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BACKGROUND: In environmental epidemiology, we use an array of tools from various, related disciplines to answer key questions about environmental exposures in relation to health outcomes. Typically, we ask questions related to what, who, where, when, and how. We value these questions because they contribute to novel scientific discovery and our understanding of disease etiology linked to environmental exposures. In addition, these questions help us better understand who might be at highest risk of exposure and subsequent risk of disease. Although necessary for the goals of environmental epidemiology, these questions are insufficient for addressing environmental health disparities. Specifically, these questions may be able to help us describe exposure-health outcome associations but are limited in their ability to move beyond identification to intervening on observed disparities to achieve environmental health equity. OBJECTIVES: We sought to emphasize the need to value and routinely add the key question of 'Why?' in environmental epidemiological studies. In asking this additional critical question, we can identify and incorporate the structural determinants and drivers of environmental exposure disparities and determine whether these factors are linked to existing and historically recalcitrant health disparities. Further, we can design effective studies that build on existing frameworks to address the fundamental causes of environmental health disparities. DISCUSSION: This commentary underscores the need to routinely incorporate 'why' questions in the practice of environmental epidemiology. By asking and addressing 'Why?' we can employ better, more solution-oriented study designs, improve data collection, and enhance our ability to collaborate with diverse study populations through trust-building and community-engaged research. Incorporating these approaches will move environmental epidemiology forward from mostly documenting to actively addressing environmental health disparities. https://doi.org/10.1289/EHP14513, Introduction Environmental epidemiology addresses the role of environmental factors as predictors of disease risk and prevention. The goal is to evaluate associations between a given environmental risk factor, patterns of [...]

BACKGROUND: Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity. OBJECTIVES: Our study aimed to estimate associations between prenatal exposure to OPEs and fetal growth, including both ultrasound (head circumference, abdominal circumference, femur length, and estimated fetal weight) and delivery [birth weight z-score, small-for-gestational age (SGA), and large-for-gestational age (LGA)] measures of growth. METHODS: In the LIFECODES Fetal Growth Study (2008-2018), an enriched case--cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models. RESULTS: Most OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; 1.31 ng=mL) increase in bis(2-chloroethyl) phosphate concentration was associated with larger z-scores in head circumference [mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17], abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: -0.08, 0.17). At delivery, an IQR (1.00 ng=mL) increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94). CONCLUSIONS: In a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. https://doi.org/10.1289/EHP14647, Introduction Organophosphate esters (OPEs) are high-production chemicals in widespread global use. (1) They are organic esters of phosphoric acid--containing alkyl chains or aryl groups, which may be halo-genated or nonhalogenated. [...]

Background: Widespread exposure to organophosphate ester (OPE) flame retardants with potential reproductive toxicity raises concern regarding the impacts of gestational exposure on birth outcomes. Previous studies of prenatal OPE exposure and birth outcomes had limited sample sizes, with inconclusive results. Objectives: We conducted a collaborative analysis of associations between gestational OPE exposures and adverse birth outcomes and tested whether associations were modified by sex. Methods: We included 6,646 pregnant participants from 16 cohorts in the Environmental influences on Child Health Outcomes (ECHO) Program. Nine OPE biomarkers were quantified in maternal urine samples collected primarily during the second and third trimester and modeled as [log.sub.2]-transformed continuous, categorized (high/low/nondetect), or dichotomous (detect/nondetect) variables depending on detection frequency. We used covariate-adjusted linear, logistic, and multinomial regression with generalized estimating equations, accounting for cohort-level clustering, to estimate associations of OPE biomarkers with gestational length and birth weight outcomes. Secondarily, we assessed effect modification by sex. Results: Three OPE biomarkers [diphenyl phosphate (DPHP), a composite of dibutyl phosphate and di-isobutyl phosphate (DBUP/DIBP), and bis (1,3-dichloro-2-propyl) phosphate] were detected in >85% of participants. In adjusted models, DBUP/DIBP [odds ratio (OR) per doubling=1.07; 95% confidence interval (CI): 1.02, 1.12] and bis(butoxyethyl) phosphate (OR for high vs. nondetect= 1.25; 95% CI: 1.06, 1.46), but not other OPE biomarkers, were associated with higher odds of preterm birth. We observed effect modification by sex for associations of DPHP and high bis(2chloroethyl) phosphate with completed gestational weeks and odds of preterm birth, with adverse associations among females. In addition, newborns of mothers with detectable bis(1-chloro-2-propyl) phosphate, bis(2-methylphenyl) phosphate, and dipropyl phosphate had higher birth weight-forgestational-age z-scores (b for detect vs. nondetect = 0.04-0.07); other chemicals showed null associations. Discussion: In the largest study to date, we find gestational exposures to several OPEs are associated with earlier timing of birth, especially among female neonates, or with greater fetal growth. https://doi.org/10.1289/EHP13182, Introduction Organophosphate esters (OPEs) have been increasingly used as flame retardants over the last decade as polybrominated diphenyl ether (PBDE) flame retardants were phased out in the mid-2000s over concerns [...]

BACKGROUND: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth. OBJECTIVES: We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity. METHODS: We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate- adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/ Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity- stratified logistic regression to characterize associations between phthalate metabolites and preterm birth. RESULTS: In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants. CONCLUSIONS: Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831, Introduction Preterm birth is a major cause of neonatal mortality and morbidity that may perpetuate impacts on intergenerational health. (1) In the United States, preterm birth rates increased over the [...]

Background: Ambient air pollution may be a developmental endocrine disruptor. In animal models, gestational and perinatal exposure to diesel exhaust and concentrated particulate matter alters anogenital distance (AGD), a marker of prenatal androgen activity, in both sexes. Little is known in humans. Objectives: We examined exposure to fine particulate matter (P[M.sub.2.5]) and nitrogen dioxide (N[O.sub.2]) in relation to human AGD at birth and at 1 year of age, focusing on exposures during critical windows of reproductive development: the male programming window (MPW; gestational weeks 8-14) and mini-puberty (postnatal months 1-3). Methods: The Infant Development and Environment Study (TIDES) recruited first trimester pregnant women (n = 687) at four U.S. sites (Minneapolis, Minnesota; Rochester, New York; San Francisco, California; and Seattle, Washington) from 2010 to 2012. We measured anus to clitoris (AGD-AC) and anus to fourchette (AGD-AF) in female infants at birth; in males, we measured anus to penis (AGD-AP), anus to scrotum (AGDAS), and penile width at birth and at 1 year of age. Using advanced spatiotemporal models, we estimated maternal exposure to P[M.sub.2.5] and N[O.sub.2] in the MPW and mini-puberty. Covariate-adjusted, sex-stratified linear regression models examined associations between P[M.sub.2.5] and N[O.sub.2] and AGD. Results: In males, a 1-[micro]g/[m.sup.3] increase in P[M.sub.2.5] exposure during the MPW was associated with shorter AGD at birth, but a longer AGD at 1 year of age (e.g., birth AGD-AP: [beta] = -0,35 mm; 95% CI: -0,62, -0,07; AGD-AS: [beta] = 0,37 mm; 95% CI: 0.02, 0.73). Mini- pubertal P[M.sub.2.5] exposure was also associated with shorter male AGD-AP ([beta] = -0,50 mm; 95% CI: -0,89, - 0,11) at 1 year of age. Although not associated with male AGD measures, 1-ppb increases in N[O.sub.2] exposure during the MPW ([beta] = -0,07 mm; 95% CI: -0,02, -0,12) and mini-puberty ([beta] = -0,04 mm; 95% CI: -0,08, 0.01) were both associated with smaller penile width at 1 year of age. Results were similar in multipollutant models, where we also observed that in females AGD-AC was inversely associated with P[M.sub.2.5] exposure, but positively associated with N[O.sub.2] exposure. Discussion: P[M.sub.2.5] and N[O.sub.2] exposures during critical pre- and postnatal windows may disrupt reproductive development. More work is needed to confirm these novel results and clarify mechanisms. https://doi.org/10.1289/EHP12627, Introduction Together, indoor and outdoor air pollution are estimated to account for 7 million deaths worldwide per year, mostly due to respiratory and cardiovascular diseases, including lung cancer, heart disease, [...]

Background: Population studies support the adverse associations of air pollution exposures with child behavioral functioning and cognitive performance, but few studies have used spatiotemporally resolved pollutant assessments. Objectives: We investigated these associations using more refined exposure assessments in 1,967 mother-child dyads from three U.S. pregnancy cohorts in six cities in the ECHO-PATHWAYS Consortium. Methods: Pre- and postnatal nitrogen dioxide (N[O.sub.2]) and particulate matter (PM) [less than or equal to]2.5 [micro]m in aerodynamic diameter (P[M.sub.2.5]) exposures were derived from an advanced spatiotemporal model. Child behavior was reported as Total Problems raw score using the Child Behavior Checklist at age 4-6 y. Child cognition was assessed using cohort-specific cognitive performance scales and quantified as the Full-Scale Intelligence Quotient (IQ). We fitted multivariate linear regression models that were adjusted for sociodemographic, behavioral, and psychological factors to estimate associations per 2-unit increase in pollutant in each exposure window and examined modification by child sex. Identified critical windows were further verified by distributed lag models (DLMs). Results: Mean N[O.sub.2] and P[M.sub.2.5] ranged from 8.4 to 9.0ppb and 8.4 to 9.1 [micro]g/[m.sup.3], respectively, across pre- and postnatal windows. Average child Total Problems score and IQ were 22.7 [standard deviation (SD): 18.5] and 102.6 (SD: 15.3), respectively. Children with higher prenatal N[O.sub.2] exposures were likely to have more behavioral problems [[beta]: 1.24; 95% confidence interval (CI): 0.39, 2.08; per 2 ppb N[O.sub.2]], particularly N[O.sub.2] in the first and second trimester. Each 2-[micro]g/[m.sup.3] increase in P[M.sub.2.5] at age 2-4 y was associated with a 3.59 unit (95% CI: 0.35, 6.84) higher Total Problems score and a 2.63 point (95% CI: -5.08, -0.17) lower IQ. The associations between P[M.sub.2.5] and Total Problems score were generally stronger in girls. Most predefined windows identified were not confirmed by DLMs. Discussion: Our study extends earlier findings that have raised concerns about impaired behavioral functioning and cognitive performance in children exposed to N[O.sub.2] and P[M.sub.2.5] in utero and in early life. https://doi.org/10.1289/EHP10248, Introduction Early brain morphology in humans begins in the third week post conception and rapidly develops by midgestation. (1-3) Ongoing structural change and functional development continue for an extended period [...]

Objectives The main objective of the PERI-HELPE study (Perception of Risk-HEaLth Professionals and Environment Study) was to describe the knowledge of perinatal health professionals about phthalates and the preventive advice they give to pregnant women about exposure to these chemicals. The secondary objective was to determine whether giving preventive advice was associated with the perception of phthalates. Methods A cross-sectional study was performed in 2015 in France. One hundred and eighty-nine perinatal health professionals (obstetricians, midwives and general practitioners) replied to an online self-administered questionnaire (participation rate: 11%). Results Only 17% of health professionals felt able to provide appropriate answers to pregnant women about phthalates. Advice was given by 23% (avoid plastic kitchen cling film) to 75% (prefer homemade dishes) about eating habits, by less than 42% for the use of cosmetics and less than 25% for that of consumer products. After adjusting for covariates, the awareness that pregnant women are daily exposed to phthalates (44% of professionals) was associated with dietary advice [avoid pre-packaged food (OR 2.2; 95% CI 1.1-4.4), prefer homemade dishes (OR 2.6; 95% CI 1.2-5.9) and avoid plastic kitchen cling film (OR 2.4; 95% CI 1.0-5.6)] but not with advice about cosmetics or consumer products. The perception of phthalate exposure as a high risk (66%) was not associated with preventive advice. Conclusions for Practice Our sample size was not very large but the findings nevertheless show the lack of knowledge of perinatal health professionals about phthalates. If they are to take on a preventive role, health professionals in France need to be better informed about phthalates and more fully trained in environmental health in general., Author(s): Cécile Marie [sup.1] , Didier Lémery [sup.2] [sup.3] , Françoise Vendittelli [sup.2] [sup.3] , Marie-Pierre Sauvant-Rochat [sup.4] Author Affiliations: (Aff1) Université Clermont Auvergne, CNRS, SIGMA Clermont, Institut Pascal, CHU [...]

Background: Prenatal phthalate exposure has been associated with lower birth weight but also higher weight in childhood. Few studies have examined weight or adiposity from birth to childhood and thus cannot assess growth trajectories associated with exposure. OBJECTIVE: We assessed associations between maternal phthalate exposures in pregnancy and child weight and adiposity measured prenatally through childhood (3-6 years of age). Methods: Within The Infant Development and the Environment Study (TIDES), a prospective pregnancy cohort, we analyzed a panel of phthalate metabolites in urine collected at two visits from early and late gestation (N = 780). We estimated average phthalate metabolite associations with child weight z-scores from ~ 20 wk gestation (estimated by ultrasound), birth, and 1,3,4, and 6 years of age using linear mixed- effects (LME) models. We also modeled associations with adiposity z-scores from birth (weight for length) and 1,3,4, and 6 years of age [body mass index (BMI)] using LME models. Results: For weight, we observed inverse associations between several phthalate metabolites and birth weight z-scores, but no associations were observed with postnatal weight z-scores in LME models. Regarding adiposity, we observed inverse associations between phthalate metabolites and weight-for-length z-scores at birth, but positive associations were observed with BMI z-scores at 3-4 years of age in LME models. For example, mono-ethyl phthalate was associated with a 0.17-unit decrease in birth weight-for-length z-score [95% confidence interval (CI): -0.29, -0.05] and a 0.18-unit increase in 4-years-of-age BMI z-score (95% CI: 0.04, 0.32). Discussion: We observed associations between prenatal exposure to phthalates and lower weight at birth but not at childhood follow-up visits. However, for adiposity, we observed an interesting pattern of association with low adiposity at delivery as well as high adiposity at 3-4 years of age. Although it is not clear from our results whether these associations occur within the same children, such a pattern of adiposity in early life has been linked to cardiometabolic disease in adulthood and deserves special attention as an outcome in the study of prenatal exposures in the developmental origins of health and disease. https://doi.org/10.1289/EHP10077, Introduction Phthalates are found ubiquitously in the environment in personal care products, food and beverage packaging materials, and vinyl products. Prenatal exposure to some phthalates has been associated with lower [...]

BACKGROUND: Phthalates are commonly used endocrine-disrupting chemicals that are ubiquitous in the general population. Prenatal phthalate exposure may alter placental physiology and fetal development, leading to adverse perinatal and childhood health outcomes. OBJECTIVE: We examined associations between prenatal phthalate exposure in the second and third trimesters and the placental transcriptome at birth, including genes and long noncoding RNAs (lncRNAs), to gain insight into potential mechanisms of action during fetal development. METHODS: The ECHO PATHWAYs consortium quantified 21 urinary phthalate metabolites from 760 women enrolled in the CANDLE study (Shelby County, TN) using high-performance liquid chromatography-tandem mass spectrometry. Placental transcriptomic data were obtained using paired-end RNA sequencing. Linear models were fitted to estimate separate associations between maternal urinary phthalate metabolite concentration during the second and third trimester and placental gene expression at birth, adjusted for confounding variables. Genes were considered differentially expressed at a Benjamini-Hochberg false discovery rate (FDR) p < 0.05. Associations between phthalate metabolites and biological pathways were identified using self-contained gene set testing and considered significantly altered with an FDR-adjusted p < 0.2. RESULTS: We observed significant associations between second-trimester phthalate metabolites mono (carboxyisooctyl) phthalate (MCIOP), mono-2ethyl-5-carboxypentyl phthalate, and mono-2-ethyl-5-oxohexyl phthalate and 18 genes in total, including four lncRNAs. Specifically, placental expression of NEAT1 was associated with multiple phthalate metabolites. Third-trimester MCIOP and mono-isobutyl phthalate concentrations were significantly associated with placental expression of 18 genes and two genes, respectively. Expression of genes within 27 biological pathways was associated with mono-methyl phthalate, MCIOP, and monoethyl phthalate concentrations. DISCUSSION: To our knowledge, this is the first genome-wide assessment of the relationship between the placental transcriptome at birth and prenatal phthalate exposure in a large and diverse birth cohort. We identified numerous genes and lncRNAs associated with prenatal phthalate exposure. These associations mirror findings from other epidemiological and in vitro analyses and may provide insight into biological pathways affected in utero by phthalate exposure. https://doi.org/10.1289/EHP8973, Introduction Phthalates are ubiquitous chemicals used as plasticizers in numerous consumer products, leading to pervasive human exposure (Ferguson et al. 2014; Sathyanarayana 2008). Parent phthalate compounds undergo hydrolysis to monoesters, [...]

Background: Prenatal exposures to endocrine-disrupting chemicals (EDCs) during critical developmental windows have been implicated in the etiologies of a wide array of adverse perinatal and pediatric outcomes. Epidemiological studies have concentrated on the health effects of individual chemicals, despite the understanding that EDCs act together via common mechanisms, that pregnant women are exposed to multiple EDCs simultaneously, and that substantial toxicological evidence of adverse developmental effects has been documented. There is a move toward multipollutant models in environmental epidemiology; however, there is no current consensus on appropriate statistical methods. Objectives: We aimed to review the statistical methods used in these studies, to identify additional applicable methods, and to determine the strengths and weaknesses of each method for addressing the salient statistical and epidemiological challenges. Methods: We searched Embase, MEDLINE, and Web of Science for epidemiological studies of endocrine-sensitive outcomes in the children of mothers exposed to EDC mixtures during pregnancy and identified alternative statistical methods from the wider literature. Discussion: We identified 74 studies and analyzed the methods used to estimate mixture health effects, identify important mixture components, account for nonmonotonicity in exposure-response relationships, assess interactions, and identify windows of exposure susceptibility. We identified both frequentist and Bayesian methods that are robust to multicollinearity, performing shrinkage, variable selection, dimension reduction, statistical learning, or smoothing, including methods that were not used by the studies included in our review. Conclusions: Compelling motivation exists for analyzing EDCs as mixtures, yet many studies make simplifying assumptions about EDC additivity, relative potency, and linearity, or overlook the potential for bias due to asymmetries in chemical persistence. We discuss the potential impacts of these choices and suggest alternative methods to improve analyses of prenatal exposure to EDC mixtures. https://doi.org/10.1289/EHP2207, Introduction A growing body of evidence suggests that prenatal exposures to environmental chemicals during critical windows of development may have lasting effects throughout the life course (Gillman 2005; Soto et [...]

BACKGROUND: Phthalates are used as plasticizers in soft polyvinyl chloride (PVC) and in a large number of consumer products. Because of reported health risks, diisononyl phthalate (DiNP) has been introduced as a replacement for di(2-ethylhexyl) phthalate (DEHP) in soft PVC. This raises concerns because animal data suggest that DiNP may have antiandrogenic properties similar to those of DEHP. The anogenital distance (AGD)--the distance from the anus to the genitals--has been used to assess reproductive toxicity. OBJECTIVE: The objective of this study was to examine the associations between prenatal phthalate exposure and AGD in Swedish infants. METHODS: AGD was measured in 196 boys at 21 months of age, and first-trimester urine was analyzed for 10 phthalate metabolites of DEP (diethyl phthalate), DBP (dibutyl phthalate), DEHP, BBzP (benzylbutyl phthalate), as well as DiNP and creatinine. Data on covariates were collected by questionnaires. RESULTS: The most significant associations were found between the shorter of two AGD measures (anoscrotal distance; AGDas) and DiNP metabolites and strongest for oh-MMeOP [mono(4-methyl-7-hydroxyloctyl) phthalate] and oxo-MMeOP [mono-(2-ethyl-5-oxohexyl) phthalate]. However, the AGDas reduction was small (4%) in relation to more than an interquartile range increase in DiNP exposure. CONCLUSIONS: These findings call into question the safety of substituting DiNP for DEHP in soft PVC, particularly because a shorter male AGD has been shown to relate to male genital birth defects in children and impaired reproductive function in adult males and the fact that human levels of DiNP are increasing globally. citation: Bornehag CG, Carlstedt F, Jonsson BA, Lindh CH, Jensen TK, Bodin A, Jonsson C, Janson S, Swan SH. 2015. Prenatal phthalate exposures and anogenital distance in Swedish boys. Environ Health Perspect 123:101-107; http://dx.doi.org/ 10.1289/ehp.1408163, Introduction Diesters of 1,2-benzenedicarboxylic acid (phthalic acid), commonly referred to as phthalates, belong to a group of chemicals with endocrine-disrupting properties, meaning that they can interfere with our normal hormonal [...]

We assessed the effects of prenatal exposure to environmental tobacco smoke on fetal growth and length of gestation. The study population consisted of 389 nonsmoking women who were selected from [...]