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Background/aims: Pregnant women are exposed to persistent environmental contaminants, including per- and polyfluoroalkyl substances (PFAS) that disrupt thyroid function. However, it is unclear if PFAS alter maternal sex-steroid hormone levels, which support pregnancy health and fetal development., Methods: In Illinois women with relatively high socioeconomic status (n = 460), we quantified perfluorononanoic (PFNA), perfluorooctane sulfonic (PFOS), perfluorooctanoic (PFOA), methyl-perfluorooctane sulfonamide acetic acid, perfluorohexanesulphonic (PFHxS), perfluorodecanoic (PFDeA), and perfluoroundecanoic (PFUdA) acid concentrations in fasting serum samples at median 17 weeks gestation, along with plasma progesterone, testosterone, and estradiol. We evaluated covariate-adjusted associations of ln-transformed hormones with each ln-transformed PFAS individually using linear regression and with the PFAS mixture using quantile-based g-computation (QGComp)., Results: Interquartile range (IQR) increases in PFOS were associated with higher progesterone (%Δ 3.0; 95%CI: -0.6, 6.6) and estradiol (%Δ: 8.1; 95%CI: 2.2, 14.4) levels. Additionally, PFHxS was positively associated with testosterone (%Δ: 10.2; 95%CI: 4.0, 16.7), whereas both PFDeA and PFUdA were inversely associated with testosterone (%Δ: -5.7; 95%CI: -10.3, -0.8, and %Δ: -4.1; 95%CI: -7.6, -0.4, respectively). The IQR-standardized PFAS mixture was not associated with progesterone (%Δ: 1.6; 95%CI: -5.8, 9.2), due equal partial positive (%Δ: 9.2; driven by PFOA) and negative (%Δ: -7.4; driven by PFOS) mixture associations. Similarly, the mixture was not associated with testosterone (%Δ: 5.3; 95%CI: -9.0, 20.1), due to similar partial positive (%Δ: 23.6; driven by PFHxS) and negative (%Δ: -17.4; driven by PFDeA) mixture associations. However, we observed a slightly stronger partial positive (%Δ: 25.6; driven by PFOS and PFUdA) than negative (%Δ: -16.3; driven by PFOA) association resulting in an overall non-significant positive trend between the mixture and estradiol (%Δ: 8.5; 95%CI: -3.7, 20.9)., Conclusion: PFAS mixture modeled using QGComp was not associated with maternal sex-steroid hormones due to potential opposing effects of certain PFAS. Additional prospective studies could corroborate these findings., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background/objectives: Pregnant women are exposed to numerous endocrine disrupting chemicals (EDCs) that can affect hormonal pathways regulating pregnancy outcomes and fetal development. Thus, we evaluated overall and fetal sex-specific associations of phthalate/replacement, paraben, and phenol biomarkers with sex-steroid and thyroid hormones., Methods: Illinois women (n = 302) provided plasma for progesterone, estradiol, testosterone, free T4 (FT4), total T4 (TT4), and thyroid stimulating hormone (TSH) at median 17 weeks gestation. Women also provided up-to-five first-morning urine samples monthly across pregnancy (8-40 weeks), which we pooled to measure 19 phthalate/replacement metabolites (reflecting ten parent compounds), three parabens, and six phenols. We used linear regression to evaluate overall and fetal sex-specific associations of biomarkers with hormones, as well as weighted quantile sum and Bayesian kernel machine regression (BKMR) to assess cumulative associations, non-linearities, and chemical interactions., Results: In women of relatively high socioeconomic status, several EDC biomarkers were associated with select hormones, without cumulative or non-linear associations with progesterone, FT4, or TT4. The biomarker mixture was negatively associated with estradiol (only at higher biomarker concentrations using BKMR), testosterone, and TSH, where each 10% mixture increase was associated with -5.65% (95% CI: -9.79, -1.28) lower testosterone and -0.09 μIU/mL (95% CI: -0.20, 0.00) lower TSH. Associations with progesterone, testosterone, and FT4 did not differ by fetal sex. However, in women carrying females, we identified an inverted u-shaped relationship of the mixture with estradiol. Additionally, in women carrying females, each 10% increase in the mixture was associated with 1.50% (95% CI: -0.15, 3.18) higher TT4, whereas in women carrying males, the mixture was associated with -1.77% (95% CI: -4.08, 0.58) lower TT4 and -0.18 μIU/mL (95% CI: -0.33, -0.03) lower TSH. We also identified select chemical interactions., Conclusion: Some biomarkers were associated with early-to-mid pregnancy hormones. There were some sex-specific and non-linear associations. Future studies could consider how these findings relate to pregnancy/birth outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to a wide array of adverse maternal and child health outcomes. However, studies examining PFAS in relation to offspring cognition have been inconclusive., Objective: We examined whether prenatal exposure to a mixture of PFAS was related to cognition in 7.5-month-old infants., Methods: Our analytic sample included participants enrolled in the Chemicals in Our Bodies (CIOB) and Illinois Kids Development Study (IKIDS) cohorts (N = 163). Seven PFAS were measured in 2nd trimester maternal serum samples and were detected in >65% of participants. Infant cognition was measured with a visual recognition memory task using an infrared eye tracker when infants were 7.5 months old. This task included familiarization trials where each infant was shown two identical faces and test trials where each infant was shown the familiar face paired with a novel face. In familiarization, we assessed average run duration (time looking at familiarization stimuli before looking away) as a measure of information processing speed, in addition to time to familiarization (time to reach 20 s of looking at stimuli) and shift rate (the number of times infants looked between stimuli), both as measures of attention. In test trials, we assessed novelty preference (proportion of time looking to the novel face) to measure recognition memory. Linear regression was used to estimate associations of individual PFAS with cognitive outcomes, while Bayesian kernel machine regression (BKMR) was used to estimate mixture effects., Results: In adjusted single-PFAS linear regression models, an interquartile range increase in PFNA, PFOA, PFOS, PFHxS, PFDeA, and PFUdA was associated with an increase in shift rate, reflecting better visual attention. Using BKMR, increasing quartiles of the PFAS mixture was similarly associated with a modest increase in shift rate. There were no significant associations between PFAS exposure and time to reach familiarization (another measure of attention), average run duration (information processing speed), or novelty preference (visual recognition memory)., Conclusion: In our study population, prenatal PFAS exposure was modestly associated with an increase in shift rate and was not strongly associated with any adverse cognitive outcomes in 7.5-month-old infants., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was supported by grants RD83543301 and RD83543401 from the United States Environmental Protection Agency Children's Environmental Health and Disease Prevention Research Center, P30 ES019776, P30 ES030284, P01 ES022841P01 ES022848 and R01ES02705 from the National Institute of Environmental Health Sciences, and UG3OD023272, UH3OD023272, and 5U2COD023375-05 from the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) program. Stephanie Eick's participation was partially supported by the JPB Environmental Health Fellowship., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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 β = - 0.15 [95% confidence interval (CI): - 0.27 , - 0.03 ], β = - 0.14 (95% CI: - 0.28 , - 0.002 ), β = - 0.22 (95% CI: - 0.23 , - 0.10 ), β = - 0.06 (95% CI: - 0.18 , 0.06), and β = - 0.25 (95% CI: - 0.37 , - 0.14 ), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age: OR PFNA = 0.56 (95% CI: 0.38, 0.83), OR PFDA = 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.

Background/aims: Phthalates and their replacements are endocrine/metabolic disruptors that may impact gestational weight gain (GWG) - a pregnancy health indicator. We investigated overall and fetal sex-specific associations of individual and cumulative phthalate/replacement biomarkers with GWG., Methods: Illinois women (n = 299) self-reported their weight pre-pregnancy and at their final obstetric appointment before delivery (median 38 weeks). We calculated pre-pregnancy body mass index and gestational age-specific GWG z-scores (GWGz). We quantified 19 phthalate/replacement metabolites (representing 10 parent compounds) in pools of up-to-five first-morning urine samples, collected approximately monthly between 8 and 40 weeks gestation. We used linear regression, quantile-based g-computation (QGComp), and weighted quantile sum regression (WQSR) to evaluate associations of ten biomarkers (individual metabolites or parent molar-sums) individually or as mixtures (in interquartile range intervals) with GWGz. We evaluated associations in all women and stratified by fetal sex., Results: Individually, sums of metabolites of di(2-ethylhexyl) phthalate (ƩDEHP), di(isononyl) cyclohexane-1,2-dicarboxylate (ƩDiNCH), and di(2-ethylhexyl) terephthalate (ƩDEHTP) had consistent inverse associations with GWGz, and some associations were fetal sex-specific. When evaluating phthalates/replacements as a mixture, QGComp identified ƩDEHP, ƩDEHTP, and mono-(3-carboxypropyl) phthalate, along with sum of di(isononyl) phthalate metabolites (ƩDiNP) and monobenzyl phthalate as notable contributors to lower and higher GWGz, respectively, resulting in a marginal inverse joint association in all women (β: -0.29; 95% CI: -0.70, 0.12). In women carrying females, ƩDEHP contributed to the marginal inverse joint association (β: -0.54; 95% CI: -1.09, 0.03). However, there was no overall association in women carrying males (β: 0.00; 95% CI: -0.60, 0.59), which was explained by approximately equal negative (driven by ƩDEHTP) and positive (driven by ƩDiNP) partial associations. WQSR analyses consistently replicated these QGComp findings., Conclusions: Biomarkers of phthalates/replacements were fetal sex-specifically associated with GWGz. Because ƩDEHTP contributed substantively to mixture associations, additional studies in pregnant women may be needed around this plasticizer replacement., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Phthalates are ubiquitous endocrine-disrupting chemicals, and research indicates that prenatal exposure to some phthalates may affect neurodevelopment. In a prospective birth cohort study, five first-morning urine samples collected across pregnancy were pooled and the following phthalate biomarkers assessed: sum of di-(2-ethylhexyl) phthalate metabolites (ΣDEHP), sum of diisononyl phthalate metabolites (ΣDINP), sum of dibutyl phthalate metabolites (ΣDBP), sum of anti-androgenic metabolites (ΣAA), monoethyl phthalate (MEP), and sum of all phthalate metabolites (ΣAll). The Ages & Stages Questionnaires® (ASQ), a standardized parent-reported, age-adapted screening tool, measured communication, personal-social, problem solving, and motor domains in infants at 4.5 and 7.5 months (n = 123). Adjusting for maternal age, annual household income, gestational age at birth, infant age at assessment, and sex, repeated-measures generalized linear regression models were used to examine associations between prenatal phthalate urine biomarker concentrations and domain scores (assuming a Poisson distribution). Beta estimates were exponentiated back to the domain scale for ease of interpretation. Mothers were mostly white and college-educated, and most reported an annual household income of ≥$60,000. Associations of phthalate concentrations with ASQ outcomes are presented as follows: (1) anti-androgenic phthalate metabolites (ΣDEHP, ΣDINP, ΣDBP, and ΣAA), (2) MEP, which is not anti-androgenic, and (3) ΣAll. Overall, anti-androgenic phthalates were associated with higher (i.e., better) scores. However, there were exceptions, including the finding that a one-unit increase in ΣDBP was associated with a 12% increase in problem solving scores in 4.5-month-old females (β = 1.12; 95% CI: 0.99, 1.28; p = 0.067) but a 85% decrease for 7.5-month-old females (β = 0.54; 95% CI: 0.3, 0.99; p = 0.047). In contrast, MEP was associated with poorer scores on several outcomes. Sex- and timepoint-specific estimates demonstrated a one-unit increase in MEP was associated with: a 52% decrease in personal-social scores in 7.5-month-old males (β = 0.66; 95% CI: 0.46, 0.95; p = 0.02), a 39% decrease in fine motor scores in 7.5-month-old males (β = 0.72; 95% CI: 0.52, 0.98; p = 0.035), and a 6% decrease in fine motor scores in 4.5-month-old females (β = 0.94; 95% CI: 0.88, 0.99; p = 0.03). A one-unit increase in ΣAll was associated with a 4% increase in personal-social scores in 4.5-month-old males (β = 1.04; 95% CI: 0.99, 1.1; p = 0.08) but a 17% decrease in 7.5-month-old males (β = 0.85; 95% CI: 0.73, 0.99; p = 0.03). These data suggest age- and sex-specific associations of prenatal phthalates with infant neurobehavior. The current findings should be confirmed by longitudinal studies with larger sample sizes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Prenatal exposure to individual per‑ and poly‑fluoroalkyl substances (PFAS) and psychosocial stressors have been associated with reductions in fetal growth. Studies suggest cumulative or joint effects of chemical and non-chemical stressors on fetal growth. However, few studies have examined PFAS and non-chemical stressors together as a mixture, which better reflects real life exposure patterns. We examined joint associations between PFAS, perceived stress, and depression, and fetal growth using two approaches developed for exposure mixtures., Methods: Pregnant participants were enrolled in the Chemicals in Our Bodies cohort and Illinois Kids Development Study, which together make up the ECHO.CA.IL cohort. Seven PFAS were previously measured in 2nd trimester maternal serum samples and were natural log transformed for analyses. Perceived stress and depression were assessed using self-reported validated questionnaires, which were converted to t-scores using validated methods. Quantile g-computation and Bayesian kernel machine regression (BKMR) were used to assess joint associations between PFAS, perceived stress and depression t-scores and birthweight z-scores (N = 876)., Results: Individual PFAS, depression and perceived stress t-scores were negatively correlated with birthweight z-scores. Using quantile g-computation, a simultaneous one quartile increase in all PFAS, perceived stress and depression t-scores was associated with a slight reduction in birthweight z-scores (mean change per quartile increase = -0.09, 95% confidence interval = -0.21,0.03). BKMR similarly indicated that cumulative PFAS and stress t-scores were modestly associated with lower birthweight z-scores. Across both methods, the joint association appeared to be distributed across multiple exposures rather than due to a single exposure., Conclusions: Our study is one of the first to examine the joint effects of chemical and non-chemical stressors on fetal growth using mixture methods. We found that PFAS, perceived stress, and depression in combination were modestly associated were lower birthweight z-scores, which supports prior studies indicating that chemical and non-chemical stressors are jointly associated with adverse health outcomes., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background/objectives: Pregnant women are exposed to multiple phthalates and their replacements, which are endocrine disrupting chemicals associated with adverse maternal and child health outcomes. Identifying maternal characteristics associated with phthalate/replacement exposure during pregnancy is important., Methods: We evaluated 13 maternal sociodemographic and lifestyle factors, enrollment year, and conception season as determinants of exposure biomarkers of phthalates and their replacements in 482 pregnant women from the Illinois Kids Development Study (I-KIDS, enrolled 2013-2018). We quantified 19 phthalate/replacement metabolites in pools of five first-morning urines collected across pregnancy. K-means clustering identified women with distinct patterns of biomarker concentrations and principal component analysis (PCA) identified principal component (PC) profiles of biomarkers that exist together. We used multivariable regression models to evaluate associations of predictors with identified k-means clusters and PCs., Results: K-means clustering identified two clusters of women: 1) low phthalate/di(2-ethylhexyl) terephthalate (∑DEHTP) and 2) high phthalate/∑DEHTP biomarker concentrations. PCA identified four PCs with loadings heaviest for biomarkers of plasticizer phthalates [di-isononyl, di-isodecyl, di-n-octyl phthalates] (PC1), of other phthalates [dibenzyl, di-n-butyl, di-iso-butyl phthalates] (PC2), of phthalate replacements [∑DEHTP, di(isononyl) cyclohexane-1,2-dicarboxylate (∑DiNCH)] (PC3), and of monoethyl phthalate [MEP] (PC4). Overall, age, marital status, income, parity, pre-pregnancy BMI, caffeine intake, enrollment year, and conception season were independently associated with k-means cluster membership and at least one PC. Additionally, race/ethnicity, education, employment, pregnancy intention, smoking status, alcohol intake, and diet were associated with at least one PC. For instance, women who conceived in the spring, summer, and/or fall months had lower odds of high phthalate/∑DEHTP cluster membership and had lower plasticizer phthalate, phthalate replacement, and MEP PC scores., Conclusions: Conception season, enrollment year, and several sociodemographic/lifestyle factors were predictive of phthalate/replacement biomarker profiles. Future studies should corroborate these findings, with a special focus on replacements to which pregnant women are becoming increasingly exposed., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/objectives: Pregnant women are ubiquitously exposed to phthalates from food packaging materials and personal care products. Phthalates alter estrogen and testosterone concentrations in experimental models, but their ability to impact these hormones in human pregnancy is not well characterized., Methods: We recruited women ages 18-40 into the Illinois Kids Development Study (I-KIDS) in early pregnancy. Participants provided up to 5 first-morning urine samples across pregnancy (8-40 weeks gestation) that we pooled for quantification of 19 phthalate or phthalate alternative metabolites. Either individual (ng/mL) or molar sums (nmol/mL) of metabolites were used as exposure biomarkers. We summed urinary concentrations (ng/mL) of eight major estrogen (SumEstrogens) and two major testosterone (SumTestosterones) metabolites measured at median 13, 28, and 34 weeks gestation. We also estimated the ratio of estrogens-to-androgens. Linear mixed-effects models assessed relationships of phthalates/alternatives as continuous measures or as concentration quartiles with SumEstrogens, SumTestosterones, and the Estrogen/Androgen ratio in 434 women. In our models, we controlled for age, race, education, parity, smoking in the first trimester, pre-pregnancy body mass index, diet quality, conception season, fetal sex, and gestational age at hormone assessment. We also explored whether gestational age at hormone assessment or fetal sex modified these associations. All biomarkers and outcomes were specific gravity-adjusted, and continuous exposures and outcomes were also natural log-transformed., Results: Most participants were non-Hispanic white (80.9%), college educated (82.2%), and had urinary phthalate/alternative metabolite concentrations similar to those of reproductive-aged U.S. women. Overall, select phthalate metabolites were positively associated with SumEstrogens and SumTestosterones, but negatively associated with the Estrogen/Androgen ratio. For example, SumEstrogens was 5.1% (95%CI: 1.8, 8.5) higher with every 2-fold increase in sum of di(2-ethylhexyl) phthalate metabolites, while SumTestosterones was 7.9% (95%CI: 1.0, 15.3) higher and Estrogen/Androgen ratio was -7.7% (95%CI: -13.6, -1.4) lower with every 2-fold increase in monoethyl phthalate. However, phthalate alternatives were only positively associated with SumEstrogens, which was 2.4% (95%CI: 0.4, 4.5) and 3.2% (95%CI: 0.7, 5.8) higher with every 2-fold increase in sum of di(isononyl) cyclohexane-1,2-dicarboxylate metabolites and sum of di(2-ethylhexyl) terephthalate metabolites, respectively. Gestational age- and fetal sex-specific associations were only consistently observed for associations of phthalates/alternatives with SumEstrogens, where associations were strongest in mid-to-late pregnancy in women carrying females., Conclusion: Phthalates/alternatives may impact gestational hormones, with potential for gestational age- and fetal sex-specific associations. Whether maternal urinary estrogens and testosterones mediate associations of phthalates/alternatives with pregnancy and fetal outcomes merits further investigation., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Phthalates are endocrine disrupting chemicals that have been associated with adverse neurobehavior, but little is known about their influence on infant cognition., Methods: A visual recognition memory task was used to assess cognition in 244 7-8-month-old infants (121 females; 123 males) from a prospective cohort study. Phthalate metabolites were quantified in maternal urines pooled from across pregnancy. The task included familiarization trials (infant shown 2 identical faces) and test trials (infant shown the now familiar face paired with a novel one). Half of the infants saw one set of faces as familiar (set 1) and half saw the other set as familiar (set 2). During familiarization trials, average run duration (time looking at stimuli before looking away, measure of processing speed), and time to familiarization (time to reach 20 s looking at the stimuli, measure of attention) were assessed. During test trials, novelty preference (proportion of time looking at the novel face, measure of recognition memory) was assessed. Multivariable generalized linear models were used to assess associations of monoethyl phthalate (MEP), sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP), sum of di(isononyl) phthalate metabolites (ΣDINP), and sum of anti-androgenic phthalate metabolites (ΣAA) with each outcome., Results: Mothers were mostly white and college educated, and urine phthalate concentrations were similar to those in reproductive age women in the U.S., Population: All phthalate exposure biomarkers, except MEP, were associated with increases in average run duration. However, depending on the phthalate, associations were only in males or infants who saw the set 2 stimuli as familiar. Unexpectedly, ΣAA was associated with a shorter time to reach familiarization. Phthalate biomarkers also were associated with modest decrements in novelty preference, but these associations were nonsignificant., Conclusion: Prenatal exposure to phthalates may be related to slower information processing and poorer recognition memory in infants., (Published by Elsevier B.V.)

The association of prenatal phthalate exposure with physical reasoning was assessed in 159 (78 female; 81 male) 4.5-month-old infants from a prospective cohort. Phthalate metabolites were quantified in urine from 16-18 gestational weeks and a pool of five urines from across pregnancy. Infants' looking times to physically impossible and possible events were recorded via infrared eye-tracking. Infants that recognize that one of the events is impossible will look at that event longer. Associations of phthalate biomarkers with looking time differences (impossible-possible) were adjusted for maternal age, infant sex, and order of event presentation, and effect modification by infant sex was assessed. Each interquartile range (IQR) increase of monoethyl phthalate in the pooled sample was associated with females' increased looking time (β = 1.0; 95%CI = 0.3, 1.7 s) to the impossible event. However, for males, an IQR increase in monoethyl phthalate at 16-18 weeks (β = -2.5; 95%CI = -4.4,-0.6 s), the sum of di(isononyl) phthalate metabolites in the pooled sample (β = -1.0; 95%CI = -1.8, -0.1 s), and the sum of all phthalate metabolites in both samples (β = -2.3; 95%CI = -4.4, -0.2 s) were associated with increased looking to the possible event, suggesting that higher prenatal phthalate exposure is associated with poorer physical reasoning in male infants.

Background: Infants whose mothers experience greater psychosocial stress and environmental chemical exposures during pregnancy may face greater rates of preterm birth, lower birth weight, and impaired neurodevelopment., Methods: ECHO.CA.IL is composed of two cohorts, Chemicals in Our Bodies (CIOB; n = 822 pregnant women and n = 286 infants) and Illinois Kids Development Study (IKIDS; n = 565 mother-infant pairs), which recruit pregnant women from San Francisco, CA and Urbana-Champaign, IL, respectively. We examined associations between demographic characteristics and gestational age, birth weight z-scores, and cognition at 7.5 months across these two cohorts using linear models. We also examined differences in biomarkers of exposure to per- and polyfluoroalkyl substances (PFAS), measured in second-trimester serum, and psychosocial stressors by cohort and participant demographics., Results: To date, these cohorts have recruited over 1300 pregnant women combined. IKIDS has mothers who are majority white (80%), whereas CIOB mothers are racially and ethnically diverse (38% white, 34% Hispanic, 17% Asian/Pacific Islander). Compared to CIOB, median levels of PFOS, a specific PFAS congener, are higher in IKIDS (2.45 ng/mL versus 1.94 ng/mL), while psychosocial stressors are higher among CIOB. Across both cohorts, women who were non-white and single had lower birth weight z-scores relative to white women and married women, respectively. Demographic characteristics are not associated with cognitive outcomes at 7.5 months., Conclusions: This profile of the ECHO.CA.IL cohort found that mothers and their infants who vary in terms of socioeconomic status, race/ethnicity, and geographic location are similar in many of our measures of exposures and cognitive outcomes. Similar to past work, we found that non-white and single women had lower birth weight infants than white and married women. We also found differences in levels of PFOS and psychosocial stressors based on geographic location.

The Environmental influences on Child Health Outcomes (ECHO) Program is a research initiative funded by the National Institutes of Health that capitalizes on existing cohort studies to investigate the impact of early life environmental factors on child health and development from infancy through adolescence. In the initial stage of the program, extant data from 70 existing cohort studies are being uploaded to a database that will be publicly available to researchers. This new database will represent an unprecedented opportunity for researchers to combine data across existing cohorts to address associations between prenatal chemical exposures and child neurodevelopment. Data elements collected by ECHO cohorts were determined via a series of surveys administered by the ECHO Data Analysis Center. The most common chemical classes quantified in multiple cohorts include organophosphate pesticides, polychlorinated biphenyls, polybrominated diphenyl ethers, environmental phenols (including bisphenol A), phthalates, and metals. For each of these chemicals, at least four ECHO cohorts also collected behavioral data during infancy/early childhood using the Child Behavior Checklist. For these chemicals and this neurodevelopmental assessment (as an example), existing data from multiple ECHO cohorts could be pooled to address research questions requiring larger sample sizes than previously available. In addition to summarizing the data that will be available, the article also describes some of the challenges inherent in combining existing data across cohorts, as well as the gaps that could be filled by the additional data collection in the ECHO Program going forward., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Studies suggest that exposure to endocrine disrupting chemicals (EDCs), including phthalates, phenols, and parabens may influence childhood behavior, but the relationship during adolescence has not been assessed., Objective: We investigated the association between urinary biomarker concentrations of potential EDCs, including some phthalate and bisphenol A replacement chemicals, and behavior in adolescents., Methods: Participants were from the New Bedford Cohort (NBC), a prospective birth cohort of residents near the New Bedford Harbor Superfund site in Massachusetts. We measured urinary concentrations of 16 phthalate metabolites or replacements, 8 phenols, and 4 parabens in 205 NBC adolescents and estimated associations between select EDCs and adolescent behavior assessed with the Behavior Assessment System for Children, Second Edition -Teacher Rating Scale (BASC-2). Of note, up to 32 of the 205 in our assessment had missing outcome information imputed., Results: Increased urinary concentrations of the sum of 11 antiandrogenic phthalate metabolites were associated with an increase in maladaptive behaviors (Externalizing Behavior, Behavioral Symptoms Index, and Developmental Social Disorders or DSD), and a decrease in Adaptive Skills. For example, a doubling of urinary concentrations of antiandrogenic phthalate metabolites was associated with an increased risk of Externalizing Behavior (RR=1.04; 95% CI: 1.01-1.08). While associations were generally stronger in males, sex differences were not statistically significant. Urine concentrations of phenols and parabens were not associated with adverse behavior., Conclusion: Our findings support the importance of exposure to antiandrogenic phthalates during adolescence as a potential correlate of maladaptive behaviors including Externalizing Behavior, DSD behaviors, and decrements in Adaptive Skills., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A recent systematic review (SR) and meta-analysis of human studies found an association between prenatal serum polybrominated diphenyl ethers (PBDE) concentrations and a decrease in the IQ of children. A SR of experimental developmental animal PBDE-mediated neurotoxicity studies was performed in the present study. Outcomes assessed included measures related to learning, memory, and attention, which parallel the intelligence-related outcomes evaluated in the human studies SR. PubMed, Embase, and Toxline were searched for relevant experimental non-human mammalian studies. Evaluation of risk of bias (RoB) and overall body of evidence followed guidance developed by the National Toxicology Program. Animal studies using varying designs and outcomes were available for BDEs 47, 99, 153, 203, 206, and 209 and the technical mixture DE-71. Study reporting of methods and results was often incomplete leading to concerns regarding RoB. A meta-analysis of 6 Morris water maze studies showed evidence of a significant increase in last trial latency (effect size of 25.8 [CI, 20.3 to 31.2]) in PBDE-exposed animals with low heterogeneity. For most endpoints, there were unexplained inconsistencies across studies and no consistent evidence of a dose-response relationship. There is a "moderate" level of evidence that exposure to BDEs 47, 99, and 209 affects learning. For other PBDEs and other endpoints, the level of evidence was "low" or "very low". The meta-analysis led to stronger conclusions than that based upon a qualitative review of the evidence. The SR also identified RoB concerns that might be remedied by better study reporting.

Male reproductive alterations found in animals and humans following in utero phthalate exposure include decreased anogenital distance (AGD) and other reproductive-tract malformations. The aim of this investigation was to conduct systematic reviews of human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. PubMed, Embase, and Toxline were searched for relevant human and experimental animal studies on August 15, 2016. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated for quality and data extracted for analysis. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. The search yielded 6 relevant human studies and 19 animal studies. Meta-analysis of 5 human observational prospective cohort studies showed that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in boys (-4.07 [CI, -6.49 to -1.66] % decrease per log 10 rise in DEHP metabolites). Meta-analysis and meta-regression of the 19 experimental animal studies found reduced AGD with DEHP treatment, with a dose-response gradient, and with heterogeneity explained by species and strain. There is a moderate level of evidence from human investigations and a high level of data from animal studies that in utero exposure to DEHP decreases AGD. Based upon the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans on the basis of effects on AGD.

Developmental PCB exposure impairs hearing and induces brainstem audiogenic seizures in adult offspring. The degree to which this enhanced susceptibility to seizure is manifest in other brain regions has not been examined. Thus, electrical kindling of the amygdala was used to evaluate the effect of developmental exposure to an environmentally relevant PCB mixture on seizure susceptibility in the rat. Female Long-Evans rats were dosed orally with 0 or 6mg/kg/day of the PCB mixture dissolved in corn oil vehicle 4 weeks prior to mating and continued through gestation and up until postnatal day (PND) 21. On PND 21, pups were weaned, and two males from each litter were randomly selected for the kindling study. As adults, the male rats were implanted bilaterally with electrodes in the basolateral amygdala. For each animal, afterdischarge (AD) thresholds in the amygdala were determined on the first day of testing followed by once daily stimulation at a standard 200μA stimulus intensity until three stage 5 generalized seizures (GS) ensued. Developmental PCB exposure did not affect the AD threshold or total cumulative AD duration, but PCB exposure did increase the latency to behavioral manifestations of seizure propagation. PCB exposed animals required significantly more stimulations to reach stage 2 seizures compared to control animals, indicating attenuated focal (amygdala) excitability. A delay in kindling progression in the amygdala stands in contrast to our previous finding of increased susceptibility to brainstem-mediated audiogenic seizures in PCB-exposed animals in response to a an intense auditory stimulus. These seemingly divergent results are not unexpected given the distinct source, type, and mechanistic underpinnings of these different seizure models. A delay in epileptogenesis following focal amygdala stimulation may reflect a decrease in neuroplasticity following developmental PCB exposure consistent with reductions in use-dependent synaptic plasticity that have been reported in the hippocampus of developmentally PCB exposed animals., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Developmental exposure of rats to polychlorinated biphenyls (PCBs) causes impairments in hearing and in the functioning of peripheral and central auditory structures. Additionally, recent work from our laboratory has demonstrated an increase in audiogenic seizures. The current study aimed to further characterize the effects of PCBs on auditory brain structures by investigating whether developmental exposure altered the magnitude of activation in the auditory cortex (AC) in response to electrical stimulation of thalamocortical afferents. Long-Evans female rats were fed cookies containing either 0 or 6mg/kg of an environmental PCB mixture daily from 4 weeks prior to breeding until postnatal day 21. Brain slices containing projections from the thalamus to the AC were collected from adult female offspring and were bathed in artificial cerebrospinal fluid (aCSF) alone, aCSF containing a gamma-aminobutyric acid (GABA) receptor antagonist (200nM SR95531), and aCSF containing an and N-methyl-d-aspartate (NMDA) receptor antagonist (50μM AP5). During each of these drug conditions, electrical stimulations ranging from 25 to 600μA were delivered to the thalamocortical afferents. Activation of the AC was measured using flavoprotein autofluorescence imaging. Although there were no differences seen between treatment groups in the aCSF condition, there were significant increases in the ratio of aCSF/SR95531 activation in slices from PCB-exposed animals compared to control animals. This effect was seen in both the upper and lower layers of the AC. No differences in activation were noted between treatment groups when slices were exposed to AP5. These data suggest that developmental PCB exposure leads to increased sensitivity to antagonism of GABA A receptors in the AC without a change in NMDA-mediated intrinsic excitability., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Developmental exposure to polychlorinated biphenyls (PCBs) causes auditory deficits. Thus, we recently conducted a study to investigate if developmental PCB exposure would exacerbate noise-induced hearing loss in adulthood. Unexpectedly, some PCB-exposed rats exhibited seizure-like behaviors when exposed to loud noise. Therefore, we conducted the current experiment to determine if adult rats perinatally exposed to PCBs are more susceptible to audiogenic seizures when tested in a standard audiogenic seizure paradigm. Adult male and female rats exposed to PCBs during gestation and lactation (0, 1, 3 or 6 mg/kg/day) and previously tested in the noise-induced hearing loss study were presented with a 100 dB noise stimulus. If they did not exhibit clonus in response to the 100 dB noise, they were exposed to a 105 dB stimulus 24-48 h later. This was followed by an 110 dB stimulus 24-48 h later if they did not exhibit clonus at 105 dB. Female and male rats exposed to either 3 or 6 mg/kg PCBs exhibited a significantly higher incidence of audiogenic seizures, shorter latency to onset of seizures, and greater severity of seizures compared to controls. Thyroxine measured in littermates at weaning was significantly lower in all PCB groups compared to controls, suggesting a potential mechanism for the increased incidence of audiogenic seizures. This is the first study to show that developmental PCB exposure increases the susceptibility to audiogenic seizures in adulthood., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Attention deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurobehavioral disorder of childhood, yet its etiology is not well understood. In this review we present evidence that environmental chemicals, particularly polychlorinated biphenyls (PCBs) and lead, are associated with deficits in many neurobehavioral functions that are also impaired in ADHD., Data Sources: Human and animal studies of developmental PCB or lead exposures that assessed specific functional domains shown to be impaired in ADHD children were identified via searches of PubMed using "lead" or "PCB exposure" in combination with key words, including "attention," "working memory," "response inhibition," "executive function," "cognitive function," "behavior," and "ADHD.", Data Synthesis: Children and laboratory animals exposed to lead or PCBs show deficits in many aspects of attention and executive function that have been shown to be impaired in children diagnosed with ADHD, including tests of working memory, response inhibition, vigilance, and alertness. Studies conducted to date suggest that lead may reduce both attention and response inhibition, whereas PCBs may impair response inhibition to a greater degree than attention. Low-level lead exposure has been associated with a clinical diagnosis of ADHD in several recent studies. Similar studies of PCBs have not been conducted., Conclusions: We speculate that exposures to environmental contaminants, including lead and PCBs, may increase the prevalence of ADHD.

Objectives: Attention deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed childhood neurobehavioral disorder. Much research has been done to identify genetic, environmental, and social risk factors for ADHD; however, we are still far from fully understanding its etiology. In this review we provide an overview of diagnostic criteria for ADHD and what is known about its biological basis. We also review the neuropsychological functions that are affected in ADHD. The goal is to familiarize the reader with the behavioral deficits that are hallmarks of ADHD and to facilitate comparisons with neurobehavioral deficits associated with environmental chemical exposures., Data Sources: Relevant literature on ADHD is reviewed, focusing in particular on meta-analyses conducted between 2004 and the present that evaluated associations between measures of neuropsychological function and ADHD in children. Meta-analyses were obtained through searches of the PubMed electronic database using the terms "ADHD," "meta-analysis," "attention," "executive," and "neuropsychological functions." Although meta-analyses are emphasized, nonquantitative reviews are included for particular neuropsychological functions where no meta-analyses were available., Data Synthesis: The meta-analyses indicate that vigilance (sustained attention), response inhibition, and working memory are impaired in children diagnosed with ADHD. Similar but somewhat less consistent meta-analytic findings have been reported for impairments in alertness, cognitive flexibility, and planning. Additionally, the literature suggests deficits in temporal information processing and altered responses to reinforcement in children diagnosed with ADHD. Findings from brain imagining and neurochemistry studies support the behavioral findings., Conclusions: Behavioral, neuroanatomical, and neurochemical data indicate substantial differences in attention and executive functions between children diagnosed with ADHD and non-ADHD controls. Comparisons of the neurobehavioral deficits associated with ADHD and those associated with exposures to environmental chemicals may help to identify possible environmental risk factors for ADHD and/or reveal common underlying biological mechanisms.

The reproducibility of urinary phthalate metabolite concentrations has not been well characterized in non-pregnant women of reproductive age. Our primary study objectives were to describe the distribution of urinary phthalate metabolites concentrations among a population of Hmong women of reproductive age, and to evaluate intra- and inter-individual variability of phthalate metabolite concentrations. Ten phthalate metabolites were measured in first-morning urine samples collected from 45 women and 20 of their spouses, who were members of the Fox River Environment and Diet Study cohort in Green Bay, Wisconsin. Repeated first-morning urine samples were collected and analyzed from 25 women, who provided up to three samples over approximately 1 month. Measurement variability was assessed using intraclass correlations (ICCs) and surrogate category analysis. Linear mixed models were used to evaluate the associations between participant characteristics and phthalate metabolite concentrations. Nine of the 10 phthalate metabolites were detected in >80% of all analyzed samples, of which seven were detected in all samples. As a measure of reliability, ICCs were strongest for monobenzyl phthalate (0.64) and weakest for the metabolites of di(2-ethylhexyl)phthalate (DEHP) (ranging from 0.13 to 0.22). Similarly, surrogate category analysis suggested that a single urine sample characterized an average 1-month exposure with reasonable accuracy across low, medium and high tertiles for all metabolites, except the DEHP metabolites. Geometric mean concentrations of monoethyl phthalate increased with age, but patterns by education, income, body mass index, environmental tobacco smoke or season were not observed when measures were adjusted for urinary dilution. Our results suggest that the participant characteristics assessed in this study have limited influence on inter-individual variability of phthalate metabolite concentrations. With regard to intra-individual variability, our results suggest that urinary concentrations of some phthalate metabolites are more reproducible over time and are less subjected to exposure misclassification than others (e.g., metabolites of DEHP).

Schedule-controlled responding was examined in offspring of rats exposed to a PCB mixture formulated to mimic the PCB congener profile in fish from the Fox River in Green Bay, WI. Female rats were administered 0, 1, 3, or 6 mg/kg/day of the PCB mixture beginning four weeks prior to breeding until weaning on postnatal day 21. When offspring were approximately 235 days old, they were tested on three different schedules of a differential reinforcement of high rate (DRH) operant task (DRH 2:1, DRH 4:2, and DRH 8:4). DRH testing was followed by testing on the differential reinforcement of low rate (DRL) operant task in which rats had to inhibit responding until 15 s had elapsed (DRL 15) from the previous response in order to obtain a food reinforcer. After completion of DRL 15 testing, 3 days of extinction testing were conducted (DRL EXT) during which no reinforcers were delivered. Developmental exposure to the higher PCB doses resulted in shorter inter-response times (IRTs) and shorter response durations during DRH 8:4, which translated into a greater percentage of reinforced trials. For DRL 15, no significant exposure-related effects were observed on the number of responses or reinforcers earned, or the number or proportion of responses with long or short inter-response times during acquisition or steady state performance. However, during DRL EXT, rats developmentally exposed to the highest PCB dose responded more than controls, produced significantly more short IRT responses, and had a significantly lower proportion of long IRT responses. Overall, exposure to this PCB mixture resulted in increased responding which was suggestive of a deficit in inhibitory control.

Recent studies raise concern for combined exposure to polychlorinated biphenyls (PCBs) and methylmercury (MeHg), two environmental contaminants that are found in fish and seafood. Past accidental poisonings in humans show that exposure to high levels of either contaminant is associated with motor impairments, including alterations in cerebellar functions such as balance and coordination. Epidemiological studies of lower level exposures suggest some neuromotor impairment in exposed children, but the majority of these studies have focused on cognitive endpoints rather than examining a full-range of motor function. In particular, the cerebellum could be a sensitive target for combined PCB and MeHg toxicity. MeHg exposure during development damages the cerebellum along with cortical areas, and PCBs may also cause cerebellar damage via thyroid hormone disruption during development. In addition, in vitro studies report interactive effects of PCBs and MeHg on ryanodine-sensitive calcium signaling. Ryanodine receptors are found especially within the cerebellum, and alterations in calcium signaling within the cerebellum could impair long-term depression and subsequent motor learning. This article reviews the motor impairments reported in humans and laboratory animals following exposure to PCBs and/or MeHg during development. There is need for a better understanding of the interactive effects of PCBs and MeHg, especially in regard to motor function.

Previous studies have indicated that developmental exposure to polychlorinated biphenyls (PCBs) may result in hearing impairment in rats. The cochlea is the suggested site of action, based upon one study demonstrating a loss of outer hair cells on the basilar membrane, and another demonstrating deficits in distortion product otoacoustic emissions (DPOAEs). The current study was conducted to assess the possible ototoxic effects of a unique PCB mixture formulated to model the congener profile of PCBs found in fish consumed by a human population in northeastern Wisconsin. Female Long-Evans rats were dosed orally with the PCB mixture beginning 28 days prior to breeding and continuing until the pups were weaned. Dams were fed one-half of a cookie onto which was pipetted 0, 1, 3, or 6 mg/kg of the PCB mixture dissolved in a corn oil vehicle. On postnatal day (PND) 21, pups were weaned, and one male and one female from each litter were randomly selected for auditory assessment. DPOAEs were measured to assess cochlear function, and auditory brainstem responses (ABRs) were measured to determine effects on central nervous system auditory pathways. DPOAE amplitudes were decreased, and DPOAE and ABR thresholds were elevated across a range of frequencies in PCB-exposed rats. These results support and extend previous reports of auditory impairment in PCB-exposed rats. Developmental exposure to PCBs may also result in subtle auditory impairments in humans, and if so, this may contribute to some of the cognitive deficits that have been observed in epidemiological studies.

Epidemiological and laboratory studies indicate that polychlorinated biphenyls (PCBs) and methyl mercury (MeHg) may have additive or interactive adverse effects on nervous system function. Prior studies have shown that high doses of MeHg target the cerebellum and impair balance and coordination, but the effects of PCBs on cerebellar function were unknown. In addition, the combined effects of PCBs and MeHg on cerebellar function have not been studied previously. Therefore, we investigated the effects of developmental exposure to PCBs, MeHg, or PCBs + MeHg on three motor tasks that involve cerebellar functions. Female Long-Evans rats were exposed to MeHg (0.5 ppm in drinking water), PCBs (6-mg/kg/d Aroclor 1254), PCBs + MeHg, or vehicle only beginning 4 weeks prior to breeding, through pregnancy, and continuing through postnatal day (PND) 16. Starting at approximately PND 60, one male and one female from each litter were tested on three motor tasks that involve cerebellar function. PCB + MeHg-exposed rats were impaired relative to the controls on a task requiring them to traverse a rotating rod. Rats exposed to PCBs alone were also somewhat impaired relative to the controls, whereas MeHg-exposed rats were not significantly different from the controls. There were no statistically significant deficits related to PCB or MeHg exposure on a vertical rope-climbing test or a parallel bar test. Our results demonstrate that the possibility of additive neurotoxic effects of PCBs and MeHg needs to be seriously considered.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant that has been shown to alter spatial and visual learning following developmental exposure. The current study examined the effects of gestational and lactational exposure to TCDD on spatial and visual discrimination/reversal learning (spatial and visual RL) in rats using two-lever operant testing chambers. Pregnant Sprague-Dawley rats (10 per dose) received either 0 or 0.1 microg/kg TCDD per orem in corn oil from gestational day (GD) 10 to GD 16. One male and one female from each litter were tested beginning at 100 days of age. For spatial RL, animals were reinforced for pressing the lever associated with the correct spatial location (either left or right). For visual RL, the animals were reinforced for pressing the lever associated with the correct visual stimulus (either the illuminated or nonilluminated cuelight). After reaching 85% correct for two consecutive days, the opposite spatial location or visual cue was reinforced. Five reversals were conducted for spatial RL, and two reversals for visual RL. For spatial RL, there were no differences between the TCDD-exposed and control rats in total number of errors committed. However, an in-depth analysis of errors in four different phases of the learning process revealed that TCDD-exposed rats made more errors early in learning when they were just beginning to learn the new reinforcement contingencies. The importance of this increase in errors during the initial stage of learning is unclear, given that there was no increase in overall errors to criterion. For visual RL, there was a reduction in errors on original learning (OL) for TCDD-exposed males, while TCDD-exposed females exhibited a reduction in errors on the second reversal. Subsequent response pattern analyses revealed that the facilitation in performance was due to a more rapid transition through the early phase of learning. Why males were improved on OL and females were not until the second reversal is unknown, but the different patterns could reflect differences in learning style in male and female rats. In keeping with previous research, the results of the current study underscore the fact that (1) alterations in cognitive function observed following early TCDD exposure are very subtle and (2) under some conditions, learning is actually facilitated, rather than impaired, in TCDD-exposed animals.

Consumption of sport-caught fish from the Great Lakes is a recognized source of human exposure to polychlorinated biphenyls (PCBs). Understanding temporal changes in PCB body burden is crucial for evaluating exposure levels and augmenting validity of studies investigating their relationship to adverse health effects. Using data collected from 1980 to 1995, we evaluated longitudinal changes in serum PCB levels among 179 fisheaters and non-fisheaters of the Michigan Fisheater Cohort. Participants identified as fisheaters in 1980 ate 26 lb or more of sport-caught fish per year, whereas non-fisheaters ate less than 6 lb per year. We found a monotonic decline in serum PCB levels among all participants from a mean value of 24 ppb in 1980 to 12 ppb in 1994. This was paralleled by an 83% decrease in mean fish consumption among all participants over the same period. We combined demographic, lifestyle, and fish consumption information with PCB data and evaluated the data using regression models to identify predictors of PCB body burden over a 16-year period. Results of the mixed-effects linear regression model suggest that consumption of Lake Michigan fish before 1980, amount of sport-caught fish eaten in the past year, age, and year of data collection were significant determinants of current PCB body burden over the 16-year study period. PCB levels were particularly elevated for males who were classified as fisheaters in 1980, which may reflect higher levels of sport-caught fish consumption compared with female fisheaters.

In the last decade advances in the analytic methods for quantification of polychlorinated biphenyls (PCBs) have resulted in widespread availability of congener-specific analysis procedures, and large amounts of data on PCB congener profiles in soil, air, water, sediments, foodstuffs, and human tissues have become available. These data have revealed that the PCB residues in environmental media and human tissues may not closely resemble any of the commercial PCB mixtures, depending on source of exposure, bioaccumulation through the food chain, and weathering of PCBs in the environment. At the same time, toxicological research has led to a growing awareness that different classes of PCB congeners have different profiles of toxicity. These advances in analytic techniques and toxicological knowledge are beginning to influence the risk assessment process. As the data from ongoing PCB studies assessing the mediators of neurobehavioral outcomes in children are published, the weight of evidence for PCB effects on neurodevelopment is growing. Studies in Taiwan, Michigan (USA), New York (USA), Holland, Germany, and the Faroe Islands have all reported negative associations between prenatal PCB exposure and measures of cognitive functioning in infancy or childhood. The German study also reported a negative association between postnatal PCB exposure and cognitive function in early childhood--a result that had not been found in previous studies. Only one published study in North Carolina (USA) has failed to find an association between PCB exposure and cognitive outcomes. Despite the fact that several more recent studies have used congener-specific analytic techniques, there have been only limited attempts to assess the role of specific PCB congeners or classes of congeners in mediating neurodevelopmental outcomes. From a statistical standpoint, attempts to determine the role of individual congeners in mediating outcomes are hampered by the fact that concentrations of most individual congeners are highly correlated with each other and with total PCBs. From a toxicological standpoint, these efforts are hampered by the fact that many of the PCB congeners present in human tissues have never been studied in the laboratory, and their relative potency to produce nervous system effects is unknown. More complete information on the health effects of various congeners or congener classes would allow more informed scientific and risk assessment decisions.

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that are a potential health hazard to human and wildlife populations. Low-frequency auditory impairments have previously been documented in Aroclor 1254 (A 1254)-exposed rats, including elevated behavioral auditory thresholds and decreased amplitude and prolonged latency auditory evoked brain stem responses (ABRs). Furthermore, outer hair-cell loss on the basilar membrane of the cochlea has been documented, demonstrating that the cochlea is a target organ for PCB ototoxicity. The current experiment assessed the effects of A1254 on cochlear function by measuring distortion product otoacoustic emissions (DPOAEs). ABRs were measured to determine the effects of A1254 on the central nervous system auditory pathways. Pregnant Long-Evans rats received either 0 or 6 mg/kg A1254 (po) in corn oil from gestation day 6 to lactational day 21. The auditory function of male and female offspring was assessed at approximately 18 months of age. The rats were anesthetized and a probe-unit, consisting of 2 insert earphones and a microphone, was positioned in the ear canal. DPOAE amplitudes were reduced and thresholds increased in the A1254-exposed rats. The deficits were most pronounced at the lowest frequencies tested (2.1-3.2 kHz), but deficits were also observed at higher frequencies (3.7-8.6 kHz). Males and females were equally affected at the lower frequencies, but females were more impaired at the higher frequencies. In contrast, ABR latencies and amplitudes were not altered by A1254 exposure. These findings provide the first functional evidence supporting a cochlear site of damage in PCB-induced hearing loss.

An association between in utero polychlorinated biphenyl (PCB) exposure and impaired childhood intellectual functioning has been reported, but the potential impact of PCB exposure during adulthood on intellectual functioning has received little attention. We assessed the impact of PCBs and other fish-borne contaminants on intellectual functioning in older adults. The subjects were 49- to 86-year-old Michigan residents recruited from an existing cohort. Fish eaters ate > 24 lb of sport-caught Lake Michigan fish per year and non-fish eaters ate < 6 lb of Lake Michigan fish per year. A battery of cognitive tests including tests of memory and learning, executive function, and visual-spatial function was administered to 180 subjects (101 fish eaters and 79 non-fish eaters). Blood samples were analyzed for PCBs and 10 other contaminants. We evaluated cognitive outcomes using multiple regression. PCBs and dichlorodiphenyl dichloroethene (DDE) were markedly elevated in fish eaters. After controlling for potential confounders PCB, but not DDE, exposure was associated with lower scores on several measures of memory and learning. These included the Weschler Memory Scale verbal delayed recall (p = 0.001), the semantic cluster ratio (p = 0.006), and list A, trial 1 (p = 0.037), from the California Verbal Learning Test. In contrast, executive and visual-spatial function were not impaired by exposure to either PCBs or DDE. In conclusion, PCB exposure during adulthood was associated with impairments in memory and learning, whereas executive and visual-spatial function were unaffected. These results are consistent with previous research showing an association between in utero PCB exposure and impairments of memory during infancy and childhood.

Recently, we reported that in utero and lactational exposure to 2,3, 7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in a task-specific reduction of errors on the radial arm maze (RAM), without similar improvements on other spatial learning tasks including the Morris water maze. The effect was more pronounced in males than in females. This study further investigated the effects of in utero and lactational exposure to TCDD on RAM performance by testing male and female TCDD-exposed rats on either an eight-arm RAM with all arms baited or a 12-arm RAM with 8 of the 12 arms baited. If the rats have improved spatial learning or memory on the RAM, then they should be improved on both RAM tasks; whereas, if they are using adjacent arm selection or some other response strategy to solve the task, they should not show enhanced performance on the 12-arm RAM where not all the arms are rewarded. Time-mated Sprague-Dawley dams were gavaged with corn oil vehicle or one of two doses of TCDD in vehicle (0.1 or 0.2 microg/kg body weight) on gestational days 10 to 16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and female from each litter was tested on the eight-arm RAM with all arms baited. As in our previous studies, the 0.1-microg/kg TCDD-exposed male rats showed a significant decrease in the number of errors. However, the 0.2-microg/kg males did not differ from the controls. Neither group of TCDD-exposed females differed from the controls. None of the TCDD-exposed rats differed from the controls in adjacent arm selection behavior. An additional male and female from each litter were tested on the 12-arm RAM with only 8 of the 12 arms baited. In this task, neither TCDD group differed from the controls. These results suggest that the reduction of errors on the eight-arm RAM may be due to increased response patterning or use of intramaze cues rather than to improved spatial learning or memory. Also, the reduction in errors was only present at the lower dose of TCDD suggesting that the improvement in performance is only present at very low, nonovertly toxic doses of TCDD.

The State of Michigan has a long history of research into human exposure to environmental contaminants through consumption of recreationally caught fish. A large cohort of Lake Michigan residents who eat fish (fish-eaters) and those who do not eat fish (nonfish-eaters) established in 1980 served as the basis for the congener-specific polychlorinated biphenyl (PCB) exposure evaluation reported here. In this paper we present the serum PCB congener profile for a subset of this cohort who were over 50 years of age. Serum samples were collected in 1993-1995 and were evaluated by a dual column capillary column gas chromatography procedure capable of detecting over 90 PCB congeners. This evaluation demonstrated significant PCB exposure in the fish-eaters (mean serum PCB of 14.26 ppb; n = 101). This elevated exposure allowed the establishment of a detailed profile of the PCB congeners found in humans exposed by this route. Twenty-two congeners of varying concentrations were the most prevalent and constituted over 95% of the total PCB present in most subjects. Four congeners, 138/163 (2,2',3,4,4',5-PCB/2,3,3',4', 5,6-PCB), 180 (2,2',3,4,4',5,5'-PCB), and 153 (2,2',4,4',5,5'-PCB), accounted for 55-64% of the total PCB load. Other congeners, some of toxicologic significance, were also detected by this analytical protocol. Nonfish-eaters had lower total serum PCB levels (mean = 4. 56; n = 78), but the same general pattern of PCB congeners was present. It was demonstrated that careful selection of a subset of prevalent PCB congeners could provide a cost-effective assessment of exposure without losing critical scientific information.