United States
Environmental Protection
Jf lkAgency
EPA/600/R-23/061
March 2023
www.epa.gov/isa
Integrated Science
Assessment for Lead
Appendix 8: Reproductive and
Developmental Effects
External Review Draft
March 2023
Health and Environmental Effects Assessment Division
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
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DISCLAIMER
1 This document is an external review draft for peer review purposes only. This information is
2 distributed solely for the purpose of predissemination peer review under applicable information quality
3 guidelines. It has not been formally disseminated by the Environmental Protection Agency. It does not
4 represent and should not be construed to represent any agency determination or policy. Mention of trade
5 names or commercial products does not constitute endorsement or recommendation for use.
6
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DOCUMENT GUIDE
This Document Guide is intended to orient readers to the organization of the Lead (Pb) Integrated Science
Assessment (ISA) in its entirety and to the sub-section of the ISA at hand (indicated in bold). The ISA consists of
the Front Matter (list of authors, contributors, reviewers, and acronyms), Executive Summary, Integrated Synthesis,
and 12 appendices, which can all be found at https://cfpub.epa.gov/ncea/isa/recordisplay.cfm?deid=357282.
Front Matter
Executive Summary
Integrative Synthesis
Appendix 1. Lead Source to Concentration
Appendix 2. Exposure, Toxicokinetics, and Biomarkers
Appendix 3. Nervous System Effects
Appendix 4. Cardiovascular Effects
Appendix 5. Renal Effects
Appendix 6. Immune System Effects
Appendix 7. Hematological Effects
Appendix 8. Reproductive and Developmental Effects
Appendix 9. Effects on Other Organ Systems and Mortality
Appendix 10. Cancer
Appendix 11. Effects of Lead in Terrestrial and Aquatic Ecosystems
Appendix 12. Process for Developing the Pb Integrated Science Assessment
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CONTENTS
LIST OF TABLES 8-v
LIST OF FIGURES 8-vi
ACRONYMS AND ABBREVIATIONS 8-vii
APPENDIX 8 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS 8-0
8.1 Introduction and Summary of the 2013 Integrated Science Assessment 8-0
8.1.1 Effects on Pregnancy and Birth Outcomes 8-1
8.1.2 Effects on Development 8-1
8.1.3 Effects on Female Reproductive Function 8-2
8.1.4 Effects on Male Reproductive Function 8-2
8.2 Scope 8-3
8.3 Effects on Pregnancy and Birth Outcomes 8-4
8.3.1 Maternal Health During Pregnancy 8-5
8.3.2 Prenatal Growth 8-9
8.3.3 Preterm Birth 8-16
8.3.4 Birth Defects 8-19
8.3.5 Spontaneous Abortion and Pregnancy Loss and Fetal and Infant Mortality 8-21
8.3.6 Placental Function 8-24
8.3.7 Other Pregnancy and Birth Outcomes 8-26
8.4 Effects on Development 8-28
8.4.1 Effects on Postnatal Growth 8-28
8.4.2 Effects on Puberty among Females 8-33
8.4.3 Effects on Puberty among Males 8-36
8.4.4 Other Developmental Effects 8-39
8.5 Effects on Female Reproductive Function 8-40
8.5.1 Effects on Hormone Levels and Menstrual/Estrous Cycle 8-40
8.5.2 Effects on Female Fertility 8-44
8.5.3 Effects on Morphology and Histology of Female Sex Organs (Ovaries, Uterus,
Fallopian Tubes/Oviducts, Cervix, Vagina, and Mammary Glands) 8-46
8.6 Effects on Male Reproductive Function 8-47
8.6.1 Effects on Sperm/Semen Production, Quality, and Function 8-47
8.6.2 Effects on Hormone Levels in Males 8-50
8.6.3 Effects on Male Fertility 8-53
8.6.4 Effects on Morphology and Histology of Male Sex Organs 8-54
8.7 Biological Plausibility 8-56
8.7.1 Pubertal Onset 8-57
8.7.2 Male Reproduction Function 8-58
8.8 Summary and Causality Determination 8-60
8.8.1 Summary of Effects on Pregnancy and Birth Outcomes 8-60
8.8.2 Summary of Effects on Development 8-63
8.8.3 Summary of Effects on Female Reproductive Function 8-66
8.8.4 Summary of Effects on Male Reproductive Function 8-68
8.9 Evidence Inventories - Data Tables to Summarize Study Details 8-77
8.10 References 8-241
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LIST OF TABLES
Table 8-1 Summary of evidence contributing to causality determinations for Pb exposure and
reproductive and developmental effects. 8-72
Table 8-2 Epidemiologic studies of exposure to Pb and maternal health outcomes. 8-77
Table 8-3 Animal toxicological studies of Pb exposure and pregnancy and birth outcomes. 8-93
Table 8-4 Epidemiologic studies of Pb exposure and prenatal growth. 8-98
Table 8-5 Epidemiologic studies of Pb exposure and preterm birth. 8-130
Table 8-6 Epidemiologic studies of Pb exposure and birth defects. 8-142
Table 8-7 Epidemiologic studies of Pb exposure and fetal and infant mortality and spontaneous
abortion and pregnancy loss. 8-149
Table 8-8 Epidemiologic studies of Pb exposure and placental function. 8-153
Table 8-9 Epidemiologic studies of Pb exposure and other pregnancy and other birth outcomes. 8-155
Table 8-10 Epidemiologic studies of Pb exposure and postnatal growth. 8-161
Table 8-11 Animal toxicological studies of Pb exposure and development. 8-182
Table 8-12 Epidemiologic studies of exposure to Pb and puberty in females and puberty in males. 8-189
Table 8-13 Epidemiologic studies of exposure to Pb and other developmental effects. 8-202
Table 8-14 Epidemiologic studies of exposure to Pb and female reproductive effects. 8-208
Table 8-15 Animal toxicological studies of Pb exposure and female reproductive effects. 8-218
Table 8-16 Epidemiologic studies on exposure to Pb and male reproductive effects. 8-221
Table 8-17 Animal toxicologic studies of exposure to Pb and male reproductive effects. 8-238
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LIST OF FIGURES
Figure 8-1 Potential biological pathways for reproductive and developmental effects following
exposure to Pb. 8-57
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ACRONYMS AND ABBREVIATIONS
AAS atomic absorption spectrometry
AGD anogenital distance
AGDap anopenile distance
AGDas anoscrotal distance
ALAD aminolevulinic acid dehydratase
ALSPAC Avon Longitudinal Study of Parents
and Children
AMH anti-Mullerian hormone
As arsenic
AQCD Air Quality Criteria Document
ART Assisted reproductive technology
BKMR Bayesian kernel machine regression
BLL blood lead level
BMI body mass index
BMIZ BMI-for-age Z-score
BW birth weight
BWGA birth weight-for-gestational age
BWZ birth weight Z-score
C-ABCS China-Anhui Birth Cohort Study
CANDLE Conditions Affecting Neurocognitive
Development and Learning in Early
Childhood
CCG Charlotte-Concord-Gastonia
Cd cadmium
CD cephalic diameter
CHD congenital heart disease
CHECK Children's Health and Environmental
Chemicals in Korea
CHL crown-to-heel length
CI confidence interval
CMS Charlotte Motor Speedway
d day(s)
DBP diastolic blood pressure
E2 estradiol
ELEMENT Early Life Exposures in Mexico to
Environmental Toxicants
ELISA enzyme-linked immunoassay
EMASAR Study on the Environment and
Reproductive Health
ETS environmental tobacco smoke
fE2 free estradiol
FLEHS Flemish Environment and Health
Studies
FSH follicle stimulating hormone
fT free testosterone
fT3 free triiodothyronine
fT4 free thyroxine
GA gestational age
GDM gestational diabetes mellitus
GEE generalized estimating equation
GFAAS graphite furnace atomic absorption
spectrometry
GnRH gonadotropin-releasing hormone
GSI global severity index
HAZ height-for-age Z-score
HC head circumference
HCAZ head circumference for age Z-scores
hCG human chorionic gonadotropin
HFIAS Household Food Insecurity Access
Scale
Hg mercury
HOME Home Observation for Measurement of
the Environment
HTZ height Z-score
hr hour(s)
ICP-AES inductively coupled plasma atomic
emission spectroscopy
ICP-MS inductively coupled plasma mass
spectrometry
ICP-QQQ inductively coupled plasma triple quad
IgE immunoglobulin E
IGF insulin-like growth factor 1
IGT impaired glucose tolerance
IL-33 interleukin-33
INMA Instituto de Nanociencia y Materiales
de Aragon
IQR interquartile range
ISA Integrated Science Assessment
IUGR intrauterine growth restriction
IVF in vitro fertilization
JECS Japan Environment and Children's
Study
K6 Kessler Psychological Distress Scale
K-XRF K-shell X-ray fluorescence
LA-ICP-MS laser ablation-inductively coupled
plasma-mass spectrometry
LBW low birth weight
LGA large for gestational age
LH luteinizing hormone
LIFE Longitudinal Investigation of Fertility
and the Environment
LMP last menstrual period or last missed
period
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In natural log-transformed
LOD limit of detection
MAL-ED Interactions of Malnutrition and Enteric
Infections: Consequences for Child
Health and Development
Mil metaphase II
min minute(s)
MIREC Maternal-Infant Research on
Environmental Chemicals
miRNA micro RNA
MMP matrix metalloproteinases
Mn manganese
mo month(s)
MOCEH Mothers'and Children's
Environmental Health
MSA Metropolitan Statistical Area
mtDNA mitochondrial DNA
NASCAR National Association for Stock Car
Auto Racing
NHANES National Health and Nutrition
Examination Survey
NICE Nutritional impact on Immunological
maturation during Childhood in relation
to the Environment
NTD neural tube defects
OFC orofacial clefts
OGTT oral glucose tolerance test
PECOS Population, Exposure, Comparison,
Outcome, and Study
PI Ponderal Index
PIR poverty-to-income ratio
PND postnatal day
PROGRESS Programming Research in Obesity,
Growth, Environment and Social
Stressors
PROM premature rupture of membranes
PROTECT Puerto Rico Test site for Exploring
Contamination Threats
QUS quantitative ultrasound
ROS reactive oxygen species
RRR relative risk ratio
rTL relative telomere length
SBP systolic blood pressure
SD standard deviation
Se selenium
SE standard error
SES socioeconomic status
SGA small for gestational age
SHBG sex hormone binding globulin
SNP single nucleotide polymorphisms
SPECT Survey on the Prevalence in East China
for Metabolic Diseases and Risk
Factors
T testosterone
TL telomere length
TPOAb thyroid peroxidase antibodies
TSH thyroid-stimulating hormone
TSLP thymic stromal lymphopoietin
tT total testosterone
tT3 total triiodothyronine
tT4 total thyroxine
TV testicular volume
UCB umbilical cord blood
WAZ weight for age Z-score
WC waist circumference
wk week(s)
WHEALS Wayne County Health, Environment,
Allergy and Asthma Longitudinal
Study
WHO World Health Organization
yr year(s)
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APPENDIX 8 REPRODUCTIVE AND
DEVELOPMENTAL EFFECTS
i
Summary of Causality Determinations for Pb Exposure and
Reproductive and Developmental Effects
This appendix characterizes the scientific evidence that supports causality
determinations for Pb exposure and reproductive and developmental effects. The types
of studies evaluated within this appendix are consistent with the overall scope of the
ISA as detailed in the Process Appendix (see Section 12.4). In assessing the overall
evidence, the strengths and limitations of individual studies were evaluated based on
scientific considerations detailed in Table 12-5 of the Process Appendix (Section
12.6.1). More details on the causal framework used to reach these conclusions are
included in the Preamble to the ISA (U.S. EPA. 2015). The evidence presented
throughout this chapter supports the following causality conclusions:
Outcome Group
Causality Determination
Effects on Pregnancy and Birth Outcomes
Suggestive
Effects on Development
Causal
Effects on Female Reproductive Function
Suggestive
Effects on Male Reproductive Function
Causal
The Executive Summary, Integrated Synthesis, and all other appendices of this Pb
ISA can be found at https://cfpub.cpa.gov/ncca/isa/rccordisplav.cfm'Mcid=357282.
8.1 Introduction and Summary of the 2013 Integrated Science
Assessment
2 This appendix evaluates the epidemiologic and toxicological literature related to the potential
3 effects of lead (Pb) on reproductive and developmental outcomes, divided into four sections: (1) effects
4 on pregnancy and birth outcomes; (2) effects on development; (3) effects on female reproductive
5 function; and (4) effects on male reproductive function. Based on the epidemiologic and toxicological
6 studies reviewed in the 2013 Pb Integrated Science Assessment (ISA) (U.S. EPA. 2013). the determination
7 for effects on pregnancy and birth outcomes was based on the mix of inconsistent results of the
8 epidemiologic and toxicological studies on various birth outcomes, but with some associations observed
9 in some epidemiologic studies of preterm birth and low birth weight and fetal growth. The determination
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for developmental effects was informed by evidence from toxicological studies reporting delayed female
sexual maturity and supported by epidemiologic studies of delayed pubertal onset for both girls and boys.
The determination for effects on female reproductive effects was based on epidemiologic and
toxicological studies for reproductive function among females reviewed including endpoints of hormone
levels, fertility, estrous cycle changes, and morphology or histology of female reproductive organs
including the placenta. Of the epidemiologic and toxicological studies reviewed for effects on female
reproductive function, the studies were high-quality and well-designed and examined different exposure
periods in conjunction with a number of outcomes related to female reproductive effects. The
determination for effects on male reproductive function were based on strong toxicological evidence with
supporting epidemiologic evidence that showed detrimental effects on semen quality, sperm, and
fecundity/fertility with supporting evidence in epidemiologic studies of associations between Pb exposure
and detrimental effects on sperm. The summary of the determinations from the 2013 Pb ISA are
detailed below.
8.1.1 Effects on Pregnancy and Birth Outcomes
The 2013 Pb ISA (U.S. EPA. 2013) reported the associations between Pb exposure and birth
outcomes were inconsistent. There were some associations observed between Pb and low birth weight
when epidemiologic studies used measures of postpartum maternal bone Pb or air exposures. The
associations were less consistent for maternal blood Pb measured during pregnancy or at delivery or
umbilical cord and placenta Pb (maternal blood Pb or umbilical cord and placenta Pb were the biomarkers
most commonly used in studies of low birth weight) but some associations between increased Pb
biomarker levels and decreased low birth weight/fetal growth were observed. Animal studies
investigating the effects of Pb exposure during gestation on litter size, implantation, and birth weight had
varying results between studies. Based on the mix of inconsistent results of studies on various birth
outcomes but some associations observed in select epidemiologic studies of preterm birth and low birth
weight/fetal growth, the evidence in the 2013 Pb ISA was suggestive of a causal relationship between Pb
exposure and birth outcomes.
8.1.2 Effects on Development
The 2013 Pb ISA (U.S. EPA. 2013) reported Pb associated effects on development in
epidemiologic and toxicological studies. Previous toxicological studies indicated that delayed pubertal
onset may be one of the more sensitive developmental effects of Pb exposure with effects observed after
gestational exposures leading to blood Pb levels (BLLs) in the female pup of 1.3-13 (ig/dL (lavicoli el al..
2006; lavicoli et al.. 2004). Toxicological studies have reported delayed male sexual maturity as measured
with sex organ weight, seeing significant decrements at BLLs of 20-34 (ig/dL (Ronis etal.. 1998c; Sokolet
al.. 1985). The 2013 Pb ISA also presented findings from a toxicological study that suggests Pb may act
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through disruption of insulin-like growth factor 1 (IGF-1) to delay the onset of puberty, demonstrated by
the attenuation of Pb-induced delays in pubertal onset in female rats supplemented with IGF-1 (Pine el al..
2006). Thus, data from the toxicological literature and from epidemiologic studies demonstrated that
puberty onset in both males and females is delayed with Pb exposure. Findings from epidemiologic
studies of the effect of Pb on postnatal growth were inconsistent and findings from the toxicological
literature of the effect of Pb exposure were mixed with recent growth findings showing adult-onset male
obesity after gestational and lactational Pb exposure. The 2013 Pb ISA concluded that, based on the
findings of delayed pubertal onset among males and females, there was sufficient evidence to conclude a
causal relationship between Pb exposure and developmental effects.
8.1.3 Effects on Female Reproductive Function
The 2013 Pb ISA (U.S. EPA. 2013) found some evidence of a potential relationship between Pb
exposure and female fertility; however, findings were inconsistent. Epidemiological studies were largely
cross-sectional and adjustments for important confounding factors were not included in all studies. Some
toxicological studies reported effects on placental pathology and inflammation, decreased ovarian
antioxidant capacity, and altered hormone levels. Overall, the relationship observed with female
reproductive outcomes, such as fertility, placental pathology, and hormone levels in some epidemiologic
and toxicological studies was sufficient for the 2013 Pb ISA to conclude that evidence was suggestive of
a causal relationship between Pb exposure and female reproductive function.
8.1.4 Effects on Male Reproductive Function
The 2013 Pb ISA (U.S. EPA. 2013) reported multiple studies in rodents and non-human primates
that observed Pb-induced sperm DNA damage, reduced sperm quality, reduced sperm production, and
histological and ultrastructural damage to male reproductive organs. Other toxicological studies reported
that Pb exposure was associated with decreases in reproductive organ weights, histological changes in the
testes and germ cell, and subfecundity. The 2013 Pb ISA also presented toxicological evidence suggesting
that Pb may damage sperm cells and sex organ tissue through induction of oxidative stress (Salawu et al..
2009; Shan et al.. 2009; Madhavi et al.. 2007; Rubio et al.. 2006; Wang et al.. 2006). Specifically, one study
reported Pb-induced increases in oxidative stress markers and reductions of levels of antioxidant enzymes
in testicular plasma (Salawu etal.. 2009). In addition, several studies reported attenuation of Pb-induced
reductions in sperm count, motility, and viability when animals were co-administered substances with
known antioxidant properties (Salawu et al.. 2009; Shan etal.. 2009; Madhavi et al.. 2007; Rubio et al.. 2006;
Wang etal.. 2006). Epidemiologic studies were limited due to lack of consideration of potential
confounding factors or the use of men attending a fertility clinic, which could result in a biased sample.
However, a well-conducted epidemiologic study that enrolled men going to a clinic for either infertility
issues or to make a semen donation and controlled for other metals as well as smoking reported a
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positive association with various detrimental effects in sperm (Tclisman et al.. 2007). Studies in the 2013
Pb ISA that investigated the effects of Pb on hormone levels reported inconsistent results, resulting in
uncertainty as to whether Pb exerts its toxic effects on the reproductive system by affecting the
responsiveness of the hypothalamic-pituitary-gonad axis, by suppressing circulating hormone levels, or
by some other pathway. Based on the consistency and coherence of findings of the detrimental effects of
Pb exposure on sperm and semen in the toxicological literature, the support from epidemiologic studies,
and biological plausibility provided by mode of action evidence; however, the evidence in the 2013 Pb
ISA was sufficient to conclude a causal relationship between Pb exposures and male reproductive
function.
8.2 Scope
The scope of this section is defined by Population, Exposure, Comparison, Outcome, and Study
Design (PECOS) statements. The PECOS statements define the objectives of the review and establishes
study inclusion criteria thereby facilitating identification of the most relevant literature to inform the Pb
ISA.1 In order to identify the most relevant literature, the body of evidence from the 2013 Pb IS A was
considered in the development of the PECOS statements for this Appendix. Specifically, well-established
areas of research; gaps in the literature; and inherent uncertainties in specific populations, exposure
metrics, comparison groups, and study designs identified in the 2013 Pb ISA inform the scope of this
Appendix. The 2013 Pb ISA used different inclusion criteria than the current ISA, and the studies
referenced therein often do not meet the current PECOS criteria (e.g., due to higher or unreported
biomarker levels). Studies that were included in the 2013 Pb ISA, including many that do not meet the
current PECOS criteria, are discussed in this appendix to establish the state of the evidence prior to this
assessment. With exception of supporting evidence used to demonstrate the biological plausibility of Pb-
associated effects on reproductive and developmental health, studies evaluated and subsequently
discussed within this section were only included if they satisfied all the components of the following
discipline-specific PECOS statement:
Epidemiologic Studies:
Population: Any human population, including specific populations or lifestages that might be at
increased risk of a health effect.
Exposure: Exposure to Pb2 as indicated by biological measurements of Pb in the body - with a
1 The following types of publications are generally considered to fall outside the scope and are not included in the
ISA: review articles (which typically present summaries or interpretations of existing studies rather than bringing
forward new information in the form of original research or new analyses), Pb poisoning studies or clinical reports
(e.g., involving accidental exposures to very high amounts of Pb described in clinical reports that may be extremely
unlikely to be experienced under ambient air exposure conditions), and risk or benefits analyses (e.g., that apply
concentration-response functions or effect estimates to exposure estimates for differing cases).
2 Recent studies of occupational exposure to Pb were considered insofar as they addressed a topic area that was of
particular relevance to the National Ambient Air Quality Standards (NAAQS) review (e.g., longitudinal studies
designed to examine recent versus historical Pb exposure).
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specific focus on Pb in blood, bone, and teeth; validated environmental indicators of Pb
exposure;1 or intervention groups in randomized trials and quasi-experimental studies.
Comparison: Populations, population subgroups, or individuals with relatively higher versus
lower levels of the exposure metric (e.g., per unit or log unit increase in the exposure metric,
or categorical comparisons between different exposure metric quantiles).
Outcome: Reproductive effects, including but not limited to altered age of puberty onset, reduced
fertility, poor semen quality/motility, and miscarriage. Developmental effects including but
not limited to adverse pregnancy outcomes (e.g., reduced fetal growth, preterm birth, small
for gestational age [SGA], birth defects), as well as postnatal developmental effects.
Study Design: Epidemiologic studies consisting of longitudinal and retrospective cohort studies,
case-control studies, cross-sectional studies with appropriate timing of exposure for the health
endpoint of interest, randomized trials and quasi-experimental studies examining
interventions to reduce exposures.
Experimental Studies:
Population: Laboratory nonhuman mammalian animal species (i.e., mouse, rat, Guinea pig,
minipig, rabbit, cat, dog; whole organism) of any lifestage (including preconception, in utero,
lactation, peripubertal, and adult stages).
Exposure: Oral, inhalation, or intravenous routes administered to a whole animal (in vivo) that
results in a blood Pb level (BLL) of 30 (ig/dL or below.2'3
Comparators: A concurrent control group exposed to vehicle-only treatment or untreated
control.
Outcomes: Reproductive and developmental effects.
Study design: Controlled exposure studies of animals in vivo.
8.3 Effects on Pregnancy and Birth Outcomes
The 2013 Pb ISA reported inconsistent findings in the epidemiologic and toxicological literature
for birth outcomes. Among the epidemiologic studies, there were inconsistent associations between Pb
exposure and preterm birth. A single study of neural tube defects (NTDs) found no associations in the
2013 Pb ISA, but studies within the 2006 Air Quality Criteria Document for lead (Pb AQCD) (U.S. EPA.
2006) reported associations between Pb exposure and NTDs. There were some associations reported
between Pb and low birth weight when epidemiologic studies used measures of postpartum maternal bone
Pb or air exposures. There were less consistent associations for maternal blood Pb measured during
pregnancy or at delivery or umbilical cord and placenta Pb (maternal blood Pb or umbilical cord and
1 Studies that estimate Pb exposure by measuring Pb concentrations in PMio and PM2 5 ambient air samples are only
considered for inclusion if they also include a relevant biomarker of exposure. Given that size distribution data for
Pb-PM are fairly limited, it is difficult to assess the representativeness of these concentrations to population
exposure [Section 2.5.3 (U.S. EPA. 201311. Moreover, data illustrating the relationships of Pb-PMio and Pb-PM2 5
with blood Pb level (BLLs) are lacking.
2 Pb mixture studies are included if they employ an experimental arm that involves exposure to Pb alone.
3 This level represents an order of magnitude above the upper end of the distribution of U.S. young children's BLLs.
The 95th percentile of the 2011-2016 National Health and Nutrition Examination Survey (NHANES) distribution of
BLL in children (1-5 years; n = 2,321) is 2.66 (ig/dL (CDC, 2019) and the proportion of individuals with BLLs that
exceed this concentration varies depending on factors including (but not limited to) housing age, geographic region,
and a child's age, sex and nutritional status.
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placenta Pb were the biomarkers most commonly used in studies of low birth weight). The effects of Pb
exposure during gestation in animal toxicological studies included mixed findings, but most studies
reported reductions in birth weight of pups or birth weight of litters when dams were treated with Pb.
The recent epidemiologic and toxicological studies are detailed in the following sections. Effects
on pregnancy and birth outcomes encompass a large range of outcomes. The following sections relating to
pregnancy and outcomes are categorized into seven main sections: (1) maternal health during pregnancy;
(2) prenatal growth; (3) preterm birth; (4) birth defects; (5) spontaneous abortion and pregnancy loss and
fetal and infant mortality; (6) placental function; and (7) other pregnancy and birth outcomes. The recent
epidemiologic and toxicological studies reported inconsistent findings across the seven main health
outcomes evaluated. While recent epidemiologic studies reported consistent null associations with
gestational diabetes mellitus (GDM), among all other pregnancy and birth outcomes (prenatal growth,
preterm birth, birth defects, spontaneous abortion and pregnancy loss, and placental function, and other
outcomes), there were inconsistent results. These inconsistent findings may be the result of the cross-
sectional designs, timing of the exposure, biomarkers examined for Pb, and in some instances, small
sample sizes. The recent evidence from the toxicological studies mostly reported no effects of Pb across
pregnancy and birth outcomes. This may be due to the exclusion of toxicological studies with BLLs
greater than 30 (ig/dL, indicating the possibility that most pregnancy and birth outcomes are only affected
in laboratory animals at levels higher than most environmentally relevant Pb exposure levels.
8.3.1 Maternal Health During Pregnancy
Maternal health during pregnancy encompasses a wide range of health effects. The details of the
recent epidemiologic and toxicological studies evaluating the association between Pb exposure and
maternal health during pregnancy are provided in Table 8-2 and Table 8-3, respectively.
8.3.1.1 Epidemiologic Studies on Maternal Health During Pregnancy
The main maternal health outcomes evaluated in this section are GDM and epigenetic studies.
Although there are a limited number of epigenetic studies, these studies may help to add support for
biological plausible pathways for which Pb exposure may affect maternal health during pregnancy.
8.3.1.1.1 Epidemiologic Studies on Gestational Diabetes Mellitus
There were no studies on GDM in the 2013 Pb ISA. There were several recent epidemiologic
studies that evaluated the association between Pb exposure and GDM and/or impaired glucose tolerance
(IGT) (Tatsuta et al.. 2022a; Zheng et al.. 2021; Zhou et al.. 2021b; Qguri et al.. 2019; Soomro et al.. 2019; Wang
etal.. 2019; Shapiro et al.. 2015). Generally, across the studies there were null associations between Pb
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exposure and GDM and IGT, and/or GDM or IGT. In studies that evaluated Pb in maternal blood with
GDM outcomes, the timing of when Pb was measured differed between trimesters, but the difference in
what trimester Pb was measured did not impact the associations (Qgurietal.. 2019; Soomro etal.. 2019;
Wangetal.. 2019; Shapiro etal.. 2015). Additionally, while maternal blood was the primary biomarker used
to measure Pb exposure, some studies have used other biomarkers such as maternal serum (Zhou et al..
2021b) and maternal erythrocytes (Zheng etal.. 2021); however, the type of biomarker measurement did not
influence the pattern of associations. Only one study reported a decrease of 0.5 (95% CI: -1.6, -0.6)
mg/dL difference in mid-gestational glucose concentration associated with an interquartile range (IQR)
(17.6 ng/g) change in blood erythrocyte Pb exposure (Zheng et al.. 2021). Furthermore, multiple studies
also considered co-exposure to other metals in addition to Pb, but the associations remained null (Zheng et
al.. 2021; Zhou etal.. 2021b; Qgurietal.. 2019; Wangetal.. 2019). Overall, the associations between Pb
exposure and GDM, IGT, and GDM or IGT were null, and the null associations persisted across the
different trimesters of when Pb levels were measured, the different biomarkers for Pb exposure, and
adjustment for co-exposure to other metals.
8.3.1.1.2 Epidemiologic Studies on Epigenetic Effects During Pregnancy
There were no studies on epigenetic effects during pregnancy evaluated in the 2013 Pb ISA. The
recent epidemiologic studies on epigenetic effects during pregnancy are limited but provide insight on
potential mechanistic pathways in which Pb exposure may impact pregnancy. A single study by Sanders et
al. (2015) assessed the association between maternal Pb levels in blood, patella, and tibial bone and altered
micro RNA (miRNA) expression in the cervix during the second trimester of pregnancy in a subset of 60
women enrolled in a prospective birth cohort, Programming Research in Obesity, Growth, Environment
and Social Stressors (PROGRESS), in Mexico City. Changes in cervical miRNA expression are a
potential mechanism that could alter gene expression leading to aberrant changes in cervix tissue function
and subsequently impact parturition (Sanders et al.. 2015). Expression of certain miRNAs in the cervix
during pregnancy have been associated with subsequent gestational age (GA) at delivery (Sanders etal..
2015). During mid-pregnancy (16-19 weeks gestation), samples from cervical exams were collected and
analyzed for the expression profiles of 800 miRNAs. Overall, there were distinct miRNAs measured in
cervical samples during pregnancy that are associated with the subsequent GA of offspring. Sanders et al.
(2015) also identified differentially expressed miRNAs with respect to preterm compared term birth in a
subset of women. There were two miRNAs expressed in the cervix that were identified in association
with maternal second trimester BLLs, seven miRNAs that were identified in association with maternal
patella bone Pb levels, and six miRNAs that were identified in association with maternal tibia Pb levels
(see Table 8-2). In another epigenetics study in the same PROGRESS cohort, Sanchez-Guerra et al. (2019)
assessed the association of blood Pb exposure during pregnancy with mitochondrial DNA (mtDNA)
content, which is a sensitive marker of mitochondrial function and oxidative stress, in cord blood.
Maternal blood Pb samples were obtained at three time points (second trimester n = 410, third trimester
n = 356, and at delivery n = 354), and cord blood (n = 346) Pb samples were obtained at delivery.
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Maternal Pb levels during the second trimester ((3: 0.017 [95% CI: 0.002, 0.031]) was associated with
higher mtDNA content; however, there were null associations between cord BLLs at delivery ((3: 0.016
[95% CI: 0.001, 0.03]), maternal third trimester blood Pb ([3: 0.015 [95% CI 0.00, 0.03]), and maternal
BLLs at delivery ([3: 0.013 [95% CI: -0.001, 0.027]). These epigenetic studies provide support of
potential mechanistic pathways in which Pb exposure are associated with maternal health during
pregnancy.
8.3.1.1.3 Epidemiologic Studies on Other Outcomes Related to Maternal Health During
Pregnancy
There were several other outcomes related to maternal health during pregnancy. More specific
study details, including Pb levels, study population characteristics, potential confounders, and select
results from these studies are highlighted in Table 8-2. In other outcomes related to maternal health
during pregnancy, Pb exposure has been associated with decreased free thyroxine (fT4) during mid-
pregnancy (Kahnetal.. 2014); increased thyroid peroxidase antibodies (TPOAb) during mid-pregnancy
(Kahnetal.. 2014); small increases in umbilical cord blood Pb and elevations in systolic blood pressure
and diastolic blood pressure during labor and delivery (Wells etal.. 2011); changes in global severity index
(GSI), depression and anxiety symptom scores (Li etal.. 2017b); bone mineral density of the patella
(Osorio-Yafiez et al.. 2021); increased matrix metalloproteinases (MMP), regulators of uterine remodeling
(Kim etal.. 2022); and increased risk of preeclampsia (Gaiewska et al.. 2021; Wuetal.. 2021). However, there
was no associations between Pb exposure and reduced Cortisol awakening response (Braunetal.. 2014);
maternal depression (Ishitsuka et al.. 2020); anti-Miillerian hormone (AMH), a suggested marker of ovarian
function and biological marker of female fecundity (Christensen et al.. 2016); hormone levels in pregnancy
(Gustinetal.. 2021); and thyroid function (Corrales Vargas et al.. 2022).
8.3.1.2 Toxicological Studies on Maternal Health During Pregnancy
Previous Pb ISAs and AQCDs did not report any toxicological studies that investigated the
effects of Pb on maternal health during pregnancy. Despite this lack of prior studies to compare to, recent
toxicological studies have reported on the effects of Pb on maternal weight gain during pregnancy (Table
8-3). Maternal weight gain is often used as an indicator of fetal growth and maternal overt toxicity.
Additionally, maternal weight gain shares associations with gestational conditions in humans (Santos etal..
2019). Recent studies dosed Sprague-Dawley rats with Pb via gavage for the first 20 days of pregnancy
and reported that the 160 ppm Pb treatment group exhibited reduced weight gain during pregnancy
(maternal BLLs on GD 20 were reported to be 23.9-27.7 (ig/dL) (Salehetal.. 2019; Saleh etal.. 2018). Of
note is that both studies by Saleh et al. (Saleh etal.. 2019; Salehetal.. 2018) reported reduced brain weight
of dams, indicating that overt toxicity may have contributed to the overall reduction in maternal weight.
Further, the reported maternal BLLs were higher than those observed in the following studies that
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investigated the same outcomes. Corv-Slechta et al. (20131 and Schneider et al. (20161 both dosed C57BL/6
mice with 100 ppm Pb via drinking water starting two months prior to mating and reported no effects on
maternal bodyweight gain and observed much lower maternal BLLs with Corv-Slechta et al. (20131
reporting 12.12 (ig/dL at weaning and Schneider et al. (20161 reporting 12.61 (ig/dL on lactation day 21.
Similarly, Wang etal. (20141 reported no effects in Wistar rats dosed with Pb via drinking water for various
durations during pregnancy. In Wang etal. (20141 dosing from GD 1-10, GD 11-20, and GD 1-20 resulted
in maternal BLLs of 26.4, 12.4, and 36.0 (ig/dL, respectively, at termination of the study on GD 20.
Although some of these BLLs overlap with those seen in the studies by Salehetal. (20181 and Saleh et al.
(20191 wherein suppression of maternal weight gain was observed, it is possible that the use of different
strains or different dosing routes could be attributed to the observed difference in effect on maternal
weight gain. Additionally, the reduction of brain weight observed in the dams used in the studies by Saleh
etal. (20181 and Salehetal. (20191 suggest that maternal overt toxicity may be responsible for the observed
reduction in maternal weight gain.
8.3.1.3 Integrated Summary of Effects on Maternal Health During Pregnancy
The 2013 Pb ISA did not include epidemiologic and/or toxicological studies that evaluated the
relationship between Pb exposure and maternal health during pregnancy. Overall, the recent
epidemiologic and toxicological studies have reported inconsistent findings related to maternal health
during pregnancy and Pb exposure. There were consistent null associations between Pb exposure and
GDM among the recent epidemiologic studies. While the critical window for GDM is unknown, these
studies had different time points during pregnancy in which Pb exposure was measured and different
biomarkers of exposure (blood, serum, and erythrocyte) and the null associations persisted. A few of the
studies were limited by the cross-sectional study design and the small number of GDM cases.
Additionally, a few of the recent epidemiological studies incorporated mixture methods to consider Pb
exposure in conjunction with co-exposure to other metals to evaluate associations with GDM, which
helps to reduce uncertainties regarding co-pollutant confounding. The limited number of epigenetic
studies provide support of potential mechanistic pathways in which Pb exposure are associated with
selected maternal health during pregnancy. Furthermore, there was a small body of evidence across
various additional pregnancy-related endpoints in the epidemiologic literature; however, the small number
limits the ability to judge coherence and consistency across these studies, although the positive
associations observed demonstrate that Pb exposure could result in physiological responses that
contribute to adverse pregnancy outcomes (e.g., changes in thyroid function, maternal mental health,
changes in blood pressure, preeclampsia). In the recent toxicological literature, there were a limited
number of studies that investigated the relationship between Pb exposure and maternal weight gain during
pregnancy; however, the only studies that observed changes in maternal weight gain also reported signs of
possible overt toxicity (reduced brain weight), indicating that weight gain during pregnancy may not have
been a direct effect of Pb exposure. The majority of recent toxicological studies in rodents reported that
maternal weight gain during pregnancy was unaffected by Pb exposure.
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8.3.2
Prenatal Growth
The recent epidemiologic and toxicological studies that examined the relationship between Pb
exposure and prenatal growth, which includes outcomes such as fetal growth, birth weight, body length at
birth, and GA, are summarized in the text below. Study details of the recent epidemiologic studies are
included in Table 8-4 and the recent toxicological studies are in Table 8-3.
8.3.2.1 Epidemiologic Studies on Prenatal Growth
The epidemiologic studies in the 2013 Pb ISA reported associations between maternal bone Pb
and low birth weight and with studies of Pb air exposures and birth weight. The associations were less
consistent when using maternal blood Pb or umbilical cord and placenta Pb as the exposure measurement,
although some studies did demonstrate associations. The studies of Pb exposure and fetal growth were
limited by their cross-sectional study design, small sample size, high air Pb concentrations (air Pb as high
as 30 (ig/m3), and in some studies, the lack of control of confounders.
A large number of epidemiologic studies have been published since the 2013 Pb ISA on exposure
to Pb and prenatal growth. The studies in this section focus on these prenatal growth outcomes, including
birth weight; low birth weight; body length, crown-to-heel length, head circumference (HC), Ponderal
Index (PI; weight/height3), GA, SGA, and large for gestational age (LGA). Multiple cross-sectional and
cohort studies have been conducted that examined the relationship between Pb exposure and prenatal
growth; however, the findings from the recent epidemiologic studies are inconsistent. There are
differences in study design, timing of the exposure (at different points during pregnancy, at delivery),
differences in biomarkers examined for Pb (maternal blood, maternal serum, cord blood, maternal red
blood cells, placental tissue), and small sample sizes in some studies. The study details, including
information on study population, biomarker of exposure, and outcome, are in Table 8-4.
Several cross-sectional studies that used cord blood to assess Pb exposure reported null
associations with birth weight (Lee etal.. 2021; Govarts et al.. 2020; Tatsuta et al.. 2017; Wang et al.. 2017b;
Govarts et al.. 2016; Garria-Esauinas et al.. 2013; Xie etal.. 2013). while a single cross-sectional study
reported a reduction in birth weight (Xu el al.. 2012). Among these cross-sectional studies, there were also
inconsistent associations when examining cord blood Pb exposure and birth weight among infant sex.
Tatsuta et al. (20171 evaluated the associations between cord blood Pb and birth weight between male and
female infants, but the associations remained null. While there were null associations with birth weight,
birth length, HC, and PI when infant sexes were analyzed together, analyses stratifying by infant sex
reported associations in male infants, including increased birth weight ((3: 206.50 [95% CI: 46.15,
366.86]) and decreased HC ((3: -0.65 [95% CI: -1.24, -0.06]) per 1-unit increase logio-Pb cord blood
concentration. Among female infants, there was only a reduction in PI ([3: -0.16 [95% CI: -0.30, -0.02])
per 1-unit increase in the logio-Pb cord blood concentration (Wang etal.. 2017b).
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In addition to birth weight, there were several other prenatal growth outcomes in these cross-
sectional studies that were evaluated in association with cord blood Pb; however, the associations were
inconsistent. Garria-Esauinas et al. (20131 also reported null associations between cord blood Pb and birth
length, and 1- and 5-minute Apgar scores from the 144 newborns who were a part of cross-sectional
biomonitoring study of the BioMadrid Project. Xuetal. (20121 also reported decreased mean GA of
0.57 weeks (95% CI: 0.51, 0.63), with increased risk of low birth weight rate (OR: 1.61 [95% CI: 1.37,
1.90]), and increased risk of intrauterine growth retardation rate (OR: 2.12 [95% CI: 1.68, 2.69]). Xie et al.
(20131 reported a negative association with birth length ([3: -0.84 cm [95% CI: -1.52, -0.16]) per square
root 1-jj.g/dL increase in cord blood Pb, but null associations with birth weight ([3: -99.33 g [95% CI:
-217.33, 20.67]) and HC ([3: -0.36 [95% CI: -0.81, 0.03]). A single cross-sectional study that was
conducted among 1,578 mother-infant pairs in Saudi Arabia reported no associations between cord BLLs
and PI below the 10th percentile (OR: 0.66 [95% CI: 0.42, 1.05]) (Al-Saleh et al.. 2014).
Maternal blood was also used to measure Pb exposure in association with prenatal growth
outcomes in multiple cross-sectional studies, but the associations were inconsistent. Xie etal. (20131
reported a negative association with birth weight ([3: -148.99g [95% CI: -286.33,-11.66]) per square
root 1-jj.g/dL increase in maternal blood Pb, but null associations with birth length ([3: -0.46 cm [95% CI:
-1.25, 0.34]) and HC ([3: -0.37 cm [95% CI: -0.78, 0.19]) among 252 mother-infant pairs in a rural area
located on the south coast of Laizhou Bay, China between 2010 and 2011. However, Kim et al. (20201
reported negative associations between maternal blood natural log-transformed (ln)-Pb and HC ([3:
-0.75 cm [95% CI: -1.17, -0.32]) and PI ([3: -0.62 kg/m3 [95% CI: -1.13, -0.11]), but there were null
associations with birth weight ([3: 60 g [95% CI: -15, 135]), BMI ([3: -0.14 kg/m2 [95% CI: -0.39, 0.11]),
and SGA (OR: 0.69 [95% CI: 0.33, 1.46]) among participants of e-waste Recycling Exposure and
Community Health (e-REACH) Study. A study by Xu et al. (2022b1 reported that a one ln-unit increase in
maternal BLLs was associated with increased GA ([3: 0.18 weeks [95% CI: 0.05, 0.31]), decreased birth
length ([3: -0.39 cm [95% CI: -0.66, -0.22]), and decreased HC ([3: -0.22 cm [95% CI: -0.39, -0.06]),
but a null association with birth weight. There were also null associations across tertiles of maternal BLLs
and low birth weight.
In addition to cord blood and maternal blood, other biomarkers such as maternal serum, cord
blood serum, and placental tissue were used to assess Pb exposure with birth weight among other cross-
sectional studies and reported inconsistent associations (Yang etal.. 2020: Freire et al.. 2019: Mikelson et al..
2019: Tang etal.. 2016: Hu el al.. 2015). A study that measured Pb in both maternal serum and cord blood
serum reported null associations with birth weight for both biomarkers (Hu el al.. 2015). while another
study reported null associations birth weight-for-gestational-age Z-score, when modeled continuously or
categorized by quintiles (Yang etal.. 2020). Although there were null associations with birth weight and
GA, there was a decrease in birth height and a decrease in HC per ln-Pb increase in umbilical cord serum
among 103 mother-newborn pairs from an island in the East China Sea (Tang etal.. 2016). When placental
tissue was the biomarker of exposure for Pb, a single cross-sectional study reported null associations with
birth weight, low birth weight, birth, head, GA, and SGA (Freire etal.. 2019). but another reported a
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decrease in birth weight of 58.3 g (95% CI: -97.9, -18.8) per ln-Pb increase in placental tissue (Mikclson
etal.. 2019).
The use of advanced statistical methods to evaluate the impact of co-exposure to other metals, or
mixtures, helps to address uncertainties of co-pollutant confounding. To assess the associations between
metal mixtures (arsenic [As], cadmium [Cd], manganese [Mn], and Pb) in umbilical cord blood and birth
weight, birth length, and HC, 1,088 participants of a birth cohort in Bangladesh were assessed in a cross-
sectional study (Lee etal.. 2021). There were null associations with birth weight ((3: -0.04 g [95% CI:
-0.19, 0.11]), birth length ([3: -0.06 cm [95% CI: -0.20, 0.09]), andHC ([3: 0.08 cm [95% CI: -0.06,
0.23]) in association with an IQR increase in ln-Pb cord blood concentrations, when adjusted for
confounders and other metals. In addition to the multivariable regression analysis, Lee etal. (20211 also
used Bayesian kernel machine regression (BKMR) to estimate the effects of co-exposure to metal
mixtures. BKMR is a method that estimates the multivariable exposure-response function in a flexible
and parsimonious way, conducts variable selection on the (potentially high-dimensional) vector of
exposures, and allows for a grouped variable selection approach that can accommodate highly correlated
exposures. In the BKMR analysis, there was an inverse association between the metal mixture overall and
birth length when all four metal concentrations were >60th percentile and HC when all four metals were
>5 5th percentile, compared to their median values, with stronger associations as the concentrations of the
four metals increased. However, when estimating the difference in birth size with an IQR increase in each
individual metal when the other metals were fixed at their 25th, 50th, or 75th percentiles, the associations
with Pb were null.
Overall, in the multiple longitudinal birth cohort studies, there were inconsistent findings between
various Pb exposure biomarkers and prenatal growth outcomes. The multiple longitudinal birth cohort
studies have reported inconsistent associations. These studies collected maternal samples during different
time periods during pregnancy and utilized different biomarkers to measure Pb exposure to evaluate
associations with a variety of prenatal growth outcomes. In the longitudinal studies that measured Pb
exposure from maternal blood, there were inconsistent patterns of association with prenatal growth
outcomes, regardless of the trimester Pb exposure was measured or prenatal growth outcome (see Table
8-4). Several studies reported null associations with birth weight (Shihetal.. 2021; Woods etal.. 2017;
Taylor etal.. 2016; Bloom etal.. 2015; Garria-Esauinas et al.. 2014; Rabito et al.. 2014) and birth weight Z-score
(BWZ) (Daniali et al.. 2023). while others reported reductions in birth weight (Goto etal.. 2021; Hu et al..
2021; Rodosthenous et al.. 2017; Taylor etal.. 2015). Of note, Rodosthenous et al. (2017) measured Pb levels in
maternal blood during the second trimester among 944 mother-infant pairs in the PROGRESS cohort in
association with birth weight using both linear and quantile regression. While the linear regression
reported a null association with birth weight-for-gestational-age Z-score ([3: -0.06 [95% CI: -0.13,
0.003]) per log2-Pb blood level increase, the quantile regression analysis revealed larger magnitudes of
the association maternal blood Pb and birth weight-for-gestational-age Z-score. The magnitude of the
association was largest in the lowest (<30th) Z-score percentiles (difference in Z-score ranged from -0.13
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to -0.08). The use of quantile regression provides insights to potential sensitivity to Pb exposure for
smaller infants, an association that was not detected by linear regression.
While some studies reported null associations with birth length (Daniali et al.. 2023; Shih et al..
2021; Bloom etal.. 2015). a single study reported a 0.20 cm decrease (95% CI: -0.30, -0.10) in birth length
per 1 (ig/dL increase in maternal BLL (collected during the during the second or third trimester) among
participants of the Japan Environment and Children's Study (JECS) (Goto etal.. 2021). A single study
reported a reduction in HC of 0.03 cm (95% CI -0.06, -0.00) per 1 (ig/dL increase of first trimester
maternal blood Pb (Taylor etal.. 2016). but other studies reported null associations with HC and first
trimester maternal blood Pb (Daniali et al.. 2023; Taylor etal.. 2015). pre-pregnancy maternal and parental
blood (Bloom etal.. 2015). or second or third trimester maternal blood Pb (Shih etal.. 2021). While there
was reported decreased GA ((3: -1.9 days [95% CI: -3.1, -0.5]) per IQR increase in second trimester
maternal ln-Pb blood level among those in Puerto Rico Testsite for Exploring Contamination Threats
(PROTECT) cohort (Ashrap et al.. 2020). there were null associations with gestational and pre-pregnancy
maternal and parental blood (Bloom etal.. 2015) and maternal BLLs during the second or third trimester
among the JECS (Goto etal.. 2021); however, Goto et al. (2021) did report an increased risk of SGA (OR:
1.34 [95% CI: 1.16, 1.55]) and increased risk of low birth weight (OR: 1.34 [95% CI: 1.16, 1.55]) per
1 (ig/dL increase in maternal BLL, but other studies did not report increased risk of SGA (Thomas et al..
2015) and maternal blood (collected during the first and third trimesters of pregnancy) or second trimester
maternal blood (Ashrap etal.. 2020). There were consistent null associations with PI and maternal blood
(Shih etal.. 2021; Bloom et al.. 2015) and crown-to-heel length and first trimester maternal blood Pb (Taylor
et al.. 2016; Taylor etal.. 2015).
In addition, some of the longitudinal studies considered different effect modifiers when assessing
the associations between maternal BLLs and prenatal growth outcomes. Among participants in the
Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study, there null associations
between maternal blood (collected during the first and third trimesters of pregnancy) and SGA across
tertiles of maternal blood Pb (Thomas etal.. 2015). In addition, an exploratory analysis was conducted to
examine the potential effect modification of single nucleotide polymorphisms (SNP) in GSTP1 and
GSTOl genes on the relationship of maternal blood Pb and SGA. There was a marginal interaction
between maternal Pb exposure and the GSTP1 Al 14V SNP (p = 0.06), but there was no indication of
effect modification by other GSTP1 and GSTO1 SNPs on the associations between maternal blood Pb
and SGA. In another study in the PROTECT cohort, the modifying effect of psychosocial stress on the
association between maternal blood Pb exposure and GA, BWZ, SGA, and LGA were examined in a
subset of 682 pregnant women (Ashrap et al.. 2021). Maternal blood samples were collected at
18 ± 2 weeks gestation and 26 ± 2 weeks gestation. Among mothers who reported "good" psychosocial
status, there was decreased gestation age ([3: -1.9 days [95% CI: -3.2, -0.6]); however, there were null
associations with BWZ ([3: 0.1 [95% CI: 0.0, 0.2]), SGA (OR: 0.86 [95% CI: 0.65, 1.14]), and LGA (OR:
0.89 [95% CI: 0.64, 1.23]). The associations for mothers who reported "poor" psychosocial status were
null across the birth outcomes.
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In addition to the associations between prenatal growth outcomes and Pb levels, there were sex-
stratified differences. In a study by Garria-Esauinas et al. (20141. 97 mother-father-infants in the BioMadrid
Study were used to evaluate associations between prenatal Pb exposure and fetal development from three
biomarkers (maternal and paternal blood Pb at 34 weeks gestation and cord blood at delivery) with
different growth metrics at birth. While there were no associations between log-Pb blood levels (maternal,
paternal, or cord) and gestation age, birth weight, birth length, abdominal diameter, or cephalic diameter
(CD), associations were observed when analyses were stratified by infant sex. Among female infants,
there was decreased birth length of 1.06 cm (95% CI: -2.03, -0.08) and CD of-0.55 cm (95% CI: -1.03,
-0.07) per two-fold increase in paternal BLLs (|ig/L). but there were no associations among male infants.
In the study by Shihetal. (20211. there were null associations between maternal blood log2-Pb
concentrations (collected between 6 and 32 weeks of gestation) and prenatal growth outcomes (GA, birth
weight, birth length, HC, and PI). However, when stratified by infant sex, there were reductions in GA ((3:
-0.98 weeks [95% CI: -1.67, -0.30]), birth weight ((3: -381 g [95% CI: -583, -178]), birth length ([3:
-1.44 cm [95% CI: -2.45, -0.42]), and HC ([3: -1.10 cm [95% CI: -1.70, -0.50]), but had a null
association with PI ([3: -1.07 kg/m3 [95% CI: -1.56, 0.39]) among female infants, while the associations
for these same outcomes were null among male infants.
There were also a limited number of studies that considered co-exposure to other pollutants. From
the MIREC study, 1,857 mother-infant pairs were analyzed to examine the relationship between prenatal
exposure to a mixture of endocrine-disrupting chemicals, including Pb, and birth weight using BKMR
(Hu el al.. 2021). Maternal blood was collected during the first trimester of pregnancy. In the adjusted
model for log2-Pb, every two-fold increase in Pb concentration was associated with a mean birth weight
reduction of 82.22 g (95%: -145.46, -18.97), and when adjusted for other metals, the reduction in mean
birth weight was 75.89 g (95% CI: -141.24, -10.54). In the mixtures analysis, Pb was the main
contributor to the adverse effect on birth weight in the metal mixture consisting of As, Cd, mercury (Hg),
Mn, and Pb. An increase in the log2-Pb concentration from the 25th to the 75th percentile was associated
with a posterior mean of -47g, meaning that there was a reduction in mean birth weight of 47 g, while
holding the other components in the metal mixture constant at their median values.
In addition to maternal blood Pb, other biomarkers such as maternal erythrocytes, maternal
serum, and teeth were used to assess Pb exposure with prenatal birth outcomes, including birth weight,
birth length, or HC. Maternal erythrocytes from blood samples were collected during the third trimester
(mean: gestational week 29) from 584 mothers in the Nutritional impact on Immunological maturation
during Childhood in relation to the Environment (NICE) study in Northern Sweden (Guslin etal.. 2020).
Maternal erythrocytes reflect exposure over the past 1-3 months. A doubling of maternal erythrocyte Pb
concentration was not associated with birth weight ([3: -13 g [95% CI: -66, 41]), birth length ([3:
-0.080 cm [95% CI; -0.31, 0.15]), or HC ([3: 0.059 cm [95% CI: -0.22, 0.34] for maternal erythrocyte Pb
concentration less than the median of 14 j^ig/kg and [3: -0.24 cm [95% CI: -0.53, 0.056] for maternal
erythrocyte Pb concentration greater than median of 14 j^ig/kg). There was no interaction by infant sex.
When mutually adjusted for other maternal metal exposure to Cd and Hg, the null associations persisted.
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In a subset of the Project Via prospective pre-birth cohort, individual and joint effects of metal mixture
components on birth weight, length, HC, and GA were estimated in association with maternal erythrocyte
Pb concentrations collected during early pregnancy (11.3 ± 2.8 weeks of gestation) from 1,423 mother-
infant pairs (Rahman et al.. 2021). In single metal model, an IQR increase in maternal erythrocyte Pb
concentration was associated with a 33.9 g (95% CI: -65.3, -2.5) decrease in birth weight, but there were
no associations with birth length ((3: -0.10 cm [95% CI: -0.29, 0.09]), HC ((3: -0.07 cm [95% CI: -0.17,
0.04]), or GA ([3: 0.03 weeks [95% CI: -0.10, 0.16]). When stratified by infant sex, the associations were
null for both male and female infants and birth weight, birth length, HC, and GA. There were no
associations between Pb and birth weight, birth length, HC, and GA in the metal mixture analysis overall
or in the infant sex-stratified analyses.
A total of 3,125 mother-infant pairs were recruited from the China-Anhui Birth Cohort Study (C-
ABCS) to investigate the associations between maternal serum Pb levels the first trimester (median of
11 weeks gestation) and in the second trimester (median of 16 weeks gestation) with growth metrics
(Wang etal.. 2017a). Overall maternal serum Pb during pregnancy had a negative association with birth
weight ([3: -2.74 g [95% CI: -5.17,-0.31]), but null associations with birth length, HC, and chest
circumference. When stratified by trimester, the negative association with birth weight persisted, with a
reduction of 4.40 g (95% CI: -8.22, -0.58) for first trimester maternal serum Pb and a 1.64 g (95% CI:
-4.80, -0.58) reduction for second trimester maternal serum Pb. There were no associations by trimester
maternal serum Pb for birth length, HC, or chest circumference. In addition, there was increased risk of
SGA of 1.45 (95% CI: 1.04, 2.02) for subjects with medium-Pb maternal serum (1.18-1.70 (ig/dL) and
increased risk of SGA of 1.69 (95% CI: 1.22, 2.34) in subjects with high-Pb maternal serum
(>1.71 (ig/dL), compared to low-Pb maternal serum (<1.18 (.ig/dL). When stratified by infant sex, there
was increased risk of SGA among female infants (OR: 1.51 [95% CI: 0.99, 2.31] for medium-Pb maternal
serum and OR: 1.68 [95% CI: 1.12, 2.54] for high-Pb maternal serum), but among male infants, the
associations were null. There was an increased risk of SGA with high first trimester maternal serum Pb
(OR: 2.13 [95% CI: 1.24, 3.38]), but there were null associations among second trimester maternal serum
Pb.
In a small cohort study, second and third trimester Pb levels were estimated from baby teeth from
145 participants in the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study
(WHEALS) (Cassidv-Bushrow et al.. 2019). There were no associations between tooth Pb in the second or
third trimester and BWZ ([3: -0.15 [95% CI: -0.35, 0.05] for second trimester and [3: -0.06 [95% CI:
-0.24, 0.12] for third trimester) or GA at delivery ([3: 0.08 [95% CI: -0.19, 0.35] for second trimester and
[3: 0.14 [95% CI: -0.11, 0.39] for third trimester) in the fully adjusted models. There was no indication
that there was a time effect (difference between the effect estimates in the second and third trimesters) for
birth weight for Z-score ([3: -0.31 [95% CI: -0.90, 0.28]) or GA at delivery ([3: -0.22 [95% CI: -1.08,
0.64]). Additionally, when stratified by child's sex, there were no associations between tooth Pb in the
second or third trimester and BWZ or GA at delivery.
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In a study by Bui et al. (20221. effects of short-term maternal exposure to airborne Pb during
pregnancy on birth weight, low birth weight, and SGA was estimated using a quasi-experimental variation
in airborne Pb exposure based on the National Association for Stock Car Auto Racing (NASCAR)'s
deleading of racing fuel in a difference-in-difference model in the Charlotte-Concord-Gastonia
Metropolitan Statistical Area in North Carolina. There was an average increase in birth weight of
102.50 g (95% CI: 45.73, 159.2), decreased probability of low birth weight of 0.0445 (95% CI: -0.0697,
-0.0194), and reduction in the probability of SGA of 0.0396 (95% CI: -0.0638, -0.0155) among children
born to mothers residing less than 4000 meters of the Charlotte Motor Speedway, compared with those
residing greater than 10,000 meters.
8.3.2.2 Toxicological Studies on Prenatal Growth
The 2013 Pb ISA discussed a few studies that reported reduced birth weight of offspring from Pb-
treated dams (Masso-Gonzalez and Antonio-Garria. 2009; Wang et al.. 2009; Teiion et al.. 2006). Recent
toxicological studies consistently report no effects of Pb on birth weight (Table 8-3). Most studies began
exposure of the dam prior to conception of the offspring (Zhao etal.. 2021; Tartaglione et al.. 2020; Rao
Barkur and Bairv. 2016; Schneider et al.. 2016; Barkur and Bairv. 2015; Weston etal.. 2014; Corv-Slechta et al..
2013) and a few studies began exposure of the dam at the time of conception (GD 0) (Rao Barkur and Bairv.
2016; Barkur and Bairv. 2015; Barkur etal.. 2011). Of note is that Teiion et al. (2006). a study discussed in the
2013 Pb ISA, elaborated that the observed reduction in litter weights born to Pb-treated dams was largely
driven by the reduced size of female pups, whereas males were unaffected. In agreement, some recent
studies that reported no effect of Pb on birth weight assessed weight in male pups only (Barkur and Bairv.
2015; Barkur etal.. 2011). However, all other recent studies included females in birth weight analyses and
reported no effects of Pb on birth weight of exposed offspring.
8.3.2.3 Integrated Summary of Effects on Prenatal Growth
The epidemiologic studies in the 2013 Pb ISA reported associations between maternal bone Pb
and low birth weight and with studies of Pb air exposures and birth weight. The associations were less
consistent when using maternal blood Pb or umbilical cord and placenta Pb as the exposure measurement
although some studies did demonstrate associations. The studies of Pb exposure and fetal growth were
limited by cross-sectional study design, small sample size, high Pb concentrations (air Pb as high as
30 (ig/m3), and in some studies, the lack of control of confounders. Overall, the recent epidemiologic
studies reported inconsistent associations between Pb exposure and prenatal growth outcomes, while the
toxicological studies consistently reported no effects of Pb on offspring birth weight. The inconsistent
findings from the recent epidemiologic studies may be due to differences in study design, timing of when
the exposure was measured (e.g., during pregnancy, at delivery), biomarkers examined for Pb (e.g.,
maternal blood, cord blood, maternal red blood cells, maternal serum, placental tissue), difference in
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growth metrics assessed (e.g., birth weight, birth length, GA), and small sample sizes in some studies.
While there were inconsistencies in the findings among the epidemiologic studies, the recent
epidemiologic studies were able to address a few of the uncertainties in the 2013 Pb ISA, with many of
the recent studies were conducted in well-designed longitudinal birth cohorts, considered the differences
in effects by infant sex, and controlled for wide range of confounders, including GA (when not an
outcome of interest), and maternal health factors (e.g., smoking, parity, BMI). Additionally, some
epidemiologic studies controlled for other metal exposure, and other studies evaluated the associations
with joint effects or as a mixture. A few toxicological studies were reviewed in the 2013 Pb ISA, all of
which reported reductions in birth weight of offspring born from Pb-exposed dams. However, recent
toxicological studies do not support previous studies and consistently report no effects of Pb on offspring
birth weight.
8.3.3 Preterm Birth
The recent epidemiologic and toxicological studies that examined the relationship between Pb
exposure and preterm birth are summarized in the text below. Study details of the recent epidemiologic
studies are included in Table 8-5 and the recent toxicological studies are in Table 8-3.
8.3.3.1 Epidemiologic Studies on Preterm Birth
The epidemiologic studies reviewed in the 2013 Pb ISA reported inconsistent findings regarding
a relationship between indicators of Pb exposure and preterm birth. There were no apparent patterns
within the type of exposure measurement or Pb level. Many of these studies are limited by the small
number of preterm births and their cross-sectional design (i.e., studies of umbilical cord blood may not
adequately characterize BLLs earlier in pregnancy). Among the longitudinal cohort studies, the results
were mixed, with some studies reporting associations between maternal blood Pb during pregnancy and
preterm birth. Most studies controlled for potentially important confounders, such as maternal age and
smoking.
In the recent epidemiologic studies examining the risk of preterm birth and Pb exposure, the
findings were inconsistent (Table 8-5). In a cross-sectional study, cord blood samples were obtained from
432 infants born in an area with e-recycling (Guiyu) and 99 from an area without e-recycling (Xiamen) in
China, but there was no increased risk of preterm birth (OR: 1.09 [95% CI: 0.93, 1.28]) (Xu el al.. 2012).
In a cross-sectional study of 696 mother-infant pairs in the Study on the Environment and Reproductive
Health (EMASAR) cohort in Argentina, the relationship between maternal Pb levels, which were
collected 36 ± 12 hours postpartum, and preterm birth was examined (Xu et al.. 2022b). Among tertiles of
maternal Pb levels, there were null associations with preterm birth (OR: 1.24 [95% CI: 0.35, 4.4] in tertile
2 and OR: 1.26 [95% CI: 0.32, 5.00] in tertile 3). In another cross-sectional study, placental tissue Pb
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levels were assessed in association with preterm birth among 327 mother-infant pairs who were part of
the Instituto de Nanociencia y Materiales de Aragon (INMA) Project in Spain and found no association
with risk of preterm birth (OR: 0.40 [95% CI: 0.04, 4.70]) (Frcirc et al.. 2019).
In a case-control study, maternal serum Pb, collected during the first or second trimester, was not
associated with risk of spontaneous preterm birth (OR: 1.46 [95% CI: 0.97, 2.18]) among 147 cases and
381 controls (Yu el al.. 2019). When stratified by the trimester of collection of maternal serum Pb, there
was null association for spontaneous preterm birth (OR: 1.63 [95% CI: 0.91, 2.91]) with first trimester
maternal serum Pb only or second trimester maternal serum Pb only (OR: 1.27 [95% CI: 0.71, 2.28]). In a
nested case-control study, the association between exposure to 41 metals/metalloids, including Pb, during
early pregnancy measured in maternal serum and risk of spontaneous preterm birth was investigated (Xu
el al.. 2022a). There were 74 cases of spontaneous preterm birth and 74 controls. In the highest quartile of
maternal serum Pb levels, there was an increased risk of spontaneous preterm birth of 4.09 (95% CI: 1.31,
12.77) and there was evidence of potential exposure-response across the quartiles (p for trend: 0.017).
Tsuiietal. (20181 used data on 14,847 pregnant women who were participants of the JECS to
assess the association between second and third trimester maternal blood (collected at gestational weeks
14-39) and early preterm (22 to <34 weeks) and late preterm (34 to <37 weeks). Among the quartiles of
Pb exposure, there was no increased risk in early preterm birth or late preterm birth. There was also no
evidence of a linear exposure-response trend among the Pb exposure quartiles in either the early preterm
births (p for trend: 0.134) or late preterm (p for trend: 0.920). In another cohort study using data from the
JECS, per each 0.1 (ig/dL increase in maternal BLL, there was no increased risk of preterm delivery (OR:
0.90 [95% CI: 0.70, 1.16]) (Goto et al.. 2021).
In a small cohort (n = 98) from the Conditions Affecting Neurocognitive Development and
Learning in Early Childhood (CANDLE) study in Shelby County, TN, Pb was measured cord blood and
from maternal blood collected during the second and third trimester, at delivery (Rabito etal.. 2014). Each
0.1-unit increase in maternal blood Pb in the second trimester (OR: 1.66 [95%CI: 1.23, 2.23]) and third
trimester (OR: 1.24 [95% CI: 1.01, 1.52]) was positively associated with preterm birth, but there was no
increased risk of early-term birth (>37 to <39 weeks) associated with maternal blood Pb in the second
trimester (OR: 0.87 (95% CI: 0.63, 1.20]) and third trimester (OR: 0.88 [95% CI: 0.69, 1.13]).
In the Avon Longitudinal Study of Parents and Children, maternal blood samples were collected
as early as possible in pregnancy, with a median GA of 11 weeks at the time of sampling (range 1-
42 weeks, IQR 9-13 weeks) (Taylor etal.. 2015). There was increased risk of preterm delivery (OR: 2.00
[95% CI: 1.35, 3.00]) for maternal BLLs >5 (ig/dL. Li et al. (2017a) investigated the associations between
maternal serum Pb levels and risk of preterm birth in a population-based birth cohort (n = 3,125), part of
the China-Anhui Birth Cohort. Maternal serum Pb levels were categorized into tertiles: low-Pb
(<1.18 (ig/dL), medium-Pb (1.18-1.70 (ig/dL), and high-Pb (>1.71 (ig/dL). There was an increased risk of
preterm birth in the medium-Pb tertile (OR: 2.33 [95% CI: 1.49, 3.65]) and high-Pb tertile (OR: 3.09
[95% CI: 2.01,4.76]).
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In a study by Ashrap et al. (20201. individual and mixture effects of metals and metalloids on
preterm birth among 731 pregnant women in the PROTECT cohort were examined. Maternal blood was
collected at 16-20 and 24-28 weeks gestation. There was an increased risk of preterm birth (OR: 1.63
[95% CI: 1.17,2.28]) and spontaneous preterm birth (OR: 1.53 [95% CI: 1.00, 2.35]) per IQR increase in
maternal blood Pb in the individual pollutant model. The mixture pollutant models and elastic net
regularization identified Pb and zinc as the most important predictors of preterm birth, while BKMR
method identified Pb, zinc, and Mn as most predictive of preterm birth. In another study in the PROTECT
cohort, the modifying effect of psychosocial stress on the association between Pb and overall preterm
birth (<37 completed weeks of gestation) and spontaneous preterm birth (<37 completed weeks of
gestation defined as presentation of premature rupture of the membranes, spontaneous preterm labor, or
both) (Ashrap el al.. 2021). There was an increased risk of overall preterm birth among mothers who
reported "good" psychosocial status (OR: 1.72 [95% CI: 1.14, 2.58]), but null association among mothers
who reported "poor" psychosocial status (OR: 1.43 [95% CI: 0.69, 2.97]). There were null associations
among mothers who reported "good" psychosocial status and "poor" psychosocial status and spontaneous
preterm birth (OR: 1.56 [95% CI: 0.93, 2.6] and OR: 1.22 [95% CI: 0.42,3.56], respectively).
In a study by Bui et al. (20221. the effects of short-term maternal exposure to airborne Pb during
pregnancy on preterm birth was estimated using a quasi-experimental variation in airborne Pb exposure
based on NASCAR's deleading of racing fuel in a difference-in-difference model in the Charlotte-
Concord-Gastonia Metropolitan Statistical Area in North Carolina. There was decreased probability of
preterm birth of 0.295 (95% CI: -0.0572, -0.000185) among children born to mothers residing less than
4000 meters of the Charlotte Motor Speedway, compared to those residing greater than 10,000 meters.
8.3.3.2 Toxicological Studies on Preterm Birth
Both the 2013 Pb ISA and the 2006 Pb AQCD did not describe any studies that reported on the
effects of Pb on preterm birth in animals. Only one recent study was found that reports on gestation
duration (Betharia and Maher. 2012). Betharia and Maher (20121 reported no effect of Pb on gestation term
when Sprague-Dawley rats were dosed from GD 0 to postnatal day (PND) 20. BLLs were measured in
offspring and reported to be 9.03 (ig/dL on PND 2, 0.976 (ig/dL on PND 25, 0.0318 (ig/dL on PND 60.
8.3.3.3 Integrated Summary of Effects on Preterm Birth
In summary, there were inconsistencies in the recent epidemiologic studies examining the
relationship between Pb exposure and risk of preterm birth, similar to the 2013 Pb ISA. There was no
apparent pattern associated with any biomarker of Pb exposure. Several of the recent epidemiologic
studies were conducted in well-designed, longitudinal birth cohorts, and controlled for wide range of
confounders, including GA, other metals, and maternal health factors (e.g., smoking, parity, BMI). The
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inconsistent findings may be due to differences in study design, timing of the exposure (e.g., during
pregnancy, at delivery), biomarkers examined for Pb (e.g., maternal blood, cord blood, maternal red blood
cells, maternal serum, placental tissue), and small sample sizes in some studies. There were no
toxicological studies that investigated the effects of Pb on preterm birth in the 2013 Pb ISA and the 2006
Pb AQCD, and recent toxicological data are sparse with only a single PECOS-relevant study available,
which reported no effects of Pb on gestation duration, making it difficult for toxicological data to support
epidemiological evidence.
8.3.4 Birth Defects
The recent epidemiologic and toxicological studies that examined the relationship between Pb
exposure and birth defects are summarized in the text below. Study details of the recent epidemiologic
studies are included in Table 8-6 and the recent toxicological studies are in Table 8-3.
8.3.4.1 Epidemiologic Studies on Birth Defects
In the 2013 Pb ISA, there were only a few studies available for review evaluating associations
between Pb exposure and birth defects, specifically NTDs. These studies did not report associations
between Pb exposure and NTDs. These studies were limited by the timing of Pb measurements, whether
taken at delivery or postnatally, and the lack of potential confounders.
A few recent epidemiologic studies examined the relationship between Pb levels and birth
defects. Several studies evaluated the association between NTDs in different biomarkers (placental tissue,
umbilical cord tissue, and maternal serum) (Liu el al.. 2021; Tianetal.. 2021; Jin el al.. 2013). The cross-
sectional studies that measured Pb exposure from placental tissue or umbilical cord tissue reported no
increased risk for NTDs overall or by subtype (Liu el al.. 2021; Jinetal.. 2013) (see Table 8-6 for details).
However, in a case-control study which evaluated the single and joint effects of 10 metals measured in
maternal serum during pregnancy, there was increased risk for NTDs (Tianetal.. 2021). In the single
pollutant model, there was increased risk of NTD of 2.05 (95% CI: 1.05, 4.02) in the second tertile and
3.51 (95% CI: 1.76, 6.98) in the third tertile, relative to the lowest tertile of maternal serum Pb levels,
indicating an exposure-response relationship (p for trend: <0.001). There was also increased risk by NTD
subtype. There was increased risk of spina bifida of 2.16 (95% CI: 1.00, 4.88) in the second tertile and
5.16 (95% CI: 2.24, 11.87) in the third tertile, relative to the lowest tertile of maternal serum Pb levels,
with an indication of an exposure-response relationship (p for trend: 0.022). For anencephaly, there was
increased risk of 2.97 (95% CI: 1.09, 8.12) in the second tertile and 5.54 (95% CI: 1.89, 16.19) in the
third tertile, relative to the lowest tertile of maternal serum Pb levels, with an indication of an exposure-
response (p for trend: 0.002). Among female infants, there was increased risk of NTD of 6.45 (95% CI:
2.20, 18.95) in the highest tertile, relative to the lowest tertile of maternal serum Pb levels, with exposure-
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response relationship (p for trend: 0.001). Among male infants, there was increased risk ofNTD of 2.16
(95% CI: 1.03, 4.59), and an indication of an exposure-response relationship (p for trend: 0.048).
Pi et al. (20181 investigated the associations between placental Pb concentrations and the risk of
orofacial cleft defects among 103 cases and 206 controls in northern China. With increasing tertiles of
placenta Pb concentrations (p for trend <0.001), there was increased odds of orofacial defects of 3.88
(95% CI: 1.78, 8.42) for those in the second (57.5-96.8 ng/g dry weight) tertile of placenta Pb exposure
and5.17 (95%CI: 2.37, 11.29) for those in the highest (>96.8 ng/g dry weight) tertile of placenta Pb
exposure, compared to the lowest (<57.5 ng/g dry weight). When restricting to those with higher than the
median placenta Pb concentration (>77.2 ng/g), there was increased risk of 3.08 (95% CI: 1.74, 5.47) of
orofacial cleft defects among 71 cases and 84 controls. However, in a nested case-control study among a
subset of participants in the JECS, Takeuchi et al. (20221 did not find increased risk of cleft lip and palate
(n = 192 cases and n = 1,920 matched controls) and second trimester maternal blood Pb concentrations
(OR: 1.10 [95% CI: 0.55, 2.21]), which controlled for co-exposure to three other metals (Hg, Cd, and Mn)
in the multivariate model.
In another study of the JECS, maternal serum Pb samples were collected during mid- and late
gestation and were evaluated in association with congenital abdominal malformations (Mivashita el al..
2021). There were 139 cases and 89,134 controls. There were null associations across the quartiles of
maternal serum Pb concentrations and any abdominal malformations, with no exposure-response
relationship across quartiles (p for trend: 0.233). The null associations persisted for the subtypes of
congenital abdominal malformations, but there was an inverse exposure-response relationship observed
across the quartiles of maternal serum Pb and omphalocele (p for trend: 0.033).
A single study explored the associations between umbilical cord serum Pb levels and congenital
heart disease (CHD) birth defects among 97 case and 201 controls (Liu etal.. 2018). In the highest
umbilical serum Pb group (>8.26 ng/mL), the odds of CHD were 1.67 (95% CI: 0.88, 3.17) compared to
the those in the lowest umbilical serum Pb group (<6.69 ng/mL). The odds by CHD subtypes were near
null, (CIs include 1) (see Table 8-6).
8.3.4.2 Toxicological Studies on Birth Defects
The 2013 Pb ISA did not report any toxicological studies that investigated the effects of Pb on
birth defects. The 2006 Pb AQCD described studies that reported Pb-induced birth defects; however,
these findings were confounded by maternal toxicity (Dev etal.. 2001; Ronis etal.. 1996; Flora and Tandon.
1987). Two recent studies published since the 2013 Pb ISA have investigated Pb-induced birth defects in
offspring in rodents (Table 8-3). Both studies dosed Wistar rats with 0.2% Pb in the drinking water for
varying duration, including dosing starting 30 days prior to gestation and ending the day prior to mating,
dosing from GD 0 to PND 21, and dosing from GD 0 to 21 (Rao Barkur and Bairv. 2016; Barkur and Bairv.
2015). Offspring BLLs measured on PND 22 varied between 3.02-3.03 (ig/dL for animals from dams
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dosed prior to gestation, 5.30-5.51 (ig/dL for animals from dams dosed during gestation, and 31.6-
32.0 (ig/dL for animals from dams dosed from the beginning of gestation to lactation day 21. No maternal
toxicity was apparent in any of the recent studies, suggesting that the contrast found between the lack of
malformations observed in these recent publications and the reported malformations described in the 2006
Pb AQCD may be attributed to a lack of maternal toxicity due to the use of lower doses in more recent
studies.
8.3.4.3 Integrated Summary of Effects on Birth Defects
The studies reviewed in the 2013 Pb ISA did not report associations between Pb exposure and
NTDs. Among the recent epidemiologic studies, there were inconsistent associations with Pb exposure
and NTDs, congenital heart defects, and orofacial clefts defects. While the associations were generally
null for NTDs and CHDs, there were positive associations with orofacial cleft defects. These findings are
limited by the different birth defects of interest, the small sample sizes, timing of Pb exposure (no
exposure measurements during pregnancy), differences in the biomarker tested, and the confounders
considered in the analyses. The recent epidemiologic studies controlled for a wide range of potential
confounders; however, which was a limitation from the 2013 Pb ISA. Further, some studies considered
co-exposure to other metals and differences by infant sex. Some previous toxicological studies reported
that Pb exposure resulted in birth defects in offspring, but it was noted that these studies often used doses
so high that maternal toxicity occurred as well. Recent toxicological studies report no effects of Pb on
birth defects in offspring and also do not report that maternal toxicity occurred, further supporting that
maternal toxicity may have been involved with the birth defects observed in previous studies.
8.3.5 Spontaneous Abortion and Pregnancy Loss and Fetal and Infant
Mortality
The 2013 Pb ISA concluded that the toxicological and epidemiologic data provided inconsistent
findings for the role of Pb in spontaneous abortions, while there were no available epidemiologic or
toxicological studies on the relationship between Pb levels and infant mortality. The recent epidemiologic
and toxicological studies examining the relationship between Pb exposure and spontaneous abortion,
pregnancy loss, and fetal and infant mortality are summarized in the text below. Study details of the
recent epidemiologic studies are included in Table 8-7 and the recent toxicological studies are in Table 8-
3.
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8.3.5.1 Epidemiologic Studies on Spontaneous Abortion and Pregnancy Loss and
Fetal and Infant Mortality
In the 2013 Pb ISA, there was a limited number of epidemiologic studies that examined Pb
exposure and spontaneous abortion or pregnancy loss with inconsistent findings. Studies that examine
spontaneous abortion or pregnancy loss are difficult to conduct, as many spontaneous abortions or
pregnancy losses occur during the first trimester. Women may miscarry before being enrolled in a study
and/or women may not have known they were pregnant when they miscarried, further limiting the ability
to detect subtle effects, especially if higher Pb exposures do lead to increased risk of early spontaneous
abortions or pregnancy loss. In addition, some studies are limited by their retrospective examination of
current Pb biomarker levels in relation to previous miscarriages. The epidemiologic studies reviewed in
the 2013 Pb ISA had limited sample sizes and little control for potential confounding factors, with some
studies including no potential confounders in their analyses. There were no epidemiologic studies of Pb
exposure and fetal and infant mortality reviewed in the 2013 Pb ISA and there were no recent PECOS-
relevant epidemiologic studies of Pb exposure and fetal and infant mortality.
There were only a few recent epidemiologic studies that evaluated Pb exposure and spontaneous
abortion and pregnancy loss. There were inconsistent findings among the studies and no apparent pattern
of association by biomarker of Pb exposure. In a cross-sectional study, cord blood samples were obtained
from 432 infants born in an area with e-recycling (Guiyu) and 99 from an area without e-recycling
(Xiamen) in China (Xu et al.. 2012). There was an increased risk of 4.20 (95% CI: 3.40, 5.18) of stillbirth
rate with cord BLLs comparing infants from the area with e-recycling (Guiyu) compared to infants from
the area without e-recycling (Xiamen). In a recent cohort study, couples (n = 344) were prospectively
followed to explore the relationship between blood Pb concentrations at enrollment and with pregnancy
followed to estimate the risk of incident of pregnancy loss (Louis etal.. 2017). Each participant's blood Pb
concentration and time to pregnancy loss was modeled individually and as a couple. In the individual
partner models, there was no increased risk of pregnancy loss for female partner blood Pb (HR: 1.01
[95% CI: 0.82, 1.25]) or male partner blood Pb (HR: 0.95 [95% CI: 0.77, 1.17]). In the couple-based
model, the associations were unchanged (female partner HR: 1.01 [95% CI: 0.80, 1.28] and male partner
HR: 0.96 [95% CI: 0.77, 1.22]). Among a cohort of 166 women in Iran, there was no increased risk (OR:
1.08 [95% CI: 0.98, 1.20]) of spontaneous abortion with maternal BLLs in early pregnancy (VigehetaL
2021). In another prospective cohort among women seeking treatment at a fertility clinic in Turkey, blood
Pb concentrations were assessed in association with ongoing pregnancy (Tolunav et al.. 2016). The study
participants were categorized into patients with ongoing pregnancy (n = 20) and patients who experienced
assisted reproductive technology (ART) failure, miscarriage, or biochemical pregnancy (n = 81). There
was a 2.2% lower risk (RR: 0.978 [95% CI: 0.957, 0.999]) for ongoing pregnancy for each 1 (ig/dL higher
blood Pb concentration. Among a cohort of 1,184 women undergoing assisted reproductive therapy in
China, associations between maternal serum Pb concentrations and spontaneous abortion before
gestational week 12 were evaluated (Lietal.. 2022). There was an increased risk of 1.39 (95% CI: 1.02,
1.91) of spontaneous abortion before gestational week 12 with increasing maternal Pb serum levels. When
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categorized into tertiles, the associations between maternal Pb serum levels and spontaneous abortion
before gestational week 12 were null.
8.3.5.2 Toxicological Studies on Spontaneous Abortion and Pregnancy Loss and
Fetal and Infant Mortality
The 2013 Pb ISA did not report any toxicological studies that investigated the effects of Pb on
offspring mortality at any stage of development. Some studies that investigated the effects of Pb on
offspring mortality were summarized in the 2006 Pb AQCD. Overall, these studies found that gestational
exposure increased pregnancy loss and implantation loss (BLLs >32 (ig/dL) (Pinon-Latailladc et al.. 1995;
Singh etal.. 1993; Piasek and Kostial. 1991; Logdberg et al.. 1987). Some recent studies have also investigated
the effects of Pb exposure on offspring mortality (Table 8-3). However, recent studies reported that Pb did
not have effects on measures of pre- or postnatal mortality, including litter size. Rodent studies that dosed
prior to and during gestation reported no increase in stillbirth or decrease in number of pups born to
treated dams (Saleh etal.. 2018; Rao Barkur and Bairv. 2016; Barkur and Bairv. 2015; Weston etal.. 2014; Corv-
Slechta et al.. 2013; Betharia and Maher. 2012). BLLs, sources (e.g., BLLs from dams or BLLs from
offspring), and times of measurement were variable between these studies (0.0318-27.7 j^ig/dL; GD 20-
PND 60), but in general, BLLs in recent studies were lower than those reported in previous studies. The
contrast in the effects of Pb exposure on offspring mortality observed between previous studies and recent
studies may be attributed to the lower BLLs achieved in recent studies compared to the higher BLLs in
previous studies.
Postnatal offspring mortality was also investigated in some rodent studies, and some studies
reported on measures of offspring mortality that included postnatal death and survival until certain
timepoints after birth (e.g., weaning). These studies also did not report any effects of Pb exposure on
postnatal survival. Most studies utilized dosing paradigms that dosed before or during gestation (Barkur
and Bairv. 2015; Betharia and Maher. 2012) and reported BLLs at different times postnatally (PND 2-60;
0.0318 (ig/dL-5.30 (ig/dL) with BLLs tending to be lower in time points with the longest amount of time
since cessation of exposure. Some studies utilized a dosing paradigm that exclusively exposed animals
postnatally (Barkur and Bairv. 2015; Graham etal.. 2011). In agreement, these studies also reported no
effects of offspring mortality during postnatal time points (PND 4-29; BLLs 3.27-26.65 (ig/dL).
8.3.5.3 Integrated Summary of Effects on Spontaneous Abortion and Pregnancy Loss
and Fetal and Infant Mortality
The 2013 Pb ISA reported inconsistent findings from the epidemiologic studies on Pb exposure
and spontaneous abortion and pregnancy loss. The findings from recent epidemiologic studies on Pb
exposure and spontaneous abortion and pregnancy loss were also inconsistent. A single cross-sectional
study reported increased risk of stillbirth with cord blood Pb. While recent cohort studies among healthy
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participants did not find increased risk of pregnancy loss or spontaneous abortion, women seeking
treatment from a fertility clinic had increased risk of spontaneous abortion before gestational week 12 or
decreased risk of an on-going pregnancy. The women seeking fertility treatment that were recruited as
participants may be different from those in the general population, limiting the generalizability of the
results as the study populations may not be representative of the general population. Previous
toxicological studies reported increased rates of pregnancy loss and implantation loss in animals dosed
with Pb during gestation. This contrasts with more recent literature which did not report any effect of Pb
on pre- or postnatal offspring mortality. Although not always consistent, BLLs were generally lower in
recent toxicological literature when compared to previous literature, possibly explaining the observed
contrast in results.
8.3.6 Placental Function
In the 2013 Pb ISA, there were no epidemiological or toxicological studies available that
evaluated Pb concentrations and associations with placenta function. Recent epidemiologic and
toxicological studies evaluating the association between Pb exposure and placental function are limited.
The epidemiologic studies were cross-sectional studies. Study details for the recent epidemiological
studies are included in Table 8-8 and the toxicological studies are included in Table 8-3.
8.3.6.1 Epidemiologic Studies on Placental Function
In the 2013 Pb ISA, there were no epidemiological studies available that evaluated Pb
concentrations and associations with placenta function. In the recent cross-sectional epidemiological
studies, there were different markers of placental function evaluated. One marker of placental function
that was evaluated was placental thickness, which can restrict intrauterine fetal growth (Al-Saleh el al..
2014). Maternal BLLs measured at delivery were found to be associated with the risk of placental
thickness below the 10th percentile (OR: 1.64 [95% CI: 1.12, 2.41]). In another study, using a cross-
section from the JECS, the relationship between maternal blood Pb collected during the second trimester
and placental previa and placenta accreta among 16,019 women was examined (Tsuii etal.. 2019). Placenta
previa is a condition in which the placenta is attached to the lower uterine segment and completely or
partially covers the internal cervix, and when chorionic villi abnormally invade to myometrium, placenta
accreta occurs (Tsuii el al.. 2019). There was increased odds of placenta previa in the second quartile
(4.80-5.95 ng/g) of maternal blood Pb (OR: 2.59 [95% CI: 1.40, 4.80]), but null associations the third
quartile (5.96-7.44 ng/g) maternal blood Pb (OR: 1.32 [95% CI: 0.66, 2.64]) and fourth quartile
(>7.45 ng/g) maternal blood Pb (OR: 1.34 [95% CI: 0.67, 2.67]). There were null associations for
placenta accreta across the blood Pb quartiles (Table 8-8).
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8.3.6.2
Toxicological Studies on Placental Function
The 2013 Pb ISA reported a single study that investigated the effects of Pb exposure on placental
function. Wang et al. (20091 reported decreased placental weight in Wistar rats along with dose-dependent
increasing pathology of cytoarchitecture and cytoplasmic organelles. Focusing on different gestational
periods, this study exposed dams to 0.025% Pb via drinking water from either GD 1-10, GD 11-20, or
GD 1-20 (maternal BLLs on GD 20 were 26.3, 12.4 (ig/dL, and 36.0 (ig/dL, respectively). Some recent
studies have reported on similar placental outcomes (Table 8-3). Wang et al. (20141 also dosed using the
same dosing paradigm (dosing during GD 1-10, GD 11-20, or GD 1-20 via drinking water) and reported
that placentae collected from pregnant Wistar rats on GD 20 showed similar dose-dependent decreases in
weight and histopathological abnormalities such as vascular congestion, trophoblast degeneration,
chorionic villi interstitial edema, irregularity of trophoblast cells in the labyrinth and trophospongium,
degeneration of trophoblast cells, and chorionic villi vacuolization (maternal Pb levels on GD 20 were
reported to be between 12.4-36.0 (ig/dL and varied by dosing window). Two other studies that dosed
pregnant Sprague-Dawley rats via gavage from GD 0-20 and similarly reported reduced placental
weights (maternal blood Pb on GD 20 was 23.9-27.7 (ig/dL) (Saleh etal.. 2019; Saleh etal.. 2018). Of note
is that both of these recent studies by Saleh et al. (Saleh etal.. 2019; Saleh etal.. 2018) also reported reduced
brain weights in dams which is indicative of overt toxicity. Thus, it is possible the altered placental
weight could be attributed to overt toxicity experienced by the dams.
8.3.6.3 Integrated Summary of Effects on Placental Function
There were no epidemiological studies available that evaluated Pb concentrations and
associations with placenta function in the 2013 Pb ISA. The recent epidemiological studies reviewed that
assessed the relationship of Pb exposure and placental are limited. These cross-sectional studies provide
insight into associations between concurrent Pb exposure and placental function. However, the studies are
limited by their cross-sectional design, making it difficult to establish the temporality of the effects or the
critical window of exposure to Pb results in changes in the placenta during pregnancy, and there were
only a small number of cases placental previa and placenta accrete. The differences in the different
markers of placental function make it difficult to judge coherence and consistency across these studies,
but these positive associations are an indication that exposure to Pb may result in effects on placental
function during pregnancy. Previous toxicological data on the effects of Pb on placental weight are
limited to a single study which reported decreased placental weight and histological alterations. Recent
studies also reported that dams dosed with Pb had reduced placental weight, but of note is that these
studies also reported reduced brain weight in dams, suggesting that overt toxicity may have occurred and
could be related to the observed reductions in placental weight.
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8.3.7
Other Pregnancy and Birth Outcomes
There were several recent studies that evaluated associations between Pb exposure and other
pregnancy and birth outcomes in the epidemiologic and toxicological literature. More specific study
details for the epidemiologic studies, including Pb levels, study population characteristics, potential
confounders, and select results from these studies are highlighted in Table 8-9. Specific study details for
the toxicological studies are provided in Table 8-3.
8.3.7.1 Epidemiologic Studies on Other Pregnancy and Birth Outcomes
There were several recent studies with other outcomes related to pregnancy and birth. More
specific study details, including Pb levels, study population characteristics, potential confounders, and
select results from these studies are highlighted in Table 8-9. In studies of other pregnancy and birth
outcomes, maternal Pb blood concentrations were associated with high levels of leptin, a fetal marker of
metabolic function (Ashley-Martin et al.. 2015a); and cord blood Pb concentrations were negatively
associated with cord blood relative telomere length (rTL) (Hcrlin el al.. 2019). However, there was a null
association between maternal serum Pb levels and nuchal translucency, the subcutaneous space in the
fetal neck and is visible with ultrasound imaging in the first trimester and increased thickness in the first
trimester have been reported to be at risk for chromosomal abnormalities, genetic syndromes, congenital
heart defects, structural abnormalities, intrauterine infection, neurodevelopmental delay, and fetal demise
(Liao etal.. 2015); maternal blood Pb concentrations and thymic stromal lymphopoietin (TSLP) and
interleukin-33 (IL-33), which are biomarkers of fetal immune system (Ashley-Martin et al.. 2015b);
maternal blood Pb concentrations and elevated cord blood concentrations of immunoglobulin E (IgE)
(Ashley-Martin et al.. 2015b); maternal blood Pb and markers of fetal metabolic function (low leptin, low
adiponectin, and high adiponectin) (Ashley-Martin et al.. 2015b). Additionally, there were inconsistent
associations between maternal BLLs during pregnancy and secondary sex ratio. Among participants in the
Avon Longitudinal Study of Parents and Children in the United Kingdom, Taylor etal. (2014) reported no
associations among quintiles of maternal Pb levels during the first trimester of pregnancy and secondary
sex ratio (odds of having a male child). Participants of the Longitudinal Investigation of Fertility and the
Environment (LIFE) cohort, there were associations with secondary sex ratio (ratio of live male to female
births, reflecting a male excess) and both maternal and parental blood samples were measured for Pb at
baseline (before pregnancy) (Bloom etal.. 2015). However, Tatsuta et al. (2022b) reported increased odds
male births (secondary sex ratio) of 1.279 (95% CI: 1.224, 1.336) in the highest quintile of maternal blood
Pb among a subset of participants in the JECS.
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8.3.7.2
Toxicological Studies on Other Pregnancy and Birth Outcomes
The 2013 Pb ISA summarized a single study reporting on other birth outcomes such as sex ratio.
Dumitrescu et al. (2008a') reported an increased female:male ratio in offspring born to Wistar rats that were
dosed with 100 or 150 ppb of Pb in the drinking water starting three months prior to mating and
continuing until birth. This study did not report on BLLs in dams or offspring, resulting in more
challenges when comparing this study to more recently published studies (Table 8-3). Weston etal. (20141
was the only recent study to report an effect of Pb exposure on the sex ratio of pups born to exposed
dams. In agreement with Dumitrescu et al. (2008a'). Weston etal. (20141 reported that Long-Evans rats dosed
starting 76 days prior to mating and continuing through birth gave birth to female skewed litters when
compared to control. However, it is worth noting that in Weston etal. (20141 control litters had unusually
high numbers of males that resulted in a 1.5 male:female ratio of pups born, whereas Pb-treated litters had
a more even distribution that resulted in a ratio closer to 1:1 (BLLs were 14.6 and 15.7 (ig/dL in female
and male pups, respectively, on PNDs 5-6). Other recent studies contrast with these studies and report no
effects on sex ratio in Pb-treated females. One study using a dosing paradigm similar to the two studies
above (exposure beginning two months prior to dosing and continuing through birth) reported no effects
of Pb on sex ratio (BLLs 12.12 (ig/dL in dams at weaning) in C57BL/6 mice (Corv-Slechta et al.. 2013).
Similarly, Tartaglione et al. (20201 dosed Wistar rats from four weeks prior to mating through birth and
reported no changes in sex ratio (BLLs 25.5 |_ig/dL on PND 23 in pups). Additional studies in rats dosed
females from the beginning of pregnancy through birth and also reported no changes in sex ratio (BLLs
6.68-9.03 |_ig/dL in pups taken at ages PND 2 and PND 28 and (Betharia and Maher. 2012) and
(Baranowska-Bosiacka et al.. 2013). respectively). With the only recent study reporting alterations in sex
ratio also reporting unusual sex ratios in the control group, the effects of Pb exposure on sex ratio is
equivocal.
8.3.7.3 Integrated Summary of Effects on Other Pregnancy and Birth Outcomes
There was a small body of recent epidemiologic studies across various other pregnancy and birth
outcomes; however, the small number of studies limits the ability to judge coherence and consistency
across these studies, although the associations reported demonstrate that Pb exposure could result in
physiological responses that contribute to adverse pregnancy and birth outcomes, such as markers of fetal
metabolic function, fetal immune system biomarkers, and rTL. Toxicological evidence regarding other
pregnancy and birth outcomes are equivocal. While the 2013 Pb ISA reported a study that found that Pb
exposure led to female-skewed litters, a few recent studies reported no effects of Pb on the ratio of male
to female pups born to Pb-exposed dams.
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8.4 Effects on Development
The 2013 Pb ISA (U.S. EPA. 2013) concluded that the collective body of evidence integrated
across epidemiologic and toxicological studies, based on the findings of delayed pubertal onset among
males and females, was sufficient to conclude that there is a causal relationship between Pb exposure and
developmental effects. The current epidemiological and toxicological studies continue to support
associations between Pb exposure and developmental effects, particularly the delayed onset of puberty in
both males and females. This section does not cover associations between Pb exposure and
neurodevelopmental outcomes, which are discussed in detail in Appendix 3 Nervous System Effects. The
recent epidemiologic and toxicological studies of Pb exposure and effects on development are detailed in
the following sections. The developmental endpoints in subsequent sections are based on postnatal
growth, bodyweight, and stature; puberty among females; and puberty among males.
8.4.1 Effects on Postnatal Growth
The recent epidemiologic and toxicological studies that examine the relationship between Pb
exposure and postnatal growth are detailed below. More specific study details for the epidemiologic
studies, including Pb levels, study population characteristics, potential confounders, and select results
from these studies are highlighted in Table 8-10. Specific study details for the toxicological studies are
provided in Table 8-11.
8.4.1.1 Epidemiologic Studies on Postnatal Growth
The 2013 Pb ISA found inconsistent results between Pb exposure and postnatal growth.
Longitudinal epidemiologic studies had inconsistent findings regarding the association between Pb levels
and postnatal growth. There were further inconsistencies in the findings of the cross-sectional studies
evaluated. While multiple cross-sectional studies reported an association between Pb levels and impaired
growth, several other cross-sectional studies did not report associations between Pb and growth. The
inconsistencies across the studies may be due to study design and differences in the timing of exposure to
Pb (e.g., prenatal, at delivery, or postnatal). However, the longitudinal studies were controlled for
multiple potential confounders, such as age and parity.
There were multiple recent epidemiologic studies that evaluated the relationship between Pb
exposure and postnatal growth. Overall, there were negative associations between Pb exposure and
specific postnatal growth outcomes among the cross-sectional studies. However, among cohort studies,
there were some inconsistencies in the associations of Pb exposure and different postnatal growth
outcomes. These inconsistencies in the cohort studies may be due to differences in the timing of when Pb
exposure was measured, the biomarker of Pb exposure, and the timing of the outcome.
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Among the other cross-sectional studies of Pb exposure and postnatal growth, there were
consistent negative associations. In an NHANES (2013-2016) analysis of 6-11-year-old children
(n = 1,634), there were negative associations between an IQR difference in blood Pb concentrations
(median: 0.5 j^ig/dL) and standing height ((3: -3.116 cm [95% CI: -5.03, -1.202]), waist circumference
(WC; (3: -5.742 cm [95% CI: -8.769, -2.715]), upper arm length ([3: -1.068 cm [95% CI: -0.625,
-0.512]), and BMI ([3: -2.092 kg/m2 (95% CI: -3.227, -0.957)] (Signes-Pastor et al.. 2021). Among male
participants, the negative associations with postnatal growth outcomes persisted. Among female
participants, there were negative associations with BMI, WC, and upper arm length, but null associations
with standing height. Similarly, in a study of primary school children aged 7-11 years in China, there
were negative associations with concurrently measured BLLs (median: 2.61 (ig/dL) and height ([3:
-3.21 cm [95% CI: -4.24,-2.17]), weight ([3: -1.96 kg [95% CI: -3.11, 0.82]), bust circumference ([3:
-2.77 cm [95% CI: -3.79, -1.76]), and waistline ([3: -3.65 cm [95% CI: -4.78, 2.52]); however, there
was a null associations with BMI ([3: 0.20 kg/m2 [95% CI: —0.65, 0.25]) (Kuang etal.. 2020).
When standardizing postnatal growth metrics by z-score, the associations with Pb exposure were
mixed, even with all median BLLs across studies less than 5 (ig/dL (range: 0.663-4.6 (ig/dL). In a cross-
sectional study, among children <6 years of age (n = 1,678) in China, there were negative associations
between children's logio-BLLs and weight-for-age Z-score (WAZ) ([3: -0.33 [95% CI: -0.56, -0.11]) and
height-for-age Z-score (HAZ) ([3: -0.38 [95% CI: -0.63, -0.14]), but null associations with BMIZ (Zhou
etal.. 2020). When the BLLs were grouped by tertiles, the children in the highest (>5 (ig/dL) had lower
WAZ ([3: -0.42 [95% CI: -0.62, -0.23]), lower HAZ ([3: -0.36 [95% CI: -0.58, -0.15]), and lower BMIZ
([3: -0.29 [95% CI: -0.50, -0.07]) than those in the lowest tertile (<2.5 (ig/dL). The patterns of
association held when stratified by child's sex (see Table 8-10). Among children ranging in age from 8 to
23 months in South Korea, BLLs was associated with post-birth weight gain (WAZ-BWZ, or the
difference of the weight for age Z-scores at the time of the study and birth weight Z-scores) ([3: -0.238
[-0.391, -0.085], standard error [SE]: 0.078) and current HC for age Z-scores (HCAZs; [3: -0.213
[-0.366, -0.06], SE:0.078) (Choi etal.. 2017). However, among participants in the Canadian MIREC Child
Development Plus Study, there were no associations reported between blood Pb measured at two and
five years of age and HAZ, WAZ, or BMIZ overall or when stratified by child's sex (Ashley-Martin et al..
2019).
Multiple cohort studies examined the relationship between Pb exposure at different time periods
(prenatally and/or at different time periods during childhood) with growth metrics, mainly height and
weight. Among the cohort studies that measured Pb in cord blood, there were inconsistent associations.
While a study among children in Krakow, Poland found no associations with change in mean height over
a nine-year follow-up period (Jedrvchowski et al.. 2015). a study in the Children's Health and
Environmental Chemicals in Korea (CHECK) study, reported positive associations with Z-scores for
weight and BMI at 24 months of age (weight [3: 0.717 [95% CI: 0.195, 1.239] and BMI [3: 0.695 [95% CI:
0.077, 1.313], respectively) (Kim etal.. 2017). However, there were no associations between cord blood Pb
and the Z-scores of the child's weight, height, or BMI at any other time point (see Table 8-10 for details).
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When stratified by children's sex, cord blood Pb was positively associated with an increase of birth height
((3: 0.017 [95% CI: 0.003, 0.031]) and a decrease of PI at birth ((3: -0.055 [95% CI: -0.103, -0.006]) in
boys, but not in girls.
Among participants (n = 1,150) in the Mothers and Children's Environmental Health (MOCEH)
study in South Korea, maternal BLLs at delivery were negatively associated with Z-scores of weight for
age ([3: -0.33 [95% CI: -0.53, -0.13]) and length for age ([3: -0.30 [95% CI -0.53, -0.08]) at 24 months,
meaning that a 1 -j^ig/dL increase in late pregnancy Pb levels decreased weight and length at 24 months by
0.33 kg and 0.30 cm, respectively (Hong etal.. 2014). However, there were no associations between
maternal BLLs in early pregnancy (before 20 weeks gestation) and cord blood Pb with weight and length.
Several cohort studies conducted in Mexico measured Pb exposure during pregnancy in maternal
blood, cord blood, and maternal bone and various postnatal growth outcomes. Renzetti etal. (20171
investigated how Pb exposure during pregnancy is associated with children's growth outcomes, including
height, weight, BMI, and percentage body fat, measured between ages 4-6 years old in a Mexico City
pregnancy cohort (PROGRESS). Maternal blood Pb was measured during the second and third trimester
of pregnancy, as well as at delivery. Cord blood was measured at delivery. Bone Pb levels in the tibia and
patella were also assessed in mothers as a long-term biomarker one month postpartum. There were
negative associations between maternal third trimester BLLs and height-for-age ([3: -0.10 [95% CI:
-0.19, -0.01]) and weight for age ([3: -0.11 [95% CI: -0.22, -0.003]), but there were no associations
between any other marker of Pb exposure (maternal second trimester blood, cord blood Pb, maternal
blood at delivery) and height-for-age, weight for age, BMI, or percentage of body fat (see Table 8-10). In
the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) project, Liu et al. (2019a')
assessed Pb exposure in maternal bone (as a proxy for cumulative fetal exposure) at one month
postpartum and also in blood samples from children annually from 1 to 4 years in association with BMIZ,
WC, sum of skinfolds, and body fat percentage in 248 children aged 8-16 years. Maternal patella Pb
levels were associated with lower child BMIZ ([3: -0.02 [95% CI: -0.03, -0.01]), WC ([3: -0.12 cm [95%
CI: -0.22, -0.03]), sum of skinfolds ([3: -0.29 mm [95% CI: -0.50, -0.08]), and body fat percentage ([3:
-0.09% [95% CI: -0.17, -0.01]). However, there were no associations detected from the postnatal
exposure period (blood samples in children). In another study, children born between 1994 and 2005 in
Mexico City had Pb exposure measured in maternal patella Pb concentrations, a marker of prenatal period
exposure, and from infant and childhood measured in blood at birth to 24 months and 30-48 months
(Afciche etal.. 2012). Among infants with BLL exceeding the median (4.5 (ig/dL), there was a decrease in
height of 0.84 cm (95% CI: -1.43, -0.26) compared to children with a level below the median. There
were no associations between prenatal Pb or childhood Pb and height and there were no associations with
BMI at any time point (prenatal, infancy, or childhood). In cohort of Mexican children aged 6-8 years
old, growth (height, HAZ, and knee height) were assessed in association with BLLs at baseline, after
6 months, and 12 months (Kerr etal.. 2019). Additionally, as BLLs may differ by the aminolevulinic acid
dehydratase (ALAD) genotype, comparing children with the ALADi_2/2-2 genotype to children with the
ALADi i genotype. There were negative associations with height ([3: -0.11 cm [95% CI: -0.18, -0.04]),
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knee height ((3: -0.04 cm [95% CI: -0.07, -0.02]), andHAZ ((3: -0.02 cm [95% CI: -0.03, -0.01]).
Children with ALADi i had decreased height, knee height, and HAZ, while children with the A LA D i 2 2 2
had reduced knee height and HAZ, but not height. There were no associations between BLLs and growth
at 6- or 12-month follow-up was reported, irrespective of ALAD genotype. This epigenetic study
proposes a potential mechanistic pathway of BLLs differing by genotypes and the associations with
growth metrics during child developmental periods.
There were several studies that explored the associations between Pb exposure and postnatal
growth specifically by sex. In a study by Burns etal. (20171. associations of BLLs were assessed with
longitudinal age-adjusted height (HAZ) and BMI (BMIZ) among male participants in the Russian
Children's Study. Over 10 years of follow-up, after covariate adjustment, boys with higher (>5 (ig/dL)
BLLs compared with lower BLLs were shorter (adjusted mean difference in HAZ: -0.43 [95% CI -0.60,
-0.25]), translating to a 2.5 cm lower height at age 18 years. The decrement in height for boys with higher
BLLs was most pronounced at 12 to 15 years of age (interaction p: 0.03). However, boys with higher
BLLs were leaner (adjusted mean difference in BMIZ: -0.22 [95% CI: -0.45, 0.01]). Deierlein et al. (20191
used data from the Breast Cancer and the Environment Research Program to investigate associations of
childhood blood Pb concentrations and anthropometric measurements among a multi-site, multiethnic
cohort of girls (n = 683). Blood Pb concentrations were collected before 10 years of age and height, BMI,
WC, percent body fat was measured between 7-14 years of age. There were decreases in height (range:
-2.0 to -1.5 cm), BMI (range: -0.9 to -0.7 kg/m2), WC (range: -3.0 to -2.2 cm), percent body fat (range:
-2.9 to -1.7%) among girls ages 7 through 14 with BLLs of >1 (ig/dL compared to <1 (ig/dL (Table 8-
10).
There were a limited number of studies that examined stunting with exposure to Pb in children. A
single cross-sectional study in a subset of participants in the Interactions of Malnutrition & Enteric
Infections: Consequences for Child Health and Development (MAL-ED) study in Bangladesh reported
increased odds of stunting (OR: 1.78 [95% CI: 1.07, 2.99]) and being underweight (OR: 1.63 [95% CI:
1.02, 2.61]) with elevated (>5 (ig/dL) BLLs, but not wasting (OR: 1.18 [95% CI: 0.64, 2.19]) (Raihanet
al.. 2018). In a cohort study among rural Bangladeshi children, Pb exposure was assessed from umbilical
cord blood at birth and blood Pb at 20-40 months of age with stunting (Gleason etal.. 2016). The odds of
stunting at 20-40 months was 1.12 (95% CI: 1.02, 1.22) per each 1 (ig/dL increase in childhood BLL;
however, there was no association was found between cord BLL and risk of stunting (OR: 0.97 [95% CI:
0.94-1.00]).
8.4.1.2 Toxicological Studies on Postnatal Growth
The 2013 Pb ISA summarized several current studies and several from the 2006 Pb AQCD that
reported on the effects of Pb on offspring bodyweight and size. The reported effects were fairly
consistent, and nearly all studies reported reductions in bodyweight of offspring exposed to Pb during
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developmental periods. Gestational exposure to Pb proved to be sufficient to reduce offspring bodyweight
and body length in rodent studies (Masso-Gonzalez and Antonio-Garria. 2009; Wang et al.. 2009; Tciion el al..
2006; Ronis et al.. 2001; Ronis et al.. 1998a; Ronis et al.. 1998c; Ronisetal.. 1996). The only study in the 2013
Pb ISA that did not report a reduction in bodyweight was Leasure et al. (20081. which reported that
bodyweight increased at one year of age in male C57BL/6 offspring that were dosed starting prior to
conception and ending on PND 10.
Many recent publications have also reported on the effects of Pb-induced changes in bodyweight
of offspring (Table 8-11). In contrast with the 2013 Pb ISA, only some studies reported that Pb exposure
affected offspring bodyweight. One study that dosed Sprague-Dawley rat pups with 1 or 10 mg/kg/d
directly via gavage from PND 4 to 28 reported that bodyweight was decreased in male offspring in both
groups on PND 26 (BLLs 3.27-12.5 (ig/dL on PND 29) (Graham et al.. 2011). Another study dosed Wistar
rat dams via drinking water (30 mg/L Pb) from birth until weaning, at which point offspring were weaned
onto the same dosage of Pb in their drinking water as their dam until outcome assessment (de Figueiredo et
al.. 2014). In agreement with Graham etal. (2011). this study by de Figueiredo et al. (2014) reported
reductions in bodyweight of male Wistar rat offspring on PND 60 that were exposed from conception
through PND 60, although female offspring were not evaluated (BLLs 7.2 (ig/dL on PND 60). Similarly,
one study exposed CD-I mice offspring to Pb via dam drinking water (27 or 109 ppm Pb) from PND 1 to
21 and reported reductions in body weight of pups on PNDs 11, 15, and 19 (BLLs 19.57-29.16 |_ig /dL on
PND 18) (Duanetal.. 2017). In contrast, one study conducted in Sprague-Dawley rats that were exposed
from GD 0 to PND 21 via the dam's drinking water (10 (ig/mL Pb) reported increased bodyweight in
offspring on PND 1 and increased bodyweights in females only on PND 49 and 56 (BLLs 9.03 (ig/dL on
PND 2, 0.976 (ig/dL on PND 25, 0.0318 (ig/dL on PND 60 in pups) (Betharia and Maher. 2012).
Contrasting these recent studies and previous studies discussed in the 2013 Pb ISA are several
studies that reported no effects of Pb exposure on bodyweight in offspring. Studies in both mice and rats
utilizing dosing paradigms that begin exposure prior to conception (Albores-Garcia et al.. 2021; Zhao etal..
2021; Sobolewski et al.. 2020; Rao Barkur and Bairv. 2016; Barkur and Bairv. 2015) reported no effects of Pb
exposure on bodyweight at any time point measured (BLLs ranged between 0.4-15.7 j^ig/dL across
various time points and studies). Similar null findings were reported in other rodent studies utilizing other
exposure windows including gestational (Rao Barkur and Bairv. 2016; Barkur and Bairv. 2015). lactation (Rao
Barkur and Bairv. 2016; Barkur and Bairv. 2015; Basgen and Sobin. 2014). and a combination thereof (Basha
andReddv. 2015; Barkur etal.. 2011) (BLLs ranged between 2.74-26.86 (ig/dL).
8.4.1.3 Integrated Summary of Effects on Postnatal Growth
There were inconsistencies in the associations between Pb exposure and postnatal growth among
the recent epidemiologic studies, much like the 2013 Pb ISA. The inconsistencies may be the result of the
differences in the timing of Pb exposure measurement (prenatally or postnatally) and the biomarker to
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measure Pb exposure (maternal blood, maternal bone, cord blood). Additionally, there was limited
evidence that there are potential differences in the associations between Pb exposure and growth metrics
between males and females. There is also limited evidence of potential epigenetic effects of BLLs
differing by genotypes and the associations with growth metrics during child developmental periods.
While cross-sectional studies are limited by the concurrent measurement of Pb and postnatal growth
outcomes, there were several well-designed cohort studies that support the associations of Pb exposure
and decreased growth. These studies accounted for a wide range of potential confounders, including co-
exposure to other metals; however, some studies did not consider prenatal growth (birth weight, birth
length) or maternal characteristics (height, weight, BMI, smoking), which could potentially influence
postnatal growth. While there was a small body of literature examining the associations between stunting
and exposure to Pb, there was consistent increased odds in stunting with Pb exposure. Previous
toxicological studies tended to report reductions in postnatal weight of offspring exposed to Pb; however,
recent literature is inconsistent. Some studies reported reductions of offspring weight following exposure
to Pb in prenatal or early postnatal life, while others report no effects of Pb on postnatal weight in
offspring. Discerning reasons for the observed inconsistencies are difficult because studies still reported
results that contrasted with other studies that used similar dosing windows, doses, and animal species.
8.4.2 Effects on Puberty among Females
The recent epidemiologic and toxicological studies examining the relationship between Pb
exposure and effects on puberty among females are summarized in the text below. Study details of the
recent epidemiologic studies are included in Table 8-12.
8.4.2.1 Epidemiologic Studies on Puberty among Females
The epidemiologic studies reviewed in the 2013 Pb ISA found consistent associations between
higher concurrent blood Pb and delayed pubertal development in females. The association persisted in
populations with mean and/or median concurrent BLLs of 1.2-9.5 (ig/dL. While most of the studies had
large sample sizes and controlled for potential confounders, they were cross-sectional study designs, so
there are some uncertainties regarding temporality between Pb exposure and pubertal onset; additionally,
these studies were not able to separate out the influence of past Pb exposure, including prenatal
exposures, from more recent exposures.
The recent epidemiologic studies assessing the associations between blood Pb and onset of
puberty among females used different markers of puberty. A single cross-sectional study of NHANES
(2011-2012) data evaluated the associations between blood Pb concentration and circulating serum total
testosterone levels in 6-19-year-old children and adolescents (Yao etal.. 2019). Testosterone is a principal
sex hormone needed for normal physiologic processes during all life stages and for females, testosterone
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is of crucial importance for bone density and necessary for normal ovarian and sexual function, libido,
energy, and cardiovascular and cognitive functions (Yao etal.. 2019). While there were no associations
between blood Pb and testosterone in female children (6-11 years), serum testosterone levels were
14.85% greater (95% CI: 0.83%, 30.81%) in female adolescents (12-19 years) in the lowest quartile of
BLLs (<0.35 (ig/dL) than those in the highest quartile (>0.63 (ig/dL) in the fully adjusted model. For both
female children and adolescents, there were no significant trends with increasing quartiles of exposure (p
for trend 0.63 and 0.08, respectively).
In a cross-sectional study in Poland, two different groups of adolescent girls aged 7-16 years
(n = 436 in 1995 and n = 361 in 2007) were assessed for effects of Pb on the age attaining menarche
(Slawinska et al.. 2012). While the associations between blood Pb and menarche from either group of girls
were null (1995 OR: 0.70 [95% CI: 0.27, 1.85] and 2007 OR: 0.31 [95% CI: 0.09, 1.06]), the patterns of
association between these two times periods suggest delayed menarche. Of note, not only did the
distribution in blood Pb decline over the time period, girls in the 2007 group were significantly taller,
weighed more, and had a higher BMI. In another cross-sectional study among school-age girls (n = 490)
in Poland, there was a pattern of decreased odds between blood Pb and age at menarche, whether
controlled for BMI (OR: 0.54 [95% CI: 0.26, 1.13]), percentage of body fat (OR: 0.52 [95% CI: 0.25,
1.08]), or sum of skinfolds (OR: 0.53 [95% CI: 0.26, 1.10]) (Gomula et al.. 2022). While these cross-
sectional studies reported imprecise associations, the pattern of association is important to note. As BLLs
decline, the association between blood Pb and age of menarche may be attenuated by potential
confounders such as body weight and/adiposity.
Three successive, cross-sectional Flemish Environment and Health Studies (FLEHS I, FLEHS II
and FLEHS III) were conducted among adolescents (aged 14-5 years old) in Belgium between 2002-
2015 (De Craemer et al.. 2017). Female puberty markers of age at menarche, breast development, and pubic
hair development were evaluated in relation to blood Pb exposure. There was a consistent pattern of
delayed age at menarche across the three study cohorts (FLEHS I OR: 0.039 [95% CI: -0.072, 0.15];
FLEHS II OR: 0.257 [95% CI: 0.091, 0.424]; FLEHS III OR: 0.126 [95% CI: -0.021, 0.273]). The
associations between blood Pb and breast development were inconsistent, but there was indication of
delayed development among FLEHS I participants (OR: 0.798 [95% CI: 0.653, 0.969]). There were no
associations between blood Pb and development of pubic hair among adolescent females across the three
study cohorts.
Multiple cohort studies examined the associations between Pb exposure and puberty in females.
These studies used different biomarkers of exposure and different markers of puberty (Liu etal.. 2019b:
Jansenetal.. 2018: Nkomo etal.. 2018). Cord BLLs and BLLs at age 13 were evaluated in association with
puberty progression (development of pubic hair and development of breasts) among 684 females in the
Birth to Twenty Plus (BT20+) birth cohort in South Africa (Nkomo etal.. 2018). In females with elevated
BLLs (>5 (ig/dL) at age 13, there was lower level of maturation (development of breasts) relative risk
ratio [RRR]: 0.45 [95% CI: 0.29, 0.68]) and slower progression of pubic hair (RRR: 0.46 [95% CI: 0.27,
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0.77]), but there were no associations between cord blood Pb and pubic hair or breast development at age
13. In a cohort of Mexican children, cumulative blood Pb from 1-4 years old was associated with delayed
breast development (OR: 0.96 [95% CI: 0.92, 0.99]) and delayed pubic hair development (OR: 0.95 [95%
CI: 0.92, 0.99]), but maternal patella Pb and maternal tibia Pb were not associated with either breast or
pubic hair development in girls between 9-18 years old (n = 283) (Liu el al.. 2019b). Additionally, the
highest tertile of maternal patella Pb and the second tertile of cumulative blood Pb from 1-4 years of age
was associated with delayed menarche. In a subset of the ELEMENT project cohort (n = 200), maternal
blood was measured during each trimester of pregnancy and daughters (mean age at follow-up assessment
13.8 ± 2.0 years) were asked about the occurrence of their first menstrual cycle (Jansen etal.. 2018). Only
second trimester maternal BLLs were associated with later age at menarche (HR: 0.59 [95% CI: 0.28,
0.90]).
8.4.2.2 Toxicological Studies on Puberty among Females
There were no recent animal toxicological studies on the effects of Pb on puberty in females. The
2013 Pb ISA reported that one research group Iavicoli et al. (lavicoli et al.. 2006; Iavicoli et al.. 2004)
observed that offspring exposed to Pb prior to birth and through puberty (BLLs 0.7-13 (ig/dL) resulted in
a dose-dependent delay in multiple markers of sexual maturation (e.g., vaginal opening, age at first
estrus). The latter study by this group utilized a multigenerational dosing paradigm in which they
observed delays of pubertal onset in the F2 generation similar to those seen in the Fi. The 2013 Pb ISA
also summarized a study in which Fisher 344 rats were dosed daily via gavage (12 mg/mL Pb) starting
30 days prior to breeding through weaning of the offspring (PND 23), resulting in delayed age at vaginal
opening in the offspring (BLLs of dams just prior to breeding averaged 39.8 (ig/dL) (Pine etal.. 2006). Of
particular interest is that the observed delay in vaginal opening was attenuated in offspring that received
IGF-1 injections starting on PND 28 until vaginal opening was observed, demonstrating that IGF-1 is a
critical element to Pb-induced pubertal onset delays. Reports of delayed puberty due to Pb exposure in the
2013 Pb ISA are consistent with studies in the 2006 Pb AQCD which observed delays in puberty in
female Fisher 344 and Sprague-Dawley rats exposed to Pb during gestation and/or lactation (Dearth et al..
2004; Dearth et al.. 2002; Ronis et al.. 1998c; Ronis etal.. 1996).
8.4.2.3 Integrated Summary of Effects on Puberty among Females
There were several markers of puberty among females that were assessed for associations with Pb
exposures in the recent epidemiologic studies. Multiple cross-sectional studies and a single cohort study
reported an association between blood Pb and delayed menarche among females, with relevant BLLs
(Gomula et al.. 2022; Jansen etal.. 2018; De Craemer et al.. 2017; Slawinska et al.. 2012). While these cross-
sectional studies reported imprecise associations, the pattern of association is important to note. As BLLs
decline, the association between blood Pb and age of menarche may be attenuated by potential
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confounders such as body weight and/adiposity. There was also indication of slower breast development,
but the studies assessing breast development were limited (Nkomo etal.. 2018; De Craemer et al.. 2017).
Additionally, there were a limited number of studies that evaluated the development of pubic hair, but
these results were inconsistent (Liu el al.. 2019b; Nkomo etal.. 2018; De Craemer et al.. 2017). A single study
among NHANES participants reported increased serum total testosterone levels in female adolescents.
The recent epidemiologic studies assessing the associations between Pb exposure and puberty among
females were limited by the timing of the exposure to Pb and biomarker of exposure (blood, maternal
bone, cord blood). However, these studies consider a wide range of confounders, including height,
weight, and BMI, and the associations reported demonstrate that Pb exposure could result in
physiological responses that contribute to changes in puberty in females.
No recent PECOS-relevant toxicological studies investigated the effects of Pb on puberty.
However, studies from the 2013 Pb ISA and the 2006 Pb AQCD provide toxicological evidence that
indicates that Pb delays onset of puberty in female rodents. Several studies report delays in pubertal
markers such as vaginal opening and first estrus. Of note is that one study, Pine et al. (20061 reported that
the observed delays in vaginal opening in Pb-treated animals was attenuated when Pb treated animals
were supplemented with IGF-1 starting on PND 28. This strongly suggests that the mechanism through
which Pb induces delays pubertal onset in females is dependent on IGF-1 disruption.
8.4.3 Effects on Puberty among Males
The recent epidemiologic and toxicological studies examining the relationship between Pb
exposure and effects on puberty among males are summarized in the text below. Study details of the
recent epidemiologic studies are included in Table 8-12.
8.4.3.1 Epidemiologic Studies on Puberty among Males
The epidemiologic studies reviewed in the 2013 Pb ISA demonstrated an inverse relationship of
Pb on pubertal development among males at low blood Pb (mean and/or median BLLs of 3.0 to
9.5 (ig/dL). The studies were mostly cross-sectional, but the findings from these studies were supported
by those from a prospective longitudinal study (Williams et al.. 2010). Boys with higher (>5 (ig/dL) BLLs
at ages 8-9 years old had 24% to 31% reduction of pubertal onset based on testicular volume (TV),
genitalia staging, and pubic hair staging (Williams et al.. 2010). While temporality of effects is difficult to
establish due to the nature of the cross-sectional study design, the larger studies controlled for potential
confounders, with a few studies considering the inclusion of dietary factors, but did not control of other
metal exposures that may impact the associations.
Multiple recent cross-sectional and cohort epidemiologic studies evaluated associations between
Pb exposure at different time points (maternal, at birth, and adolescents) and markers of puberty in males
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(Liu etal.. 2019b; Williams et al.. 2019; Yao et al.. 2019; Nkomo et al.. 2018; De Craemer et al.. 2017; Fleisch et
al.. 2013). Overall, there were inconsistent associations between Pb exposure and markers of puberty in
males.
In an NHANES (2011-2012) analysis, concurrent BLLs and serum total testosterone levels were
measured in 6-19-year-old children and adolescents (Yao etal.. 2019). Testosterone is a principal sex
hormone needed for the normal physiologic processes during all life stages. In males, testosterone is
essential for the development and maintenance of secondary sexual traits, and can also influence bone
mass, muscle strength, mood, and intellectual capacity. When comparing the highest quartile of blood Pb
to the lowest, there was no association between serum testosterone levels in either male children ((3:
-13.09% [95% CI: -34.45%, 15.22%]) or male adolescents ((3: 6.32% [95% CI: -14.62%, 32.4%]).
Among three successive, cross-sectional Flemish Environment and Health Studies (FLEHS I, FLEHS II
and FLEHS III) of adolescents in Belgium between 2002-2015, blood Pb was negatively associated with
free estradiol (fE2; OR: 0.908 [95% CI: 0.839, 0.983]) and free testosterone (OR: 0.909 [95% CI: 0.828,
0.997]) in FLEHS II, but not in FLEHS I (De Craemer et al.. 2017). The associations between blood Pb and
estradiol (E2), testosterone, sex hormone binding globulin (SHBG), luteinizing hormone (LH), and
follicle stimulating hormone (FSH) were generally null (see Table 8-12). In addition to sex hormones, De
Craemer etal. (20171 also evaluated the associations between blood Pb and genital development and pubic
hair development among male adolescents. Across the three cross-sectional studies, there was delayed
onset of genital development (FLEHS I OR: 0.843 [95% CI: 0.717, 0.99]; FLEHS II OR: 0.697 [95% CI:
0.462, 0.998]; FLEHS III OR: 0.621 [95% CI: 0.388, 0.967]) and pubic hair development (FLEHS I OR:
0.808 [95% CI: 0.686, 0.949]; FLEHS II OR: 0.849 [95% CI: 0.563, 1.365]; FLEHS III OR: 0.515 [95%
CI: 0.327, 0.774]) in males with blood Pb exposure.
In the Birth to Twenty Plus (BT20+) birth cohort in South Africa, cord BLLs and blood levels at
age 13 were evaluated in association to puberty progression pubic hair development and genital
development in 732 males (Nkomo etal.. 2018). In males, elevated cord BLLs (>5 (ig/dL) was associated
with slower pubic hair development (RRR: 0.28 [95% CI: 0.11, 0.74]). There were no associations
between cord blood Pb and genital development or BLLs at age 13 with pubic hair development or genital
development. Similarly, there were no associations between maternal patella Pb, maternal tibia Pb, and
cumulative blood Pb from 1-4 years old and pubertal development (genitalia, pubic hair, and TV) in boys
(Liuetal.. 2019b).
However, in a longitudinal cohort of boys from the Russian Children's Study, higher BLLs
(>5 (ig/dL) measured at age 8-9 years old (baseline) had pubertal onset 7.7-8.4 months later, on average,
than those with lower BLLs (<5 (ig/dL) (Williams et al.. 2019). Boys with higher BLLs at baseline had later
adjusted mean age at sexual maturity, with 4.2-5.1 months later attainment compared to boys with lower
BLLs. There was a shift in mean age for age a pubertal onset for stage 2 genitalia (G2) of 8.40 months
(95% CI: 3.70, 13.10), 8.12 months (95% CI: 3.46, 12.78) for stage 2 pubic hair (P2), and 7.68 months
(95% CI: 3.46, 11.90) for TV >3 mL. There was a shift in mean age for age at sexual maturity for stage 5
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genitalia (G5) of 4.20 months (95% CI: 0.56, 7.84) and 5.14 months (95% CI: 1.70, 8.58) for TV >20 mL,
but a null association for stage 5 pubic hair (4.23 months [95% CI: -0.31, 8.77]). Furthermore, there was
no shift in the mean age for duration of pubertal progression for genitalia (G2 to G5), pubic hair (P2 to
P5), or TV (>3 mL to >20 mL). In a mediation analysis, growth measurements at age 11 were included to
better understand what portion of the shift in mean age at sexual maturity was attributable to the effect of
BLL on growth. The association of peripubertal BLL with height Z-score (HTZ) at age 11 accounted for
34-53% of the total effect of BLLs on age at maturity, while BMI Z-score at age 11 only accounted for
6-23%. In another Russian Children's Study, Fleischetal. (20131 longitudinally measured serum insulin-
like growth factor (IGF-1) to assess the association with childhood BLLs. BLLs were measured at
baseline only and IGF-1 levels were only measured during the follow-up periods. Boys were enrolled
between the ages of 8-9 years and were prospectively followed, with IGF-1 measurements obtained at
two-year follow-up (ages 10-11 years) and at four-year follow-up (ages 12-13 years). The overall mean
IGF-1 concentration was 29.2 ng/mL lower (95% CI: -43.8, -14.5) for boys with high BLLs at age 8-
9 years (>5 (ig/dL [max is 31 |ig/dL|) versus those with lower baseline BLLs (<5 (ig/dL) in adolescence
among boys.
8.4.3.2 Toxicological Studies on Puberty among Males
There were no recent toxicological studies on the effects of Pb on puberty in males, as was also
the case at the time of the 2013 Pb ISA. The 2006 Pb AQCD reported that one study found that prenatal
exposure to Pb delayed sexual maturation in a dose-dependent manner in male rats (Ronis etal.. 1998c).
Specifically, Ronis etal. (1998c) reported that prostate weight (used in this study as a marker of sexual
maturation) was reduced in male rat offspring treated with Pb from GD 5 through sacrifice.
8.4.3.3 Integrated Summary of Effects on Puberty among Males
The epidemiologic studies reviewed in the 2013 Pb ISA demonstrated an inverse relationship of
Pb on pubertal development among males at low blood Pb (mean and/or median BLLs of 3.0 to
9.5 (ig/dL). However, the recent epidemiologic studies assessing the associations between Pb exposure
and puberty among males reported more inconsistent findings at low BLLs. Differences in markers of
puberty in male (hormone levels, pubic hair development, genital development, TV) may explain the
inconsistency in findings across the studies. Additionally, there were differences in the timing of exposure
to Pb and different biomarkers of Pb exposure (maternal blood, maternal bone, cord blood, or concurrent
blood). The recent epidemiologic studies were able to consider a wide range of confounders, including
height, weight, and BMI, and some studies were conducted among established longitudinal cohorts. No
recent toxicological studies reported on the effects of Pb on male puberty. Similarly, the 2013 Pb ISA
reported no studies investigating Pb and male puberty. One study reported by the 2006 Pb AQCD
investigated the effects of Pb on puberty using prostate weight as a marker of sexual maturity in male rats
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exposed to Pb starting on GD 5. Treatment with Pb resulted in reductions in prostate weight around the
time of puberty, possibly indicating that Pb delayed the onset of sexual maturation in Pb-treated animals
when compared to control.
8.4.4 Other Developmental Effects
There were several recent studies that evaluated associations between Pb exposure and other
developmental effects in the epidemiologic and toxicological literature. Study details of the recent
epidemiologic studies are included in Table 8-13 and the recent toxicological studies are in Table 8-11.
8.4.4.1 Epidemiological Studies on Other Developmental Effects
There were several recent studies with other outcomes related to developmental effects. In studies
of other related to developmental effects, there was a negative association with child blood Pb and
mitochondrial DNA copy number (Alegria-Torres et al.. 2020); positive associations between maternal Pb
exposure and diurnal Cortisol rhythms in infants (Tamavo v Ortiz et al.. 2016); and lower salivary sialic acid
levels (a metric for oral anti-inflammatory potential which may increase the risk of dental caries) (Hon et
al.. 2020). but no associations between tooth Pb levels (second trimester, third trimester, or postnatal) and
alpha diversity metrics (bacterial or fungal), indictors of gut microbiota (Sitarik el al.. 2020) or child blood
Pb and telomere length (Alegria-Torres et al.. 2020).
8.4.4.2 Toxicological Studies on Other Developmental Effects
The 2013 Pb ISA and the 2006 Pb AQCD did not report any studies that investigated the effects
of Pb exposure on developmental milestones. However, some recent studies have investigated these
outcomes (Table 8-11). One study dosed Wistar dams via drinking water (0.2% Pb) either prior to
conception, during gestation only, during lactation only, or during both gestation and lactation and
reported that only exposure during both gestation and lactation elicited impacts on developmental
milestones (Rao Barkur and Bairv. 2016). Specifically, the age at eye opening was reduced. However,
although this exposure paradigm was the only one that produced effects on age at eye opening, it was also
the only paradigm that resulted in BLLs higher than 30 (ig/dL and reported a BLL of 31.59 (ig/dL in pups
on PND 22. Rao Barkur and Bairv (2016) also investigated other developmental milestones such as pinna
detachment and tooth eruption but reported no Pb-induced changes in either of these outcomes. An
additional study investigated the effects of Pb on similar outcomes including eye opening, eye slit
formation, fur development, tooth eruption, and pinna detachment, but reported no effects when Wistar
dams were dosed via drinking water (0.2% Pb) from GD 6 to 21 (BLLs 11.2 (ig/dL in pups on PND 21)
(Basha and Reddv. 2015).
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8.4.4.3 Integrated Summary of Other Developmental Effects
The recent epidemiologic studies have the potential to provide initial support of potential
mechanistic pathways for diurnal Cortisol rhythms, lower salivary sialic acid levels, and DNA oxidative
stress damage from Pb exposure among children during developmental periods. However, the small
number of studies limits the ability to judge coherence and consistency across the outcomes evaluated in
these studies, although the associations with diurnal Cortisol rhythms, lower salivary sialic acid levels, and
decrease in mitochondrial DNA copy number indicate that Pb exposure could result in physiological
responses that may contribute to adverse developmental effects. Recent toxicological studies on other
developmental effects of Pb largely pertain to the effects of Pb on developmental milestones of offspring.
Of the few toxicological studies available, no effects of Pb on developmental milestones were reported
with the only exception being a reduction at the age of eye opening, but this treatment group had BLLs
higher than 30 (ig/dL.
8.5 Effects on Female Reproductive Function
The 2013 Pb ISA concluded that the relationship observed with female reproductive outcomes,
such as fertility and hormone levels in some epidemiologic and toxicological studies was sufficient
evidence to conclude a suggestive causal relationship between Pb exposure and female reproductive
function. Epidemiologic studies provided information on different exposure periods and support the
conclusion that Pb possibly affects at least some aspects of female reproductive function. However,
toxicological studies were less supportive for suggesting a causal relationship between Pb exposure and
female reproductive function. This may primarily be due to a lack of variety in female reproductive
endpoints investigated by studies identified in the literature. The only outcomes reported by PECOS-
relevant toxicological studies include litter size, number of litters, and maternal body weight.
Subsequently, no evidence was available for outcomes such as cyclicity, female hormones, sex organ
histopathology (including ovarian follicular counts), or female fertility indicators (e.g., latency to
pregnancy, implantation counts, conception rate). Additionally, the available toxicological evidence was
inconclusive, and the only studies that reported effects on female reproductive outcomes also reported Pb-
induced reductions in brain weight, indicating the possibility that animals were experiencing overt
toxicity from Pb (Saleh el al.. 2019; Saleh etal.. 2018). The recent epidemiologic and toxicological studies
of Pb exposure and female reproductive function are detailed in the following sections.
8.5.1 Effects on Hormone Levels and Menstrual/Estrous Cycle
The recent epidemiologic and toxicological studies examining the relationship between Pb
exposure and hormone levels and menstrual/estrous cycle are summarized in the text below. Study details
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of the recent epidemiologic studies are included in Table 8-14 and the recent toxicological studies are in
Table 8-15.
8.5.1.1 Epidemiologic Studies on Hormone Levels and Menstrual/Estrous Cycle
The epidemiologic studies reviewed in the 2013 Pb ISA reported associations between
concurrent/closely time BLLs and hormone levels in female adults. However, while there were changes in
hormone levels, there were inconsistencies in the hormones that were evaluated across the different
studies. A limitation of some the epidemiological studies evaluated was the cross-sectional design, which
leaves uncertainty regarding Pb exposure magnitude, timing, duration, and frequency that contributed to
the observed associations. Additionally, the covariates included in statistical models as potential
confounders varied among studies, which could contribute to between study heterogeneity. Another
limitation of the epidemiologic studies is that not all of the studies investigated important confounders,
such as other metal exposures or smoking. The recent epidemiologic studies are divided into studies on
hormone levels and studies on menstrual/estrous cycle. The recent epidemiologic studies on hormone
levels in the following section are specific to hormones related to reproductive function and recent
epidemiologic studies on other hormones are described in Section 9.4.2 in the Other Health Effects
Appendix.
8.5.1.1.1 Epidemiologic Studies on Hormone Levels in Females
There were a few cross-sectional studies that evaluated the associations between Pb exposure and
different hormones in females (Lee etal.. 2019; Chenetal.. 2016; Krieg and Feng. 2011). These studies used
population-based surveys to evaluate associations between blood Pb and hormones and found consistent
positive associations with FSH in post-menopausal women. In an NHANES (1999-2002) analysis, Krieg
and Feng (20111 evaluated serum FSH and LH. Serum FSH slope increased per every logio-blood Pb
increase in the post-menopausal women ((3: 26.38 [95% CI: 13.39, 39.38]), women who had both ovaries
removed ((3: 27.71 [95% CI: 1.64, 53.78]), and pre-menopausal women ([3: 11.97 [95% CI: 3.27, 20.66]),
but serum FSH was not associated with BLLs in pregnant women, women who were menstruating, or
women who were taking birth control pills. Serum LH slope increased per every logio-blood Pb increase
in the post-menopausal women ([3: 11.63 [95% CI: 4.40, 18.86]) and women who had both ovaries
removed ([3: 20.59 [95% CI: 2.14, 39.04]), but serum LH was not associated with BLLs in the pregnant
women, women who were menstruating, women who were taking birth control pills, and pre-menopausal
women. In another cross-sectional, population-based survey in China, Chenetal. (20161 examined the
associations between blood Pb and total testosterone (tT), E2, and SHBG, in addition to LH and FSH in
postmenopausal women (age >55 years). When comparing the highest quartile of blood Pb (>5.98 (ig/dL)
to the lowest (<2.70 (ig/dL), there were positive associations with BLLs and SHBG ([3: 0.048, SE: 0.016,
p < 0.01), FSH ([3: 0.046, SE: 0.016, p < 0.01), and LH ([3: 0.037, SE: 0.016, p < 0.05). There were null
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associations between BLLs and tT or E2. Across the quartiles of blood Pb, there were also positive trends
observed with SHBG (p for trend: 0.002), FSH (p for trend: 0.001), and LH (p for trend: 0.026),
suggesting a potential linear exposure response between blood Pb and these hormones. In a study of the
Korea National Health and Nutrition Examination Survey (KNHANES) (2012-2014), blood Pb and
serum FSH levels were assessed in postmenopausal women (aged 50 or older) (Lee etal.. 2019). Serum
FSH levels were positively associated with increasing blood log-Pb ((3: 2.929 [95% CI: 0.480, 5.377]).
8.5.1.1.2 Epidemiologic Studies on Menstrual/Estrous Cycle
There were no available epidemiologic studies in the 2013 Pb ISA that evaluated Pb exposure
with menopause. There are a limited number of studies that examined the relationship between Pb
exposure and menopause, and these recent studies reported consistent positive associations. A recent
cross-sectional study, NHANES (1999-2010) data was used to examine the associations between blood
Pb and menopause among women aged 45-55 years (age range where menopause is likely to occur)
(Mendola et al.. 2013). In the overall study sample (NHANES 1999-2010), with increasing quartiles of
blood Pb, there were increasing odds of menopause. Comparing the lowest BLLs (<1.0 (ig/dL), the odds
for Q2 through Q4 were 1.7 (95% CI: 1.0, 2.8), 2.1 (95% CI: 1.2, 3.6), and 4.3 (2.6, 7.2), respectively.
When adjusting for bone measurements (either bone alkaline phosphatase or femoral neck bone density),
the associations were similar. In a subset (n = 434) of the Nurse's Health Study, the associations between
bone Pb levels and age at menopause were explored (Eumetal.. 2014). Compared with women in the
lowest tertile of tibia Pb (<6.5 |_ig/g). those in the highest tertile (>13 jj.g/g) were 1.21 years younger at
menopause on average (95% CI: -2.08, -0.35; p for trend: 0.006). Women in the highest tertile of tibia Pb
had an increased odds of 5.30 (95% CI: 1.42, 19.78; p for trend: 0.006) for early menopause (menopause
before age 45) compared with women in the lowest tertile. The associations with early menopause were
null across tertiles for patella Pb and BLLs.
8.5.1.2 Toxicological Studies on Hormone Levels and Menstrual/Estrous Cycle
There are no recent animal toxicological studies on the effects of Pb on the menstrual/estrous
cycle. The 2013 Pb ISA did not report any studies that investigated the effects of Pb on the
menstrual/estrous cycle, however some studies were summarized in the 2006 Pb AQCD. Specifically,
studies conducted in non-human primates found that Pb exposure increased menstrual cycle variability,
reduced days of menstrual flow, increased cycle length, and reduced progesterone (Franks etal.. 1989;
Laughlin et al.. 1987). Another study with a lower BLL than the previous studies (<40 (ig/dL versus 44-
89 (ig/dL); however, did not report an effect on the menstrual cycle in a non-human primate species
(Foster etal.. 1992). Impacts of Pb on estrous cyclicity were examined in two rat studies that both utilized
multiple dosing paradigms to assess the varying impacts Pb exposure may have during different
developmental periods. Specifically, one study used the following exposure windows: gestation only,
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lactation only, gestation and lactation, postnatal (from birth and continued past weaning), and continuous
(from the beginning of gestation continued past weaning) (Ronis el al.. 1998a). This study reported that
offspring in the postnatal and continuous exposure groups had fewer females who were regularly cycling.
The other study was conducted by the same research group and utilized the following dosing windows:
post-pubertal (PND 60 to PND 74), pre-pubertal (PND 24 to PND 74), and in utero (GD 5 to PND 85)
(Ronis etal.. 1996). Rats in the pre-pubertal and in utero exposure paradigm groups experienced estrous
cyclicity disruption. While this study seems to indicate that pre-pubertal periods are more sensitive to
chemical insult, the previous study by Ronis etal. (1998a) suggests that normal cyclicity is recoverable
after cessation of exposure. However, it is worth noting that in both of these studies the BLLs were very
high, with a range of 63.2-264 (ig/dL for treatment groups that displayed treatment-related effects.
There are no recent animal toxicological studies on the effects of Pb on reproductive hormones.
The 2013 Pb ISA reported on a few studies that investigated the effects of Pb on reproductive hormones,
but none on cyclicity. Rodent studies reported that gestational and lactational exposure decreased
circulating levels of progesterone and E2 (Pillai etal.. 2010; Nampoothiri and Gupta. 2008). Dumitrescu et al.
(2008b) reported similar findings in adult female Wistar rats that were exposed to Pb for 6 months via
drinking water. Dumitrescu et al. (2008b') reported reductions in E2, progesterone, and FSH and increases in
LH and testosterone. The 2006 Pb AQCD reports findings from some toxicological studies that show
effects of Pb on hormones and cyclicity. Reductions in progesterone were observed in a study wherein
monkeys had BLLs of 25 to 30 (ig/dL, but no such reductions in progesterone were observed in monkeys
with even lower BLLs (10 to 15 (ig/dL) (Foster et al.. 1996).
8.5.1.3 Integrated Summary of Effects on Hormone Levels and Menstrual/Estrous
Cycle
The recent cross-sectional, population-based survey epidemiologic studies found consistent
positive associations between blood Pb and FSH in women who were post-menopausal. While these
studies are limited by their study design, the studies were conducted in well-established population-based
surveys. These studies considered a range of confounders, including controlling for BMI and smoking,
even co-exposure to other metals. The recent studies examining the relationship between menopause and
Pb exposure found consistent positive associations. The results from concurrent exposure of blood Pb
with menopause were supported by the results from a longitudinal cohort that examines bone Pb, a
cumulative biomarker of Pb exposure, and menopause, both the difference in age at menopause and risk
of early menopause. No recent PECOS-relevant toxicological studies reported on the effects of Pb on
hormone levels in females or menstrual or estrous cyclicity. However, previous toxicological evidence
suggests that Pb may disrupt reproductive hormones and menstrual and estrous cyclicity in females. Two
toxicological studies in rats reported disruptions in estrous cyclicity, and two toxicological studies based
in non-human primates reported alterations to different menstrual cycle aspects (e.g., length of cycle,
length of menstruation) and reproductive hormone levels. Additional rodent studies reported effects of Pb
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on circulating reproductive hormone levels, including sex steroid hormones (progesterone, testosterone,
and E2) and gonadotropin hormones (LH and FSH).
8.5.2 Effects on Female Fertility
Multiple epidemiologic and toxicological studies have examined the relationship between Pb and
female fertility. These studies are summarized in the text below. Study details of the recent epidemiologic
studies are included in Table 8-14 and the recent toxicological studies are in Table 8-15.
8.5.2.1 Epidemiologic Studies on Female Fertility
The epidemiologic studies reviewed in the 2013 Pb ISA examined a variety of fertility-related
endpoints. Although some studies demonstrated an association between higher Pb biomarker levels and
fertility/pregnancy, the results are inconsistent across studies. One limitation in most of these studies is
that the participants were women seeking help for fertility problems. The participants were not samples of
the general population and therefore cannot be generalized to all women of childbearing age. This may
also have introduced substantial selection bias into the study.
The recent epidemiologic studies also evaluated different outcomes to measure fertility. In an
NHANES (2013-2014 and 2015-2016) study, Lee et al. (20201 assessed whether BLLs were associated
with self-reported infertility by comparing BLLs of infertile women (n = 42) to pregnancy women
(n = 82). There was increased risk of 2.60 (95% CI: 1.05, 6.41) per two-fold increase in BLLs of
infertility. When BLLs were categorized into tertiles, risk of infertility was more pronounced (OR: 5.40
[95% CI: 1.47, 19.78] interfile 2 (0.41-0.62 (ig/dL) and OR: 5.62 [95% CI: 1.13, 27.90] interfile 3
(0.63-5.37 (ig/dL), respectively). In the LIFE Study, a cohort of couples were followed prospectively to
assess persistent environmental chemicals and human fecundity (Louis etal.. 2012). BLLs in both the
female and male partners were collected at baseline. Female BLLs were not associated with increased
time to pregnancy in the female exposure model (OR: 0.97 [95% CI: 0.85, 1.11]) or the couple exposure
model (OR: 1.06 [95% CI: 0.91, 1.24]). However, there was decreased odds, or longer time to pregnancy,
for male BLLs in both the male exposure model (OR: 0.85 [95% CI: 0.73, 0.98]) and the couple exposure
model (OR: 0.82 [95% CI: 0.68, 0.97]).
In studies conducted among couples undergoing in vitro fertilization (IVF), there were
inconsistent associations. In a cross-sectional study among infertile women in Taiwan, Lai etal. (20171
examined the associations between BLLs and diagnosis of endometriosis, which can cause infertility.
Increasing tertiles of BLLs was associated with increasing odds of endometriosis (OR: 2.59 [95% CI:
1.11, 6.06] for T3 compared to Tl). In a cohort study, among couples undergoing the first IVF cycle,
maternal Pb levels were assessed with pregnancy outcomes (Li etal.. 2022). Pb levels in serum were
collected before oocyte retrieval. With increasing maternal serum Pb levels, there was a reduction in
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successful implantation (OR: 0.85 [95% CI: 0.77, 0.94]) and clinical pregnancy (OR: 0.95 [95% CI: 0.91,
0.99]). Additionally, when maternal serum Pb was categorized into tertiles, there was a decreased rate of
successful implantation (OR: 0.58 [95% CI: 0.40, 0.85]) in the highest Pb tertile, compared to the lowest
Pb tertile. Among tertiles of Pb serum levels, the associations were null for clinical pregnancy.
Furthermore, there was a negative association with maternal serum Pb and high-quality embryo rate ([3:
-0.14 [95% CI: -0.32, -0.04]), but there were null associations with all other embryo quality indicators
(Table 8-14). In a cohort of 195 couples undergoing IVF, Pb was measured in serum and follicular fluid
from the female partner and semen from the male partner in association with six IVF outcomes (Zhou et
al.. 202 la). There were no associations between serum or follicular fluid Pb levels and any IVF outcomes
- normal fertilization, good embryo, blastocyst formation, high-quality blastocyst, pregnancy, or live
birth.
8.5.2.2 Toxicological Studies on Female Fertility
The 2013 Pb ISA reported some studies that investigated the effects of Pb on female fertility. A
handful of these studies reported that exposure to Pb reduced litter sizes in exposed female rats
(Dumitrescu et al.. 2008a: Teiion et al.. 2006) and mice (lavicoli et al.. 2006). Contrasting this is a study that
found no changes in fertility rate or litter size in female rats treated prior to mating through pregnancy
(Nampoothiri and Gupta. 2008). Recent studies corroborate the findings of Nampoothiri and Gupta (2008) and
do not demonstrate any effects of Pb on female fertility in terms of litter size or number of litters
produced by dosed dams in mice (Schneider et al.. 2016: Corv-Slechta et al.. 2013) or rats (Rao Barkur and
Bairv. 2016: Barkur and Bairv. 2015: Weston etal.. 2014: Betharia and Maher. 2012). Among these recent
studies, a variety of dosing paradigms were utilized, including exposure during preconception, lactation,
gestation, and combinations thereof (BLLs ranged between 3.02-26.86 (ig/dL in pups on PND 2-22). The
contrast in effects on litter size between studies that do and do not report effects of Pb on litter size is
perplexing, and the inconsistencies of BLL measurements (e.g., some measured Pb levels in offspring,
some measured in dams, some studies did not report BLLs at all) between studies further exacerbates the
difficulty of reconciling these contrasts. However, some plausible explanations for these differences exist
and primarily involve differences in study design. Studies that reported reductions in litter size due to Pb
exposure tended to either use higher doses (Teiion etal.. 2006). longer dosing durations (lavicoli et al..
2006). or dosed sires in addition to dosing dams (Dumitrescu et al.. 2008a) when compared to studies that
did not report reductions in litter sizes.
8.5.2.3 Integrated Summary of Effects on Female Fertility
Among the recent epidemiologic studies, there were inconsistent associations between Pb
exposure and female fertility. In studies among participants in the general population, there was an
increased risk of self-reported infertility and longer time to pregnancy. However, among studies with
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women who were either seeking help at a fertility clinic or reported infertility, the associations were
inconsistent. Because the study participants included only a small sample of women who were either
seeking help at a fertility clinic or reported infertility, which may have resulted in selection bias and limits
the generalizability of the results. Additionally, the recent epidemiologic studies were limited by the
concurrently measured exposure and outcome, different biomarkers of exposure (blood, serum, and
follicular fluid), and a small number of participants. These studies did include adjustment for potential
confounders, however, including age, BMI, and partner exposure. Previous toxicological evidence
reported inconsistent effects of Pb on fertility in females. All recent toxicological studies reported that
female fertility was not affected by Pb exposure, even when a variety of dosing paradigms were used.
8.5.3 Effects on Morphology and Histology of Female Sex Organs (Ovaries,
Uterus, Fallopian Tubes/Oviducts, Cervix, Vagina, and Mammary
Glands)
Recent epidemiologic and toxicological studies evaluating the association between Pb exposure
and morphology or histology of female sex organs (ovaries, uterus, fallopian tubes/oviducts, cervix,
vagina, and/or mammary glands) are limited. Study details for the single cross-sectional epidemiological
study are included in Table 8-14 and the toxicological studies are included in Table 8-15.
8.5.3.1 Epidemiologic Studies of Morphology and Histology of Female Sex Organs
(Ovaries, Uterus, Fallopian Tubes/Oviducts, Cervix, Vagina, and Mammary
Glands)
In the 2013 Pb ISA, there were no epidemiological studies available that evaluated Pb
concentrations and associations with morphology or histology of female sex organs (ovaries, uterus,
fallopian tubes/oviducts, cervix, vagina, and/or mammary glands). A recent cross-sectional study
examined the association between BLLs and rate of uterine fibroids and uterine fibroid volume (Ye el al..
2017). Among 288 (46 with fibroids and 242 without) pre-menopausal women included in the study, there
were null associations between blood Pb and the presence of uterine fibroids (OR: 1.39 [95% CI: 0.75.
2.56]) and volume of the largest fibroids ((3: 0.12 [95% CI: -2.26, 2.51]). When blood Pb was categorized
into quartiles, the association with volume of uterine fibroids remained null. While the associations
between blood Pb and rate of uterine fibroids and uterine fibroid volume were generally null, the women
with uterine fibroids had higher geometric mean BLLs than women without fibroids (1.43 (ig/dL versus
1.35 (ig/dL, respectively).
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8.5.3.2 Toxicological Studies of Morphology and Histology of Female Sex Organs
(Ovaries, Uterus, Fallopian Tubes/Oviducts, Cervix, Vagina, and Mammary
Glands)
There are no recent animal toxicological studies on the effects of Pb on morphology or histology
of female sex organs. The 2013 Pb ISA discussed a single study that reported Pb exposure increased
membrane fluidity in granulosa cells in Charles Foster rats that were dosed by intraperitoneal injection
doses for 15 days (Nampoothiri and Gupta. 2006). The 2006 Pb AQCD also reported that exposure to Pb
during early pregnancy caused structural changes in the uterine epithelium in mice (Nilsson el al.. 1991;
Wide and Nilsson. 1979).
8.5.3.3 Integrated Summary of Morphology and Histology of Female Sex Organs
(Ovaries, Uterus, Fallopian Tubes/Oviducts, Cervix, Vagina, and Mammary
Glands)
There was a single recent epidemiologic study evaluating associations between Pb exposure and
uterine fibroids. Although this was a small cross-sectional study, it was able to control for a large range of
confounders. The results from this single study are limited by the small sample size and concurrent
measurements of blood Pb and fibroids. Toxicological evidence regarding Pb exposure and female sex
organs is scarce. No recent PECOS-relevant toxicological studies were available. Previous studies
discussed in the 2013 Pb ISA and the 2006 Pb AQCD reported no effects of Pb on female sex organ
morphology or histology.
8.6 Effects on Male Reproductive Function
The 2013 Pb ISA concluded that there was toxicological evidence with supporting epidemiologic
evidence to conclude that a causal relationship exists between Pb exposure and effects on male
reproductive function. The key evidence was provided by toxicological studies in rodents, non-human
primates, and rabbits showing detrimental effects on semen quality, sperm, and fecundity/fertility with
supporting evidence in epidemiologic studies of associations between Pb exposure and detrimental effects
on sperm. Recently published research has continued to support an association between Pb and
sperm/semen production, quality, and function. Studies of Pb and male reproductive function are
described in the sections below.
8.6.1 Effects on Sperm/Semen Production, Quality, and Function
Multiple epidemiologic and toxicological studies have examined the relationship between Pb and
sperm and semen production, quality, and function. These studies are summarized in the text below.
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Study details of the recent epidemiologic studies are included in Table 8-16 and the recent toxicological
studies are in Table 8-17. The majority of the recent epidemiologic studies are cross-sectional with
concurrent measurements of Pb levels in biological samples and sperm-related outcomes. Recent
toxicological studies use a variety of dosing paradigms, and those that dose for longer periods of time
(>30 days) or during a developmental window most often reported effects of Pb exposure on aspects of
sperm and semen quality.
8.6.1.1 Epidemiologic Studies on Sperm/Semen Production, Quality, and Function
The 2013 Pb ISA epidemiologic studies of Pb exposure and sperm and semen production, quality,
and function were cross-sectional, mostly in occupational cohorts, with concurrent measurements of Pb
levels in biological samples and sperm-related outcomes. The multiple epidemiologic studies in
occupational cohorts had mean BLLs over 40 (ig/dL for individuals occupationally exposure to Pb. The
occupational studies also had limited consideration for potential confounding factors, such as other
workplace exposures, which may impact the associations. The epidemiologic studies of men attending
fertility clinics may be subject to selection bias, and the results may not be generalizable. Additionally,
these studies reported imprecise estimates, did not control for other potential confounders such as other
metals, and had small sample sizes.
Several recent cross-sectional studies have explored the relationship between Pb exposure and
sperm and semen production, quality, and function. These studies were all conducted in males attending
fertility clinics and reported inconsistent associations for various metrics of sperm/semen production,
quality, and function. There were other cross-sectional studies that also examined associations with sperm
and semen production, quality, and function using different and Pb measured in semen, seminal fluid, and
seminal plasma, but these findings were more inconsistent.
Among the cross-sectional studies that evaluated associations with blood Pb, there was lower
normal sperm morphology with increasing BLLs (Shi etal.. 2021; Sukhnetal.. 2018; Li el al.. 2015).
Additionally, Li etal. (20151 reported increased odds of lower semen quality, sperm concentration,
numbers of sperm, total motility sperm, and progressive motility sperm with increasing BLLs, whereas
Sukhnetal. (20181 reported null associations with sperm volume, concentration, total count, progressive
motility, viability, and World Health Organization (WHO) morphology and Shi etal. (20211 reported null
associations between blood Pb and semen parameters of semen volume, sperm concentration, total sperm
count, sperm motility, total motile sperm count, sperm vitality, DNA fragmentation index, or percentage
of acrosome reacted sperm (see Table 8-16). Furthermore, there were differences in BLLs between men
categorized as having low-quality semen and those classified as having normal or high-quality semen
(Sukhnetal.. 2018; Li etal.. 2015). Li etal. (20151 reported mean blood Pb for men in the low-quality semen
group was 3.43 j^ig/dL and 2.38 (ig/dL for those in the high-quality semen group and Sukhnetal. (20181
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reported the mean blood Pb for low-quality semen group of 5.198 (ig/dL and 3.575 (ig/dL for the normal-
quality semen group.
Other cross-sectional studies examined the relationship between Pb measured in seminal fluid and
metrics of sperm/semen production, quality, and function, but the associations were inconsistent (JiaetaL
2022; Sukhnetal.. 2018; Pantetal.. 2014). Pantetal. (20141 measured Pb in semen and metrics of
sperm/semen production, quality, and function, and reported associations of higher sperm Pb with
decreased sperm motility ((3: -2.43% [95% CI: -4.87%, -0.001%]), decreased sperm concentration ((3:
1.97 106/mL [95% CI: -3.16, -0.33]), increased tail length ([3: 3.79 [95% CI: 0.56, 7.02]), increased
percent DNA in tail ([3: 1.31 [95% CI: 0.17, 3.74]), and increased tail moment ([3: 1.20 [95% CI: 0.23,
2.16]). However, Sukhnetal. (20181 assessed sperm characteristic relationships with Pb in seminal fluid
and reported increased odds of below-reference sperm viability and WHO morphology with higher
seminal fluid Pb, but null associations with volume, concentration, total count, and progressive motility.
Jia et al. (20221 reported no associations between seminal plasma Pb concentrations and semen parameters
(semen volume, sperm concentration, total sperm number, progressive motility, and normal
morphological rate).
A recent cohort study examined the associations between peripubertal blood Pb, collected at
enrollment, and parameters of sperm and semen production, quality, and function for 223 participants in
the Russian Children's Study, with the semen sample collected 10 years after enrollment (Williams et al..
2022). There were null associations between peripubertal blood Pb and sperm parameters (sperm
concentration, total count, progressive motility, and total progressive motile sperm count, or probability
of having low semen quality based on sperm count/motility), whether blood Pb was modeled
continuously, categorized as tertiles, or categorized as low (<5 (ig/dL) blood Pb versus high (>5 (ig/dL)
blood Pb (see Table 8-16).
8.6.1.2 Toxicological Studies on Sperm/Semen Production, Quality, and Function
The 2013 Pb ISA summarized several toxicological studies that investigated the effects of Pb
exposure on sperm-related outcomes. Utilizing a variety of dosing paradigms and animal models,
previously published studies have demonstrated that Pb exposure reduced sperm counts, reduced numbers
of viable sperm, reduced motility, and increased morphological abnormalities (Pillaietal.. 2012; Anium et
al.. 2011; Allouche et al.. 2009; Oliveira et al.. 2009; Salawu et al.. 2009; Shan et al.. 2009; Tapisso et al.. 2009;
Massanvi et al.. 2007; Piao etal.. 2007; Wang etal.. 2006). Results from recently published studies tend to
suggest that Pb exposure impacts sperm and semen parameters (Table 8-17). All available studies that
reported outcomes on sperm and semen parameters were conducted in mice. Only one study utilized a
developmental exposure paradigm and dosed lactating CD-I mice from PND 0 to 21 which resulted in
reduced numbers of sperm at PND 70 in male offspring in the highest dose group (BLLs 19.1 (ig/dL)
(Wang etal.. 2013a). Other studies that directly exposed male mice after weaning also reported Pb-induced
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sperm alterations including increased incidence of abnormal morphology, reduced density, and reduced
viability (BLLs 9.4-11.92 (ig/dL) (Zhang etal.. 2021; Xie et al.. 2020; Godinez-Sohs et al.. 2019). However,
some studies also reported no Pb-induced effects on sperm motility, concentration, count, or viability
(BLLs 9.4-11.8 (ig/dL) (Pavlova et al.. 2021; Godinez-Sohs et al.. 2019). It is worth noting that while Pavlova
etal. (20211 reported no Pb-induced effects on sperm count, Pb-treated animals had sperm counts 25%
lower than those of control mice, but this effect failed to reach statistical significance (p = 0.146). In
terms of patterns in the reported data, studies that utilized long-term exposure (>30 days) or dosed during
developmental periods tended to reported effects of Pb on sperm or semen parameters, and Pavlova et al.
(20211 the only study to use short-term exposure during adulthood, was the only study to report no effects
at all on any sperm or semen parameters.
8.6.1.3 Integrated Summary of Effects on Sperm/Semen Production, Quality, and
Function
Among the recent epidemiologic studies that evaluated associations between Pb exposure
(measured in blood, semen, seminal fluid, or seminal plasma) and effects on sperm/semen production,
quality, and function, there were inconsistent findings, which was similar to the conclusion in the 2013 Pb
ISA. More consistent associations were observed for blood Pb with decreased sperm/semen production,
quality, and function than for Pb measured in semen, seminal fluid, or plasma; however, there are
limitations in the recent epidemiologic studies. All the cross-sectional studies were conducted in males
attending fertility clinics, which may have resulted in selection bias and limits the generalizability of the
results. Further, the small sample size from these cross-sectional studies also reduces the statistical power
to determine the precision of the associations. With concurrent measurement of Pb exposure with
outcomes related to sperm/semen production, quality, and function, temporality cannot be established.
Lastly, the use of different biomarkers (e.g., blood, semen, seminal fluid, or seminal plasma) to measure
Pb exposure and the different metrics of sperm/semen production, quality, and function limits the ability
to judge coherence and consistency across studies. Despite these limitations, it is important to note that a
wide variety of potential confounders were controlled for, including hormone levels, which could
potentially impact sperm/semen production, quality, and function. Previous and recent toxicological
studies generally reported that Pb alters some aspect of sperm or semen quality, such as sperm density,
motility, morphology, and viability, especially those studies that employed dosing during developmental
periods or for periods 30 days or longer. All recent toxicological evidence was produced from mouse
strains, but previous toxicological studies report similar effects in other species such as rats and rabbits.
8.6.2 Effects on Hormone Levels in Males
The epidemiologic and toxicological studies reviewed in the 2013 Pb ISA reported inconsistent
results regarding changes in hormone levels in men and associations with Pb exposure. The results from
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the 2013 Pb ISA were similar to the findings from the 2006 Pb AQCD. Recent epidemiologic and
toxicological studies are reported below. Epidemiologic studies were mostly cross-sectional with blood
Pb measured concurrently with hormone levels. Study details for the epidemiologic studies, including
BLLs, study population characteristics, potential confounder, and select results, are in Table 8-16.
Previous toxicological evidence regarding the effect of Pb on hormones in males is somewhat
inconsistent, but most studies reported impacts of Pb on hormone levels. Recent toxicological studies are
extremely limited, but support previous toxicological studies reported in the 2013 Pb ISA that observed
Pb-induced effects on hormones in males. Study details for the recent toxicological studies are in Table 8-
17.
8.6.2.1 Epidemiologic Studies on Hormone Levels in Males
In the 2013 Pb ISA, there were a few epidemiologic studies that evaluated hormone levels in
males in association with Pb exposure. The findings of these studies were inconsistent. The epidemiologic
studies were limited by their sample populations, often occupational cohorts or men recruited from
fertility clinics, which may not be representative of the general populations and limits the generalizability
of the results. More specifically, the occupational cohorts may have other metal exposures that were not
considered and may confound the associations, while studies conducted with subjects from fertility clinics
are subject to selection bias. While these studies included important confounders such as smoking, other
factors, such as exposure to other metals, were often absent. The cross-sectional study design of some of
the epidemiological studies reviewed makes it difficult for temporality of effects to be established.
Additionally, most of the epidemiologic studies examined concurrent Pb exposure and hormone levels,
which may not reflect changes resulting from long-term exposures.
The recent epidemiologic studies on hormone levels detailed in this section are specific to
hormones related to reproductive function and recent epidemiologic studies on other hormones are
described in Section 9.4.2 in the Other Health Effects Appendix.
There are a few recent epidemiologic cross-sectional studies that evaluated the associations
between hormone levels in males and Pb exposure. There were consistent positive associations between
blood Pb and testosterone among these studies. One NHANES analysis combined three consecutive
cycles of NHANES (1999-2000, 2001-2002, and 2003-2004) to investigate the associations between
blood Pb and various sex hormones: testosterone, free testosterone, E2, fE2, androstenedione glucuronide,
and SHBG among men over 20 years old (Krcsovich et al.. 2015). Comparing the highest quartile of blood
Pb exposure (>3.20 (ig/dL) to the lowest (<1.40 (ig/dL), testosterone was positively associated with blood
Pb ((3: 0.79, SE: 0.22) and there was an indication of exposure-response (p for trend: 0.0026). There were
null associations between blood Pb and all other sex hormones. In another NHANES (2011-2012) study,
blood Pb and serum testosterone were measured in men of reproductive age (18-55 years old) (Lewis and
Meeker. 2015). Of the 484 men included in the analysis, there was a 6.65% (95% CI: 2.09%, 11.41%)
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change in the serum testosterone concentration associated with a doubling (100% increase) in blood Pb
concentration. Chenetal. (20161 also reported positive associations between concurrent testosterone and
blood Pb concentrations. Utilizing data from a population-based survey, the Survey on the Prevalence in
East China for Metabolic Diseases and Risk Factors (SPECT)-China, 2,286 men were included in the
analysis to investigate the relationship between quartiles of BLLs and multiple reproductive hormones -
tT, SHBG, E2, LH, and FSH. When comparing the highest quartile of blood Pb (>6.249 (ig/dL) to the
lowest (<2.90 (ig/dL), there were positive associations with BLLs and tT ((3: 0.033, SE: 0.010, p < 0.01),
SHBG ((3: 0.038, SE: 0.012, p < 0.01), FSH ((3: 0.030, SE: 0.015, p < 0.05), and LH ((3: 0.028, SE: 0.013,
p < 0.05), but null associations with E2 ((3: -0.003, SE: 0.017). Across the quartiles of blood Pb, there
were also positive trends observed with tT (p for trend: 0.012), SHBG (p for trend <0.001), FSH (p for
trend <0.001), and LH (p for trend <0.001), suggesting a potential linear concentration response.
While there were consistent positive associations between blood Pb and serum testosterone in the
cross-sectional studies, a single cohort study reported null associations. Among a subset of participants
(n = 453) in the Russian Children's Study, there were no associations between peripubertal BLLs and
hormones levels (testosterone, LH, or FSH) measured between 8-19 years of age, whether blood Pb was
modeled continuously or categorized (<5 (ig/dL versus >5 (ig/dL) (Williams et al.. 2022).
8.6.2.2 Toxicological Studies on Hormone Levels in Males
The 2013 Pb ISA discussed several studies that reported on the effects of Pb on hormone levels in
males. All studies were conducted in rats, and all directly dosed the tested animals save for one that
exposed gestating and lactating dams and measured hormones in offspring. Dosing durations varied from
21 days to 24 weeks, and most studies reported reductions in testosterone (Pillai etal.. 2012: Anium et al..
2011: Biswas and Ghosh. 2006: Rubio et al.. 2006). One study observed increased testosterone (Allouche et al..
2009) and another reported reductions in LH and FSH (Biswas and Ghosh. 2006). However, not all studies
observed effects on male hormones due to Pb exposure. One study observed no change in testosterone
(Salawuetal.. 2009) and another reported no change in FSH and LH levels despite reporting increased
testosterone levels (Allouche et al.. 2009). Only one recent PECOS-relevant toxicological study was
published that investigated the effects of Pb exposure on hormones in males (Table 8-17). This study
dosed nursing CD-I mice from PND 0 to 21 and reported reduced serum testosterone at weaning and
PND 70 and reduced testicular testosterone at weaning in the highest dose group (19.1 (ig/dL) (Wang et
al.. 2013a).
8.6.2.3 Integrated Summary of Effects on Hormone Levels in Males
The recent cross-sectional epidemiological studies reported consistent associations between blood
Pb and testosterone; however, a single cohort study reported no associations. Of note, the recent cross-
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sectional studies were in adult men, whereas the single cohort study were in male adolescents.
Additionally, the study by Chenetal. (20161 provides further support of a positive association with SHBG,
FSH, and LH and blood Pb. The positive trends among quartiles of blood Pb and testosterone, SHBG,
FSH, and LH provide insight on the possible concentration-response relationship. These studies have
robust sample sizes drawn from population-based surveys and controlled for a number of confounders,
including smoking, but the temporality of effects is difficult to establish due to the nature of cross-
sectional study design. Recent toxicological evidence regarding the effects of Pb on hormones in males is
extremely limited, but in agreement with most studies summarized in the 2013 Pb ISA which report
effects of Pb on hormones in males.
8.6.3 Effects on Male Fertility
The recent epidemiologic and toxicological studies examining the relationship between Pb
exposure and male fertility are summarized in the text below. The epidemiologic studies on Pb exposure
and male fertility are limited. Previous epidemiologic studies were conducted among with men seeking
help at fertility clinics. Study details of the recent epidemiologic studies are in Table 8-16. Previous and
recent toxicological evidence regarding the effect of Pb on male fertility is scarce, but generally reports
reduced fertility in males exposed to Pb. Study details of the recent toxicological studies are in Table 8-
17.
8.6.3.1 Epidemiologic Studies on Male Fertility
The epidemiologic studies included in the 2013 Pb ISA that assessed associations between Pb
exposure and male fertility reported inconsistent findings. The few studies available for review were
limited were conducted with cases that included men seeking help at fertility clinics, resulting in limited
generalizability of the studies because the study populations are not representative of the general
population. Additionally, by recruiting men who were seeking help at fertility clinics, there could be
selection bias, as their fertility status is already known and those seeking help at fertility clinics may be
different from men who have fertility issues who may be unaware of their condition and not seeking help
at a fertility clinic. Another study was conducted among occupationally exposed men, which may result in
differential exposures compared to the general population. Furthermore, another study did not control for
potential confounders.
There were a limited number of recent epidemiologic studies that examined associations between
Pb and male fertility. In the LIFE Study, a cohort of couples were followed prospectively to assess
persistent environmental chemicals and human fecundity (Louis etal.. 2012). BLLs in both female and
male partners were collected at baseline. While female blood Pb was not associated with increased time to
pregnancy, there was decreased odds, or increased time to pregnancy, for male BLLs in both the male
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exposure model (OR: 0.85 [95% CI: 0.73, 0.99]) and the couple exposure model (OR: 0.82 [95% CI:
0.68, 0.97]). In a cohort of 195 couples undergoing IVF, Pb was measured in blood serum and follicular
fluid from the female partner and semen from the male partner in association with six IVF outcomes
(Zhou el al.. 2021a). There was a positive association between Pb in seminal plasma and the possibility of
obtaining a good embryo (RR: 1.86 [95% CI: 1.05, 3.11]), but the associations were null across all other
IVF outcomes (normal fertilization, blastocyst formation, high-quality blastocyst, pregnancy, or live
birth).
8.6.3.2 Toxicological Studies on Male Fertility
Only a few studies on the effects of Pb on male fertility were summarized in the 2013 Pb ISA.
These studies reported that Pb-exposed males produced smaller litters and fewer implantations and
fetuses per dam (Anium el al.. 2011; Sainath et al.. 2011). Only a single recent study investigated fertility
outcomes in males exposed to Pb (Table 8-17). This study exposed ICR-CD-I mice from PND 91 to 136
via drinking water and reported that sperm from treated mice had reduced fertilization capacity, resulting
in fewer fertilized oocytes in vitro (9.4 (ig/dL) (Godmcz-Soli's et al.. 2019).
8.6.3.3 Integrated Summary of Male Fertility
Similar to the 2013 Pb ISA, there were only a few epidemiologic studies evaluating associations
between Pb exposure and male fertility and the findings were inconsistent. The results from these studies
are limited by the small sample size and the study population was recruited from a fertility clinic, which
may have resulted in selection bias and limits generalizability. Additionally, different biomarkers were
used to assess Pb exposure, as well as different metrics of male fertility across the studies. In terms of
toxicological evidence, previous and recent studies are few in number. However, all report a reduction of
male fertility in Pb-treated animals using outcomes such as litter size, implantations, and fertilized
oocytes.
8.6.4 Effects on Morphology and Histology of Male Sex Organs
The toxicological studies in the 2013 Pb ISA supported historical findings that showed an
association between Pb exposure and changes in the sex organs as well as germ cells. There were no
epidemiological studies available for review for the 2013 Pb ISA that examined the relationship between
Pb exposure and morphology or histology of male sex organs. The current epidemiologic and
toxicological studies examining the relationship between Pb exposure and effects on morphology and
histology of male sex organs are summarized in the text below with study details in Table 8-16 and Table
8-17, respectively.
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8.6.4.1
Epidemiologic Studies of Morphology and Histology of Male Sex Organs
In the 2013 Pb ISA, there were no epidemiological studies available that evaluated Pb
concentrations and associations with morphology or histology of male sex organs. A recent cohort study
evaluated the associations between prenatal metal exposure and reproductive development in boys at 2-
3 years (Huang etal.. 2020). Serum concentrations of multiple metals, including Pb, were obtained from
mothers in the Guangxi Birth Cohort Study throughout pregnancy, while reproductive development was
measured as TV and anogenital distance (AGD), categorized as anopenile distance (AGDap) and
anoscrotal distance (AGDas), in 2-3-year-old male children. When maternal serum Pb levels were
categorized by quartiles, infants in the highest quartile (serum Pb >1.23 (ig/L) had, on average, a
0.064 mL (95% CI: -0.124, -0.004) smaller TV, 0.060 cm (95% CI: -0.110, -0.011) shorter AGDap, and
0.115 cm (95% CI: -0.190, -0.039) shorter AGDas than infants in the lowest quartile (serum Pb <
0.54 jig/L).
8.6.4.2 Toxicological Studies of Morphology and Histology of Male Sex Organs
This section is divided into the two main outcomes for the male sex organs: changes in weight of
male sex organs and changes in histology/morphology of male sex organs. The 2013 Pb ISA summarized
several studies that investigated the effects of Pb exposure on male sex organ weights. Several studies
reported decreases in weights of organs such as the testis, epididymides, vas deferens, seminal vesicles,
and prostate (Anium et al.. 2011; Pillai et al.. 2010; Dong et al.. 2009; Salawu et al.. 2009; Biswas and Ghosh.
2006; Rubio etal.. 2006). The direction of effect was consistent, and any effects observed were only
decreases in organ weights. However, the 2013 Pb ISA noted that there were many other studies that did
not report effects on male reproductive organ weights even when using similar doses as those studies that
did observe effects, indicating that the impact of Pb on reproductive organ weights is somewhat
inconsistent. Recent studies have also investigated the effects of Pb exposure on male sex organ weight
(Table 8-17). Wang etal. (2013 a') reported that dosing male CD-I mouse pups via their dams' drinking
water from PND 0 to 21 led to reduced absolute weight of testes in both treatment groups at weaning and
reduced relative testis weight in the highest treatment group at weaning (BLLs 19.1-21.2 (ig/dL on
PND 22 and 3.24-4.40 (ig/dL on PND 70). However, they observed no effect on the weight of the
prostate, seminal vesicle, or epididymides at weaning and no effects on relative weights of any
reproductive organ on PND 70. Similarly, another study reported that dosing Sprague-Dawley rats from
GD -10 to PND 183 had reduced absolute and relative testis weights (BLLs 18.6 (ig/dL) (Wang etal..
2013b). However, some studies reported that Pb did not alter the weights of testes or epididymides in ICR
mice (BLLs 6.02-21.66 (ig/dL) (Pavlova et al.. 2021; Satapathv and Panda. 2017).
The 2013 Pb ISA reported on studies that investigated the effects of Pb on the histopathology of
male sex organs in rodents exposed to Pb. One of the most common outcomes was alterations of
seminiferous tubule pathology, such as reduced length of some spermatogenic cycle stages within
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seminiferous tubules, tubule damage, and tubule atrophy (El Shafai et al.. 2011; Shanetal.. 2009; Massanvi et
al.. 2007; Rubio et al.. 2006; Wang etal.. 2006). A few recent Pb studies have also reported Pb-induced
histopathological changes in male sex organs (Table 8-17). All recent studies were conducted in mice,
and exposure paradigms used between recent studies varied from developmental to exposure only during
adulthood. One study in CD-I mice that utilized developmental exposure (dosing dams from lactational
day 0 to 21) reported that Leydig cell numbers in the testes were reduced in the highest dose group at
weaning and layers of spermatogenic cells within the seminiferous tubules were decreased in both dose
groups at weaning and PND 70 (BLLs at weaning 19.1-21.1 (ig/dL; BLLs at PND 70 3.24-5.09 (ig/dL)
(Wang etal.. 2013a). Some studies dosing mice for 90 days following weaning reported disruptions that
epithelial cells within the epididymis were "randomly arranged" (BLLs 6.02-11.8 j^ig/dL) (Xie et al.. 2020)
and that spermatogenic cells within seminiferous tubules were reduced in number (BLLs at 11.92 (ig/dL)
(Zhang etal.. 2021). Lastly, a study that dosed mice from PND 60 to 74 reported that the epithelium of the
seminiferous tubules was disorganized, the luminal region contained undifferentiated germ cells, and
some tubules had decreased diameter and germ cell number and displayed incomplete spermatogenesis
(BLLs 21.7 (ig/dL) (Pavlova et al.. 2021).
8.6.4.3 Integrated Summary of Morphology and Histology of Male Sex Organs
In the 2013 Pb ISA, there were no epidemiological studies available that evaluated Pb
concentrations and associations with morphology or histology of male sex organs. A recent cohort study
reported decreased TV, shorter AGD, shorter anopenile distance, and shorter anoscrotal distance in 2-3-
year-old male children. While it is difficult to judge coherence and consistency from the findings of a
single study, this well-designed longitudinal cohort study does provide limited evidence of changes in
morphology and histology of male sex organs. Previous and recent toxicological studies are consistent in
reporting that Pb affects different aspects of sex organ histopathology. The most consistent effects appear
to be disruptions of histopathology of seminiferous tubules within the testes. However, there exists a data
gap regarding the effects of Pb on histopathology of other male sex organs such as the prostate,
epididymides, and seminal vesicles.
8.7 Biological Plausibility
This section describes the biological pathways that potentially underlie some reproductive and
developmental health effects from exposure to Pb. Figure 8-1 graphically depicts the proposed pathways
as a continuum of pathophysiological responses - connected by arrows - that may ultimately lead to the
observed delayed onset in both males and females and reduced sperm/semen production, quality, and
function. This discussion of how exposure to Pb may lead to these reproductive and/or developmental
events also provides biological plausibility for the epidemiologic results reported previously in this
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Appendix. In addition, most studies cited in this subsection are discussed in greater detail earlier in this
Appendix.
Disruption of
GnRH levels
and
hypothalamic-
pituitary-gonadal
Pb
Exposure
Delayed Pubertal
Onset in Males and
Females
Reduced
Sperm/Semen
Production, Quality,
and Function
Note: The boxes above represent the effects for which there is experimental or epidemiologic evidence related to Pb exposure, and
the arrows indicate a proposed relationship between those effects. Solid arrows denote evidence of essentiality as provided, for
example, by an inhibitor of the pathway or a genetic knockout model used in an experimental study involving Pb exposure. Shading
around multiple boxes is used to denote a grouping of these effects. Arrows may connect individual boxes, groupings of boxes, and
individual boxes within groupings of boxes. Progression of effects is generally depicted from left to right and color-coded (gray,
exposure; green, initial effect; blue, intermediate effect; orange, effect at the population level or a key clinical effect). Here,
population level effects generally reflect results of epidemiologic studies. When there are gaps in the evidence, there are
complementary gaps in the figure and the accompanying text below.
Pb = lead; GnRH = gonadotropin-releasing hormone
Figure 8-1 Potential biological pathways for reproductive and developmental
effects following exposure to Pb.
8.7.1 Pubertal Onset
When considering the available health evidence, plausible pathways connecting Pb exposure to
two health endpoints reported in epidemiologic and toxicological studies are proposed in Figure 8-1. The
first endpoint addressed in the figure above is delayed pubertal onset due to Pb exposure. Several
previous epidemiologic and toxicological studies that reported delays in pubertal onset in females
(Gollenberg et al.. 2010; Naicker et al.. 2010; Dumitrescu et al.. 2008a; Iavicoli et al.. 2006; Denliam et al.. 2005;
Selevanetal.. 2003; Wu et al.. 2003) and males (Williams et al.. 2010; Hauser et al.. 2008) were summarized in
the 2013 Pb ISA and several toxicological studies were summarized the 2006 Pb AQCD (Pine et al.. 2006;
Dearth et al.. 2004; Iavicoli et al.. 2004; Dearth et al.. 2002; Ronis et al.. 1998a. 1996). Some toxicological
studies from the 2006 Pb AQCD also reported delays in pubertal onset in males (Ronis et al.. 1998c; Sokol
et al.. 1985). While no recent PECOS-relevant toxicological studies that investigated the effects of Pb on
pubertal onset were available, several recent epidemiologic studies reported associations between Pb
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exposure and delayed onset of puberty in males (Williams et al.. 2019; Nkomo etal.. 2018; De Craemer et al..
2017) and females (Gomula et al.. 2022; Jansen etal.. 2018; Nkomo et al.. 2018; De Craemer et al.. 2017;
Slawiriska et al.. 2012). The proposed biologically plausible pathway through which Pb induces delays in
pubertal onset begins with the Pb-induced disruption of the gonadotropin-releasing hormone (GnRH)
levels which may occur through reduction of circulating IGF-1 levels. GnRH is a key hormone in the
hypothalamic-pituitary-gonadal axis and hormonal signaling pathways related to reproduction and
pubertal onset. A recent epidemiologic study found negative associations between BLLs at 8-9 years of
age and IGF-1 in boys two and four years later (Flcisch el al.. 2013) and toxicological studies have reported
reduced IGF-1 levels and IGF-1R expression in the brains of animals exposed to Pb (Li etal.. 2016; Li et
al.. 2014; Dearth et al.. 2002; Ronisetal.. 1998b). IGF-1 is known to act on GnRH neurons and affect GnRH
secretion (Dees etal.. 2021; Daftarv and Gore. 2005). which is responsible for the release of LH and FSH
from the anterior pituitary, resulting in stimulation of the gonads to begin producing sex steroid hormones
and mature oocytes and spermatozoa. One toxicological study conducted in female Fisher 344 rats found
that Pb-induced delays of pubertal onset could be reversed by supplementation with IGF-1 (Pine etal..
2006). This study reported that supplementation with IGF-1 also restored GnRH and LH levels in Pb-
exposed rats, demonstrating that IGF-1 disruption is a key component in delays in the onset of puberty
mediated by Pb at BLLs at/above 35 (ig/dL.
Pb has also been shown in some in vitro studies to directly alter steroidogenic enzyme expression
(e.g., steroidogenic acute regulatory protein, 3(3-hydroxysteroid dehydrogenase, and aromatase) and levels
of sex steroid hormones important for proper sexual maturation, including progesterone, E2, and
testosterone (Huang and Liu. 2004; Srivastava et al.. 2004; Taupeau et al.. 2003; Huang et al.. 2002; Thoreux-
Manlav etal.. 1995). Additionally, although not all studies report relationships between Pb and hormone
levels, some epidemiologic have reported associations, and some toxicological studies have demonstrated
effects, of Pb exposure on steroidogenic enzymes and sex steroid hormones (Pollack et al.. 2011; Tomoum
et al.. 2010; Dumitrescu et al.. 2008b; Nampoothiri and Gupta. 2008; Telisman et al.. 2007; Rubio et al.. 2006;
Sokoletal.. 1985). Pb-induced disruptions of the hypothalamic-pituitary-gonadal axis, steroidogenic
enzymes and their sex steroid products are plausible explanations for the observed delays in pubertal
onset reported in epidemiologic and toxicological studies.
8.7.2 Male Reproduction Function
The other health outcome proposed in Figure 8-1 is male reproductive function. Recent
epidemiologic studies have reported that Pb exposure is associated with reductions in a variety of semen
parameters, including sperm motility, sperm concentration, and normal sperm morphology (Shi etal..
2021; Sukhnetal.. 2018; Li etal.. 2015; Pant etal.. 2014). These findings are generally consistent with the
epidemiologic evidence presented in the 2013 Pb ISA (U.S. EPA. 2013). Further, toxicological studies
provide supporting evidence that Pb negatively impacts male reproductive function (see Section 8.6.1)
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(Aniiim cl al.. 2011; Sainathetal.. 2011). Figure 8-1 shows a plausible biological pathway through which Pb
may act to reduce reproductive function in males.
The 2013 Pb ISA concluded that the evidence indicates a causal relationship between Pb
exposure and reduced quality of sperm, and that this relationship was likely mediated through the
generation of reactive oxygen species, leading to cellular damage (U.S. EPA. 2013). Specifically, the 2013
Pb ISA summarized one study that reported Pb-induced increases in oxidative stress markers and
reductions in antioxidant enzyme levels in testicular plasma of rats (Salawu el al.. 2009). In addition,
several studies in the 2013 Pb ISA reported attenuation of Pb-induced reductions in sperm count, motility,
and viability when animals were co-administered substances with known antioxidant properties (Salawu et
al.. 2009; Shan et al.. 2009; Madhavi et al.. 2007; Rubio et al.. 2006; Wang et al.. 2006). Further supporting the
proposed pathway through which oxidative stress mediates Pb-induced effects are additional studies that
report that Pb exposure dysregulates antioxidant enzymes, leading to oxidative stress and DNA damage in
the affected tissues (Lopes etal.. 2016; Kagi and Vallee. 1960; Ommati et al.. In Press). Additionally, recent
studies that report an attenuation of Pb-induced effects on aspects of male reproductive function (e.g.,
subfecundity, reduced sperm count) in animals supplemented with antioxidants (Zhang etal.. 2021;
Abdelhamid et al.. 2020; Alotaibi et al.. 2020; Naderi et al.. 2020; Udefa et al.. 2020; Abdrabou et al.. 2019; Hassan
et al.. 2019; Ommati et al.. 2019; BaSalamah et al.. 2018; Hasanein et al.. 2018; Mabrouk. 2018; El Shafai et al..
2011; Leivaetal.. 2011; Sainathetal.. 2011; Ommati et al.. In Press). Although many studies report negative
effects of Pb on supporting somatic cells that have key functions in the spermatogenic cycle (e.g., Leydig
cells, Sertoli cells), Pb may also have negative effects directly on sperm cells. Direct contact of Pb with
sperm cells has been documented by multiple studies (Jiaetal.. 2022; Sukhnetal.. 2018; Pant etal.. 2014).
One recent study reported that incubating sperm from healthy adult men for 4 hours with 30 (ig/mL or
8 hours with either 15 or 30 (ig/mL Pb increased DNA fragmentation, possibly due to oxidative stress and
Pb binding to DNA phosphate residues, disrupting the process of chromatin condensation (Gomes etal..
2015). In another study, 4 hours of incubation of semen samples from healthy adult men with Pb reduced
intracellular levels of cyclic adenosine monophosphate (cAMP) (10, 50, and 100 (.iM) and Ca2+ (2.5, 10,
50, and 100 (iM), both of which are important in regulating sperm cell function (He etal.. 2016). In support
of this alternative mechanism of action is one study that reported an attenuation of Pb-induced effects on
reproduction in Pb-intoxicated male mice that were supplemented with CaCh (Golshan Iranpour and Kheiri.
2016). Disruption of intracellular levels of key components such as cAMP and Ca2+ is another way in
which Pb can directly affect sperm health and function outside of oxidative stress.
In summary, pathways are suggested by which Pb exposure can delay pubertal onset and reduce
sperm/semen production, quality, and function. Studies indicate that Pb exposure likely impacts the
hypothalamic-pituitary-gonadal axis in both males and females, leading to disruption of the onset of
puberty, a developmental period with increasing regard for its sensitivity to insult due to the vulnerability
of the various endocrinological events for which it is known. In addition, Pb exposure alters multiple
aspects of male reproductive function. The production of adequate quantities of viable sperm is essential
for proper male fertility and reproduction. Pb exposure hampers this by negatively impacting both the
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sperm cell and the supportive somatic cells that play key roles in the spermatogenic cycle through
increased oxidative stress and disruption of other important intracellular functions.
8.8 Summary and Causality Determination
The 2013 Pb ISA (U.S. EPA. 2013) made four causality determinations for Pb exposure and (1)
effects on pregnancy and birth outcomes; (2) effects on development; (3) effects on female reproductive
function; and (4) effects on male reproductive function. The 2013 Pb ISA concluded that the evidence is
"suggestive" of a causal relationship between Pb exposure and effects on birth outcomes; a causal
relationship between Pb exposure and effects on development, based on the findings of delayed pubertal
onset among males and females; suggestive of a causal relationship between Pb exposure and effects on
female reproductive function; and a causal relationship between Pb exposure and effects on male
reproductive function. The following sections detail the causality determinations based on the recent
epidemiologic and toxicological studies.
8.8.1 Summary of Effects on Pregnancy and Birth Outcomes
The 2013 Pb ISA concluded that based on the mix of inconsistent results of studies on various
birth outcomes and some associations observed in epidemiologic studies of preterm birth and low birth
weight/fetal growth, the evidence was suggestive of a causal relationship between Pb exposure and birth
outcomes. Some associations were observed between Pb and low birth weight in epidemiologic studies
that used postpartum maternal bone Pb or air Pb concentrations. Although associations were less
consistent for low birth weight with maternal blood Pb measured, during pregnancy or at delivery, or with
Pb measured in the umbilical cord and placenta (maternal blood Pb or umbilical cord and placenta Pb
were the biomarkers most commonly used in studies of low birth weight), some negative associations
between Pb biomarker levels and low birth weight or other measures of fetal growth were observed. The
effects of Pb exposure during gestation in animal toxicological studies included mixed findings, but most
studies reported reductions in birth weight of pups or birth weight of litters when dams were treated with
Pb. Thus, although evidence available was mixed, some associations observed in epidemiologic studies of
preterm birth and low birth weight or fetal growth provided suggestive evidence of a causal relationship
between Pb exposure and birth outcomes.
While there were no epidemiologic or toxicological studies examining Pb exposure and maternal
in the 2013 Pb ISA, recent epidemiologic and toxicological studies, reported inconsistent results
regarding maternal health outcomes and different maternal health outcomes were evaluated between the
epidemiologic and toxicological studies. Among the epidemiologic studies, there were consistent null
associations between maternal blood (blood, serum, and erythrocytes) and GDM, and with the reported
mean/median blood Pb below 10 (ig/dL. Although some recent epidemiological studies investigated
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various pregnancy-related endpoints, the small number limits the ability to judge coherence and
consistency across these studies. Among the few toxicological studies that investigated maternal health,
the only outcome reported was maternal weight gain during pregnancy. Most studies reported no effects
of Pb on maternal weight gain during pregnancy, and the few that reported reductions in maternal weight
gain also reported reductions in dam brain weight, a marker often indicative of overt toxicity. This
suggests that the observed reduction in maternal weight gain during pregnancy reported in these studies
may not be directly due to Pb exposure and may have been influenced by overt toxicity experienced by
the dams.
The recent epidemiologic and toxicological studies of birth outcomes reported inconsistent
findings overall. Among the recent epidemiologic studies of prenatal growth and Pb exposure, the
findings were inconsistent and no effects on birth weight were reported in the toxicological studies,
similar to the conclusion in the 2013 Pb ISA. The inconsistencies in the recent epidemiologic studies of
prenatal growth and Pb exposure may be due to differences in study design, the timing of the exposure,
differences in biomarkers of exposure, and the wide variation in prenatal growth outcomes assessed (birth
weight, birth length, HC, GA). A few studies were further limited by small sample size, which may cause
imprecision in the measures of association.
While a single recent toxicological study reported no effects of Pb exposure on gestation length,
there were inconsistent associations reported in the recent epidemiologic studies examining the
relationship between Pb exposure and risk of preterm birth, which was similar to the 2013 Pb ISA. While
the recent epidemiologic studies of preterm birth included populations for which mean/median maternal
blood Pb values were below 10 j^ig/dL and controlled for wide range of confounders, including GA, other
metals, and maternal health factors (e.g., smoking, parity, BMI), there were limitations among these
recent studies, including timing of the exposure (during pregnancy, at delivery), biomarkers examined for
Pb (maternal blood, cord blood, maternal red blood cells, maternal serum, placental tissue), small sample
sizes in some studies, and cross-sectional study design in some studies.
The recent epidemiologic studies of Pb exposure and birth defects, specifically NTDs, CHDs,
orofacial clefts defects and abdominal congenital malformations, reported inconsistent associations.
While the associations were generally null for Pb exposure (measured in placental tissue, umbilical tissue,
maternal blood serum, and umbilical cord serum) and NTDs, CHDs, and abdominal congenital
malformations, there were positive associations with orofacial cleft defects when Pb was measured in
placental tissue or maternal blood. The small number of studies limits the ability to judge consistency and
coherence across studies of different birth defects (e.g., NTDs, CHDs, orofacial clefts defects, and
abdominal congenital malformations), timing of Pb exposure (e.g., second trimester, third trimester, and
at delivery), differences in biomarkers (e.g., placental tissue, umbilical tissue, maternal blood serum, and
umbilical cord serum, maternal blood), and confounders considered in the analyses. Additionally, the
relatively small sample sizes in some studies reduce the statistical power to determine the precision of the
associations. Recent toxicological studies report no effects of Pb on birth defects in offspring. This
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contrasts with some previously reviewed studies that reported defects in offspring of Pb-exposed dams.
However, dams in these previous studies also experienced overt toxicity due to the high Pb doses used,
which did not occur in recent toxicological studies, suggesting that maternal toxicity may have been
involved with the birth defects observed in previous studies.
There were only a few recent epidemiologic studies that evaluated Pb exposure and spontaneous
abortion and pregnancy loss. Studies that examine spontaneous abortion are difficult to conduct as many
spontaneous abortions or pregnancy losses occur during the first trimester. Women may miscarry before
being enrolled in a study and/or women may not have known they were pregnant when they miscarried,
thus limiting the ability of a study to detect subtle effects, e.g., if higher Pb exposures lead to increased
risk of early spontaneous abortions. In the recent epidemiologic studies, some of the studies assessing
spontaneous abortion and/or pregnancy loss were among women who were undergoing treatment at
fertility clinics, which may result in selection bias and limited generalizability of the results because the
study populations are not representative of the general population. In the recent toxicological studies,
there were no reported effects of Pb exposure on pre- or postnatal offspring mortality. Although not
always consistently so, BLLs were generally lower in recent toxicological literature when compared to
previous literature, possibly explaining the observed contrast in results.
There were no epidemiological studies available that evaluated Pb concentrations and
associations with placental function in the 2013 Pb ISA. There were a limited number of recent
epidemiological studies in this area. These cross-sectional studies provide insight into associations
between concurrent Pb exposure and placental function, but are limited by their cross-sectional design,
making it difficult to establish the temporality of the effects or the critical window of exposure to Pb that
might result in changes in the placenta during pregnancy. Further, there were only a small number of
cases, which may result in imprecise associations. While previous toxicological decreased placental
weight and histological alterations, the findings were limited to a single study. Recent toxicological
studies reported that dams dosed with Pb had reduced placental weight, but some of these studies also
reported reduced brain weight in dams, suggesting that overt toxicity may have occurred and could be
related to the observed reductions in placental weight.
There were also a number of recent epidemiologic studies that evaluated other outcomes related
to maternal health during pregnancy such as biomarkers of fetal immune system, fetal marker for
metabolic function, and rTL, but the small number limits the ability to judge the coherence and
consistency across these studies. The only additional pregnancy outcome investigated in recent
toxicological literature was sex ratio of offspring born to Pb-treated dams. Although most toxicological
studies reported no effects of Pb on sex ratio, a single study reported that Pb produced female-skewed
litters when compared to control. It is worth noting, however, that the non-Pb-exposed groups were male-
skewed and had male:female offspring ratios of 1.4-1.5, whereas Pb-treated groups had male:female
ratios of 1 to 1.
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Overall, there were inconsistent findings reported among the recent epidemiologic and
toxicological studies on Pb exposure and pregnancy and birth outcomes (Table 8-1). The recent
epidemiologic studies reported consistent null associations with GDM, but among all other pregnancy and
birth outcomes (prenatal growth, preterm birth, birth defects, spontaneous abortion and pregnancy loss,
placental function, and other outcomes) there were inconsistent results. Additionally, recent
epidemiological studies were often limited by cross-sectional design, timing of the exposure, biomarkers
examined for Pb, and in some instances, small sample sizes. Of note, the cohorts in the recent
epidemiologic literature would generally be expected to have had appreciable past exposures to Pb;
however, the extent to which adult BLLs in these cohorts reflect the higher exposure histories is unknown
as to the extent to which these past Pb exposures (magnitude, duration, frequency) may or may not elicit
effects on pregnancy and birth outcomes. The recent evidence from the toxicological studies mostly
reported no effects of Pb across pregnancy and birth outcomes. This may be due to the exclusion of
toxicological studies with BLLs greater than 30 (ig/dL, indicating the possibility that most pregnancy and
birth outcomes are only affected in laboratory animals at levels higher than most environmentally relevant
Pb exposure levels. In summary, the collective evidence is suggestive of, but not sufficient to infer, a
causal relationship between Pb exposure and effects on pregnancy and birth outcomes.
8.8.2 Summary of Effects on Development
The 2013 ISA concluded that the collective body of evidence integrated across epidemiologic and
toxicological studies, based on the findings of delayed pubertal onset among males and females, was
sufficient to conclude that there is a causal relationship between Pb exposure and developmental effects.
Multiple epidemiologic studies of Pb and puberty in the 2013 Pb ISA showed associations between
concurrent BLLs and delayed pubertal onset for girls and boys. In cross-sectional epidemiologic studies
of girls (ages 6-18 years) with mean and/or median concurrent BLLs from 1.2 to 9.5 (ig/dL, consistent
associations with delayed pubertal onset (measured by age at menarche, pubic hair development, and
breast development) were observed. In boys (ages 8-15 years), fewer epidemiologic studies were
conducted but associations between BLLs and delayed puberty were observed, including associations
among boys in a longitudinal study. These associations were consistently observed in populations with
mean or median BLLs of 3.0 to 9.5 (ig/dL. Potential confounders considered in the epidemiologic studies
of both boys and girls that performed regression analyses varied. Most studies controlled for age and
BMI. Other variables, such as measures of diet, socioeconomic status (SES), and race/ethnicity, were
included in some of the studies. Adjustment for nutritional factors was done less often and this could be
an important confounder. A study using a cohort of girls from NHANES controlled for various dietary
factors as well as other potential confounders and reported an association between increased concurrent
BLLs and delayed pubertal onset (Sclcvan el al.. 2003). A limitation across most of the epidemiologic
studies of BLLs and delayed puberty was the cross-sectional design, which does not allow for an
understanding of temporality. There was uncertainty with regard to the exposure frequency, timing,
duration, and level that contributed to the associations observed in these studies. Additionally, the
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toxicological studies reviewed in the 2013 Pb ISA indicated that delayed pubertal onset may be one of the
more sensitive developmental effects of Pb exposure with effects observed after gestational exposures
leading to BLLs in the female pup of 1.3-13 (ig/dL (lavicoli et al.. 2006; Iavicoli et al.. 2004). An additional
study reviewed in the 2013 Pb ISA reported increases in age at vaginal opening in Wistar rats that were
dosed prior to conception and in utero, but BLLs were not reported (Dumitrcscu et al.. 2008a'). These results
are supported by studies reviewed in the 2006 Pb AQCD that reported delays in pubertal onset in female
rats and mice as measured by age at vaginal opening and age at first estrus (Pine et al.. 2006; Dearth el al..
2004; Dearth et al.. 2002; Ronis etal.. 1998a; Ronis etal.. 1998c; Ronisetal.. 1996). BLL varied greatly
between studies with some reporting effects occurring in dose groups with levels below 30 (ig/dL (Dearth
etal.. 2004; Dearth etal.. 2002) while others only report effects in groups with BLLs higher than 30 (ig/dL
(Ronis et al.. 1998a; Ronis et al.. 1998c; Ronisetal.. 1996). A key study reviewed in the 2006 Pb AQCD, Pine
etal. (2006) reported increased age at vaginal opening in Fisher 344 rats that was attenuated by
supplementation of IGF-1. However, Pine et al. (2006) only reported BLLs of dams, making it difficult to
determine what BLLs in the offspring may have been achieved to elicit such effects on puberty.
Toxicological studies have also reported delayed male sexual maturity as measured by sex organ weight,
among other outcomes, seeing significant decrements at BLLs of 20-34 (ig/dL (Ronis etal.. 1998c; Sokolet
al.. 1985). Thus, the 2013 Pb ISA concluded that the data from the toxicological literature and from
epidemiologic studies demonstrated puberty onset in both males and females was delayed with Pb
exposure.
In the 2013 Pb ISA, findings from epidemiologic studies of the effect of Pb on postnatal growth
were inconsistent. Findings from the toxicological literature of the effect of Pb exposure on postnatal
growth summarized in the 2013 Pb ISA and the 2006 Pb AQCD were fairly consistent, and most studies
showed decreases in body weight of Pb-exposed offspring at postnatal time points, while one study
reported an increase in body weight at one year of age in male offspring only.
The 2013 Pb ISA summarized some toxicological evidence that demonstrated the effect of Pb on
other developmental outcomes, including impairment of retinal development, effects on the lens of the
eye, and alterations in the developing hematopoietic, hepatic systems and teeth. No studies that
investigated more classic toxicological developmental milestones (e.g., eye slit formation, eye opening,
pinna detachment) were reported in the 2013 Pb ISA.
In the recent epidemiologic and toxicological literature, the relationship between Pb exposure and
puberty onset in both females and males, as well as postnatal growth, was reviewed. While there were no
recent PECOS-relevant toxicological studies in puberty in either females or males, the recent
epidemiologic studies reported consistent pattern of associations between blood Pb exposure and delayed
age of menarche (Gomula et al.. 2022; Jansen etal.. 2018; De Craemer et al.. 2017; Slawinska et al.. 2012). and
some indication of slower breast development (Nkomo etal.. 2018; De Craemer et al.. 2017) in females,
which is similar to the findings from the epidemiologic studies reviewed in the 2013 Pb ISA. However,
the associations between Pb exposure and male pubertal onset were inconsistent. The differences in
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markers of puberty in males (hormone levels, pubic hair development, genital development, TV) may
explain the inconsistencies in findings across recent studies. While the studies assessing Pb exposure and
female and male puberty were limited by differences in the timing of exposure to Pb or Pb biomarker
(blood, maternal bone, cord blood), these studies consider a wide range of confounders, including height,
weight, and BMI.
The recent toxicological and epidemiologic studies that evaluated the relationship between Pb
exposure and postnatal growth were inconsistent. The majority of recent toxicological studies did not
report changes in postnatal growth due to Pb exposure (Zhao et al.. 2021; Xie et al.. 2020; Rao Barkur and
Bairv. 2016; Basha and Reddv. 2015; Basgen and Sobin. 2014). However, some recent toxicological studies
reported decreases (Duan el al.. 2017; de Figueiredo et al.. 2014; Graham etal.. 2011) and increases (Bctharia
andMaher. 2012) in body weight of offspring due to Pb exposure. The recent epidemiologic studies also
reported inconsistent findings overall. However, among epidemiologic studies that evaluated the
associations between blood Pb and postnatal growth in children (older than four years) there were more
consistent patterns of associations of decreased height and weight (Signes-Pastor et al.. 2021; Kuang et al..
2020; Zhou et al.. 2020; Deierlein et al.. 2019; Kerr etal.. 2019; Choi et al.. 2017). The inconsistencies in the
associations in the epidemiologic literature seem to be due to different timings of exposure, different
biomarkers (maternal blood, maternal bone, cord blood, infant blood, childhood blood), and difference
timing of outcome measurement. The current inconsistent findings of exposure to Pb and postnatal
growth are similar to those reported in the 2013 Pb ISA.
There was a small body of epidemiologic studies across various other developmental effects;
however, the small number of studies limits the ability to judge coherence and consistency across these
studies, although the associations reported demonstrate that Pb exposure could result in physiological
responses that contribute to adverse developmental effects, including changes to diurnal Cortisol rhythms,
lower salivary sialic acid levels, and DNA oxidative stress damage from Pb exposure among children
during developmental periods. However, the small number of studies limits the ability to judge coherence
and consistency across the outcomes evaluated in these studies. Recent studies that investigate other
developmental outcomes such as developmental milestones are scarce. Some toxicological studies
investigated developmental milestones in rodents (pinna detachment, eye slit formation, eye opening,
tooth eruption, and fur development). No effects of Pb exposure were reported on any of these milestones
in groups with PECOS-relevant BLLs.
In summary, there is consistent evidence across the recent epidemiological studies that reported
delayed age of menarche with blood Pb and this is supported by findings from previous toxicological and
epidemiologic evidence (Table 8-1). However, there were inconsistent findings in the toxicological and
epidemiologic studies that evaluated the relationship between Pb exposure and postnatal growth. There
was some indication of reduced body weight in the toxicological studies, however, and decreased height
and weight in children in the epidemiological studies of blood Pb. The cohorts in the recent epidemiologic
literature would generally be expected to have had appreciable past exposures to Pb; however, the extent
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to which adult BLLs in these cohorts reflect the higher exposure histories is unknown as to the extent to
which these past Pb exposures (magnitude, duration, frequency) may or may not elicit developmental
effects, such as postnatal growth or puberty. Despite uncertainty due to inconsistent findings across the
recent epidemiologic studies, some toxicological evidence exists that supports biologically plausible
pathways of how Pb exposure exerts its effects on pubertal onset (Li etal.. 2016; Lietal.. 2014; Pine et al..
2006; Dearth et al.. 2002; Ronis etal.. 1998b). In summary, toxicological studies suggest that Pb may impact
pubertal onset via dysregulation of IGF-1, resulting in a cascade of effects that alters levels of hormones
important during the pubertal period. Further, epidemiologic and toxicological studies both suggest that
Pb may impact sperm and semen quality primarily through oxidative stress. In summary, toxicological
studies suggest that Pb may impact pubertal onset via dysregulation of IGF-1, resulting in a cascade of
effects that alters the levels of hormones important during the pubertal period. Further, epidemiologic and
toxicological studies both suggest that Pb may impact sperm and semen quality primarily through
oxidative stress. Overall, the collective evidence is sufficient to conclude a causal relationship
between Pb exposure and effects on development.
8.8.3 Summary of Effects on Female Reproductive Function
The 2013 ISA concluded that the relationship observed with female reproductive function, such
as fertility and hormone levels in some epidemiologic and toxicological studies is sufficient to conclude
that evidence is suggestive of a causal relationship between Pb exposure and female reproductive
function. Epidemiologic and toxicological studies of reproductive function among females investigated
whether Pb biomarker levels were associated with hormone levels, fertility, estrous cycle changes, and
morphology or histology of female reproductive organs. Some of the epidemiologic studies reviewed in
the 2013 Pb ISA reported associations with concurrent BLLs and altered hormone levels in adults, but
results varied among studies, possibly due to the different hormones examined and the different timing in
menstrual and life cycles. There was some evidence of a potential relationship between Pb exposure and
female fertility, but findings were mixed. The majority of the epidemiologic studies were cross-sectional
and adjustment for potential confounders varied from study to study, with some potentially important
confounders, such as BMI, not included in all studies. Further, most of the epidemiologic studies on
female reproductive function reviewed in the 2013 Pb ISA had small sample sizes and were generally
conducted in women attending infertility clinics. Toxicological study design often employed prenatal or
early postnatal Pb exposures at relevant Pb levels, with Pb contributing to decreased ovarian antioxidant
capacity, altered ovarian steroidogenesis, and aberrant gestational hormone levels (U.S. EPA. 2013).
Although epidemiologic and toxicological studies provide information on different exposure periods, both
types of studies, including some high-quality epidemiologic and toxicological studies, support the
conclusion that Pb may affect some aspects of female reproductive function.
There were no recent PECOS-relevant toxicological studies of the effects of Pb exposure on
hormone levels in females or menstrual/estrous cyclicity; however, there were several recent
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epidemiologic studies. The recent epidemiological studies examining the relationship between Pb
exposure and hormone levels reported consistent positive associations between blood Pb and FSH and LH
in women who were post-menopausal. While these studies were limited by their cross-sectional study
design, the studies were conducted in well-established population-based surveys. These studies
considered a range of confounders, including controlling for BMI, smoking, and co-exposure with Cd, but
not all studies adjusted for some potential important confounders such as age at menarche, pregnancy
history, oral contraceptive use, and female hormone use, such as IVF or hormone therapy. Additionally,
the recent studies examining the relationship between menopause and Pb exposure found consistent
positive associations of early risk of menopause. The results from a study of concurrent exposure of blood
Pb with menopause were supported by the results from a longitudinal cohort that reported that bone Pb, a
cumulative biomarker of Pb exposure, was associated with difference in age at menopause and risk of
early menopause.
Among the recent epidemiologic studies, there were inconsistent associations between Pb
exposure and female fertility. In studies among participants in the general population, there was an
increased risk of self-reported infertility and longer time to pregnancy (Lee et al.. 2020; Louis etal.. 2012).
However, among studies with women who were either seeking help at a fertility clinic or reported
infertility, the associations were inconsistent. Because the study participants included only a small sample
of women who were either seeking help at a fertility clinic or self-reported infertility, selection bias may
exist and limits the generalizability of the results. Additionally, these studies were limited by the
concurrently measured exposure and outcome, different biomarkers of exposure (blood, serum, and
follicular fluid), and a small number of participants. These studies did include adjustment for potential
confounders, including age, BMI, and partner exposure. The recent toxicological studies in female
fertility did not observe alterations in the number of litters or the litter size in Pb-exposed dams that began
dosing prior to conception.
There was only a single recent epidemiologic study evaluating the association between Pb
exposure and morphology or histology of female sex organs (ovaries, uterus, fallopian tubes/oviducts,
cervix, vagina, and/or mammary glands) and no recent PECOS-relevant toxicological studies. The results
from the single epidemiologic study reported null associations between blood Pb and rate of uterine
fibroids and uterine fibroid volume, but women with uterine fibroids had higher geometric mean BLLs
than women without fibroids (1.43 (ig/dL versus 1.35 (ig/dL, respectively).
In summary, there was inconsistent evidence from recent epidemiologic and toxicological studies
of Pb exposure and female reproductive function overall (Table 8-1). The recent epidemiologic studies
reported consistent positive associations between blood Pb and FSH and LH in women who were post-
menopausal and positive associations of early risk of menopause with blood Pb. While these studies were
limited by their cross-sectional study design, the studies considered a range of confounders, including
controlling for BMI, smoking, and co-exposure with Cd, but not all studies adjusted for some potential
important confounders such as age at menarche, pregnancy history, oral contraceptive use, and female
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hormone use, such as IVF or hormone therapy. The evidence from the recent toxicological studies did not
observe alterations to female fertility, while the recent epidemiologic studies reported inconsistent
findings with Pb exposure and female fertility. The inconsistencies in the epidemiologic studies may be
the result of concurrently measured exposure and outcome, different biomarkers of exposure (blood,
serum, and follicular fluid), exposure circumstances (magnitude, duration, timing, and frequency), and a
small number of participants who were either seeking help at a fertility clinic or self-reported infertility,
which may have resulted in selection bias and limits the generalizability of the results. Overall, the
collective evidence is suggestive of, but not sufficient to infer, a causal relationship between Pb
exposure and female reproductive function.
8.8.4 Summary of Effects on Male Reproductive Function
The 2013 ISA concluded that based on the consistency and coherence of findings for the
detrimental effects of Pb exposure on aspects of sperm and semen quality in the toxicological literature,
with support from epidemiologic studies, and biologically plausible pathways, there was sufficient of a
causal relationship between Pb exposures and male reproductive function. Toxicological studies with
relevant Pb exposure routes reported effects on rodent sperm quality and sperm production rate (BLL
range: 34-37 (ig/dL) (Sokol and Berinan. 1991; Sokoletal.. 1985). sperm DNA damage with BLL of 19 and
22 (ig/dL (Nava-Hcrnandc/ et al.. 2009). and histological or ultrastructural damage to the male reproductive
organs in studies from rodents at BLL of 5.1 (ig/dL (El Shafaietal.. 2011) and non-human primates (BLL
of 43 (ig/dL) (Cullcn el al.. 1993). These effects were found in animals exposed to Pb during peripuberty or
adulthood for 1 week to 3 months. The toxicological studies reported that Pb exposure decreased
reproductive organ weight and caused histological changes in the testes and germ cells. Subfecundity
(decreased number of pups born/litter) was reported in unexposed females mated to Pb-exposed males.
Also, sperm from Pb-exposed rats (BLLs: 33 to 46 (ig/dL) used for in vitro fertilization of eggs harvested
from unexposed females yielded lower rates of fertilization (Sokoletal.. 1994). Supporting evidence was
provided by decrements in sperm quality from rabbits administered Pb subcutaneously (BLLs of
25 (ig/dL) (Moorman etal.. 1998).
The 2013 Pb ISA reported detrimental effects of Pb on sperm observed in epidemiologic studies
with concurrent BLLs of 25 (ig/dL and greater among men occupationally exposed (Hsu et al.. 2009;
Kasperczvk et al.. 2008; Naha and Manna. 2007; Naha and Chowdhurv. 2006). Findings of these epidemiologic
studies are limited due to these high exposure levels among the occupational cohorts and the lack of
consideration for potential confounding factors, including occupational exposures other than Pb. Studies
among men with lower Pb levels were limited to infertility clinic studies, which may produce a biased
sample and findings that lack generalizability. However, a well-conducted epidemiologic study that
enrolled men going to a clinic for either infertility issues or to make a semen donation and controlled for
other metals, as well as smoking, reported a positive association of blood Pb with various detrimental
effects in sperm (Telisman et al.. 2007). The median concurrent BLL in this study was 4.92 (ig/dL (range:
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1.13-14.91). A similar study also reported possible associations between concurrent blood Pb and various
semen parameters, but the results were extremely imprecise (large confidence intervals [CIs]), making it
difficult to draw conclusions (Meeker el al.. 2008).
The epidemiologic and toxicological studies in the 2013 Pb ISA reported inconsistent results
regarding hormone aberrations associated with Pb exposure. Due to the complexity of the reproductive
system, uncertainty exists as to whether Pb exerts its toxic effects on the reproductive system by affecting
the responsiveness of the hypothalamic-pituitary-gonadal axis by suppressing circulating hormone levels
or by some other pathway. Inconsistent findings were also apparent among epidemiologic studies of
fertility among men.
Toxicological studies from the 2013 Pb ISA suggested that oxidative stress was a major
contributor to the effects of Pb exposure on the male reproductive system, providing mode of action
support. The effects of reactive oxygen species (ROS) may involve interference with cellular defense
systems leading to increased lipid peroxidation and free radical attack on lipids, proteins, and DNA.
Several studies showed that Pb induced an increased generation of ROS within the male sex organs and
germ cell injury, as evidenced by aberrant germ cell structure and function. Co-administration of Pb with
various antioxidant compounds either eliminated Pb-induced injury or greatly attenuated its effects. In
addition, many studies that observed increased oxidative stress also observed increased apoptosis, which
is likely a critical underlying mechanism in Pb-induced germ cell dysfunction.
Recent epidemiologic and toxicological studies examined Pb exposure and male reproductive
function, including sperm/semen production, quality, and function; hormone levels; fertility; and
morphology and histology of male sex organs. Among the studies that evaluated the relationship of Pb
exposure and sperm/semen production and quality, there was consistent evidence of effects when the
exposure metric was blood Pb. In the recent epidemiologic studies, there were consistent associations of
decreased sperm/semen production and quality with increased blood Pb, but there were inconsistent
associations when Pb was measured in seminal fluid or seminal plasma. The majority of the
epidemiologic studies that evaluated the associations of Pb and sperm/semen production and quality were
cross-sectional studies conducted in males attending fertility clinics, limiting the generalizability of the
results. The studies were further limited by concurrent measurement of exposure and outcome, different
biomarkers of Pb, different seminal parameters, exposure circumstances (historical exposure, magnitude,
duration, timing, and frequency), and small sample sizes. Despite these limitations, it is important to note
that a wide variety of potential confounders were considered, including controlling for hormone levels.
The recent toxicological studies support the findings from the epidemiologic studies. Among the recent
toxicological studies, the majority reported that Pb exposure negatively impacted sperm/semen production
and quality, although these studies were limited to a single species, and no recent toxicological studies
reported on the effects of Pb on sperm or semen parameters in any other laboratory animal species.
There were a limited number of recent epidemiologic and toxicological studies that examined the
relationship between Pb and hormones in males. While recent epidemiologic and toxicological studies
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reported changes in hormone levels among males, the direction of the observed relationships differed
across disciplines. Specifically, the epidemiologic studies reported Pb-associated increases in
testosterone, whereas the toxicological studies reported a reduction in testosterone following exposure to
Pb. Additionally, recent cross-sectional epidemiologic studies reported inconsistent associations between
blood Pb and other sex hormones. One study reported positive associations between blood Pb and SHBG,
FSH, and LH, as well as positive trends among quartiles of blood Pb, suggestive of a potential exposure-
response relationship. In contrast, an NHANES study reported null associations between blood Pb and
E2, fE2, androstenedione glucuronide, and SHBG. Recent toxicological evidence regarding the effects of
Pb on male sex hormones is limited to a single study that reported that exposure through the dam's milk
from birth to weaning (PND 21) in CD-I mice was sufficient to reduce testosterone in the serum at
weaning and on PND 70.
The recent epidemiologic and toxicological studies of Pb exposure and male fertility were
limited. In the recent epidemiologic studies, male fertility was measured by IVF outcomes. There were
inconsistent associations with Pb exposure and male fertility, with one study reporting blood Pb was
associated with longer time to pregnancy, but another reported a positive association between Pb in
seminal plasma and the possibility of obtaining a viable embryo. Differences in Pb biomarkers and
difference in outcomes might explain the inconsistencies of the associations among these studies. The
males in these studies were also recruited from fertility clinics, which might have resulted in selection
bias and limits the generalizability of the results. A single recent toxicological study reported that sperm
from Pb-exposed mice had reduced fertilization capacity, resulting in fewer fertilized oocytes in vitro.
There were a limited number of studies of Pb exposure and morphology or histology of male sex
organs. There was only a single recent epidemiologic study that reported decreased TV, shorter anopenile
distance, and shorter anoscrotal distance with maternal serum Pb exposure. Among the recent
toxicological studies, Pb exposure resulted in effects in the morphology or histology of male sex organs.
Alterations in testis weight were inconsistent with some studies reporting Pb-induced decreases in testis
weight and some reporting that testis weight was unaffected by Pb treatment. However, of the studies that
reported on this outcome, only those that dosed prior to weaning reported that Pb treatment reduced testis
weight, suggesting that this outcome may be more sensitive to developmental exposures. Few studies
investigated the effects of Pb on accessory sex organ weight in males, and of the few studies available, no
effects of Pb were reported on weight of the prostate, seminal vesicles, or epididymides. Testicular
histopathology was consistently altered by Pb exposure, often resulting in visible changes to the
seminiferous tubules and surrounding tissue. Toxicological studies also reported Pb-induced changes in
cellular structures in the epididymides.
In summary, there is coherent evidence across the epidemiologic and toxicological studies of
detrimental effects of Pb exposure on male reproductive function (Table 8-1). While recent epidemiologic
and toxicological studies suggest that Pb exposure may result in alterations in testosterone levels, fertility,
and changes in morphology or histology of male sex organs, the strongest evidence of effects of Pb on
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male reproductive function is seen in consistency of the reported effects of Pb on sperm and semen
parameters. Epidemiologic studies consistently report associations with Pb measured in blood and
decreased sperm/semen production and quality, and toxicological studies consistently report Pb-induced
reductions of a variety of semen parameters such as sperm density, motility, viability, and normal sperm
morphology. There are biological plausible pathways through which Pb exposure may alter sperm/semen
production and quality. Specifically, Pb exposure has been shown to cause oxidative stress, which can
damage the supportive somatic cells in the testis (Leydig cells and Sertoli cells) as well as damage the
sperm cells directly. Supportive somatic cells are responsible for regulating producing sex steroid
hormones and regulating spermatogenesis, and disruption of either of these functions can impact the
quality and quantity of the sperm produced. Overall, the collective evidence is sufficient to conclude a
causal relationship between Pb exposure and male reproductive function.
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Table 8-1 Summary of evidence contributing to causality determinations for Pb exposure and reproductive
and developmental effects.
Rationale for Causality
Determination3
Key Evidence13
Key References'3
Pb Biomarker Levels Associated with
Effects0
Effects on Pregnancy and Birth Outcomes - Suggestive
A few high-quality
epidemiologic studies show
associations with relevant
BLLs but findings are
overall inconsistent.
Inconsistent findings for studies for maternal health
outcomes, prenatal growth, birth defects, preterm
birth, spontaneous abortion and pregnancy loss, and
placental function. There is uncertainty related to
exposure patterns resulting in likely higher past Pb
exposure, especially among maternal Pb levels.
Additional uncertainties regarding biomarker of
exposure (maternal blood, maternal serum, maternal
bone, maternal erythrocytes, cord blood, cord blood
serum, placental tissue) and the critical window of
exposure.
See Section 8.3
Maternal BLLs: 0.32-6.7 pg/dL
Cord blood Pb: 0.37-10.78 pg/dL
Inconsistent toxicological
evidence
Previous studies report reduced birth weight, but
recent studies report few impacts of Pb on birth
weight, abortion, still birth, maternal weight gain, birth
defects, or placental weight and histology.
See Section 8.3
Placental weight altered at BLLs as low
as 12.42 pg/dL
Effects on Development - Causal
Delay Puberty Onset
Consistent associations
with relevant BLLs in high-
quality epidemiologic
studies
Consistent evidence in multiple cross-sectional and See Section 8.4.2.1
longitudinal epidemiologic studies for females and Section 8.4.3.1
males. Most of these studies have large sample sizes
and controlled for potential confounding by covariates
such as age and BMI.
and Female Puberty
BLLs: 0.65-6.57 pg/dL
Male Puberty
BLLs: 0.66-6.5
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Rationale for Causality
Determination3
Key Evidence13
Key References'3
Pb Biomarker Levels Associated with
Effects0
Consistent toxicological
evidence with relevant Pb
exposures
Consistent toxicological evidence from multiple
laboratories of delayed male and female puberty
onset with Pb exposure via diet, drinking water, or
oral gavage in rodents
Pine et al. (2006)
Iavicoli et al. (2006)
Dumitrescu et al. (2008a)
Ronis et al. (1998a)
Ronis et al. (19980)
Dearth et al. (2002)
Dearth et al. (2004)
Ronis et al. (1996)
Iavicoli et al. (2004)
Sokol et al. (1985)
Markers of pubertal onset reduced in
animals with BLLs as low as 12.7 [jg/dL
Evidence clearly describes
biological plausibility
Toxicological evidence supports hypothalamic-
pituitary-gonadal axis dysfunction and changes in
IGF-1 contributing to Pb-induced delay in puberty
onset.
Pine et al. (2006)
Dearth et al. (2002)
Pine et al. (2006)
reported dam BLLs to be 39.8 [jg/dL at
the time of matinq: Dearth et al. (2002)
reported dam BLLs to be 25.4 [jg/dL at
weaning
Postnatal Growth
Available epidemiologic
evidence is inconsistent
Multiple studies, mostly cross-sectional, for children
of varying ages have reported inconsistent results for
the association between BLLs and various measures
of growth. There is uncertainty related to exposure
patterns resulting in likely higher past Pb exposure,
especially among maternal Pb levels. Additional
uncertainties regarding biomarkers of exposure
(maternal blood, maternal serum, maternal bone,
maternal erythrocytes, cord blood, cord blood serum,
placental tissue) and the critical window of exposure.
See Section 8.4.1.1
Maternal BLLs: 0.5-10.1 pg/dL
Cord blood Pb: 0.91-3.1 pg/dL
Available toxicological
evidence is inconsistent
There are inconsistent findings in the toxicological
literature on Pb exposure and postnatal growth.
See Section 8.4.1.2
BLLs ranged from 0.0318-29.16 pg/dL
Effects on Female Reproductive Function - Suggestive
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Rationale for Causality
Determination3
Key Evidence13
Key References'3
Pb Biomarker Levels Associated with
Effects0
A few high-quality
epidemiologic studies of Pb
levels and hormones
demonstrate associations
Evidence in some high-quality cross-sectional
epidemiologic studies demonstrates associations with
hormone levels but results are mixed based on the
hormone examined. There is uncertainty related to
exposure patterns resulting in likely higher past Pb
exposure.
Krieg and Feng (20111
Chenetal. (20161
Lee et al. (20191
BLLs: 1.6-4.1 pg/dL
A few high-quality Evidence in some high-quality epidemiologic studies Mendola et al. (20131 BLLs: 1.21-3.0 pg/dL
epidemiologic studies of Pb demonstrates associations with menopause. There is gum ^ (2014)
levels and menopause uncertainty related to exposure patterns resulting in
demonstrate associations likely higher past Pb exposure.
Lack of large, well-
conducted epidemiologic
studies examining
associations between Pb
levels and fertility, but
overall inconsistent
evidence
Epidemiologic studies of this association are limited
by the small sample sizes included in those studies.
In addition, most of the study populations were drawn
from women undergoing IVF and/or attending
infertility clinics. There is uncertainty related to
exposure patterns resulting in likely higher past Pb
exposure.
See Section 8.5.2.1
BLLs: 0.50-2.13 pg/dL
Available toxicological
evidence is inconsistent.
Recent toxicological evidence is scarce and reports
no effects of Pb on litter size and number of litters.
Previous evidence reports inflammation, decreased
ovarian antioxidant capacity, altered ovarian
steroidogenesis.
See Section 8.5
See Section 4.8.4 from U.S.
EPA (20131
BLLs ranged from 7.72-12.61 pg/dL in
dams in recent literature
Effects on Male Reproductive Function - Causal
Sperm/Semen Production, Quality, and Function
Available epidemiologic The few epidemiologic studies examining this See Section 8.6.1.1 BLLs: 2.18-3.26 pg/dL
evidence is inconsistent outcome generally have small samples sizes and are
drawn from men attending infertility clinics. There is
uncertainty related to exposure patterns resulting in
likely higher past Pb exposure and biomarker of
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Rationale for Causality
Determination3
Key Evidence13
Key References'3
Pb Biomarker Levels Associated with
Effects0
exposure (blood, semen, seminal plasma, seminal
fluid).
Available toxicological
evidence consistently
reports alterations of sperm
and semen parameters
Consistent reductions of sperm with normal
morphology, sperm density, and sperm viability.
See Section 8.6.1
BLLs ranged from 5.09-11.8 pg/dL at
time of outcome assessment
Hormone Levels
A few high-quality
epidemiologic studies of Pb
levels and hormones
demonstrate associations
Evidence in some high-quality cross-sectional
epidemiologic studies demonstrates associations with
testosterone levels and adult males, but inconsistent
associations with other hormones. A longitudinal
study among male adolescents reported null
associations with hormone levels.
See Section 8.6.2.1
Concurrent BLLs: 1.0-4.4 [jg/dL
Available toxicological
evidence is inconsistent
Evidence for testosterone is inconsistent across
studies and few studies are available for other male
sex hormones.
See Section 8.6.2
See Section 4.8.3.2 from U.S.
EPA (2013)
Recent study reported effects at BLLs of
5.09 and 19.1 pg/dLattime of outcome
assessment
Fertility
Lack of large, well-
conducted epidemiologic
studies but overall
inconsistent evidence
The few epidemiologic studies examining this
outcome generally have small samples sizes and are
drawn from men attending infertility clinics. There is
uncertainty related to exposure patterns resulting in
likely higher past Pb exposure and biomarker of
exposure (blood, semen).
See Section 8.6.3.1
BLLs: 1.03-1.27 pg/dL
Limited toxicological
evidence
Few toxicological studies investigate male fertility, but
most report reductions in fertility outcomes such as
fertilized oocytes in recent literature and number of
offspring per litter in previous studies
See Section 8.6.3
See Section 4.8.3.3 from U.S.
EPA (2013)
Recent study reported effects at BLLs of
9.4 [jg/dL
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Rationale for Causality
Determination3
Key Evidence13
Key References'3
Pb Biomarker Levels Associated with
Effects0
BLL = blood lead level; BMI = body mass index; BW = birth weight; IGF-1 = insulin-like growth factor 1; IVF = in vitro fertilization; Pb = lead.
aBased on aspects considered in judgments of causality and weight of evidence in causal framework in Table I and Table II of the Preamble to the ISAs (U.S. EPA. 2015).
bDescribes the key evidence and references, supporting or contradicting, contributing most heavily to causality determination and, where applicable, to uncertainties or
inconsistencies. References to earlier sections indicate where the full body of evidence is described.
°Describes the Pb biomarker levels at which the evidence is substantiated.
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8.9
Evidence Inventories - Data Tables to Summarize Study Details
Table 8-2 Epidemiologic studies of exposure to Pb and maternal health outcomes.
Reference and
Study Design
Study Population
Exposure Assessment Outcome
Confounders
Effect Estimates and 95%
Clsa
Gestational Diabetes Mellitus
Shapiro et al. (20151
Canada
2008-2011
Cohort
MIREC
n: 1274
Women at least
18 years of age during
the first trimester of
pregnancy (6 to
<14 weeks gestation)
Blood
Maternal blood was
measured by ICP-MS
Age at Measurement:
Maternal age during first
with singleton, live births trimester of pregnancy
Geometric mean:
Normal glucose: 0.6 [jg/dL
IGT cases: 0.6 [jg/dL GDM
cases: 0.6 [jg/dL
Quartiles (|jg/dL):
Q1
Q2
Q3
Q4
0.2-0.4
0.5-0.6
0.6-0.9
0.9—4.1
Maternal health during
pregnancy: GDM
IGT and GDM were
assessed by chart review
based on the results of a
50-g glucose challenge test
and 75 or 100-g oral
glucose tolerance test
(OGTT)
Age at outcome:
Maternal age at IGT or
GDM diagnosis during
pregnancy
Logistic regression models OR (95% CI):
were adjusted for maternal GDM vs norma| g|UCOse
age, race, pre-pregnancy
BMI, and education
Q1
Q2
Q3
Q4
Reference
0.8 (0.3, 1.9)
0.6 (0.2, 1.6)
1.1 (0.5, 2.6)
p for trend: 0.87
IGT vs. normal glucose
Q1
Q2
Q3
Q4
Reference
0.8 (0.4, 1.8)
0.6 (0.2, 1.3)
0.9 (0.4, 2.1)
p for trend: 0.62
GDM or IGT vs. normal
glucose
Q1
Q2
Q3
Q4
Reference
0.8 (0.4, 1.5)
0.6 (0.3, 1.1)
1.0 (0.6, 1.8)
p for trend: 0.76
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Soomro et al. (20191
Poitiers and Nancy
France
February 2003 to
January 2006
Cross-sectional
Etude des Determinants
pre et post natals du
developpement de la
sante de I'Enfant study
n: 623
Pregnant women
between 24 and
28 weeks of gestation
Blood
Maternal blood measured
by EAAS with Zeeman
background correction
Age at Measurement:
Maternal age at 24-
28 weeks gestation
Geometric mean0:
1.62 [jg/dL
Median0: 1.7 |jg/dL
75th°: 2.2 pg/dL
95thc: 3.8 pg/dL
Maxc: 8.0 pg/dL
Maternal health during
pregnancy: GDM
At 24-28 weeks, maternal
blood glucose
concentrations were
measured 1 hr after a 50 g
glucose challenge. The
GDM was diagnosed by
using the OGTT when there
were >2 blood glucose
concentrations greater than
the following cut points:
fasting = 95 mg/dL, at
1 hr = 180 mg/dL, at
2 hr= 155 mg/dL, and at
3 hr = 140 mg/dL
Age at outcome:
Maternal age at 24-
28 weeks gestation
Multiple logistic regression
models were adjusted for
maternal smoking,
maternal age, maternal
BMI, maternal education
level, pregnancy-induced
hypertension, and number
of siblings
OR (95% CI):
GDM vs. normal glucose:
1.318 (0.895, 1.94)
IGT vs. normal glucose:
0.853 (0.676, 1.077)
GDM or IGT vs. normal
glucose: 0.86 (0.682, 1.084)
Qguri etal. (20191
Japan
January 2011 to
March 2014
Cross-sectional
Japan Environment and
Children's Study
n: 16,955
Pregnant women from
15 Regional Centers
throughout Japan who
had single pregnancies,
did not have a history of
diabetes, or receive
insulin treatment, and
hypoglycemic agents
during pregnancy; did
not use steroids during
pregnancy
Blood
Maternal blood was
measured by ICP-MS
Age at Measurement:
Maternal age at 22 to
28 weeks of gestation
Geometric mean
non-GDM: 6.05 ng/g
GDM: 6.13 ng/g
Max: 70.9 ng/g
Quartiles (ng/g):
Q1: <5.00
Q2: 5.1-10.0
Maternal health during
pregnancy: GDM
Pregnant women were
diagnosed with GDM if the
results of a 75 g, 2 hr
OGTT exceeded:
fasting = 92 mg/dL
(5.1 mmol/L);
1 hr = 180 mg/dL
(10.0 mmol/L); and
2 hr= 153 mg/dL
(8.5 mmol/L)
Age at outcome:
maternal age at diagnosis
of GDM
Logistic regression models
adjusted for maternal age
at birth, pre-pregnancy
BMI, pregnancy-induced
hypertension, and pack-
years in the nulliparous
models and maternal age
at birth, pre-pregnancy
BMI, history of GDM,
pregnancy-induced
hypertension, and pack-
years in the parous
models; Model 1 was a
multi-pollutant model with
both Cd and Pb; Model 3
was a single pollutant
model of Pb
OR (95% CI):
Model 1:
Nulliparous:
Q1
Reference
Q2
1.22 (0.75,
1.97)
Q3
1.60 (0.72,
3.55)
Q4
2.51 (0.72,
8.72)
Parous:
Q1
Reference
Q2
0.88 (0.65,
1.20)
Q3
0.79 (0.41,
1.41)
Q4
0.31 (0.04,
2.29)
Model 3:
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Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Q3: 10.1-15.0
Nulliparous:
Q4: >15.1
Q1
Reference
Q2
1.19 (0.74, 1.91)
Q3
1.55 (0.70, 3.42)
Q4
2.42 (0.70, 8.40)
Parous:
Q1
Reference
Q2
0.89 (0.66, 1.20)
Q3
0.75 (0.41, 1.39)
Q4
0.30 (0.04, 2.23)
Waneetal. (2019)
Taiyuan
China
2012-2016
Case-control
n: 776 cases and 776
controls
Women aged 18 years
or older with GA of
20 weeks or more and
without mental illness
were eligible for the
study. Women who had
stillbirths or birth
defects, who had
multiple births, who did
not donate blood
samples, or who had
gestational weeks less
than 29 weeks were
excluded
Blood
Maternal blood was
measured by ICP-MS
Age at Measurement:
Mean maternal age for
GDM: 31.00 years
Mean maternal age for non-
GDM: 30.97 years
Median0: 2.7968 [jg/dL
75thc: 3.5981 pg/dL
Tertiles (pg/dL):
Low: <2.254
Middle: 2.254-3.323
High: >3.323
Maternal health during
pregnancy: GDM
GDM diagnosis was based
on a 75 g OGTT during
gestational weeks 24 and
28. Women who met one or
more of the following
criteria were diagnosed
with GDM: (1) fasting blood
glucose was more than
5.1 mmol/L, (2) 1 h blood
glucose >10.0 mmol/L, or
(3) 2 h blood glucose
>8.5 mmol/L
Age at outcome:
maternal age at gestational
weeks 24-28
Logistic regression models
adjusted for pre-
pregnancy BMI,
gestational weight gain,
physical activity, parity,
family history of diabetes,
and month of conception;
the multi-pollutant model
was also adjusted for
nickel, As, Cd, antimony,
thallium, Hg, and Pb
OR (95% CI):
Single Pollutant Pb Model:
Low: Reference
Middle: 1.04 (0.81, 1.35)
High: 1.01 (00.78, 1.30)
p for trend: 0.963
Multi-pollutant Model:
Low: Reference
Middle: 1.06 (0.80, 1.41)
High: 110 (0.80, 1.51)
p for trend: 0.622
Zhou et al. (2021b)
China
n: 8169
Pregnant women of GA
in the first trimester
(<14 weeks) and
Blood
Maternal (serum) analyzed
by polarography method
Maternal health during
pregnancy: GDM
GDM was diagnosed by the
75 g OGTT according to
Logistic regression
analyses: Model 1
adjusted for maternal age,
parity, first trimester BMI,
history of spontaneous
abortion, history of ectopic
OR (95% CI)
Model 1:
Tertile 1: Reference
Tertile 2: 1.05 (0.90, 1.21)
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Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
January 2017-
December 2018
Cohort
singleton pregnancy
with no diabetes prior to
pregnancy were
recruited from their first
prenatal visit to the
Southern Medical
University Affiliated
Foshan Women and
Children's Hospital.
Age at measurement:
maternal mean age:
30.14 years
Median20: 2.53 |jg/dL
75thc: 4.00 pg/dL
Tertiles (pg/dl_):
Tertile 1
Tertile 2
Tertile 3
<1.96
1.961-3.41
>3.411
the International
Association for Diabetes in
Pregnancy Study Group's
criteria.
Age at outcome: maternal
mean age: 30.14 years
pregnancy, family history
of diabetes, family history
of hypertension; Model 2
adjusted for Model 1 plus
other five (Mn, copper,
calcium, zinc, and
magnesium) metals
Tertile 3: 0.89 (0.76, 1.03)
Model 2:
Tertile 1:
Tertile 2:
Tertile 3:
Reference
1.05 (0.90,
0.89 (0.76,
1.22)
1.04)
Zheng et al. (20211
Boston,
Massachusetts
United States
1999-2002
Cohort
Project Viva
n: 1311
Pregnant women
participating in Project
Viva were included in
this study; women were
those of singleton
gestation, able to
answer questions in
English, and GA
<22 weeks at
recruitment.
Blood
Maternal blood
(erythrocyte) measured in
the first trimester measured
by ICP-MS
Age at measurement:
maternal age during first
trimester mean (standard
deviation, SD): 32.3
(4.6) years
Median: 17.6 ng/g
75th: 23.6 ng/g
Maternal health during
pregnancy: gestational
glucose
Glucose tolerance test 26-
28 weeks gestation, as
measured by non-fasting
50 g oral glucose challenge
test.
Age at outcome: maternal
age at 26-28 weeks
gestation mean (SD): 32.3
(4.6) years
BKMR models adjusted
for maternal age, self-
identified race/ethnicity,
pre-pregnancy BMI, GDM
in prior pregnancy,
smoking, maternal
education, diabetes status
of biological mother, and
gestational week at blood
collection for metals
measurements
Difference in mid-gestational
glucose concentration
(mg/dL) associated with IQR
changes of Pb exposure, with
all other metals fixed at their
medians (95% credible
interval)15: -0.5 (-1.6, -0.6)
Tatsuta et al. (2022a)
Japan
2011-2014
JECS
n: 78,964
Women who delivered a
live infant with singleton
pregnancy. Women
Blood
Maternal blood measured
by ICP-MS
Age at measurement:
Maternal health during
pregnancy: GDM
GDM diagnosed by OGTT
in second or third trimester
Logistic regression
adjusted for pre-
pregnancy BMI, age at
blood collection,
smoking/drinking habits
during pregnancy, history
of GDM, history of
OR (95% CI):
Q1
Q2
Q3
Q4
Reference
1.026 (0.872, 1.206)
0.968 (0.821, 1.141)
1.007 (0.854, 1.187)
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Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Cross-sectional
were excluded if there
was a missed blood
sample, missed
diagnosis of GDM,
missing HbA1c data,
HbA1c >6.5% at <24
gestational weeks, or a
history of type 1 or type
2 diabetes.
Maternal age at second or
third trimester; non-GDM
mean age 31.0 years; GDM
mean age 33.3 years
Median: 5.9 ng/g
95th: 10.6 ng/g
overt GDM diagnosed prior
to OGTT was excluded.
Age at outcome: maternal
age at second or third
trimester; non-GDM mean
age 31.0 years; GDM mean
age 33.3 years
delivering a macrosomia,
regional center, fish intake
and co-exposure to Cd,
Mn, and Se
Q5: 0.974 (0.824, 1.151)
Epigenetic Effects During Pregnancy
Sanders et al. (20151
Mexico City
Mexico
2007-2011
Cohort
PROGRESS birth cohort
n: 60
This study was
conducted on a sub-
cohort of 60 Mexican
women aged 18-
40 years participating in
the PROGRESS birth
cohort in Mexico City,
and who consented to a
cervical swab during
mid-pregnancy (16-
19 weeks gestation) for
miRNA, thereby
participating in the
PROGRESS Cervix
Study.
Blood and bone
Maternal blood was
measured with a dynamic
reaction cell ICP-MS.
Maternal bone was
measured with spot-source
109Cd K-shell X-ray
fluorescence (K-XRF)
instrument within 1 month
of delivery
Age at Measurement:
Maternal age at exposure
sampling (mean 27.9 years
with a range of 18-40)
Mean:
Blood: 2.85 pg/dL
Patellad: 4.16
Tibiad: 1.45
Max:
Blood: 9.38 pg/dl_
Patella3: 20.90
Tibia3: 19.45
Maternal health during
pregnancy: altered miRNA
expression in the cervix
Cervical cells were
collected in a method
similar to a standard Pap
smear protocol, where a
cotton swab was used to
collect cells from the
endocervix. Total RNAwas
extracted using the Exiqon
miRCURY kit. MiRNAs
were quantified by using a
NanoPhotometer P-300.
MiRNA expression was
assessed using the
NanoString nCounter
system.
Age at outcome:
Maternal age at
assessment (mean
27.9 years with a range of
18-40)
Multivariable linear (3 (95% Cl)b, interpreted as %
regression models were expression change
adjusted for maternal age,
education, smoke Blood, per 10-fold increase in
exposure in the home, and p^.
panty hsa-miR-297: 84.0 (15.7,
192.8)
hsa-miR-188: 48.5 (7.9,
1.04.2)
Bone Pb, per 1 -unit increase
in Pb:
Patella:
hsa-miR-320e: -4.7 (-7.3,
-1.4)
hsa-miR-22-3p: -4.7 (-8.6,
-0.7)
hsa-miR-93-5p: -6.7 (-12.3,
-0.7)
hsa-miR-769-5p: -5.4 (-9.9,
-0.7)
hsa-miR-297: 2.1 (0.0, 4.2)
hsa-miR-425-5p: -6.7
(-12.3, 0.0)
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Outcome
Confounders
Effect Estimates and 95%
Clsa
hsa-miR-361-3p: 2.8 (0.0,
5.7)
Tibia:
hsa-miR-575: -4.1 (-6.7,
-1.4)
hsa-miR-4286: -8.6 (-13.5,
-3.4)
hsa-miR-15a-5p: 7.2 (1.4,
14.1)
hsa-miR-142-3p: 5.7 (0.7,
11.7)
hsa-miR-193b-3p: -7.3
(-12.9, -0.7)
hsa-miR-494: -4.1 (-8.0, 0.0)
Sanchez-Guerra et al.
(20191
Mexico City, Mexico
December 2007-
2011
Cohort
¦July
PROGRESS Study
n: 410 mother-infant
pairs
Participants who were
<20 weeks gestation;
maternal age of
>18 years and without
medical history of heart
or kidney disease) who
underwent clinical
examinations at different
hospitals from Mexican
Social Security System
Blood
Maternal blood (collected at
second and third trimester
and delivery) and umbilical
cord blood were measured
by ICP-QQQ
Age at measurement:
maternal age at
measurement (mean age
27.22 years)
Mean
second trimester:
3.79 [jg/dL; third trimester:
3.90 [jg/dL; at delivery:
4.16 [jg/dL; cord blood:
3.50 [jg/dL
75th
second trimester:
4.51 [jg/dL; third trimester:
Maternal health during
pregnancy: altered cord
blood mitochondrial DNA
(mtDNA) content
Venous cord blood
measured the relative
mtDNA content through
mitochondrial-to-nuclear
DNA ratio in cord blood
Age at outcome:
Maternal age at delivery
(Mean age 27.22 years)
Multivariate linear
regression models were
adjusted for sex, mother's
age, mother's BMI, SES,
smoke exposure, PM2.5
levels, GA, platelets and
leucocytes in cord blood,
C-section, premature
rupture of membranes
(PROM), preeclampsia,
and date of visit
(3 (95% CI)
Maternal blood
Second trimester: 0.017
(0.002, 0.031)
Third trimester: 0.015 (0.00,
0.03)
At delivery: 0.013 (-0.001,
0.027)
Cord blood
At delivery: 0.016(0.001,
0.03)
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Effect Estimates and 95%
Clsa
4.73 [jg/dL; at delivery:
5.28 [jg/dL; cord blood:
4.45 [jg/dL
Other Outcomes Related to Maternal Health During Pregnancy
Kahnetal. (2014)
Mitrovoca and
Pristina,
Kosovo
May 1985 and
December 1986
Cohort
Yugoslavia Prospective
Study of Environmental
Lead Exposure
n: 291
Women in their second
trimester of pregnancy
were invited to
participate in a study of
pregnancy outcomes at
their first prenatal visit to
government clinics
located at the centers of
two towns in Kosovo.
Women with singleton
births, between 18 and
44 weeks of gestation,
had no major central
nervous system defects,
no chromosomal
abnormalities, and
residing <10 km from
clinic
Blood
Maternal blood (serum)
collected at mid-pregnancy
(no method reported)
Age at Measurement:
Pristina Mean: 26.6 years;
Mitrovica Mean: 26.7 years
Mean:
Pristina: 5.57 [jg/dL;
Mitrovica: 20 [jg/dL
Max:
Pristina: 18.60 pg/dL;
Mitrovica: 41.30 [jg/dL
Maternal health during
pregnancy: thyroid function
during pregnancy
Maternal thyroid function
during pregnancy was
assessed using 1T4, TSH,
and TPOAb. 1T4 and
TPOAb were measured by
a radioimmunoassay
procedure, and TSH was
measured using an
immunoradiometric assay
procedure.
Age at outcome:
Pristina Mean: 26.6 years;
Mitrovica Mean: 26.7 years
Multiple linear regression
analysis: 1T4 models
adjusted for height,
ethnicity, BMI, fetal GA,
maternal education, adults
per room; TSH models:
hemoglobin, ethnicity,
BMI, fetal GA, maternal
age; TPOAb models
(continuous and
dichotomous): ethnicity,
fetal GA, maternal age,
adults per room
(3 (95% Cl)b
1T4: -0.074 (-0.10, -0.046)
TSH: 0.026 (-0.065, 0.12)
TPOAb: 0.31 (0.17, 0.46)
OR (95% Cl)b
TPOAb: 2.41 (1.53, 3.82),
comparing >10 lU/mLvs.
<10 lll/mL
Wells etal. (20111
Baltimore, MD
United States
November 2004 and
March 2005
Cross-sectional
Baltimore Tracking
Health Related to
Environmental
Exposures Study
n: 285
Singleton births with
cord blood available,
with complete covariates
data
Blood
Umbilical cord blood (UCB)
was measured by ICP-MS
Age at Measurement:
Maternal age at delivery
(range: 14-43, mean: 26)
Geometric mean:
Maternal health during
pregnancy: blood pressure
in late pregnancy
Hospital personnel
measured maternal blood
pressure at admission for
labor and delivery and
continuously during
hospitalization. Three pairs
Multivariable linear
regression models were
adjusted for maternal age,
maternal race,
neighborhood median
household income, prima
parity, smoking during
pregnancy, pre-pregnancy
BMI, and anemia
(3 (95% CI), as change in
blood pressure (mmHg):
Admission SBP:
Q1: Referent
Q2 2.89 (-2.16, 7.94)
Q3: 1.05 (-4.04, 6.14)
Q4: 6.87 (1.51, 12.21)
p for trend: 0.033
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Reference and
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Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
0.66 [jg/dL
75th: 0.96 pg/dL
Max: 6.47 [jg/dL
of blood pressure
measurements from each
mother were recorded:
systolic blood pressure
(SBP) and diastolic blood
pressure (DBP) at
admission, the maximum
SBP and corresponding
DBP, and the minimum
SBP and corresponding
DBP.
Age at outcome:
maternal age at delivery
(range: 14-43, mean: 26)
Admission DBP:
Q1
Q2
Q3
Q4
Referent
0.00 (-3.95, 3.96)
0.81 (-3.17, 4.80)
4.40 (0.21, 8.59)
p for trend: 0.036
Maximum SBP:
Q1
Q2
Q3
Q4
Referent
2.47 (-3.08, 8.02)
-1.76 (-7.36, 3.85)
7.72 (1.83, 13.60)
p for trend: 0.055
Maximum DBP:
Q1
Q2
Q3
Q4
Referent
3.93 (-2.86, 10.72)
-0.42 (-7.27, 6.43)
8.33 (1.14, 15.53)
p for trend: 0.086
Lietal. (IQllb)
Shanghai
China
2010
Cross-sectional
N: 1,485
Pregnant women during
late pregnancy (28-36
gestational weeks)
Blood
Maternal blood was
measured by background
corrected GFAAS collected
gestational week 28-36
Age at measurement:
42 years old
Geometric mean:
3.99 pg/dL
13-
Maternal health during
pregnancy: maternal stress
Maternal life event stress
and emotional stress were
assessed using the Life-
Eve nt-Sca le-fo r-P reg n a nt-
Women (LESPW) and
Symptom-Checklist-90-
Revised (SCL-90-R),
respectively.
Generalized additive
models were adjusted for
maternal age, ethnicity,
maternal education, family
monthly income, years
living in Shanghai
(3 (95% Cl)b
Log-blood Pb
GSI: 0.01 (-0.05, 0.07)
Depression: 0.03 (-0.05,
0.10)
Anxiety: 0.01 (-0.06, 0.08)
Log-blood Pb <0.41 pg/dL
GSI: 0.22 (0.05, 0.40)
Depression: 0.34 (0.12, 0.56)
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Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Max: 14.84 pg/dL
Age at outcome: 13-
42 years old
Anxiety: 0.01 (-0.06, 0.08)
Log-blood Pb >0.41 [jg/dL
GSI: -0.07 (-0.16, 0.01)
Depression: -0.09 (-0.19,
0.02)
Anxiety: -0.08 (-0.18, 0.02)
Osorio-Yafiez et al.
(20211
Mexico
2007-2011
Cohort
PROGRESS
n: 668
Women enrolled during
second trimester of
pregnancy, were
>18 years of age, lived
in Mexico City for the
following 3 years
Blood and bone
Maternal blood was
measured by ICP-QQQ;
bone Pb measured by K-
shell X-ray fluorescence
and obtained two estimated
for patella and tibia (one for
each leg), which were
measured 26-55 days
postpartum
Age at measurement:
Median (SD): 27 (5.5) years
Median
Blood - 2nd Trimester:
2.80 [jg/dL
Blood - 3rd Trimester:
2.99 [jg/dL
Bone, tibia: 2.84 |jg/g
Bone, patella: 3.49 |jg/g
Max:
Blood:
2nd Trimester: 20.70 [jg/dL
Maternal health during
pregnancy: bone
remodeling
Bone speed of sound
measured at the second
and third trimesters of
pregnancy at the distal
radius and medium
phalange using quantitative
ultrasound (QUS).
Age at outcome: Median
(SD): 27 (5.5) years
Linear models adjusted for
maternal age,
socioeconomic status,
parity, BMI, and GA at the
time of Z-score
measurement; linear
mixed model adjusted for
maternal age, SES, parity,
BMI, and GA at the time of
QUS measurement;
models with blood were
mutually adjusted for other
(Cd and As) metals
(3 (95% Cl)1
Bone (radius) QUS Z-score at
2nd Trimester
Blood (pg/dL): -0.06 (-0.18,
0.07)
Tibia (pg/g bone mineral):
0.002 (-0.07, 0.07)
Patella (pg/g bone mineral):
-0.08 (-0.15, -0.01)
Bone (radius) QUS Z-score at
3rd Trimester
Blood (pg/dL): -0.03 (-0.16,
0.10)
Tibia: 0.017 (-0.05, 0.09)
Patella: -0.03 (-0.10, 0.05)
Bone (radius) QUS Z-score
during pregnancy
Blood (pg/dL): -0.04 (-0.13,
0.04)
Tibia (pg/g bone mineral):
0.006 (-0.04, 0.06)
Patella (pg/g bone mineral):
-0.06 (-0.10, -0.01)
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Study Design
Study Population Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
3rd Trimester: 28.25 [jg/dL
Tibia: 30.1 |jg/g
Patella: 43.2 |jg/g
Kim et.a.1. (20221
Puerto Rico and
United States
2010
Cohort
PROTECT
n: 617
Pregnant women in the
first trimester or early
second trimester of
pregnancy that resided
in the Northern Karst
aquifer region, known
for a large number of
Superfund and other
hazardous waste sites.
Blood
Maternal blood, collected at
up to two study visits
(median 18- and 26-weeks
gestation), was measured
by ICP-MS
Age at measurement:
Mean (SD) age at
enrollment: 26.9 (5.5) years
Median:
Enrollment: 0.32 ng/mL
Follow up:0.32 ng/mL
75th:
Enrollment: 0.42 ng/mL
Follow up: 0.43 ng/mL
Max:
Enrollment: 2.18 ng/mL
Follow-up: 1.51 ng/mL
Maternal health during
pregnancy: matrix
metalloproteinases
Expression levels of MMP1,
MMP2, and MMP9
measured using
customized Luminex assay
from Invitrogen
Age at outcome: Mean
(SD) age at enrollment:
26.9 (5.5) years
Linear mixed effects
models adjusted for
maternal age, education,
exposure to second-hand
tobacco smoke, and pre-
pregnancy BMI
B (95% Cl)1 as percent
change in MMP per IQR
increase in blood Pb
MMP1
MMP2
MMP9
23.6 (12.9, 35.2)
5.89 (2.23, 9.67)
-3.31 (-8.12, 1.75)
Females:
MMP1
MMP2
MMP9
16.3 (5.74, 28.0)
5.48 (1.50, 9.62)
-1.89 (-7.35, 3.90)
Males:
MMP1
MMP2
MMP9
10.5 (1.15, 20.6)
2.24 (-1.25, 5.86)
-5.14 (-9.85, -0.17)
Gaiewska et al.
(20211
Poland
2018-2020
Case-control
n: 146 (66 with
preeclampsia)
Healthy pregnant
women and healthy non-
pregnant women visiting
the Independent Public
Clinical Hospital No 4 in
Lublin for a stay in the
Blood
Maternal blood was
measured by ICP-MS
Age at measurement:
Mean: 29.16 years
Median: 28 years
Range: 18-47 years
Maternal health during
pregnancy: preeclampsia
Diagnosis of preeclampsia
was based on the definition
from the American College
of Obstetrics and
Gynecologists.
Age at outcome:
Logistic regression
adjusted by the pregnant
woman's age, place of
resident (urban/rural), GA,
multiplicity of pregnancy,
and number of previous
pregnancies
OR (95% CI)1:
5.86)
2.65 (1.2,
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Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
hospital or routine
testing.
All Participants:
Mean (SD): 2.63
(1.34) [jg/dL
Median: 2.6 [jg/dL
Preeclampsia Participants:
Mean (SD) 3.36 (1.23)
Median: 3.49 [jg/dL
Mean: 29.16 years
Median: 28 years
Range: 18-47 years
Max:
All Participants: 6.1 [jg/dL
Preeclampsia Participants:
6.1 [jg/dL
Wu et al. f202D
China,
Foshan, Guangdong
Province
August 2019-
November 2019
(participants followed
from 8-12 week of
pregnancy to birth)
Cohort
n: 2174
Pregnant women that
were registered,
checkup, and delivering
in the Foshan
Chancheng Central
Hospital were included
in the study.
Blood
Maternal blood, collected
between 12 and 27 (±6)
weeks of pregnancy and
before date of diagnosed
preeclampsia, was
measured by AAS
Age at measurement:
Mean age at delivery (SD):
29.04 (4.25) years
Median: 3.60 [jg/dL
Quartiles (|jg/dL):
Q1
Q2
Q3
Q4
2.00-2.90
3.00-3.60
3.70-4.40
4.50-7.90
Maternal health during
pregnancy: preeclampsia
Preeclampsia was based
on electronic medical
records. Preeclampsia was
defined as newly diagnosed
hypertension and
proteinuria occurring after
20 weeks of gestation.
Hypertension was defined
as systolic >140 mmHg or
diastolic >90 mmHg, 2
occasions, 4 hr apart in a
previously normotensive
woman. Proteinuria was
defined as >300 mg/24-hr
urine collections, or
protein/creatinine >0.3, or
dipstick reading >1
Age at outcome: maternal
age after 28 weeks
gestation
Logistic regression models OR (95% CI)
were adjusted for age at
delivery, pre-pregnancy
BMI, parity, method of
conception (natural
conception, ART
conception), and
education level; logistic
Dose-effect analysis of the
relationship between BLLs
and the risk of preeclampsia
Linear regression modelb:
1.43 (1.17, 1.74)
BLLs <4.2 |jg/dLb: 0.79 (0.50,
1.24)
BLLs >4.2 |jg/dLb: 2.05 (1.50-
2.81)
Preeclampsia:
Continuous modelb: 1.43
(1.17, 1.74)
Q1: Reference
Q2
Q3
Q4
1.48 (0.64, 3.39)
0.85 (0.33, 2.20)
2.38 (1.13, 5.03)
p for trend: 0.02
Mild Preeclampsia:
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Continuous modelb: 1.62
(1.27, 2.06)
Q1
Q2
Q3
Q4
Reference
2.63 (0.81, 8.63)
1.33 (0.35, 5.06)
4.26 (1.41, 12.89)
p for trend: 0.01
Severe Preeclampsia:
Continuous modelb: 1.10
(0.72, 1.68)
Q1: Reference
Q2: 0.69 (0.19, 2.49)
Q3: 0.51 (0.13, 2.05)
Q4: 1.12 (0.38, 3.27)
p for trend: 0.78
Braunetal. (20141 n: 1054
Mexico City,
Mexico
July 2007 and
February 2011
Cohort
Participants for this
study were enrolled from
an ongoing prospective
birth cohort in Mexico
City. Pregnant women
receiving health
insurance and prenatal
care through the
Mexican Social Security
System were invited to
participate in the study.
To be eligible for
participation in the
study, women had to be
<20 week gestation,
>18 years old, free of
heart or kidney disease,
have access to a
Blood and bone
Maternal blood was
measured by GFAAS
during the second trimester.
Maternal bone was
measured by K-shell X-ray
fluorescence instrument
~1 month postpartum
Age at measurement:
>18 years old
Mean:
blood: 3.7 [jg/dL
tibia: 2.7 |jg/g
Maternal health during
pregnancy: hypothalamic-
pituitary-adrenal axis
function measured from
salivary Cortisol
concentrations
Between 14 and 35 weeks
of gestation (mean [SD]:
19.7 [2.4] week), pregnant
women provided five saliva
samples each day over 2
consecutive days during
the week or weekend.
Women were instructed to
provide samples using the
passive drool technique
upon awakening, 45 min
after waking, 4 hr after
waking, 10 hr after waking,
Linear mixed models with
random intercepts for day
and participant were
adjusted for maternal age,
marital status, years of
education, parity, and
smoking status (never,
former, and current), BMI,
and stress or depressive
symptoms
(3 (95% CI), as % difference in
Cortisol area under the curve
nmol-hours
Blood Pb Quintiles
Q1
Reference
Q2
8 (-1, 18)
Q3
9 (0, 19)
Q4
8 (-1, 18)
Q5
CM
CO
CM
Tibia Pb Quintiles:
Q1
Reference
Q2
-5 (-14, 5)
Q3
2 (-8, 13)
Q4
0 (-10, 10)
Q5
00
CD
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
telephone, plan to reside
in Mexico City for the
next 3 years, not use
steroids (including
glucocorticoids) or anti-
epilepsy drugs, and not
consume alcohol on a
daily basis.
patella: 4.6 |jg/g
Blood Pb Quintiles
Q1
Q2
Q3
Q4
Q5
0—<1.8 |jg/dL
1.8-<2.4 Mg/dL
2.4-<3.4 [jg/dL
3.4-<5.1 |jg/dL
>5.1 [jg/dL
Tibia Pb Quintiles
Q1
Q2
Q3
Q4
Q5
<2 pg/g
2-<4.3 |jg/g
4.3-<6.7 |jg/g
6.7—<11.1 |jg/g
>11.1 |jg/g
and at bedtime. Saliva
samples were assayed in
Patella Pb Quintiles:
the same batch in duplicate
Q1
Reference
for Cortisol using a
chemiluminescence assay
Q2
1 (-8, 12)
with sensitivity of
Q3
-6 (-14, 4)
-0.16 ng/ml.
Q4
"3"
CM
CM
Q5
CD
CO
Age at outcome:
maternal age at the time of
outcome measurement
Patella Pb Quintiles
Q1: <2 |jg/g
Q2: 2-<4.5 |jg/g
Q3: 4.5-<7.8 |jg/g
Q4: 7.8-<12.7 pg/g
Q5: >12.7-43.2 |jg/g
Ishitsuka et al.
(20201
Japan
January 2011 -
March 204
Cross-sectional
JECS
n: 17,267
Pregnant women from
15 Regional Centers
throughout Japan who
had single pregnancies,
did not have a history of
diabetes, or receive
insulin treatment, and
hypoglycemic agents
during pregnancy; did
Blood
Maternal blood was
measured by ICP-MS
Age at measurement:
maternal age at 27 weeks
of gestation (mean age:
31 ± 5 years)
Maternal health during
pregnancy: maternal
depression
Psychological symptoms
during middle or late
pregnancy were assessed
using the Kessler
Psychological Distress
Scale (K6).
Age at outcome:
Multivariable logistic
regression models
adjusted for age, parity,
marital status, education,
employment status,
household income, and
smoking and alcohol
status
OR (95% CI)
Pb per one-unit increase
K6 >13: 1.00 (0.76, 1.32)
K6 >5: 0.98 (0.88, 1.09)
K6 >13:
Q1
Q2
Q3
Q4
Reference
0.94 (0.69, 1.27)
0.97 (0.71, 1.31)
0.92 (0.68, 1.25)
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
not use steroids during
pregnancy
maternal age at 27 weeks
Q5: 0.87 (0.64,
1.19)
Geometric mean:
of gestation (mean age:
0.58 [jg/dL
31 ± 5 years)
K6 >5:
Q1
Reference
Quintiles (|jg/dL):
Q2
1.03 (0.92,
1.16)
Q1
0.143-0.433
Q3
1.07 (0.95,
1.19)
Q2
0.444-0.523
Q4
0.98 (0.87,
1.10)
Q3
0.524-0.616
Q5
1.01 (0.90,
1.13)
Q4
0.617-0.7533
Q5
0.754-6.752
Christensen et al.
(20161
Ukraine and
Greenland
2002-2004
Climate Change,
Environmental
Contaminants, and
Reproductive Health
n: 117
Women at least
18 years old and born in
the country of the study.
Blood
Maternal blood was
measured by ICP-MS
Age at measurement: >18
Mean0: 1.74 [jg/dL
Median0: 1.457 [jg/dL
Tertiles°(|jg/dL):
T1
T2
T3
0.544-1.013
1.013-1.902
1.902-14.088
Maternal health during
pregnancy: anti-mullerian
hormone (AMH)
Concentrations of AMH
were assessed by the
Immunotech enzyme
immunoassay
AMH/Mullerian-inhibiting
substance assay from
serum.
Age at outcome: >18
General linear models
were adjusted for GA,
maternal age, research
site, parity, fish intake,
BMI, ever smoker and
pelvic diseases and
infections
(3 (95% Cl)b per one-unit In-
Pb increase: -0.0423
(-0.4989, 0.4144)
Gustinetal. (20211
Sweden,
Norrbotten county
Enrollment: 2015-
2018, follow-up
through 29
gestational weeks
NICE
n: 544
Pregnant women visiting
their local maternity
clinics who were
residents of southern or
eastern Norrbotten
count and planned to
give birth at Sunderby
Blood
Maternal blood
(erythrocyte) was measured
by ICP-MS
Age at measurement:
Median: 30 years
Maternal health during
pregnancy: hormone Levels
(1T4, tT4, 1T3, tT3, TSH,
1T4:tT4, 1T3:tT3, 1T3:1T4)
Plasma samples from
gestation week 29 analyzed
via
electrochemiluminescence
immunoassays
Multivariate linear
regression models
adjusted for parity,
maternal education,
maternal pre-pregnancy
smoking
(3 (95% CI)b:
1T4 (pmol/L): 0.014 (-0.21,
0.18)
tT4 (nmol/L): 0.90 (-1.5, 3.3)
1T3 (pmol/L): 0.036 (-0.018,
0.090)
tT3 (nmol/L): 0.038 (-0.015,
0.091)
TSH (mlU/L): -0.023 (-0.13,
0.087)
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Reference and
Study Design
Cohort
Study Population
Exposure Assessment
Hospital. Only first
pregnancies and
singleton births
included. Those with
thyroid dysfunction were
excluded.
Median: 11 |jg/kg
95th: 27 pg/kg
Outcome
Confounders
Effect Estimates and 95%
Clsa
1T4:tT4: -0.001 (-0.002,
0.001)
1T3:tT3: -0.009 (-0.031,
0.014)
1T3:fT4: 0.004 (-0.003, 0.011)
Corrales Vargas et al. n: 344
(20221
Matina County,
Limon
Coast Rica
2010-2011
Cohort
Blood
Maternal blood measured
by ICP-MS
Age at measurement:
Maternal age at collection
(recruited <33 weeks
gestation with 2nd blood
sample 10 weeks later)
Median: 0.666 pg/dL
75th: 0.908 pg/dL
90th: 1.211 pg/dL
Max: 3.43 pg/dL
Maternal health during
pregnancy: thyroid function
TSH, 1T4, and 1T3
measured in serum using
electrochemiluminescence
Linear regression models (3 (95% CI) for % change in
adjusted for age, GA,
cotinine detection, pre-
pregnancy BMI, and
severe vomiting during
pregnancy
1st measurement of
outcomes per 10% increase
in blood Pb (pg/L) at
enrollment:
TSH (mlU/L): -2.3 (-16.15,
11.55)
1T4 (pmol/L): 0.99 (-0.11,
2.09)
1T3 (pmol/L): -0.21 (-0.52,
0.10)
(3 (95% CI) for % change in
2nd measurement of
outcomes per 10% increase
in blood Pb (pg/L) at
enrollment, excluding outliers:
TSH (mlU/L): -0.08 (-0.22,
0.07)
1T4 (pmol/L): 1.96 (0.66, 3.25)
1T3 (pmol/L): 0.24 (-0.13,
0.61)
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Reference and
Study Design
Study Population Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
AAS = atomic absorption spectrometry; AMH = anti-Mullerian hormone; ART = assisted reproductive technology; BKMR = Bayesian kernel machine regression; BMI = body mass index;
Cd = cadmium; CI = confidence interval; DBP = diastolic blood pressure; EAAS: = electrothermal atomic absorption spectrometry; fT3 = free triiodothyronine; fT3:fT4 = ratio of free
triiodothyronine to free thyroxine; fT3:tT3 = ratio of free triiodothyronine to total triiodothyronine; fT4 = free thyroxine; fT4:tT4 = ratio of free thyroxine to total thyroxine; GDM = gestational
diabetes mellitus; GFAAS = graphite furnace atomic absorption spectrometry; GSI = global severity index; ICP-MS = inductively coupled plasma mass spectrometry; ICP-QQQ = inductively
coupled plasma triple quad; IGT = impaired glucose tolerance; IQR = interquartile range; Japan Environment and Children's Study = JECS; K6 = Kessler Psychological Distress Scale; K-
XRF = K-shell X-ray fluorescence; matrix metalloproteinases = MMP; MIREC = Maternal-Infant Research on Environmental Chemicals; miRNA = micro RNA; mtDNA = mitochondrial DNA;
NICE = Nutritional impact on Immunological maturation during Childhood in relation to the Environment; OGTT = oral glucose tolerance test; OR = odds ratio; PM2.5 = fine particulate
matter; PROGRESS = Programming Research in Obesity, Growth, Environment and Social Stressors; PROM = premature rupture of membranes; PROTECT = Puerto Rico Testsitefor
Exploring Contamination Threats; Q = quartile; QUS = quantitative ultrasound; SBP = systolic blood pressure; SD = standard deviation; Se = selenium; SES = socioeconomic status;
TPOAb = thyroid peroxidase antibodies; TSH = thyroid-stimulating hormone; tT3 = total triiodothyronine; tT4 = total thyroxine; UCB = umbilical cord blood.
aEffect estimates are standardized to a 1 |jg/dL increase in blood Pb or a 10 |jg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect estimates are
standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated interval. Categorical
effect estimates are not standardized.
bEffect estimates unable to be standardized.
°Pb measurements were converted from |jg/L to |jg/dL.
dNo units provided.
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Table 8-3 Animal toxicological studies of Pb exposure and pregnancy and birth outcomes.
Study
Species (Stock/Strain), n, Timing of
Sex Exposure
Exposure Details
(Concentration, Duration)
BLL As Reported (|jg/dL)
Endpoints
Examined
Salehetal. (70181
Rat (Sprague-Dawley)
Control (vehicle), F, n = 8
dams
160 ppm Pb, F, n = 8 dams
320 ppm Pb, F, n = 8 dams
GD 1 to 20 Dams were dosed via oral
gavage. Authors report a
significant decrease in brain
weight occurred, indicating
potential overt toxicity.
Dams (GD 20):
5.1 [jg/dL for control
27.7 |jg/dL for 160 ppm Pb
41.5 |jg/dL for 320 ppm Pb
Abortion, Placental
Weight
Salehetal. (2019)
Rat (Sprague-Dawley)
Control (vehicle), F, n = 8
dams
160 ppm Pb, F, n = 8 dams
320 ppm Pb, F, n = 8 dams
GD 1 to 20 Dams were dosed via oral
gavage. Authors report a
significant decrease in brain
weight occurred, indicating
potential overt toxicity.
Dams (GD 20):
5.26 [jg/dL for control
23.9 |jg/dL for 160 ppm Pb
42.9 |jg/dL for 320 ppm Pb
Placental Weight
Corv-Slechta et al.
(20131
Mouse (C57BL/6)
Control (untreated), M/F,
n = 16-29 (8-17/8-12) pups
100 ppm Pb, M/F, n = 16-29
(8-17/8-12) pups
GD -61 to Dams were dosed via
PND 365 drinking water starting
2 months prior to mating.
Offspring were continued on
the same exposure as their
dams until the end of the
experiment at 12 months of
age. Sample sizes are only
available for "Final" group
sizes for males and females
in Table 1.
Dams at weaning (PND 24):
0.22 [jg/dL for control
12.12 |jg/dL for 100 ppm Pb
Birth Weight, Sex
Ratio
Schneider et al.
(20161
Mouse (C57BL/6)
Control (untreated), F,
n = NR
100 ppm Pb, F, n = NR
GD -61 to Dams were dosed via
PND 21 drinking water starting
2 months prior to mating
through lactation (weaning
assumed to be PND 21).
Dams were also treated to a
Dams at weaning (assumed
PND 21): 0.22 pg/dL for control
12.61 pg/dL for 100 ppm Pb
Birth Weight
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Study
Species (Stock/Strain), n,
Sex
Timing of
Exposure
Exposure Details
(Concentration, Duration)
BLL As Reported (|jg/dL)
Endpoints
Examined
non-stress or prenatal stress
condition. Only data from
dams in the non-stress
condition were used.
Pups (PND 5-6): 0.37 pg/dL for
control
10.2 pg/dL for 100 ppm Pb
Waneetal. (2014)
GD 1-20
Rat (Wistar) GD 1-10, or
Control (untreated), F, n = 17 or
dams
0.25% Pb GD 1-10, F,
n = 16 dams
0.25% Pb GD 11-20, F,
n = 15 dams
Dams were dosed via
drinking water during different
windows of pregnancy.
Assumed termination of study
on GD 20.
Dams (assumed GD 20):
0.828 pg/dL for control
26.29 pg/dL for 0.25% Pb GD 1-
10
12.4 pg/dL for 0.25% Pb GD 11-
20
36.02 pg/dL for 0.25% Pb GD 1-
20
Placenta
Histopathology,
Placental Weight
0.25% Pb GD 1-20, F,
n = 15 dams
Weston etal. (20141
Rat (Long-Evans)
Dams
Control (untreated), F, n = 20
50 ppm Pb, F, n = 19
Pups
Control (untreated), M/F,
n = 12.4 (7/5.4 average
number of male and female
pups per litter in control)
50 ppm Pb, M/F, n = 7.4
(6.3/1.1 average number of
male and female pups per
litter in Pb non-stress group)
GD -76 to Dams were dosed via
PND 21 drinking water starting 2-3
months prior to breeding.
Exposure ended at weaning
(PND 21).
Dams (PND 21):
0.500 pg/dL for control
7.72 pg/dL for 50 ppm Pb
Pups (PND 5-6):
0.603 pg/dL for control males
0.690 pg/dL for control females
15.7 pg/dL for 50 ppm Pb males
14.6 pg/dL for 50 ppm Pb females
Birth Weight, Sex
Ratio
Rao Barkur and Bain
(20161
Rat (Wistar)
GD -30 to GD -
GD Oto GD 21;
PND 1 to
Dams were dosed via
drinking water for varying
amounts of time:
Pregestation Only (1 month
Pups (PND 22):
0.19 pg/dL for control
Stillborn Pups,
Birth Weight
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Study
Species (Stock/Strain), n,
Sex
Timing of
Exposure
Exposure Details
(Concentration, Duration)
BLL As Reported (|jg/dL)
Endpoints
Examined
Control (untreated), F, n = 6
dams
0.2% Pb Pregestation Only,
n = 6 dams
0.2% Pb Gestation Only,
n = 6 dams
0.2% Pb Lactation Only,
n = 6 dams
0.2% Pb Gestation and
Lactation, F, n = 6 dams
PND21; GD 0 to
PND21
prior to conception),
Gestation Only (21 days),
Lactation Only (21 days), and
Gestation and Lactation (42
days).
3.03 [jg/dL for 0.2% Pb in
Pregestation Only group
5.51 [jg/dL for 0.2% Pb in
Gestation Only group
26.86 |jg/dL for 0.2% Pb in
Lactation Only group
31.59 |jg/dL for 0.2% Pb in
Gestation and Lactation group
Barkur and Bain
(20151
Rat (Wistar)
Control (untreated), F, n = 6
dams
0.2% Pb Pregestation Only,
F, n = 6 dams
0.2% Pb Gestation Only,
F, n = 6 dams
0.2% Pb Lactation Only, F,
n = 6 dams
GD -30 to GD -1
GD 0 to GD 21;
PND 0 to
PND21; GD 0 to
PND 21
Dams were dosed via
drinking water for varying
amounts of time:
Pregestation Only (1 month
prior to conception),
Gestation Only (21 days),
Lactation Only (21 days), and
Gestation and Lactation (42
days).
Pups (PND 22):
0.18 [jg/dL for control
3.02 [jg/dL for 0.2% Pb in
Pregestation Only group
5.30 [jg/dL for 0.2% Pb Gestation
Only group
26.7 [jg/dL for 0.2% Pb in
Lactation Only group
32.0 [jg/dL for 0.2% Pb in
Gestation and Lactation group
Stillborn Pups,
Birth Weight
0.2% Pb Gestation and
Lactation, F, n = 6 dams
Tartaglione et al.
(20201
Rat (Wistar)
Control, M/F, n = NR
50 mg/L Pb, M/F, n = NR
GD -28 to Dams were dosed via
PND 23 drinking water starting
4 weeks prior to mating until
weaning (PND 23).
Pups (PND 23):
0.700 [jg/dL for 0 mg/L Pb
25.5 [jg/dL for 50 mg/L Pb
Birth Weight, Sex
Ratio
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8-95
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Study
Species (Stock/Strain), n,
Sex
Timing of
Exposure
Exposure Details
(Concentration, Duration)
BLL As Reported (|jg/dL)
Endpoints
Examined
Zhao et al. (20211
Rat (Sprague-Dawley)
Control (untreated), F, n = 6
dams
109 ppm Pb, F, n = 6 dams
GD-14to Dams were dosed via
PND 10 drinking water starting
2 weeks prior to mating and
continued until PND 10.
Pups:
PND 0
0.87 [jg/dL for control
48.2 |jg/dL for 109 ppm Pb
PND 10
0.87 [jg/dL for control
11.5 pg/dL for 109 ppm Pb
PND 21
0.87 pg/dL for control
2.81 pg/dL for 109 ppm Pb
PND 30
0.87 pg/dL for control
1.20 pg/dL for 109 ppm Pb
Birth Weight
Barkur et al. (20111
Rat (Wistar) GD 0 to PND 21
Control (untreated), F, n = 6
dams
0.2% Pb GD Oto PND 21,
F, n = 6 dams
Dams were dosed via
drinking water throughout
gestation until weaning
(PND 21). Only male pups
were examined.
Pups:
PND 22
0.266 pg/dL for control
31.2 pg/dL for 0.2% Pb
PND 120
0.234 pg/dL for control
0.468 pg/dL for 0.2% Pb
Birth Weight
Betharia and Maher
(20121
Rat (Sprague-Dawley)
Control (untreated), M/F,
n = 36-48 (18-24/18-24)
pups
10 pg/mL Pb, M/F, n = 36-
48 (18-24/18-24) pups
GD 0 to PND 20
Dams were dosed via
drinking water throughout
pregnancy until weaning
(PND 20).
Pups:
PND 2
0.188 pg/dL for control
9.03 pg/dL for 10 pg/mL Pb
PND 25:
Stillborn Pups, Sex
Ratio
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Study
Species (Stock/Strain), n,
Sex
Timing of
Exposure
Exposure Details
(Concentration, Duration)
BLL As Reported (|jg/dL)
Endpoints
Examined
0.088 [jg/dL for control
0.976 [jg/dL for 10 |jg/mL Pb
PND60:
0.0244 [jg/dL for control
0.0318 [jg/dL for 10 |jg/mL Pb
Graham et al. (20111
Rat (Sprague-Dawley)
Control (vehicle), M/F,
n = 14-16 (7-8/7-8)
1 mg/kg Pb, M/F, n = 14-16
(7-8/7-8)
10 mg/kg Pb, M/F, n = 14-16
(7-8/78)
PND 4 to 28 Offspring were dosed via oral PND 29:
°Lh™day fr0m °-267 Hg/dL for 0 mg/kg
3.27 |jg/dL for 1 mg/kg
12.5 |jg/dL for 10 mg/kg
PND 4 until PND 28.
Offspring Mortality
Baranowska-Bosiacka Rat (Wistar) GD 1 to PND 21
et al. (2013) Control (untreated), F, n = 3
dams
0.1% Pb, F, n = 3 dams
Dams were dosed via
drinking water throughout
pregnancy until weaning
(PND 21).
Pups (PND 28):
0.93 [jg/dL for control
6.86 [jg/dL for 0.1% Pb
Sex Ratio
Control, M/F, n = 36 (17/19)
pups
0.1% Pb, M/F, n = 36 (18/18)
pups
BLL = blood lead level; F = female; GD = gestational day; M = male; Pb = lead; PND =postnatal day.
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Table 8-4 Epidemiologic studies of Pb exposure and prenatal growth.
Reference and Study Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Design Clsa
Xieetal. (70131
Shandong Province
China
September 2010 and
December 2011
Cross-sectional
n: 252
Pregnant women aged
18 years or older,
planning to deliver at
the Binhai hospital, and
more than 3 years of
residence in the
Laizhou Bay; exclusion
criteria included
diagnoses of
gestational or
preexisting diabetes,
hypertension, HIV, or
AIDS; GA <28 weeks;
known occupational
exposure to heavy
metals; with history of
participation in an
assisted reproduction
program; difficulties
with communication;
and infants with severe
neonatal illnesses
Blood and cord blood
Maternal blood and UCB
were measured by GFAAS.
Age at Measurement:
at delivery (within 3 days
before delivery)
Mean (SD):
Maternal: 3.53 (1.51) pg/dL
UCB: 2.92 (1.58) pg/dL
Median:
Maternal: 3.20 pg/dL
UCB: 2.52 pg/dL
75th:
Maternal: 4.18 pg/dL
UCB: 3.95 pg/dL
Max:
Maternal: 11.91 pg/dL
UCB: 10.60 pg/dL
Prenatal growth: Birth
weight (BW), birth
length, head
circumference (HC)
BW, birth length, and
HC were measured by
several trained
midwives within 1 hour
after birth
Age at outcome:
birth
Multiple linear regression
models were adjusted for
infant sex, maternal
education, maternal age,
GA, pre-pregnancy BMI,
parity, and weight gain
during pregnancy
(3 (95% Cl)b
Maternal blood:
BW (g): -148.99 (-286.33,
-11.66)
BL (cm): -0.46 (-1.25,
0.34)
HC (cm): -0.37 (-0.78,
0.19)
UCB:
BW (g): -99.33 (-217.33,
20.67)
BL (cm): -0.84 (-1.52,
-0.16)
HC (cm): -0.36 (-0.81,
0.03)
Garria-Esauinas et al.
(20131
Madrid
Spain
October 2003 to May
2004
Cross-sectional
BioMadrid Project
n: 112
Father-pregnant
woman-newborn trios
residing in two areas of
the Madrid
Autonomous Region, a
municipal district in the
city of Madrid (urban
area) and a second
zone lying in the
Greater Madrid
Blood and cord blood
Blood collected from both
parents during pregnancy
and UCB was collected at
delivery and measured by
AAS
Age at measurement:
maternal age: >15; birth
Geometric mean (95% Cl)c
Prenatal growth: BW,
length, 1-and 5-minute
Apgar scores
Anthropometric data
were measured once,
before breastfeeding
started. Apgar score
was measured on a
scale from 1 to 10, at 1
and 5 min after
delivery. Infants were
evaluated on a scale of
Multivariable linear
regression models were
adjusted for newborn's
sex, GA, maternal age,
maternal cigarette
smoking and sampling
season
(3 (95% Cl)b
UCB:
BW (g): 123 (-37.9, 284)
BL (cm): 0.52 (-0.39, 1.44)
1-min Apgar score: 0.67
(-0.19, 1.16)
5-min Apgar score: 0.29
(-0.04, 0.54)
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Reference and Study Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Design Clsa
Metropolitan Belt
(metropolitan area);
women were required
to be aged over
15 years, to be
expecting a single
pregnancy, and to
intend to deliver their
babies at the public
hospital assigned to
them, lived in the study
area for more than a
year, and did not have
a blood transfusion in
the previous year
Maternal blood: 1.98 (1.816,
2.162) [jg/dL
Paternal blood: 3.30 (3.048,
3.564) [jg/dL
UCB: 1.409 (1.277,
1.555) [jg/dL
Median0:
Maternal blood: 1.898 [jg/dL
Paternal blood: 3.324 [jg/dL
UCB: 1.380 pg/dL
75thc:
Maternal blood: 2.721 pg/dL
Paternal blood: 4.321 pg/dL
UCB: 1.911 pg/dL
0 to 2 according to five
categories (skin color,
muscle tone, reflexes,
respiratory effort, and
heart rate), and the
points from each
category added
together to determine
the total score.
Age at outcome:
birth
Govarts et al. (20161
5 provinces of
Flanders,
Belgium
August 2008-July
2009
Cross-sectional
Flemish human
environmental health
survey (FLEHS II)
n: 248
Women with
uncomplicated live-born
singleton pregnancies,
living in Flanders for at
least 10 years, ability to
fill in a Dutch
questionnaire, and
giving birth in one out
often randomly
selected maternities
Cord blood
UCB was measured by HR-
ICP-MS
Age at Measurement:
birth
Geometric mean0:
0.864 pg/dL
75thc: 1.138 pg/dL
Prenatal growth: BW
BWwas obtained from
the medical records
Age at outcome:
birth
Linear regression models
were adjusted for GA,
child's sex, smoking of the
mother during pregnancy,
parity, and maternal pre-
pregnancy BMI
(3 (95% CI)b for an increase
of Z-score of UCB Pb IQR
increase: -37.14 g (-93.64,
19.36)
Tatsuta et al. (20171 Tohoku Study of Child Cord blood
Tohoku
Japan
2000-2003
Development
n: 489
Singleton pregnancy,
Japanese as the first
language, neonates
UCB was measured by ICP-
MS
Prenatal growth: BW Multiple regression models (3 (p-value)b
BWwas obtained from
medical records
were adjusted for GA,
parity, BMI before
pregnancy,
smoking/drinking habits
All infants: -0.011 g
(0.784)
Male infants: 0.023 g
(0.692)
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Reference and Study Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Design Clsa
born at term (36- Age at Measurement: Age at outcome: during pregnancy, and Female infants: -0.039 g
Cross-sectional 42 weeks of gestation) birth birth fish/seafood intake (0.513)
with BW of more than
2400 g, and no Median: 1.0 [jg/dL
congenital anomalies or Ma,e infants: 1 0 Mg/dL
diseases Female infants: 1.0 [jg/dL
95th: 1.7 [jg/dL
Male infants: 1.7 [jg/dL
Female infants: 1.7 [jg/dL
Wane et al. (20YM
Shanghai
China
September 2008 and
October 2009
Cross-sectional
n: 1,009 mother-infant
pairs
Singleton pregnant
women who had lived
in Shanghai for at least
2 years, were aged
18 years or older, and
were delivering at the
selected hospitals were
recruited. Pregnant
women were excluded
if they had chronic
diseases before
pregnancy, pregnancy
complications, or a
history of occupational
heavy metal exposure.
Infants who had severe
disorders or congenital
malformations at birth
were also excluded.
Cord blood
UCB measured by GFAAS
Age at Measurement:
birth
Geometric mean: 4.07 [jg/dL
(95% CI: 3.98, 4.17)
Prenatal growth: BW,
birth length, HC, and
the ponderal index
Neonatal
anthropometry,
including BW, birth
length, and HC, was
performed by trained
delivery room staff with
standardized
equipment, and the
results were recorded.
PI was calculated
Age at outcome:
birth
Multiple linear regression
models; models for BW,
HC, and PI were adjusted
for maternal age, GA,
maternal BMI before
delivery, parity, sex of
baby, monthly household
income per capita, mode
of delivery; models for
birth length were maternal
age, GA, maternal BMI
before delivery, parity, sex
of baby, monthly
household income per
capita; all models for
female infants and BL
model for male infants
were adjusted for maternal
age, GA, maternal BMI
before delivery, parity,
monthly household income
per capita; models for
male infants for BW, HC,
and PI were adjusted for
maternal age, GA,
maternal BMI before
delivery, parity, monthly
(3 (95% Cl)b
All Infants
BW (g): 50.68 (-69.53,
170.88)
birth length (cm): 0.36
(-0.13, 0.86)
HC (cm): -0.39 cm (-0.80,
0.02)
PI (g/cm3): -0.03 (-0.12,
0.07)
Female Infants
BW (g): -139.15 (-317.89,
39.59)
birth length (cm): 0.32
(-0.38, 1.03)
HC (cm): -0.13 (-0.71,
0.44)
PI (g/cm3): -0.16 (-0.30,
-0.02)
Male Infants
BW (g): 206.50 g (46.15,
366.86)
birth length (cm): 0.35
(-0.35, 1.05)
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Reference and Study Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Design Clsa
household income per
capita, mode of delivery
HC (cm): -0.65 (-1.24,
-0.06)
PI (g/cm3): 0.09 (-0.04,
0.21)
Govarts et al. (20201
Belgium
FLEHS I: 2002-2004;
FLEHS II: 2008-2009;
FLEHS III: 2013-
2014; 3xG: 2010-
2015
Cross-sectional
Flemish Environment
and Health Studies
(FLEHS I, II and III) and
a regional birth cohort
(3xG)
n: 1,579 mother-
newborn pairs: FLEHS
I n = 957, II n = 224, III
n = 273, and 3xG
n = 125
Inclusion criteria were
to be able to fill out a
Dutch questionnaire
and to live at least
five years in the
selected study areas
(FLEHS I), at least
10 years in Flanders
(FLEHS II), at least
5 years in Flanders
(FLEHS III), or living in
the recruitment area
(3xG). Live-born
singleton births
Cord blood
UCB measured by HR-ICP-
MS
Age at Measurement:
birth
Median0:
FLEHS I: 1.42 pg/dL
FLEHS II: 0.83 pg/dL
FLEHS III: 0.61 pg/dL
3xG: 0.61 pg/dL
pooled: 0.97 pg/dL
75thc:
FLEHS I: 2.41 pg/dL
FLEHS II: 1.13 pg/dL
FLEHS III: 0.87 pg/dL
3xG: 0.72 pg/dL
pooled: 1.78 pg/dL
Prenatal growth: BW
BW was recorded
shortly after delivery
Age at outcome:
birth
Multiple linear regression
models were adjusted for
other exposures, GA
(linear and quadratic
terms), sex of the
newborn, maternal age at
delivery, maternal pre-
pregnancy BMI, parity,
smoking during pregnancy
and cohort
(3 (95% CI)b, interpreted as
the change in mean BW
per interquartile fold
change (the fold change of
the 75th percentile over the
25th percentile in
exposure) in In-Pb: 16.98 g
(-13.14, 47.11) per2.94
interquartile fold change in
In-Pb
Lee etal. (20211 Dhaka Community
Hospital Trust
Sirajdikhan and Pabna n: 1088
Sadar regions
Bangladesh
2008-2011
Cord blood
UCB measured by acid
digestion and ICP-MS
Age at measurement:
birth
Prenatal growth: BW,
birth length, HC
Trained staff measured
anthropometer at birth;
GA estimated using
<16-weeks ultrasound.
Linear models adjusted for (3 (95% CI)b, per IQR
maternal age, maternal
BMI at enrollment, child
sex, GA, household
income, second-hand
smoke, site daily tea
(heavy metals) and cord
blood As, Cd, Mn
concentrations
increase in In-cord blood
Pb:
Birth Z-scores
BW (g): -0.04 (-0.19, 0.11)
BL (cm): -0.06 (-0.20,
0.09)
HC (cm): 0.08 (-0.06, 0.23)
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Design Clsa
Cross-sectional
Geometric mean (Geometric
SD): 3.18 (2.35) pg/dL
Median: 3.07 [jg/dL
75th: 6.04 pg/dL
Max: 83.5 [jg/dL
Age at outcome: birth
Untransformed birth size
measurements
BW (g): -20.68 (-78.43,
37.08)
BL (cm): -0.23 (-0.61,
0.15)
HC (cm): 0.08 (-0.10, 0.25)
Xuetal. (20121
Guiyu and Xiamen
China
2001-2008
Cross-sectional
n: 531 (n = 432 from
Guiyu and n = 99 from
Xiamen)
Women who gave birth
in Guiyu or non-urban
area of Xiamen
between 2001 and
2008
Cord blood
UCB measured by GFAAS
Age at Measurement:
birth
Median:
Guiyu: 10.78 pg/dL
Xiamen: 2.25 [jg/dL
Max:
Guiyu: 47.46 |jg/dL
Xiamen: 7.22 [jg/dL
Prenatal growth: BW,
low BW(LBW) rate,
intrauterine growth
restriction (IUGR) rate,
gestational age
Obtained from birth
records; LBWwas
defined as <2500 g
Age at outcome:
birth
Multiple linear and logistic
regression models were
adjusted for maternal age
and infant sex
(3 (95% Cl)b
Mean BW(g): -91 (-180,
-75)
Mean GA (weeks): 0.57
(0.51, 0.63)
OR (95% Cl)b
LBW: 1.61 (1.37, 1.90)
IUGR: 2.12 (1.68, 2.69)
Al-Saleh et al. (20141 n: 1,578
Cord blood
Al-Kharj
Saudi Arabia
2005-2006
Cross-sectional
Women aged 16- , ,, „„„
50 years who delivered UCB measured by AAS
in Al-Kharj hospital,
Saudi Arabia Age at Measurement:
maternal age 16-50; birth
Mean (SD):
UCB: 2.551 (2.592) pg/dL
Median:
UCB: 2.057 pg/dL
75th:
Prenatal growth: PI
PI was calculated as
BW (kilograms) divided
by birth height (m)
cubed
Age at outcome:
birth
Logistic regression model
was adjusted for maternal
age, parity, mother's third
trimester BMI, urinary
cotinine, geographical
distribution of current
dwelling, newborn
mother's highest
education, total family
income, and GA
OR (95% Cl)b: 0.766
(0.502, 1.167)
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Reference and Study Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Design Clsa
UCB: 2.689 pg/dL
Max:
UCB: 56.511 pg/dL
Kim et.a.1. (20201
Guiyu and Haojiang
China
Cross-sectional
e-waste Recycling
Exposure and
Community Health (e-
REACH) Study
n: 314
Women 18 years or
older with a singleton
pregnancy, had lived in
their respective town
for the duration of their
pregnancy, and
consented to
participate in the study.
Women were excluded
if they had a multiple
pregnancy, used
assistive reproductive
technology to become
pregnant, had a history
of psychiatric or thyroid
disorders, or lived
outside of their
respective town for a
cumulative of 3 months
or more during their
pregnancy
Blood
Maternal blood, collected at
delivery, was measured by
GFAAS
Age at Measurement:
>18 (age at delivery)
Geometric mean:
Guiyu: 6.7 pg/dL
Haojiang: 3.8 pg/dL
Max:
Guiyu: 27 pg/dL
Haojiang: 16 pg/dL
Prenatal growth: BW,
HC, GA, newborn BMI,
PI
GA was calculated
based on the last
menstrual period or last
missed period (LMP)
and the date of
delivery. Newborn BMI
and PI were calculated
using the recorded BW
and BL.
Age at outcome:
>18 (age at delivery)
Multiple linear and logistic
regression models were
adjusted for maternal age,
maternal education,
maternal occupation,
maternal BMI, gravidity,
environmental tobacco
smoke (ETS), and neonate
sex
(3 (95% CI)b, interpreted as
the difference in BW, HC,
BMI, or PI, per 1 -unit
increase In-Pb maternal
blood
BW (g): 60 (-15, 135)
HC (cm): -0.75 (-1.17,
-0.32)
BMI (kg/m2):
-0.14 (-0.39, 0.11)
PI (kg/m3): -0.62 (-1.13,
-0.11)
OR (95% Cl)b
SGA: 0.69 (0.33, 1.46)
Xu et al. (2022b)
Ushuaia (South,
higher income) and
Salta (North, lower
income)
Argentina
EMASAR
Blood
Prenatal growth: GA, Linear models adjusted for (3 (95% CI):
n- ggg BW, birth length, HC,
LBW
Maternal blood measured by
Women who either ICP-MS
were about to deliver or Medical records were
had given birth within Age at measurement: ^J^S'hir+h
the last 48 hours at one measures at birth.
maternal age, pre-
pregnancy BMI, parity,
smoking, and education
BW (g): -47.23 (-94.46,
0.004)
BL (cm):
-0.439 (-0.658, -0.219)
HC (cm):
-0.223 (-0.385, -0.061)
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Reference and Study
Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
2011-2012
Cross-sectional
of the two hospitals.
Women had to be
above 18 years of age.
birth
Age at outcome: birth
GA (weeks): 0.18 (0.05,
0.309)
Median0:
Overall: 1.34 pg/dL
Ushuaia: 0.98 [jg/dL
Salta 1.50 pg/dL
OR (95%CI)
LBW:
Tertile 1: Reference
Tertile 2: 0.59 (0.10, 3.55)
Geometric mean0:
Tertile 3: 0.53 (0.09, 3.16)
Overall: 1.393 pg/dL
Ushuaia: 1.01 pg/dL
Salta 1.58 pg/dL
75th°:
Overall: 1.851 pg/dL
Ushuaia: 1.30 pg/dL
Salta: 2.09 pg/dL
Huetal. (70151
Beigin, Lanzhou,
Taiyuan, Xiamen
China
June-August 2011
Cross-sectional
n: 81
Mother-infant pairs that
were enrolled from 4
hospitals in 4 cities in
China
Blood and cord blood
Maternal blood (serum) and
UCB (serum) were
measured by ICP-MS
Age at Measurement:
median maternal age: 28.5
years (range: 18-44); at
birth
Median:
Maternal: 23.1 ng/g
UCB: 22.0 ng/g
75th:
Maternal: 33.2 ng/g
UCB: 33.7 ng/g
Prenatal growth: BW
BWwas obtained from
the medical delivery
records
Age at outcome:
birth
Multivariate linear
regression models were
adjusted for infant gender,
maternal age, gestational
week, and maternal BMI
(3 (95% Cl)b
Maternal serum Pb: -1.7 g
(-9.1, 5.6)
UCB serum Pb: -1.5 g
(-5.2, 8.2)
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Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Yane et al. (2020)
Births at Women and
Children Medical and
Wuhan
Healthcare Center of
China
Wuhan
n: 734
2014-2015
The participants were
Cross-sectional
enrolled at their first
antenatal examination
^gestational
16 weeks). The
inclusion criteria were
(1) residence in Wuhan
city; (2) with a single
gestation; (3) willing to
take the following
prenatal care during
pregnancy and give
birth at the study
hospital; (4) willing to
complete
questionnaires and
provide blood samples
from the umbilical cord
at delivery.
Cord blood
UCB (serum) was measured
by ICP-MS
Age at Measurement:
birth
Geometric mean: 1.65 |jg/L
Median: 2.71 |jg/L
75th: 4.29 pg/L
Quartiles5
Q1
Q2
Q3
<25th percentile
25th - 50th percentile
50th - 75th percentile
Q4: >75th percentile
Prenatal growth: BW
(birth weight-for-
gestational-age Z-
score [BWGA])
Midwives immediately
measured BW after
delivery and was
standardized for
gestational weeks to
construct BWZ.
Age at outcome:
birth
Generalized linear
regression models
adjusted for maternal age,
annual household income
levels, pre-pregnancy BMI,
parity, passive smoking
during pregnancy,
maternal weight gain
during pregnancy, fetal
sex
(3 (95% Cl)b, per unit
increase in In-Pb UCB
serum
Continuous: 0.01 (-0.002,
0.05)
Quartiles:
Q1
Q2
Q3
Q4
Reference
0.11 (-0.09, 0.30)
-0.05 (-0.24, 0.14)
0.05 (-0.14, 0.24)
p for trend: 0.84
Tang et al. (20161
Shengsi Island,
Hangzhou
China
July 2011 to May 2012
Cross-sectional
n: 103
Eligible pregnant
women included those
planning to deliver at
the only hospital,
without apparent
clinical symptoms,
without any maternal
history of illness, and
no poor habits such as
drug use. Eligible
infants were singleton
Cord blood
UCB (serum) measured by
ICP-MS
Age at Measurement:
birth
Mean (SD)C: 12.841
(28.646) [jg/dL
Median0: 7.620 pg/dL
75thc: 11.580 pg/dL
Prenatal growth: BW,
length (height), and HC
and gestational age
All of these infant
anthropometric
measurements were
collected at birth by
professional healthcare
workers. GAwas
obtained using the
reported date of the
last menstrual period
and delivery date.
Multivariable linear
regression models were
adjusted for maternal BMI,
maternal age, education
level, newborn gender,
number of abortions,
parity, and pregnancy
weight gain
(3 (95% Cl)b
BW (g): -0.019 (-0.045,
0.006)
BL (cm): 0.29 (-0.50,
-0.09)
HC (cm): -0.22 (-0.44,
-0.00)
GA (weeks): -0.21 (-0.44,
0.03)
BW, in g:
T1: Reference
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Design Clsa
Freire et al. (20191
Spain
2000-2008
Cross-sectional
births and had no
congenital diseases.
Tertiles (|jg/dL)c:
T1: <5.633
T2: 5.633-9.197
T3: >9.197
Age at outcome:
birth
T2: -0.15 (-0.41, 0.11)
T3: -0.05 (-0.30, 0.21)
BL, in cm:
T1
T2
T3
Reference
-0.13 (-0.39, 0.13)
-0.15 (-0.40, 0.11)
HC, in cm:
T1
T2
T3
Reference
-0.31 (-0.59, -0.02)
-0.13 (-0.40, 0.14)
GA, in weeks:
T1
T2
T3
Reference
-0.23 (-0.50, 0.05)
-0.20 (-0.49, 0.08)
Other: Placenta
Environment and
Childhood (INMA)
Project
n: 327
Pregnant women of
general population
resident in each study
area [Ribera d'Ebre,
Menorca, Granada,
Valencia, Sabadell,
Asturias and Gipuzkoa]
and their children.
Criteria for inclusion of
the mothers were: (i) to
be resident in one of
the study areas, (ii) to
be at least 16 years
old, (iii) to have a
Placenta (including maternal
and fetal sides as well as
central and peripheral parts)
measured with GFAAS
using AAS with Zeeman
background correction
Median: <6.5 ng/g (limit of
detection [LOD])
75th: <6.5 ng/g (LOD)
Prenatal growth: BW,
length, HC, LBW, GA,
and SGA
Neonatal
anthropometric
measurements were
obtained by the
attending midwife or
nurse; GA was
calculated as the
number of weeks from
the self-reported last
menstrual period to the
end of pregnancy; LBW
was defined by a BW
of less than 2500 g at
term, newborns were
defined as SGA when
Linear models or logistic
regression models were
adjusted for adjusted for
cohort (random effect),
newborn sex, and co-
exposure to other metals
(As, Hg, Cd, Mn, Cr); BW
and LBW models were
additionally adjusted for
GA, maternal smoking
during pregnancy,
maternal working during
pregnancy, and pre-
pregnancy BMI; BL
models were additionally
adjusted for GA and
maternal smoking during
pregnancy; HC models
were additionally adjusted
(3 (95% Cl)b
BW (g): 54.57 (-70.84,
180.0)
BL (cm): -0.26 (-0.97,
0.44)
HC (cm): -0.10 (-0.57,
0.36)
GA (weeks): -0.11 (-0.57,
0.36)
OR (95% Cl)b
LBW: 2.94 (0.38, 28.34)
SGA: 1.69 (0.53, 8.82)
Age at Measurement:
birth
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Outcome
Confounders
Effect Estimates and 95%
Clsa
singleton pregnancy,
below the 10th
for GA, maternal smoking
(iv) to not have followed
percentile of the
during pregnancy, pre-
any program of
expected weight
pregnancy BMI, and
assisted reproduction,
according to the
cesarean delivery; GA
(v) to wish to deliver in
Spanish BW curve
models were additionally
the reference hospital
adjusted for GA and
adjusted for maternal
and (vi) to have no
sex
education level; SGA
communication
models were additionally
problems
Age at outcome:
adjusted for father's
birth
education and maternal
working during pregnancy
Mikelson et al. (20191 n: 374
Chattanooga, TN
United States
Cross-sectional
Singleton births of HIV
and hepatitis negative
mothers over 18 years
of age, with GA greater
than 34 weeks, and
infants with no major
morphological or
chromosomal
abnormalities
Other: Placenta
Placenta tissue measured
by ICP-MS
Age at Measurement:
birth
Mean (SD): 37.97
(270.5) pg/kg
Median: 12.03 pg/kg
75th: 23.23 pg/kg
Max: 5073 pg/kg
Prenatal growth: BW
Obtained at birth
records
Age at outcome:
birth
Multivariable regression
models adjusted maternal
pre-pregnancy BMI,
maternal age, GA, race,
infant sex, and smoking
while pregnant
(3 (95% Cl)b: -58.3 g
(-97.9, -18.8)
(3 (95% CI)b, as estimated
change in BW from 25th to
75th percentile: -72.7 g
(-122, -23.4)
Bloom et al. (20151
Michigan (4 counties)
and Texas (12
counties)
United States
2005-2009
Cohort
LIFE
n: 235
Potential participants
were identified, using
fishing license
registries or a
commercially available
direct marketing data
base, from 12 counties
in Texas and four in
Michigan, respectively,
with presumed
exposure to persistent
Blood
Maternal and paternal blood,
collected before pregnancy
(baseline), were measured
by ICP-MS
Age at Measurement:
>18, maternal mean age:
29.75 (SD: 3.73) years and
paternal mean age: 31.52
(SD:4.57) years
Prenatal growth: GA,
BW, birth length, HC,
PI, and secondary sex
ratio
Women were followed
until delivery when they
completed and
returned birth
announcements that
captured date and sex
of birth, weight and
length, and HC.
Secondary sex ratio is
Multiple regression models
for continuous outcomes:
effect of maternal
exposure adjusted for
paternal exposure,
maternal age, difference in
maternal and paternal age,
and maternal and paternal
smoking, income, race,
serum lipids (mg/dL), and
creatinine for urine
(mg/dL); effect of paternal
exposure adjusted for
maternal exposure,
(3 (95% CI):
GA, in days
Maternal Exposure:
T1: Reference
T2: 0.43 (-0.48, 1.35)
T3: 0.14 (-0.81, 1.09)
p for trend: 0.671
Paternal Exposure:
T1: Reference
T2: 0.19 (-0.70, 1.08)
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Reference and Study Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
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organic pollutants.
Inclusion criteria
comprised a committed
heterosexual
relationship, women
aged 18-40 years (men
>18), English or
Spanish speaker, no
use of an injectable
contraceptive within 12
months, and a
menstrual cycle length
of 21-42 days.
Mean (SD):
Maternal: 0.71 (0.30) pg/dL
Paternal: 1.13 (0.63) pg/dL
Median:
Maternal: 0.66 pg/dL
Paternal: 0.98 pg/dL
Max:
Maternal: 2.23 pg/dL
Paternal: 6.43 pg/dL
Tertiles (pg/dL):
Maternal Blood Pb
T1: <0.55 (<33rd percentile)
T2: 0.55-0.73 (33rd to 67th
percentile)
T3: >0.73 (>67th percentile)
Paternal Blood Pb
T1: <0.84 (<33rd percentile)
T2: 0.84-1.16 (33rd to 67th
percentile)
T3: >1.16 (>67th percentile)
the ratio of live male to
female births, reflecting
a male excess.
Age at outcome:
birth
paternal age, difference in
maternal and paternal age,
and maternal and paternal
smoking, income, race,
serum lipids (mg/dL), and
creatinine for urine
(mg/dL)
T3: 0.61 (-0.31, 1.53)
p for trend: 0.416
BW, in kg
Maternal Exposure:
T1: Reference
T2: 81.80 (-79.94,
2238.55)
T3: -34.885 (-197.76,
128.06)
p for trend: 0.202
Paternal Exposure:
T1: Reference
T2: 20.46 (-134.17,
175.09)
T3: 62.91 (-94.73, 220.55)
p for trend: 0.882
BL, in cm
Maternal Exposure:
T1: Reference
T2: 0.43 (-0.48, 1.35)
T3: 0.14 (-0.81, 1.09)
p for trend: 0.671
Paternal Exposure:
T1: Reference
T2: 0.19 (-0.70, 1.08)
T3: 0.61 (-0.31, 1.53)
p for trend: 0.416
HC, in cm
Maternal Exposure:
T1: Reference
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Design Clsa
T2: 0.03 (-0.68, 0.74)
T3: -0.33 (-1.07, 0.41)
p for trend: 0.132
Paternal Exposure:
T1: Reference
T2: 0.12 (-0.57, 0.80)
T3: -0.03 (-0.72, 0.67)
p for trend: 0.971
PI, in kg/cm3
Maternal Exposure:
T1: Reference
T2: 0.82 (-7.66, 9.31)
T3: -4.26 (-13.16, 4.64)
p for trend: 0.321
Paternal Exposure:
T1: Reference
T2: -0.22 (-8.50, 8.05)
T3: -5.19 (-13.71, 3.33)
p for trend: 0.150
Rabito et al. (20141
Shelby County,
Tennessee
United States
2008-2011
Cohort
Conditions Affecting
Neurocognitive
Development and
Learning in Early
Childhood (CANDLE)
study
n: 98
Healthy pregnant
woman between the
ages of 16 and
40 years, carrying a
single fetus with the
intent to deliver the
fetus, residence within
Blood and cord blood
Maternal blood and UCB
were measured by ICP-MS
Age at Measurement:
Maternal age at collection
(second or third trimester or
delivery) (median:
29.50 years); birth
Median:
Second trimester:
0.43 [jg/dL
Third trimester: 0.43 |jg/dL
Prenatal growth: BW
BWwas obtained from
medical records
Age at outcome:
birth
Linear regression models
were adjusted for gravidity,
marital status, and GA (in
weeks)
(3 (95% Cl)b, per 0.1 -unit
increase in second
trimester maternal blood
Pb: -43.21 g (-88.6, 2.18)
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Design Clsa
Shihetal. (2021)
United States
January 2009-
September 2010
Cohort
Blood
Maternal blood was
Prenatal growth: birth
length, HC, BW, GA,
and PI
At delivery: 0.50 [jg/dL
Cord blood: 0.37 [jg/dL
Geometric mean (SD):
Second trimester: 0.42
(0.20) [jg/dL
Third trimester: 0.45
(0.28) [jg/dL
At delivery: 0.50
(0.35) [jg/dL
Cord blood: 0.37
(0.32) [jg/dL
Shelby County,
Tennessee, and having
the intent to deliver at
one of three area-
based hospitals
Initial Vanguard Study
of the National
Children's Study
n: 125 (68 males, 57
females)
Mother-infant pairs
enrolled in the National
Children's Study.
Max:
Second trimester:
1.22 [jg/dL
Third trimester: 2.10 |jg/dL
At delivery: 2.47 [jg/dL
Cord blood: 1.80 [jg/dL
measured using dynamic
reaction cell ICP-MS.
Age at measurement:
Maternal age at 6-32 weeks
of gestation
Median:
Overall: 0.34 [jg/dL
Male infants: 0.35 [jg/dL
Female infants: 0.33 [jg/dL
Birth outcomes
measured during
physical examination of
infants at birth; BL (cm)
and HC (cm) were
measured twice, and
the average of the two
readings was used. For
those without
measures at birth,
medical records were
extracted by the
National Children's
Study. GA and BW
were obtained from
medical records.
Linear regression models
adjusted for maternal age,
race/ethnicity, education,
income, smoking status
during pregnancy, number
of prior livebirths,
continuous BMI, and infant
sex
(3 (95% CI)b, as expected
change for birth outcomes
GA (weeks)
Overall: -0.558 (-2.297,
1.181)
Males: 1.084 (-0.855,
3.024)
Females: -4.335 (-7.365,
-1.305)
BW (g)
Overall: -403.593
(-916.671, 109.485)
Males: 141.814 (-431.7,
715.329)
Females: -1685.349
(-2581.105, -789.592)
BL (cm)
Max:
Overall: 2.86 [jg/dL
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Design Clsa
Male infants: 2.86 [jg/dL Overall: -0.343 (-2.92,
Female infants: 0.85 pg/dL A9e at outcome: birth 2.233)
Males: 2.211 (-0.667,
5.089)
Females: -6.37 (-10.86,
-1.88)
HC (cm)
Overall: -1.245 (-2.769,
0.279)
Males: 0.292 (-1.397,
1.981)
Females: -4.866 (-7.52,
-2.212)
PI (kg/m3)
Overall: -3.134 (-6.698,
0.429)
Males: -2.377 (-6.486,
1.731)
Females: -4.733 (-11.191,
1.725)
Woods etal. (70171
Cincinnati, Ohio
United States
2003-2006
Cohort
Home Observation for
Measurement of the
Environment (HOME)
Study
n: 272
Women were recruited
between 13 and
19 weeks of pregnancy
from prenatal clinics
and were >18 years
old, <19 weeks
gestation at the time of
enrollment, and living in
a residence built before
1987
Blood
Maternal blood was
measured by sensitive and
specific liquid or gas
chromatography mass
spectrometry
Age at measurement:
maternal age at 16-
26 weeks gestation
Geometric mean (geometric
SD): 0.7 (1.4) pg/dL
Median: 0.7 pg/dL
75th: 0.8 pg/dL
Prenatal growth: BW
BW was abstracted
from birth records
Age at outcome:
birth
Bayesian hierarchical
linear models were
adjusted for maternal race,
age at delivery, infant sex,
maternal education,
tobacco exposure,
household annual income,
employment, maternal
insurance status, marital
status, pre-natal vitamin
use, and maternal BMI;
sensitivity analysis
included gestational age
Posterior mean (95%
credible interval)15, as the
difference in BW per 10-
fold increase in maternal
blood Pb: -44.8 g (-110,
21.7)
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Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Taylor etal. (20161
Bristol, UK
April 1991-December
1992
Cohort
Avon Longitudinal
Study of Parents and
Children (ALSPAC)
n: 4,190
All pregnant women in
the former Avon Health
Authority with an
expected delivery date
between April 1,1991
and December 31,
1992 were eligible for
the study; 14,541
pregnant women were
initially enrolled,
resulting in a cohort of
14,062 live births
Blood
Maternal blood was
measured by ICP-MS
Age at measurement:
maternal age at
measurement (median GA
of sampling: 11 weeks)
Median: 3.40 [jg/dL
75th: 4.33 pg/dL
Max: 19.41 pg/dL
Prenatal growth: BW,
HC, crown-heel length
HC and crown-heel
length (CHL) were
measured by trained
study staff where the
mother gave
permission or if these
data were missing, the
values were extracted
from the medical
records by trained
study staff. BW was
derived from obstetric
data and from central
birth notification data:
where values
disagreed by <100 g
then the lowest value
was accepted; if the
values disagreed by
>100 g then the value
was coded as missing.
Age at outcome:
birth
Multivariable fractional
polynomials and modeled
adjusted for maternal
educational attainment,
smoking, GA (centered at
40 weeks), maternal
height and pre-pregnancy
weight, and sex of the
infant
(3 (95% CI)
BW (g): -9.93 (-20.27,
0.41)
HC (cm): -0.03 (-0.06,
0.00)
CHL (cm): -0.05 (-0.10,
0.00)
Garria-Esauinas et al.
(20141
Madrid
Spain
October 2003-May
2004
Cohort
BioMadrid Project
n: 97
Women were required
to be aged over
15 years, to be
expecting a single
pregnancy, intend to
deliver their babies at
the public hospital
assigned to them, lived
in the study area
Blood and cord blood
Blood, from both parents,
and UCB measured by AAS
with a transversely heated
graphite atomizer furnace
assembly and longitudinal
Zeeman-effect background
correction
Age at measurement:
maternal and paternal age
at median gestational week
Prenatal growth: GA,
BW, birth length,
abdominal diameter
(AD), or cephalic
diameter (CD)
GA, BW, birth length,
AD, or CD was
collected at delivery
Age at outcome:
birth
Multivariable linear
regression models were
adjusted for sampling
maternal age, maternal
tobacco smoke, area
(metropolitan/urban), and
in non-stratified models,
newborn's sex
(3 (95% CI)b, as mean
difference per two-fold
increase in BLL
Maternal blood Pb
BW (g): 62.4 (-73.1, 197.8)
BL (cm): 0.17 (-0.56, 0.91)
AD (cm): 0.31 (-0.52, 1.15)
CD (cm): 0.15 (-0.21, 0.51)
GA (weeks): 0.02 (-0.44,
0.47)
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(Madrid Autonomous
Region) for more than a
year, and did not have
a blood transfusion in
the previous year
-0.00)
CD (cm): -0.32 (-0.65,
0.00)
GA (weeks): -0.17 (-0.59,
0.26)
UCB Pb
BW (g): 80.0 (-36.8, 196.6)
BL (cm): 0.30 (-0.33, 0.93)
AD (cm): 0.56 (-0.12, 1.24)
CD (cm): -0.16 (-0.47,
0.15)
GA (weeks): -0.04 (-0.44,
0.35)
Male Infants
Maternal blood Pb
BW (g): 62.6 (-145.2,
270.4)
BL (cm): 0.29 (-0.83, 1.41)
AD (cm): 1.10 (-0.25, 2.45)
CD (cm): -0.16 (-0.47,
0.15)
GA (weeks): 0.11 (-0.58,
0.81)
Paternal blood Pb
was 33.9 (IQR 31.6-35.7)
and at birth
Geometric mean0:
Maternal: 1.83 [jg/dL
Paternal: 3.17 [jg/dL
UCB: 0.45 ug/dL
Paternal blood Pb
BW (g): -110.8 (-235.6,
6.0)
BL (cm): -0.44 (-1.12,
0.23)
AD (cm): -0.81 (-1.64,
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Reference and Study Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Design Clsa
BW (g): -93.5 (-269.6,
82.5)
BL (cm): 0.13 (-0.81, 1.06)
AD (cm): -0.64 (-1.89,
0.61)
CD (cm): -0.11 (-0.57,
0.35)
GA (weeks): 0.06 (-0.53,
0.65)
UCB Pb
BW (g): 80.0 (-66.0, 226.0)
BL (cm): 0.66 (-0.11, 1.44)
AD: 0.76 cm (-0.16, 1.67)
CD: -0.11 cm (-0.37, 0.39)
GA: 0.06 weeks (-0.53,
0.65)
Female Infants
Maternal blood Pb
BW (g): 62.2 (-128.0,
252.4)
BL (cm): 0.08 (-0.95, 1.10)
AD (cm): -0.21 (-1.30,
0.88)
CD (cm): -0.05 (-0.55,
0.46)
GA (weeks): -0.06 (-0.70,
0.57)
Paternal blood Pb
BW (g): -129.4 (-312.3,
53.4)
BL (cm): -1.06 (-2.03,
-0.08)
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Design
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
AD (cm): -1.94 cm (-2.06,
0.18)
CD (cm): -0.55 (-1.03,
-0.07)
GA (weeks): -0.41 (-1.02,
0.21)
UCB Pb
BW (g): 80.0 (-115.7,
275.7)
BL (cm): -0.37 (-1.41,
0.67)
AD (cm): 0.31 (-0.73, 1.35)
CD (cm): -0.47 (-0.98,
0.05)
GA (weeks): -0.13 (-0.79,
0.65)
Daniali et al. (20231
Isfahan, Iran
2019-2020
Cress-sectional
Prospective
Epidemiological
Research Studies in
Iran - Isfahan Center
n: 263
Pregnant Iranian
women who have lived
in Isfahan for at
least 1 yr, and did not
have any history of
infertility, those
in the first trimester of
pregnancy, and those
who intended to give
birth in hospitals of
Isfahan city. All
participants with major
Blood
Maternal blood was
measured by ICP-MS
Age at measurement:
maternal age at first
trimester (mean maternal
age 29.94 years)
Geometric mean ± SD:
2.534 ± 0.205 pg/dL
Median: 2.786 pg/dL
25th: 1.741 pg/dL
75th: 4.01 pg/dL
Prenatal growth: BW,
HC, birth length
Standardized neonatal
anthropometric
measurements were
obtained by trained
midwives using
calibrated instruments.
Age at outcome: birth
Infant sex, and maternal
age, BMI at enrollment
(12-14 weeks gestation),
income, secondhand
smoke exposure, parity,
and education.
(3 (95%CI)
BW (g): -0.057 (-0.099,
-0.014)
BL (cm): 0.01 (-0.034,
0.054)
HC (cm): -0.036 (-0.076,
0.004)
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Design Clsa
risks of SGA and IUGR
such
as serious medical
complications
(hypertension or
diabetes or kidney
disease), cerclage until
24 weeks of pregnancy,
history of stillbirth or
preterm labor, multiple
pregnancies, or
abnormal sonographic
evidence were
excluded from the
study.
Taylor etal. (20151
Bristol
UK
April 1991-December
1992
Cohort
ALSPAC
n: 4,285
All pregnant women in
the former Avon Health
Authority with an
expected delivery date
between April 1, 1991,
and December 31,
1992 were eligible for
the study
Blood
Maternal blood was
measured by ICP-MS
Age at measurement:
maternal age at
measurement (median GA
of sampling: 11 weeks)
Mean (SD): 3.67
(1.47) [jg/dL
Geometric mean: 3.43 [jg/dL
Median: 3.42 [jg/dL
Max: 19.14 pg/dL
Prenatal growth: BW,
HC, crown-to-heel
length (CHL), and LBW
BW, HC, and CHL
were measured by
trained staff or
extracted from medical
records; LBW was
<2500 g
Age at outcome:
birth
Linear regression models
were adjusted for maternal
height, maternal pre-
pregnancy weight,
maternal educational
attainment, parity, number
of cigarettes per day, sex
of baby, GA at delivery or
death; logistic regression
models for LBW were
adjusted for maternal
height, maternal pre-
pregnancy weight,
maternal educational
attainment, parity, number
of cigarettes per day, sex
of baby and GA at delivery
or death
(3 (95% CI)
BW (g): -1.62 (-2.909,
-0.331)
HC (cm): -0.005 (-0.043,
0.033)
CHL (cm): -0.006 (-0.013,
0.001)
OR (95% CI)
LBW: 1.37 (0.86, 2.18)
Huetal. (20211
Canada
MIREC
n: 1857
Women from the
MIREC cohort who
Blood
Maternal blood was
measured by ICP-MS
Prenatal growth: BW
Infant BW (g)
abstracted from
Maternal age, race, (3 (95% CI), as two-fold
education, pre-pregnancy increase in Pb blood
BMI, smoking status,
parity, infant sex, cubic- Sing|e poNutant mode|:
spline GA; multi-pollutant -q2.22 g (-145.46, -18.97)
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Study Population
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Outcome
Confounders
Effect Estimates and 95%
Clsa
2008-2011
Cohort
delivered singleton live
births, had complete
sociodemographic
information, and
provided biological
samples during the first
trimester of the
pregnancy.
Age at Measurement:
Maternal age during first
trimester
Geometric mean0:
0.62 [jg/dL
Median0: 0.60 [jg/dL
75th°: 0.85 pg/dL
medical records and
examined continuously.
Age at outcome: birth
model was also adjusted
for As, Cd, Hg, and Mn
Multi-pollutant model:
-75.89 g (-141.24, -10.54)
Goto et al. (2021)
Japan
January 2011-March
2014
Cohort
JECS
n: 16,423
Pregnant women living
in the study area and
understanding ofthe
Japanese language.
Participants were
excluded: if they did not
meet the Pb
measurement quality
control criteria
(n = 2,002); if mothers
who: were lost to
follow-up; had severe
maternal conditions
preceding pregnancy,
such as chronic
hypertension,
pregestational diabetes
or cardiac disease,
during pregnancy; or
had pregnancies
ending in abortions or
stillbirths (n = 1,209); if
infants had
chromosomal or major
congenital anomalies
Blood
Maternal blood was
measured by ICP-MS
Age at measurement:
maternal age at second or
third trimester (mean age at
delivery: 31 ± 5.0 years)
Mean: 0.69 pg/dL
Median: 0.63 pg/dL
75th: 0.78 pg/dL
Max: 7.4 pg/dL
Prenatal growth: BW,
SGA, and LBW
BWwas the primary
outcome.
Anthropometric data
were measured by
trained delivery room
staff. Gestational
dating was performed
from the first accurate
ultrasound examination
during the first
trimester. SGA was
defined as a BW below
the 10th percentile of
the national BWs
reported in the
Japanese standard
growth chart, which
also considers GA,
infant sex, and
maternal parity. LBW
was defined as a BW
below 2500 g,
regardless of GA.
Multivariable linear
regression models were
adjusted for maternal age
at birth, BMI before
pregnancy, weight gain
during pregnancy,
maternal educational
background, a history of
preterm birth, alcohol
consumption during
pregnancy, smoking habit
during pregnancy, and
parity
(3 (95% CI), per 0.1 pg/dL
increase in maternal blood
Pb
BW (g): -54 (-74.5, -33.5)
HC (cm): -0.10 (-0.05,
-0.15)
BL (cm): -0.20 (-0.30,
-0.10)
GA (days): 0.20 d (-0.35,
0.75)
(3 (95% CI), per doubling
increment in maternal
blood Pb
BW (g): -86.595 (-112.16,
-61.03)
HC (cm): -0.152 (-0.25,
-0.054)
BL (cm): -0.326 (-0.468,
-0.185)
GA (days): 0.087 (-0.566,
0.74)
OR (95% CI), per 0.1 pg/dL
increase in maternal BLL
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Design Clsa
(n = 263) or multiple
births (n = 283)
Age at outcome:
birth
SGA: 1.34 (1.16, 1.55)
LBW: 1.34 (1.16, 1.55)
OR (95% CI), per doubling
increment in maternal
blood Pb
SGA: 1.952 (1.526, 2.498)
LBW: 1.34 (1.16, 1.55)
Rodosthenous et al.
(20171
Mexico City
Mexico
2007-2011
Cohort
PROGRESS
n: 944
Inclusion criteria:
singleton pregnancy,
GA <20 weeks,
maternal age of
>18 years, expectation
to live in Mexico City for
the following 3 years,
and have access to a
telephone; exclusion
criteria: chronic medical
conditions such as
heart or kidney
disease; use of steroids
or anti-epilepsy drugs;
drug addiction; and
daily consumption of
alcoholic beverages
due to its association
with adverse fetal
outcomes
Blood
Maternal blood measured by
ICP-QQQ
Age at measurement:
maternal age at -20 weeks
gestation
Mean (SD): 3.7 (2.7) pg/dL
Quartile Mean (SD) (pg/dL):
Q1: 1.4 (0.3)
Q2: 2.4 (0.2)
Q3: 3.6 (0.5)
Q4: 7.3 (2.8)
Median: 2.8 pg/dL
75th: 4.5 pg/dL
Max: 22.9 pg/dL
Quartiles (pg/dL)
Q1: <1.93
Prenatal growth:
BWGA, SGA
Infants with a BWGA Z-
score <10th percentile
as SGA
Age at outcome:
birth
Q2
Q3
1.93-2.79
2.80-4.53
Multivariable linear
regression models were
adjusted for maternal age,
BMI, SES, hemoglobin
levels, and infant sex
Quantile regression
models were adjusted for
maternal age, BMI, SES,
hemoglobin levels, and
infant sex
Multivariable logistic
regression models were
adjusted for maternal age,
BMI, SES, hemoglobin
levels, and infant sex
Q4: >4.53
P (95% CI)b, as difference
in BWGA Z-score per log2
increase in maternal BLL:
-0.06 (-0.013, 0.03)
(3 (95% Cl)b, as the BWGA
Z-score per log2 increase in
maternal BLL
QL 0.05: -0.08 (-0.19,
0.03)
QL 0.10: -0.13 (-0.25,
-0.004)
QL 0.15: -0.11 (-0.22,
-0.002)
QL 0.20: -0.12 (-0.20,
-0.03)
QL 0.25: -0.10 (-0.19,
-0.02)
QL 0.30: -0.11 (-0.18,
-0.04)
QL 0.35: -0.04 (-0.12,
0.04)
QL 0.40: -0.06 (-0.14,
0.03)
QL 0.45: -0.05 (-0.13,
0.04)
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Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
QL 0.50:
0.01)
QL 0.55:
0.01)
QL 0.60:
0.01)
QL 0.65:
0.04)
QL 0.70:
0.03)
QL 0.75:
0.06)
QL 0.80:
QL 0.85:
0.04)
QL 0.90:
0.02)
QL 0.95:
0.09)
-0.07
-0.07
-0.07
-0.04
-0.04
-0.01
-0.02
-0.06
-0.06
-0.02
-0.16,
-0.16,
-0.15,
-0.12,
-0.12,
-0.08,
-0.1, 0.06)
-0.16,
-0.16,
-0.13,
OR (95% CI) for SGA:
Q1: Reference
Q2: 1.30 (0.79, 2.15)
Q3: 1.15 (0.92, 1.45)
Q4: 1.09 (1.00, 1.18)
p for trend: 0.06
Ashrap et al. (20201
Puerto Rico
2010-2017
Cohort
PROTECT
n: 731
Participants were
recruited at
approximately
14 ± 2 weeks of
gestation at seven
prenatal clinics and
Blood
Maternal blood was
measured by ICP-MS
Age at measurement:
18-40 (collection between
18 and 26 weeks of
Prenatal growth: GA,
SGA, LGA, BWZ
All the birth outcome
data were extracted
from medical records.
GA was calculated;
BWZ was defined as
the number of SDs by
Logistic regression models
were adjusted for maternal
age, maternal education
level, pre-pregnancy BMI,
and exposure to second-
hand smoking
(3 (95% CI)b, per change
per IQR increase in
maternal blood In-Pb
GA (days):
-0.5)
Tertilesd:
GA (days):
¦1.8 (-3.1,
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Design Clsa
Thomas et al. (20151
Canada
2008-2011
Cohort
hospitals throughout
Northern Puerto Rico
and followed until birth;
maternal age between
18 and 40 years;
residence inside of the
Northern Karst aquifer
region; disuse of oral
contraceptives within
the 3 months prior to
pregnancy; disuse of in
vitro fertilization to
become pregnant; and
free of any major
medical or obstetrical
complications, including
pre-existing diabetes.
Each woman
participated in a total of
up to three study visits
(18 ± 2 weeks,
22 ± 2 weeks, and
26 ± 2 weeks of
gestation).
gestation)
Geometric mean (SD):
Preterm births: 0.39
(1.6) pg/dL
Term births: 0.32 (1.5) pg/dL
Median:
Preterm births: 0.36 pg/dL
Term births: 0.32 pg/dL
which a birth weight is
above or below the
mean; SGA births were
defined as below the
10th percentile of
BWZs; LGA births were
defined as above the
90th percentile of
BWZs
Age at outcome:
birth
T1: Reference
T2: -0.2 (-2.9, 2.4)
T3: -2.9 (-5.5, -0.2)
BW Z-score:
T1: Reference
T2: -0.12 (-0.32, 0.07)
T3: 0.09 (-0.11, 0.29)
OR (95% CI)b, per change
per IQR increase in
maternal blood In-Pb
SGA: 0.91 (0.69, 1.2)
Tertilesd:
SGA
T1
T2
T3
LGA
T1
T2
T3
Reference
1.58 (0.88, 2.83)
0.62 (0.30, 1.26)
Reference
1.13 (0.63, 2.03)
0.74 (0.40, 1.40)
MIREC Study
n: 1,835
Pregnant women were
recruited in the first
trimester of pregnancy
from 10 study sites
across Canada.
Exclusion criteria
included: inability to
communicate and
consent in either
Blood
Maternal blood, collected
during the first and third
trimesters of pregnancy,
was measured by ICP-MS
Age at Measurement:
Maternal age at first and
third trimesters
Prenatal growth: SGA
SGA births were
identified as those
weighing less than the
10th percentile for a
reference population
based on the same
completed week of
gestation and infant
sex
Log binomial multivariate
regression models
estimated relative risk and
adjusted for smoking and
parity
RR (95% CI):
T1
T2
T3
Reference
1.33 (0.88, 1.99)
1.19 (0.65, 2.18)
RR (95% CI) for GSTP1
A114V
CC
Pb <0.08 pg/dL: Reference
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Outcome
Confounders
Effect Estimates and 95%
Clsa
French or English,
>14 weeks gestation at
the time of recruitment,
<18 years of age,
diagnosed with a fetal
anomaly or a history of
major chronic disease.
Excluded from the
analysis were: 18
women who withdrew
during the study, 51
women who gave birth
to multiples, 9
stillbirths, 32
spontaneous abortions,
13 therapeutic
abortions, 28 with no
metal exposure data,
and 15 with no infant
sex, weight, or GA
recorded
Median: 0.59 [jg/dL
75th: 0.81 pg/dL
Max: 4.04 pg/dL
Tertiles (pg/dL):
Age at outcome:
birth
T1
T2
T3
<0.52
0.52-1.04
>1.04
Pb >0.08 pg/dL: 0.90 (0.57,
1.41)
TC + tT
Pb <0.08 pg/dL: Reference
Pb >0.08 pg/dL: 2.25 (0.95,
5.16)
p for interaction: 0.06
RR (95% CI) for GSTP1
1105V
AA
Pb <0.08 pg/dL: Reference
Pb >0.08 pg/dL: 1.22 (0.69,
2.15)
AG + GG
Pb <0.08 pg/dL: Reference
Pb >0.08 pg/dL: 0.95 (0.54,
1.66)
p for interaction: 0.53
RR (95% CI) for GST01
A104A
CC
Pb <0.08 pg/dL: Reference
Pb >0.08 pg/dL: 0.94 (0.52,
1.69)
CA + AA
Pb <0.08 pg/dL: Reference
Pb >0.08 pg/dL: 1.20 (0.70,
2.06)
p for interaction: 0.54
Ashrap et al. (20211 PROTECT Blood Prenatal growth: GA, Linear and logistic (3 (95% CI)b, per IQR
n = g32 BWZ, small for regression models were increase in in maternal
adjusted for maternal age, blood In-Pb
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Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Puerto Rico
2011-2017
Cohort
Participants were
recruited at
approximately
14 ± 2 weeks of
gestation at seven
prenatal clinics and
hospitals throughout
Northern Puerto Rico
and followed until birth;
maternal age between
18 and 40 years;
residence inside of the
Northern Karst aquifer
region; disuse of oral
contraceptives within
the 3 months prior to
pregnancy; disuse of in
vitro fertilization to
become pregnant; and
free of any major
medical or obstetrical
complications, including
pre-existing diabetes.
Each woman
participated in a total of
up to three study visits
(18 ± 2 weeks,
22 ± 2 weeks, and
26 ± 2 weeks of
gestation)
Maternal blood was
measured by ICP-MS
Age at measurement:
18-40 (collection between
18 and 26 weeks of
gestation)
Geometric mean: 3.1 [jg/dL
Median: 3.1 [jg/dL
75th: 4.1 [jg/dL
95th: 6.5 pg/dL
Max: 15.1 pg/dl_
gestation, large for
gestation
Birth outcomes were
extracted from medical
records. Psychosocial
status was evaluated
using four
questionnaires
Age at outcome: birth
maternal education, pre-
pregnancy BMI, second-
hard smoke exposure
GA, change in days
Good Psychosocial Status:
-1.9 (-3.2, -0.6)
Poor Psychosocial Status:
-1.3 (-4.0, 1.5)
BWZ, change in Z-score
Good Psychosocial Status:
0.1 (0.0, 0.2)
Poor Psychosocial Status:
-0.1 (-0.3, 0.2)
OR (95% CI)b, per IQR
increase in in maternal
blood In-Pb
SGA
Good Psychosocial Status
0.86 (0.65, 1.14)
Poor Psychosocial Status:
1.49 (0.67, 3.33)
LGA
Good Psychosocial Status
0.89 (0.64, 1.23)
Poor Psychosocial Status:
1.10 (0.57, 2.10)
Gustin et al. (2020)
Norrbotten County
Sweden
2015-2018
Cohort
NICE
n: 589
The cohort was
established in the
catchment area of
Sunderby hospital in
Norrbotten county,
Sweden. At the routine
Blood
Maternal blood (erythrocyte)
was measured by ICP-MS
Age at measurement:
Maternal age at gestational
week 24-36 (mean:
Prenatal growth: BW,
birth length, and HC
Information on the
infants' weight (g),
length (cm), and HC
(cm) at birth was
collected from the
hospital records at
Multivariable-adjusted
linear and spline
regression models were
adjusted for maternal age,
early-pregnancy BMI,
parity, education, pre-
pregnancy smoking, pre-
pregnancy snuff or non-
smoking tobacco use, pre-
(3 (95% CI)b:
BW (g): -13 (-66, 41)
p for interaction with infant
sex: 0.88
BL (cm): -0.080 (-0.31,
0.15)
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Design Clsa
Rahman et al. (20211
Massachusetts
United States
1999-2002
Cohort
ultrasound in
gestational week 17-
18, parents who were
interested in
participation were given
more information and
an informed consent to
sign at home and send
back. To be included in
the study, families had
to be residents in
Norrbotten county and
be able to
communicate in written
and spoken Swedish.
31 years, range 19-
45 years)
Mean: 14 [jg/kg
Median: 11 |jg/kg
Max: 148 |jg/kg
Sunderby hospital.
Age at outcome:
birth
pregnancy alcohol
consumption, and
marital/cohabitant status;
infant sex and GA at birth
(in days); models were
also mutually adjusted for
other maternal metals (Cd
and Hg)
p for interaction with infant
sex: 0.43
HC (cm):
Less than median: 0.059
(-0.22, 0.34)
p for interaction with infant
sex: 0.84
Greater than median:
-0.24 (-0.53, 0.056)
p for interaction with infant
sex: 0.23
Mutually adjusted for other
maternal metals
BW (g): -0.0091 (-0.077,
0.058)
BL (cm): -0.0078 (-0.079,
0.064)
HC (cm):
Less than median: 0.018
(-0.058, 0.094)
Greater than median:
-0.050 (-0.13, 0.0026)
Project Viva Blood Prenatal growth: BW,
n- -|3g-| birth length, HC, GA
Women were recruited
at prenatal care visits at
eight urban and
suburban practices of a
multi-specialty group
practice in eastern
Massachusetts.
Exclusion criteria
included multiple
gestation, inability to
Maternal blood (erythrocyte)
was measured by ICP-MS.
Age at measurement:
maternal age at collection
(mean 11.3 ± 2.8 weeks
gestation); mean maternal
age
(SD): 32.3 (4.7) years
GA from reported last
menstrual period, BW,
birth length, and HC
from medical records
Age at outcome: birth
Multivariable linear
regression models were
adjusted for maternal age,
education, pre-pregnancy
BMI, parity, smoking
status, race/ethnicity,
household income, infant
sex, and GA at delivery
(except when GA is an
outcome)
(3 (95% CI)b, per IQR
(10.1 ng/g) increase:
BW (g):
Full Cohort: -33.9 (-65.3,
-2.5)
Males: -32.5 (-77.4, 12.5)
Females: -34.6 (-77.2,
8.1)
BL (cm):
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Design Clsa
answer questions in
English, GA >22 weeks
at recruitment and
plans to move away
from the study area
before delivery.
Geometric mean: 17.99 ng/g
Median: 17.7 ng/g
75th: 23.6 ng/g
Full Cohort: -0.10 (-0.29,
-0.09)
Males: -0.08 (-0.35, 0.19)
Females: -0.13 (-0.39,
0.13)
HC (cm)
Full Cohort: -0.07 (-0.17,
0.04)
Males: -0.14 (-0.29, 0.02)
Females: 0.00 (-0.15,
0.15)
GA (weeks)
Full Cohort: 0.03 (-0.10,
0.16)
Males: 0.12 (-0.07, 0.30)
Females: -0.04 (-0.22,
0.14)
Wang et al. (2017a')
China
2009
Cohort
C-ABCS
n: 3,125
Pregnant women with
singleton, live births
Blood
Maternal blood (serum) was
detected by GFAAS
Age at measurement:
maternal age at collection
(first trimester, median:
11 weeks) and second
trimester (median:
16 weeks) (mean age:
27.5 years)
Mean:
Overall: 1.50 [jg/dL
First trimester: 1.52 [jg/dL
Prenatal growth: SGA,
BW, birth length, HC,
and chest
circumference
SGA was defined as
live-born infants with
birth weight below 10th
percentile for the
babies of the same GA
according to a global
reference; BW, birth
length, HC, and CC
were measured at birth
Age at outcome:
birth
Multivariate linear and
logistic regression models
were adjusted for pre-
pregnancy BMI, maternal
age, gravidity, monthly
income, parity, and time of
serum collection
(3 (95% Cl)b
Maternal serum during
pregnancy
BW (g): -2.74 (-5.17,
-0.31)
BL (cm): -0.013 (-0.026,
0.001)
HC (cm): -0.008 (-0.019,
0.004)
CC (cm): -0.008 (-0.018,
-0.002)
First trimester maternal
serum
BW: -4.40 g (-8.22, -0.58)
BL: -0.022 cm (-0.048,
0.005)
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Design Clsa
Second trimester:
1.49 [jg/dL
Median:
Overall: 1.43 pg/dL
First trimester: 1.43 |jg/dL
Second trimester:
1.43 [jg/dL
Max:
Overall: 5.46 [jg/dL
First trimester: 5.16 [jg/dL
Second trimester:
5.46 [jg/dL
Tertiles (|jg/dL):
Low: <1.18
Medium: 1.18-1.70
High: >1.71
HC: -0.007 cm (-0.022,
0.007)
CC: -0.015 cm (-0.030,
<0)
Second trimester maternal
serum
BW (g): -1.64 (-4.80,
-0.58)
BL (cm): -0.006 (-0.020,
0.009)
HC (cm): -0.008 (-0.024,
0.008)
CC (cm): -0.002 (-0.016,
-0.011)
OR (95% CI)
SGA
All Infants
Low: Reference
Medium: 1.45 (1.04, 2.02)
High: 1.69 (1.22, 2.34)
Males
Low: Reference
Medium: 1.44 (0.83, 2.50)
High: 1.75 (1.03, 2.99)
Females
Low: Reference
Medium: 1.51 (0.99, 2.31)
High: 1.68 (1.12, 2.54)
First trimester maternal
serum
Low: Reference
Medium: 1.19 (0.65, 2.19)
High: 2.13 (1.24, 3.38)
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Design Clsa
Cassidv-Bushrow et
al. (70191
Wayne County, Ml
United States
September 2003 and
December 2007
(December 2011 and
January 2015)
Cohort
Second trimester maternal
serum
Low: Reference
Medium: 1.57 (1.05, 2.34)
High: 1.48 (0.98, 2.21)
WHEALS
n: 145
Pregnant women were
in their second
trimester or later, were
aged 21-49 years, and
were living in a
predefined geographic
area in Wayne and
Oakland counties that
included the city of
Detroit as well as the
suburban areas
immediately
surrounding the city
Teeth
Teeth, representing second
and third trimester exposure,
measured by laser ablation-
inductively coupled plasma-
mass spectrometry (LA-ICP-
MS)
Mean (SD)6:
Second trimester: 0.04
(0.03) |jg/g
Third trimester: 0.05
(0.04) ijg/g
Prenatal growth: BWZ
and GA
BWZ and GA obtained
from prenatal and birth
records
Age at outcome:
birth
Linear regression models
adjusted for batch, tooth
attrition, tooth type, race,
urban, ETS, anemic,
maternal age, and year
house built; the effect of
time is the difference in
effect estimates from the
second and third
trimesters
(3 (95% CI)b:
BW Z-score
Second trimester: -0.15
(-0.35, 0.05)
Third trimester: -0.06
(-0.24, 0.12)
Effect of Time: -0.31
(-0.90, 0.28)
Boys
Second trimester: -0.20
(-0.47, 0.07)
Third trimester: -0.04
(-0.31, 0.23)
Girls
Second trimester: -0.12
(-0.39, 0.15)
Third trimester: -0.06
(-0.33, 0.21)
GA (weeks)
Second trimester: 0.08
(-0.19, 0.35)
Third trimester: 0.14
(-0.11, 0.39)
Effect of time: -0.22
(-1.08, 0.64)
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Design Clsa
Bui et al. (20221
North Carolina
United States
2004-2009
Quasi-experimental
Boys
Second trimester: 0.08
(-0.41, 0.57)
Third trimester: 0.01
(-0.44, 0.46)
Girls
Second trimester: 0.12
(-0.21, 0.45)
Third trimester: 0.27
(-0.06, 0.60)
Charlotte-Concord-
Gastonia (CCG)
Metropolitan Statistical
Area (MSA)
n: 147,673 live births in
the CCG MSA;
Treatment group n:
1,138; Control group n:
13,398
Exogenous variation in
Pb exposure resulting
from NASCAR's
deleading of racing fuel
in 2007 was used as a
quasi-experiment.
Charlotte Motor
Speedway (CMS),
located in the CCG,
was the only NASCAR
racetrack in North
Carolina that held races
every year during our
sample period. Races
occurred bi-annually, in
October and May,
Births where the mother's
residential address was
within 4,000 meters of CMS
were classified as the
treatment group, while births
where mother's residential
address was in the CCG
MSA but at least 10,000 m
from the CMS centroid.
Prenatal growth: birth
weight, LBW, and SGA
BW was the newborn's
weight, in grams. LBW
was defined as BW
<2500 g. SGA was
defined as BW below
the tenth percentile for
clinical GA.
Age at outcome: birth
Difference-in-difference
models were used to
compare birth outcomes in
a non-randomized
treatment group before
and after deleading to
those in the control group.
Models were adjusted for
mother's age, education,
race, and smoking
behavior; father's age,
education, and race;
infant's birth order and
sex; as well as proximity to
a Toxic Releases
Inventory (TRI) facility or
airport, median household
income, and age of
housing stock; a set of
census tract, month, and
year indicator variables
were also included
(3 (95% Cl)b, as estimated
average treatment effect of
treatment group
BW (g)
All births
Any exposure: 102. 5
(45.73, 152.2)
Trimester 1: 418.6 (205.1,
632.1)
Trimester 2: 47.68 (-40.01,
135.4)
Trimester 3: 262 (97.01,
427.1)
Full-term births
Any exposure: 24.08
(-15.14, 63.29)
Trimester 1: 104.7 (-54.65,
264)
Trimester 2: 44.16 (-36.35,
124.7)
Trimester 3: 80.19 (-30.44,
190.8)
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Design Clsa
ensuring that all full and
near full-term births in
the sample were
prenatally exposed via
the mother to at
least one NASCAR
event.
LBW
All births
Any exposure: -0.045
(-0.07, -0.019)
Trimester 1: -0.062
(-0.178, 0.054)
Trimester 2: -0.022
(-0.061, 0.017)
Trimester 3: -0.158
(-0.314, -0.001)
Full-term births
Any exposure: 0.001
(-0.014, 0.016)
Trimester 1: 0.05 (-0.038,
0.138)
Trimester 2: -0.035
(-0.054, -0.016)
Trimester 3: -0.006 (-0.07,
0.057)
SGA
All births
Any exposure: -0.04
(-0.064, -0.016)
Trimester 1: -0.042
(-0.242, 0.158)
Trimester 2: -0.058
(-0.118. 0.002)
Trimester 3: -0.038
(-0.122, 0.045)
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Design Clsa
Full-term births
Any exposure: -0.028
(-0.051, -0.004)
Trimester 1: -0.053
(-0.274, 0.168)
Trimester 2: -0.049
(-0.103, 0.004)
Trimester 3: 0.022 (-0.081,
0.125)
AAS: atomic absorption spectrometry; AD = abdominal diameter; ALSPAC = Avon Longitudinal Study of Parents and Children; As = arsenic; BL = birth length; BMI = body mass
index; BW = birth weight; BWGA = birth weight-for-gestational age; BWZ = birth weight Z-score; CANDLE = Conditions Affecting Neurocognitive Development and Learning in Early
Childhood; CC = chest circumference; CCG = Charlotte-Concord-Gastonia; Cd = cadmium; CD = cephalic diameter; CHL = crown-to-heel length; CMS = Charlotte Motor Speedway;
Cr = chromium; EMASAR = Study on the Environment and Reproductive Health; ETS = environmental tobacco smoke; GA = gestational age; GFAAS = graphite furnace atomic
absorption spectrometry; HC = head circumference; Hg = mercury; HR-ICP-MS = high resolution inductively coupled plasma mass spectrometry; ICP-MS = inductively coupled
plasma mass spectrometry; ICP-QQQ = inductively coupled plasma triple quad; INMA = Instituto de Nanociencia y Materiales de Aragon; IQR = interquartile range;
IUGR = intrauterine growth restriction; LBW = low birth weight; LA-ICP-MS = laser ablation-inductively coupled plasma-mass spectrometry; LGA = large for gestational age;
LIFE = Longitudinal Investigation of Fertility and the Environment; LMP = last menstrual period or last missed period; In = natural log-transformed; LOD = limit of detection;
m = meters; MIREC = Maternal-Infant Research on Environmental Chemicals; min = minute(s); Mn = manganese; MSA = Metropolitan Statistical Area; NICE = Nutritional impact on
Immunological maturation during Childhood in relation to the Environment; PI = Ponderal index; PROGRESS = Programming Research in Obesity, Growth Environment and Social
Stress; PROTECT = Puerto Rico Test site for Exploring Contamination Threats; SD = standard deviation; SES = Socioeconomic status; SGA = small for gestational age;
UCB = umbilical cord blood; WHEALS = Wayne County Health, Environment, Allergy and Asthma Longitudinal Study.
aEffect estimates are standardized to a 1 |jg/dL increase in blood Pb or a 10 |jg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect
estimates are standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated
interval. Categorical effect estimates are not standardized.
bEffect estimates unable to be standardized.
°Pb measurements were converted from |jg/L to |jg/dL.
dNo cut points provided for the categorizations.
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Table 8-5 Epidemiologic studies of Pb exposure and preterm birth.
Reference and Study
Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Xuetal. (2012)
n: 531 (n = 432 from Guiyu
and n = 99 from Xiamen)
Cord blood
Preterm birth rate
Multiple logistic regression
models were adjusted for
OR (95% Cl)b: 1.09
(0.93, 1.28)
Guiyu and Xiamen
Women who gave birth in
UCB measured by GFAAS
Preterm birth was defined
maternal age and infant sex
China
as birth <37 weeks
2001-2008
Guiyu or non-urban area of
Xiamen between 2001 and
2008
Age at measurement:
birth
gestation
Age at outcome: birth
Cross-sectional
Median:
Guiyu: 10.78 pg/dL
Xiamen: 2.25 [jg/dL
Max:
Guiyu: 47.46 |jg/dL
Xiamen: 7.22 [jg/dL
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Reference and Study
Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Xu et al. (2022b)
Argentina
2011-2012
Cross-sectional
EMASAR
696
n
Women who either were
about to deliver or had given
birth within the last 48 hour
at one of the two hospitals.
Women had to be above
18 years of age.
Blood
Maternal blood measured
by ICP-MS
Age at measurement:
birth
Median0:
Overall: 1.34 pg/dL
Ushuaia: 0.98 [jg/dL
Salta 1.50 pg/dL
Geometric mean0:
Overall: 1.393 pg/dL
Ushuaia: 1.01 pg/dL
Salta 1.58 pg/dL
75th°:
Overall: 1.851 pg/dL
Ushuaia: 1.30 pg/dL
Salta: 2.09 pg/dL
Preterm birth
Medical records were
used to obtain measures
at birth.
Age at outcome: birth
Logistic models adjusted for
maternal age, pre-pregnancy
BMI, parity, smoking,
education, and LBW
OR (95%CI)
Tertile 1: Reference
Tertile 2: 1.24 (0.35,
4.40)
Tertile 3: 1.26 (0.32,
5.00)
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Reference and Study
Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Freire et al. (20191
Spain
2000-2008
Cross-sectional
INMA Project
n: 327
Pregnant women of general
population resident in each
study area [Ribera d'Ebre,
Menorca, Granada,
Valencia, Sabadell, Asturias
and Gipuzkoa] and their
children. Criteria for
inclusion of the mothers
were: (i) to be resident in
one of the study areas, (ii) to
be at least 16 yeayrs old, (iii)
to have a singleton
pregnancy, (iv) to not have
followed any program of
assisted reproduction, (v) to
wish to deliver in the
reference hospital and (vi) to
have no communication
problems
Other: Placenta
Placenta (including
maternal and fetal sides as
well as central and
peripheral parts) measured
by GFAAS with Zeeman
background correction
Age at measurement:
birth
Median: <6.5 ng/g (LOD)
75th: <6.5 ng/g (LOD)
Preterm delivery
Preterm birth was defined
as live birth before
37 weeks of pregnancy,
Age at outcome:
birth
Logistic regression models
were adjusted for cohort
(random effect), newborn sex,
co-exposure to other metals
(As, Hg, Cd, Mn, Cr), and
maternal education level
OR (95% Cl)b:
(0.04, 4.70)
0.40
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RefereDCesignnd Study Population Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Yuetal. (70191
Shanxi Province
China
December 2009-
December 2013
Case-control
n: 528
Women with prenatal
examination at <22
gestational weeks,
>18 years old, and living in
the local counties for >1
year
Blood
Maternal blood (serum) was
measured by ICP-MS
Age at measurement:
maternal age at first
trimester (<12 weeks
gestation) or second
trimester (13-28 weeks)
Mediand
Overall: 0.0482 pg/dL
First trimester:
0.0489 pg/dL
Second trimester:
0.0476 pg/dL
75thd:
Overall: 0.0751 pg/dL
First trimester:
0.0783 pg/dL
Second trimester:
0.0735 pg/dL
Spontaneous preterm
birth
Spontaneous preterm
birth is defined as a live
birth at <37 weeks GA
without iatrogenic causes,
including spontaneous
preterm labor with intact
membranes and PROM
Age at outcome:
birth
Unconditional logistic
regression models were
adjusted for maternal age, BMI,
education, occupation,
residence, gravidity, parity,
spontaneous abortion history,
folic acid use, drug use,
passive smoking, and child
gender
OR (95% Cl)b
Overall: 1.46 (0.97, 2.18)
First trimester: 1.63
(0.91, 2.91)
Second trimester: 1.27
(0.71, 2.28)
Xu et al. (2022a)
Pingding, Shouyang,
and Taigu Counties
Shanxi Province
China
December 2009-
December 2013
Case-Control
n: 148 (74 cases, 74
controls)
Pregnant women were
recruited if over 18 years
old, living locally for at least
one year, seeking first
prenatal visit at or before 22
gestational weeks, and
seeking to manage
birth/pregnancy at Maternal
and Child Health Hospitals
of study counties.
Blood
Maternal blood (serum)
measured by ICP-MS
Age at measurement:
maternal age during 4-22
gestational week
Mediand: 0.049 pg/dL
75thd: 0.078 pg/dL
Spontaneous preterm
birth
Information about
spontaneous preterm birth
was collected from
pregnancy health records
at the hospitals
Age at outcome: birth
Unconditional logistic
regression with adjustment for
age, BMI, education,
occupation, residence,
gravidity, parity, spontaneous
abortion history, folic acid use,
medication use, passive
smoking, infant sex, fasting
blood collection, and sampling
time.
OR (95% CI):
Q1
Q2
Q3
Q4
Reference
1.63 (0.53, 5.04)
1.81 (0.60, 5.52)
4.09 (1.31, 12.77)
p for trend: 0.017
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Reference and Study
Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Tsuii et al. (20181
Japan
January 2011 and
March 2014
Cohort
JECS
n: 14,847
Women who delivered live
birth infant with singleton
pregnancies without missing
exposure or covariate data
Blood
Maternal blood measured
by ICP-MS
Age at measurement:
Maternal age at gestational
weeks 14-39 (mean
maternal age 31.4 years)
Median: 5.96 ng/g
75th: 7.44 ng/g
Quartiles (ng/g)
Q1
Q2
Q3
Q4
<4.49
4.80-5.95
5.96-7.43
>7.44
Preterm birth
Preterm births were
divided into early
(<34 weeks) and late
preterm births (34 to
<37 weeks)
Age at outcome:
birth
Multivariable logistic regression
analysis adjusted for age, pre-
pregnancy BMI, smoking,
smoking habits of partner,
drinking habits, gravidity,
parity, the number of cesarean
sections, uterine infection,
household income, educational
levels, and sex of infant
OR (95% CI)
Early preterm
Q1
Reference
Q2
0.66 (0.37, 1.20)
Q3
0.80 (0.46, 1.41)
Q4
1.22 (0.74, 2.02)
p for trend: 0.134
Late preterm
Q1
Reference
Q2
0.99 (0.78, 1.26)
Q3
0.98 (0.77, 1.25)
Q4
0.92 (0.72, 1.18)
p for trend: 0.920
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RefereDCesignnd Study Population Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Goto et al. (2021)
Japan
January 2011 to
March 2014
Cohort
JECS
n: 16423
First, data from participants
who withdrew from the study
or did not meet the Pb
measurement quality control
criteria were excluded
(n = 2,002). Second, data
from mothers who: were lost
to follow-up; had severe
maternal conditions
preceding pregnancy, such
as chronic hypertension,
pregestational diabetes or
cardiac disease, during
pregnancy; or had
pregnancies ending in
abortions or stillbirths
(n = 1,209) was excluded.
Third, data from infants with
chromosomal or major
congenital anomalies
(n = 263) or multiple births
(n = 283) was excluded.
Blood
Maternal blood measured
by ICP-MS
Age at measurement:
Maternal age at second or
third trimester (mean age at
delivery: 31 ± 5.0 years)
Mean: 0.69 [jg/dL
Median: 0.63 [jg/dL
75th: 0.78 pg/dL
Max: 7.4 pg/dL
Preterm birth (<37
gestational weeks) risk
Preterm birth was defined
as a GA of less than 37
completed weeks.
Age at outcome:
birth
Multivariable linear regression
models were adjusted for
maternal age at birth, body
mass index before pregnancy,
weight gain during pregnancy,
maternal educational
background, a history of
preterm birth, alcohol
consumption during pregnancy,
smoking habit during
pregnancy, and parity
OR (95% CI), per
0.1 pg/dL increase in
maternal blood Pb: 0.90
(0.70, 1.16)
OR (95% CI), per
doubling increment in
maternal blood Pb: 0.978
(0.689, 1.39)
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RefereDCesignnd Study Population Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Rabito et al. (20141
Shelby County,
Tennessee
United States
2008-2011
Cohort
CANDLE study
n: 98
Healthy pregnant woman
between the ages of 16 and
40 years, carrying a single
fetus with the intent to
deliver the fetus, residence
within Shelby County,
Tennessee, and having the
intent to deliver at one of
three area-based hospitals
Blood and cord blood
Maternal blood, collected at
second and third trimester
and at delivery, and cord
blood, collected at deliver,
were measured by ICP-MS
Age at measurement:
Maternal age at collection
(median: 29.50 years)
Median:
Second trimester:
0.43 [jg/dL
Third trimester: 0.43 |jg/dL
At delivery: 0.50 [jg/dL
Cord blood: 0.37 [jg/dL
Preterm birth
Preterm birth
(<37 weeks), early term
birth (37-39 weeks), or
full-term birth (>39 weeks)
based on GA, which was
determined by expected
due data and LMP
Age at outcome:
birth
Logistic regression models
were adjusted for marital
status, maternal education
level, and maternal income
OR (95% Cl)b, per 0.1-
unit increase in maternal
blood Pb
Preterm birth
Second trimester: 1.66
(1.23, 2.23)
Third trimester: 1.24
(1.01, 1.52)
Early term birth
Second trimester: 0.87
(0.63, 1.20)
Third trimester: 0.88
(0.69, 1.13)
Geometric mean (SD):
Second trimester: 0.42
(0.20) [jg/dL
Third trimester: 0.45
(0.28) [jg/dL
At delivery: 0.50
(0.35) [jg/dL
Cord blood: 0.37
(0.32) [jg/dL
Max:
Second trimester:
1.22 [jg/dL
Third trimester: 2.10 |jg/dL
At delivery: 2.47 [jg/dL
Cord blood: 1.80 [jg/dL
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RefereDCesignnd Study Population Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Taylor etal. (20151
Bristol
UK
April 1991-December
1992
Cohort
ALSPAC
n: 4,285
All pregnant women in the
former Avon Health
Authority with an expected
delivery date between April
1, 1991 and December 31,
1992 were eligible for the
study
Blood
Maternal blood measured
by ICP-MS, collected as
early as possible in
pregnancy (median GA of
sampling: 11 weeks)
Age at measurement:
Maternal age at
measurement
Preterm delivery
Preterm delivery was less
than 37 weeks of
gestation
Age at outcome:
birth
Logistic regression models for
preterm birth were adjusted for
maternal height, maternal pre-
pregnancy weight, maternal
educational attainment, parity,
number of cigarettes per day,
sex of baby
OR (95% Cl)b:
(1.35, 3.00)
2.00
Mean (SD): 3.67
(1.47) [jg/dL
Geometric mean:
3.43 [jg/dL
Median: 3.42 [jg/dL
Max: 19.14 pg/dL
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Reference and Study
Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Li etal. r2017a1
China
January 1 to
December 31, 2009
Cohort
C-ABCS
n: 3,125
Mother-and-singleton-
offspring pairs from Hefei
City who provided informed
consent, did not drink
alcohol or smoke cigarettes
during pregnancy, did not
have mental disorders, did
not have pregnancy-induced
hypertension, preeclampsia,
gestational diabetes, heart
disease, thyroid-related
disease, a history of >3
previous miscarriages, or
plans to leave location
before delivery
Blood
Maternal blood (serum)
measured by GFAAS
coupled with a deuterium-
lamp background correction
system, collected in the first
and second trimesters
(median time for serum
collection: 14 gestational
weeks; range from 4 to 27
gestational week)
Mean: 1.50 [jg/dL
Max: 5.46 [jg/dL
Tertiles:
low-Pb: <1.18 |jg/dL
medium-Pb: 1.18-
1.70 [jg/dL
high-Pb: >1.71 pg/dL
Preterm birth
Gestational week was
calculated using mother's
last menstrual period.
Preterm birth was defined
as a live birth at less than
37 completed gestational and parity
weeks and preterm birth
can be further sub-divided
into early preterm birth
(<32 gestational weeks),
moderate preterm birth
(32 to <34 gestational
weeks) and late preterm
birth, 34 to <37
gestational weeks)
Age at outcome:
birth
Multiple logistic regression
models estimated the
association between maternal
serum Pb level and risk of
preterm birth, adjusted for
maternal age, pre-pregnancy
OR (95% CI):
Low-Pb: Reference
Medium-Pb: 2.33 (1.49,
3.65)
High-Pb: 3.09 (2.01,
BMI, monthly income, gravidity, 4.76)
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Reference and Study
Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Ashrap et al. (20201
Puerto Rico
2010-2017
Cohort
PROTECT
n: 731
Participants were recruited
at approximately
14 ± 2 weeks of gestation at
seven prenatal clinics and
hospitals throughout
Northern Puerto Rico and
followed until birth; maternal
age between 18 and
40 years; residence inside of
the Northern Karst aquifer
region; disuse of oral
contraceptives within the
3 months prior to pregnancy;
disuse of in vitro fertilization
to become pregnant; and
free of any major medical or
obstetrical complications,
including pre-existing
diabetes. Each woman
participated in a total of up
to three study visits
(18 ± 2 weeks,
22 ± 2 weeks, and
26 ± 2 weeks of gestation)
Blood
Maternal blood was
measured by ICP-MS
Age at measurement:
18-40 (collection between
18 and 26 weeks of
gestation)
Geometric mean (SD):
Preterm births: 0.39
(1.6) pg/dL
Term births: 0.32
(1.5) pg/dL
Median:
Preterm births: 0.36 pg/dL
Term births: 0.32 pg/dL
Preterm birth (overall and
spontaneous preterm
birth)
All the birth outcome data
were extracted from
medical records. Preterm
birth was defined as <37
completed weeks of
gestation with further
classification of
spontaneous preterm birth
(presentation of
premature rupture of the
membranes, spontaneous
preterm labor, or both)
and non-spontaneous
preterm birth (preterm
births with preeclampsia
or with both artificial
membrane rupture and
induced labor)
Age at outcome:
birth
Logistic regression models
were adjusted for maternal
age, maternal education level,
pre-pregnancy BMI, and
exposure to second-hand
smoking
OR (95% Cl)b, per IQR
increase in maternal
blood In-Pb
Preterm birth
Overall: 1.63 (1.17, 2.28)
Spontaneous: 1.53 (1.00,
2.35)
Tertilese:
Overall preterm birth:
T1: Reference
T2: 1.27 (0.65, 2.47)
T3: 1.93 (1.02, 3.62)
Spontaneous preterm
birth:
T1
T2
T3
Reference
0.69 (0.29, 1.66)
1.50 (0.71, 3.18)
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Reference and Study
Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Ashrap et al. (20211
Puerto Rico
2011-2017
Cohort
PROTECT
n = 682
Participants were recruited
at approximately
14 ± 2 weeks of gestation at
seven prenatal clinics and
hospitals throughout
Northern Puerto Rico and
followed until birth; maternal
age between 18 and
40 years; residence inside of
the Northern Karst aquifer
region; disuse of oral
contraceptives within the
3 months prior to pregnancy;
disuse of in vitro fertilization
to become pregnant; and
free of any major medical or
obstetrical complications,
including pre-existing
diabetes. Each woman
participated in a total of up
to three study visits
(18 ± 2 weeks,
22 ± 2 weeks, and
26 ± 2 weeks of gestation)
Blood
Maternal blood was
measured by ICP-MS
Age at measurement:
18-40 (collection between
18 and 26 weeks of
gestation)
Geometric mean: 3.1 [jg/dL
Median: 3.1 [jg/dL
75th 4.1 |jg/dL
95th: 6.5 pg/dL
Max: 15.1 pg/dl_
Preterm birth (overall and Logistic regression models
spontaneous preterm
birth)
Birth outcomes were
extracted from medical
records. Psychosocial
status was evaluated
using four questionnaires
Age at outcome: birth
were adjusted for maternal
age, maternal education, pre-
pregnancy BMI, and exposure
to secondhand smoking
OR (95% Cl)b, per IQR
increase in in maternal
blood In-Pb
Preterm birth:
Good Psychosocial
Status: 1.72 (1.14, 2.58)
Poor Psychosocial
Status: 1.43 (0.69, 2.97)
Spontaneous preterm
birth:
Good Psychosocial
Status: 1.56 (0.93, 2.60)
Poor Psychosocial
Status: 1.22 (0.42, 3.56)
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Reference and Study
Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Bui et al. (20221
North Carolina
United States
2004-2009
Quasi-experimental
CCG MSA
n: 147,673 live births in the
CCG MSA; Treatment group
n: 1,138; Control group n:
13,398
Exogenous variation in Pb
exposure resulting from
NASCAR's deleading of
racing fuel in 2007 was used
as a quasi-experiment.
CMS, located in the CCG,
was the only NASCAR
racetrack in North Carolina
that held races every year
during our sample period.
Races occurred bi-annually,
in October and May,
ensuring that all full and
near full-term births in the
sample were prenatally
exposed via the mother to at
least one NASCAR event.
Births where the mother's
residential address was
within 4,000 meters of CMS
were classified as the
treatment group, while
births where mother's
residential address was in
the CCG MSA but at least
10,000 m from the CMS
centroid.
Preterm birth
Preterm birth was defined
as clinical GA <37 weeks.
Age at outcome: birth
Difference-in-difference models
were used to compare birth
outcomes in a non-randomized
treatment group before and
after NASCAR deleading to
those in the control group.
Models were adjusted for
mother's age, education, race,
and smoking behavior; father's
age, education, and race;
infant's birth order and sex; as
well as proximity to a TRI
facility or airport, median
household income, and age of
housing stock; a set of census
tract, month, and year indicator
variables were also included
(3 (95% Cl)b, as
estimated average
treatment effect of
treatment group
All births
Any exposure: -0.03
(-0.057, -0.002)
Trimester 1: -0.247
(-0.438, -0.057)
Trimester 2: 0.019
(-0.042, 0.079)
Trimester 3: -0.163
(-0.277, -0.049)
ALSPAC = Avon Longitudinal Study of Parents and Children; As = arsenic; BMI = body mass index; CANDLE = Conditions Affecting Neurocognitive Development and Learning in Early
Childhood; CCG = Charlotte-Concord-Gastonia; Cd = cadmium; Cr = chromium; CMS = Charlotte Motor Speedway; EMASAR = Study on the Environment and Reproductive Health;
GA = gestational age; GFAAS = graphite furnace atomic absorption spectrometry; Hg = mercury; ICP-MS = inductively coupled plasma mass spectrometry; INMA = Instituto de Nanociencia y
Materiales de Aragon; LBW = low birth weight; LMP = last menstrual period or last missed period; LOD = limit of detection; MSA = Metropolitan Statistical Area; PROM = premature rupture of
membranes; PROTECT = Puerto Rico Testsite for Exploring Contamination Threats; SD = standard deviation.
aEffect estimates are standardized to a 1 |jg/dL increase in blood Pb or a 10 |jg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect estimates are
standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated interval. Categorical effect
estimates are not standardized.
bEffects estimates unable to be standardized.
°Pb measurements were converted from |jg/L to |jg/dL.
dPb measurements were converted from ng/mLto |jg/dL.
eNo cut points provided for the categorizations.
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Table 8-6 Epidemiologic studies of Pb exposure and birth defects.
Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Jinetal. (70131
Shanxi Province
China
October 2002 -
onward
Case-control
n: 210: 80 controls, 50 any
NTD case; 36 cases of
anencephaly; and 44 cases
of spina bifida
Once a fetus with a neural
tube defect was identified as
a case, a healthy newborn
without congenital
malformations was selected
as a control. The control was
of the same sex as the case
and had a mother residing in
the same county as that of
the case. In this study, we
randomly selected 36 cases
of newborns with
anencephaly and 44 cases
of newborns with spina bifida
as case groups and 50
healthy term newborns as a
control group.
Other: Placenta
Placental tissue, collected
at delivery or pregnancy
termination, was
measured with ICP-MS
Age at Measurement:
delivery or pregnancy
termination
Mean (SD)
Controls: 22.38 (16.35)
ng/g; NTD cases: 23.30
(22.42) ng/g;
Anencephaly cases:
19.30 (15) ng/g
Spina bifida cases: 23.04
(20.03) ng/g
Median
Controls: 16.9 ng/g
NTD cases: 17.59 ng/g
Anencephaly cases:
10.96 ng/g Spina bifida
cases: 17.38 ng/g
75th:
Controls: 28.83 ng/g
NTD cases: 28.15 ng/g
Anencephaly cases:
28.86 ng/g
Spina bifida cases:
28.86 ng/g
Birth defects: Neural
tube defects
Trained local health
workers made primary
diagnoses by physical
examination of the
fetal/newborn body for
any pregnancy
outcomes and filled in
a reporting form for
each case. Three
pediatricians
independently
reviewed the case
report forms and
photographs before
assigning the final
diagnostic codes
Age at outcome:
birth or pregnancy
termination
No attempt was made
to adjust for
confounding factors in
our analyses of Pb
because no differences
in their placental
concentrations were
present between cases
and controls.
OR (95% Cl)b:
Any NTD: 1.14 (0.56, 2.30)
Anencephaly: 1.08 (0.46,
2.56)
Spina bifida: 1.19 (0.53, 2.67)
Liu et al. (20211
n: 332
Other: Umbilical cord
tissue
Birth defects: NTDs
Multivariate logistic
regression model
OR (95% CI)b: 1.23 (0.78,
1.94)
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Reference and
Study Design
Study Population Exposure Assessment Outcome
Confounders Effect Esti™*fs and 95%
Shanxi, China
2004-2016
Case-control
Fetuses from elective
pregnancy terminations and
newborns from the Shanxi
Province in China. Cases
were defined as those with
NTD and controls were
healthy newborns matched
by maternal residence and
date of last menstruation.
Umbilical cord tissue
measured by ICP-MS
Age at measurement:
At delivery or elective
termination
Median: 26.18 ng/g
75th: 48.58 ng/g
Max: 225.572 ng/g
NTD cases were
diagnosed by fetal
ultrasound scan or
physical examination
at birth or pregnancy
termination.
Age at outcome:
birth or pregnancy
termination
adjusted for folic acid
supplementation
Categorization:
Low exposure
(<1.10 ng/g)
High exposure
(>=1.10 ng/g)
Tianetal. (20211 n: 750
Shanxi province,
China
2003-2016
Case control
Participants were recruited
from six counties or cities in
the Shanxi province of
northern China.
Blood
Maternal blood (serum)
was measured by ICP-MS
Age at measurement:
Maternal age at collection
Median0:
Controls: 0.087 [jg/dL
Case: 0.115 |jg/dL
75thc:
Controls: 0.197 [jg/dL
Cases: 0.268 [jg/dL
Birth defects: NTDs
Diagnoses of
malformation are
made by local health
workers through
physical examination
of the newborns or
electively terminated
fetuses, in
combination with fetal
ultrasound scans.
Age at outcome: birth
or pregnancy
termination
Multilevel mixed effects
logistic regression
model adjusted for
maternal age, maternal
BMI, education,
gestational weeks, sex
of the fetus,
periconceptional folic
acid use, maternal flu,
or fever.
OR (95% CI):
Tertilesd
NTDs
Lowest: Reference
Medium: 2.05 (1.05, 4.02)
Highest: 3.51 (1.76, 6.98)
p for trend: <0.001
Spina bifida
Lowest: Reference
Medium: 2.16 (1.00, 4.88)
Highest: 5.16 (2.24, 11.87)
p for trend: 0.022
Anencephaly
Lowest: Reference
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Reference and
Study Design
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Confounders Effect Esti™*fs and 95%
Pietal. (70181
Shanxi Province
(Pingding, Xiyang,
Taigu, and Zezhou)
China
2005-2007
Case-control
Medium: 2.97 (1.09, 8.12)
Highest: 5.54 (1.89, 16.19)
p for trend: 0.002
Female Infants
NTDs
Lowest: Reference
Medium: 2.63 (0.99, 7.24)
Highest: 6.45 (2.20, 18.95)
p for trend: 0.001
Male Infants
NTDs
Lowest: Reference
Medium: 2.11 (1.02, 4.34)
Highest: 2.16 (1.03, 4.59)
p for trend: 0.048
n: 103 cases and 206
controls
Newborns or terminated
fetuses with any major
external structural defects,
including orofacial clefts
(OFCs), NTDs, congenital
hydrocephalus, limb defects
were recruited from five rural
counties in Shanxi Province
Other: Placenta
Placental tissue, collected
immediately after delivery,
was measured by ICP-MS
Age at Measurement:
birth
Mean (SD)
Controls 72.6 (34.8) ng/g
Case: 130.9 (95.7) ng/g
Median
Controls: 67.9 ng/g
Cases: 96.1 ng/g
75th
Controls: 98.1 ng/g
Cases: 176.4 ng/g
Birth defects: OFCs
Diagnoses of
newborns/fetuses with
major birth defects
were done through
physical examination
or prenatal ultrasound
examination by county
healthcare workers.
Once a newborn/fetus
with a major birth
defect was identified
as a case, a healthy
newborn with no
congenital
malformation was
selected as a control
to match the case by
residence of the
mother (the same
Binary logistic
regression adjusted for
occupation, newborn
sex, gestational weeks,
previous history of birth
defects, maternal flu or
fever, and passive
smoking during the
periconceptional period
OR (95% CI)
Orofacial defects:
T1
T2
T3
Reference
3.88 (1.78, 8.42)
5.17 (2.37, 11.29)
p for trend: <0.001
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Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
county), date of the
Tertiles (ng/g):
last menstrual period
T1: <57.5
(±4 weeks), and
T2: 57.5-96.8
newborn sex.
T3: >96.8
Age at outcome:
at diagnosis
Takeuchi et al.
(20221
Japan
2011-2014
Case-control
JECS
n:192 cases,
controls
1920 matched
Pregnant women living in the
study area and
understanding of the
Japanese language.
Participants were excluded if
they had missing data
(heavy metal data, matching
variables, and/or both).
Covariates for matching
were maternal age,
psychological stress
measured by the K6 score,
gestational weeks of blood
sampling during second
trimester, folic acid intake
estimated from a food-
frequency questionnaire,
alcohol intake (self-reported),
smoking (self-reported),
education level, BMI before
pregnancy, diabetes before
pregnancy, intake of
supplements (self-reported),
and regional center
Blood
Maternal blood measured
by ICP-MS
Age at measurement:
Maternal age at collection
(second trimester)
Mediane
Cohort: 0.585 [jg/dL
Cases: 0.584 [jg/dL
Controls: 0.575 [jg/dL
75the
Cohort: 0.73 [jg/dL
Cases: 0.72 [jg/dL
Controls: 0.71 [jg/dL
Birth defects: Cleft
palate and cleft lip
(isolated)
Validated medical
records were used to
identify isolated cleft
lip and palate.
Conditional logistic
regression adjusted for
sex and concentrations
of Hg, Cd and Mn
OR (95% CI), per 0.1 pg/dL
increase in maternal blood
Pb: 1.10 (0.55, 2.21)
Mivashita et al.
(20211
JECS.
n: 89,273
Blood
Birth defects:
Abdominal congenital
malformations
Multivariate logistic
regression models were
adjusted for maternal
OR (95% CI)
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Japan
January 2011-
2014
Cohort
¦March
Pregnant women and their
newborns recruited for the
JECS. Singleton, live births
were included.
Maternal blood (serum)
measured by ICP-MS.
Age at measurement:
maternal age at collection
(mid-late pregnancy)
Median
Cohort: 5.84 ng/g
Controls: 5.85 ng/g
Cases: 5.53
75th
Cohort: 7.32 ng/g
Controls: 7.32 ng/g
Cases: 7.00 ng/g
Max
Cohort: 110 ng/g
Quartiles (ng/g):
Q1
Q2
Q3
Q4
<4.7
4.7-<5.84
5.84 -<7.32
>7.32
Abdominal congenital
malformations
(including
omphalocele,
gastroschisis,
esophageal atresia
with/without fistula,
duodenal atresia,
intestinal atresia,
anorectal atresia,
diaphragmic hernia)
were identified from
birth records or
records one month
post birth
Age at outcome: birth
to month post birth
age, smoking habit,
drinking habit, paternal
smoking habit, birth
year of child, sex of
child
Abdominal congenital
malformations
Q1
Q2
Q3
Q4
Reference
1.19 (0.76, 1.84)
0.77 (0.47, 1.26)
0.85 (0.52, 1.38)
p for trend: 0.233
Diaphragmic hernia
Q1
Q2
Q3
Q4
Reference
1.24 (0.51, 2.99)
0.89 (0.34, 2.31)
0.81 (0.30, 2.20)
p for trend: 0.543
Omphalocele
Q1: Reference
Q2: 0.72 (0.29,
Q3: 0.35 (0.11,
Q4: 0.35 (0.11,
1.81)
1.12)
1.13)
p for trend: 0.033
Gastroschisis
Q1: Reference
Q2
Q3
Q4
1
1.00 (0.14, 7.09)
2.63 (0.50, 13.70)
p for trend: 0.212
Esophageal atresia
with/without fistula
Q1
Q2
Q3
Q4
Reference
0.49 (0.04, 5.43)
0.95 (0.13, 6.80)
1.88 (0.33, 10.50)
p for trend: 0.346
Duodenal atresia/stenosis
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Reference and
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Confounders Effect Esti™*fs and 95%
Liu et al. (20181
China
February 2010-
October2011
Case-control
Q1: Reference
Q2: 0.25 (0.03, 2.27)
Q3: 0.50 (0.09, 2.75)
Q4: 0.99 (0.24, 4.06)
p for trend: 0.910
Intestinal atresia/stenosis
Q1: Reference
Q2: 1.40 (0.31, 6.29)
Q3: 1.06 (0.21, 5.27)
Q4: 1.12 (0.22, 5.64)
p for trend: 0.989
Anorectal atresia/stenosis
Q1: Reference
Q2: 1.65 (0.74, 3.67)
Q3: 0.57 (0.19, 1.68)
Q4: 0.62 (0.21, 1.83)
p for trend: 0.158
n: 97 cases with CHDs and
201 controls without any
abnormalities
Cord blood
UCB (serum) was
measured by ICP-MS
Age at Measurement:
birth
Median0
Cases: 0.791 [jg/dL
Controls: 0.740 ug/dL
75thc
Case: 0.922 [jg/dL
Controls: 0.877 [jg/dL
Tertiles (|jg/dL):
Low: <0.696
Birth defects: CHDs
Cardiac defects
diagnosed during
prenatal examination
were recruited as the
case group.
Age at outcome: age
at diagnosis
Logistic regression
models were adjusted
for maternal age,
maternal pre-pregnancy
BMI, maternal
education level, folic
acid supplement, and
parental smoking
OR (95% CI)
CHD, Overall
Low: Reference
Medium: 1.46 (0.77, 2.77)
High: 1.67 (0.88, 3.17)
Septal Defects
Low: Reference
Medium: 1.20 (0.57, 2.52)
High: 1.61 (0.78, 3.32)
Conotruncal Defects
Low: Reference
Medium: 1.35 (0.60, 3.06)
High: 1.47 (0.65, 3.34)
Eligible fetuses with cardiac
defects diagnosed during
prenatal examination were
recruited as the case group.
For each case, one pregnant
control without any fetal
malformation was selected in
the same hospital with a
gestation age within 2 weeks
of the case fetus. Cases and
controls with gestational
ages from 14 to 40 weeks
were selected for this study
after the following exclusion
criteria were applied: (1)
multiple pregnancies; (2)
CHD family history; (3) fetus
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Outcome
Confounders
Effect Estimates and 95%
Clsa
diagnosed with a
chromosomal abnormality or
hereditary syndrome; (4)
fetus with extra cardiac
malformations; (5)
uncompleted questionnaire
for some reason. CHD cases
were classified into six
subtypes based on the
anatomic lesion: (i) septal
defects, (ii) conotruncal
defects, (iii) left sided outflow
tract deformity, (iv) right-
sided outflow tract deformity,
(v) anomalous pulmonary
venous return, and (vi) other
cardiac structural
abnormalities.
Medium: 0.696-0.826
High: >0.826
Right-sided Outflow Tract
Deformity
Low: Reference
Medium: 0.92 (0.37, 2.26)
High: 1.21 (0.50, 2.94)
Left-sided Outflow Tract
Deformity
Low: Reference
Medium: 2.29 (0.62, 8.41)
High: 1.32 (0.29, 5.91)
Anomalous Pulmonary
Venous Return
Low: Reference
Medium: 1.71 (0.37, 7.83)
High: 1.49 (0.30, 7.44)
Other Cardiac Structural
Abnormalities
Low: Reference
Medium: 1.10 (0.36, 3.40)
High: 1.41 (0.47, 4.22)
BMI = body mass index; Cd = cadmium; CHD = congenital heart diseases/defects; GFAAS = graphite furnace atomic absorption spectrometry; Hg = mercury; ICP-MS = inductively
coupled plasma mass spectrometry; Mn = manganese; NTD = neural tube defects; OFC = orofacial clefts; SD = standard deviation; UCB = umbilical cord blood.
aEffect estimates are standardized to a 1 |jg/dL increase in blood Pb or a 10 |jg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect
estimates are standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated
interval. Categorical effect estimates are not standardized.
bEffects estimates unable to be standardized.
°Pb measurements were converted from ng/mL to |jg/dL.
dNo cut points provided for the categorizations.
ePb measurements were converted from |jg/L to |jg/dL.
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Table 8-7 Epidemiologic studies of Pb exposure and fetal and infant mortality and spontaneous abortion and
pregnancy loss.
Reference and Study
Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates
and 95% Clsa
Xuetal. (2012)
Guiyu and Xiamen
China
2001-2008
Cross-sectional
n: 531 (n = 432 from Guiyu
and n = 99 from Xiamen)
Women who gave birth in
Guiyu or non-urban area of
Xiamen between 2001 and
2008
Cord blood
UCB measured by
GFAAS
Age at Measurement:
birth
Median:
Guiyu: 10.78 pg/dL
Xiamen: 2.25 [jg/dL
Max:
Guiyu: 47.46 |jg/dL
Xiamen: 7.22 [jg/dL
Stillbirth rate
Stillbirth was defined as
fetal death before complete
expulsion or extraction from
the mother at >20 weeks of
gestation
Age at outcome:
birth
Multiple logistic regression
models were adjusted for
maternal age and infant sex
OR (95% CI)b: 4.20
(3.40, 5.18)
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Exposure Assessment
Outcome
Confounders
Effect Estimates
and 95% Clsa
Louis et al. (20171
Michigan and Texas
United States
2005-2009
Cohort
LIFE Study
n: 344
Female partners aged 18-40
and male partners aged
>18 years who were in a
committed relationship; no
physician diagnosis of
infertility/sterility; off
contraception <2 months; and
an ability to communicate in
English or Spanish. Female
partners also had to have
menstrual cycles ranging
between 21 and 42 days as
required by the fertility monitor
and without the use of
injectable hormonal
contraceptives in the past year
given the uncertain timing for
ovulation return
Blood
Blood from femal and
male partners was
measured by ICP-MS
Age at Measurement:
18-40 for females and
>18 for males
Median
Females: 0.66 [jg/dL
Males: 1.00 [jg/dL
75th:
Females: 0.82 [jg/dL
Males: 1.37 [jg/dL
Pregnancy loss
Pregnancy was
prospectively captured by
women's use of the
Clearblue® digital home
pregnancy test, which is
sensitive in detecting
25 mlU/mL of human
chorionic gonadotropin
(hCG) and accurately used
by women. Depending upon
timing of loss, it was
detected by conversion to a
negative pregnancy test,
clinical confirmation, or
return of menses.
Age at outcome:
18-40 years
Cox proportional hazard
models; individual partner
model adjusted for age, BMI,
history of prior loss conditional
on gravidity, average number
of daily alcoholic drinks
consumed, and cigarettes
smoked during the
preconception and early
pregnancy windows for
females and preconception for
males; couples based model
adjusted for each partner's
metal concentration, age,
difference in couples' ages,
BMI, average number of daily
alcoholic drinks consumed and
cigarettes smoked during the
preconception and early
pregnancy window for females
and preconception for males,
and history of prior loss
conditional on gravidity
HR (95% Cl)b
Individual partner
model
Female partner:
1.01 (0.82, 1.25)
Male partner: 0.95
(0.77, 1.17)
Couple based
model
Female partner:
1.01 (0.80, 1.28)
Male partner: 0.96
(0.77, 1.22)
Vieeh et al. (20211
Tehran
Iran
March 2016-October
2017
Cohort
Tehran Environment and
Neurodevelopmental Disorder
n: 166 (spontaneous abortion
n: 25 and ongoing pregnancy
n: 141)
Pregnant women with GA of
10-16 weeks and of Iranian
nationality and Tehran city
inhabitant were invited to
participate in the study.
Blood
Maternal blood was
measured using ICP-MS
Age at measurement:
maternal age at first
trimester
Mean0: 4.96 |jg/dL
Maxc: 70.982 [jg/dL
Spontaneous abortion
Spontaneous abortion
defined as fetal demise
before 20 weeks gestation
and reported by study
participant or research
hospital.
Age at outcome: before
20 weeks of gestation
Logistic regression models
adjusted for maternal age,
primipara, and previous
abortion
OR (95% CI), per
0.1 [jg/dL increase
in maternal blood
Pb: 1.08 (0.98, 1.20)
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Design
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Exposure Assessment
Outcome
Confounders
Effect Estimates
and 95% Clsa
Tolunav et al. (20161 n: 101
Ankara
Turkey
January 2012 and July
2012
Cohort
The study group consisted of
patients with ongoing
pregnancy (n = 20) and the
reference group consisted of
patients experienced ART
failure, miscarriage, or
biochemical pregnancy
(n = 81)
Blood
Maternal blood was
measured by AAS
Age at Measurement:
20-40
Median
Study group: 2.34 [jg/dL
Reference: group
5.11 [jg/dL
Max
Study group: 7.97 [jg/dL
Reference group:
10.47 [jg/dL for
reference group
Pregnancy loss
Clinical pregnancy was
defined as the presence of
an embryo with a heartbeat
at 6th gestational week.
Ongoing pregnancy was
defined when the
pregnancy had completed
20 weeks of gestation.
Implantation rate was
calculated separately for
each woman as the number
of gestational sacs divided
by the number of
transferred embryos
multiplied by 100.
Age at outcome:
completion of 20 weeks of
gestation
Log binominal regression
analysis adjusted for age and
BMI
RR (95% CI): 0.978
(0.957, 0.999)
Li et al. (20221
Hefei
China
October 2019-
January 2020
Cohort
n: 1184
Participants were selected
from First Affiliated Hospital of
Anhui Medical University while
seeking IVF treatment and
diagnosed with infertility with
their partner. Inclusion criteria:
women were aged between
20 and 45 years; couples
were diagnosed with infertility
(failure to establish a clinical
pregnancy with unprotected
intercourse for at least 1 yr);
and IVF indicators were tubal
factor, ovulation failure, or
other factors for female
Blood
Maternal blood (serum)
was measured by ICP-
MS
Age at measurement:
maternal age at
collection (day before
oocytes were retrieved
for IVF); mean age was
30.22 years
Geometric meand:
0.0877 [jg/dL
Mediand: 0.0924 [jg/dL
Spontaneous abortion
Spontaneous abortion
before gestational weeks 12
was followed upon the 65th
day after embryo transfer.
Age at outcome: maternal
age at outcome (before
gestational week 12)
Logistic regression model for
successful implantation
adjusted for: maternal age,
BMI, treatment protocol,
numbers of retrieved oocytes,
embryo quality
OR (95%CI)b:
Spontaneous
abortion: 1.39 (1.02,
1.91)
Tertiles
Low: Reference
Medium: 1.49 (0.84,
2.63)
High: 1.55 (0.87,
2.79)
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Outcome
Confounders
Effect Estimates
and 95% Clsa
partner or male factor or
unexplained fertility.
75thd: 0.14399 pg/dL
Tertilesd (pg/dL):
Low: 0.002-0.065
Medium: 0.065-0.125
High: 0.125-0.481
AAS = atomic absorption spectrometry; BMI = body mass index; GFAAS = graphite furnace atomic absorption spectrometry; hCG = human chorionic gonadotropin; ICP-MS = inductively
coupled plasma mass spectrometry; IVF = in vitro fertilization; OR = odds ratio; UCB = umbilical cord blood.
aEffect estimates are standardized to a 1 pg/dL increase in blood Pb or a 10 pg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect estimates are
standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated interval. Categorical
effect estimates are not standardized.
bEffects estimates unable to be standardized.
°Pb measurements were converted from pg/L to pg/dL.
dPb measurements were converted from ng/Lto pg/dL.
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Table 8-8 Epidemiologic studies of Pb exposure and placental function.
Reference and Study
Design
Study Population Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Al-Saleh et al. (20141 n: 1,578
Al-Kharj
Saudi Arabia
2005-2006
Cross-sectional
Women aged 16-
50 years who delivered
in Al-Kharj hospital,
Saudi Arabia
Blood, cord blood, and
other: placenta
Maternal blood, UCB,
and placental tissue
measured by AAS
Age at Measurement:
maternal age 16-50;
birth
Placental function:
Placental thickness
Placental weight and
placental thickness were
recorded by obstetrician in and GA
delivery room
Age at outcome:
birth
Logistic regression model was
adjusted for maternal age, parity,
mother's third trimester BMI,
urinary cotinine, mother's highest
education, total family income,
OR (95% Cl)b, per unit
increase in maternal blood
Pb: 1.64 (1.12, 2.41)
Mean ± SD:
Maternal blood:
2.897 ± 1.851 [jg/dL
UBC:
2.551 ± 2.592 pg/dL
Placenta:
0.579 ±2.176 pg/g
Median:
Maternal blood:
2.540 pg/dL
UCB: 2.057 pg/dL
Placenta: 0.450 pg/g
75th:
Maternal blood:
3.314 pg/dL
UCB: 2.689 pg/dL
Placenta: 0.630 pg/g
Max:
Maternal blood:
25.955 pg/dL
UCB: 56.511 pg/dL
Placenta: 78 pg/g
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Reference and Study
Design
Study Population Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Tsuii et al. (20191
Japan
January 2011-March
2014
Cross-sectional
JECS
n: 16,019
Mothers who delivered
a singleton pregnancy
Blood
Maternal blood, collected
during the second
trimester, was measured
by ICP-MS
Age at Measurement:
maternal age at second
trimester
Median: 5.96 ng/g
75th: 7.45 ng/g
Quartiles:
Q1
Q2
Q3
Q4
<4.79 ng/g
4.80-5.95 ng/g
5.96-7.44 ng/g
>7.45ng/g
Placental function:
Placenta previa and
placenta accreta
Data for those with and
without placenta previa
and placenta accreta were
obtained from medical
records.
Age at outcome:
maternal age at diagnosis
Multivariable logistic regression
models were adjusted for age,
smoking, smoking habits of the
partner, drinking habits, gravidity,
parity, number of cesarean
deliveries, and geographic
region; Placenta previa was
added as a covariate when
comparisons were performed
with or without placenta accreta
OR (95% CI):
Placenta previa
Q1
Q2
Q3
Q4
Reference
2.59 (1.40, 4.80)
1.32 (0.66, 2.64)
1.34 (0.67, 2.67)
p for trend: 0.007
Placenta accreta
Q1: Reference
Q2: 1.46 (0.57, 3.76)
Q3: 1.68 (0.66, 4.24)
Q4: 0.79 (0.27, 2.30)
p for trend: 0.345
AAS = atomic absorption spectrometry; BMI = body mass index; CI = confidence interval; ICP-MS = inductively coupled plasma mass spectrometry; GA = gestational age; JECS = Japan
Environment and Children's Study; OR = odds ratio; Q = quartile; SD = standard deviation; UCB = umbilical cord blood.
aEffect estimates are standardized to a 1 |jg/dL increase in blood Pb or a 10 |jg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect estimates are
standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated interval. Categorical
effect estimates are not standardized.
bEffect estimates unable to be standardized.
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Table 8-9 Epidemiologic studies of Pb exposure and other pregnancy and other birth outcomes.
Reference and Study
Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and
95% Clsa
Ashley-Martin et al.
(2015a1
Vancouver, Edmonton,
Winnipeg, Sudbury,
Ottawa, Kingston,
Toronto, Hamilton,
Montreal, and Halifax
Canada
2008-2011
Cohort
MIREC study
n: 1,260
Women were recruited from
10 Canadian sites during
their first trimester and
consented to provide urine
and blood samples. Women
were eligible for inclusion if
they were <14 weeks
gestation at the time of
recruitment, >18years of
age, able to communicate in
French or English, and
planning to deliver at a local
hospital
Blood
Maternal blood was
measured by ICP-MS
Age at Measurement:
Maternal age during 1st
and 3rd trimester
Geometric mean (SD):
0.88 (1.61) pg/dL
Quartiles (pg/dL):
Q1
Q2
Q3
<0.63
0.64 to <0.87
0.88 to <1.20
Q4: >1.20
Other Pregnancy and Birth
Outcomes: Fetal metabolic
function
Leptin and adiponectin were
measured in plasma from
1363 stored UCB samples by
enzyme-linked immunoassay
(ELISA) using kits from Meso
Scale Discovery. All samples
were above the LOD.
Age at outcome:
birth
Logistic regression models
were adjusted for maternal
age at delivery, pre-
pregnancy BMI, parity, and
BWZ
OR (95% CI)
Low leptin and maternal
blood Pb:
Q1
Q2
Q3
Q4
Reference
0.9 (0.5, 1.6)
0.6 (0.3, 1.1)
0.9 (0.5, 1.5)
High leptin and maternal
blood Pb:
Q1
Q2
Q3
Q4
Reference
1.2 (0.7, 2.1)
1.0 (0.6, 1.8)
1.7 (1.0, 2.9)
Low adiponectin and
maternal blood Pb:
Q1
Q2
Q3
Q4
Reference
1.3 (0.8, 2.2)
0.8 (0.5, 1.4)
1.1 (0.6, 1.9)
High adiponectin and
maternal blood Pb:
Q1
Q2
Q3
Q4
Reference:
0.9 (0.5, 1.5)
1.1 (0.7, 1.9)
0.9 (0.5, 1.5)
Herlin et al. (2019) n: 194 enrolled of the 221 Blood, cord blood, and Other Pregnancy and Birth Multivariable-adjusted (3 (95% CI)c
pregnant women other: placenta Outcomes: rTL linear regression models;
Salta Province (Andean models with maternal blood
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Outcome
Confounders
Effect Estimates and
95% Clsa
part)
Argentina
October 2012-
December 2013
Cohort
All pregnant women living in
the Andean part of the Salta
province northern Argentina
with estimated delivery date
between October 2012 and
December 2013, were
invited to participate
Maternal blood, UCB,
and placenta were
measured using ICP-MS
Age at Measurement:
birth
Median:
Maternal bloodb:
2.1 [jg/dL
UCBb: 1.4 Mg/dL
Placenta: 5.8 [jg/kg
Max:
Maternal bloodb:
9.9 [jg/dL
UCBb: 6.0 [jg/dL
Placenta: 38 [jg/kg
The rTLwas measured in
maternal blood leukocytes
(blood samples collected in
late pregnancy, mainly third
trimester), cord blood
leukocytes, and placental
tissue. We obtained high-
quality DNA and measured
rTL in 169 blood samples of
the pregnant women, 99 of
their placentas, and 98 cord
blood samples of their
babies. The rTL was
measured as the ratio
between the signal intensity
of the telomere sequences
and the signal intensity of a
single-copy gene
(hemoglobin (3 chain), using
real-time polymerase chain
reaction.
Age at outcome:
birth
Pb were adjusted for
maternal age, pre-
pregnancy BMI, and
education; models with
placenta were also
adjusted for GA at birth;
models with UCB were
adjusted for maternal age,
pre-pregnancy BMI, GA at
birth, and BW.
UCB: -0.038 (-0.074,
-0.002)
Maternal blood: 0.026
(-0.043, 0.095)
Placenta: -0.029 (-0.074,
0.016)
Liao et al. (20151
Taiwan
March-December 2010
Cross-sectional
n: 113
Pregnant women were
recruited from a single
institution in northern
Taiwan
Blood
Maternal blood
(plasma), collected at
the first trimester
(between 10 and
14 weeks of gestation),
was measured by ICP-
MS
Age at Measurement:
Maternal age at first
trimester (mean age
30.92 ± 3.09 years)
Other Pregnancy and Birth
Outcomes: Fetal nuchal
translucency thickness
Fetal nuchal translucency
thickness was measured at
10-14 weeks of gestation by
a gynecologist and three
trained sonographers
Age at outcome:
Age at scan (between
gestational week 10 and 14)
Multiple linear regression
models were adjusted for
maternal age, gestational
weeks, pre-pregnancy BMI,
supplement use, and
medication
(3 (95% CI)c: 0.022 mm
(-0.06, 0.10)
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Effect Estimates and
95% Clsa
Geometric mean:
0.048 |jg/L
Ashley-Martin et al.
(2015b')
Canada
2008-2011
Cohort
MIREC Study
n: 1256
Pregnant women in Canada
who had singleton, term
birth (>37 weeks)
Blood
Maternal blood was
measured by ICP-MS
Age at measurement:
maternal age at first and
third trimester
Median: 0.62 [jg/dL
75th: 1.03 pg/dL
Max: 4.14 pg/dL
Other Pregnancy and Birth
Outcomes: Fetal immune
system biomarkers
Immune system biomarkers
were measured in the
plasma of UCB samples;
thymic stromal lymphopoietin
(TSLP) concentrations were
determined using a
commercial antibody kit; IL-
33 concentrations were
analyzed using antibodies
from an R & D systems duo
set; IgE was determined from
ELISA kits
Logistic regression
adjusted for maternal age
OR (95% CI)
Maternal log-io-Pb blood
concentrations with elevated
(>80%) cord blood
concentrations of IL-33 and
TSLP: 0.79 (0.62, 1.01)
Maternal log-io-Pb blood
concentrations with elevated
(>0.5 kU/L) cord blood
concentrations of IgE: 0.99
(0.77, 1.26)
Age at outcome:
birth
Taylor etal. (20141
Bristol
UK
April 1991-December
1992
Cohort
ALSPAC study
n: 4,285
Pregnant women enrolled in
the ALSPAC study at a
median GA of 11 weeks
Blood
Maternal blood was
measured by ICP-MS
Age at Measurement:
Maternal age at
measurement (median
GA of sampling:
11 weeks)
Median:
Quintile 1
Quintile 2
Quintile 3
2.11 pg/dL
2.82 pg/dL
3.43 pg/dL
Other Pregnancy and Birth
Outcomes: Secondary sex
ratio
The sex of the infant was
recorded at birth
Age at outcome:
birth
Logistic regression models
adjusted for maternal and
paternal age, and parity
OR (95% CI)
Q1
Q2
Q3
Q4
Q5
Reference
1.04 (0.86, 1.42)
0.90 (0.70, 1.15)
1.01 (0.79, 1.30)
1.06 (0.82, 1.37)
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Effect Estimates and
95% Clsa
Quintile 4: 4.13 pg/dL
Quintile 5: 5.00 [jg/dL
Max:
Q1: 2.53 [jg/dL
Q2: 3.11 [jg/dL
Q3: 3.71 [jg/dL
Q4: 4.63 pg/dL
Q5: 19.14 [jg/dL
Bloom et al. (20151
Michigan (4 counties)
and Texas (12 counties)
United States
2005-2009
Cohort
LIFE
n: 235
Potential participants were
identified, using fishing
license registries or a
commercially available
direct marketing data base,
from 12 counties in Texas
and four in Michigan,
respectively, with presumed
exposure to persistent
organic pollutants. Inclusion
criteria comprised a
committed heterosexual
relationship, women aged
18-40 years (men >18),
English or Spanish speaker,
no use of an injectable
contraceptive within 12
months, and a menstrual
cycle length of 21-42 days.
Blood
Maternal and paternal
blood, collected before
pregnancy (baseline),
were measured by ICP-
MS
Age at Measurement:
>18, maternal mean
age: 29.75 (SD:
3.73) years and paternal
mean age: 31.52
(SD:4.57) years
Mean (SD):
Maternal: 0.71
(0.30) [jg/dL
Paternal: 1.13
(0.63) [jg/dL
Median:
Maternal: 0.66 pg/dL
Paternal: 0.98 pg/dL
Max:
Maternal: 2.23 pg/dL
Paternal: 6.43 pg/dL
Other Pregnancy and Birth
Outcomes: Secondary sex
ratio
Women were followed until
delivery when they
completed and returned birth
announcements that
captured date and sex of
birth, weight and length, and
HC. Secondary sex ratio is
the ratio of live male to
female births, reflecting a
male excess.
Age at outcome:
birth
Log-binomial models for
secondary sex ratio: effect
of maternal exposure
adjusted for paternal
exposure, maternal age,
difference in maternal and
paternal age, and maternal
and paternal smoking,
income, race, serum lipids
(mg/dL), and creatinine for
urine (mg/dL); effect of
paternal exposure adjusted
for maternal exposure,
paternal age, difference in
maternal and paternal age,
and maternal and paternal
smoking, income, race,
serum lipids (mg/dL), and
creatinine for urine (mg/dL)
RR (95% CI)
Maternal Exposure:
T1: Reference
T2: 0.97 (0.78, 1.22)
T3: 1.00 (0.81, 1.24)
p for trend: 0.884
Paternal Exposure:
T1
T2
T3
Reference
1.12 (0.89, 1.41)
1.06 (0.84, 1.34)
p for trend: 0.854
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95% Clsa
Tertiles (|jg/dL):
Maternal Blood Pb
T1: <0.55 (<33rd
percentile)
T2: 0.55-0.73 (33rd to
67th percentile)
T3: >0.73 (>67th
percentile)
Paternal Blood Pb
T1: <0.84 (<33rd
percentile)
T2: 0.84-1.16 (33rd to
67th percentile)
T3: >1.16 (>67th
percentile)
Tatsuta et al. (2022b)
Japan
January 2011-March
2014 (followed through
birth)
Cohort
JECS
n: 85,171
Pregnant women and their
paternal partners were
recruited from 15 regions of
Japan. Participants
delivered a live infant with
singleton pregnancy and
had child sex information.
Participants were excluded
is they had a stillbirth,
abortion, multiple births, or
withdrew before birth;
missing blood sample
information; missing
confounders; or without
partner's consent and with
paternal age or occupational
exposure to Pb deficits
Blood
Maternal blood was
measured by ICP-MS.
Age at measurement:
maternal age at
collection (middle or late
pregnancy)
Median: 5.85 ng/g
Max: 110 ng/g
Quartiles (ng/g)
Q1
Q2
Q3
1.20-4.46
4.47-5.39
5.40-6.35
Other Pregnancy and Birth
Outcomes: Secondary sex
ratio
Sex of the infant obtained
from the medical record
transcripts by physicians,
midwives, nurses, or trained
research coordinators.
Logistic regression models
were adjusted for maternal
age at parturition, season
of birth, pre-pregnancy
BMI, annual household
income, gravidity, fertility
treatments, score of the
K6, maternal smoking
status during pregnancy,
passive smoking status
during pregnancy, birth
year and study area
(regional center)
OR (95% CI)
Q1: Reference
Q2: 1.082 (1.037, 1.129)
Q3: 1.122 (1.074, 1.171)
Q4: 1.214 (1.163, 1.268)
Q5: 1.279 (1.224, 1.336)
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Effect Estimates and
95% Clsa
Q4: 6.36-7.76
Q5: 7.77-110
AAS = atomic absorption spectrometry; ALSPAC = Avon Longitudinal Study of Parents and Children; BMI = body mass index; BW = birth weight; BWZ = birth weight Z-score; ELISA = enzyme-
linked immunoassay; GFAAS = graphite furnace atomic absorption spectrometry; HC = head circumference; ICP-MS = inductively coupled plasma mass spectrometry; IgE = immunoglobulin E;
IL-33 = interleukin-33; JECS =Japan Environment and Children's Study; LIFE = Longitudinal Investigation of Fertility and the Environment; LOD = limit of detection K6 = Kessler Psychological
Distress Scale; MIREC = Maternal-Infant Research on Environmental Chemicals; Q = quartile; RR = relative risk; rTL = relative telomere length; SD = standard deviation; T = fertile;
TSLP = thymic stromal lymphopoietin; UCB = umbilical cord blood.
aEffect estimates are standardized to a 1 |jg/dL increase in blood Pb or a 10 |jg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect estimates are
standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated interval. Categorical effect
estimates are not standardized.
bPb measurements were converted from |jg/L to |jg/dL.
°Effect estimates unable to be standardized.
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Table 8-10 Epidemiologic studies of Pb exposure and postnatal growth.
Reference and
Study Design
Study Population Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Signes-Pastor et al.
(20211
United States
2013-2016
Cross-sectional
NHANES
n: 1,634
Children aged 6-
11 years old
participating in the
2013-2014 and 2015-
2016 NHANES cycles
Blood
Blood was measured by
ICP-MS
Age at measurement: 6-
11 years old
Median:
Overall: 0.5 [jg/dL
Girls: 0.5 [jg/dL
Boys: 0.5 [jg/dL
75th:
Overall: 0.8 [jg/dL
Girls: 0.7 [jg/dL
Boys: 0.8 [jg/dL
Max:
Overall: 5.8 [jg/dL
Girls: 5.8 [jg/dL
Boys: 5.0 [jg/dL
Postnatal growth: weight,
WC, upper arm length,
standing height, and BMI
Physical examination was
performed to obtain body
measurements.
Age at outcome: 6-
11 years old
Linear regression
models were adjusted
for total calorie intake,
race, poverty-to-income
ratio, children's age,
smoker(s) in the
household, outside-of-
school and at-school
activity scores,
children's sex, and co-
exposure to fluoride,
Mn, Hg, and Se
(3 (95% CI)
BMI (kg/m2): -2.092 (-3.227,
-0.957)
Standing height (cm): -3.116
(-5.03, -1.202)
WC (cm): -5.742 (-8.769,
-2.715)
Upper arm length (cm): -1.068
(-1.625, -0.512)
Girls
BMI (kg/m2): -3.204 (-5.654,
-0.754)
Standing height (cm): -2.89
(-6.691, 0.911)
WC (cm): -6.659 (-12.911,
-0.408)
Upper arm length (cm): -1.696
(-2.859, -0.534)
Boys
BMI (kg/m2): -1.959 (-3.45,
-0.467)
Standing height (cm): -3.828
(-6.588, -1.068)
WC (cm): -6.81 (-10.995,
-2.626)
Upper arm length (cm): -0.89
(-1.691, -0.089)
Kuang et al. (20201 n: 395
Blood
Students aged 7-
11 years (grades 2 to 4)
Postnatal growth: height,
weight, bust, waistline,
and BMI
General linearized
models were adjusted
for age and gender
(3 (95% CI)
Height (cm): -3.21 (-4.24,
-2.17)
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Effect Estimates and 95%
Clsa
Nanjing
China
2012
Cross-sectional
were recruited from
public primary schools in
Nanjing, an industry city
from East China.
Students with congenital
mental retardation (third-
degree relatives
included) and other
serious diseases were
excluded. Students and
their parents were
informed of the research
content and purpose.
Only completely
matched groups of
samples, including
questionnaire
information, blood
samples, growth indexes
and school
performances, were
included in the study.
Blood was measured by
ICP-MS
Age at Measurement:
7-11 years
Mean (SD)b: 3.04
(1.72) pg/dL
Medianb: 2.61 pg/dL
Growth: Individual
measurements were
carried out by the medical
staff according to the
standard protocols of
WHO. Height was
measured using a
mechanical height gauge
to the nearest 0.1 cm.
Weight was measured
using digital scales to the
nearest 100 g.
Age at outcome:
7-11 years
Weight (kg): -1.96 (-3.11,
-0.82)
Bust (cm): -2.77 (-3.79, -1.76)
Waistline (cm): -3.65 (-4.78,
-2.52)
BMI (kg/m2): -0.20 (-0.65,
0.25)
Zhou et al. (20201 n: 1,678
Taizhou
China
April 2013-
November 2013
Cross-sectional
Children 6 years or older
Blood
Blood was measured by
GFAAS
Age at Measurement:
>6 years
Meanb: 5.684 pg/dL
Geometric meanb:
4.904 pg/dL
Medianb: 4.644 pg/dL
75thb: 6.4 pg/dL
Maxb: 46.8 pg/dL
Tertilesb (pg/dL)
Postnatal growth: HAZ,
WAZ and BMIZ
Children's body weight
and supine length or
standing height were
measured. BMI was
calculated by the formula
BMI = weight (kg)/height
(m)2; Z-scores of
anthropometric
parameters, such as HAZ,
WAZ and BMI-for-age Z-
score (BMIZ), were
calculated with the WHO
Child Growth Standards.
Multivariable linear
models were adjusted
for age, sex, BW,
maternal education
(3 (95% Cl)c:
WAZ: -0.33 (-0.56, -0.11)
HAZ: -0.38 (-0.63, -0.14)
BMIZ: -0.13 (-0.37, 0.12)
WAZ Tertiles
T1
T2
T3
Reference
-0.28 (-0.47, -0.09)
-0.42 (-0.62, -0.23)
HAZ Tertiles
T1
T2
T3
Reference
-0.26 (-0.47, -0.04)
-0.36 (-0.58, -0.15)
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Effect Estimates and 95%
Clsa
T1: <2.5
T2: 2.5-5.0
T3: >5.0
Age at outcome:
>6 years
BMIZ Tertiles
T1: Reference
T2: -0.18 (-0.39, 0.04)
T3: -0.29 (-0.50, -0.07)
Males:
WAZ: -0.36 (-0.67, -0.06)
HAZ: -0.38 (-0.72, -0.04)
BMIZ: -0.15 (-0.49, 0.19)
WAZ Tertiles:
T1: Reference
T2: -0.42 (-0.71, -0.13)
T3: -0.52 (-0.81, -0.24)
HAZ Tertiles:
T1: Reference
T2: -0.36 (-0.69, -0.004)
T3: -0.43 (-0.75, -0.11)
BMIZ Tertiles:
T1: Reference
T2: -0.28 (-0.60, 0.04)
T3: -0.35 (-0.68, -0.03)
Females
WAZ: -0.29 (-0.61, 0.03)
HAZ: -0.35 (-0.71, 0.01)
BMIZ: -0.10 (-0.45, 0.26)
WAZ Tertiles:
T1: Reference
T2: -0.17 (-0.42, 0.09)
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T3
-0.36 (-0.62, -0.09)
HAZ Tertiles:
T1
Reference
T2
-0.17 (-0.45, 0.11)
T3
-0.31 (-0.60, -0.02)
BMIZ Tertiles:
T1
Reference
T2
-0.10 (-0.38, 0.18)
T3
-0.25 (-0.54, 0.04)
Choi etal. (20171 n: 210
Seoul
South Korea
July 2014 to June
2016
Cross-sectional
Children ranging from 8
to 23 months in age and
healthy; no intake of
herbal medicine, iron, or
zinc supplements in the
past 3 months; no acute
febrile disease or acute
gastrointestinal disease
in the past 2 weeks; and
no evidence of other
acute or chronic
diseases affecting
growth on physical
examination or in
medical history
Blood
Blood was measured by
ICP-MS
Age at Measurement:
8-23 months
Geometric mean:
0.96 [jg/dL Median:
0.83 [jg/dL
75th: 1.23 pg/dL
Max: 3.5 pg/dL
Postnatal growth: Weight,
height, HC
Each infant's weight,
height, and HC were
measured by experienced
nurse; iron deficiency and
iron deficiency anemia,
complete blood count,
serum iron and ferritin
concentrations, as well as
total iron-binding capacity
were measured from the
venous blood samples of
infants
Age at outcome:
8-23 months
Linear regression
models; BW,
sociodemographic and
feeding-related factors,
and iron and anemia
status
(3 (95% CI):
WAZ-BWZ (difference of the
weight for age Z-scores at the
time of the study and birth
weight Z-scores): -0.238
(-0.391, -0.085)
HC for age Z-score: -0.213
(-0.366, -0.06)
Ashley-Martin et al. MIREC Study
(20191 n: 449
Vancouver,
Edmonton,
Winnipeg, Sudbury,
Ottawa, Kingston,
MIREC study is a
national-level pregnancy
cohort of 2001 women
from 10 cities across
Blood
Blood was measured by
ICP-MS
Age at Measurement:
2-5 years
Postnatal growth: HAZ,
WAZ, BMIZ
Child anthropometry was
performed during the
home visit and served as
a measure of growth at
Linear regression
models adjusted for
maternal education,
maternal country of
birth, age, postnatal
BMI, maternal prenatal
smoking, and paternal
(3 (95% Cl)b
HAZ
Overall:
T1: Reference
T2: -0.015 (-0.23, 0.20)
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Effect Estimates and 95%
Clsa
Toronto, Hamilton,
Montreal, and
Halifax
Canada
2008-2011
Cross-sectional
Canada including
Vancouver, Edmonton,
Winnipeg, Sudbury,
Ottawa, Kingston,
Toronto, Hamilton,
Montreal, and Halifax.
Participants were
recruited in the first
trimester of pregnancy
between 2008 and 2011
and followed through
delivery.
Median: 0.663 [jg/dL
75th: 0.962 pg/dL
Max: 5.49 pg/dL
Tertiles (pg/dL)
T1
T2
T3
<0.54
0.54-0.82
>0.82
that time. Weight and
height were measured
using a calibrated scale
and calibrated
stadiometer. All
measurements were
completed in duplicate or,
if warranted due to
predefined differences in
duplicate measurements,
in triplicate.
Age at outcome:
2-5 years
BMI; models were
additionally adjusted for
maternal metal
concentrations
T3: 0.025 (-0.20, 0.25)
Male
T1
T2
T3
Reference
0.003 (-0.28, 0.29)
-0.039 (-0.32, 0.24)
Female
T1
T2
T3
Reference
0.022 (-0.31, 0.35)
0.095 (-0.26, 0.45)
WAZ
Overall
T1
T2
T3
Reference
0.064 (-0.12, 0.25)
-0.004 (-0.20, 0.19)
Male
T1
T2
T3
Reference
0.11 (-0.15, 0.36)
0.074 (-0.18, 0.33)
Female
T1
T2
T3
Reference
0.050 (-0.22, 0.32)
-0.11 (-0.40, 0.18)
BMIZ
Overall
T1: Reference
T2: 0.097 (-0.098, 0.29)
T3: -0.041 (-0.24, 0.16)
Male
T1: Reference
T2: 0.15 (-0.13, 0.42)
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Outcome
Confounders
Effect Estimates and 95%
Clsa
T3: 0.14 (-0.14, 0.41)
Female
T1: Reference
T2: 0.039 (-0.24, 0.32)
T3: -0.26 (-0.55, 0.033)
Adjusted for maternal
exposure:
HAZ
Overall:
T1: Reference
T2: -0.030 (-0.25, 0.19)
T3: -0.008 (-0.25, 0.23)
Male
T1: Reference
T2: -0.007 (-0.30, 0.28)
T3: -0.067 (-0.38, 0.24)
Female
T1: Reference
T2: 0.013 (-0.33, 0.36)
T3: 0.081 (-0.30, 0.46)
WAZ
Overall
T1: Reference
T2: 0.041 (-0.15, 0.23)
T3: -0.05 (-0.26, 0.16)
Male
T1: Reference
T2: 0.09 (-0.16, 0.35)
T3: 0.04 (-0.24, 0.32)
Female
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Outcome
Confounders
Effect Estimates and 95%
Clsa
T1
T2
T3
Reference
0.024 (-0.26, 0.30)
-0.15 (-0.46, 0.17)
BMIZ
Overall
T1
T2
T3
Reference
0.076 (-0.12, 0.28)
-0.086 (-0.30, 0.14)
Male
T1
T2
T3
Reference
0.14 (-0.14, 0.41)
0.11 (-0.19, 0.41)
Female
T1
T2
T3
Reference
0.006 (-0.28, 0.29)
-0.32 (-0.64, 0.0036)
Jedrvchowski et al. Krakow Cohort Study
(20151 n: 379
Krakow
Poland
January 2001-
February 2004
Cohort
The present analysis
was restricted to 379
term-babies (born
>36 weeks of gestation)
who took part in the 9-
year follow-up. Women
who were residents of
Krakow, one of the
major cities in Poland,
and attended
ambulatory prenatal
clinics in the first and
second trimesters of
pregnancy were eligible
for the study. Enrollment
Blood and cord blood
Maternal and UCB,
obtained at delivery, and
blood (capillary),
obtained at age 5, were
measured by high-
performance liquid
chromatography
atmospheric-pressure
ionization tandem mass
spectrometry
Age at Measurement:
Maternal age at delivery
and 5 years old
Postnatal growth: Height
gain
At ages of 3-9 children
were invited annually for
pediatric examination
during which height
measurements were
done.
Age at outcome:
3-9 years old
Generalized estimating
equation (GEE) models
were adjusted for
maternal height, birth
length, pre-pregnancy
maternal weight,
gestational weight gain,
prenatal and postnatal
ETS, breastfeeding,
maternal education, and
parity
(3 (95% CI), as mean height
growth (cm) by UCB tertiles
T1
T2
T3
Reference
-0.671 (-1.610, 0.267)
-0.736 (-1.779, 0.307)
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Outcome
Confounders
Effect Estimates and 95%
Clsa
Kim et.a.1. (20171
Korea
January 2011-
December 2012
Cohort
included only
nonsmoking women with
singleton pregnancies
between the ages of 18
and 35 years who were
free from such chronic
diseases as diabetes
and hypertension.
Geometric mean:
UCB: 1.21 Mg/dL
Blood: 2.05 pg/dL
UBC Tertiles (pg/dL)
T1: <1.0
T2: 1.1-1.4
T3: >1.4
CHECK
n: 280
Healthy pregnant
women with mature term
singleton were recruited,
who did not have
preterm delivery,
medical predisposition,
or history of
occupational exposure
Cord blood
UCB was measured by
GFAAS
Age at measurement:
birth
Mean:
Overall: 1.31 pg/dL
Males: 1.39 pg/dL
Females: 1.21 pg/dL
Postnatal growth: Weight,
height, and BMI
Weight and height were
measured by the health
professionals
Age at outcome:
3, 6, 9, 12, 15, 18, 24, and
27 months of age
Generalized linear
model adjusted for
maternal age, maternal
BMI, gestational period,
cesarean section, and
smoking
(3 (95% Cl)b
Weight
At birth: 0.037 (-0.128, 2.01)
3 months: -0.039 (-0.414,
0.335)
6 months: -0.391 (-0.814,
0.033)
9 months: 0.000 (-0.356,
0.357)
12 months: 0.125 (-0.302,
0.552)
15 months: 0.093 (-0.396,
0.582)
18 months: 0.897 (-0.171,
1.965)
24 months: 0.717 (0.195,
1.239)
27 months: 0.316 (-0.345,
0.977)
Height
At birth: 0.176 (-0.003, 0.354)
3 months: -0.023 (-0.384,
0.337)
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Confounders
Effect Estimates and 95%
Clsa
6 months: 0.033 (-0.458,
0.523)
9 months: 0.049 (-0.346,
0.444)
12 months: -0.058 (-0.531,
0.415)
15 months: 0.226 (-0.220,
0.671)
18 months: 0.909 (-0.222,
2.040)
24 months: 0.138 (-0.530,
0.806)
27 months: 0.354 (-0.497,
1.205)
BMI
At birth: -0.167 (-0.357, 0.023)
3 months: -0.019 (-0.431,
0.392)
6 months: -0.461 (-0.937,
0.014)
9 months: -0.031 (-0.430,
0.369)
12 months: -0.020 (-0.492,
0.452)
15 months: -0.098 (-0.481,
0.285)
18 months: 0.157 (-1.266,
1.580)
24 months: 0.695 (0.077,
1.313)
27 months: 0.409 (-0.398,
1.216)
Males
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Outcome
Confounders
Effect Estimates and 95%
Clsa
Weight
At birth: 0.088 (-0.140, 0.316)
3 months: -0.008 (-0.597,
0.581)
6 months: -0.023 (-0.543,
0.497)
9 months: 0.167 (-0.398,
0.733)
12 months: 0.202 (-0.631,
1.034)
15 months: 0.365 (-0.467,
1.197)
18 months: 1.324 (0.023,
2.626)
24 months: 0.962 (0.181,
1.743)
27 months: 0.417 (-0.631,
1.465)
Height
At birth: 0.270 (0.037, 0.502)
3 months: 0.232 (-0.262,
0.726)
6 months: -0.077 (-0.695,
0.540)
9 months: 0.166 (-0.363,
0.695)
12 months: -0.147 (-1.153,
0.859)
15 months: 0.433 (-0.147,
1.013)
18 months: 1.648 (0.270,
3.026)
24 months: 1.062 (-0.132,
2.255)
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Outcome
Confounders
Effect Estimates and 95%
Clsa
27 months: 1.618 (-0.450,
3.686)
BMI
At birth: -0.194 (-0.413, 0.025)
3 months: -0.130 (-0.800,
0.540)
6 months: 0.003 (-0.558,
0.563)
9 months: -0.009 (-0.522,
0.504)
12 months: 0.314 (-0.689,
1.318)
15 months: -0.049 (-0.569,
0.470)
18 months: 0.319 (-1.496,
2.135)
24 months: 0.472 (-0.172,
1.116)
27 months: 0.966 (-1.390,
3.322)
Females
Weight
At birth: 0.006 (-0.236, 0.248)
3 months: -0.072 (-0.640,
0.496)
6 months: -0.828 (-1.502,
-0.154)
9 months: -0.098 (-0.602,
0.407)
12 months: 0.101 (-0.443,
0.644)
15 months: -0.039 (-0.722,
0.643)
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Outcome
Confounders
Effect Estimates and 95%
Clsa
18 months: -0.826 (-15.627,
13.976)
24 months: 0.821 (-0.087,
1.728)
27 months: 0.236 (-1.089,
1.561)
Height
At birth: 0.102 (-0.177, 0.381)
3 months: -0.249 (-0.875,
0.378)
6 months: 0.106 (-0.732,
0.945)
9 months: 0.104 (-0.526,
0.734)
12 months: -0.057 (-0.608,
0.493)
15 months: 0.121 (-0.664,
0.905)
18 months: -0.788d
24 months: -0.176 (-1.225,
0.874)
27 months: -0.153 (-1.405,
1.100)
BMI
At birth: -0.142 (-0.474, 0.189)
3 months: 0.098 (-0.491,
0.687)
6 months: -0.974 (-1.778,
-0.170)
9 months: -0.143 (-0.805,
0.519)
12 months: -0.147 (-0.688,
0.393)
15 months: -0.103 (-0.712,
0.505)
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Reference and Study Population Exposure Assessment
Study Design
Outcome
Confounders
Effect Estimates and 95%
Clsa
Hong et al. (20141
Seoul, Cheonan,
and Ulsan
South Korea
May 2006 to
December 2010
Cohort
18 months: -2.263d
24 months: 1.108 (-0.147,
2.362)
27 months: 0.439 (-1.581,
2.460)
MOCEH
n: 1,751
This research was
conducted as a part of
MOCEH, which is a
multicenter prospective
hospital and community-
based birth cohort study.
Women who lived in
these cities were
enrolled in the first
trimester. The
participants fulfilled the
inclusion criterion of age
>18 years. Written
informed consent was
obtained at the initial
visit from all enrolled
mothers on behalf of
themselves and their
children. The study
subjects were restricted
to those in which
maternal and cord BLLs
were assessed, and
postnatal growth
measurements were
performed. Exclusion
criteria: LBW(<2500 g);
preterm birth
(gestational week <37);
and missing information
on maternal age, BMI,
Blood and cord blood
Maternal blood, obtained
during early pregnancy
(before gestational week
20) and at delivery, and
UCB were measured by
AAS
Age at Measurement:
maternal age at week 20
and at delivery; delivery
Mean:
Early pregnancy:
1.25 [jg/dL Late
pregnancy: 1.25 [jg/dL
UCB: 0.91 [jg/dL
Median:
Early pregnancy:
1.29 [jg/dL
Late pregnancy:
1.27 [jg/dL
UCB: 0.93 pg/dL
75th:
Early pregnancy:
1.65 [jg/dL
Late pregnancy:
1.64 [jg/dL
Postnatal growth: weight
Z-score, length z-cores
Weights and lengths at 6
and 12 months were
taken by using an
infantometer by laying
infants on the center of a
scale and were read to 1
decimal place for weight
(0.1 kg) and length
(0.1 cm). At 24 months of
age, weights and lengths
were obtained by using an
automatic measuring
station for weight and
length by standing
on the center of the scale
on both feet, and placing
their heels, bottom, back,
and posterior head on the
measuring rod.
Age at outcome:
6, 12 and 24 months
Multivariable regression
models were adjusted
for mother's age,
education, pre-
pregnancy BMI, GA,
gender of the child, and
clinic location, and
calcium intake
(3 (95% Cl)b
Maternal Blood: Early
pregnancy Pb
Weight Z-scores
At birth: -0.05 (-0.16, 0.07)
6 months: -0.03 (-0.19, 0.13)
12 months: -0.10 (-0.26, 0.06)
24 months: -0.05 (-0.23, 0.12)
Length Z-scores
At birth: 0.01 (-0.15, 0.18)
6 months: -0.17 (-0.37, 0.02)
12 months: 0.04 (-0.15, 0.24)
24 months: -0.15 (-0.35, 0.04)
Maternal Blood: Late
Pregnancy Pb
Weight Z-scores
At birth: -0.01 (-0.15, 0.12)
6 months: -0.15 (-0.34, 0.03)
12 months: -0.15 (-0.34, 0.03)
24 months: -0.33 (-0.53,
-0.13)
Length Z-scores
At birth: -0.07 (-0.25, 0.11)
6 months: -0.05 (-0.28, 0.16)
12 months: 0.10 (-0.12, 0.33)
24 months: -0.30 (-0.53,
-0.08)
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Reference and
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Outcome
Confounders
Effect Estimates and 95%
Clsa
education level, and
gestational week;
subjects with >2 SD for
mean maternal BLLs
and child BW or length
UCB: 1.19 [jg/dL
Max:
Early pregnancy:
2.63 [jg/dL
Late pregnancy:
2.52 [jg/dL
UCB: 1.90 [jg/dL
UCB Pb
Weight Z-scores
At birth: 0.08 (-0.04, 0.21)
6 months: 0.10 (-0.07, 0.28)
12 months: 0.06 (-0.10, 0.24)
24 months: -0.01 (-0.21, 0.18)
Length Z-scores
At birth: 0.14 (-0.03, 0.32)
6 months: 0.11 (-0.11, 0.33)
12 months: 0.22 (0.01, 0.44)
24 months: 0.004 (-0.22, 0.22)
Renzetti et al.
(20171
Mexico City
Mexico
July 2007-February
2011
Cohort
PROGRESS
n: 513
Women were
considered eligible for
enrollment if they were
18 years or older,
pregnant at <20 weeks
of gestation, free of
heart or kidney disease,
did not use steroids or
anti-epilepsy drugs, did
not consume alcohol on
a daily basis, had
access to a telephone,
and planned to reside in
Mexico City for the
following 3 years
Blood, cord blood, and
bone
Maternal blood, collected
in the second and third
trimester of pregnancy
and within 12 hours of
delivery, and UCB,
collected within 12 hours
of delivery, were
measured by ICP-QQQ.
Maternal bone,
measured at 1-month
postpartum from tibia
(cortical bone) and
patella (trabecular bone),
were measured using a
K-shell X-ray
fluorescence instrument
Age at Measurement:
Maternal age at second
and third trimester and at
birth; child's age at
Postnatal growth: HAZ,
WAZ, BMIZ, and
percentage body fat
Trained research
assistants collected
measures of
anthropometry at the age
4-6-yr visit in which child
weight and standing
height were measured
using a professional
digital scale. BMI was
calculated from height and
weight and to determine
BMIZ-score for age and
sex based on WHO
norms. Tetrapolar
bioelectrical impedance
was measured to estimate
body fat mass and
percent body fat
Age at outcome:
4-6 years old
Multivariable linear
regression adjusted for
mother's age, BMI
(height when the
outcome is HAZ),
education, GA (weeks),
primiparity, smoke
exposure, delivery
mode, breastfeeding,
sex of the child, food
frequency questionnaire
total dietary intake,
LeadCare childhood
blood Pb, and child's
age (when the outcome
is percent body fat)
(3 (95% Cl)c
HAZ
Maternal blood, second
trimester: -0.04 (-0.13, 0.04)
Maternal blood, third trimester:
-0.10 (-0.19, -0.01)
Maternal blood, at delivery:
-0.04 (-0.13, 0.05)
UCB: -0.04 (-0.14, 0.06)
Maternal patella: 0.01 (-0.003,
0.02)
Maternal tibia: -0.003 (-0.01,
0.01)
WAZ
Maternal blood, second
trimester: -0.02 (-0.13, 0.09)
Maternal blood, third trimester:
-0.11 (-0.22, -0.003)
Maternal blood, at delivery:
-0.03 (-0.13, 0.08)
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Outcome
Confounders
Effect Estimates and 95%
Clsa
follow-up (4-6 years)
Mean (SD):
Maternal blood - second
trimester: 3.7 (2.6) [jg/dL
Maternal blood - third
trimester: 3.9 (2.8) [jg/dL
Maternal blood - at
delivery: 4.3 (3.1) [jg/dL
UCB: 3.5 (2.7) pg/dL
Patella: 4.7 (8.8) pg/g
Tibia: 2.9 (8.6) pg/g
Geometric mean:
Maternal blood - second
trimester: 3.0 pg/dL
Maternal blood - third
trimester: 3.1 pg/dL
Maternal blood - at
delivery: 3.5 pg/dL
UCB: 2.8 pg/dL
Max:
Maternal blood - second
trimester: 17.8 pg/dL
Maternal blood - third
trimester: 28.3 pg/dL
Maternal blood - at
delivery: 21.9 pg/dL
UCB: 18.5 pg/dL
Patella: 43.2 pg/g
Tibia: 30.1 pg/g
UCB: -0.03 (-0.15, 0.09)
Maternal patella: 0.01 (-0.01,
0.02)
Maternal tibia: -0.0003 (-0.01,
0.01)
BMIZ-score
Maternal blood, second
trimester: 0.04 (-0.07, 0.15)
Maternal blood, third trimester:
-0.01 (-0.12, 0.10)
Maternal blood, at delivery:
-0.03 (-0.08, 0.14)
UCB: 0.05 (-0.08, 0.17)
Maternal patella: 0.01 (0.01,
0.02)
Maternal tibia: 0.01 (-0.01,
0.02)
Percentage of body fat
Maternal blood, second
trimester: -0.13 (-0.75, 0.49)
Maternal blood, third trimester:
-0.21 (-0.82, 0.41)
Maternal blood, at delivery:
-0.12 (-0.74, 0.50)
UCB: 0.31 (-0.37, 0.99)
Maternal patella: 0.01 (-0.06,
0.07)
Maternal tibia: 0.01 (-0.06,
0.08)
Liu et al. (2019a') ELEMENT Blood and bone
n: 248
Postnatal growth: BMIZ, Multivariable linear (3 (95% Cl)c
WC, sum of skinfolds, and regression models were bmiz
body fat percentage adjusted for maternal
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Study Design
Outcome
Confounders
Effect Estimates and 95%
Clsa
Mexico City
Mexico
1994-2003
Cohort
Pregnant women who
were recruited from
three maternity hospitals
in Mexico City and
followed for 12 months
post-partum and
children followed
through age 4
Maternal tibia (cortical)
and patella (trabecular)
bone, measured at 1-
month postpartum, were
measured using a
noninvasive spot-source
Cd K-shell X-ray
fluorescence instrument
constructed at Harvard
University. Blood,
obtained from each child
annually from 1 to
4 years, was measured
by GFAAS
At the follow-up visit, child
weight, height, WC, and
skinfold thickness (biceps,
subscapular and
suprailiac) were measured
Age at outcome:
8-16 years old
age, parity, education
and calcium treatment
group, and children's
age, sex, and pubertal
stage
Age at Measurement:
maternal age at delivery
and 1-4 years old
Mean:
Maternal patella:
12.3 |jg/g
Maternal tibia: 8.9 |jg/g
Blood (cumulative):
19.6 [jg/dL
Median:
Maternal patella:
10.6 |jg/g
Maternal tibia: 8.3 |jg/g
Blood (cumulative):
17.7 [jg/dL
75th:
Maternal patella:
19.7 |jg/g
Maternal tibia: 15.2 |jg/g
Blood (cumulative):
23.5 [jg/dL
Max:
Patella: -0.02 (-0.03, -0.01)
Tibia: -0.00 (-0.02, 0.01)
Blood: 0.02 (-0.40, 0.45)
WC (cm)
Patella: -0.12 (-0.22, -0.03)
Tibia: -0.07 (-0.21, 0.07)
Blood: -0.38 (-3.74, 2.97)
Sum of skinfolds (mm)
Patella: -0.29 (-0.50, -0.08)
Tibia: -0.10 (-0.38, 0.19)
Blood: -1.62 (-8.76, 5.52)
Body of fat percentage (%)
Patella: -0.09 (-0.17, -0.01)
Tibia: -0.01 (-0.13, 0.10)
Blood: 2.08 (-0.98, 5.13)
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Outcome
Confounders
Effect Estimates and 95%
Clsa
Afeiche et al.
(20121
Mexico City
Mexico
1994-2005
Cohort
Maternal patella:
50.1 |jg/g
Maternal tibia: 38.6 |jg/g
Blood (cumulative):
55.0 [jg/dL
n: 773 Blood and bone
Mothers were recruited
from maternity hospitals
serving low-to-moderate
income populations in
Mexico City; preterm
(<37 weeks) and LBW
(<2500 g) were
excluded
Maternal bone, assessed
at approximately 1 month
postpartum, measured
by in vivo K-X-ray
fluorescence from the
mid-tibial shaft (cortical
bone) and the patella
(trabecular bone); blood,
obtained from children at
24 months or 30-
48 months, was
measured by GFAAS.
Age at Measurement:
Maternal age 1 month
postpartum, with average
age at delivery: 25.7 (SD:
5.3) years; birth—
24 months; 30-
48 months
Postnatal growth: Attained
height and BMI
Children's weight and
height were measured
and recorded by trained
staff members at birth and
Linear regression
models were adjusted
for maternal height and
calf circumference,
number of previous
pregnancies, marital
status, education level,
breastfeeding for
6 months, cohort,
calcium treatment group
assignment during
lactation and
pregnancy, age at
delivery, and child sex
and GA at birth; all
height models were
additionally adjusted for
birth length; BMI models
were additionally
adjusted for BW
(3 (95% CI)
Height differences (cm)
Prenatal: -4.6 (-10.25, 1.05)
Infant blood: -0.84 (-1.43,
-0.26)
Childhood blood: 0.41 (-0.17,
0.99)
BMI difference (kg/m2)
Prenatal: -0.70 (-3.05, 1.65)
Infant blood: -0.07 (-0.32,
0.18)
Childhood blood: 0.09 (-0.15,
0.33)
age 48 months using
standard protocols
Age at outcome:
birth and 48 months
Median:
Maternal tibia: 8.2 |jg/g
Maternal patella: 9.4 |jg/g
Infant blood (average
from birth to 24 months):
4.5 [jg/dL
Childhood blood
(average from 30-
48 months): 5.6 [jg/dL
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Reference and
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Outcome
Confounders
Effect Estimates and 95%
Clsa
Kerretal. (20191 n: 538
Torreon
Mexico
February 2001-
June 2002
Cohort
Children attending nine
public elementary
schools located within a
3.5 km radius from a
foundry close to the city
center participated in the
study. Participants were
randomized into one of
four groups: iron (30 mg
of ferrous fumarate),
zinc (30 mg zinc oxide),
a combination of iron
and zinc or a placebo
(sugar pill)
Blood
Blood, collected at
baseline (T1), 6 months
after baseline (T2), and
12 months after baseline
(T3), was measured by
GFAAS
Age at Measurement:
6-8 years old
Median: 10.1 pg/dL
75th: 23.7 pg/dL
Postnatal growth: height,
knee height, and HAZ
A single trained individual
took anthropometric
measures at each time
point (T1, T2, T3),
according to standard
methods recommended
by the WHO; Height and
knee height were
measured without shoes
using a standardized
measuring board or a
knemometer, respectively,
to the nearest 1 mm;
Age at outcome:
6-8 years old
Multivariable linear
regression adjusted for
age, sex, mother's
education, crowding,
and hemoglobin at
baseline; HAZ models
were not adjusted for
age or sex; models
were also stratified by
ALAD genotype
(3 (95% CI)
Height: -0.11 cm ( -0.18,
-0.04)
Knee height: -0.04 cm (-0.07,
-0.02)
HAZ: -0.02 cm ( -0.03, -0.01)
ALADl-2/2-2
Height: -0.38 cm (-0.68, 0.09)
Knee height: -0.14 cm (-0.25,
-0.02)
HAZ: -0.07 (-0.12, -0.02)
ALAD1-1
Height: -0.09 cm (-0.16,
-0.02)
Knee height: -0.04 cm (-0.06,
-0.01)
HAZ: -0.02 (-0.03, -0.004)
Burns et al. (20171
Chapaevsk
Russia
2003-2005 (2012—
2015)
Cohort
Russian Children's
Study
n: 499
The Russian Children's
Study is a prospective
cohort of 499 boys
residing in Chapaevsk,
Russia, enrolled in
2003-2005 at ages 8-
9 years and followed
annually through 2012-
2015 to age
18 years. For this
analysis, 10 boys in the
original cohort were
excluded due to chronic
Blood
Blood measured by
GFAAS with Zeeman
background corrected
Age at Measurement:
8-9 at enrollment
Median: 3.0 pg/dL
Max: 31 pg/dL
Postnatal growth: HAZ
and BMIZ
At study entry and annual
follow-up visits, a
standardized
anthropometric
examination was
performed according to a
written protocol. Height
was measured to the
nearest 0.1 cm using a
stadiometer. Weight was
measured to the nearest
100 g with a metric scale.
HAZ and BMIZ were
calculated using the WHO
Mixed effects linear
regression models were
adjusted for BW,
preterm birth, percent
calories from protein at
baseline, and age for
the HAZ models and
BW, no biological father
in home, percent
calories from fat at
baseline, and age for
BMIZ models
(3 (95% CI)b, as estimated
mean growth Z-scores
comparing higher (>5 pg/dL) to
lower (<5 pg/dL) BLL
HAZ: -0.43 (-0.60, -0.25)
BMIZ: -0.22 (-0.45, 0.006)
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Reference and Study Population Exposure Assessment
Study Design
Outcome
Confounders
Effect Estimates and 95%
Clsa
Deierlein et al.
(20191
New York City, NY;
Cincinnati, OH; and
San Francisco, CA
United States
2004-2007
Cohort
illnesses that could
affect growth and/or
pubertal development.
standards
Age at outcome:
8-9 at enrollment and
annually through age 18
Breast Cancer and
Environment Research
Program
n: 683
Girls ages 6-8 years
were enrolled in 2004-
2007 at three sites: New
York City, Cincinnati,
and San Francisco; girls
have no underlying
endocrine medical
conditions, be of black
or Hispanic
race/ethnicity (New York
City site only), and have
been born in the Kaiser
Permanente system
(San Francisco)
Blood
Blood was measured by
ICP-MS
Age at Measurement:
6-10 years
Median: 0.99 [jg/dL
Mean (SD): 1.16
(0.67) [jg/dL
Geometric mean:
1.03 [jg/dL (95% CI:
0.99, 1.07)
Max: 5.40 [jg/dL
Postnatal growth: height,
BMI, WC, and percent
body fat
Weight (kg), standing
height (cm), and umbilical
WC (cm) were collected at
baseline and at biannual
(Cincinnati) or annual
(New York City and San
Francisco Bay Area)
follow-up visits by trained
interviewers using a
standard protocol; BMI
was calculated as weight
divided by squared height
(kg/m2). Percent body fat
was estimated using
bioelectrical impedance
analysis
Age at outcome:
7-14 years
Linear mixed effects
models with an
unstructured correlation
matrix were adjusted for
age, age squared, race,
an interaction term
between age and blood
Pb concentrations, an
interaction term
between age squared
and blood Pb
concentrations, and an
interaction term
between race and age
(3 (95% CI)
Height (cm)
Age 7:
-2.0 (-
-3.0,
-1.0)
Age 8:
-1.9 (-
-2.8,
-0.9)
Age 9:
-1.7 (-
-2.7,
-0.8)
Age 10
-1.6
(-2.6
-0.7)
Age 11
-1.6
(-2.5,
-0.6)
Age 12
-1.5
(-2.5,
-0.5)
Age 13
-1.5
(-2.5,
-0.5)
Age 14
-1.5
(-2.5,
-0.4)
BMI (kg/m2)
Age 7:
-0.7 (-
-1.2,
-0.2)
Age 8:
-0.8 (-
-1.3,
-0.3)
Age 9:
-0.9 (-
-1.4,
-0.4)
Age 10
-0.9
(-1.4,
-0.4)
Age 11
-0.9
("1.5,
-0.3)
Age 12
-0.9
("1.5,
-0.3)
Age 13
-0.8
("1.5,
-0.2)
Age 14
-0.8
("1.5,
-0.02)
WC (cm)
Age 7:
-2.2
-3.8,
-0.6)
Age 8:
-2.5 (-
-3.8,
-1.1)
Age 9:
"2.7 (-
-4.0,
-1.4)
Age 10
-2.9
(-4.9,
1.4)
Age 11
-3.0
(-4.5,
-1.4)
Age 12
-3.0
(-4.7,
-1.3)
Age 13
-3.0
(-4.8,
-1.1)
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Reference and Study Population Exposure Assessment
Study Design
Outcome
Confounders
Effect Estimates and 95%
Clsa
Age 14: -2.9 (-4.8, -0.9)
Percent body fat (%)
Age 7: -1.8 (-3.2, -0.4)
Age 8: -2.0 (-3.3, -0.7)
Age 9: -2.1 (-3.4, -0.8)
Age 10: -2.2 (-3.4, -0.9)
Age 11: -2.1 (-3.4, -0.9)
Age 12: -2.1 (-3.4, -0.8)
Age 13: -1.9 (-3.2, -0.6)
Age 14: -1.7 (-3.1, -0.4)
Raihan et.al. (20181 MAL-ED study
n: 729
Mirpur, Dhaka
Bangladesh
Children under the age
of 2
November 2009-
December 2012
Cross-sectional
Blood
Blood was measured
using GFAAS
Age at measurement:
under the age of 2
Mean: 8.25 [jg/dL
Postnatal growth:
Stunting, wasting,
underweight
Child's length and weight
were measured using
Seca 417 infantometer
(precision: ± 1 mm) and
Seca 354 Dual Purpose
Baby Scale (precision:
10 gm).
Age at outcome:
under the age of 2
Logistic regression
models were adjusted
for child's gender,
weight, maternal
education, BMI, average
household income and
Household Food
Insecurity Access Scale
(HFIAS) categories in
stunting models; child's
gender, age, maternal
education, BMI, average
household income and
HFIAS categories in the
wasting models; and
child's gender, length,
maternal education,
BMI, average household
income and HFIAS
categories in the
underweight models
OR (95% CI)
Stunting: 1.78 (1.07, 2.99)
Wasting: 1.18 (0.64, 2.19)
Underweight: 1.63 (1.02, 2.61)
Gleason et al.
(20161
Sirajdikhan and
n: 618
Children of mother's
from Sirajdikhan and
Pabna Upazilas of
Cord blood
UCB were measured by
ICP-MS and child's
Postnatal growth: Stunting
Stunting status of children
was determined using the
WHO macros (Version
Logistic regression
models were adjusted
for maternal weight,
maternal education,
maternal protein intake,
OR (95% CI)
UCB: 0.97 (0.93, 1.00)
Blood at 20-40 months: 1.15
(1.00, 1.33)
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Reference and Study Population Exposure Assessment
Study Design
Outcome
Confounders
Effect Estimates and 95%
Clsa
Pabna Upazilas
Bangladesh
Bangladesh between
2008 and 2011;
Between 2010 and
2013, when children
were aged 12 to
40 months, healthcare
workers from Dhaka
Community Hospital
invited families to enroll
their children in follow-
up studies
blood, collected at 20 to 3.2.2)
40 months, was
measured by portable Age at outcome:
LeadCare II instruments 12-40 months
and HOME Inventory
score were all modeled
as continuous variables;
average water As and
2008-2011(2010—
2013)
Mn levels were included
as continuous variables
Cohort
Age at Measurement:
at birth and 12-
40 months
Median:
UCB: 3.1 [jg/dL
Blood: 4.2 [jg/dL
75th:
UCB: 6.3 [jg/dL
Blood: 7.6 [jg/dL
ALAD = aminolevulinic acid dehydratase; BMI = body mass index; BMIZ = BMI-forage Z-score; BW = birth weight; BWZ = birth weight Z-score; CI = confidence interval;
CHECK = Children's Health and Environmental Chemicals in Korea; ELEMENT = Early Life Exposure in Mexico to Environmental Toxicants; ETS = environmental tobacco smoke;
GEE = generalized estimating equation; GFAAS = graphite furnace atomic absorption spectrometry; HAZ = height-for-age Z-score; HFIAS = Household Food Insecurity Access
Scale; HOME = Home Observation for Measurement of the Environment; hr = hour(s); ICP-MS = inductively coupled plasma mass spectrometry; ICP-QQQ = inductively coupled
plasma triple quad; LBW = low birth weight; MAL-ED = Interactions of Malnutrition and Enteric Infections: Consequences for Child Health and Development; MIREC = Maternal-Infant
Research on Environmental Chemicals; MOCEH = Mothers' and Children's Environmental Health; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio;
PROGRESS = Programming Research in Obesity, Growth, Environment and Social Stressors; SD = standard deviation; T = fertile; UCB = umbilical cord blood; WAZ = weight for
age Z-score; WC = waist circumference; WHO = World Health Organization.
aEffect estimates are standardized to a 1 |jg/dL increase in blood Pb or a 10 |jg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect
estimates are standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated
interval. Categorical effect estimates are not standardized.
bPb measurements were converted from |jg/L to |jg/dL.
°Effect estimates unable to be standardized.
dNo CI reported.
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Table 8-11 Animal toxicological studies of Pb exposure and development.
Study
Species (Stock/Strain), n, Sex
Timing of Exposure
Exposure
Details
(Concentration,
Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
Graham et.al. (20111 Rat (Sprague-Dawley)
Control (vehicle), M/F, n = 14-16 (7-8/7-8)
1 mg/kg Pb, M/F, n = 14-16 (7-8/7-8)
10 mg/kg Pb, M/F, n = 14-16 (7-8/7-8)
PND 4 to 28
Offspring were
dosed via gavage
every other day
from PND 4 until
PND 28.
PND 29
0.267 [jg/dL for
control
3.27 [jg/dL for
1 mg/kg
12.5 [jg/dL for
10 mg/kg
Offspring Body
Weight
de Figueiredo et al.
(20141
Rat (Wistar)
28 d old Control (untreated), M,
n = 10
60 d old Control (untreated), M, n = 12
28 d old 30 mg/L Pb, M, n = 10
60 d old Control (assumed untreated), M,
n = 12
60 d old 30 mg/L Pb, M, n = 17
PND 0 to PND 28 or
PND 0 to PND 60
Male Wistar rats PND 28
were dosed via
drinking water
from birth to
PND 28 or 60.
Offspring Body
1.2 pg/dL for control Weight
8.0 pg/dL 30 mg/L Pb
PND 60
1.6 pg/dL for control
7.2 pg/dL for 30 mg/L
Pb
Duanetal. (20171
Mouse (CD-1)
Dams
Control (0 ppm Pb), F, n = 3
Low dose (27 ppm Pb), F, n = 3
High dose (109 ppm Pb), F, n = 3
Pups
Control (0 ppm Pb), NR, n = 9
Low dose (27 ppm Pb), NR, n = 9
PND 1 to PND 21
Dams were dosed
via drinking water
starting on GD 1
and continued
through weaning
(PND 21).
Pups:
PND 1
1.29 pg/dL for control
1.29 pg/dL for low
dose
1.29 pg/dL for high
dose
PND 18
1.62 pg/dL for control
Offspring Body
Weight
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Study
Species (Stock/Strain), n, Sex
Timing of Exposure
Exposure
Details
(Concentration,
Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
High dose (109 ppm Pb), NR, n = 9
19.6 [jg/dL for low
dose
29.16 |jg/dL for high
dose
PND 35
1.51 |jg/dL for control
28.7 [jg/dL for low
dose
38.0 [jg/dL for high
dose
Betharia and Maher
(20121
Rat (Sprague-Dawley)
Dams
Control (untreated), F, n = 6
10 |jg/mL Pb, F, n = 6
Pups
Control (untreated), M/F, n = 36-48 (18—
24/18-24)
10 |jg/mL Pb, M/F, n = 36^8 (1824/18-24)
GD Oto PND 20
Dams dosed via
drinking water
starting on GD 0
through weaning
(PND 20).
Pups:
PND 2
0.188 [jg/dL for
control
9.03 [jg/dL for
10 |jg/ml_ Pb
PND 25
0.0880 [jg/dL for
0 |jg/mL
0.976 [jg/dL for
10 |jg/ml_ Pb
Offspring Body
Weight
PND 60
0.0244 [jg/dL for
control
0.0318 [jg/dL for
10 |jg/ml_ Pb
Zhao et al. (20211
Rat (Sprague-Dawley)
Control (untreated), F, n = 6 dams
GD -14 to PND 10
Dams were dosed Pups:
via drinking water g
Offspring Body
Weight
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Study Species (Stock/Strain), n, Sex Timing of Exposure Exposure BLL As Reported Endpoints
Details (|jg/dL.) Examined
(Concentration,
Duration)
109 ppm Pb, F, n = 6 dams
starting 2 weeks
prior to mating
and continued
until PND 10.
0.87 [jg/dL for control
48.2 [jg/dL for
109 ppm Pb
PND 10
0.87 [jg/dL for control
11.5 [jg/dL for
109 ppm Pb
PND 21
0.87 [jg/dL for control
2.81 [jg/dL for
109 ppm Pb
PND 30
0.87 [jg/dL for control
1.20 [jg/dL for
109 ppm Pb
Rao Barkur and Bain Rat (Wistar)
(2016) Control (untreated), F, n = 6 dams
0.2% Pb Pregestation Only, n = 6 dams
0.2% Pb Gestation Only, n = 6 dams
0.2% Pb Lactation Only, n = 6 dams
0.2% Pb Gestation and Lactation, F, n = 6
dams
GD -30 to GD -1; GD 0
to GD 21; PND 1 to
PND 21; GD 0 to PND 21
Dams were dosed
via drinking water
for varying
amounts of time:
Pregestation Only
(1 month prior to
conception),
Gestation Only
(21 days),
Lactation Only
(21 days), and
Gestation and
Lactation
(42 days).
Pups (PND 22):
0.19 [jg/dL for control
3.03 [jg/dL for 0.2%
Pb in Pregestation
Only group
5.51 [jg/dL for 0.2%
Pb in Gestation Only
group
26.86 [jg/dL for 0.2%
Pb in Lactation Only
group
31.59 [jg/dL for 0.2%
Pb in Gestation and
Lactation group
Offspring Body
Weight, Pinna
Detachment, Eye
Opening, Tooth
Eruption
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Study
Species (Stock/Strain), n, Sex
Timing of Exposure
Exposure
Details
(Concentration,
Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
Barkur and Bain
(20151
Rat (Wistar)
Control (untreated), F, n = 6 dams
0.2% Pb Pregestation Only, n = 6 dams
0.2% Pb Gestation Only, n = 6 dams
0.2% Pb Lactation Only, n = 6 dams
0.2% Pb Gestation and Lactation, F, n = 6
dams
GD -30 to GD -1, or
GD 0 to 21, or PND 0 to
21, or GD 0 to PND 21
Dams were dosed
via drinking water
for varying
amounts of time:
Pregestation Only
(1 month prior to
conception),
Gestation Only
(21 days),
Lactation Only
(21 days), and
Gestation and
Lactation
(42 days).
Pups (PND 22):
0.18 [jg/dL for control
3.02 [jg/dL for 0.2%
Pb in Pregestation
Only group
5.30 [jg/dL for 0.2%
Pb Gestation Only
group
26.7 [jg/dL for 0.2%
Pb in Lactation Only
group
32.0 [jg/dL for 0.2%
Pb in Gestation and
Lactation group
Offspring Body
Weight
Sobolewski et al.
(20201
Mouse (C57BL/6)
Control (untreated) F, n = 10,
100 ppm Pb, F, n = 10
GD -61 to PND 21 of F1
only
Dams were dosed
via drinking water
beginning
2 months prior to
breeding and
ending on
PND 21 of the F1
(weaning).
F1
PND 6-7
0.0 [jg/dL for control,
12.5 [jg/dL for
100 ppm Pb
F3
Postnatal Month 6-7
0.0 [jg/dL for control,
0.4 |jg/dL for 100 ppm
Pb
Offspring Body
Weight
Albores-Garcia et al.
(2021)
Rat (Long-Evans)
Evaluated on PND 14
Controls (untreated), F, n = 11 dams
Controls (untreated), M/F, n = 14 (7/7) pups
1500 ppm Pb, F, n = 7 dams
1500 ppm Pb, M/F, n = 13 (6/7) pups
Continuous exposure
starting at GD -10
Dams were dosed
via the diet
starting 10 days
prior to mating.
After weaning
(PND 21),
offspring were put
onto the same
Pups
PND 14
<1.9 [jg/dL for control
males
<1.9 [jg/dL for control
females
Offspring Body
Weight
External Review Draft
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Study
Species (Stock/Strain), n, Sex
Timing of Exposure
Exposure
Details
(Concentration,
Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
Evaluated on PND 28
Controls (untreated), F, n = 9 dams
Controls (untreated), M/F, n = 16 (8/8) pups
1500 ppm Pb, F, n = 8 dams
1500 ppm Pb, M/F, n = 13 (7/6) pups
Evaluated on PND 50
Controls (untreated), F, n = 15 dams
Controls (untreated), M/F, n = 15 (7/8) pups
1500 ppm Pb, F, n = 14 dams
1500 ppm, M/F, n = 15 (7/6) pups
Evaluated on PND 120
Controls (untreated), F, n = 13 dams
Control (untreated), M/F, n = 13 (7/6) pups
1500 ppm Pb, F, n = 9 dams
1500 ppm Pb, M/F, n = 12 (6/6) pups
diet as their
dams.
36.1 [jg/dL for
1500 ppm Pb males
37 [jg/dL for
1500 ppm Pb females
PND 28
<1.9 [jg/dL for control
males
<1.9 [jg/dL for control
females
21.1 [jg/dL for
1500 ppm Pb males
20.9 [jg/dL for
1500 ppm Pb females
PND 50
<1.9 [jg/dL for control
males
<1.9 [jg/dL for control
females
20.2 [jg/dL for
1500 ppm Pb males
22.1 [jg/dL for
1500 ppm Pb females
PND 120
<1.9 [jg/dL for control
males
<1.9 [jg/dL for control
females
19.6 [jg/dL for
1500 ppm Pb males
24.3 [jg/dL for
1500 ppm Pb females
External Review Draft
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Study
Species (Stock/Strain), n, Sex
Timing of Exposure
Exposure
Details
(Concentration,
Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
Bassen and Sobin
(20141
Mouse (C57BL/6)
Control (untreated), M/F, n = 12 (6/6)
30 ppm Pb, M/F, n = 12 (6/6)
330 ppm Pb, M/F, n = 12 (6/6)
PND Oto PND 28
Dams were dosed
via drinking water
from birth of
offspring until
PND 28.
PND 28
0.03 [jg/dL for control
males
0.03 [jg/dL for control
females
3.63 [jg/dL for 30 ppm
Pb males
2.74 |jg/dL for 30 ppm
Pb females
16.02 [jg/dL for
330 ppm Pb males
13.35 [jg/dL for
330 ppm Pb females
Offspring Body
Weight
Barkuretal. (20111 Rat (Wistar)
Control (untreated), F, n = 6 dams
0.2% Pb, F, n = 6 dams
GD 1 to PND 21
Dams were dosed
via drinking water
from GD 1 to
PND 21. Only
male pups were
retained for
measurements of
body weight.
Pups (males only):
PND 22
0.266 [jg/dL for
control
31.2 [jg/dL for 0.2%
Pb
PND 120
0.234 [jg/dL for
control
Offspring Body
Weight
0.468 [jg/dL for 0.2%
Pb
Basha and Reddv
Rat (Wistar)
GD 6 to 21
Dams were dosed
Pups (males only):
Pinna
(2015s)
via drinking water
PND 21
Detachment,
from GD 6 to
0.21 [jg/dL for control
Tooth Eruption,
Fur
PND 21. Only
External Review Draft
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Study
Species (Stock/Strain), n, Sex
Timing of Exposure
Exposure
Details
(Concentration,
Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
Control (untreated), F, n = 8 dams
0.2% Pb, F, n = 8 dams
male pups were
retained for
measurements of
body weight and
developmental
milestones.
11.2 [jg/dL for 0.2%
Pb
PND 28
0.33 [jg/dL for control
12.3 [jg/dL for 0.2%
Pb
Postnatal Month 4
0.19 [jg/dL for control
5.9 |jg/dL for 0.2% Pb
Development,
Eye Slit
Formation, Eye
Opening,
Offspring Body
Weight, Offspring
Body Size
BLL = blood lead level; GD = gestational day; F = female; M = male; Pb = lead; PND = postnatal day.
External Review Draft
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Table 8-12 Epidemiologic studies of exposure to Pb and puberty in females and puberty in males.
Reference and Dnn.,i,tinn
Study Design Study P°P"'at"on
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Effects on Puberty in Females
Yaoetal. (2019)
United States
2011-2012
Cross-sectional
NHANES
n: 426 female children,
and 470 female
adolescents
Female children (age
6-11 years) and
female adolescents
(age 12-19 years) in
NHANES 2011-2012
Blood
Blood was measured by ICP-
MS
Age at Measurement:
6-19 years old
Geometric mean:
Female children: 0.68 [jg/dL
Female adolescents:
0.47 [jg/dL
Median:
Female children: 0.65 [jg/dL
Female adolescents:
0.47 [jg/dL
75th:
Female children: 0.93 [jg/dL
Female adolescents:
0.63 [jg/dL
Quartiles (|jg/dL):
Female children:
Q1: <0.48
Q2: 0.48-0.65
Q3: 0.65-0.93
Q4: >0.93
Female adolescents:
Q1: <0.35
Q2: 0.35-0.47
Puberty among females:
Serum tT levels
Serum tT levels were
analyzed by isotope-
dilution liquid
chromatography-tandem
mass spectrometry
Age at outcome:
6-19 years old
Weighted multivariable
linear regression
models; Model 1
controlled for age, race,
and BMI. Model 2
controlled for poverty-
to-income ratio (PIR),
seasons of collection,
times of venipuncture,
and serum cotinine, in
addition to the
covariates of model 1
(3 (95% CI), as percent
difference in serum tT
Model 1:
Female children
Q1: Reference
Q2: 14.34 (-3.75, 35.81)
Q3: -5.00 (-21.05, 14.32)
Q4: -5.73 (-23.13, 15.61)
p for trend: 0.36
Female adolescents
Q1
Q2
Q3
Q4
Reference
-8.55 (-18.52, 2.63)
-1.95 (-13.04, 10.56)
13.12 (0.06, 27.88)
p for trend: 0.14
Model 2:
Female children
Q1: Reference
Q2: 14.9 (-3.54, 36.86)
Q3: -0.96 (-17.80, 19.34)
Q4: -2.40 (-21.00, 20.57)
p for trend: 0.63
Female adolescents
Q1
Q2
Q3
Q4
Reference
-7.83 (-18.22, 3.88)
-1.07 (-12.67, 12.06)
14.85 (0.83, 30.81)
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Outcome
Confounders
Effect Estimates and 95%
Clsa
p for trend: 0.08
Reference and
Study Design
Study Population
Exposure Assessment
Q3: 0.47-0.63
Q4: >0.63
Slawiriska et al.
(20121
Legnica-Glogow
District
Poland
1995-2007
Cross-sectional
1995 n:436; 2007
n:346
Menarche status of
school girls 7-
16 years from villages
in southwestern
Poland was surveyed
in 1995, 2001, 2004,
and 2007.
Blood
Blood was measured by
GFAAS with a Zeeman
correction for background
Age at Measurement:
7-16 years old
Mean
1995: 6.57 pg/dL
2007: 4.24 pg/dL
Puberty among females:
Short-term secular
change in menarche
Menarche through survey
Age at outcome:
7-16 years
Logistic regression
models were adjusted
for age, height (linear
growth), BMI (weight-
for-height), and Pb
group (low Pb group:
2-5 pg/dL; high Pb
group: 5.10-
33.90 pg/dL)
OR (95% CI)
1995: 0.70 (0.27,
2007: 0.31 (0.09,
1.85)
1.06)
OR (95% CI)
Model with BMI: 0.54(0.26,
1.13)
Model with percent body fat:
0.52 (0.25, 1.08)
Model with sum of skinfolds:
0.53 (0.26, 1.10)
Mean
Total: 3.6 pg/dL
<3.7 pg/dL: 2.9 pg/dL
>3.7 pg/dL: 4.4 pg/dL
Median
Total: 3.6 pg/dL
<3.7 pg/dL: 2.8 pg/dL
>3.7 pg/dL: 4.3 pg/dL
Gomula et al. (20221 n: 490
Polkowice
Poland
2008
Cross-sectional
Girls aged 7-16 years
who were attending
several schools in
Polkowice in 2008.
Blood
Blood was measured by AAS
with Zeeman background
correction
Age at measurement: 7-
16 years old
Puberty among females:
age at menarche
Menarche through survey
Age at outcome: 7-
16 years old
Logistic regression
models were adjusted
for age and (1) BMI; (2)
percent body fat; and
(3) sum of skinfolds
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
De Craemer et al.
(20171
Belgium
FLEHS I: 2002-2006,
FLEHS II: 2007-
2011, and FLEHS III:
2012-2015
Cross-sectional
Flemish Environment Blood
and Health Studies
(FLEHS I, FLEHS II
and FLEHS III)
n: FLEHS I: n = 1659,
FLEHS II: n = 606, and
FLEHS III: n = 406
Blood Pb was measured by
ICP-MS
Age at Measurement:
14-15 years old
Adolescents aged 14-
15 years
Geometric meanb
FLEHS I: 2.13 pg/dL
FLEHS II: 1.38 pg/dL
FLEHS III: 0.926 pg/dL
Maxb
FLEHS I: 21.2 pg/dL
FLEHS II: 7.69 pg/dL
FLEHS III: 3.86 pg/dL
Puberty among females:
Hormones and sexual
maturation in adolescents
Development of breasts in
adolescent females and
pubic hair was scored
using the international
scoring criteria of
Marshall and Tanner,
where stage 1
corresponds to the start of
puberty and stage 5 to the
adult stage. Information
on menarche was
obtained through self-
assessed questionnaires.
Age at outcome:
14-15 years old
Logistic regression
models for female pubic
hair development and
breast development
were adjusted for age
BMI, contraceptive pill
usage; linear
regression models for
age at menarche were
adjusted for age, BMI
OR (95% Cl)c
Breast development
FLEHS I: 0.798 (0.653,
0.969)
FLEHS II: 1.318 (0.936,
2.055)
FLEHS III: 1.187 (0.886,
1.627)
Pubic hair development
FLEHS I: 1.113 (0.922,
1.349)
FLEHS II: 1.322 (0.938,
2.083)
FLEHS III: 0.919 (0.677,
1.229)
(3 (95% Cl)c
Age of menarche
FLEHS I: 0.039 (-0.072,
0.15)
FLEHS II: 0.257 (0.091,
0.424)
FLEHS III: 0.126 (-0.021,
0.273)
Nkomo et al. (20181
Johannesburg
South Africa
Cohort
Birth to Twenty Plus
(BT20+) birth cohort
n: 683
Singleton births in
which the infant
resides in
Johannesburg area for
at least 6 months after
birth; participants must
have data for BLL at
Blood and cord blood
UCB collected at birth and
blood at collected at age 13
were measured by AAS with
a Zeeman background
correction
Age at Measurement:
birth and age 13
Puberty among females:
Pubertal trajectory
classes
Tanner stages of pubertal
development refer to a
standard clinical method
used to describe physical
measurements of
secondary sexual
characteristics using
Multinomial logistic
regression was used to
predict pubertal growth
trajectory class based
on BLLs at age
13 years and cord BLLs
adjusted for ethnicity
and height at age 8
RRR (95% CI)
Development of pubic hair
UCB
Blood, >5 pg/dL vs.
<5 pg/dL
Trajectory Class 1:
Reference
Trajectory Class 2: 0.45
(0.29, 0.68)
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
age 13 and pubertal
growth trajectory
classes
Mean (SD)
UCB: 5.8 (2.1) pg/dL
Blood: 5.0 (1.9) pg/dL
Median
UCB: 6.0 pg/dL
Blood: 4.8 pg/dL
75th
UCB: 7.0 pg/dL
Blood: 7.9 pg/dL
drawings to signal stage
of pubertal development
where stage 1 signifies
lowest level of pubertal
maturation and stage 5
denotes highest level of
pubertal maturation in
girls
Age at outcome:
9-16 years old
Trajectory Class 3: 0.55
(0.26, 1.17)
Development of breasts
Blood, >5 pg/dL vs.
<5 pg/dL
Trajectory Class 1:
Reference
Trajectory Class 2: 0.72
(0.47, 1.11)
Trajectory Class 3: 0.63
(0.42, 0.94)
Trajectory Class 4: 0.46
(0.27, 0.77)
Liuetal. r2019b1
Mexico City
Mexico
Cohort
n: 547 (283 girls and
264 boys)
Pregnant women were
recruited at three
public maternity
hospitals (Manuel Gea
Gonzalez Hospital,
Mexican Social
Security Institute and
the National Institute
of Perinatology) in
Mexico City; and
Children at age 9.8-
18.0 years who had at
least one
measurement of
maternal bone Pb or
childhood blood Pb
Blood and bone
Maternal bone, measured at
the mid-tibial shaft (cortical
bone) and patella (trabecular
bone) was measured by X-
ray fluorescence instrument;
blood samples from children
were measured by GFAAS
Age at Measurement:
Maternal age 1-month
postpartum; blood measured
between 1 and 4 years
Median
Patella: 8.20 pg/g
Tibia: 7.63 pg/g
Blood, cumulative 1-4 years:
13.83 pg/dL
75th
Puberty among females:
Pubertal stages
In girls, the stages of
pubertal development
were defined by a
pediatrician using Tanner
staging scales for the
breast maturation and
pubic hair growth.
Menarche was measured
via a self-reported
questionnaire.
Age at outcome:
9.8-18 years
Ordinal regression
models were adjusted
for child age at visit,
maternal education and
marital status, and
number of siblings at
birth; Cox proportional
hazard regression
models were adjusted
for number of siblings
at birth, maternal
education, and marital
status
OR (95% CI), per IQR
increase in Pb
Breast development
Patella: 0.79 (0.61, 1.01)
Tibia: 1.01 (0.75, 1.36)
Blood, cumulative 1-
4 years: 0.96 (0.92, 0.99)
Pubic hair development
Patella: 0.96 (0.76, 1.22)
Tibia: 1.12 (0.84, 1.49)
Blood, cumulative 1-
4 years: 0.95 (0.92, 0.99)
HR (95% CI)
Patella
Continuous: 0.16 (0.02,
1.07)
T1: Reference
T2: 1.10 (0.76, 1.58)
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Patella: 15.45 |jg/g
Tibia: 13.80 |jg/g
Blood, cumulative 1-4 year:
18.76 [jg/dL
IQR
Patella: 13.57 |jg/g
Tibia: 13.30 |jg/g
Blood, cumulative 1-4 year:
7.66 [jg/dL
Tertiles
Patella (pg/g)
T1: <3.9
T2: 4.0-12.9
T3: 13.0-45.3
Tibia (|jg/g)
T1: <4.6
T2: 4.7-11.3
T3: 11.4-37.3
Blood, cumulative 1-4 years
(Hg/dL)
T1
T2
T3
<12.0
12.1-16.1
16.2-51.5
T3: 0.60 (0.41, 0.88)
Tibia
Continuous: 1.11 (0.12,
9.84)
T1: Reference
T2: 1.30 (0.86, 1.96)
T3: 1.14 (0.75, 1.72)
Blood, cumulative 1-4 years
Continuous: 0.91 (0.77,
1.08)
T1
T2
T3
Reference
0.65 (0.46, 0.91)
0.76 (0.55, 1.06)
Jansenetal. (20181 ELEMENT project
Mexico City
Mexico
1997-2004(2015)
Cohort
n: 200
Mothers were
recruited from prenatal
clinics ofthe Mexican
Social Security
Institute in Mexico City
who were not planning
to leave the area
Blood
Maternal blood was
measured by GFAAS
Age at Measurement:
maternal age at sampling
Median
Puberty among females:
Menarche
Girls were asked about
menarche during the
follow-up visit (between
age 9.8 and 18.1 years).
They were asked whether
or not menarche had
occurred (Yes, no, or
Interval-censored Cox
regression models,
comparing the hazard
of menarche among
girls with prenatal
maternal blood Pb
>5 [jg/dL to those with
prenatal maternal BLL
<5 [jg/dL, were
adjusted for maternal
HR (95% CI)
Interval-censored Cox
models
First trimester maternal
blood
<5 [jg/dL: Reference
>5 [jg/dL: 0.85 (0.46, 1.24)
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
within 5 years; had a
history of infertility,
diabetes, or psychosis;
consuming alcoholic
beverages daily during
pregnancy; addiction
to illegal drugs;
diagnosis of a high-
risk pregnancy; or
being pregnant with
multiples
First trimester: 4.8 [jg/dL
Second trimester: 4.0 [jg/dL
Third trimester: 4.5 [jg/dL
75th:
First trimester: 7.1 [jg/dL
Second trimester: 6.4 [jg/dL
Third trimester: 6.6 [jg/dL
don't know/refused) and,
if so, to recall the age
(in years and months) it
occurred.
Age at outcome:
age of menarche
age, maternal parity,
maternal education,
and prenatal calcium
treatment status; Cox
regression models,
using self-reported age
at menarche as the
time to event, were
adjusted for maternal
age, maternal parity,
maternal education,
and prenatal calcium
treatment status; Cox
regression models were
also restricted to girls
<14.5 years at the time
of the interview and
adjusted for maternal
age, maternal parity,
maternal education,
and prenatal calcium
treatment status
Second trimester maternal
blood
<5 [jg/dL: Reference
>5 [jg/dL: 0.59 (0.28, 0.90)
Third trimester maternal
blood
<5 [jg/dL: Reference
>5 [jg/dL: 0.85 (0.42, 1.27)
Cox models
First trimester maternal
blood
<5 [jg/dL: Reference
>5 [jg/dL: 0.92 (0.65, 1.29)
Second trimester maternal
blood
<5 [jg/dL: Reference
>5 [jg/dL: 0.91 (0.65, 1.27)
Third trimester maternal
blood
<5 [jg/dL: Reference
>5 [jg/dL: 0.97 (0.69, 1.37)
Cox models restricted to
girls <14.5 years at
interview
First trimester maternal
blood
<5 [jg/dL: Reference
>5 [jg/dL: 0.80 (0.52, 1.25)
Second trimester maternal
blood
<5 [jg/dL: Reference
>5 [jg/dL: 0.64 (0.38, 1.09)
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Third trimester maternal
blood
<5 [jg/dL: Reference
>5 [jg/dL: 0.89 (0.56, 1.41)
Effects on Puberty Among Males
Yaoetal. (2019)
United States
2011-2012
Cross-sectional
NHANES
n: 431 male children,
493 male adolescents
Male children (age 6-
11 years) and male
adolescents (age 12-
19 years) in NHANES
2011-2012
Blood
Blood was measure by ICP-
MS
Age at Measurement:
6-19 years old
Geometric mean
Male children: 0.76 [jg/dL
Male adolescents: 0.68 [jg/dL
Median
Male children: 0.72 [jg/dL
Male adolescent: 0.66 [jg/dL
75th
Male children: 1.02 [jg/dL
Male adolescents: 0.96 [jg/dL
Quartiles (|jg/dL):
Male children:
Q1: <0.52
Q2: 0.52-0.72
Q3: 0.72-1.02
Q4: >1.02
Male adolescents:
Q1: <0.47
Puberty among males:
Serum tT levels in male
children and adolescents
Serum tT levels were
analyzed by isotope-
dilution liquid
chromatography-tandem
mass spectrometry
Age at outcome:
6-19 years old
Weighted multivariable
linear regression
models; Model 1
controlled for age, race,
and BMI. Model 2
controlled for PIR,
seasons of collection,
times of venipuncture,
and serum cotinine, in
addition to the
covariates of model 1
(3 (95% CI), as percent
difference in serum tT
Model 1:
Male children
Q1: Reference
Q2: 4.1 (-18.47, 32.9)
Q3: -6.13 (-27.64, 21.77)
Q4: -12.83 (-33.68, 14.58)
p for trend: 0.36
Male adolescents
Q1
Q2
Q3
Q4
Reference
-3.36 (-20.98, 18.2)
14.99 (-7.77, 43.37)
15.62 (-7.07, 43.86)
p for trend: 0.18
Model 2:
Male children
Q1: Reference
Q2: 11.75 (-13.06, 43.65)
Q3: -4.63 (-26.97, 24.55)
Q4: -13.09 (-34.45, 15.22)
p for trend: 0.42
Male adolescents
Q1: Reference
Q2: -4.35 (-21.22, 16.14)
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Outcome
Confounders
Effect Estimates and 95%
Clsa
Q3: 8.15 (-12.91, 34.3)
Q4: 6.32 (-14.62, 32.4)
p for trend: 0.58
Reference and
Study Design
Study Population
Exposure Assessment
Q2
Q3
Q4
0.47-0.66
0.66-0.96
>0.96
De Craemer et al.
(20171
Belgium
FLEHS I: 2002-2006,
FLEHS II: 2007-
2011, and FLEHS III:
2012-2015
Cross-sectional
Flemish Environment
and Health Studies
(FLEHS I, FLEHS II
and FLEHS III)
FLEHS I n: 1659,
FLEHS II n: 606, and
FLEHS III n: 406
Adolescents aged 14-
15 years
Blood
Blood was analyzed by ICP-
MS
Age at Measurement:
14-15 years old
Geometric meanb
FLEHS I: 2.13 pg/dL
FLEHS II: 1.38 pg/dL
FLEHS III: 0.926 pg/dL
Maxb:
FLEHS I: 21.2 pg/dL
FLEHS II: 7.69 pg/dL
FLEHS III: 3.86 pg/dL
Puberty among males:
Hormones and sexual
maturation in adolescents
Development of genitals
in adolescent males and
pubic hair was scored
using the international
scoring criteria of
Marshall and Tanner,
where stage 1
corresponds to the start of
puberty and stage 5 to the
adult stage. Sex
hormones investigated in
this study were E2,
testosterone (T), fE2 and
IT, SHBG, LH, and FSH.
Hormone levels in
adolescent males were
measured in blood serum
using commercial
immunoassays.
Age at outcome:
14-15 years old
Logistic regression
models for male public
hair development and
genital development
were adjusted for age
and BMI; linear
regression models for
hormones (ratio T/E2,
E2, fE2, T, IT) were
adjusted for age, hour
of blood collection,
BMI, smoking status;
SHBG: age, fasting,
BMI, smoking status,
hour of blood collection;
LH and FSH: age, BMI,
smoking status
OR (95% Cl)c
Pubic hair development
FLEHS I: 0.808 (0.686,
0.949)
FLEHS II: 0.849 (0.563,
1.365)
FLEHS III: 0.515 (0.327,
0.774)
Genital development
FLEHS I: 0.843 (0.717,
0.99)
FLEHS II: 0.697 (0.462,
0.998)
FLEHS III: 0.621 (0.388,
0.967)
(3 (95% Cl)c
FLEHS I:
Ratio T/E2: 1.022 (0.985,
1.059)
E2: 1.011 (0.991, 1.031)
fE2: 1.003 (0.975, 1.033)
T: 1.039 (0.993, 1.087)
IT: 1.026 (0.967, 1.09)
SHBG: 1.024 (0.992, 1.056)
LH: 0.995 (0.959, 1.033)
FLEHS II:
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
ratio T/E2: 1.002 (0.958,
1.049)
E2: 0.968 (0.923, 1.016)
fE2: 0.908 (0.839, 0.983)
T: 0.959 (0.906, 1.015)
IT: 0.909 (0.828, 0.997)
SHBG: 1.005 (0.961, 1.052)
LH: 0.974 (0.923, 1.028)
FSH: 0.995 (0.942, 1.05)
Nkomo et al. (20181
Johannesburg
South Africa
Cohort
Birth to Twenty Plus
(BT20+) birth cohort
n: 683
Singleton births in
which the infant
resides in
Johannesburg area for
at least 6 months after
birth; participants must
have data for BLL at
age 13 and pubertal
growth trajectory
classes
Blood and cord blood
UCB collected at birth and
blood at collected at age 13
were measured by AAS with
a Zeeman background
correction
Age at Measurement:
birth and age 13
Mean (SD)
UCB: 5.9 (2.0) pg/dL
Blood: 6.6 (2.6) pg/dL
Median
UCB: 6.0 pg/dL
Blood: 6.5 pg/dL
75th
UCB: 7.0 pg/dL
Blood: 6.0 pg/dL
Puberty among males:
Pubertal trajectory
classes
Tanner stages of pubertal
development refer to a
standard clinical method
used to describe physical
measurements of
secondary sexual
characteristics using
drawings to signal stage
of pubertal development
where stage 1 signifies
lowest level of pubertal
maturation and stage 5
denotes highest level of
pubertal maturation in
boys
Age at outcome:
9-16 years old
Multinomial logistic
regression models were
used to predict pubertal
growth trajectory class
based on (1) UCB Pb
and adjusted for
ethnicity; (2) blood Pb
and adjusted for
ethnicity and height at
age 8
RRR (95% CI)
UCB
Pubic hair development
Trajectory Class 1:
Reference
Trajectory Class 2: 0.61
(0.25, 1.43)
Trajectory Class 3: 0.28
(0.11, 0.74)
Genital development
Trajectory Class 1:
Reference
Trajectory Class 2: 0.27
(0.03, 2.26)
Trajectory Class 3: 0.24
(0.03, 1.89)
Trajectory Class 4: 0.13
(0.01, 1.24)
Blood
Pubic hair development
Trajectory Class 1:
Reference
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Trajectory Class 2: 0.94
(0.63, 1.39)
Trajectory Class 3: 1.35
(0.73, 2.47)
Genital development
Trajectory Class 1:
Reference
Trajectory Class 2: 0.77
(0.33, 1.77)
Trajectory Class 3: 0.88
(0.38, 2.01)
Trajectory Class 4: 1.02
(0.37, 2.83)
Liuetal. r2019b1
Mexico City
Mexico
Cohort
n: 547 (283 girls and
264 boys)
Pregnant women were
recruited at three
public maternity
hospitals (Manuel Gea
Gonzalez Hospital,
Mexican Social
Security Institute and
the National Institute
of Perinatology) in
Mexico City; and
Children at age 9.8-
18.0 years who had at
least one
measurement of
maternal bone Pb or
childhood blood Pb
Blood and bone
Maternal bone was measured
at the mid-tibial shaft (cortical
bone) and patella (trabecular
bone) and determined using
the X-ray fluorescence
instrument; blood samples
from children were measured
by GFAAS
Age at Measurement:
Maternal age 1-month
postpartum; blood measured
between 1 and 4 years
Median
Patella: 7.44 |jg/g
Tibia: 7.10 |jg/g
Blood, cumulative 1-4 years:
14.33 [jg/dL
75th
Puberty among males:
Pubertal stages
In boys, the stage of
sexual maturation was
defined by the
pediatrician using Tanner
staging scales for the
development of genitalia
and pubic hair.
Age at outcome:
9.8-18 years
Ordinal regression
models for genitalia
and pubic hair and
logistic regression
models for TV were
adjusted for adjusted
for child age at visit,
maternal education and
marital status, and
number of siblings at
birth
OR (95%), per IQR increase
in Pb
Genital development
Patella: 0.963 (0.734,
1.264)
Tibia: 1.00 (0.711, 1.406)
Blood, cumulative 1-
4 years: 0.995 (0.948,
1.044)
Pubic hair development
Patella: 1.094 (0.836,
1.432)
Tibia: 1.00 (0.715, 1.398)
Blood, cumulative 1-
4 years: 1.004 (0.969, 1.04)
TV
Patella: 1.158 (0.804,
1.667)
Tibia: 0.885 (0.503, 1.558)
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Patella: 14.56 |jg/g
Tibia: 15.93 |jg/g
Blood, cumulative 1-4 years:
18.90 [jg/dL
Blood, cumulative 1-
4 years: 1.013 (0.954,
1.075)
IQR
Patella: 13.57 |jg/g
Tibia: 13.30 |jg/g
Blood, cumulative 1-4 years:
7.66 [jg/dL
Williams et al. (20191
Chapaevsk
Russian
2003-2005(2017)
Cohort
Russian Children's
Study
n: 516
Healthy male children
who were 8-9 years
old between 2003 and
2005 in Chapaevsk,
Russia.
Blood
Blood was measured by
Zeeman background
corrected flameless GFAAS
Age at Measurement:
8-9 years old
Median: 3 [jg/dL
Max: 31 [jg/dL
Puberty among males:
Male sexual maturity
Pubertal status was
staged from 1 to 5 via
examination by a single
clinician according to
internationally accepted
criteria. Pubarche (pubic
hair stage, P) was
determined by the extent
of terminal hair growth.
Genital staging (G) was
assessed by genital size
and maturity. TV was
measured using an
orchidometer. Three
different measures of
sexual maturity were
considered as separate
indicators: TV >20 mL of
either testis, genitalia
stage 5 (G5), and pubic
hair stage 5 (P5).
Duration of pubertal
progression was defined
as time from pubertal
onset (TV >3 mL,
Interval-censored
models were fit
assuming a normal
distribution for age at
sexual maturity using
accelerated failure time
models to compare
pubertal outcomes
between boys with
'higher' (>5 |jg/dL)
versus 'lower'
(<5 |jg/dL) peripubertal
BLLs. Models were
adjusted for boy's BW,
prenatal exposure to
maternal alcohol and
tobacco, maternal age
at son's birth,
household
characteristics including
income level, parental
education, and whether
the biological father
lived in the same
household, the boy's
physical activity, and
his nutritional status
determined by caloric
(3 (95% Cl)c, as shift in
mean age in months
Age at pubertal onset
Genitalia (G2): 8.40 (3.70,
13.10)
Pubic hair (P2): 8.12 (3.46,
12.78)
TV (>3 mL): 7.68 (3.46,
11.90)
Age at sexual maturity
Genitalia (G5): 4.20 (0.56,
7.84)
Pubic hair (P5): 4.23 -0.31,
8.77)
TV (>20 mL): 5.14 (1.70,
8.58)
Duration of puberal
progression
Genitalia (G2 to G5): -3.76
(-7.93, 0.42)
Pubic hair (P2 to P5): -1.82
(-6.91, 3.28)
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Effect Estimates and 95%
Clsa
genitalia stage >2 (G2),
pubic hair stage >2 (P2),
respectively) to sexual
maturity, separately for
each pubertal indicator.
Age at outcome:
age at follow-up in 2017
intake and percent of
fat and protein intake.
Mediation analysis was
conducted to partition
the effect of higher vs.
lower BLLs on the age
at sexual maturity into a
direct effect of Pb
exposure and indirect
effect of Pb acting
through HTZ and BMIZ-
score (mediators) at
age 11.
TV (>3 mL to >20 mL):
-1.19 (-4.92, 2.54)
Mediation Analysis, as % of
total
HTZ
G5: 53.0% ((3: 2.37 months)
P5: 47.5% ((3: 2.36 months)
TV >20 mL: 34.2% ((3:
1.78 months)
BMIZ-score
G5: 14.3% ((3: 0.64 months)
P5: 23.4% ((3: 1.16 months)
TV >20 mL: 6.1% ((3:
0.32 months)
Fleisch et al. (20131
Chapaevsk
Russia
2003-2005
Follow-up: 2-yr (at
10-11 years) and 4-
yr (at 12-13 years)
Cohort
Russian Children's
Study
n: 394
Boys ages 8-9 years
old from Chapaevsk,
Russia
Blood
Blood was measured by
Zeeman background
corrected flameless GFAAS
Age at Measurement:
8-9 years old
Median: 3 [jg/dL
75th: 5 [jg/dL
Max: 31 [jg/dL
Puberty among males:
insulin-like growth factor 1
(IGF-1)
Serum IGF-1
concentrations were
measured by a
chemiluminescent
immunometric assay
using Siemens Immulite
2000.
Age at outcome:
10-11 years (at 2-year
follow-up); 12-13 (at 4-
year follow-up)
Linear regression
models using a GEE
approach to account for
the repeated measures
were fitted to predict
the mean levels of
serum concentrations
of IGF-1 (ng/mL) in
relation to BLLs,
adjusted for baseline
parental education,
BW, nutritional intake,
and baseline and
follow-up age and BMI
(3 (95% CI)c, as adjusted
mean change
BLL <5 [jg/dL: Reference
BLL >5 ug/dL: -29.2 ng/mL
(-43.8, -14.5)
Pre-puberty
BLL <5 [jg/dL: Reference
BLL >5 ug/dL: -14.1 ng/mL
(-0.9, -27.2)
Early puberty:
BLL <5 [jg/dL: Reference
BLL >5 [jg/dL: -18.0 (-3.5,
-32.5)
Mid-puberty
BLL <5 [jg/dL: Reference
BLL >5 ug/dL: -41.9 ng/mL
(-15.1, -68.7)
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Confounders
Effect Estimates and 95%
Clsa
AAS = atomic absorption spectrometry; BMI = body mass index; BW = birth weight; E2 = estradiol; ELEMENT = Early Life Exposure in Mexico to Environmental Toxicants; fE2 = free
estradiol; FLEHS = Flemish Environment and Health Studies; FSH = follicle stimulating hormone; fT = free testosterone; GEE = generalized estimating equation; GFAAS = graphite
furnace atomic absorption spectrometry; HTZ = height Z-score; ICP-MS = inductively coupled plasma mass spectrometry; IGF-1 = insulin-like growth factor 1; LH = luteinizing
hormone; NHANES = National Health and Nutrition Examination Survey; PIR = poverty-to-income ratio; RRR = relative risk ratio; SD = standard deviation; SHBG = sex hormone
binding globulin; T = testosterone; tT = total testosterone; TV = testicular volume; UCB = umbilical cord blood.
aEffect estimates are standardized to a 1 |jg/dL increase in blood Pb or a 10 |jg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect
estimates are standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated
interval. Categorical effect estimates are not standardized.
bPb measurements were converted from |jg/L to |jg/dL.
°Effect estimates unable to be standardized.
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Table 8-13 Epidemiologic studies of exposure to Pb and other developmental effects.
Reference and Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Study Design Clsa
Alegria-Torres et al.
(20201
Salamanca
Mexico
Cross-sectional
n: 86
Healthy children 6-
15 years of age were
recruited from four
primary schools
Blood
Blood was measured by
ICP-MS
Age at Measurement:
6-15 years old
Mean (SD): 3.78
(3.73) [jg/dL
Max: 22.61 pg/dL
Other developmental
effects: Telomeric
lengthening and
mitochondrial DNA effects
DNA was isolated from
peripheral blood and
relative telomere length
and the mitochondrial
DNA copy number were
determined by real-time
polymerase chain reaction
Age at outcome:
6-15 years old
Linear regression
analyses; TL models
were adjusted for mtDNA
copy number, sex, age,
and total white blood cell
count; mtDNAcn models
adjusted for TL, sex,
age, and total white
blood cell count
(3 (95% Cl)b
TL: 0.088 (-0.027, 0.097)
mtDNA copy number: -0.198
(-2.81, -0.17)
Tamavo v Ortiz et al.
(20161
Mexico City
Mexico
2007-2011
Cohort
PROGRESS birth
cohort
n: 255 for 12 months
n: 150 for 18-
24 months
Women were invited to
participate during their
prenatal care visits at 4
clinics belonging to the
Mexican Social Security
System
Blood and bone
Maternal blood, collected
twice during pregnancy
(second and third
trimesters), was
measured by ICP-MS.
Maternal bone, from the
mid-tibial shaft, was
measured using a K-shell
X-ray fluorescence
instrument (K-XRF) during
the first month postpartum
visit
Age at Measurement:
Maternal age at second
trimester, third trimester,
and one month
postpartum
Other developmental
effects: Cortisol levels
Four saliva samples per
day from their child at
home; saliva samples
were analyzed in
duplicate using a
chemiluminescence-assay
Age at outcome:
12 or 18-24 months
Longitudinal functional
mixed effects regression
models with penalized
splines were adjusted for
child's sex and maternal
age at delivery,
education, and pre-
pregnancy BMI
(3 (95% Cl)b
12-month infants
Second trimester maternal
blood
Lower Pb: Reference
Moderate Pb: -0.07 (-0.24,
0.10)
Higher Pb: -0.51 (-0.85,
-0.18)
Third trimester maternal
blood
Lower Pb: Reference
Moderate Pb: -0.14 (-0.31,
0.03)
Higher Pb: -0.02 (-0.31,
0.26)
Tibia
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Study Design Clsa
Hou et al. (2020)
Guiyu and Haojiang
China
November-
December 2017
Mean
2nd trimester blood for
12-month-old infants:
3.5 [jg/dL
2nd trimester blood for
18-24-month-old infants:
3.9 [jg/dL
3rd trimester blood for 12-
month-old infants:
3.7 [jg/dL
3rd trimester blood for 18-
24-month-old infants:
4.2 [jg/dL
Tibia for 12-month-old
infants: 5.6 |jg/g
Tibia for 18-24-month-old
infants: 4.9 |jg/g
Tertiles
Lower Pb: <5 [jg/dL
Moderate Pb: 5 < Pb
<10 |jg/dL
High Pb: >10 pg/dL
Lower Pb: Reference
Moderate Pb: 0.02 (-0.14,
0.19)
Higher Pb: -0.03 (-0.21,
0.14)
18-24-month infants
Second trimester maternal
blood
Lower Pb: Reference
Moderate Pb: 0.11 (-0.08,
0.30)
Higher Pb: 0.23 (-0.19, 0.65)
Third trimester maternal
blood
Lower Pb: Reference
Moderate Pb: 0.01 (-0.17,
0.20)
Higher Pb: -0.05 (-0.51,
0.41)
Tibia
Lower Pb: Reference
Moderate Pb: 0.10 (-0.13,
0.32)
Higher Pb: 0.14 (-0.08, 0.35)
n: 574 (357 from Guiyu
and 217 from Haojiang)
Children 2.5-6 years of
age that lived in Guiyu,
an e-waste
contaminated town or
Haojiang, a city with
Blood
Blood was measured by
GFAAS
Age at Measurement:
2.5-6 years old
Other developmental
effects: Oral anti-
inflammatory potential
Participants were
instructed to sit up straight
and slightly forward in
their chair. A sputum cup
Multivariable linear
regression model
adjusted for gender, age,
BMI, outdoor activities,
the sucking/biting of toys
and pencils, diet (sweet
consumption, bean
products, marine
(3 (95% CI)b: -3.65 (-8.07,
0.77)
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Effect Estimates and 95%
Clsa
Cross-sectional
similar culture but no e-
waste recycling activity
Median
Reference group:
3.47 [jg/dL
Exposed group:
4.86 [jg/dL
75th
Reference group:
4.07 [jg/dL
Exposed group:
4.86 [jg/dL
was used to collect the
saliva. Decayed
deciduous teeth were
detected under natural
and artificial light. The
concentration of salivary
sialic acids was
determined using a
quantitative competitive
ELISA kit.
Age at outcome:
2.5-6 years old
products), family
member smoking,
paternal education
levels, monthly
household income
Sitarik et al. (20201
Detroit, Ml
United States
September 2003-
December 2007
(December 2011-
September 2019)
Cohort
WHEALS birth cohort
n: 146
All women were in their
second trimester or
later, were aged 21-
49 years, and were
living in a predefined
geographic area in
Wayne and Oakland
counties of Michigan.
Teeth were selected for
metal measurement if
(1) the child had at
least some outcome
data available (birth
outcomes and/or a 2-yr
clinic visit) or early life
microbiome data; and
(2) the tooth sample
met laboratory quality
control/quality
assurance guidelines
Teeth
Teeth were measured by
LA-ICP-MS. Teeth were
sectioned and the
neonatal line (a
histological feature formed
in enamel and dentine at
the time of birth) and
incremental markings
were used to assign
temporal information to
sampling points. Second
trimester, third trimester,
postnatal (birth through 1
year), and childhood (age
1 to tooth shedding) Pb
levels.
Age at measurement:
Estimated exposure from
2nd trimester, 3rd
trimester, and postnatally
(<1 yr of age)
Other developmental
effects: Gut microbiota (in
infants)
Families were asked to
retain the most recent
soiled diaper prior to the
home visit and stool
samples from infants ages
1-6 months.
Age at outcome:
1-6 months
Permutational
multivariate analysis of
variance models were
adjusted for tooth type,
tooth attrition, tooth
batch, exact age at stool
sample collection, and
child race
(3 (SE)b
Alpha diversity metrics
Second trimester
Richness - Bacterial
1 months: 5.53 (6.98)
6 months: -7.77 (7.31)
Richness - Fungal
1 months: 0.29 (1.65)
6 months: 1.7 (1.51)
Evenness - Bacterial
1 months: 0 (0.01)
6 months: -0.02 (-0.01)
Evenness - Fungal
1 months: 0.03 (0.05)
6 months: -0.02 (0.05)
Faith's Diversity - Bacterial
1 months: 0.16 (0.39)
6 months: -0.19 (0.37)
Faith's Diversity - Fungal
1 months: Not reported
6 months: Not reported
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Study Design Clsa
Shannon Diversity -
Bacterial
1 months: 0.01 (0.08)
6 months: -0.11 (0.07)
Shannon Diversity - Fungal
1 months: 0.06 (0.15)
6 months: 0 (0.14)
Third trimester
Richness - Bacterial
1 months: 2.52 (6.37)
6 months: -13.11 (8.36)
Richness - Fungal
1 months: 0.69 (1.82)
6 months: 2.54 (1.56)
Evenness - Bacterial
1 months: -0.01 (0.01)
6 months: -0.02 (-0.01)
Evenness - Fungal
1 months: 0.03 (0.05)
6 months: 0.03 (0.05)
Faith's Diversity - Bacterial
1 months: 0.03 (0.35)
6 months: -0.52 (0.42)
Faith's Diversity - Fungal
1 months: Not reported
6 months: Not reported
Shannon Diversity -
Bacterial
1 months: -0.05 (0.07)
6 months: -0.12 (0.08)
Shannon Diversity - Fungal
1 months: 0.09 (0.16)
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Study Design Clsa
6 months: 0.15 (0.15)
Postnatal
Richness - Bacterial
1 months: 2.18 (7.16)
6 months: -2.55 (6.42)
Richness - Fungal
1 months: -1.85 (2.54)
6 months: -0.35 (1.05)
Evenness - Bacterial
1 months: -0.02 (0.01)
6 months: -0.01 (0.01)
Evenness - Fungal
1 months: 0.07 (0.1)
6 months: 0.06 (0.06)
Faith's Diversity - Bacterial
1 months: -0.08 (0.39)
6 months: 0.11 (0.32)
Faith's Diversity - Fungal
1 months: Not reported
6 months: Not reported
Shannon Diversity -
Bacterial
1 months: -0.1 (-0.08)
6 months: -0.05 (-0.06)
Shannon Diversity - Fungal
1 months: -0.07 (0.23)
6 months: -0.05 (0.1)
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Study Design Clsa
BMI = body mass index; ELISA = enzyme-linked immunoassay; GFAAS = graphite furnace atomic absorption spectrometry; ICP-MS = inductively coupled plasma mass
spectrometry; K-XRF = K-shell X-ray fluorescence instrument; LA-ICP-MS = laser ablation-inductively coupled plasma-mass spectrometry; SD = standard deviation; SE = standard
error; TL = telomere length; WHEALS = Wayne County Health, Environment, Allergy and Asthma Longitudinal Study
aEffect estimates are standardized to a 1 |jg/dL increase in blood Pb or a 10 |jg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect
estimates are standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated
interval. Categorical effect estimates are not standardized.
bEffect estimates unable to be standardized.
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Table 8-14 Epidemiologic studies of exposure to Pb and female reproductive effects.
Reference and Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Study Design Clsa
Effects on Hormones Levels and Menstrual/Estrous Cycle
Krieg and Feng
(20111
United States
1999-2002
Cross-sectional
NHANES
n: 649
Women aged 35-
60 years old
Blood
Blood was measured by
AAS
Age at Measurement:
35-60 years
Geometric mean:
1.4 [jg/dL Mean:
1.6 Mg/dL
Max: 17.0 pg/dL
Female reproductive
function: Serum FSH and
LH
Serum FSH and LH were
measured using a
microparticle enzyme
immunoassay
Age at outcome:
35-60 years
Regression analyses:
the slopes were
adjusted forage, Iog10
serum bone alkaline
phosphatase, log 10
urine N-telopeptides,
Iog10 serum cotinine,
alcohol use, currently
breastfeeding,
hysterectomy, one
ovary removed, Depo-
Provera use, medical
conditions or
treatments, hormone
pill use, and hormone
patch use
(3 (95% CI)b, as slope for
serum FSH and LH per
Iog10 blood Pb increase
Serum FSH (IU/L)
Post-menopausal: 26.38
(13.39, 39.38)
Pregnant: -0.08 (-1.11,
0.95)
Menstruating: 1.50 (-2.29,
5.30)
Both ovaries removed:
27.71 (1.64, 53.78)
Birth control pills: -0.33
(-6.52, 5.86)
Pre-menopausal: 11.97
(3.27, 20.66)
Serum LH (IU/L)
Post-menopausal: 11.63
(4.40, 18.86)
Pregnant: 2.12 (-14.62,
18.86)
Menstruating: 0.87 (-2.20,
3.94)
Both ovaries removed:
20.59 (2.14, 39.04)
Birth control pills: 2.19
(-1.35, 5.72)
Pre-menopausal: 7.44
(-0.26, 15.14)
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Study Design Clsa
Chenetal. (20161
Shanghai, Jiangxi
Province and
Zhejiang province
China
2014
Cross-sectional
SPECT-China
n: 2286 men and 1571
postmenopausal women
SPECT-China is a
population-based cross-
sectional survey on the
prevalence of metabolic
diseases and risk factors
in East China. Men and
postmenopausal women
(age >55 years) who
were not taking hormone
replacement therapy,
without a history of
hysterectomy and
oophorectomy were
recruited.
Blood
Blood was measured by
AAS
Age at measurement:
Median age 63 (IQR: 59-
68)
Median0: 4.1 [jg/dL
75thc: 5.981 pg/dL
Quartile0 (pg/dL)
Q1
Q2
Q3
Q4
<2.7
2.7-4.099
4.1-5.980
>5.980
Female reproductive
function: Reproductive
hormone levels
Venous blood samples were
drawn from all subjects after
an overnight fast of at least
8 hr. HbA1c was assessed
via high-performance liquid
chromatography (MQ-
2000PT, China). tT, E2, LH
and FSH levels were
measured using
chemiluminescence assays
(Siemens Immulite 2000,
Germany). SHBG levels
were detected using Cobas
e601
electrochemiluminescence
immunoassays (Roche,
Switzerland).
Age at outcome:
Median age 63 (IQR: 59-68)
Linear regression
models were adjusted
for age, current
smoking status, BMI,
SBP, diabetes, and
blood Cd level
(3 (SE)d
SHBG
Q1
Q2
Q3
Q4
tT
Q1
Q2
Q3
Q4
E2
Q1
Q2
Q3
Q4
Reference
0.010 (0.015)
0.018 (0.015)
0.048 (0.016)
Reference
-0.033 (0.019)
-0.017 (0.019)
-0.016 (0.020)
Reference
-0.001 (0.019)
-0.020 (0.019)
-0.021 (0.020)
FSH
Q1
Q2
Q3
Q4
Reference
0.013 (0.015)
0.047 (0.015)
0.046 (0.016)
LH
Q1
Q2
Q3
Q4
Reference
0.022 (0.015)
0.027 (0.016)
0.037 (0.016)
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Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Lee et al. (20191
Busan
Korea
2012-2014
Cross-sectional
Second Korean National Blood
Environmental Health
Survey
n: 4,689 adults
2,763 men and 1,926
postmenopausal women
aged 50 years or over
Blood was measured by
GFAAS
Age at Measurement:
50 years or older
Median: 2.05 [jg/dL
75th: 2.67 pg/dL
Female reproductive
function: Follicle-stimulating
hormone levels
Serum FSH levels were
measured using a
chemiluminescence
immunoassay
(chemiluminescent
immunoassay; ADVIA
Centaur XP; Siemens,
Tarrytown, NY, United
Multiple linear
regression adjusted for
age, BMI, smoking
status, and alcohol
consumption
(3 (95% CI)b: 2.929 (0.480,
5.377)
Mendola et al. (20131 NHANES
United States
1999-2010
Cross-sectional
n: 3,221 (2,158
menstruating and 1,063
menopause)
Women aged 45-
55 years
Blood
Blood was measured by
AAS in 1999-2002 and
ICP-MS in 2003-2010
Age at measurement: 45-
55 years
Geometric mean:
Menopausal women:
1.71 [jg/dL
Menstruating women
1.23 [jg/dL
Quartiles (pg/dL)
Q1
Q2
Q3
Q4
LOD-1.0
1.0-1.4
1.4-2.1
2.1-22.4
Female reproductive:
Menopause
Menopause was
dichotomized: women with
at least one menstrual cycle
in the past 12 months were
categorized as "No" and
those with natural
menopause were "Yes"
Age at outcome:
45-55 years
Logistic regression
models were adjusted
for age, race/ethnicity,
current hormone use,
poverty, and smoking;
NHANES 1999-2002
models also adjusted
for bone alkaline
phosphatase; and
NHANES 2005-2008
models also adjusted
for femoral neck bone
density
OR (95% CI)
NHANES 1999-2010
Q1
Q2
Q3
Q4
Reference
1.7 (1.0, 2.8)
2.1 (1.2, 3.6)
4.3 (2.6, 7.2)
NHANES 1999-2002
Q1: Reference
Q2: 1.0 (0.3, 3.5)
Q3: 1.3 (0.4, 4.5)
Q4: 5.1 (1.4, 18.0)
Adjusted for bone alkaline
phosphatase
Q1
Q2
Q3
Q4
Reference
1.1 (0.3, 3.9)
1.2 (0.3, 4.7)
4.2 (1.2, 15.5)
NHANES 2005-2008
Q1: Reference
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Study Design Clsa
Eumetal. (20141
Boston, MA
United States
1990-1994(2001
2004)
Cohort
Q2: 3.0 (0.9, 9.8)
Q3: 4.9 (1.5, 16.1)
Q4: 10.5 (3.1, 35)
Adjusted for femoral neck
bone density
Q1: Reference
Q2: 3.4 (0.9, 12.2)
Q3: 4.1 (1.1, 15.2)
Q4: 9.7 (2.8, 33)
Nurse's Health Study
n: 434
Female registered
nurses, 30 to 55 years of
age and living in 11 U.S.
states, completed a
questionnaire on their
medical history and
health-related behaviors;
analysis restricted to
women in the Boston
area who did not have a
history of a major,
chronic disease; and
were not obese from
1990-1994 and women
no history of chronic
diseases (no reported
diagnosis of
hypertension,
cardiovascular disease,
renal disease, diabetes,
or malignancies) invited
to participate from 2001
through 2004
Blood and bone
Bone was measured by
K-shell X-ray fluorescence
(K-XRF) at each woman's
mid-tibial shaft and
patella. Blood was
measured by GFAAS with
Zeeman background
correction
Age at measurement:
46 years or older at the
time of bone Pb
measurement
Median
Tibia: 10 |jg/g
Patella: 12 |jg/g
Blood: 3 [jg/dL
75th
Tibia: 15 |jg/g
Patella: 18 |jg/g
Blood: 4 [jg/dL
Female reproductive
function: Early menopause
Menopausal status was
determined on the first
Nurse's Health Study
questionnaire in 1976 and
then again on each biennial
questionnaire by asking
whether the participants'
menstrual periods had
ceased permanently; early
menopause as natural
menopause occurring
before 45 years of age
Age at outcome:
Age at reporting of
menopausal status
Ordinary least-squares
linear regression to
analyze age at
menopause adjusted
for sub-study group,
age at bone Pb
measure, age at bone
Pb measure squared,
year of birth, age at
menarche, months of
oral contraceptive use,
parity, and pack-years
of smoking; logistic
regression for early
menopause adjusted
for sub-study group,
age at bone Pb
measure, age at bone
Pb measure squared,
year of birth, age at
menarche, months of
oral contraceptive use,
parity, and pack-years
of smoking
(3 (95% CI), as difference in
age at natural menopause
(year)
Tibia
T1: Reference
T2: -0.80 (-1.67, 0.06)
T3: -1.21 (-2.08, -.035)
p for trend: 0.006
Patella
T1: Reference
T2: -0.32 (-1.18, 0.55)
T3: -0.00 (-0.88, 0.87)
p for trend: 0.99
Blood
T1: Reference
T2: 0.08 (-0.80, 0.96)
T3: -0.28 (-1.13, 0.56)
p for trend: 0.54
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Reference and Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Study Design Clsa
Tertiles
Tibia (|jg/g)
T1: <6.5
T2: 6.513
T3: >13
Patella (pg/g)
T1: <8
T2: 8-15
T3: >15
Blood (|jg/dL)
T1: <3
T2: 3
T3: >3
Effects on Female Fertility
Lee et al. (2020)
United States
2013-2014 and
2015-2016
Cross-sectional
NHANES (2013-2014
and 2015-2016)
n: 124
Women aged 20-
39 years without a history
of hysterectomy and/or
bilateral oophorectomy
Blood
Blood was measured by
ICP-MS
Age at Measurement:
20-39 years
Geometric mean:
0.50 [jg/dL (95% CI: 0.43,
0.57)
Female reproductive
function: Female infertility
Infertility is defined as the
absence of pregnancy with
unprotected intercourse for
one year and was assessed
through a self-reported
questionnaire
Age at outcome:
20-39 years
Logistic regression
analyses were adjusted
for age, ethnicity,
annual family income,
education, marital
status, smoking history,
alcohol consumption,
physical activity, and
BMI
Tertiles (pg/dL)
T1
T2
T3
0.11-0.38
0.41-0.62
0.63-5.37
OR (95% CI)b: 2.60 (1.05,
6.41) per 2-fold increase in
BLLs
OR (95% CI)
T1: Reference
T2: 5.40 (1.47, 19.78)
T3: 5.62 (1.13, 27.90)
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Louis et al. (20121
Michigan (4 counties)
and Texas (12
counties)
United States
2005-2009
Cohort
LIFE Study
n: 501
Female ages 18-44 year
and male ages
>18 years; in a
committed relationship;
ability to communicate in
English or Spanish;
menstrual cycles
between 21 and 42 days;
no hormonal
contraception injections
during past year; and no
sterilization procedures
or physician diagnosed
infertility
Blood
Blood was measured by
ICP-MS
Age at Measurement:
19-40 years
Geometric mean
Pregnant female:
0.66 [jg/dL
Not pregnant female:
0.76 [jg/dL
Tertiles (pg/dL)
T1: 0.23-0.57
T2
0.58-0.78
T3: 0.79-5.84
Female reproductive
function: Fecundity
Women were instructed in
the use of the Clearblue
Easy fertility monitors
consistent with the
manufacturer's guidance
commencing on day six for
tracking daily levels of
estrone-3-glucuronide (E3G)
and LH. Women also used
the digital Clearblue Easy
home pregnancy test upon
enrollment to ensure the
absence of pregnancy at
study start and on the day
menses was expected for
each cycle under
observation in the study.
Age at outcome:
Average age with
pregnancy: 29.8
Average age without
pregnancy: 30.6
Cox models for
discrete survival time,
which is a proportional
odds model, adjusted
for age, body mass
index, cotinine, parity,
serum lipids, and site
(Texas/Michigan)
OR (95% CI), as
fecundability OR
Female only exposure:
0.97 (0.85, 1.11)
Couple exposure:
Female exposure: 1.06
(0.91, 1.24)
Male exposure: 0.82 (0.68,
0.97)
Lai et al. (20171
Taipei
Taiwan
2008-2010
Cross-sectional
n: 190 infertile women
including 68 patients with
endometriosis and 122
controls
Women who visited the
infertility clinic first time
for a specific
gynecologist at Taipei
Medical University
Hospital; women with
diagnoses such as
ovarian cyst, premature
Blood
Blood was measured by
ICP-MS
Age at measurement:
Mean age for women with
endometriosis: 35.3 (SD:
4.1)
Female reproductive
function: Endometriosis
among infertile women
Endometriosis status was
determined by laparoscopy
Age at outcome:
Mean age for women with
endometriosis: 35.3 (SD:
4.1)
Multivariate logistic
regression adjusted for
age, body fat
proportion, educational
level, age at menarche,
and regularity of
menstrual cycle
OR (95% CI)
T1
T2
T3
Reference
1.73 (0.77,
2.59 (1.11,
3.88)
6.06)
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Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
ovarian failure, repeated
implantation failure or
pregnancy were
excluded
Mean age for women
without endometriosis:
35.3 (SD: 5.0)
Geometric mean0
Women with
endometriosis:
1.337 [jg/dL
Women without
endometriosis:
0.853 [jg/dL
Mean age for women
without endometriosis:
(SD: 5.0)
35.3
Median0
Women with
endometriosis:
2.130 [jg/dL
Women without
endometriosis:
0.464 [jg/dL
Tertiles0 (|jg/dL)
T1: <0.38
T2: 0.38-3.05
T3: >3.05
Li et al. (20221
Hefei
China
October 2019-
January 2020
Cohort
n: 1184
Participants selected
from First Affiliated
Hospital of Anhui Medical
University while seeking
IVF treatment and
diagnosed infertility with
their partner. Inclusion
criteria: women were
aged between 20 and
45 years; couples were
diagnosed with infertility
Blood
Maternal blood (serum)
was measured by ICP-MS
Age at measurement:
Maternal age at collection
(day before oocytes were
retrieved for IVF); female
partner mean age was
30.22 years
Female reproductive
function - Effects on female
fertility: Fertility - successful
implantation, clinical
pregnancy
A serum hCG level
>25 mlU/mL on the 14th day
after embryo transfer was
considered as successful
implantation. Clinical
pregnancy was defined as
an ultrasound-confirmed
Logistic regression
model for successful
implantation adjusted
for maternal age, BMI,
treatment protocol,
FSH levels, sperm
viability, cycle type,
and embryo quality.
Logistic regression
model for clinical
pregnancy adjusted for
maternal age, BMI,
treatment protocol,
OR (95%CI)b:
Successful implantation
Continuous: 0.85 (0.77,
0.94)
Tertiles
Low: Reference
Medium: 1.11 (0.75, 1.63)
High: 0.58 (0.40, 0.85)
Clinical pregnancy
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
(failure to establish a
clinical pregnancy with
unprotected intercourse
for at least 1 yr); and IVF
indicators were tubal
factor, ovulation failure,
or other factors for
female partner or male
factor or unexplained
fertility.
Geometric meane:
0.0877 [jg/dL
Mediane: 0.0924 [jg/dL
75the: 0.14399 pg/dL
Tertilese (pg/dL)
Low: 0.002-0.065
Medium: 0.065-0.125
High: 0.125-0.481
intrauterine pregnancy on
the 30th day after embryo
transfer.
Age at outcome:
Female partner mean age:
30.22 years
endometrial thickness
on hCG day, and
embryo quality. Linear
regression models for
metaphase II (Mil) rate,
fertility rate, 2PN rate,
blastocyte rate, and
high-quality embryo
rate were adjusted for
maternal age, BMI,
education level,
infertility type, FSH and
sperm concentration
Continuous: 0.95 (0.91,
0.99)
Tertiles
Low: Reference
Medium: 0.72 (0.37, 1.38)
High: 0.56 (0.29, 1.06)
(3 (95% CI)b:
Mil rate: 0.090 (-0.024,
0.204)
Fertility rate: -0.033
(-0.151, 0.086)
2PN rate: -0.019 (-0.100,
0.062)
Blastocyst rate: 0.046
(-0.052, 0.144)
High quality embryo rate:
-0.143 (-0.322, -0.037)
Zhou et al. (202la) n: 195
China
2018-2019
Cohort
Couples undergoing IVF.
Women with
endometriosis,
hydrosalpinx, abnormal
uterine cavity and men
with azoospermia, severe
oligozoospermia,
asthenospermia and
dysspermia were
excluded from the study.
Blood
Maternal blood (serum),
follicular fluid, and
seminal plasma from male
partner
Age at Measurement:
Female partner mean
age: 30.27 years
Male partner mean age:
31.57 years
Mean0
Maternal serum:
0.301 pg/dL
Female reproductive Poisson regression
function - Effects on female models were adjusted
fertility: IVF outcome for age and BMI
The IVF outcomes included
were normal fertilization,
good embryo, blastocyst
formation, high-quality
blastocyst, pregnancy, and
live birth
Age at outcome:
Female partner mean age:
30.27 years
Male partner mean age:
31.57 years
RR (95% Cl)b
Normal fertilization
Maternal serum: 0.94
(0.42, 1.93)
Follicular fluid: 0.82 (0.18,
2.39)
Seminal plasma: 1.55
(0.64, 3.3)
Good embryo
Maternal serum: 1.00
(0.36, 2.38)
Follicular fluid: 0.78 (0.09,
3.03)
Seminal plasma: 1.86
(1.05, 3.11)
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Study Design Clsa
Follicular fluid:
0.742 [jg/dL
Seminal plasma:
0.882 [jg/dL
Median0
Maternal serum:
0.245 [jg/dL
Follicular fluid:
0.178 [jg/dL
Seminal plasma:
0.486 [jg/dL
75thc
Maternal serum:
0.317 [jg/dL
Follicular fluid:
0.326 [jg/dL
Seminal plasma:
1.245 [jg/dL
Blastocyst formation
Maternal serum: 1.06 (0.2,
3.91)
Follicular fluid: 0.41 (0,
3.63)
Seminal plasma: 1.77
(0.78, 3.58)
High-quality blastocyst
Maternal serum: 1.68
(0.15, 9.43)
Follicular fluid: 0.35 (0,
7.11)
Seminal plasma: 2.66
(0.67, 8)
Pregnancy
Maternal serum: 0.18
(0.01, 1.91)
Follicular fluid: 0.01 (0,
0.03)
Seminal plasma: 0.04 (0,
1.45)
Live birth
Maternal serum: 0.25
(0.01, 2.8)
Follicular fluid: 0 (0, 0.09)
Seminal plasma: 0.01 (0,
1.08)
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Reference and Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Study Design Clsa
Effects on Morphology or Histology of Female Sex Organs (Ovaries, Uterus, Fallopian Tubes/Oviducts, Cervix, Vagina, and/or Mammary Glands)
Yeetal. (70171
Seoul
South Korea
September to
November 2014
Cross-sectional
n: 288 (46 with fibroids
and 242 without)
Premenopausal women
between 30 and 49 years
old, who were not
pregnant or
breastfeeding, whose
heavy metal levels at the
time might have been
influenced by these
circumstances and might
have been less
representative of heavy
metal levels at the time of
diagnosis, and who had
received hysterectomies
Blood
Blood was measured by
GFAAS
Age at Measurement:
30-49 years
Geometric mean:
1.36 [jg/dL
Quartiles (pg/dL)
Q1
Q2
Q3
Q4
<1.1
1.1-1.3
1.3-1.8
1.8-3.2
Female reproductive
function - Effects on
morphology and histology of
female sex organs: Uterine
fibroids
Diagnosis of uterine fibroids
was based on pelvic
ultrasonography and two
questions
Age at outcome:
30-49 years
Logistic regression
models adjusted for
age, BMI, gravidity,
oral contraceptive pill
administration history,
regularity of menstrual
cycle, hemoglobin
level, and serum
cotinine levels; linear
regression models
were adjusted for age,
BMI, gravidity, oral
contraceptive pill
administration history,
regularity of menstrual
cycle, hemoglobin
level, and serum
cotinine levels
OR (95% Cl)b
Presence of uterine
fibroids: 1.39 (0.75, 2.56)
(3 (95% Cl)b
Volume of uterine fibroids:
0.12 (-2.26, 2.51)
Q1: Reference
Q2: -0.42 (-2.69, 1.85)
Q3: 0.85 (-1.67, 3.37)
Q4: -1.23 (-3.74, 1.29)
2PN = oocytes with two pronuclei; AAS = atomic absorption spectrometry; BMI = body mass index; E2 = estradiol; FSH = follicle stimulating hormone; GFAAS = graphite furnace
atomic absorption spectrometry; hCG = human chorionic gonadotropin; ICP-MS = inductively coupled plasma mass spectrometry; IQR = interquartile range; IVF = in vitro fertilization;
K-XRF = K-shell X-ray fluorescence instrument; LH = luteinizing hormone; LIFE = Longitudinal Investigation of Fertility and the Environment; LOD = limit of detection;
Mil = metaphase II; NHANES = National Health and Nutrition Examination Survey; SD = standard deviation; SHBG = sex hormone binding globulin; SPECT = Survey on the
Prevalence in East China for Metabolic Diseases and Risk Factors; tT = total testosterone.
aEffect estimates are standardized to a 1 |jg/dL increase in blood Pb or a 10 |jg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect
estimates are standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated
interval. Categorical effect estimates are not standardized.
bEffects estimates unable to be standardized.
°Pb measurements were converted from |jg/L to |jg/dL.
dNo CIs provided.
ePb measurements were converted from ng/Lto |jg/dL.
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Table 8-15 Animal toxicological studies of Pb exposure and female reproductive effects.
Study
Species (Stock/Strain), n, Sex Timing of Exposure
Exposure Details
(Concentration, Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
Corv-Slechta et al.
(20131
Mouse (C57BL/6)
Control (untreated), F, n = 16
100 ppm, F, n = 16
GD -61 to PND 365
Dams were dosed starting
2 months prior to mating.
Offspring were continued on the
same exposure as their dams
until the end of the experiment
at 12 months of age.
0.22 [jg/dL for control
dams at weaning
12.12 [jg/dL for
100 ppm dams at
weaning
Litter Size,
Maternal
Body Weight
Weston etal. (20141
Rat (Long-Evans)
Dams
Control (untreated), F, n = 20
50 ppm Pb, F, n = 19
Pups
Control (untreated), M/F, n = 12.4
(7/5.4 average number of male and
female pups per litter in control)
50 ppm Pb, M/F, n = 7.4 (6.3/1.1
average number of male and
female pups per litter in Pb NS
group)
GD -76 to PND 21
Dams were dosed via drinking
water starting 2-3 months prior
to breeding. Exposure ended at
weaning (PND 21).
Dams (PND 21):
0.500 [jg/dL for control
7.72 [jg/dL for 50 ppm
Pb
Pups (PND 5-6):
0.603 [jg/dL for control
males
0.690 [jg/dL for control
females
15.7 [jg/dL for 50 ppm
Pb males
14.6 [jg/dL for 50 ppm
Pb females
Litter Size,
Number of
Litters
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Study
Species (Stock/Strain), n, Sex Timing of Exposure
Exposure Details
(Concentration, Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
Betharia and Maher
(20121
Rat (Sprague-Dawley)
Control (untreated), F, n = 6 dams
10 |jg/mL Pb, F, n = 6 dams
GD Oto PND 20
Dams were dosed via drinking
water throughout pregnancy
until weaning (PND 20).
Pups:
PND 2
0.188 [jg/dL for control
9.03 [jg/dL for 10 |jg/ml_
Pb
Litter Size
PND 25:
0.088 [jg/dL for control
0.976 [jg/dL for
10 |jg/ml_ Pb
PND 60:
0.0244 [jg/dL for control
0.0318 [jg/dL for
10 |jg/ml_ Pb
Schneider et al. (20161 Mouse (C57BL/6)
Control (untreated), F, n = NR
100 ppm Pb, F, n = NR
GD -61 to PND 21
Dams were dosed via drinking
water starting 2 months prior to
mating through lactation
(weaning assumed to be
PND 21).
Dams were also treated to a
non-stress or prenatal stress
condition. Only data from dams
in the non-stress condition were
used.
Dams at weaning
(assumed PND 21):
0.22 [jg/dL for control
12.61 [jg/dL for
100 ppm Pb
Pups (PND 5-6):
0.37 [jg/dL for control
10.2 |jg/dL for 100 ppm
Pb
Maternal
Body
Weight,
Litter Size
Salehetal. (20181
Rat (Sprague-Dawley)
Control (vehicle), F, n =
160 ppm Pb, F, n = 8
320 ppm Pb, F, n = 8
GD 1 to 20
Dams were dosed via oral
gavage. Authors report a
significant decrease in brain
weight occurred, indicating
potential overt toxicity.
Dams (GD 20):
5.1 [jg/dL for control
27.7 |jg/dL for 160 ppm
Pb
41.5 |jg/dL for 320 ppm
Pb
Maternal
Body Weight
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Study
Species (Stock/Strain), n, Sex
Timing of Exposure
Exposure Details
(Concentration, Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
Baranowska-Bosiacka
Rat (Wistar)
GD 1 to PND 21
Dams were exposed via
NR for Dams
Sex Ratio
etal. (^2013^
Control (untreated), F, n = 3 dams
drinking water throughout
0.1% Pb, F, n = 3 dams
pregnancy until weaning
(PND 21).
Pups (PND 28):
Control, M/F, n = 36 (17/19) pups
0.93 [jg/dL for control
0.1% Pb, M/F, n = 36 (18/18) pups
6.86 [jg/dL for 0.1% Pb
Salehetal. (2019)
Rat (Sprague-Dawley)
Control (vehicle), F, n = 8 dams
160 ppm Pb, F, n = 8 dams
320 ppm Pb, F, n = 8 dams
GD 1 to 20
Dams were dosed via oral
gavage. Authors report a
significant decrease in brain
weight occurred, indicating
potential overt toxicity.
Dams (GD 20):
5.26 [jg/dL for control
23.9 [jg/dL for 160 ppm
Pb
42.9 |jg/dL for 320 ppm
Pb
Maternal
Body Weight
BLL blood lead level; F = female; GD = gestational day; M = male; NR = not reported; Pb = lead; PND = postnatal day.
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Table 8-16 Epidemiologic studies on exposure to Pb and male reproductive effects.
Reference and Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Study Design Clsa
Effects on Sperm/Semen Production, Quality, and Function
Li etal. (70151
Taiwan
May 2012 to
February 2013
Cross-sectional
n: 154
Male participants were
recruited from a
reproductive medical
center and did not have
obstructive azoospermia,
cryptorchidism,
varicoceles, hydrocele,
orchitis, or epididymitis;
did not have testicular
injury or underwent
testicular surgery before
the study period
Blood
Blood was measured by
ICP-MS
Age at Measurement:
Mean age: 34.8 years
Mean (SD)b: 2.78 (1.85)
pg/dL
Male reproductive effects:
Seminal parameters
From semen samples the
following parameters were
assessed: sperm
concentration, semen
volume, number of sperm,
percentage of total motility
sperm, percentage of
progressive motility sperm,
and percentage of sperm
with normal morphology
Age at outcome:
Mean age: 34.8 years
Multiple logistic
regression models were
adjusted for FSH, LH,
prolactin, and
testosterone were input
into the model and then
adjusted for age and
education
OR (95% CI)
Low-quality semen: 1.040
(1.011, 1.069)
Sperm concentration: 1.046
(1.015, 1.078)
Numbers of sperm: 1.041
(1.012, 1.071)
Total motility sperm: 1.057
(1.026, 1.089)
Progressive motility sperm:
1.047 (1.014, 1.080)
Sperm with normal
morphology: 1.071 (1.025,
1.118)
Sukhnetal. (20181
Beirut
Lebanon
January 2003 and
December 2009
Cross-sectional
Environment and Male
Infertility study
n: 116
Male partners of infertile
heterosexual couples who
attended the fertility clinic
at the American University
of Beirut Medical Center
were recruited. Men were
18 to 55 years of age, had
a BMI of 18 to 30 kg/m2,
and had not been on any
hormone therapy for the
past 6 months, no
diabetes, endocrine
disease, fertility-related
genetic disorders,
Blood and other: seminal
fluid
Blood and seminal fluid
were measured by ICP-
MS equipped with a cell
dynamic range
Age at Measurement:
18-55 years
Meanb
Blood
Overall: 3.121 pg/dL
Low-quality semen group:
5.198 [jg/dL
Male reproductive effects:
Semen quality
Participants with a semen
volume <1.5 mL, sperm
concentration
<15 million/mL, total count
<39 million, progressive
motility <32%, viability
<58%, and/or normal
WHO morphology <30%
were assigned to the low
quality semen group A.
Participants whose semen
analyses expressed better
results in all the above
parameters were assigned
to the normal-quality
Logistic regression;
age, cigarette smoking,
alcohol intake, and
period of sexual
abstinence
OR (95% CI)
Blood
Volume (<1.5 mL)
Q1
Q2
Q3
Q4
Reference
0.53 (0.11, 2.44)
0.24 (0.02, 2.24)
1.32 (0.33, 2.56)
p for trend: 0.26
Concentration (<15 M/mL)
Q1
Q2
Q3
Q4
Reference
0.51 (0.16, 1.63)
1.17 (0.37, 3.73)
1.58 (0.53, 4.68)
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
obstructive azoospermia,
cryptorchidism, varicocele,
hydrocele, orchitis,
epididymitis, and/or history
of testicular injury or
surgery
Normal quality semen
group 3.575 [jg/dL
Seminal fluid
Overall: 0.540 [jg/dL
Low-quality semen group:
1.626 [jg/dL
Normal quality semen
group: 1.285 |jg/dL
Medianb
Blood
Low-quality semen group:
3.257 [jg/dL
Normal quality semen
group: 3.098 [jg/dL
Seminal fluid
Low-quality semen group:
0.588 [jg/dL
Normal quality semen
group: 0.470 |jg/dL
Quartilesb (pg/dL)
Q1
Q2
Q3
Q4
LOD-2.199
2.200-3.256
3.257-5.357
>5.358
semen group B. Sperm
concentration (million/mL)
and progressive motility
(%) were determined
manually using a Makler®
counting chamber. Total
sperm count (million) was
calculated as sperm
concentration * semen
volume. Sperm
morphology was
determined by high-power
magnification (x 1000) on
air-dried smears stained
with a Wright Giemsa stain
based on the WHO
guidelines.
Age at outcome:
18-55 years
p for trend: 0.26
Total count (<39 M)
Q1
Q2
Q3
Q4
Reference
0.36 (0.11, 1.18)
0.83 (0.26, 2.65)
1.35 (0.46, 3.96)
p for trend: 0.15
Progressive motility (<32%)
Q1
Q2
Q3
Q4
Reference
0.70 (0.19, 2.62)
0.78 (0.19, 3.19)
1.47 (0.43, 5.02)
p for trend: 0.66
Viability (<58%)
Q1
Q2
Q3
Q4
Reference
0.44 (0.14, 1.39)
0.68 (0.21, 2.21)
1.35 (0.46, 3.96)
p for trend: 0.23
WHO morphology (<30%)
Q1
Q2
Q3
Q4
Reference
0.50 (0.15, 1.66)
0.93 (0.28, 3.10)
0.84 (0.26, 2.66)
p for trend: 0.68
Seminal Fluid
Blood
Volume (<1.5 mL)
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Study Design Clsa
Q1: Reference
Q2: 0.86 (0.16, 4.67)
Q3: 1.34 (0.25, 7.17)
Q4: 2.07 (0.37, 11.51)
p for trend: 0.95
Concentration (<15 M/mL)
Q1: Reference
Q2: 1.57 (0.50, 4.92)
Q3: 1.99 (0.62, 6.38)
Q4: 1.94 (0.59, 6.35)
p for trend: 0.64
Total count (<39 M)
Q1: Reference
Q2: 1.66 (0.51, 5.46)
Q3: 3.33 (1.01, 10.99)
Q4: 2.00 (0.58, 6.85)
p for trend: 0.24
Progressive motility (<32%)
Q1: Reference
Q2: 4.36 (0.83, 22.81)
Q3: 6.35 (1.21, 33.19)
Q4: 2.40 (0.39, 14.49)
p for trend: 0.09
Viability (<58%)
Q1: Reference
Q2: 8.00 (1.59, 40.30)
Q3: 12.00 (2.34, 61.52)
Q4: 10.15 (1.95, 52.92)
p for trend: 0.006
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Study Design Clsa
WHO morphology (<30%)
Q1
Q2
Q3
Q4
Reference
3.83 (0.924, 15.90)
6.57 (1.57, 27.43)
2.02 (0.426, 9.55)
p for trend: 0.06
Shietal. (70211
Hong Kong
November 2015-
November 2016
Cross-sectional
n: 288
Male subjects who
underwent semen
analysis (SA) as part of
the fertility assessment at
the andrologyjaboratory
of Prince of Wales
Hospital. Participants were
excluded with medical
conditions azoospermia;
andrological conditions
(which are known to affect
semen parameters
including genetic
conditions); history of
mumps orchitis, severe
varicocele, undescended
testis; history of testicular
torsion or scrotal injury,
congenital bilateral
absence of vas deferent,
and urogenital infections;
taking medication known
to affect semen
parameters, including
steroid, finasteride,
calcium channel blockers;
history of malignant
disease; known mental
disorders; drug abuse;
Blood
Blood was measured by
ICP-MS
Age at Measurement
Mean age: 37 9 years
Geometric meanb:
3 175 [jg/dL
Medianb: 2 719 pg/dL
75thb: 3 437 [jg/dL
Quartilesb (pg/dL)
Q1
Q2
Q3
Q4
<2 159
>2 159-2 719
>2 719-3 437
>3.437
Male reproductive effects:
Seminal parameters
Semen volume was
measured by a wide-bore
graduated pipette_with the
graduation of 0.1-
ml. Sperm
concentration and motility
were examined under
a phase contrast
microscope with the
magnification of x 200 or
400. Diff-Quik staining kit
(Dade Behring AG,
Dudingen, Switzerland)
and Tygerberg Strict
Criteria were used to
evaluate the sperm
morphology. Sperm DNA
fragmentation was
measured by sperm
chromatin structure assay.
Age at outcome:
Mean age: 37 9 years
Multivariate linear
regression adjusted for
(1) male age and daily
coffee intake for semen
volume models; (2)
abstinence time,
average sleep duration
for sperm concentration
models; (3) male age,
abstinence time, and
daily coffee intake for
total sperm count
models; (4) male age
and daily juice intake
for the sperm motility
models; (5) male age
and abstinence time for
total motility count
models; (6) no
adjustment for normal
morphology or sperm
vitality models; (7) male
age, abstinence time,
and irregular sleeping
habit for DNA
fragmentation index
models; (8) daily juice
intake for percentage of
acrosome reacted
sperm models.
(3 (95% CI)
Semen volume
Q1
Q2
Q3
Q4
Reference
-0.05 (-0.70, 0.37)
0.04 (-0.39, 0.65)
0.08 (-0.32, 0.83)
p for trend: 0.48
Sperm concentration
Q1
Q2
Q3
Q4
Reference
0.02 (-0.45, 0.58)
-0.02 (-0.57, 0.43)
-0.10 (-0.85, 0.26)
p for trend: 0.34
Total sperm count
Q1
Q2
Q3
Q4
Reference
-0.01 (-0.60, 0.53)
-0.03 (-0.66, 0.43)
-0.05 (-0.76, 0.44)
p for trend: 0.55
Sperm motility
Q1: Reference
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Study Design Clsa
failure to complete the
Q2
-0.09 (-10.21, 3.02)
lifestyle questionnaire; and
Q3
-0.15 (-12.47, 0.49)
refusal to donate blood or
Q4
semen samples.
-0.08 (-10.26, 4.02)
p for trend: 0.77
Total motility count
Q1
Reference
Q2
-0.07 (-0.97, 0.38)
Q3
-0.08 (-0.97, 0.36)
Q4
-0.12 (-1.20, 0.25)
p for trend: 0.16
Normal morphology
Q1
Reference
Q2
-0.13 (-1.16, 0.13)
Q3
-0.20 (-1.43, -0.16)
Q4
-0.20 (-1.52, -0.10)
p for trend: 0.20
Sperm vitality
Q1
Reference
Q2
0.12 (-0.04, 0.17)
Q3
0.01 (-0.10, 0.12)
Q4
-0.13 (-0.19, 0.04)
p for trend: 0.13
Percentage of acrosome
reacted sperm
Q1
Reference
Q2
-0.22 (-18.60, 0.97)
Q3
-0.05 (-11.60, 7.71)
Q4
-0.12 (-15.70, 5.79)
p for trend: 0.75
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Pantetal. (20141 n: 60
New Delhi
India
Cross-sectional
Male partners of couples
age 21-40 years old
attending the Andrology
Laboratory of the
Reproductive Biology
Department, All India
Institute of Medical
Sciences, New Delhi,
India for semen analysis
to assess their inability to
achieve a pregnancy were
selected.
Other: Semen
Semen measured by ICP-
AES
Age at Measurement:
mean age: 31.81 (SD:
5.27)
Mean (SD): 6.18
(2.16) pg/dL
Male reproductive effects:
Semen quality
Semen of volunteers was
collected and analyzed the
protocols of the WHO.
Sperm morphology was
determined according to
Kruger's strict criteria.
Comet assay: prepared
sperm samples were
observed under a
fluorescence microscope
with a total of 100 cells
were scored. The
percentage of tail DNA, tail
length, and tail moment
was evaluated by the
CometScore software
image analysis system.
Age at outcome:
mean age: 31.81 (SD:
5.27)
Multiple regressions,
adjusted for toxicants
(Cd, diethyl phthalate,
dibutyl phthalate, di[2-
ethylhexyl] phthalate),
age, BMI, tobacco,
smoking, alcohol, and
diet
(3 (95% Cl)c
Sperm motility (%): 2.43
(-4.87, -0.001)
Sperm concentration
(106/ml): -1.97 (-3.16,
-0.33)
Tail length: 3.79 (0.56, 7.02)
Percent DNA in tail: 1.31
(0.172, 3.74)
Tail moment: 1.20 (0.23,
2.16)
Jia et al. (20221
Henan Province
China
December 2017 to
August 2018
Cross-sectional
n: 841
Males ranging from 18 to
50 years of age with no
history of testicular injury,
urologist diagnosed
inflammation of the
urogenital system; history
of epididymitis; treatment
history of varicocele;
history of incomplete
orchiocatabasis or any of
the following that was
detected by an urologist at
physical examination:
Other: Semen
Seminal plasma was
measured by analyzed
using the kinetic energy
discrimination-based
Thermo iCAP Q ICP-MS
Age at Measurement
Mean ± SD:
29 55 ± 5 45 years
Median: 1.70 ppb
Male reproductive effects:
Seminal parameters
Semen of volunteers was
collected and analyzed the
protocols of the WHO.
Computer-assisted sperm
analysis technology was
used to analyze the
collected semen samples.
The quality indicators were
complete liquefaction,
semen volume, sperm
concentration, total sperm
count, progressive motility,
Multilinear regression
models were adjusted
for age, BMI, smoking,
and alcohol
consumption
(3 (95% Cl)c, per increase in
In-Pb seminal plasma
Semen volume: -0.10
(-0.27, 0.07)
Sperm concentration: 1.83
(-4.45, 8.12)
Total sperm number: 0.80
(-17.61, 19.21)
Progressive motility: 0.06
(-2.09, 2.21)
Normal morphological rate:
-0.04 (-0.41, 0.34)
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Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
absence of prominentia
laryngea, absence of
pubes, abnormal breast,
absence of testis,
abnormal penis,
epididymal knob, or
varicocele
75th: 2.36 ppb
non-progressive motility,
sperm motility, and sperm
motility parameters, such
as curve line velocity
(|jm/s), straight line
velocity (|-im/s), velocity of
average path (|-im/s),
lateral head movement
(amplitude of lateral head
displacement, |jm),
average motion degree (°),
linearity (%), straightness
(%), wobble, and beat
cross frequency (beat
cross frequency, Hz).
Curve line velocity: 0.35
(-1.17, 1.88)
Straight line velocity: 0.54
(-0.50, 1.58)
Velocity of average path:
0.37 (-0.96, 1.70)
Linearity: 0.49 (-0.88, 1.86)
Straightness: 0.46 (-1.07,
1.99)
Wobble: 0.22 (-1.33, 1.77)
Average motion degree:
-0.33 (-1.22, 0.56)
Beat cross frequency: 0.01 (-
0.14, 0.15)
Lateral head movement:
-0.04 (-0.11, 0.03)
Williams et al.
(20221
Russia
2003-2005 (follow-
up annually for
10 years)
Cohort
Russian Children's Study
n: 223
Boys enrolled at age 8-
9 years in 2003-2005 and
followed them annually for
10 years.
Blood
Blood was measured by
Zeeman background
corrected flameless
GFAAS
Age at measurement: 8-
9 years
Median: 3 [jg/dL
75th: 5 [jg/dL
Categories
Lower: <5 [jg/dL
Higher: >5 [jg/dL
Tertiles
Male reproductive effects:
Semen parameters
All semen samples were
assessed by a single
andrology technician and
analyzed according to
criteria of the Nordic
Association for
Andrology and European
Society of Human
Reproduction and
Embryology-Special
Interest Group in
Andrology and serum
hormonal levels were
analyzed using the
Architect i1000SR and
chemiluminescent
Mixed effect linear
regression models
adjusted for boys' BW,
total caloric intake,
height Z-score at entry,
breastfeeding duration,
monthly household
income, and abstinence
time
(3 (95% CI)b, as adjusted
mean
Semen volume (mL)
Continuous, per log-blood
Pb: -0.40 (-0.82, 0.03)
Categories
Lower: 2.83 (2.61, 3.06)
Higher: 2.60 (2.27, 2.93)
Tertiles
Low: 2.92 (2.50, 3.34)
Medium: 2.79 (2.52, 3.06)
High: 2.60 (2.27, 2.93)
p for trend: 0.24
Sperm concentration
(mill/mL)
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Study Design Clsa
Low: <2 [jg/dL
Medium: 3-4 [jg/dL
High: >5 [jg/dL
microparticle
immunoassay.
Age at outcome: 18 years
or older
Continuous, per log-blood
Pb: 0.09 (-0.13, 0.31)
Categories
Lower: 47.0 (41.3, 53.4)
Higher: 49.0 (37.8, 63.4)
Tertiles
Low: 41.3 (33.2, 51.3)
Medium:50.3 (42.8, 59.0)
High: 49.1 (38.0, 63.6)
p for trend: 0.33
Total sperm count (mill)
Continuous, per log-blood
Pb: -0.02 (-0.27, 0.23)
Categories
Lower: 111 (95.6, 129)
Higher: 107 (80.0, 143)
Tertiles
Low: 99 (76.4, 128)
Medium: 118 (95.5, 141)
High: 107 (80.3, 143)
p for trend: 0.68
Progressive sperm motility
(%)
Continuous, per log-blood
Pb: 1.77 (-0.55, 4.08)
Categories
Lower: 53.2 (51.7, 54.7)
Higher: 53.1 (50.9, 55.2)
Tertiles
Low: 51.2 (48.6, 53.9)
Medium: 54.3 (52.5, 56.1)
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Study Design Clsa
High: 53.2 (50.9, 55.3)
p for trend: 0.29
Total progressive motile
sperm count (mill)
Continuous, per log-blood
Pb: 0.01 (-0.27, 0.29)
Categories
Lower: 57.7 (48.9, 68.1)
Higher: 55.7 (40.6, 76.4)
Tertiles
Low: 49.4 (36.8, 66.2)
Medium: 62.6 (51.3, 76.5)
High: 56.0 (40.8, 76.8)
p for trend: 0.57
Low semen quality
(probability)
Continuous, per log-blood
Pb: 0.20 (-0.22, 0.65)
Categories
Lower: 0.51 (0.44, 0.58)
Higher: 0.49 (0.39, 0.59)
Tertiles
Low: 0.43 (0.31, 0.55)
Medium: 0.55 (0.46, 0.63)
High: 0.49 (0.39, 0.59)
p for trend: 0.43
Effects of Hormone Levels
Kresovich et al. NHANES
(2015) n: 869
Blood
Male reproductive effects:
Hormones
Linear regression
models were adjusted
for age, BMI, race,
(3 (SE)d
Testosterone (ng/mL)
Q1: Reference
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
United States
1999-2004
Cross-sectional
Males who were aged
>20 years, no reported
steroid or thyroid
mediation use, and no
reported thyroid disease.
Blood was measured by
AAS (1999-2002) or ICP-
MS (2003-2004).
Age at measurement:
>20 years
Median (weighted):
2.0 [jg/dL
75th: 2.8 pg/dL
Quartiles (pg/dL)
Q1
Q2
Q3
Q4
<1.40
1.40-2.10
2.10-3.20
>3.20
Testosterone,
androstanedione
glucuronide, and SHBG
were measured in blood
serum, and E2 in plasma.
All sex hormones were
detected by immunoassay.
Age at outcome:
>20 years
diabetes status
(including prediabetes),
smoking status, and
alcohol intake; and Cd
Q2
Q3
Q4
0.39 (0.21)
0.56 (0.22)
0.81 (0.20)
p for trend: 0.0008
E2 (pg/mL)
Q1
Q2
Q3
Q4
Reference
-0.01 (0.03)
-0.01 (0.04)
-0.01 (0.04)
p for trend: 0.7849
Free testosterone (ng/dL)
Q1
Q2
Q3
Q4
Reference
0.83 (0.47)
0.55 (0.48)
0.81 (0.48)
p for trend: 0.2374
fE2 (pg/ml)
Q1
Q2
Q3
Q4
Reference
-0.01 (0.03)
-0.02 (0.04)
-0.03 (0.04)
p for trend: 0.4428
Androstanedione
glucuronide (ng/mL)
Q1: Reference
Q2: 0.03 (0.03)
Q3: -0.01 (0.03)
Q4: 0.02 (0.04)
p for trend: 0.8917
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Study Design Clsa
SHBG (nmol/L)
Q1: Reference
Q2: 0.01 (0.02)
Q3: 0.05 (0.02)
Q4: 0.05 (0.02)
p for trend: 0.0187
Adjusted for Cd
Testosterone (ng/mL)
Q1: Reference
Q2: 0.38 (0.23)
Q3: 0.54 (0.21)
Q4: 0.79 (0.22)
p for trend: 0.0026
E2 (pg/mL)
Q1: Reference
Q2: 0.00 (0.03)
Q3: 0.01 (0.04)
Q4: 0.02 (0.04)
p for trend: 0.6600
Free testosterone (ng/dL)
Q1:
Reference
Q2:
0.95 (0.50)
Q3:
0.70 (0.51)
Q4:
1.06 (0.51)
p for trend: 0.1388
fE2 (pg/ml)
Q1: Reference
Q2: 0.01 (0.03)
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Study Design Clsa
Lewis and Meeker
(20151
United States
2011-2012
Cross-sectional
Q3: 0.00 (0.04)
Q4: 0.01 (0.04)
p for trend: 0.9456
Androstanedione
glucuronide (ng/mL)
Q1: Reference
Q2: 0.03 (0.03)
Q3: -0.02 (0.03)
Q4: 0.01 (0.04)
p for trend: 0.7620
SHBG (nmol/L)
Q1: Reference
Q2: -0.01 (0.02)
Q3: 0.03 (0.02)
Q4: 0.03 (0.03)
p for trend: 0.1333
NHANES
n: 484
Men that were 18-
55 years old, that had
complete data on the
metals of interest, serum
T, body mass index (BMI),
PIR, race, serum cotinine,
or urinary creatinine
Blood
Blood was measured by
inductively coupled
dynamic reaction-plasma
mass spectrometry
Age at Measurement:
18-55 years
Geometric mean:
1.06 [jg/dL
75th: 1.59 pg/dL
Male reproductive effects:
Testosterone
Serum testosterone (total)
were measured by isotope
dilution-high performance
liquid chromatography-
tandem mass
spectrometry
Age at outcome:
18-55 years
Multiple linear
regression, adjusted for
age, BMI, PIR, race,
and serum cotinine
(3 (95% CI)c, as percent
change in serum T
associated with a doubling
(100% increase) in blood Pb
concentration: 6.65 (2.09,
11.41)
Chenetal. (20161 SPECT-China Blood
n: 2286 men
Male reproductive effects: Linear regression (3 (SE)d
Reproductive hormone models were adjusted SHBG
levels for age and current
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Shanghai, Jiangxi
Province and
Zhejiang province
China
2014
Cross-sectional
SPECT-China is a
population-based cross-
sectional survey on the
prevalence of metabolic
diseases and risk factors
in East China. Men and
postmenopausal women
(age >55 years) who were
not taking hormone
replacement therapy,
without a history of
hysterectomy and
oophorectomy were
recruited.
Blood was measured by
AAS
Age at Measurement:
Median (IQR) age: 54
(44-63)
Medianb: 4.400 |jg/dL
75thb: 6.230 pg/dL
Quartilesb (pg/dL)
Q1
Q2
Q3
<2.900
2.900-4.399
4.400-6.229
Q4: >6.229
Venous blood samples
were drawn from all
subjects after an overnight
fast of at least 8 hr. HbA1c
was assessed via high-
performance liquid
chromatography. tT, E2,
LH and FSH levels were
measured using
chemiluminescence
assays. SHBG levels were
detected using
electrochemiluminescence
immunoassays.
Age at outcome:
Median (IQR) age: 54 (44-
63)
smoking status, BMI,
SBP, diabetes and,
blood Cd level
Q1
Q2
Q3
Q4
Reference
<0.001 (0.011)
0.021 (0.011)
0.038 (0.012)
p for trend: <0.001
tT
Q1
Q2
Q3
Q4
Reference
0.001 (0.010)
0.010 (0.010)
0.033 (0.010)
p for trend: 0.001
E2
Q1
Q2
Q3
Q4
Reference
-0.008 (0.016)
0.014 (0.017)
-0.003 (0.017)
p for trend: 0.794
FSH
Q1: Reference
Q2: 0.010 (0.014)
Q3: 0.004 (0.014)
Q4: 0.030 (0.015)
p for trend: 0.067
LH
Q1: Reference
Q2: 0.018 (0.013)
Q3: 0.015 (0.013)
Q4: 0.028 (0.013)
p for trend: 0.065
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Study Design Clsa
Effects on Fertility
Louis et al. (20121
Michigan (4
counties) and Texas
(12 counties)
United States
2005-2009
Cohort
LIFE Study
n: 501
Female ages 18-44 years
and male ages >18 years;
in a committed
relationship; ability to
communicate in English or
Spanish; menstrual cycles
between 21 and 42 days;
no hormonal contraception
injections during past
year; and no sterilization
procedures or physician
diagnosed infertility
Blood
Blood was measured by
ICP-MS
Age at Measurement:
Average age for male
partner with pregnancy:
31.6 years
Average age for male
partner without
pregnancy: 32.4 years
Geometric mean
Male partner with
pregnancy result:
1.03 [jg/dL
Male partner without
pregnant result:
1.18 Mg/dL
Male reproductive effects:
Fecundity
Women were instructed in
the use of the Clearblue
Easy fertility monitors
consistent with the
manufacturer's guidance
commencing on day six for
tracking daily levels of
estrone-3-glucuronide
(E3G) and LH. Women
also used the digital
Clearblue Easy home
pregnancy test upon
enrollment to ensure the
absence of pregnancy at
study start and on the day
menses was expected for
each cycle under
observation in the study.
Age at outcome:
Average age for males
with pregnancy: 31.6 years
Average age for males
without pregnancy:
32.4 years
Cox models for discrete
survival time, which is a
proportional odds
model, adjusted for
age, BMI, cotinine,
parity, serum lipids, and
site (Texas/Michigan)
OR (95% CI), as
fecundability OR
Male only exposure: 0.85
(0.73, 0.99)
Couple exposure:
Female exposure: 1.06
(0.91, 1.24)
Male exposure: 0.82 (0.68,
0.97)
Zhou et al. (202 la) n: 195
Blood, other: follicular Male reproductive effects: Poisson regression
China
2018-2019
Cohort
fluid, and other: semen IVF outcome
Couples undergoing IVF.
Women with
endometriosis,
hydrosalpinx, abnormal
uterine cavity and men
with azoospermia, severe
oligozoospermia,
Maternal blood (serum),
follicular fluid, and
seminal plasma from
male partner
The IVF outcomes
included were normal
fertilization, good embryo,
blastocyst formation, high-
models were adjusted
for age and BMI
RR (95% Cl)c
Normal fertilization
Maternal serum: 0.94 (0.42,
1.93)
Follicular fluid: 0.82 (0.18,
2.39)
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Reference and Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Study Design Clsa
asthenospermia and
dysspermia were excluded Age at Measurement:
from the study. Female partner mean
age: 30.27 years
Male partner mean age:
31.57 years
Mean0
Maternal serum:
0.301 [jg/dL
Follicular fluid:
0.742 [jg/dL
Seminal plasma:
0.882 [jg/dL
Median0
Maternal serum:
0.245 [jg/dL
Follicular fluid:
0.178 [jg/dL
Seminal plasma:
0.486 [jg/dL
75th°
Maternal serum:
0.317 [jg/dL
Follicular fluid:
0.326 [jg/dL
Seminal plasma:
1.245 [jg/dL
quality blastocyst,
pregnancy, and live birth
Age at outcome:
Female partner mean age:
30.27 years
Male partner mean age:
31.57 years
Seminal plasma: 1.55 (0.64,
3.3)
Good embryo
Maternal serum: 1.00 (0.36,
2.38)
Follicular fluid: 0.78 (0.09,
3.03)
Seminal plasma: 1.86 (1.05,
3.11)
Blastocyst formation
Maternal serum: 1.06 (0.2,
3.91)
Follicular fluid: 0.41 (0, 3.63)
Seminal plasma: 1.77 (0.78,
3.58)
High-quality blastocyst
Maternal serum: 1.68 (0.15,
9.43)
Follicular fluid: 0.35 (0, 7.11)
Seminal plasma: 2.66 (0.67,
8)
Pregnancy
Maternal serum: 0.18 (0.01,
1.91)
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Reference and
Study Design
Study Population
Exposure Assessment
Outcome
Confounders
Effect Estimates and 95%
Clsa
Follicular fluid: 0.01 (0, 0.03)
Seminal plasma: 0.04 (0,
1.45)
Live birth
Maternal serum: 0.25 (0.01,
2.8)
Follicular fluid: 0 (0, 0.09)
Seminal plasma: 0.01 (0,
1.08)
Effects on Morphology or Histology of Male Sex Organs
Huang et al (20201 Guangxi Birth Cohort
Guangxi
China
July 2015 to
September 2018
Cohort
Study
n: 564 mother-child pairs
Women with singleton
pregnancies that were
included from 8 Maternity
and Child Healthcare
Hospitals in 6 cities of
Guangxi, China
Blood
Maternal blood (serum)
was measured by ICP-
MS
Age at Measurement:
Maternal age at time of
measurement (mean age:
28.76 (SD: 4.66) years)
Medianb: 0.077 |jg/dL
75thb: 0.123 pg/dL
Quartilesb (pg/dL)
Q1
Q2
Q3
Q4
<0.054
0.055-0.077
0.078-0.123
>0.123
Male reproductive effects:
TV and anogenital
distance in infant boys
TV, and AGD-TV
measurements were
undertaken by trained
sonographers using
ultrasonography.
Transverse and
longitudinal grey-scale
images were used to
calculate TV as
tt/6 x length * width * heig
ht. The volumes of both
testes were measured and
an average taken. Two
different measurements of
AGD were obtained using
vernier calipers: the longer
AGD was measured from
the center of the anus to
the cephalad insertion of
the penis (AGDap), and
the shorter AGD was
measured from the center
Multiple linear
(3 (95% Cl)c
regression models were jy
adjusted for BW, GA,
blood sampling time
(mother), alcohol use
pre-pregnancy, BMI,
and age at examination
Q1
Q2
Q3
Q4
Reference
-0.017 (-0.077, 0.043)
-0.024 (-0.085, 0.036)
-0.064 (-0.124, -0.004)
Anopenile distance
Q1
Q2
Q3
Q4
Reference
-0.039 (-0.085, 0.008)
-0.037 (-0.085, 0.010)
-0.060 (-0.110, -0.011)
Anoscrotal distance
Q1
Q2
Q3
Q4
Reference
-0.020 (-0.091, 0.052)
-0.033 (-0.105, 0.039)
-0.115 (-0.190, -0.039)
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Reference and Study Population Exposure Assessment Outcome Confounders Effect Estimates and 95%
Study Design Clsa
of the anus to the posterior
base of the scrotum
(AGDas).
Age at outcome:
birth
AAS = atomic absorption spectrometry; AGD = anogenital distance; AGDap = anopenile distance; AGDas = anoscrotal distance; BMI = body mass index; BW = birth weight;
CI = confidence interval; E2 = estradiol; fE2 = free estradiol; fT = free testosterone; FSH = follicle stimulating hormone; GA = gestational age; GFAAS = graphite furnace atomic
absorption spectrometry; ICP-AES = inductively coupled plasma-atomic emission spectrometry; ICP-MS = inductively coupled plasma mass spectrometry; IVF = in vitro fertilization;
LH = luteinizing hormone; LIFE = Longitudinal Investigation of Fertility and the Environment; LOD = limit of detection; NHANES = National Health and Nutrition Examination Survey;
Q = quartile; OR = odds ratio; PIR = poverty-to-income ratio; SD = standard deviation; SE = standard error; SHBG = sex hormone binding globulin; SPECT = Survey on the
Prevalence in East China for Metabolic Diseases and Risk Factors; T = testosterone; tT = total testosterone; TV = testicular volume; WHO = World Health Organization.
aEffect estimates are standardized to a 1 |jg/dL increase in blood Pb or a 10 |jg/g increase in bone Pb, unless otherwise noted. If the Pb biomarker is log-transformed, effect
estimates are standardized to the specified unit increase for the 10th—90th percentile interval of the biomarker level. Effect estimates are assumed to be linear within the evaluated
interval. Categorical effect estimates are not standardized.
bPb measurements were converted from |jg/L to |jg/dL.
°Effects estimates unable to be standardized.
dNo CIs provided.
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Table 8-17 Animal toxicologic studies of exposure to Pb and male reproductive effects.
Study
Species (Stock/Strain), n, Sex
Timing of
Exposure
Exposure Details
(Concentration,
Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
El Shafaietal. (20111 Rat (Wistar)
Control (untreated), M, n = 8
Control (vehicle), M, n = 8
25 mg/kg Pb, M, n = 8
Adulthood (specific
PND NR)
Adult male rats were
dosed via oral gavage for
3 months. One control
group was not gavaged
(untreated control) and
another control group
was gavaged with vehicle
(vehicle control).
4.26 [jg/dL for
control (untreated)
4.27 [jg/dL for
control (vehicle)
5.27 [jg/dL for
25 mg/kg Pb
Sex Organ
Histopathology
Waneetal. (2013b)
Rat (Sprague-Dawley)
Control (untreated), M, n = 15
0.8/0.3 g/L Pb, M, n = 15
1.5/0.9 g/L Pb, M, n = 15
GD -10 to Dams were dosed via
PND 183 drinking water (0, 0.8, or
1.5 g/L Pb) starting 10
days prior to mating
through weaning. At
weaning 15 males from
each group were dosed
via drinking water to
lower levels of Pb than
their dams (0, 0.3, or
0.9 g/L) until 6 months of
age (approx. PND 183).
2.65 [jg/dL for
control
18.6 [jg/dL for
0.8/0.3 g/L Pb
55.0 [jg/dL for
1.5/0.9 g/L Pb
Testicular
Weight
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Study
Species (Stock/Strain), n, Sex
Timing of
Exposure
Exposure Details
(Concentration,
Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
Wang et al. (2013a')
Mouse (CD-1)
Control (untreated), M, n = 12
200 ppm Pb, M, n = 12
2000 ppm Pb, M, n = 12
PNDOto PND21
Dams were dosed via
drinking water from
PNDOto 21.
Pups:
PND 22
17.4 [jg/dL for
control
21.2 [jg/dL for
200 ppm Pb
19.1 [jg/L for
2000 ppm Pb
Testosterone
Levels, Sex
Organ
Histopathology,
Accessory Male
Reproductive
Organ Weight,
Testicular
Weight, Semen
Parameters
PND 70
4.40 |jg/dL for
control
3.24 [jg/dL for
200 ppm Pb
5.09 [jg/dL for
2000 ppm Pb
Godinez-Solis et al.
(20191
Mouse (ICR-CD-1)
Control (untreated), M, n = 4
0.01% Pb, M, n = 6
PND 91 to 136
12 week old mice were
acclimated for a week
before being dosed via
drinking water for
45 days.
BLL NR for controls
9.4 |jg/dL for
0.01% Pb
Semen
Parameters,
Sperm
Morphology, IVF
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Study
Species (Stock/Strain), n, Sex
Timing of
Exposure
Exposure Details
(Concentration,
Duration)
BLL As Reported
(pg/dL)
Endpoints
Examined
Xie et al. (2020)
Mouse (SPF ICR)
Control (untreated), M, n = 15
50 mg/L Pb, M, n = 15
200 mg/L Pb, M, n = 15
PND 28 to
PND 118
21 day old mice were
acclimated for a week
before being dosed for
90 days via drinking
water.
0.602 |jg/dL for
control
6.02 |jg/dL for
50 mg/L Pb
11.8 |jg/dL for
200 mg/L Pb
Semen
Parameters,
Sperm
Morphology,
Sex Organ
Histopathology,
Testicular
Weight,
Accessory Male
Reproductive
Organ Weight
Pavlova et al. (2021)
Mouse (ICR)
Control (vehicle), M, n = 10
80 mg/kg Pb, M, n = 10
PND 60 to 74
60 day old mice were
dosed via oral gavage for
2 weeks. Two weeks
following cessation of
exposure, animals were
sacrificed.
1.45 |jg/dL for
control
21.66 |jg/dL for
80 mg/kg Pb
Testicular
Weight, Semen
Parameters, Sex
Organ
Histopathology
BLL = blood lead level; F = female; GD = gestational day; IVF = in vitro fertilization; M = male; NR = not reported; Pb = lead; PND = postnatal day.
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