Search

Background: Although diet and activity are key factors in the obesity epidemic, laboratory studies suggest that endocrine disrupting chemicals may also affect obesity.Methods: We analyzed associations between six phthalate metabolites measured in urine and body mass index (BMI) and waist circumference (WC) in National Health and Nutrition Examination Survey (NHANES) participants aged 6-80. We included 4369 participants from NHANES 1999-2002, with data on mono-ethyl (MEP), mono-2-ethylhexyl (MEHP), mono-n-butyl (MBP), and mono-benzyl (MBzP) phthalate; 2286 also had data on mono-2-ethyl-5-hydroxyhexyl (MEHHP) and mono-2-ethyl-5-oxohexyl (MEOHP) phthalate (2001-2002). Using multiple regression, we computed mean BMI and WC within phthalate quartiles in eight age/gender specific models.Results: The most consistent associations were in males aged 20-59; BMI and WC increased across quartiles of MBzP (adjusted mean BMI = 26.7, 27.2, 28.4, 29.0, p-trend = 0.0002), and positive associations were also found for MEOHP, MEHHP, MEP, and MBP. In females, BMI and WC increased with MEP quartile in adolescent girls (adjusted mean BMI = 22.9, 23.8, 24.1, 24.7, p-trend = 0.03), and a similar but less strong pattern was seen in 20-59 year olds. In contrast, MEHP was inversely related to BMI in adolescent girls (adjusted mean BMI = 25.4, 23.8, 23.4, 22.9, p-trend = 0.02) and females aged 20-59 (adjusted mean BMI = 29.9, 29.9, 27.9, 27.6, p-trend = 0.02). There were no important associations among children, but several inverse associations among 60-80 year olds.Conclusion: This exploratory, cross-sectional analysis revealed a number of interesting associations with different phthalate metabolites and obesity outcomes, including notable differences by gender and age subgroups. Effects of endocrine disruptors, such as phthalates, may depend upon endogenous hormone levels, which vary dramatically by age and gender. Individual phthalates also have different biologic and hormonal effects. Although our study has limitations, both of these factors could explain some of the variation in the observed associations. These preliminary data support the need for prospective studies in populations at risk for obesity. [ABSTRACT FROM AUTHOR]

Background: From May 1968 through March 1980, vinyl-lined asbestos-cement (VL/AC) water distribution pipes were installed in New England to avoid taste and odor problems associated with asbestos-cement pipes. The vinyl resin was applied to the inner pipe surface in a solution of tetrachloroethylene (perchloroethylene, PCE). Substantial amounts of PCE remained in the liner and subsequently leached into public drinking water supplies.Methods: Once aware of the leaching problem and prior to remediation (April-November 1980), Massachusetts regulators collected drinking water samples from VL/AC pipes to determine the extent and severity of the PCE contamination. This study compares newly obtained historical records of PCE concentrations in water samples (n = 88) with concentrations estimated using an exposure model employed in epidemiologic studies on the cancer risk associated with PCE-contaminated drinking water. The exposure model was developed by Webler and Brown to estimate the mass of PCE delivered to subjects' residences.Results: The mean and median measured PCE concentrations in the water samples were 66 and 0.5 microg/L, respectively, and the range extended from non-detectable to 2432 microg/L. The model-generated concentration estimates and water sample concentrations were moderately correlated (Spearman rank correlation coefficient = 0.48, p < 0.0001). Correlations were higher in samples taken at taps and spigots vs. hydrants (rho = 0.84 vs. 0.34), in areas with simple vs. complex geometry (rho = 0.51 vs. 0.38), and near pipes installed in 1973-1976 vs. other years (rho = 0.56 vs. 0.42 for 1968-1972 and 0.37 for 1977-1980). Overall, 24% of the variance in measured PCE concentrations was explained by the model-generated concentration estimates (p < 0.0001). Almost half of the water samples had undetectable concentrations of PCE. Undetectable levels were more common in areas with the earliest installed VL/AC pipes, at the beginning and middle of VL/AC pipes, at hydrants, and in complex pipe configurations.Conclusion: PCE concentration estimates generated using the Webler-Brown model were moderately correlated with measured water concentrations. The present analysis suggests that the exposure assessment process used in prior epidemiological studies could be improved with more accurate characterization of water flow. This study illustrates one method of validating an exposure model in an epidemiological study when historical measurements are not available. [ABSTRACT FROM AUTHOR]

Background: Diet is known to impact cardiovascular disease (CVD) risk, but evidence for the essential minerals of magnesium (Mg), calcium (Ca), and potassium (K) is inconsistent. Methods: We conducted a case-cohort study within a non-smoking subgroup of the Danish Diet, Cancer and Health cohort, a prospective study of 50-64-year-olds recruited between 1993-1997. We identified incident heart failure (HF), acute myocardial infarction (AMI) and stroke cases through 2015 with an 1135-member subcohort. We measured the dietary intake of minerals, also known as elements, and calculated a combined dietary intake (CDI) score based on joint Ca, Mg and K intakes (mg/d) from Food Frequency Questionnaires. We estimated adjusted hazard ratios (HRs) with Cox proportional hazard models. Results: Most HRs examining associations between CDI score and CVD were null. However, the third quartile of CDI was associated with a lower risk for heart failure (HR: 0.89; 95% CI: 0.67, 1.17), AMI (HR: 0.79; 95% CI: 0.60, 1.04), and stroke (HR: 0.63; 95% CI: 0.44, 0.88). Conclusions: We did not find consistent evidence to suggest that higher levels of essential minerals are associated with incident HF, AMI, and stroke, though results suggest a potential U-shaped relationship between select minerals and CVD outcomes.

Due to differences in chemical properties and half-lives, best practices for exposure assessment may differ for legacy versus novel brominated flame retardants (BFRs). Our objective was to identify the environment matrix that best predicted biomarkers of children's BFR exposures. Paired samples were collected from children aged 3-6 years and their homes, including dust, a small piece of polyurethane foam from the furniture, and a handwipe and wristband from each child. Biological samples collected included serum, which was analyzed for 11 polybrominated diphenyl ethers (PBDEs), and urine, which was analyzed for tetrabromobenzoic acid (TBBA), a metabolite of 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB). Significant positive correlations were typically observed between BFRs measured in dust, handwipes and wristbands, though wristbands and handwipes tended to be more strongly correlated with one another than with dust. PBDEs, EH-TBB and BEH-TEBP were detected in 30% of the sofa foam samples, suggesting that the foam was treated with PentaBDE or Firemaster® 550/600 (FM 550/600). PBDEs were detected in all serum samples and TBBA was detected in 43% of urine samples. Statistically significant positive correlations were observed between the environmental samples and serum for PBDEs. Urinary TBBA was 6.86 and 6.58 times more likely to be detected among children in the highest tertile of EH-TBB exposure for handwipes and wristbands, respectively (95 % CI: 2.61, 18.06 and 1.43, 30.05 with p < 0.001 and 0.02, respectively). The presence of either PentaBDE or FM 550/600 in furniture was also associated with significantly higher levels of these chemicals in dust, handwipes and serum (for PBDEs) and more frequent detection of TBBA in urine (p = 0.13). Our results suggest that children are exposed to a range of BFRs in the home, some of which likely originate from residential furniture, and that silicone wristbands are a practical tool for evaluating external exposure to both legacy and novel BFRs., 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 Elsevier Ltd. All rights reserved.)

Environmental toxicants (ETs) are associated with adverse health outcomes. Here we hypothesized that exposures to ETs are linked with obesity and insulin resistance partly through a dysbiotic gut microbiota and changes in the serum levels of secondary bile acids (BAs). Serum BAs, per- and polyfluoroalkyl substances (PFAS) and additional twenty-seven ETs were measured by mass spectrometry in 264 Danes (121 men and 143 women, aged 56.6 ± 7.3 years, BMI 29.7 ± 6.0 kg/m 2 ) using a combination of targeted and suspect screening approaches. Bacterial species were identified based on whole-genome shotgun sequencing (WGS) of DNA extracted from stool samples. Personalized genome-scale metabolic models (GEMs) of gut microbial communities were developed to elucidate regulation of BA pathways. Subsequently, we compared findings from the human study with metabolic implications of exposure to perfluorooctanoic acid (PFOA) in PPARα-humanized mice. Serum levels of twelve ETs were associated with obesity and insulin resistance. High chemical exposure was associated with increased abundance of several bacterial species (spp.) of genus (Anaerotruncus, Alistipes, Bacteroides, Bifidobacterium, Clostridium, Dorea, Eubacterium, Escherichia, Prevotella, Ruminococcus, Roseburia, Subdoligranulum, and Veillonella), particularly in men. Conversely, females in the higher exposure group, showed a decrease abundance of Prevotella copri. High concentrations of ETs were correlated with increased levels of secondary BAs including lithocholic acid (LCA), and decreased levels of ursodeoxycholic acid (UDCA). In silico causal inference analyses suggested that microbiome-derived secondary BAs may act as mediators between ETs and obesity or insulin resistance. Furthermore, these findings were substantiated by the outcome of the murine exposure study. Our combined epidemiological and mechanistic studies suggest that multiple ETs may play a role in the etiology of obesity and insulin resistance. These effects may arise from disruptions in the microbial biosynthesis of secondary BAs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matej Oresic reports financial support was provided by Research Council of Finland. Tuulia Hyotylainen reports financial support was provided by Novo Nordisk Foundation. Tuulia Hyotylainen reports financial support was provided by Swedish Research Council Formas. Tuulia Hyotylainen reports financial support was provided by Swedish Research Council. If there are other authors, they 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 Author(s). Published by Elsevier Ltd.. All rights reserved.)

A key goal of environmental health research is to assess the risk posed by mixtures of pollutants. As epidemiologic studies of mixtures can be expensive to conduct, it behooves researchers to incorporate prior knowledge about mixtures into their analyses. This work extends the Bayesian multiple index model (BMIM), which assumes the exposure-response function is a nonparametric function of a set of linear combinations of pollutants formed with a set of exposure-specific weights. The framework is attractive because it combines the flexibility of response-surface methods with the interpretability of linear index models. We propose three strategies to incorporate prior toxicological knowledge into construction of indices in a BMIM: (a) imposing directional homogeneity constraints on the weights, (b) structuring index weights by exposure transformations, and (c) placing informative priors on the index weights. We propose a novel prior specification that combines spike-and-slab variable selection with an informative Dirichlet distribution based on relative potency factors often derived from previous toxicological studies. In simulations we show that the proposed priors improve inferences when prior information is correct and can protect against misspecification suffered by naïve toxicological models when prior information is incorrect. Moreover, different strategies may be mixed-and-matched for different indices to suit available information (or lack thereof). We demonstrate the proposed methods on an analysis of data from the National Health and Nutrition Examination Survey and incorporate prior information on relative chemical potencies obtained from toxic equivalency factors available in the literature., (© 2023 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Background: Biomarker concentrations of metals are associated with neurodevelopment, and these associations may be modified by nutritional status (e.g., iron deficiency). No prior study on associations of metal mixtures with neurodevelopment has assessed effect modification by iron status., Objectives: We aimed to quantify associations of an industry-relevant metal mixture with verbal learning and memory among adolescents, and to investigate the modifying role of iron status on those associations., Methods: We used cross-sectional data from 383 Italian adolescents (10-14 years) living in proximity to ferroalloy industry. Verbal learning and memory was assessed using the California Verbal Learning Test for Children (CVLT-C), and metals were quantified in hair (manganese, copper, chromium) or blood (lead) using inductively coupled plasma mass spectrometry. Serum ferritin, a proxy for iron status, was measured using immunoassays. Covariate-adjusted associations of the metal mixture with CVLT subtests were estimated using Bayesian Kernel Machine Regression, and modification of the mixture associations by ferritin was examined., Results: Compared to the 50th percentile of the metal mixture, the 90th percentile was associated with a 0.12 standard deviation [SD] (95% CI = -0.27, 0.50), 0.16 SD (95% CI = -0.11, 0.44), and 0.11 SD (95% CI = -0.20, 0.43) increase in the number of words recalled for trial 5, long delay free, and long delay cued recall, respectively. For an increase from its 25th to 75th percentiles, copper was beneficially associated the recall trials when other metals were fixed at their 50th percentiles (for example, trial 5 recall: β = 0.31, 95% CI = 0.14, 0.48). The association between copper and trial 5 recall was stronger at the 75th percentile of ferritin, compared to the 25th or 50th percentiles., Conclusions: In this metal mixture, copper was beneficially associated with neurodevelopment, which was more apparent at higher ferritin concentrations. These findings suggest that metal associations with neurodevelopment may depend on iron status, which has important public health implications., 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 © 2023 Elsevier Inc. All rights reserved.)

Organofluorines occur in human serum as complex mixtures of known and unidentified compounds. Human biomonitoring traditionally uses targeted analysis to measure the presence of known and quantifiable per- and polyfluoroalkyl substances (PFAS) in serum, yet characterization of exposure to and quantification of PFAS are limited by the availability of methods and analytical standards. Studies comparing extractable organofluorine (EOF) in serum to measured PFAS using organofluorine mass balance show that measurable PFAS only explain a fraction of EOF in human serum and that other sources of organofluorine may exist. The gap in fluorine mass balance has important implications for human biomonitoring because the total body burden of PFAS cannot be characterized and the chemical species that make up unidentified EOF are unknown. Many highly prescribed pharmaceuticals contain organofluorine (e.g., Lipitor, Prozac) and are prescribed with dosing regimens designed to maintain a therapeutic range of concentrations in serum. Therefore, we hypothesize organofluorine pharmaceuticals contribute to EOF in serum. We use combustion ion chromatography to measure EOF in commercial serum from U.S. blood donors. Using fluorine mass balance, we assess differences in unexplained organofluorine (UOF) associated with pharmaceutical use and compare them with concentrations of organofluorine predicted based on the pharmacokinetic properties of each drug. Pharmacokinetic estimates of organofluorine attributable to pharmaceuticals ranged from 0.1 to 55.6 ng F/mL. Analysis of 44 target PFAS and EOF in samples of commercial serum (n = 20) shows the fraction of EOF not explained by Σ 44 PFAS ranged from 15% to 86%. Self-reported use of organofluorine pharmaceuticals is associated with a 0.36 ng F/mL (95% CL: -1.26 to 1.97) increase in UOF, on average, compared to those who report not taking organofluorine pharmaceuticals. Our study is the first to assess sources of UOF in U.S. serum and examine whether organofluorine pharmaceuticals contribute to EOF. Discrepancies between pharmacokinetic estimates and EOF may be partly explained by differences in analytical measurements. Future analyses using EOF should consider multiple extraction methods to include cations and zwitterions. Whether organofluorine pharmaceuticals are classified as PFAS depends on the definition of PFAS.

An important goal of environmental health research is to assess the risk posed by mixtures of environmental exposures. Two popular classes of models for mixtures analyses are response-surface methods and exposure-index methods. Response-surface methods estimate high-dimensional surfaces and are thus highly flexible but difficult to interpret. In contrast, exposure-index methods decompose coefficients from a linear model into an overall mixture effect and individual index weights; these models yield easily interpretable effect estimates and efficient inferences when model assumptions hold, but, like most parsimonious models, incur bias when these assumptions do not hold. In this paper, we propose a Bayesian multiple index model framework that combines the strengths of each, allowing for non-linear and non-additive relationships between exposure indices and a health outcome, while reducing the dimensionality of the exposure vector and estimating index weights with variable selection. This framework contains response-surface and exposure-index models as special cases, thereby unifying the two analysis strategies. This unification increases the range of models possible for analysing environmental mixtures and health, allowing one to select an appropriate analysis from a spectrum of models varying in flexibility and interpretability. In an analysis of the association between telomere length and 18 organic pollutants in the National Health and Nutrition Examination Survey (NHANES), the proposed approach fits the data as well as more complex response-surface methods and yields more interpretable results., (© 2021 The International Biometric Society.)

There are 9,000+ per- and polyfluoroalkyl substances (PFAS) in existence, which makes studying and regulating PFAS individually, or even as small mixtures, infeasible. Multiple PFAS definitions based on structure have been proposed, yet these definitions do not consider the implications for the full suite of organofluorine chemicals. For example, organofluorine pharmaceuticals, whose use may be essential and are found in human serum and wastewater, are not uniformly identified across all definitions. Using nine definitions prepared by various stakeholders, we screened the 360 organofluorine pharmaceuticals approved and used globally between 1954 and 2021. Definitions ranged in their inclusion of organofluorine pharmaceuticals (1%-100%). The most inclusive definitions include several top prescribed pharmaceuticals, e.g., Prozac and Lipitor. This analysis provides a framework against which organizations can make decisions about how best to proceed when defining PFAS., Competing Interests: W.H-B and R.G. are members of the Toxic Use Reduction Institute Science Advisory Board in Massachusetts. The authors declare no other competing interests., (© 2022 The Author(s).)

Background & Aims: Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms linking EC exposure with NAFLD remain poorly understood and there is no data on their impact on the human liver metabolome. Herein, we hypothesized that exposure to ECs, particularly perfluorinated alkyl substances (PFAS), impacts liver metabolism, specifically bile acid metabolism., Methods: In a well-characterized human NAFLD cohort of 105 individuals, we investigated the effects of EC exposure on liver metabolism. We characterized the liver (via biopsy) and circulating metabolomes using 4 mass spectrometry-based analytical platforms, and measured PFAS and other ECs in serum. We subsequently compared these results with an exposure study in a PPARa-humanized mouse model., Results: PFAS exposure appears associated with perturbation of key hepatic metabolic pathways previously found altered in NAFLD, particularly those related to bile acid and lipid metabolism. We identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables (liver fat content, HOMA-IR), in females than males. Specifically, we observed PFAS-associated upregulation of bile acids, triacylglycerols and ceramides, and association between chemical exposure and dysregulated glucose metabolism in females. The murine exposure study further corroborated our findings, vis-à-vis a sex-specific association between PFAS exposure and NAFLD-associated lipid changes., Conclusions: Females may be more sensitive to the harmful impacts of PFAS. Lipid-related changes subsequent to PFAS exposure may be secondary to the interplay between PFAS and bile acid metabolism., Lay Summary: There is increasing evidence that specific environmental contaminants, such as perfluorinated alkyl substances (PFAS), contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, it is poorly understood how these chemicals impact human liver metabolism. Here we show that human exposure to PFAS impacts metabolic processes associated with NAFLD, and that the effect is different in females and males., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Humans are exposed to a diverse mixture of chemical and non-chemical exposures across their lifetimes. Well-designed epidemiology studies as well as sophisticated exposure science and related technologies enable the investigation of the health impacts of mixtures. While existing statistical methods can address the most basic questions related to the association between environmental mixtures and health endpoints, there were gaps in our ability to learn from mixtures data in several common epidemiologic scenarios, including high correlation among health and exposure measures in space and/or time, the presence of missing observations, the violation of important modeling assumptions, and the presence of computational challenges incurred by current implementations. To address these and other challenges, NIEHS initiated the Powering Research through Innovative methods for Mixtures in Epidemiology (PRIME) program, to support work on the development and expansion of statistical methods for mixtures. Six independent projects supported by PRIME have been highly productive but their methods have not yet been described collectively in a way that would inform application. We review 37 new methods from PRIME projects and summarize the work across previously published research questions, to inform methods selection and increase awareness of these new methods. We highlight important statistical advancements considering data science strategies, exposure-response estimation, timing of exposures, epidemiological methods, the incorporation of toxicity/chemical information, spatiotemporal data, risk assessment, and model performance, efficiency, and interpretation. Importantly, we link to software to encourage application and testing on other datasets. This review can enable more informed analyses of environmental mixtures. We stress training for early career scientists as well as innovation in statistical methodology as an ongoing need. Ultimately, we direct efforts to the common goal of reducing harmful exposures to improve public health.

Human exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous, with mixtures of PFAS detected in drinking water, food, household dust, and other exposure sources. Animal toxicity studies and human epidemiology indicate that PFAS may act through shared mechanisms including activation of peroxisome proliferator activated receptor α (PPARα). However, the effect of PFAS mixtures on human relevant molecular initiating events remains an important data gap in the PFAS literature. Here, we tested the ability of modeling approaches to predict the effect of diverse PPARα ligands on receptor activity using Cos7 cells transiently transfected with a full length human PPARα (hPPARα) expression construct and a peroxisome proliferator response element-driven luciferase reporter. Cells were treated for 24 h with two full hPPARα agonists (pemafibrate and GW7647), a full and a partial hPPARα agonist (pemafibrate and mono(2-ethylhexyl) phthalate), or a full hPPARα agonist and a competitive antagonist (pemafibrate and GW6471). Receptor activity was modeled with three additive approaches: effect summation, relative potency factors (RPF), and generalized concentration addition (GCA). While RPF and GCA accurately predicted activity for mixtures of full hPPARα agonists, only GCA predicted activity for full and partial hPPARα agonists and a full agonist and antagonist. We then generated concentration response curves for seven PFAS, which were well-fit with three-parameter Hill functions. The four perfluorinated carboxylic acids (PFCA) tended to act as full hPPARα agonists while the three perfluorinated sulfonic acids (PFSA) tended to act as partial agonists that varied in efficacy between 28-67 % of the full agonist, positive control level. GCA and RPF performed equally well at predicting the effects of mixtures with three PFCAs, but only GCA predicted experimental activity with mixtures of PFSAs and a mixture of PFCAs and PFSAs at ratios found in the general population. We conclude that of the three approaches, GCA most accurately models the effect of PFAS mixtures on hPPARα activity in vitro. Understanding the differences in efficacy with which PFAS activate hPPARα is essential for accurately predicting the effects of PFAS mixtures. As PFAS can activate multiple nuclear receptors, future analyses should examine mixtures effects in intact cells where multiple molecular initiating events contribute to proximate effects and functional changes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Understanding the temporal trends and change of concentrations of per- and polyfluoroalkyl substances (PFAS) is important to evaluate the health impact of PFAS at both the individual- and population-level, however, limited information is available for pre-diabetic adults in the U.S., Objectives: Determine trends and rate of change of plasma PFAS concentrations in overweight or obese U.S. adults and evaluate variation by sex, race/ethnicity, and age., Methods: We described temporal trends of plasma PFAS concentrations using samples collected in 1996-1998, 1999-2001, and 2011-2012 from 957 pre-diabetic adults enrolled in the Diabetes Prevention Program (DPP) trial and Outcomes Study (DPPOS) and compared to serum concentrations from the National Health and Nutrition Examination Survey (NHANES 1999-2000, 2003-2016, adults with BMI ≥ 24 kg/m 2 ). We examined associations between participants' characteristics and PFAS concentrations and estimated the rate of change using repeated measures in DPP/DPPOS assuming a first-order elimination model., Results: Longitudinal measures of PFAS concentrations in DPP/DPPOS individuals were comparable to NHANES cross-sectional populational means. Plasma concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid, perfluorohexanesulfonic acid (PFHxS), N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA), and N-methylperfluorooctane sulfonamido acetic acid (MeFOSAA) started to decline after the year 2000 and concentrations of perfluorononanoic acid (PFNA) increased after 2000 and, for NHANES, decreased after 2012. We consistently observed higher PFOS, PFHxS and PFNA among male, compared to female, and higher PFOS and PFNA among Black, compared to white, participants. The estimated time for concentrations to decrease by half ranged from 3.39 years for EtFOSAA to 17.56 years for PFHxS., Discussion: We observed a downward temporal trend in plasma PFOS concentrations that was consistent with the timing for U.S. manufacturers' phaseout. Male and Black participants consistently showed higher PFOS and PFNA than female and white participants, likely due to differences in exposure patterns, metabolism or elimination kinetics., (Copyright © 2021. Published by Elsevier Ltd.)

Introduction: Understanding the neurodevelopmental effects of manganese (Mn) is complicated due to its essentiality for growth and development. While evidence exists for the harmful effects of excess Mn, pediatric epidemiologic studies have observed inconsistent associations between Mn and child cognition., Objective: We sought to estimate prospective associations between Mn measured in three different early-life time windows with adolescent cognition using deciduous teeth biomarkers., Methods: Deciduous teeth were collected from 195 participants (ages 10-14 years) of the Public Health Impact of Manganese Exposure (PHIME) study in Brescia, Italy. Measurements of tooth Mn represented prenatal (∼14 weeks gestation - birth), early postnatal (birth - 1.5 years) and childhood (∼1.5 - 6 years) time windows. Neuropsychologists administered the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), to obtain composite IQ and subtest scores. Associations between tooth Mn at each time window and adolescent WISC-III scores were estimated using multivariable linear regression. We tested differences in associations between Mn and outcomes across time windows using multiple informant models. Sex-specific associations were explored in stratified models., Results: Adjusted associations between tooth Mn and composite IQ scores were positive in the prenatal period and negative in the childhood period. Associations were strongest for subtest scores that reflect working memory, problem solving, visuospatial ability and attention: prenatal Mn was positively associated with Digits backward [SD change in score per interquartile range increase in Mn: β = 0.20 (95 % CI: 0.02, 0.38)] and Block design [β = 0.21 (0.01, 0.41)] and early postnatal Mn was positively associated with Digits forward [β = 0.24 (0.09, 0.40)], while childhood Mn was negatively associated with Coding [β = -0.14 (-0.28, -0.001)]. Sex-stratified analyses suggested different Mn-cognition associations for boys and girls and was also dependent on the time window of exposure., Conclusion: Our results suggest that exposure timing is critical when evaluating Mn associations between Mn and cognition. Higher prenatal Mn was beneficial for adolescent cognition; however, these beneficial associations shifted towards harmful effects in later time windows. Cognitive domains most sensitive to Mn across time windows included visuospatial ability, working memory, attention and problem-solving., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Quaternary ammonium compounds (QACs) are commonly used in a variety of consumer, pharmaceutical, and medical products. In this study, bioaccumulation potentials of 18 QACs with alkyl chain lengths of C8-C18 were determined in the in vitro-in vivo extrapolation (IVIVE) model using the results of human hepatic metabolism and serum protein binding experiments. The slowest in vivo clearance rates were estimated for C12-QACs, suggesting that these compounds may preferentially build up in blood. The bioaccumulation of QACs was further confirmed by the analysis of human blood (sera) samples ( n = 222). Fifteen out of the 18 targeted QACs were detected in blood with the ΣQAC concentrations reaching up to 68.6 ng/mL. The blood samples were collected during two distinct time periods: before the outbreak of the COVID-19 pandemic (2019; n = 111) and during the pandemic (2020, n = 111). The ΣQAC concentrations were significantly higher in samples collected during the pandemic (median 6.04 ng/mL) than in those collected before (median 3.41 ng/mL). This is the first comprehensive study on the bioaccumulation and biomonitoring of the three major QAC groups and our results provide valuable information for future epidemiological, toxicological, and risk assessment studies targeting these chemicals.

Early life exposure to per- and polyfluoroalkyl substances (PFAS) may adversely impact neurodevelopment, but epidemiological findings are inconsistent. In the Project Viva pre-birth cohort, we examined associations of prenatal and childhood PFAS plasma concentrations with parent and teacher assessments of children's behavior problems [Strengths and Difficulties Questionnaire (SDQ)] and executive function abilities [Behavior Rating Inventory of Executive Function (BRIEF)] at age 6-10 years (sample sizes 485-933). PFAS concentrations in pregnant Project Viva mothers (in 1999-2002) and children at ages 6-10 (in 2007-10) were similar to concentrations at similar time points in women and children in the nationally representative U.S. National Health and Nutrition Examination Survey. We observed no consistent associations of prenatal PFAS concentrations with behavior or executive function. Childhood concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA) and perfluorodecanoate (PFDA) were associated with higher parent-rated SDQ Total Difficulties scores (mean = 6.7, standard deviation (SD) = 4.9), suggesting greater behavioral problems (top (Q4) versus bottom (Q1) quartile PFOA: 1.5, 95% confidence interval (CI): 0.3, 2.7; PFOS: 1.4, 95% CI: 0.3, 2.5; PFHxS: 1.2, 95% CI: 0.1, 2.3; PFNA: 1.2, 95% CI: 0.1, 2.2; PFDA: 1.1, 95% CI: 0.0, 1.1); teacher-rated SDQ scores did not show associations. Higher childhood PFOS was associated with higher (indicating more problems) parent-rated BRIEF General Executive Composite (GEC) scores (standardized to mean = 50, SD = 10) (Q4 vs. Q1: 2.4, 95% CI: 0.2, 4.6), while teacher BRIEF GEC scores indicated more problems among children with higher PFHxS (Q4 vs. Q1: 3.5, 95% CI: -0.8, 6.3). There were no consistent patterns of sexual dimorphism in associations. In a cohort of U.S. children, we observed cross-sectional associations of childhood PFAS concentrations with greater behavioral and executive function problems, but no consistent associations with prenatal PFAS., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Per- and polyfluoroalkyl substances (PFAS) are pervasive in the environment resulting in nearly universal detection in people. Human serum PFAS concentrations are strongly associated with increased serum low-density lipoprotein cholesterol (LDL-C), and growing evidence suggests an association with serum triacylglycerides (TG). Here, we tested the hypothesis that perfluorooctanoic acid (PFOA) dysregulates liver and serum triacylglycerides in human peroxisome proliferator activated receptor α (hPPARα)-expressing mice fed an American diet. Mice were exposed to PFOA (3.5 mg/L) in drinking water for 6 weeks resulting in a serum concentration of 48 ± 9 μg/ml. In male and female hPPARα mice, PFOA increased total liver TG and TG substituted with saturated and monounsaturated fatty acids. Lack of expression of PPARα alone also increased total liver TG, and PFOA treatment had little effect on liver TG in PPARα null mice. In hPPARα mice, PFOA neither significantly increased nor decreased serum TG; however, there was a modest increase in TG associated with very low-density cholesterol particles in both sexes. Intriguingly, in female PPARα null mice, PFOA significantly increased serum TG, with a similar trend in males. PFOA also modified fatty acid and TG homeostasis-related gene expression in liver, in a hPPARα-dependent manner, but not in adipose. The results of our study and others reveal the importance of context (serum concentration and genotype) in determining the effect of PFOA on lipid homeostasis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Per- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals that have been associated with cardiovascular risk factors including elevated body weight and hypercholesterolemia. Therefore, PFAS may contribute to the development of atherosclerosis and cardiovascular disease (CVD). However, no previous study has evaluated associations between PFAS exposure and arterial calcification., Methods and Results: This study used data from 666 prediabetic adults enrolled in the Diabetes Prevention Program trial who had six PFAS quantified in plasma at baseline and two years after randomization, as well as measurements of coronary artery calcium (CAC) and ascending (AsAC) and descending (DAC) thoracic aortic calcification 13-14 years after baseline. We performed multinomial regression to test associations between PFAS and CAC categorized according to Agatston score [low (<10), moderate (11-400) and severe (>400)]. We used logistic regression to assess associations between PFAS and presence of AsAC and DAC. We adjusted models for baseline sex, age, BMI, race/ethnicity, cigarette smoking, education, treatment assignment (placebo or lifestyle intervention), and statin use. PFAS concentrations were similar to national means; 53.9% of participants had CAC > 11, 7.7% had AsAC, and 42.6% had DAC. Each doubling of the mean sum of plasma concentrations of linear and branched isomers of perfluorooctane sulfonic acid (PFOS) was associated with 1.49-fold greater odds (95% CI: 1.01, 2.21) of severe versus low CAC. This association was driven mainly by the linear (n-PFOS) isomer [1.54 (95% CI: 1.05, 2.25) greater odds of severe versus low CAC]. Each doubling of mean plasma N-ethyl-perfluorooctane sulfonamido acetic acid concentration was associated with greater odds of CAC in a dose-dependent manner [OR = 1.26 (95% CI:1.08, 1.47) for moderate CAC and OR = 1.37 (95% CI:1.07, 1.74) for severe CAC, compared to low CAC)]. Mean plasma PFOS and n-PFOS were also associated with greater odds of AsAC [OR = 1.67 (95% CI:1.10, 2.54) and OR = 1.70 (95% CI:1.13, 2.56), respectively], but not DAC. Other PFAS were not associated with outcomes., Conclusions: Prediabetic adults with higher plasma concentrations of select PFAS had higher risk of coronary and thoracic aorta calcification. PFAS exposure may be a risk factor for adverse cardiovascular health among high-risk populations., (Copyright © 2021. Published by Elsevier Ltd.)

Per- and polyfluoroalkyl substances (PFAS) are ubiquitously detected in populations worldwide and may hinder kidney function. The objective of the study was to determine longitudinal associations of plasma PFAS concentrations with estimated glomerular filtration rate (eGFR) and evaluate whether a lifestyle intervention modify the associations. We studied 875 participants initially randomized to the lifestyle or placebo arms in the Diabetes Prevention Program (DPP, 1996-2002) trial and Outcomes Study (DPPOS, 2002-2014). We ran generalized linear mixed models accounting a priori covariates to evaluate the associations between baseline PFAS concentrations and repeated measures of eGFR, separately, for six PFAS (PFOS, PFOA, PFHxS, EtFOSAA, MeFOSAA, PFNA); then used quantile-based g-computation to evaluate the effects of the six PFAS chemicals as a mixture. The cohort was 64.9% female; 73.4% 40-64 years-old; 29.4% with hypertension; 50.5% randomized to lifestyle intervention and 49.5% to placebo and had similar plasma PFAS concentrations as the general U.S. population in 1999-2000. Most participants had normal kidney function (eGFR > 90 mL/min/1.73 m 2 ) over the approximately 14 years of follow-up. We found that plasma PFAS concentrations during DPP were inversely associated with eGFR during DPPOS follow-up. Each quartile increase in baseline plasma concentration of the 6 PFAS as a mixture was associated with 2.26 mL/min/1.73 m 2 lower eGFR (95% CI: -4.12, -0.39) at DPPOS Year 5, approximately 9 years since DPP randomization and PFAS measurements. The lifestyle intervention did not modify associations, but inverse associations were stronger among participants with hypertension at baseline. Among prediabetic adults, we found inverse associations between baseline plasma PFAS concentrations and measures of eGFR throughout 14 years of follow-up. The lifestyle intervention of diet, exercise and behavioral changes did not modify the associations, but persons with hypertension may have heightened susceptibility., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In this study, we sought to expand our previous research on associations between bioactivities in dust and associated organic contaminants. Dust samples were collected from central NC homes (n = 188), solvent extracted, and split into two fractions, one for analysis using three different bioassays (nuclear receptor activation/inhibition and adipocyte development) and one for mass spectrometry (targeted measurement of 124 organic contaminants, including flame retardants, polychlorinated biphenyls, perfluoroalkyl substances, pesticides, phthalates, and polycyclic aromatic hydrocarbons). Approximately 80% of dust extracts exhibited significant adipogenic activity at concentrations that are comparable to estimated exposure for children and adults (e.g. ~20 μg/well dust) via either triglyceride accumulation (65%) and/or pre-adipocyte proliferation (50%). Approximately 76% of samples antagonized thyroid receptor beta (TRβ), and 21% activated peroxisome proliferator activated receptor gamma (PPARγ). Triglyceride accumulation was significantly correlated with TRβ antagonism. Sixty-five contaminants were detected in at least 75% of samples; of these, 26 were correlated with adipogenic activity and ten with TRβ antagonism. Regression models were used to evaluate associations of individual contaminants with adipogenic and TRβ bioactivities, and many individual contaminants were significantly associated. An exploratory g-computation model was used to evaluate the effect of mixtures. Contaminant mixtures were positively associated with triglyceride accumulation, and the magnitude of effect was larger than for any individually measured chemical. For each quartile increase in mixture exposure, triglyceride accumulation increased by 212% (RR = 3.12 and 95% confidence interval: 1.58, 6.17). These results suggest that complex mixtures of chemicals present in house dust may induce adipogenic activity in vitro at environmental concentrations and warrants further research., 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 © 2020 Elsevier B.V. All rights reserved.)

Nail polishes have evolved considerably. Toxic elements, such as lead, have been found in nail polish, and it is unclear if new finishes using metallic effect pigments may be contributing to metals exposure in nail technicians. We characterized concentrations of trace elements in 40 nail polishes, 9 technicians' urine, and 20 technicians' toenail clippings from 8 nail salons in the Boston area in 2017. We also collected 24 salon surface wipes from 3 of the salons. Antimony was not disclosed as a nail polish ingredient, yet concentrations (<15 μg/g) were above existing cosmetics guidelines (0.5 μg/g) in five (13%) of the samples. Aluminum (<11,450 μg/g), barium (<11,250 μg/g), iron (<3,270 μg/g), and magnesium (<2375 μg/g) were disclosed as ingredients and were also found on salon surfaces where nail polish was stored or used. Heavy metal impurities in nail polish were not detected for cadmium. Lead and nickel were found at low concentrations (<0.40 μg/g lead, <0.67 μg/g nickel). Tin (p = 0.003) concentrations were higher in nail polish with finishes compared to without. Barium and strontium (both p = 0.0001) concentrations were higher for red nail polishes compared to all other colors. Of those elements in nail polish and salon surfaces, aluminum and iron were detected in toenails, manganese was detected in urine and toenails, and barium was detected in urine at comparable levels to the general population. Besides preventable antimony levels in nail polish, individual metals in nail polish did not appear to be from impurities but mainly from colorants (i.e., pigments) and not major contributors to nail technician exposure. It is unclear if low-level chronic metals mixtures in nail salons are of health concern., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

We synthesize current understanding of the magnitudes and methods for assessing human and wildlife exposures to poly- and perfluoroalkyl substances (PFAS). Most human exposure assessments have focused on 2 to 5 legacy PFAS, and wildlife assessments are typically limited to targeted PFAS (up to ~30 substances). However, shifts in chemical production are occurring rapidly, and targeted methods for detecting PFAS have not kept pace with these changes. Total fluorine measurements complemented by suspect screening using high-resolution mass spectrometry are thus emerging as essential tools for PFAS exposure assessment. Such methods enable researchers to better understand contributions from precursor compounds that degrade into terminal perfluoroalkyl acids. Available data suggest that diet is the major human exposure pathway for some PFAS, but there is large variability across populations and PFAS compounds. Additional data on total fluorine in exposure media and the fraction of unidentified organofluorine are needed. Drinking water has been established as the major exposure source in contaminated communities. As water supplies are remediated, for the general population, exposures from dust, personal care products, indoor environments, and other sources may be more important. A major challenge for exposure assessments is the lack of statistically representative population surveys. For wildlife, bioaccumulation processes differ substantially between PFAS and neutral lipophilic organic compounds, prompting a reevaluation of traditional bioaccumulation metrics. There is evidence that both phospholipids and proteins are important for the tissue partitioning and accumulation of PFAS. New mechanistic models for PFAS bioaccumulation are being developed that will assist in wildlife risk evaluations. Environ Toxicol Chem 2021;40:631-657. © 2020 SETAC., (© 2020 SETAC.)

Background: People are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit. Challenges involved in designing research studies to evaluate the joint action of chemicals on cancer risk include the time taken to perform the experiments because of the long latency and choosing an appropriate experimental design., Objectives: The objectives of this work are to present the case for developing a research program on mixtures of environmental chemicals and cancer risk and describe recommended approaches., Methods: A working group comprising the coauthors focused attention on the design of mixtures studies to inform cancer risk assessment as part of a larger effort to refine the key characteristics of carcinogens and explore their application. Working group members reviewed the key characteristics of carcinogens, hallmarks of cancer, and mixtures research for other disease end points. The group discussed options for developing tractable projects to evaluate the joint effects of environmental chemicals on cancer development., Results and Discussion: Three approaches for developing a research program to evaluate the effects of mixtures on cancer development were proposed: a chemical screening approach, a transgenic model-based approach, and a disease-centered approach. Advantages and disadvantages of each are discussed. https://doi.org/10.1289/EHP8525.

Background: Environmental phenols, such as parabens, bisphenol A, and triclosan, are ubiquitous in indoor environments because of their use in packaging, plastics, personal care products, and as anti-microbials. The primary pathways of exposure, as well as habits and behaviors that may lead to greater exposure, are still unclear., Objectives: Herein, we investigate the relationships between phenols found in residential environments by comparing levels in paired samples of house dust and hand wipes with children's urine. In addition, phenols were analyzed in a novel exposure tool, the silicone wristbands, to investigate which external matrix best correlates with individual exposure based on urinary phenol biomarkers., Methods: Children aged 3-6 years in central North Carolina, United States, provided paired hand wipe (n = 202), wristband (n = 76), and spot urine samples (n = 180), while legal guardians completed questionnaires on habits and behaviors. House dust samples (n = 186) were collected from the main living area during home visits completed between 2014 and 2016., Results: Environmental phenols were detected frequently in all matrices investigated. Ethyl, methyl, and propylparaben levels observed in hand wipes, dust, and on wristbands were significantly correlated to their associated urinary biomarkers. In addition, intra-paraben correlations were noted, with biomarkers of ethyl, methyl, and propylparabens generally positively and significantly correlated, which suggests co-application of parabens in products. Triclosan levels in dust were positive and significantly correlated with levels in hand wipes and wristbands and with urinary concentrations, suggesting non-personal care product sources may be important in children's overall triclosan exposure. Generally, chemicals on wristbands were more highly correlated with urinary biomarkers than with chemicals in hand wipes or house dust. In addition, more frequent lotion use was positively associated with urinary concentrations of paraben biomarkers., Conclusions: Our results suggest that the home environment is an important source of exposure which has been under-investigated for some environmental phenols (e.g., triclosan in house dust). Associations between wristbands and biomarkers of exposure, which were stronger than for hand wipes and house dust, suggest that silicone wristbands may provide a suitable exposure assessment tool for some phenols., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Environmental exposures often occur in complex mixtures and at low concentrations. Generalized concentration addition (GCA) is a method used to estimate the joint effect of receptor ligands that vary in efficacy. GCA models have been successfully applied to mixtures of aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor gamma (PPARγ) ligands, each of which can be modeled as a receptor with a single binding site. Here, we evaluated whether GCA could be applied to homodimer nuclear receptors, which have two binding sites, to predict the combined effect of full glucocorticoid receptor (GR) agonists with partial agonists. We measured transcriptional activation of GR using a cell-based bioassay. Individual concentration-response curves for dexamethasone (full agonist), prednisolone (full agonist), and medroxyprogesterone 17-acetate (partial agonist) were generated and applied in three additivity models, GCA, effect summation (ES), and relative potency factor (RPF), to generate response surfaces. GCA and RPF yielded adequate predictions of the experimental data for two full agonists. However, GCA fit experimental data significantly better than ES and RPF for all other binary mixtures. This work extends the application of GCA to homodimer nuclear receptors and improves prediction accuracy of mixture effects of GR agonists., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Humans are exposed to per- and polyfluoroalkyl substances (PFAS) in their drinking water, food, air, dust, and by direct use of consumer products. Increased concentrations of serum total cholesterol and low density lipoprotein cholesterol are among the endpoints best supported by epidemiology. The objectives of this study were to generate a new model for examining PFAS-induced dyslipidemia and to conduct molecular studies to better define mechanism(s) of action. We tested the hypothesis that perfluorooctanoic acid (PFOA) exposure at a human-relevant level dysregulates expression of genes controlling cholesterol homeostasis in livers of mice expressing human PPARα (hPPARα). Female and male hPPARα and PPARα null mice were fed a diet based on the "What we eat in America" analysis and exposed to PFOA in drinking water (8 μM) for 6 weeks. This resulted in a serum PFOA concentration of 48 μg/ml. PFOA increased liver mass, which was associated with histologically-evident lipid accumulation. Pooled analyses of serum lipoprotein cholesterol suggest that PFOA increased serum cholesterol, particularly in male mice. PFOA induced PPARα and constitutive androstane receptor target gene expression in liver. Expression of genes in four pathways regulating cholesterol homeostasis were also measured. PFOA decreased expression of Hmgcr in a PPARα-dependent manner. PFOA decreased expression of Ldlr and Cyp7a1 in a PPARα-independent manner. Apob expression was not changed. Sex differences were evident. This novel study design (hPPARα mice, American diet, long term exposure) generated new insight on the effects of PFOA on cholesterol regulation in the liver and the role of hPPARα., 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 © 2020 Elsevier Inc. All rights reserved.)

Concentration/dose addition is widely used for compounds that act by similar mechanisms. But it cannot make predictions for mixtures of full and partial agonists for effect levels above that of the least efficacious component. As partial agonists are common, we developed generalized concentration addition, which has been successfully applied to systems in which ligands compete for a single binding site. Here, we applied a pharmacodynamic model for a homodimer receptor system with 2 binding sites, the androgen receptor, that acts according to the classic homodimer activation model: Each cytoplasmic monomer protein binds ligand, undergoes a conformational change that relieves inhibition of dimerization, and binds to DNA response elements as a dimer. We generated individual dose-response data for full (dihydroxytestosterone, BMS564929) and partial (TFM-4AS-1) agonists and a competitive antagonist (MDV3100) using reporter data generated in the MDA-kb2 cell line. We used the Schild method to estimate the binding affinity of MDV3100. Data for individual compounds fit the homodimer pharmacodynamic model well. In the presence of a full agonist, the partial agonist had agonistic effects at low effect levels and antagonistic effects at high levels, as predicted by pharmacological theory. The generalized concentration addition model fits the empirical mixtures data-full/full agonist, full/partial agonist, and full agonist/antagonist-as well or better than relative potency factors or effect summation. The ability of generalized concentration addition to predict the activity of mixtures of different types of androgen receptor ligands is important as a number of environmental compounds act as partial androgen receptor agonists or antagonists., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Research on the health effects of chemical mixtures has focused mainly on early life rather than adolescence, a potentially important developmental life stage., Objectives: We examined associations of a metal mixture with general cognition in a cross-sectional study of adolescents residing near ferromanganese industry, a source of airborne metals emissions., Methods: We measured manganese (Mn), lead (Pb), copper (Cu), and chromium (Cr) in hair, blood, urine, nails, and saliva from 635 Italian adolescents 10-14 years of age. Full-scale, verbal, and performance intelligence quotient (FSIQ, VIQ, PIQ) scores were assessed using the Wechsler Intelligence Scale for Children-III. Multivariable linear regression and Bayesian kernel machine regression (BKMR) were used to estimate associations of the metal mixture with IQ. In secondary analyses, we used BKMR's hierarchical variable selection option to inform biomarker selection for Mn, Cu, and Cr., Results: Median metal concentrations were as follows: hair Mn, 0.08 μ g / g ; hair Cu, 9.6 μ g / g ; hair Cr, 0.05 μ g / g ; and blood Pb, 1.3 μ g / dL . Adjusted models revealed an inverted U-shaped association between hair Cu and VIQ, consistent with Cu as an essential nutrient that is neurotoxic in excess. At low levels of hair Cu (10th percentile, 5.4 μ g / g ), higher concentrations (90th percentiles) of the mixture of Mn, Pb, and Cr ( 0.3 μ g / g , 2.6 μ g / dL , and 0.1 μ g / g , respectively) were associated with a 2.9 (95% CI: - 5.2 , - 0.5 )-point decrease in VIQ score, compared with median concentrations of the mixture. There was suggestive evidence of interaction between Mn and Cu. In secondary analyses, saliva Mn, hair Cu, and saliva Cr were selected as the biomarkers most strongly associated with VIQ score., Discussion: Higher adolescent levels of Mn, Pb, and Cr were associated with lower IQ scores, especially at low Cu levels. Findings also support further investigation into Cu as both beneficial and toxic for neurobehavioral outcomes. https://doi.org/10.1289/EHP6803.

The objective of the study was to determine the human serum elimination half-life of polybrominated diphenyl ethers (PBDEs) adjusted for ongoing exposure in subjects moving from a higher exposure region (North America) to a lower exposure region (Australia). The study population was comprised of exchange students and long-term visitors from North America moving to Brisbane, Australia (N = 27) and local residents (N = 23) who were followed by repeated serum sampling every other month. The local residents were sampled to adjust for ongoing exposure in Australia. Only one visitor remained in Australia for a period of time similar to the elimination half-life and had a sufficiently high initial concentration of PBDEs to derive a half-life. This visitor arrived in Australia in March of 2011 and remained in the country for 1.5 years. Since the magnitude of PBDE exposure is lower in Australia than in North America we observed an apparent 1st order elimination curve over time from which we have estimated the serum elimination half-lives for BDE28, BDE47, BDE99, BDE100, and BDE153 to be 0.942, 1.19, 1.03, 2.16, and 4.12 years, respectively. Uncertainty in the estimates were estimated using a Monte Carlo simulation. The human serum elimination half-life adjusted for ongoing exposure can allow us to assess the effectiveness and reduction in exposure in the general population following phase out of commercial penta- and octaBDE in 2004 in the United States., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Maternal and neonatal thyroid function is critical for growth and neurodevelopment. Exposure to individual per- and polyfluoroalkyl substances (PFAS) can alter circulating thyroid hormone levels, but few studies have investigated effects of combined exposure to multiple PFAS., Objectives: Estimate associations of exposure to multiple PFAS during early pregnancy with maternal and neonatal thyroid function., Methods: The study population consisted of 726 mothers and 465 neonates from Project Viva, a Boston, Massachusetts area longitudinal pre-birth cohort. We measured six PFAS [perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), 2-(N-ethyl-perfluorooctane sulfonamido)acetate (EtFOSAA), and 2-(N-methyl-perfluorooctane sulfonamido)acetate (MeFOSAA)] and thyroxine (T 4 ), Free T 4 Index (FT 4 I), and thyroid stimulating hormone (TSH) in maternal plasma samples collected during early pregnancy, and neonatal T 4 in postpartum heel sticks. We estimated individual and joint effects of PFAS exposure with thyroid hormone levels using weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR), and evaluated potential non-linearity and interactions among PFAS using BKMR., Results: Higher concentrations of the PFAS mixture were associated with significantly lower maternal FT 4 I, with MeFOSAA, EtFOSAA, PFOA, and PFHxS contributing most to the overall mixture effect in BKMR and WQS regression. In infants, higher concentrations of the PFAS mixture were associated with lower T 4 levels, primarily in males, with PFHxS and MeFOSAA contributing most in WQS, and PFHxS contributing most in BKMR. The PFAS mixture was not associated with maternal T 4 or TSH levels. However, in maternal BKMR analyses, ln-PFOS was positively associated with T 4 levels (Δ25 th to 75th percentile: 0.21 µg/dL; 95% credible interval: -0.03, 0.47) and ln-PFHxS was associated with a non-linear effect on TSH levels., Conclusions: These findings support the hypothesis that there may be combined effects of prenatal exposure to multiple PFAS on maternal and neonatal thyroid function, but the direction and magnitude of these effects may vary across individual PFAS., 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 © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Organophosphate esters (OPEs) are applied as additive flame retardants, and along with phthalates, are also used as plasticizers in consumer products. As such, human exposure is common and chronic. Deployed as personal passive samplers, silicone wristbands have been shown to detect over a thousand industrial and consumer product chemicals; however, few studies have evaluated chemical concentrations with their corresponding biomarkers of exposure, especially in children. Further, little is known about how well the wristbands predict individual exposure compared to existing validated external exposure tools such as indoor air, dust, and hand wipes. Here, we analyzed wristbands worn by children (ages 3-6) for 18 OPEs and 10 phthalates and compared them to corresponding urinary biomarkers. In wristbands, 13 of 18 OPEs and all phthalates were detected in >80% of wristbands, and 6 OPEs and 4 phthalates were significantly associated with corresponding urinary metabolites ( r s = 0.2-0.6, p < 0.05). When compared to paired hand wipes and house dust, wristbands were found to have similar or greater correlation coefficients with respective urinary biomarkers. These results suggest that wristbands can serve as effective and quantitative assessment tools for evaluating personal exposure to some OPEs and phthalates, and for certain chemicals, may provide a better exposure estimate than indoor dust.

Diet is assumed to be the main source of exposure to per- and polyfluoroalkyl substances (PFAS) in non-occupationally exposed populations, but studies on the diet-PFAS relationship in the United States are scarce. We extracted multiple dietary variables, including daily intakes of food group, diet scores, and dietary patterns, from self-reported dietary data collected at baseline (1996-1999) from adults with pre-diabetes enrolled in the Diabetes Prevention Program, and used linear regression models to evaluate relationships of each dietary variable with plasma concentrations of six PFAS (perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid (EtFOSAA), 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA), perfluorononanoic acid (PFNA) adjusting for covariates. Participants (N = 941, 65% female, 58% Caucasian, 68% married, 75% with higher education, 95% nonsmoker) had similar PFAS concentrations compared to the general U.S. population during 1999-2000. Using a single food group approach, fried fish, other fish/shellfish, meat and poultry had positive associations with most PFAS plasma concentrations. The strongest effect estimate detected was between fried fish and PFNA [13.6% (95% CI: 7.7, 19.9) increase in median concentration per SD increase]. Low-carbohydrate and high protein diet score had positive association with plasma PFHxS. Some food groups, mostly vegetables and fruits, and the Dietary Approaches to Stop Hypertension diet score had inverse associations with PFOS and MeFOSAA. A vegetable diet pattern was associated with lower plasma concentrations of MeFOSAA, while high-fat meat and low-fiber and high-fat grains diet patterns were associated with higher plasma concentrations of PFOS, PFHxS, MeFOSAA and PFNA. We summarized four major dietary characteristics associated with variations in PFAS plasma concentrations in this population. Specifically, consuming more meat/fish/shellfish (especially fried fish, and excluding Omega3-rich fish), low-fiber and high-fat bread/cereal/rice/pasta, and coffee/tea was associated with higher plasma concentrations while dietary patterns of vegetables, fruits and Omega-3 rich fish were associated with lower plasma concentrations of some PFAS., 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 © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The relationship of plasma concentration of per- and polyfluoroalkyl substances (PFAS) with blood pressure (BP) is uncertain. This study examined cross-sectional and prospective associations of PFAS with BP and hypertension. We quantified plasma PFAS concentrations from 957 participants enrolled in the lifestyle and placebo arms of the Diabetes Prevention Program (DPP), a randomized controlled trial with approximately 15 years of follow-up. We used multivariable linear and logistic regressions to test cross-sectional associations of six PFAS, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA), N-methyl-perfluorooctane sulfonamido acetic acid (MeFOSAA), and perfluorononanoic acid (PFNA), with BP and hypertension prevalence, respectively, at baseline. We used generalized linear mixed models to estimate longitudinal associations between baseline PFAS and the rate of BP changes, and Cox-Proportional hazard models to estimate risk of developing hypertension relative to baseline PFAS. Models were adjusted for baseline age, sex, race/ethnicity, treatment arm, educational attainment, income, marital status, smoking habit, alcohol drinking, and diet. We tested for effect modification by the treatment arm and sex, and accounted for multiple comparisons using the False-Discovery Rate (FDR). PFAS concentrations and hypertension prevalence within the study population (65.3% female, 57.7% White, 65.3% aged 40-59 years) were comparable to the general U.S. population. Cross-sectionally, we found small but statistically significant associations of baseline plasma concentrations of PFOA with systolic BP (β per doubling: 1.49 mmHg, 95% CI: 0.29, 2.70); and MeFOSAA with hypertension (RR = 1.09 per doubling, 95% CI: 1.01, 1.19). Estimates were not statistically significant after FDR adjustment. Longitudinally, we observed null associations in the placebo arm, but some inverse associations of baseline PFOS and MeFOSAA with systolic BP in the lifestyle arm, perhaps due to regression toward the mean. Baseline PFAS concentrations also were not prospectively associated with hypertension risk. Overall, there were modest and mostly null associations of plasma PFAS concentrations with BP and hypertension., 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 © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tetrachloroethylene (PCE) is a common contaminant in both occupational and community settings. High exposure levels in the workplace have been shown to have adverse impacts on reproduction and development but few epidemiological studies have examined these effects at the lower levels commonly seen in community settings. We were presented with a unique opportunity to examine the reproductive and developmental effects of prenatal exposure to PCE-contaminated drinking water resulting from the installation of vinyl-lined water pipes in Massachusetts and Rhode Island from the late 1960s through 1980. This review describes the methods and findings of two community-based epidemiological studies, places their results in the context of the existing literature, and describes the strengths and challenges of conducting epidemiological research on a historical pollution episode. Our studies found that prenatal exposure to PCE-contaminated drinking water is associated with delayed time-to-pregnancy, and increased risks of placental abruption, stillbirths stemming from placental dysfunction, and certain birth defects. No associations were observed with pregnancy loss, birth weight, and gestational duration. Important strengths of this research included the availability of historical data on the affected water systems, a relatively high exposure prevalence and wide range of exposure levels, and little opportunity for recall bias and confounding. Challenges arose mainly from the retrospective nature of the exposure assessments. This research highlights the importance of considering pregnant women and their developing fetuses when monitoring, regulating, and remediating drinking water contaminants.

Relatively little is known about the exposure of nail technicians to semivolatile organic compounds (SVOCs) in nail salons. We collected preshift and postshift urine samples and silicone wrist bands (SWBs) worn on lapels and wrists from 10 female nail technicians in the Boston area in 2016-17. We analyzed samples for phthalates, phthalate alternatives, and organophosphate esters (OPEs) or their metabolites. Postshift urine concentrations were generally higher than preshift concentrations for SVOC metabolites; the greatest change was for a metabolite of the phthalate alternative di(2-ethylhexyl) terephthalate (DEHTP): mono(2-ethyl-5-carboxypentyl) terephthalate (MECPTP) more than tripled from 11.7 to 36.6 μg/g creatinine. DEHTP biomarkers were higher in our study participants' postshift urine compared to 2015-2016 National Health and Nutrition Examination Survey females. Urinary MECPTP and another DEHTP metabolite were moderately correlated ( r = 0.37-0.60) with DEHTP on the SWBs, suggesting occupation as a source of exposure. Our results suggest that nail technicians are occupationally exposed to certain phthalates, phthalate alternatives, and OPEs, with metabolites of DEHTP showing the largest increase across a work day. The detection of several of these SVOCs on SWBs suggests that they can be used as a tool for examining potential occupational exposures to SVOCs among nail salon workers.

Background: Phthalates and their potential replacements, including non-phthalate plasticizers, are ubiquitous in home environments due to their presence in building materials, plastics, and personal care products. As a result, exposure to these compounds is universal. However, the primary pathways of exposure and understanding which products in the home are associated most strongly with particular exposures are unclear., Objectives: We sought to investigate the relationships between phthalates and non-phthalate plasticizers in paired samples of house dust, hand wipes, and their corresponding metabolites in children's urine samples (n = 180). In addition, we compared product use or presence of materials in the household against all compounds to investigate the relationship between product use or presence and exposure., Methods: Children aged 3-6 years provided hand wipe and urine samples. Questionnaires were completed by mothers or legal guardians to capture product use and housing characteristics, and house dust samples were collected from the main living area during home visits., Results: Phthalates and non-phthalate replacements were detected frequently in the environmental matrices. All urine samples had at least 13 of 19 phthalate or non-phthalate replacement metabolites present. Hand wipe mass and dust concentrations of diisobutyl phthalate, benzyl butyl phthalate (BBP), bis(2-ethylhexyl) phthalate, and di-isononyl phthalate were significantly associated with their corresponding urinary metabolites (r s  = 0.18-0.56, p < 0.05). Bis(2-ethylhexyl) terephthalate (DEHTP) in dust was also significantly and positively correlated with its urinary metabolites (r s  = 0.33, p < 0.001). Vinyl flooring was most significantly and positively associated with particular phthalate exposures (indicated by concentrations in environmental matrices and urinary biomarkers). In particular, children who lived in homes with 100% vinyl flooring had urinary concentrations of monobenzyl phthalate, a BBP metabolite, that were 15 times higher than those of children who lived in homes with no vinyl flooring (p < 0.0001). Levels of BBP in hand wipes and dust were 3.5 and 4.5 times higher, respectively, in those homes with 100% vinyl flooring (p < 0.0001 for both)., Conclusions: This paper summarizes one of the most comprehensive phthalate and non-phthalate plasticizer investigation of potential residential exposure sources conducted in North America to date. The data presented herein provide evidence that dermal contact and hand-to-mouth behaviors are important sources of exposure to phthalates and non-phthalate plasticizers. In addition, the percentage of vinyl flooring is an important consideration when examining residential exposures to these compounds., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Concentration addition/dose addition (CA) has proved to be a powerful tool for estimating the combined effect of mixtures that act by similar mechanisms. We earlier proposed generalized concentration addition (GCA) to deal with the inability of CA to estimate effects of mixtures above the level of the least efficacious component. GCA requires specifying mathematical concentration response functions for each mixture component that must be invertible, yielding real numbers. We construct concentration response functions using pharmacodynamic models of ligand-receptor interaction, an important molecular initiating event for adverse outcome pathways. Here, we extend our earlier work in two novel ways. First, we show how composite functions can be used to extend these predictions to downstream events. Second, we show that GCA can accommodate not only receptors with single binding sites but also receptors that bind ligand at each monomer and then dimerize. The derived concentration response functions for receptors that homodimerize meet the requirements for using GCA., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are suspected endocrine disruptors widely detected across populations. We examine the extent to which PFASs are associated with diabetes incidence and microvascular disease. Secondarily, we tested whether a lifestyle intervention modifies associations and decreases concentrations., Research Design and Methods: We analyzed data from a prospective cohort of 957 participants from the Diabetes Prevention Program (DPP) trial and Diabetes Prevention Program Outcomes Study (DPPOS). At baseline, participants were randomized to an intensive lifestyle intervention of diet, physical activity, and behavior modification or a placebo medication. We quantified plasma concentrations of six PFASs at baseline and 2 years after randomization. Participants were monitored for ∼15 years, repeatedly tested for diabetes, and evaluated for microvascular disease at the end of the follow-up., Results: A doubling in baseline branched perfluorooctanoic acid concentration was associated with a 14% increase in diabetes risk for the placebo (hazard ratio [HR] 1.14, 95% CI 1.04, 1.25) but not in the lifestyle intervention group (HR 1.01, 95% CI 0.92, 1.11, P interaction = 0.11). Mean change in plasma baseline branched perfluorooctanoic acid concentration was greater for the placebo (0.96 ng/mL; 95% CI 0.71, 1.22) compared with the lifestyle intervention group (0.31 ng/mL; 95% CI 0.14, 0.48) 2 years after randomization. Each doubling in N -ethyl-perfluorooctane sulfonamido acetic acid was associated with 17% greater odds of prevalent microvascular disease (OR 1.17, 95% CI 1.05, 1.31), and a similar association was observed for perfluorodimethylhexane sulfonic acid (OR 1.18, 95% CI 1.04, 1.35), regardless of treatment., Conclusions: Some plasma PFASs were associated with diabetes and microvascular disease. Our results suggest that exercise and diet may attenuate the diabetogenic association of PFASs., (© 2019 by the American Diabetes Association.)

Exposure to per- and polyfluoroalkyl substances (PFASs) may interfere with lipid regulation. However, most previous studies were cross-sectional with the risk of reverse causation, suggesting a need for long-term prospective studies. We examined the relationship of baseline plasma PFAS concentrations with repeated measures of blood lipids. We included 888 prediabetic adults from the Diabetes Prevention Program (DPP) and DPP Outcomes Study, who had measurements of 6 plasma PFAS concentrations at baseline (1996-1999) and repeated measures of blood lipids over 15 years of follow-up, and were initially randomized to placebo or a lifestyle intervention. We used linear regression to examine cross-sectional associations of PFAS concentrations and lipid levels at baseline, and evaluated prospective risks of hypercholesterolemia and hypertriglyceridemia using Cox proportional hazard models, and tested for effect modification by study arm. Participants (65.9% female, 57.0% White, 65.9% aged 40-59 years) had comparable PFAS concentrations [e.g., median (IQR) perfluorooctanoic acid (PFOA) 4.9 ng/mL (3.2)] with the general U.S. population in 1999-2000. We observed higher total cholesterol at baseline per doubling of PFOA (β: 6.1 mg/dL, 95% CI: 3.1, 9.04), perfluorohexane sulfonic acid (PFHxS, β: 2.2 mg/dL, 95% CI: 0.2, 4.3), and perfluorononanoic acid (PFNA, β: 2.9 mg/dL, 95% CI: 0.7, 5.0). Prospectively, baseline concentrations of several PFASs, including PFOA, PFOS, PFHxS and PFNA, predicted higher risks of incident hypercholesterolemia and hypertriglyceridemia, but only in the placebo group and not the lifestyle intervention group. For example, participants in the placebo group with PFOA concentration > median (4.9 ng/mL) were almost twice as likely (HR: 1.90, 95% CI: 1.25, 2.88) to develop hypertriglyceridemia compared to those ≤median. Findings suggest adverse effects of some PFASs on lipid profiles in prediabetic adults. However, the detrimental effect was attenuated with a lifestyle intervention., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Nail technicians are exposed to volatile organic compounds (VOCs) from nail products, but no studies have previously measured VOC biomarkers for these workers. This study of 10 nail technicians aimed to identify VOCs in nail salons and explore relationships between air concentrations and biomarkers. Personal and area air samples were collected using thermal desorption tubes during a work shift and analyzed using gas chromatography/mass spectrometry (GC/MS) for 71 VOCs. Whole blood samples were collected pre-shift and post-shift, and analyzed using GC/MS for 43 VOCs. Ventilation rates were determined using continuous CO 2 measurements. Predominant air VOC levels were ethyl methacrylate (median 240 µg/m 3 ), methyl methacrylate (median 205 µg/m 3 ), toluene (median 100 µg/m 3 ), and ethyl acetate (median 639 µg/m 3 ). Blood levels were significantly higher post-shift than pre-shift for toluene (median pre-shift 0.158 µg/L and post-shift 0.360 µg/L) and ethyl acetate (median pre-shift <0.158 µg/L and post-shift 0.510 µg/L); methacrylates were not measured in blood because of their instability. Based on VOCs measured in these seven nail salons, we estimated that emissions from Greater Boston area nail salons may contribute to ambient VOCs. Ventilation rates did not always meet the ASHRAE guideline for nail salons. There is a need for changes in nail product formulation and better ventilation to reduce VOC occupational exposures., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Humans are exposed to a complex mixture of environmental chemicals that impact bone and metabolic health, and traditional exposure assessments struggle to capture these exposure scenarios. Peroxisome proliferator activated receptor-gamma (PPARγ) is an essential regulator of metabolic and bone homeostasis, and its inappropriate activation by environmental chemicals can set the stage for adverse health effects. Here, we present the development of the Serum PPARγ Activity Assay (SPAA), a simple and cost-effective method to measure total ligand activity in small volumes of serum., Methods: First, we determined essential components of the bioassay. Cos-7 cells were transfected with combinations of expression vectors for human PPARγ and RXRα, the obligate DNA-binding partner of PPARγ, along with PPRE (DR1)-driven luciferase and control eGFP reporter constructs. Transfected cells were treated with rosiglitazone, a synthetic PPARγ ligand and/or LG100268, a synthetic RXR ligand, to characterize the dose response and determine the simplest and most efficacious format. Following optimization of the bioassay, we assessed the cumulative activation of PPARγ by ligands in serum from mice treated with a PPARγ ligand and commercial human serum samples., Results: Cos-7 cells endogenously express sufficient RXR to support efficacious activation of transfected PPARγ. Co-transfection of an RXR expression vector with the PPARγ expression vector did not increase PPRE transcriptional activity induced by rosiglitazone. Treatment with an RXR ligand marginally increased PPRE transcriptional activity in the presence of transfected PPARγ, and co-treatment with an RXR ligand reduced rosiglitazone-induced PPRE transcriptional activity. Therefore, the final bioassay protocol consists of transfecting Cos-7 cells with a PPARγ expression vector along with the reporter vectors, applying rosiglitazone standards and/or 10 μL of serum, and measuring luminescence and fluorescence after a 24 h incubation. Sera from mice dosed with rosiglitazone induced PPRE transcriptional activity in the SPAA in a dose-dependent and PPARγ-dependent manner. Additionally, human serum from commercial sources induced a range of PPRE transcriptional activities in a PPARγ-dependent manner, demonstrating the ability of the bioassay to detect potentially low levels of ligands., Conclusions: The SPAA can reliably measure total PPRE transcriptional activity in small volumes of serum. This system provides a sensitive, straightforward assay that can be reproduced in any cell culture laboratory.

In the 2000s, nail polish manufacturers started promoting "3-Free" products, phasing out three widely publicized toxic chemicals: toluene, formaldehyde, and dibutyl phthalate (DnBP). However, DnBP was sometimes replaced by another endocrine-disrupting plasticizer, triphenyl phosphate (TPHP). Many new " n-Free" labels have since appeared, without any standardization on which n chemicals are excluded. This study aimed to compare measured plasticizer content against nail polish labels. First, we summarized definitions of labels. Then, we measured 12 phthalate and 10 organophosphate plasticizers in 40 nail polishes from 12 brands selected for popularity and label variety. We found labels ranging from 3- to 13-Free; 10-Free was the most inconsistently defined (six definitions). Our samples contained TPHP and bis(2-ethylhexyl) phthalate (DEHP) at up to 7940 and 331 μg/g, respectively. The 5- to 13-Free samples had lower TPHP levels than unlabeled or 3-Free samples (median <0.002 vs 3730 μg/g, p < 0.001). The samples that did not contain TPHP had higher DEHP levels (median 68.5 vs 1.51 μg/g, p < 0.05). We measured plasticizers above 100 μg/g in five brands that did not disclose them and in two that excluded them in labels. This study highlights inconsistencies in nail polish labels and identifies TPHP and DEHP as ingredient substitutes for DnBP.

Semi-volatile organic compounds (SVOCs) are used extensively in consumer and personal care products; electronics; furniture; and building materials and are detected in most indoor environments. As a result, human exposure to mixtures of SVOCs is wide-spread. However, very few studies have measured biomarkers of exposure to multiple SVOC classes, and exposure determinants have not been thoroughly explored, particularly for young children. In this study, we investigated biomarkers of exposure to SVOCs among children (age 3-6 years), who may experience higher exposures and be more susceptible to adverse health outcomes than other age groups. We enrolled 203 participants in the Toddlers Exposure to SVOCs in Indoor Environments (TESIE) study (181 provided urine samples and 90 provided serum samples).We quantified 44 biomarkers of exposure to phthalates, organophosphate esters (OPEs), parabens, phenols, antibacterial agents and per- and polyfluoroalkyl substances (PFASs); we detected 29 of the 44 biomarkers in >95% of samples, and many biomarkers were detected at higher median concentrations than those previously reported in the U.S. general population. Demographic characteristics were associated with differences in concentrations. In general, non-Hispanic white race and higher maternal education were associated with lower concentrations, even after adjusting for other potential confounding variables. Our results suggest that outdoor temperature at the time of biospecimen collection may be a particularly important and under-evaluated predictor of biomarker concentrations; statistically significant relationships were observed between 10 biomarkers and outdoor temperature at the time of collection. A complex correlation structure was also observed among the biomarkers assessed. By and large, statistically significant correlations between biomarkers of exposure to phthalates, parabens, phenols, and OPEs were positive. Conversely, although PFASs were positively correlated with one another, they tended to be negatively correlated with other biomarkers where significant associations were observed. Taken together, our results provide evidence that the assessments of SVOC-associated health impacts should focus on chemical mixtures., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are ubiquitous synthetic chemicals that are suspected endocrine disruptors., Objectives: To determine the extent to which PFASs are associated with increases in weight and body size and evaluate whether a lifestyle intervention modifies this association., Design, Setting, and Participants: This prospective cohort study included 957 individuals who participated in the Diabetes Prevention Program trial, conducted from July 1996 to May 2001, and the Diabetes Prevention Program Outcomes Study, conducted from September 2002 to January 2014. Statistical analysis was conducted from September 1, 2017, to May 25, 2018., Interventions and Exposures: The initial lifestyle intervention consisted of training in diet, physical activity, and behavior modification, with the major goals of achieving 7% weight loss with subsequent maintenance and a minimum of 150 minutes per week of physical activity. Participants randomized to placebo received standard information about diet and exercise. A total of 6 plasma PFASs were quantified at baseline and 2 years after randomization, means were calculated from baseline and year 2 concentrations, and means were summed to assess total PFAS burden., Main Outcomes and Measures: Weight, waist circumference, and hip girth were measured at baseline and at scheduled visits., Results: Of the 957 participants, 625 (65.3%) were women and 731 participants (76.4%) were between 40 and 64 years of age; 481 participants were randomized to the lifestyle intervention and 476 participants were randomized to the placebo arm. The PFAS concentrations were not different by treatment arm and were similar to concentrations reported for the US population in 1999-2000. The association of PFAS and weight change differed by treatment. Each doubling in total PFAS concentration was associated with an increase of 1.80 kg (95% CI, 0.43-3.17 kg; P = .01) from baseline to 9 years after randomization for the placebo group but not the lifestyle intervention group (-0.59 kg; 95% CI, -1.80 to 0.62 kg; P = .34). Similarly, each doubling in PFAS was associated with a 1.03-cm increase in hip girth in the Diabetes Prevention Program trial for the placebo group (95% CI, 0.18-1.88 cm; P = .02) but not the lifestyle intervention group (-0.09 cm; 95% CI, -0.82 to 0.63 cm; P = .80). No associations were observed for changes in mean waist circumference., Conclusions and Relevance: Among adults at high risk for diabetes, higher plasma PFAS concentration was associated with increases in weight and hip girth over time, but a lifestyle intervention attenuated these associations. Diet and exercise may mitigate the obesogenic effects of environmental chemicals., Trial Registration: ClinicalTrials.gov Identifier: NCT00004992 and NCT00038727.

Background: Following the phase-out of polybrominated diphenyl ethers (PBDEs), organophosphate esters (OPEs) have been increasingly used in consumer products and building materials for their flame retardant and plasticizing properties. As a result, human exposure to these chemicals is widespread as evidenced by common detection of their metabolites in urine. However, little is known about the major exposure pathways, or factors that influence children's exposure to OPEs. Furthermore, little data is available on exposure to the novel aryl OPEs., Objectives: To examine predictors of children's internal exposure, we assessed relationships between OPEs in house dust and on hand wipes and levels of their corresponding metabolites in paired urine samples (n = 181). We also examined associations between urinary metabolites and potential covariates, including child's age and sex, mother's educational attainment and race, and average outdoor air temperature., Methods: Children aged 3 to 6 years provided urine and hand wipe samples. Mothers or legal guardians completed questionnaires, and a house dust sample was taken from the main living area during home visits. Alkyl chlorinated and aryl OPEs were measured in dust and hand wipes, and composite urine samples were analyzed for several metabolites., Results: Tris(2-chloroethyl) phosphate (TCEP), tris(2-chloroisopropyl) phosphate (TCIPP), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), 2-ethylhexyl diphenyl phosphate (EHDPHP), triphenyl phosphate (TPHP), and 2-isopropylphenyl diphenyl phosphate (2IPPDPP) were detected frequently in hand wipes and dust (>80%), indicating that these compounds were near-ubiquitous in indoor environments. Additionally, bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate (BCIPHIPP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), mono-isopropyl phenyl phenyl phosphate (ip-PPP), and mono-tert-butyl phenyl phenyl phosphate (tb-PPP) were detected in >94% of tested urine samples, signifying that TESIE participants were widely exposed to OPEs. Contrary to PBDEs, house dust OPE concentrations were generally not correlated with urinary OPE metabolite levels; however, hand wipe levels of OPEs were associated with internal dose. For example, children with the highest mass of TDCIPP on hand wipes had BDCIPP levels that were 2.73 times those of participants with the lowest levels (95% CI: 1.67, 4.48, p < 0.0001). Of the variables examined, hand wipe level was the most consistent and strongest predictor of OPE urinary metabolite concentrations. Outdoor air temperature was also a significant predictor of urinary BDCIPP concentrations, with a 1 °C increase in temperature corresponding to a 4% increase in urinary BDCIPP (p < 0.0001)., Conclusions: OPE exposures are highly prevalent, and data provided herein further substantiate hand-to-mouth contact and dermal absorption as important pathways of OPE exposure, especially for young children., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Per- and polyfluoroalkyl substances (PFASs) are suspected developmental toxicants, but epidemiological evidence on neurodevelopmental effects of PFAS exposure is inconsistent. We examined associations of prenatal and childhood PFAS exposure with performance on assessments of cognition in children., Methods: We included mother-child pairs from Project Viva, a longitudinal Boston-area birth cohort enrolled during 1999-2002. We quantified concentrations of eight PFASs, including perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexane sulfonate (PFHxS), in plasma collected from women during pregnancy (median 9.7 weeks gestation) and from children at a visit in mid-childhood (median age 7.7 years). In early childhood (median age 3.2 years) we administered standardized assessments of visual motor skills and vocabulary comprehension, and in mid-childhood we assessed visual motor skills, visual memory, and verbal and non-verbal intelligence. Using multivariable regression, we estimated associations of prenatal and childhood PFAS plasma concentrations with children's cognitive assessment scores, adjusted for relevant covariates including breastfeeding, maternal intelligence, parental education, and household income. Samples sizes ranged from 631 to 971, depending on analysis., Results: Prenatal PFAS concentrations were associated with both better and worse cognitive performance; children with top quartile prenatal concentrations of some PFASs had better visual motor abilities in early childhood and non-verbal IQ and visual memory in mid-childhood, while children with upper quartile prenatal PFOA and PFOS had lower mid-childhood visual-motor scores. In cross-sectional analyses of mid-childhood PFAS concentrations and cognitive assessments, visual-motor scores on the Wide Range Assessment of Visual Motor Abilities (WRAVMA) (standardized mean = 100, standard deviation = 15) were lower among children with higher PFHxS (fourth quartile (Q4) vs. Q1: -5.0, 95% confidence interval (CI): -9.1, -0.8). Upper quartiles of childhood PFOA and PFOS were also associated with somewhat lower childhood WRAVMA scores, but childhood PFASs were not associated with verbal or non-verbal IQ or visual memory., Conclusions: We present evidence suggesting associations of prenatal and childhood PFAS exposure with lower childhood visual motor abilities. Other results were inconsistent, with higher prenatal PFASs associated in some cases with better cognitive outcomes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)