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Single-pollutant methods to evaluate associations between endocrine disrupting chemicals (EDCs) and thyroid cancer risk may not reflect realistic human exposures. Therefore, we evaluated associations between exposure to a mixture of 18 EDCs, including polychlorinated biphenyls (PCBs), brominated flame retardants, and organochlorine pesticides, and risk of papillary thyroid cancer (PTC), the most common thyroid cancer histological subtype. We conducted a nested case-control study among U.S. military servicemembers of 652 histologically-confirmed PTC cases diagnosed between 2000 and 2013 and 652 controls, matched on birth year, sex, race/ethnicity, military component (active duty/reserve), and serum sample timing. We estimated mixture odds ratios (OR), 95% confidence intervals (95% CI), and standard errors (SE) for associations between pre-diagnostic serum EDC mixture concentrations, overall PTC risk, and risk of histological subtypes of PTC (classical, follicular), adjusted for body mass index and military branch, using quantile g-computation. Additionally, we identified relative contributions of individual mixture components to PTC risk, represented by positive and negative weights (w). A one-quartile increase in the serum mixture concentration was associated with a non-statistically significant increase in overall PTC risk (OR = 1.19; 95% CI = 0.91, 1.56; SE = 0.14). Stratified by histological subtype and race (White, Black), a one-quartile increase in the mixture was associated with increased classical PTC risk among those of White race (OR = 1.59; 95% CI = 1.06, 2.40; SE = 0.21), but not of Black race (OR = 0.95; 95% CI = 0.34, 2.68; SE = 0.53). PCBs 180, 199, and 118 had the greatest positive weights driving this association among those of White race (w = 0.312, 0.255, and 0.119, respectively). Findings suggest that exposure to an EDC mixture may be associated with increased classical PTC risk. These findings warrant further investigation in other study populations to better understand PTC risk by histological subtype and race., Competing Interests: Declaration of competing interest The authors report no competing interests. Disclosures The authors have no disclosures to report., (Published by Elsevier B.V.)

Per- and polyfluoroalkyl substances (PFAS) are a class of man-made chemicals that are persistent in the environment. They can be transferred across the placenta to fetuses and through human milk to infants. The American Academy of Pediatrics advises that the benefits of breastfeeding infants almost always outweigh the potential risks of harm from environmental chemicals. However, there are few chemical-specific summaries of the potential harms of exposure to PFAS during the neonatal period through breastfeeding. This systematic review explores whether exposure to PFAS through breastfeeding is associated with adverse health outcomes among infants and children using evidence from human and animal studies. Systematic searches identified 4297 unique records from 7 databases. The review included 37 total articles, including 9 animal studies and 1 human study measuring the direct contribution of exposure of the infant or pup through milk for any health outcome. Animal studies provided evidence of associations between exposure to PFOA through breastfeeding and reduced early life body weight gain, mammary gland development, and thyroid hormone levels. They also provided limited evidence of associations between PFOS exposure through breastfeeding with reduced early life body weight gain and cellular changes in the hippocampus. The direct relevance of any of these outcomes to human health is uncertain, and it is possible that many adverse health effects of exposure through breastfeeding have not yet been studied. This review documents the current state of science and highlights the need for future research to guide clinicians making recommendations on infant feeding., (Published by Oxford University Press on behalf of the Society of Toxicology 2023.)

Central North Carolina (NC) is highly contaminated with per- and polyfluoroalkyl substances (PFAS), in part due to local fluorochemical production. Little is known about the exposure profiles and long-term health impacts for humans and animals that live in nearby communities. In this study, serum PFAS concentrations were determined using liquid chromatography high-resolution mass spectrometry and diagnostic clinical chemistry endpoints were assessed for 31 dogs and 32 horses that reside in Gray's Creek NC at households with documented PFAS contamination in their drinking water. PFAS were detected in every sample, with 12 of the 20 PFAS detected in ≥50% of samples from each species. The average total PFAS concentrations in horses were lower compared to dogs who had higher concentrations of PFOS (dogs 2.9 ng/mL; horses 1.8 ng/mL), PFHxS (dogs 1.43 ng/mL, horses < LOD), and PFOA (dogs 0.37 ng/mL; horses 0.10 ng/mL). Regression analysis highlighted alkaline phosphatase, glucose, and globulin proteins in dogs and gamma glutamyl transferase in horses as potential biomarkers associated with PFAS exposure. Overall, the results of this study support the utility of companion animal and livestock species as sentinels of PFAS exposure differences inside and outside of the home. As in humans, renal and hepatic health in domestic animals may be sensitive to long-term PFAS exposures.

As part of federal programs to reduce nutrient pollution, states across the Midwest have developed nutrient reduction strategies, which focus on implementation of agricultural conservation practices (ACPs) or best management practices (BMPs). Despite several decades of federal investment in implementing ACPs/BMPs for reducing nutrient pollution, nutrient pollution is a continuing and growing challenge with profound implications for water quality and public health as well as ecological functions. Pollutant transport depends on water and sediment fluxes, which are governed by local hydrology. Therefore, knowing how flow conditions affect nutrients export is critical to develop effective nutrient reduction strategies. The objective of this study was to investigate the role of streamflow duration curve in controlling nutrient export in the western Lake Erie Basin and the Mississippi River Basin. To achieve this goal, we used long-term monitoring data collected by the National Center for Water Quality Research. We focused on the percentage of the annual pollutant load (nitrate-NO 3 -N, dissolved reactive phosphorus-DRP, total phosphorus-TP, and total suspended solids-TSS) exported during five flow intervals that spanned the flow duration curve: High Flows (0-10th percentile), Moist Conditions (10-40th percentile), Mid-Range Flows (40-60th percentile), Dry Conditions (60-90th percentile), and Low Flows (90-100th percentile). The results show that the top 10% of flows (i.e., high flows) transported more than 50% of the annual nutrient loads in most of the studying watersheds. Meanwhile, the top 40% of flows transported 54-98% of the annual NO 3 -N loads, 55-99% of the annual DRP loads, 79-99% of the annual TP loads, and 86-100% of the annual TSS loads across the studying watersheds. The percentage of the annual loads released during high flows increased as the percentage of the agricultural land use in the watershed increased, but it decreased as the watershed area increased across different watersheds. Finally, flow condition/nutrient export relationships were consistent over studying period. Therefore, reducing nutrient loads during high flow condition is the key for effective nutrient reduction., 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 Ltd. All rights reserved.)

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants associated with negative health impacts. Assessments of tubing-related measurement bias for volatile PFAS are lacking, as gas-wall interactions with tubing can delay quantification of gas-phase analytes. We use online iodide chemical ionization mass spectrometry measurements to characterize tubing delays for three gas-phase oxygenated PFAS - 4:2 fluorotelomer alcohol (4:2 FTOH), perfluorobutanoic acid (PFBA), and hexafluoropropylene oxide dimer acid (HFPO-DA). Perfluoroalkoxy alkane and high-density polyethylene tubing yielded relatively short absorptive measurement delays, with no clear dependence on tubing temperature or sampled humidity. Sampling through stainless steel tubing led to prolonged measurement delays due to reversible adsorption of PFAS to the tubing surface, with strong dependence on tubing temperature and sample humidification. Silcosteel tubing afforded shorter measurement delays than stainless steel due to diminished surface adsorption of PFAS. Characterizing and mitigating these tubing delays is crucial for reliable quantification of airborne PFAS. Implications: Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants. Many PFAS are sufficiently volatile to exist as airborne pollutants. Measurements and quantification of airborne PFAS can be biased from material-dependent gas-wall interactions with sampling inlet tubing. Thus, characterizing these gas-wall interactions are crucial for reliably investigating emissions, environmental transport, and fates of airborne PFAS.

Background and Objectives: Although polychlorinated biphenyls (PCBs) were banned decades ago, populations are continuously exposed to PCBs due to their persistence and bioaccumulation/biomagnification in the environment. Results from limited epidemiologic studies linking PCBs to thyroid cancer have been inconclusive. This study aimed to investigate the association between individual PCBs and PCB mixture and papillary thyroid cancer (PTC), the most common thyroid cancer histologic subtype., Methods: We carried out a nested case-control study including 742 histologically confirmed PTC cases diagnosed in 2000-2013 and 742 individually matched controls among U.S. military service members. Pre-diagnostic serum samples that were collected on average nine years before PTC diagnosis were used to measure PCB congeners by gas chromatography isotope dilution high resolution mass spectrometry (GC/ID-HRMS). Conditional logistic regression, Bayesian kernel machine regression (BKMR), and weighted quantile sum (WQS) regression were employed to estimate the association between single PCB congeners as well as their mixture and PTC., Results: Four PCB congeners (PCB-74, PCB-99, PCB-105, PCB-118) had significant associations and dose-response relationships with increased risk of PTC in single congener models. When considering the effects from all measured PCBs and their potential interactions in the BKMR model, PCB-118 showed positive trends of association with PTC. Increased exposure to the PCB congeners as a mixturewas also associated with an increased risk of PTC in the WQS model, with the mixture dominated by PCB-118, followed by PCB-74 and PCB-99. One PCB congener, PCB-187, showed an inverse trend of association with PTC in the mixture analysis., Discussion: This study suggests that exposure to certain PCBs as well as a mixture of PCBs were associated with an increased risk of PTC. The observed association was mainly driven by PCB-118, and to a lesser extent by PCB-74 and PCB-99. The findings warrant further investigation., (Published by Elsevier Inc.)

Volatile chemical products (VCPs) are a significant source of reactive organic carbon emissions in the United States with a substantial fraction (>20% by mass) serving as secondary organic aerosol (SOA) precursors. Here, we incorporate a new nationwide VCP inventory into the Community Multiscale Air Quality (CMAQ) model with VCP-specific updates to better model air quality impacts. Model results indicate that VCPs mostly enhance anthropogenic SOA in densely populated areas with population-weighted annual average SOA increasing 15-30% in Southern California and New York City due to VCP emissions (contribution of 0.2-0.5 μg m -3 ). Annually, VCP emissions enhance total population-weighted PM 2.5 by ∼5% in California, ∼3% in New York, New Jersey, and Connecticut, and 1-2% in most other states. While the maximum daily 8 h ozone enhancements from VCP emissions are more modest, their influence can cause a several ppb increase on select days in major cities. Printing Inks, Cleaning Products, and Paints and Coatings product use categories contribute ∼75% to the modeled VCP-derived SOA and Cleaning Products, Paints and Coatings, and Personal Care Products contribute ∼81% to the modeled VCP-derived ozone. Overall, VCPs enhance multiple criteria pollutants throughout the United States with the largest impacts in urban cores.

Background: Endocrine disrupting chemical (EDC) exposure is ubiquitous. EDC exposure during critical windows of development may interfere with the body's endocrine system, affecting growth. Previous human studies have examined one EDC at a time in relation to infant growth. By studying mixtures, the human experience can be better approximated., Aims: We investigated the association of prenatal exposure to persistent EDCs (per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs)) as mixtures with postnatal body size among female offspring., Subjects: We used a sub-sample of the Avon Longitudinal Study of Parents and Children (N = 425), based in the United Kingdom., Study Design: We quantified 52 EDCs in maternal serum collected during pregnancy. We used Bayesian kernel machine regression with a random intercept to examine the association of prenatal concentrations of EDC mixtures with longitudinal postnatal body size measures for each EDC class separately (PFAS, PCBs, and OCPs) and for all three classes combined., Outcome Measures: Weight and height measures at 0, 2, 9, and 19 months were obtained by health professionals as part of routine child health surveillance., Results: The mixture representing all three classes combined (31 chemicals) (n = 301) was inversely associated with postnatal body size. Holding all EDCs in the 31-chemical mixture at the 75th percentile compared to the 50th percentile was associated with 0.15 lower weight-for-age z-score (95% credible interval -0.26, -0.03). Weak inverse associations were also seen for height-for-age and body mass index-for-age scores., Conclusions: These results suggest that prenatal exposure to mixtures of persistent EDCs may affect postnatal body size., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Previous studies of endocrine-disrupting chemicals have examined one of these chemicals at a time in association with an outcome; studying mixtures better approximates human experience. We investigated the association of prenatal exposure to mixtures of persistent endocrine disruptors (perfluoroalkyl and polyfluoroalkyl substances [PFAS], polychlorinated biphenyls [PCBs], and organochlorine pesticides) with birth size among female offspring in the Avon Longitudinal Study of Parents and Children (ALSPAC), based in the United Kingdom in 1991-1992., Methods: We quantified concentrations of 52 endocrine-disrupting chemicals in maternal serum collected during pregnancy at median 15-week gestation. Birth weight, crown-to-heel length, and head circumference were measured at birth; ponderal index and small for gestational age were calculated from these. We used repeated holdout Weighted Quantile Sum (WQS) regression and Bayesian kernel machine regression to examine mixtures in 313 mothers., Results: Using WQS regression, all mixtures (each chemical class separately and all three together) were inversely associated with birth weight. A one-unit increase in WQS index (a one-decile increase in chemical concentrations) for all three classes combined was associated with 55 g (β = -55 g, 95% confidence interval [CI] = -89, -22 g) lower birth weight. Associations were weaker but still inverse using Bayesian kernel machine regression. Under both methods, PFAS were the most important contributors to the association with birth weight. We also observed inverse associations for crown-to-heel length., Conclusions: These results are consistent with the hypothesis that prenatal exposure to mixtures of persistent endocrine-disrupting chemicals affects birth size., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Deiodinase enzymes are critical for tissue-specific and temporal control of activation or inactivation of thyroid hormones during vertebrate development, including amphibian metamorphosis. We previously screened ToxCast chemicals for inhibitory activity toward human recombinant Type 3 iodothyronine deiodinase enzyme (hDIO3) and subsequently produced Xenopus laevis recombinant dio3 enzyme (Xldio3) with the goals to identify specific chemical inhibitors of Xldio3, to evaluate cross-species sensitivity and explore whether the human assay results are predictive of the amphibian. We identified a subset of 356 chemicals screened against hDIO3 to test against Xldio3, initially at a single concentration (200 μM), and further tested 79 in concentration-response mode. Most chemicals had IC 50 values lower for hDIO3 than for Xldio3 and many had steep Hill slopes (a potential indication of non-specific inhibition). However, eight of the most potent chemicals are likely specific inhibitors, with IC 50 values of 14 μM or less, Hill slopes near -1 and curves not significantly different between species likely due to conservation of catalytically active amino acids. Controlling for assay conditions, human in vitro screening results can be predictive of activity in the amphibian assay. This study lays the groundwork for future studies using recombinant non-mammalian proteins to test cross-species sensitivity to chemicals. DISCLAIMER: The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. Mention of trade names or commercial products does not constitute endorsement or recommendation for use., (Published by Elsevier Ltd.)

Exposure to endocrine disrupting chemicals (EDCs) is ubiquitous. EDC exposure, especially during critical periods of development like the prenatal window, may interfere with the body's endocrine system, which can affect growth and developmental outcomes such as puberty. Most studies have examined one EDC at a time in relation to disease; however, humans are exposed to many EDCs. By studying mixtures, the human experience can be more closely replicated. We investigated the association of prenatal exposure to persistent EDCs (poly- and perfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs)) as mixtures with early menarche among female offspring in a nested case-control study within the Avon Longitudinal Study of Parents and Children (ALSPAC) recruited in the United Kingdom in 1991-1992. Concentrations of 52 EDCs were quantified in maternal serum samples collected during pregnancy. Daughter's age at menarche was ascertained through mailed questionnaires sent annually. We used repeated holdout weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) to examine the association between prenatal exposure to multiple EDCs and early menarche (<11.5 (n = 218) vs. ≥11.5 years (n = 230)) for each chemical class separately (PFAS, PCBs, and OCPs) and for all three classes combined. Models adjusted for maternal age at menarche, maternal education, parity, pre-pregnancy body mass index, maternal age, prenatal smoking, and gestational week at sample collection. Mixture models showed null associations between prenatal exposure to EDC mixtures and early menarche. Using WQS regression, the odds ratio for early menarche for a one-decile increase in chemical concentrations for all three classes combined was 0.89 (95% CI: 0.76, 1.05); using BKMR, the odds ratio when all exposures were at the 60th percentile compared to the median was 0.98 (95% CI: 0.91, 1.05). Results suggest the overall effect of prenatal exposure to persistent EDC mixtures is not associated with early menarche., 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 © 2021 Elsevier Ltd. All rights reserved.)

Emissions from solid-fuel burning cookstoves are associated with 3 to 4 million premature deaths annually and contribute significantly to impacts on climate. Pellet-fueled gasifier stoves have some emission factors (EFs) approaching those of gas-fuel (liquid petroleum gas) stoves; however, their emissions have not been evaluated for biological effects. Here we used a new International Organization for Standardization (ISO) testing protocol to determine pollutant- and mutagenicity-EFs for a stove designed for pellet fuel, the Mimi Moto, and for two other forced-draft stoves, Xunda and Philips HD4012, burning pellets of hardwood or peanut hulls. The Salmonella assay-based mutagenicity-EFs (revertants/megajoule delivered ) spanned three orders of magnitude and correlated highly (r = 0.99; n = 5) with EFs of the sum of 32 particle-phase polycyclic aromatic hydrocarbons (PAHs). The Mimi Moto/hardwood pellet combination had total-PAH- and mutagenicity-EFs 99.2 and 96.6% lower, respectively, compared to data published previously for the Philips stove burning non-pelletized hardwood, and 100 and 99.8% lower, respectively, compared to those of a wood-fueled three-stone fire. The Xunda burning peanut hull pellets had the highest fuel energy-based mutagenicity-EF (revertants/megajoule thermal ) of the pellet stove/fuel combinations tested, which was between that of diesel exhaust, a known human carcinogen, and a natural-draft wood stove. Although the Mimi Moto burning hardwood pellets had the lowest fuel energy-based mutagenicity-EF, this value was between that of utility coal and utility wood boilers. This advanced stove/fuel combination has the potential to greatly reduce emissions in contrast to a traditional stove, but adequate ventilation is required to approach acceptable levels of indoor air quality., 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.)

Advancements in measurement and modeling capabilities are providing unprecedented access to estimates of chemical exposure and bioactivity. With this influx of new data, there is a need for frameworks that help organize and disseminate information on chemical hazard and exposure in a manner that is accessible and transparent. A case study approach was used to demonstrate integration of the Adverse Outcome Pathway (AOP) and Aggregate Exposure Pathway (AEP) frameworks to support cumulative risk assessment of co-exposure to two phthalate esters that are ubiquitous in the environment and that are associated with disruption of male sexual development in the rat: di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DnBP). A putative AOP was developed to guide selection of an in vitro assay for derivation of bioactivity values for DEHP and DnBP and their metabolites. AEPs for DEHP and DnBP were used to extract key exposure data as inputs for a physiologically based pharmacokinetic (PBPK) model to predict internal metabolite concentrations. These metabolite concentrations were then combined using in vitro-based relative potency factors for comparison with an internal dose metric, resulting in an estimated margin of safety of ~13,000. This case study provides an adaptable workflow for integrating exposure and toxicity data by coupling AEP and AOP frameworks and using in vitro and in silico methodologies for cumulative risk assessment., 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. Published by Elsevier Ltd.)

Time courses of compound concentrations in plasma are used in chemical safety analysis to evaluate the relationship between external administered doses and internal tissue exposures. This type of experimental data is rarely available for the thousands of non-pharmaceutical chemicals to which people may potentially be unknowingly exposed but is necessary to properly assess the risk of such exposures. In vitro assays and in silico models are often used to craft an understanding of a chemical's pharmacokinetics; however, the certainty of the quantitative application of these estimates for chemical safety evaluations cannot be determined without in vivo data for external validation. To address this need, we present a public database of chemical time-series concentration data from 567 studies in humans or test animals for 144 environmentally-relevant chemicals and their metabolites (187 analytes total). All major administration routes are incorporated, with concentrations measured in blood/plasma, tissues, and excreta. We also include calculated pharmacokinetic parameters for some studies, and a bibliography of additional source documents to support future extraction of time-series. In addition to pharmacokinetic model calibration and validation, these data may be used for analyses of differential chemical distribution across chemicals, species, doses, or routes, and for meta-analyses on pharmacokinetic studies.

High-throughput and computational tools provide a new opportunity to calculate combined bioactivity of exposure to diverse chemicals acting through a common mechanism. We used high throughput in vitro bioactivity data and exposure predictions from the U.S. EPA's Toxicity and Exposure Forecaster (ToxCast and ExpoCast) to estimate combined estrogen receptor (ER) agonist activity of non-pharmaceutical chemical exposures for the general U.S. population. High-throughput toxicokinetic (HTTK) data provide conversion factors that relate bioactive concentrations measured in vitro (µM), to predicted population geometric mean exposure rates (mg/kg/day). These data were available for 22 chemicals with ER agonist activity and were estimated for other ER bioactive chemicals based on the geometric mean of HTTK values across chemicals. For each chemical, ER bioactivity across ToxCast assays was compared to predicted population geometric mean exposure at different levels of in vitro potency and model certainty. Dose additivity was assumed in calculating a Combined Exposure-Bioactivity Index (CEBI), the sum of exposure/bioactivity ratios. Combined estrogen bioactivity was also calculated in terms of the percent maximum bioactivity of chemical mixtures in human plasma using a concentration-addition model. Estimated CEBIs vary greatly depending on assumptions used for exposure and bioactivity. In general, CEBI values were <1 when using median of the estimated general population chemical intake rates, while CEBI were ≥1 when using the upper 95th confidence bound for those same intake rates for all chemicals. Concentration-addition model predictions of mixture bioactivity yield comparable results. Based on current in vitro bioactivity data, HTTK methods, and exposure models, combined exposure scenarios sufficient to influence estrogen bioactivity in the general population cannot be ruled out. Future improvements in screening methods and computational models could reduce uncertainty and better inform the potential combined effects of estrogenic chemicals., Competing Interests: Declaration of Competing Interest Caroline L. Ring is now employed by ToxStrategies, Inc., a scientific consulting firm whose clients include private industry, trade associations, and governmental entities. However, Dr. Ring received no funding from ToxStrategies or any of its clients for this project, and neither ToxStrategies nor any of its clients was involved in the development or approval of this research or this report., (Published by Elsevier Ltd.)

The present study adapted an existing high content imaging-based high-throughput phenotypic profiling (HTPP) assay known as "Cell Painting" for bioactivity screening of environmental chemicals. This assay uses a combination of fluorescent probes to label a variety of organelles and measures a large number of phenotypic features at the single cell level in order to detect chemical-induced changes in cell morphology. First, a small set of candidate phenotypic reference chemicals (n = 14) known to produce changes in the cellular morphology of U-2 OS cells were identified and screened at multiple time points in concentration-response format. Many of these chemicals produced distinct cellular phenotypes that were qualitatively similar to those previously described in the literature. A novel workflow for phenotypic feature extraction, concentration-response modeling and determination of in vitro thresholds for chemical bioactivity was developed. Subsequently, a set of 462 chemicals from the ToxCast library were screened in concentration-response mode. Bioactivity thresholds were calculated and converted to administered equivalent doses (AEDs) using reverse dosimetry. AEDs were then compared to effect values from mammalian toxicity studies. In many instances (68%), the HTPP-derived AEDs were either more conservative than or comparable to the in vivo effect values. Overall, we conclude that the HTPP assay can be used as an efficient, cost-effective and reproducible screening method for characterizing the biological activity and potency of environmental chemicals for potential use in in vitro-based safety assessments., Competing Interests: Declaration of Competing Interest None, (Published by Elsevier Inc.)

Children may be more vulnerable to the combined interactions of chemical and non-chemical stressors from their built, natural, and social environments when compared to adults. Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed childhood neurodevelopmental disorder and is considered a major public health issue, as 75% of childhood cases persist into adulthood. ADHD is characterized by developmentally inappropriate levels of hyperactivity, impulsivity, and inattention, with the neurotransmitter serotonin regulating these symptoms. Monoamine oxidase A (MAOA) aids in serotonin uptake and is often implicated in behavioral and emotional disorders, including ADHD. When children are exposed to cigarette smoke, bisphenol A (BPA), or organophosphate pesticides, MAOA activity is inhibited. Non-chemical stressors, such as traumatic childhood experiences, and lifestyle factors, complicate the relationship between genotype and exposures to chemical stressors. But the co-occurrence among outcomes between exposures to chemical stressors, non-chemical stressors, and the low activity MAOA genotype suggest that mental illness in children may be influenced by multiple interacting factors. In this systematic review, we examine the existing literature that combines exposures to chemical and non-chemical stressors (specifically childhood trauma), MAOA characteristics, and ADHD diagnosis to investigate the interrelationships present. We observe that chemical (lead [Pb], phthalates/plasticizers, persistent organic pollutants, and cigarette smoke) exposure is significantly related to ADHD in children. We also observed that existing literature examining the interaction between MAOA, exposures to chemical stressors, and traumatic experiences and their effect on ADHD outcomes is sparse. We recommend that future studies investigating childhood ADHD include chemical and non-chemical stressors and inherent characteristics to gain a holistic understanding of childhood mental health outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Environmental lead (Pb) contamination is a persistent public health issue that prominently impacts communities across the United States. Multimedia Pb exposure assessments are utilized to provide a holistic evaluation of Pb exposure and inform the development of programs and regulations that are protective of human health. To conduct multimedia exposure assessments, robust, media-specific environmental Pb concentration data are necessary. To support this effort, systematic review and meta-analysis methods were used to conduct a comprehensive synthesis of research measuring Pb in multiple environmental media (soil, dust, water, food, and air) over a 20-year period within the United States. The breadth of the resulting database allowed for the evaluation of sample characteristics that can serve as indicators of environmental Pb contamination. Random effects models run on literature and national survey datasets generated overall mean estimates of Pb concentrations that can be used for multimedia Pb exposure modeling for general and high-exposure-risk populations. Results from our study highlighted several important trends: 1) The mean estimate of Pb in residential soils is three times higher for urbanized areas than non-urbanized areas; 2) The mean estimate of Pb in produce reported in the literature is approximately three orders of magnitude greater than commercially-sourced raw produce monitored in national surveys; 3) The mean estimate of Pb in soils from shooting ranges is two times greater than non-residential Pb contaminated Superfund sites reported in the literature; 4) Research reporting environmental Pb concentrations for school and daycare sites is very limited; 5) Inconsistent sample collection and reporting of results limited synthesis efforts; and 6) The U.S. EPA's Air Quality System was the most robust, publicly available national survey resource. Results from these analyses will inform future multimedia Pb exposure assessments and be useful in prioritizing future research and program development., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In 2014, we conducted a longitudinal study [Anniston Community Health Survey (ACHS II)] 8 y after the baseline (ACHS I)., Objectives: We investigated the relationship between persistent chlorinated compounds and hypertension in residents living around the former polychlorinated biphenyl (PCB) production plant in Anniston, Alabama. We also examined the potential role of inflammatory cytokines in those with hypertension., Methods: A total of 338 participants had their blood pressure measured and medications recorded, gave a blood sample, and completed a questionnaire. Prevalent hypertension was defined as taking antihypertensive medication or having systolic blood pressure > 140   mmHg and/or diastolic pressure > 90   mmHg ; incident hypertension used similar criteria in those who developed hypertension since the baseline in 2005-2007. PCB congeners were categorized into structure-activity groups, and toxic equivalencies (TEQs) were calculated for dioxin-like compounds. Descriptive statistics, logistic and linear regressions, as well as Cox proportional hazard models, were used to analyze the associations between exposures and hypertension., Results: Prevalent hypertension (78%) in ACHS II showed statistically significant adjusted odds ratios (ORs) for PCBs 74, 99, 138, 153, 167, 177, 183, and 187, ranging from 2.18 [95% confidence interval (CI): 1.10, 4.33] to 2.76 (95% CI: 1.14, 6.73), as well as for two estrogenic-like PCB groups, and the thyroid-like group [ORs ranging from 2.25 (95% CI: 1.07, 4.75) to 2.54 (95% CI: 1.13, 5.74)]. Furthermore, analysis of quartiles demonstrated a monotonic relationship for dioxin-like non-ortho (non- o )-PCB TEQs [fourth vs. first quartile: 3.66 (95% CI: 1.40, 9.56)]. Longitudinal analyses of incident hypertension supported those positive associations. The results were strongest for the di- o -PCBs [ hazard   ratio   ( HR ) = 1.93 (95% CI: 0.93, 4.00)] and estrogenic II PCB group [ HR = 1.90 (95% CI: 0.96, 3.78)] but were weaker for the dioxin TEQs., Discussion: Findings supportive of positive associations were reported for dioxin-like mono- o - and non- o -PCBs as well as for nondioxin-like estrogenic and thyroid-like congeners with prevalent and incident hypertension, suggesting that multiple pathways may be involved in hypertension development. https://doi.org/10.1289/EHP5272.

Perfluoroalkyl substances (PFAS) are chemicals used in the manufacture of consumer products. PFAS may act as endocrine disruptors, influencing metabolic pathways and weight-related outcomes. Previous studies observed an association between perfluorooctane sulfonic acid (PFOS) and higher gestational weight gain among under-/normal weight mothers. We analyzed associations of maternal serum pregnancy concentrations of PFAS with gestational weight gain (GWG) using data from 905 women in a subsample of the Avon Longitudinal Study of Parents and Children. Women were routinely weighed in antenatal check-ups; absolute GWG was determined by subtracting the first weight measurement from the last. Linear regression was used to explore associations of maternal PFAS concentrations with absolute GWG, stratified by prepregnancy body mass index. Associations of maternal PFOS, perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid (PFHxS) concentrations with absolute GWG were null; 10% higher PFOS was associated with GWG of -0.03 kg (95% CI: -0.11, 0.06) among under-/normal weight mothers. Ten percent higher perfluorononanoic acid (PFNA) was associated with a higher GWG of 0.09 kg (95% CI: 0.02, 0.16) among under-/normal weight mothers. Overall, findings suggest no association between maternal PFOA, PFOS, and PFHxS concentrations and GWG, and a weak positive association between maternal PFNA and GWG., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Maritime greenhouse gas emissions are projected to increase significantly by 2050, highlighting the need for reliable inventories as a first step in analyzing ship emission control policies. The impact of ship power models on marine emissions inventories has garnered little attention, with most inventories employing simple, load-factor-based models to estimate ship power consumption. The availability of more expansive ship activity data provides the opportunity to investigate the inventory impacts of adopting complex power models. Furthermore, ship parameter fields can be sparsely populated in ship registries, making gap-filling techniques and averaging processes necessary. Therefore, it is important to understand of the impact of averaged ship parameters on ship power and emission estimations. This paper examines power estimation differences between results from two complex, resistance-based and two simple, load-factor-based power models on a baseline inventory with unique ship parameters. These models are additionally analyzed according to their sensitivities toward average ship parameters. Automated Identification System (AIS) data from a fleet of commercial marine vessels operating over a 6-month period off the coast of the southwestern United States form the basis of the analysis. To assess the inventory impacts of using averaged ship parameters, fleet-level carbon dioxide (CO 2 ) emissions are calculated using ship parameter data averaged across ship types and their subtype size classes. Each of the four ship power models are used to generate four CO 2 emissions inventories, and results are compared with baseline estimates for the same sample fleet where no averaged values were used. The results suggest that a change in power model has a relatively high impact on emission estimates. They also indicate relatively little sensitivity, by all power models, to the use of ship characteristics averaged by ship and subtype. Implications : Commercial marine vessel emissions inventories were calculated using four different models for ship engine power. The calculations used 6 months of Automated Identification System (AIS) data from a sample of 248 vessels as input data. The results show that more detailed, resistance-based models tend to estimate a lower propulsive power, and thus lower emissions, for ships than traditional load-factor-based models. Additionally, it was observed that emission calculations using averaged values for physical ship parameters had a minimal impact on the resulting emissions inventories.

The application of toxic equivalency factors (TEFs) or toxic units to estimate toxic potencies for mixtures of chemicals which contribute to a biological effect through a common mechanism is one approach for filling data gaps. Toxic Equivalents (TEQ) have been used to express the toxicity of dioxin-like compounds (i.e., dioxins, furans, and dioxin-like polychlorinated biphenyls (PCBs)) in terms of the most toxic form of dioxin: 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). This study sought to integrate two data gap filling techniques, quantitative structure-activity relationships (QSARs) and TEFs, to predict neurotoxicity TEQs for PCBs. Simon et al. (2007) previously derived neurotoxic equivalent (NEQ) values for a dataset of 87 PCB congeners, of which 83 congeners had experimental data. These data were taken from a set of four different studies measuring different effects related to neurotoxicity, each of which tested overlapping subsets of the 83 PCB congeners. The goals of the current study were to: (i) evaluate an alternative neurotoxic equivalent factor (NEF) derivations from an expanded dataset, relative to those derived by Simon et al. and (ii) develop QSAR models to provide NEF estimates for the large number of untested PCB congeners. The models used multiple linear regression, support vector regression, k-nearest neighbor and random forest algorithms within a 5-fold cross validation scheme and position-specific chlorine substitution patterns on the biphenyl scaffold as descriptors. Alternative NEF values were derived but the resulting QSAR models had relatively low predictivity (RMSE ∼0.24). This was mostly driven by the large uncertainties in the underlying data and NEF values. The derived NEFs and the QSAR predicted NEFs to fill data gaps should be applied with caution., (Published by Elsevier Inc.)

Non-targeted analysis (NTA) methods are increasingly used to discover contaminants of emerging concern (CECs), but the extent to which these methods can support exposure and health studies remains to be determined. EPA's Non-Targeted Analysis Collaborative Trial (ENTACT) was launched in 2016 to address this need. As part of ENTACT, 1269 unique substances from EPA's ToxCast library were combined to make ten synthetic mixtures, with each mixture containing between 95 and 365 substances. As a participant in the trial, we first performed blinded NTA on each mixture using liquid chromatography (LC) coupled with high-resolution mass spectrometry (HRMS). We then performed an unblinded evaluation to identify limitations of our NTA method. Overall, at least 60% of spiked substances could be observed using selected methods. Discounting spiked isomers, true positive rates from the blinded and unblinded analyses reached a maximum of 46% and 65%, respectively. An overall reproducibility rate of 75% was observed for substances spiked into more than one mixture and observed at least once. Considerable discordance in substance identification was observed when comparing a subset of our results derived from two separate reversed-phase chromatography methods. We conclude that a single NTA method, even when optimized, can likely characterize only a subset of ToxCast substances (and, by extension, other CECs). Rigorous quality control and self-evaluation practices should be required of labs generating NTA data to support exposure and health studies. Accurate and transparent communication of performance results will best enable meaningful interpretations and defensible use of NTA data. Graphical abstract ᅟ.

In August 2015, the US Environmental Protection Agency (EPA) convened a workshop entitled "Advancing non-targeted analyses of xenobiotic chemicals in environmental and biological media." The purpose of the workshop was to bring together the foremost experts in non-targeted analysis (NTA) to discuss the state-of-the-science for generating, interpreting, and exchanging NTA measurement data. During the workshop, participants discussed potential designs for a collaborative project that would use EPA resources, including the ToxCast library of chemical substances, the DSSTox database, and the CompTox Chemicals Dashboard, to evaluate cutting-edge NTA methods. That discussion was the genesis of EPA's Non-Targeted Analysis Collaborative Trial (ENTACT). Nearly 30 laboratories have enrolled in ENTACT and used a variety of chromatography, mass spectrometry, and data processing approaches to characterize ten synthetic chemical mixtures, three standardized media (human serum, house dust, and silicone band) extracts, and thousands of individual substances. Initial results show that nearly all participants have detected and reported more compounds in the mixtures than were intentionally added, with large inter-lab variability in the number of reported compounds. A comparison of gas and liquid chromatography results shows that the majority (45.3%) of correctly identified compounds were detected by only one method and 15.4% of compounds were not identified. Finally, a limited set of true positive identifications indicates substantial differences in observable chemical space when employing disparate separation and ionization techniques as part of NTA workflows. This article describes the genesis of ENTACT, all study methods and materials, and an analysis of results submitted to date. Graphical abstract ᅟ.

Phthalates are used in a wide range of consumer goods, resulting in exposures to specific phthalates that vary over time in accordance with changes in product use and how phthalates are utilized. We investigated trends in estimates of daily intake dose and several cumulative risk metrics, including the Hazard Quotient (HQ), Hazard Index (HI), and Maximum Cumulative Ratio (MCR) for six phthalates from 2005 to 2014 using metabolite biomonitoring data collected from spot urine samples under the National Health and Nutrition Examination Survey (NHANES). Over this period, there was a 2.2-fold decrease in the mean HI (0.34 to 0.15) and a 7.2-fold decrease in the percentage of participants with an HI > 1 (5.7% to 0.8%), indicating an overall decrease in combined exposure to these phthalates. Children (aged 6-11 years) had higher mean HI values than either adolescents (aged 12-19 years) or adults (aged 20+ years) during this period. MCR values were generally low and inversely correlated with HI. This indicated that a single phthalate usually drove the hazards for highly exposed individuals. However, the average value of MCR increased 1.2-fold (1.7-2.1) over this period indicating an increasing need to consider exposures to multiple phthalates in this group.

The 2014 follow-up of the Anniston Community Health Survey (ACHS II) consisted of 338 surviving participants from the 2005-2007 baseline study (ACHS) who had previous polychlorinated biphenyl (PCB) measurements, were not pregnant, and were not institutionalized. Questionnaires and blood samples provided the demographic, personal history, and chemical concentration data of the Anniston residents. Approximately 51% of participants were African American, 72% were female, and the mean age was 63 years old. The objectives of this study were to provide an exposure assessment of dioxin-like chemicals in the ACHS II participants and compare the measurements with the general United States (U.S.) population via the National Health and Nutrition Examination Survey (NHANES). Stratified analyses revealed significantly higher average total dioxin toxic equivalencies (TEQs) among African Americans compared to Whites (33.1 vs. 19.2 pg/g lipid), and in females compared to males (29.8 vs. 17.0 pg/g lipid). When adjusting for age, sex, and race in linear regression, we found ACHS II participants to have significantly higher total dioxin TEQ than the general 2014 U.S. population that we estimated for using half-life and NHANES 2003/04 data (most recent NHANES individual samples data), by 16.7 pg/g lipid. Principal component analyses showed that non-ortho and mono-ortho PCBs were separated from the other dioxin-like chemicals among the Anniston residents, whereas the chemicals were all clustered together for estimated NHANES 2014. The concentrations of dioxin-like chemicals, especially non-ortho and mono-ortho PCBs, in Anniston residents who resided near the former PCB production plant were higher than those in the general U.S., Population: Although data strongly supported this difference, these inferences are limited because NHANES 2013/14 data were unavailable and we used estimated NHANES 2014 levels that we imputed from NHANES 2003/04 data in conjunction with half-life values estimated from Milbrath et al., 2009., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Human health risk assessment methods have advanced in recent years to more accurately estimate risks associated with exposure during childhood. However, predicting risks related to infant exposures to environmental chemicals in breast milk and formula remains challenging., Objectives: Our goal was to compile available information on infant exposures to environmental chemicals in breast milk and formula, describe methods to characterize infant exposure and potential for health risk in the context of a risk assessment, and identify research needed to improve risk analyses based on this type of exposure and health risk information., Methods: We reviewed recent literature on levels of environmental chemicals in breast milk and formula, with a focus on data from the United States. We then selected three example publications that quantified infant exposure using breast milk or formula chemical concentrations and estimated breast milk or formula intake. The potential for health risk from these dietary exposures was then characterized by comparison with available health risk benchmarks. We identified areas of this approach in need of improvement to better characterize the potential for infant health risk from this critical exposure pathway., Discussion: Measurements of chemicals in breast milk and formula are integral to the evaluation of risk from early life dietary exposures to environmental chemicals. Risk assessments may also be informed by research investigating the impact of chemical exposure on developmental processes known to be active, and subject to disruption, during infancy, and by analysis of exposure-response data specific to the infant life stage. Critical data gaps exist in all of these areas., Conclusions: Better-designed studies are needed to characterize infant exposures to environmental chemicals in breast milk and infant formula as well as to improve risk assessments of chemicals found in both foods. https://doi.org/10.1289/EHP1953.

Background: The benefits of breastfeeding to the infant and mother have been well documented. It is also well known that breast milk contains environmental chemicals, and numerous epidemiological studies have explored relationships between background levels of chemicals in breast milk and health outcomes in infants and children., Objectives: In this paper, we examine epidemiological literature to address the following question: Are infant exposures to background levels of environmental chemicals in breast milk and formula associated with adverse health effects? We critically review this literature a) to explore whether exposure-outcome associations are observed across studies, and b) to assess the literature quality., Methods: We reviewed literature identified from electronic literature searches. We explored whether exposure-outcome associations are observed across studies by assessing the quality (using a modified version of a previously published quality assessment tool), consistency, and strengths and weaknesses in the literature. The epidemiological literature included cohorts from several countries and examined infants/children either once or multiple times over weeks to years. Health outcomes included four broad categories: growth and maturation, morbidity, biomarkers, and neurodevelopment., Results: The available literature does not provide conclusive evidence of consistent or clinically relevant health consequences to infants exposed to environmental chemicals in breast milk at background levels., Conclusions: It is clear that more research would better inform our understanding of the potential for health impacts from infant dietary exposures to environmental chemicals. A critical data gap is a lack of research on environmental chemicals in formula and infant/child health outcomes. https://doi.org/10.1289/EHP1954.

Endocrine and metabolism disrupting chemicals (EDCs/MDCs) have been associated with environmental liver diseases including toxicant-associated steatohepatitis (TASH). TASH has previously been characterized by hepatocellular necrosis, disrupted intermediary metabolism, and liver inflammation. Polychlorinated biphenyls (PCBs) are environmental EDCs/MDCs associated with the genesis and progression of steatohepatitis in animal models and human liver injury in epidemiology studies. The cross-sectional Anniston Community Health Survey (ACHS) investigates ortho-substituted PCB exposures and health effects near a former PCB manufacturing complex. The rates of obesity, diabetes, and dyslipidemia were previously determined to be high in ACHS. In this study, 738 ACHS participants were categorized by liver disease status using the serum cytokeratin 18 biomarker. Associations between PCB exposures and mechanistic biomarkers of intermediary metabolism, inflammation, and hepatocyte death were determined. The liver disease prevalence was high (60.2%), and 80.7% of these individuals were categorized as having TASH. Sex and race/ethnicity differences were noted. TASH was associated with increased exposures to specific PCB congeners, insulin resistance, dyslipidemia, proinflammatory cytokines, and liver necrosis. These findings are consistent with PCB-related steatohepatitis. ΣPCBs was inversely associated with insulin resistance/production, leptin, and hepatocyte apoptosis, while other adipocytokines were increased. This is possibly the largest environmental liver disease study applying mechanistic biomarkers ever performed and the most comprehensive analysis of PCBs and adipocytokines. It provides insight into the mechanisms of PCB-related endocrine and metabolic disruption in liver disease and diabetes. In the future, associations between additional exposures and liver disease biomarkers will be evaluated in the ACHS and follow-up ACHS-II studies.

Prioritizing the risk posed by thousands of chemicals potentially present in the environment requires exposure, toxicity, and toxicokinetic (TK) data, which are often unavailable. Relatively high throughput, in vitro TK (HTTK) assays and in vitro-to-in vivo extrapolation (IVIVE) methods have been developed to predict TK, but most of the in vivo TK data available to benchmark these methods are from pharmaceuticals. Here we report on new, in vivo rat TK experiments for 26 non-pharmaceutical chemicals with environmental relevance. Both intravenous and oral dosing were used to calculate bioavailability. These chemicals, and an additional 19 chemicals (including some pharmaceuticals) from previously published in vivo rat studies, were systematically analyzed to estimate in vivo TK parameters (e.g., volume of distribution [Vd], elimination rate). For each of the chemicals, rat-specific HTTK data were available and key TK predictions were examined: oral bioavailability, clearance, Vd, and uncertainty. For the non-pharmaceutical chemicals, predictions for bioavailability were not effective. While no pharmaceutical was absorbed at less than 10%, the fraction bioavailable for non-pharmaceutical chemicals was as low as 0.3%. Total clearance was generally more under-estimated for nonpharmaceuticals and Vd methods calibrated to pharmaceuticals may not be appropriate for other chemicals. However, the steady-state, peak, and time-integrated plasma concentrations of nonpharmaceuticals were predicted with reasonable accuracy. The plasma concentration predictions improved when experimental measurements of bioavailability were incorporated. In summary, HTTK and IVIVE methods are adequately robust to be applied to high throughput in vitro toxicity screening data of environmentally relevant chemicals for prioritizing based on human health risks.

Advancements in measurement technologies and modeling capabilities continue to result in an abundance of exposure information, adding to that currently in existence. However, fragmentation within the exposure science community acts as an obstacle for realizing the vision set forth in the National Research Council's report on Exposure Science in the 21 st century to consider exposures from source to dose, on multiple levels of integration, and to multiple stressors. The concept of an Aggregate Exposure Pathway (AEP) was proposed as a framework for organizing and integrating diverse exposure information that exists across numerous repositories and among multiple scientific fields. A workshop held in May 2016 followed introduction of the AEP concept, allowing members of the exposure science community to provide extensive evaluation and feedback regarding the framework's structure, key components, and applications. The current work briefly introduces topics discussed at the workshop and attempts to address key challenges involved in refining this framework. The resulting evolution in the AEP framework's features allows for facilitating acquisition, integration, organization, and transparent application and communication of exposure knowledge in a manner that is independent of its ultimate use, thereby enabling reuse of such information in many applications.

A few different exposure prediction tools were evaluated for use in the new in vitro-based safety assessment paradigm using di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DnBP) as case compounds. Daily intake of each phthalate was estimated using both high-throughput (HT) prediction models such as the HT Stochastic Human Exposure and Dose Simulation model (SHEDS-HT) and the ExpoCast heuristic model and non-HT approaches based on chemical specific exposure estimations in the environment in conjunction with human exposure factors. Reverse dosimetry was performed using a published physiologically based pharmacokinetic (PBPK) model for phthalates and their metabolites to provide a comparison point. Daily intakes of DEHP and DnBP were estimated based on the urinary concentrations of their respective monoesters, mono-2-ethylhexyl phthalate (MEHP) and monobutyl phthalate (MnBP), reported in NHANES (2011-2012). The PBPK-reverse dosimetry estimated daily intakes at the 50th and 95th percentiles were 0.68 and 9.58 μg/kg/d and 0.089 and 0.68 μg/kg/d for DEHP and DnBP, respectively. For DEHP, the estimated median from PBPK-reverse dosimetry was about 3.6-fold higher than the ExpoCast estimate (0.68 and 0.18 μg/kg/d, respectively). For DnBP, the estimated median was similar to that predicted by ExpoCast (0.089 and 0.094 μg/kg/d, respectively). The SHEDS-HT prediction of DnBP intake from consumer product pathways alone was higher at 0.67 μg/kg/d. The PBPK-reverse dosimetry-estimated median intake of DEHP and DnBP was comparable to values previously reported for US populations. These comparisons provide insights into establishing criteria for selecting appropriate exposure prediction tools for use in an integrated modeling platform to link exposure to health effects., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The thousands of chemicals present in the environment (USGAO, 2013) must be triaged to identify priority chemicals for human health risk research. Most chemicals have little of the toxicokinetic (TK) data that are necessary for relating exposures to tissue concentrations that are believed to be toxic. Ongoing efforts have collected limited, in vitro TK data for a few hundred chemicals. These data have been combined with biomonitoring data to estimate an approximate margin between potential hazard and exposure. The most "at risk" 95th percentile of adults have been identified from simulated populations that are generated either using standard "average" adult human parameters or very specific cohorts such as Northern Europeans. To better reflect the modern U.S. population, we developed a population simulation using physiologies based on distributions of demographic and anthropometric quantities from the most recent U.S. Centers for Disease Control and Prevention National Health and Nutrition Examination Survey (NHANES) data. This allowed incorporation of inter-individual variability, including variability across relevant demographic subgroups. Variability was analyzed with a Monte Carlo approach that accounted for the correlation structure in physiological parameters. To identify portions of the U.S. population that are more at risk for specific chemicals, physiologic variability was incorporated within an open-source high-throughput (HT) TK modeling framework. We prioritized 50 chemicals based on estimates of both potential hazard and exposure. Potential hazard was estimated from in vitro HT screening assays (i.e., the Tox21 and ToxCast programs). Bioactive in vitro concentrations were extrapolated to doses that produce equivalent concentrations in body tissues using a reverse dosimetry approach in which generic TK models are parameterized with: 1) chemical-specific parameters derived from in vitro measurements and predicted from chemical structure; and 2) with physiological parameters for a virtual population. For risk-based prioritization of chemicals, predicted bioactive equivalent doses were compared to demographic-specific inferences of exposure rates that were based on NHANES urinary analyte biomonitoring data. The inclusion of NHANES-derived inter-individual variability decreased predicted bioactive equivalent doses by 12% on average for the total population when compared to previous methods. However, for some combinations of chemical and demographic groups the margin was reduced by as much as three quarters. This TK modeling framework allows targeted risk prioritization of chemicals for demographic groups of interest, including potentially sensitive life stages and subpopulations., (Published by Elsevier Ltd.)

Background: Through the food and water they ingest, the air they breathe, and the consumer products with which they interact at home and at work, humans are exposed to tens of thousands of chemicals, many of which have not been evaluated to determine their potential toxicities. Furthermore, while current chemical testing tends to focus on individual chemicals, the exposures that people actually experience involve mixtures of chemicals. Unfortunately, the number of mixtures that can be formed from the thousands of environmental chemicals is enormous, and testing all of them would be impossible., Objectives: We seek to develop and demonstrate a method for identifying those mixtures that are most prevalent in humans., Methods: We applied frequent itemset mining, a technique traditionally used for market basket analysis, to biomonitoring data from the 2009-2010 cycle of the continuous National Health and Nutrition Examination Survey (NHANES) to identify combinations of chemicals that frequently co-occur in people., Results: We identified 90 chemical combinations consisting of relatively few chemicals that occur in at least 30% of the U.S. population, as well as three supercombinations consisting of relatively many chemicals that occur in a small but nonnegligible proportion of the U.S. population., Conclusions: We demonstrated how FIM can be used in conjunction with biomonitoring data to narrow a large number of possible chemical combinations down to a smaller set of prevalent chemical combinations. https://doi.org/10.1289/EHP1265.

Perfluoroalkyl substances (PFAS), chemicals used to make products stain and stick resistant, have been linked to health effects in adults and adverse birth outcomes. A growing body of literature also addresses health effects in children exposed to PFAS. This review summarizes the epidemiologic evidence for relationships between prenatal and/or childhood exposure to PFAS and health outcomes in children as well as to provide a risk of bias analysis of the literature. A systematic review was performed by searching PubMed for studies on PFAS and child health outcomes. We identified 64 studies for inclusion and performed risk of bias analysis on those studies. We determined that risk of bias across studies was low to moderate. Six categories of health outcomes emerged. These were: immunity/infection/asthma, cardio-metabolic, neurodevelopmental/attention, thyroid, renal, and puberty onset. While there are a limited number of studies for any one particular health outcome, there is evidence for positive associations between PFAS and dyslipidemia, immunity (including vaccine response and asthma), renal function, and age at menarche. One finding of note is that while PFASs are mixtures of multiple compounds few studies examine them as such, therefore the role of these compounds as complex mixtures remains largely unknown., Competing Interests: The authors declare no conflict of interest.

Cumulative risk assessments (CRAs) address exposures to multiple chemical and nonchemical stressors and often focus on characterization of health risks in vulnerable populations. Evaluating complex exposure-response relationships in CRAs requires the use of formal and rigorous methods for causal inference. Directed acyclic graphs (DAGs) are graphical causal models used to organize and communicate knowledge about the underlying causal structure that generates observable data. Using existing graphical theories for causal inference with DAGs, risk analysts can identify confounders and effect measure modifiers to determine if the available data are both internally valid to obtain unbiased risk estimates and are generalizable to populations of interest. Conditional independencies implied by the structure of a DAG can be used to test assumptions used in a CRA against empirical data in a selected study and can contribute to the evidence evaluations related to specific causal pathways. This can facilitate quantitative use of these data, as well as help identify key research gaps, prioritize data collection activities, and evaluate risk management alternatives. DAGs also enable risk analysts to be explicit about sources of uncertainty and to determine whether a causal effect can be estimated from available data. Using a conceptual model and DAG for a hypothetical community located near a concentrated animal feeding operation (CAFO), we illustrate the advantages of using DAGs for evaluating causality in CRAs. DAGs also can be used in conjunction with weight of evidence (WOE) methodology to improve causal analysis for CRA, which could lead to more effective interventions to reduce population health risks., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Serum concentrations of polybrominated diphenyl ethers (PBDEs) in U.S. women are believed to be among the world's highest; however, little information exists on the partitioning of PBDEs between serum and breast milk and how this may affect infant exposure., Objectives: Paired milk and serum samples were measured for PBDE concentrations in 34 women who participated in the U.S. EPA MAMA Study. Computational models for predicting milk PBDE concentrations from serum were evaluated., Methods: Samples were analyzed using gas chromatography isotope-dilution high-resolution mass spectrometry. Observed milk PBDE concentrations were compared with model predictions, and models were applied to NHANES serum data to predict milk PBDE concentrations and infant intakes for the U.S. population., Results: Serum and milk samples had detectable concentrations of most PBDEs. BDE-47 was found in the highest concentrations (median serum: 18.6; milk: 31.5 ng/g lipid) and BDE-28 had the highest milk:serum partitioning ratio (2.1 ± 0.2). No evidence of depuration was found. Models demonstrated high reliability and, as of 2007-2008, predicted U.S. milk concentrations of BDE-47, BDE-99, and BDE-100 appear to be declining but BDE-153 may be rising. Predicted infant intakes (ng/kg/day) were below threshold reference doses (RfDs) for BDE-99 and BDE-153 but above the suggested RfD for BDE-47., Conclusions: Concentrations and partitioning ratios of PBDEs in milk and serum from women in the U.S. EPA MAMA Study are presented for the first time; modeled predictions of milk PBDE concentrations using serum concentrations appear to be a valid method for estimating PBDE exposure in U.S. infants.

Recent international efforts have led to proposals for modified carcinogenicity testing paradigms based on data from shorter-term studies. The main goal of the current study was to evaluate the negative predictive value (NPV) of short-term toxicity indicators on carcinogenicity study outcomes and cancer classifications for chemicals previously reviewed by the U.S. Environmental Protection Agency (EPA). Pathology data were analyzed from over 900 acceptable 2-sex guideline subchronic (3-month) and carcinogenicity studies in the U.S. EPA Toxicity Reference Database. Chemical cancer classifications were obtained from annual reports of the U.S. EPA Office of Pesticide Programs. Histopathologic risk signals and evidence of hormonal perturbation in subchronic rat studies provided 56% NPV for any tumor outcome in the rat or mouse and 75% NPV for cancer classifications not requiring quantitative risk assessment (qRA). In comparison, lack of activity in a battery of 35 in vitro cytotoxicity assays from the U.S. EPA ToxCast library provided 49% NPV for any tumor outcome and 80% NPV for cancer classifications not requiring qRA. These findings support the idea that the absence of short-term bioactivity may provide useful information for prioritizing chemicals based on potential carcinogenic risk. Additional data streams are needed to further refine these models., (Published by Oxford University Press on behalf of the Society of Toxicology 2016. This work is written by US Government employees and is in the public domain in the US.)

The US Environmental Protection Agency's (EPA) Endocrine Disruptor Screening Program (EDSP) is using in vitro data generated from ToxCast/Tox21 high-throughput screening assays to assess the endocrine activity of environmental chemicals. Considering that in vitro assays may have limited metabolic capacity, inactive chemicals that are biotransformed into metabolites with endocrine bioactivity may be missed for further screening and testing. Therefore, there is a value in developing novel approaches to account for metabolism and endocrine activity of both parent chemicals and their associated metabolites. We used commercially available software to predict metabolites of 50 parent compounds, out of which 38 chemicals are known to have estrogenic metabolites, and 12 compounds and their metabolites are negative for estrogenic activity. Three ER QSAR models were used to determine potential estrogen bioactivity of the parent compounds and predicted metabolites, the outputs of the models were averaged, and the chemicals were then ranked based on the total estrogenicity of the parent chemical and metabolites. The metabolite prediction software correctly identified known estrogenic metabolites for 26 out of 27 parent chemicals with associated metabolite data, and 39 out of 46 estrogenic metabolites were predicted as potential biotransformation products derived from the parent chemical. The QSAR models estimated stronger estrogenic activity for the majority of the known estrogenic metabolites compared to their parent chemicals. Finally, the three models identified a similar set of parent compounds as top ranked chemicals based on the estrogenicity of putative metabolites. This proposed in silico approach is an inexpensive and rapid strategy for the detection of chemicals with estrogenic metabolites and may reduce potential false negative results from in vitro assays.

Background: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies., Objective: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system., Methods: We used U.S. EPA's animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA's in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features., Results: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network., Conclusion: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s., Citation: Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050-1061; http://dx.doi.org/10.1289/ehp.1510385.

Newin vitrotesting strategies make it possible to design testing batteries for large numbers of environmental chemicals. Full utilization of the results requires knowledge of the underlying biological networks and the adverse outcome pathways (AOPs) that describe the route from early molecular perturbations to an adverse outcome. Curation of a formal AOP is a time-intensive process and a rate-limiting step to designing these test batteries. Here, we describe a method for integrating publicly available data in order to generate computationally predicted AOP (cpAOP) scaffolds, which can be leveraged by domain experts to shorten the time for formal AOP development. A network-based workflow was used to facilitate the integration of multiple data types to generate cpAOPs. Edges between graph entities were identified through direct experimental or literature information, or computationally inferred using frequent itemset mining. Data from the TG-GATEs and ToxCast programs were used to channel large-scale toxicogenomics information into a cpAOP network (cpAOPnet) of over 20 000 relationships describing connections between chemical treatments, phenotypes, and perturbed pathways as measured by differential gene expression and high-throughput screening targets. The resulting fatty liver cpAOPnet is available as a resource to the community. Subnetworks of cpAOPs for a reference chemical (carbon tetrachloride, CCl4) and outcome (fatty liver) were compared with published mechanistic descriptions. In both cases, the computational approaches approximated the manually curated AOPs. The cpAOPnet can be used for accelerating expert-curated AOP development and to identify pathway targets that lack genomic markers or high-throughput screening tests. It can also facilitate identification of key events for designing test batteries and for classification and grouping of chemicals for follow up testing., (Published by Oxford University Press on behalf of the Society of Toxicology 2016. This work is written by US Government employees and is in the public domain in the United States.)

There is a growing need in the field of exposure science for monitoring methods that rapidly screen environmental media for suspect contaminants. Measurement and analysis platforms, based on high resolution mass spectrometry (HRMS), now exist to meet this need. Here we describe results of a study that links HRMS data with exposure predictions from the U.S. EPA's ExpoCast™ program and in vitro bioassay data from the U.S. interagency Tox21 consortium. Vacuum dust samples were collected from 56 households across the U.S. as part of the American Healthy Homes Survey (AHHS). Sample extracts were analyzed using liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS) with electrospray ionization. On average, approximately 2000 molecular features were identified per sample (based on accurate mass) in negative ion mode, and 3000 in positive ion mode. Exact mass, isotope distribution, and isotope spacing were used to match molecular features with a unique listing of chemical formulas extracted from EPA's Distributed Structure-Searchable Toxicity (DSSTox) database. A total of 978 DSSTox formulas were consistent with the dust LC-TOF/molecular feature data (match score≥90); these formulas mapped to 3228 possible chemicals in the database. Correct assignment of a unique chemical to a given formula required additional validation steps. Each suspect chemical was prioritized for follow-up confirmation using abundance and detection frequency results, along with exposure and bioactivity estimates from ExpoCast and Tox21, respectively. Chemicals with elevated exposure and/or toxicity potential were further examined using a mixture of 100 chemical standards. A total of 33 chemicals were confirmed present in the dust samples by formula and retention time match; nearly half of these do not appear to have been associated with house dust in the published literature. Chemical matches found in at least 10 of the 56 dust samples include Piperine, N,N-Diethyl-m-toluamide (DEET), Triclocarban, Diethyl phthalate (DEP), Propylparaben, Methylparaben, Tris(1,3-dichloro-2-propyl)phosphate (TDCPP), and Nicotine. This study demonstrates a novel suspect screening methodology to prioritize chemicals of interest for subsequent targeted analysis. The methods described here rely on strategic integration of available public resources and should be considered in future non-targeted and suspect screening assessments of environmental and biological media., (Published by Elsevier Ltd.)

Background: Experimental animal studies, in vitro experiments, and clinical assessments have shown that metal toxicity can impair immune responses. We analyzed data from a United States representative National Health and Nutrition Examination Survey (NHANES) to explore associations between chronic infections and elevated blood concentrations of lead and cadmium among non-smoking NHANES participants., Methods: NHANES data from 1999 to 2012 were examined and weighted to represent the United States population. Multivariable logistic regression was used to estimate adjusted odds ratios (AOR) and 95 % confidence intervals (CI) for heavy metal associations with seropositivity for Helicobacter pylori, Toxoplasma gondii, and Hepatitis B virus (HBV) infections., Results: Available 2-year survey cycles for infection seroprevalence varied by pathogen, from 1 to 7 cycles. Available sample size, disease seroprevalence, and participant age range also varied by pathogen of interest. After controlling for demographic characteristics and general health condition, an elevated blood lead level above the survey population median was significantly associated with seropositivity for all three pathogens (AORs = 1.2-1.5). In addition, an elevated blood cadmium level above the median was significantly associated with HBV (AOR = 1.5; 95 % CI = 1.2-2.0) and H. pylori (AOR = 1.5; 95 % CI = 1.2-1.7) seropositivity. Age-specific analyses for H. pylori and T. gondii indicated stronger associations among children under 13 years of age, particularly for lead exposure and H. pylori seropositivity, and weaker associations among those over 35 years of age., Conclusions: The results of this cross-sectional human health survey suggest that the immunological effects of lead and cadmium toxicity may be associated with an increased susceptibility to chronic infections.

High serum concentrations of polychlorinated biphenyls (PCBs) have been reported previously among residents of Anniston, Alabama, where a PCB production facility was located in the past. As the second of two cross-sectional studies of these Anniston residents, the Anniston Community Health Survey: Follow-Up and Dioxin Analyses (ACHS-II) will yield repeated measurements to be used to evaluate changes over time in ortho-PCB concentrations and selected health indicators in study participants. Dioxins, non-ortho PCBs, other chemicals, heavy metals, and a variety of additional clinical tests not previously measured in the original ACHS cohort will be examined in ACHS-II. The follow-up study also incorporates a questionnaire with extended sections on diet and occupational history for a more comprehensive assessment of possible exposure sources. Data collection for ACHS-II from 359 eligible participants took place in 2014, 7 to 9 years after ACHS.

Background: There are > 80,000 chemicals in commerce with few data available describing their impacts on human health. Biomonitoring surveys, such as the NHANES (National Health and Nutrition Examination Survey), offer one route to identifying possible relationships between environmental chemicals and health impacts, but sparse data and the complexity of traditional models make it difficult to leverage effectively., Objective: We describe a workflow to efficiently and comprehensively evaluate and prioritize chemical-health impact relationships from the NHANES biomonitoring survey studies., Methods: Using a frequent itemset mining (FIM) approach, we identified relationships between chemicals and health biomarkers and diseases., Results: The FIM method identified 7,848 relationships between 219 chemicals and 93 health outcomes/biomarkers. Two case studies used to evaluate the FIM rankings demonstrate that the FIM approach is able to identify published relationships. Because the relationships are derived from the vast majority of the chemicals monitored by NHANES, the resulting list of associations is appropriate for evaluating results from targeted data mining or identifying novel candidate relationships for more detailed investigation., Conclusions: Because of the computational efficiency of the FIM method, all chemicals and health effects can be considered in a single analysis. The resulting list provides a comprehensive summary of the chemical/health co-occurrences from NHANES that are higher than expected by chance. This information enables ranking and prioritization on chemicals or health effects of interest for evaluation of published results and design of future studies., Citation: Bell SM, Edwards SW. 2015. Identification and prioritization of relationships between environmental stressors and adverse human health impacts. Environ Health Perspect 123:1193-1199; http://dx.doi.org/10.1289/ehp.1409138.

Toxicokinetic (TK) models link administered doses to plasma, blood, and tissue concentrations. High-throughput TK (HTTK) performs in vitro to in vivo extrapolation to predict TK from rapid in vitro measurements and chemical structure-based properties. A significant toxicological application of HTTK has been "reverse dosimetry," in which bioactive concentrations from in vitro screening studies are converted into in vivo doses (mg/kg BW/day). These doses are predicted to produce steady-state plasma concentrations that are equivalent to in vitro bioactive concentrations. In this study, we evaluate the impact of the approximations and assumptions necessary for reverse dosimetry and develop methods to determine whether HTTK tools are appropriate or may lead to false conclusions for a particular chemical. Based on literature in vivo data for 87 chemicals, we identified specific properties (eg, in vitro HTTK data, physico-chemical descriptors, and predicted transporter affinities) that correlate with poor HTTK predictive ability. For 271 chemicals we developed a generic HT physiologically based TK (HTPBTK) model that predicts non-steady-state chemical concentration time-courses for a variety of exposure scenarios. We used this HTPBTK model to find that assumptions previously used for reverse dosimetry are usually appropriate, except most notably for highly bioaccumulative compounds. For the thousands of man-made chemicals in the environment that currently have no TK data, we propose a 4-element framework for chemical TK triage that can group chemicals into 7 different categories associated with varying levels of confidence in HTTK predictions. For 349 chemicals with literature HTTK data, we differentiated those chemicals for which HTTK approaches are likely to be sufficient, from those that may require additional data., (Published by Oxford University Press on behalf of Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.)

Background: Many environmental factors have been independently associated with preterm birth (PTB). However, exposure is not isolated to a single environmental factor, but rather to many positive and negative factors that co-occur. The environmental quality index (EQI), a measure of cumulative environmental exposure across all US counties from 2000-2005, was used to investigate associations between ambient environment and PTB., Methods: With 2000-2005 birth data from the National Center for Health Statistics for the United States (n = 24,483,348), we estimated the association between increasing quintiles of the EQI and county-level and individual-level PTB; we also considered environmental domain-specific (air, water, land, sociodemographic and built environment) and urban-rural stratifications., Results: Effect estimates for the relationship between environmental quality and PTB varied by domain and by urban-rural strata but were consistent across county- and individual-level analyses. The county-level prevalence difference (PD (95% confidence interval) for the non-stratified EQI comparing the highest quintile (poorest environmental quality) to the lowest quintile (best environmental quality) was -0.0166 (-0.0198, -0.0134). The air and sociodemographic domains had the strongest associations with PTB; PDs were 0.0196 (0.0162, 0.0229) and -0.0262 (-0.0300, -0.0224) for the air and sociodemographic domain indices, respectively. Within the most urban strata, the PD for the sociodemographic domain index was 0.0256 (0.0205, 0.0307). Odds ratios (OR) for the individual-level analysis were congruent with PDs., Conclusion: We observed both strong positive and negative associations between measures of broad environmental quality and preterm birth. Associations differed by rural-urban stratum and by the five environmental domains. Our study demonstrates the use of a large scale composite environment exposure metric with preterm birth, an important indicator of population health and shows potential for future research.

The peer-reviewed literature on the health and ecological effects of lead (Pb) indicates common effects and underlying modes of action across multiple organisms for several endpoints. Based on such observations, the United States (U.S.) Environmental Protection Agency (EPA) applied a cross-species approach in the 2013 Integrated Science Assessment (ISA) for Lead for evaluating the causality of relationships between Pb exposure and specific endpoints that are shared by humans, laboratory animals, and ecological receptors (i.e., hematological effects, reproductive and developmental effects, and nervous system effects). Other effects of Pb (i.e., cardiovascular, renal, and inflammatory responses) are less commonly assessed in aquatic and terrestrial wildlife limiting the application of cross-species comparisons. Determinations of causality in ISAs are guided by a framework for classifying the weight of evidence across scientific disciplines and across related effects by considering aspects such as biological plausibility and coherence. As illustrated for effects of Pb where evidence across species exists, the integration of coherent effects and common underlying modes of action can serve as a means to substantiate conclusions regarding the causal nature of the health and ecological effects of environmental toxicants., (Published by Elsevier Ireland Ltd.)

The Anniston Community Health Survey was a community-based cross-sectional study of Anniston, Alabama, residents who live in close proximity to a former PCB production facility to identify factors associated with serum PCB levels. The survey comprises 765 Anniston residents who completed a questionnaire interview and provided a blood sample for analysis in 2005-2007. Several reports based on data from the Anniston survey have been previously published, including associations between PCB exposure and diabetes and blood pressure. In this study we examine demographic, behavioral, dietary, and occupational characteristics of Anniston survey participants as predictors of serum PCB concentrations. Of the 765 participants, 54% were White and 45% were African-American; the sample was predominantly female (70%), with a mean age of 55 years. Serum PCB concentrations varied widely between participants (range for sum of 35 PCBs: 0.11-170.4 ng/g wet weight). Linear regression models with stepwise selection were employed to examine factors associated with serum PCBs. Statistically significant positive associations were observed between serum PCB concentrations and age, race, residential variables, current smoking, and local fish consumption, as was a negative association with education level. Age and race were the most influential predictors of serum PCB levels. A small age by sex interaction was noted, indicating that the increase in PCB levels with age was steeper for women than for men. Significant interaction terms indicated that the associations between PCB levels and having ever eaten locally raised livestock and local clay were much stronger among African-Americans than among White participants. In summary, demographic variables and past consumption of locally produced foods were found to be the most important predictors of PCB concentrations in residents living in the vicinity of a former PCB manufacturing facility., (Published by Elsevier B.V.)

Background: The Navigation Guide is a novel systematic review method to synthesize scientific evidence and reach strength of evidence conclusions for environmental health decision making., Objective: Our aim was to integrate scientific findings from human and nonhuman studies to determine the overall strength of evidence for the question "Does developmental exposure to perfluorooctanoic acid (PFOA) affect fetal growth in humans?", Methods: We developed and applied prespecified criteria to systematically and transparently a) rate the quality of the scientific evidence as "high," "moderate," or "low"; b) rate the strength of the human and nonhuman evidence separately as "sufficient," "limited," "moderate," or "evidence of lack of toxicity"; and c) integrate the strength of the human and nonhuman evidence ratings into a strength of the evidence conclusion., Results: We identified 18 epidemiology studies and 21 animal toxicology studies relevant to our study question. We rated both the human and nonhuman mammalian evidence as "moderate" quality and "sufficient" strength. Integration of these evidence ratings produced a final strength of evidence rating in which review authors concluded that PFOA is "known to be toxic" to human reproduction and development based on sufficient evidence of decreased fetal growth in both human and nonhuman mammalian species., Conclusion: We concluded that developmental exposure to PFOA adversely affects human health based on sufficient evidence of decreased fetal growth in both human and nonhuman mammalian species. The results of this case study demonstrate the application of a systematic and transparent methodology, via the Navigation Guide, for reaching strength of evidence conclusions in environmental health.