................................................................................... 7 3.1 Wha t Does It Mean to Refer to Blood Pb <10 μg/dL?

...................................................................... 7 3.2 Biomark ers of Pb Exposure

............................................................................................................... 8 3.3 Sour ces of Pb

................................................................................................................................... 12 3.4 Modifier s of Pb Exposure

................................................................................................................ 16 3.5 Summar y

......................................................................................................................................... 18iv N TP Monograph on Health Effects of Low-Level Lead 4.0 Neur ological Effects

......................................................................................................................... 19 4.1 Conclusion s

..................................................................................................................................... 19 4.2 Ho w Conclusions Were Reached

.................................................................................................... 19 4.2.1 Princip al Measures of Neurological Effects

........................................................................ 20 4.2.2 Princip al Conclusions from the 2006 EPA and 2007 ATSDR Pb Documents

........................ 21 4.3 E vidence for Pb-Related Effects on Neurological Outcomes

........................................................... 22 4.3.1 Cogniti ve Function

.............................................................................................................. 22 4.3.2 Beha vior

............................................................................................................................. 31 4.3.3 Neur odegeneration

............................................................................................................ 38 4.3.4 Sensor y Organs

................................................................................................................... 40 4.4 Conclusion s

..................................................................................................................................... 42

5.0 Immune E ffects

........................................... .................................................................................... 45 5.1 Conclusion s

..................................................................................................................................... 45 5.2 Ho w Conclusions Were Reached

..................................................................................................... 45 5.2.1 Princip al Measures of Immune Effects

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

........................ 46 5.3 E vidence for Pb-Related Immune Effects

........................................................................................ 47 5.3.1 Incr eased Serum IgE and Allergic Sensitization

.................................................................. 47 5.3.2 IgG, IgM , IgA, and Antibody Response

............................................................................... 52 5.3.3 T L ymphocytes (T-cells)

....................................................................................................... 53 5.3.4 Monoc yte/Macrophages

.................................................................................................... 55 5.3.5 Neutr ophils

......................................................................................................................... 55 5.4 Suscep tible Populations or Life Stages

............................................................................................ 56 5.5 Pb Exposu re Measurements

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

... .......... 57 5.7 Conclusion s

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

6.0 Car diovascular Effects

..................................................................................................................... 61 6.1 Conclusion s

..................................................................................................................................... 61 6.2 Ho w Conclusions Were Reached

.................................................................................................... 61 6.2.1 Princip al Measures of Cardiovascular Effects

..................................................................... 62 6.2.2 Princip al Conclusions from the 2006 EPA and 2007 ATSDR Pb Documents

........................ 63 6.3 E vidence for Pb-related Effects on Cardiovascular Outcomes

......................................................... 63 6.3.1 Blood P ressure (BP) and Hypertension

.............................................................................. 63 6.3.2 Heart R ate Variability

.......................................................................................................... 68 6.3.3 Electr ocardiogram Abnormalities

....................................................................................... 70 6.3.4 Clinic al Cardiovascular Disease

........................................................................................... 70 6.3.5 Car diovascular Mortality

.................................................................................................... 72 6.4 Suscep tible Populations and Modifiers of Pb Exposure

.................................................................. 72 6.5 Conclusion s

..................................................................................................................................... 74

7.0 R enal Effects

................................................................................................................................... 77 7.1 Conclusion s

..................................................................................................................................... 77 7.2 Ho w Conclusions Were Reached

..................................................................................................... 77 7.2.1 Princip al Measures of Kidney Effects

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

........................ 78 7.3 E vidence for Pb-related Effects on Kidney Function

........................................................................ 80 7.3.1 Kidne y Effects in Adults

...................................................................................................... 80 7.3.2 Occupa tional Exposures

..................................................................................................... 84NTP Monograph on Health Effects of Low-Level Lead v 7.4 Suscep tible Populations or Life Stages

............................................................................................ 84 7.4.1 Childr en

.............................................................................................................................. 84 7.4.2 Hypert ensives, Diabetics, and Kidney Disease Patients

...................................................... 87 7.5 Conclusion s

..................................................................................................................................... 87

8.0 R eproductive/Developmental Effects

.............................................................................................. 89 8.1 Conclusion s

..................................................................................................................................... 89 8.2 Ho w Conclusions Were Reached

..................................................................................................... 90 8.2.1 Princip al Measures of Reproductive and Developmental Effects

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

.............................. 90 8.3 E vidence for Pb-Related Effects on Reproductive and Developmental Outcomes

.......................... 91 8.3.1 Dela yed Puberty

...... ........................................................................................................... 91 8.3.2 P ostnatal Growth

................................................................................................................ 94 8.3.3 Sperm

................................................................................................................................. 98 8.3.4 F ertility/Delayed Conception Time

.................................................................................. 104 8.3.5 Spon taneous Abortion

...................................................................................................... 107 8.3.6 Stillbirt h

............................................................................................................................ 109 8.3.7 F etal Growth and Lower Birth Weight

.............................................................................. 109 8.3.8 Pr eterm Birth and Gestational Age

................................................................................... 112 8.3.9 Endocr ine Effects

.............................................................................................................. 114 8.3.10 Cong enital Malformations

................................................................................................ 116 8.4 Conclusion s

................................................................................................................................... 117

9.0 References

.................................................................................................................................... 119 9.1 Ex ecutive Summary

....................................................................................................................... 119 9.2 Me thods

........................................................................................................................................ 119 9.3 Exposur e

........................................................................................................................................ 120 9.4 Neur ological Effects

....................................................................................................................... 125 9.5 Immune E ffects

............................................................................................................................. 131 9.6 Car diovascular Effects

................................................................................................................... 135 9.7 R enal Effects

.................................................................................................................................. 138 9.8 R eproductive/Developmental Effects

............................................................................................ 140

Appendices (not in printed copy. PDF files included on CD) Appenidx P age Appendix A: Human Studie s of Neurological Effects of Lead Considered in Developing Conclusions

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

Appendix B: Human Studie s of Immune Effects of Lead Considered in Developing Conclusions

................................................................................... 115

Appendix C: Human Studie s of Cardiovascular Effects of Lead Considered in Developing Conclusions

................................................................................... 145

Appendix D: Human Studie s of Renal Effects of Lead Considered in Developing Conclusions

................................................................................... 191

Appendix E: Human Studie s Appendices of Reproductive and Developmental Effects of Lead Considered in Developing Conclusions

................................................................................... 207vi N TP Monograph on Health Effects of Low-Level Lead 

## LIST OF TABLES

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

............................................................ xix

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

.................................. xx

Table 4.1: Major neurological effects considered

.................................................................................................. 20

Table 4.2: Main conclusions for neurological effects in the 2006 EPA AQCD for Lead and the 2007 ATSDR Toxicological Profile for Lead

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

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

...................................................................... 43

Table 5.1: Major immune effects considered

......................................................................................................... 46

Table 5.2: Main conclusions for immunological effects in the 2006 EPA AQCD for Lead and the 2007 ATSDR Toxicological Profile for Lead

............................................................................... 46

Table 5.3: Studies of serum IgE, sensitization, and eczema with low-level Pb used to develop conclusions for children

............................................................................................. 48

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

............................................................................. 59

Table 6.1: Major Pb-related cardiovascular outcomes/effects

.............................................................................. 62

Table 6.2: Main conclusions for cardiovascular effects in the 2006 EPA AQCD for Lead and the 2007 ATSDR Toxicological Profile for Lead

.............................................................................. 63

Table 6.3: Studies of the association between bone Pb and blood pressure and hypertension used to develop conclusions

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

Table 6.4: Studies of Pb and blood pressure and hypertension during pregnancy used to develop conclusions

................................................................................................................. 67

Table 6.5: Studies of childhood Pb exposure and BP

............................................................................................. 69

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

................................... 71

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

............................................ 73

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

.......................................................................... 75

Table 7.2: Main conclusions for kidney effects in 2006 EPA AQCD for Lead and the 2007 ATSDR Toxicological Profile for Lead

.............................................................................. 78

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

.................................... 79

Table 7.3: Studies of kidney outcomes in adults

.................................................................................................... 81

Table 7.4: Studies of kidney outcomes in children

................................................................................................. 85

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

................................................................................ 88 

## LIST OF TABLESNTP Monograph on Health Effects of Low-Level Lead vii Table 8.1: Major reproductive/developmental effects considered

....................................................................... 91

Table 8.2: Main conclusions for repro ductiv e/developmental effects in the 2006 EPA AQCD for Lead and the 2007 ATSDR Toxicological Profile for Lead

............................................................................... 91

Table 8.3: Studies of biomarkers of puberty associated with low-level Pb exposure used to develop conclusions

................................................................................................................. 92

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

................................................................................................................. 95

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

................................................................................................................. 99

Table 8.6: NTP conclusions on reproductive and developmental effects of low-level Pb

................................... 118viii N TP Monograph on Health Effects of Low-Level Lead 

## LIST OF FIGURES

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

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

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

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

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

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

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

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

## LIST OF FIGURESNTP Monograph on Health Effects of Low-Level Lead ix 

## CONTRIBUTORS
Office of Health Assessment and Translation (OHAT), Division of the National Toxicology Program (DNTP) Conducted technical evaluation Andrew A. Rooney, PhD (Project Lead) Abee L. Boyles, PhD Kyla Taylor, MS Kembra L. Howdeshell, PhD Vickie R. Walker Michael D. Shelby, PhD Kristina A. Thayer, PhD 

### (Director, OHAT)


### Office of Liaison, Policy and Review (OLPR), DNTP Managed peer review and release of the Monograph Mary Wolfe, PhD (Director, OLPR and Deputy Division Director for Policy) Danica Andrews Denise Lasko Lori White, PhD


### GLP Support Services Provided support for development of appendix tables Judy Stevens



### Technical Advisors Provided scientific input and reviewed a pre-public release draft of the Monograph David Bellinger, PhD Professor, Department of Environmental Health, Harvard School of Public Health, Boston, MA
David Lawrence, PhD Chief, Laboratory of Clinical and Experimental Endocrinology and Immunology, Wadsworth Center, New York State Department of Health, Albany, NY
Barbara Materna, PhD, CIH Chief, Occupational Health Branch, California Department of Public Health, Richmond, CA
Ana Navas-Acien, MD, PhD Assistant Professor, Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
Virginia Weaver, MD, MPH Associate Professor, Department of Environmental Health Sciences, Division of Occupational and Environmental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore,MD
Elizabeth A. Whelan, PhD Chief, Industrywide Studies Branch, Division of Surveillance, Hazard Evaluations, and Field Studies, National Institute for Occupational Safety and Health, Cincinnati, OHx NTP Monograph on Health Effects of Low-Level Lead 

## PEER REVIEW OF THE DRAFT NTP MONOGRAPH

Peer r eview of t he Dr aft N TP M onograph w as c on

ducted b y an ad hoc expert panel a t a public mee ting held No vember 17-18, 2011, a t the Na tional Ins titute of En vironmental Health Sciences, R esearch T riangle Park, NC (see http://ntp.niehs.nih.gov/go/37090 for materials, minut es, and pane l r ecommendations from th e p eer r eview mee ting). T he s election o f panel member s and c onduct of the peer r eview w ere performed i n acc ordance wi th th e F ederal Ad visory Committee Act and F ederal policies and r egulations. The panel member s ser ved as independen t scien tists,
not as r epresentatives of an y ins titution, c ompany, or governmental ag ency. In this c apacity, pane l me m

bers had tw o major r esponsibilities in r eviewing the draft NTP Mon ograph: (1) t o de termine whe ther the scientific in formation cit ed in the dr aft monog raph is t echnically c orrect, cle arly s tated, and obje ctively presented and (2) t o de termine whe ther the scie n

tific e vidence pr esented in the dr aft monogr aph sup

ports the NTP ’s c onclusions r egarding health e ffects of low-level lead (Pb). The pane l agr eed with the dr aft N TP o verall c on

clusions on c ardiovascular, r enal, and immune health effects associa ted with blood Pb le vels <10 μg /dL. The panel r ecommended ch anging th e d raft su mmary conclusion f or ne urological e ffects in childr en and f or reproductive e ffects in adult w omen fr om sufficient evidence of an associa tion a t blood Pb le vels <10 ug / dL t o sufficient e vidence of an associa tion a t blood Pb levels <5 ug /dL. Commen ts fr om the peer r eviewers and writt en publ ic c omments r eceived on the dr aft monograph w ere c onsidered during finaliz ation of the document. The N TP c oncurred with the e xpert pane l

on al l of i ts r ecommendations on the c onclusions regarding health effects of Pb in this final document.



### Peer-Review Panel

Joel Pounds, PhD (chair) Scientist, Divi sion of Bi ological S ciences, P acific North west National Laboratory, Richland, WA

Deborah Cory-Slechta, PhD Professor, De partment of En vironmental Me dicine, U niversity of Rochester School of Medicine and Dentistry, Rochester, NY

Pam Factor-Litvak, PhD Associate P rofessor of Clinic al Epide miology, M ailman Sc hool of Public Health, Columbia University, New York, NY

Eliseo Guallar, MD, DrPH Associate P rofessor, De partment of Epide miology, W elch Ce nter f or Prevention, Jo hns Ho pkins Un iversity Bl oomberg S chool o f Pu blic Health, Baltimore, MD

Bruce Lanphear, MD, MPH, TM Senior Scien tist, Child and F amily R esearch Ins titute, BC Childr en’s Hospital, U niversity of B ritish Colum bia, V ancouver, B ritish Columbia, Canada

Michael Pollard, PhD Associate Pr ofessor, W .M. K eck Aut oimmune Di sease Cen ter, Department of Molecular and Experimen tal Medicine, The Scripp s Research Institute, San Diego, CA Stephen Rothenberg, PhD Senior In vestigator, Ce nter f or R esearch in P opulation He alth, National Ins titute of Public Health, Minis try of Me xico, Cuerna vaca, Morelos, Mexico

Nostratola Vaziri, MD, MACP Chief, Division of Nephr ology and Hypert ension, Univ ersity of Cali

fornia, Irvine Medical Center, Orange, CA

Richard Wedeen, MD Clinical Pr ofessor, Departmen t of En vironmental and Community Medicine, UMDNJ-R obert W ood Jo hnson Med ical S chool, Ne w Brunswick, NJNTP Monograph on Health Effects of Low-Level Lead xi 

## ABBREVIATIONS

ABLES Adult Blood Lead Epidemiology and Sur veillance ACCLPP Advisor y Committee on Childhood Lead Poisoning Prevention ADHD a ttention deficit hyperactivity disorder ALAD δ- aminolevulinic acid dehydratase ALS am yotrophic lateral sclerosis AQCD Air Quality Crit eria Document ATSDR Ag ency for Toxic Substances and Disease Registry BAEP br ainstem auditory evoked potential BMI body mass inde x BP blood pr essure CBCL Child Beha vior Checklist BTQ Bos ton Teacher Questionnaire CDC Cen ters for Disease Control and Prevention CI c onfidence interval CKD chr onic kidney disease DBP dias tolic blood pressure DSM Diagnostic and Statistical Manual of Mental Disorders DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th edition (1994) DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (2000) DTH dela yed-type hypersensitivity E 2 es tradiol-17β EBE early biologic al effect marker ECG electr ocardiographic EDTA e thylenediaminetetraacetic acid eGFR es timated glomerular filtration rate EPA En vironmental Protection Agency, U.S. ERG electr oretinographic ETS en vironmental tobacco smoke FR f ecundability ratio FSH f ollicle-stimulating hormone FSIQ full-sc ale IQ GCI Gener al Cognitive Index from the McCarthy Scales of Children’s Abilities GFR glomerular filtr ation rate HFE hemochr omatosis HR haz ard ratio HRV heart r ate variability IgA immunoglobulin A IgE immunoglobulin E IGF-1 insulin-lik e growth factor 1 IgG Immunoglobulin G IgM immunoglobulin M IQ in telligence quotient IVF in vitr o fertilization KTEA K aufman Test of Educational Achievement LH leutinizing hormone MDI Men tal Developmental Index from the Bayley Scales of Infant Development MMSE Mini-Men tal State Examinationxii N TP Monograph on Health Effects of Low-Level Lead NAG N-ace tyl-β-D-glucosaminidase NHANES Na tional Health and Nutrition Examination Survey NIEHS Na tional Institute of Environmental Health Sciences NO nitric o xide NTP Na tional Toxicology Program Pb lead O 2 - super oxide OR odds r atio PBPK ph ysiologically based pharmacokinetic PFC plaque- forming cell PIQ perf ormance IQ PRL pr olactin RBP r etinol-binding protein RR r elative risk SBP s ystolic blood pressure SD s tandard deviation SES socioec onomic status SPT skin prick t est T t estosterone T 3 triiodothr yonine T 4 th yroxin Th-1 type 1 helper T -cell Th-2 type 2 helper T -cell TNF-α tumor necr osis factor-α TSH th yroid-stimulating hormone VEP visual e voked potential VDR vit amin D receptor VIQ v erbal IQ WHILA S wedish Women’s Health in the Lund Area WISC W echsler Intelligence Scale for Children WISC-III W echsler Intelligence Scale for Children, 3rd edition (1991) WISC-R W echsler Intelligence Scale for Children, revised edition (1974) WISC-IV W echsler Intelligence Scale for Children, 4th edition (2003) WPPSI-R W echsler Preschool and Primary Scale of Intelligence WRAT-R Wide Rang e Achievement Test-Revised ZPP zinc pr otoporphyrinNTP Monograph on Health Effects of Low-Level Lead xiii 

## ABSTRACT

Although reductions in lead (Pb) exposure for the U.S. population have resulted in lower blood Pb levels over time, epidemiological studies continue to provide evi

dence of health effects at lower and lower blood Pb levels. Low-level Pb was selected for evaluation by the National Toxicology Program (NTP) because of (1) the availability of a large number of epidemiological studies of Pb, (2) a nomination by the National Insti

tute for Occupational Safety and Health for an assess

ment of Pb at lower levels of exposure, and (3) public concern for effects of Pb in children and adults. This evaluation summarizes the evidence in humans and presents conclusions on health effects in children and adults associated with low-level Pb exposure as indi

cated by less than 10 micrograms of Pb per deciliter of blood (<10 μg/dL). The assessment focuses on epi

demiological 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 Assess

ment and Translation (OHAT, formerly the Center for the Evaluation of Risks to Human Reproduction) and completed in April of 2012. The results of this evaluation are published in the NTP Monograph on Health Effects of Low-Level Lead. The document and appendices are available
at http://ntp.niehs.nih.gov/go/evals. This document provides background on Pb exposure and includes a review of the primary epidemiological literature for evidence that low-level Pb is associated with neurological, immunological, cardiovascular, renal, and/or reproductive and developmental effects. The NTP Monograph presents specific conclusions for each health effect area. Overall, the NTP concludes that there is sufficient evidence that blood Pb levels <10 μg/dL and <5 μg/dL are associated with adverse health effects in children and adults. This conclusion was based on a review of the pri

mary epidemiological literature, scientific input from technical advisors that reviewed pre-public release drafts of each chapter summarizing the evidence for specific health effects associated with low-level Pb, public comments received during the course of the evaluation, and comments from an expert panel of ad hoc reviewers during a public meeting to review the Draft NTP Monograph on November 17-18, 2011 ( http://ntp.niehs.nih.gov/go/37090 ).xiv N TP Monograph on Health Effects of Low-Level Lead THIS PAGE LEFT INTENTIONALLY BLANKExecutiveSummary

NTP Monograph on Health Effects of Low-Level Lead xv 

## 1.0 EXECUTIVE SUMMARY

1.1 Introduction Lead (Pb) exposure remains a significant health con

cern despite policies and practices that have resulted in continued progress in reducing exposure and low

ering blood Pb levels in the U.S. population. Pb is one of the most extensively studied environmental toxi

cants, with more than 28,900 publications on health effects and exposure in the peer-reviewed literature 1

. While the toxicity associated with exposure to high levels of Pb was recognized by the ancient Greeks and Romans, the adverse health effects associated with low-level Pb exposure became widely recognized only in the second half of the 20th century. Over the past 40 years, epidemiological studies, particularly in chil

dren, continue to provide evidence of health effects at lower and lower blood Pb levels. In response, the Centers for Disease Control and Prevention (CDC) has repeatedly lowered the concentration of Pb in blood that is considered “elevated” in children (from 30 μg/ dL to 25 μg/dL in 1985 and to the current level of 10 μg/dL in 1991). The purpose of this evaluation is to summarize the evidence in humans and to reach conclusions about whether health effects are associated with low-level Pb exposure as indicated by less than 10 micrograms of Pb per deciliter of blood (<10 μg/ dL), with specific focus on the life stage (child

hood, adulthood) associated with these health effects. This evaluation focuses on epidemiologi

cal evidence at blood Pb levels <10 μg/dL because health effects at higher blood Pb levels are well established such that the definition of an elevated blood Pb level is ≥10 μg /dL for both children and adults (ABLES 2009, CDC 2010a). Pb was nominated by the National Institute for Occupational Safety and Health for a National Toxicology Program (NTP) evaluation to assess the reproductive and develop

mental effects of Pb (see http://ntp.niehs.nih.gov/ mtg?date=20100510&meeting=BSC ). The scope of the evaluation has been expanded from the origi

nal nomination to include an evaluation of health effects other than reproduction and development (e.g., cardiovascular effects in adults) in order to maximize the utility of the evaluation.

1 Based on an April 2012 PubMed search for keyword (MeSH) “lead” or “lead poisoning.” 

### 1.2 Methods The key questions and general approach for develop

ing the conclusions on the health effects of low-level Pb are outlined below. Section 2.0 of this document contains additional details on the authoritative sources considered, the literature search strategy, and the peer-review process.



### 1.2.1 Key Questions What is the evidence that adverse health effects are associated with blood Pb <10 μg/dL?

6 What reproductive, developmental, neurological, immune, cardiovascular, and renal health effects are associated with blood Pb levels <10 μg/dL? 6 What is the blood Pb level associated with a given health effect (i.e., <10 μg/dL or <5 μg/dL)? 6 At which life stages (childhood or adulthood) is the effect identified? 6 Are there data to evaluate the association between bone Pb and the health effect, and how does the association to this biomarker of Pb expo

sure compare to the association with blood Pb?



### 1.2.2 Approach to Develop Health Effects Conclusions Conclusions in the NTP evaluation of Pb-related health effects in humans associated with low-level Pb were derived by evaluating the data from epide

miological studies with a focus on blood Pb levels <10 μg/dL. The evaluation includes a review of the primary epidemiological literature for evidence that low-level Pb is associated with neurological, immu

nological, cardiovascular, renal, and/or reproductive and developmental effects. These health effect areas were selected because there is a relatively large data

base of human studies in each area. The NTP con

sidered four possible conclusions for specific health effects within each area: Sufficient Evidence of an Association: An association is observed between the expo

sure and health outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. Limited Evidence of an Association: An association is observed between the expo

sure and health outcome in studies in which chance, bias, and confounding could not be ruled out with reasonable confidence.xvi NTP Monogr aph on Health Effects of Low-Level LeadExecutiveSummary Inadequate Evidence of an Association: The available studies are insufficient in quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association between exposure and health outcome, or no data in humans are available. Evidence of No Association: Several adequate studies covering the full range of levels of exposure that humans are known to encounter (in this case limited to blood Pb levels <10 μg/dL) are mutually consistent in not showing an association between exposure to the agent and any studied endpoint.

The discussion of each health effect begins with a statement of the NTP’s conclusion regarding whether the specific effect is associated with a blood Pb level <10 μg/dL or <5 μg/dL and the age group (childhood or adulthood) in which it is or is not identified, as well as the timing of exposure associated with the effect (prenatal, childhood, concurrent) if available. Then key data and principal studies considered in devel

oping the NTP’s conclusions are discussed in detail. General strengths and limitations of study designs were considered when developing conclusions, with prospective studies providing stronger evidence than cross-sectional or case-control studies. Each section concludes with a summary discussing each health effect, describing experimental animal data that relate to the human data, and stating the basis for the NTP conclusions. For the purposes of this evaluation, “children” refers to individuals <18 years of age unless otherwise specified. In addition to the blood Pb level of <10 μg /dL, a lower effect level of <5 μg/dL was also selected because it is commonly used in epidemiological stud

ies to categorize health effects data by exposure levels; therefore, data are often available to evaluate health effects for groups above and below this value as well.



### 1.2.3 Appendices of Studies Considered The information to support the NTP’s conclusions for individual health effects is presented in each chapter. In addition, human studies of groups with low-level Pb exposure that were considered in developing the conclusions are also abstracted for further reference and included in separate appendices for neurological effects, immune effects, cardiovascular effects, renal effects, and reproductive and developmental effects. 

### 1.2.4 Authoritative Sources and Peer Review In this evaluation, the NTP made extensive use of recent government assessments of the health effects of Pb, especially the U.S. Environmental Protection Agency (EPA) 2006 Air Quality Criteria Document (AQCD) for Lead (U.S. EPA 2006 and a draft updated version, 2012), which has undergone extensive exter

nal 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 Toxi

cological Profile for Lead (ATSDR 2007) and the CDC’s Advisory Committee on Childhood Lead Poisoning Prevention reports, such as the 2010 Guidelines for the Identification and Management of Lead Exposure in Pregnant and Lactating Women (CDC 2010b). The NTP used independent subject matter experts as technical advisers to provide scientific input and to review pre-public release drafts of each chapter summarizing the evidence that health effects are associated with low-level Pb, the appendices, and Section 3.0 that provides background on Pb exposure (see Contributors for a list of technical advisers). Peer review of the draft document was conducted by an expert panel of ad hoc reviewers at a public meeting held November 17-18, 2011, in Research Triangle Park, NC (see Peer-Review of the Draft NTP Monograph for details). Comments from peer reviewers and written public comments received on the draft monograph were considered during finalization of the document. The NTP concurred with the expert panel on all of the conclusions regarding health effects of Pb in this final document.



### 1.3 What Does It Mean to Refer to Blood Pb Levels <10 μg/dL? The overwhelming majority of human epidemio

logical studies with Pb exposure data measured Pb in whole blood, and this measure of exposure serves as the basis for the evaluation of Pb levels <10 μg/dL. An individual’s blood Pb level reflects an equilibrium between current environmental Pb exposure and the preexisting amount of Pb in the body, stored pri

marily in bone (Factor-Litvak et al. 1999, Brown et al. 2000, Chuang et al. 2001). In adults, bone and teeth store 90-95% of the total body burden of Pb, while in young children, bone Pb represents a smaller fraction (down to 70%) (Barry 1981, for review, see Barbosa et al. 2005, Hu et al. 2007). The body eliminates half ofExecutiveSummary

NTP Monograph on Health Effects of Low-Level Lead xvii the Pb in circulating blood (half-life) in approximately one month, while bone is a more stable repository for Pb and, therefore, bone Pb levels reflect cumulative exposure to Pb integrated over years or even decades (reviewed in Hu et al. 1998, Hu et al. 2007). The halflife of Pb in bone ranges from 10 to 30 years, depend

ing 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 con

stant bone remodeling, and bone Pb is exchanged with blood Pb much more frequently than in adults (reviewed in Barbosa et al. 2005, Hu et al. 2007). This evaluation focuses on the relationship between health effects and blood Pb levels because blood Pb is the most widely available measure of exposure, blood Pb reflects the equilibrium between current and past exposure, as described above, and numerous studies have reported an association between blood Pb levels and health outcomes. How

ever, measuring Pb in one tissue at one point in time does not present a complete picture of either currentor cumulative Pb exposure, and bone Pb reflects longterm stores of Pb in the body better than does blood Pb (reviewed in Barbosa et al. 2005, Hu et al. 2007); therefore, bone Pb data were also considered when available. Note that measuring bone Pb is expensive, requires specialized equipment that is not generally accessible, and requires study subjects to travel to the location of the measurement apparatus (K-x-ray fluorescence); thus, fewer Pb data are available for bone than for blood. Before bans on Pb in paint, solder, and gasoline, environmental Pb levels in the United States were higher, so older adults accumulated more Pb as chil

dren than children do today. Average blood Pb levels in children 1-5 years of age have decreased 10-fold over the last 30 years, from 15.1 μg/dL in 1976-1980 to 1.51 μg/dL in 2007-2008 (geometric means; CDC 2007, 2011). This is clearly good news for current populations of children and represents a significant public health accomplishment. However, most U.S. adults who were born before 1980 had blood Pb levels >10 μg /dL during early childhood, so health effects in adults today may have been influenced by blood Pb levels >10 μg /dL that many individuals experienced earlier in life. Keeping childhood blood Pb levels in mind, there are data on multiple health effects in adults for which studies report a significant relationship between concurrent blood Pb levels as adults and the health effect (e.g., elevated blood pressure, reduced kidney function, or decreases in specific measures of cognitive function). There is a considerable body of evidence that these health effects are associated with Pb exposure, and multiple studies report a sig

nificant association with concurrent blood Pb levels <10 μg/dL. Furthermore, the association with blood Pb is supported by the consistency of effects among epidemiological studies and biological coherence with animal data. It is well recognized that the role of early-life Pb exposure cannot be discriminated from the role of concurrent blood Pb without additional long-term studies. To eliminate the potential role of early-life blood Pb levels >10 μg/dL on health effects observed in adults with blood Pb levels <10 μg/dL

, prospective studies (following a group over time) would be required in a group with blood Pb levels consistently <10 μg/dL from birth until measurement of the outcome of interest. As described in Section 1.2.2 , the NTP’s conclu

sions were derived by evaluating data from epide

miological studies with a focus on blood Pb levels <10 μg/dL. The evidence discussed for specific health outcomes within each chapter varies by study design and type of analyses used to examine the relation

ship of the health outcome with blood Pb across the hundreds of studies evaluated. In some cases, studies examined only groups with blood Pb levels <10 μg/dL

, <5 μg/dL, or even lower, and the association of the health effect with the blood Pb level is clear. For example, Lanphear et al. (2000) reported that higher blood Pb levels were associated with lower academic performance in a cross-sectional study (examining one point in time) of 4,853 children 6-16 years of age from the NHANES III data set. When they analyzed only children with blood Pb <10 μg/ dL (n=4,681) or <5 μg/dL (n=4,043), the association with blood Pb was still significant (p<0.001 for <10 μg/ dL and <5 μg/dL). In other cases, studies reported a signifi

cant association between blood Pb and an effect in a group whose mean blood Pb level was <10 μg /dL (e.g., higher blood Pb levels were associated with higher blood pressure in 964 adults in the Baltimore Memory Study (Martin et al. 2006)). These analyses support an effect of a blood Pb level <10 μg/dL , but they do not exclude the possibility that individuals significantly above or below the mean blood Pb level are driving the effect, or that past exposure levels arexviii NTP Monogr aph on Health Effects of Low-Level LeadExecutiveSummary driving the effect. Finally, some studies compared effects between two groups with higher and lower blood Pb levels. For example, Naicker et al. (2010) compared the effect of a blood Pb level ≥5 μg/d L with a blood Pb level <5 μg/dL on developmental markers of puberty in 13-year-old girls in South Africa (n=682) and found that a blood Pb level ≥5 μg/dL was signifi

cantly associated with delayed breast development, pubic hair development, and age of menarche.



### 1.4 Health Effects Evidence

1.4.1 NTP Conclusions The NTP concludes that there is sufficient evidence for adverse health effects in children and adults at blood Pb levels <10 μg/dL , and <5 μg/dL as well (see Table 1.1 for summary of effect by life stage at which the effect is identified). A major strength of the evi

dence supporting effects of low-level Pb comes from the consistency demonstrated by adverse effects associated with blood Pb <10 μg/ dL across a wide range of health outcomes, across major physiological systems from reproductive to renal, among multiple groups, from studies using substantially different methods and techniques, and for health effects in both children and adults. In children, there is sufficient evidence that blood Pb levels <5 μg/dL are associated with increased diag

nosis of attention-related behavioral problems, greater incidence of problem behaviors, and decreased cogni

tive performance as indicated by (1) lower academic achievement, (2) decreased intelligence quotient (IQ), and (3) reductions in specific cognitive measures. There is also limited evidence that blood Pb <5 μg/dL is associated with delayed puberty and decreased kidney function in children ≥12 years of age. There is sufficient evidence that blood Pb levels <10 μg/ dL in children are associated with delayed puberty and reduced postnatal growth. There is limited evidence that blood Pb levels <10 μg/d L are associated with elevated serum immunoglobulin E (IgE), which is a principal mediator of hypersensitivity; consistent with this effect, there is limited evidence that blood Pb lev

els <10 μg/dL are associated with changes to an IgErelated health effect, allergy diagnosed by skin prick test to common allergens. There is inadequate evi

dence of an association between blood Pb <10 μg/dL in children and other allergic diseases, such as eczema or asthma. There is also inadequate evidence of an association between blood Pb <10 μg/dL and cardio

vascular effects in children of any age, or renal func

tion in children <12 years of age. In adults, there is sufficient evidence that blood Pb levels <5 μg/dL are associated with decreased renal function and that blood Pb levels <10 μg/dL are associated with increased blood pressure and hyper

tension. There is sufficient evidence that maternal blood Pb levels <5 μg/dL are associated with reduced fetal growth and limited evidence that maternal blood Pb levels <10 μg/dL are associated with increased spontaneous abortion and preterm birth. There is sufficient evidence that blood Pb levels <10 μg /dL, and limited evidence that blood Pb levels <5 μg /dL, are associated with essential tremor in adults. There is also limited evidence for an association between blood Pb <10 μg /dL and increased cardiovascularrelated mortality, decreased auditory function, the neurodegenerative disease amyotrophic lateral scle

rosis (ALS), and decreases in specific measures of cog

nitive function in older adults. The NTP conclusions of associations between blood Pb levels <10 μg/dL in adults and health effects cannot completely elimi

nate the potential contributing effects of early-life blood Pb levels, as discussed in Section 1.3

. Although the relationship between many health effects and bone Pb as a measure of exposure has not been examined, the data support the importance of cumulative Pb exposure on cardio vascular effects of Pb in adults, as well as neuro cog nitive decline in adults, because the association between Pb and these endpoints is more consistent for bone Pb than for blood Pb.



### 1.4.2 Neurological Effects The NTP concludes that there is sufficient evidence that blood Pb levels <5 μg/d L are associated with adverse neurological effects in children and limited evidence that blood Pb levels <10 μg/dL are associ

ated with adverse neurological effects in adults (see Table 1.2 for summary of effects). Unlike the data set for most other health effect areas, there are a number of prospective studies of neurological effects that include measures of prena

tal exposure (either maternal blood or umbilical cord blood Pb levels). These prospective studies provide limited evidence that prenatal exposure to blood Pb levels <5 μg/dL is associated with decreases in measures of general and specific cognitive functionNTP Monograph on Health Effects of Low-Level Lead xixExecutiveSummaryTable 1.1: NTP conclusions on health effects of low-level Pb by life stageLife StageBlood PbLevelNTPConclusionPrincipal Health EffectsBone Pb EvidenceChildren<5μg/dLSufficientDecreased academic achievement, IQ, and specific cognitive measures; increased incidence of attention-relatedbehaviors and problem behaviorsTibia and dentin Pb are associated with attentionrelated behaviors, problem behaviors, and cognition.LimitedDelayed puberty and decreased kidney function in children ≥12 years of ageThe one available study of bone Pb in children does notsupport an association with postnatal growth.<10μg/dLSufficientDelayed puberty, reduced postnatal growth, decreasedIQ, and decreased hearingNo dataLimitedIncreased hypersensitivity/allergy by skin prick test toallergens and increased IgE* (not a health outcome)No dataInadequateAny age –asthma, eczema, nonallergy immune function,cardiovascular effects;<12 years of age –renal functionNo dataAdults<5μg/dLSufficientDecreased glomerular filtration rate; maternal blood Pbassociated with reduced fetal growthThe 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 fetalgrowth.LimitedIncreased incidence of essential tremorNo data<10μg/dLSufficientIncreased blood pressure, increased risk of hypertension,and increased incidence of essential tremorThe association between bone Pb and cardiovasculareffects is more consistent than for blood Pb.LimitedPsychological effects, decreased cognitive function, decreased hearing, increased incidence of ALS, and increasedcardiovascular-related mortality; maternal blood Pb associated with increased incidence of spontaneous abortionand preterm birthThe association between bone Pb and cognitive declineis more consistent than for blood Pb.InadequateImmune function, stillbirth, endocrine effects, birth defects,fertility or time to pregnancy**, sperm parameters**No dataAbbreviations: ALS, amyotrophic lateral sclerosis; IgE, immunoglobulin E; IQ, intelligence quotient*Increased serum IgE is associated with hypersensitivity; however, as described inSection 1.4.3, increased IgE does not equate to disease.**The NTP concludes that there isinadequateevidence that blood Pb levels <10μg/dL are associated with fertility, time to pregnancy, and sperm parameters; however, giventhe basis of the original nomination, the NTP evaluated the evidence that higher blood Pb levels (i.e., >10μg/dL) are associated with reproductive and developmental effects,and those conclusions are discussed inSection 1.4.6and presented inTable 1.2.xx NTP Monograph on He alth Effects of Low-Level LeadExecutiveSummaryTable 1.2: NTP conclusions on health effects of low-level Pb by major health effect areasHealth AreaPopulation orExposure WindowNTPConclusionPrincipal Health EffectsBlood PbEvidenceBone PbEvidenceNeurologicalPrenatalLimitedDecrease in measures of cognitive functionYes, <5μg/dLNo dataLimitedDecreased IQ, increased incidence of attention-related and problem behaviors, decreased hearingYes, <10μg/dLNo dataChildrenSufficientDecreased academic achievement, IQ, and specificcognitive measures; increased incidence of attention-related and problem behaviorsYes, <5μg/dLTibia and dentin Pb are associated with attention, behavior,and cognition.SufficientDecreased hearingYes, <10μg/dLNo dataAdultsSufficientIncreased incidence of essential tremorYes, <10μg/dLNo dataLimitedPsychiatric effects, decreased hearing, decreasedcognitive function, increased incidence of ALSYes, <10μg/dLThe association between bonePb and cognitive decline is moreconsistent than blood.LimitedIncreased incidence of essential tremorYes, <5μg/dLImmuneChildrenLimitedIncreased hypersensitivity/allergy by skin pricktest to common allergens and IgE* (not a healthoutcome)Yes, <10μg/dLNo dataInadequateAsthma, eczemaUnclearNo dataAdultsInadequate–UnclearNo dataCardiovascularChildrenInadequate–UnclearNo dataAdultsSufficientIncreased blood pressure and increased risk ofhypertensionYes, <10μg/dLThe association between bonePb and cardiovascular effects ismore consistent than blood.LimitedIncreased cardiovascular-related mortality and ECGabnormalitiesYes, <10μg/dLRenalChildren <12 years oldInadequate–UnclearNo dataChildren ≥12 years oldLimitedDecreased glomerular filtration rateYes, <5μg/dLNo dataAdultsSufficientDecreased glomerular filtration rateYes, <5μg/dLYes, one studyReproductive andDevelopmentalPrenatalLimitedReduced postnatal growthYes, <10μg/dLNo dataChildrenSufficientDelayed puberty, reduced postnatal growthYes, <10μg/dLOne study does not supporteffects of bonePb on growth.LimitedDelayed pubertyYes, <5μg/dLAdultsWomenSufficientReduced fetal growthYes, <5μg/dLMaternal tibia Pb is associatedLimitedIncrease in spontaneous abortion and pretermbirthYes, <10μg/dLNo dataMenSufficientAdverse changes in sperm parameters and increased time to pregnancyYes,≥15-20μg/dLNo dataLimitedDecreased fertilityYes, ≥10μg/dLNo dataLimitedIncreased spontaneous abortionYes, >31μg/dLNo dataAdultsInadequateStillbirth, endocrine effects, birth defectsUnclearNo dataAbbreviations:ALS, amyotrophic lateral sclerosis; ECG, electrocardiography; IgE, immunoglobulin E; IQ, intelligence quotient.*Increased serum IgE is associated with hypersensitivity; however, as described inSection 1.4.3, increased IgE does not equate to disease.NTP Monograph on Health Effects of Low-Level Lead xxiExecutiveSummary evaluated in children. There is also limited evidence that prenatal exposure to blood Pb levels <10 μg/dL is associated with decreased IQ, increased incidence of attention-related behaviors and antisocial behavior problems, and decreased hearing measured in chil

dren. However, conclusions about effects of prena

tal Pb exposure for outcomes evaluated as children are complicated by the high degree of correlation between prenatal and childhood blood Pb levels and as described below, blood Pb levels during childhood are also associated with these effects. In children, there is sufficient evidence that blood Pb levels <5 μg/dL are associated with decreases in broad based and specific indices of cognitive func

tion and an increase in attention-related behavioral problems and antisocial behavioral problems. The association between blood Pb and decreased IQ has been demonstrated in multiple prospective studies of children with blood Pb levels <10 μg/dL , pooled analy

ses 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 achieve

ment, 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 func

tion has been demonstrated in prospective and crosssectional studies using a wide range of tests to assess cognitive function. Increases in attention-related and problem behaviors are consistently reported in studies with mean blood Pb levels <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-associated behavioral effects in the area of attention, of which ADHD is one example on the more severe end of the spectrum, and (2) determination of ADHD in children from available studies are not as precise as an ADHD diagnosis by trained clinicians using specific DSMIV-TR criteria. There is sufficient evidence that blood Pb levels <10 μg/dL in children are associated with decreased auditory acuity. Multiple cross-sectional studies reported hearing loss, as indicated by higher hearing thresholds and increased latency of brainstem auditory evoked potentials (BAEPs), in children with blood Pb levels <10 μg/dL. In adults, there is limited evidence that blood Pb levels <10 μg/d L are associated with psychiatric out

comes (including anxiety and depression), decreased auditory function, ALS, and decreases in specific measures of cognitive function in older adults. There is sufficient evidence that blood Pb levels <10 μg/dL are associated with essential tremor in adults, and limited evidence for blood Pb levels <5 μg /dL. Asso

ciations with decreases in cognitive function in adults are more consistent for bone Pb than for blood Pb, suggesting a role for cumulative Pb exposure.



### 1.4.3 Immune Effects The NTP concludes that there is limited evidence that blood Pb levels <10 μg/dL are associated with adverse immune effects in children and that there is inadequate evidence in adults (see Table 1.2 ). In children, there is limited evidence that blood Pb levels <10 μg /dL are associated with changes to an immune-related health outcome such as allergy or increased hypersensitivity. There is also limited evi

dence that blood Pb levels <10 μg/dL are associated with elevated serum IgE levels. Five studies of groups with mean blood Pb levels of 10 μg/ dL and below support the relationship between blood Pb and increased serum IgE. Two of these studies reported an association at blood Pb levels of ≥10 μg/dL rather than <10 μg/dL, and only one of the remaining studies adjusted for age, a particularly important confounder in analyses of IgE in children. Although increases in serum levels of total IgE are not definitive indicators of allergic disease, elevated levels of IgE are primary mediators of hypersensitivity associated with sensi

tization and allergic disease. Therefore, the studies demonstrating Pb-related increases in IgE suggest a link to hypersensitivity and support more definitive data such as a prospective study that found blood Pb levels <10 μg/dL were associated with increased hypersensitivity (or allergy by skin prick testing) in children. These data support the conclusion of limited evidence that increased hypersensitivity responses or allergy are associated with blood Pb levels <10 μg/dL in children; however, there is inadequate evidence of an association between blood Pb and other allergic diseases such as eczema or asthma. There is inadequate evidence in adults to ad ­dress the potential association between blood Pb <10 μg/dL and IgE, allergy, eczema, or asthma. Few studies have investigated the relationship betweenxxii NTP Monogr aph on Health Effects of Low-Level LeadExecutiveSummary immune function and Pb in humans, and most studies reported general observational markers of immunity rather than function. There is inadequate evidence that blood Pb levels <10 μg/d L are associated with observational immune effects such as altered lym

phocyte 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 avail

able data are inconsistent. There is also inadequate evidence that blood Pb levels <10 μg/dL are associ

ated with changes in immune function other than hypersensitivity, because few studies have examined immune function at lower blood Pb levels. Bone Pb levels may be particularly relevant for cells of the immune system and immune function. All of the white blood cells or leukocytes that develop after birth are derived from progenitor cells in the bone marrow. Unfortunately, very few studies of immune effects have measured exposure other than blood Pb; therefore, the relative importance of blood or bone Pb levels for immune effects of Pb is unknown.



### 1.4.4 Cardiovascular Effects The NTP concludes that there is sufficient evidence that blood Pb levels <10 μg/d L in adults are associ

ated with adverse effects on cardiovascular function and that there is inadequate evidence to evaluate cardiovascular effects in children (see Table 1.2 for summary of effects). There is sufficient evidence of a bone Pb-related increase in the risk of hypertension and increases in blood pressure in adults. Two prospective studies and five cross-sectional studies support a significant asso

ciation between bone Pb and blood pressure or hyper

tension in groups with blood Pb levels <10 μg/dL. Stud

ies show less consistent associations between blood Pb and blood pressure or hypertension than for bone Pb; however, most of the recent studies with mean blood Pb levels <5 μg/dL found significant associations between concurrent blood Pb levels and increased blood pressure. There is sufficient evidence that blood Pb levels <10 μg/dL increase the risk of hypertension during pregnancy, supported by one prospective study and five cross-sectional studies with blood Pb levels during pregnancy <10 μg/dL. There is limited evidence of increased risk of cardiovascular mortality associ

ated with blood Pb levels <10 μg/ dL. An association between increased cardiovascular mortality and blood Pb is supported by three prospective studies (two of which used the same NHANES III sample) but is not supported by two other prospective studies. One of the studies that did not find an association with blood Pb (at a mean blood Pb level of 5.6 μg/dL) reported a significant association between bone Pb levels and increased cardiovascular mortality. There is limited evi

dence for Pb effects on other cardiovascular outcomes, including electrocardiography (ECG) abnormalities and clinical cardiovascular disease primarily due to lack of replication studies. Chronic Pb exposure appears to be more critical than current Pb exposure, as shown by more consistent associations between chronic cardiovascular effects and bone Pb than for blood Pb. Studies support an association with concurrent blood Pb levels; however, the potential effect of early-life blood Pb levels on cardiovascular outcomes in adults cannot be discriminated from the effect of concurrent blood Pb levels without additional prospective studies in a population for which blood Pb levels remain con

sistently below 10 μg/dL from birth until evaluation of the various cardiovascular outcomes as described in Section 1.3 . There is inadequate evidence for Pb effects on heart rate variability, due to a lack of rep

licated studies. There is inadequate evidence to assess whether children or menopausal women present a sensitive life stage for cardiovascular effects of Pb. No prospec

tive studies have followed children with early-life Pb measures and evaluated cardiovascular health in adulthood. During periods of bone demineralization such as menopause and with osteoporosis, Pb stored in bone may enter the blood stream at a higher rate, increasing circulating Pb levels; for example, increased blood Pb levels have been demonstrated in women after menopause in several studies (e.g., Silbergeld et al. 1988, Symanski and Hertz-Picciotto 1995, Webber et al. 1995, Korrick et al. 2002). Too few studies have examined Pb-related cardiovascular health risks in postmenopausal women to enable conclusions. Although hypertension can contribute to adverse renal effects, and kidney dysfunction can contribute to increased blood pressure, effects are considered separately in this evaluation because most studies examined one outcome or the other, rather than test

ing both systems comprehensively.



### 1.4.5 Renal Effects The NTP concludes that there is sufficient evidence that blood Pb levels <5 μg/d L are associated withExecutiveSummary

NTP Monograph on Health Effects of Low-Level Lead xxiii adverse renal effects in adults (see Table 1.2 for sum

mary 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 lev

els <5 μg/dL are associated with adverse effects on kidney function in adults. Most of the 13 epidemio

logical 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 kid

ney function. The associations are typically stronger in studies of groups with hypertension or diabetes. Few studies have examined other markers of Pb exposure, such as bone Pb; therefore, it is unknown whether blood or bone Pb levels would be a better measure of exposure for kidney effects related to Pb. Epidemiological data from the general population support an association with concurrent blood Pb lev

els in adults; however, the potential effect of early-life blood Pb levels on kidney function in adults cannot be discriminated from the effect of concurrent blood Pb levels without additional prospective studies in a group for which blood Pb levels remain consistently below 10 μg/dL from birth until evaluation of kidney function as described in Section 1.3

. There is inadequate evidence to address the potential association between blood Pb levels <10 μg/dL in children <12 years of age and impaired kidney function, because results are inconsistent and available studies of kidney function in young children are less reliable in general because tests of kidney function lack clear predictive value in this age group. There is limited evidence that blood Pb levels <5 μg/dL are associated with adverse effects on kidney function in children ≥12 years of age. This conclusion is based on one study of NHANES data, which reported effects in children ≥12 years of age that are consistent with reduced eGFR reported in adults in several NHANES studies.



### 1.4.6 Reproduction and Developmental Effects The NTP concludes that there is sufficient evidence that blood Pb levels <10 μg/d L are associated with adverse health effects on development in children and that blood Pb levels <5 μg/ dL are associated with adverse health effects on reproduction in adult women (see Table 1.2 for summary of effects). Because most data on reproductive effects come from studies of occupational exposure, many of the available studies are for blood Pb levels >10 μg/ dL. For this reason, and because the original nomination focused on reproductive and developmental effects, the evaluation of health effects in this area includes higher blood Pb levels, unlike other sections of this document. Consideration of these higher blood Pb levels resulted in several conclusions for Pb-related reproductive effects in men but did not affect the conclusions for women or children. Unlike the data for most other health effect areas, a number of prospective studies of developmental effects have included prenatal measures of expo

sure (either maternal blood or umbilical cord blood). These prospective studies provide limited evidence that prenatal exposure to blood Pb levels <10 μg/dL is associated with reduced postnatal growth in children. Conclusions about effects of prenatal Pb exposure in children are complicated because blood Pb levels <10 μg/dL during childhood are also associated with reduced postnatal growth, and prenatal Pb levels are highly correlated with childhood Pb levels. In children, there is sufficient evidence that blood Pb levels <10 μg/d L are associated with delayed puberty and limited evidence for this effect at blood Pb levels <5 μg /dL. Nine studies reported that con

current blood Pb levels <10 μg/dL in children are associated with delayed puberty. There is sufficient evidence that blood Pb levels <10 μg/dL are associ

ated with decreased postnatal growth. Numerous cross-sectional studies, including studies with large sample sizes such as the NHANES data sets, reported that concurrent blood Pb <10 μg/ dL in children is associated with reduced head circumference, height, or other indicators of growth. In adults, there is sufficient evidence that mater

nal blood Pb levels <5 μg/dL are associated with reduced fetal growth or lower birth weight. Three prospective studies with maternal blood Pb data dur

ing pregnancy, a large retrospective study (examining medical history) of >43,000 mother-infant pairs with a mean maternal blood Pb level of 2.1 μg/d L, and several cross-sectional studies of Pb levels in mater

nal or cord blood at delivery support an associationxxiv NTP Monograph on Health E ffects of Low-Level LeadExecutiveSummary between higher blood Pb and reduced fetal growth at mean blood Pb levels from 1 to 10 μg/dL. Although maternal or paternal bone Pb data are not available in most studies of reproductive health outcomes, a set of studies of a single group reported that higher maternal bone Pb is related to lower fetal growth. There is also limited evidence that maternal blood Pb levels <10 μg/dL are associated with preterm birth and spontaneous abortion. Although several prospective studies reported an association between maternal blood Pb and preterm birth, the conclusion of limited evidence is due to inconsistent results and a retrospec

tive study with a large cohort of >43,000 mother-infant pairs not finding an association between maternal blood Pb levels and preterm birth. The conclusion of limited evidence for an association with spontaneous abortion is based primarily on the strength of a single prospective nested case-control study in women, with additional support provided by occupational studies that reported an association with Pb exposure but lacked blood Pb measurements. In men, there is inad

equate evidence that blood Pb levels <10 μg/dL a re associated with effects on reproduction. In men there is sufficient evidence that blood Pb levels ≥15 μg/dL a re 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 con

centration have been reported in multiple retrospec

tive and cross-sectional occupational studies of men with mean blood Pb levels from 15 to 68 μg/dL. Four studies reported increased time to pregnancy in women whose male partners had blood Pb levels of 20-40 μg/dL. A single retrospective occupational study reported increased risk of infertility among men with blood Pb levels ≥10 μg/dL, and the consistency of this observation with other studies reporting effects on time to pregnancy at higher blood Pb levels supports a conclusion of limited evidence that blood Pb levels ≥10 μg/dL in men are associated with other measures of reduced fertility. There is also limited evidence that paternal blood Pb levels >31 μg/dL are associated with spontaneous abortion, based primarily on the strength of a single retrospective nested case-control study in men, with additional support provided by occupational studies that reported an association with Pb exposure but lacked blood Pb measurements.



### 1.5 Future Research There are robust data and sufficient evidence that blood Pb levels <10 μg/dL in children and adults are associated with adverse health effects across a wide range of health outcomes, as described above. Over time, epidemiological studies have provided data to support health effects at lower and lower blood Pb levels, particularly in children. Prospective studies in children better address the lower limits of Pb expo

sure associated with health effects because they focus on children whose blood Pb levels remain <10 μg/dL or <5 μg/dL with certainty throughout their lifetime. Studies of health effects in adults cannot eliminate the potential effects of early-life blood Pb levels on health effects observed as adults. This is particularly important in an evaluation of the health effects of blood Pb levels <10 μg/dL because older adults were likely to have had blood Pb levels >10 μg/dL as childr en (see discussion in Section 1.3 ), compared with only 0.8% of children with confirmed blood Pb levels >10 μg/dL in 2008. Clarification of the effects of early-life blood Pb levels relative to the effects of concurrent blood Pb levels remains a significant issue for evaluating Pb-related health effects in adults. Epidemiological data from adults support an association between concurrent blood Pb levels <5 μg/dL and decreased renal function and between concurrent blood Pb levels <10 μg/dL and incr eased blood pressure and hypertension. Future research should be directed at clarifying the extent to which early life exposure (e.g., blood Pb levels >10 μg/dL) con tribute to health effects observed in adults. Long-term prospective studies in a group for which blood Pb levels remain consistently <10 μg/dL from birth until the outcome of interest is measured would take one step in this direction by eliminating the potential role of early-life blood Pb levels >10 μg/dL on health effects observed in adults with concurrent blood Pb levels <10 μg/dL.Methods

NTP Monograph on Health Effects of Low-Level Lead 1 

## 2.0 METHODS

The NTP’s conclusions on health effects of low-level Pb are based on evaluation of data from epidemiological studies with a focus on blood Pb levels <10 μg/dL. The methodological approach began with a statement of the key questions addressed by this evaluation. The general approach for developing the NTP’s conclusions on evidence of an association between blood Pb levels <10 μg/dL and specific health effects is described below, along with the format and definitions used throughout the document. The structure of appendix tables sum

marizing the relevant literature for each health effect area is also described below. The NTP considered sev

eral recent government evaluations of the health effects of Pb as authoritative sources to supplement a review of the primary epidemiological literature, and these docu

ments 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 the evidence for health effects associated with low-level Pb, as well as the appendices and background exposure section. The literature search strategy and details of the peer-review process are also described below.



### 2.1 Key Questions What is the evidence that adverse health effects are associated with blood Pb <10 μg/dL?

6 What reproductive, developmental, neurological, immune, cardiovascular, and renal health effects are associated with blood Pb levels <10 μg/dL? 6 What is the blood Pb level associated with a given health effect (i.e., <10 μg/dL or <5 μg/dL)? 6 At which life stages (childhood or adulthood) is the effect identified? 6 Are there data to evaluate the association be twee n bone Pb and the health effect, and how does the association to this biomarker of Pb exposure com

pare 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 epide

miological studies with a focus on blood Pb levels <10 μg/dL. The evaluation includes a review of the primary epidemiological literature, and these studies formed the basis for the NTP conclusions. The qual

ity of individual studies was considered in reaching health effects conclusions, including consideration of known confounders, appropriateness of the method of diagnosis, strength of the study design, and the sample size. General strengths and limitations of study designs were considered when developing con

clusions, with prospective studies providing stronger evidence than cross-sectional or case-control studies. Consistency of effects across the body of evidence and important factors such as the number of studies, exposure levels, biological plausibility, and support from the animal literature were all assessed when developing the NTP conclusions. Draft NTP conclusions were evaluated for con

sistency with health effect conclusions from recent government evaluations considered authoritative sources: the U.S. EPA 2006 Air Quality Criteria Docu

ment (AQCD) for Lead ( U.S. EPA 2006 ) and the ATSDR 2007 Toxicological Profile for Lead ( ATSDR 2007 ) (see Section 2.4 for discussion). Technical advisors with relevant subject matter expertise served as another authoritative source (see Section 2.4.4 for details). Technical advisors were asked to critically evaluate every one of the NTP’s conclusions regarding the potential for adverse health effects to occur at blood Pb levels <10 μg/dL and to determine whether the sci

ence cited was technically correct, clearly stated, and supported the NTP’s conclusions in pre-public release drafts of each chapter addressing specific health effect areas. As described in Section 2.6 and Peer-Review of the Draft NTP Monograph , a draft version of the Monograph was released for public comment and peer review by an expert panel of ad hoc reviewers. Written public comments and comments from peer reviewers were considered during finalization of the document.Studies were evaluated for evidence that lowlevel Pb is associated with neurological, immunologi

cal, cardiovascular, renal, and/or reproductive and developmental effects. These health effects areas were selected because there is a relatively large database of human studies in each area. The NTP con

sidered four possible conclusions for specific health effects within each area. Sufficient Evidence of an Association: An association is observed between the expo

sure and health outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence.2 N TP Monograph on Health Effects of Low-Level Lead Limited Evidence of an Association: An association is observed between the expo

sure and health outcome in studies in which chance, bias, and confounding could not be ruled out with reasonable confidence. Inadequate Evidence of an Association: The available studies are insufficient in quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association between exposure and health outcome, or no data in humans are available. Evidence of No Association: Several adequate studies covering the full range of levels of exposure that humans are known to encounter (in this case limited to blood Pb levels <10 μg /dL) are mutually consistent in not showing an association between exposure to the agent and any studied endpoint.

The discussion of each health effect begins with a statement of the NTP’s conclusion regarding whether the specific effect is associated with a blood Pb level <10 μg /dL or <5 μg /dL and the age group in which it is or is not identified (childhood or adult

hood), as well as the timing of exposure associated with the effect (prenatal, childhood, concurrent) when available. Then key data and principal studies considered in developing the NTP’s conclusions are then discussed in detail. Each section concludes with a summary discussing each health effect, describing experimental animal data that relate to the human data, and stating the basis for the NTP’s conclusions. For the purposes of this evaluation, “children” refers to individuals <18 years of age unless oth

erwise specified. In addition to the blood Pb level of <10 μg /dL, a lower effect level of <5 μg /dL was also selected because it is commonly used in epide

miological studies to categorize health effect data by exposure levels; therefore, data are often available to evaluate health effects for groups above and below this value as well. Findings described in the text as having an “association” or “significant association” reflect a statistically significant result with a p-value <0.05 unless otherwise indicated.



### 2.3 Appendices of Studies Considered The information to support the NTP’s conclusions for individual health effects is presented in each chapter. Human studies from groups with low-level Pb exposure that were considered in developing the conclusions are also abstracted for further reference and are included in separate appendices for each health effect area. Each appendix table includes the following col

umn headings: Description: study design, reference, and geo

graphic location Population: sample size, description, years of study, and percent male Age: mean age and standard deviation of the subjects Blood Pb: mean blood Pb level and standard deviation (in μg/dL) Outcomes: health effects assessed Statistical: methods used and cofactors in clud e d in analyses Findings: summary of results (bolded if statistical significance tests had a p-value <0.05) Observed Effect: conclusion (Effect/No Effect/ Equivocal) and description

Potential overlap of subjects in multiple pub

lications from the same epidemiological study is indicated in the first column of each appendix. These studies were not considered as independent findings to be evaluated in developing the NTP’s conclusions. The grouping of studies within each appendix table varied by health effects considered: Appendix A. Neurological Effects: no grouping, meta-analyses shaded Appendix B. Immune Effects: grouped by low (<15 μg/dL) and high (>15 μg/dL) exposure Appendix C. Cardiovascular Effects: grouped by outcome, meta-analyses shaded Appendix D. Renal Effects: no grouping Appendix E. Reproductive and Developmental Effects: grouped by outcome

Within each grouping, studies are listed alpha

betically by first author and then chrono l ogic al ly by publication date. For the appendix tables grouped by outcome, if a publication contained results that applied to more than one group, results specific to each outcome group were included. The NTP’s conclusions are based on the evi

dence from human studies with blood Pb levels of <10 μg /dL and therefore the abstracted studies inMethods

NTP Monograph on Health Effects of Low-Level Lead 3 the appendices are mainly those with a mean blood Pb level of <10 μg/dL. However, studies with data reflecting mean exposure levels up to 15 μg/dL were also included so that effects at and around 10 μg/dL were not missed during the evaluation. Reproductive effects in studies with mean blood Pb levels >15 μg /dL were included in the evaluation because the data set of human studies on these effects associated with lower blood Pb levels is limited. For this reason, and because the original nomination focused on repro

ductive and developmental effects, the evaluation of health effects in this area includes higher blood Pb levels. The immunological effects database was adequate to make conclusions on several effects at blood Pb levels <10 μg/ dL; however, because the NTP makes limited reference to studies in humans at higher blood Pb levels, Appendix B also includes human studies with higher blood Pb levels (i.e., >15 μg/dL).



### 2.4 Authoritative Sources Considered Recent government evaluations of the health effects of Pb include the U.S. EPA 2006 AQCD for Lead ( U.S. EPA 2006 ), the ATSDR 2007 Toxicological Profile for Lead ( ATSDR 2007 ), and the CDC’s Advisory Com

mittee on Childhood Lead Poisoning Prevention (ACCLPP) Reports, such as the 2010 Guidelines for the Identification and Management of Lead Expo

sure 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 exten

sive external public peer review. NTP considered the conclusions and data summaries from the EPA and ATSDR documents. In general, NTP concurred with the conclusions and agreed that the data support them. Differences between the NTP’s conclusions and the 2007 ATSDR Toxicological Profile for Lead ( ATSDR 2007 ) and the EPA’s 2006 AQCD ( U.S. EPA 2006 ) are identified for specific endpoints in this document. The database of studies on health effects in humans is supported by an equally large body of experimental animal studies. In this document, the experimental animal data are considered when rel

evant to reaching conclusions primarily based on the human literature. The reader is referred to the U.S. EPA AQCD for Lead ( U.S. EPA 2006 ) and ATSDR Toxicological Profile for Lead ( ATSDR 2007 ) for more in-depth reviews of the animal data. 

### 2.4.1 U.S. EPA 2006 Air Quality Criteria Document (AQCD) for Lead The EPA’s AQCD is an exhaustive review and assess

ment (>1,200 pages with an additional 900 pages of tables and other annex material) of the scientific information related to human health and ecological effects associated with Pb in ambient air ( U.S. EPA 2006 ). The EPA’s AQCDs are published periodically (the latest draft document, released February of 2012, updates the review with literature published since the U.S. EPA 2006 AQCD for Lead ( U.S. EPA 2006 )) to provide key scientific assessment of evidence to support periodic review of the current Pb National Ambient Air Quality Standards. The 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) is an extensively reviewed document that was subject to public comment and review by the Clean Air Scientific Advisory Commit

tee 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 avail

able 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 toxi

cological and epidemiological data on Pb. The toxi

cological profile is organized around a public health statement summarizing the toxicological and adverse health effects for Pb. ATSDR’s peer-review process for their toxicological profiles includes release for public comment and a peer review by a panel of experts.



### 2.4.3 CDC Lead Panel Documents CDC’s fifth revision of the statement on preventing Pb poisoning in young children includes a companion doc

ument developed by the ACCLPP that reviews the sci

entific evidence for adverse health effects in children at blood Pb levels <10 μg/dL. The committee concluded that the “overall weight of the evidence supports an inverse (negative) association between BLLs [blood lead levels] <10 μg/dL and the cognitive function in children” ( CDC 2005 ). The report focuses primarily on cognitive function, but the committee also concluded that additional health effects (e.g., other neurological functions, stature, sexual maturation) were associated with blood Pb levels <10 μg/dL in children. The ACCLPP has also prepared a draft report providing Guidelines for the Identification and4 NTP Monograph on He alth Effects of Low-Level LeadMethods Management of Lead Exposure in Pregnant and Lactating Women ( CDC 2010 ). The report provides “practical considerations regarding preventing lead exposure during pregnancy, assessment and blood lead testing during pregnancy, medical and envi

ronmental management to reduce fetal exposure, breastfeeding and follow-up of infants and children exposed to lead in utero.” The document summa

rizes the evidence from human studies through 2008 for health effects of Pb in pregnant women and the developing child (concentrating on exposure during gestation and from breastfeeding) and provides guid

ance for clinicians.



### 2.4.4 Technical Advisors The primary mechanism for obtaining scientific input during development of the draft NTP Monograph on Health Effects of Low-Level Pb was through technical advisors (see Contributors for list of technical advi

sors). Technical advisors with relevant subject matter expertise were asked to provide input on issues of sci

entific complexity, adequacy of the literature review, and overall presentation of a pre-public release ver

sion of the draft NTP monograph. These advisors critically evaluated each of the NTP’s health effects conclusions and the basis for those conclusions, as well as the appendices and the background exposure section. Individuals who served as technical advisors were screened for potential conflict of interest.



### 2.5 Literature Search Strategy The 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) and the 2007 ATSDR Toxicological Profile for Lead ( ATSDR 2007 ) were screened for citations on health effects assessed at low-level Pb exposure. The NTP’s con

clusions are based on the evidence from human studies with blood Pb levels of <10 μg/dL with data reflecting mean exposure levels up to 15 μg/dL also considered so that effects at and around 10 μg/dL were not missed during the evaluation. Primary lit

erature searches in MEDLINE®, Web of Science, Sco

pus, Embase, and TOXNET were conducted on March 1-5, 2010, to identify relevant studies published subsequent to the 2006 EPA and 2007 ATSDR docu

ments. Search terms included the following MeSH subject headings: lead or lead poisoning; “diseases category” or “anatomy category” for health effects; and humans[mh or Medical Subject Headings in MEDLINE] or epidemiology[sh or SubHeadings in MEDLINE] or epidemiologic studies[mh] or age groups[mh] for limiting to human studies. Because of the heteronym nature of the term “lead,” text word searching used four approaches: (1) searched for “lead” in title; (2) used various com

binations to focus on low-level exposure: “low lead” or “low blood lead” or “lower lead” or “lower blood lead” or “low level” or “low levels” or “lower level” or “lower levels” or “lead level” or “lead levels” or “low dose” or “lead induced” or “lead intake” or “blood lead”; (3) combined “lead” with heavy metals or cad

mium or mercury or arsenic; and (4) when necessary
, excluded “lead to” or “leads to” from search results. For databases that allowed proximity searching, “lead” and “low or lower” were required to be in the same sentence. This strategy would retrieve articles such as “low cadmium and lead levels” or “low blood and urine lead levels” or “lower concentrations of lead in the blood.” Text words used to retrieve human studies included human(s), resident(s), inhabitant(s), popula

tion, people, subject(s), patient(s), case(s), women, men, girls, boys, parent(s), mother(s), father(s), adult(s), child, children, childhood, adolescent(s), infant(s), toddler(s), newborn(s), occupation(al), work, workplace, worker(s), employee(s), laborer(s), and staff. An updated search was performed September 12-15, 2011, to identify any additional references published since the last search. Technical advisors who were involved in the review of the draft docu

ment (see below) were also asked to identify relevant studies. In addition, NTP published a Federal Register notice regarding the low-level Pb evaluation, inviting submission of information about recently published/ in-press studies that might be relevant for consider

ation in the evaluation (75 FR 51815).



### 2.6 Peer-Review Process Peer review of the Draft NTP Monograph was con

ducted by an expert panel of ad hoc reviewers with relevant scientific background (i.e., expertise in Pb or metals related to reproductive and developmental toxicology, neurotoxicology, immunotoxicology, car

diovascular toxicology, renal toxicology, and exposure) at a public meeting held November 17-18, 2011 in Research Triangle Park, NC (see Peer Review of the Draft NTP Monograph for list of panel members). The selection of panel members and conduct of the peer review were performed in accordance with theMethods

NTP Monograph on Health Effects of Low-Level Lead 5 Federal Advisory Committee Act and Federal policies and regulations. The panel was charged to determine whether the science cited in the draft NTP Monograph on Low-Level Lead was technically correct, was clearly stated, and supported NTP’s conclusions regarding the potential for adverse health effects to occur at blood Pb levels <10 μg /dL. Public comments received as part of the NTP’s evaluation of health effects of low-level Pb, meeting minutes, and other materials from the peer-review meeting are available at http://ntp.niehs. nih.gov/go/37090. Written public comments and com

ments from peer reviewers were considered during finalization of the document.6 N TP Monograph on Health Effects of Low-Level Lead THIS PAGE LEFT INTENTIONALLY BLANKNTP Monograph on Health Effects of Low-Level Lead 7 

## 3.0 EXPOSURE

Studies of health effects of Pb in humans commonly use one of several biomarkers to reflect the level of Pb exposure in an individual. The overwhelming major

ity of studies measure whole-blood Pb because blood samples are routinely collected and stored in large epidemiological studies; furthermore, the methods for measuring Pb in whole blood are widespread and extensively validated. Bone Pb is more likely to reflect cumulative exposure but must be measured by spe

cialized equipment and requires measurements to be made on subjects present at a research clinic. Mea

sures of Pb in urine and hair have been used in some studies, but how well they reflect the body burden of Pb is less clear. Pb is ubiquitous in the environment, but the level of exposure to Pb that individuals experience can vary and depends on many factors, including occupation, geography, and life stage. This chapter briefly discusses common routes of exposure to Pb and associated fac

tors that may affect the risk of exposure. The NTP made extensive use of recent govern

ment evaluations of Pb exposure and associated health effects in developing the current assessment. The EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ) both contain extensive review and discussion of Pb exposure, with the AQCD document particularly focusing on Pb in air. The NTP also used two CDC doc

uments focused on particularly vulnerable groups: the 2010 Guidelines for the Identification and Man

agement of Lead Exposure in Pregnant and Lactating Women and the 2005 Preventing Lead Poisoning in Young Children report ( CDC 2005b
, 2010 ). The EPA is in the process of revising the AQCD and has released an external review draft that also includes extensive discussion of Pb exposures ( U.S. EPA 2012 ).



### 3.1 What Does It Mean to Refer to Blood Pb <10 μg/dL? This evaluation focuses on the relationship between health effects and blood Pb levels <10 μg/dL because (1) whole-blood Pb is the most widely available mea

sure of exposure, (2) blood Pb reflects an equilibrium between current environmental Pb exposures and Pb stored in bone from prior exposures, and (3) numer

ous studies have reported an association between blood Pb levels and health effects. However, measuring Pb in one tissue at one point in time does not present a complete picture of either current or cumulative Pb exposure. Bone Pb is considered superior to blood Pb in reflecting the long-term stores of Pb in the body ( e.g., Rabi

nowitz 1991
, reviewed in Barbosa et al. 2005
, Hu et al. 2007 ). When available, bone Pb data were also considered in this evaluation. However, measuring bone Pb is expensive and requires subjects to travel the location of the specialized measurement appara

tus (K-x-ray fluorescence). A number of authors have hypothesized that blood Pb may provide a better measure of Pb exposure in children or other subjects with active bone remodeling (see reviews by Barbosa et al. 2005
, Hu et al. 2007 ). However, few studies in children have examined the usefulness of bone Pb data as a measure of exposure in children to test this hypothesis, other than studies that reported Pb lev

els in shed deciduous teeth (baby teeth). When data were available for multiple measures of exposure, the association between health effects and either blood Pb or bone Pb levels was evaluated in this document. While the vast majority of exposure data were in the form of blood Pb measurements, in some cases there was enough data to begin to com

pare 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 rela

tive strength of the association between measures of exposure and the health outcome has not been widely examined, in some cases bone and blood Pb measure

ments are available in the same group or study and the data have been analyzed in a method that allows such a comparison. For example, multiple studies have reported that blood Pb levels were associated with decreased IQ in the Yugoslavia Prospective Study (see discussion in Section 4.3.1 ). Wasserman et al. ( 2003 ) demonstrated a stronger association between bone Pb and IQ than for blood in a subset analysis of 167 chil

dren 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 dramati

cally declined over the last 30 years after bans on Pb in paint, solder, and gasoline, representing a significant8 NTP Monograph on He alth Effects of Low-Level Lead public health accomplishment and protection for current populations of children. However, children born in the United States in the 1970s had a mean blood Pb of 15 μg/dL during early childhood. Conse

quently, health effects in adults today may have been influenced by blood Pb levels >10 μg/dL tha t many individuals experienced earlier in life. Keeping these childhood blood Pb levels in mind, there are data on multiple health effects in adults for which studies report a significant relationship with concurrent blood Pb levels (e.g., elevated blood pressure, reduced kidney function, or decreases in specific measures of cognitive function). There is a considerable body of evidence that these health effects are associated with Pb exposure, and mul

tiple studies report a significant association with concurrent blood Pb levels <10 μg/dL. Fur thermore the association with blood Pb is supported by the consistency of effects across epidemiological studies, as well as biological coherence with animal data. It is well recognized that the role of early-life Pb exposure cannot be discriminated from the role of concurrent blood Pb without additional long-term studies. As described in Section 2.2 , the NTP’s conclusions were derived by evaluating data from epidemiologi

cal studies with a focus on blood Pb levels <10 μg/dL. The evidence discussed for specific health outcomes within each chapter varies by study design and type of analyses used to examine the relationship of the health outcome with blood Pb across the hundreds of studies evaluated. In some cases, studies examined only groups with blood Pb levels <10 μg/dL, <5 μg/dL, or even lower, and the association of the health effect with the blood Pb level is clear. For example, Lanphear et al. ( 2000 ) reported that higher blood Pb was associated with lower academic performance in a cross-sectional study of 4,853 children ages 6-16 from the NHANES III data set. When they analyzed only children with blood Pb <10 μg/d L (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 asso

ciation between blood Pb and an effect in a group whose mean blood Pb level <10 μg/dL (e .g., higher blood Pb level was associated with higher blood pressure in a study of 964 adults in the Baltimore Memory Study ( Martin et al. 2006 )). These analyses support an effect of a blood Pb level <10 μg/dL, but they do not exclude the possibility that individuals significantly above or below the mean blood Pb level are driving the effect, or that past exposure levels are driving the effect. Finally, some studies compared effects between two groups with higher and lower blood Pb levels. For example, Naicker et al. ( 2010 ) compared the effect of a blood Pb level ≥5 μg/dL with a blood Pb level <5 μg/dL on developmental markers of puberty in 13-year-old girls in South Africa (n=682) and found that blood Pb ≥5 μg/dL w as significantly associated with delayed breast development, pubic hair development, and age of menarche.



### 3.2 Biomarkers of Pb Exposure The large majority of human epidemiological studies that report individual Pb exposure levels measured Pb in blood samples. This chapter discusses U.S. blood Pb levels and trends for age, gender, and race or ethnicity. Bone Pb has been measured in some studies and is considered to more accurately reflect cumulative body burden of Pb because of the lon

ger 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 avail

able biomarker for Pb exposure (and is the basis for this evaluation of Pb levels <10 μg/dL), plasma Pb is the portion of blood Pb that is available to cross cell membranes and enter specific tissues of the body ( Cavalleri et al. 1978 ). Plasma Pb represents <5% of the whole-blood Pb concentration, but the proportion of whole-blood Pb in plasma Pb can vary widely and can be influenced by bone Pb levels ( e.g., Hernandez-Avila et al. 1998
, and reviewed in Hu et al. 1998 ). Measuring plasma Pb is technically difficult, requires specialized equipment not widely available, and is not typically measured in research or clinical settings ( CDC 2010 ). Variation in whole blood or plasma collection methods and Pb quantification techniques may limit comparability across studies, particularly when a method with a relatively high level of detection is used in a population with lower Pb exposures. The National Health and Nutrition Examination Surveys (NHANES) include whole-blood Pb measure

ments on a cross section of the U.S. population. Spe

cific outcomes in subgroups of the study are routinelyNTP Monograph on Health Effects of Low-Level Lead 9 published and are included in the chapters of this document covering specific health effects. General trends in blood Pb levels from NHANES data are pre

sented in Figures 7.1, 7.2, and 7.3 (from Mahaffey et al. ( 1982 ), Brody, et al. ( 1994 ), and the CDC ( 2005a
, 2011b ) including the updated tables for CDC (2009b )). Blood Pb levels have decreased over the last 30 years for all age groups (see Figure 3.1 ). The declining blood Pb levels follow declines in Pb exposure related to bans on leaded gasoline, paint, and use of solder in food cans and plumbing in the United States (see Sec

tion 3.3 Sources of Pb ). Prior to the 1970’s blood Pb levels were not routinely measured for research pur

poses, but tooth Pb measurements estimate that peak exposure occurred around 1960 and this is supported by Pb levels in lake sediments ( Robbins et al. 2010 ). Unfortunately, the burden of Pb exposure is not uniformly low in all racial and ethnic subgroups (see Figure 3.2 ). Non-Hispanic blacks have higher blood Pb levels than do non-Hispanic whites across all ages, and being non-Hispanic black is a major risk factor for higher Pb levels in children ( Jones et al. 2009 ). When comparing Pb levels for non-Hispanic blacks to those for non-Hispanic whites, almost every age and gender group among blacks had Pb levels statistically significantly higher in both 1991-1994 and 1999-2002 ( CDC 2005a ). In a study of 249 children in Rochester, NY followed from age 6 to 24 months, black children had higher blood Pb levels even after accounting for exposure level and other modifying factors ( Lanphear et al. 2002 ). Males also consistently have higher blood Pb levels than do females (see Figure 3.3 ), and this trend was observed in NHANES across most age groups and all racial/ethnic groups ( CDC 2005a ). Given an accumulating body burden of Pb and higher past levels of Pb exposure, blood Pb levels are expected to go up with age; however, young children (ages 1-5 years) consistently have higher blood Pblevels than do older children, likely due to hand-tomouth behavior in this age group (see Figure 3.2 ). Sev

eral 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 reduc

tion programs because of these higher levels and the established developmental impairments associated with Pb exposure (e.g., CDC’s Childhood Lead Poi

soning Prevention Program see http://www.cdc.gov/ nceh/lead/about/program.htm ) ( CDC 2005b
, Clark et al. 2011 ). Blood Pb levels in young children (1-5 years of age) have decreased 10-fold over the last 30 years (geometric means: for 1976-1980, 15.1 μg/dL; for 2007-2008, 1.51 μg/dL ( CDC 2007b
, 2011b )). In 2008, only 0.8% of children had confirmed blood Pb levels >10 μg/dL, d own from 7.6% in 1997 ( http://www.cdc.gov/nceh/lead/data/national.htm ). However, blood Pb levels have remained consistently higher in non-Hispanic black children, which may be linked to a variety of factors contributing to higher Pb exposure, such as lower socioeconomic status, liv

ing in older, urban housing, or having lower calcium intake (see Figure 3.2 ; discussed further in Section 3.3 Sources of Pb and Section 3.4 Modifiers of Pb Exposure ) ( Haley and Talbot 2004 ). Pb exposure in this critical developmental period can have immedi

ate impacts on children’s health and contribute to a lifetime of exposure from Pb. An individual’s blood Pb level reflects an equilib

rium between current exogenous environmental Pb exposure and the internal (endogenous) body bur

den of Pb ( Factor-Litvak et al. 1999
, Brown et al. 2000
, Chuang et al. 2001 ). The body quickly eliminates met

als 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 approxi

mately 1 month, while the half-life in bone ranges from 10 to 30 years depending on the bone turnover rate, which varies by type of bone and life stage ( Rabinowitz 1991 ). An estimated 45-70% of blood Pb comes from Pb released from endogenous tissue Pb stores, primarily in bone ( Gulson et al. 1995 ).Toxico

kinetic models often include other tissues within the model for blood because Pb levels rapidly equilibrate between tissues and blood ( e.g., Rabinowitz 1991 ); however, data on turnover in other organs is limited. The distribution of Pb in tissues changes with life stage. The distribution is also heterogeneous within bone. Bone and teeth store 90-95% of the total body burden of Pb in adults and from 70% to 95% of the total body burden in children (reviewed in Barbosa et al. 2005
, Hu et al. 2007 ). Bone Pb was the source of between 40% and 70% of blood Pb in individuals undergoing hip or knee replacement surgery ( Smith et al. 1996 ). Pregnancy, lactation, menopause, and osteoporosis are periods of bone demineralization, which may release Pb from bone stores and contrib

ute to increased Pb exposure to other tissues, or to10 N TP Monograph on Health Effects of Low-Level Lead 

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

Years and ages are grouped based on available published data:

• 1976-1980 (Mahaffey et al. 1982)

• 1988-1991 (Brody et al. 1994)

• 1991-1994, 1999-2002 (CDC 2005a)

• 2003-2008 (C DC (2005a, 2011b)) 0 4 8 12 16Mean Blood Pb (μg/dL)

NHANES Years 197 6- 1980 198 8- 1991 1991-1994 1999-2002 2003-2008 2 6 10 14 Children, 1-5 years Children, 6-19 years Adults, 20 years



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

Mean blood Pb level and 95% CIs for different ages of non-Hispanic whites (open circle), non-Hispanic blacks (closed circle), and Mexican Americans (shaded circle) (CDC 2005a). 1.0 1.5 2.0 2.5 3.0
Blood Pb Levels (Geometric Mean ± 95% CI)JJJJJJJJJJJJ 1-5 years (1,610) White, non-Hispanic Black, non-Hispanic Mexican American
6-19 years (6,283) White, non-Hispanic Black, non-Hispanic Mexican American
20-59 years (5,876) White, non-Hispanic Black, non-Hispanic Mexican American
60 years (3,056) White, non-Hispanic Black, non-Hispanic Mexican American Age (N, all races)

Race/EthnicityNTP Monograph on Health Effects of Low-Level Lead 11 Pb exposure for a developing fetus from Pb released from maternal bone. This hypothesis has been sup

ported 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 demin

eralization 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, continu

ous growth results in constant bone remodeling, and bone Pb is likely to be exchanged with blood Pb much more frequently than in adults (reviewed in Barbosa et al. 2005
, Hu et al. 2007 ). Additional factors that can increase risks to women and children are discussed further in the Section 3.4 Modifiers of Pb Exposure

. Bone Pb is typically measured by K-x-ray fluo

rescence (also called KXRF); however, few research institutions possess this technology and staff trained to use it. The most commonly used KXRF devices have a high detection limit (~10 μg/g bone mineral) and a wide error of measurement, so studies that use this method may underestimate the effect on health. Newer configurations of KXRF with a lower detection limit and less measurement error may improve these estimates, particularly in populations with lower exposure to Pb ( Behinaein et al. 2011 ). A more portable x-ray fluorescence device for in vivo (within the body) bone Pb measures was developed using lower energy L-band x-rays which measure Pb concentration in the outermost layer of bone ( Nie et al. 2011 ). Both of these methods are impacted by the thickness of skin over the measurement site which may be a concern in health effects related to obe

sity. Comparison of bone Pb levels between research groups is challenging without a common standard for calibration of instruments. Another modeling approach estimates bone Pb levels from blood Pb measures and covariates typically collected in epide

miological studies ( Park et al. 2009 ). This approach could be used to estimate bone Pb in existing stud

ies that do not have the ability to measure bone Pb directly. While blood Pb is by far the most common measure of exposure, it may not be as appropriate as bone Pb, particularly for studies of chronic health conditions (reviewed in Barbosa et al. 2005
, Hu et al. 

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

Mean blood Pb level and 95% CIs for men (closed squares) and women (open circles) (CDC 2011b). 1999-2000 Male Female

2001-2002 Male Female

2003-2004 Male Female

2005-2006 Male Female

2007-2008 Male Female N 3,913 4,057

4,339 4,606

4,132 4,241

4,092 4,315

4,147 4,119

1.00 1.25 1.50 1.75 2.00 2.25
Blood Pb Levels (Geometric Mean ± 95% CI)JJJJJ Years Gender12 NTP Monograph on He alth Effects of Low-Level Lead 2007 ). Physiologically based pharmacokinetic (PBPK) models have been created to combine current blood and bone Pb measures to estimate the Pb levels at the time of the exposure, allowing a more com

plete model of the individual’s lifetime Pb exposure ( Leggett 1993
, Coon et al. 2006 ). Pb has also been measured in hair, urine, and other materials that are easier to obtain; but in general Pb levels fluctuate more rapidly in these materials than in bone. Hair collection is minimally invasive, and hair is easier to ship and store; how

ever, there are no reliable standardized protocols for hair collection, and hair is subject to contamination from environmental sources of Pb (reviewed in Seidel et al. 2001
, Harkins and Susten 2003
, Barbosa et al. 2005 ). In 2001 an ATSDR expert panel concluded that there were too many unresolved scientific issues for hair to be a useful source for evaluating exposures to trace metals, including Pb ( ATSDR 2001 ). Collection of urine is noninvasive, and urine has also been used to measure Pb; however, urine Pb levels vary rapidly and independently of blood Pb and require correc

tion for creatinine levels and glomerular filtration rates to estimate plasma Pb levels at a specific col

lection time (reviewed in Barbosa et al. 2005
, Hu et al. 2007 ). Fecal Pb levels reflect both excreted biliary Pb and unabsorbed ingested Pb but must be completely collected over several days to accurately reflect Pb exposures ( reviewed in Barbosa et al. 2005 ). In studies designed to examine reproductive effects, Pb levels in other tissue and fluids have been measured, including semen ( e.g., Naha and Manna 2007 ), ovarian follicles (e.g., Silberstein et al. 2006
, Al-Saleh et al. 2008 ), and placenta (e.g., Odland et al. 2004
, Llanos and Ronco 2009
, Gundacker et al. 2010 ). Most studies report a single measure of exposure and do not directly compare the relationship between a health effect and different measures of Pb exposure (i.e., tissue Pb compared to blood Pb). Therefore, the usefulness of semen Pb, follicular Pb, or placental Pb as a measure of exposure rather than blood Pb is dif

ficult to ascertain. At this time, blood Pb is a more widely available and is a well-established measure of exposure that is associated with multiple adverse health effects. Unlike these fluctuating measures, teeth accu

mulate Pb like other bone, lose Pb at a slower rate than other bone, and for childhood exposure studies, primary teeth (baby teeth) are readily available when lost after 6 years of age ( e.g., Manea-Krichten et al. 1991 ). In addition, the layers of the tooth provide a timeline of Pb exposure, including in utero (enamel) and early-childhood (primary tooth dentin) expo

sures, which may be separately measurable (by laser ablation/inductively coupled plasma/mass spectrom

etry) without removing the tooth ( Uryu et al. 2003 ). Some studies used indirect measures to esti

mate 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 com

ponent of several iron-containing proteins including hemoglobin, the protein that transports oxygen in blood. ALAD can be measured in urine, blood, and plasma and is inversely related to Pb levels ( reviewed in Barbosa et al. 2005 ). While not widely used, ALAD levels in blood may be a better marker of long-term exposure than blood Pb measures, but urine ALAD is not sensitive and so is not a good indicator at low Pb exposure levels ( Alessio et al. 1981
, Telisman et al. 1982 ). Pb can also impair heme formation by inhibit

ing ferrochelatase such that zinc is used in place of iron, increasing levels of zinc protoporphyrin (ZPP) ( reviewed in Barbosa et al. 2005 ). ZPP levels in blood have been used as an indicator of Pb poisoning, but ZPP testing is not sensitive when blood Pb levels are <25 μg/dL ( Wildt et al. 1987
, Parsons et al. 1991
, Labbe et al. 1999 ).



### 3.3 Sources of Pb The primary routes of exposure in the general popula

tion are oral exposure to Pb from ingesting contami

nated water and food or inhaling air and soil contain

ing Pb. For an extensive discussion of environmental sources of Pb, see the EPA’s 2006 AQCD ( U.S. EPA 2006 ). Hand-to-mouth behavior in young children increases their risk of exposure to Pb in dust, toys, and paint. Occupational exposures in Pb industries are often associated with elevated Pb levels in workers and can also contribute to Pb exposures in coworkers who do not work with Pb, or in family members exposed to dust brought into the home from the person who works with Pb ( Hipkins et al. 2004 ). Tap water once contributed to as much as 10-20% of total Pb exposure in the United States before amendments to the Clean Water Act ( U.S. EPA 2006 ), and some older pipes, taps, and pre-1986 pipeNTP Monograph on Health Effects of Low-Level Lead 13 solder still contain Pb. Source drinking water rarely contains Pb, and the Pb enters tap water through corrosion of Pb from pipes and plumbing fixtures. Corrosion creates exposure from Pb deposits even after previous sources of Pb have been removed from water lines, as well as actual Pb pipes or Pb solder. This corrosion can significantly increase the Pb con

tent in drinking water after changes in water disin

fection processes, particularly with use of chloramine ( Miranda et al. 2007
, Jean Brown et al. 2011 ). In a highly publicized incident, the District of Columbia’s water supply exceeded the 15 μg/L actio n level for Pb several times between 2000 and 2004 because of corrosion of Pb scales in service pipes after a switch to chloramine to reduce disinfection byproducts ( U.S. EPA 2007 ). Monitoring in homes with Pb service lines in the district found a small increase in the incidence of blood Pb levels >5 μg/dL, but not over the 10 μg/dL CDC level of concern for children; however, further analysis showed that children in homes with Pb ser

vice lines were at risk for blood Pb levels >10 μg/dL even during periods when Pb levels in water were below the action level ( CDC 2004
, Jean Brown et al. 2011 ). In addition, the incidence of blood Pb levels >10 μg/dL was increased in infants less than 1.3 years of age during the DC drinking water event ( Edwards et al. 2009 ). Infants may be at an increased risk from contaminated water if they drink infant formula made with tap water, because they typically consume 6 oz/kg of formula daily, so infants may have higher exposure relative to body weight than do others in the same household ( Bearer 1995 ). Die tary Pb sources in the United States have been reduced through several changes in practice, such as removing Pb solder from cans and banning Pb-ar senate pesticides ( Bolg er et al. 1996 ), and cur

ren t Pb levels in the U.S. food supply are low ( CDC 20 10 ). Contaminated food, particularly if imported fr om other countries, can be a source of dietary Pb
exposur e. A study of pregnant women in Monterey, Cal ifornia, identified prepared grasshoppers sent from Oaxaca, Mexico, as a source of Pb poisoning ( Handley et al. 2007 ), and tamarind candies imported fro m Mexico were linked to several cases of Pb poison

ing in children ( CDC 2002 ). Spices, herbs, nutritional
sup plements, and traditional medicines have been shown to contain or be contaminated with Pb as well ( K o 1998
, CDC 1999
, 2002
, Buettn er et al. 2009
, Lin
et al. 2010 ). Pottery with a Pb glaze can contaminate food if used for cooking or storage ( CDC 2010 ). While high , acute exposures have been reported from Pb from pottery leaching into food ( Matt e et al. 1994 ), long-term use may cause a low, chronic exposure and raise the body burden of Pb ( Hernande z Avila et al. 1991 ). Use of Pb-glazed ceramics was a major source of cum ulative Pb exposure in a study of women in Mexic o ( Br own et al. 2000 ). Pb crystal glassware can

re lease Pb into alcoholic beverages at levels above the EP A’s maximum allowable level for drinking water ( Grazi ano and Blum 1991 ). In addition, approximately 25% o f home-distilled alcohol (moonshine) samples
tes ted by the U.S. Bureau of Alcohol Tobacco and Firearms between 1995 and 2001 had Pb concentra

tions >400 μg/dL from the use of inappropriate mate

rial s in the distillation process (e.g., car radiators or

we lded metal parts). These concentrations are high enough to produce blood Pb levels >25 μg/dL if one liter was consumed ( Morgan et al. 2004 ). Moonshine
consump tion has been associated with blood Pb lev

els >15 μg/dL and Pb-related deaths ( Pegues et al. 1993
, K aufmann et al. 2003 ). Inhaled Pb is another source of Pb exposure ( U.S. EPA 2006 ). During the renovation of buildings built before 1978, dust from Pb paint can be inhaled, and residual contamination after a renovation with inadequate cleanup may continue to expose build

ing occupants to Pb. The U.S. Department of Housing and Urban Development estimated that 40% of U.S. housing contains Pb paint, which presents a potential Pb hazard when it is disturbed or deteriorates ( HUD 2001 ). Leaded gasoline is another inhaled source of Pb in parts of Asia, Eastern Europe, the Middle East, and South America. In the United States, leaded gaso

line was banned in 1996 after being phased out for more than 20 years, and average ambient air Pb lev

els fell 93% between 1980 and 2009 ( Figure 3.4 ) ( U.S. EPA 2006 ). While Pb paint and leaded gasoline are no longer major sources of Pb in the United States, Pb from these sources remains in soil and dust, as well as inside people’s bodies in bone and other organs as part of the body burden of Pb from earlier exposures to Pb paint and leaded gasoline ( U.S. EPA 2006
, Zota et al. 2011 ). Smoking or exposure to passive smoke may lead to increased exposure to Pb in environmental tobacco smoke (ETS). Tobacco itself contains Pb, in part at least, from ambient air sources: the levels of Pb in mainstream smoke from Canadian-grown tobacco14 NTP Monograph on He alth Effects of Low-Level Lead cigarettes decreased by 62% from 1968 to 1988 as ambient air Pb levels declined ( Rickert and Kaiserman 1994 ). Serum cotinine (a metabolite of nicotine that can be used as a biomarker of tobacco exposure) and postnatal exposure to ETS were significantly associ

ated with blood Pb levels of children in NHANES III; these levels did not decrease with age, indicating inha

lation was more likely than hand-to-mouth behavior in younger children ( Lanphear et al. 2000
, Mannino et al. 2003 ). In studies of outcomes causally linked to ETS exposure, such as neurodevelopment or cardiovascu

lar disease, ETS may confound the observed associa

tions of Pb and the health effect ( CDC 2005a ). Contaminated soil also contributes to Pb expo

sure in humans if inhaled as dust or eaten. Ingested Pb from soil is 26% bioavailable when consumed on an empty stomach and 2.5% bioavailable after a meal ( Maddaloni et al. 1998 ). Clay tablets sold in Mexico, Central America, and parts of Africa are eaten for reli

gious reasons, health promotion, or simply taste and texture ( CDC 2010 ). Children and people (particularly pregnant women) with pica, a disorder causing an urge to eat nonfood items, such as dirt or chalk, can also ingest Pb ( Klitzman et al. 2002 ). Children are most commonly exposed to Pb in paint, household dust, and soil – particularly if they reside in pre-1978, deteriorated housing – and can increase their risk of exposure by natural mouthing tendencies ( Lanphear et al. 1998
, U.S. EPA 2006 ). There are few direct data on Pb absorption from toys or other consumer products, but it is clear that Pb is absorbed from toys in some cases. Pb concentration in toys is mainly associated with use of Pb in paints, color

ing agents, and plastic stabilizers in polyvinyl chloride (PVC) plastics ( Godoi et al. 2009
, Greenway and Ger

stenberger 2010 ). A 4-year-old boy had an extremely high Pb level (123 μg/dL blood Pb) after swallowing a vending machine necklace pendant that contained 39% Pb ( VanArsdale et al. 2004 ), and similar products could cause lower Pb exposure levels if chewed but not swallowed. Publications have not been identified that provide quantitative measures of the differences in Pb absorption between Pb paint and Pb embedded in plastics as a coloring agent or stabilizer. However, Sanchez-Nazario et al. ( 2003 ) demonstrated that toy chewing, along with Pb levels in window sills and soil eating habits, were significant predictors of blood Pb levels in children. Toy chewing may be a route of dust ingestion as well as absorption of Pb from the toy. Chil

dren may be exposed to Pb in other consumer prod

ucts, including plastic window blinds, Pb core candle wicks, or backpacks ( Sanborn et al. 2002 ). 

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

U.S. Pb air concentration (μg/m 3 ) from 1980-2009 based on annual maximum 3-month average. National trend based on 20 sites. U.S. Environmental Protection Agency ( http://www.epa.gov/air/airtrends/lead.html, accessed 1 August, 2011). 

### 1980 1990 2000 2010 0 1 2 3 4Pb Concentration (μg/m3)



### Year National Standard (

--- ) Current standar d= 0.15μg/m 3 (as of October 2008) The previous standard of 1.5μg/m 3 (from 1978 to 2008) is not shownNTP Monograph on Health Effects of Low-Level Lead 15 Renovating, repairing, or painting a pre-1978 building can release particles of Pb-based paint and is associated with increases in blood Pb levels in children and adults who live in the home ( CDC 2009a
, 2011a ). Thorough cleaning after completion of remodeling is effective in removing most of the Pb dust from a renovated residence ( Yiin et al. 2004 ). Proper mainte

nance of housing by people trained in lead-safe prac

tices, 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 remod

eling must be certified through the EPA Lead-Safe Certification Program and use safe work practices to reduce Pb exposures to their clients, employees, and themselves. Additional certification at the state or Federal level is required for abatement to permanently eliminate Pb-based paint hazards from a home ( http:// www.epa.gov/lead/pubs/traincert.htm ). Some hobbies or recreational activities are potential sources of Pb exposure ( e.g., Sanborn et al. 2002 ). Hobbies include furniture refinishing, jewelry making, creating stained glass, print-making, enamel

ing copper, casting bronze or lead figurines, leaded glass blowing, working with Pb solder on electron

ics, and using Pb-containing paints or pottery glazes ( CDC 2010 ). Fishing and hunting can contribute to Pb exposure when making fishing weights, casting ammunition, or eating animals contaminated with Pb after ingesting Pb shot or fishing weights ( CDC 2010
, 2011a ). Air Pb levels in indoor firing ranges were sig

nificantly higher in ranges that used powder charges (660 μg/m 3 ) than in those that used air guns (4.6 μg/

m 3 ) or in archery ranges (0.11 μg/m 3 ), and blood Pb levels were significantly higher for marksmen using powder charges during the indoor shooting season ( Svensson et al. 1992 ). Pb exposures from these hobbies can be significant: a potter and her family experienced elevated Pb levels from Pb glazes used in a home studio (48 μg /dL for the potter, 54 μg /dL for her daughter, and 20 μg/d L for her husband), and a man whose hobbies included melting Pb weights to make figurines and shooting firearms at an indoor fir

ing range had a blood Pb level of 39 μg/dL ( Fischbein et al. 1992 ). Occupational exposures to Pb occur in more than 100 industries where Pb or Pb-containing materials are used or disturbed by workers ( CDC 2010 ). Approximately 95% of all elevated blood Pb levels reported in adults in the United States are work-related ( CDC 2011a ). The prevalence rate of workers with blood Pb levels >25 μg/dL decreased by more than 50% from 1994 to 2009 (from 14 to 6.3 per 100,000 adult workers), and in 2009 the Adult Blood Lead Epidemiology and Surveillance (ABLES) program lowered their definition for elevated blood Pb level from 25 to 10 μg /dL because of increased concern over health risks from lower blood Pb levels ( ABLES 2009 ). The lowest blood Pb level required to be reported under state laws varies by state; however, of the 10 states that collected all test levels in 2004, 32% of women with blood Pb >5 μg/dL reported occupational exposures, mostly in manufacturing ( CDC 2007a ). Occupational sources of Pb can also expose workers’ families because Pb dust travels home on clothes and in vehicles ( Hipkins et al. 2004
, CDC 2009c ). Living near Pb mining, smelting, and manufacturing sites may expose the surrounding community to low Pb levels, particularly in countries without environmental regulations or monitoring programs ( Benin et al. 1999 ). These groups have been the subject of many older studies of health effects associated with Pb exposure and continue to be a source of study subjects with higher exposure levels ( e.g., a study of birth outcomes for women living near a Pb smelter plant with a damaged pollution-control device Berkowitz et al. 2006 ). Because the focus of this evaluation is on blood Pb levels <10 μg/d L, studies with mean blood Pb levels >15 μg /dL were not included in this evalua

tion except as specified in Section 8.0 Reproduc

tive/Developmental Effects (e.g., groups in studies by Kromhout et al. ( 1985 ) and Locket and Arbuckle ( 1987 ) had mean blood Pb levels ≥15 μg /dL and were not included in the evaluation of cardiovascular effects). Stratified analyses of only subjects with Pb levels above and below 10 μg/dL have indicated that associations with some health effects can be stronger at lower exposure levels (e.g., Pb-related intellectual deficits ( Lanphear et al. 2005 )). Excluded occupa

tional 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.16 NTP Monograph on He alth Effects of Low-Level Lead 

### 3.4 Modifiers of Pb Exposure Individual-level differences in exposure and biology affect the amount of Pb that reaches a target tissue to impact health. These differences may influence contact with environmental Pb, as well as Pb metab

olism and remobilization of Pb stores. Modifiers of Pb exposure include age, life stage, gender, diet, socioeconomic status, immigrant status, and genetic variants. These factors are often correlated with one another as well. Blood Pb levels increase with age from bone Pb stores that accumulate over time, as previously discussed in Section 3.2 Biomarkers of Pb Exposure

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

ronmental Pb levels in the United States were higher, so older adults accumulated more Pb as children than children do today. Several authors have suggested that the aging process contributes to Pb exposure as bone begins to deteriorate, particularly if coupled with osteo

porosis ( Silbergeld et al. 1988
, Campbell and Auinger 2007 ). The data supporting this hypothesis come from cross-sectional studies and therefore the studies are only able to infer the temporal sequence. A particular challenge comes in relating increased blood Pb levels to mobilization of Pb from bone stores due to osteo

porosis, because animal studies have demonstrated that Pb exposure results in lower bone density or bone strength ( Hamilton et al. 1994
, Ronis et al. 2001 ) and support a causal effect of Pb on bone density, rather than the other way around. A study of adults in New York found that age was not a risk factor for higher blood Pb levels (≥10 μg/dL) ( Gelberg and Fletcher 2010 ); however, blood Pb levels <10 μg/dL w ere not reported. Recent NHANES data support an association between higher blood Pb levels and increased age in older children and adults with generally low blood Pb levels (well below 10 μg/dL; see Figure 3.2 ) ( CDC 2005a ). Young children are an exception to this age trend and have higher blood Pb levels than do infants and older children ( CDC 2007b ). Young children show marked increases in blood Pb levels after birth, with a peak around 2 years of age ( Rothenberg et al. 1999b ). Initially, maternal sources of Pb could contribute to a child’s exposure levels. Mothers’ blood Pb levels at delivery are highly correlated with umbilical cord blood Pb levels, with umbilical cord blood levels slightly lower ( Graziano et al. 1990
, Rothenberg et al. 1999b ). The CDC con

cluded that in utero exposure risks to children are greatest if mothers had a significant past Pb exposure ( CDC 2010 ). Maternal blood and milk Pb levels are correlated as well, but the efficiency of Pb transfer from blood to milk varies at low levels, and Koyashiki et al. ( 2010 ) concluded that there are no established health risks from breast milk. Current CDC guidelines are to continue breastfeeding up to high blood Pb levels (40 μg/dL blood Pb levels in the mother) ( CDC 2010 ). A study in mice showed that gestational and lactational Pb exposure from the mother increases Pb levels in the offspring, with declining blood Pb lev

els after weaning ( Snyder et al. 2000 ). There is some evidence that Pb from dietary sources is more readily absorbed and retained in young children and infants than in adults ( Ziegler et al. 1978 ). Young children are also exposed to environmental Pb because of normal mouthing behaviors, as discussed in Section 3.3 Sources of Pb . A number of authors have hypoth

esized 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 exam

ined Pb levels in shed primary teeth, few studies in children have examined the usefulness of bone Pb data as a measure of exposure in children that might be associated with health effects of Pb. On average, adult men have higher levels of Pb in blood and bone than do adult women, and men are much more likely to be exposed to occupa

tional sources of Pb. However, women typically go through more stages of life where demineralization of bone may be associated with mobilization of bone stores Pb into circulating Pb. Therefore, a number of authors have supported the hypothesis that women are at risk from increased blood Pb levels mobilized from bone stores during pregnancy and menopause and due to osteoporosis (e.g., Silbergeld et al. 1988
, Manton et al. 2003
, Hu et al. 2007 ). Blood Pb levels in pregnant women are generally low in the United States (NHANES geometric mean <5 μg/dL) and do not vary by the age of the mother ( Jones et al. 2010 ). Pregnancy-associated increases in blood Pb have been demonstrated in a number of case stud

ies (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 secondNTP Monograph on Health Effects of Low-Level Lead 17 half of pregnancy ( Rothenberg et al. 1994 ). Overall blood Pb levels decrease during subsequent pregnan

cies, so the first pregnancies pose the most risk of Pb toxicity, particularly if the mother had significant past Pb exposures ( Manton et al. 2003
, CDC 2010 ). A number of studies have demonstrated increased blood Pb levels in postmenopausal women (e.g., Silbergeld et al. 1988
, Symanski and Hertz-Picciotto 1995
, Webber et al. 1995
, Korrick et al. 2002
, Nash et al. 2004 ). Data from Symanski et al. ( 1995 ) also sup

port a greater relative increase in blood Pb levels in postmenopausal women that have never been preg

nant, supporting both increased mobilization of Pb associated with menopause as well as mobilization and clearing of body burdens of Pb during pregnancy. To a lesser extent, studies also support increased blood Pb levels associated with osteoporosis ( e.g., Campbell and Auinger 2007 ), although as discussed above, studies in laboratory animals demonstrate that Pb exposure causes reduced bone density and therefore cause-and-effect is particularly difficult to establish between osteoporosis and blood Pb levels. Nutritional deficiencies can be related to Pb lev

els. Deficiencies in calcium, iron, and zinc were associ

ated with increased Pb levels at 6 months of age, and iron deficiency continued to be associated with Pb at 12 months of age ( Schell et al. 2004 ). Low iron intake may contribute by increasing Pb absorption in these infants, who had a mean 12-month blood Pb level of 5.1 μ g/dL ( Schell et al. 2004 ). In older people, calcium deficiency can increase bone turnover and circulating Pb levels ( CDC 2010 ). Pb absorption is higher when there is less food in the digestive tract, making dietary habits and gastric emptying rates another source of individual variation in the body burden of Pb ( James et al. 1985
, Maddaloni et al. 1998 ). Low socioeconomic status (SES) is associated with higher blood Pb levels (e.g., Wibowo et al. 1986
, Greene et al. 1992
, Schnaas et al. 2004
, Bell

inger 2008 ). People with low SES may be exposed to a collection of risk factors, including living in older, deteriorated housing with Pb in paint, household dust, pipes, or urban air; consuming diets lower in nutrients and calories; playing with potentially con

taminated inexpensive toys; working in jobs with occupational Pb exposure; and other environmental hazards (reviewed in Sexton 1997
, Strike and Step

toe 2004 ). The best strategy for preventing new Pb exposures in housing is to remove the Pb paint and dust, but authors such as Wakefield et al. ( 2002 ) have noted that Pb abatement can cost over $10,000 per home, and they suggest that this cost may result in remediation of less than 0.1% of seriously danger

ous homes per year. Care has to be taken during the remediation, and workers performing the job should receive special training, because as discussed earlier, general repair and renovation can be associated with increased Pb exposure and higher blood Pb levels in building occupants and workers performing the repairs ( CDC 2009a
, 2011a ). Many immigrants face SES-related exposure risks, but they may have additional risk factors as well. If their home country has relatively high Pb exposure levels, immigrants carry a larger body burden of Pb ( CDC 2010 ). Exposure to leaded gasoline emissions, as estimated from time spent in Mexico City, was a major source of cumulative Pb exposure in a study of postpartum women in Mexico ( Brown et al. 2000 ). In a study of pregnant women, a Pb-related increase in blood pressure was only seen in immigrants, pre

dominantly from Latin America, even without mark

edly higher blood Pb levels than nonimmigrants ( Rothenberg et al. 1999a ). In some cultures, pica dur

ing pregnancy is common and accepted ( CDC 2010 ). In a study of pregnant women in New York, pica was the most frequently reported source of Pb exposure (13 women, 39% of those with levels >20 μ g/dL) ( Klitzman et al. 2002 ). Immigrant status could increase exposure to Pb contaminated products, including alternativeremedies, 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 metab

olism rates can be partially explained by genetic variation. The relationship between Pb exposure and a particular health effect may be modified by the presence of a single nucleotide polymorphism (i.e., variation in a single DNA nucleotide between individuals or groups) or by other genetic variations. When studying genetic risk factors in observational studies, selection for the study is independent of genotype, which remains unknown to the subject, so sources of bias that may confound other risk factors are minimized. If specific genetic variants are found to increase or decrease the association of Pb with a18 N TP Monograph on Health Effects of Low-Level Lead health effect, there is a stronger biological basis for that relationship, and the gene function may give an indication of the mechanism of action. Genes studied for variations in Pb metabolism include hemochro

matosis (HFE) and aminolevulinate dehydratase ( ALAD ), and specific study details are presented in the appendices for each chapter. Interactions between many of the previously discussed factors make it difficult to separate the increases in risk from each individual factor. While many measures taken to reduce Pb exposure have decreased blood Pb levels in the U.S. population, economically disadvantaged young children in older housing or pregnant immigrants using contaminated products are still at risk for significant Pb exposures.



### 3.5 Summary While Pb can be measured in a variety of human tis

sues, whole-blood Pb is the most common measure used in both research and clinical settings. Blood Pb levels fluctuate and represent both current exposures from the environment and internal (endogenous) sources of Pb, primarily stored in bone. Bone Pb is a better measure of the cumulative body burden of Pb and therefore it is commonly hypothesized that bone Pb may show more consistent associations with long-term health effects. Pb continues to be used in industrial processes and in manufactured products in the United States and worldwide and is persistent in the environment. Humans are exposed to Pb via water, air, soil, food, and consumer products. Several Pb reduction efforts have significantly reduced expo

sure levels over the last 30 years, and blood Pb levels have dropped considerably in the United States. Pb exposure levels vary greatly by age, life stage, gender, and socioeconomic level; and even at low levels with blood Pb <10 μg /dL there are health risks. The other chapters of this document outline the evidence for specific health effects from blood Pb levels <10 μg /dL. A discussion of Pb exposures in potentially suscep

tible populations for specific health effects is included in individual chapters.NTP Monograph on Health Effects of Low-Level Lead 19 

## 4.0 NEUROLOGICAL EFFECTS

4.1 Conclusions The NTP concludes that there is sufficient evidence that blood Pb levels <5 μg/dL are associated with adverse neurological effects in children and limited evidence that blood Pb levels <10 μg/dL are associ

ated with adverse neurological effects in adults. Amajor strength of the evidence for effects of lowlevel Pb on neurological outcomes is the consistency of results for an adverse effect of blood Pb <10 μg/dL across multiple indices of neurological effects (e.g., cognition, behavior, and sensory function), through multiple groups, with a wide age range from early childhood to older adults, and from studies using substantially different methods and techniques. Unlike the data set for most other health out

comes, there are a number of prospective studies of neurological effects include measures of prenatal exposure (either maternal blood or umbilical cord blood). These prospective studies provide limited evidence that prenatal exposure to blood Pb levels <5 μg/dL are associated with decreases in measures of general and specific cognitive function evaluated in children. There is also limited evidence that prenatal exposure to blood Pb levels <10 μg/dL are associatedwith decreased IQ, increased incidence of attentionrelated and antisocial behavior problems, and decreased hearing measured in children. Conclusions on effects of prenatal exposure for outcomes evalu

ated as children are complicated by the high degree of correlation in childhood blood Pb levels over time, and as described below, blood Pb levels during child

hood are also associated with these outcomes. In children, there is sufficient evidence that blood Pb levels <5 μg/dL are associated with broadbased and specific indices of reduced cognitive func

tion and an increase in attention-related behavior diagnosis and antisocial problem behaviors. The association between blood Pb and decreased IQ has been demonstrated in multiple prospective studies of children with blood Pb levels <10 μg/dL, the pooled analyses that reported effects with peak blood Pb levels <7.5 μg/dL ( Lanphear et al. 2005), and multiple cross-sectional studies that reported effects with mean blood Pb levels <5 μg/dL. Lower levels of aca

demic achievement, as determined by class rank and achievement tests, have been reported in multiple prospective and cross-sectional studies of children with blood Pb <5 μg/dL. An association between blood Pb levels <5 μg/dL and de creases in specific measures of cognitive function have been demon

strated in prospective and cross-sectional studies using a wide range of tests for assessment. Increases in attention-related and problem behaviors are con

sistently reported in studies with mean blood Pb lev

els <5 μg/dL. There is sufficient evidence that blood Pb levels <10 μg/dL in children are associated with decreased auditory acuity. Multiple cross-sectional studies reported hearing loss, as indicated by higher hearing thresholds and increased latency of BAEPs, in children with blood Pb levels <10 μg/dL. In adults, there is limited evidence that blood Pb levels <10 μg/dL ar e associated with psychiatric out

comes (including anxiety and depression), decreased auditor y function, decreases in specific measures of
cog nitive function in older adults, and the neurode

ge nerative disease ALS. There is sufficie nt ev idence that blood Pb levels <10 μg/dL are associated with essential tremor in adults, and limite d evide nce for blood Pb levels <5 μg/dL. As with other studies of health effects of Pb in adults, long-term prospective studies in a group for which blood Pb levels remained consistently below 10 μg/dL from birth until measure

ment of the outcome of interest would eliminate the potential role of early-life blood Pb levels >10 μg/dL on health effects observed in adults with concurrent blood Pb levels <10 μg/dL. Ther e are more consis

ten t associations between bone Pb and decreases in
cog nitive function in older adults than for blood Pb,
sugg esting a role for cumulative Pb exposure.



### 4.2 How Conclusions Were Reached Conclusions in the NTP evaluation of Pb-relatedneurological effects in humans associated with lowlevel Pb are derived by evaluating the data from epidemiological studies with a focus on blood Pb levels <10 μg/dL. Data reflecting exposure levels up to 15 μg/dL were also considered so that effects at and around 10 μg/dL we re not excluded from the evaluation. There is a relatively large database of human studies for a wide range of neurological effects (see Table 4.1 ) of low-level Pb and therefore, the docu

ment makes limited use of the data from laboratory animals to support the human evidence. Major end

points considered as potential indicators of neuro

logical effects of Pb are listed and briefly described20 NTP Monogr aph on Health Effects of Low-Level Lead in Section 4.2.1 . This document is not a review of neurotoxicity, and the reader is directed to pub

lished reviews for additional background. Key data and principal studies considered in developing the NTP conclusions are discussed in detail in Section 4.3: Evidence for Pb-related Effects on Neurological Outcomes. The discussion of each neurological effect begins with a statement of the NTP’s conclusion that the specific effect is associated with a blood Pb level <10 μg/dL or <5 μg/ dL and the age group in which it is identified (childhood or adulthood), as well as the timing of exposure associated with the effect (prenatal, childhood, or concurrent), when available. Although the information necessary to support the NTP’s conclusions is presented in Section 4.3 , the complete data set of human studies considered for evaluation of neurological effects with low-level Pb is included in Appendix A: Neurological Effects, where individual studies are abstracted for further refer

ence. The NTP made extensive use of recent govern

ment 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 end

points evaluated in epidemiological studies on the

Table 4.1: Major neurological effects considered
Effect Description
Cognitive Function Intelligence quotient (IQ) Full-scale IQ (FSIQ), verbal IQ (VIQ), and performance IQ (PIQ) are evaluated with a variety of tests, e.g., the Wechsler Intelligence Scales for Children (WISC) or the Stanford-Binet Intelligence Scale. WISC is a normative measure for assessing intelligence in children, allowing cross-study comparison (e.g., Lanphear et al. 2005).
Academic achievement Academic performance is measured with a variety of tests, e.g., the Boston Teacher Ques

tionnaire (BTQ), Wide Range Achievement Test-Revised (WRAT-R), and, more recently, end-of-grade testing and standard assessment tests. General and specific cognitive abilities Cognitive function is measured with numerous tests including general measures, e.g., the Mental Development Index (MDI) and the General Cognitive Index (GCI); or specific mea

sures 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/ Diagnos

tic and Statistical Manual of Mental Disorders (DSM). Conduct or problem behavior outcomes are measured with a variety of evaluation tools, e.g., Teacher Report Form-Delinquent Behavior or self-reported delinquent behavior. Psychiatric outcomes Mood disorders are diagnosed with various tests, e.g., the Child Behavior Checklist (CBCL) or Brief Symptom Inventory. Neurodegeneration
Various diseases Diagnoses of amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, essential tremor, or Parkinson’s disease. Sensory Function
Audio Several measures of auditory function, e.g., higher hearing thresholds and altered brain

stem auditory evoked potentials (BAEPs).

Vision Several measures of visual function, e.g., altered visual evoked potentials (VEPs) and electro

retinographic (ERG) testing.NTP Monograph on Health Effects of Low-Level Lead 21 effects of Pb exposure and identifies representative tests that have been used to evaluate major neuro

logical effects of Pb. A list or review of the full range of tests and tools used to evaluate neurocognitive, neurobehavioral, psychiatric, and neurophysiological outcomes is beyond the scope of this evaluation. The data available to evaluate each of the major effects are discussed in separate subheadings under Section 4.3 below.



### 4.2.2 Principal Conclusions from the 2006 EPA and 2007 ATSDR Pb Documents The EPA’s 2006 AQCD for Lead ( U.S. EPA 2006) and ATSDR’s Toxicological Profile for Lead (ATSDR 2007) both concluded that negative effects of Pb on neu

rocognitive ability and neurobehavioral outcomes in children are observed across numerous studies at blood Pb levels <10 μg/dL e ven after adjusting for confounding factors (see Table 4.2 ).

The Lanphear et al. (2005) pooled analysis is cited by both EPA and ATSDR as supporting evidence for a decline of up to 6 full-scale IQ (FSIQ) points for an increase in blood Pb from 1 to 10 μg/dL in chil

dren. The 2006 EPA AQCD for Lead (U.S. EPA 2006) and the 2005 CDC statement on Preventing Lead Poisoning in Young Children (CDC 2005) highlight the evidence for a supralinear dose-response rela

tionship 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 expo

sure are in turn associated with decreased academic achievement and notes that negative effects of Pb on attention may contribute to underachievement or delinquent behavior in children. The EPA 2006 AQCD for Lead (U.S. EPA 2006) concludes that the negative impacts of Pb on neurocognition and behavior persist into young adulthood and that there is clear evidence that blood Pb levels in children of 5-10 μg/d L (and possibly lower) are associated with these adverse effects. In adults, both ATSDR and EPA noted that chronic occupational Pb exposure is associated with decreased nerve conduction velocity and postural balance abnormalities. The EPA 2006 AQCD for Lead (U.S. EPA 2006) identified ≥14 μg/dL blood Pb level as a possible threshold for these effects, as well as for visuomotor and memory impairment, and effects on the visual and auditory systems (prolonged visual evoked potentials (VEPs) and BAEPs). The EPA 2006 AQCD for Lead (U.S. EPA 2006) characterized the evidence for impairments in cognitive performance associated with Pb levels in adults as mixed, although bone Pb (and therefore long-term cumulative expo

sure) was associated with decreased cognitive perfor

mance. The EPA 2006 AQCD for Lead (U.S. EPA 2006) stated that four studies reported that past occupa

tional exposure to Pb increased the risk of develop

ing ALS and motor neuron disease and two studies reported that essential tremor was associated with low blood Pb levels (a mean of 3 μg/dL). EPA is in the process of revising the AQCD for Lead, and the conclusions of the external draft (U.S. EPA 2012) are largely in line with the 2006 AQCD for Lead (U.S. EPA 2006), plus additional review of the evidence for attention-related behaviors, including ADHD. The NTP considered the conclusions and data summaries from the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006) and ATSDR’s Toxicological Profile for Lead (ATSDR 2007). In general, the NTP accepted the conclusions and agreed that the data support them. Differences from the ATSDR and EPA documents are identified for specific endpoints. Table 4.2: Main conclus ions for neurological effects in the 2006 EPA AQCD for Lead and the 2007 ATSDR Toxicological Profile for Lead

“....effects on neurobehavior in children have been observed with remarkable consistency across numerous studies of various designs, populations, and developmental assessment protocols. The negative impacts of Pb on neurocognitive ability and other neurobehavioral outcomes persist in most recent studies even after adjustment for numerous confounding factors, including social class, quality of caregiving, and parental intelligence.” (U.S. EPA 2006, pg 6-269) “...the preponderance of the evidence indicates that lead exposure is associated with decrements in cognitive function. Meta-analyses conducted oncross-sectional studies or a combination of crosssectional and prospective studies suggest that an IQ decline of 1-5 points is associated with an increase in PbB [blood Pb level] of 10 μg/dL. Mos t importantly, no threshold for the effects of lead on IQ has been identified...” (ATSDR 2007, pg 25)22 NTP Monograph on He alth Effects of Low-Level Lead 

### 4.3 Evidence for Pb-Related Effects on Neurological Outcomes

4.3.1 Cognitive Function There is sufficient evidence that blood Pb levels <5 μg/dL are associated with decreased cognitive function in children. There are many tests and mea

sures used to evaluate cognitive function and blood Pb levels are associated with decreases in broad-based measures in children such as academic achievement or FSIQ, as well as specific cognitive measures evalu

ated 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 iden

tified, although decreased performance on individual domains for attention, executive function, language, learning and memory, and visual-spatial processing have been reported (U.S. EPA 2006, ATSDR 2007 ). Generally, the lack of clear differences in sensitivity and specificity for individual domains is attributed in part to difficulty discriminating focused effects because test performance covers multiple neurobe

havioral processes ( U.S. EPA 2006). The discussion of cognitive function below is divided into three sections: (1) academic achie ve

ment – a practical and perhaps more objective mea

sure of cognitive function in children that may relate to achievement in life through education-based achievement measures, (2) IQ in children, and (3) other general and specific measures of cognitive abilities in children and adults.



### Academic Achievement There is suffic ient ev idence that blood Pb levels <5 μg/dL are associated with decreases in various measures of academic achievement in children 6-18 of ag e (see Appendix A: Neurological Effects for full list of studies). An inverse association between blood Pb level and performance in tests of academic per

for mance, class rank, or end-of-grade testing has bee n reported in multiple prospective and crosssection al studies involving children with blood Pb levels from 2 to 10 μg/dL fr om populations in North America, Europe, and Africa. Studies demonstrated that early -childhood Pb levels in blood (9-36 months age) or tooth dentin (6-8 years of age) are associated with decreased academic achievement measured when childr en were from 10 to 18 years of age. Data from cross-sectional studies also support a negative eff ect of concurrent blood Pb levels (between 5 and 10 μg/dL) on academic achievement. However, there is inadequate evidence that prenatal blood Pb levels <10 μg/dL are associated with academic achievement in children because of a lack of academic perfor

mance studies that include Pb exposure data from
prena tal time points. A numbe r of studies have used academic achieve

ment as an indicator of effects of Pb on cognitive func

tion in children. Many of the earlier studies of academic achiev ement used tooth dentin Pb as the measure of Pb exposure and compared measures of educational att ainment in children with earlier dentin or blood Pb l evels. For example, higher tooth dentin Pb levels
at 6-8 years of age were associated with: lower class
st anding in 132 children in Massachusetts at 18 years of ag e (Needleman et al. 1990); reading and spelling difficultie s in 8-year-old girls (n=1923 boys and girls) assessed with the Boston Teacher Questionnaire (BTQ) (Levit on et al. 1993); and various measures of achieve

ment assessed from 8 to 18 years of age in 1,265 chil

dr en from the Christchurch Health and Development Study cohort, including number of school certificate
pas ses and Burt Word Reading test assessed at 8, 12, and 18 years of age (Fergusson et al. 1988, 1993
, 1997 ). Belling er et al. ( 1992) r eported that blood Pb levels (mean, 6.5 μg/dL) a t 2 years of age, but not umbilical cord blood Pb or children’s blood Pb levels at 6, 12, 18, or 57 months of age, were significantly associated with lo wer scores in the Kaufman Test of Educational Achie vement (KTEA) in 148 children 10 years of age from the Boston area. In general, the data support a
per sistent negative effect on cognitive achievement tha t results in reduced educational attainment. How

ev er, at least one study reported that tooth dentin Pb le vels were not associated with achievement: Rabi

now itz et al. (1992) stated that tooth Pb levels were not associa ted with scores on the BTQ in a study of 493 Taiw anese children. More recent studies have demonstrated a nega

tiv e effect of concurrent or early-childhood blood Pb l evels 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 NHANE S III data set, Lanphear e t al. (2000) dem

onstrated that concurrent blood Pb levels <5 μg/dL (geometric mean, 1.9 μg/d L) were associated with decreased achievement measured by the Wide Rang e Achievement Test-Revised (WRAT-R). As withNTP Monograph on Health Effects of Low-Level Lead 23 other cross-sectional studies of Pb, an important limitation is that blood Pb during early childhood is likely to have been higher than blood Pb measured during the study; and therefore, blood Pb may have been >10 μ g/dL at earlier time points for children in this study. In a cross-sectional analysis of 511 U.S. children between 6 and 10 years of age, concurrent blood Pb ≥5 μg /dL was associated with lower scores on the Wechsler Individual Achievement Test (Surkan et al. 2007). In a cross-sectional study of 533 girls in Saudi Arabia between 6 and 12 years of age, Al-Saleh et al. (2001) reported that class rank percentile was inversely associated with concurrent blood Pb levels (mean, 8 μg /dL). Wang et al. (2002) found a similar inverse relationship between concurrent blood Pb level (mean, 5.5 μ g/dL) and class ranking of 934 Tai

wanese children 9 years of age for individual subject areas (e.g., natural sciences and Chinese). Min et al. (2009) reported that blood Pb <5 μg /dL measured at 4 years of age was significantly associated with decreased school reading scores (Woodcock-Johnson III Tests of Achievement) at 9 and 11 years of age in a subgroup analysis as part of a prospective study of 278 inner-city children from Cleveland, OH. Chandra

mouli et al. (2009) demonstrated that educational performance on standard achievement tests at 7-8 years of age was inversely associated with blood Pb levels ≥5 μ g/dL measured at 30 months of age in a prospective study of 582 children in the United King

dom. Surkan et al. (2007) reported that blood Pb of 5-10 μ g/dL was associated with decreased perfor

mance in the Wechsler Individual Achievement Test in a study of 6- to 11-year-old children in Maine and Massachusetts. Miranda et al. (2007) reported that blood Pb levels down to 2 μg /dL (collected as part of Pb screening programs when the children were <5 years of age) were negatively related to test perfor

mance 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 effect of blood Pb levels down to 2 μg /dL on end-of-grade reading scores compared to the reference group with blood Pb levels of 1 μg/dL. No studies were located that evaluated mater

nal Pb levels and educational achievement; however, Bellinger et al. (1992) reported that umbilical cord blood Pb levels (29% of the study group had levels ≥10 μg /dL) were not significantly associated with lower scores in the KTEA in 148 children 10 years of age from the Boston area. Confounding variables were considered in all of the studies listed above to some degree, but the stud

ies of Miranda et al. (2007, 2009 ), Chandramouli et al. (2009), and Lanphear et al. (2000) included a large number of confounders, such as socioeconomic vari

ables, sex, race/ethnicity, age of blood Pb measure

ment, parental education, and tobacco exposure, and demonstrated that the effects on achievement were independent of known confounders. The Miranda et al. (2009) study found evidence of differential effects in students with lower test scores, reporting that children with the lowest test scores had a larger adverse effect of blood Pb on lowering the test score. Lower SES and lower parental education also had a larger adverse effect on children with lower test scores, suggesting that Pb and other confounders all have a greater impact in individuals that already have lower levels of achievement. The studies of Surkan et al. (2007) and Bellinger et al. (1992) reported a negative effect of Pb on academic achievement while controlling for the child’s IQ, suggesting that IQ and academic performance may serve as somewhat inde

pendent measures of cognitive function.

Summary of Support for Conclusions Animal data support a Pb-associated decrease in neu

robehavioral tests of learning including fixed-interval operant conditioning at blood Pb levels ≥11 μg /dL (see U.S. EPA 2006 for recent reviews of the animal data, ATSDR 2007 ). The human data include multiple prospective and cross-sectional studies supporting a Pb-associated decrease in educational attainment at blood Pb levels from 2 to 10 μg /dL. The conclusion of sufficient evidence for decreased academic achieve

ment in children 6-18 years of age with blood Pb levels <5 μg /dL measured in early childhood through 18 years of age is based on the consistency of effects on several measures of academic achievement in multiple studies. The Bellinger et al. ( 1992) study includes multiple blood Pb measurements and only found a negative effect of blood Pb measured at 2 years of age on later life aca

demic performance. Multiple studies (e.g., Miranda et al. 2007, Chandramouli et al. 2009
, Miranda et al. 2009 ) reported that early-childhood Pb exposure is24 NTP Monogr aph on Health Effects of Low-Level Lead associated with later performance. However, clear evi

dence that early-childhood Pb exposure is associated with academic performance at later ages is compli

cated by the high degree of correlation in childhood blood Pb levels over time (e.g., see Dietrich et al. 1993a, Lanphear et al. 2005 ). Current evidence can be used to support the importance of both early-life exposure and current blood Pb levels. The conclusion of inadequate evidence that prenatal blood Pb levels <10 μg /dL are associated with academic achievement in children is based on the lack of studies of academic performance in children with Pb exposure data from prenatal time points. The NTP’s conclusions for sufficient evidence that decreased academic achievement in children 6-18 years of age is associated with Pb levels <5 μg/dL extends the conclusions from EPA’s 2006 AQCD for Lead ( U.S. EPA 2006) and ATSDR’s 2007 Toxicological Profile for Lead (ATSDR 2007), which were limited to blood Pb levels <10 μg/dL; however, the EPA’s 2012 draft (U.S. EPA 2012) currently supports a lower blood Pb level.



### IQ There is suffi cient e vidence that blood Pb levels <5 μg/dL are associated with decreases in FSIQ, a global measure of cognitive ability in children 4-13
y ears of age (see Appendix A: Neurological Effects for full list of studies). The NTP conclusion of suffi cient evidence that blood Pb levels <5 μg/dL are associ

a ted with decreased IQ is based on several lines of

e vidence, including multiple cross-sectional studies of children reporting lower IQ associated with mean blood Pb levels <5 μg/dL , pooled analyses demonstrat

ing reduced IQ with peak blood Pb levels <7.5 μg /dL, and multiple prospective studies reporting decreased IQ at blood Pb levels <10 μg/d L. 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 popu

la tions in North America, Australia, Europe, and Asia b y a range of different tests to assess IQ. Many recent

s tudies have used the Wechsler Intelligence Scales for Childr en (WISC) and have adopted similar protocols
t o assist in cross-study comparison and greater gener

aliz ation of the findings. The most recently published poole d analysis of IQ data, Lanphear e t al. (2005),
t ook advantage of the similarity in study design of

se ven prospective studies and concluded that blood Pb levels <10 μg /dL in children (and specifically in children with maximal blood Pb levels <7.5 μg /dL) are associated with intellectual deficits. The pooled analy sis of Lanphear e t al. (2005) estimated that 3.9 IQ points (95% CI: 2.4, 5.3) w ere lost with an increase in blood Pb from 2.4 μg/dL to 10 μg/dL. Data from crosssectional studies also support an association between concurrent blood Pb levels <5 μg/dL and decreased IQ in children up to 13 years of age. The evidence is mixed f or an association between maternal or umbilical cord blood Pb and decreased IQ in children evaluated at

a later age. Therefore, there is l imited e vidence that prenatal blood Pb levels <10 μg/dL are associated with decreased IQ in children. There is some evidence that the association between decreased IQ might be more

c onsistent for bone Pb than for blood Pb, but those da ta come from a group known to have blood Pb levels >10 μg/dL during early childhood. A number of prospective studies have reported an association between blood Pb <10 μg/dL and decreased IQ score in children from 4 to 13 years of
ag e. 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

s tudy of 148 children with serial blood Pb measure

men ts from birth through 10 years of age, Bellinger

e t al. (1992) (reanalyzed in Bellinger and Needleman 2 003) demonstrated that blood Pb levels at 2 years of age (mean, 6.5 μg /dL), but not other ages, were significantly associated with decreases in FSIQ and

v erbal IQ (VIQ) assessed by the WISC-R at 10 years of age in a cohort from the Brigham and Women’s Ho spital; the association with performance IQ (PIQ)

w as not significant (p=0.091). Min e t al. (2009) demons trated that blood Pb measured at 4 years of age (mean, 7 μg/dL) was significantly associated with decreased FSIQ by the Wechsler Preschool and P rimary Scale of Intelligence (WPPSI-R) at 4 years of age and with decreased FSIQ by the full WISC-IV

a t 9 and 11 years of age in a prospective study of 278 inner-city children from Cleveland, OH. How

e ver, 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, Bagh urst e t al. (1992) reported that blood Pb levels during early childhood up to 4 years of age (but not

ma ternal blood Pb, umbilical cord blood Pb, or aver

ag e through 7 years of age) were significantly associ

a ted with decreased FSIQ and VIQ scores evaluated b y the WISC-R at 7 years of age in 494 children in Port Pirie, Australia; however, mean blood Pb levels in thisNTP Monograph on Health Effects of Low-Level Lead 25 cohort were >10 μg/dL a fter birth. A similar associa

tion be tween blood Pb and decreased FSIQ has been demo nstrated in a number of prospective studies with cumulative mean blood Pb levels >10 μg/dL tha t evaluated IQ in children at 5-13 years of age (Dietrich
et al. 1993b, Tong et al. 1996
, Wasserman et al. 1997
, Fact or-Litvak et al. 1999
, Canfie ld et al. 2003a
, Was

serman e t al. 2003
, Jusk o e t al. 2008 ). An association between concurrent blood Pb <10 μg/dL as well as <5 μg/dL and decreased IQ has been reported in multiple studies. For example, the two studies by Chiodo et al. ( 2004, 2007 ) evaluated a range of neurodevelopmental endpoints in 240 and 500 African-American inner-city children 7-9 years of age with mean concurrent blood Pb levels of 5.4 μg/dL; these levels were related to decreased FSIQ, PIQ, and VIQ, as well as behavioral endpoints evaluated with the WISC-III. When grouped by cut

off points of 10, 7.5, 5, and 3 μg/dL blood Pb, the study supported significant effects on IQ at blood Pb levels of ≥5 μg/d L, 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) w as sig

nificantly 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 low

est 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 fr om 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 signifi

cantly associated with concurrent blood Pb levels at 6 years of age and blood Pb for the year before (down to age 3 for PIQ); however, IQ was not associated with maternal blood Pb, umbilical cord blood Pb, or blood Pb levels during early childhood. Hornung et al. (2009) analyzed the age of greatest susceptibility for blood Pb to contribute to lower IQ scores as evaluated with the WISC-R in a combined cohort from the Cincin

nati and Rochester lead studies (n=397 total), with peak blood Pb mean of 13.6 μg/d L and concurrent blood Pb at 6 years of age = 6 μg/dL. A t 6 years of age, blood Pb measured concurrently (β=-3.48; p<0.001) and the prior year (at age 5; β=-4.39; p<0.001) had the strongest effect on IQ, compared to blood Pb at earlier ages (e.g., age 1; β=-0.08;p=0.934). Note that peak childhood blood Pb in the Cincinnati and Rochester cohorts was >10 μg/dL; ther efore, it is not clear that the observed decreases in IQ reported in Dietrich et al. (1993b) and Hornung et al. (2009) are strictly associated with a blood Pb level <10 μg/dL. No clear evidence was located that maternal or umbilical cord blood Pb levels <10 μg/dL are associ

ated with decreased IQ in children. Many studies, such as Baghurst et al. (1992), Bellinger et al. (1992), and Dietrich et al. (1993b) described earlier, did not find a significant association with prenatal blood Pb levels in groups for which prenatal blood Pb was <10 μg/dL. In a prospective study that examined the relationship between maternal blood Pb during early and late preg

nancy and FSIQ in children as measured by the WISC-R, Schnaas et al. (2006) reported that maternal blood Pb levels at 28-36 weeks of pregnancy (mean, 7.8 μg/dL) were related to reduced IQ in children 6-10 years of age. However, as in other studies, the mean blood Pb in this cohort was >10 μg/dL during early childhood. The evidence for a Pb-related decrease in IQ has been the subject of four key meta-analyses com

bining data across several studies (Needleman and Gatsonis 1990, Pocock et al. 1994
, Schwartz 1994
, Lanphear et al. 2005 ) and was extensively reviewed in the 2006 EPA AQCD for Lead (U.S. EPA 2006) and ATSDR Toxicological Profile for Lead (ATSDR 2007). These analyses provide strong support that blood Pb and tooth Pb are significantly associated with decreases in IQ in children; however, many of the cross-sectional and prospective studies included in these analyses are based on cohorts with blood Pb levels >10 μg/dL at some age between birth and age of IQ test. The Schwartz et al. (1994) and Lanphear et al. (2005) meta-analyses support effects at blood Pb levels <10 μg/dL (and with peak blood Pb levels <7.5 μg/dL), although these analyses face challenges of confounding and the different tests used to assess IQ across studies. However, the 2005 pooled analysis (Lanphear et al. 2005) reduced these confounders by pooling data from seven prospective studies that used similar test protocols (e.g., relying principally on the WISC) and included 1,333 children from several countries. The analyses supported an association between blood Pb levels <10 μg/dL and decreased IQ, and the authors concluded that blood Pb levels26 NTP Monograph on He alth Effects of Low-Level Lead <10 μg/dL (and specifically <7.5 μg/dL) in children are associated with intellectual deficits. Lanphear et al. (2005) reported significant decreases in IQ in analy

ses restricted to children with a maximum blood Pb level <10 μg/dL. The authors also attempted to char

acterize the shape of the dose-response between blood Pb and IQ (addressed further in the following discussion). Although some earlier studies of Pb and cognitive function did not include adjustment for maternal IQ or other confounders, these studies were also generally in children with blood Pb levels >10 μg/d L. More recent studies of the relationship between blood Pb and IQ in children with blood Pb levels <10 μg/dL c onsidered a wide range of potential confounders. For example, the Lanphear et al. ( 2005) pooled analysis included maternal IQ, maternal education, score for the Home Observation for Measurement of the Environment (an assessment of the stimulation in the environment in which the child is raised), and birth weight in the final model; however, prenatal smoking, prenatal alcohol use, mother’s marital status, maternal age, the child’s sex, and birth order were also considered and did not to influence the analyses. Some studies have also considered the effects of co-exposure to other metals or toxicants. For example, Kim et al. (2009) demon

strated that children with higher levels of manganese in their blood had greater decreases in IQ for a givenlevel of Pb; the results of this study suggest that coexposure to other metals should be considered in studies of cognitive effects of Pb. In one example, the extensive data on poten

tial covariates and the thorough characterization of exposure measurements based on serial blood Pb assessments over time allowed comparison of the strength of the association between Pb and decreased IQ for two measures of exposure: blood Pb and bone Pb. As part of the Yugoslavia Prospective Study, 290 children were assessed with the WISC-III at 10-12 years of age, and 167 of these individuals had with tibia bone Pb measurements (Wasserman et al. 2003). Both bone Pb and average lifetime blood Pb levels were significantly associated with decreased FSIQ, PIQ, and VIQ. Bone and blood Pb measure

ments were highly correlated (concurrent Pb r=0.75; lifetime average Pb r=0.85; p<0.01) in children from Titova Mitrovica (a Pb smelter town with higher Pb exposure levels) but not in Pristina, the town with lower Pb exposure levels. Tibia Pb was a significant predictor of FSIQ or PIQ with or without adjustment for current or average lifetime blood Pb levels. In contrast, average or current blood Pb levels were not associated with IQ in models that included tibia Pb levels. Therefore, the authors concluded that the association with decreased IQ is stronger for bone Pb than for blood Pb (Wasserman et al. 2003). In is important to note two points in this analysis. First, blood Pb measurements were >10 μg/dL f or most children in these groups. Second, this is one of the few studies in children that examined the usefulness of bone Pb data as a measure of exposure, although a number of studies have measured Pb levels in shed deciduous teeth.

Shape of the Dose-Response Curve There is abundant discussion in the Pb literature on the shape of the dose-response curve in the lower range of exposure (i.e., at blood Pb levels <10 μg/dL) for neurodevelopmental effects of Pb. This discussion centers around several studies that have reported greater neurocognitive effects (principally on IQ and specific measures of cognitive function) of an incremental increase in blood Pb levels at lower concentrations compared to the effects for an incre

mental increase at higher blood Pb levels (Canfield et al. 2003a, Lanphear et al. 2005
, Rothenberg and Rothenberg 2005
, Kordas et al. 2006 ). This indicates a steeper slope (greater effect per unit increase) in the dose-response curve at lower blood Pb levels. The 2006 EPA AQCD for Lead ( U.S. EPA 2006) discusses this issue extensively and reviews the evidence that the dose-response curve has a steeper slope at lower blood Pb levels. The 2005 CDC (CDC 2005) review of the epidemiological evidence for neurological effects in children also noted that there was evidence for a steeper slope in the dose-response curve at lowerblood 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 neu

robehavioral 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 bloodNTP Monograph on Health Effects of Low-Level Lead 27 Pb levels <10 μg/dL and lower FSIQ scores in chil

dren 4-13 years of age. The conclusion of sufficient evidence that decreases in IQ scores in children are associated with blood Pb levels <10 μg/dL measur ed 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 stud

ies (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 cor

relation in childhood blood Pb levels over time (e.g.,

see Dietrich et al. 1993a, Lanphear et al. 2005 ). The conclusion of limited evidence that prenatal blood Pb levels <10 μg/dL ar e associated with decreased IQ in children is based on mixed evidence for an associa

tion with maternal or umbilical cord blood Pb. The NTP’s conclusions for sufficient evidence that blood Pb levels <10 μg/dL ar e associated with decreased IQ in children 4-13 years of age is consistent with the conclusions from EPA’s 2006 AQCD for Lead ( U.S. EPA 2006) and ATSDR’s 2007 Toxicological Profile for Lead (ATSDR 2007).



### Other General and Specific Measures of Cognitive Function There is sufficient evidence that blood Pb levels <5 μg/dL are associated with decreases in various general and specific measures of cognitive func

tion 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 abilitieshas 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, execu

tive function, language, learning and memory, and visual-spatial processing, the lack of a clear pattern of effects has contributed to difficulty in distinguishing specific, focused effects, because test performance covers multiple neurobehavioral processes (U.S. EPA 2006, ATSDR 2007 ). Although relatively few studies have examined the potential effects of Pb in adults without occupational exposure, a number of studies have reported Pb-associated decreases in specific measures of cognitive function in groups of older adults, such as the Normative Aging Study. Several of these studies reported an association between concurrent blood Pb levels <10 μg/dL and decreased performance in the Mini-Mental State Examination (MMSE) and other cognitive measures. Six studies also demonstrated that bone Pb levels were associ

ated with decreased cognitive performance. How

ever, other studies did not find an association with concurrent blood Pb levels. There is limited evidence that blood Pb levels <10 μg/dL are associated with decreases in specific measures of cognitive function in older adults, because of the mixed results for an association with blood Pb and the more consistent support for an association with bone Pb. There are a large number of tests used to evalu

ate cognitive function, with tests specific for subjects of different ages and designed to explore different cognitive domains (see Appendix A: Neurological Effects under outcomes measured for tests used in individual studies). Two of the more common tests that demonstrated effects of Pb in younger subjects measure general cognitive function: the Mental Developmental Index (MDI) from the Bayley Scales of Infant Development and the overall General Cognitive Index (GCI) from the McCarthy Scales of Children’s Abilities and individual measures. Data on older chil

dren evaluated with the WISC were discussed earlier in the context of Pb-related decreases of IQ, which is also a general measure of cognitive function; how

ever, 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 (lo wer than the 10 μg/dL blood Pb levels generally associated with effects on FSIQ). Multiple tests are used to evaluate cognitive function in adults, including the MMSE. An association between increased blood Pb level and decreased MDI score was demonstrated in multiple studies at blood Pb levels from <2 to 10 μg/dL. Maternal blood Pb levels <10 μg/dL and umbilical cord blood Pb levels <5 μg/dL have been reported to be associated with decreased cognitive performance in children up to 3 years of age by the MDI. Recent studies ( Gomaa et al. 2002, Al-Saleh et al. 2009
, Jedrychowski et al. 2009a
, Jedrychowski et al. 2009b
, Pilsner et al. 2010 ) reported effects in chil

dren with blood Pb levels that remained consistently28 NTP Monogr aph on Health Effects of Low-Level Lead below 10 μg/dL; however, early-childhood blood Pb increased to levels >10 μg/dL for some of the groups examined. Two recent studies reported that concur

rent blood Pb levels <10 μg/dL are associated with decreased MDI scores, but there is less evidence that concurrent blood Pb is associated with MDI than there is for an association with measures of prenatal Pb exposure. The overwhelming majority of prospective studies found that prenatal exposure determined by either umbilical cord or maternal blood Pb levels <10 μg/dL were associated with decreased MDI in chil

dren through 3 years of age. Significantly lower MDI scores in children tested at 3-36 months of age were associated with prenatal exposure based on umbilical cord blood Pb at the following levels: ≥1 μg/dL in chil

dren evaluated at 24 and 36 months of age in a study of 457 children in Poland (effects significant for boys and girls combined, but likely driven by boys ( Jedry

chowski et al. 2009a, Jedrychowski et al. 2009b )); 2.7 μg/dL with MDI evaluated in 6-month-old chil

dren in Saudi Arabia (n=119) ( Al-Saleh et al. 2009); 6.4 μg/dL with MDI evaluated in 3-month-old chil

dren from the Cincinnati Lead Study (n=266) (Dietrich et al. 1987); 6.6 μg/dL with MDI evaluated in children 6, 12, 18, and 24 months of age from Brigham and Women’s Hospital (n=182-249) (Bellinger et al. 1984, Bellinger et al. 1986
, Bellinger et al. 1987 ); 6.7 μg/dL with MDI evaluated in 24-month-old children from Mexico City (n=197) ( Gomaa et al. 2002, Pilsner et al. 2010 ); and 9.2 μg/dL evaluated at 3, 6, and 12 months of age in a study of 133 children in China (Shen et al. 1998). Although most of the studies demonstrated a Pb-associated decrease in MDI, Cooney et al. (1989a) reported that umbilical cord and maternal blood Pb levels (mean, 8-9 μg/dL) in participants in the Sydney Lead Study (n=215-274) were not related to change in MDI tested at 6, 12, 24, or 36 months of age. Several prospective studies reported an asso

ciation between maternal blood Pb and decreased MDI, with no relationship to umbilical cord blood or a less consistent relationship (e.g., Dietrich et al. 1987, Ernhart et al. 1987
, 1988
, 1990
, Hu et al. 2006 ). Hu et al. ( 2006) examined maternal blood Pb during the first, second, and third trimester of pregnancy and found that first-trimester blood Pb level (mean, 7 μg/dL) was associated with lower MDI in children at 24 months of age in a study of 146 mother-infant pairs from Mexico City; however, the association with umbilical cord blood Pb or maternal Pb during other time periods was not significant. Dietrich et al. (1987, 1990 ) reported that maternal blood Pb sampled dur

ing pregnancy (mean, 8 μg /dL) was associated with decreased MDI tested at 3, 6, and 24 months of age in children from the Cincinnati Lead Study and that umbilical cord blood was only associated with MDI evaluated at 3 months of age. Ernhart et al. ( 1987) reported that decreased MDI evaluated at 6 months of age was associated with maternal blood Pb at deliv

ery (mean, 6.5 μg/dL) in children from the Cleveland Lead Study; however, neither umbilical cord blood Pb or maternal Pb was associated with MDI evaluated at later time points (1-3 years of age). It is important to note that the blood Pb of infants from both the Cincinnati and Cleveland lead studies increased after birth and that childhood blood Pb levels for these groups were >10 μg/dL (mean, 16-17 μg/dL at 2 years of age), therefore, the lack of association with pre

natal Pb levels may be influenced by the high child

hood blood Pb levels. A follow-up study by Ernhart et al. (1988) did not find an association with MDI and early-childhood blood Pb or concurrent blood Pb levels; however, as noted above, the blood Pb levels in this cohort was >10 μg/dL. In contrast, Bellinger et al. (1990) found that postnatal blood Pb was associ

ated with a change in cognitive performance from 24 months of age (evaluated by the MDI) to 57 months of age (evaluated by the GCI) in a study of a group with a similar age range. Few studies have examined the relationship between MDI and measures of exposure other than blood Pb. Gomma et al. (2002) reported that maternal patellar (knee cap) Pb level was significantly associated with a decrease in MDI scores evaluated in children at 24 months of age in a study of 197 mother-infant pairs in Mexico City. Several studies have also demonstrated that concurrent blood Pb levels <10 μg/ dL were associated with lower MDI scores in children from 6 to 36 months of age. For example, Solon et al. (2008) reported that concurrent blood Pb (mean, 7.1 μg/ dL) was associated with decreased MDI in children from 6 to 36 months of age. Similar results (Pb-related decrease in MDI) were reported in children evaluated at 24 months of age in Mexico City (Tellez-Rojo et al. 2006) with mean concurrent blood Pb level of 4.9 μg/dL. Similar to the data supporting a negative effect of blood Pb on MDI scores, findings from several studiesNTP Monograph on Health Effects of Low-Level Lead 29 support an association with decreased performance on the GCI in children. In a study of 170 children from the Brigham and Women’s Hospital, Bellinger et al. (1991) reported that GCI scores and the McCarthy subscale score for perceptual performance evaluated at 57 months of age were inversely associated with blood Pb levels in the children at 24 months (mean, 6.4 μg/dL) but not at other ages. Similarly, Schnaas et al. (2000) reported that blood Pb levels from 24 to 36 months of age were associated with decreased performance on the GCI, but effects at earlier ages or later ages up to 56 months were not significant, in a study of 112 children from the Mexico City Prospec

tive Study. Blood Pb was consistently below 10 μg/dL in the cohorts from both the Bellinger et al. (1991) and Schnaas et al. (2000) studies. It is also important to note that some studies did not find a significant association between blood Pb and performance on the GCI; for example, maternal blood Pb (9 μg/dL), umbilical cord Pb (8 μg /dL), or current blood Pb were not associated with performance on the GCI in a study of 207 children from the Sydney Lead Study evaluated at 48 months of age (Cooney et al. 1989b). Multiples studies have reported that concurrent and early-childhood blood Pb levels <10 μg/d L are associated with decreases in specific indices of cog

nitive function in children from 4 to 16 years of age. Examples include studies demonstrating decreased performance on subsets of the WISC. In a cross-sec

tional study of 384 children in Germany, Walkowiak et al. (1998) reported that concurrent blood Pb (mean, 4.7 μg/d L) in 6-year-olds was associated with 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 Pb levels <10 μg/d L (geometric mean, 1.9 μg/d L) were associated with decrements in the Block Design and Digit Span subsets of the WISC-R. In subgroup analy

sis, Min et al. (2009) reported that blood Pb <5 μg/dL measured at 4 years of age was significantly associ

ated with decreased performance by the WPPSI-R at 4 years of age and with perceptual reasoning scores of the WISC at 9 years of age in a prospective study of 278 inner-city children from Cleveland, OH. Chiodo et al. (2004, 2007 ) evaluated a range of neurocognitive effects in inner-city African American children 7-9 years of age (n=243 and 506, respectively) with concurrent blood Pb levels <10 μg/dL (mean 5.4 μg/dL; blood Pb levels were related to decreased performance in mul

tiple tests, including the Block Design and Digit Span subsets of the WISC and various tests of executive function, memory, and attention. When grouped by cutoff points of 10, 7.5, 5, and 3 μg/dL blood Pb, the studies found significant effects on some tests at levels of ≥3 μg/dL (e.g., Block Design). Most studies of the effects of Pb on cognitive function in adults involved occupationally exposed individuals with blood Pb levels >10 μg/dL , and fewer studies have been reported in adults from the gen

eral population. A number of studies in older adults reported a decrease in cognitive function associated with Pb, with more consistent evidence for an asso

ciation with bone Pb than for concurrent blood Pb levels. Payton et al. (1998) reported that concurrent blood Pb (mean, 5.5 μg /dL) levels in 141 older men (mean age, 67 years) from the Normative Aging Study were associated with decreases in specific measures of cognitive function from a battery of tests admin

istered, including slower pattern comparison speed, vocabulary, word list memory, constructional praxis, and the Boston Naming Test. Tibia Pb level (but not patellar Pb) was associated with decreased perfor

mance in a test of spatial ability. In a study of 736 older men (mean age, 69 years) also from the Norma

tive Aging Study, Wright et al. (2003) reported that blood Pb (mean, 4.5 μg/dL), patellar Pb, and tibia Pb were all associated with decreased performance on the MMSE. Muldoon et al. (1996) evaluated cog

nitive 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/d L) was associated with decreased performance on the Trail Making Test (for blood Pb >8 μg/dL , OR=2.60 (95% CI: 1.04, 6.49); f or blood Pb 4-7 μg /dL, OR=2.05 (95 % CI: 1.05
, 4.0 2); relative to referents with blood Pb ≤3 μg/dL) and the Digit Symbol Substitution test (for blood Pb >8 μg/dL

, OR=3.73 (95% CI: 1.57, 8.84); f or blood Pb 4-7 μg/dL

, OR=2.03 (95% CI: 1.0 6, 3.8 8); relative to referents with blood Pb ≤3 μg /dL), but only in the rural population and not the urban population (Muldoon et al. 1996). There are also several studies that reported an association between bone Pb and decreased performance but did not find an association with blood Pb levels. Shih et al. (2006) reported a lack30 NTP Monogr aph on Health Effects of Low-Level Lead of an association between current blood Pb (mean, 3.5 μg/dL) and cognitive function in a study of 985 older adults in the Baltimore Memory Study (mean age, 60 years). However, tibia Pb levels were sig

nificantly associated with lower scores in all seven domains of the cognitive test battery (Shih et al. 2006). Weuve et al. (2009), reported that tibia Pb lev

els were associated with reduced cognitive function by the Telephone Interview for Cognitive Status in a study of 587 older women (mean age, 61 years) from the Nurses Health Study; blood Pb and patellar Pb levels were not significantly related to the test score. Two studies did not find an association with blood Pb levels and did not collect bone Pb data: Nordberg et al. (2000) did not find an association between blood Pb level (mean, 3.7 μg/d L) 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 sig

nificantly related with cognitive function in as study of 188 people (mean age, 69 years) from rural China assessed with a test battery that included the Com

munity Screening Interview for Dementia. Several studies have reported a greater effect on changes in cognitive function over time, rather than a single cross-sectional examination. Weisskopf et al. ( 2004) tested cognitive function in 466 men (mean age, 67 years) from the Normative Aging Study over several years and reported that higher patella Pb was associated with a greater decline in performance on the MMSE over a 3.5-year period between retest

ing; 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 cov

ering 1,089 men, Weisskopf et al. (2007) reported similar results, stating that there was little associa

tion between blood or bone Pb levels and cognitive test scores on a cross-sectional basis; however, patel

lar 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 Bal

timore Memory Study (59 years of age at baseline), but not with other measures of cognitive function in a battery of 20 standardized tests. Fewer studies have examined cognitive perfor

mance 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 asso

ciated with performance on neurobehavioral tests. Krieg et al. (2005, 2009
, 2009
, 2010 ) did not find a significant relationship between blood Pb (mean, 3.3 μg/dL) and neurobehavioral tests for simple reaction time, symbol-digit substitution, and serial digit learning. In a portion of the study that included both children and adults from the same NHANES data set, Krieg et al. ( 2010) demonstrated that vitamin D receptor (VDR) genotype did affect the relationship between blood Pb and performance on the WISC-R Digit Span and WRAT-R math scores; however, they found no clear pattern in terms of the effect of VDR genotype on the relationship between blood Pb and cognitive function. Most of the recent studies of the relationship between blood Pb and specific measures of cognitive function considered a range of potential confounders, such as age, sex, education, and race/ethnicity. Some studies have also examined potential physical, genetic, and psychological confounders. In a study of 47 health adults 55-67 years of age in Rochester, NY, van Wijn

gaarden et al. (2009) found that higher tibia and cal

caneus (heel bone) Pb levels were significantly corre

lated with measures of memory impairment; however, the relationship with bone Pb was not significant after adjusting for hypertension. Several studies of cognitive function in children and adults have also investigated the potential modifying effect of gene polymorphisms (e.g., ALAD
, HFE
, APOE , and VDR genotypes) and other factors (Weuve et al. 2006, Rajan et al. 2008
, Glass et al. 2009
, Krieg et al. 2010 ). In particular, Wang et al. ( 2007) demonstrated a significant effect of HFE poly

morphism on the rate of decline in MMSE score in 358 participants from the Normative Aging Study. Krieg et al. (2010) and Rajan et al. (2008) reported that there was no clear pattern of ALAD or VDR genes modifying the relationship of Pb and cognitive function. Glass et al. (2009) found that tibia Pb was associated with impaired executive function and that there was a sig

nificant interaction with neighborhood psychosocial hazards in a study of 1,001 older adults (mean age, 59 years) from the Baltimore Memory Study. Surkan et al. (2008) reported that higher maternal self-esteem attenuated the Pb-associated decrease in MDI score in a study of 309 children 2 years of age from Mexico City. Peters et al. (2010) reported that blood Pb (mean,NTP Monograph on Health Effects of Low-Level Lead 31 5 μg/dL) was significantly associated with decreased cognition as measured by the MMSE, but that bone Pb and stress were modifiers of the association with Pb in a study of 811 older men (mean age, 68 years) in Normative Aging Study.

Summary of Support for Conclusions Animal data support a Pb-associated decrease in neurobehavioral tests of learning (including fixed interval operant conditioning) at blood Pb levels ≥11 μg/dL and mixed evidence for effects on memory (see U.S. EPA 2006 for recent reviews of the animal data, ATSDR 2007 ). The human data include multiple prospective and cross-sectional studies supporting a Pb-associated decrease in specific measures of cog

nitive function in children at blood Pb levels from 1 to 10 μg/dL. The conclusion of sufficient evidence for decreases in specific measures of cognitive function in children 3 months to 16 years of age with blood Pb levels <5 μg/dL measured in concurrent blood or in early childhood is based on the consistency of effects on multiple measures of cognitive function in mul

tiple studies. Multiple studies ( e.g., Min et al. 2009) reported that early-childhood Pb exposure is associ

ated with decreases in cognitive function observed at later ages. However, as discussed for IQ, clear evidence that early-childhood or prenatal Pb expo

sure is associated with decreases in specific indices of cognitive function at later ages is complicated by the high degree of correlation in childhood blood Pb levels over time (e.g., see Dietrich et al. 1993a, Lan

phear et al. 2005 ). Multiple studies (e.g., Bellinger et al. 1984, Al-Saleh et al. 2009
, Jedrychowski et al. 2009a ) also reported that levels of Pb in umbilical cord blood are associated with decreases in cogni

tive 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 ar e associated decreases in specific measures of cognitive function in children is based on strong consistent support for an association between umbilical cord blood and MDI scores, and the mixed evidence for maternal blood Pb and MDI or other measures of cognitive func

tion in children. The conclusion of limited evidence that blood Pb levels <10 μg/dL are associated with decreases in specific measures of cognitive function in older adults is based on the mixed evidence that concurrent blood Pb levels <10 μg/dL ar e associated with reduced cognitive function and the consistent support that bone Pb is associated with decreases in specific measures of cognitive function or with change in these measures through time in older adults. The EPA’s 2006 AQCD for Lead (U.S. EPA 2006) suggests that cumulative exposure to Pb may be critical in contributing to neurocognitive deficits in adults because of the significant associations with bone Pb; EPA also highlights the mixed evidence for an association with blood Pb. As with other studies of health effects of Pb in adults, prospective studies in a group for which the data demonstrated that blood Pb levels remained consistently below 10 μg/dL fr om birth until measurement of the outcome of interest would eliminate the potential role of early-life blood Pb levels above 10 μg/dL on health effects observed in adults with concurrent blood Pb levels <10 μg/dL. The NTP’s conclusion of sufficient evidence that blood Pb levels <5 μg/dL ar e associated with decreases in general and specific measures of cognitive function in children 3 months to 16 years of age extends the conclusions from EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 2007 Toxicological Profile for Lead (ATSDR 2007), which were limited to blood Pb levels <10 μg/dL; however, the EPA’s 2012 draft (U.S. EPA 2012) currently supports a lower blood Pb level.



### 4.3.2 Behavior

Attention-Related Behaviors There is sufficient evidence that blood Pb levels <5 μg/dL are associated with attention-related behav

ioral problems in children 3-18 years of age (see Appendix A: Neurological Effects for full list of stud

ies). This conclusion is for an association with atten

tion-related behaviors, rather than ADHD alone, for two reasons: (1) “att ention-related behaviors” is an inclusive expression that more accurately reflects the data supporting a range of Pb-associated behavioral effects in the area of attention, of which ADHD is one example on the more severe end of the spectrum of effects; and (2) in the a vailable studies, designations of “ADHD” in children generally lack the strength of an ADHD diagnosis by trained clinicians using DSM-IV-TR criteria. Most of the studies that demonstrated a sig

nificant association between Pb and attention-related behaviors are studies that report behavioral testing and concurrent blood Pb levels. Increased diagnosis of ADHD and attention-related behaviors (e.g., inat

tention and hyperactivity) are consistently reported32 NTP Monogr aph on Health Effects of Low-Level Lead in studies with mean blood Pb levels <5 μg/dL and in several studies at blood Pb levels <2 μg/dL. The diagnostic criteria for attention-related behaviors can include multiple categories of behavioral deficits in addition to inattention, hyperactivity, and the over

all diagnosis of ADHD (Aguiar et al. 2010). A review of individual behavioral domains, such as response inhibition, flexibility, and planning aspects, was pub

lished by Eubig et al. (2010); however, data on those individual domains will not be covered here because a sufficient number of studies examine overall ADHD diagnosis, inattention, and hyperactivity to develop more general conclusions on the overall classifica

tion of attention-related behaviors. There is limited evidence that prenatal blood Pb levels <10 μg/dL are associated with attention-related behaviors in child

hood. 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 years of age); however, early-childhood blood Pb levels in some of these individuals were >10 μg/dL; therefore, the effect may not be strictly associated with blood Pb levels <10 μg/dL. A clear majority of recent cross-sectional studies (more than 10 publications since 2000) demonstrate an association between current blood Pb at mean levels from 1 to 11 μg/dL and attention-related behavioral problems, ADHD, or other indicators of decreased attention or increased hypersensitivity in children from 3 to 18 years of age. Multiple studies reported an association with blood Pb of ≤5 μg/d L. In a case-control study of 1,260 children 4-12 years of age in China (n=630 ADHD cases and 630 matched controls), Wang et al. ( 2008) reported a significant association between concurrent blood Pb levels >5 μg/dL and ADHD determined from a structured diagnostic interview. An increase in attention-related behavioral problems, particularly inattention, was observed on the teachers’ and parents’ ratings using a German questionnaire version of the Conners’ Rating Scale (namely the Fremdbeurteilungsbo

genfür Auf-merksamkeits-Hyperaktivitäts-Störung (FBB-ADHS)) and German-KITAP (Testbatterie zur

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

ment; therefore, 18- to 20-year-olds in the study are con

sidered adults. Aufmerksamkeitsprüfung fü Kinder) test battery in a study of 83 children 8-12 years of age in Romania with concurrent mean blood Pb levels 3-5 μg/dL (Nicolescu et al. 2010). Two studies by Chiodo et al. (2004, 2007 ) evaluated a range of neurodevelopmental measures in inner-city African American children 7-9 years of age (n=243 and 506, respectively) with concurrent blood Pb levels (mean, 5.4 μg/dL); blood Pb levels were related to higher ADHD and inattention scores on the Barkley-DuPaul Scale, greater hyperactivity on the PROBS-14 Problem Behavior Scale, and poor attention on the Achenbach Child Behavior Checklist Teacher Report Form. When they grouped the chil

dren 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 chil

dren from the NHANES (1999-2002) data set ( Braun et al. 2006, Froehlich et al. 2009 ) reported an associa

tion 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 paren

tal reported previous diagnosis or use of stimulant medication. In children 8-15 years of age from the same NHANES data set (n=2,588), Froehlich et al. (2009) found that children with concurrent blood Pb >1.3 μg/dL (the third tertile of Pb exposure) had a sig

nificantly 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 expo

sure) with 0.8 μg/dL blood Pb; the determination of ADHD was based the Diagnostic Interview Schedule for Children. Several other cross-sectional studies support an association between concurrent blood Pb levels of ≤2 μg/dL and attention-related behaviors, ADHD, or symptoms of inattention and or hyperactivity. In a cross-sectional study of 639 children 8-11 years of age in Korea, Cho et al. (2010) reported a significant asso

ciation between blood Pb levels (mean, 1.9 μg/dL) and ADHD ratings in the inattention, hyperactiv

ity, and total scores using the teacher evaluation of the Korean version of the ADHD rating scale. Higher concurrent blood Pb level (mean, 1.8 μg/dL) wasNTP Monograph on Health Effects of Low-Level Lead 33 associated with increased score on the Korean ver

sion of the abbreviated Conners’ scale for ADHD in a study of 1,778 children 7 years of age in South Korea in the Children’s Health and Environment Research Study (Ha et al. 2009). In a pair of studies of 236 children, Nigg et al. (2008, 2010 ) reported that con

current blood Pb levels were significantly higher in ADHD-combined type children 6-17 years of age than in controls, and that blood Pb levels (mean, 1 μg/dL) were significantly correlated with aspects of ADHD diagnosis by two experienced clinicians, including hyperactivity, oppositional behaviors, ADHD index, and attention problems evaluated with the Conners’ ADHD Rating Scale, revised. Nigg et al. ( 2008, 2010 ) found that measures of hyperactivity-impulsivity were more consistently associated with blood Pb measurements than were inattention symptoms. However, the consistent association with hyper

activity over inattention observed by Nigg et al. ( 2008, 2010 ) is not universal, and several other studies have found an association with blood Pb and ADHD or measures of inattention. Kim et al. ( 2010) found increased inattention and hyperactivity symptoms on the teacher-completed Korean version of the ADHD Rating Scale in children with blood Pb ≥2.2 μg/dL compared to referents with lower blood Pb levels in a study of 275 South Korean children 8-10 years of age. Roy et al. (2009) reported an increase in the ADHD index (β=0.17; p=0.05), and ratings on the DSM-IV inattentive scale (β=0.24; p=0.01), but not ratings on the DSM-IV hyperactive scale (β=0.17; p=0.13) by the Connors’ ADHD/ Diagnostic and Statistical Manual of Mental Disorders (4th edition ( DMS-IV )) scales, in 3- to 7-year-old children in India with con

current mean blood Pb of 11 μg/ dL; increased anxi

ety and social problems were also noted. Inattention and hyperactivity in 11-year-olds evaluated by the Rutter Parent and Teacher Behavior Questionnaires were also correlated with blood Pb (mean, 11 μg/dL) in a cross-sectional study of 579 children from the Dunedin Multidisciplinary Health and Development Study in New Zealand (Silva et al. 1988). Canfield et al. (2003b) reported that blood Pb at 4 years of age was associated with decreased focused attention by the Shape School Task at 4-5 years of age in 172 children in Rochester, NY. The relationship between concurrent blood Pb levels and attention-related behaviors is supported by multiple studies, but there are also data supporting a role for early-life prenatal or early-childhood Pb expo

sure and attention-related behaviors in older children. In a prospective study with Pb exposure measures spanning prenatal and early childhood to 6 years of age, Ris et al. (2004) reported that attention in 15- to 17-year-old children by the Continuous Performance Test-Conners’ Version was inversely associated with maternal blood Pb during the first or second trimester of pregnancy (mean, 8.9 μg/dL), average childhood blood Pb <5 years of age, and blood Pb at 6.5 years of age in a study of 195 children from the Cincinnati Lead Study); however, blood Pb levels during early childhood were above 10 μg/dL in this cohort (Diet

rich et al. 1993a, Wright et al. 2008), so it is not clear that this is strictly associated with blood Pb levels <10 μg/dL. Chandramouli et al. (2009) found that attention in 7- and 8-year-olds in the United Kingdom, as assessed with the Test of Everyday Attention for Children, was not significantly related to blood Pb (mean, 4.2 μg /dL) at 30 months of age (n=582), but there was a greater odds for teacher-rated hyperac

tivity (OR=2.82 (95% CI: 1.08, 7.35)) in children with blood Pb >10 μg/dL. Cord blood Pb (mean, 6.8 μg/dL) and tooth dentin Pb were associated with inflexible behavior in 8-year-olds in the Task domain of the BTQ, but there was no relationship with hyperactiv

ity, 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 inatten

tion and restlessness at 12-13 years of age by the Rutter and Conners parental and teacher question

naires in a study of 1,265 children from the Christ

church Health and Development Study cohort. In a similar study of 79 young adults 2 19-20 years of age, Bellinger et al. (1994a) reported that both dentin Pb levels in shed teeth (6-8 years of age) and tibia Pb levels were significantly associated with specific mea

sures of attention.

Summary of Support for Conclusions Animal data support a Pb-associated reduced perfor

mance on neurobehavioral tasks (including increased distractibility), with effects observed down to approxi

mately 10 μg/ dL (e.g., deficits in waiting behavior in rats Brockel and Cory-Slechta 1998, U.S. EPA 2006 for

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

ment; therefore, 19- and 20-year-olds in the study are con

sidered adults.34 NTP Monogr aph on Health Effects of Low-Level Lead recent reviews of the animal data
, see ATSDR 2007 ). In general the animal data are unlikely to represent thresholds because the lowest levels of effect have yet to be studied. The human data supporting a Pb-asso

ciated increase in attention-related behaviors such as ADHD, inattention, and hyperactivity include multiple cross-sectional studies of children from 3 to 18 years of age with blood Pb levels of 1-11 μg/dL. The conclusion of sufficient evidence for a positive association with attention-related behaviors in children at blood Pb levels <5 μg/dL is based on the consistency of effects in these studies and supports effects down to and below 2 μg/dL blood Pb. This conclusion is for an asso

ciation with attention-related behaviors rather than ADHD alone for two reasons. First, “attention-related behaviors” is a more inclusive term that more accu

rately reflects the support for a range of Pb-associated behavioral changes in the area of attention, of which ADHD is one example on the more severe end of the spectrum of effects. Second, diagnostic criteria in the available studies, with the exception of the two Nigg et al. ( 2008, 2010 ) reports, are based largely on the par

ent reporting a physician’s diagnosis, untrained teacher evaluations, or that the child is taking ADHD medica

tion; therefore, they lack the additional strength that would be provided by studies that incorporate diag

nostic evaluations by trained clinicians or physicians to identify ADHD using DSM-IV-TR criteria. Recent stud

ies found effects on attention-related behaviors after controlling for a large number of confounders, such as socioeconomic variables, sex, race/ethnicity, age of blood Pb measurement, parental education, and tobacco exposure. Several studies reported that blood Pb levels were significantly associated with ADHD even after controlling for potential mediating effects of child IQ (e.g., Nigg et al. 2008, Nigg et al. 2010 ). Although several studies reported an association between con

current blood Pb and attention-related behaviors in children up to 15 or 17 years of age ( Braun et al. 2006, Nigg et al. 2008
, Froehlich et al. 2009
, Nigg et al. 2010 ), or between bone Pb measured as children and atten

tion evaluated as young adults 19 and 20 years of age (Bellinger et al. 1994a), no studies were located that examined the relationship between blood Pb levels in adults and ADHD or attention-related behaviors. There is inadequate evidence to evaluate the potential asso

ciation between blood Pb <10 μg /dL and effects on attention-related behaviors in adults. The conclusion of limited evidence for an association between blood Pb levels and attention-related behaviors in children with prenatal Pb exposure at blood Pb levels <10 μg /dL is based on the evidence for an association with prenatal blood Pb <10 μg/ dL that may include childhood expo

sure >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 such as inattention or hyperactivity. Existing data supportthe importance of current Pb exposure for attentionrelated behaviors but does not allow a clear distinction between the role of early-life Pb exposure and current exposure. The NTP’s conclusions for sufficient evidence that attention-related behaviors in children 3-18 years of age are associated with Pb levels <5 μg/dL are stron

ger than the limited relationship with behavioral fea

tures of ADHD outlined in the EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 2007 Toxicological Profile for Lead (ATSDR 2007); however, given the growth of the database in recent years, the EPA’s 2012 draft (U.S. EPA 2012) currently supports an association with ADHD and biological plausibility supported by Pb-associated increases in attention-related behaviors.



### Problem Behaviors The discussion of problem behaviors below is divided into two sections: (1) delinque nt, criminal, or anti

social behavior; and (2) ps ychiatric outcomes. Most of the studies of Pb effects on problem behaviors focused on studies of conduct problems or criminal behavior. Recent studies of mood disorders or psychi

atric outcomes such as anxiety and depression have also reported an association with blood Pb levels.

Delinquent, Criminal, or Antisocial Behaviors There is sufficient evidence that blood Pb levels <5 μg/dL are associated with antisocial behavioral problems or actual criminal behavior in children from 6 to 15 years of age (see Appendix A: Neurological Effects for full list of studies). Recent studies, including studies with large sample sizes such as the NHANES data sets, have reported effects down to blood Pb lev

els <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 prob

lem 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 prospectiveNTP Monograph on Health Effects of Low-Level Lead 35 studies have reported a significant association between prenatal blood Pb <10 μg /dL and delinquent behavior or criminal arrests as children; however, childhood blood Pb levels in some of these individu

als are >10 μg /dL; therefore, the effect may not be strictly associated with blood Pb levels <10 μg /dL. Several studies have also reported that umbilical cord blood Pb was not associated with antisocial problem behaviors in children. Although several studies have reported an association between prenatal Pb levels <10 μg/dL and criminal arrests in young adults 3 up to 24 years of age, no studies of antisocial behavioral problems were located with Pb levels in adults. There is inadequate evidence to evaluate the potential asso

ciation between blood Pb <10 μg /dL and effects on behavior problems in adults. Braun et al. (2008) reported a significant increase in the odds ratio (OR=7.24 (95% CI: 1.1, 49.5)) for con

duct disorder among children 8-15 years of age with blood Pb levels ≥0.8 μg /dL compared to referents with blood Pb ≤0.7 μg /dL (conduct disorder measured using criteria described in DSM-IV ; n= 3,081 from the NHANES 2001-2004 data set). This study extended the findings from earlier cross-sectional studies that found associations between current blood Pb at and above 10 μg /dL and behavioral problems or criminal behavior in children from 6 to 13 years of age (i.e., mean blood Pb 10-15 μg/dL in Yule et al. 1984, Silva et al. 1988
, Thomson et al. 1989
, Burns et al. 1999 ). For example, in a cross-sectional study of 11-year-old children (n=579) in New Zealand, blood Pb (mean, 11 μg /dL) was significantly correlated with behav

ioral problems evaluated with the Rutter Parent and Teacher Behavior Questionnaires ( Silva et al. 1988). Burns et al. (1999) reported that increased behav

ioral 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 chil

dren 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, Was

serman et al. 2001
, Chen et al. 2007 ). Results of some studies support a stronger or more consistent

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

ment; therefore, 19- to 24-year-olds in these studies are considered adults. relationship between bone Pb or concurrent blood Pb and behavioral outcomes than for prenatal or early-childhood blood Pb. For example, Bellinger et al. (1994b) reported that problem behaviors in 8-year-old children in Boston (n=1,782 judged by the Teacher Report Form of the Child Behavior Profile) were significantly associated with tooth dentin Pb levels; however, there was no association with umbil

ical 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 behav

ior symptoms mediated through IQ and direct effects on school problems and behavioral symptoms index evaluated with the Behavioral Assessment System for Children (Chen et al. 2007); however, there was no association with earlier blood Pb levels that were significantly above 10 μg /dL at 2 years of age (mean, 26 μg/dL) or 5 years of age (mean, 12 μg/dL). In contrast, other prospective studies support an association with prenatal or early-childhood exposure with problem behaviors at a later age. Dietrich et al. (2001) found significant associations between maternal blood Pb (mean, 8.9 μg /dL) and childhood blood Pb measures ≤7 years of age with self-report of delinquent behavior in children from the Cincinnati Lead Study evaluated at 15-17 years of age (concurrent mean, 3 μg /dL); however, as in the study by Chen et al. (2007), blood Pb levels dur

ing early childhood were above 10 μg /dL, so it is not clear that this is strictly associated with blood Pb levels <10 μg /dL. Similar results were reported for umbilical cord blood and concurrent blood Pb and behavior problems in 3-year-olds from the Yugoslavia Prospective Study; however, blood Pb levels (means of 5.5 μg /dL in Pristina and 22 μg /dL in Mitrovica) in many children in this study were also >10 μ g/dL (Wasserman et al. 1998). Chandramouli et al. (2009) found that the odds ratio for antisocial behaviors (OR=2.90 (9 5% CI : 1 .05, 8 .03)) in 7- and 8-year-olds(n=582) in the United Kingdom assessed by the Antisocial Behavior Interview was significantly elevated with blood Pb >10 μ g/dL at 30 months of age. Two studies have also reported an association with pre

natal or childhood blood Pb levels and antisocial behavior problems as young adults 4 . Higher rates

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

ment; therefore, 19- to 24-year-olds in the following stud

ies are considered adults.36 NTP Monograph on Health E ffects of Low-Level Lead for total criminal arrests in 19- to 24-year-olds for a 5 μg/dL increase in blood Pb were significantly associated with higher maternal blood Pb during the first or early second trimester of pregnancy (mean, 8.3 μg/dL; relative risk (RR)=1.4 (95% CI: 1.07, 1.85)) as well as blood Pb at 6 years of age (mean, 8.3 μg/dL; RR=1.27 (95% CI: 1.03, 1.57)) in a s tudy of 250 young adults from the Cincinnati Lead Study (Wright et al. 2008). Hornung et al. (2009) reported that blood Pb at 6 years of age was more strongly related to adult criminal arrests (age was not reported) than was blood Pb at 2 years of age in a similar analysis reported for the combined cohort from the Cincin

nati and Rochester lead studies, with a peak blood Pb mean of 13.6 μg/dL and c oncurrent blood Pb at 6 years of age of 6 μg/dL; the re was a strong correla

tion 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 anti

social problem behaviors but did not provide blood Pb measurements for comparison. Bone Pb levels were associated with antisocial behavior, includ

ing 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 delin

quent behavior that resulted in a court appearance (OR=3.7 (95% CI: 1.3, 10.5)) in a c ase-control study of 194 delinquent and 146 nondelinquent youths from the same high schools in Pennsylvania. Fergusson et al. (2008) reported a significant association between tooth dentin Pb of shed primary teeth (6-8 years of age) and officially reported crime at 21 years of age in a study of 1,265 young adults from the Christchurch Health and Development Study cohort. A meta-analysis of 19 studies of Pb exposure and conduct problems in children 3-18 years of age reported a significant overall correlation (r=0.19; p<0.001) or medium effect size across the 19 studies evaluated, consisting of 8,561 total children (Marcus et al. 2010). Although conduct problems were more common in boys than in girls, the percentage of boys in the study did not appear to attenuate the relation

ship with Pb, nor did adjustment for other confound

ers such as age, socioeconomic status, parental IQ, or home environment. Marcus et al. (2010) note that effects were similar whether Pb exposure was measured by blood Pb, by bone Pb measured in tooth dentin, or by bone Pb measured with K-x-ray analysis; however, a larger effect of hair Pb was found in three studies from the same laboratory (Marlowe and Errera 1982, Marlowe et al. 1985, Marlowe and Bliss 1993 ) that used hair as the measure of exposure. Marcus et al. (2010) cannot explain why the hair Pb data displayed a stronger relationship and noted that multiple studies have determined that hair Pb is less accurate than blood Pb measurements for determin

ing Pb exposure (e.g., ATSDR 2001)(see discussion in Section in Section 3.2 Biomarkers of Pb Exposure ). This suggests that the Marlowe et al. studies contain a bias or other population factor that may explain the stronger relationship in these studies.

Summary of Support for Conclusions Animal data support a Pb-associated neurobehav

ioral deficits (including reduced ability to inhibit inappropriate responding) at blood Pb levels close to levels reported in human studies (i.e., approximately 10 μg/dL) (see U.S. EPA 2006 for recent reviews of the animal data, ATSDR 2007 ). The human data from multiple prospective and cross-sectional studies sup

port a Pb-associated increase in antisocial problem behaviors or criminal behavior in children from 6 to 15 years of age with concurrent blood Pb levels of <1-15 μg/dL. The conclusion of sufficient evidence for a positive association with behavior problems in children at blood Pb levels <5 μg/dL is based on the consistency of effects in these studies and the Braun et al. ( 2008) study from the NHANES 2001-2004 data set that reported conduct disorder at blood Pb levels ≥0.8 μg/dL blood Pb. Most of the recent studies in the database include a large number of confounders, such as socioeconomic variables, sex, race/ethnicity, age of blood Pb measurement, parental education, and tobacco exposure. Several studies reported that blood Pb levels were significantly associated with antisocial behavioral problems even after controlling for child IQ through model adjustments or by path analysis (Silva et al. 1988, Burns et al. 1999
, Chen et al. 2007 ). Although the Wright et al. (2008) study reported that criminal arrests in young adults 19-24 years of age were associated with prenatal and childhood blood Pb levels, and the Fergusson et al. (2008) study found an association between reported crimes in 21-year-olds and dentin Pb of shed primary teeth at 6-8 years of age, no studies of antisocial behavioral problems wereNTP Monograph on Health Effects of Low-Level Lead 37 located that used Pb levels in adults. There is inad

equate 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 expo

sure to blood Pb <10 μg/dL and beha vioral problems in children is based on the mixed results of studies with prenatal exposure data. The NTP’s conclusion of sufficient evidence that antisocial behavior problems in children are associated with Pb levels <5 μg/dL is stronger than the discussion of Pb effects on mood and behavior that may extend into increased risk for delinquent behavior described in the EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 2007 Toxicologi

cal Profile for Lead (ATSDR 2007); however, given the growth of the database in recent years, the EPA’s 2012 draft (U.S. EPA 2012) currently supports an association with problem behavior.

Psychiatric Outcomes, Including Anxiety and Depression There is inadequate evidence to evaluate the poten

tial association between blood Pb <10 μg/dL and anxiety- or depression-related psychiatric outcomes in children (see Appendix A: Neurological Effects for full list of studies). There is limited evidence that blood Pb <10 μg/dL in adults is associated with psy

chiatric symptoms that include anxiety and depres

sion. Although relatively few studies of children or adults with low blood Pb levels address these mood symptoms, the available data in adults are from sev

eral large cross-sectional studies (n=526-1,987) and support an effect of concurrent blood Pb or bone Pb on these psychiatric outcomes. Most studies of behavior in children that have identified an association with Pb exposure have been in the area of attention-related behaviors or conduct problems. However, several studies have reported an association between blood Pb at and above 10 μg/dL and anxiety- or depression-related behaviors in chil

dren. Wasserman et al. ( 1998) reported that umbili

cal cord blood Pb (means of 5.5 μg/dL in Pris tina and 22 μg/dL in Mitrovica) and concurrent blood Pb levels in 3-year-olds were associated with somatic prob

lems, anxious-depressed and withdrawn behavior by the CBCL in a study of 293 children from the Yugosla

via Prospective Study; however, many children in this study had blood Pb levels above 10 μg/dL, so these effects may not be associated with blood Pb levels <10 μg/dL. Roy et al. (2009) reported increased anxi

ety and social problems evaluated by teachers using the Conners’ Teacher Rating Scales in 3- to 7-year-old children in India with concurrent mean blood Pb of 11 μg/dL. In a small study of 42 children 3-5 years of age with a mean blood Pb of 2 μg/dL , higher blood Pb was associated with lower teacher ratings of social confidence and sociability in girls but not to measures of anxiety or aggression in boys or girls (Hubbs-Tait et al. 2007). Several studies have demonstrated an asso

ciation between concurrent blood Pb <10 μg/dL in adults and psychiatric symptoms, including anxiety, depression, and panic disorder. However, these studies do not include cohorts in which it has been demonstrated that blood Pb levels were consistently below 10 μg/dL from birth to behavioral assessment. Bouchard et al. (2009) reported a significant increase in the odds ratio for diagnoses of major depression disorder (OR=2.32 (95% CI: 1.13, 4.75)) and panic disorder (OR=4.94 (95% CI: 1.32, 18.48)) at c oncur

rent blood Pb levels of ≥2.11 μg/dL in a study of 1987 adults 20-39 years of age from the NHANES 1999- 2004 data set; a diagnosis of generalized anxiety disorder was not associated with blood Pb levels in this study. In a study of 526 men in the Normative Aging Study (mean age, 67 years), blood Pb (mean, 6.3 μg/dL), tibia Pb (mean, 22 μg/g), and patella Pb (mean, 32 μg/g ) were significantly associated with combined measure of mood, including elevated anxiety, depression, and phobic anxiety (Rhodes et al. 2003). In a further study of 744 men from the Normative Aging Study, an interquartile increase in tibia bone Pb (14 μg/g ) or patella Pb (20 μg/g ) was associated with increased risk of psychiatric symp

toms of somatization and increased global severity index (Rajan et al. 2007).

Summary of Support for Conclusions There are some examples of Pb-associated increases in depression-related outcomes in rats and mice at blood Pb levels down to 17 μg/dL (e .g., Dyatlov and Lawrence 2002, U.S. EPA 2006 for recent reviews of the animal data
, see ATSDR 2007 ). The data set of human studies to evaluate the association with psy

chiatric 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 evidence38 NTP Monograph on He alth Effects of Low-Level Lead to evaluate the potential association between blood Pb <10 μg/dL in children and anxiety- or depressionrelated psychiatric outcomes is based on the lack of studies at blood Pb levels <10 μg/dL. The conclusion of limited evidence that concurrent adult blood Pb levels <10 μg/dL are associated with psychiatric symp

toms including anxiety and depression is based on the small number of studies supporting an effect (one at blood Pb <10 μg/dL and one at blood Pb <5 μg/dL ) and because two of the three studies are from a single cohort, the Normative Aging Study. As with other stud

ies of health effects of Pb in adults, prospective stud

ies in a group for which blood Pb levels remained con

sistently below 10 μg/dL fr om birth until assessment of anxiety, depression, or other psychiatric outcomes would eliminate the potential role of early-life blood Pb levels above 10 μg/dL on health effects observed in adults with concurrent blood Pb levels <10 μg/dL. The 2007 ATSDR Toxicological Profile for Lead ( ATSDR 2007) and 2006 EPA AQCD for Lead (U.S. EPA 2006) discuss evidence that effects of Pb may extend into increased risk for antisocial and delinquent behavior. The 2006 EPA AQCD for Lead (U.S. EPA 2006) does not have specific conclusions on the potential association between Pb exposure and anxiety. The 2007 ATSDR Toxicological Profile for Lead (ATSDR 2007) highlights the evidence for neurobehavioral effects in older adults at blood Pb levels >4 μg/dL.



### 4.3.3 Neurodegeneration

Amyotrophic Lateral Sclerosis (ALS) There is limited evidence that blood Pb levels <10 μg/dL are associated with increased risk for ALS. A number of case-control studies have reported a significant association between blood Pb and ALS diagnosis, with most of the studies coming from two patient groups (see Appendix A: Neurological Effects for full list of studies). The data present limited evi

dence because of issues with potential reverse cau

sality, because an association between ALS and bone turnover might lead to higher Pb levels among ALS patients, and issues with bias because a reported increased survival time in ALS patients relative to control patients might also lead to higher Pb levels. In a small case-control study of 19 ALS patients and 39 controls (mean age, 64-66 years), mean blood Pb was not significantly different (p=0.38) between ALS patients (12.7 μg/dL) and controls (10.8 μg/dL) (Vinceti et al. 1997). The relative risk of ALS was sig

nificantly associated with blood Pb (continuous mea

sure: OR=1.9 (95% CI: 1.4, 2.6); categorical variable, 3-4 μg/dL: OR=14.3 (95% CI: 3, 69)), but the associa

tion 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)) c ompared to con

trols, and odds ratio for having ALS was significantly associated with lifetime days of Pb exposure greater than 2,000 hours (OR=2.3 (95% CI: 1.1, 4.9)). The sig

nificant association with lifetime exposure is interest

ing because bone Pb was not significantly associated with ALS in the study, and bone Pb is considered a better measure of cumulative exposure. The issue of reverse causality (the possibility that increased blood Pb is related to greater bone Pb mobilization from the reduced physical activity in ALS patients) was exam

ined in a separate case-control study of 184 ALS cases and 194 controls among U.S. veterans (Fang et al. 2010). Fang et al. (2010) reported that blood Pb was significantly higher among the ALS patients (mean, 2.4 μg/dL) than among controls (1.8 μg/dL). The odds ratio for having ALS was significantly associated with blood Pb (OR=2.6 (95% CI: 1.9, 3.7) for a doubling of blood Pb). The study examined the potential influence of measures of bone turnover and genetic factors and reported a significant interaction between blood Pb–ALS and plasma biomarkers for bone turnover (procollagen type-1 amino-terminal peptide (PINP)) and resorption (C-terminal telopeptides of type 1 collagen (CTX)), but not the K59N polymorphism in the ALAD gene (Fang et al. 2010). However, adjusting the model to account for differences in biomarkers of bone turnover did alter the association between blood Pb and ALS to a large degree. The authors state that reverse causality is unlikely because the Pb-ALS association persisted after adjusting for biomark

ers of Pb mobilization from bone, but that reverse causality cannot be entirely ruled out because of the cross-sectional nature of the data. In further study of the population in New Eng

land, Kamel et al. (2003, 2005 ) reported that the ALAD gene was associated with altered bone Pb levels, but not with blood Pb, and the effect on ALS was not significant. In a second, follow-up study, Kamel et al. (2008) demonstrated that tibia bone Pb was signifi

cantly associated with greater survival time betweenNTP Monograph on Health Effects of Low-Level Lead 39 diagnosis and death (HR=0.3 (95% CI: 0.1, 0.7)), while the association between greater survival time and patella Pb (HR=0.5 (95% CI: 0.2, 1.0)) or blood Pb (HR=0.9 (95% CI: 0.8, 1.0)) had only borderline significance. The association of bone and blood Pb with greater survival time in ALS patients relative to control patients introduces the possibility of bias, because the case groups in these case-controls stud

ies may be individuals with longer survival time, and higher Pb levels may be related to a longer period of exposure or more time for Pb to be released from bone stores.

Summary of Support for Conclusions Several recent animal studies have demonstrated findings similar to the human data supporting a relationship between Pb and ALS. For example, Bar

beito et al. (2010) reported that blood Pb levels of 27 μg/dL were associated with increased survival time in a mouse model of severe ALS, analogous to the longer survival time in ALS patients with higher blood Pb levels observed by Kamel et al. (2008). The NTP concluded that there is limited evidence that blood Pb levels <10 μg/dL are associated with diagnosis of ALS because the case-control studies that reported an association with blood Pb have potential issues with reverse causality and bias due to a reported increased survival time in ALS patients relative to control patients, both of which might also lead to higher Pb levels in ALS patients. The data from Fang et al. (2010) addressed some of the reverse causality issues by controlling for factors associated with bone turnover. As with other studies of health effects of Pb in adults, studies that demonstrate an association between ALS and blood Pb in a group for which blood Pb levels remained consis

tently below 10 μg/dL from birth until diagnosis of ALS would eliminate the potential role of early-life blood Pb levels above 10 μg/dL on health effects observed in adults with concurrent blood Pb levels <10 μg/dL. The NTP’s conclusions for limited evidence that blood Pb levels <10 μg/dL are associated with diagnosis of ALS is consistent with the four studies highlighted in EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 2007 Toxicological Profile for Lead (ATSDR 2007).



### Alzheimer’s Disease There is inadequate evidence to evaluate the poten

tial association between blood Pb <10 μg/dL and Alzheimer’s disease because no studies examining Alzheimer’s disease in groups with blood Pb levels <10 μg/dL were located. Although the ATSDR’s 2007 Toxicological Profile for Lead ( ATSDR 2007) and EPA’s 2006 AQCD for Lead (U.S. EPA 2006) have similar con

clusions on the lack of epidemiological evidence for an association between Pb and Alzheimer’s disease, the EPA’s 2006 AQCD for Lead (U.S. EPA 2006) high

lights the evidence from studies of laboratory ani

mals that early-life exposure to Pb is associated with Alzheimer-like pathologies at later ages. In particular, exposure of rats (Basha et al. 2005) and monkeys (Zawia and Basha 2005) to Pb during development was associated with overexpression of the amyloid precursor protein associated with Alzheimer’s dis

ease; however, Pb exposure in adult animals did not result in increased amyloid deposits in the brain. It should also be noted that laboratory animal data have not demonstrated dementia in existing models.



### Essential Tremor There is sufficient evidence that blood Pb levels <10 μg/dL and limited evidence that blood Pb levels <5 μg/dL in adults are associated with increased risk for diagnosis of essential tremor, a type of involun

tary tremor. A number of case-control studies have reported a significant association between blood Pb and essential tremor diagnosis, with most of the stud

ies coming from New York and similar results reported for a population in Turkey (see Appendix A: Neuro

logical Effects for full list of studies). The data present consistent evidence for an association between blood Pb and essential tremor from two distinct groups in dif

ferent countries, but reflect a total sample size of only approximately 300 cases of essential tremor. Louis et al. (2003) reported that blood Pb was sig

nificantly higher in essential tremor patients (3.3 μg/dL ) than in controls (2.7 μg/dL) in a case-control study of 100 essential tremor cases (mean age, 66 years) and 143 matched controls (mean age, 71 years) from New York. Blood Pb was significantly associated with an increased odds ratio for essential tremor diagnosis OR=1.21 (95% CI: 1, 1 .39). Louis et al. (2005, 2011 ) also examined the interaction between blood Pb and other modifying factors such as ALAD genetic poly

morphisms and exposure to harmane (a β-carboline alkaloid compound associated with essential tremor) in this New York cohort. The odds of essential tremor were significantly, and to a large degree, elevated in individuals with the ALAD -2 allele and higher blood Pb40 NTP Monogr aph on Health Effects of Low-Level Lead (OR=80 (95% CI: 3, 2096)) in a case-control study of 63 essential tremor cases and 101 matched controls ( Louis et al. 2005). In a further case-control study of 106 essential tremor cases and 151 controls, Louis et al. (2011) found that essential tremor score was high

est in individuals with higher concentrations of both Pb and harmane; they concluded that there was an additive effect of Pb and harmane on essential tremor severity. Louis collaborated with researchers in Turkey to examine essential tremor and Pb in Turkey, a popula

tion distinct from the New York-based group in earlier publications. In a case-control study in 105 essential tremor patients and 105 controls from Turkey, Dogu et al. (2007) reported that blood Pb (mean, 3.2 μg/dL in cases and 1.6 μg/dL in controls) was associated with a significantly greater odds ratio for essential tremor diagnosis (OR=4.19 (2.59,6.78)).

Summary of Support for Conclusions Animal data support Pb-associated neurological effects, including tremor, at higher Pb exposure lev

els (e.g., Booze et al. 1983, see U.S. EPA 2006
, ATSDR 2007 for recent reviews of the animal data ). The NTP concluded that there is sufficient evidence that blood Pb levels <10 μg/dL and limited evidence that blood Pb levels <5 μg/dL are associated with diagnosis of essential tremor. The data are considered to provide sufficient evidence because the case-control studies that reported an association with blood Pb are from two distinct, widely separated groups which report the same pattern of effects. Given that the two studies represent a small total number of essential tremor patients (sample size of about 300), a con

clusion of limited evidence at the lower blood Pb level <5 μg/dL is supported. As with other studies of health effects of Pb in adults, prospective studies in a group for which blood Pb levels remained con

sistently below 10 μg/dL from birth until diagnosis of essential tremor would eliminate the potential role of early-life blood Pb levels >10 μg/dL on health effects observed in adults with concurrent blood Pb levels <10 μg/d L. The NTP’s conclusions for sufficient evidence that blood Pb levels <10 μg/dL and limited evidence that blood Pb levels <5 μg /dL are associated with diagnosis of essential tremor is consistent with the blood Pb level of 3 μg/dL highlighted in the two studies listed in EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 2007 Toxicological Profile for Lead (ATSDR 2007). 

### Parkinson’s Disease There is inadequate evidence to evaluate the poten

tial association between blood Pb <10 μg/dL and Parkinson’s disease, because few studies examining this association were located, and no studies were identified in groups with blood Pb levels <10 μg/d L. Two studies were found that reported a significant association between lifetime Pb or bone Pb and inci

dence of Parkinson’s disease. In a case-control study of 121 Parkinson’s disease patients and 414 controls in Michigan, Coon et al. (2006) reported that the odds ratio of a diagnosis of Parkinson’s disease was increased for whole-body lifetime Pb exposure (blood and bone combined, by a physiologically based phar

macokinetic 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 asso

ciation with bone Pb alone. Weisskopf et al. (2010) reported that the odds ratio for Parkinson’s disease was increased (OR=3.21 (95% CI: 1.17, 8.83)) f or high

est quartile of tibia Pb compared to the lowest quar

tile in a case-control study of 330 Parkinson’s disease patients and 308 controls in Boston.



### 4.3.4 Sensory Organs

Auditory There is sufficient evidence that blood Pb levels <10 μg/dL in children are associated with decreased hearing (decreased auditory acuity). Cross-sectional studies reported a Pb-related increase in hearing thresholds and an increase in latency of BAEPs in chil

dren and young adults 5 4-19 years of age, and altered BAEPs in newborns (see Appendix A: Neurological Effects for full list of studies). Hearing loss indicated by higher hearing thresholds have been demonstrated at blood Pb levels <10 μg/dL , and increased BAEP latency has been reported at slightly higher blood Pb levels (<10 μg/dL). There is limited evidence that prenatal blood Pb levels <10 μg/dL are associated with auditory effects because few studies have addressed low-level Pb exposure during this developmental period. There is also limited evidence that blood Pb levels <10 μg/dL in adults are associated with decreased auditory acuity due to the limited number of studies with blood Pb data <10 μg/dL and auditory effects in adults.

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

ment; therefore, 18- and 19-year-olds in the study are con

sidered adults.NTP Monograph on Health Effects of Low-Level Lead 41 In a cross-sectional study of 4,519 children and young adults 4-19 years of age from the NHANES II data set, Schwartz and Otto ( 1987) reported a signifi

cant association between blood Pb level and hearing loss as determined by an increase in hearing thresh

olds for pure-tone frequencies from 500 to 4,000 Hz. In a second study using the same measures of hearing, Schwartz and Otto (1991) found that mean hearing thresholds were significantly increased in association with blood Pb levels in a large cross-sectional study of 3,545 children and young adults 6-19 years of age from the Hispanic Health and Nutrition Examination Survey. Hearing loss was observed at blood Pb levels ≥8 μg/dL, and a 2-decibel hearing loss at all frequencies was reported with an increase in blood Pb from 6 to 18 μg/dL (Schwartz and Otto 1991). Similar results were observed in a study of 155 Polish children 4-14 years of age, with hearing loss demonstrated by increased hear

ing thresholds at blood Pb levels <10 μg/dL (median blood Pb, 7.2 μg/d L); there were also increased laten

cies of peak I BAEPs that were significant for blood Pb levels >10 μg/dL compared to children with blood Pb <4.6 μg/dL (Osman et al. 1999). Increased latencies of BAEP waves I-IV have also been reported at higher blood Pb levels (10 μg/dL) in adults and children (reviewed in Otto and Fox 1993), and in two studies of children with higher mean blood Pb that included some subjects with blood Pb levels <10 μg/dL (Ott o et al. 1985, Rob

inson et al. 1985 ). An effect of prenatal exposure is sup

ported by data from the Rothenberg et al. ( 1994, 2000 ) studies demonstrating that the latency and interpeak interval of BAEPs were significantly altered in infants (n=30 born to mothers with pregnancy Pb levels of 2.5- 35 μg/dL) and 5- and 6-year-olds (n=100) born to moth

ers with mean blood Pb levels of 8 μg/dL. Dietrich et al. ( 1992) reported that performance on the screening test for auditory processing disorders at 5 years of age was inversely affected in a study of 259 children from the Cincinnati Lead Study with mean prenatal blood Pb 8 μg/dL, and infant blood Pb of 5 μg/dL; however, mean blood Pb levels from 1 to 5 years of age ranged from 10 to 17 μg/dL, so effects may not be associated with blood Pb levels <10 μg/dL. Four studies in adults addressed individuals with lower blood Pb levels. Forst et al. (1997) reported that blood Pb level (mean, 5 μg/dL; range, 1-18 μg/dL) w as associated with an elevated hearing threshold at 4,000 Hz, but not at other frequencies, examined in a study of 183 workers. Hwang et al. (2009) found that hearing thresholds were significantly increased in a study of 259 steel plant workers in Taiwan at blood Pb levels ≥7 μg/dL (mean blood Pb, 5 μg/dL) for frequencies from 3,000 to 8,000 Hz but not for lower frequencies. In a case-control study of 121 adult cases referred for hearing testing with geometric mean blood Pb 10.7 μg/dL and 173 workers with normal hearing (mean blood Pb, 4 μg/dL), blood Pb was significantly associated with higher hearing thresholds (Chuang et al. 2007). In a cross-sectional analysis of 448 men in the Normative Aging Study (mean age, 65 years at time of bone Pb measurement), tibia Pb (mean, 23 μg/g) and patella Pb (mean, 33 μg/g) were significantly associ

ated with hearing loss indicated by higher hearing thresholds at 2,000-8,000 Hz and pure-tone averages (Park et al. 2010). Although blood Pb and the potential relationship between blood Pb and hearing were not examined in the Park et al. (2010) study, other studies reported mean concurrent blood Pb levels in members of this cohort as <10 μg/dL (Rajan et al. 2007). Addi

tional support for effects in adults is provided by the large cross-sectional studies of individuals from 4 to 19 years of age (Schwartz and Otto 1987, 1991 ) described earlier; these studies included young adults in the age range of the group studied (i.e., individuals 18 and 19 years of age are considered adults).

Summary of Support for Conclusions Animal data support a Pb-associated effect on audi

tory acuity determined by an increase in the latency of BAEPs at blood Pb levels higher than the level observed in human studies (i.e., 33-100 μg/dL) (se e U.S. EPA 2006 for recent reviews of the animal data, ATSDR 2007 ). The human data from several cross-sec

tional and prospective studies support a Pb-associated decrease in auditory acuity and increase in latency of BAEPs in children with blood Pb levels <10 μg/dL. The conclusion of sufficient evidence for decreased audi

tory acuity at concurrent blood Pb levels <10 μg/dL in children is based on the consistency of effects between hearing loss as determined by increased hearing thresholds and increased latency of BAEPs. In adults, the conclusion of limited evidence for similar effects at concurrent blood Pb levels <10 μg/dL is based on the small number of studies supporting an effect (two at blood Pb <10 μg/dL with total n <450), the two Schwartz and Otto ( 1987, 1991 ) cross-sectional studies that included adults 18 and 19 years of age in studies primarily focused on children, and supporting42 NTP Monograph on Health Eff ects of Low-Level Lead evidence from occupational studies at higher blood Pb levels ( e.g., Bleecker et al. 2003) plus additional supporting evidence of an effect of Pb from bone Pb data in a group of elderly men. As with other studies of health effects of Pb in adults, prospective studies in a group for which blood Pb levels remained consistently below 10 μg/dL from birth until measurement of audi

tory acuity would eliminate the potential role of earlylife blood Pb levels above 10 μg/dL on auditor y effects observed in adults with concurrent blood Pb levels <10 μg/dL. The conclusion of limited evidence that prenatal exposure to blood Pb <10 μg/dL is associat ed with auditory effects is based on the two Rothenberg et al. (1994, 2000 ) studies and the Dietrich et al. ( 1992) study that demonstrated an effect of maternal expo

sure but provided data only on 100 individuals with blood Pb <10 μg/dL th at remained <10 μg/dL u ntil auditory function was tested. The NTP’s conclusion for sufficient evidence that blood Pb levels <10 μg/dL are associated with decreased auditory acuity in children is in line with the supportive evidence of a relationship with auditory processing decrements outlined in EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 2007 Toxicological Profile for Lead (ATSDR 2007).



### Visual There is inadequate evidence to evaluate the poten

tial association between blood Pb <10 μg/dL and effects on vision in children or adults. Multiple stud

ies reported an inverse relationship between blood Pb levels ≤10 μg/dL an d visual-motor performance evaluated with tests such as the Beery Developmen

tal Test (e.g., Wasserman et al. 2000, Al-Saleh et al. 2001
, Chiodo et al. 2004 ); however, few epidemio

logical studies addressed the effects of low-level Pb exposure on visual function. Only three studies were located that examined the impact of blood Pb levels <10 μg/dL and retinal or visual function. Maternal blood Pb at 12 weeks of pregnancy (mean, 8.5 μg/dL) in 45 participants of the Mexico City Prospective Study was associated with altered retinal function in 7- to 10-year-old children, as indicated by changes in electroretino graphic (ER G) testing results ( Rothen

berg et al. 2002). In a study of 100-200 children in Artic Quebec at 5 and 11 years of age, Boucher et al. (2009) demonstrated that umbilical cord blood Pb (mean, 5 μg/dL) was signific antly associated with changes in visual brain signals (event-related poten

tial P3b wave amplitude) at 5 years but not at 11 years of age. Altmann et al. (1998) reported that blood Pb levels (mean, 4 μg/dL) in 6-y ear-old children (n= 384) in Germany were associated with altered visual func

tion as determined by changes in interpeak latency of VEPs. Animal data include evidence for retinal and visual cortical structural and functional abnormali

ties 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 asso

ciation between blood Pb <10 μg/dL and eff ects on vision because of the general lack of human data on retinal or visual function in individuals with blood Pb levels <10 μg/dL. Increased latency in VEPs has been demonstrated in studies of adults with higher blood Pb levels (e.g., 60 down to 17 μg/dL in Abbate et al. 1995). The report of a potential lower threshold of 14 μg/dL for postural sway in adults with higher occupational Pb exposure (Iwata et al. 2005) pro

vides some support for an effect on the auditory and visual systems, because postural sway requires the integration of visual and vestibular input along with peripheral sensory input and motor output. The NTP’s conclusions for inadequate evidence that blood Pb levels <10 μg/dL are associated with effects on vision in humans are in line with the supportive evidence of a relationship with auditory processing decrements outlined in the EPA’s 2006 AQCD for Lead (U.S. EPA 2006) and ATSDR’s 2007 Toxicological Profile for Lead (ATSDR 2007) and identification of a potential thresh

old of 14-20 μg/dL for e ffects including VEPs in adults.



### 4.4 Conclusions The NTP concludes there is sufficient evidence that blood Pb levels <5 μg/dL ar e associated with neu

rological effects in children and limited evidence that blood Pb levels <10 μg/dL ar e associated with adverse neurological effects in adults (see Table 4.3: NTP conclusions on neurological effects of low-level Pb for complete list of conclusions). A major strength of the evidence for effects of low-level Pb on neuro

logical outcomes is in the consistency of results for an adverse effect of blood Pb <10 μg/dL across multiple indices of neurological effects (e.g., cognition, behav

ior, and sensory function), through multiple groups, with a wide age range from early childhood to olderNTP Monograph on Health Effects of Low-Level Lead 43 adults, and from studies using substantially different methods and techniques. In some studies, blood Pb levels of 2 μg/dL are associated with effects in chil

dren ( e.g., academic achievement in Miranda et al. 2007, ADHD in Cho et al. 2010 ). In children, there is sufficient evidence that blood Pb levels <5 μg/dL are associated with various indices of reduced cognitive function, increased incidence of attention-related behavior diagnosis, and increased behavioral prob

lems, and there is sufficient evidence that blood Pb levels of 10 μg/dL are associated with decreased audi

tory function. In adults, there is sufficient evidence that blood Pb levels <10 μg/dL and limited evidence that blood Pb levels <5 μg/d L are associated with essential tremor. There is also limited evidence that blood Pb levels <10 μg/dL in adults are associated with psychiatric outcomes, including anxiety and depression, as well as decreases in auditory function, decreases in specific measures of cognitive function in older adults, and the neurodegenerative disease ALS. There are more consistent associations between bone Pb and decreases in cognitive function in older adults than for blood Pb, suggesting a role for cumulative Pb exposure in Pb-related cognitive decline.

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

Health Effect Population or Exposure

Window NTP Conclusion Blood Pb Evidence Bone Pb Evidence

Cognitive Function Academic achievement Prenatal Inadequate No studies located Not studied Children Sufficient Yes, <5 μg/dL Yes, tooth dentin Pb IQ Prenatal Limited Yes, <10 μg/dL Not studied Children Sufficient Yes, <5 μg/dL Yes, tibia and tooth dentin Pb Other general and specific measures Prenatal Limited Yes, <5 μg/dL Not studied Children Sufficient Yes, <5 μg/dL Yes, tibia and tooth dentin Pb Older adults Limited Yes, <10 μg/dL Yes, tibia and patella Pb Behavior Attention-related behaviors Prenatal Limited Yes, <10 μg/dL Not studied
Children Sufficient Yes, <5 μg/dL Yes, tibia and tooth dentin Pb
Adults Inadequate No studies located Not studied Behavioral problems Prenatal Limited Yes, <10 μg/dL Not studied Children Sufficient Yes, <5 μg/dL Yes, tooth dentin Pb, bone, hair Adults Inadequate No studies located Not studied Psychological Effects Depression, anxiety, other Prenatal Inadequate No studies located Not studied Children Inadequate Unclear, some data >10 μg/dL Not studied

Adults Limited Yes, <10 μg/dL Tibia and patella Pb
Neuro

degeneration ALS Adults Limited Yes, <10 μg/dL Yes, tibia and patella Alzheimer’s disease Adults Inadequate No studies <10 μg/dL located Not studied

Essential tremor Adults Sufficient Yes, <10 μg/dL Not studied Limited Yes, <5 μg/dL Not studied Parkinson’s disease Adults Inadequate No studies <10 μg/dL located Yes, tibia and PBPK (cumulative) Sensory Function Auditory Prenatal Limited Yes, <10 μg/dL Not studied Children Sufficient Yes, <10 μg/dL Not studied Adults Limited Yes, <10 μg/dL Yes, tibia and patella Visual Prenatal Inadequate Yes, <10 μg/dL Not studied Children Inadequate Yes, <10 μg/dL Not studied Adults Inadequate No studies <10 μg/dL located Not studied

Abbreviation: ALS, amyotrophic lateral sclerosis; PBPK, physiologically based pharmacokinetic.44 N TP Monograph on Health Effects of Low-Level Lead THIS PAGE LEFT INTENTIONALLY BLANKNTP Monograph on Health Effects of Low-Level Lead 45 

## 5.0 IMMUNE EFFECTS

5.1 Conclusions The NTP concludes that there is limited evidence that blood Pb levels <10 μg/dL are associated with adverse immune effects in children and that there is inadequate evidence in adults. In children, there is limited evidence that blood Pb levels <10 μg/dL are associated with increased hypersensitivity responses and allergic sensitization diagnosed by skin prick testing to common allergens. Five studies with mean blood Pb levels of 10 μg/dL and below support the relationship between blood Pb and increased serum IgE (see Table 5.3 ). Two of these studies report an association at blood Pb levels of 10 μg/dL or above, rather than <10 μg/dL ( Lutz et al. 1999
, Sun et al. 2003 ). Only one of the remaining studies, Karmaus et al. ( 2005 ), considers age as a co-factor in the analyses of IgE ( Karmaus et al. 2005
, Hon et al. 2009
, Hon et al. 2010
, Hon 2011 ). Given these limitations, and particularly the known age-dependent ranges for IgE, these studies provide the basis for the conclusion of limited evi

dence that blood Pb levels <10 μg/dL are associated with elevated serum IgE in children up to 17 years of age. Although increases in serum levels of total IgE do not equate to disease, elevated levels of IgE are the primary mediators of type I hypersensitivity associated with allergic sensitization, and the data demonstrating Pb-related increases in IgE support an association with hypersensitivity. Further support of an association between blood Pb levels <10 μg/dL and hypersensitivity is provided by a prospective study on Pb-related increased allergic sensitization demonstrated by positive response to skin prick test

ing to common allergens. Together these data sup

port the conclusion of limited evidence that blood Pb levels <10 μg/dL are associated with increased hyper

sensitivity. However, there is inadequate evidence of an association between blood Pb and other allergic diseases such as eczema or asthma. There is inadequate evidence in adults to address the potential association between blood Pb <10 μg/dL and IgE, allergy, eczema, or asthma. Few studies have investigated the relationship between immune func

tion and Pb in adults or children, and most studies report general observational markers of immunity rather than function. There is inadequate evidence that blood Pb levels <10 μg/dL are associated with observational immune endpoints such as altered lym

phocyte counts or serum levels of IgG, IgM, or IgA in the blood of children or adults because of a general lack of studies at the lower dose and inconsistency in available data. There is inadequate evidence that blood Pb levels <10 μg/dL ar e associated with changes in immune function other than hypersensitivity, because there are few studies of Pb and immune func

tion in humans, particularly at lower blood Pb levels. Very few studies examine markers of exposure other than blood Pb levels, and therefore it is unknown if blood or bone Pb levels would be more consistently associated with immune effects.



### 5.2 How Conclusions Were Reached Conclusions in the NTP’s evaluation of Pb-related immunological effects in humans associated with low-level Pb are derived by evaluating the data from epidemiological studies with a focus on blood Pb levels <10 μg/dL. Although there is a large database of immune studies of Pb in laboratory animals, the data

base of human studies is somewhat limited, particu

larly at blood Pb levels <10 μg/dL. The NTP’s conclu

sions are based on the evidence from human studies with blood Pb levels of <10 μg/dL, with data reflecting exposure levels up to 15 μg/dL also considered so that effects at and around 10 μg/dL we re not excluded from the evaluation. Given the limited database of human studies available to evaluate immune effects associ

ated with blood Pb levels <10 μg/dL, a discussion of immune effects associated with higher blood Pb levels is also included in the evaluation. The discussion below also assesses the biological plausibility and support for Pb-associated immune effects provided by the data

base of studies in laboratory animals. Major endpoints considered as potential indicators of effects of Pb on the immune system are listed and briefly described in Section 5.2.1 . This document is not a review of the immune system or immunotoxicity, and the reader is directed to published reviews for additional back

ground. Key data and principal studies considered in developing the NTP’s conclusions are discussed in detail in Section 5.3 Evidence for Pb-related Immune Effects

. The discussion of each immune effect begins with a statement of the NTP’s conclusion that the spe

cific 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 expo

sure associated with the effect (prenatal, childhood,46 NTP Monograph on Health E ffects of Low-Level Lead concurrent) when available. Although the informa

tion necessary to support the NTP’s conclusions is presented in Section 5.3 , the complete data set of human studies considered for evaluation of immune effects with low-level Pb is included in Appendix B: Immune Effects, and individual studies are abstracted for further reference. The NTP made extensive use of recent government evaluations of health effects of Pb in the current assessment, and the relevant conclu

sions 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 immu

notoxicity, and markers of immune function, which are considered better indicators of potential adverse immune effects. Functional assays can be performed in humans, including specific antibody response to vaccination, delayed-type hypersensitivity (DTH) response, phagocytic activity of neutrophils and macrophages, and oxidative burst of neutrophils and macrophages ( Tryphonas 2001 ). However, human epidemiological data are much more likely to be restricted to observational data, such as circulating immunoglobulin levels, lymphocyte counts, and cyto

kine levels. The data available to evaluate each of the major effects are discussed in separate subheadings under Section 5.3 below. 

### 5.2.2 Principal Conclusions from the 2006 EPA and 2007 ATSDR Pb Documents The EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATS

DR’s Toxicological Profile for Lead ( ATSDR 2007 ) both list a number of immune parameters (see Table 5.2 for principal conclusions and original documents for com

plete conclusions) that have been reported as altered in populations exposed to Pb, including increased serum IgE levels, altered T-cell and B-cell numbers, changes in macrophage and neutrophil activation, suppressed neutrophil chemotaxis, and phagocytosis. Table 5.1: Major immune effects considered
Effect Description
Observational Immunoglobulin (Ig) or antibodies Serum IgE, IgM, IgG; IgA, and IgD (A and D not routinely measured)

Immunophenotyping White blood cell differential (T-cells, B-cells, NK-cells, monocytes/macrophages, etc.)
Functional Antibody response Production of Ig to challenge: Hypersensitivit y 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 Type 1 helper T cells and macrophage-dependent DTH response to antigen challenge

Neutrophils Peripheral blood mononuclear leukocyte phagocytosis, respiratory burst, migration Monocyte/macrophages Phagocytosis, respiratory burst (monocytes circulate and mature into tissue macrophages) Allergy, asthma, eczema, etc. Clinical manifestation of hypersensitivity

T able 5.2: Main conclusions for immunological effects in the 2006 EPA AQCD for Lead and the 2007 ATSDR Toxicological Profile for Lead
“...effects include changes in serum immunoglobulin lev

els; perturbation of peripheral lymphocyte phenotype profiles, including decreases in peripheral blood T-cell abundance and changes in T-cell to B-cell abundance ratios; suppression of lymphocyte activation; and sup

pression of neutrophil chemotaxis and phagocytosis. Studies of biomarkers of humoral immunity in children have consistently found significant associations between increasing blood Pb concentrations and serum IgE levels at blood Pb levels <10 μg/dL.” (U.S. EPA 2006, pg 6-272) “Altered immune parameters have been described in lead workers with PbB [blood Pb level] in the range of 30-70 μg/dL. Reported effects included changes in some T-cell subpopulations, response to T-cell mitogens, and reduced chemotaxis of polymorphonuclear leukocytes. Several studies of children reported significant associa

tions between PbB and increases in serum IgE levels...” (ATSDR 2007, pg 22)NTP Monograph on Health Effects of Low-Level Lead 47 The 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) states that studies have consistently found consistent evidence of increased serum IgE levels in children at blood Pb <10 μg/dL but that results from studies in adults are mixed. The 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) also states that the principal functional immune changes associated with Pb exposure are (1) increases in type 2 helper T-cell (Th-2)-associated production of IgE; (2) suppressed type 1 helper T-cell (Th-1) responses (i.e., DTH); (3) shifting the balance of Th-1/Th-2 cytokines toward a Th-2 response; and (4) stimulating macrophages into a hyper-inflamma

tory state. The EPA notes that functional changes had not been rigorously evaluated in human studies at the time of the 2006 AQCD for Lead ( U.S. EPA 2006 ), and that the available epidemiological studies rely primarily on observational data detailing circulating immunoglobulin levels and lymphocyte counts. The EPA is in the process of revising the AQCD, and the conclusions of the external draft ( U.S. EPA 2012 ) are largely in line with the 2006 AQCD for Lead. The NTP considered the conclusions and data summaries from the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ). In general, the NTP concurred with the conclusions and agreed that the data support them. Differences from the ATSDR and EPA documents are identified for specific endpoints in the document.



### 5.3 Evidence for Pb-Related Immune Effects

5.3.1 Increased Serum IgE and Allergic Sensitization There is limited evidence that blood Pb levels <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 chil

dren from multiple groups in North America, Europe, and China. An association between increased blood Pb and increased IgE has been observed in children at mean blood Pb values from 1.9 to 14 μg/dL and sub

jects ranging from 1 month to 17 years of age. Three of the five available studies ( Karmaus et al. 2005
, Hon et al. 2009
, Hon et al. 2010
, Hon 2011 ) report an association between blood Pb levels <10 μg/dL and increased serum IgE, but only one of the stud

ies ( Karmaus et al. 2005 ) reports an association with blood Pb levels <10 μg/dL in an analyses that adjusted for age, an important confounder when consider

ing IgE levels, particularly in children. The database for potential association between blood Pb and IgE in children is restricted to cross-sectional studies and therefore the data only inform the association between current blood Pb and current IgE. The influ

ence of prenatal Pb exposure on IgE was the subject of a single study ( Annesi-Maesano et al. 2003 ) that dem

onstrated an association between increased IgE and increased infant hair Pb levels but provided equivocal data on the association between maternal blood Pb and infant IgE at birth. Although increases in serum levels of total IgE do not equate to disease, elevated IgE is the primary mediator of type I hypersensitiv

ity associated with allergic sensitization and allergic diseases such as asthma ( Beeh et al. 2000
, Ahmad Al Obaidi et al. 2008 ). The data supporting Pb-related increases in IgE, together with a prospective study on allergic sensitization (diagnosed by skin prick testing), provide limited evidence that blood Pb <10 μg/dL is associated with increased hypersensitivity responses in children. However, there is inadequate evidence of an association between blood Pb and eczema or asthma in children because the results of the few available studies are generally negative for asthma and because the eczema data come from a pair of studies of a single group of children from a dermatol

ogy clinic. There are fewer studies of the association between low level Pb (blood <10 μg/dL) a nd hyper

sensitivity in adults than for children, and available data that address IgE and related endpoints are mixed. There is inadequate evidence in adults to address the potential association between blood Pb <10 μg/dL and IgE, allergy, eczema, or asthma.Increased serum IgE was reported in five crosssectional studies of children from 1 month to 17 years of age and mean blood Pb from 1.9 to 14 μg/dL ( Lutz et al. 1999
, Sun et al. 2003
, Karmaus et al. 2005
, Hon et al. 2009
, Hon et al. 2010
, Hon 2011 ). Higher serum IgE correlated (r=0.22; p=0.0004) with higher blood Pb levels in a study of 279 children in Missouri 9 months to 6 years of age ( Lutz et al. 1999 ). Lutz et al. ( 1999 ) stated that 64% of the children in their study had blood Pb <10 μg/dL; ho wever, the authors do not report mean blood Pb levels and therefore the data may reflect an effect of blood Pb levels above 10 μg/dL. Serum IgE was also correlated with blood Pb levels (r=0.48; p=0.002) in children with blood Pb levels ≥10 μg/dL in a subsample of 72 children48 N TP Monograph on Health Effects of Low-Level LeadiiImmuneEffectsTable 5.3: Studies of serum IgE, sensitization, and eczema with low-level Pb used to develop conclusions for childrenRelevance toConclusionsStudyDescriptionStudyDesignKey Immunological FindingsReferenceIncreased IgEEffect374 newborns in ParisStudy A: 1985Study B: 1991-1992CrosssectionalIncreased serum IgEin umbilical cord blood was associated with infant hair levels of Pb.IgE was also associated with maternal blood Pb in study B (Pb=6μg/dL) not in studyA (Pb=13μg/dL) or with infant blood in either study.Annesi-Maesano (2003)Effect331 children 7-10 yearsold in GermanyCrosssectionalIncreased serum IgEwas associated with current blood Pb (mean Pb, 2.7μg/dL).Karmaus (2005)Equivocal318 children 0.5 -7 yearsold in EgyptCrosssectionalSerum IgEdiffered by blood Pb (mean Pb, 9.2μg/dL). However, authors report that IgEis not correlated with blood Pb.Hegazy (2011)Effect279 children0.75 - 6years old in MissouriCrosssectionalIncreased serum IgEwas associated with current blood Pb (mean not reported, 64%had blood Pb <10μg/dL).Lutz (1999)Effect72 children aged 3-6 inChina of 217 in studyCrosssectionalIncreased serum IgEwas correlated with blood Pb in children with Pb ≥10μg/dL.Increased serum IgE in girls with blood Pb≥10 μg/dL relative to Pb <10μg/dL; not boys.Sun (2003)Hong Kong Eczema PatientsCrosssectionalIncreased serum IgEwas positively correlated with blood Pb (mean Pb, 1.9μg/dL) inchildren with eczema (age > 1 month; mean age, 10 years).Hon (2010,2011); may over-lap with Hon (2009)Effect110 children age ≤17Effect58 children age 10CrosssectionalIncreased serum IgEwas positively correlated with blood Pb (mean Pb, 1.9μg/dL) inchildren with eczema (age > 1 month; authors state average age of 10 years).Hon (2009)Also for eczemaEffect2,470 children aged 5 -14in GermanyEcologicalOdds ratios for increase in specific IgEto common allergens were elevated in childrenfrom a polluted area in Germany that had higher Pb dustfall; no blood Pb data.Heinrich (1999)Also for sensitivity & eczemaEvidence of Enhanced Sensitization Based On Skin Prick Test (SPT)Effect224 children 5 years oldin PolandProspectiveFrequency of atopy (positive SPT) associated with cord Pb (mean, 1.2μg/dL) and maternalblood Pb (mean, 1.6μg/dL); not current Pb.Risk ratio for SPT/atopy related to cord Pb;authors state that prenatal Pb may enhance sensitization to aeroallergens.Jedrychowski (2011)Effect2,470 children aged 5 -14in GermanyEcologicalOdds ratio for sensitization (positive SPT) or allergy (doctor diagnosis) was elevated inchildren from a polluted area in Germany that had higher Pb dustfall; no blood Pb data.Heinrich (1999)Also for IgE & eczema.Eczema And Atopic DermatitisNo effect1,768 children born inBoston 1979 -1981RetrospectiveRelative risk of eczema in childhood (age not reported) did not differ for children withumbilical cord blood Pb >10μg/dL compared to rest of the population.Rabinowitz (1990)Hong Kong Eczema PatientsCrosssectionalAtopic dermatitis severity, eczema severity score, and children’s dermatology lifequality index were positively correlated with blood Pb (mean, 1.9μg/dL).Hon (2010,2011); may over-lap with Hon (2009)Effect110 children age ≤17Effect58 children age 10CrosssectionalAtopic dermatitis severity, eczema severity score, and children’s dermatology life qual-ity index were positively correlated with blood Pb (mean, 1.9μg/dL; mean age, 10).Hon (2009)Also for IgEEffect2,470 children aged 5 -14in GermanyEcologicalOdds ratio for eczema was elevated in children from a polluted area in Germany thatalso had higher Pb dustfall; no blood Pb data.Heinrich (1999)Also for IgE & sensitivityEpidemiological studies of low-level Pb exposure, immunoglobulin E (IgE), sensitization, and eczema are listed by decreasing cohort size and grouped together for overlapping studygroups. Blood Pb levels up to 15μg/dL were included so that effects at and around 10μg/dL were not excluded from the evaluation.NTP Monograph on Health Effects of Low-Level Lead 49 with a mean blood Pb level of 14 μg/dL fr om a larger study of 217 children 3-6 years of age with overall mean blood Pb of 9.5 μg/dL in China ( Sun et al. 2003 ). Although the Lutz et al. ( 1999 ) and Sun et al. ( 2003 ) studies report an effect of blood Pb at levels near 10 μg/dL, additional studies demonstrate increased IgE at mean blood Pb levels in the range of 2 μg/dL. Higher serum IgE was correlated with higher blood Pb (mean, 1.9 μg/dL) in 110 children with eczema in which the age ranged from 1 month to 17 years for the participants recruited from a dermatology clinic in Hong Kong ( Hon et al. 2009
, Hon et al. 2010
, Hon 2011 ). Karmaus et al. ( 2005 ) reported increased serum IgE in a study of 331 children 7-10 years of age in Germany at blood Pb levels >2.8 μg/dL, the median for the group. The studies by Lutz et al. ( 1999 ), Sun et al. ( 2003 ), and Karmaus et al. ( 2005 ) include adjustments for age and sex in their analyses of the relationship between blood Pb and IgE. These are important considerations because of the strong age- and sex-related effects on serum IgE: higher IgE levels are observed in boys, and increased IgE levels are expected with increasing age up to puberty, with slowly decreasing levels observed thereafter ( Lind

berg and Arroyave 1986
, Blackwell et al. 2011 ). There is some evidence that in children the association of IgE with blood Pb may exhibit a non

monotonic (or bi-phasic) dose response: increased IgE levels are reported at the lower end of blood Pb levels, from 2 to 20 μg/dL, but decreasing serum IgE levels occur at higher blood Pb levels (i.e., >20 μg/dL). Nonmonotonic dose responses are thought to re flect multiple mechanisms of toxicant action that affect a given endpoint (including immune effects) differently at different doses ( Welshons et al. 2003 ). For example, Narita et al. ( 2007 ) described stimulation of IgEmediated release of allergic mediators from human mast cells with surface-bound IgE in response to toxi

cants, including Aroclor 1242; a nonmonotonic dose response was reported for IgE-mediated release of β-hexosaminidase, with lower doses resulting in acti

vation of this key step in allergic reactions and higher doses having no effect. Blood Pb levels >20 μg/dL ( 23- 42 μg/dL determined graphically from Wagnerova et al. 1986 ) were associated with decreased IgE in a study of 11-year-old children in Czechoslovakia in which both the exposed and reference group had blood Pb lev

els >10 μg/dL ( Wagnerova et al. 1986 ). In the Lutz et al. ( 1999 ) study described earlier, serum IgE differed significantly (p<0.05 Kruskal-Wallis) by blood Pb levels stratified by CDC blood Pb classification levels (I=<10, IIA=10-14, IIB=15-19, and III=20-44 μg/dL); however, IgE was not increased in the group with blood Pb lev

els >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 correla

tion 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 exam

ine the relationship between blood Pb and serum IgE at later time points in children. However, in a study of newborns in Paris, Annesi-Maesano et al. ( 2003 ) demonstrated an association between higher umbilical cord IgE and higher infant hair Pb (p<0.001). Maternal blood Pb and infant blood Pb were not correlated to umbilical cord IgE levels, although the authors report that the association between mater

nal blood Pb and umbilical cord IgE was at borderline significance (p<0.1) ( Annesi-Maesano et al. 2003 ). As discussed in Section 3.2 , hair Pb has been examined in a number of studies because collection is easy and minimally invasive; however, an ATSDR expert panel concluded that widespread use is not recommended because of unresolved scientific issues in collection and analysis ( ATSDR 2001 ). As discussed above, elevated levels of total IgE are associated with allergic sensitization and allergic disease such as asthma ( Beeh et al. 2000
, KotaniemiSyrjanen et al. 2002
, Ahmad Al Obaidi et al. 2008
, Donohue et al. 2008 ). However, there is limited evi

dence that blood Pb levels <10 μg/dL are associated with increased incidence of allergic sensitization in children. This conclusion is based two lines of evi

dence: (1) a prospe ctive study reporting a significant association between maternal or umbilical cord blood Pb <10 μg/dL and greater incidence of sensitization to common allergens in children, and (2) data support

ing Pb-associated increases in serum IgE in children. In a prospective study of the children of 224 women50 NTP Monogr aph on Health Effects of Low-Level Lead in Poland recruited in the second trimester of preg

nancy, allergic sensitization or atopy was determined by skin prick test to common allergens administered when the children were 5 years of age ( Jedrychowski et al. 2011 ). Frequency of sensitization was signifi

cantly associated with maternal blood Pb (p=0.006; mean Pb, 1.6 μg/dL) and with umbilical cord blood Pb (p=0.001; mean Pb, 1.2 μg/dL), but not with current blood Pb levels in the 5-year-olds (p=0.43; mean Pb, 2.0 μg/dL). In an analysis of the relative risk, umbilical cord blood Pb in the Jedrychowski et al. ( 2011 ) study was associated with an increased relative risk (RR=2.28 (95% CI: 1.1, 4.6)) of atopy as indicated by at least one positive skin prick test. The 224 individuals included in the statistical analysis all had umbilical cord blood Pb levels <2.5 μg/dL , because the authors state that out

liers above the 95 th percentile were removed before analysis. The effect of the removal of individuals with higher blood Pb levels is unknown. No other studies were located that reported blood Pb and sensitization; however, an ecological study supports the association between higher Pb exposure and higher sensitization in children ( Heinrich et al. 1999 ). The odds ratio for posi

tive skin prick test (OR=1.38 (95% CI: 1.02, 1.86)) and increased specific IgE (OR=1.75 (95% CI: 1.31, 2.33)) to common allergens were also elevated in children from an area in Germany with higher Pb dustfall and Pb emissions. The study examined 2,470 children 5-14 years of age; it lacked blood Pb data but compared children from areas with high Pb dustfall to children in the reference group living in a low-Pb-dustfall area ( Heinrich et al. 1999 ). There are few studies of eczema or atopic der

matitis in children, and the evidence of an association with blood Pb is restricted to a single group of 110 children at a dermatology clinic, which may represent a sensitive subpopulation. In two overlapping studies of 110 patients with eczema from a Hong Kong pedi

atric 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 eczemapatients is supported by the objective measure of a Pbrelated increase in eosinophil count (r=0.27; p=0.001). The Hon et al. ( 2009
, 2010
, 2011 ) studies report an association between blood Pb and multiple clinical parameters rating severity of symptoms of atopic dermatitis, but not the incidence of eczema. Blood Pb levels did not differ between 110 eczema patients and 41 patients at the dermatology clinic with other skin conditions that did not have eczema (p=0.160); however, the study did not have a nonatopic refer

ence group. The Heinrich et al. ( 1999 ) ecological study described earlier also reported an increased odds ratio for eczema (OR=1.52 (95% CI: 1.03, 2.24)) among children living in the area with higher Pb dustfall. However, a retrospective study of 1,768 chil

dren born in Boston between 1979 and 1981, which determined relative risk of eczema in childhood with umbilical cord blood Pb levels, did not find a differ

ence between children with umbilical cord blood Pb levels above and below 10 μg/ dL ( Rabinowitz et al. 1990 ). This study differs from the two Hon et al. ( 2009
, 2010 ) studies in the timing of the Pb exposure measurement and in the reporting of incidence rather than severity of eczema. The Rabinowitz et al. ( 1990 ) study compared umbilical cord blood Pb to incidence of eczema years later (exact timing not reported) and addressed incidence (present vs. not present) rather than severity of eczema. Although four retrospective studies examined the potential relationship between Pb exposure and asthma in children, the results are primarily negative, and only one of the four studies reported an association between asthma and blood Pb. Blood Pb levels >10 μg/dL were associated with an increased odds ratio for doctor diagnosis of asthma (OR=7.5 (95% CI: 1.3, 42.9)) in a study of 356 children <13 years of age in the STELLAR database in Michi

gan ( Pugh Smith and Nriagu 2011 ). The analysis in Pugh Smith et al. ( 2011 ) was thoroughly adjusted for risk factors associated with asthma or confound

ers related to Pb exposure, such as age, gender, and exposure to passive smoke, cats, dogs, cockroaches, and other factors known to contribute to asthma. A retrospective study of 4,634 children in managed care in Michigan did not find an association between blood Pb at 1-3 years of age and incidence of asthma based on insurance records or dispensed medication in an analysis adjusted for income, birth weight, and sex ( Joseph et al. 2005 ). A retrospective study of 1,768 children born in Boston between 1979 and 1981 that determined relative risk of asthma in childhood with umbilical cord blood Pb levels did not find a difference between children with umbilical cord blood Pb levels above and below 10 μg/dL in an analysis that did notNTP Monograph on Health Effects of Low-Level Lead 51 include adjustment for confounders ( Rabinowitz et al. 1990 ). Myers et al. ( 2002 ) reported that the incidence of asthma based on medical records did not differ between 151 patients in Chicago with high blood Pb levels (≥25 μg/dL) and a reference group with blood Pb <5 μg/dL. The Myers et al. ( 2002 ) tested for effects of high blood levels and did not report any adjust

ments for confounders. The data from Sun et al. ( 2003 ) in girls and Pizent et al. ( 2008 ) in women suggest that Pb expo

sure may have a stronger effect on IgE in females. The results also indicate that analyses of Pb and IgE should consider sex as a potential confounder, which is not unexpected because sex differences in serum IgE are apparent early in childhood ( Blackwell et al. 2011
, Hunninghake et al. 2011 ), and other toxicantinduced or exacerbated hypersensitivity reactions have a gender bias ( Corsini and Kimber 2007 ). All of the studies of IgE adjust for age, except the Hon et al. ( Hon et al. 2009
, Hon et al. 2010
, 2011 ) set of stud

ies. Therefore, as noted above, only the Karmaus et al. ( 2005 ) study reports an association with blood Pb levels <10 μg/dL in an analyses that adjusted for age. This represents a limitation in the data set because there are well-established age-dependent changes in serum IgE: increased IgE levels are expected with increasing age up to puberty, and slowly decreas

ing levels are observed thereafter ( Blackwell et al. 2011 ). Smoking or exposure to passive smoke has also been associated with IgE. The effects of smoke exposure may be two-fold, as exposure may increase IgE directly or it may lead to increased exposure to Pb because of the Pb content in tobacco smoke. In a study of 318 children in Egypt under 8 years of age, Hegazy et al. ( 2011 ) reported a significant cor

relation (r=0.133; p<0.05) between blood Pb and parental tobacco smoking. The analysis of IgE in the Karmaus et al. ( 2005 ) study was particularly thorough in its consideration and adjustment for confounders, including gender, age, number of infections in the last 12 months, exposure to passive smoke, and exposure to other toxicants including DDE (a metabolite of DDT that is also associated with increased IgE). In adults, the results are mixed for an association between blood Pb and IgE or sensitization-related endpoints, but there are only three relevant studies in adults with blood Pb levels <10 μg/dL : a study of 523 office workers in Korea ( Min et al. 2008 ), a study of 216 office workers in Croatia ( Pizent et al. 2008 ), and a study of 94 Italians without occupational expo

sure to Pb ( Boscolo et al. 1999
, Boscolo et al. 2000 ). There was no correlation between blood Pb levels and serum IgE in men or women in the Boscolo et al. ( 1999
, 2000 ) publications. Serum IgE was correlated to blood Pb levels in the women office workers in the Pizent et al. ( 2008 ) study, but not in the men. The Pizent et al. ( 2008 ) study also examined functional endpoints (sensitization to allergens by positive skin prick test and nonspecific bronchial reactivity by his

tamine 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 bron

chial reactivity. In men, blood Pb (range, 1-7 μg/dL) was not associated with serum IgE, and blood Pb was associated with decreased hypersensitivity responses, including decrease in sensitization to allergens and decrease in nonspecific bronchial reactivity ( Pizent et al. 2008 ). In contrast, Min et al. ( 2008 ) reported a sig

nificant association between higher blood Pb (mean, 3 μg/dL) and higher nonspecific bronchial reactivity (by methacholine bronco-provocation test) in both male and female office workers. Two additional stud

ies of IgE in adults support an association with Pb at higher blood Pb levels. Higher serum IgE was corre

lated with higher blood Pb levels in two studies: a study of 47 Pb refinery workers in Osaka with mean blood Pb 50 μg/dL ( Horiguchi et al. 1992 ) and a study of 606 Pb battery workers in Korea with mean blood Pb 23 μg/dL in which IgE was elevated in workers with blood Pb >30 μg/dL compared with workers with blood Pb <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 Pb levels <10 μg/dL are negative for effects in men and report mixed results in women ( Boscolo et al. 1999
, Boscolo et al. 2000
, Pizent et al. 2008 ). An increase in symptoms of asthma and rhinitis was also reported in male industrial workers in the United Arab Emirates with extremely high blood Pb levels (mean, 78 μg/dL) relative to referents that also had high blood Pb levels (20 μg/dL) ( Bener et al. 2001 ). In adults with blood Pb levels <10 μg/dL, the data for asthma or respiratory symptoms are conflicting, with one study reporting increased bronchial responsiveness ( Min et al. 2008 )52 NTP Monogr aph on Health Effects of Low-Level Lead and one study reporting decreased bronchial respon

siveness or no effect of Pb ( Pizent et al. 2008 ). The data for sensitization with blood Pb are negative, with no effect in female office workers and reduced sensi

tization with increasing blood Pb in males, although data are from a single study ( Pizent et al. 2008 ).



### Summary of Support for Conclusions Animal data support an increase in IgE in adult mice at high Pb levels (50 μg inject ed subcutaneously three times per week for 3 weeks) and associated with devel

opmental 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 pro

duction, versus a type 1 helper T-cell (Th-1) response,which is associated with host resistance and delayedtype hypersensitivity (reviewed in Dietert and Piepenbrink 2006
, U.S. EPA 2006 ). The human data supporting a Pb-associated increase in serum IgE in children are restricted to cross-sectional studies. The determination of causation from cross-sectional stud

ies has the inherent limitation of making conclusions based on current blood Pb measurements and lacking information on cumulative Pb or Pb exposure at ear

lier time points. The demonstration that infant hair Pb in newborns was associated with umbilical cord IgE levels from the Annesi-Maesano et al. ( 2003 ) study suggests that Pb exposure at earlier time points is associated with IgE in children, but prospective stud

ies are lacking. The most relevant time for measuring exposure relative to IgE may include both earlier time points relating to mechanisms of Th-2 skewing ( Par

ronchi et al. 2000 ) or current blood Pb directly related to secretion of IgE because IgE in serum has a half-life of less than 2 days. Five cross-sectional studies report a correlation between blood Pb (mean levels from 2 to 14 μg/dL) and serum IgE in children up to 17 years of age. Elevated levels of serum IgE were reported in children with increasing blood Pb across multiple studies from different populations in analyses that adjusted or controlled for age, sex, and in some cases smoking and exposure to other contaminants known to effect serum IgE. However, only the Karmaus et al. ( 2005 ) study reports an association at blood Pb levels <10 μg/dL in analyses that adjusted for age; there

fore, the NTP concluded there is limited evidence that blood Pb <10 μg /dL is associated with elevated serum IgE in children. The conclusion of limited evi

dence for increased hypersensitivity responses at blood Pb <10 μg/d L in children is supported by the evidence for Pb-related increases in IgE together with the Jedrychowski et al. ( 2011 ) prospective study on allergic sensitization (diagnosed by skin prick test

ing). 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 associa

tion with asthma are restricted to a single study. For adults, there are only three studies of IgE or sensiti

zation-related effects of people with blood Pb levels <10 μg/dL. There is inadequate evidence in adults to address the potential association between blood Pb <10 μg/dL and IgE, allergy, eczema, or asthma. The NTP’s conclusions for limited evidence for increased serum IgE in children at blood Pb levels <10 μg/dL are in line with other agencies, although the conclusions of a consistent association from the 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) and significant associations in ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ) suggest slightly stronger conclusions by these agen

cies that may reflect the data from studies with blood Pb levels above 10 μg/dL.



### 5.3.2 IgG, IgM, IgA, and Antibody Response There is inadequate evidence that blood Pb levels <10 μg/dL are associated with serum levels of IgG, IgM, or IgA in the blood of children or adults (see Appendix B: Immune Effects). Studies that exam

ined serum immunoglobulins found no evidence of a consistent change, either increase or decrease, associated with blood Pb below or above 10 μg/ dL. There is inadequate evidence that blood Pb at anyNTP Monograph on Health Effects of Low-Level Lead 53level is associated with changes to the IgM- or IgGspecific functional antibody response. Two studies were located that evaluated an antibody response in humans in conjunction with blood Pb levels, and both reported that there was no effect of blood Pb level on the antibody response. There was no effect of blood Pb levels on the anti-rubella IgG antibody titer to a previous antigen (Rubella vaccine) in 279 children in Missouri from 9 months to 6 years of age ( mean not reported, 65% had blood Pb <10 μg/dL Lutz et al. 1999 ), and there was no difference in tetanus toxoidspecific antibodies between children with very high blood Pb levels (45 μg/dL) and high blood Pb levels (23 μg/dL) ( Reigart and Graber 1976 ). The few studies that examined serum immunoglobulin levels (other than serum IgE discussed in the previous section) in children or adults with blood Pb levels <10 μg/dL report inconsistent results. Serum levels of IgG were correlated (r=0.31; p=0.002) with blood Pb levels (mean, <2 μg/dL), but IgM was not related to blood Pb in a study of umbilical cord blood from 101 new

borns in Quebec ( Belles-Isles et al. 2002 ). There was no effect of blood Pb level (mean, 3 μg/dL) on serum IgG, IgM, or IgA in a study of 331 children 7-10 years of age in Germany ( Karmaus et al. 2005 ). Serum IgG, IgM, and IgA were increased in children with blood Pb ≥15 μg/dL compared to children with Pb <5 μg/dL in children <3 years of age at mean blood Pb level of 7 μg/dL; immunoglobulin levels were not related to blood Pb in children >3 years of age or in adults ( Sara

sua et al. 2000 ). In contrast, serum IgG and IgM were decreased in children in China 3-6 years of age with blood Pb >10 μg/dL fr om a sample of 72 children 3-6 years of age in China with mean blood Pb of 9.5 μg/dL ( Sun et al. 2003 ). Blood Pb was not correlated with serum IgA, IgM, or IgG in a study of atopic and nonal

lergic men in Italy without occupational exposure to Pb (mean Pb, 11 μg/dL; ( n=34 Boscolo et al. 1999 ).



### Summary of Support for Conclusions Animal data are mixed for an effect of Pb on the anti

body response and most studies do not report serum immunoglobulin levels (see U.S. EPA 2006 for recent reviews of the animal data
, ATSDR 2007 ). Studies in mice report no effect, suppression, or stimulation of the T dependent antibody response (plaque-forming cell (PFC) assay to sheep red blood cell challenge) at blood Pb levels of 25-130 μg/dL ( Blakley and Archer 1981
, Mudzinski et al. 1986 ), while suppression of the PFC response was observed in rats at 29 μg/dL ( Luster et al. 1978 ). The conclusion of inadequate evidence that blood Pb levels <10 μg/dL ar e associated with serum levels of IgG, IgM or IgA or functional antibody response in children or adults is based on the inconsistent results for serum IgG, IgM, and IgA and the general lack of human studies on Pb and the antibody response. The 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) and the 2007 ATSDR Toxicological Profile for Lead ( ATSDR 2007 ) do not make strong conclusions on the antibody response or serum immunoglobulins; however, the NTP’s con

clusions 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 the evidence presented in these documents.



### 5.3.3 T Lymphocytes (T-cells) There is inadequate evidence that blood Pb levels <10 μg/dL are associated with altered T lymphocyte (T-cell) numbers or percentages in the blood of chil

dren or adults (see Appendix B: Immune Effects). The results of studies at lower blood Pb levels (<10 μg/dL) are inconsistent; however, there are a number of occupational studies that report decreased absolute numbers or percentages of T-cells or T-cell popula

tions or subsets (particularly CD4+ T-helper cells), and some include a corresponding increase in B-cells at blood Pb <15 or <30 μg/dL. An association between higher blood Pb and higher numbers of naive T-cells (CD45RA+ or CD45RO-; cells not yet programmed for a specific immune response) is reported in several studies at low (<10 μg/dL) and high blood Pb levels. The results of studies in children and adults with blood Pb levels <10 μg/dL ar e inconsistent for a poten

tial relationship between blood Pb and T-cell numbers. In a study of 70 children 3-6 years of age in China, the percentage of T-cells was unchanged, the percentage of CD4+ T-cells was decreased, and the percentage of CD8+ T-cells was increased in children with blood Pb levels >10 μg/dL compared to children <10 μg/dL ( Zhao et al. 2004
, Li et al. 2005 ). In contrast, Sarasua et al. ( 2000 ) reported decreased percentage of T-cells, no change in CD4+ or CD8+ T-cells, and increased percentage of B-cells in children under 3 years of age at mean blood Pb level of 7 μg/dL. Lymphocyte populations were not related to blood Pb levels in children >3 years of age or in adults ( Sarasua et al. 2000 ). Four additional studies in children reported no effect of blood Pb on lymphocyte populations at54 NTP Monogr aph on Health Effects of Low-Level Lead mean blood Pb levels ranging from <2 μg/dL to 9 μg/dL in 318 children <8 years of age in Egypt ( Hegazy et al. 2011 ), in 279 children from 9 months to 6 years of age in Missouri ( Lutz et al. 1999 ), in 331 children 7-10 years of age in Germany ( Karmaus et al. 2005 ), or in 101 newborns in Quebec ( Belles-Isles et al. 2002 ). In adults with blood Pb levels <10 μg /dL, the results of studies that examined the relationship between blood Pb and lymphocyte populations are mixed. Higher blood Pb was correlated with higher numbers of CD4+ T-cells in atopic and nonallergic men ( n=34 Boscolo et al. 1999 ) and with higher numbers of CD8+ T-cells in nonallergic women, but not in atopics, in Italy without occupational exposure to Pb (mean Pb, 5-11 μg/d L; n=60)( n=60 Boscolo et al. 2000 ) . Increased blood Pb was also correlated with increased numbers of CD4/ CD45RO- naive CD4 T-cells in both nonallergic men and women, but not in atopics ( Boscolo et al. 1999
, Boscolo et al. 2000 ). Naive CD4/CD45RA+ CD4 T-cells were also increased in three-wheel drivers in India (mean, Pb=7 μg/dL; n=26) compared to a reference group (mean Pb, 5 μg/dL; n=59), but CD4+ T-cells were decreased ( Mishra et al. 2010 ). For higher blood Pb levels (i.e., >15 μg /dL), anumber of occupational studies report altered Tor B-cells concentrations. In general, the absolute numbers or percentages of T-cell subsets (particu

larly CD4+ T-helper cells) are decreased and there is a corresponding increase in B-cells. No clear and consistent cell group is related to Pb levels, although several studies have shown an association between higher blood Pb and greater numbers of naive T-cells. The numbers and percentages of T-cells and CD4+ T-cells were decreased in firearms instructors in the United States (mean Pb, 15 (n=36) and 31 μg /dL (n=15)) ( Fischbein et al. 1993 ). The number of CD4 T-cells was reduced in 25 Pb battery workers in Tur

key with very high mean blood Pb levels of 75 μg/dL ( Undeger et al. 1996
, Basaran and Undeger 2000 ). In a separate study of Pb battery workers with very high mean blood Pb of 132 μg/dL (n=33 in India), Mishra et al. ( 2010 ) reported that the percentage of CD4+ T-cells were decreased and percentages of CD45RA+ (naive) T-cells were increased. In contrast, Pinkerton et al. ( 1998 ) reported no effect on CD4+ T-cells, that higher B-cell counts were associated with higher Pb exposure, and that lower CD4/CD45RA+ naive CD4 T-cell counts were correlated with higher cumulative Pb exposure in a study of U.S. Pb smelter workers (median Pb, 39 μg /dL; n=145). Several studies have reported that CD4+ T-cells were not related to blood Pb but found either decreases in CD8+ T-cells ( GarciaLeston et al. 2011 ) and decreased CD8+ T-cells along with decreased B-cells ( Kuo et al. 2001 ), or increased percentages of CD8+ T-cells ( Sata et al. 1998 ). The issue of reverse causality is also possible because Pb in whole blood is largely contained in the circulating blood cells, although this is gener

ally attributed to the red blood cells, not to the white blood cells or leukocytes (lymphocytes are a subpopulation of leukocytes). Choi and Kim ( 2005 ) reported that boys with higher blood Pb levels had higher counts for leukocytes, and these counts cor

related significantly with blood Pb levels (mean, 3 μg/dL; r=0.39; p<0.05) in a study of 251 adolescents 13-15 years of age in South Korea; the authors did not report data for lymphocytes or for specific lympho

cyte subsets (e.g., T-cells). Higher blood Pb levels in these individuals may cause higher leukocyte counts, or higher circulating leukocyte counts may lead to higher measurements of blood Pb if the leukocytes contain substantial amounts of Pb.



### Summary of Support for Conclusions Animal data support a Pb-associated effect on T-cell maturation, and particularly a shift toward the type 2 helper T-cell (Th-2) phenotype, which is associated with allergy and increased IgE production, versus a type 1 helper T-cell (Th-1) response, which is associ

ated with host resistance and DTH response (reviewed in Dietert and Piepenbrink 2006
, U.S. EPA 2006 ). Some animal data support Pb-associated decreases in T-cell populations ( e.g., decreased thymic CD4 and CD8 T-cells with Pb exposure and Listeria infection in BALB/c mice at blood Pb <25 μg/dL Dyatlov and Lawrence 2002 ); however, decreased T-cell popula

tions with Pb exposure are not widely reported in the experimental animal literature. White blood cell dif

ferentials with enumeration of lymphocyte subsets (T-cells, B-cells, CD4 and CD8 T-cells) are among the most common immune assays used in human stud

ies, in part because of the relative ease of the assay and ability to obtain data from a small blood sample. Values typically have a large degree of variation that is influenced by sex, race, age, and methodological differences in obtaining and processing the samples. It is worth noting that lymphocyte subset analysis does not evaluate immune function, although it isNTP Monograph on Health Effects of Low-Level Lead 55 an accepted part of a tiered screening approach to the evaluation of potential immunotoxicity of a given chemical ( Luster et al. 1992 ). Differential white blood cell counts are not particularly sensitive indicators of immunotoxicity, and statistically significant effects associated with exposure often fall within normal ranges for the population. Pb-associated changes in T-cell counts or percentages at lower exposure levels are relatively small and may be without a functional impact on the immune response of individuals. How

ever, on a population level, a small change in cell numbers or percentages may be adverse. A good example is the demonstration that increased mortal

ity risk is associated with small decreases in CD4 and total white blood cell counts in a study of people ≥85 years of age ( Izaks et al. 2003 ). Although no clear or consistent cell popula

tion relates to Pb levels, changes in T-cell popula

tions are reported in a wide range of human stud

ies. Decreased T-cells or CD4 T-cells (particularly at blood Pb >15 μg/dL) and increased naive T-cells may be a biological signal of Pb exposure in humans. The NTP’s conclusion of inadequate evidence that blood Pb levels <10 μg /dL are associated with altered T-cell abundance in the blood of children or adults is based on the lack of a clear pattern of results in studies with lower blood Pb levels. Changes in T-cell populations do not equate to a functional immune outcome, although they may be relevant to changes in the DTH response. Although a large body of 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 the DTH response were located in humans. The EPA 2006 AQCD for Lead ( U.S. EPA 2006 ) and 2007 ATSDR Toxi

cological Profile for Lead ( ATSDR 2007 ) both include changes in T-cell subpopulations as characteristic immune effects identified with Pb exposure at higher levels (e.g., 30-70 μg/dL in ATSDR).



### 5.3.4 Monocyte/Macrophages There is inadequate evidence that blood Pb levels <10 μg/dL are associated with changes in macrophage function. The human data on macrophage function are limited to a single study of 65 children 6-11 years of age in Mexico living near a Pb smelter (mean blood Pb levels of 21 and 30 μg /dL) compared to children with blood Pb levels of 7 μg/dL ( Pineda-Zavaleta et al. 2004 ). The study investigated nitric oxide (NO) and increased superoxide (O 2 – ) production by macrophages. At appropriate levels, both NO and O 2 – are involved in destruction of bacteria by macrophages and other cells. Decreased macro

phage NO and increased O 2 – production after indirect (phytohemagglutinin) stimulation through lympho

cytes as well as direct (interferon-γ/lipopolysaccharide) stimulation of the macrophages were observed in cellcultures from the Pb-exposed boys but not from Pbexposed girls. Animal data provide strong support for decreased NO and increased O2- or reactive oxygen intermediate production by macrophages after in vivo or in vitro exposure to Pb but generally lack blood Pb data (see U.S. EPA 2006 for recent reviews of the ani

mal data
, ATSDR 2007 ). Production of the proinflam

matory cytokine (tumor necrosis factor-α (TNF-α)) by

macro phages is also associated with Pb exposure, and the animal data suggest that production of TNF-α by macrophages is linked to increased sensitivity to bac

teria-derived endotoxin ( see U.S. EPA 2006 for recent reviews of the animal data ). In vitro studies of human macrophages and other mononuclear cells in blood demonstrated increased production of TNF-α with Pb exposure ( Villanueva et al. 2000 ) in the presence of lipo

polysaccharide plus Pb ( Guo et al. 1996 ). However, low levels of Pb were associated with suppression of TNF-α release in human mononuclear cells from blood in the presence of heat-killed Salmonella enteritidis ( Hem

dan et al. 2005 ). The 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) identifies stimulation of a hyper-inflammatory state in macrophages as one of the principal immune effects of Pb; however, it notes that there is a general lack of human epidemiological data in this area.



### 5.3.5 Neutrophils There is inadequate evidence that blood Pb levels <10 μg/dL are associated with changes in neutrophil function. There are limited human data on the poten

tial association between Pb exposure and neutro

phils, and the studies are restricted to occupationally exposed individuals with mean blood Pb levels that are >30 μg/dL (see Appendix B: Immune Effects). Several studies report that movement of neutrophils toward their targets (chemotaxis) may be reduced in Pb workers at high blood Pb levels ( Governa et al. 1988
, Queiroz et al. 1993 ) or after in vitro exposure to Pb ( Governa et al. 1987 ). There is also evidence that lytic activity of Candida may be reduced ( Queiroz et al.56 NTP Monograph on He alth Effects of Low-Level Lead 1994 ) but phagocytic activity is relatively unaffected in Pb workers ( Guillard and Lauwerys 1989
, Queiroz et al. 1994 ). There are few animal data on neutrophil function, and in humans there is a complete lack of data with lower blood Pb levels. Additional studies of neutrophil function are required to clarify the poten

tial 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 consis

tent finding with Pb exposure; however, the studies do not include blood Pb levels <10 μg/dL.



### 5.4 Susceptible Populations or Life Stages Segments of the population that are may be more susceptible to health effects of Pb are discussed more extensively in Section 3.0 Exposure . A significant body of literature supports the developmental period as a susceptible window for immunotoxicity, with immune effects of developmental toxicant exposures occurring at lower doses and adverse effects may be more per

sistent than similar exposures in adults ( Luebke et al. 2006
, Dietert 2008 ). As described above, the database of immune studies of Pb in humans provides limited evidence that blood Pb levels <10 μg/dL ar e associated with increased hypersensitivity responses and allergic sensitization diagnosed by skin prick testing in children; however, there is inadequate evidence to assess these effects in adults. Children may represent a sensitive life stage for the effects of Pb on IgE and IgE-related effects, but there is not enough data on these endpoints in adults with low blood Pb levels to make this determination. There are some established age-related dif

ferences in immunity including a general decline in IgE and allergic symptoms with increasing age that is more pronounced in the elderly ( Mediaty and Neuber 2005 ). However, there is some evidence that the apparent age-related decrease in hypersensitiv

ity may be associated with more than age-related decline, and the difference may reflect an increase in IgE and sensitization rates in recent cohorts ( Jarvis et al. 2005 ). In either case, childhood and prenatal exposure periods are potentially susceptible life stages because of the elevated background level of IgE and IgE-mediated hypersensitivity. In addition, young children have higher levels of Pb exposure related to early hand-to-mouth behaviors. Therefore, children may experience higher levels of Pb during a life stage that is already characterized by elevated IgE. There are also gender-related differences in immune function, with many studies reporting higher total IgE levels in boys and men than in girls or women ( e.g., see Raby et al. 2007 ). A recent meta-analysis of over 550 studies reported that boys make up 64% of children age 18 or younger with allergies but that women make up 65% of adults above the age of 18 with allergies ( Kelly and Gangur 2009 ). The Pb epide

miological data include two studies that report signifi

cant effect of gender on the effects of Pb on IgE. Sun et al. ( 2003 ) reported that increased IgE was statistically significantly correlated with blood Pb in girls in China with blood Pb ≥10 μg/dL 3-6 years of age but that the effect was not significant in boys. Similarly, Pizent et al. ( 2008 ) reported that serum IgE was correlated to blood Pb levels in female office workers in Croatia, but not in the males. These data suggest that females may be more susceptible to the effects of Pb on IgE and allergy. Alternatively, the higher basal IgE levels in males may make it more difficult to detect the effects of Pb. The risk factors for hypersensitivity and allergies include age and sex discussed above, but evidence suggests that heredity is by far the most important factor ( De Swert 1999 ). This may manifest as a dif

ference by race; for example, Joseph et al. ( 2005 ) reported that African American children were at statistically significantly greater risk of asthma com

pared to Caucasians, regardless of blood Pb level. The general or background allergic status of mothers or of children may be relevant to the effects of Pb on IgE and hypersensitivity. Annesi-Maesano et al. ( 2003 ) reported that the association between infant hair Pb levels and umbilical cord blood IgE were affected by the allergic status of the mothers. In analyses divid

ing mothers by history of IgE-mediated allergic status (either allergic, as indicated by asthma, allergic rhi

nitis, or eczema, or nonallergic), the study reported that infant hair Pb was statistically significantly asso

ciated with increased IgE in children born to nonal

lergic mothers (r=0.21; p<0.01), but the relationship was not significant for children born to allergic moth

ers (r=0.12; p>0.05). The authors suggest that family history of allergy (in other words, atopy) may over

shadow the effect of Pb on IgE in children. It is unclear from these data whether this reflects genetic factors predisposing the children to allergy (e.g., Raby et al. 2007
, Hunninghake et al. 2008
, Hunninghake et al. 2011 ) or whether prenatal exposure to cytokines,NTP Monograph on Health Effects of Low-Level Lead 57 histamine, or other factors are important. In the one prospective study available, Jedrychowski et al. ( 2011 ) controlled for maternal allergic history (or atopy) in the analysis that demonstrated a statistically significant association between higher umbilical cord blood Pb and atopic status as indicated by a positive skin prick test to at least one common allergen in the children at 5 years of age. Furthermore, adjustment for maternal atopy, as well as child’s gender, parity, maternal age, maternal education, and environmen

tal 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)). T he association with maternal blood Pb also had a rela

tively small effect, but it did change the results from statistically significant to borderline (before adjust

ment: RR=1.81 (95% CI: 1.10, 3.00); after adjustment: R=1.72 (95% CI: 0.98, 3.00)) ( Jedrychowski et al. 2011 ).



### 5.5 Pb Exposure Measurements The following brief discussion outlines several Pb exposure issues that are directly relevant to immune effects of Pb. An expanded discussion is included in a separate section of this document (see Section 3.0 Exposure ). No studies of immune effects in humans were located that used a measure of exposure other than blood Pb and hair Pb. However, it is important to note that blood Pb is only one measure of expo

sure, and it reflects only a portion of the Pb that is present in a given subject. The half-life of Pb in blood is approximately 35 days and therefore blood Pb is considered a good indicator of recent exposure. Most of the Pb is stored in bones (approximately 90% in adults, 80% in adolescents, and 66% in children under 5 years of age), and Pb from past environmental exposure is released into the blood, contributing to a chronic internal source of exposure ( Leggett 1993 ). The higher levels of Pb in bone may be particu

larly relevant for cells of the immune system and immune function. All of the white blood cells or leukocytes that develop postnatally are derived from progenitor cells in the bone marrow in a process termed hematopoiesis . Elevated Pb concentrations in bone are therefore of direct concern for the devel

opment of immune cells, and future studies should more closely consider the potential relationship between bone Pb levels and immune effects. Mecha

nistic studies in animals support the importance of Pb exposure on the development and differentiation of leukocytes. For example, Gao et al. ( 2007 ) reported that Pb modified bone-marrow-derived dendritic cells to promote Th-2 phenotype and immune responses associated with allergy and increased IgE production. The location of Pb within blood is also of particular relevance to immune function. The Pb in blood is mainly contained in cells, primarily in red blood cells, with less than 1% in serum. As discussed in Section 5.3.3 T lymphocytes (T-cells) above, Choi and Kim ( 2005 ) reported that blood Pb concentra

tions (mean, 3 μg/dL) w ere 2 fold higher in boys with higher leukocyte counts, and leukocyte counts correlated significantly with blood Pb levels (r=0.39; p<0.05), in a study of 251 adolescents 13-15 years of age in South Korea. The issue of reverse causality is suggested: higher blood Pb levels in these individuals may cause higher leukocyte counts, or higher circulat

ing leukocyte counts may result in elevated blood Pb concentrations if the leukocytes contain substantial amounts of Pb in the boys in this study.



### 5.6 Delayed-Type Hypersensitivity (DTH) and Pb-Related Immune Effects in Animal Studies There is a large body of laboratory animal data on immune effects of Pb. The effects in animal mod

els support the human data, as discussed above for increased IgE, with evidence to support a Th-2-related mechanism and proinflammatory shift in macrophage function. However, the major effect on immune function associated with Pb exposure appears to be suppression of the delayed-type hypersensitivity (DTH) response. Animal data provide strong and consistent support for Pb-associated sup

pression of DTH response (see U.S. EPA 2006
, ATSDR 2007 for recent reviews of the animal data ). The DTH response depends on priming and expansion of antigen-specific T-cells that are Th-1 dependent and therefore the Pb-associated suppression of Th-1 responses is consistent with the Pb-associated sup

pression of DTH. The DTH response is a functional immune endpoint that is widely accepted as an indi

cator of cell-mediated function ( Luster et al. 1992
, U.S. EPA 1998 ). Although DTH response can be evalu

ated as a measure of immune response in humans ( e.g., Vukmanovic-Stejic et al. 2006 ), no studies were located that evaluate the relationship between blood Pb and DTH in humans. Studies on the DTH response in humans with low blood Pb levels are recommended58 NTP Monograph on He alth Effects of Low-Level Lead because of the lack of data in humans and the clear and consistent Pb-related suppression of the DTH response in mice, rats, goats, and chickens. Exposure to Pb is associated with suppression of the DTH response in mice, rats, goats, and chickens, and following both acute and subchronic exposures of up to 16 weeks. Although blood Pb levels are not available in all studies, decreased DTH response has been reported at blood Pb levels from 29 to 87 μg/dL. Wistar rats that were the offspring of dams exposed from premating to weaning, and continued to receive 25 or 50 ppm Pb acetate in drinking water until tested, had suppressed DTH at blood Pb level of 29 and 52 μg/dL ( Faith et al. 1979 ). Adult BALB/c mice exposed to 32, 128, 512, or 2048 ppm Pb acetate in drinking water for 3 weeks had blood Pb levels of 9, 49, 87, and 169 μg/dL, and the blood Pb level correlated with suppressed DTH response ( McCabe et al. 1999 ). Although McCabe et al. ( 1999 ) report that the DTH response in the mice with 87 μg/dL blood Pb level was statistically suppressed, it is not clear from the paper if blood Pb 9 μg/dL (a more environmentally relevant level) was associated with suppressed DTH response. In a study of maternal exposure of Fisher 344 rats to 250 ppm Pb acetate, maternal blood Pb levels were as high as 66 μg/dL; ho wever, there was no effect of Pb exposure in the dams 8 weeks after parturition and the Pb exposure was stopped ( Chen et al. 2004 ). In contrast, the offspring with blood Pb levels between 6 and 8 μg/dL measured 4 weeks after the dams were last exposed had significantly suppressed DTH response. The developmental nature of this study and the early removal of Pb exposure to the dams suggest that the DTH effect of Pb has a clear developmental component. No experimental animal data report a blood Pb level associated with a “no effect” level, and therefore the lower blood Pb range associated with effects is unknown, even in laboratory animals. 

### 5.7 Conclusions The NTP concludes that there is limited evidence that blood Pb levels <10 μg/dL ar e 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 evi

dence that blood Pb levels <10 μg/dL are associated with increased hypersensitivity responses and allergic sensitization diagnosed by skin prick testing to com

mon 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 sen

sitization to common allergens indicated by positive skin prick test ( e.g., Jedrychowski et al. 2011 ). There is inadequate evidence of an association between blood Pb and eczema or asthma in children and inadequate evidence in adults to address the potential association between blood Pb <10 μg/dL and IgE, allergy, eczema, or asthma. There is inadequate evidence that blood Pb levels <10 μg/dL ar e associated with observational data such as altered lymphocyte counts or serum levels of IgG, IgM, or IgA in the blood of children or adults because of a general lack of studies at the lower dose and inconsistency in available data. There is inadequate evidence that blood Pb levels <10 μg/dL are associ

ated with changes in immune function other than hypersensitivity because there are few studies of Pb and immune function in humans, particularly at lower blood Pb levels. Very few studies examine markers of exposure other than blood Pb levels, and therefore it is unknown if blood or bone Pb levels would be a better measure of exposure for Pb-related immune effects.NTP Monograph on Health Effects of Low-Level Lead 59 Table 5.4: NTP conclusions on immune effects of low-level Pb

Health Effect Population or Exposure

Window NTP Conclusion Blood Pb Evidence Bone Pb Evidence

Increased serum immunoglobulin E (IgE) Prenatal Inadequate Unclear Hair Pb data
Children Limited Yes, <10 μg/dL No data
Adults Inadequate Unclear No data Increased hypersensitivity and allergy (e.g., positive skin prick test) Prenatal Limited Maternal and umbilical cord <10 μg/dL No data
Children Limited Yes, <10 μg/dL No data
Adults Inadequate Unclear No data Asthma, eczema, etc. Prenatal Inadequate Unclear No data
Children Inadequate Unclear No data
Adults Inadequate Unclear No data Altered serum IgG, IgM Prenatal Inadequate No data No data
Children Inadequate Unclear No data
Adults Inadequate Unclear No data Altered antibody response Prenatal Inadequate No data No data
Children Inadequate No data No data
Adults Inadequate No data No data Immunophenotyping (e.g., T-cells, B-cells) Prenatal Inadequate No data No data
Children Inadequate Unclear No data
Adults Inadequate Unclear; >15 μg /dL data suggest changes in T-cells or T-cell subpopulations No data

Monocyte/macrophage function Prenatal Inadequate No data No data
Children Inadequate Unclear (one study) No data
Adults Inadequate No data No data Neutrophil function Prenatal Inadequate No data No data
Children Inadequate No data No data
Adults Inadequate Unclear; >30 μg/dL data suggest changes in chemotaxis and lytic activity No data

Delayed-type hypersensitivity (DTH) response Prenatal Inadequate No data No data
Children Inadequate No data No data
Adults Inadequate No data No data60 N TP Monograph on Health Effects of Low-Level Lead THIS PAGE LEFT INTENTIONALLY BLANKNTP Monograph on Health Effects of Low-Level Lead 61 

## 6.0 CARDIOVASCULAR EFFECTS

6.1 Conclusions NTP concludes that there is sufficient evidence that blood Pb levels <10 μg/dL in adults are associated with adverse effects on cardiovascular function. There is sufficient evidence of a bone-Pbrelated increase in blood pressure (BP) and the risk of hypertension. Two prospective studies and five cross-sectional studies found a statistically signifi

cant association between bone Pb and increased BP or hypertension. These studies were in populations or samples with blood Pb levels <10 μg/dL, and most of them had mean levels <5 μg/dL. Blood Pb was less consistently associated with BP and hypertension in adults. Studies of groups with mean blood Pb levels <5 μg/dL (often more recent studies) have found sig

nificant associations between concurrent blood Pb and higher BP. The NTP recognizes that an individual with blood levels <10 μg/dL dur ing adulthood may have had higher blood Pb levels earlier in life, and the role of early-life Pb exposure cannot be discriminated from the role of concurrent blood Pb. There is sufficient evidence that blood Pb lev

els <10 μg/dL are associated with an increased risk of hypertension during pregnancy. One prospective study and five cross-sectional studies supported an association, all with mean blood Pb levels <10 μg/dL. There is limited evidence of increased risk of cardio

vascular-related mortality associated with blood Pb levels <10 μg/dL based on three prospective studies that report an association with blood Pb, and two prospective studies that did not support an asso

ciation 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 dis

ease including cerebrovascular disease and periph

eral arterial disease, because there are few replicated studies of blood Pb effects. There is inadequate evidence to assess whether children present a sensitive life stage for cardio

vascular effects of Pb. No prospective studies have followed children with early-life Pb measures with determination of cardiovascular health after child

hood, and the few studies of blood Pb and BP during childhood had inconsistent results. There is some evidence that menopause is associated with higher blood Pb levels, associated with mobilization of bone stores of Pb, and this could put women at greater risk of Pb-related cardiovascular effects. However, there are few studies and inadequate evidence to assess cardiovascular effects of Pb in menopausal women. One cross-sectional study (mean blood Pb) found a stronger statistically significant association between blood Pb and hypertension in postmenopausal women ( Nash et al. 2003 ), but two smaller studies found no association ( Pizent et al. 2001
, Al-Saleh et al. 2005 ). There is inadequate evidence for Pb effects on heart rate variability or specific types of cardio

vascular disease; due to few replicated studies. Chronic Pb exposure appears to be more critical than current Pb exposure, as indicated by more con

sistent associations with bone Pb than with blood Pb for chronic cardiovascular effects such as hyperten

sion and mortality from cardiovascular causes. The data are inadequate to evaluate prenatal or child

hood Pb exposure with health effects at later stages of development or in adulthood. Although the cardiovascular and renal systems are intimately linked, effects are considered sepa

rately in this evaluation because studies generally reported individual effects rather than testing both systems comprehensively. Nevertheless, it is rec

ognized that kidney dysfunction can contribute to increased BP and that hypertension can contribute to adverse renal effects. The EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ) both conclude that cardiovascular and renal effects of Pb may share biological mecha

nisms. As discussed in Section 6.4 , multiple studies suggest that individuals with decreased renal func

tion are a susceptible population for adverse cardio

vascular effects of Pb.



### 6.2 How Conclusions Were Reached Conclusions in the NTP evaluation of Pb-related cardiovascular effects in humans associated with low-level Pb were derived by evaluating the data from epidemiological studies with a focus on blood Pb levels <10 μg/dL. The NTP ’s conclusions are based on the evidence from human studies with blood Pb levels of <10 μg/dL , with data reflecting exposure levels up to 15 μg/dL. This section of the evaluation focuses primarily on the human data for cardiovas

cular effects of Pb because there is a relatively large database of human studies for these endpoints. Major endpoints considered as potential indicators of effects of Pb on cardiovascular functions are listed62 NTP Monograph on Health Eff ects of Low-Level Lead and briefly described in Section 6.2.1 . This document is not a review of the cardiovascular system or toxicity, and the reader is directed to published reviews for additional background. Key data and principal studies considered in developing the NTP conclusions are dis

cussed in detail in Section 6.3 Evidence for Pb-related Effects on Cardiovascular Outcomes . The discussion of each cardiovascular effect begins with a state

ment of the NTP conclusion of whether the specific effect is associated with a blood Pb level <10 μg/dL or <5 μg/dL and the age group in which it is identified (childhood or adulthood). Most studies are prospec

tive or cross-sectional within a life stage (childhood or adulthood exposure and outcome) unless otherwise indicated. The discussion also highlights the extent to which experimental animal data support the association between Pb exposure and cardiovascular effects. Although the information necessary to sup

port the NTP conclusions is presented in Section 6.3
, the complete data set of human studies with data on cardiovascular endpoints from Pb-exposed groups is included in Appendix C: Cardiovascular Effects, and individual studies are abstracted for further refer

ence. The NTP made extensive use of recent govern

ment 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 end

points commonly evaluated in epidemiological stud

ies (as defined by the American Heart Association Cardiac Glossary ( http://www.heart.org/HEARTORG/ Conditions/HeartAttack/HeartAttackToolsResources/ Cardiac-Glossary_UCM_303945_Article.jsp ) or stud

ies of pulse pressure and heart rate variability cited below). Blood pressure (BP) is the most widely mea

sured cardiovascular effect in studies of Pb exposure and is evaluated as a continuous measure (range, in mmHg) or as categories (dichotomized as hyperten

sion vs. no hypertension). High BP increases the risk of myocardial infarction and stroke, and BP control is one of the primary strategies to prevent the devel

opment of cardiovascular disease, with evidence of efficacy in patients without prior heart disease ( Law et al. 2009 ). Pulse pressure is the difference between systolic and diastolic blood pressure (SBP and DBP),
Table 6.1: Major Pb-related cardiovascular outcomes/effects

Cardiovascular Effect Description Blood pressure (BP) The force exerted by the heart against the walls of the arteries (measured in millimeters of mercury (mmHg)), with a maximum during the pumping phase of the heartbeat (systolic, SBP) and a minimum when the heart muscle relaxes between beats (diastolic, DBP). Hypertension Medical term for high blood pressure (currently, SBP ≥140 or DBP ≥90) compared to an opti

mal BP of <120/80 mmHg. BPs of 120-139/80-89 mmHg are considered prehypertension. Pulse pressure The difference between SBP and DBP; a marker of arterial stiffness. Heart rate variability Changes in the interval between heart beats. Decreased variability is a marker of abnormal autonomic nervous system functioning. Electrocardiographic (ECG) conduction abnormalities Changes in the typical pattern of electrical activity of the heart, including the P wave (atrial activity), QRS wave (ventricle activity), and T wave (return to resting state). Peripheral artery disease Narrowing of arteries carrying blood to the arms and legs, caused by atherosclerosis. Coronary heart disease Narrowing of the arteries that supply blood and oxygen to the heart muscle, caused by athero

sclerosis, and which can result in a myocardial infarction (also called ischemic heart disease). Myocardial infarction Medical term for a heart attack: damage to heart muscle resulting from a blocked blood supply.
Stroke Death or injury to brain cells when a blood clot blocks an artery in or leading to the brain (ischemic) or when a blood vessel ruptures (hemorrhagic). Cardiovascular mortality Death attributed to heart or circulatory causes. American Heart Association Cardiac Glossary: ( http://www.heart.org/HEARTORG/Conditions/HeartAttack/ HeartAttackToolsResources/Cardiac-Glossary_UCM_303945_Article.jsp )NTP Monograph on Health Effects of Low-Level Lead 63 and increases reflect arterial stiffness, a critical cardio

vascular risk factor ( Lakatta and Levy 2003 ). Heart rate variability is an indicator of cardiac autonomic func

tion, with decreased variability being associated with risk of heart disease and mortality, and with clinical relevance in relation to Pb exposure ( Park et al. 2006 ). Electrocardiographic (ECG) conduction abnor

malities 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 (cerebrovascu

lar 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 Car

diovascular Outcomes below.



### 6.2.2 Principal Conclusions from the 2006 EPA and 2007 ATSDR Pb Documents The EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ) both concluded that epidemiological studies sup

port a relationship between higher Pb exposure and decreases in cardiovascular health, including increased SBP and DBP, higher incidence of hyper

tension, and increased incidence of cardiovascular disease and cardiovascular-related mortality (see Table 6.2 for principal conclusions; see the original documents for complete conclusions). The asso

ciation between elevated blood Pb and increased BP (SBP and DBP) is supported by a large body of literature, including cross-sectional (e.g., NHANES), prospective cohort (e.g., Boston Normative Aging Study), and occupational studies, as well as several meta-analyses ( Staessen et al. 1994
, Schwartz 1995
, Nawrot et al. 2002 ). The EPA ( U.S. EPA 2006 ) and ATSDR ( ATSDR 2007 ) both stated that the data sup

port 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 contri

bution to Pb-related increases in BP. Every 10 μg/g increase in bone Pb was associated with an odds ratio for hypertension of 1.28 to 1.86 over a bone Pb range of <1.0 μg/g to 96 μg/g ( U.S. EPA 2006 ). ATSDR also highlighted the potential mechanistic link between cardiovascular and renal effects of Pb. The NTP considered the conclusions and data summaries from the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ). In general, the NTP accepted the conclusions and agreed that the data support them. Differences from the ATSDR and EPA documents are identified for specific endpoints. The focus of EPA’s document did not clearly discriminate effects below and above 10 μg/dL. Most of the studies of the quantitative relationship between blood Pb and SBP report mean blood Pb levels <10 μg/dL ( e.g., table 6-2 in U.S. EPA 2006 ). However, the conclusion on the increase in BP associated with a doubling of blood Pb did not specify whether this doubling occurred at blood Pb levels <10 μg/dL. Some studies considered by the EPA, particularly those conducted before 1990 or in occupational settings, had more than 90% of their subjects with blood Pb >10 μg/dL ( Kromhout et al. 1985
, Lockett and Arbuckle 1987
, Gartside 1988 ). Such studies were not considered for the NTP conclu

sions on Pb effects at levels <10 μg/dL.



### 6.3 Evidence for Pb-related Effects on Cardiovascular Outcomes

6.3.1 Blood Pressure (BP) and Hypertension There is sufficient evidence that blood Pb levels <10 μg/dL are associated with increases in BP and risk of hypertension (see the Blood Pressure (BP) and Hypertension section of Appendix C: Cardiovascular Effects). BP is the most widely studied cardiovascular Table 6.2: Main conclusions for cardiovascular effects in the 2006 EPA AQCD for Lead and the 2007 ATSDR Toxicological Profile for Lead
“Epidemiologic studies support the relationship between increased lead exposure and increased del

eterious cardiovascular outcomes, including increased blood pressure and increased incidence of hyperten

sion. ... The evidence for an association of Pb with car

diovascular morbidity and mortality is limited but sup

portive.” (U.S. EPA 2006, pg 6-271) “Population studies suggest that there is a significant association between bone-lead levels and elevated blood pressure. Blood lead levels (PbBs) also have been associated with small elevations in blood pressure.“ (ATSDR 2007, pg 21)CardiovascularEffects

64 NTP Monograph on He alth Effects of Low-Level Lead measure in studies of Pb, because it is routinely and easily measured. An association between higher Pb levels and higher BP is most consistent in studies of bone Pb (see Table 6.3 ). Women are at particular risk: there is sufficient evidence that blood Pb <10 μg/dL increases the risk of hypertension during pregnancy. Adults with concurrent blood Pb levels <10 μg/d L may have had higher Pb levels in the past, so the role of current blood Pb cannot be separated from an effect of early-life Pb exposure. There is inadequate evidence for Pb effects on BP or hypertension in children. The size of the increase in BP that is detected is relatively small (1-2 mmHg). It is well established, however, that small increases in BP levels at the population level can have a sub

stantial public health impact by increasing the risk of hypertension and incident cardiovascular disease ( Whelton et al. 2002 ). Despite some inconsistency across human stud

ies, meta-analyses conclude that Pb exposure is asso

ciated with increased BP levels ( Nawrot et al. 2002
, Navas-Acien et al. 2008 ). Meta-analyses can account for the relative contributions of each study and mul

tiple publications on overlapping data sets. Several recent meta-analyses support a small increase in BP from both blood ( Nawrot et al. 2002 ) and bone Pb ( Navas-Acien et al. 2008 ). Small but significantly increased risks of hypertension were found with tibia Pb (for a 10 μg/ g increase: OR=1.04 (95% CI: 1.01, 1.07)), and nonsignificant increases for patella Pb (for a 10 μg/g increase: OR=1.04 (95% CI: 0.96, 1.12) and blood Pb (for a 5 μg/dL incr ease: OR=1.02 (95% CI: 0.93, 1.13)) ( Navas-Acien et al. 2008 ). Neither metaanalysis focused on low-level Pb exposure; for exam

ple, of the 10 studies included in the Navas-Acien et al. ( 2008 ) meta-analysis, two had mean blood Pb levels over 30 μg/dL, while the other eight were <10 μg/dL.

Bone Pb : Long-term exposure to Pb is often reflected in bone Pb levels, and several studies reported a sig

nificant association of BP with bone Pb but not with blood Pb ( Cheng et al. 2001
, Gerr et al. 2002
, Rothen

berg et al. 2002 ). However, bone Pb must be mea

sured 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 togetherfor overlapping or shared study groups. Most crosssectional studies found an association with bone Pb and hypertension in the general population ( Hu et al. 1996
, Rothenberg et al. 2002
, Elmarsafawy et al. 2006
, Martin et al. 2006 ). One cross-sectional study did not find bone Pb to significantly increase the risk of hypertension, while blood Pb was significantly associated ( Schwartz and Stewart 2000 ).

Blood Pb : Studies of blood Pb and BP do not consis

tently support an association as compared to studies of bone Pb and BP (see Blood Pressure (BP) and Hyper

tension 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 ( Grand

jean et al. 1989
, Moller and Kristensen 1992
, Staessen et al. 1996 ). The prospective studies that did not find a significant association were in groups with higher mean blood Pb levels (between 10 and 15 μg/dL a t baseline in Møller and Kristensen ( 1992 ) and Staessen et al. ( 1996 )) than in the supportive study (4.6 μg/dL in Glenn et al. ( 2003 )). The Glostrup Population Study, which did not support an association, was also larger than the supportive cohort (1,052 subjects in Møller and Kristensen ( 1992 ) vs. 496 in Glenn et al. ( 2003 )). Thus, the studies that do not support an association between blood Pb levels and increased BP are not necessarily underpowered or include less exposedgroups compared to the supportive studies. Twentynine publications of cross-sectional analyses with mean blood Pb levels <15 μg/dL support a small increase in SBP or DBP, while 17 did not support a relationship (some studies had multiple publications, so not all results are independent; see Blood Pressure (BP) and Hypertension section of Appendix C: Cardio

vascular Effects for a complete list of studies consid

ered). Analysis of NHANES 1999-2006 restricted to subjects with blood Pb <10 μg/d L (n=16,222) found a significant association with increased SBP and DBP ( Scinicariello et al. 2011 ). Three prospective studies failed to find an association between blood Pb and hypertension ( Grandjean et al. 1989
, Staessen et al. 1996
, Cheng et al. 2001 ), although one of them did find an asso

ciation with bone Pb ( Cheng et al. 2001 ). Blood Pb was associated with increased prevalence of hyper

tension in 10 cross-sectional studies, but one study found no association ( Kim et al. 2008 ). Black men had a significantly increased risk of hypertensionNTP Monograph on Health Effects of Low-Level Lead 65CardiovascularEffectsTable 6.3: Studies of the association between bone Pb and blood pressure and hypertension used to develop conclusionsRelevancetoConclusionsStudy DescriptionStudyDesignKey Cardiovascular FindingsReferenceEffect496 former Pb workers, USAProspectiveIn men with past occupational Pb exposure (mean blood Pb, 4.6μg/dL),blood and tibia Pb were associated with annual increases in SBP, but notDBP, over 3 years of follow-up.Glenn (2003)Normative Aging Study, USAEffect474 menProspectiveBone Pb was correlated with increased SBP at baseline and an increasedrisk of hypertension 3-6 years later, while blood Pb was not associated.Cheng (2001)619 menCross-sectionalA positive association between pulse pressure and bone Pb in a group ofolder men was modified by genetic variations in the HFE gene.Zhang (2010)593 menCross-sectionalIn a group of older men, tibia Pb was positively association with pulse pressure, but not blood Pb, which was positively correlated with DBP.Perlstein (2007)590 menCross-sectionalBone and blood Pb levels were higher in hypertensives (mean blood Pb,<7μg/dL), and tibia Pb independently increased the risk of hypertension.Hu (1996)471 menCross-sectionalThe relationship between blood Pb, tibia Pb, or patella Pb and hypertensionor BP may be modified by dietary calcium intake in a group of men withlow Pb levels.Elmarsafawy (2006)No effect750 older men (513 withhypertension)Case-controlBone Pb in the patella and tibia was not associated with risk of hypertension in these older men with low blood Pb levels (mean, 6.3μg/dL).Peters (2007)Effect667 third-trimester or postpartum women, USACross-sectionalCalcaneus bone Pb measured postpartum was associated with increasedBP and hypertension during the third trimester (mean blood Pb, 2.3μg/dLpostpartum).Rothenberg (2002)Effect964 adults, Baltimore Memory Study, USACross-sectionalIn these older adults, blood Pb (mean, 3.5μg/dL) was associated with BP,while bone Pb was associated with risk of hypertension.Martin (2006)Effect543 former Pb workers, USACross-sectionalIn men with prior occupational exposure, blood Pb was associated withincreased BP and an increased risk of hypertension, but not tibia or DMSAchelatable Pb.Schwartz (2000)Effect508 young adults, half livednear Pb as children, USACross-sectionalIn young adults, some with childhood Pb exposure, SBP and DBP were significantly increased in those with the highest bone Pb levels (>10μg/g,blood Pb 3.15μg/dL).Gerr (2002)Effect284 women (89 with hypertension), Nurses’ Health StudyCase-controlPatella Pb was associated with an increased risk of hypertension in thesemiddle-age women without occupational exposures (mean, 3μg/dL), buttibia and blood Pb were not significantly associated.Korrick (1999)Epidemiological studies of bone Pb exposure and blood pressure and hypertension are listed by study type and decreasing study size, grouped together for 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.CardiovascularEffects

66 NTP Monograph on Health Eff ects 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) percen

tile) when restricted to 1,767 subjects with blood Pb <10 μg/dL from NHANES 1999-2006 ( Scinicariello et al. 2011 ). Case-control studies of hypertension were also inconsistent: supporting blood Pb ( Bakhtiarian et al. 2006 ), not supporting blood Pb while support

ing bone Pb ( Korrick et al. 1999 ), and not support

ing either blood Pb ( Al-Saleh et al. 2005 ) or bone Pb ( Peters et al. 2007 ).

Pulse Pressure : Higher pulse pressure (the differ

ence between SBP and DBP) is a marker of arterial stiffness, and there was no association with blood Pb in the Normative Aging, but tibia Pb above the median was associated with an increase of 4 mmHg in pulse pressure ( Perlstein et al. 2007
, Zhang et al. 2010 ). In Mexican-American male NHANES subjects with blood Pb <10 μg/dL (n=1925), the re was a sig

nificant 1.4 mmHg increase in pulse pressure per unit increase in the natural log of blood Pb ( Scinicariello et al. 2011 ).

Differential Impacts : Blood Pb and bone Pb may reflect variable cardiovascular effects of Pb with acute effects on transient measures, such as BP, and chronic effects on clinical disease, such as hypertension – the more permanent state of elevated BP ( Navas-Acien et al. 2008 ). Martin et al. ( 2006 ) proposed this hypoth

esis when they reported a significant association between blood Pb and BP as well as between bone Pb and hypertension. A prediction model for bone Pb based on the Normative Aging Study was developed by Park et al. ( 2009b ). When it was applied to data from NHANES III, they found relatively more signifi

cant associations between estimated bone Pb and hypertension ( Park et al. 2009b ). This data should be considered cautiously because it was developed with a new method for modeling exposure. However, it should be noted that the model-building Normative Aging Study population only included older men, and factors such as age, menopause, and past pregnan

cies are associated with the mobilization of bone Pb ( Symanski and Hertz-Picciotto 1995 ).

Modifiers : Blood pressure itself is a transient measure influenced by important cofactors that may modify an association with Pb (see Section 6.4 Susceptible Pop

ulations and Modifiers of Pb Exposure ). The increase in BP that is supported by the data is 1-2 mmHg per doubling of blood Pb, and on a population basis the impact is likely to be larger in susceptible populations such as pregnant women or individuals with a par

ticular metabolic gene variant. Pregnancy puts women at greater risk of hyper

tension, which can contribute to preeclampsia and other complications. The mobilization of bone Pb during pregnancy ( Gulson et al. 1997
, Rothenberg et al. 2000 ) (see further discussion in Section 3.4 Modi

fiers of Pb Exposure ) may contribute to the more consistent association of Pb exposure with hyper

tension and the greater magnitude of the change in BP during pregnancy (see Table 6.4 ). The change (increase) in blood Pb levels during pregnancy was associated with hypertension during pregnancy in a prospective study ( Sowers et al. 2002 ); similarly, maternal blood Pb levels during pregnancy were associated with hypertension in cross-sectional stud

ies ( Rabinowitz et al. 1987
, Yazbeck et al. 2009 ) and a case-control study ( Vigeh et al. 2004 ). One study did not find an association between umbilical cord blood Pb and hypertension in the mother but did find a significant association with maternal SBP and DBP before delivery ( Wells et al. 2011 ). All of these studies had mean blood Pb levels <10 μg/dL, and two of the supportive studies were had mean Pb levels <2 μg/dL ( Sowers et al. 2002
, Yazbeck et al. 2009 ). Additional studies in pregnant women support an association between higher blood Pb and higher BP ( Rothenberg et al. 1999
, Magri et al. 2003 ) and between higher bone Pb and higher BP ( Rothenberg et al. 2002 ). Women experiencing menopause may be at an increased risk due to mobilization of bone Pb stores that may be associated with periods of demineralization; increased blood Pb levels have been demonstrated in postmenopausal women in several studies (e.g., Silbergeld et al. 1988
, Syman

ski and Hertz-Picciotto 1995
, Webber et al. 1995
, Korrick et al. 2002 ). In NHANES III, among women 40-59 years of age untreated for hypertension, the association between blood Pb and hypertension was stronger in postmenopausal women, with statisti

cally 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 womenNTP Monograph on Health Effects of Low-Level Lead 67Table 6.4: Studies of Pb and blood pressure and hypertension during pregnancy used to develop conclusionsRelevancetoConclusionsStudy DescriptionStudyDesignKey Cardiovascular FindingsReferenceEffect705 pregnant women, USAProspectiveChange in blood Pb concentration during pregnancy (mean, 1.2μg/dL)was associated with hypertension in pregnancy, including the seriouscomplications of preeclampsia and toxemia.Sowers (2002)Effect3,851 women at birth of child, USACross-sectionalThere was an increase in women’s BP during labor with increasedumbilical cord blood Pb, as well as an increased risk of pregnancyhypertension from low Pb levels (6.3μg/dL), but not preeclampsia.Rabinowitz (1987)Pregnant Women, Los Angeles, USAEffect1,627 pregnant womenCross-sectionalIn the third trimester of pregnancy, increased blood Pb was associatedwith increased BP only in immigrant women, primarily Latina (meanblood Pb, 2.3μg/dL).Rothenberg (1999)667 third trimester or postpartumwomenCross-sectionalPostpartum calcaneus bone Pb was associated with increased BP andhypertension during the third trimester (mean blood Pb, 2.3μg/dLpostpartum).Rothenberg (2002)Effect971 pregnant women, EDEN Study,FranceCross-sectionalBlood Pb levels in the second trimester (mean, 1.9μg/dL) were correlated with BP before and after 36 weeks gestation and increased therisk of pregnancy induced hypertension, particularly in parous women.Yazbeck (2009)Effect285 pregnant women, BaltimoreTHREE Study, USACross-sectionalUmbilical cord blood Pb of the child was associated with increasedBP in the mother during labor and delivery (Q4 ≥ 0.96μg/dL vs. Q1≤ 0.46μg/dL), but not with other BP-related pregnancy conditions.Wells (2011)Effect143 third trimester primigravidwomen, MaltaCross-sectionalBlood Pb during the third trimester was higher in pregnant womenwith hypertension during pregnancy (mean, 9.6 vs. 5.8μg/dL) andcorrelated with SBP and DBP in all pregnant women.Magri (2003)Effect110 pregnant women, half withgestational hypertension, IranCase-controlBlood Pb at delivery was higher in women with hypertension duringpregnancy (5.7 vs. 4.8μg/dL), but Pb levels did not correlate with BPin the hypertensive women.Vigeh (2004)Epidemiological studies of Pb exposure and blood pressure and hypertension during pregnancy are listed by study type and decreasing size, grouped together 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.68 NTP Monograph on Health E ffects of Low-Level Lead were around 1.5 and were not statistically significant. Other, smaller studies found no association between blood Pb and BP or hypertension in postmenopausal women ( Pizent et al. 2001
, Al-Saleh et al. 2005 ). Children are at greater risk of Pb exposure due to early hand-to-mouth behaviors (see further dis

cussion in Section 3.0 Exposure ). Few studies evalu

ating the effects of Pb on BP have been conducted in children (see Table 6.5 ). Young adults with child

hood Pb exposure had higher bone Pb and 3-4 mmHg higher SBP and DBP (>10 μg/dL vs. <1 μg/g, p<0.05) ( Gerr et al. 2002 ). In the Oswego Children’s Study, umbilical cord blood Pb levels were associated with BP at 9.5 years of age, and early-childhood blood Pb (mean age, 2.6 years) was associated with increased BP in response to acute stress tasks at 9.5 years of age – particularly in children with low socioeconomic status ( Gump et al. 2005
, Gump et al. 2007 ). Other studies of blood Pb in children did not find an effect on BP ( Factor-Litvak et al. 1996
, Factor-Litvak et al. 1999
, Chen et al. 2006 ). The adult origin of disease from childhood Pb exposure has not been sufficiently studied to inform a conclusion on cardio vascular risks from early or chronic Pb exposure. While most of the literature supports a role for Pb in risk of hypertension, the definition of hyper

tension is not consistent across studies. The current standard is ≥140 mmHg SBP and/or ≥90 mmHg DBP, but several studies used a higher ( Grandjean et al. 1989
, Apostoli et al. 1990
, Bakhtiarian et al. 2006
, Elmarsafawy et al. 2006 ), lower ( Al-Saleh et al. 2005 ), or “borderline” (140-159 mmHg SBP and/or 91-94 mmHg DBP) ( Staessen et al. 1996 ) definition of hyper

tension. Studies also differed by how subjects taking anti-hypertensive medication were included, with one study excluding these subjects from analyses of BP ( Scinicariello et al. 2010 ) and several considering subjects hypertensive based only on medication use ( Hu et al. 1996
, Staessen et al. 1996
, Nash et al. 2003
, Al-Saleh et al. 2005
, Muntner et al. 2005
, Martin et al. 2006
, Scinicariello et al. 2010 ).



### Summary of Support for Conclusions on BP and Hypertension Animal studies provide strong evidence for low-level Pb elevating BP in humans and contributing to the onset of hypertension, even after the exposure to Pb has stopped ( U.S. EPA 2006 pg 5-103
, ATSDR 2007 pg 28 ). In rats, blood Pb levels as low as 2.15 μg/dL sho wed significant increases in both SBP and DBP compared to unexposed rats, while exposures resulting in blood Pb levels >29 μg/dL did not show further increases in BP ( Tsao et al. 2000 ). Many in vivo and in vitro studies sup

port oxidative stress as the mechanism by which Pb con

tributes to the pathogenesis of hypertension ( see U.S. EPA 2006 for further review of animal and mechanistic studies ). Experimental animals do not show consistent dose-dependent increases in risk of hypertension: low, but not high, levels cause hypertension in some mod

els ( U.S. EPA 2006 pg 5-124 ). This nonmonotonic (or bi-phasic) relationship could partially explain inconsis

tency observed in human studies, where studies with mean blood Pb levels <5 μg/dL wer e generally more supportive of a relationship with BP and hypertension (see Blood Pressure (BP) and Hypertension section of Appendix C: Cardiovascular Effects). The conclusion of sufficient evidence for a Pbrelated increase in BP and risk of hypertension is based on a large body of literature in humans, with significant associations that are more consistently found with bone Pb as a measure of exposure than with blood Pb.There is a small but sufficient literature supporting Pbrelated increases in hyper tension during pregnancy, while there is inadequate evidence for Pb effects on BP or hypertension in children. The NTP’s conclusions for sufficient evidence for BP and hypertension at blood Pb levels <10 μg/dL expand the conclusions of EPA’s 2006 AQCD for Pb ( U.S. EPA 2006 ) and ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ).



### 6.3.2 Heart Rate Variability There is inadequate evidence to evaluate a potential association between Pb exposure and heart rate vari

ability (HRV). HRV reflects sympathetic (low frequency only) and parasympathetic (high and low frequency) autonomic nervous system function, with decreases in variability indicating abnormal autonomic function ( Park et al. 2006 ). The literature contained only four publications of Pb and HRV with mean blood Pb levels <10 μg/dL, and the results were not consistent ( Jhun et al. 2005
, Park et al. 2006
, Park et al. 2008
, Gump et al. 2011 ). In the Oswego Children’s Study, concurrent blood Pb in children 9-11 years of age (median blood Pb, 0.94 μg/dL ) was significantly associated with impaired autonomic response to acute stress tasks as evaluated by HRV ( Gump et al. 2011 ). In adults there was an indication that Pb may modify the effect of other metals ( Jhun et al. 2005 ) or air pollution ( ParkNTP Monograph on Health Effects of Low-Level Lead 69Table 6.5: Studies of childhood Pb exposure and BPRelevance toConclusionsStudy DescriptionStudyDesignKey Cardiovascular FindingsReferenceOswego Children’s Study, USAEffect122 childrenProspectiveCord blood Pb levels (mean, 3μg/dL) were associated with increasedSBP at 9.5 years old, while childhood Pb levels (mean, 4.6μg/dL at 2.6years old) were associated with an increased DBP, decreased stroke vol-ume, and increased total peripheral resistance response to acute stress.Gump (2005)122 childrenProspectiveFamily socioeconomic status interacted with blood Pb to increase BPand may interact with blood Pb to increase total peripheral resistanceresponse to acute stress tasks in these children with low blood Pb(mean, 4.6μg/dL at 2.6 years old).Gump (2007)140 children, 9-11 years oldCross-sectionalConcurrent blood Pb (median, 0.94μg/dL) was not associated with BPor BP responses to acute stress in these children, but blood Pb wasassociated with measures of impaired cardiac function in response toacute stress tasks.Gump (2011)No effect780 children with moderatelyhigh Pb, half treated with suc-cimer, USACross-sectionalIn these children with Pb exposure (20-44μg/dL), there was no associa-tion between blood Pb and BP, including after 5 years of follow-up whenmean blood levels were 8μg/dL. Chelation of Pb with succimer had noeffect on BP.Chen (2006)Effect508 young adults, half livednear Pb as children, USACross-sectionalIn young adults, some of whom had childhood Pb exposure, SBP andDBP was significantly increased in those with the highest bone Pb levels(>10μg/g, blood Pb 3.15μg/dL).Gerr (2002)No effect144 children in the town unex-posed to Pb; Pristina, KosovoCross-sectionalFor the children residing in the town without Pb exposure, the smallpositive correlation of blood Pb with BP was not statistically significant.Factor-Litvak (1996)Epidemiological studies of childhood Pb exposure and blood pressure and hypertension are listed by study type and decreasing size, grouped together for overlappingor shared study groups.Abbreviations:BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure.70 NTP Monograph on He alth Effects of Low-Level Lead et al. 2008 ) on HRV. The EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) mentions HRV as a possible inter

mediary between Pb exposure and cardiovascular mortality, and HRV is not considered in the ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ).



### 6.3.3 Electrocardiogram Abnormalities There is limited evidence for Pb effects on electrocar

diogram (ECG) abnormalities. The Normative Aging Study supports a role for bone Pb and ECG abnormali

ties 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 relation

ships ( Park et al. 2009a ). The Oswego Children’s Study found that early-childhood blood Pb and concurrent blood Pb were associated with decreased stroke volume and increased total peripheral resistance in response to acute stress tasks at 9.5 years of age, espe

cially in subjects with lower socioeconomic status who had higher blood Pb (overall mean, 4.6 μg/dL at age 2.6) ( Gump et al. 2005
, Gump et al. 2007
, Gump et al. 2011 ). The studies of ECG abnormalities by Cheng et al. ( 1998 ) and Gump et al. ( 2005 ) were included in the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and the ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ), but no conclusions were reached.



### 6.3.4 Clinical Cardiovascular Disease There is limited evidence that blood Pb levels <5 μg/dL are associated with clinical cardiovascular disease (see Table 6.6 and Clinical Cardiovascular Disease sec

tion of Appendix C: Cardiovascular Effects). A positive association has been reported between blood Pb level and several related cardiovascular diseases, includ

ing peripheral arterial disease and coronary artery disease, as well as blood flow measures indicative of atherosclerotic vascular resistance. For cardiovascular disease in general, particu

larly conditions exacerbated by increases in BP, there was an increased risk from Pb exposure. In large studies that found a relationship between Pb and BP, Pb was also associated with an increased incidence of coronary artery disease (Normative Aging Study: ( Jain et al. 2007 )) and prevalence of peripheral artery disease (NHANES: ( Navas-Acien et al. 2004
, Muntner et al. 2005
, Guallar et al. 2006 )), while in the Glostrup Population Study there was no association between Pb and BP or cardiovascular disease ( Moller and Kris

tensen 1992 ). In prospective analyses, the Normative Aging Study reported an increased risk of coronary heart disease (myocardial infarction or angina) with blood Pb (log blood Pb adjusted HR=1.45 (95% CI: 1.0 1, 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 pro

spective Glostrup Population Study in Denmark with a mean blood Pb at baseline of 11.6 μg/dL f ailed to find an increased risk of coronary heart disease or cardio

vascular disease ( Moller and Kristensen 1992 ). A large cross-sectional study in Korea with low blood Pb (geometric mean, 6 μg/dL) f ound no increased risk for coronary heart disease or cerebral vascular disease ( Kim et al. 2008 ). Two cross-sectional studies with mean blood Pb levels >10 μg/d L do support a relationship between blood Pb and coronary heart dis

ease and stroke ( Pocock et al. 1988
, Schwartz 1991 ). In cross-sectional studies of peripheral artery disease, risk increased with blood Pb in NHANES 1999-2002 studies with very low Pb levels (mean, 1.6-2.1 μg/dL) ( NavasAcien et al. 2004
, Muntner et al. 2005
, Guallar et al. 2006 ), independent of an unadjusted association with homocysteine level and accounting for renal function ( Guallar et al. 2006 ). Several studies used vascular measures as indi

cators of arterial function in the absence of physiciandiagnosed disease, but there was inadequate infor

mation 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) w as associated with decreased finger blood flow in response to a postural change, consistent with an atherosclerotic effect, but four other measures of cardiac function were not asso

ciated ( 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 photoplethysmo

gram 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/d L), intima-media thickness of the common and carotid arteries was increased with blood Pb, while there was no association with increases in eight other metals tested ( Zeller et al. 2010 ). The associations of blood Pb with these tests of cardiovascular functions haveNTP Monograph on Health Effects of Low-Level Lead 71Table 6.6: Studies of Pb and clinical cardiovascular disease used to develop conclusionsRelevance toConclusionsStudy DescriptionStudyDesignKey Cardiovascular FindingsReferenceNo effect1,052 adults, >40 yearsold, Glostrup PopulationStudy, DenmarkProspectiveAfter 14 years of follow-up, blood Pb levels dropped, but there was no associationwithcoronary heart diseaseorcardiovascular disease(fatal and nonfatal cases)in adults with 11.5μg/dL mean blood Pb at baseline 40 years of age in 1976.Møller (1992)Effect837 men, NAS, USAProspectiveBlood and patella bone Pb were associated with an increased risk ofcoronaryheart diseaselater in life in these older men with low blood Pb levels (mean,6.3μg/dL).Jain (2007)No effect13,043 Pb workers,SHSP, South KoreaCross-sectionalPb workers showed no increased risk ofcoronary heart diseaseorcerebralvascular diseaseat low levels of exposure (5-10μg/dL vs. <5μg/dL).Kim (2008)NHANES (≥ 1999)Effect9,961 adults, 1999-2002Cross-sectionalPeripheral artery diseaseprevalence and risk increased with increasingquartiles of blood Pb (highest ≥2.47μg/dL) in these adults from the generalpopulation.Muntner (2005)4,447 adults, > 40 yearsold, 1999-2002Cross-sectionalBlood Pb was associated withperipheral artery diseasein these older adultswith low levels (mean, 1.95μg/dL) after adjustment, including renal function.Guallar (2006)2,125 adults, > 40 yearsold, 1999-2000Cross-sectionalThese older subjects withperipheral artery diseasehad higher blood Pb, therisk ofperipheral artery diseaseincreased with increasing Pb (highest quartile:>2.9μg/dL).Navas-Acien (2004)Effect420 male bus drivers,Bangkok, ThailandCross-sectionalAging index of second derivative finger photoplethysmogram waveform(SDPTG-AI), an assessment of arterial properties, is correlated with blood Pb inmale bus drivers (mean, 6.3μg/dL) and may be an independent cardiovascularrisk factor.Kaewboonchoo(2010)Effect197 women, ARFYS,AustriaCross-sectionalIntima-media thickness of the common and carotid arterieswas increased atvery low levels of Pb (highest tertile = >0.82μg/dL).Zeller (2010)Effect128 ceramic painters,JapanCross-sectionalIncreases in blood Pb were associated with decreases in postural changes infinger blood flow volumeconsistent with an atherosclerotic effect, althoughmost of the subjects had Pb levels >10μg/dL and other cardiac function testswere not associated.Ishida (1996)Effect130 myocardial infarction patients, 61 controls, PakistanCase-controlPatients admitted formyocardial infarctionhad higher hair Pb levels, increas-ing for second and thirdmyocardial infarction, and survival of thirdmyocardialinfarctiondecreased with higher hair Pb.Afridi (2010)Epidemiological studies of Pb exposure and cardiovascular morbidities are listed by study type and decreasing size, grouped together for overlapping or shared study groups.Abbreviations:ARFYFS, Atherosclerosis Risk Factors in Young Females Study NAS, Normative Aging Study (Boston area, began in 1963 by the Veterans Administration);NHANES, National Health and Nutrition Examination Survey; SHSP, Special Health Surveillance Program.72 NTP Monograph on Health E ffects of Low-Level Lead not been replicated, but they suggest a role for Pb in early hallmarks of impaired cardiovascular function without a diagnosis of clinical cardiovascular disease.



### Summary of Support for Conclusions on Clinical Cardiovascular Disease The EPA’s 2006 AQCD presents a small animal litera

ture supporting an atherogenic effect of chronic Pb exposure, as well as impacts on vascular tissue and smooth muscle cells ( see U.S. EPA 2006 for further review of these studies ). They reported effects of Pb as conducive to thrombosis, hyperlipidemia, arte

riosclerosis, and vascular remodeling. The human data are consistent with these findings but diverse in scope, hampering the ability to form conclusions on specific cardiovascular disease endpoints. The NTP’s conclusion of limited evidence for clinical cardiovascular disease is based on a hetero

geneous group of related cardiovascular outcomes in studies that mostly found significant effects associ

ated with blood Pb <5 μg/dL.



### 6.3.5 Cardiovascular Mortality There is limited evidence that blood Pb levels <10 μg/dL are associated with increased mortality from cardiovascular causes (see Table 6.7 and Car

diovascular Mortality section of Appendix C: Cardio

vascular Effects). A association between increased cardiovascular mortality and increased blood Pb was supported by three prospective studies but was not supported by two prospective studies, one of which reported a significant association with bone Pb. One of the supportive studies had a mean blood Pb level above 10 μg/dL (12.64 μg/dL) ( Moller and Kristensen 1992 ), and one reported mean blood Pb levels of 2.58 μg/dL ( Menke et al. 2006 ). Large studies that found associations between Pb and BP also indicated an increased risk of mortal

ity from cardiovascular causes. In NHANES III, after 12 years of follow-up using the National Death Index, there was increased mortality associated with base

line blood Pb levels ( Menke et al. 2006
, Schober et al. 2006 ). In the Normative Aging Study, bone Pb, but not blood Pb at mean Pb level of 5.6 μg/dL, w as associated with BP and cardiovascular mortality ( Weisskopf et al. 2009 ). In the Glostrup Population Study, there was no association between blood Pb and BP, cardio vascular disease, or total mortality after 14 years of follow-up ( Moller and Kristensen 1992 ). While Pb levels were not associated with incidence of myocardial infarction, subjects who died of a third myocardial infarction had significantly higher hair Pb levels ( Afridi et al. 2010 ).



### Summary of Support for Conclusions on Cardiovascular Mortality Mortality from cardiovascular causes is not addressed in the EPA’s 2006 AQCD summary of the animal data. The conclusion of limited evidence for Pb in cardio

vascular mortality is based on consideration of the three studies (two of which used the same NHANES III sample) with a significant effect of blood Pb and the two studies that did not find an association with blood Pb levels. The NTP’s conclusions for limited evi

dence for cardiovascular mortality at blood Pb levels <10 μg/dL expands upon the conclusion from ATSDR’s Toxicological Profile ( ATSDR 2007 ) on increased cere

brovascular mortality.



### 6.4 Susceptible Populations and Modifiers of Pb Exposure Segments of the population that are more susceptible to health effects of Pb are discussed more exten

sively in Section 3.0 Exposure . It is unknown whether chronic exposure and other cardiovascular risk factors can modify the relationship between Pb and BP, put

ting some portions of the population at greater risk of cardiovascular disease. These other factors may also impair the ability to detect an association of Pb with BP in some general population studies, even those with higher Pb levels. This concept was proposed by Orssaud et al. ( 1985 ): “The increase in blood lead con

centration parallels the increase in blood pressure until some limit value, so that such a trend is apparent only when other factors (such as age) do not competitively increase blood pressure by greater amounts..

Susceptible Populations : Pb exposure may dispro

portionately affect populations with preexisting con

ditions that can be exacerbated by a small increase in BP (see Section 7.0 Renal Effects ). A prospective study of dialysis patients found significantly increased cardiovascular mortality over 18 months of follow-up for the middle range of Pb levels (second tertile, 8.5- 12.6 μg/dL: HR=3.7 (95% CI: 2.1, 6.5)) and high levels of Pb (third tertile, >12.6 μg/dL: HR=9.7 (95% CI: 2.1, 23.3)) compared to the low Pb range (first tertile, <8.5 μg/dL) ( Lin et al. 2011 ).NTP Monograph on Health Effects of Low-Level Lead 73Table 6.7: Studies of Pb and cardiovascular mortality used to develop conclusionsRelevance toConclusionsStudy DescriptionStudyDesignKey Cardiovascular FindingsReferenceNHANES IIIEffect13,946 adultsProspectiveMortality was increased with higher Pb levels for death from all causes,cardiovascular disease, myocardial infarction, and stroke – but not can-cer – for these adults from the general population with low blood Pb levels(geometric mean=2.58μg/dL) and up to 12 years of follow-up.Menke (2006)9,757 adults, >40 years oldProspectiveIn this cohort of older NHANES III participants followed for up to 12 years,blood Pb was associated with higher mortality from all causes, cardiovas-cular disease, and cancer, at blood Pb levels of 5-10μg/dL.Schober (2006)No effect1,052 adults, 14-year follow-up,Glostrup Population Study,DenmarkProspectiveIn adults with 11.5μg/dL mean blood Pb at 40 years old, there was noassociation with all-cause mortality after 14 years of follow-up, while therewere reductions in blood Pb levels over this time.Møller (1992)Effect927 dialysis patients, 18 monthsof follow-up, TaiwanProspectiveIn these hemodialysis patients, baseline blood Pb >12.64μg/dL (median,16.4μg/dL) was associated with higher all-cause, cardiovascular cause, andinfection cause mortality over 18 months of follow-up.Lin (2011)Effect860 men in NAS with bone Pb,1,235 with blood Pb (1994) andfollow-up (2007)ProspectiveBone Pb >35μg/g increased the risk of mortality from all causes and fromcardiovascular causes, but not cancer mortality. Blood Pb was not associ-ated with mortality (highest >6μg/dL).Weisskopf (2009)Epidemiological studies of Pb exposure and cardiovascular mortality are listed by decreasing size, grouped together for overlapping or shared study groups.Abbreviations:NAS, Normative Aging Study (Boston area, began in 1963 by the Veterans Administration); NHANES, National Health and Nutrition ExaminationSurvey.74 NTP Monograph on Health E ffects of Low-Level Lead As discussed in Section 6.3.1 Blood Pressure (BP) and Hypertension , pregnant women, meno

pausal women, and children may be at greater risk of Pb related increases in BP (see further discussion in Section 3.4 Modifiers of Pb Exposure ). The evidence for an effect of Pb on BP in children is limited, but blood Pb at 2 years of age was also associated with ECG abnormalities at 9.5 years of age, particularly in subjects with lower socioeconomic status ( Gump et al. 2005
, Gump et al. 2007 ).

Modifiers : Age is associated with higher BP and increased risk of cardiovascular disease, and Pb levels are also strongly correlated with age ( Den Hond et al. 2002 ). It is unclear if this is an effect of higher Pb exposures in earlier eras in this group, or if the elderly are more susceptible to cardiovascular effects of Pb (see further discussion in Section 3.4 Modifiers of Pb Exposure ). Many studies adjusted for age in their analyses, while others did analyses within specific age groups (stratified analyses). One study of sub

jects over age 75 years of age found no association between blood Pb and BP ( Nordberg et al. 2000 ). Gender and ethnicity are also correlated with Pb exposure and cardiovascular risk and are frequently adjusted for in analyses. Many general population studies found higher blood Pb, higher BP, and more hypertension in non-Caucasian groups ( Rothenberg et al. 1999
, Den Hond et al. 2002
, Scinicariello et al. 2010 ). Men generally have higher blood Pb and BP than do women ( Staessen et al. 1990
, Hense et al. 1993
, 1994
, Chu et al. 1999
, Den Hond et al. 2002 ). Many occupational studies only included male sub

jects, even in those with low occupational Pb expo

sure (mean Pb levels, <10 μg/dL) ( Orssaud et al. 1985
, Sharp et al. 1990
, Schuhmacher et al. 1994
, Wolf et al. 1995
, Sirivarasai et al. 2004
, Kaewboonchoo et al. 2007 ), while only the Nurses’ Health Study focused on female workers ( Korrick et al. 1999 ). Numerous other studies included gender in their adjustment factors. Genetic variation is an important biological fac

tor that can characterize a susceptible population and modify the relationship between an exposure and disease via altered absorption or metabolism. Unlike other relevant cofactors such as gender and age group, genotype is almost always blinded from subjects and investigators and so is less likely to bias exposure or ascertainment. In the three studies that included genetic variants in evaluation of Pb and cardiovascular effects, the genotyped polymorphisms were not independent risk factors for increased pulse pressure, hypertension, or QT prolongation, but car

riers of genetic variants had stronger associations between Pb and effects ( Park et al. 2009a
, Scini

cariello et al. 2010
, Zhang et al. 2010 ). These genetic modifications of the effect of Pb on cardiovascular outcomes have not been sufficiently studied to judge their reproducibility. However, if genetic variants can modify the impact of Pb exposure, it supports a bio

logical basis for associations between Pb and effects beyond what might spuriously arise by unmeasured confounding factors. Dietary factors may also modify the relation

ship between Pb and BP. People who drank alcohol had higher blood Pb and stronger associations between Pb and BP ( Hense et al. 1994
, Menditto et al. 1994
, Pizent et al. 2001 ). Among black male bus drivers, infrequent caffeine users had a stronger positive relationship between blood Pb and BP than did habitual users ( Sharp et al. 1990 ). There is some indication from the literature that there is an inter

action between Pb and calcium intake ( Dolenc et al. 1993 ), with low calcium related with higher blood Pb ( Pizent et al. 2001 ) and a higher risk of hypertension ( Elmarsafawy et al. 2006 ). However, a 12-week cal

cium supplement intervention had no effect on blood Pb, indicating that any effect of calcium on BP is not via interaction with Pb ( Morris et al. 1990 ).



### 6.5 Conclusions The NTP concludes that there is sufficient evidence for a small, but detectable, increase in BP associ

ated with Pb exposure in groups with mean blood Pb levels <10 μg/dL (see Table 6.8 for complete list of cardiovascular effects conclusions). There is sufficient evidence for an increase in BP and hypertension dur

ing pregnancy at levels <10 μg/dL . There is limited evidence for increased mortality from cardiovascular causes from Pb levels <10 μg/dL. There is limited evi

dence of an increase in early markers of impaired car

diac function (ECG abnormalities) and cardiovascular disease in general. There is inadequate evidence to evaluate Pb effects at levels <10 μg/dL on heart rate variability, specific cardiovascular morbidities, or any cardiovascular effects in children. There is inadequate evidence to evaluate Pb effects at levels <10 μg/dL on hypertension or other cardiovascular diseases in menopausal women.NTP Monograph on Health Effects of Low-Level Lead 75 Bone Pb reflects chronic Pb exposure and is more consistently associated with increased BP, hypertension, cardiovascular disease, and mortality. Not all human studies conducted at low levels of exposure support these associations. The animal data strongly support a causative relationship, even at low levels relevant to human exposure ( e.g., BP increases in rats with blood Pb as low as 2.15 μg/d L Tsao et al. 2000 ). The observed heterogeneity across the human literature may be partially explained by variation in biologically susceptible groups with other Pb-related risk factors for cardiovascular disease, such as age, alcohol, caffeine, or calcium intake, or genetic polymorphisms in metabolic genes. Menopausal women and children may also be at increased risk of cardiovascular effects from Pb expo

sure, but they have been inadequately studied.

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

Health Effect Population Conclusion Blood Pb Evidence Bone Pb Evidence Blood pressure and hypertension Adults Sufficient Yes, <10 μg/dL Yes
Children Inadequate Unclear Yes (one study) Pregnant women Sufficient Yes, <10 μg/dL Not studied Menopausal women Inadequate Unclear Not studied Heart rate variability Adults Inadequate Unclear Yes (one study) Electrocardiogram abnormalities Men Limited No Yes (one study)
Children Limited Yes, <5 μg/dL (one study) Not studied
Clinical cardiovascular disease (general) Adults Limited Yes, <5 μg/dL Yes (one study)

Clinical cardiovascular disease (specific) Adults Inadequate Unclear Yes (one study)

Cardiovascular mortality Adults Limited Yes, <10 μg/dL Yes (one study)76 N TP Monograph on Health Effects of Low-Level Lead THIS PAGE LEFT INTENTIONALLY BLANKNTP Monograph on Health Effects of Low-Level Lead 77 

## 7.0 RENAL EFFECTS

7.1 Conclusions The NTP concludes that there is sufficient evidence that blood Pb levels <5 μg/dL in adults are associated with adverse effects on kidney function adults. With few exceptions, epidemiological studies of the gen

eral population reported associations between blood Pb levels <10 μg/dL and (1) increased risk of chronic kidney disease (CKD) and (2) decreased estimated glomerular filtration rate (eGFR) and creatinine clearance. The associations are typically stronger in people with hypertension or diabetes ( Muntner et al. 2003
, Tsaih et al. 2004 ). The NTP recognizes that an individual with blood levels <10 μg/dL during adult

hood may have had higher blood Pb levels earlier in life, and the role of early-life Pb exposure cannot be discriminated from the role of concurrent blood Pb. Comparatively few studies examined markers of exposure other than blood Pb levels; therefore, it is unknown if blood or bone Pb levels are more consis

tently associated with kidney effects. The data are inadequate to evaluate whether prenatal exposure to Pb is associated with impaired kidney function later in life. No studies were iden

tified that evaluated prenatal blood Pb and kidney function in children or adults. Relatively few studies have assessed kidney measures in children in asso

ciation with low-level Pb exposure. The findings from these studies are less consistent than are studies in adults. Most of these studies also use kidney bio

markers, whose prognostic value for renal function is less clear compared to GFR measures and biomark

ers, such as microalbuminuria, commonly measured in the adult studies. Thus, there is currently inade

quate evidence to conclude that blood Pb <10 μg/dL is associated with impaired kidney function in chil

dren <12 years old. In contrast, there is limited evi

dence that blood Pb levels <5 μg/dL ar e associated with adverse effects on kidney function in children ≥12 years old. A recent study of children and young adults 12-20 years of age in NHANES 1988-1994 with mean blood Pb of 1.5 μg/dL r eported a reduction in eGFR rate per doubling of blood Pb ( Fadrowski et al. 2010 ). The reduction in GFR demonstrated in Fad

rowski et al. ( 2010 ) is consistent with results from adults within NHANES and supports adverse effects on kidney function in children age 12 and over at blood Pb <5 μg/dL. Although the cardiovascular and renal systems are intimately linked, effects are considered sepa

rately in this evaluation because studies generally reported individual effects rather than testing both systems comprehensively. Nevertheless, it is recog

nized that hypertension can contribute to adverse renal effects and that kidney dysfunction can con

tribute to increased blood pressure (BP) and hyper

tension. Cardiovascular and renal effects of Pb may share the same biological mechanisms ( U.S. EPA 2006
, ATSDR 2007 ). As discussed in Section 7.4.2
, the human literature supports a strong association between BP and renal effects of Pb, and multiple studies suggest that people with hypertension are a susceptible population for adverse renal effects of Pb. This interrelationship of effects is also supported in animal models; for example, Pb exposure acceler

ates chronic renal disease by raising BP in male rats ( Roncal et al. 2007 ).



### 7.2 How Conclusions Were Reached Conclusions in the NTP evaluation of Pb-related kidney effects in humans associated with low-level Pb are derived from epidemiological studies with a focus on blood Pb levels <10 μg/dL. F or this evalu

ation we did not consider studies with mean blood Pb >15 μg/dL, because in those studies, the subjects with Pb <10 μg/d L are often used as the referencegroup and are not appropriate for evaluating lowlevel Pb effects. This evaluation focuses on the human data for kidney effects of Pb because there is a relatively large database of human studies for these effects; therefore, the document makes only limited use of the data from laboratory animals to support the human evidence. Major endpoints considered as potential indicators of kidney effects of Pb are listed and briefly described in Section 7.2.1 . This document is not a review of kidney toxicity, and the reader is directed to published reviews for additional back

ground. Key data and principal studies considered in developing the NTP’s conclusions are discussed in detail in Section 7.3 Evidence for Pb-related Effects on Kidney Function . The discussion of each kidney effect begins with a statement of the NTP conclusion whether the specific effect is associated with a blood Pb level <10 μg/dL or <5 μg/dL and the age group in which it is identified (childhood, or adulthood), as well as the timing of exposure associated with the effect (prenatal, childhood, concurrent) when78 NTP Monograph on He alth Effects of Low-Level Lead available. Although the information necessary to sup

port the NTP’s conclusions is presented in Section 7.3
, the complete data set of human studies considered for evaluation of kidney effects of low-level Pb is included in Appendix D: Renal Effects, and individual studies are abstracted for further reference. The NTP made extensive use of recent government evalua

tions of health effects of Pb in the current assessment, and the relevant conclusions of the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ) are briefly described in Section 7.2.2 below.



### 7.2.1 Principal Measures of Kidney Effects Table 7.1 lists a number of kidney endpoints com

monly evaluated in epidemiological studies. The most clinically accepted measure of kidney function is glo

merular filtration rate (GFR), which is the flow rate of filtered fluid through the kidney. The gold standard method of determining GFR is through the use of radionuclide or radiocontrast markers, which is both costly and time consuming. GFR can be approximated by creatinine clearance, which compares creatinine levels in blood and urine to calculate the volume of blood plasma cleared per milliliter of creatinine per unit time. Direct measurement of creatinine clearance requires 24-hour urine collection. There are also a number of equations for estimating GFR or creatinine clearance based on serum biomarkers (e.g., creati

nine, cystatin C) and consideration of other variables such as age, sex, race, or weight. Historically, serum creatinine has been used most often, although serum cystatin C is increasingly being used as an alternative or complementary approach to serum creatinine for estimating GFR. GFR is notoriously insensitive ( Levey et al. 1999 ), and “early biological effect markers” (EBEs), such as N-acetyl-β-D-glucosaminidase (NAG), are thought to be more sensitive because they areoften elevated when GFR measures are not abnormal. However, the validity and reliability of EBEs for long-term prognos

tic value are unclear. The epidemiological studies in children more often assess EBEs for kidney rather than eGFR or creatinine clearance. It should also be noted that the list of biomarkers of EBEs presented in Table 7.1 is not comprehensive and reflects those most commonly reported in the Pb epidemiological studies. Other biomarkers of kidney function con

tinue to be assessed within kidney epidemiology research, especially for acute kidney injury, with recent attention focusing on urinary proteins such as neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and liver-type fatty acid binding protein ( Devarajan 2010
, Tesch 2010 ).



### 7.2.2 Principal Conclusions from the 2006 EPA and 2007 ATSDR Pb Documents The EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ) both concluded that epidemiologic studies support a relationship between Pb exposure kidney effects at lower blood Pb levels ( Table 7.2 ). The EPA states that most studies in general adult and patient populations published between 1986 and 2006 indicate that Pb, at much lower doses than those causing Pb nephropathy, acts as a cofactor with other more established renal risks to increase the risk for renal dysfunction. Other explanations, such as residual confounding or reverse causality, are not likely to account for the observed associations between Pb dose and kidney dysfunction. It should

Table 7.2: Main conclusions for kidney effects in 2006 EPA AQCD for Lead and the 2007 ATSDR Toxicological Profile for Lead

“General population studies are the most important advance in this regard. These studies provide strong evidence that renal effects occur at much lower blood Pb levels than previously recognized. These effects are clinically relevant in U.S. subpopulations who continue to have higher Pb exposure than the general popula

tion. At levels of exposure in the general U.S. population overall, Pb combined with other risk factors, such as dia

betes, hyper tension, or chronic renal insufficiency from non-Pb related causes, can result in clinically relevant effects. Notably, the size of such susceptible populations is increasing in the US due to obesity...The threshold for Pb-related nephro toxic ity cannot be determined based on current data. However, associations with clinically relevant renal outcomes have been observed in popula

tions with mean blood Pb levels as low as 2.2 μg/dL.” (U.S. EPA 2006, pg 6-113)
“The overall dose-effect pattern suggests an increasing severity of nephrotoxicity associated with increasing PbB [blood Pb level], with effects on glomerular filtration evi

dent at PbBs below 20 μg/dL, enzymuria and proteinuria becoming evident above 30 μg/dL, and severe deficits in function and pathological changes occurring in association with PbBs exceeding 50 μg/dL.” (ATSDR 2007, pg 79)NTP Monograph on Health Effects of Low-Level Lead 79RenalEffectsTable 7.1: Commonly used indicators of kidney function in the Pb literature referencesKidneyEndpointMeasurementDescriptionIndication of ImpairedKidney FunctionClinical Indicators of Impaired Kidney FunctionGlomerularfiltration rate(GFR)Serum creatinine (most common)Breakdown product of creatine phosphate in muscles; commonly used measure of GFR (considered less precise thancystatin C); can be influenced by non-kidney function variablesthat affect muscle mass (gender, age, race, weight, diet)↑ serum concentrationSerum cystatin CA cysteine protease inhibitor protein used as an alternative toserum creatinine or complementary measure to estimate GFR↑ serum concentrationeGFR (estimated GFR, based on equations)Modification of Diet in Kidney Disease (MDRD) Study:Clinical standard of estimated GFR based on creatinine but underestimates at levels in normal rangeCKD-Epidemiology Collaboration (CKD-EPI):More recent wayto estimate GFR based on creatinine; better accuracy in normalrange than MDRD↓ eGFRCreatinine clearance (based on timed urinecollections)Cockcroft-Gault:Oldest, estimates creatinine clearance↓ creatinine clearanceBlood urea nitrogenMeasures the amount of nitrogen in blood in the form of urea(a waste product of protein digestion)↑ serum concentration125I-iothalamate, iohexol, and other radioisotopesRadioactive markers used to measure GFR by timed sequentialblood samples or imaging (invasive and time consuming)↓ urinary clearanceIndicators of Early Biological Effect Markers (EBEs)Functionβ2-microblobulin (only validated EBE marker)↑ urine concentrationTotal protein, albumin, low- to intermediatemolecular-weight proteins (e.g., retinol-bindingprotein (RBP)), Clara cell protein, transferrin)↑ urine concentrationBiochemicalor histologicalalterationBiochemical:Urinary eicosanoids,(e.g., prostaglandin E2(PGE2), prostaglandin F2 alpha, 6-keto-pros-taglandin F1 alpha(6-keto-PGF), and thromboxane B2(TXB2)), fibronectinVaries/not necessarily known1(e.g., ↓ urine PGE2, 6-keto-PGF; ↑ TXB2)Histological:Brush border antigen, fibronectin(glomerular fibrosis)CytotoxicityN-acetyl-β-D-glucosaminidase (NAG)Lysosomal enzyme involved in the breakdown of glycoproteins↑ activityOtherUrate/uric acidUrate is a salt derived from uric acid; can build up in the bodywhen uric acid is not adequately metabolized, e.g., in casesof gout↑urine concentration1(Cardenas et al. 1993,Rose and Post 2011).80 NTP Monograph on He alth Effects of Low-Level Lead be noted that the EPA is in the process of revising the AQCD, and the conclusions of the external draft ( U.S. EPA 2012 ) are largely in line with the 2006 AQCD plus additional review of the evidence for reduced kidney function at low blood Pb. The NTP considered the conclusions and data summaries from the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATSDR’s Toxicological Profile for Lead ( ATSDR 2007 ). In general, the NTP concurred with the conclusions and agreed that the data support them.



### 7.3 Evidence for Pb-related Effects on Kidney Function

7.3.1 Kidney Effects in Adults There is sufficient evidence available for an association between current blood Pb levels <5 μg/dL in adults, measured at the time of the study, and reduced kid

ney function in general populations ( Table 7.3 , see also Appendix A: Neurological Effects). Associations between low-level blood Pb and impaired kidney function have been reported in studies assessing participants in NHANES ( Muntner et al. 2003
, Munt

ner et al. 2005
, Navas-Acien et al. 2009 ), the Norma

tive Aging Study ( Payton et al. 1994
, Kim et al. 1996
, Tsaih et al. 2004 ), the Swedish Women’s Health in the Lund Area (WHILA) study ( Akesson et al. 2005 ), and native and nonnative residents in rural Taiwan ( Lai et al. 2008 ). The blood Pb levels associated with kidney effects in these studies were ≤10 μg/dL and <5 μg/dL in the NHANES and WHILA studies. There is no apparent threshold for kidney effects. Significant increases in risk of CKD based on an eGFR <60 mL/min/1.73 m 2 have been reported in NHANES for blood Pb levels of >1.63 μg/dL (adjus ted OR=1.89 (95% CI: 1.09, 3.30) ( Muntner et al. 2005 )) and >2.4 μg/dL (adjus ted 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/d L) were significantly associated with reduced eGFR (adjusted β=-0.2 (95% CI: -0.32
, -0.09 ) ( Akesson et al. 2005 )). No significant associations with blood Pb and either serum creatinine or creatinine clearance were observed in a study of 709 men in the Norma

tive Aging Study (β coefficients not reported) ( Wu et al. 2003 ); however, this study did report a significant association between higher patella Pb and lower creatinine clearance. Higher blood Pb levels were associated with lower crea t­i nine 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 ) con

sidered 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/d L) to the 95th percentile (4.6 μg/dL ) had the same effect on glomerular filtration as an increase in age of 4.7 years or 7 kg/m 2 in body mass index (BMI) ( U.S. EPA 2006 ). A 10-fold increase from 1 to 10 μg/dL w ould result in a 16.2 mL/min decrease in estimated creatinine clearance ( U.S. EPA 2006 ). As discussed below under Section 7.4 Susceptible Populations or Life Stages
, the impacts of Pb on kidney function in people with diabetes, hypertension, or CKD from non-Pb related causes are expected to be higher ( U.S. EPA 2006 ). Many of the studies that support an association between blood Pb and kidney outcomes included statistical adjustments for factors such as age and sex, with studies based on the Normative Aging Study, NHANES, WHILA, and rural Taiwanese groups including additional variables for smoking status and/or alcohol consumption. The significant associations remaining after adjustment suggest that these factors were not sufficient to account for the observed associations between blood Pb and kidney outcomes ( Payton et al. 1994
, Kim et al. 1996
, Muntner et al. 2003
, Tsaih et al. 2004
, Akesson et al. 2005
, Muntner et al. 2005
, Lai et al. 2008
, Navas-Acien et al. 2009 ). Most of these stud

ies also included blood pressure (BP) or hypertension status as an adjustment factor, which is expected to underestimate the association between Pb exposure and kidney effects (i.e., bias towards the null) given the positive relationship that exists between Pb and BP in the general population ( U.S. EPA 2006 ). The studies that were considered equivocal or not supportive of an association typically assessed kidney effect by mea

surement of serum creatinine and did not consider the impact of potential or modifying variables at all ( de Burbure et al. 2003 ) or to the same extent as the stud

ies cited above that assessed GFR or creatinine clear

ance ( Pocock et al. 1984
, Staessen et al. 1990
, Mortada et al. 2004 ). An additional limitation to interpretation of the nonsupportive findings of de Burbure et al. ( 2003 ) is that the average blood Pb levels between the “exposed” and reference groups were quite simi

lar and actually higher in men in the reference group than in men considered exposed based on living near a smelter for ≥8 years (average blood Pb in referents:RenalEffectsTable 7.3: Studies of kidney outcomes in adultsRelevancetoConclusionsStudy DescriptionStudy DesignKey Kidney FindingsReferenceNormative Aging Study, USAEffectMen 43-90 years old; n=744Cross-sectionalCreatinine clearance (natural log (Ln)) was inversely associated with Lnblood Pb (adjusted β (SE) =-0.0403 (0.0198)μg/dL; p=0.0426). Averageblood Pb, 8.1μg/dL (range, <5 to 26μg/dL).Payton (1994)EffectMen 34-88 years old; n=459ProspectiveBlood Pb ≤10μg/dL positively associated with concurrent serum creatinine(β(SE) = 0.060 (0.019); p=0.002), but not with a change in serumcreatinine(β(SE) = 0.039 (0.025); p=0.13).Kim (1996)EffectMen average age of 66 yearsfollowed for 6 years; n=448ProspectiveSignificant association with change in serum creatinine with baselineblood Pb in diabetics (adjusted β(SE) = 0.076(0.023); p<0.05) but notnondiabetics (adjusted β(SE) = 0.006(0.005);p=not significant). Average baseline blood Pb, 6.5μg/dLTsaih (2004)Cadmibel, BelgiumEffectAdults 20-88 years old participating in the Cadmibel study;n=1,981Cross-sectional10-fold increase in blood Pb associated with reduction in creatinine clearance of 10 mL/min (female) to 13 mL/min (male); adjusted OR (95%CI)for 10-fold increase in blood Pb and impaired kidney function = 3.76 (1.37,10.4). Average (range) blood Pb of 11.4 (2.3, 72.5)μg/dL in males and 7.5(1.7,60.3)μg/dL in females.Staessen (1992)NHANES, USAEffectAdults >20 years old included inNHANES 1988-1994; n=15,211total; 4,813 hypertensivesCross-sectionalIncreased risk in hypertensives (but not normotensives) for elevatedserum creatinine (Q2 (2.5-3.8μg/dL) vs. Q1 (0.7-2.4); adjusted OR (95%CI)=1.47 (1.03, 2.10)) and CKD (Q3 (3.9-5.9μg/dL) vs. Q1 (0.7-2.4); adjustedOR (95% CI) = 1.85 (1.32, 2.59)).Munter (2003)EffectAdults ≥20 years of age includedin NHANES 1999-2006; n=14,778Cross-sectionalRisk of having a reduced GFR(defined at <60 mL/minute/1.73 m2) washigher for blood Pb of >2.4μg/dL vs. ≤1.1μg/dL (adjusted OR=1.56 (95% CI:1.17, 2.08); ptrend<0.001); significant trend for albuminuria (ptrend≤0.001).Navas-Acien (2009)EffectAdults 18-75 years old fromNHANES 1999-2002; n=9,961Cross-sectionalIncreased risk for CKD (GFR <60 mL/min)associated with blood Pb of>1.63μg/dL (Q3 (1.63-2.47μg/dL) vs. Q1 (<1.06μg/dL); adjusted OR(95%CI) = 1.89 (1.09, 3.30)).Muntner (2005)PatientsEffectCKD Taiwanese patients 25-82years old followed for 4 years;n=121Prospective1μg/dL higher blood Pb at baseline associated with a 4.0 mL/min/1.73m2reduction in eGFR over 4 years. Average (range) blood Pb, 4.2μg/dL(1-13.4μg/dL).Yu (2004)EffectChronic renal insufficiencypatients 25-80 years old followed for 2 years; n=202ProspectiveBaseline chelatable Pb was significantly associated with risk for achieving anincrease 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.Lin (2003)

NTP Monograph on Health Effects of Low-Level Lead 81RenalEffects

82 N TP Monograph on Health Effects of Low-Level LeadTable 7.3:Studies of kidney outcomes in adults(continued)RelevancetoConclusionsStudy DescriptionStudy DesignKey Kidney FindingsReferenceEffectCKD patients 30-80 years old followed for 2 yearsProspectiveBaseline chelatable Pb was significantly associated with risk for achieving anincrease 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; 16patients on chelation therapy during months 24-51 had better GFRoutcomes.Lin (2006a)EffectDiabetes patients 33-79 yearsold followed for 1 yearProspectiveBaseline chelatable Pb was significantly associated with risk for achieving an increase in serum creatinine to 1.5 times baseline (HR(95%CI) = 1.01(1.01, 1.02)). Average (range) blood Pb at baseline, 6.5(1.9-19.1)μg/dL; 15 patients on 3-month chelation therapy during months13-24 had better GFR outcomes.Lin (2006b)OtherEffectAdult women from WHILA studyin Sweden; n=820Cross-sectionalInverse association with GFR (β (95% CI) = -0.20 (-0.32, -0.09)) and creatinine clearance (β (95% CI) = -0.18 (-0.30, -0.06)). Mean (5-95% percentiles)blood Pb, 2.2 (1.1, 4.6)μg/dL. No association with NAG or α1-microglobulin.Akesson (2005)EffectAdult native and nonnative ruralTaiwanese; n=2565Cross-sectionalIncreased risk of serum creatinine >1.2 mg/dL for blood Pb >7.5 versus≤ 7.5μg/dL (adjusted OR=1.92 (95%CI:1.18,3.10)).Lai (2008)No effectAdults 18-51 years old livingnear two smelters in France;n=300 and 300 age/gendermatched referentsCross-sectionalNo difference in any kidney parameters in adults living in reference area(average blood Pb: males, 7.1μg/dL; females, 4.2μg/dL) and polluted area(average blood Pb: males, 6.8μg/dL; females: 5.3μg/dL) (serum creatinine,total protein, albumin, transferrin, β2-microblobulin, RBP, brush borderantigen, and NAG).de Burbure (2003)EquivocalMen 40-59 years old participating in the Regional Heart Studyin England; n=7,364Cross-sectionalBlood Pb associated with log-transformed serum urate(β=0.06) andserum urea (β=-0.05); no association with serumcreatinine. Blood Pb levels ranged from <12.4 to 37.3μg/dL (authors considered the magnitudeof the changes to be small and unlikely to be of biological importance)Pocock (1984)EquivocalAdult London civil servants inEngland 37-58 years old; n=531Cross-sectionalIn males, significant correlation between serum creatinine and logblood Pb (r=0.10, p=0.04). In females, no correlation with serum creatinine and log blood Pb (r=0.03, p=not significant).Staessen (1990)No effectMen 25-38 years old in Egypt;n=35 smokers, 33 nonsmokersCross-sectionalNo significant correlations were found between Pb and markers of kidney damage in smokers (14.4μg/dL) or nonsmokers (10.2μg/dL).Mortada (2004)Epidemiological studies of blood Pb exposure and kidney function are listed by study are listed by study type and decreasing study size, grouped together for 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, standarderror; WHILA, Women’s Health in the Lund Area.NTP Monograph on Health Effects of Low-Level Lead 83 males, 7.1 μg/dL; females, 4.2 μg/dL; vs. “exposed”: males, 6.8 μg/dL; females, 5.3 μg/dL). Most of the studies summarized in Table 7.3
, were cited in the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and considered in relation to potential reverse causality, which would occur if impaired kidney excre

tion leads to less efficient elimination of Pb, and thus higher estimates of internal Pb exposure, resulting in a bias towards detecting associations between Pb and impaired kidney function. The EPA did not consider potential reverse causality to be sufficient to explain the associations between Pb and kidney outcomes ( U.S. EPA 2006 ). There are three lines of evidence that argue against reverse causality as an explanation link

ing higher blood Pb levels and reduced kidney func

tion: (1) there is no experimental evidence supporting reverse causality; (2) there is evidence against reverse causality; and (3) there is no evidence that renal failure changes blood Pb concentrations. Evidence against reverse causality is found in (1) direct bone biopsies, (2) EDTA (ethylenediaminetetraacetic acid) chelation tests, and (3) blood Pb measurement per

formed in subjects without renal failure, with renal failure of known non-Pb etiology, and with chronic Pb nephropathy, indicating that renal failure per se does not increase bone Pb stores or blood Pb and does not mobilizable Pb ( Van de Vyver et al. 1988 ). The absence of excessive Pb retention caused by renal failure is fur

ther supported by the finding that EDTA mobilizable Pb in patients with Pb-associated renal failure is the same as in subjects without renal failure ( Emmerson 1973
, Batuman et al. 1983 ). Additional data against reverse causality comes from the longitudinal study by Yu et al. ( 2004 ) of CKD patients in Taiwan, where both baseline blood and EDTA-chelatable Pb levels predicted kidney function decline over 4 years. Also, two publications from the Normative Aging Study report associations between blood Pb and serum creatinine across the entire range of serum creatinine ( Kim et al. 1996
, Tsaih et al. 2004 ), including at levels in the normal range where reverse causality would not be occurring. Other evidence considered in the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ), cited as an April 12, 2006, personal communication from Agneta Ǻkesson to Virginia Weaver, is that higher urine Pb
was associated with lower estimated creatinine clear

ance in Swedish women in the WHILA study. Urinary excretion of Pb should decrease as kidney function declines. 

### Summary of Support for Conclusions Data from animal studies provide strong support for an association of Pb-associated kidney toxicity, including histopathological changes and decreased glomerular filtration rate (GFR), with chronic expo

sure that results in high blood Pb levels (>40μg/dL in rats; see U.S. EPA 2006 for recent reviews of the animal data
, ATSDR 2007 ). Rodent studies also sup

port hyperfiltration, or increased GFR as part of an early phase of kidney injury ( e.g., Khalil-Manesh et al. 1992b ). Many in vivo and in vitro studies sup

port oxidative stress as the mechanism by which Pb contributes to the pathogenesis of kidney disease ( see U.S. EPA 2006 for further review of animal and mechanistic studies ). Although animal data support a role for oxidative stress and a potential role for metallothionein in kidney effects associated with Pb exposure, the animal studies are generally at higher Pb exposure levels (20-60 μg/dL) than the blood Pb levels associated with decreased GFR in humans (<10 μg/dL). The human data include multiple studies that reported an association between blood Pb levels <10 μg/dL and increased risk of CKD, as well as inverse associations with GFR and creatinine clearance in the general population and even stronger evidence in people with hypertension or diabetes. A number of studies reported effects at blood Pb levels in the 2-3 μg/dL range (e.g., Akesson et al. 2005
, Muntner et al. 2005
, Navas-Acien et al. 2009 ). Collectively, these data provide sufficient evidence that blood Pb levels <5 μg/dL are associated with adverse effects on kid

ney function in adults. The NTP recognizes that blood levels measured during adulthood in this range do not preclude the possibility that an individual might have had past exposure to higher blood levels. Although several studies of groups with high occupational Pb exposure have demonstrated an association between elevated bone Pb levels and serum creatinine (e.g., Weaver et al. 2003
, Weaver et al. 2005
, Weaver et al. 2009 ), few studies of groups with low blood Pb levels have included bone Pb or other measures of expo

sure. Currently, the only data on bone Pb and kidney effects in the general population are from Tsaih et al. ( 2004 ) on men followed up in the Normative Aging Study for 6 years. In this study, baseline tibia Pb, but not patella Pb, was significantly associated in diabet

ics with baseline serum creatinine, follow-up serum creatinine, and changes in serum creatinine. Tibia Pb was also associated with a change in serum creatinine84 NTP Monograph on He alth Effects of Low-Level Lead in men with hypertension. No significant associations were reported in nondiabetics or normotensives. The associations were stronger for tibia Pb than for blood Pb, measured either at baseline or follow-up.



### 7.3.2 Occupational Exposures Assessment of kidney effects at higher blood Pb, such as those experienced in occupational cohorts, is beyond the scope of this evaluation but is addressed in the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ), with an expanded discussion in EPA’s current external review draft document ( U.S. EPA 2012 ). Historically, research in occupational settings where Pb levels are higher (≥30 μg/dL) has been less consistent than findings from general population studies ( U.S. EPA 2006 ). For example, several of these studies reported inverse associations, including higher Pb dose with lower blood urea nitrogen, serum creatinine, and/ or higher creatinine clearance. These seemingly paradoxical effects compared to findings at lower Pb exposure levels may indicate different mechanisms of Pb-mediated kidney toxicity in different subgroups, namely, Pb-related hyperfiltration ( U.S. EPA 2006 ), a condition where a sustained increase in the kidney filtration rate can lead to kidney damage over time. However, studies published since the EPA’s 2006 AQCD Lead document ( U.S. EPA 2006 ) more consistently report worse kidney outcomes in exposed workers ( Alinovi et al. 2005
, Garcon et al. 2007
, Lin and TaiYi 2007
, Patil et al. 2007
, Khan et al. 2008
, Sun et al. 2008 ). These more recent studies in workers at higher exposure levels also lessen a previous concern that the kidney effects reported in the general populations are due to reverse causality, because no effects were observed in workers at higher exposure levels.



### 7.4 Susceptible Populations or Life Stages

7.4.1 Children There is inadequate evidence available to address the potential association between low-level blood Pb in children <12 years of age and impaired kidney function, but limited evidence that blood Pb levels <5 μg/dL are associated with adverse effects on kid

ney function in children ≥12 years of age. Relatively few studies have addressed kidney function or serum creatinine in children compared to adults; more often early biological effect markers (EBEs) are reported ( Table 7.4 ; see also Appendix A: Neurological Effects). How well EBEs predict impaired kidney function is not well established, even in adults ( U.S. EPA 2006 ). However, Fadrowski et al. ( 2010 ) analyzed data from 769 children and young adults 12-20 years of age in NHANES 1988-1994 and reported a reduced mean decrease in eGFR (based on cystatin C) of 2.9 mL/min/1.73 m 2 (95% CI: -0.7, -5.0) per doubling of blood Pb in the fully adjusted model. When the data were analyzed based on categories of Pb expo

sure, 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 m 2 (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 asso

ciation between low-level Pb and impaired kidney function in children and is restricted to children ≥12 years of age. It is unknown from the analysis reported in Fadrowski et al. ( 2010 ) whether or not the effect is driven by the older children in the study (i.e., whether decreased eGFR in children ≥17 years of age was responsible for the significant decline in the entire group from 12 to 20 years of age). The conclusion of limited evidence that blood Pb levels <5 μg/d L are associated with adverse effects on kidney function in children ≥12 years of age is based mainly on the Fad

rowski et al. ( 2010 ) study, with support provided by the consistency of the data with effects observed at similar levels in adults. These findings are also consis

tent with reduced eGFR reported in adults ( Muntner et al. 2003
, Akesson et al. 2005
, Muntner et al. 2005
, Navas-Acien et al. 2009 ). This conclusion is supported by the increased serum levels of cystatin C reported in children in Belgium ( Staessen et al. 2001 ), a measure that is becoming more widely accepted and used. The existing literature does not permit a deter

mination on relative sensitivity in children and adults. One challenge in interpreting the data for kidney effects in children is the potential for renal compli

cations to be asymptomatic and may not become detectable until many years after exposure. This relatively slow response to Pb is supported by the animal data in which male rats exposed to Pb-acetate in drinking water did not display decreased GFR until 6 or 12 months of exposure (e.g., Khalil-Manesh et al. 1992a
, Khalil-Manesh et al. 1992b
, Khalil-Manesh et al. 1993 ). Young children with an age less than theNTP Monograph on Health Effects of Low-Level Lead 85Table 7.4: Studies of kidney outcomes in childrenRelevance toConclusionsStudy DescriptionStudyDesignKey Kidney FindingsReferenceEffect769 children and young adults age12-20 in NHANES 1988-1994Cross-sectionalReduced GFR associated with blood Pb of >2.9μg/dL versus <1μg/dL(β (95%CI)= -6.6 (-0.7, -12.6))Fadrowski(2010)EffectChildren age 17 living near indus-trial areas in Belgium; n=100 Pbexposed and 100 referentsCross-sectionalIncreased levels of serum cystatin C and β2-microblobulin in children withhigher blood Pb (mean, 2.7μg/dL) compared to referents (mean, 1.5μg/dL)Staessen(2001)EffectChildren 1-6 years old of workersin Pakistani Pb plants; n=123 Pbexposed and 123 referentsCross-sectionalIncreased levels of serum creatinine and urea in Pb-exposed children comparedto controls (median Pb, 8.1 and 6.7μg/dL, respectively; p≤0.01 for both measures in unadjusted analyses)Khan(2010)EquivocalChildren 12-15 years old in CzechRepublic living near two smelters:area 1, n=91; area 2, n=53; reference site, n=51CrosssectionalIncreased levels of urinary levels ofβ2-microblobulin, Clara cell protein, andNAG in children living in area 1 (mean blood Pb: males, 10.9μg/dL; females,9.44μg/dL) compared to referents (mean blood Pb: males, 8.7μg/dL; females,8.39μg/dL),but not area 2, where blood Pb levels were highestmean blood Pb:males, 14.9μg/dL; females, 12.9μg/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)Bernard(1995)EquivocalChildren 10 years old in Poland living near Pb-producing factories;n=62 exposed and 50 referentsCrosssectionalAltered urinary biomarkers (transferrin, 6-keto-PGF1α, NAG B, β2-microblobulin,Clara cell protein, EGF, PGE2) between 62 exposed (mean blood Pb, 13.3μg/dL)and 50 control (mean blood Pb=3.9μg/dL) children.No difference in serum creatinine or serum Clara cell protein; no difference in other urine biomarkers(e.g.,fibronectin, NAG, α1-microglobulin, RBP, total protein, and albumin laminin)Fels(1998)No effectChildren 8.5-12.3 years old inFrance living near two smelters;n=200 exposed and 200 matchedreferentsCrosssectionalNo difference in any kidney parameters in children living in reference (meanblood Pb: males, 3.4μg/dL; females, 2.7μg/dL) and polluted areas (meanblood Pb: males, 4.2μg/dL; females, 3.7μg/dL) (total protein, albumin, transferrin, β2-microblobulin, RBP, brush border antigen, and NAG)de Burbure(2003)No effectbecause ofdirection ofeffectChildren 8.5-12.3 years old inEurope living near two smelters;n=364 exposed and 352 matchedreferentsCrosssectionalInverse relationship (regression coefficients) with blood Pb and serum creati-nine (-0.026, p=0.007), serum cystatin C (-0.056, p=0.02), and β2-microblobulin(-0.095, p=0.01) in children living near smelters (mean Pb: males, 4.2; females,3.6μg/dL) compared to controls (mean Pb: males, 3.4; females, 2.8μg/dL)de Burbure(2006)Abbreviations:CI, confidence interval; EGF, epidermal growth factor; GFR, glomerular filtration rate; NAG, N-acetyl-β-D-glucosaminidase; NHANES, National Health andNutrition Examination Survey; PGE2, prostaglandin E2; PGF1α, prostaglandin F1α; RBP, retinol-binding protein.86 NTP Monograph on He alth Effects of Low-Level Lead latent period of clinically detectable kidney disease would not be expected to show Pb-related kidney effects. In addition, glomerular hyperfiltration during early stages of Pb nephropathy (as has been observed in rats after 3 months of exposure ( Khalil-Manesh et al. 1992b )) would also mask the effect of Pb exposure on kidney function in young children ( see also discus

sion of de Burbure et al. 2006 below ). The lack of clear evidence of adverse effects of blood Pb on children <12 years of age does not exclude the potential role of Pb exposure on development of Pb-related kidney effects later in life. The studies of serum creatinine and other blood or urine biomarkers present less indication of an effect of Pb on kidney function in children ( Table 7.4 ). De Burbure et al. ( 2006 ) reported an asso

ciation between higher blood Pb and lower serum creatinine (adjusted regression coefficient=-0.026, p=0.007); however, the opposite direction of effect, an increase in serum creatinine, would be considered to indicate decreased kidney function. Alternatively, the de Burbure et al. ( 2006 ) finding may be consis

tent with hyperfiltration. The data in children may be inconsistent because of a lack of reliable measures in children, differential effects by age (hyperfiltration vs. decreased clearance), or other factors. An earlier study found no difference in mean serum creatinine between 62 exposed (mean blood Pb, 13.3 μg/d L) and 50 control (mean blood Pb, 3.9 μg/dL) Polish children ( Fels et al. 1998 ). Khan et al. ( 2010 ) reported a correlation of blood Pb levels with serum creatinine (r=0.13; p=0.05) in a study in 1- to 6-year-old chil

dren of workers in Pakistani Pb smelters and battery recycling plants; blood Pb, serum creatinine, and urea were higher in the children of workers (n=123 exposed) compared to controls (n=123; medians=8.1 and 6.7 μg/dL; 56 and 52 μmol/L; and 4.5 and 4.3 mmol/L, respectively; p≤ 0.01 for all in unadjusted analyses). Two studies assessed associations between blood Pb and serum cystatin C and reported oppo

site findings ( Staessen et al. 2001
, de Burbure et al. 2006 ). Staessen et al. ( 2001 ) measured higher levels of serum cystatin C in 17-year-old Belgian children living in a chemical industrial region (mean blood Pb, 2.7 μg/dL) compared to the reference group (mean blood Pb, 1.5 μg/dL). de Burbure et al. ( 2006 ) found an inverse association with blood Pb in 300-600 Euro

pean children 8.5-12.3 years of age (adjusted regres

sion coefficient=-0.056, p=0.02). The same pattern of opposite direction was observed for β2-microblobulin in these two studies. Findings on urine biomarkers are also inconsistent and difficult to interpret ( Bernard et al. 1995
, Fels et al. 1998
, de Burbure et al. 2003 ) ( Table 7.4 ). For example, Bernard et al. ( 1995 ) found higher urinary levels of β2-microblobulin, Clara cell protein, and N-acetyl-β-D-glucosaminidase (NAG) in children living in one “polluted” region compared to children living the reference area, but not in another “polluted” region where average blood Pb levels were the highest. The levels of blood Pb in the com

parison groups are another factor to consider when interpreting the studies in children. No differences in kidney parameters were observed in de Burbure et al. ( 2003 ) ( Table 7.4 ). Although the average blood Pb levels between the “exposed” and reference groups were quite similar in this study (mean blood Pb in 200 referents: males, 3.4 μg/dL; females, 2.7 μg/dL; vs. 200 children considered exposed: males, 4.2 μg/dL ; females, 3.7 μg/dL ), no associations were observed when stepwise multiple regression analysis was con

ducted on the whole group of children as well. Several studies have assessed the impact of higher Pb exposures during childhood on kidney measures, but these studies do not necessarily pro

vide additional clarity ( Inglis et al. 1978
, Moel and Sachs 1992
, Verberk et al. 1996
, Coria et al. 2009 ). No nephrotoxicity was reported in a group of 77 individuals in rural Chile who were assessed 10 years after being exposed to Pb-contaminated flour as chil

dren in 1996 and subsequently treated with EDTA (Pb levels measured in 1996 ranged from 37 to 87 μg/ dL) ( Coria et al. 2009 ). Similarly, Moel et al. ( 1992 ) did not detect any significant differences between previously Pb-poisoned children and their siblings for serum creatinine, uric acid, and β 2 -microblobulin, fractional excretion of β 2 -microblobulin, urinary protein:creatinine ratio, and tubular reabsorption of phosphate. The study compared 62 patients at a Chicago Pb clinic, who were diagnosed and received chelation treatment between 1966 and 1972 for ini

tial blood Pb levels >100 μg/dL , to 19 age-matched siblings whose initial blood Pb levels were <40 μg/dL. Kidney pathology was documented in certain adult survivors of untreated childhood Pb poisoning in Queensland before its removal from paint ( Inglis et al. 1978 ). It is unclear whether differences in outcomes between those studies can be attributed to use of EDTA in Coria et al. ( 2009 ) and Moel et al. ( 1992 );NTP Monograph on Health Effects of Low-Level Lead 87 an elevated risk of low IQ was reported in that study. An impact on IQ but not on the kidney in that study may also suggest the kidney is less susceptible than the neurological system. Hu et al. ( 1991 ) reported elevated creatinine clearance rates in 21 survivors of childhood poisoning in Boston from 1930 to 1942 compared to controls matched for age, sex, race, and neighborhood (1.88 versus 1.48 mL/s per 1.73 m2). There were no differences in serum creatinine levels between subjects and controls. The creatinine clear

ance finding is opposite results reported in adults in the general population discussed above but is consistent with the suggestion that Pb may induce kidney hyperfiltration in certain subpopulations. Verberk et al. ( 1996 ) looked at a number of kidney biomarkers in 151 children 3-6 years of age living near a Pb smelter in Baia Mare, Romania. The average Pb levels in the subgroups (based on proximity to the smelter) ranged from 34.2 to 43.8 μg/dL ( Verberk et al. 1996 ). An increase in NAG per 100 μg/dL blood Pb was reported, but there were no associations with albumin, α 1 -microglobulin, retinol-binding protein, or alanine aminopeptidase.



### 7.4.2 Hypertensives, Diabetics, and Kidney Disease Patients The impacts of Pb on kidney function in susceptible populations, such as people with diabetes, hyperten

sions, or CKD, are expected to be higher ( U.S. EPA 2006 ). This pattern is apparent in several studies that conducted subgroup analyses of NHANES data and the Normative Aging Study and found that associations were stronger in NHANES participants with hyperten

sion ( Muntner et al. 2003 ) or men in the Normative Aging Study with diabetes ( Tsaih et al. 2004 ). Follow-up studies in people with renal disease or type II diabetes also indicate worse disease pro

gression (kidney function decline) in association with higher baseline blood Pb levels ( Lin et al. 2003
, Yu et al. 2004
, Lin et al. 2006a
, Lin et al. 2006b
, U.S. EPA 2006
, Weaver and Jaar 2010
, U.S. EPA 2012 ). Although most of the patient studies are relatively small in size (ranging from 87 to 202 subjects), they are longitudinal in design, with follow-up ranging from 1.1 to 3.87 years. They provide additional sup

port for kidney effects at low-levels of blood Pb and also support the conclusion that reverse causality is not likely to account for the effects of Pb on kidney function at low levels. In the study with the longest period of follow-up, 4 years, a 1 μg/dl higher blood Pb at baseline in patients with chronic renal insufficiency was associated with a 4.0 mL/min/1.73 m 2 reduction in eGFR ( Yu et al. 2004 ). The average blood Pb level in the sample of 121 patients was 4.2 μg/dL. In order to be eligible, patients were required to have baseline EDTA-chelatable Pb below a level thought to indicate risk for Pb-related kidney toxicity. Across these stud

ies, the decline in eGFR per 1 SD increase in Pb dose at baseline per year ranged from 0.16 ( Lin et al. 2003 ) to 3.87 4.0 mL/min/1.73 m 2 ( Lin et al. 2006b ). The magnitude of decline in eGFR in the study with the lowest baseline blood Pb (2.9 μg/dL) w as 1.1 per 1 SD increase in Pb dose at baseline per year ( Lin et al. 2006b ). A collection of Taiwanese patient studies included intervention arms with chelation therapy ( Lin et al. 2003
, Lin et al. 2006a
, Lin et al. 2006b
, Lin and Tai-Yi 2007 ); these studies show less kidney func

tion decline in patients undergoing chelation therapy compared to those receiving the placebo. However, interpreting these studies is complex because of dif

ficulty in separating outcomes that may be due to a direct beneficial effect of the chelating agent, such as via anti-oxidation, from outcomes due to Pb removal. In addition, they involve small number of patients, and the findings should be repeated in larger popula

tions in multiple centers. Thus, Pb-associated reduced kidney function in healthy individuals may not necessarily result in CKD, although Pb may be a risk factor for CKD in suscep

tible patient populations (e.g., people with kidney disease, diabetes, or obesity), in older populations, or when combined with exposure to other compounds known to cause kidney damage (e.g., cadmium, mer

cury, arsenic, zinc) ( U.S. EPA 2006 ).



### 7.5 Conclusions The NTP concludes that there is sufficient evidence that blood Pb levels <5 μg/dL are associated with adverse effects on kidney function in adults (see Table 7.5 for complete list of kidney effects conclusions). With few exceptions, epidemiological studies of the general population reported associations between blood Pb levels <10 μg/dL and (1) increased risk of CKD and (2) decreased kidney function as measured by GFR and creatinine clearance. The NTP recognizes that blood levels in this range measured during adult

hood do not preclude the possibility that an indi

vidual might have had past exposure to higher blood88 NTP Monogr aph on Health Effects of Low-Level Lead levels. As with other studies of health effects of Pb in adults, prospective studies in a group for which blood Pb levels remained consistently below 10 μg/dL from birth until measurement would eliminate the poten

tial role of early-life blood Pb levels above 10 μg/d L on health effects observed in adults with concurrent blood Pb levels <10 μg/dL. The associations are typi

cally stronger in people with hypertension or diabe

tes ( Muntner et al. 2003
, Tsaih et al. 2004 ). The NTP also concludes that there is limited evidence that blood Pb levels <5 μg/dL are associated with adverse effects on kidney function in children ≥12 years of age based on the recent cross-sectional data from the NHANES data set published by Fadrowski et al. ( 2010 ) and the consistency of effects with observations in adults. There is inadequate evidence that blood Pb levels <10 μg/dL ar e associated with kidney function in children <12 years of age because of inconsistent results and studies lacking clear predictive measures of kidney function in children. The lack of consistent predictive measures of kidney function in children makes studying the effects of Pb on this life stage difficult. The NTP’s conclusions of sufficient evidence that blood Pb levels <5 μg/d L are associated with adverse effects on kidney function in adults and lim

ited evidence in children ≥12 years of age, extend the conclusions of the 2007 ATSDR Toxicological Profile for Lead ( ATSDR 2007 ) and 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) from adults to children age 12 and older based on recent data.

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

Health Effect Population NTP Conclusions Blood Pb Evidence Bone Pb Evidence Increased chronic kidney disease (CKD) and decreased glomerular filtration rate (GFR) Adults Sufficient Yes, <5 μg/dL Not studied Children ≥12 years old Limited Yes, <5 μg/dL Not studied Children <12 years old Inadequate Unclear Not studiedNTP Monograph on Health Effects of Low-Level Lead 89 

## 8.0 REPRODUCTIVE/ DEVELOPMENTAL EFFECTS

8.1 Conclusions The NTP concludes there is sufficient evidence that blood Pb levels <10 μg/dL ar e associated with adverse health effects on development in children and that blood Pb levels <5 μg/dL are associated with adverse health effects on reproduction in adult

women. Because the database of human studies on most reproductive endpoints is limited to occupational exposure studies, many of the available studies are for blood Pb levels >10 μg/dL. Giv en this fact and the focus of the original nomination on reproductive and developmental effects, higher blood Pb levels were included in the evaluation of these health effects, unlike other sections of this document. Consider

ation of blood Pb levels >10 μg/dL r esulted in several conclusions for Pb-related reproductive effects in men but did not affect the conclusions for women or children. Unlike the data set for most other health effects, a number of prospective studies of developmental effects include prenatal measures of exposure (either maternal blood or umbilical cord blood). Maternal blood Pb <10 μg/dL is associated with decreased head circumference in children through 4 years of age, providing evidence that prenatal exposure is associated with reduced postnatal growth in chil

dren. Conclusions on effects of prenatal exposure for outcomes evaluated as children are complicated by the high degree of correlation in childhood blood Pb levels over time, and as described below, concurrent blood Pb levels <10 μg/dL in children are also associ

ated with reduced postnatal growth.



### Children In children, there is sufficient evidence that blood Pb levels <10 μg/dL ar e associated with delayed puberty in both boys and girls. Nine studies with mean blood Pb levels <10 μg/dL support the relationship between Pb and delayed puberty (see Table 8.3 ); although several studies report effects on puberty at blood Pb levels <5 μg/dL, there is also evidence indicating no effect of blood Pb <5 μg/dL. The refore, there is lim

ited evidence that delayed puberty is associated with blood Pb levels <5 μg/dL. Ther e is sufficient evidence that decreased postnatal growth is associated with blood Pb levels <10 μg/dL in children. Epidemiologi

cal studies consistently report an inverse relationship between blood Pb levels <10 μg/dL and postnatal growth (see Table 8.4 ). Developmental effects on neu

rological, immunological, renal, and cardiovascular systems are not covered in this section because they are reviewed in individual chapters.



### Women In adult women, there is sufficient evidence that maternal blood Pb levels <5 μg/dL ar e associated with reduced fetal growth or lower birth weight. The associa

tion between maternal Pb exposure and reduced fetal growth is supported by several prospective studies with maternal blood Pb data during pregnancy, a large retro

spective cohort of over 43,000 mother-infant pairs that reports a mean maternal blood Pb level of 2.1 μg/dL

, and a number of cross-sectional studies with maternal or umbilical cord blood Pb at delivery. Although mater

nal or paternal bone Pb data are not available in studies of most reproductive health outcomes, a set of studies from a single group reported that maternal bone Pb is associated with lower birth weight, birth length, and head circumference. There is limited evidence that maternal blood Pb levels <10 μg/dL ar e associated with spontaneous abortion and preterm birth or reduced gestational age. Although a number of prospective studies with maternal blood Pb levels during pregnancy and cross-sectional studies with umbilical cord blood Pb levels at delivery reported an association between prenatal blood Pb levels <10 μg/dL and preterm birth, the conclusion of limited evidence is based on the inconsistent results and because a retrospective study with a large cohort of over 43,000 mother-infant pairs did not find an association between maternal blood Pb levels and preterm birth. The conclusion of limited evidence for an association with spontaneous abortion in women is based principally on the Borja-Aburto et al. ( 1999 ) study, which has the strength of its prospective nested case-control design, with additional support provided by occupational studies that reported an association with Pb exposure but lack blood Pb mea

surements. There is inadequate evidence for other reproductive and effects of Pb associated with blood Pb levels <10 μg/dL in women.



### Men In adult men, there is inadequate evidence that blood Pb levels <10 μg/dL are associated with90 NTP Monograph on He alth Effects of Low-Level Lead effects on reproduction. There is sufficient evidence that blood Pb levels ≥15 μg/dL are associated with adverse effects on sperm or semen in men, and inadequate evidence for adverse effects on sperm at lower blood Pb levels. Decreased sperm count, density, and/or concentration has been reported in multiple retrospective and cross-sectional occu

pational studies of men with mean blood Pb levels from 15-68 μg/dL (see Table 8.5 ). There is sufficient evidence that paternal blood Pb levels ≥20 μg/dL ar e associated with delayed conception time and limited evidence that blood Pb levels ≥10 μg/dL in men are associated with other measures of reduced fertility. Four studies reported increased time to pregnancy in women whose male partners had blood Pb levels of 20-40 μg/dL. A single retrospective occupational study reported increased risk of infertility among men with blood Pb levels ≥10 μg/dL, and the conti

nuity of these data with effects on time to pregnancy supports a conclusion of limited evidence that blood Pb levels ≥10 μg/dL in men are associated with other measures of reduced fertility. There is limited evi

dence that paternal blood Pb >31 μg/dL is associated with spontaneous abortion. The conclusion of limited evidence that spontaneous abortion is associated with paternal exposure is based mainly on the ret

rospective nested case-control study by Lindbohm et al. ( 1991a ) in men, with additional support provided by occupational studies that reported an association with Pb exposure but lack blood Pb measurements.



### 8.2 How Conclusions Were Reached Conclusions in the NTP’s evaluation of Pb-related reproductive and developmental effects in humans associated with low-level Pb are derived by evalu

ating the data from epidemiological studies with a focus on blood Pb levels <10 μg/dL. Be cause the database of human studies on most reproductive endpoints is limited to occupational exposure stud

ies, many of the available studies are for blood Pb levels >10 μg/dL. Unlik e other sections of this docu

ment, reproductive effects of these higher blood Pb levels were included in the evaluation because the data set of human studies on potential reproductive effects associated with lower blood Pb levels is lim

ited. Major endpoints considered as potential indica

tors of effects of Pb on reproduction and develop

ment are listed and briefly described in Section 8.2.1

. This document is not a review of the reproductive system or reproductive and developmental toxicity, and the reader is directed to published reviews for additional background. Key data and principal stud

ies considered in developing the NTP conclusions are discussed in detail in Section 8.3 Evidence for Pbrelated Effects on Reproductive and Developmental Outcomes . The discussion of each effect begins with a statement of the NTP’s conclusion that the specific effect is associated with a blood Pb level <10 μg/dL or <5 μg/dL and the age group in which it is identified (childhood or adulthood), as well as the timing of exposure associated with the effect (prenatal, child

hood, concurrent) when available. The discussion also highlights the extent to which experimental animal data support the association between Pb exposure and reproductive effects. Although the information necessary to support the NTP conclu

sions is presented in Section 8.3 , the complete data set of human studies considered for evaluation ofreproductive and developmental effects with lowlevel Pb is included in Appendix E: Reproductive and Developmental Effects, and individual studies are abstracted for further reference. The NTP made extensive use of recent government evaluations of health effects of Pb in the current assessment, and the relevant conclusions of the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATSDR’s 2007 Toxicological Profile for Lead ( ATSDR 2007 ) are briefly described in Section 8.2.2 below.



### 8.2.1 Principal Measures of Reproductive and Developmental Effects Table 8.1 lists a number of key reproductive and developmental endpoints commonly evaluated in epidemiological studies. The data available to evalu

ate each of the major effects are discussed in sepa

rate subheadings under Section 8.3 Evidence for Pbrelated Effects on Reproductive and Developmental Outcomes below.



### 8.2.2 Principal Conclusions from 2006 EPA and 2007 ATSDR Pb Documents The EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATSDR’s 2007 Toxicological Profile for Lead ( ATSDR 2007 ) both concluded that there is evidence for reproductive effects in males at high blood Pb levels (30-40 μg/dL in ATSDR, 2007 and 45 μg/dL in U.S. EPA, 2006) and suggest that more research is needed to determine if effects occur at lower blood Pb levelsNTP Monograph on Health Effects of Low-Level Lead 91 (see Table 8.2 for principal conclusions and original documents for complete conclusions). Although the 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) cited the Borja-Aburto et al. study ( 1999 ) as a well-conducted prospective case-control study supporting a signifi

cant relationship between maternal blood Pb level at 10 μg/dL to 12 μg/dL and spontaneous abortion, the EPA concluded that, collectively, there is little evi

dence to support an association between maternal or paternal Pb exposure and incidence of spontaneous abortion. The 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) concluded that the data are inadequate to evaluate reproductive effects in females, and studies of devel

opmental effects suggest at most a small association between Pb exposure and preterm birth, congenital abnormalities, birth weight, or fetal growth. The EPA is in the process of revising the AQCD, and the conclu

sions of the external draft ( U.S. EPA 2012 ) are largely in line with the 2006 AQCD for Lead ( U.S. EPA 2006 ), plus additional review of the evidence for delayed pubertal onset. The NTP considered the conclusions and data summaries from the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) and ATSDR’s 2007 Toxicological Profile for Lead ( ATSDR 2007 ). In general, the NTP concurred with the conclusions and agreed that the data sup

port them. Differences from the ATSDR and EPA documents are identified for specific endpoints in this document.



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

8.3.1 Delayed Puberty There is sufficient evidence that blood Pb levels <10 μg/dL are associated with a delay in sexual matu

ration 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 ofsexual maturation has been reported in eight crosssectional studies and a single prospective study involv

ing children with blood Pb levels from 10 to <1 μg/dL from seven different populations in North America, Europe, and Africa. Pb-related developmental delay in a several biological markers of puberty (e.g., age Table 8.1: Major reproductive/developmental effects considered
Effect Description Delayed puberty Delay in measures of puberty (e.g., Tanner staging of genitalia, pubic hair, and breast development) Postnatal growth Slower growth (as indicated by height, head circumference, etc., for age) Sperm parameters Numerous sperm or semen measures (sperm count, motility, morphology, etc.) Conception Greater time to pregnancy or lower fecundity Pregnancy loss Spontaneous abortion (fetal loss <20 weeks gestation), stillbirth (fetal loss ≥20 weeks) Gestation length Shorter length of gestation (as a continuous measure), preterm birth (<37 weeks) Fetal growth Lower birth weight, often adjusted for gestational age
Birth defects Congenital malformations

Table 8.2: Main conclusions for repro ductiv e/ 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 out

comes, including perturbed semen quality and increased time to pregnancy. These associations appear at blood Pb levels >45 μg/d L, as most studies have only considered exposure in the occupational setting. There are no ade

quate data to evaluate associations between Pb exposure and female fertility.” (U.S. EPA 2006, pg 6-271)

“Studies of children also have shown associations between PbB [blood Pb level] and growth, delayed sexual maturation in girls, and decreased erythropoietin production. Some studies of humans occupationally or environmentally exposed to Pb have observed associa

tions between PbB and abortion and preterm delivery in women and alterations in sperm and decreased fertil

ity in men. On the other hand, there are several stud

ies that found no significant association between Pb exposure and these end points. At least for the effects in males, the threshold PbB appears to be in the range of 30-40 μg/dL.” (ATSDR 2007, pg 23)ReproductiveEffects

92 N TP Monograph on Health Effects of Low-Level LeadTable 8.3: Studies of biomarkers of puberty associated with low-level Pb exposure used to develop conclusionsRelevancetoConclusionsStudyDescriptionStudyDesignKey Reproductive/Developmental FindingsReferenceChapaevsk, RussiaEffectBoys 11-12; n=481ProspectiveDelayed puberty onset in boys with blood Pb ≥5μg/dL. Puberty measures differedby testicular volume and Tanner genital and pubic hair staging.Williams (2010)(samepopulation as Hauser)Boys 8-9; n=489CrosssectionalDelayed puberty onset in boys with blood Pb ≥5μg/dL. Puberty determined by Tan-ner genital staging and testicular volume; effects not significant for pubic hair staging.Hauser (2008)NHANES IIIEffectGirls 8-16 years ofage; n=1,235CrosssectionalDelayed puberty onset in girls with blood Pb ≥2μg/dL compared to those withblood Pb <2μg/dL. Puberty differed by Tanner pubic hair developmental stage andage at menarche; no effect on developmental stage of breasts.Wu (2003)(population overlap withGollenberg, Selevan)Girls 8-11 years old;n=705CrosssectionalGirls with higher blood Pb (blood Pb ≥5μg/dL compared with those <1μg/dL) hadlower 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.Gollenberg (2010)Girls 8-16 years old;n=600-805 per race/ethnicityCrosssectionalDelayed puberty onset in African American girls (age at menarche, Tanner breastand pubic hair developmental stage) and Mexican American girls (breast and pubichair stage) at blood Pb >3μg/dL compared to blood Pb <1μg/dL; not in non-Hispanic whites.Selevan (2003)EffectGirls 13 years old inSouth Africa; n=682-712, by endpointCrosssectionalDelayed puberty onset (determined by Tanner pubic hair and breast developmen-tal stage and age at menarche) in girls with blood Pb ≥5μg/dL, and significantassociation with blood Pb by trend analysis across for stage or age at menarche.Naicker (2010)EffectChildren aged 17 inBelgium; n=100 Pband 100 referentCrosssectionalTesticular volume was lower in boys living in areas with higher blood Pb (1.8-2.7μg/dL) compared to referents (1.5μg/dL). Genital and breast stage did notdiffer consistently and significantly between referent and exposed; comparisonby blood Pb not reported.Staessen (2001)EffectGirls aged 10-17 inAkwesasne MohawkNation; n=138CrosssectionalDelayed puberty onset (age at menarche) in girls with blood Pb above mean(≥0.49μg/dL) and a predicted delay in age at menarche of 10 months with bloodPb above median (1.2μg/dL).Denham (2005)No effectGirls 9 years old inNew York; n=139CrosssectionalBlood Pb had no effect on puberty onset in girls (by breast and pubic hair stage)with median blood Pb level of 2μg/dL.Wolff (2008)EffectChildren 10-13 yearsold in Egypt; n=41CrosssectionalDelayed puberty onset in boys and girls with blood Pb ≥10μg/dL. Puberty mea-sures differed for testes size, Tanner pubic hair and penile stage in boys, and Tanner developmental stage of breasts in girls, but not pubic hair in girls.Tomoum (2010)Epidemiological studies of Pb exposure and puberty are listed by decreasing cohort size and grouped together for overlapping or shared study groups.Abbreviations:NHANES: National Health and Nutrition Examination Survey.NTP Monograph on Health Effects of Low-Level Lead 93 at menarche and Tanner developmental staging of breasts) have been reported in cross-sectional stud

ies of girls, although there is no single measure that is consistently associated with blood Pb levels in all analyses. For boys, a Pb-related decrease in testicular volume was observed in all four publications, suggest

ing that testicular volume may be a reliable indicator of the effects of Pb on puberty in boys. The reported delay in sexual maturation with increasing blood Pb was significant across multiple studies, in various endpoints, and from different groups in analyses that adjusted for factors known to effect puberty such as race, BMI, and socioeconomic status. A conclusion of limited evidence that delayed puberty is associated with blood Pb levels <5 μg/dL is based on the four studies (three in girls and one in boys) that report delay in markers of puberty associated with blood Pb levels <5 μg/dL and the lack of association with blood Pb among girls in the Wolff et al. ( 2008 ) study with a median blood Pb level of 2 μg/dL. Three cross-sectional studies using the NHANES III data set reported delayed puberty onset in girls. Wu et al. ( 2003 ) reported delayed Tanner pubic hair stage and age at menarche in girls 8-16 years of age with blood Pb levels ≥2 μg/dL , with no effect on developmental stage of breasts. In a separate analy

sis divided by race and ethnicity, Selevan et al. ( 2003 ) reported an association between blood Pb >3 μg/dL and delayed puberty onset in African American and Mexican American girls as determined by Tanner pubic hair and breast stages. Age at menarche was also delayed at blood Pb levels >3 μg/dL in African American girls; however, there was no Pb-related effect on puberty in non-Hispanic whites. Gollenberg et al. ( 2010 ) reported that girls with blood Pb levels ≥5 μg/dL were less likely to have levels of inhibin B of >35 pg/mL, a level that the authors suggest is associated with pubic hair and breast development. A similar delay in puberty onset indicated by age at menarche was reported in 13-year-old girls in South Africa ( Naicker et al. 2010 ) and 10- to 17-year-old girls from the Mohawk Nation ( Denham et al. 2005 ). Naicker et al. ( 2010 ) also found an association with blood Pb ≥5 μg/dL and delays pubic hair and breast development stage. In contrast, Tomoum et al. ( 2010 ) reported decreased Tanner breast developmental stage and no effect on pubic hair in girls 10-13 years of age with blood Pb>10 μg/dL in Egypt. Staessen et al. ( 2001 ) reported significant (p=0.04) differences in breast development in 17-year-old girls among three groups: two study groups with blood Pb levels of 1.8 and 2.7 μg/dL and a reference group with blood Pb of 1.5 μg/dL. However, a direct comparison of breast stage by blood Pb levels was not reported, and the delay in breast stage was significant only when comparing the study group with mean blood Pb of 1.8 μg/dL to the reference group. One of the eight studies reporting data on girls did not detect a delay in any marker of puberty onset associated with blood Pb; mean blood Pb was 2 μg/d L 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 Tan

ner genital or pubic hair staging ( Staessen et al. 2001
, Hauser et al. 2008
, Tomoum et al. 2010
, Williams et al. 2010 ). In a paired cross-sectional and follow-up prospective study, blood Pb ≥5 μg/dL was associated with delayed puberty that was significant by Tanner genital staging (p<0.05) and reduced testicular vol

ume (p≤0.05) in Russian boys when they were 8-9 years of age and again at 11-12 years of age ( Hauser et al. 2008
, Williams et al. 2010 ). Testicular volume was significantly lower in 17-year-old boys living in areas with higher blood levels (1.8-2.7 μg /dL) com

pared to a reference group (1.5 μg/dL), although the authors do not include a direct comparison of testicu

lar volume by blood Pb levels ( Staessen et al. 2001 ). Blood Pb ≥10 μg/ dL was associated with decreased testes size and developmental delay in Tanner pubic hair and penile stages in 10- to 13-year-old boys in Egypt ( Tomoum et al. 2010 ).



### Summary of Support for Conclusions Animal data supports a Pb-associated developmental delay in sexual maturation, indicated by biomarkers of puberty such as reduced prostate weight and delay in vaginal opening, at high blood Pb levels in some studies (i.e., 40 to >300 μg/dL) in Fisher and Sprague Dawley rats and at blood Pb levels similar to the human stud

ies (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 interest

ing because the exposure that resulted in blood Pb from 3 to 13 μg/dL is associated with delayed puberty in female mice similar to the human data, whereas blood Pb <3 μg/dL was associated with accelerated time to puberty in mice, which suggests the pos

sibility of a different mechanism of action in mice at94 NTP Monograph on He alth Effects of Low-Level Lead blood Pb levels <3 μg/d L. The human data support

ing Pb-associated delay in puberty include the one prospective study in boys discussed above, with the rest being cross-sectional studies. The determination of causation from cross-sectional studies has a seri

ous limitation because cross-sectional studies rely on concurrent blood Pb measurements and provide no information on cumulative Pb or Pb exposure at earlier time points that may be critical for sexual maturation. However, the consistency of effects across studies, among multiple groups, and in multiple measures of puberty in both males and females lends weight to the evidence for developmental delay in puberty at blood Pb concentrations from 10 to <1 μg/dL. The conclu

sion of sufficient evidence for developmental delay in puberty in children at blood Pb levels <10 μg/dLis based on the prospective study and eight crosssectional studies that report effects above the mean blood Pb level (0.49 μg/dL to 5 μg/dL) of the group under study. A lower effect level and the conclusion of limited evidence for delayed puberty at blood Pb <5 μg/dL is supported by two of the studies ( Selevan et al. 2003
, Wu et al. 2003 ) that use the NHANES III data to examine puberty onset in girls from 8-16 years of age, the Denham et al. ( 2005 ) study of 10- to 17-yearold girls in the Mohawk Nation, and the Staessen et al. ( 2003 ) study reporting lower testicular volume in boys. The Tomoum et al. ( 2010 ) study provides additional support but reported delay in measures of puberty in boys and girls at blood Pb levels ≥10 μg/dL. The NTP’s conclusions for sufficient evidence for delay in sexual maturation in boys and girls at blood Pb levels <10 μg/dL and limited evidence at blood Pb <5 μg/dL expands the conclusion from ATSDR’s 2007 Toxicologi

cal Profile for Lead ( ATSDR 2007 ), which was limited to girls at blood Pb levels <10 μg/dL; the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) did not present specific conclusions on sexual maturation.



### 8.3.2 Postnatal Growth There is limited evidence that maternal Pb <10 μg/dL is associated with decreased head circumference in children up to 4 years of age and sufficient evidence that concurrent blood Pb <10 μg/dL in children is associated with decreased postnatal growth. Pro

spective studies in two groups ( Rothenberg et al. 1993
, Rothenberg et al. 1999
, Schell et al. 2009 ) report an inverse association between maternal blood Pb and head circumference, and one study reports the lack of an association between maternal blood Pb and height or weight through 10 years of age ( Lamb et al. 2008 ). The data from prospective studies (see Table 8.4 and Postnatal Growth section of Appendix E: Reproduc

tive and Developmental Effects) in two groups sup

port an association between higher blood Pb levels in children and lower subsequent growth ( Greene and Ernhart 1991
, Rothenberg et al. 1993
, Rothenberg et al. 1999 ). Numerous cross-sectional studies report an association between higher blood Pb in children and smaller head circumference, height, or other indica

tors of growth (e.g., weight, chest circumference, etc.). The clear majority of cross-sectional studies, includ

ing studies with large numbers of subjects, such as the NHANES data sets, demonstrate an association between higher concurrent blood Pb (means from 2 to 15 μg/dL) and lower height or other indicators of post

natal growth in children from 1 to 16 years of age. This strong evidence for an association between growth and concurrent blood Pb is based on exposure data that is largely outside the relevant time window – the relevant timing of Pb exposure to effect growth is dur

ing or before the growth that results in differences in height. Therefore, the conclusion of sufficient evi

dence that blood Pb <10 μg/dL i n children is associated with decreased growth is based on the combination of strong support from the cross-sectional studies and the additional support from the three prospective studies that evaluate blood Pb levels in children on subsequent growth rather than current height. Several prospective studies support an inverse association between maternal Pb <10 μg/d L and postnatal growth as indicated by head circumfer

ence, 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
, Rothen

berg et al. 1999 ). Schell et al. ( 2009 ) also report an effect of maternal blood Pb on head circumference, but not on height or weight, in 6- to 12-month-olds in Albany, NY. Maternal blood Pb was not related to height or weight in children from 1 to 10 years of age in the Yugoslavia Prospective Study ( Lamb et al. 2008 ). Data from the Cincinnati Pb study support a combined effect of maternal blood Pb as well as concurrent blood Pb levels in the children; height at 15 months was decreased only in children with blood Pb >3.4 μg/dL that also experienced maternal bloodReproductiveEffectsTable 8.4: Studies of postnatal growth associated with low-level Pb exposure used to develop conclusionsRelevancetoConclusionsStudyDescriptionStudyDesignKey Reproductive/Developmental FindingsReferenceCincinnati Pb StudyEffectChildren 15 monthsof age; n= 260ProspectiveConcurrent blood Pb (>3.4μg/dL) in children was inversely associated with growthrate (length) at 15 months of age in children of mothers with Pb >7.7μg/dL.Shukla (1989)(same studypopulation as Shukla, 1991)Children ≤33 monthsof age; n=235ProspectiveCurrent blood Pb was inversely associated with length at 33 months of age inchildren with higher blood Pb (>10.8μg/dL) from 3 to 15 months of age.Shukla (1991)Albany Pregnancy Infancy Pb StudyEffectChildren 0.5-1 yearsold; n=211ProspectiveMaternal blood Pb (≥3μg/dL) was inversely associated with infant head circumference at 6 and 12 months, but not with length or weight.Schell (2009)Cleveland Pb StudyEffectChildren <5 years; n=151-185 per sampleProspectiveBlood Pb at 6 months of age (10μg/dL) was related to subsequent head circumference (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.Greene (1991)Mexico City Prospective StudyEffectChildren 0.5-1 years;n=50-111 per sampleProspectiveMaternal blood Pb at 36 weeks (median, <10μg/dL) was inversely associatedwith infant head circumference at 6 and 18 months. Infant blood Pb (1 year)was inversely associated with head circumference at 36 months.Rothenberg (1993)(same study population asRothenberg, 1999)Children 0.5-4 year; n=119-199 per sampleProspectiveMaternal (36 weeks) and infant (1 year) blood Pb (median, <10μg/dL) were inverselyassociated with infant head circumference at later ages, up to 4 years of age.Rothenberg (1999)Yugoslavia Prospective StudyNo effectChildren birth, 1, 4, 6,and 10 years; n=309ProspectiveMaternal blood Pb was not correlated to height or weight in children from 1to 10 years of age.Lamb (2008)EffectChildren at 4 years ofage; n=156-175CrosssectionalConcurrent blood Pb (<15μg/dL) was inversely associated with height in Pristina,but blood Pb (20-40μg/dL) was not related to height in Titova-Mitrovica, a Pbsmelter town.Factor-Litvak (1999)NHANES IIIEffectChildren 1-7 yearsold; n=4,391CrosssectionalConcurrent blood Pb (mean, 3.6μg/dL) was inversely associated with heightand head circumference but not with weight.Ballew (1999)(same studypopulation as Selevan)Girls 8-16 years ofage; n=600-805 perrace/ethnicityCrosssectionalConcurrent blood Pb ≥3μg/dL was associated with decreased height comparedto individuals with a blood Pb of 1μg/dL but not with weight.Selevan(2003)NHANES IIEffectChildren 0.5-7 yearsof age; n=2695CrosssectionalConcurrent blood Pb (range, 5-35μg/dL) was inversely associated with height,weight, and chest circumference.Schwartz (1986)(same studypopulation as Frisancho)Mexican-Americansage 5-12; n=1,454CrosssectionalConcurrent blood Pb (mean: boys, 10.6 μg/dL; girls, 9.3μg/dL) was inverselyassociated with height.Frisancho (1991)

NTP Monograph on Health Effects of Low-Level Lead 9596 N TP Monograph on Health Effects of Low-Level LeadTable 8.4:Studies of postnatal growth associated with low-level Pb exposure used to develop conclusions(continued)Relevance toConclusionsStudyDescriptionStudyDesignKey Reproductive/Developmental FindingsReferenceEffectChildren aged 7-15 inPoland; n=899Cross-sectionalConcurrent blood Pb (mean, 7.7μg/dL) was inversely associated with height, leglength, arm length in both, trunk length in boys, weight in girls;not weight in boys,trunk in girls.Ignasiak (2006)EffectChildren aged 2-12 inDallas; n=764 (1980s:n=404; 2002: n=390)Cross-sectionalConcurrent blood Pb was inversely associated with height, weight, and headcircumference. The height-Pb relationship was not statistically different betweenchildren in 1980s (mean=24.8μg/dL) or 2002 (mean= 1.8μg/dL).Little (2009)EffectChildren 7 years oldin Mexico n=602Cross-sectionalConcurrent blood Pb (11.5μg/dL) was inversely associated with height andpositively associated with head circumference.Kordas (2004)EffectChildren aged 6-9 inGreece; n=522Cross-sectionalConcurrent blood Pb (mean, 12.3μg/dL) was inversely associated with height,head circumference, and chest circumference.Kafourou (1997)EffectBoys 8-9 in Russia;n=489Cross-sectionalConcurrent blood Pb (median, 3μg/dL) was inversely related to height butnotwith weight or BMI.Hauser (2008)EffectChildren 11-13 yearsold in Italy; n=418Cross-sectionalConcurrent blood Pb inversely associated with height, weight in 13-year-old boys(mean, 8.5μg/dL) and height in 12-year-old girls (mean, 7μg/dL),not children ofother ages.Vivoli (1993)Effect12-month-old infantsin Mexico City; n=329Prospective &cross-sectionalInfant blood Pb (6.8μg/dL) at 1 month and maternal bone Pb (tibia 10.1μg/g)were inversely related to infant weight and/or weight gain through 12 monthsof age.Sanin (2001)No effectChildren 6-9 years oldin Malaysia; n=268Cross-sectionalConcurrent blood Pb (mean, 3.75μg/dL) was not correlated to height, weight,or arm circumference for age.Zailina (2008)EffectChildren aged 7 and20 in USA; n=236Prospective &cross-sectionalDentin Pb level of teeth lost before age 7 was inversely associated with BMI at age7 and BMI at age 20,not weight or height.No association between growth & bonePb at age 20Kim (1995)EffectChildren 1-10 yearsold in Dallas; n=139Cross-sectionalConcurrent blood Pb was inversely associated with height, weight, and headcircumference.Little (1990)EffectChildren 5-13 yearsold in Korea; n=108Cross-sectionalConcurrent blood Pb (mean, 2.4μg/dL) was inversely associated with heightand arm length butnot with weight or BMI.Min (2008)No effectChildren 10-13 yearsold in Egypt; n=41Cross-sectionalMean height and weight did not differ as a percentage of median for age and sexfor individual above and below blood Pb of 10μg/dL in children with mean Pb of9.46μg/dL.Tomoum (2010)EffectChildren age 18-36mo in Omaha; n=21Cross-sectionalConcurrent blood Pb (mean, 6.4μg/dL) was inversely associated with headcircumference.Stanek (1998)Epidemiological studies of Pb exposure and growth are listed by decreasing cohort size and grouped together for overlapping or shared study groups.Abbreviations:BMI, body mass index; NHANES, National Health and Nutrition Examination Survey.NTP Monograph on Health Effects of Low-Level Lead 97 Pb >7.7 μg/dL ( Shukla et al. 1989 ). A subsequent study supported the combined effect of blood Pb at 3-15 months of age and concurrent blood Pb level for height at 33 months ( Shukla et al. 1991 ). In children from the Mexico City Prospective Study, infant blood Pb at 1 year of age was inversely associated with head circumference up to 4 years of age ( Rothenberg et al. 1993
, Rothenberg et al. 1999 ). Greene et al. ( 1991 ) reported that blood Pb in children at 6 months of age was related to subsequent growth at borderline sta

tistical 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 sup

port an inverse association between concurrent blood Pb (with mean levels of 2-15 μg/dL a nd higher) and height. Additional measures of growth such as head circumference, arm or leg length, and weight were also related to blood Pb in some studies, but these endpoints were less widely reported, and weight is less consistently associated with blood Pb. Data from NHANES II support an inverse association between concurrent blood Pb from 5 to 35 μg/dL and height, weight, and chest circumference ( Schwartz et al. 1986
, Frisancho and Ryan 1991 ). The inverse relationship between height (but not weight) and blood Pb was further supported by studies using data from NHANES III on children 1-7 years of age with mean blood Pb of 4 μg/dL ( Ballew et al. 1999 ) and in girls 8-16 years of age with blood Pb ≥3 μg/dL ( Selevan et al. 2003 ) compared to girls with blood Pb of 1 μg/dL. Other large cross-sectional studies have reported a similar inverse relationship between blood Pb and markers of growth: height and leg and arm length in Polish children 7-15 years of age (8 μg/dL m ean blood Pb and n=899) ( Ignasiak et al. 2006 ); height, weight, and head circumference in Children 2-12 years of age in Dallas (25 μg/dL mean blood Pb and n=764; 2 μg/dL mean blood Pb and n=390) ( Little et al. 2009 ); height in 7-year-olds in Mexico (12 μg/dL mean blood Pb; n=602) ( Kordas et al. 2004 ); height, head circumfer

ence, and chest circumference in children 6-9 years of age in Greece (12 μg/dL mean blood Pb; n=522) ( Kaf

ourou et al. 1997 ); and height in boys 8 and 9 years of age in Russia (3 μg/dL median blood Pb; n=489) ( Hauser et al. 2008 ). None of the studies that support an effect level <5 μg/dL con trolled for parental height, which may relate to the cross-sectional nature of the studies. However, parental height is considered in prospective studies as well as a few cross-sectional analyses that support an association with blood Pb levels <10 μg/dL ( Shukla et al. 1989
, Greene and Ern

hart 1991
, Shukla et al. 1991
, Vivoli et al. 1993
, Kaf

ourou et al. 1997
, Sanin et al. 2001
, Schell et al. 2009 ). There are also a number of smaller cross-sec

tional studies with sample sizes ranging from 330 to 21 that support an association between lower height and higher concurrent blood Pb levels (see Table 8.4 and Postnatal Growth section of Appendix E: Repro

ductive and Developmental Effects). The data are not completely consistent, because Zailina et al. ( 2008 ) did not find a correlation between blood Pb in a study of 269 children in Malaysia in the relative height for age, and Tomoum et al. ( 2010 ) did not find a differ

ence between individuals above and below 10 μg/dL in a study of 41 children 12 years of age in Egypt in the mean height as a percentage of median height. Although the finding of an association in a study with a small sample size suggests a larger magnitude of effect, it is less informative when studies with a small sample size such as the data from Egypt, fail to find an effect. In the Yugoslavia Prospective Study, higher blood Pb in 4-year-olds was associated with lower height in Pristina at blood Pb levels <15 μg/dL, but blood Pb levels from 20 to 40 μg/dL in Tit ova-Mitro

vica (a Pb smelter town) were not associated with height ( Factor-Litvak et al. 1999 ). Although Vivoli et al. ( 1993 ) reported an association between higher blood Pb and lower height in girls from 11 to 13 years of age, 12-year-old girls, and 13-year-old boys, the associa

tion was not significant for all age groups (i.e., not for all boys combined, 11-year-old boys, 11-year-old girls, 12-year-old boys, or 13-year-old girls). Few studies of growth include measures of exposure other than blood Pb data. Kim et al. ( 1995 ) reported an association between higher dentin Pb levels in teeth lost before 7 years of age and lower BMI at 20 years of age; however, neither dentin Pb at 7 years of age nor concurrent bone at 20 years of age was related to height or weight in the 20-year-olds. Sanin et al. ( 2001 ) reported an association between either maternal bone Pb or infant blood Pb and lower weight and less weight gain through 12 months of age, but the study did not report data on height.



### Summary of Support for Conclusions Animal data support a decrease in postnatal growth rate associated with prenatal and developmental Pb98 NTP Monograph on Health E ffects of Low-Level Lead exposure at high blood Pb levels in some studies (i.e., 40-100μg/dL Sprague Dawley rats; see U.S. EPA 2006 for recent reviews of the animal data
, ATSDR 2007 ). The human data include multiple prospective stud

ies and numerous cross-sectional studies. The three available prospective studies support an association between maternal blood Pb and smaller head circum

ference from 1 to 4 years of age ( Rothenberg et al. 1993
, Rothenberg et al. 1999
, Schell et al. 2009 ). The three available prospective studies addressing the potential association between maternal blood Pb and height or weight do not support an association ( Lamb et al. 2008
, Schell et al. 2009 ), although maternal Pb may be a contributing factor along with infant blood Pb lev

els ( Shukla et al. 1989 ). The prospective studies that investigated the relationship between early-life blood Pb levels in children and measures of growth support a relationship between higher Pb and lower growth. The two Rothenberg et al. ( 1993
, 1999 ) publications from the Mexico City Prospective Study reported an association between higher blood Pb in infants at 1 year of age and smaller head circumference up to 4 years of age, and Greene et al. ( 1991 ) reported that blood Pb in 1-year-old children was related to subse

quent head circumference (p=0.05), length (p=0.06), and weight (p=0.08) in children in the Cleveland Lead Study. The strength of the evidence comes from the number of cross-sectional studies, including large numbers of subjects, such as the NHANES data sets, that report an inverse association between concur

rent blood Pb (mean, 2-15 μg/dL) in children from 1 to 16 years of age and height or other indicators of postnatal growth. However, cross-sectional stud

ies have considerable limitations because they only provide concurrent blood Pb measurements and lack data on cumulative Pb or Pb exposure at earlier time points that may be critical for growth. The consistency of effects across studies, among multiple populations in both males and females, lends weight to the evi

dence that decreased growth indicated by reduced height (and, to a lesser extent, other measures) is associated with blood Pb. The conclusion of sufficient evidence that blood Pb levels <10 μg/dL in children are associated with decreased growth is based onthe combination of strong support from the crosssectional studies and the additional support from the four prospective studies that evaluate blood Pb levels in children on subsequent growth. Although several studies report an association down to blood Pb levels <5 μg/dL, these studies do not adequately control for parental height, which is a known important predictor for postnatal growth, so there is inadequate data to evaluate an association with blood Pb levels <5 μg/dL. Data from the Cincinnati Lead Study suggest that growth may depend on a combination of gestational and early-childhood exposure, so effects may only be observed in children of mothers with elevated blood Pb that subsequently experienced elevated blood Pb levels in early childhood. The conclusion of limited evidence that maternal blood Pb <10 μg/dL is associ

ated with decreased head circumference in children up to 4 years of age is based on three studies from two groups. The NTP’s conclusions on an inverse associa

tion between blood Pb and growth are in line with the 2007 ATSDR Toxicological Profile for Lead, although ATSDR does not specifically identify an effect level for growth, and the EPA’s 2006 AQCD for Lead ( U.S. EPA 2006 ) reviews the animal data in greater detail than the epidemiological data relating to growth.



### 8.3.3 Sperm There is sufficient evidence that blood Pb ≥15 μg/dL is associated with adverse effects on sperm or semen in adult men, and inadequate evidence for adverse effects on sperm at blood Pb levels <15 μg/dL. Although the re is no single measure of adverse effects that is consis

tently associated with elevated blood Pb, occupational studies report effects that include lower sperm num

bers, decreased motility, reduced semen volume, and an increased percentage with abnormal morphology. Decreased sperm count, density, and/or concentra

tion have been reported in multiple retrospective and cross-sectional studies of men with occupational exposure to Pb at mean blood Pb levels from 15 to 68 μg/dL ( Table 8.5 and Sperm section of Appendix E: Reproductive and Developmental Effects). Among men recruited from infertility or in vitro fertilization (IVF) clinics, decreased sperm concentrations and increases in the percentage of abnormal sperm are associated with blood Pb levels from 1 to 15 μg/dL in se veral stud

ies ( Chia et al. 1992
, Telisman et al. 2007
, Meeker et al. 2008 ). Men recruited from infertility clinics may repre

sent a susceptible subpopulation, and even within this group the evidence is not consistent, because several studies did not find adverse sperm effects at blood Pb levels <15 μg/dL (mean, 7-10 μg/dL) ( Xu et al. 1993
, Mendiola et al. 2011 ). The conclusion of inadequate evidence that blood Pb levels <15 μg/dL are associatedNTP Monograph on Health Effects of Low-Level Lead 99Table 8.5: Studies of sperm and semen parameters associated with low-level Pb exposure used to develop conclusionsRelevance toConclusionsStudy DescriptionStudyDesignKey Reproductive/Developmental FindingsReferenceSmelter Employees, British ColumbiaEffectMale employees;n=119RetrospectiveBlood Pb levels (>40μg/dL) were associated with decreased sperm concentra-tion,but not with motility or morphology.Alexander (1996b)Male employees; n=81of 119 originalRetrospectiveBlood Pb levels (mean, 22.8μg/dL) were associated with decreased sperm countand concentration, butnot with motility or morphology.Alexander (1998)EffectMale Pb workers inEurope; n=486Cross-sectionalBlood Pb (>50μg/dL) was associated with lower sperm count and density,butnotwith volume, density ≤20 million/mL, or chromatinin Pb workers (n=306; meanblood Pb, 31μg/dL) and 197 referents (mean blood Pb, 4.4). The authors suggesta threshold of 44μg/dL blood Pb for association with sperm concentration.Bonde (2002)EffectMen at clinic in Croatia;n=240Cross-sectionalBlood Pb (median, 4.9μg/dL) was associated with increased percentages ofpathological sperm, wide sperm, round sperm,but not with sperm count, den-sity, viability, motility, or other measures,in men at fertility clinic or donors forartificial insemination.Telisman (2007)No effectMen at infertility clinic inChina; n=221Cross-sectionalBlood Pb (mean, 8μg/dL) and semen plasma Pb (mean, 1.27μg/dL) werenot cor-related with sperm density, motility, viability, morphology, or semen volumein menscreened for infertility.Xu (1993)EffectMen at fertility clinic inMichigan; n=219Cross-sectionalBlood Pb (median, 1.5μg/dL) was associated with a greater odds ratio for below-reference sperm concentrationbut not with count, volume, motility, or morphol-ogy, for men at an infertility clinic.Meeker (2008)EffectMale Pb workers andreferents; n= 200Cross-sectionalMen with Pb exposure (blood Pb ≥41μg/dL; n=100) showed reduced sperm motilityand semen volume and increased abnormal morphology compared to technicians(n=50) and referents (n=50).Lancranjan (1975)No effectMen at fertility clinic inGermany; n=190Case-controlBlood Pb not reported; grouped by sperm concentration, motility, and percentnormal morphology, there were no differences in semen Pb among 172 infertilemen and 18 referents.Jockenhovel (1990)No effectMen at fertility clinic inFinland; n=188Cross-sectionalBlood Pb not reported;sperm density, motility, and morphology did not differbysemen Pb above and below 0.2μg/dL.Saaranen (1987)EffectMale smelter workers inBelgium; n=159Cross-sectionalSperm concentration was significantly reduced in Pb workers (mean blood Pb,31μg/dL; n=68) compared to hospital staff (referents; median, 3.4μg/dL; n=91).Mahmoud (2005)EffectMale Pb workers inCroatia; n=146Cross-sectionalBlood Pb levels were associated with decreased sperm count (blood Pb≥~25μg/dL), decreased sperm density, increased abnormal head morphology,and other parameters in Pb workers (mean blood Pb, 39μg/dL; n=98) and referents (mean, 11μg/dL; n=51).Telisman (2000)100 N TP Monograph on Health Effects of Low-Level LeadReproductiveEffectsTable 8.5:Studies of sperm and semen parameters associated with low-level Pb exposure used to develop conclusions(continued)Relevance toConclusionsStudy DescriptionStudyDesignKey Reproductive/Developmental FindingsReferenceEffectMale Pb workers inIndia; n=130Cross-sectionalOccupational exposure (mean blood Pb, 48μg/dL (n=30) and 77μg/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, 14μg/dL; n=50)Naha (2006)EffectMale battery workers inIndia; n=120Cross-sectionalOccupational Pb exposure (blood Pb ≥~14μg/dL; n=80) was associated withdecreased sperm count, density, motility, semen volume, increased abnormal morphology, and other sperm changes compared to referents (blood Pb7μg/dL; n=40).Naha (2005)EffectMale Pb workers inItaly; n=120Cross-sectionalBlood Pb levels were associated with decreased sperm count in 39 employees ofa Pb battery plant (mean Pb, 61μg/dL) and 81 workers at a cement plant (mean,18μg/dL).Assennato(1986,1987)EffectMale paint workers inIndia; n=100Cross-sectionalOccupational Pb exposure (mean blood Pb, ≥50μg/dL; n=50) was associated withdecreased sperm count, motility, semen volume, and increased abnormal morphology and DNA hyploidy, compared to non-occupationally exposed workers (n=50).Naha (2007)No effectMale battery workers inEngland; n=97Cross-sectionalSperm count, density, and motilitywere notassociated with blood(mean Pb, 53μg/dL)or semen Pb(mean Pb, 9.6μg/dL). Percent of normal sperm was reduced at p=0.06.Robins (1997)EffectMen in IVF clinic in NewYork; n=96Cross-sectionalBlood Pb not reported; semen plasma Pb (mean, 40μg/dL) was associated withdecrease in sperm motility, concentration, morphology, other sperm measures, anddecreased IVF fertilization.Benoff (2003a)EffectMale battery workers inTaiwan; n=80Cross-sectionalBlood Pb levels (mean, 40μg/dL) were associated with increased percent abnormalsperm and sperm head morphology, and DNA denaturation,butnot with spermcount, semen volume, or motility.Hsu (2009)EffectMale battery workers inArgentina; n=68Cross-sectionalMale Pb battery workers with blood Pb ≥49μg/dL (n=38) show reduced spermmotility and semen volume and increased abnormal morphology compared toreferents (n=30).Lerda (1992)Blood Pb:No effect;Semen Pb:EffectMen living near a smelterin Mexico; n=68Cross-sectionalBlood Pb (mean, 9μg/dL) wasnot associated with sperm parameters. Sperm Pb(0.05 ng/106cells) was associated with decreased sperm concentration, morphology, viability, motility; semen Pb (mean, 0.2μg/dL) was associated with decreasedvolume and increased nuclear chromatin condensation.Hernandez-Ochoa(2005)Blood Pb:No effect;Semen Pb:EffectMen at fertility clinic inSpain; n=60Cross-sectionalSperm motility, concentration, and morphology did not differ by blood Pb(mean,9.8μg/dL) for men at infertility clinic (n=30) and referents (n=30); motility wasinversely related to semen Pb (3.0μg/dL).Mendiola (2011)EffectMale metal workers inPoland; n=63Cross-sectionalPercent motile sperm was decreased in workers with high blood Pb (>40μg/dL;n=29; mean Pb, 53μg/dL) compared to workers with low Pb (<40μg/dL; n=20)or referents (mean, 8μg/dL; n=14);semen volume, sperm count, and morphology did not differ.Kasperczyk (2008)NTP Monograph on Health Effects of Low-Level Lead 101Table 8.5:Studies of sperm and semen parameters associated with low-level Pb exposure used to develop conclusions(continued)Relevance toConclusionsStudy DescriptionStudyDesignKey Reproductive/Developmental FindingsReferenceNo effectMen in China; n=56Cross-sectionalBlood Pb not reported; semen plasma Pb (mean, 0.78μg/dL) was not correlatedwith sperm count, density, motility, morphology, or viability; semen Pb was asso-ciated with 8-OHdG in men (n=56; group characteristics not reported).Xu (2003)EquivocalMen at infertility clinic inEurope; n=47Cross-sectionalBlood Pb not reported; authors state inverse correlation between Pb and flagel-lum ball, and that no correlation was detected between pathological changesand elements.Slivkova (2009)EffectMen in andrology clinicin China; n=35Cross-sectionalBlood Pb was elevated (mean, 7.2μg/dL) in men with <40% sperm motility com-pared to men with >40% sperm motility (mean blood Pb, 5.1μg/dL) .Chia (1992)No effectMen in Germany; n=22Cross-sectionalBlood Pb not reported; Pb in semen (0.98μg/dL) and semen plasma (0.77μg/dL)was not correlated to sperm density, count, motility, or morphology in men with nooccupational Pb exposure.Noack-Fuller (1993)No effectMen in Connecticut;n=21Cross-sectionalNo correlation between semen Pb(mean, 5.9μg/dL)and sperm count, density, orsemen protein in medical students and technicians; unclear if blood Pb (13.1μg/dL)effect on sperm examined.Plechaty (1977)EffectMale Pb workers in India;n=20Cross-sectionalMen with occupational Pb exposure (average blood Pb, 42.5μg/dL; n=10) hadlower sperm count, decreased percent motile sperm, and increased percentabnormal sperm compared to referents (n=10).Chowdhury (1986)EffectMale battery workers inNetherlands; n=19Cross-sectionalDecrease in blood Pb (median, 42-19μg/dL) was associated with improvednumber of motile sperm and penetration in men undergoing treatment to lowerblood Pb.Viskum (1999)EquivocalMen with high Pb andreferents; n=19Cross-sectionalMen with chronic high occupational Pb exposure (mean blood Pb, 39μg/dL; n=10)didnot differ from referents(Pb=16μg/dL; n=9)in sperm volume, motility, or percentabnormal; two men with highest Pb demonstrated peritubular fibrosis, oligospermia, and Sertoli cell vacuolization.Braunstein (1978)EffectMale semen donors inNew York; n=15Cross-sectionalBlood Pb not reported; semen plasma Pb was associated with sperm motility, premature acrosome loss, and fertilization rate in IVF but not with spermconcentration.Benoff (2003b)EffectMen with Pb toxicity inConnecticut; n=7Case-seriesTwo of 7 men with occupational Pb intoxication had no sperm; 2 had reducedsperm count; 4 of the 5 with sperm had reduced sperm motility.Cullen (1984)EffectA firearms instructor inNew YorkCase ReportA case report of increases in sperm density and total sperm count and decreases inabnormal morphology in parallel with decreasing blood Pb with chelation therapyin a 41-year-old.Fisher-Fischbein(1987)Epidemiological studies of Pb exposure and sperm effects listed by decreasing cohort size and grouped together for overlapping or shared study groupsAbbreviations:8-OHdG, 8-hydroxydeoxyguanosine; IVF, in vitro fertilization.102 NTP Monogr aph on Health Effects of Low-Level Lead with adverse effects on sperm is based on the limited number of studies with evidence of effects at these lower blood Pb levels, the lack of consistency in the sperm data from men attending infertility or IVF clin

ics, and the uncertainty in using this patient group to extrapolate to other groups. There are few studies of the relationship between sperm and blood Pb in the general population. Twelve occupational studies report adverse effects on sperm at blood Pb levels of 15-50 μg /dL using mean blood Pb levels of occupationally exposed men or blood Pb levels of workers categorized by blood Pb levels. Lower sperm counts or concentra

tion are associated with the following blood Pb con

centrations: approximately 15 μg /dL (estimated from graphs presented) in Naha et al. ( 2005 ); 20 μg/dL in De Rosa et al. ( 2003 ); approximately 25 μg/ dL (estimated from graphs presented) in Telisman et al. ( 2000 ); 31 μg/dL in Mahmoud et al. ( 2005 ); ≥40 μg/dL in Alexander et al. ( 1996b ); ≥44 μg/dL in Bonde et al. ( 2002 ); 48 μg/dL in Naha et al. ( 2006 ); and 50 μg/dL in Naha et al. ( 2007 ). Sperm motility is reduced at blood Pb levels of 20 μg /dL in De Rosa et al. ( 2003 ); 41 μg/dL blood Pb in Lancranjan et al. ( 1975 ); 49 μg/dL blood Pb in Lerda ( 1992 ); 53 μg/dL blood Pb in Kasperczyk et al. ( 2008 ); and 15 μg/d L, 48 μg/dL , and 50 μg/d L in three studies already listed above for decreased sperm count ( Naha et al. 2005
, Naha and Chowdhury 2006
, Naha and Manna 2007 ). Five of the studies sup

port effects in men with mean blood Pb levels from 15 to 31 μg/dL. Hsu et al. ( 2009 ) reported a threshold for increased abnormal sperm morphology at blood Pb levels ≥45 μg/dL in Pb battery workers, relative to workers with blood Pb <25 μg/ dL. However, the extent of DNA denaturation per cell was significantly increased at lower blood Pb levels, among workers in both the mid-Pb group (25-45 μg/dL) and high-Pb group (>45 μg/dL) workers ( Hsu et al. 2009 ). A similar threshold of approximately 25μg/dL was associated with decreased sperm count relative to workers with blood Pb <10 μg/dL in a study of 146 industrial work

ers in which Pb was dichotomized into six groups (n=25 per group) with mean blood Pb levels of <10, 12, 25, 35, 42, and 58 μg/dL (estimated from Figure 4 in Telisman et al. ( 2000 )). Naha et al. ( 2005 ) reported effects on sperm in Pb workers with mean blood Pb of approximately 15 μg/dL (estimated from data pre

sented in a graph; n=10 per group) compared to work

ers with mean blood Pb of 7 μg/dL. The Pb workers in the Naha et al. (2005) study had the lowest mean blood Pb level (15 μg/dL compared to 48-50 μg/dL ) in a series of papers from the same group ( Naha et al. 2005
, Naha and Chowdhury 2006
, Naha and Manna 2007 ) that consistently report effects on sperm count, motility, semen volume, and abnormal morphology in all Pb-exposed groups working in paint and battery factories compared to a reference group not work

ing in the factory. A cross-sectional study of 68 Pb smelter workers reported reduced sperm concentra

tion in the Pb workers (mean blood Pb, 31 μg/dL) compared to 91 hospital personnel (mean blood Pb, 3.4 μg/dL) ( Mahmoud et al. 2005 ). De Rosa et al. ( 2003 ) reported lower sperm motility, viability, penetration, and velocity in 85 tollgate workers with mean blood Pb of 20 μg /dL compared to referents with mean blood Pb of 7 μg /dL, and linear regres

sion for sperm count was also significant. The occu

pational studies of Naha et al. ( 2005 ), Telisman et al. ( 2000 ), Mahmoud et al. ( 2005 ), De Rosa et al. ( 2003 ) and Hsu et al. ( 2009 ) report adverse sperm effects down to blood Pb levels of 15-31 μg/dL. A closer examination of the reference groups in the above studies adds to evidence for a threshold closer to 20 μg/dL for adverse effects on sperm than a threshold of 40 μg/dL; however, the data are not consistent. Of the seven studies that report the higher threshold, five rely on internal reference groups with blood Pb levels >10 μg/dL ( Lerda 1992
, Alexander et al. 1996b
, Naha and Chowdhury 2006
, Naha and Manna 2007 ) or fail to report blood Pb levels in the reference group ( Lancranjan et al. 1975 ), so these studies have limited ability to detect effects in the lower concen

tration range. Among the six studies with a reference group <10 μg/dL , four reported effects on sperm at mean blood Pb levels from 15 to 31 μg/dL: ~15 μg/dL in Naha et al. ( 2005 ), 20 μg/dL in De Rosa et al. ( 2003 ), ~25 μg/dL in Telisman et al. ( 2000 ), and 31 μg/dL in Mahmoud et al. ( 2005 ). The other two studies ( Bonde et al. 2002
, Kasperczyk et al. 2008 ) report effects in men with blood Pb levels >40 μg/dL and not in men with blood Pb <40 μg/dL. While adjustment for poten

tial confounders is not described in several of the stud

ies, the studies of Telisman et al. ( 2000 ), Mahmoud et al. ( 2005 ), and Bonde ( 2002 ) are all adjusted for fac

tors known to effect sperm count or function, such as age and period of abstinence, so a lack of adjustment does not explain the difference in the effect levels identified in the studies.NTP Monograph on Health Effects of Low-Level Lead 103 In addition to the occupational Pb exposure studies, there are a number of studies of individu

als attending infertility or IVF clinics. Three of these studies reported an association between blood Pb levels <10 μg /dL and several sperm parameters, whereas two studies with similar blood Pb levels did not. In a cross-sectional study of 240 Croatian men that combined men at an infertility clinic with men donating for artificial insemination, blood Pb in the range of 1.1-14.9 μg/dL was associated with increasing percentage of pathologic sperm and wide sperm, with no effect on motility, viability, count, or other measures ( Telisman et al. 2007 ). In a study of 219 men attending infertility clinics in Michigan, blood Pb was marginally (p-trend=0.07) related to sperm concentration below reference (<20 mil./mL) ( Meeker et al. 2008 ). The odds ratio for low sperm concentration compared to the reference was signifi

cant for individuals in the second and third quartile compared to the first quartile: (second quartile, 1.1- 1.5 μg/dL: OR=0.89 (95% CI: 0.27, 2.89); third quartile, 1.5-2.0 μg/dL: OR=3.94 (95% CI: 1.15, 13.6); fourth quartile, >2.0 μg/dL : OR=2.48 (95% CI: 0.59, 10.4) ( Meeker et al. 2008 ). Chia et al. ( 1992 ) reported significantly elevated blood Pb (mean, 7.2 (SD: 6.2) μg/dL vs. 5.1 (SD: 2.4) μg/dL; p=0.0034) in men with <40% sperm motility among 35 men attending an andrology clinic in Singapore. The other two studies that report blood Pb and sperm parameters for men attending infertility clinics in China (n=221 at mean blood Pb of 8 μg/dL) and Spain (n=60 at mean blood Pb of 10 μg/dL) did not find an association between blood Pb and effects on sperm ( Xu et al. 1993
, Men

diola 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 associ

ated with blood Pb levels in the general population that were not patients at infertility clinics, and the available studies do not support an effect of blood Pb on sperm. Hernandez-Ochoa et al. ( 2005 ) and Plechaty et al. ( 1977 ) did not detect a significant asso

ciation between blood Pb (means, 9 and 13 μg/dL

, respectively) and sperm parameters, but the studies are relatively small, with fewer than 89 men sampled from the two studies combined. It is also worth not

ing that two Pb-treatment studies support the inverse association between high blood Pb levels and sperm parameters. Motility, penetration, and morphology were all improved in 19 Danish Pb-workers treated for high Pb levels in association with lowering blood Pb from a median of 42 μg/dL to 19.9 μg/dL ( Viskum et al. 1999 ). Similar results were observed in a casereport of a firearms instructor with blood Pb levels that were reduced from 88 to 30 μg/dL ( Fisher-Fisch

bein et al. 1987 ). In studies that report semen Pb levels, the results are inconsistent on whether semen Pb levels are asso

ciated with sperm parameters or whether semen Pb is a better measure of exposure than blood Pb for effects of Pb on sperm. Five reported sperm effects associated with semen Pb ( Benoff et al. 2003a
, Benoff et al. 2003b
, Hernandez-Ochoa et al. 2005
, Slivkova et al. 2009
, Mendiola et al. 2011 ), and six did not find an association ( Plechaty et al. 1977
, Saaranen et al. 1987
, Jockenhovel et al. 1990
, Noack-Fuller et al. 1993
, Robins et al. 1997
, Xu et al. 2003 ). Several stud

ies (e.g., Saaranen et al. 1987
, Jockenhovel et al. 1990
, Noack-Fuller et al. 1993
, Benoff et al. 2003a
, Benoff et al. 2003b
, Xu et al. 2003
, Slivkova et al. 2009 ) report only semen or sperm Pb, so the usefulness of semen Pb cannot be compared to blood or bone Pb as a potential biomarker of Pb exposure related to sperm parameters. In studies that report both blood and semen Pb, there is some support that both measures of exposure are equally good indicators of Pb expo

sure, 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 associa

tion that is consistent with both blood and semen Pb ( Xu et al. 1993
, Robins et al. 1997 ). Other studies have reported a significant association of sperm parameters with semen Pb (and not blood Pb) ( Hernandez-Ochoa et al. 2005
, Mendiola et al. 2011 ) or blood Pb (and not semen Pb) ( Assennato et al. 1986
, Kasperczyk et al. 2008 ). In a study of 81 employees of the Cominco smelter in British Columbia, semen and blood Pb levels were associated with decreased sperm concentration; however, after adjustment for ejaculate volume, blood Pb remained significant and semen Pb levels were no longer significantly related to sperm concentration ( Alexander et al. 1998 ).



### Summary of Support for Conclusions Animal data support adverse effects of Pb exposure on sperm and semen, including decreased sperm count, reduced sperm motility, and increased morphological104 NTP Monogr aph on Health Effects of Low-Level Lead abnormalities, in sperm in some studies (see U.S. EPA 2006 for recent reviews of the animal data
, ATSDR 2007 ). Although the animal data generally support adverse effects of Pb on sperm, effects may be asso

ciated with high doses (40-75 μg/dL in rats), and the animal data display differences in sensitivity to sperm effects by species and strain (effects observed down to 16-24 μg/dL in rabbits), differences that are likely to be exacerbated by variation in route and duration of exposure, age at initial exposure, and chemical form of Pb used in the experiment. The human data include 12 studies of men with occupational expo

sure that report effects on sperm or semen at blood Pb levels from 15 to 50 μg /dL. This is supported by six studies reporting effects on time to pregnancy or fertility at similar Pb levels (10-46 μg/d L) in men described in Section 8.3.4 Fertility/Delayed Con

ception Time below. The conclusion of sufficient evi

dence that blood Pb levels ≥15 μg/dL are associated with adverse effects on sperm or semen is based on these studies and specifically the five studies that report effects on sperm at blood Pb levels from 15 to 31 μg/dL. Although occupational studies support adverse sperm effects down to 15 μg/ dL, the lower threshold of blood Pb level associated with these effects is unclear. Several studies of men recruited from IVF or infertility clinics report effects at blood Pb levels <10 μg/dL. However, men recruited from infertility clinics may represent a susceptible subpopulation, and even within this group, the evidence is not consistent. One challenge in determining the lower limit is that much of the data come from occupa

tional studies in which the mean blood Pb level is 30-40 μg/dL. Also, as discussed above, there are few studies of effects in the general population, and many studies have a low ability to detect effects associated with lower blood Pb levels, because occupational studies generally do not include many men with lower blood Pb levels (i.e., blood Pb <10 μg/dL). A number of older studies of sperm or semen param

eters (e.g., Lancranjan et al. 1975
, Lerda 1992 ) do not adjust for confounding factors such as period of abstinence, age, and smoking. In addition, no human data were located that examine effects of early or developmental exposure on sperm parameters as adults. The NTP’s conclusion of sufficient evidence that blood Pb levels ≥15 μg/d L are associated with adverse effects on sperm or semen extends the conclusions of the 2007 ATSDR Toxicological Profile for Lead ( ATSDR 2007 ) and 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) down to 15 μg/dL blood Pb from the range of 30-45 μg/dL suggested by the 2006 EPA and 2007 ATSDR documents.



### 8.3.4 Fertility/Delayed Conception Time There is sufficient evidence that paternal blood Pb levels ≥20 μg/dL are associated with delayed concep

tion time and limited evidence that blood Pb levels ≥10 μg/dL in men are associated with other measures of reduced fertility. Four studies reported increased time to pregnancy or decreased odds of conception over a given time (fecundability) in men with blood Pb levels from 20 to 40 μg/dL , and a fifth study reported decreased odds ratio for probability of live birth in Pb workers with mean blood Pb of 46 μg/dL (see Fertil

ity /Delayed Conception Time section of Appendix E: Reproductive and Developmental Effects). A lower effect level of 10 μg/dL is supported by a single large (n=4,146) retrospective occupational study that reported increased odds of infertility among men with blood Pb ≥10 μg/dL ( Sallmen et al. 2000b ), pro

viding limited evidence for effects on fertility at blood Pb levels down to 10 μg/dL in men. The database of studies that examined male Pb exposure and fertility also includes several occupational studies that did not observe a significant relationship between blood Pb levels in men and fertility or time to pregnancy. There is inadequate evidence that blood Pb levels of ≤10 μg/dL in women are associated with decreased fertility or greater time to pregnancy because few studies address these effects, and all of them report that maternal blood Pb levels are not associated with time to pregnancy. There is one prospective study of time to pregnancy for women in the general population with blood Pb levels <10 μg/dL , and this study found no effect on time to pregnancy. Several studies of couples attending IVF or infertility clinics report an association between blood Pb levels from 1 to 30 μg/dL and a decrease in some measure of fertil

ity (e.g., fertilization or embryo quality); additional studies are required to confirm this relationship. The best studies of fertility and delayed conception time include exposure measurements in both partners, but these data are often not collected. Women and men recruited from infertility or IVF clinics may rep

resent a susceptible subpopulation, and the effects observed in this patient population should be appliedNTP Monograph on Health Effects of Low-Level Lead 105 with caution to the general population. There are not enough studies of fertility with Pb exposure data for women in the general population or even with occu

pational exposure to evaluate the potential relation

ship between Pb exposure and fertility in women. Six occupational studies in five groups report decreased fertility or greater time to pregnancy for men at blood Pb levels of 10-46 μg/dL , and four other studies report no association at similar blood Pb lev

els. In a cross-sectional study of 85 tollgate workers with blood Pb levels of 20 μg/dL compared to 85 ref

erents 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 preg

nancy and reduced odds of conception over a given time compared to referents (fecundability ratio (FR)) at blood Pb levels ≥30 μg/dL (blood Pb 30-39 μg/dL: FR=0.52 (95% CI: 0.35, 0.77); blood Pb ≥40 μg/dL: FR=0.40 (95% CI: 0.27, 0.59); ( Shiau et al. 2004 ). In retrospective occupational exposure studies of men monitored for Pb exposure by the Finnish Institute of Occupational Health, Sallmen et al. ( 2000a ) reported the decreased FR relative to the reference group (FR=0.57 (95% CI: 0.34-0.91)) among men (n=502) with blood Pb ≥31 μg/dL in analyses that included only full-term pregnancies. Apostoli et al. ( 2000 ) reported a significant delay in time to pregnancy for men with blood Pb ≥40 μg/ dL (p=0.012) in a study of 251 men working at a Pb-related factory in Italy; however, the time to pregnancy was not reduced at lower blood Pb levels, and FR analysis suggests a shorter time to pregnancy at lower blood Pb levels. In a cross-sectional study of 365 male Pb battery plant workers with mean blood Pb of 46 μg/ dL, the odds ratio for probability of live birth was decreased com

pared to workers with mean blood Pb of 10 μg/dL (OR=0.65 (95% CI: 0.43, 0.98) ) or relative to preex

posure (OR=0.43 (95% CI: 0.25, 0.73)) ( Gennart et al. 1992b ). The five studies described above support greater time to pregnancy or reduced fertility in men at blood Pb levels of 20 μg/dL , 30 μg/dL , 31 μg/dL

, 40 μg/dL, and 46 μg/dL , and a large retrospective study reported increased odds ratio of infertility at even lower blood Pb levels, down to 10 μg/d L. In a retrospective studies of men monitored for Pb exposure by the Finnish Institute of Occupational Health, Sallmen et al. ( 2000b ) reported increased odds of infertility (RR=1.27 (95% CI: 1.08, 1.51)) and decreased success ratio (SR=0.86 (95% CI: 0.77, 0.97) for pregnancy among wives of male workers (n=4,146) with blood Pb ≥10 μg/dL. Male Pb workers reporting to the New York State Heavy Metals Registry with more than 5 years of Pb work had a reduced fertil

ity rate relative to bus drivers or Pb workers with <5 years of occupational exposure; however, blood Pb levels alone were not related to fertility ( Lin et al. 1996 ). There are also four retrospective studies that report no association between time to pregnancy or odds ratio for fertility in men occupational exposed to Pb. Paternal Pb was not associated with standard

ized fertility ratio in 376 male Pb battery workers compared to preemployment group or workers with blood Pb <25 μg/dL ( Selevan et al. 1984 ). Odds ratios for reduced fertility did not differ between 1,349 Danish Pb workers with a mean blood Pb of 36 μg/dL compared to 9,596 referents (without blood Pb data) ( Bonde and Kolstad 1997 ). The odds ratios for infertil

ity did not differ between 229 Pb workers categorized by blood Pb into three groups of <40, 40-60, and >60 μg/dL and 125 reference employees classified as nonexposed ( Coste et al. 1991 ). Time to pregnancy was not increased in 638 Pb-exposed male workers (mean Pb, 29-37 μg /dL) compared to external ref

erents (n=236) or an internal control group (n=230) ( Joffe et al. 2003 ). Few studies have investigated the potential rela

tionship between Pb exposure and fertility or time to pregnancy in women. There is one prospective study of time to pregnancy for women in the general population, Bloom et al. ( 2011a ), which reported that blood Pb levels (mean, 1.5 μg /dL) were not associated with time to pregnancy in a study of 80 women in New York. Sallman et al. ( 1995 ) did not detect a relationship between odds of conception and maternal occupational blood Pb levels in a retro

spective study of 121 women in which exposure was estimated based on work descriptions and limited biological measurements. Several fertility studies report measures of expo

sure other than blood Pb levels. Three case-control studies of infertile men and two studies of men undergoing IVF examined semen Pb levels and did not report blood Pb data, so the usefulness of semen Pb cannot be compared to blood or bone Pb as a potential biomarker of Pb exposure related to sperm parameters. Semen Pb was higher in infertile men in two of the studies ( Saaranen et al. 1987
, Jockenhovel106 NTP Monogr aph on Health Effects of Low-Level Lead et al. 1990 ), but not in a third study ( Umeyama et al. 1986 ). Benoff et al. ( 2003a
, 2003b ) reported an inverse correlation between semen plasma Pb and IVF rate in two studies at IVF/ artificial insemination clinics in studies that did not include blood Pb values. Of the two studies reporting follicular Pb levels, one reported an association with fertility and one did not. In a study of 619 women undergoing IVF in Saudi Ara

bia, follicular Pb levels were not related to fertilization or pregnancy outcome, although blood Pb was asso

ciated with decreased OR for fertilization ( Al-Saleh et al. 2008a ). In a small study (n=9 women) that did not report blood Pb, follicular Pb was significantly higher from IVF patients that did not get pregnant than from women that did get pregnant ( Silberstein et al. 2006 ). Several studies of couples attending IVF or infer

tility clinics report an association between blood Pb levels and a decrease in some measure of fertility (e.g., fertilization or embryo quality). Results from studies of men or women reporting to IVF or infertility clin

ics should be interpreted with caution because they may represent a sensitive subpopulation. In a study of couples undergoing IVF in California, increased blood Pb levels in the women (n=24; mean blood Pb, 0.83 μg/dL) were associated with a decreased OR for higher embryo cell numbers (a measure of embryo quality) (OR=0.25 (95% CI: 0.07, 0.86)), or a 75% reduction in embryo quality for each 1 μg/dL increase in maternal blood Pb ( Bloom et al. 2010
, Bloom et al. 2011b ). Increased blood Pb levels in the men (n=15; mean blood Pb, 1.5 μg /dL) were also associated with a decreased OR for higher embryo cell numbers (OR=0. 58 (95% CI: 0.37, 0.91)), or a 42% reduction in embryo quality for each 1 μg /dL increase in paternal blood Pb. There are only two case-control studies of infertile patients with blood Pb levels: one comparing infertile men to fertile controls and one comparing infertile women to fertile controls. Blood Pb (36.8 μg/dL (SD: 12) vs. 23.2 μg/dL (SD: 5.6)) and semen Pb were higher in infertile men at a fertility clinic than in controls in a case-control study that examined Pb and smoking ( Kiziler et al. 2007 ). Self-reported Pb exposure did not differ between infertile men recruited from infertility clinics and fertile men from prenatal clinics ( Gracia et al. 2005 ). In a case-control study of women recruited at an infertility clinic (n=64) and controls from a postpartum clinic (n=83) in Taiwan, blood Pb levels >2 μg/dL were associated with an increased OR for infertility (OR=2.94 (95% CI: 1.18, 7.34)) ( Chang et al. 2006 ). In a study of 619 women undergoing IVF, mean blood Pb levels were significantly higher in women that failed to achieve fertilization (4.1 (SD: 3.7) μg/dL) than in women in which the IVF produced fertilized eggs (3.26 (SD: 2) μg/dL); however, blood Pb was not related to pregnancy outcome ( Al-Saleh et al. 2008a ).



### Summary of Support for Conclusions Animal data support adverse effects of Pb on fertil

ity in several studies at high blood Pb concentrations (>60μg/dL; see U.S. EPA 2006 for recent reviews of the animal data
, ATSDR 2007 ). Effects in male rodents exposed to Pb before mating include increased time to birth in mice and decreased pregnancy rate in mice or rats ( Gandley et al. 1999
, Pace et al. 2005 ). Female mice exposed to Pb during pregnancy exhibited smaller litter size in several studies ( e.g., Pinon-Latail

lade et al. 1995 ). The human data include six stud

ies of men with occupational exposure that report increased time to pregnancy or reduced fertility at blood Pb levels from 10 to 46 μg/dL. The conclusion of sufficient evidence that blood Pb levels ≥20 μg/dL are associated with delayed conception time is based on four studies reporting increased time to pregnancy with blood Pb levels of 20-40 μg /dL in men. This is supported by numerous studies reporting adverse effects on sperm at similar Pb levels (15-50 μg/dL) in men described earlier. Although some studies do not support an association between paternal blood Pb levels and time to pregnancy or fertility, the database (including the sperm data) provides sufficient evi

dence 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 associ

ated with decreased fertility is based on the above data with the addition of a single large retrospective occupational study that reported increased odds of infertility among men with blood Pb levels ≥10 μg/dL ( Sallmen et al. 2000b ). In the human data, few studies examined fertility or time to pregnancy with Pb expo

sure data in women, and both studies that examined time to pregnancy reported that maternal blood Pb was not related to time to pregnancy. The conclusion of inadequate evidence that blood ≤Pb 10 μg/d L in women are associated with increased time to preg

nancy or reduced fertility is based on the limited number of studies addressing these endpoints, and the lack of a significant association with blood Pb reported in some studies on time to pregnancy. TheNTP Monograph on Health Effects of Low-Level Lead 107 conclusion of inadequate evidence for effects on fertility in women is consistent with the 2007 ATSDR Toxicological Profile for Lead ( ATSDR 2007 ) and EPA’s 2006 AQCD for Lead; however, for men, the 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) states that epidemio

logical studies suggest a small association between blood Pb levels >45 μg/dL in men and increased time to pregnancy. The NTP conclusions of sufficient evi

dence 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 fer

tility are consistent with the conclusions of an effect of Pb in the 2006 EPA and 2007 ATSDR Lead docu

ments, but the NTP outlines the support for a lower effect level (i.e., 20 μg/dL rather than 30-45 μg/dL). While adjustment for potential confounders is not described in several of the studies, the studies of Shiau et al. ( 2004 ), Sallmen et al. ( 2000a ), and Apos

toli ( 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 consider

ation of confounders does not explain the difference between studies that identified an effect of paternal Pb and studies such as Joffe et al. ( 2003 ) that did not observe an association between blood Pb in men and time to pregnancy.



### 8.3.5 Spontaneous Abortion There is limited evidence that maternal blood Pb <10 μg/dL is associated with spontaneous abortion. In an extensive review, Hertz-Picciotto et al. ( 2000 ) concluded that there is consistent evidence from case series and epidemiologic studies in the 19th and early 20th century that Pb exposure at high lev

els appears to play a role in spontaneous abortion, but the older studies cited lack blood Pb or other biological monitoring data, so it is unclear what blood Pb level the data would support. Although >20 studies published since the 1970s address maternal or paternal Pb exposure and spontaneous abortion (see Spontaneous Abortion section of Appendix E: Reproductive and Developmental Effects), many lack biological monitoring data. Four of the five retrospec

tive studies that determine exposure by employment or residence report an association between maternal Pb exposure and spontaneous abortion ( Nordstrom et al. 1978
, 1979
, Driscoll 1998
, Tang and Zhu 2003 ). Of the studies with blood Pb data, two studies report an association between maternal Pb levels and spon

taneous abortion. One case-control study and one nested case-control study found an effect of maternal blood Pb or plasma Pb <10 μg/dL and increased risk of spontaneous abortion ( Borja-Aburto et al. 1999
, Yin et al. 2008 ). A number of studies have reported no association between maternal blood Pb levels above or below 10 μg/dL and spontaneous abortion. The conclusion of limited evidence that maternal blood Pb <10 μg/dL is associated with spontaneous abortion is based principally on the Borja-Aburto et al. ( 1999 ) study, which has the strength of the pro

spective nested case-control design, and additional supporting evidence provided by the Yin et al. ( 2008 ) data, as well as the occupational studies without blood Pb measurements. There is limited evidence that paternal blood Pb >31 μg/dL is associated with spontaneous abortion. A positive association between paternal blood Pb >31 μg/dL was reported in one occupational study ( Lindbohm et al. 1991a
, Lindbohm et al. 1991b ) and two retrospective stud

ies that determined exposure by employment but lack blood Pb data ( Beckman and Nordstrom 1982
, Al-Hakkak et al. 1986 ). Two other studies have reported no association at similar blood Pb levels (i.e., >25μg/dL Selevan et al. 1984
, Alexander et al. 1996a )). The conclusion of limited evidence that paternal blood Pb >31 is associated with spontane

ous 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 spontane

ous abortion relies primarily on the Borja-Aburto et al. ( 1999 ) prospective nested case-control study of women in Mexico. The study reported evidence for a dose response (p-trend=0.03) and significant ORs for spontaneous abortion (ORs of 2.3, 5.4, and 12.2) with maternal blood Pb during the first trimester of pregnancy of 5-9, 10-14 and ≥15 μg/dL compared to <5.0 μg/dL in the reference group ( Borja-Aburto et al. 1999 ). The analysis highlighted the careful matching of the timing of exposure measurements in the 35 cases with controls and was adjusted for a range of potential confounders, including age, smok

ing, alcohol consumption, and physical activity. Four retrospective studies support an association between maternal Pb exposure and spontaneous abortion;108 NTP Monograph on He alth Effects of Low-Level Lead however, no blood Pb data were included, and expo

sure was determined by employment or residence ( Nordstrom et al. 1978
, 1979
, Driscoll 1998
, Tang and Zhu 2003 ). Additional support is provided by a casecontrol study that reported plasma Pb levels with no blood Pb data; maternal plasma Pb (5.3 μg/dL in the 40 case women compared to 4.5 μg/dL in the 40 con

trols) was significantly higher in women with anem

bryonic pregnancy (i.e., a pregnancy that appears normal in early stages, with the embryo that is vis

ible by ultrasound never developing ( Yin et al. 2008 )). However, the study reports high levels of plasma Pb suggesting either very high blood Pb levels or a potential problem in study performance or reporting. Several studies with mean blood Pb levels from 4 to 16 μg/dL reported no association between maternal blood Pb levels and spontaneous abortion. Maternal blood Pb during the first trimester was not associated with spontaneous abortion at mean blood Pb levels of 4 μg/dL in a recent prospective study of 351 women in Iran ( Vigeh et al. 2010 ). A prospective study of women residing in a Pb-smelting community reported that maternal blood Pb was not statistically different between cases of spontaneous abortion (11.3 μg/dL) and controls (10.8 μg/dL) ( McMichael et al. 1986 ). Two retrospective studies that compared recalled pregnancy outcomes and concurrent blood Pb levels (means of 6 μg/dL in Lamadrid-Figueroa et al. ( 2007 ) and 16 μg/dL in Murphy et al. ( 1990 )) reported that concurrent blood Pb in women was not associated with previous history of spontaneous abortion. The principal evidence supporting an associa

tion between paternal blood Pb levels and spontane

ous abortion relies on three studies that report an association with paternal Pb exposure. In a retrospec

tive analysis of blood Pb measurements in men occu

pationally exposed to Pb restricted to within 1 year of the spermatogenesis period relevant to a given pregnancy, paternal blood Pb >31 μg/dL was associ

ated with higher odds ratio of spontaneous abortion (OR=3.8 (95% CI: 1.2, 12)) c ompared to men with blood Pb <21 μg/dL ( Lindbohm et al. 1991b ). Two ret

rospective studies of men with occupational exposure to Pb also reported an association between paternal Pb exposure and spontaneous abortion; however, exposure was determined by employment, and the studies lack blood Pb data ( Beckman and Nordstrom 1982
, Al-Hakkak et al. 1986 ). Two additional occu

pational studies that include blood Pb levels did not detect an association between spontaneous abortion and paternal blood Pb from 25 to >60 μg/dL ( Selevan et al. 1984
, Alexander et al. 1996a ). In analyses of other biomarkers of Pb exposure, Figueroa et al. ( 2007 ) found that women with higher ratio of Pb in plasma to Pb in blood had a greater incidence rate for previous abortion (incidence rate ratio=1.18; p=0.02 for 1 SD increase); however, when examined individually, neither blood, plasma, tibia, nor patella Pb levels were related to spontaneous abortions. In a case-control study that also reported plasma Pb levels, maternal plasma Pb (5.3 μg/dL in the 40 case women compared to 4.5 μg/dL in the 40 controls) was significantly higher in women with anembryonic pregnancy ( Yin et al. 2008 ); however, the study does not report Pb levels in whole blood, reports high levels of plasma Pb suggesting either very high blood Pb levels or a potential problem in study performance or reporting, and ratios of Pb in plasma to Pb in whole blood vary widely (from 0.27% to 0.70%), so it is unclear how plasma Pb data relates to the blood Pb data described above ( HernandezAvila et al. 1998 ). Placental Pb was significantly higher in women that had a previous miscarriage ( Gundacker et al. 2010 ).



### Summary of Support for Conclusions Animal data were not located that support an associa

tion between Pb and spontaneous abortion, although prenatal exposure to Pb has been associated with decreased litter sizes, decreased pup survival, and increased embryonic resorption at very high blood Pb levels (>200μg/dL in mice and rats; see U.S. EPA 2006 for recent reviews of the animal data
, ATSDR 2007 ). As described above, there are few human studies with blood Pb data that evaluate the poten

tial association with spontaneous abortion. The con

clusions 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 expo

sure 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.NTP Monograph on Health Effects of Low-Level Lead 109 The inconsistency of the results contributes to the determination of limited evidence. Although not all studies considered confounders, a lack of adjust

ment for confounders does not appear to explain the lack of consistency, because studies that both supportive for Pb effects on spontaneous abortion ( e.g., Borja-Aburto et al. 1999 ) and studies that are not supportive for effects of Pb ( e.g., data from Vigeh et al. 2010 ) included adjustments for maternal age, smoking, and other factors. The 2007 ATSDR Toxico

logical Profile for Lead ( ATSDR 2007 ) and 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) both highlight the lack of consistency of the data on spontaneous abortion; however, the Borja-Aburto et al. ( 1999 ) study is high

lighted as a well-conducted prospective case-control study supporting a significant relationship between maternal blood Pb and spontaneous abortion.



### 8.3.6 Stillbirth There is inadequate evidence to evaluate the poten

tial association between blood Pb at any level and incidence of stillbirth. Few studies investigate the potential association between Pb exposure and stillbirth, and only a handful have blood Pb or other biological monitoring data (see Stillbirth section of Appendix E: Reproductive and Developmental Effects). Of the studies with blood Pb data, none of the studies support an association between mater

nal or paternal blood Pb and stillbirth. For example, a prospective study of women residing in a Pb-smelting community reported that maternal blood Pb levels were not significantly different between cases of still

birth (10.3 μg/dL during pregnancy and 7.2 μg/dL at delivery) and controls (9.9 μg/d L during pregnancy and 10.4 μg/dL at delivery) ( McMichael et al. 1986 ). In a retrospective study that compared recalled preg

nancy outcome and concurrent blood Pb levels (means of 16 μg/dL in the residents in a Pb-smelter commu

nity and 5.1 μg/dL in referents), Murphy et al. ( 1990 ) reported that concurrent blood Pb was not associated with previous history of stillbirth (OR=1.0 (95% CI: 0.6, 1.5)). There are some examples of Pb-associated increases in stillbirth in animal literature at very high doses (e.g., >200μg/dL in Sprague-Dawley rats; see U.S. EPA 2006 for recent reviews of the animal data
, ATSDR 2007 ). The data set available to evaluate this association is small and includes a single prospective study. The 2007 ATSDR Toxicological Profile for Lead ( ATSDR 2007 ) and 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) do not have specific conclusions on the poten

tial association between Pb exposure and stillbirth.



### 8.3.7 Fetal Growth and Lower Birth Weight There are several measures of reduced prenatal growth or intrauterine growth restriction: small for gestational age (babies with birth weight below the 10th percentile for a given gestational age), lower birth weight (evaluated as a continuous variable), low birth weight (<2,500 g a fter at least 37 weeks of gestation), and low birth weight adjusted for gestation length. For this evaluation, any indication of reduced fetal growth is included below. There is sufficient evidence that maternal blood Pb levels <5 μg/dL are associated with reduced fetal growth and lower birth weight. The association between maternal Pb exposure and reduced fetal growth is supported by a number of prospective studies with maternal blood Pb data during preg

nancy ( Dietrich et al. 1987
, Bornschein et al. 1989
, Jelliffe-Pawlowski et al. 2006
, Gundacker et al. 2010 ), a large retrospective cohort study of over 43,000 mother-infant pairs with mean maternal blood Pb level of 2.1 μg/d L ( Zhu et al. 2010 ), and a number of cross-sectional studies with maternal or umbili

cal cord blood Pb at delivery ( Bellinger et al. 1991
, Neuspiel et al. 1994
, Odland et al. 1999
, Osman et al. 2000
, Srivastava et al. 2001
, Chen et al. 2006
, Zentner et al. 2006
, Al-Saleh et al. 2008b ) (see Fetal Growth and Lower Birth Weight section of Appendix E: Reproductive and Developmental Effects). There is also one prospective study ( Sowers et al. 2002 ) and several cross-sectional studies that report no association between maternal blood Pb and reduced fetal growth at blood Pb levels <10 μg/dL and simi

lar results at higher blood Pb levels. Although the results are not entirely consistent across studies, the supporting evidence outlined above with maternal or umbilical cord blood Pb levels <10 μg/d L frommultiple prospective, retrospective, and crosssectional studies provides sufficient evidence at maternal blood Pb levels <10 μg /dL are associated with reduced fetal growth and lower birth weight.The large retrospective study of 43,288 motherinfant pairs from the New York State Heavy Metals Registry contributes substantially to the conclusions, because the study reported a significant association between maternal blood Pb (mean, 2.1 μg /dL) and lower birth weight in such a large cohort from a study110 NTP Monogr aph on Health Effects of Low-Level Lead that included adjustment for multiple potential con

founders ( Zhu et al. 2010 ). The evidence support

ing an effect of maternal Pb exposure on reduced fetal growth is further strengthened by a number of studies from a population in Mexico demonstrating that maternal bone Pb is associated with lower birth weight, birth length, and head circumference. These studies provide limited evidence that maternal bone Pb levels >15.1 μg/ g (tibia Pb) are associated with reduced fetal growth. Unfortunately, the evidence to evaluate the potential association between maternal bone Pb and low birth weight is restricted to a single group. All five of the studies that include maternal bone Pb measurements report a significant associa

tion between increased maternal bone Pb levels and lower fetal growth, but they are all studies of women attending one of three hospitals in Mexico City from 1994 to 1995. There is inadequate evidence that paternal blood Pb at any level is associated with reduced fetal growth, because few studies of birth weight or related endpoints have included paternal Pb exposure data, and the available studies do not support an association with blood Pb in men. Most prospective or retrospective studies that evaluated the association between maternal blood Pb levels of ≤10 μg/ dL during pregnancy with mea

sures of fetal growth found an inverse association (i.e., higher Pb levels were related to reduced fetal growth), although one study did not find an effect of blood Pb. Maternal blood Pb (mean, 2.5 μg/dL) at 34-38 weeks of gestation (n=53) in women at General Hospital in Vienna was associated with lower birth weight ( Gundacker et al. 2010 ). Maternal blood Pb levels (mean, 7.5 μg/ dL) of 861 women from the Cincinnati Lead Study at 16-28 weeks of gestation (from the second trimester into the start of the third trimester) were associated with decreased birth weight ( Bornschein et al. 1989 ). This result was also supported in a smaller analysis: higher maternal blood Pb levels (mean, 8.3 μg/d L) sampled at the first prenatal visit in women (n=185) from the Cin

cinnati Lead Study were correlated with lower birth weight ( Dietrich et al. 1987 ). Maternal blood Pb ≥10 μg/dL during pregnancy in women in the Califor

nia Pb surveillance program (n=262) was associated with a greater odds ratio for small for gestational age (OR=4.2 (95% CI: 1.3, 13.9)); however, the associa

tion was not significant when analyzed for low birth weight (OR=3.6 (95% CI: 0.3, 40)) ( Jelliffe-Pawlowski et al. 2006 ). Maternal blood Pb (mean, 2.1 μg /dL) during pregnancy or at birth was associated with lower birth weight in a large retrospective study of 43,288 mother-infant pairs from the New York State Heavy Metals Registry ( Zhu et al. 2010 ). The large ret

rospective study of over 43,000 mother-infant pairs from Zhu et al. ( 2010 ) contributes substantially to the conclusions because the study reported a significant association between a maternal blood Pb level well below 10 μg/d L and lower birth weight in very large cohort from a study that included adjustment for multiple potential confounders, including maternal age, race, parity, smoking, drug abuse, infant sex, and participation in financial assistance as a measure of socioeconomic status ( Zhu et al. 2010 ). Maternal blood Pb (mean, 1.1 μg /dL) sampled at 12, 20, and 28 weeks of gestation, and the change in blood Pb levels over pregnancy in 705 women in Camden, NJ, were not associated with low birth weight or small for gestational age ( Sowers et al. 2002 ). Other than the clear difference in the sample size for the Zhu et al. study ( 2010 ), there is no obvious difference in blood Pb levels, or in statistical adjustments, between the five studies that support an effect of maternal blood Pb levels <10 μg/dL and the one that does not. Additional studies that sampled maternal or umbilical cord blood Pb at delivery also reported an association between blood Pb levels of ≤10 μg /dL and measures of fetal growth. Studies of cohorts with higher mean blood Pb levels (i.e., >10 μg/dL) are not described below because the discussion focuses on the evidence at blood Pb levels <10 μg/dL. However, as with the prospective studies described above, the results are not consistent across all studies. The principal studies with maternal blood Pb levels at delivery are listed below. The data on umbilical cord blood and blood Pb and higher mean blood Pb levels (i.e., >10 μg/dL) are not detailed below because they present similar results, but all studies are included in the Fetal Growth and Lower Birth Weight section of Appendix E: Reproductive and Developmental Effects. Mean maternal blood Pb levels at delivery of 2-13 μg/dL were associated with lower birth weight in mother-infant pairs from a case-control study of 30 births with intrauterine growth restriction (referred to as intrauterine growth retardation by the authors) and 24 normal births in India ( Srivastava et al. 2001 ); a combined population from Russia and Norway (n=262) ( Odland et al. 1999 ); and a Pb surveillanceNTP Monograph on Health Effects of Low-Level Lead 111 program in Taiwan (n=72 low-birth-weight infants of 1,611 births) ( Chen et al. 2006 ). Mean maternal blood Pb levels at delivery of 6-10 μg/dL were not associated with birth weight, birth length, or head circumference in mother-infant pairs from women in Cleveland (n=185) ( Ernhart et al. 1986 ); Karachi (n=73) ( Rahman and Hakeem 2003 ); or Mexico City (n=272-533) ( Cantonwine et al. 2010b ). Few studies of fetal growth include paternal blood Pb levels, and the available evidence provides little support for an association with blood Pb in men. Paternal occupational exposure estimated by job category was associated with low birth weight and small for gestational age in a study of 742 births in the Baltimore-Washington Infant Study ( Min et al. 1996 ). In two other studies that classified exposure by paternal job category, paternal occupation Pb exposure was not associated with low birth weight in a study of members of the printers’ unions in Oslo, Norway (n=6,251 births) ( Kristensen et al. 1993 ) or occupational exposure in Norway with possible paternal Pb exposure (n=35,930 births, although maternal Pb exposure was associated with low birth weight) ( Irgens et al. 1998 ). Paternal blood Pb (mean, 13 μg/dL) was not associated with small for gesta

tional age or low birth weight in data from a Pb sur

veillance program in Taiwan (n=72 low-birth-weight infants of 1,611 births) ( Chen et al. 2006 ). Low birth weight was associated with maternal blood Pb levels in the Chen et al. ( 2006 ) study and occupational Pb exposure in the Irgens et al. ( 1998 ) study. Paternal blood Pb was not associated with birth weight or small for gestational age; however, blood Pb levels >25 μg/dL for more than 5 years was associated with increased relative risk of low birth weight in a study of workers (n=747) reporting to the New York State Heavy Metals Registry compared to a reference group of bus drivers ( Lin et al. 1998 ). A number of studies of fetal growth include mea

sures of exposure other than blood Pb data. Data from several studies suggest that maternal bone Pb may be more consistently associated with reduced fetal growth compared to blood Pb; however, the data are restricted to a single population. In a series of stud

ies of women from one of three hospitals in Mexico City, higher maternal bone Pb measurements, but not maternal blood Pb levels, were associated with lower measures of fetal growth ( Gonzalez-Cossio et al. 1997
, Hernandez-Avila et al. 2002
, Kordas et al. 2009
, Cantonwine et al. 2010b ). Higher maternal tibia Pb (mean, 9.8 μg /g) was associated with lower birth weight at levels >15.1 μg/ g ( Gonzalez-Cossio et al. 1997 ) and shorter birth length at levels >16.6 μg/ g ( Hernandez-Avila et al. 2002 ). Higher maternal patel

lar Pb (mean, 14 μg/dL) was associated with smaller head circumference at levels >24.7 μg/ g ( Hernan

dez-Avila et al. 2002 ). In further study the authors reported that the H62D genotype may enhance the adverse effect of Pb ( Cantonwine et al. 2010b ), and folate may decrease the adverse effect of Pb ( Kordas et al. 2009 ). In a study of 100 mother-infant pairs in France, maternal and infant hair Pb levels were not associated with small for gestational age ( Huel et al. 1981 ). Several studies have investigated the association between placental Pb levels and fetal growth. Two studies (n=53 and n=79, respectively) reported a relationship between higher placental Pb and lower birth weight, shorter length, and/or smaller head circumference ( Ward et al. 1990
, Gundacker et al. 2010 ). Two case-control studies reported higher placental Pb levels in births with fetal growth restric

tion (n=20) ( Llanos and Ronco 2009 ) or intrauterine growth restriction (referred to as intrauterine growth retardation by the authors) (n=50) ( Richter et al. 1999 ). Three studies reported a lack of an association between placental Pb and birth weight: 161 women from the Yugoslavia Prospective Study ( Loiacono et al. 1992 ); 262 women constituting a combined popula

tion from Russia and Norway ( Odland et al. 2004 ); and 126 births at the Birmingham Maternal Hospital ( Wibberley et al. 1977 ). It is difficult to determine of usefulness of placental Pb as a measure of exposure rather than blood Pb for low birth weight because most studies do not report exposure data for both measures, and the results are inconsistent. In the one study that did include both placental Pb and mater

nal blood Pb levels ( Gundacker et al. 2010 ), low birth weight was associated with both maternal blood Pb levels and placental Pb, as described above.



### Summary of Support for Conclusions Animal data support an association between Pb and lower birth weight at high blood Pb levels (54- 300μg/dL in squirrel monkeys, mice, and rats; see U.S. EPA 2006 for recent reviews of the animal data
, ATSDR 2007 ). As described above, a number of epide

miological studies report effects of Pb on fetal growth112 NTP Monogr aph on Health Effects of Low-Level Lead or birth weight. The conclusion of sufficient evidence that maternal blood Pb <10 μg/dL is associated with reduced fetal growth is based on four prospective studies with maternal blood Pb during pregnancy, a large retrospective cohort study, and a number of cross-sectional studies with maternal or umbilical cord blood Pb at delivery. Although the results are not entirely consistent across studies, and some studies report that prenatal blood Pb levels <10 μg/dL are not associated, the supporting studies provide sufficient evidence that maternal blood Pb levels <10 μg/dL are associated with reduced fetal growth. In particular, the large retrospective study of 43,288 mother-infant pairs from the New York State Heavy Metals Registry contributes substantially to the conclusion of suf

ficient 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 con

founders, including maternal age, race, parity, smok

ing, drug abuse, infant sex, and participation in finan

cial assistance as a measure of socioeconomic status ( Zhu et al. 2010 ). Additional support is provided by a number of cross-sectional studies with maternal or umbilical cord blood Pb <10 μg /dL at delivery, as well as a group of studies from a single group that demonstrate a relationship between higher maternal bone Pb and lower fetal growth. The conclusion of inadequate evidence that paternal blood Pb at any level is associated with fetal growth is based on a small number of studies and general lack of observed effect. The NTP conclusion of sufficient evidence for effects of maternal blood Pb <10 μg/d L on fetal growth is stronger than the 2007 ATSDR Toxicological Profile for Lead ( ATSDR 2007 ) and the 2006 EPA AQCD for Lead ( U.S. EPA 2006 ), in which the evidence was characterized as inconsistent. The NTP conclusion of inadequate evidence for effects of parental blood Pb on fetal growth is consistent with the 2007 ATSDR Toxicological Profile for Lead ( ATSDR 2007 ) and the 2006 EPA AQCD for Lead ( U.S. EPA 2006 ).



### 8.3.8 Preterm Birth and Gestational Age There is limited evidence that maternal blood Pb levels <10 μg /dL are associated with preterm birth or reduced gestational age, because of inconsistent results in studies with low blood Pb levels. Increasing maternal blood Pb levels during pregnancy were asso

ciated with preterm birth or reduced gestational age in two prospective studies ( Cantonwine et al. 2010a
, Vigeh et al. 2011 ) and five cross-sectional studies ( Satin et al. 1991
, Fagher et al. 1993
, Odland et al. 1999
, Torres-Sanchez et al. 1999
, Patel and Prabhu 2009 ) with exposure data from maternal or umbilical cord blood Pb at delivery with mean blood Pb levels <10 μg/dL (see the Preterm section of Appendix E: Reproductive and Developmental Effects). However, a number of cross-sectional studies and several pro

spective studies (e.g., Bornschein et al. 1989
, Sowers et al. 2002 ) report no association between maternal blood Pb and preterm birth at the same blood Pb levels. In addition, the large retrospective study of 43,288 mother-infant pairs from the New York State Heavy Metals Registry did not find an association between maternal blood Pb (mean, 2.1 μg/dL) and preterm birth ( Zhu et al. 2010 ). There is inadequate evidence that paternal blood Pb at any level is associ

ated with preterm birth, because of the small num

ber of studies and general lack of observed effects in studies that report blood Pb levels in men. Studies that compare maternal blood Pb levels during pregnancy with preterm births report mixed results; four studies found an association between blood Pb (mean, 4-10 μg/d L) and preterm birth or decreased gestational age, and three did not find an effect of blood Pb (mean, 1-23 μg/dL). The data are also inconsistent when examined by maternal Pb lev

els from a specific trimester. Higher maternal blood levels (mean, 6-7 μg/ dL) in the first and second tri

mester, but not the third trimester, were associated with decreases in gestational age in a prospective study of 327 women in Mexico City ( Cantonwine et al. 2010a ). Higher maternal blood levels in the first trimester was associated with preterm birth and with decreases in gestational age in a prospective study of 348 women with mean blood of 4 μg /dL in Iran ( Vigeh et al. 2011 ). Maternal blood Pb ≥10 μg/dL was associated with preterm birth in a study of women in the California Pb surveillance program (n=262); how

ever, in contrast to the data from Mexico City and Iran, the effect was significant during the second and third trimesters, but not during the first trimester ( JelliffePawlowski et al. 2006 ). Higher maternal blood Pb levels (mean, 8.3 μg/dL) sampled at the first prena

tal visit in women (n=185) from the Cincinnati Lead Study were correlated with decreases in gestational age ( Dietrich et al. 1987 ); the results were reported as part of an analysis of neurological data, and the study group was a subset of women evaluated in aNTP Monograph on Health Effects of Low-Level Lead 113 later study that did not find a significant association ( Bornschein et al. 1989 ). Maternal blood Pb levels (mean, 7.5 μg/dL) at 16-28 weeks (second trimester into start of third trimester) of gestation were not associated with gestational age ( Bornschein et al. 1989 ). Maternal blood Pb (mean, 1.1 μg/dL) sampled at 12 weeks (first trimester), 20 weeks (second tri

mester), and 28 weeks (third trimester) of gestation in 705 women in Camden, NJ, was not associated with preterm birth ( Sowers et al. 2002 ). Maternal blood Pb levels at mid-pregnancy (second trimester, mean=20 μg/dL) and delivery (mean, 23 μg/dL) were not associated with preterm birth in women from the Yugoslavia Prospective Study (n=907) ( Factor-Litvak et al. 1991 ). Excluding the Dietrich et al. ( 1987 ) study, three prospective or retrospective studies support an association between maternal blood Pb from 4 to 10 μg/dL during pregnancy and preterm birth ( Jel

liffe-Pawlowski et al. 2006
, Cantonwine et al. 2010a
, Vigeh et al. 2011 ), and three studies do not support an association with maternal blood Pb ( Bornschein et al. 1989
, Factor-Litvak et al. 1991
, Sowers et al. 2002 ). The studies that do not support a relationship with Pb exposure are older, but all of these studies considered and adjusted for potential confounders, including maternal age, smoking, and other factors. The studies that do not support a relationship with Pb exposure also have larger sample sizes (n= 705- 907) than the studies that support an effect of Pb (n=262-348). Additional studies that sampled maternal or umbilical cord blood Pb at delivery also reported inconsistent results for these indicators of Pb exposure and preterm birth. Mean Pb levels from 1 to 15 μg/dL in maternal blood or umbilical cord blood at delivery were associated with preterm birth or reduced gesta

tional age in mother-infant pairs from studies in sev

eral locations: five cities in California (n=723) ( Satin et al. 1991 ); the Port Pirie, Australia, birth cohort study (n=721) ( McMichael et al. 1986 ); Rolla and Columbia, MO (n=502) ( Fahim et al. 1976 ); Mexico City (n=620) ( Torres-Sanchez et al. 1999 ); a combined popula

tion from Russia and Norway (n=262) ( Odland et al. 1999 ); Glasgow (n=236) ( Moore et al. 1982 ); a hos

pital in India (n=205) ( Patel and Prabhu 2009 ); and a small combined population from Poland and Sweden (gestational age) (n=17 preterm and n=13 controls) ( Fagher et al. 1993 ). Mean Pb levels from 2 to 30 μg/dL in maternal blood at delivery or umbilical cord blood were not associated with preterm delivery or reduced gestational age in mother-infant pairs from the New York State Heavy Metals Registry (n=43,288) ( Zhu et al. 2010 ); the Brigham and Women’s Hospital (n=3,503) ( Bellinger et al. 1991 ); Louisville, KY, General Hos

pital (n=635) ( Angell and Lavery 1982 ); Memphis (n=102) ( Jones et al. 2010 ); or New York City (n=100) ( Rajegowda et al. 1972 ). The database of studies that determined exposure from maternal or umbilical cord blood Pb at delivery includes a number of stud

ies that do not report appropriate adjustments ( e.g., Fahim et al. 1976 ), but there are also positive ( e.g., Torres-Sanchez et al. 1999 ) and negative studies ( e.g., Zhu et al. 2010 ) for the effects of Pb that adjusted for potential confounders, including maternal age, parity, and smoking. Few studies address the relationship between paternal blood Pb and preterm births, and the avail

able 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 paren

tal blood Pb >25 μg/dL did not affect the relative risk of preterm births (RR=0.89 (95% CI: 0.64, 1.26)) c om

pared to a reference group of bus drivers; however, continued blood Pb >25 μg/dL for more than 5 years was associated with increased relative risk of preterm births (RR=3.03 (95% CI: 1.35, 6.77)) compared to workers that did not consistently report a blood Pb level >25 μg/dL. In a similar worker surveillance pro

gram in China, paternal blood Pb (mean, 14 μg/dL) was not associated with preterm birth ( Chen et al. 2006 ). Paternal Pb exposure determined by paternal job category was also not associated with preterm birth in studies of members of the printers’ unions in Oslo, Norway (n=6,251 births) ( Kristensen et al. 1993 ) or births from the National Natality Survey and Fetal Mortality Survey in the United States ( Savitz et al. 1989 ). Occupational exposure in Norway with possible paternal Pb exposure (n=35,930 births) was associated with longer-term births, and maternal Pb exposure was associated with preterm birth ( Irgens et al. 1998 ). Several studies also address other measures of exposure such as hair or placental Pb levels. Huel et al. ( 1981 ) reported higher hair Pb levels in mothers and offspring from preterm births than from nor

mal births. Two studies reported higher placental Pb levels in preterm birth (or combined analysis of114 NTP Monogr aph on Health Effects of Low-Level Lead preterm births and births with premature rupture of membranes) than in births with normal delivery ( Ward et al. 1990
, Falcón et al. 2003 ). However, four other cross-sectional studies did not find a significant relationship between placental tissue Pb concentra

tions and preterm births ( Fahim et al. 1976
, Ward et al. 1987
, Baghurst et al. 1991
, Loiacono et al. 1992 ). Cantonwine ( 2010a ) did not find a significant asso

ciation between maternal plasma Pb and preterm birth, although the relationship was significant with maternal blood Pb levels.



### Summary of Support for Conclusions Animal data were not located that support an effect of Pb on preterm delivery, although potentially related endpoints such as pup survival and birth weight were adversely affected at high blood Pb lev

els (54-300μg/dL in squirrel monkeys, mice, and rats;

see U.S. EPA 2006 for recent reviews of the animal data
, ATSDR 2007 ). As described above, the human data are not consistent for an effect of Pb on pre

term birth. Although a number of prospective studies with maternal blood Pb levels during pregnancy and cross-sectional studies with umbilical cord blood Pb levels at delivery reported an association between prenatal blood Pb levels <10 μg/dL and preterm birth, the conclusion of limited evidence is based on the inconsistent results and because a large retrospective study did not find an association between maternal blood Pb levels and preterm birth. In particular, the large retrospective study of the New York State Heavy Metals Registry included 43,288 mother-infant pairs and did not find an association between maternal blood Pb (mean, 2.1 μg/dL) and preterm birth ( Zhu et al. 2010 ). The conclusion of inadequate evidence that paternal blood Pb at any level is associated with pre

term birth or reduced gestational age is based on a small number of studies and general lack of observed effect. Of the five studies located that address pater

nal exposure and preterm birth, three report no effect, one reports a Pb-associated increase in gestational age, and one reports an association with persistently elevated paternal Pb (>25 μg/dL for 5 years) and pre

term birth. The NTP conclusion of limited evidence for effects of maternal or umbilical cord blood Pb <10 μg/dL on preterm birth is in line with the 2007 ATSDR Toxicological Profile for Lead ( ATSDR 2007 ) and the 2006 EPA AQCD for Lead ( U.S. EPA 2006 ), in which the evidence was characterized as inconsistent. 

### 8.3.9 Endocrine Effects There is inadequate evidence to evaluate the potential association between blood Pb and major endocrine or changes in hormone levels, because of inconsistency of effects across available studies (see Endocrine section of Appendix E: Reproductive and Developmental Effects). The data are inconsistent for the effects of Pb on luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and other hormones, including estradiol-17β (E 2 ), prolactin (PRL), thyroid-stimulating hormone (TSH), thyroxin (T 4 ), triiodothryonine (T 3 ), parathyroid hor

mone, inhibin B, and insulin-like growth factor 1 (IGF1). There are inadequate studies of endocrine effects in general to determine if the lack of consistency in the data reflects variation in the potential interaction with Pb or whether it is due to well-known hormonal variation and cyclicality on a daily, monthly, and sea

sonal 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 associ

ated with serum levels of LH or FSH in a number of studies of men with occupational Pb exposure ( Assen

nato et al. 1986
, Ng et al. 1991
, Gennart et al. 1992a
, Alexander et al. 1996b
, Telisman et al. 2000
, Mahmoud et al. 2005
, Naha and Manna 2007
, Hsieh et al. 2009 ) and not at lower blood Pb levels (mean, 3-10 μg/ dL) in men or women recruited at infertility clinics ( Chang et al. 2006
, Meeker et al. 2010
, Mendiola et al. 2011 ) or men without occupational Pb exposure ( Telisman et al. 2007 ). Basal levels of LH and FSH did not differ between Pb workers and a reference group; however, gonadotropin-releasing hormone-stimulated FSH was decreased in Pb workers with median blood Pb levels of 31 μg/dL ( Erfurth et al. 2001 ). In a study of 23 Pb workers serum (mean, 60-73 μg/dL), LH was increased compared to a reference group (mean, 17 μg/ dL) ( Rodamilans et al. 1988 ). Several studies have reported that FSH was increased ( Cullen et al. 1984
, McGregor and Mason 1990
, McGregor and Mason 1991
, De Rosa et al. 2003 ) or decreased ( Gustafson et al. 1989 ) in men at blood Pb levels of 20-45 μg /dL compared to a reference group. Results of a study by Krieg et al. ( 2007 ) of women from NHANES III suggest that the effect of Pb on FSH and LH is modified by reproductive status (e.g., menopausal status) or external hormones. FSH was increased with increasing blood Pb in women from NHANES III (mean blood Pb, 2.8 μg/dL) butNTP Monograph on Health Effects of Low-Level Lead 115 decreased with increasing blood Pb in women taking birth control pills ( Krieg 2007 ). LH was increased with increasing blood Pb in postmenopausal women from NHANES III, and LH was not associated with blood Pb in other women ( Krieg 2007 ). The data are inconsistent for the effects of Pb on T, thyroid hormones (TSH, T 4 , and T 3 ), and for other hor

mones, 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
, Genn

art et al. 1992a
, Alexander et al. 1996b
, Mahmoud et al. 2005
, Naha and Manna 2007
, Hsieh et al. 2009 ). Several studies have reported lower basal or stimu

lated 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 adjust

ment for exposure to other metals ( Meeker et al. 2010 ). However, Mendiola et al. ( 2011 ) did not find an association between blood Pb (mean, 10 μg /dL) and serum T in 60 men recruited at an infertility clinic. Occupational Pb exposure in men at mean blood Pb levels 30-40 μg/dL were not associated with E2 in one study ( Mahmoud et al. 2005 ) but was associated with decreased E2 in another study ( Telisman et al. 2000 ). At blood Pb levels <10 μg /dL, Pb was associated with increased E2 in a case-control study of women recruited at an infertility clinic (n=64) and controls from a postpartum clinic (n=83) in Taiwan ( Chang et al. 2006 ). Also, at blood Pb levels <10 μg/dL , E2 was increased and PRL was decreased in association with Pb in men without occupational Pb exposure ( Telis

man et al. 2007 ). In men with occupational exposure to Pb and mean Pb levels from 30 to 60 μg/dL , blood Pb was not associated with PRL or did not differ from a reference group ( Assennato et al. 1986
, Roses et al. 1989
, Ng et al. 1991
, Telisman et al. 2000 ). Serum TSH was elevated in Pb gas station workers with blood Pb mean of 51 μg/dL compared to a reference group ( Singh et al. 2000 ). In contrast, higher blood Pb levels were related to lower TSH in women, but not in men, among people in Quebec that regularly eat freshwa

ter fish; T 3 and T 4 were not associated with Pb levels <10 μg/dL ( Abdelouahab et al. 2008 ). Serum levels of TSH, T 3 , or T 4 did not differ between men with high occupational Pb (mean, 51 μg/d L) and a reference group (21 μg/d L) ( Gennart et al. 1992a ); in male Pb workers with mean blood Pb of 31 μg/dL ( Erfurth et al. 2001 ); in male Pb workers with mean blood Pb of 24 μg/dL ( Schumacher et al. 1998 ); in a study of 24 newborns with mean blood Pb levels of 6 μg/dL ( Iijima et al. 2007 ); or in 68 children <8 years of age with range of blood Pb from 2 to 77 μg/dL ( Siegel et al. 1989 ). Two studies of men with occupational Pb expo

sure (mean Pb level, 42-51 μg/dL) reported opposite results: T 4 and free T 4 were higher in 75 Pb workers than in 68 matched controls ( Lopez et al. 2000 ); lower T 4 and free T 4 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 T 4 wasassociated with lower blood Pb in women from a Pbsmelting town (median blood Pb, 20 μg/dL) but not in a reference town (median blood Pb, 6 μg/dL) ( Lamb et al. 2008 ). Cumulative Pb exposure was associated with increased serum inhibin B levels in two studies of male Pb workers (n=181 ( Hsieh et al. 2009 ); n=68 ( Mahmoud et al. 2005 )). There are few studies of Pb and hormone lev

els in children. Two available studies suggest that Pb may decrease LH and FSH. In a study of 41 chil

dren 10-13 years of age in Egypt, boys and girls with blood Pb >10 μg/dL had lower FSH and LH; boys had lower serum T, but there was no effect of Pb on E2 ( Tomoum et al. 2010 ). Similarly, Vivoli et al. ( 1993 ) reported decreased LH and FSH in boys with blood Pb ≥10 μg/dL in a study of 418 children in Italy; T and E2 were not related to blood Pb levels. Girls 6-11 years of age in NHANES III with blood Pb ≥1 μg/dL had lower levels of inhibin B ( Gollenberg et al. 2010 ).



### Summary of Support for Conclusions Animal data support an association between Pb expo

sure and altered hormones, particularly decreased LH, FSH, and E2 in females, at high blood Pb levels (30-300μg/dL in Cynomolgus monkeys and rats; see U.S. EPA 2006 for recent reviews of the animal data
, ATSDR 2007 ). Rodent data also support an effect of Pb testosterone in some studies; however, even within the animal literature, increase, decrease, and lack of effect are all reported. Animal data also support decreased IGF-1, LH, and E2 as potential mechanisms for the Pb-associated delay in puberty. Animal data also support an effect of developmental Pb exposure116 NTP Monogr aph on Health Effects of Low-Level Lead on the hypothalamic-pituitary-adrenal axis and changes in the stress response or basal corticosteroids. The human data on potential associations between Pb and LH, FSH, and T are inconsistent, and for other hormones the data are inconsistent as well as limited in nature. Therefore, the NTP determined there was inadequate evidence to conclude that blood Pb was associated with specific hormone changes. The con

clusion of inadequate evidence for endocrine effects of Pb in humans is in line with the discussion of the general inconsistencies in the human database with the ATSDR and EPA; however, the 2006 EPA AQCD for Lead ( U.S. EPA 2006 ) states that the toxicological data (animal data) support Pb as an endocrine dis

ruptor in males and females at various points along the hypothalamic-pituitary-gonadal axis. Additional data, particularly data from prospective studies with appropriate consideration and control for timing in the reproductive cycle, age, and other factors, are required to clarify the potential relationship between blood Pb and endocrine parameters.



### 8.3.10 Congenital Malformations There is inadequate evidence to evaluate the potential association between blood Pb and congenital malfor

mations. Few studies investigate the potential asso

ciation between Pb exposure and malformations, and even fewer have blood Pb or other biological moni

toring data (see the Congenital Malformations sec

tion of Appendix E: Reproductive and Developmental Effects). Of the studies with blood Pb data, only one supports an association between blood Pb levels and congenital malformations: in a retrospective analysis, Needleman et al. ( 1984 ) found a higher relative risk of minor congenital anomaly with higher all umbilical cord blood Pb levels (6.3 μg/d L: RR=1.87 9 (1.4, 2.4); 15 μg/dL: RR=2.39 (1.7,3.4); 24 μg/d L: RR=2.73 (1.8, 4.2)). There are few other published studies; most lack blood Pb data or other biomarkers, and exposure is based on job categories or indirect measures. For example, residence in the ceramic district in Italy, an area known for higher Pb exposure levels, was asso

ciated with increased relative risk of congenital mal

formations (RR=1.48 (95% CI: 1.15, 1.89)), incl uding hydrocephalus, oral clefts, cleft lip, and malformations of the ear, heart, cardiovascular system, musculoskel

etal system, and integument ( Vinceti et al. 2001 ). Several occupational studies investigated the relationship between paternal blood Pb and congenital malformations, and the available evidence is inconsistent. Blood Pb levels determined from monitoring data for 929 employees of the Cominco smelter in British Columbia were not associated with odds ratio for still births and birth defects combined ( Alexander et al. 1996a ). Paternal occupational Pb exposure was not associated with congenital malfor

mations in a study of 764 workers at a copper smelter that compared rates of malformations between preg

nancies after employment to pregnancies that took place before occupational Pb exposure ( Beckman and Nordstrom 1982 ). Estimated paternal blood Pb levels based on job categories were associated with an increased odds ratio for congenital malformations (OR=3.2 (95% CI: 1.0, 10.2)) when evaluated along with paternal smoking ( Sallmen et al. 1992 ). A number of studies have examined the poten

tial association between Pb exposure and neural tube defects. The evidence that Pb exposure is associated with neural tube defects is inconsistent, and both studies that include blood Pb data do not support an association with Pb exposure: umbilical cord blood Pb at birth in a case-control study of mother-infant pairs in Turkey ( Zeyrek et al. 2009 ), and maternal blood Pb taken 5-6 weeks after birth in Mexican-Americans liv

ing 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 seri

ous birth defects among births in Norway with pos

sible parental occupational Pb exposure by job clas

sification, Irgens et al. ( 1998 ) reported that maternal Pb exposure (of n=1,803 exposed births) was associ

ated with a greater odds ratio for neural tube defects (OR=2.87 (95% CI: 1.05, 6.38)) but not paternal expo

sure (n=35,930 exposed births). Bound et al. ( 1997 ) reported a significant association between risk of neural tube defects in a case-control study that deter

mined Pb exposure by residence in a district in the United Kingdom known to have higher drinking water levels of Pb. Drinking water levels of Pb or residence near a hazardous waste site with known Pb were not associated with neural tube defects or anencephalus in several case-control studies ( Elwood and Coldman 1981
, Croen et al. 1997
, Macdonell et al. 2000 ). Several studies have examined the potential association between Pb exposure and cardiovascular defects. The evidence that Pb exposure is associated with cardiovascular defects is inconsistent, comesNTP Monograph on Health Effects of Low-Level Lead 117 from few studies, and lacks good exposure data. The study of residents in the Pb-associated ceramic dis

trict in Italy described above reported increased rela

tive risk of prevalence of specific heart malformations (RR=2.47 (95% CI: 1.57, 3.70)) and g eneral cardiovas

cular malformations (RR=2.59 (95% CI: 1.68, 3.82)) ( Vinceti et al. 2001 ). Drinking water levels of Pb and residence near a hazardous waste site with known Pb were not associated with congenital heart disease or cardiovascular anomalies in several case-control stud

ies ( Zierler et al. 1988
, Aschengrau et al. 1993
, Croen et al. 1997 ). A case-control study of 54 children with total anomalous pulmonary venous return (TAPVR) and 522 matched controls in the Baltimore-Washing

ton Infant Study reported significant odds ratio for paternal Pb exposure (OR=1.83 (95% CI: 1.00, 3.42) ( Jackson et al. 2004 )). Several studies have also examined the poten

tial association between Pb exposure and cleft lip or cleft palate. The evidence that Pb exposure is associ

ated with oral clefts comes from few studies, all of which lack biological exposure data. The study of residents in the Pb-associated ceramic district in Italy described above reported increased relative risk of oral clefts (RR=2.28 (95% CI: 1.16, 4.07)) and cle ft lip (RR=2.43 (95% CI: 1.13, 4.62)) ( Vinceti et al. 2001 ). A case-control study of 100 mothers of babies with oral clefts and 751 controls reported increased odds ratio of oral clefts (OR=4.0 (95% CI: 1.3, 12.2)) ( Lorente et al. 2000 ). Paternal Pb exposure by job category among 6,251 births to male members of printers’ unions in Oslo, Norway, was associated with an increased standardized morbidity ratio for cleft lip in boys (SMR=4.1 (95% CI: 1.8, 8.1)) ( Kristensen et al. 1993 ).



### Summary of Support for Conclusions Limited animal data support an effect of Pb on con

genital malformations, mainly tail defects and gen

eral external malformations in NOS rats, although increased fetal mortality was reported in some studies at high blood Pb levels (54-300μg/dL in squirrel mon

keys and mice; see U.S. EPA 2006 for recent reviews of the animal data
, ATSDR 2007 ). In the human data, there are few studies of congenital malformations with parental Pb exposure data. Although studies have reported general effects on congenital malfor

mations, and specific effects on neural tube defects, cardiovascular defects, and oral clefts, the results are inconsistent and the studies generally lack biological exposure data. The NTP determination that there is inadequate evidence to conclude parental blood Pb levels are associated with congenital malformations is consistent with the 2007 ATSDR Toxicological Pro

file for Lead ( ATSDR 2007 ) and the 2006 EPA AQCD for Lead ( U.S. EPA 2006 ).



### 8.4 Conclusions The NTP concludes there is sufficient evidence that blood Pb levels <10 μg/dL are associated with adverse effects on development in children and that blood Pb levels <5 μg/dL are associated with adverse effects on reproduction in adult women (see Table 8.6 for complete list of reproductive and developmental effects conclusions). In some studies blood Pb levels ≤2 μg/dL are associated with adverse effects (e.g., Wu et al. 2003
, Denham et al. 2005 for delayed onset of puberty ), and the ability to discriminate effects at the lower dose may depend on the availability of a refer

ence group with lower blood Pb levels or the preci

sion 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 ar e associated with reduced fetal growth and limited evidence that maternal blood Pb levels <10 μg/dL ar e associated with spontaneous abortion and preterm birth. In men there is sufficient evidence that blood Pb levels ≥15 μg/dL are associ

ated with adverse effects on sperm or semen and that blood Pb levels ≥20 are associated with delayed con

ception time. There is limited evidvence that blood Pb levels ≥10 μg/dL in men are associated with other measures of reduced fertility and that blood Pb levels >31 μg/dL are associated with spontaneous abortion.118 N TP Monograph on Health Effects of Low-Level Lead Table 8.6: NTP conclusions on reproductive and developmental effects of low-level Pb

Health Effect Population or Exposure Window NTP Conclusion Blood Pb Evidence Bone Pb Evidence

Delayed puberty Prenatal Inadequate No data No data
Children Sufficient Yes, <10 μg/dL No data
Limited Yes, <5 μg/dL Postnatal growth Prenatal Limited Yes, <10 μg/dL One study
Children Sufficient Yes, <10 μg/dL One study available, no evidence of an association Sperm parameters Children Inadequate No data No data
Men Sufficient Yes, ≥15 μg/dL No data Fertility / delayed conception time Men: time to conception Sufficient Yes, ≥20 μg/dL No data Men: fertility Limited Yes, ≥10 μg/dL (one study) No data

Women Inadequate Unclear No data Spontaneous abortion Men Limited Yes, >31 μg/dL No data
Women Limited Yes, <10 μg/dL No data
Stillbirth Adults Inadequate Unclear No data Reduced fetal growth and lower birth weight Men Inadequate Unclear No data
Women Sufficient Yes, <5 μg/dL Yes, tibia
Preterm birth and gestational age Men Inadequate Unclear No data
Women Limited Yes, <10 μg/dL No data
Endocrine effects Adults Inadequate Unclear One study
Birth defects Adults Inadequate Unclear No dataNTP Monograph on Health Effects of Low-Level Lead 119 

## 9.0 REFERENCES

9.1 Executive Summary
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### 9.2 Methods
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tion (CDC). 1-137. http://www.cdc.gov/nceh/lead/ publications/. CDC. 2010. Guidelines for the Identification and Manage

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velopment, National Center for Environmental Assess

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sessment-RTP Division. 1467

. http://cfpub.epa.gov/ ncea/isa/recordisplay.cfm?deid=235331#Download.



### 9.3 Exposure
ABLES. 2009. Adult Blood Lead Epidemiology and Surveil

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opment. Neurotox 29(2): 278-285.Tellez-Rojo MM, Bellinger DC, Arroyo-Quiroz C, LamadridFigueroa H, Mercado-Garcia A, Schnaas-Arrieta L, Wright RO, Hernandez-Avila M, Hu H. 2006. Longi

tudinal associations between blood lead concentra

tions lower than 10 microg/dL and neurobehavioral development in environmentally exposed children in Mexico City. Pediatrics 118(2): e323-e330. Thomson GO, Raab GM, Hepburn WS, Hunter R, Fulton M, Laxen DP. 1989. Blood-lead levels and children’s behaviour – results from the Edinburgh Lead Study. J Child Psychol Psychiatry 30(4): 515-528. Tong S, Baghurst P, McMichael A, Sawyer M, Mudge J. 1996. Lifetime exposure to environmental lead and children’s intelligence at 11-13 years: the Port Pirie cohort study. Bmj 312(7046): 1569-1575. U.S. EPA. 2006. Air Quality Criteria for Lead . EPA/600/R05/114aF. Washington, DC: Office of Research and De

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. U.S. EPA. 2012. Integrated Science Assessment for Lead (Second External Review Draft) . EPA/600/R-10/075B. Research Triangle Park, NC: Office of Research and Development, National Center for Environmental As

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trations and learning achievement among primary school children in Taiwan. Environ Res 89(1): 12-18. Wang FT, Hu H, Schwartz J, Weuve J, Spiro AS, Sparrow D, Nie H, Silverman EK, Weiss ST, Wright RO. 2007. Modifying effects of the HFE polymorphisms on the association between lead burden and cognitive de

cline. Environ Health Perspect 115(8): 1210-1215. Wang HL, Chen XT, Yang B, Ma FL, Wang S, Tang ML, Hao MG, Ruan DY. 2008. Case-control study of blood lead levels and attention deficit hyperactivity disorder in Chinese children. Environ Health Perspect 116(10): 1401-1406. Wasserman GA, Liu X, Lolacono NJ, Factor-Litvak P, Kline JK, Popovac D, Morina N, Musabegovic A, Vrenezi N, Capuni-Paracka S, Lekic V, Preteni-Redjepi E, Hadzi

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### 9.5 Immune Effects Ahmad Al Obaidi AH, Mohamed Al Samarai AG, Yahya Al Samarai AK, Al Janabi JM. 2008. The predictive value of IgE as biomarker in asthma. J Asthma 45(8): 654- 663. Annesi-Maesano I, Pollitt R, King G, Bousquet J, Hellier G, Sahuquillo J, Huel G. 2003. In utero exposure to lead and cord blood total IgE. Is there a connection? Al

lergy 58(7): 589-594. ATSDR. 2001. Summary Report: Hair analysis panel discus

sion: Exploring the state of the science . Atlanta, GA: Agency for Toxic Substances and Disease Registry. 1-199. http://www.atsdr.cdc.gov/HAC/hair_analysis/ pdfs.html. ATSDR. 2007. Toxicological Profile for Lead . Atlanta, GA: Agency for Toxic Substances and Disease Registry. http://www.atsdr.cdc.gov/toxprofiles/tp13.html.NTP Monograph on Health Effects of Low-Level Lead 132 Basaran N, Undeger U. 2000. Effects of lead on immune parameters in occupationally exposed workers. Am J Ind Med 38(3): 349-354. Beeh KM, Ksoll M, Buhl R. 2000. Elevation of total serum immunoglobulin E is associated with asthma in non

allergic individuals. Eur Respir J 16(4): 609-614. Belles-Isles M, Ayotte P, Dewailly E, Weber JP, Roy R. 2002. Cord blood lymphocyte functions in newborns from a remote maritime population exposed to organochlo

rines and methylmercury. J Toxicol Environ Health A 65(2): 165-182. Bener A, Almehdi AM, Alwash R, Al-Neamy FR. 2001. A pilot survey of blood lead levels in various types of workers in the United Arab Emirates. Environ Int 27(4): 311-314. Blackwell AD, Gurven MD, Sugiyama LS, Madimenos FC, Li

ebert MA, Martin MA, Kaplan HS, Snodgrass JJ. 2011. Evidence for a peak shift in a humoral response to helminths: age profiles of IgE in the Shuar of Ecuador, the Tsimane of Bolivia, and the U.S. NHANES. PLoS Negl Trop Dis 5(6): e1218. Blakley BR, Archer DL. 1981. The effect of lead acetate on the immune response in mice. Toxicol Appl Pharma

col 61(1): 18-26. Boscolo P, Di Gioacchino M, Sabbioni E, Benvenuti F, Conti P, Reale M, Bavazzano P, Giuliano G. 1999. Expres

sion of lymphocyte subpopulations, cytokine serum levels, and blood and urinary trace elements in as

ymptomatic atopic men exposed to an urban envi

ronment. Int Arch Occup Environ Health 72(1): 26-32. Boscolo P, Di Gioacchino M, Sabbioni E, Di Giacomo F, Reale M, Volpe AR, Di Sciascio MB, Conti P, Giuliano G. 2000. Lymphocyte subpopulations, cytokines and trace ele

ments in asymptomatic atopic women exposed to an urban environment. Life Sci 67(10): 1119-1126. Chen S, Golemboski K, Piepenbrink M, Dietert R. 2004. Developmental immunotoxicity of lead in the rat: in

fluence of maternal diet. J Toxicol Environ Health A 67(6): 495-511. Choi JW, Kim SK. 2005. Relationships of lead, copper, zinc, and cadmium levels versus hematopoiesis and iron parameters in healthy adolescents. Ann Clin Lab Sci 35(4): 428-434. Corsini E, Kimber I. 2007. Factors governing susceptibility to chemical allergy. Toxicol Lett 168(3): 255-259. De Swert LF. 1999. Risk factors for allergy. Eur J Pediatr 158(2): 89-94. Dietert RR, Piepenbrink MS. 2006. Lead and immune func

tion. Crit Rev Toxicol 36(4): 359-385. Dietert RR. 2008. Developmental immunotoxicology (DIT): windows of vulnerability, immune dysfunction and safety assessment. J Immunotoxicol 5(4): 401-412. Donohue KM, Al-alem U, Perzanowski MS, Chew GL, John

son A, Divjan A, Kelvin EA, Hoepner LA, Perera FP, Miller RL. 2008. Anti-cockroach and anti-mouse IgE are associated with early wheeze and atopy in an inner-city birth cohort. J Allergy Clin Immunol 122(5): 914-920. Dyatlov VA, Lawrence DA. 2002. Neonatal lead exposure potentiates sickness behavior induced by Listeria monocytogenes infection of mice. Brain Behav Im

mun 16(4): 477-492. Faith RE, Luster MI, Kimmel CA. 1979. Effect of chronic developmental lead exposure on cell-mediated im

mune functions. Clin Exp Immunol 35(3): 413-420. Fischbein A, Tsang P, Luo JC, Roboz JP, Jiang JD, Bekesi JG. 1993. Phenotypic aberrations of CD3+ and CD4+ cellsand functional impairments of lymphocytes at lowlevel occupational exposure to lead. Clin Immunol Immunopathol 66(2): 163-168. Gao D, Mondal TK, Lawrence DA. 2007. Lead effects on development and function of bone marrow-derived dendritic cells promote Th2 immune responses. Toxi

col Appl Pharmacol 222(1): 69-79. Garcia-Leston J, Roma-Torres J, Vilares M, Pinto R, Cunha LM, Prista J, Teixeira JP, Mayan O, Pasaro E, Mendez J, Laffon B. 2011. Biomonitoring of a population of Por

tuguese workers exposed to lead. Mutat Res 721(1): 81-88. Governa M, Valentino M, Visona I. 1987. In vitro impair

ment of human granulocyte functions by lead. Arch Toxicol 59(6): 421-425. Governa M, Valentino M, Visona I, Scielso R. 1988. Impair

ment of chemotaxis of polymorphonuclear leuko

cytes from lead acid battery workers. Sci Total Envi

ron 71(3): 543-546. Guillard O, Lauwerys R. 1989. In vitro and in vivo effect of mercury, lead and cadmium on the generation of chemiluminescence by human whole blood. Bio

chem Pharmacol 38(17): 2819-2823. Guo TL, Mudzinski SP, Lawrence DA. 1996. The heavy met

al lead modulates the expression of both TNF-alpha and TNF-alpha receptors in lipopolysaccharide-acti

vated human peripheral blood mononuclear cells. J Leukoc Biol 59(6): 932-939. Hegazy RM, Hamdy R, Kamel HF. 2011. Modulation of IgE levels in lead exposed children by parental cigarette smoking, qualyobia governate, Egypt. Int J Pharm Bio Sci 2(2): 272-385. Heinrich J, Hoelscher B, Wjst M, Ritz B, Cyrys J, Wichmann H. 1999. Respiratory diseases and allergies in two polluted areas in East Germany. Environ Health Per

spect 107(1): 53-62.NTP Monograph on Health Effects of Low-Level Lead 133 Hemdan NY, Emmrich F, Adham K, Wichmann G, Lehmann I, El-Massry A, Ghoneim H, Lehmann J, Sack U. 2005. Dose-dependent modulation of the in vitro cytokine production of human immune competent cells by lead salts. Toxicol Sci 86(1): 75-83. Heo Y, Lee BK, Ahn KD, Lawrence DA. 2004. Serum IgE eleva

tion correlates with blood lead levels in battery manu

facturing workers. Hum Exp Toxicol 23(5): 209-213. Hon KL, Ching GK, Hung EC, Leung TF. 2009. Serum lead levels in childhood eczema. Clin Exp Dermatol 34(7): e508-e509. Hon KL, Wang SS, Hung EC, Lam HS, Lui HH, Chow CM, Ch

ing GK, Fok TF, Ng PC, Leung TF. 2010. Serum levels of heavy metals in childhood eczema and skin diseases: friends or foes. Pediatr Allergy Immunol 21(5): 831-836. Hon KLE. 2011. Concerning heavy metals in childhood ec

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ang C, Lake SL, Hudson TJ, Spesny M, Fournier E, Syl

via JS, Freimer NB, Klanderman BJ, Raby BA, Celedon JC. 2008. Sex-stratified linkage analysis identifies a female-specific locus for IgE to cockroach in Costa Ricans. Am J Respir Crit Care Med 177(8): 830-836. Hunninghake GM, Chu JH, Sharma SS, Cho MH, Himes BE, Rogers AJ, Murphy A, Carey VJ, Raby BA. 2011. The CD4+ T-cell transcriptome and serum IgE in asthma: IL17RB and the role of sex. BMC Pulmonary Medicine 11: 17. Izaks GJ, Remarque EJ, Becker SV, Westendorp RG. 2003. Lymphocyte count and mortality risk in older per

sons. The Leiden 85-Plus Study. J Am Geriatr Soc 51(10): 1461-1465. Jarvis D, Luczynska C, Chinn S, Potts J, Sunyer J, Janson C, Svanes C, Künzli N, Leynaert B, Heinrich J, Kerkhof M, Ackermann-Liebrich U, Antó JM, Cerveri I, de Marco R, Gislason T, Neukirch F, Vermeire P, Wjst M, Burney P. 2005. Change in prevalence of IgE sensitization and mean total IgE with age and cohort. The Journal of al

lergy and clinical immunology 116(3): 675-682. Jedrychowski W, Perera F, Maugeri U, Miller RL, Rembiasz M, Flak E, Mroz E, Majewska R, Zembala M. 2011. Intrauterine exposure to lead may enhance sensiti

zation to common inhalant allergens in early child

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spect 113(7): 900-904. Karmaus W, Brooks KR, Nebe T, Witten J, Obi-Osius N, Kruse H. 2005. Immune function biomarkers in children exposed to lead and organochlorine compounds: a cross-sectional study. Environ Health 4(1): 5. Kelly C, Gangur V. 2009. Sex Disparity in Food Allergy: Evi

dence from the PubMed Database. J Allergy (Cairo) 2009: 159845. Kotaniemi-Syrjanen A, Reijonen TM, Korhonen K, Korppi M. 2002. Wheezing requiring hospitalization in early childhood: predictive factors for asthma in a six-year follow-up. Pediatr Allergy Immunol 13(6): 418-425. Kuo HW, Hsiao TY, Lai JS. 2001. Immunological effects of long-term lead exposure among Taiwanese workers. Arch Toxicol 75(10): 569-573. Leggett RW. 1993. An age-specific kinetic model of lead metabolism in humans. Environ Health Perspect 101(7): 598-616. Li S, Zhengyan Z, Rong L, Hanyun C. 2005. Decrease of CD4+ T-lymphocytes in children exposed to environ

mental lead. Biol Trace Elem Res 105(1-3): 19-25. Lindberg RE, Arroyave C. 1986. Levels of IgE in serum from normal children and allergic children as measured by an enzyme immunoassay. J Allergy Clin Immunol 78(4 Pt 1): 614-618. Luebke R, Chen D, Dietert R, Yang Y, Luster M. 2006. Im

mune system maturity and sensitivity to chemical
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moral immunity in rats following chronic develop

mental lead exposure. J Environ Pathol Toxicol 1(4): 397-402. Luster MI, Portier C, Pait DG, White KL, Jr., Gennings C, Munson AE, Rosenthal GJ. 1992. Risk assessment in immunotoxicology. I. Sensitivity and predictability of immune tests. Fundam Appl Toxicol 18(2): 200- 210. Lutz PM, Wilson TJ, Ireland J, Jones AL, Gorman JS, Gale NL, Johnson JC, Hewett JE. 1999. Elevated immuno

globulin E (IgE) levels in children with exposure to environmental lead. Toxicology 134(1): 63-78. McCabe MJ, Jr., Singh KP, Reiners JJ, Jr. 1999. Lead intoxica

tion impairs the generation of a delayed type hyper

sensitivity response. Toxicology 139(3): 255-264. Mediaty A, Neuber K. 2005. Total and specific serum IgE decreases with age in patients with allergic rhinitis, asthma and insect allergy but not in patients with atopic dermatitis. Immun Ageing 2(1): 9. Min JY, Min KB, Kim R, Cho SI, Paek D. 2008. Blood lead levels and increased bronchial responsiveness. Biol Trace Elem Res 123(1-3): 41-46. Mishra KP, Rani R, Yadav VS, Naik S. 2010. Effect of lead ex

posure on lymphocyte subsets and activation markers. Immunopharmacol Immunotoxicol 32(3): 446-449.NTP Monograph on Health Effects of Low-Level Lead 134 Mudzinski SP, Rudofsky UH, Mitchell DG, Lawrence DA.1986. Analysis of lead effects on in vivo antibodymediated immunity in several mouse strains. Toxicol Appl Pharmacol 83(2): 321-330. Myers SN, Rowell B, Binns HJ. 2002. Lead poisoning and asthma: an examination of comorbidity. Arch Pediatr Adolesc Med 156(9): 863-866. Narita S, Goldblum RM, Watson CS, Brooks EG, Estes DM, Curran EM, Midoro-Horiuti T. 2007. Environmental estrogens induce mast cell degranulation and en

hance IgE-mediated release of allergic mediators. Environ Health Perspect 115(1): 48-52. Parronchi P, Brugnolo F, Sampognaro S, Maggi E. 2000. Ge

netic and environmental factors contributing to the onset of allergic disorders. Int Arch Allergy Immunol 121(1): 2-9. Pineda-Zavaleta AP, Garcia-Vargas G, Borja-Aburto VH, Acosta-Saavedra LC, Vera Aguilar E, Gomez-Munoz A, Cebrian ME, Calderon-Aranda ES. 2004. Nitric ox

ide and superoxide anion production in monocytes from children exposed to arsenic and lead in region Lagunera, Mexico. Toxicol Appl Pharmacol 198(3): 283-290. Pinkerton LE, Biagini RE, Ward EM, Hull RD, Deddens JA, Boeniger MF, Schnorr TM, MacKenzie BA, Luster MI. 1998. Immunologic findings among lead-exposed workers. Am J Ind Med 33(4): 400-408. Pizent A, Macan J, Jurasovic J, Varnai VM, Milkovic-Kraus S, Kanceljak-Macan B. 2008. Association of toxic and essential metals with atopy markers and ventilatory lung function in women and men. Sci Total Environ 390(2-3): 369-376. Pugh Smith P, Nriagu JO. 2011. Lead poisoning and asthma among low-income and African American children in Saginaw, Michigan. Environ Res 111(1): 81-86. Queiroz ML, Almeida M, Gallao MI, Hoehr NF. 1993. De

fective neutrophil function in workers occupationally exposed to lead. Pharmacol Toxicol 72(2): 73-77. Queiroz ML, Costa FF, Bincoletto C, Perlingeiro RC, Dan

tas DC, Cardoso MP, Almeida M. 1994. Engulfment and killing capabilities of neutrophils and phagocytic splenic function in persons occupationally exposed to lead. Int J Immunopharmacol 16(3): 239-244. Rabinowitz MB, Allred EN, Bellinger DC, Leviton A, Needle

man HL. 1990. Lead and childhood propensity to in

fectious and allergic disorders: is there an associa

tion? Bull Environ Contam Toxicol 44(5): 657-660. Raby BA, Soto-Quiros ME, Avila L, Lake SL, Murphy A, Liang C, Fournier E, Spesny M, Sylvia JS, Verner A, Hudson TJ, Klanderman BJ, Freimer NB, Silverman EK, Cele

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set distributions in children and adults living in com

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### 9.6 Cardiovascular Effects Afridi HI, Kazi TG, Kazi N, Kandhro GA, Baig JA, Shah AQ, Jamali MK, Arain MB. 2010. Evaluation of toxic ele

ments in scalp hair samples of myocardial infarction patients at different stages as related to controls. Biol Trace Elem Res 134(1): 1-12. Al-Saleh I, Shinwari N, Mashhour A, Mohamed Gel D, Ghosh MA, Shammasi Z, Al-Nasser A. 2005. Is lead considered as a risk factor for high blood pressure during menopause period among Saudi women? Int J Hyg Environ Health 208(5): 341-356. Apostoli P, Maranelli G, Dei Cas L, Micciolo R. 1990. Blood lead and blood pressure: a cross sectional study in a general population group. Cardiologia 35(7): 597- 603. ATSDR. 2007. Toxicological Profile for Lead . Atlanta, GA: Agency for Toxic Substances and Disease Registry. http://www.atsdr.cdc.gov/toxprofiles/tp13.html. Bakhtiarian A, Dizaji R, Mohaghegh A, Immami-Khansari F, Ghazi-Khansari M. 2006. The study of blood lead con

centration in hypertensive and normotensive adults in Tehran’s hospitals. Journal of Medical Sciences 6(1): 103-107. Chen A, Rhoads GG, Cai B, Salganik M, Rogan WJ. 2006. The effect of chelation on blood pressure in lead-ex

posed children: a randomized study. Environ Health Perspect 114(4): 579-583. Cheng Y, Schwartz J, Vokonas PS, Weiss ST, Aro A, Hu H. 1998. Electrocardiographic conduction disturbances in association with low-level lead exposure (the Nor

mative Aging Study). Am J Cardiol 82(5): 594-599. Cheng Y, Schwartz J, Sparrow D, Aro A, Weiss ST, Hu H. 2001. Bone lead and blood lead levels in relation to baseline blood pressure and the prospective devel

opment of hypertension: the Normative Aging Study. Am J Epidemiol 153(2): 164-171. Chu NF, Liou SH, Wu TN, Chang PY. 1999. Reappraisal of the relation between blood lead concentration and blood pressure among the general population in Tai

wan. Occup Environ Med 56(1): 30-33. Den Hond E, Nawrot T, Staessen JA. 2002. The relationship between blood pressure and blood lead in NHANES III. National Health and Nutritional Examination Sur

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