Rapid identification of reproductive toxicants among environmental chemicals using an in vivo evaluation of gametogenesis in budding yeast Saccharomyces cerevisiae.

Infertility affects ∼12 % of couples, with environmental chemical exposure as a potential contributor. Of the chemicals that are actively manufactured, very few are assessed for reproductive health effects. Rodents are commonly used to evaluate reproductive effects, which is both costly and time consuming. Thus, there is a pressing need for rapid methods to test a broader range of chemicals. Here, we developed a strategy to evaluate large numbers of chemicals for reproductive toxicity via a yeast, S. cerevisiae high-throughput assay to assess gametogenesis as a potential new approach method (NAM). By simultaneously assessing chemicals for growth effects, we can distinguish if a chemical affects gametogenesis only, proliferative growth only or both. We identified a well-known mammalian reproductive toxicant, bisphenol A (BPA) and ranked 19 BPA analogs for reproductive harm. By testing mixtures of BPA and its analogs, we found that BPE and 17 ß-estradiol each together with BPA showed synergistic effects that worsened reproductive outcome. We examined an additional 179 environmental chemicals including phthalates, pesticides, quaternary ammonium compounds and per- and polyfluoroalkyl substances and found 57 with reproductive effects. Many of the chemicals were found to be strong reproductive toxicants that have yet to be tested in mammals. Chemicals having affect before meiosis I division vs. meiosis II division were identified for 16 gametogenesis-specific chemicals. Finally, we demonstrate that in general yeast reproductive toxicity correlates well with published reproductive toxicity in mammals illustrating the promise of this NAM to quickly assess chemicals to prioritize the evaluation for human reproductive harm.

Analyzing high-throughput assay data to advance the rapid screening of environmental chemicals for human reproductive toxicity.

While high-throughput (HTP) assays have been proposed as platforms to rapidly assess reproductive toxicity, there is currently a lack of established assays that specifically address germline development/function and fertility. We assessed the applicability domains of yeast (S. cerevisiae) and nematode (C. elegans) HTP assays in toxicity screening of 124 environmental chemicals, determining their agreement in identifying toxicants and their concordance with reproductive toxicity in vivo. We integrated data generated in the two models and compared results using a streamlined, semi-automated benchmark dose (BMD) modeling approach. We then extracted and modeled relevant mammalian in vivo data available for the matching chemicals included in the Toxicological Reference Database (ToxRefDB). We ranked potencies of common compounds using the BMD and evaluated correlation between the datasets using Pearson and Spearman correlation coefficients. We found moderate to good correlation across the three data sets, with r = 0.48 (95% CI: 0.28-1.00, p<0.001) and rs = 0.40 (p=0.002) for the parametric and rank order correlations between the HTP BMDs; r = 0.95 (95% CI: 0.76-1.00, p=0.0005) and rs = 0.89 (p=0.006) between the yeast assay and ToxRefDB BMDs; and r = 0.81 (95% CI: 0.28-1.00, p=0.014) and rs = 0.75 (p=0.033) between the worm assay and ToxRefDB BMDs. Our findings underscore the potential of these HTP assays to identify environmental chemicals that exhibit reproductive toxicity. Integrating these HTP datasets into mammalian in vivo prediction models using machine learning methods could further enhance the predictive value of these assays in future rapid screening efforts.

Screening and characterization of 133 physiologically-relevant environmental chemicals for reproductive toxicity.

Reproduction is a functional outcome that relies on complex cellular, tissue, and organ interactions that span the developmental period to adulthood. Thus, the assessment of its disruption by environmental chemicals would benefit significantly from scalable and innovative approaches to testing using functionally comparable reproductive models such as the nematode C. elegans. We adapted a previously described low-throughput in vivo chromosome segregation assay using C. elegans predictive of reproductive toxicity and leveraged available public data sources (ToxCast, ICE) to screen and characterize 133 physiologically-relevant chemicals in a high-throughput manner. The screening outcome was further validated in a second, independent in vivo assay assessing embryonic viability. In total, 13 chemicals were classified as reproductive toxicants with the two most active chemicals belonging to the large family of Quaternary Ammonium Compounds (QACs) commonly used as disinfectants but with limited available reproductive toxicity data. We compared the results from the C. elegans assay with ToxCast in vitro data compiled from 700+ cell response assays and 300+ signaling pathways-based assays. We did not observe a difference in the bioactivity or in the average potency (AC50) between the top and bottom chemicals. However, the intended target categories were significantly different between the classified chemicals with, in particular, an over-representation of steroid hormone targets for the high Z-score chemicals. Taken together, these results point to the value of in vivo models that scale to high-throughput level for reproductive toxicity assessment and to the need to prioritize the assessment of QACs impacts on reproduction.

The effect of per and polyfluoroalkyl substance (PFAS) exposure on gestational diabetes mellitus and its subclinical risk factors: A systematic review and meta-analysis protocol.

BACKGROUND: Multiple lines of evidence suggest that exposure to per- and polyfluoroalkyl substances (PFAS) may alter glucose homeostasis, particularly during pregnancy, and may affect risk for developing gestational diabetes mellitus (GDM). While previous systematic reviews have been conducted on this topic, they did not assess internal validity of the included studies and their search strategies were narrowly focused. OBJECTIVE: The objective of this study is to assess the effect of higher PFAS exposure (defined by individual compounds or mixtures measured before or during pregnancy) on GDM and subclinical measures of impaired glucose homeostasis (measured during pregnancy) compared to lower PFAS exposure in pregnant. METHODS: We developed our systematic review protocol in accordance with the Navigation Guide. Peer-reviewed journal and grey literature searches were piloted in to identify relevant studies and refine our search terms and strategy. We also piloted the study screening criteria and data extraction form in DistillerSR, and refined our protocol accordingly. The risk of bias assessment protocol was adapted from Navigation Guide guidance and will be piloted and performed in DistillerSR. Pending the identification of comparable studies, quantitative meta-analyses will be performed where possible. Study results that cannot be quantitatively synthesized will be included in a narrative synthesis. The quality and strength of the body of evidence will be evaluated using Navigation Guide methodology, which is informed by guidance from the Cochrane Collaboration and Grading of Recommendations Assessment, Development and Evaluation (GRADE). We also made refinements to the quality of evidence considerations based on guidance from the National Institute of Environmental Health Sciences (NIEHS) Office of Health Assessment and Translation (OHAT). FUNDING: This work was supported by the Systematizing Data on Per- and Polyfluoroalkyl Substances and Health Northeastern University TIER 1 Award.

Screening and characterization of 133 physiologically-relevant environmental chemicals for reproductive toxicity.

Reproduction is a functional outcome that relies on complex cellular, tissue, and organ interactions that span the developmental period to adulthood. Thus, the assessment of its disruption by environmental chemicals is remarkably painstaking in conventional toxicological animal models and does not scale up to the number of chemicals present in our environment and requiring testing. We adapted a previously described low-throughput in vivo chromosome segregation assay using C. elegans predictive of reproductive toxicity and leveraged available public data sources (ToxCast, ICE) to screen and characterize 133 physiologically-relevant chemicals in a high-throughput manner. The screening outcome was further validated in a second, independent in vivo assay assessing embryonic viability. In total, 13 chemicals were classified as reproductive toxicants with the two most active chemicals belonging to the large family of Quaternary Ammonium Compounds (QACs) commonly used as disinfectants but with limited available reproductive toxicity data. We compared the results from the C. elegans assay with ToxCast in vitro data compiled from 700+ cell response assays and 300+ signaling pathways-based assays. We did not observe a difference in the bioactivity or in average potency (AC50) between the top and bottom chemicals. However, the intended target categories were significantly different between the classified chemicals with, in particular, an over-representation of steroid hormone targets for the high Z-score chemicals. Taken together, these results point to the value of in vivo models that scale to high-throughput level for reproductive toxicity assessment and to the need to prioritize the assessment of QACs impacts on reproduction.

Public Health Risks of PFAS-Related Immunotoxicity Are Real.

PURPOSE OF REVIEW: The discovery of per- and polyfluoroalkyl substances (PFAS) in the environment and humans worldwide has ignited scientific research, government inquiry, and public concern over numerous adverse health effects associated with PFAS exposure. In this review, we discuss the use of PFAS immunotoxicity data in regulatory and clinical decision-making contexts and question whether recent efforts adequately account for PFAS immunotoxicity in public health decision-making. RECENT FINDINGS: Government and academic reviews confirm the strongest human evidence for PFAS immunotoxicity is reduced antibody production in response to vaccinations, particularly for tetanus and diphtheria. However, recent events, such as the economic analysis supporting the proposed national primary drinking water regulations and clinical monitoring recommendations, indicate a failure to adequately incorporate these data into regulatory and clinical decisions. To be more protective of public health, we recommend using all relevant immunotoxicity data to inform current and future PFAS-related chemical risk assessment and regulation. Biological measures of immune system effects, such as reduced antibody levels in response to vaccination, should be used as valid and informative markers of health outcomes and risks associated with PFAS exposure. Routine toxicity testing should be expanded to include immunotoxicity evaluations in adult and developing organisms. In addition, clinical recommendations for PFAS-exposed individuals and communities should be revisited and strengthened to provide guidance on incorporating immune system monitoring and other actions that can be taken to protect against adverse health outcomes.

A science-based agenda for health-protective chemical assessments and decisions: overview and consensus statement.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

Current practice and recommendations for advancing how human variability and susceptibility are considered in chemical risk assessment.

A key element of risk assessment is accounting for the full range of variability in response to environmental exposures. Default dose-response methods typically assume a 10-fold difference in response to chemical exposures between average (healthy) and susceptible humans, despite evidence of wider variability. Experts and authoritative bodies support using advanced techniques to better account for human variability due to factors such as in utero or early life exposure and exposure to multiple environmental, social, and economic stressors.This review describes: 1) sources of human variability and susceptibility in dose-response assessment, 2) existing US frameworks for addressing response variability in risk assessment; 3) key scientific inadequacies necessitating updated methods; 4) improved approaches and opportunities for better use of science; and 5) specific and quantitative recommendations to address evidence and policy needs.Current default adjustment factors do not sufficiently capture human variability in dose-response and thus are inadequate to protect the entire population. Susceptible groups are not appropriately protected under current regulatory guidelines. Emerging tools and data sources that better account for human variability and susceptibility include probabilistic methods, genetically diverse in vivo and in vitro models, and the use of human data to capture underlying risk and/or assess combined effects from chemical and non-chemical stressors.We recommend using updated methods and data to improve consideration of human variability and susceptibility in risk assessment, including the use of increased default human variability factors and separate adjustment factors for capturing age/life stage of development and exposure to multiple chemical and non-chemical stressors. Updated methods would result in greater transparency and protection for susceptible groups, including children, infants, people who are pregnant or nursing, people with disabilities, and those burdened by additional environmental exposures and/or social factors such as poverty and racism.

Presumptive Contamination: A New Approach to PFAS Contamination Based on Likely Sources.

While research and regulatory attention to per- and polyfluoroalkyl substances (PFAS) has increased exponentially in recent years, data are uneven and incomplete about the scale, scope, and severity of PFAS releases and resulting contamination in the United States. This paper argues that in the absence of high-quality testing data, PFAS contamination can be presumed around three types of facilities: (1) fluorinated aqueous film-forming foam (AFFF) discharge sites, (2) certain industrial facilities, and (3) sites related to PFAS-containing waste. While data are incomplete on all three types of presumptive PFAS contamination sites, we integrate available geocoded, nationwide data sets into a single map of presumptive contamination sites in the United States, identifying 57,412 sites of presumptive PFAS contamination: 49,145 industrial facilities, 4,255 wastewater treatment plants, 3,493 current or former military sites, and 519 major airports. This conceptual approach allows governments, industries, and communities to rapidly and systematically identify potential exposure sources.

The PFAS-Tox Database: A systematic evidence map of health studies on 29 per- and polyfluoroalkyl substances.

BACKGROUND: PFAS (per-and polyfluoroalkyl substances) are a large class of synthetic chemicals widely used in consumer products and industrial processes. The scientific literature on PFAS has increased dramatically in the last decade. Many stakeholders, including regulators, scientists, non-governmental organizations, and concerned individuals could benefit from an efficient way to access the health and toxicological literature related to PFAS. OBJECTIVE: To create a systematic evidence map of the available peer-reviewed health or toxicological research for 29 PFAS. METHODS: A protocol for conducting this systematic evidence map was initially published on Zenodo (Pelch et al. 2019c), then peer reviewed and published in Environment International (Pelch et al. 2019d). PubMed database was searched through January 25, 2021. Studies were screened for inclusion and exclusion according to the Populations, Exposures, Comparators, and Outcomes (PECO) statement. Inclusion criteria were intentionally broad and included any human, animal, and/or in vitro study that investigated exposure to one of the 29 PFAS of interest and a human health or toxicological effect. Selected study details were extracted from included studies as described in the protocol. Study appraisal was not conducted. The included studies and extracted meta-data are freely available in the online, interactive systematic evidence map at https://pfastoxdatabase.org. RESULTS: Over 15,000 studies were retrieved from the PubMed literature searches. After manual screening, 1,067 studies were identified and included as investigating the health or toxicological effect of one or more PFAS of interest. There were 505 human, 385 animal, and 220 in vitro studies. Summary tables of the extracted data and overall observations are included in this report. CONCLUSIONS: The PFAS-Tox Database is a useful tool for searching, filtering, and identifying peer reviewed research on the health and toxicological effects of the included PFAS. In this summary of the evidence map we provide examples of data gaps and clusters revealed by the database, with the goal of helping direct future research efforts, facilitate systematic reviews (e.g. on immune effects, mixtures of PFAS, or effects of short chain PFAS), inform regulatory risk assessments, and improve opportunities for cross-disciplinary coordination. We also discuss how this tool supports scientists, regulatory agencies, and other individuals by increasing awareness and access to current evidence regarding the health effects associated with PFAS exposure.

Organophosphate Flame Retardants, Highly Fluorinated Chemicals, and Biomarkers of Placental Development and Disease During Mid-Gestation.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) and organophosphate flame retardants (OPFRs) are chemicals that may contribute to placenta-mediated complications and adverse maternal-fetal health risks. Few studies have investigated these chemicals in relation to biomarkers of effect during pregnancy. We measured 12 PFASs and four urinary OPFR metabolites in 132 healthy pregnant women during mid-gestation and examined a subset with biomarkers of placental development and disease (n = 62). Molecular biomarkers included integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and matrix metalloproteinase-1 (MMP1). Morphological endpoints included potential indicators of placental stress and the extent of cytotrophoblast (CTB)-mediated uterine artery remodeling. Serum PFASs and urinary OPFR metabolites were detected in ∼50%-100% of samples. The most prevalent PFASs were perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonic acid (PFOS), with geometric mean (GM) levels of ∼1.3-2.8 (95% confidence limits from 1.2-3.1) ng/ml compared to ≤0.5 ng/ml for other PFASs. Diphenyl phosphate (DPhP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were the most prevalent OPFR metabolites, with GMs of 2.9 (95% CI: 2.5-3.4) and 3.6 (95% CI: 2.2-3.1) ng/ml, respectively, compared to <1 ng/ml for bis(2-chloroethyl) phosphate (BCEP) and bis(1-chloro-2-propyl) phosphate (BCIPP). We found inverse associations of PFASs or OPFRs with ITGA1 or CDH5 immunoreactivity and positive associations with indicators of placental stress in multiple basal plate regions, indicating these chemicals may contribute to abnormal placentation and future health risks. Associations with blood pressure and lipid concentrations warrant further examination. This is the first study of these chemicals with placental biomarkers measured directly in human tissues and suggests specific biomarkers are sensitive indicators of exposure during a vulnerable developmental period.

Racial/ethnic and geographic differences in polybrominated diphenyl ether (PBDE) levels across maternal, placental, and fetal tissues during mid-gestation.

Prenatal polybrominated diphenyl ether (PBDE) exposures are a public health concern due to their persistence and potential for reproductive and developmental harm. However, we have little information about the extent of fetal exposures during critical developmental periods and the variation in exposures for groups that may be more highly exposed, such as communities of color and lower socioeconomic status (SES). To characterize maternal-fetal PBDE exposures among potentially vulnerable groups, PBDE levels were examined in the largest sample of matched maternal serum, placenta, and fetal liver tissues during mid-gestation among a geographically, racially/ethnically, and socially diverse population of pregnant women from Northern California and the Central Valley (n = 180; 2014-16). Maternal-fetal PBDE levels were compared to population characteristics using censored Kendall's tau correlation and linear regression. PBDEs were commonly detected in all biomatrices. Before lipid adjustment, wet-weight levels of all four PBDE congeners were highest in the fetal liver (p < 0.001), whereas median PBDE levels were significantly higher in maternal serum than in the fetal liver or placenta after lipid-adjustment (p < 0.001). We also found evidence of racial/ethnic disparities in PBDE exposures (Non-Hispanic Black > Latina/Hispanic > Non-Hispanic White > Asian/Pacific Islander/Other; p < 0.01), with higher levels of BDE-100 and BDE-153 among non-Hispanic Black women compared to the referent group (Latina/Hispanic women). In addition, participants living in Fresno/South Central Valley had 34% (95% CI: - 2.4 to 84%, p = 0.07) higher wet-weight levels of BDE-47 than residents living in the San Francisco Bay Area. PBDEs are widely detected and differentially distributed in maternal-fetal compartments. Non-Hispanic Black pregnant women and women from Southern Central Valley geographical populations may be more highly exposed to PBDEs. Further research is needed to identify sources that may be contributing to differential exposures and associated health risks among these vulnerable populations.

Association of polybrominated diphenyl ether (PBDE) levels with biomarkers of placental development and disease during mid-gestation.

BACKGROUND: Polybrominated diphenyl ether (PBDE) exposures have been associated with adverse pregnancy outcomes. A hypothesized mechanism is via alterations in placental development and function. However, we lack biomarkers that can be used as early indicators of maternal/fetal response to PBDE exposures and/or perturbations in placental development or function. METHODS: To evaluate the relationship between PBDE levels and placental biomarkers during mid-gestation of human pregnancy (n = 62), we immunolocalized three molecules that play key roles in cytotrophoblast (CTB) differentiation and interstitial/endovascular uterine invasion-integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and metalloproteinase-1 (MMP1)-and assessed three morphological parameters as potential indicators of pathological alterations using H&E-stained tissues-leukocyte infiltration, fibrinoid deposition, and CTB endovascular invasion. We evaluated associations between placental PBDE levels and of biomarkers of placental development and disease using censored Kendall's tau correlation and linear regression methods. RESULTS: PBDEs were detected in all placental samples. We observed substantial variation in antigen expression and morphological endpoints across placental regions. We observed an association between PBDE concentrations and immunoreactivity of endovascular CTB staining with anti-ITGA1 (inverse) or interstitial CTBs staining with anti-CDH5 (positive). CONCLUSIONS: We found several molecular markers that may be sensitive placental indicators of PBDE exposure. Further, this indicates that placental biomarkers of development and disease could be useful barometers of exposure to PBDEs, a paradigm that could be extended to other environmental chemicals and placental stage-specific antigens.

A Pilot Biomonitoring Study of Cumulative Phthalates Exposure among Vietnamese American Nail Salon Workers.

Many California nail salon workers are low-income Vietnamese women of reproductive age who use nail products daily that contain androgen-disrupting phthalates, which may increase risk of male reproductive tract abnormalities during pregnancy. Yet, few studies have characterized phthalate exposures among this workforce. To characterize individual metabolites and cumulative phthalates exposure among a potentially vulnerable occupational group of nail salon workers, we collected 17 post-shift urine samples from Vietnamese workers at six San Francisco Bay Area nail salons in 2011, which were analyzed for four primary phthalate metabolites: mono-n-butyl-, mono-isobutyl-, mono(2-Ethylhexyl)-, and monoethyl phthalates (MnBP, MiBP, MEHP, and MEP, respectively; µg/L). Phthalate metabolite concentrations and a potency-weighted sum of parent compound daily intake (Σandrogen-disruptor, µg/kg/day) were compared to 203 Asian Americans from the 2011-2012 National Health and Nutritional Examination Survey (NHANES) using Student's t-test and Wilcoxin signed rank test. Creatinine-corrected MnBP, MiBP, MEHP (µg/g), and cumulative phthalates exposure (Σandrogen-disruptor, µg/kg/day) levels were 2.9 (p < 0.0001), 1.6 (p = 0.015), 2.6 (p < 0.0001), and 2.0 (p < 0.0001) times higher, respectively, in our nail salon worker population compared to NHANES Asian Americans. Levels exceeded the NHANES 95th or 75th percentiles among some workers. This pilot study suggests that nail salon workers are disproportionately exposed to multiple phthalates, a finding that warrants further investigation to assess their potential health significance.

Heightened susceptibility: A review of how pregnancy and chemical exposures influence maternal health.

Pregnancy is a unique period when biological changes can increase sensitivity to chemical exposures. Pregnant women are exposed to multiple environmental chemicals via air, food, water, and consumer products, including flame retardants, plasticizers, and pesticides. Lead exposure increases risk of pregnancy-induced hypertensive disorders, although women's health risks are poorly characterized for most chemicals. Research on prenatal exposures has focused on fetal outcomes and less on maternal outcomes. We reviewed epidemiologic literature on chemical exposures during pregnancy and three maternal outcomes: preeclampsia, gestational diabetes, and breast cancer. We found that pregnancy can heighten susceptibility to environmental chemicals and women's health risks, although variations in study design and exposure assessment limited study comparability. Future research should include pregnancy as a critical period for women's health. Incorporating biomarkers of exposure and effect, deliberate timing and method of measurement, and consistent adjustment of potential confounders would strengthen research on the exposome and women's health.

A review of maternal prenatal exposures to environmental chemicals and psychosocial stressors-implications for research on perinatal outcomes in the ECHO program.

Exposures to environmental chemicals and psychosocial stressors during pregnancy have been individually associated with adverse perinatal outcomes related to birthweight and gestational age, but are not often considered in combination. We review types of psychosocial stressors and instruments used to assess them and classes of environmental chemical exposures that are known to adversely impact perinatal outcomes, and identify studies relevant studies. We discuss the National Institutes of Health's Environmental influences on Child Health Outcomes (ECHO) program that has combined existing longitudinal cohorts that include more than 50,000 children across the U.S. We describe future opportunities for investigators to use this important new resource for addressing relevant and critical research questions to maternal health. Of the 84 cohorts in ECHO, 38 collected data on environmental chemicals and psychosocial stressors and perinatal outcomes. The diverse ECHO pregnancy cohorts provide capacity to compare regions with distinct place-based environmental and social stressors.

Dietary sources of cumulative phthalates exposure among the U.S. general population in NHANES 2005-2014.

BACKGROUND: Anti-androgenic phthalates are reproductive toxicants that may have additive effects on male development. Diet is the primary exposure source for most phthalates, which contaminate the food supply through food contact materials and industrialized production. OBJECTIVE: To compare dietary sources of cumulative phthalates exposure between "food at home" (e.g. food consumed from a grocery store) and "food away from home" (e.g. food consumed from fast food/restaurants and cafeterias) in the U.S. general population. METHODS: We estimated cumulative phthalates exposure by calculating daily intake from metabolite concentrations in urinary spot samples for 10,253 participants (≥6 years old) using National Health and Nutrition Examination Survey (NHANES, 2005-2014) data. We constructed a biologically relevant metric of phthalates daily intake (∑androgen-disruptor, µg/kg/day) by converting phthalates into anti-androgen equivalent terms prior to their summation. Particular foods and the percent of total energy intake (TEI) consumed from multiple dining out sources were ascertained from 24-h recall surveys. Associations with ∑androgen-disruptor levels were estimated for children, adolescents, and adults using multivariable linear regression. RESULTS: We observed a consistent positive association between dining out and Σandrogen-disruptor levels across the study population (p-trend <0.0001). Among adolescents, high consumers of foods outside the home had 55% (95% CI: 35%, 78%) higher Σandrogen-disruptor levels compared to those who only consumed food at home. The contribution of specific dining out sources to Σandrogen-disruptor levels varied by age group. For example, cafeteria food was associated with 15% (95% CI: 4.0%, 28%) and 64% (95% CI: 40%, 92%) higher Σandrogen-disruptor levels in children and adults, respectively. Particular foods, especially sandwiches (i.e. cheeseburgers), were associated with increased Σandrogen-disruptor levels only if they were purchased away from home (p < 0.01). CONCLUSION: Dining out may be an important source of biologically relevant cumulative phthalates exposure among the U.S. POPULATION: Future studies should evaluate modifiable production practices that remove phthalates from the food supply in addition to the efficacy of interventions that promote eating fresh foods prepared at home.

A Novel Method for Calculating Potency-Weighted Cumulative Phthalates Exposure with Implications for Identifying Racial/Ethnic Disparities among U.S. Reproductive-Aged Women in NHANES 2001-2012.

Phthalates are ubiquitous chemicals linked to hormonal disruptions that affect reproduction and development. Multiple antiandrogenic phthalates exposure during fetal development can have greater impacts than individual exposure; thus, the National Academy of Sciences (NAS) recommends them for cumulative assessment. Using National Health and Nutrition Examination Survey data (NHANES, 2001-2012), we developed a potency-weighted sum of daily intake (∑androgen-disruptor; µg/kg/day) of di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), butyl benzyl phthalate (BBzP), and di(2-ethylhexyl) phthalate (DEHP) based on NAS recommendations, and included diethyl phthalate (DEP) and diisononyl phthalate (DiNP) in additional metrics (2005-2012). We compared racial/ethnic differences in ∑androgen-disruptor among 2842 reproductive-aged women. In sensitivity analyses, we assessed the influence of potency assumptions, alternate urine dilution adjustment methods, and weighting phthalate metabolites directly rather than daily intake estimates of parent compounds. We found that DEHP contributed most to ∑androgen-disruptor (48-64%), and that ∑androgen-disruptor decreased over time. Black women generally had higher cumulative exposures than white women, although the magnitude and precision of the difference varied by model specification. Our approach provides a blueprint for combining chemical exposures linked to common adverse outcomes, and should be considered in future exposure, risk, and epidemiological studies.

Communicating results in post-Belmont era biomonitoring studies: lessons from genetics and neuroimaging research.

BACKGROUND: Biomonitoring is a critical tool to assess the effects of chemicals on health, as scientists seek to better characterize life-course exposures from diverse environments. This trend, coupled with increased institutional support for community-engaged environmental health research, challenge established ethical norms related to biomonitoring results communication and data sharing between scientists, study participants, and their wider communities. METHODS: Through a literature review, participant observation at workshops, and interviews, we examine ethical tensions related to reporting individual data from chemical biomonitoring studies by drawing relevant lessons from the genetics and neuroimaging fields. RESULTS: In all three fields ethical debates about whether/how to report-back results to study participants are precipitated by two trends. First, changes in analytical methods have made more data accessible to stakeholders. For biomonitoring, improved techniques enable detection of more chemicals at lower levels, and diverse groups of scientists and health advocates now conduct exposure studies. Similarly, innovations in genetics have catalyzed large-scale projects and broadened the scope of who has access to genetic information. Second, increasing public interest in personal medical information has compelled imaging researchers to address demands by participants to know their personal data, despite uncertainties about their clinical significance. Four ethical arenas relevant to biomonitoring results communication emerged from our review: tensions between participants' right-to-know their personal results versus their ability or right-to-act to protect their health; whether and how to report incidental findings; informed consent in biobanking; and open-access data sharing. CONCLUSION: Ethically engaging participants in biomonitoring studies requires consideration of several issues, including scientific uncertainty about health implications and exposure sources, the ability of participants to follow up on potentially problematic results, tensions between individual and community research protections, governance and consent regarding secondary use of tissue samples, and privacy challenges in open access data sharing.

Reducing chemical exposures in nail salons through owner and worker trainings: an exploratory intervention study.

BACKGROUND: Nail salons represent a rapidly growing industry with mainly Vietnamese immigrant workers. Workers routinely handle nail products containing hazardous compounds, yet have limited accessible information to minimize workplace exposures. METHODS: We conducted a culturally appropriate pilot intervention on workplace chemical exposure reduction strategies. We trained eight Vietnamese owners, who then trained Vietnamese workers in their salons. We conducted pre-, mid-, and post-intervention assessments with workers, including an in-person survey and personal air monitoring of volatile compounds. RESULTS: Survey results suggested statistically significant increases for chemical knowledge and behavioral changes in glove and mask use, and a reduced prevalence of nose, throat, and skin irritations. Air monitoring results showed a net reduction for methyl methacrylate and total volatile organic compounds, but not for toluene. CONCLUSIONS: Worker education disseminated through salon owners to their workers can improve work-related knowledge, behavior, health symptoms, and exposures for select air contaminants, although more research is warranted.