Gestational exposure to organophosphate ester flame retardants and risk of childhood obesity in the environmental influences on child health outcomes consortium.

INTRODUCTION: Organophosphate esters (OPEs) are increasing in use as flame retardants and plasticizers and concerns have been raised given their endocrine-disrupting activities and possible obesogenic consequences. However, longitudinal studies on gestational OPE exposure and childhood obesity are scarce. This study examined whether OPE levels in maternal urine during pregnancy were associated with the risk of childhood obesity. METHODS: OPEs were analyzed in pregnancy urine samples of 5,087 individuals from 14 studies contributing to the Environmental influences on Child Health Outcomes (ECHO) Cohort. BDCPP, DBUP/DIBP, and DPHP, detected in > 80 % of the samples, were modeled continuously and by tertiles; whereas BCPP, BBOEP, and BCETP, detected in 50-80 % of samples, were modeled categorically (not-detected, low, and high). Childhood obesity was defined by BMI z-score ≥ 95th percentile according to WHO (<2 years) and the CDC (≥2 years) metrics. Adjusted modified Poisson regression models assessed childhood obesity risk and the mixture effect was assessed using Bayesian kernel machine regression (BKMR). RESULTS: BMI measurements were available for 3,827 children in infancy (0.5-1.9 years), 3,921 children in early childhood (2.0-4.9 years), and 2,541 children in mid-childhood (5.0-10.0 years). Obesity was present in 16-21 % of children across age groups. In mid-childhood DBUP/DIBP second and third versus first tertiles were associated with increased obesity risk (RR 1.14; 95 % CI: 1.02, 1.28; and RR 1.11; 95 % CI: 0.97, 1.27; respectively); whereas BDCPP second and third versus first tertiles reflected an inverse association with obesity risk (RR 0.85; 95 % CI: 0.80, 0.91 and RR 0.91; 95 % CI: 0.77, 1.07; respectively). No association with obesity risk was observed for DPHP, BCPP, BBOEP, and BCETP. Directions observed were consistent with those seen in BKMR models. CONCLUSIONS: This study identified mixed associations between gestational OPE exposure and childhood obesity. Further investigation across a comprehensive range of OPE exposures is warranted.

Gestational exposure to organophosphate esters and autism spectrum disorder and other non-typical development in a cohort with elevated familial likelihood.

BACKGROUND: Gestational exposure to organophosphate esters (OPEs) is known to affect offspring neurodevelopment in animal studies. However, epidemiological evidence is inconsistent. METHODS: Participants were 277 mother-child pairs from MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a cohort with elevated familial likelihood of autism spectrum disorder (ASD). Nine OPE biomarker concentrations were quantified in maternal urine collected during the 2nd or 3rd trimesters of pregnancy. At age 3 years, children underwent clinical assessment for ASD and were classified into ASD, other non-typical development (non-TD), or typical development (TD). Multinomial logistic regression was used to estimate associations between each OPE biomarker and relative risk ratios for ASD and non-TD compared to TD. We examined effect modification by child sex and socioeconomic status. We also conducted a secondary analysis by using a continuous measure of ASD symptom severity as an outcome. Quantile-based g-computation was performed to examine the associations for an OPE mixture. RESULTS: Overall, no significant association was observed between the concentrations of each OPE biomarker or their mixture and relative risk for either ASD or non-TD. Effect modifications by child sex and maternal education were not observed. When the analysis was stratified by homeownership, among non-homeowners, ASD likelihood was increased with increased levels of bis(1-chloro-2-propyl) phosphate, bis(butoxyethyl) phosphate, and sum of di-n-butyl phosphate and di-iso-butyl phosphate (DBUP/DIBP) (pint < 0.10). Higher DBUP/DIBP were associated with increased ASD symptom severity scores. CONCLUSION: There was no clear evidence of gestational OPE exposure in association with relative risk for ASD; however, potential effect modification by homeownership was observed. Although our cohort includes children with elevated familial likelihood of ASD, this is the first study investigating the association between gestational OPE exposure and clinically-diagnosed ASD. Further research is needed to confirm our findings in the general population.

Personal air sampling for pesticides in the California San Joaquin Valley.

BACKGROUND: California is a leading agricultural state and with that, has significant applications of pesticides. Levels of exposure have been measured to be higher among residents in agricultural areas, but measures of personal inhalation exposure to a wide range of pesticides are lacking. Community members in the San Joaquin Valley have expressed concern over pesticide exposures. Working with community members, a wide range of pesticides in personal air samples were measured. METHODS: Adult and school-aged participants were recruited from small agricultural towns in the San Joaquin Valley. Participants wore a backpack sampler for 8-14 h on 1-3 days. Samples were collected on two tubes, one with Tenax-TA resin and the other with XAD-2 resin. In total, 21 pesticides were analyzed using both LC/MS and GC/MS methods. RESULTS: Thirty-one adult participants and 11 school aged participants were recruited, and sampling occurred on a total of 92 days. Seven adults, 22% of adult participants, and one school child had detectable levels of at least one pesticide. Pesticides detected above the limit of detection were 1,3-dichloropropene, chlorpyrifos, pyrimethanil, burprofezin and penthiopyrad. When these samples were collected, chlorpyrifos was not permitted to be used in California. IMPACT STATEMENT: California, a leading agricultural state, has significant pesticide use, leading to concern about exposures among community members. Thirty-one adult and 11 school aged participants wore personal air sampling backpacks from 1-3 days. Twenty-two percent of adult participants had detectable levels of at least one pesticide. Two pesticides with established toxicity, 1,3-dichloropropene and chlorpyrifos were detected, along with first time measurements of pyrimethanil, burprofezin and penthiopyrad in the United States, which all have potential indications of toxicity. This study suggests the need to expand which pesticides are measured in agricultural communities.

Reliability of a short diet and vitamin supplement questionnaire for retrospective collection of maternal nutrient intake.

Background: Gestational nutrition can protect against adverse neurodevelopmental outcomes. Objectives: We developed a short tool for collecting maternal nutritional intake during pregnancy to facilitate research in this area and compared its retrospective use to prospectively-collected food frequency questionnaires (FFQ). Methods: Maternal nutritional intake was retrospectively assessed using three versions (full interview, full self-administered online, and shortened interview) of the Early Life Exposure Assessment Tool (ELEAT) among participants of the MARBLES pregnancy cohort study of younger siblings of autistic children. Retrospective responses were compared with responses to supplement questions and the validated 2005 Block FFQ prospectively collected in MARBLES during pregnancies 2-7 years prior. ELEAT nutrient values were calculated using reported food intake frequencies and nutrient values from the USDA nutrient database. Correlations between retrospectively- and prospectively-reported intake were evaluated using Kappa coefficients, Youden's J, and Spearman Rank Correlation Coefficients (rs). Results: MARBLES FFQ dietary intakes were compared among 54 women who completed the ELEAT full form including 12 online, and among 23 who completed the ELEAT short form. Correlations across most foods were fair to moderate. Most ELEAT quantified nutrient values were moderately correlated (rs = 0.3-0.6) with those on the Block FFQ. Supplement questions in both MARBLES and the ELEAT were completed by 114 women. Kappas were moderate for whether or not supplements were taken, but modest for timing. Correlations varied by version and child diagnosis or concerns, and were higher when mothers completed the ELEAT when their child was 4 years old or younger. Conclusions: With recall up to several years, ELEAT dietary and supplement module responses were modestly to moderately reliable and produced nutrient values moderately correlated with prospectively-collected measures. The ELEAT dietary and vitamin supplements modules can be used to rank participants in terms of intake of several nutrients relevant for neurodevelopment.

Exposure to endocrine disrupting chemicals including phthalates, phenols, and parabens in infancy: Associations with neurodevelopmental outcomes in the MARBLES study.

BACKGROUND: Endocrine disrupting chemicals (EDCs) are widely used compounds with the potential to affect child neurodevelopmental outcomes including autism spectrum disorders (ASD). We aimed to examine the urinary concentrations of biomarkers of EDCs, including phthalates, phenols, and parabens, and investigate whether exposure during early infancy was associated with increased risk of later ASD or other non-typical development (Non-TD) or adverse cognitive development. METHODS: This analysis included infants from the Markers of Autism Risks in Babies-Learning Early Signs (MARBLES) study, a high-risk ASD cohort (n = 148; corresponding to 188 urine samples). Thirty-two EDC biomarkers were quantified in urine among infants 3 and/or 6 months of age. Trends in EDC biomarker concentrations were calculated using least square geometric means. At 36 months of age, children were clinically classified as having ASD (n = 36), nontypical development (Non-TD; n = 18), or typical development (TD; n = 81) through a clinical evaluation. Trinomial logistic regression analysis was used to test the associations between biomarkers with ASD, or Non-TD, as compared to children with TD. In single analyte analysis, generalized estimating equations were used to investigate the association between each EDC biomarkers and longitudinal changes in cognitive development using the Mullen Scales of Early Learning (MSEL) over the four assessment time points (6, 12, 24, and 36 months of age). Additionally, quantile g-computation was used to test for a mixture effect. RESULTS: EDC biomarker concentrations generally decreased over the study period, except for mono-2-ethyl-5-carboxypentyl terephthalate. Overall, EDC biomarkers at 3 and/or 6 months of age were not associated with an increased risk of ASD or Non-TD, and a few showed significant inverse associations. However, when assessing longitudinal changes in MSEL scores over the four assessment time points, elevated monoethyl phthalate (MEP) was significantly associated with reduced scores in the composite score (ß = -0.16, 95% CI: 0.31, -0.02) and subscales of fine motor skills (ß = -0.09, 95%CI: 0.17, 0.00), and visual reception (ß = -0.11, 95% CI: 0.23, 0.01). Additionally, the sum of metabolites of di (2-ethylhexyl) terephthalate (Æ©DEHTP) was associated with poorer visual reception (ß = -0.09, 95% CI: 0.16, -0.02), and decreased composite scores (ß = -0.11, 95% CI: 0.21, -0.01). Mixtures analyses using quantile g-computation analysis did not show a significant association between mixtures of EDC biomarkers and MSEL subscales or composite scores. CONCLUSION: These findings highlight the potential importance of infant exposures on cognitive development. Future research can help further investigate whether early infant exposures are associated with longer-term deficits and place special attention on EDCs with increasing temporal trends and whether they may adversely affect neurodevelopment.

Early childhood exposures to phthalates in association with attention-deficit/hyperactivity disorder behaviors in middle childhood and adolescence in the ReCHARGE study.

BACKGROUND: Early-life exposure to phthalates alters behaviors in animals. However, epidemiological evidence on childhood phthalate exposure and attention-deficit/hyperactivity disorder (ADHD) behaviors is limited. METHODS: This study included 243 children from the ReCHARGE (Revisiting Childhood Autism Risks from Genetics and Environment) study, who were previously classified as having autism spectrum disorder (ASD), developmental delay, other early concerns, and typical development in the CHARGE case-control study. Twenty phthalate metabolites were measured in spot urine samples collected from children aged 2-5 years. Parents reported on children's ADHD symptoms at ages 8-18 years using Conners-3 Parent Rating Scale. Covariate-adjusted negative binomial generalized linear models were used to investigate associations between individual phthalate metabolite concentrations and raw scores. Weighted quantile sum (WQS) regression with repeated holdout validation was used to examine mixture effects of phthalate metabolites on behavioral scores. Effect modification by child sex was evaluated. RESULTS: Among 12 phthalate metabolites detected in >75% of the samples, higher mono-2-heptyl phthalate (MHPP) was associated with higher scores on Inattentive (ß per doubling = 0.05, 95% confidence interval [CI]: 0.02, 0.08) and Hyperactive/Impulsive scales (ß = 0.04, 95% CI: 0.00, 0.07), especially among children with ASD. Higher mono-carboxy isooctyl phthalate (MCiOP) was associated with higher Hyperactivity/Impulsivity scores (ß = 0.07, 95% CI: -0.01, 0.15), especially among typically developing children. The associations of the molar sum of high molecular weight (HMW) phthalate metabolites and a phthalate metabolite mixture with Hyperactivity/Impulsivity scores were modified by sex, showing more pronounced adverse associations among females. CONCLUSION: Exposure to phthalates during early childhood may impact ADHD behaviors in middle childhood and adolescence, particularly among females. Although our findings may not be broadly generalizable due to the diverse diagnostic profiles within our study population, our robust findings on sex-specific associations warrant further investigations.

Green Space and Internalizing or Externalizing Symptoms Among Children.

Importance: Evidence suggests that living near green space supports mental health, but studies examining the association of green space with early mental health symptoms among children are rare. Objective: To evaluate the association between residential green space and early internalizing (eg, anxiety and depression) and externalizing (eg, aggression and rule-breaking) symptoms. Design, Setting, and Participants: Data for this cohort study were drawn from the Environmental Influences on Child Health Outcomes cohort; analysis was conducted from July to October 2023. Children born between 2007 and 2013 with outcome data in early (aged 2-5 years) and/or middle (aged 6-11 years) childhood who resided in 41 states across the US, drawing from clinic, hospital, and community-based cohorts, were included. Cohort sites were eligible if they recruited general population participants and if at least 30 children had outcome and residential address data to measure green space exposure. Nine cohorts with 13 sites met these criteria. Children diagnosed with autism or developmental delay were excluded, and 1 child per family was included. Exposures: Green space exposure was measured using a biannual (ie, summer and winter) Normalized Difference Vegetation Index, a satellite image-based indicator of vegetation density assigned to monthly residential history from birth to outcome assessment. Main Outcome and Measures: Child internalizing and externalizing symptoms were assessed using the Child Behavior Checklist for Ages 1½ to 5 or 6 to 18. The association between green space and internalizing and externalizing symptoms was modeled with multivariable linear regression using generalized estimating equations, adjusting for birthing parent educational level, age at delivery, child sex, prematurity, and neighborhood socioeconomic vulnerability. Models were estimated separately for early and middle childhood samples. Results: Among 2103 children included, 1061 (50.5%) were male; 606 (29.1%) identified as Black, 1094 (52.5%) as White, 248 (11.9%) as multiple races, and 137 (6.6%) as other races. Outcomes were assessed at mean (SD) ages of 4.2 (0.6) years in 1469 children aged 2 to 5 years and 7.8 (1.6) years in 1173 children aged 6 to 11 years. Greater green space exposure was associated with fewer early childhood internalizing symptoms in fully adjusted models (b = -1.29; 95% CI, -1.62 to -0.97). No associations were observed between residential green space and internalizing or externalizing symptoms in middle childhood. Conclusions and Relevance: In this study of residential green space and children's mental health, the association of green space with fewer internalizing symptoms was observed only in early childhood, suggesting a sensitive period for nature exposure. Policies protecting and promoting access to green space may help alleviate early mental health risk.

Pre-pregnancy ozone and ultrafine particulate matter exposure during second year of life associated with decreased cognitive and adaptive functioning at aged 2-5 years.

BACKGROUND: This study sought to investigate the association of prenatal and early life exposure to a mixture of air pollutants on cognitive and adaptive outcomes separately in children with or without autism spectrum disorder (ASD). METHODS: Utilizing data from the CHARGE case-control study (birth years: 2000-2016), we predicted daily air concentrations of NO2, O3, and particulate matter <0.1 µm (PM0.1), between 0.1 and 2.5 µm (PM0.1-2.5), and between 2.5 and 10 µm (PM2.5-10) using chemical transport models with ground-based monitor adjustments. Exposures were evaluated for pre-pregnancy, each trimester, and the first two years of life. Individual and combined effects of pollutants were assessed with Vineland Adaptive Behavior Scales (VABS) and Mullen Scales of Early Learning (MSEL), separately for children with ASD (n = 660) and children without ASD (typically developing (TD) and developmentally delayed (DD) combined; n = 753) using hierarchical Bayesian Kernel Machine Regression (BKMR) models with three groups: PM size fractions (PM0.1, PM0.1-2.5, PM2.5-10), NO2, and O3. RESULTS: Pre-pregnancy Ozone was strongly negatively associated with all scores in the non-ASD group (group posterior inclusion probability (gPIP) = 0.83-1.00). The PM group during year 2 was also strongly negatively associated with all scores in the non-ASD group (gPIP = 0.59-0.93), with PM0.1 driving the group association (conditional PIP (cPIP) = 0.73-0.96). Weaker and less consistent associations were observed between PM0.1-2.5 during pre-pregnancy and ozone during year 1 and VABS scores in the ASD group. CONCLUSIONS: These findings prompt further investigation into ozone and ultrafine PM as potential environmental risk factors for neurodevelopment.

Early childhood exposure to environmental phenols and parabens, phthalates, organophosphate pesticides, and trace elements in association with attention deficit hyperactivity disorder (ADHD) symptoms in the CHARGE study.

BACKGROUND: A growing body of literature investigated childhood exposure to environmental chemicals in association with attention-deficit/hyperactivity disorder (ADHD) symptoms, but limited studies considered urinary mixtures of multiple chemical classes. This study examined associations of concurrent exposure to non-persistent chemicals with ADHD symptoms in children diagnosed with autism spectrum disorder (ASD), developmental delay (DD), and typical development (TD). METHODS: A total of 549 children aged 2-5 years from the Childhood Autism Risks from Genetics and Environment (CHARGE) case-control study were administered the Aberrant Behavior Checklist (ABC). This study focused on the ADHD/noncompliance subscale and its two subdomains (hyperactivity/impulsivity, inattention). Sixty-two chemicals from four classes (phenols/parabens, phthalates, organophosphate pesticides, trace elements) were quantified in child urine samples, and 43 chemicals detected in > 70% samples were used to investigate their associations with ADHD symptoms. Negative binomial regression was used for single-chemical analysis, and weighted quantile sum regression with repeated holdout validation was applied for mixture analysis for each chemical class and all chemicals. The mixture analyses were further stratified by diagnostic group. RESULTS: A phthalate metabolite mixture was associated with higher ADHD/noncompliance scores (median count ratio [CR] = 1.10; 2.5th, 97.5th percentile: 1.00, 1.21), especially hyperactivity/impulsivity (median CR = 1.09; 2.5th, 97.5th percentile: 1.00, 1.25). The possible contributors to these mixture effects were di-2-ethylhexyl phthalate (DEHP) metabolites and mono-2-heptyl phthalate (MHPP). These associations were likely driven by children with ASD as these were observed among children with ASD, but not among TD or those with DD. Additionally, among children with ASD, a mixture of all chemicals was associated with ADHD/noncompliance and hyperactivity/impulsivity, and possible contributors were 3,4-dihydroxy benzoic acid, DEHP metabolites, MHPP, mono-n-butyl phthalate, and cadmium. CONCLUSIONS: Early childhood exposure to a phthalate mixture was associated with ADHD symptoms, particularly among children with ASD. While the diverse diagnostic profiles limited generalizability, our findings suggest a potential link between phthalate exposure and the comorbidity of ASD and ADHD.

Prediction of internalizing and externalizing symptoms in late childhood from attention-deficit/hyperactivity disorder symptoms in early childhood.

Limited analyses based on national samples have assessed whether early attention-deficit/hyperactivity disorder (ADHD) symptoms predict later internalizing and externalizing symptoms in youth and the influence of sex and pubertal timing on subsequent psychiatric symptoms. This study analyzed data (n = 2818) from the Environmental influences on Child Health Outcomes Program national cohort. Analyses used data from early childhood (mean age = 5.3 years) utilizing parent-reported ADHD symptoms to predict rates of internalizing and externalizing symptoms from late childhood/adolescence (mean age = 11.9 years). Within a subsample age at peak height velocity (APHV) acted as a proxy to assess pubertal timing from early childhood (mean age = 5.4 years) to adolescence (mean age = 12.3 years). Early-childhood ADHD symptoms predicted later psychiatric symptoms, including anxiety, depression, aggressive behavior, conduct problems, oppositional defiant disorder, and rule-breaking behavior. Earlier APHV was associated with increased Conduct Disorder symptoms from late childhood to adolescence for females only. A stronger relation between ADHD symptoms and later aggression was observed in females with earlier APHV, whereas this same pattern with aggression, conduct problems and depression was observed in males with later APHV. Clinicians should consider that both young girls and boys with elevated ADHD symptoms, particularly with off-set pubertal timing, may be at risk for later psychiatric symptoms.

Prenatal exposure to per- and polyfluoroalkyl substances and child behavioral problems.

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may adversely affect child behaviors; however, findings of epidemiologic studies are inconsistent. We examined prenatal PFAS exposure in association with child behavioral problems. METHODS: Participants were 177 mother-child pairs from MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a cohort with elevated familial likelihood of autism spectrum disorder (ASD). We quantified nine PFAS in maternal serum (1-3 samples per mother) collected from the 1st to 3rd trimesters of pregnancy. Child behavioral problems were assessed at 3 years of age using the Child Behavior Checklist (CBCL), developed to test for various behavioral problems of children. We examined associations of the CBCL scores with individual PFAS concentrations and with their mixture using negative binomial regression and weighted quantile sum regression models. RESULTS: Higher prenatal perfluorononanoate (PFNA) concentrations were associated with higher scores of externalizing problems [ß = 0.16, 95% CI (0.01, 0.32)] and aggressive behavior [ß = 0.17 (0.01, 0.32)]. Higher PFNA, perfluorooctane sulfonate (PFOS), and perfluorodecanoate (PFDA) were associated with higher scores of sleep problems [ß = 0.34 (0.15, 0.54) for PFNA, ß = 0.20 (0.02, 0.37) for PFOS, and ß = 0.19 (0.00, 0.37) for PFDA]. No significant associations observed for typically developing children, whereas PFOS, PFNA, and PFDA were associated with several behavioral problems among children diagnosed with ASD or other neurodevelopmental concerns. Exposure to a mixture of PFAS was associated with higher scores of sleep problems and aggressive behavior, mostly contributed by PFNA and PFDA. CONCLUSIONS: Our study showed that prenatal exposure to some PFAS could increase child behavioral problems at 3 years of age. However, our results should be interpreted with caution because we relied on data from a cohort with increased familial likelihood of ASD and thereby had more behavioral problems.

Per- and Polyfluoroalkyl Substances (PFAS) in Serum of 2 to 5 year-Old Children: Temporal Trends, Determinants, and Correlations with Maternal PFAS Concentrations.

Young children may experience higher per- and polyfluoroalkyl substances (PFAS) exposure than adults due to breastfeeding, higher dust ingestion rates, and frequent hand-to-mouth activities. We explored temporal trends and determinants of child serum PFAS concentrations and their correlations with paired maternal PFAS concentrations. From 2009 to 2017, we collected one blood sample from each of 541 children aged 2-5 years participating in the Childhood Autism Risks from Genetics and Environment (CHARGE) study and quantified 14 PFAS in serum. For nine frequently detected PFAS (>65% of samples), we performed multiple regression adjusting for potential determinants to estimate mean percent concentration changes. For a subset of 327 children, we also quantified nine PFAS in their mother's serum collected at the same visit and computed Spearman correlation coefficients (rsp) between maternal and child PFAS concentrations. During 2009-2017, child serum concentrations of all nine PFAS decreased by 6-25% annually. Several PFAS concentrations were higher among non-Hispanic white children and those with highly educated parents. Most maternal and child PFAS concentrations were moderately correlated (rsp = 0.13-0.39), with a strong correlation for N-methyl perfluorooctane sulfonamido acetic acid (rsp = 0.68). Breastfeeding duration appeared to contribute to higher child and lower maternal PFAS concentrations, resulting in relatively weak correlations between maternal and child PFAS concentrations for samples collected in early childhood. Considering that more than half of our study children had neurodevelopmental concerns, the generalizability of our findings might be limited.

Associations of Organophosphate Ester Flame Retardant Exposures during Pregnancy with Gestational Duration and Fetal Growth: The Environmental influences on Child Health Outcomes (ECHO) Program.

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 log2-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(2-chloroethyl) 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-for-gestational-age z-scores (ß 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.

Ultrafine particulate matter exposure during second year of life, but not before, associated with increased risk of autism spectrum disorder in BKMR mixtures model of multiple air pollutants.

Prenatal and early postnatal air pollution exposures have been shown to be associated with autism spectrum disorder (ASD) risk but results regarding specific air pollutants and exposure timing are mixed and no study has investigated the effects of combined exposure to multiple air pollutants using a mixtures approach. We aimed to evaluate prenatal and early life multipollutant mixtures for the drivers of associations of air pollution with ASD. This study examined 484 typically developing (TD) and 660 ASD children from the CHARGE case-control study. Daily air concentrations for NO2, O3, ultrafine (PM0.1), fine (PM0.1-2.5), and coarse (PM2.5-10) particles were predicted from chemical transport models with statistical bias adjustment based on ground-based monitors. Daily averages were calculated for each exposure period (pre-pregnancy, each trimester of pregnancy, first and second year of life) between 2000 and 2016. Air pollution variables were natural log-transformed and then standardized. Individual and joint effects of pollutant exposure with ASD, and potential interactions, were evaluated for each period using hierarchical Bayesian Kernel Machine Regression (BKMR) models, with three groups: PM size fractions (PM0.1, PM0.1-2.5, PM2.5-10), NO2, and O3. In BKMR models, the PM group was associated with ASD in year 2 (group posterior inclusion probability (gPIP) = 0.75), and marginally associated in year 1 (gPIP = 0.497). PM2.5-10 appeared to drive the association (conditional PIP (cPIP) = 0.64) in year 1, while PM0.1 appeared to drive the association in year 2 (cPIP = 0.76), with both showing a moderately strong increased risk. Pre-pregnancy O3 showed a slight J-shaped risk of ASD (gPIP = 0.55). No associations were observed for exposures during pregnancy. Pre-pregnancy O3 and year 2 p.m.0.1 exposures appear to be associated with an increased risk of ASD. Future research should examine ultrafine particulate matter in relation to ASD.

Associations between area-level arsenic exposure and adverse birth outcomes: An Echo-wide cohort analysis.

BACKGROUND: Drinking water is a common source of exposure to inorganic arsenic. In the US, the Safe Drinking Water Act (SDWA) was enacted to protect consumers from exposure to contaminants, including arsenic, in public water systems (PWS). The reproductive effects of preconception and prenatal arsenic exposure in regions with low to moderate arsenic concentrations are not well understood. OBJECTIVES: This study examined associations between preconception and prenatal exposure to arsenic violations in water, measured via residence in a county with an arsenic violation in a regulated PWS during pregnancy, and five birth outcomes: birth weight, gestational age at birth, preterm birth, small for gestational age (SGA), and large for gestational age (LGA). METHODS: Data for arsenic violations in PWS, defined as concentrations exceeding 10 parts per billion, were obtained from the Safe Drinking Water Information System. Participants of the Environmental influences on Child Health Outcomes Cohort Study were matched to arsenic violations by time and location based on residential history data. Multivariable, mixed effects regression models were used to assess the relationship between preconception and prenatal exposure to arsenic violations in drinking water and birth outcomes. RESULTS: Compared to unexposed infants, continuous exposure to arsenic from three months prior to conception through birth was associated with 88.8 g higher mean birth weight (95% CI: 8.2, 169.5), after adjusting for individual-level confounders. No statistically significant associations were observed between any preconception or prenatal violations exposure and gestational age at birth, preterm birth, SGA, or LGA. CONCLUSIONS: Our study did not identify associations between preconception and prenatal arsenic exposure, defined by drinking water exceedances, and adverse birth outcomes. Exposure to arsenic violations in drinking water was associated with higher birth weight. Future studies would benefit from more precise geodata of water system service areas, direct household drinking water measurements, and exposure biomarkers.

Perinatal Factors and Emotional, Cognitive, and Behavioral Dysregulation in Childhood and Adolescence.

OBJECTIVE: This cohort study assessed perinatal factors known to be related to maternal and neonatal inflammation and hypothesized that several would be associated with emotional, cognitive, and behavioral dysregulation in youth. METHOD: The Environmental influences on Child Health Outcomes (ECHO) is a research consortium of 69 pediatric longitudinal cohorts. A subset of 18 cohorts that had both Child Behavior Checklist (CBCL) data on children (6-18 years) and information on perinatal exposures including maternal prenatal infections was used. Children were classified as having the CBCL-Dysregulation Profile (CBCL-DP) if the sum of their T scores for 3 CBCL subscales (attention, anxious/depressed, and aggression) was ≥180. Primary exposures were perinatal factors associated with maternal and/or neonatal inflammation, and associations between these and outcome were assessed. RESULTS: Approximately 13.4% of 4,595 youth met criteria for CBCL-DP. Boys were affected more than girls (15.1% vs 11.5%). More youth with CBCL-DP (35%) were born to mothers with prenatal infections compared with 28% of youth without CBCL-DP. Adjusted odds ratios indicated the following were significantly associated with dysregulation: having a first-degree relative with a psychiatric disorder; being born to a mother with lower educational attainment, who was obese, had any prenatal infection, and/or who smoked tobacco during pregnancy. CONCLUSION: In this large study, a few modifiable maternal risk factors with established roles in inflammation (maternal lower education, obesity, prenatal infections, and smoking) were strongly associated with CBCL-DP and could be targets for interventions to improve behavioral outcomes of offspring. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Birth Outcomes in Relation to Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Stress in the Environmental Influences on Child Health Outcomes (ECHO) Program.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress. OBJECTIVES: We estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships. METHODS: We included 3,339 participants from 11 prospective prenatal cohorts in the Environmental influences on the Child Health Outcomes (ECHO) program to estimate the associations of five PFAS and birth outcomes. We stratified by perceived stress scale scores to examine effect modification and used Bayesian Weighted Sums to estimate mixtures of PFAS. RESULTS: We observed reduced birth size with increased concentrations of all PFAS. For a 1-unit higher log-normalized exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), we observed lower birthweight-for-gestational-age z-scores of ß=-0.15 [95% confidence interval (CI): -0.27, -0.03], ß=-0.14 (95% CI: -0.28, -0.002), ß=-0.22 (95% CI: -0.23, -0.10), ß=-0.06 (95% CI: -0.18, 0.06), and ß=-0.25 (95% CI: -0.37, -0.14), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age: ORPFNA=0.56 (95% CI: 0.38, 0.83), ORPFDA=0.52 (95% CI: 0.35, 0.77). For a 1-unit increase in log-normalized concentration of summed PFAS, we observed a lower birthweight-for-gestational-age z-score [-0.28; 95% highest posterior density (HPD): -0.44, -0.14] and decreased odds of large-for-gestational-age (OR=0.49; 95% HPD: 0.29, 0.82). Perfluorodecanoic acid (PFDA) explained the highest percentage (40%) of the summed effect in both models. Associations were not modified by maternal perceived stress. DISCUSSION: Our large, multi-cohort study of PFAS and adverse birth outcomes found a negative association between prenatal PFAS and birthweight-for-gestational-age, and the associations were not different in groups with high vs. low perceived stress. This study can help inform policy to reduce exposures in the environment and humans. https://doi.org/10.1289/EHP10723.

Early childhood exposure to environmental phenols and parabens, phthalates, organophosphate pesticides, and trace elements in association with attention deficit hyperactivity disorder (ADHD) symptoms in the CHARGE study.

Background: Agrowing body of literature investigated childhood exposure to environmental chemicals in association with attention deficit hyperactivity disorder (ADHD) symptoms, but limited studies considered urinary mixtures of multiple chemical classes. This study examined associations of concurrent exposure to non-persistent chemicals with ADHD symptoms in children diagnosed with autism spectrum disorder (ASD), developmental delay, and typical development. Methods: A total of 574 children aged 2-5 years from the Childhood Autism Risks from Genetics and Environment (CHARGE) case-control study was administered the Aberrant Behavior Checklist (ABC). This study focused on the Hyperactivity subscale and its two subdomains (hyperactivity/impulsivity, inattention). Sixty-two chemicals from four classes (phenols/parabens, phthalates, organophosphate pesticides, trace elements) were quantified in child urine samples, and 43 chemicals detected in >70% samples were used in statistical analyses. Weighted quantile sum regression for negative binomial outcomes with repeated holdout validation was performed to investigate covariate-adjusted associations between mixtures and ABC scores in 574 children. The mixture analyses were further restricted to 232 children with ASD. Results: Phthalate metabolite mixtures, weighted for mono-n-butylphthalate (MNBP), mono-2-heptyl phthalate, and mono-carboxy isononyl phthalate, were associated with the Hyperactivity subscale (mean incidence rate ratio [mIRR] = 1.11; 2.5th, 97.5th percentile: 1.00, 1.23), especially the hyperactivity/impulsivity subdomain (mIRR = 1.14; 2.5th, 97.5th percentile: 1.06, 1.26). These associations remained similar after restricting to children with ASD. The inattention subdomain was associated with a phenols/parabens mixture, weighted for several parabens and bisphenols (mIRR = 1.13; 2.5th, 97.5th percentile: 1.00, 1.28) and a total mixture, weighted for 3,4-dihydroxy benzoic acid, MNBR and mono-(2-ethyl-5-carboxypentyl) phthalate (mIRR = 1.11; 2.5th, 97.5th percentile: 1.01,1.25) only among children with ASD. Conclusions: Concurrent exposure to phthalate mixtures was associated with hyperactivity in early childhood. Though causal inference cannot be made based on our cross-sectional findings, this study warrants further research on mixtures of larger number of chemicals from multiple classes in association with ADHD-related behaviors in young children.

Addressing systemic problems with exposure assessments to protect the public's health.

BACKGROUND: Understanding, characterizing, and quantifying human exposures to environmental chemicals is critical to protect public health. Exposure assessments are key to determining risks to the general population and for specific subpopulations given that exposures differ between groups. Exposure data are also important for understanding where interventions, including public policies, should be targeted and the extent to which interventions have been successful. In this review, we aim to show how inadequacies in exposure assessments conducted by polluting industries or regulatory agencies have led to downplaying or disregarding exposure concerns raised by communities; that underestimates of exposure can lead regulatory agencies to conclude that unacceptable risks are, instead, acceptable, allowing pollutants to go unregulated; and that researchers, risk assessors, and policy makers need to better understand the issues that have affected exposure assessments and how appropriate use of exposure data can contribute to health-protective decisions. METHODS: We describe current approaches used by regulatory agencies to estimate human exposures to environmental chemicals, including approaches to address limitations in exposure data. We then illustrate how some exposure assessments have been used to reach flawed conclusions about environmental chemicals and make recommendations for improvements. RESULTS: Exposure data are important for communities, public health advocates, scientists, policy makers, and other groups to understand the extent of environmental exposures in diverse populations. We identify four areas where exposure assessments need to be improved due to systemic sources of error or uncertainty in exposure assessments and illustrate these areas with examples. These include: (1) an inability of regulatory agencies to keep pace with the increasing number of chemicals registered for use or assess their exposures, as well as complications added by use of 'confidential business information' which reduce available exposure data; (2) the failure to keep assessments up-to-date; (3) how inadequate assumptions about human behaviors and co-exposures contribute to underestimates of exposure; and (4) that insufficient models of toxicokinetics similarly affect exposure estimates. CONCLUSION: We identified key issues that impact capacity to conduct scientifically robust exposure assessments. These issues must be addressed with scientific or policy approaches to improve estimates of exposure and protect public health.