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BackgroundDNA methylation alterations may underlie associations between gestational perfluoroalkyl substances (PFAS) exposure and later-life health outcomes. To the best of our knowledge, no longitudinal studies have examined the associations between gestational PFAS and DNA methylation.ObjectivesWe examined associations of gestational PFAS exposure with longitudinal DNA methylation measures at birth and in adolescence using the Health Outcomes and Measures of the Environment (HOME) Study (2003-2006; Cincinnati, Ohio).MethodsWe quantified serum concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) in mothers during pregnancy. We measured DNA methylation in cord blood (n=266) and peripheral leukocytes at 12 years of age (n=160) using the Illumina HumanMethylation EPIC BeadChip. We analyzed associations between log2-transformed PFAS concentrations and repeated DNA methylation measures using linear regression with generalized estimating equations. We included interaction terms between children's age and gestational PFAS. We performed Gene Ontology enrichment analysis to identify molecular pathways. We used Project Viva (1999-2002; Boston, Massachusetts) to replicate significant associations.ResultsAfter adjusting for covariates, 435 cytosine-guanine dinucleotide (CpG) sites were associated with PFAS (false discovery rate, q

Background: Phthalate exposure is ubiquitous and may affect biological pathways related to regulators of blood pressure. Given the profound changes in vasculature during pregnancy, pregnant women may be particularly susceptible to the potential effects of phthalates on blood pressure. Objectives: We examined associations of phthalate exposure during pregnancy with maternal blood pressure trajectories from mid-pregnancy through 72 months postpartum. Methods: Women with singleton pregnancies delivering a live birth in Mexico City were enrolled during the second trimester (n=892). Spot urine samples from the second and third trimesters were analyzed for 15 phthalate metabolites. Blood pressure and covariate data were collected over nine visits through 72 months postpartum. We used linear, logistic, and linear mixed models; latent class growth models (LCGMs); and Bayesian kernel machine regression to estimate the relationship of urinary phthalate biomarkers with maternal blood pressure. Results: As a joint mixture, phthalate biomarker concentrations during pregnancy were associated with higher blood pressure rise during mid-to-late gestation. With respect to individual biomarkers, second trimester concentrations of monobenzyl phthalate (MBzP) and di(2-ethylhexyl) phthalate biomarkers (ΣDEHP) were associated with higher third trimester blood pressure. Two trajectory classes were identified by LCGM, characterized by increasing blood pressure through 72 months postpartum (“increase–increase”) or decreased blood pressure through 18 months postpartum with a gradual increase thereafter (“decrease–increase”). Increasing exposure to phthalate mixtures during pregnancy was associated with higher odds of being in the increase–increase class. Similar associations were observed for mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and dibutyl phthalate (ΣDBP) biomarkers. When specific time periods were examined, we observed specific temporal relationships were observed for ΣDEHP, MECPTP, MBzP, and ΣDBP. Discussion: In our cohort of pregnant women from Mexico City, exposure to phthalates and phthalate biomarkers was associated with higher blood pressure during late pregnancy, as well as with long-term changes in blood pressure trajectories. https://doi.org/10.1289/EHP8562

Background: Prenatal exposure to mixtures of nonpersistent chemicals is universal. Most studies examining these chemicals in association with fetal growth have been restricted to single exposure models, ignoring their potentially cumulative impact. Objective: We aimed to assess the association between prenatal exposure to a mixture of phthalates, bisphenols, and organophosphate (OP) pesticides and fetal measures of head circumference, femur length, and weight. Methods: Within the Generation R Study, a population-based cohort in Netherlands (n=776), urinary concentrations of 11 phthalate metabolites, 3 bisphenols, and 5 dialkylphosphate (DAP) metabolites were measured at 25 weeks of gestation and averaged. Ultrasound measures of head circumference, femur length, and estimated fetal weight (EFW) were taken at 18–25 and >25 weeks of gestation, and measurements of head circumference, length, and weight were performed at delivery. We estimated the difference in each fetal measurement per quartile increase in all exposures within the mixture with quantile g-computation. Results: The average EFW at 18–25 wk and >25wk was 369 and 1,626g, respectively, and the average birth weight was 3,451g. Higher exposure was associated with smaller fetal and newborn growth parameters in a nonlinear fashion. At 18–25 wk, fetuses in the second, third, and fourth quartiles of exposure (Q2–Q4) had 26g [95% confidence intervals (CI):−38, −13], 35g (95% CI: −55, −15), and 27g (95% CI: −54, 1) lower EFW compared with those in the first quartile (Q1). A similar dose–response pattern was observed at >25wk, but all effect sizes were smaller, and no association was observed comparing Q4 to Q1. At birth, we observed no differences in weight between Q1–Q2 or Q1–Q3. However, fetuses in Q4 had 91g (95% CI: −258, 76) lower birth weight in comparison with those in Q1. Results observed at 18–25 and >25wk were similar for femur length; however, no differences were observed at birth. No associations were observed for head circumference. Discussion: Higher exposure to a mixture of phthalates, bisphenols, and OP pesticides was associated with lower EFW in the midpregnancy period. In late pregnancy, these differences were similar but less pronounced. At birth, the only associations observed appeared when comparing individuals from Q1 and Q4. This finding suggests that even low levels of exposure may be sufficient to influence growth in early pregnancy, whereas higher levels may be necessary to affect birth weight. Joint exposure to nonpersistent chemicals may adversely impact fetal growth, and because these exposures are widespread, this impact could be substantial. https://doi.org/10.1289/EHP9178

Background: Per- and polyfluoroalkyl substances (PFAS) may impair bone accrual and strength via endocrine disruption and nuclear receptor agonism, but human studies are primarily of adults or cross-sectional. Objectives: We assessed associations of individual PFAS and their mixture during pregnancy with child bone mineral content (BMC) and areal bone mineral density (aBMD) at age 12 y. Methods: Among 206 mother–child pairs enrolled in a prospective cohort (2003–2006), we quantified perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS) in maternal serum collected during gestation or delivery. When children were age 12 y, we performed dual energy X-ray absorptiometry and calculated BMC, aBMD, and bone mineral apparent density (BMAD) z-scores for six skeletal sites. We estimated covariate-adjusted z-score differences per doubling of individual PFAS using linear regression and assessed the PFAS mixture using quantile g-computation and Bayesian kernel machine regression. We explored whether associations were modified by child’s sex or mediated by whole-body lean mass. Results: In covariate-adjusted models, we found that higher maternal serum concentrations of PFOA, PFNA, and the PFAS mixture were associated with lower total hip and forearm (one-third distal radius) BMC z-scores in children. Differences in forearm BMC z-scores were −0.17 [95% confidence interval (CI): −0.35, 0.01] and −0.24 (95% CI: −0.44, −0.05) per doubling of PFOA and PFNA, respectively, and −0.18 (95% CI: −0.34, −0.02) per quartile increase in the PFAS mixture. Child’s sex modified PFOA associations for some skeletal sites; for example, differences in spine BMAD z-score per doubling were −0.31 (95% CI: −0.58, −0.03) among males and 0.07 (95% CI: −0.16, 0.30) among females (modification p=0.04). Except for PFNA among females, these associations were not mediated by whole-body lean mass. Discussion: Maternal PFAS concentrations during pregnancy may be associated with lower bone mineral accrual and strength in early adolescence. https://doi.org/10.1289/EHP9424

Background:Prenatal polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) exposures may influence children’s neurodevelopment.Objective:We examined the association of prenatal...

Background: Although previous epidemiological studies have explored associations of phthalate metabolites with thyroid function, no studies to date have assessed associations of mixtures with thyroid function and autoimmunity among potentially susceptible subgroups such as subfertile women. Objective: We aimed to explore associations of mixtures of urinary phthalate metabolites with serum markers of thyroid function and autoimmunity. Methods: This cross-sectional study included 558 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2005–2015). We quantified urinary concentrations of eight phthalate metabolites using mass spectrometry, and biomarkers of thyroid function [thyroid-stimulating hormone (TSH), free and total thyroxine (fT4, TT4) and triiodothyronine (fT3, TT3), and autoimmunity [thyroid peroxidase and thyroglobulin antibodies (TPOAb and TgAb, respectively)] in serum using electrochemiluminescence assays. We applied principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) to identify the main patterns of urinary phthalate metabolites. We used linear mixed models to assess the association between PCA-derived factor scores in quintiles and serum thyroid function and autoimmunity, adjusting for age, body mass index (BMI), specific gravity (SG), and, for the PCA, other factor scores. Results: We observed two factors using PCA, one representing the di(2-ethylhexyl) (DEHP) and another non-DEHP metabolites. Compared to women in the lowest quintile of the DEHP factor scores, women in the highest quintile had significantly lower serum concentrations of fT4, TT4, fT3, and TT3 [absolute difference: −0.62; 95% confidence interval (CI): −0.12, −0.01; p=0.04; absolute difference: −8.31; 95% CI: −13.8, −2.85; p=0.003; absolute difference: −0.37; 95% CI: 0.54, −0.19; p

Background: Bisphenol A (BPA) is an endocrine disruptor that affects fetal growth in experimental studies. Bisphenol F (BPF) and bisphenol S (BPS), which have been substituted for BPA in some consumer products, have also shown endocrine-disrupting effects in experimental models. However, the effects of BPF and BPS on fetal growth in humans are unknown. Objectives: Our goal was to investigate trimester-specific associations of urinary concentrations of BPA, BPF, and BPS with size at birth. Methods: The present study included 845 pregnant women from Wuhan, China (2013–2015), who provided one urine sample in each of the first, second, and third trimesters. Linear regressions with generalized estimating equations were applied to estimate trimester-specific associations of urinary bisphenol concentrations with birth weight, birth length, and ponderal index. Linear mixed-effects models were used to identify potential critical windows of susceptibility to bisphenols by comparing the exposure patterns of newborns in the 10th percentile of each birth anthropometric measurement to that of those in the 90th percentile. Results: Medians (25th–75th percentiles) of urinary concentrations of BPA, BPF, and BPS were 1.40 (0.19–3.85), 0.65 (0.34–1.39), and 0.38 (0.13–1.11) ng/mL, respectively. Urinary BPA concentrations in different trimesters were inversely, but not significantly, associated with birth weight and ponderal index. Urinary concentrations of BPF and BPS during some trimesters were associated with significantly lower birth weight, birth length, or ponderal index, with significant trend p-values (ptrend

Background: Emerging studies suggest that ambient temperature during pregnancy may be associated with fetal growth, but the existing evidence is limited and inconsistent. Objectives: We aimed to evaluate the association of trimester-specific temperature with risk of being born small for gestational age (SGA) and birth weight—markers of fetal growth—among term births in the contiguous United States. Methods: We included data on 29,597,735 live singleton births between 1989 and 2002 across 403 U.S. counties. We estimated daily county-level population-weighted mean temperature using a spatially refined gridded climate data set. We used logistic regression to estimate the association between trimester-specific temperature and risk of SGA and linear regression to evaluate the association between trimester-specific temperature and term birth weight z-score, adjusting for parity, maternal demographics, smoking or drinking during pregnancy, chronic hypertension, and year and month of conception. We then pooled results overall and by geographic regions and climate zones. Results: High ambient temperatures (>90th percentile) during the entire pregnancy were associated with higher risk of term SGA {odds ratio [OR] = 1.041 [95% confidence interval (CI): 1.029, 1.054]} and lower term birth weight [standardized to −15g (95% CI: −17g, −13g) reduction in birth weight for infants born at 40 weeks of gestation]. Low temperatures (≤10th percentile) during the entire pregnancy were not associated with SGA [OR = 1.003 (95% CI: 0.991, 1.015)] but were associated with a small decrement in term birth weight [standardized to −6g (95% CI: −8g, −4g)]. Risks of term SGA and birth weight were more strongly associated with temperature averaged across the second and third trimesters, in areas the Northeast, and in areas with cold or very cold climates. Conclusions: Above-average temperatures during pregnancy were associated with lower fetal growth. Our findings provide evidence that temperature may be a novel risk factor for reduced fetal growth. https://doi.org/10.1289/EHP4648

Background: Early-life phthalate exposure may influence child adiposity, but prior studies have not determined if there are periods of enhanced vulnerability to phthalates. Objective: To examine the relationship between child adiposity at 8 y of age and repeated urinary biomarkers of phthalate exposure from gestation through childhood to determine if there are distinct periods of vulnerability. Methods: In 219 mother–child pairs from Cincinnati, Ohio, we quantified nine urinary phthalate metabolites up to two times prenatally and six times from 1–8 y of age. We measured child body mass index (BMI), waist circumference, and percent body fat at 8 y of age. To identify periods of vulnerability, we used two statistical methods to estimate phthalate–adiposity associations at each visit, test differences in phthalate–adiposity associations across visits, and model trajectories of phthalate concentrations for children at different levels of adiposity. Results: Prenatal phthalate concentrations were not associated with excess child adiposity. Monobenzyl phthalate (MBzP) concentrations during pregnancy and childhood were inversely associated with adiposity. The associations of di(2-ethylhexyl) phthalate (∑DEHP) metabolites and monoethyl phthalate (MEP) with child adiposity depended on the timing of exposure. A 10-fold increase in ∑DEHP at 1 and 5 y was associated with a 2.7% decrease [95% confidence interval (CI): −4.8, −0.5] and 2.9% increase (95% CI: 0.3, 5.5) in body fat, respectively. MEP concentrations at 5 and 8 y of age were associated with higher child adiposity, but earlier childhood concentrations were not. Conclusion: In this cohort, we did not find evidence of an obesogenic effect of prenatal phthalate exposure. Positive associations between postnatal MEP and ∑DEHP concentrations depended on the timing of exposure. https://doi.org/10.1289/EHP1022

Background: Exposure to triclosan, an endocrine disrupting chemical, may affect thyroid hormone homeostasis and adversely affect neurodevelopment. Objective: Using a longitudinal pregnancy and birth cohort, we investigated associations between triclosan exposures during different time windows, and cognitive test scores at 8 y of age in 198 children from the HOME Study. Methods: We quantified triclosan in urine samples from mother–child pairs up to nine times between the second trimester of gestation and 8 y of age. The Wechsler Intelligence Scale for Children-IV [i.e., Full-Scale Intelligence Quotient (IQ)] assessment was administered to HOME Study children at 8 y of age. We estimated covariate-adjusted triclosan–IQ associations at each visit. We also tested whether associations between triclosan concentrations and cognitive test scores varied among exposure at different time periods. Results: Full-Scale IQ was not significantly associated with urinary triclosan concentrations during gestation or childhood but was significantly associated with a 10-fold increase in maternal urinary triclosan concentration at delivery [−4.5 points (95% CI: −7.0, −2.0)]. Perceptual Reasoning Index (PRI) scores were significantly decreased in association with urinary triclosan concentrations at delivery and at 2 y of age. Associations between repeated triclosan concentrations and cognitive test scores significantly varied among exposure at different time periods for Full-Scale IQ, PRI, Verbal Comprehension Index, and Working Memory (triclosan–visit interaction p≤0.04). Conclusion: Urinary triclosan concentrations at delivery, but not during mid to late pregnancy and childhood, were associated with significantly lower children’s cognitive test scores at 8 y of age in this cohort of U.S. children. https://doi.org/10.1289/EHP2777

BACKGROUND: Personal care products (PCPs) are exposure sources to phthalates and parabens; however, their contribution to men's exposure is understudied.OBJECTIVES: We examined the association between PCP use and urinary concentrations of phthalate metabolites and parabens in men.METHODS: In a prospective cohort, at multiple study visits, men self-reported their use of 14 PCPs and provided a urine sample (2004-2015, Boston, MA). We measured urinary concentrations of 9 phthalate metabolites and methylparaben, propylparaben, and butylparaben. We estimated the covariate-adjusted percent change in urinary concentrations associated with PCP use using linear mixed and Tobit mixed regressions. We also estimated weights for each PCP in a weighted binary score regression and modeled the resulting composite weighted PCP use.RESULTS: Four hundred men contributed 1,037 urine samples (mean of 3/man). The largest percent increase in monoethyl phthalate (MEP) was associated with use of cologne/perfume (83%, p-valueCONCLUSIONS: We identified 10 PCPs of relevance and demonstrated that their use within 6 h of urine collection strongly predicted MEP and paraben urinary concentrations. https://doi.org/10.1289/EHP1374.

Background: Prenatal polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) exposures may influence children’s neurodevelopment. Objective: We examined the association of prenatal PBDE and PCB exposures with children’s reading skills at ages 5 and 8 years, Full-Scale Intelligence Quotient (FSIQ), and externalizing behavior problems at age 8 years. Methods: From 239 mother–child pairs recruited (2003–2006) in Cincinnati, Ohio, we measured maternal serum PBDE and PCB concentrations, assessed child’s reading skills using the Woodcock–Johnson Tests of Achievement III (WJ-III) at age 5 years and the Wide Range Achievement Test-4 (WRAT-4) at age 8 years, tested FSIQ using the Wechsler Intelligence Scale for Children-IV (WISC-IV), and externalizing behavior problems using the Behavioral Assessment System for Children-2 (BASC-2) at age 8 years. We used multiple linear regression to examine the association of prenatal PBDE and PCB concentrations and reading, FSIQ, and externalizing behavior problems after adjusting for covariates. Results: An increase of Sum4PBDEs (BDE-47, BDE-99, BDE-100, and BDE-153) by 10 times was not significantly associated with reading scores at age 5 years at the p = 0.05 level but was inversely associated with Reading Composite scores (β: –6.2, 95% CI: –11.7, –0.6) and FSIQ (β: –5.3, 95% CI: –10.6, –0.02) at age 8 years; it was positively associated with the score for externalizing behavior problems (β: 3.5, 95% CI: –0.1, 7.2) at age 8 years. Prenatal Sum4PCBs (PCB-118, -153, -138-158, and -180) was not significantly associated with a child’s reading skills, FSIQ, and externalizing behavior problems. Conclusion: Prenatal PBDE concentration was inversely associated with reading skills and FSIQ and positively associated with externalizing behavior problems at age 8 years. No significant associations were found in prenatal PCB concentration. Citation: Zhang H, Yolton K, Webster GM, Sjödin A, Calafat AM, Dietrich KN, Xu Y, Xie C, Braun JM, Lanphear BP, Chen A. 2017. Prenatal PBDE and PCB exposures and reading, cognition, and externalizing behavior in children. Environ Health Perspect 125:746–752; http://dx.doi.org/10.1289/EHP478

Background: Early-life exposure to bisphenol A (BPA) may increase childhood obesity risk, but few prospective epidemiological studies have investigated this relationship. Objective: We sought to determine whether early-life exposure to BPA was associated with increased body mass index (BMI) at 2–5 years of age in 297 mother–child pairs from Cincinnati, Ohio (HOME Study). Methods: Urinary BPA concentrations were measured in samples collected from pregnant women during the second and third trimesters and their children at 1 and 2 years of age. BMI z-scores were calculated from weight/height measures conducted annually from 2 through 5 years of age. We used linear mixed models to estimate BMI differences or trajectories with increasing creatinine-normalized BPA concentrations. Results: After confounder adjustment, each 10-fold increase in prenatal (β = –0.1; 95% CI: –0.5, 0.3) or early-childhood (β = –0.2; 95% CI: –0.6, 0.1) BPA concentrations was associated with a modest and nonsignificant reduction in child BMI. These inverse associations were suggestively stronger in girls than in boys [prenatal effect measure modification (EMM) p-value = 0.30, early-childhood EMM p-value = 0.05], but sex-specific associations were imprecise. Children in the highest early-childhood BPA tercile had lower BMI at 2 years (difference = –0.3; 95% CI: –0.6, 0.0) and larger increases in their BMI slope from 2 through 5 years (BMI increase per year = 0.12; 95% CI: 0.07, 0.18) than children in the lowest tercile (BMI increase per year = 0.07; 95% CI: 0.01, 0.13). All associations were attenuated without creatinine normalization. Conclusions: Prenatal and early-childhood BPA exposures were not associated with increased BMI at 2–5 years of age, but higher early-childhood BPA exposures were associated with accelerated growth during this period. Citation: Braun JM, Lanphear BP, Calafat AM, Deria S, Khoury J, Howe CJ, Venners SA. 2014. Early-life bisphenol A exposure and child body mass index: a prospective cohort study. Environ Health Perspect 122:1239–1245; http://dx.doi.org/10.1289/ehp.1408258

Background: Endocrine-disrupting chemicals (EDCs) may be involved in the etiology of autism spectrum disorders, but identifying relevant chemicals within mixtures of EDCs is difficult. Objective: Our goal was to identify gestational EDC exposures associated with autistic behaviors. Methods: We measured the concentrations of 8 phthalate metabolites, bisphenol A, 25 polychlorinated biphenyls (PCBs), 6 organochlorine pesticides, 8 brominated flame retardants, and 4 perfluoroalkyl substances in blood or urine samples from 175 pregnant women in the HOME (Health Outcomes and Measures of the Environment) Study (Cincinnati, OH). When children were 4 and 5 years old, mothers completed the Social Responsiveness Scale (SRS), a measure of autistic behaviors. We examined confounder-adjusted associations between 52 EDCs and SRS scores using a two-stage hierarchical analysis to account for repeated measures and confounding by correlated EDCs. Results: Most of the EDCs were associated with negligible absolute differences in SRS scores (≤ 1.5). Each 2-SD increase in serum concentrations of polybrominated diphenyl ether-28 (PBDE-28) (β = 2.5; 95% CI: –0.6, 5.6) or trans-nonachlor (β = 4.1; 95% CI: 0.8–7.3) was associated with more autistic behaviors. In contrast, fewer autistic behaviors were observed among children born to women with detectable versus nondetectable concentrations of PCB-178 (β = –3.0; 95% CI: –6.3, 0.2), β-hexachlorocyclohexane (β = –3.3; 95% CI: –6.1, –0.5), or PBDE-85 (β = –3.2; 95% CI: –5.9, –0.5). Increasing perfluorooctanoate (PFOA) concentrations were also associated with fewer autistic behaviors (β = –2.0; 95% CI: –4.4, 0.4). Conclusions: Some EDCs were associated with autistic behaviors in this cohort, but our modest sample size precludes us from dismissing chemicals with null associations. PFOA, β-hexachlorocyclohexane, PCB-178, PBDE-28, PBDE-85, and trans-nonachlor deserve additional scrutiny as factors that may be associated with childhood autistic behaviors. Citation: Braun JM, Kalkbrenner AE, Just AC, Yolton K, Calafat AM, Sjödin A, Hauser R, Webster GM, Chen A, Lanphear BP. 2014. Gestational exposure to endocrine-disrupting chemicals and reciprocal social, repetitive, and stereotypic behaviors in 4- and 5-year-old children: the HOME Study. Environ Health Perspect 122:513–520; http://dx.doi.org/10.1289/ehp.1307261

Summary: Quantifying the impact of exposure to environmental chemical mixtures is important for identifying risk factors for diseases and developing more targeted public health interventions. The National Institute of Environmental Health Sciences (NIEHS) held a workshop in July 2015 to address the need to develop novel statistical approaches for multi-pollutant epidemiology studies. The primary objective of the workshop was to identify and compare different statistical approaches and methods for analyzing complex chemical mixtures data in both simulated and real-world data sets. At the workshop, participants compared approaches and results and speculated as to why they may have differed. Several themes emerged: a) no one statistical approach appeared to outperform the others, b) many methods included some form of variable reduction or summation of the data before statistical analysis, c) the statistical approach should be selected based upon a specific hypothesis or scientific question, and d) related mixtures data should be shared among researchers to more comprehensively and accurately address methodological questions and statistical approaches. Future efforts should continue to design and optimize statistical approaches to address questions about chemical mixtures in epidemiological studies.

Background: Prenatal exposure to organophosphate (OP) insecticides, a widely used class of pesticides, may be associated with decreased gestational age and lower birth weight. Single nucleotide polymorphisms in paroxanase (PON1) enzyme genotypes may modify the relationships between OP exposure and perinatal outcomes. Objective: We examined the relationship of prenatal OP insecticide exposure, measured using urinary dialkyl phosphate (DAP) metabolite concentrations, with gestational age and birth weight. Methods: We measured the concentrations of six nonspecific DAP metabolites of OP insecticides in two maternal spot urine samples collected in a prospective birth cohort. We performed multivariable regression to examine associations between the sum of six DAP concentrations (ΣDAP) with gestational age and birth weight. We also examined whether these associations differed according to infant PON1192 and PON1–108 genotypes. Results: Among 306 mother–infant dyads, a 10-fold increase in ΣDAP concentrations was associated with a decrease in covariate-adjusted gestational age [–0.5 weeks; 95% confidence interval (CI): –0.8, –0.1] and birth weight (–151 g; CI: –287, –16); the decrements in birth weight were attenuated after adjusting for gestational age. The relationship between ΣDAP concentrations and gestational age was stronger for white (–0.7 weeks; CI: –1.1, –0.3) than for black (–0.1 weeks; 95% CI: –0.9, 0.6) newborns. In contrast, there was a greater decrease in birth weight with increasing urinary ΣDAP concentrations for black (–188 g; CI: –395, 19) than for white (–118 g; CI: –296, 60) newborns. Decrements in birth weight and gestational age associated with ΣDAP concentrations were greatest among infants with PON1192QR and PON–108CT genotypes. Conclusions: Prenatal urinary ΣDAP concentrations were associated with shortened gestation and reduced birth weight in this cohort, but the effects differed by race/ethnicity and PON1192/108 genotypes.

Context: Most of the U.S. population is exposed to the high-production-volume chemical bisphenol A (BPA), but targetable sources of exposure remain to be determined. Animal studies and one human st...

Summary Humans are exposed to a large number of environmental chemicals: Some of these may be toxic, and many others have unknown or poorly characterized health effects. There is intense interest in determining the impact of exposure to environmental chemical mixtures on human health. As the study of mixtures continues to evolve in the field of environmental epidemiology, it is imperative that we understand the methodologic challenges of this research and the types of questions we can address using epidemiological data. In this article, we summarize some of the unique challenges in exposure assessment, statistical methods, and methodology that epidemiologists face in addressing chemical mixtures. We propose three broad questions that epidemiological studies can address: a) What are the potential health impacts of individual chemical agents? b) What is the interaction among agents? And c) what are the health effects of cumulative exposure to multiple agents? As the field of mixtures research grows, we can use these three questions as a basis for defining our research questions and for developing methods that will help us better understand the effect of chemical exposures on human disease and well-being.

Background: Prenatal exposure to endocrine disruptors has been associated with increased risk of childhood obesity. However, epidemiologic studies on polybrominated diphenyl ethers (PBDEs) are limited despite animal studies indicating PBDEs’ potential role as an obesogen. Objectives: We investigated whether maternal concentrations of BDEs 28, 47, 99, 100, 153, and ΣPBDEs during pregnancy were associated with anthropometric measures in children aged 1–8 years. Methods: We examined 318 mother–child pairs in the Health Outcomes and Measures of the Environment (HOME) Study, a birth cohort enrolled from 2003 through 2006 (Cincinnati, OH). Serum PBDEs were measured at 16 ± 3 weeks gestation. We measured child height (1–8 years), weight (1–8 years), body mass index (BMI) (2–8 years), waist circumference (4–8 years), and body fat (8 years). To account for repeated measures, we used linear mixed models and generalized estimating equations to estimate associations between maternal PBDEs and child anthropometric measures. Results: We found no statistically significant associations between prenatal PBDEs and height or weight z-score. A 10-fold increase in maternal serum BDE-153 was associated with lower BMI z-score (β = –0.36; 95% CI: –0.60, –0.13) at 2–8 years, smaller waist circumference (β = –1.81 cm; 95% CI: –3.13, –0.50) at 4–8 years, and lower percent body fat (β = –2.37%; 95% CI: –4.21, –0.53) at 8 years. A decrease in waist circumference at 4–8 years was observed with a 10-fold increase in BDE-100 (β = –1.50 cm; 95% CI: –2.93, –0.08) and ΣPBDEs (β = –1.57 cm; 95% CI: –3.11, –0.02). Conclusions: Reverse causality may have resulted in prenatal PBDEs, particularly BDE-153, and decreased BMI, waist circumference, and body fat. Citation: Vuong AM, Braun JM, Sjödin A, Webster GM, Yolton K, Lanphear BP, Chen A. 2016. Prenatal polybrominated diphenyl ether exposure and body mass index in children up to 8 years of age. Environ Health Perspect 124:1891–1897; http://dx.doi.org/10.1289/EHP139

We are grateful for the opportunity to comment on the importance of careful interpretation and communication of epidemiological results. We concur with Burstyn et al. that scientists have a great responsibility to present their findings accurately. Indeed, scientists have a duty not only to generate research results but also to engage in dialog about the interpretation and meaning of these results. We also agree that our study on maternal smoking in pregnancy and the risk of autism spectrum disorders (ASDs) had limitations, including heterogeneous outcome groupings, residual confounding, and exposure misclassification (Kalkbrenner et al. 2012). We do not, however, share the conviction that these limitations void the validity and contribution of our study or that our results should not be accompanied with an interpretation. Our study improved upon previous studies of tobacco exposures and ASDs in several ways. It incorporated population-based data from the United States. Much of the existing body of research on this subject has been conducted in Europe where social patterns of both smoking and ASD diagnoses differ from patterns in the United States. Furthermore, adjusting for maternal education, marital status, and maternal race/ethnicity was an improvement over many previous studies that were not able to adjust for these factors. Although residual social class confounding is possible, it would more likely have masked—rather than produced—the observed elevated associations. Finally, we included a large number of children with ASD and had some phenotypic information beyond a binary ASD/non-ASD classification. By including and reporting on several ASD functional subclassifications, we performed replicates within one study, increased the transparency and completeness of reporting, and enhanced the comparability with previous reports. The consistent pattern of results across subclassifications strengthened our interpretation that the overall pattern we observed was not due wholly to biases or random error. Most puzzling to us is the null hypothesis testing approach described by Burstyn et al. in their letter, in which associations were dichotomized to conclude a “link” when confidence limits excluded the null value, or “no link” otherwise. This dichotomy of complex results is not only a grave oversimplification, but it is awash with assumptions that do not hold in observational epidemiology (Poole 2001; Savitz 1993). Instead, we prefer a more meta-analytic mindset, in which a given study is considered as a contribution to a broader literature, with the weight of contribution proportional to its precision. Valid and precise results are interpreted for their public health or clinical importance, judged by the magnitude of effect. As an illustration of the meta-analytic perspective, with no intention of definitively answering whether maternal smoking causes any subgroup of ASDs, we have performed a simple combination of results from our study (Kalkbrenner et al. 2012) with those from a similar recent population-based study of maternal smoking in pregnancy and ASDs (Lee et al. 2011). Using strict null-hypothesis testing interpretation, all original adjusted prevalence ratios support “no link” because the 95% confidence limits include the null value of 1.0 (Table 1). In contrast, a more nuanced interpretation of results, focusing on patterns of magnitude and precision, yields a conclusion that associations between maternal smoking and ASD may differ by the presence of co-occurring intellectual disabilities, consistent with the meta-analytic combined results. Table 1 Meta-analytic perspective showing adjusted prevalence ratios (95% confidence limits). In summary, the quality of our data, analytic approach, and interpretation improved upon previous studies of this important question. It is always possible to go further, and we are intrigued by the suggestion of Burstyn et al. to conduct an extended, multiple-bias sensitivity analysis. We explored the impact of underrecognition of ASD varying by social class (an important bias not previously addressed in the literature), but we did not evaluate this error together with the underreporting of tobacco use in pregnancy and residual social class confounding. The mathematical methods to explore and correct such interwoven biases are being developed and made available, opening up the possibility of better modeling these errors. This analysis should be explored in future work, and on this point perhaps we are in agreement with Burstyn et al.

In their letter, Haighton et al. recommend that we review Bradford Hill guidelines for establishing causality. As noted in our article (Sathyanarayana et al. 2011), we did not try to establish cause and effect with this single case study and cautioned against doing so. In medical research, new syndromes or toxicants have often been identified by the report of unusual cases or exposures, even though it is not always apparent with the initial case report. Thus, we believe that it is important to highlight this and other unusual cases to identify potential causative agents of neurobehavioral abnormalities in childhood. This case study does not stand in isolation; there is a growing body of animal and human literature documenting the neurodevelopmental impacts of bisphenol A (BPA) exposure (Braun et al. 2009; National Toxicology Program, Center for the Evaluation of Risks to Human Reproduction 2008; Yolton et al. 2011).

Background: Gestational phthalate and bisphenol A (BPA) exposure may increase the risk of adverse maternal/child health outcomes, but there are few data on the variability of urinary biomarkers before and during pregnancy. Objective: We characterized the variability of urinary phthalate metabolite and BPA concentrations before and during pregnancy and the ability of a single spot urine sample to classify average gestational exposure. Methods: We collected 1,001 urine samples before and during pregnancy from 137 women who were partners in couples attending a Boston fertility clinic and who had a live birth. Women provided spot urine samples before (n ≥ 2) and during (n ≥ 2) pregnancy. We measured urinary concentrations of monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-iso-butyl phthalate, monobenzyl phthalate (MBzP), four metabolites of di-(2-ethylhexyl) phthalate (DEHP), and BPA. After adjusting for specific gravity, we characterized biomarker variability using intraclass correlation coefficients (ICCs) and conducted several surrogate category analyses to determine whether a single spot urine sample could adequately classify average gestational exposure. Results: Absolute concentrations of phthalate metabolites and BPA were similar before and during pregnancy. Variability was higher during pregnancy than before pregnancy for BPA and MBzP, but similar during and before pregnancy for MBP, MEP, and ΣDEHP. During pregnancy, MEP (ICC = 0.50) and MBP (ICC = 0.45) were less variable than BPA (ICC = 0.12), MBzP (ICC = 0.25), and ΣDEHP metabolites (ICC = 0.08). Surrogate analyses suggested that a single spot urine sample may reasonably classify MEP and MBP concentrations during pregnancy, but more than one sample may be necessary for MBzP, DEHP, and BPA. Conclusions: Urinary phthalate metabolites and BPA concentrations were variable before and during pregnancy, but the magnitude of variability was biomarker specific. A single spot urine sample adequately classified MBP and MEP concentrations during pregnancy. The present results may be related to unique features of the women studied, and replication in other pregnancy cohorts is recommended.

Background Prenatal bisphenol A (BPA) exposure may be associated with developmental toxicity, but few studies have examined the variability and predictors of urinary BPA concentrations during pregnancy. Objective Our goal was to estimate the variability and predictors of serial urinary BPA concentrations taken during pregnancy. Methods We measured BPA concentrations during pregnancy and at birth in three spot urine samples from 389 women. We calculated the intraclass correlation coefficient (ICC) to assess BPA variability and estimated associations between log10-transformed urinary BPA concentrations and demographic, occupational, dietary, and environmental factors, using mixed models. Results Geometric mean (GM) creatinine-standardized concentrations (micrograms per gram) were 1.7 (16 weeks), 2.0 (26 weeks), and 2.0 (birth). Creatinine-standardized BPA concentrations exhibited low reproducibility (ICC = 0.11). By occupation, cashiers had the highest BPA concentrations (GM: 2.8 μg/g). Consuming canned vegetables at least once a day was associated with higher BPA concentrations (GM = 2.3 μg/g) compared with those consuming no canned vegetables (GM = 1.6 μg/g). BPA concentrations did not vary by consumption of fresh fruits and vegetables, canned fruit, or store-bought fresh and frozen fish. Urinary high-molecular-weight phthalate and serum tobacco smoke metabolite concentrations were positively associated with BPA concentrations. Conclusions These results suggest numerous sources of BPA exposure during pregnancy. Etiological studies may need to measure urinary BPA concentrations more than once during pregnancy and adjust for phthalates and tobacco smoke exposures.

Background Prenatal exposure to bisphenol A (BPA) increases offspring aggression and diminishes differences in sexually dimorphic behaviors in rodents. Objective We examined the association between prenatal BPA exposure and behavior in 2-year-old children. Methods We used data from 249 mothers and their children in Cincinnati, Ohio (USA). Maternal urine was collected around 16 and 26 weeks of gestation and at birth. BPA concentrations were quantified using high-performance liquid chromatography–isotope-dilution tandem mass spectrometry. Child behavior was assessed at 2 years of age using the second edition of the Behavioral Assessment System for Children (BASC-2). The association between prenatal BPA concentrations and BASC-2 scores was analyzed using linear regression. Results Median BPA concentrations were 1.8 (16 weeks), 1.7 (26 weeks), and 1.3 (birth) ng/mL. Mean (± SD) BASC-2 externalizing and internalizing scores were 47.6 ± 7.8 and 44.8 ± 7.0, respectively. After adjustment for confounders, log10-transformed mean prenatal BPA concentrations were associated with externalizing scores, but only among females [β = 6.0; 95% confidence interval (CI), 0.1–12.0]. Compared with 26-week and birth concentrations, BPA concentrations collected around 16 weeks were more strongly associated with externalizing scores among all children (β = 2.9; 95% CI, 0.2–5.7), and this association was stronger in females than in males. Among all children, measurements collected at ≤ 16 weeks showed a stronger association (β = 5.1; 95% CI, 1.5–8.6) with externalizing scores than did measurements taken at 17–21 weeks (β = 0.6; 95% CI, −2.9 to 4.1). Conclusions These results suggest that prenatal BPA exposure may be associated with externalizing behaviors in 2-year-old children, especially among female children.

Conduct disorder (CD) is characterized by persistent behavioral patterns that violate social rules and the rights of individuals (American Psychiatric Association 2000). Children with CD display aggression toward people and animals, intentionally destroy others’ property, and chronically steal or deceive. Children with CD are at increased risk for drug and alcohol abuse, antisocial personality disorder, and anxiety-related disorders (Goldstein et al. 2006; Gunter et al. 2006). Public expenditures related to general and mental health care, school services, and juvenile justice for children with CD exceed $10,000 per child per year (Foster and Jones 2005). The national prevalence of CD is unknown. It is estimated from community-based regional samples that 0.4–3.3% of children and adolescents have CD, with males two to three times more likely than females to receive a CD diagnosis (Lahey et al. 2000; Loeber et al. 2000; Maughan et al. 2004). Prior variation in CD prevalence estimates may be related to the informant, the diagnostic instrument, the version of Diagnostic and Statistical Manual of Mental Disorders (DSM) used (3rd ed., 3rd ed. rev., or 4th ed.), participants’ age, socioeconomic status, and degree of urbanicity (Loeber et al. 2000). To date, no studies have provided an estimate of the national prevalence of CD in U.S. children using criteria of the 4th edition of the DSM (DSM-IV; American Psychiatric Association 2000). Questions also persist about the underlying risk factors for the development of CD (Burke et al. 2002). Prenatal tobacco smoke exposure has been consistently associated with disruptive behavior disorders, such as oppositional defiant disorder and CD, even after controlling for potential confounders, including sociodemographic factors, prenatal insults, and parental psychopathology (Fergusson et al. 1993, 1998; Wakschlag et al. 1997, 2002; Weissman et al. 1999). Results from a prospective cohort in New Zealand indicate that children exposed to tobacco smoke in utero had CD symptom rates approximately two times higher than unexposed children (Fergusson et al. 1998). Another prospective study of approximately 6,000 Finnish males found that prenatal tobacco smoke exposure was associated with a 1.74-fold increased odds of committing a delinquent act in late childhood or early adulthood (Rantakallio et al. 1992). Although prior studies have documented associations between prenatal tobacco smoke exposure and CD, the relationship between postnatal environmental tobacco smoke (ETS) exposure and CD is less clear (Fergusson et al. 1998; Weitzman et al. 1992). Weitzman et al. (1992) reported significant increases in the number of behavior problems among children whose mothers smoked only after pregnancy. Compared with children of nonsmoking women, children exposed to postnatal ETS had a 2-fold increased odds of having extreme behavior problems on the Behavior Problem Index of the Child Behavior Checklist (CBCL) (Weitzman et al. 1992). Similarly, in a New Zealand cohort, Fergusson et al. (1998) found an increased number of CD symptoms among children exposed to post-natal ETS. To date, none of these studies has used a biomarker of tobacco smoke exposure to measure the association between ETS and behavior problems. This limitation can result in exposure misclassification, because a substantial proportion of women who report no ETS exposure have measurable cotinine levels (DeLorenze et al. 2002). The relationship between environmental lead exposure and violent, aggressive, and oppositional behavior was first reported by Byers and Lord (1943). They observed that among 20 lead-poisoned children, 19 who had “recovered” from lead poisoning failed high school or had behavioral problems. Since then, elevated bone and blood lead levels have been associated with an increased risk of juvenile delinquency in late childhood and early adulthood in case–control and prospective cohort studies (Dietrich et al. 2001; Needleman et al. 1996, 2002). Earlier studies observed children with higher blood lead levels than the levels currently seen; thus, inferences may not be directly relevant to contemporary children with lower blood lead levels (Dietrich et al. 2001; Needleman et al. 1996, 2002). Additionally, recent studies have observed associations between blood lead levels below the current Centers for Disease Control and Prevention recommended action level of 10 μg/dL and cognitive and behavioral deficits (Braun et al. 2006; Lanphear et al. 2005). It is unclear whether lower blood lead levels are associated with more severe behavioral problems such as CD in children. The purpose of this study was to provide an estimate of the national prevalence of CD defined using DSM-IV criteria and to test the hypothesis that exposures to ETS and childhood lead exposure were associated with CD in a large nationally representative sample of U.S. children.

Objective The purpose of this study was to examine the association of exposures to tobacco smoke and environmental lead with attention deficit hyperactivity disorder (ADHD). Methods Data were obtained from the National Health and Nutrition Examination Survey 1999-2002. Prenatal and postnatal tobacco exposure was based on parent report; lead exposure was measured using blood lead concentration. ADHD was defined as having current stimulant medication use and parent report of ADHD diagnosed by a doctor or health professional. Results Of 4,704 children 4-15 years of age, 4.2% were reported to have ADHD and stimulant medication use, equivalent to 1.8 million children in the United States. In multivariable analysis, prenatal tobacco exposure [odds ratio (OR) = 2.5; 95% confidence interval (CI), 1.2-5.2] and higher blood lead concentration (first vs. fifth quintile, OR = 4.1; 95% CI, 1.2-14.0) were significantly associated with ADHD. Postnatal tobacco smoke exposure was not associated with ADHD (OR = 0.6; 95% CI, 0.3-1.3; p = 0.22). If causally linked, these data suggest that prenatal tobacco exposure accounts for 270,000 excess cases of ADHD, and lead exposure accounts for 290,000 excess cases of ADHD in U.S. children. Conclusions We conclude that exposure to prenatal tobacco and environmental lead are risk factors for ADHD in U.S. children.