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Introduction: Organophosphate esters (OPEs) are increasing in use as flame retardants and plasticizers and concerns have been raised given their endocrine-disrupting activities and possible obesogenic consequences. However, longitudinal studies on gestational OPE exposure and childhood obesity are scarce. This study examined whether OPE levels in maternal urine during pregnancy were associated with the risk of childhood obesity. Methods: OPEs were analyzed in pregnancy urine samples of 5,087 individuals from 14 studies contributing to the Environmental influences on Child Health Outcomes (ECHO) Cohort. BDCPP, DBUP/DIBP, and DPHP, detected in > 80 % of the samples, were modeled continuously and by tertiles; whereas BCPP, BBOEP, and BCETP, detected in 50–80 % of samples, were modeled categorically (not-detected, low, and high). Childhood obesity was defined by BMI z-score ≥ 95th percentile according to WHO (

Abstract Background Research and clinical practice rely heavily on caregiver‐report measures, such as the Child Behavior Checklist 1.5–5 (CBCL/1.5‐5), to gather information about early childhood behavior problems and to screen for child psychopathology. While studies have shown that demographic variables influence caregiver ratings of behavior problems, the extent to which the CBCL/1.5‐5 functions equivalently at the item level across diverse samples is unknown. Methods Item‐level data of CBCL/1.5‐5 from a large sample of young children (N = 9087) were drawn from 26 cohorts in the Environmental influences on Child Health Outcomes program. Factor analyses and the alignment method were applied to examine measurement invariance (MI) and differential item functioning (DIF) across child (age, sex, bilingual status, and neurodevelopmental disorders), and caregiver (sex, education level, household income level, depression, and language version administered) characteristics. Child race was examined in sensitivity analyses. Results Items with the most impactful DIF across child and caregiver groupings were identified for Internalizing, Externalizing, and Total Problems. The robust item sets, excluding the high DIF items, showed good reliability and high correlation with the original Internalizing and Total Problems scales, with lower reliability for Externalizing. Language version of CBCL administration, education level and sex of the caregiver respondent showed the most significant impact on MI, followed by child age. Sensitivity analyses revealed that child race has a unique impact on DIF over and above socioeconomic status. Conclusions The CBCL/1.5‐5, a caregiver‐report measure of early childhood behavior problems, showed bias across demographic groups. Robust item sets with less DIF can measure Internalizing and Total Problems equally as well as the full item sets, with slightly lower reliability for Externalizing, and can be crosswalked to the metric of the full item set, enabling calculation of normed T scores based on more robust item sets.

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

Abstract 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.

Abstract 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.

Abstract Human health risk assessment currently uses the reference dose or reference concentration (RfD, RfC) approach to describe the level of exposure to chemical hazards without appreciable risk for non-cancer health effects in people. However, this “bright line” approach assumes that there is minimal risk below the RfD/RfC with some undefined level of increased risk at exposures above the RfD/RfC and has limited utility for decision-making. Rather than this dichotomous approach, non-cancer risk assessment can benefit from incorporating probabilistic methods to estimate the amount of risk across a wide range of exposures and define a risk-specific dose. We identify and review existing approaches for conducting probabilistic non-cancer risk assessments. Using perchloroethylene (PCE), a priority chemical for the U.S. Environmental Protection Agency under the Toxic Substances Control Act, we calculate risk-specific doses for the effects on cognitive deficits using probabilistic risk assessment approaches. Our probabilistic risk assessment shows that chronic exposure to 0.004 ppm PCE is associated with approximately 1-in-1,000 risk for a 5% reduced performance on the Wechsler Memory Scale Visual Reproduction subtest with 95% confidence. This exposure level associated with a 1-in-1000 risk for non-cancer neurocognitive deficits is lower than the current RfC for PCE of 0.0059 ppm, which is based on standard point of departure and uncertainty factor approaches for the same neurotoxic effects in occupationally exposed adults. We found that the population-level risk of cognitive deficit (indicating central nervous system dysfunction) is estimated to be greater than the cancer risk level of 1-in-100,000 at a similar chronic exposure level. The extension of toxicological endpoints to more clinically relevant endpoints, along with consideration of magnitude and severity of effect, will help in the selection of acceptable risk targets for non-cancer effects. We find that probabilistic approaches can 1) provide greater context to existing RfDs and RfCs by describing the probability of effect across a range of exposure levels including the RfD/RfC in a diverse population for a given magnitude of effect and confidence level, 2) relate effects of chemical exposures to clinical disease risk so that the resulting risk assessments can better inform decision-makers and benefit-cost analysis, and 3) better reflect the underlying biology and uncertainties of population risks.

Abstract Background Hazard identification, risk assessment, regulatory, and policy activity are usually conducted on a chemical-by-chemical basis. Grouping chemicals into categories or classes is an underutilized approach that could make risk assessment and management of chemicals more efficient for regulators. Objective and methods While there are some available methods and regulatory frameworks that include the grouping of chemicals (e.g.,same molecular mechanism or similar chemical structure) there has not been a comprehensive evaluation of these different approaches nor a recommended course of action to better consider chemical classes in decision-making. This manuscript: 1) reviews current national and international approaches to grouping; 2) describes how groups could be defined based on the decision context (e.g., hazard/risk assessment, restrictions, prioritization, product development) and scientific considerations (e.g., intrinsic physical-chemical properties); 3) discusses advantages of developing a decision tree approach for grouping; 4) uses ortho-phthalates as a case study to identify and organize frameworks that could be used across agencies; and 5) discusses opportunities to advance the class concept within various regulatory decision-making scenarios. Results Structural similarity was the most common grouping approach for risk assessment among regulatory agencies (national and state level) and non-regulatory organizations, albeit with some variations in its definition. Toxicity to the same target organ or to the same biological function was also used in a few cases. The phthalates case study showed that a decision tree approach for grouping should include questions about uses regulated by other agencies to encourage more efficient, coherent, and protective chemical risk management. Discussion and conclusion Our evaluation of how classes of chemicals are defined and used identified commonalities and differences based on regulatory frameworks, risk assessments, and business strategies. We also identified that using a class-based approach could result in a more efficient process to reduce exposures to multiple hazardous chemicals and, ultimately, reduce health risks. We concluded that, in the absence of a prescribed method, a decision tree approach could facilitate the selection of chemicals belonging to a pre-defined class (e.g., chemicals with endocrine-disrupting activity; organohalogen flame retardants [OFR]) based on the decision-making context (e.g., regulatory risk management).

Abstract This letter responds to the US Environmental Protection Agency’s Integrated Risk Information System (IRIS) program letter by Radke et al. (2021) that was published in response to the application of the IRIS risk of bias tool in our recent study “Assessing risk of bias in human environmental epidemiology studies using three tools: different conclusions from different tools.” Their letter stated that we misrepresented the IRIS approach. Here, we respond to their three points raised and how we did not misrepresent their tool and also identified areas for improvement: (1) why it should be expected that different reviewers could reach different conclusions with the IRIS tool, as ratings are subject to reviewer judgment; (2) why our interpretation that “low” or “uninformative” studies could be excluded from a body of evidence was reasonable; and (3) why we believe the use of a rating system that generates an overall rating based on an individual domain or a combination of identified deficiencies essentially acts as a score and assumes that we know empirically how much each risk of bias domain should contribute to the overall rating for that study. We have elaborated on these points in our letter.

Background: Exposure to per- and poly-fluoroalkyl substances (PFAS) remains an important public health issue due to widespread detection and persistence in environmental media, slow metabolism in humans, and influences on physiological processes such as neurological signaling. Maternal depression is highly prevalent during pregnancy and postpartum and is potentially sensitive to PFAS. The health risks associated with PFAS may be further amplified in historically marginalized communities, including immigrants. Objective: Evaluate maternal concentrations of PFAS in association with depression scores during pregnancy and whether effects differ between US born and immigrant women. Methods: Our study sample included 282 US born and 235 immigrant pregnant women enrolled in the Chemicals in Our Bodies prospective birth cohort based in San Francisco, CA. We measured 12 PFAS in serum samples collected in the second trimester and depressive symptom scores were assessed using the Center for Epidemiologic Studies Depression Scale. Associations were estimated using linear regression, adjusting for maternal age, education, pre-pregnancy body mass index, and parity. Associations with a PFAS mixture were estimated using quantile g-computation. Results: In adjusted linear regression models, a twofold increase in two PFAS was associated with higher depression scores in the overall sample, and this association persisted only among immigrant women (β [95 % confidence interval]: perfluorooctane sulfonic acid (2.7 [0.7–4.7]) and methyl-perfluorooctane sulfonamide acetic acid (2.9 [1.2–4.7]). Quantile g-computation indicated that simultaneously increasing all PFAS in the mixture by one quartile was associated with increased depressive symptoms among immigrant women (mean change per quartile increase = 1.12 [0.002, 2.3]), and associations were stronger compared to US born women (mean change per quartile increase = 0.09 [-1.0, 0.8]). Conclusions: Findings provide new evidence that PFAS are associated with higher depression symptoms among immigrant women during pregnancy. Results can inform efforts to address environmental factors that may affect depression among US immigrants.

Abstract Background Evidence-to-decision (EtD) frameworks provide a structured and transparent approach for groups of experts to use when formulating recommendations or making decisions. While extensively used for clinical and public health recommendations, EtD frameworks are not in widespread use in environmental health. This review sought to identify, compare and contrast key EtD frameworks for decisions on interventions used in clinical medicine, public health or environmental health. This information can be used to develop an EtD framework suitable for formulating recommendations for interventions in environmental health. Methods We identified a convenience sample of EtD frameworks used by a range of organizations. We searched Medline for systematic reviews of frameworks. We summarized the decision criteria in the selected frameworks and reviews in a qualitative manner. Findings Fourteen organizations provided 18 EtD frameworks; most frameworks focused on clinical medicine or public health interventions; four focused on environmental health and three on economic considerations. Harms of interventions were examined in all frameworks and benefits in all but one. Other criteria included certainty of the body of evidence (15 frameworks), resource considerations (15), feasibility (13), equity (12), values (11), acceptability (11), and human rights (2). There was variation in how specific criteria were defined. The five identified systematic reviews reported a similar spectrum of EtD criteria. Interpretation The EtD frameworks examined encompassed similar criteria, with tailoring to specific audience needs. Existing frameworks are a useful starting point for development of one tailored to decision-making in environmental health. Funder JPB Foundation.

Background: Oxidative stress from excess reactive oxygen species (ROS) is a hypothesized contributor to preterm birth. Per- and polyfluoroalkyl substances (PFAS) exposure is reported to generate ROS in laboratory settings, and is linked to adverse birth outcomes globally. However, to our knowledge, the relationship between PFAS and oxidative stress has not been examined in the context of human pregnancy. Objective: To investigate the associations between prenatal PFAS exposure and oxidative stress biomarkers among pregnant people. Methods: Our analytic sample included 428 participants enrolled in the Illinois Kids Development Study and Chemicals In Our Bodies prospective birth cohorts between 2014 and 2019. Twelve PFAS were measured in second trimester serum. We focused on seven PFAS that were detected in >65 % of participants. Urinary levels of 8-isoprostane-prostaglandin-F2α, prostaglandin-F2α, 2,3-dinor-8-iso-PGF2α, and 2,3-dinor-5,6-dihydro-8-iso-PGF2α were measured in the second and third trimesters as biomarkers of oxidative stress. We fit linear mixed-effects models to estimate individual associations between PFAS and oxidative stress biomarkers. We used quantile g-computation and Bayesian kernel machine regression (BKMR) to assess associations between the PFAS mixture and averaged oxidative stress biomarkers. Results: Linear mixed-effects models showed that an interquartile range increase in perfluorooctane sulfonic acid (PFOS) was associated with an increase in 8-isoprostane-prostaglandin-F2α (β = 0.10, 95 % confidence interval = 0, 0.20). In both quantile g-computation and BKMR, and across all oxidative stress biomarkers, PFOS contributed the most to the overall mixture effect. The six remaining PFAS were not significantly associated with changes in oxidative stress biomarkers. Conclusions: Our study is the first to investigate the relationship between PFAS exposure and biomarkers of oxidative stress during human pregnancy. We found that PFOS was associated with elevated levels of oxidative stress, which is consistent with prior work in animal models and cell lines. Future research is needed to understand how prenatal PFAS exposure and maternal oxidative stress may affect fetal development.

Abstract Background Per- and polyfluoroalkyl substances (PFAS) and polybrominated diphenyl ethers (PBDEs) are endocrine disrupting chemicals with widespread exposures across the U.S. given their abundance in consumer products. PFAS and PBDEs are associated with reproductive toxicity and adverse health outcomes, including certain cancers. PFAS and PBDEs may affect health through alternations in telomere length. In this study, we examined joint associations between prenatal exposure to PFAS, PBDEs, and maternal and newborn telomere length using mixture analyses, to characterize effects of cumulative environmental chemical exposures. Methods Study participants were enrolled in the Chemicals in Our Bodies (CIOB) study, a demographically diverse cohort of pregnant people and children in San Francisco, CA. Seven PFAS (ng/mL) and four PBDEs (ng/g lipid) were measured in second trimester maternal serum samples. Telomere length (T/S ratio) was measured in delivery cord blood of 292 newborns and 110 second trimester maternal whole blood samples. Quantile g-computation was used to assess the joint associations between groups of PFAS and PBDEs and newborn and maternal telomere length. Groups considered were: (1) all PFAS and PBDEs combined, (2) PFAS, and (3) PBDEs. Maternal and newborn telomere length were modeled as separate outcomes. Results T/S ratios in newborn cord and maternal whole blood were moderately correlated (Spearman ρ = 0.31). In mixtures analyses, a simultaneous one quartile increase in all PFAS and PBDEs was associated with a small increase in newborn (mean change per quartile increase = 0.03, 95% confidence interval [CI] = -0.03, 0.08) and maternal telomere length (mean change per quartile increase = 0.03 (95% CI = -0.03, 0.09). When restricted to maternal–fetal paired samples (N = 76), increasing all PFAS and PBDEs combined was associated with a strong, positive increase in newborn telomere length (mean change per quartile increase = 0.16, 95% CI = 0.03, 0.28). These associations were primarily driven by PFAS (mean change per quartile increase = 0.11 [95% CI = 0.01, 0.22]). No associations were observed with maternal telomere length among paired samples. Conclusions Our findings suggest that PFAS and PBDEs may be positively associated with newborn telomere length.

Background: Per-and polyfluoroalkyl substances (PFAS) are a class of widely-used chemicals that persist in the environment and bioaccumulate in humans and animals, becoming an increasing cause for global concern. While PFAS have been commercially produced since the 1940s, their toxicity was not publicly established until the late 1990s. The objective of this paper is to evaluate industry documents on PFAS and compare them to the public health literature in order to understand this consequential delay. Methods: We reviewed a collection of previously secret industry documents archived at the UCSF Chemical Industry Documents Library, examining whether and how strategies of corporate manipulation of science were used by manufacturers of PFAS. Using well-established methods of document analysis, we developed deductive codes to assess industry influence on the conduct and publication of research. We also conducted a literature review using standard search strategies to establish when scientific information on the health effects of PFAS became public. Results: Our review of industry documents shows that companies knew PFAS was “highly toxic when inhaled and moderately toxic when ingested” by 1970, forty years before the public health community. Further, the industry used several strategies that have been shown common to tobacco, pharmaceutical and other industries to influence science and regulation – most notably, suppressing unfavorable research and distorting public discourse. We did not find evidence in this archive of funding favorable research or targeted dissemination of those results. Conclusions: The lack of transparency in industry-driven research on industrial chemicals has significant legal, political and public health consequences. Industry strategies to suppress scientific research findings or early warnings about the hazards of industrial chemicals can be analyzed and exposed, in order to guide prevention.

Background: Widespread environmental contamination can directly interact with human immune system functions. Environmental effects on the immune system may influence human susceptibility to respiratory infections as well as the severity of infectious diseases, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Furthermore, the efficacy of vaccines to respiratory diseases may be impacted by environmental exposures through immune perturbations. Given the quick pace of research about COVID-19 and associated risk factors, it is critical to identify and curate the streams of evidence quickly and effectively. Objective: We developed this systematic evidence map protocol to identify and organize existing human and animal literature on high-priority environmental chemical classes (Per- and polyfluoroalkyl substances, pesticides, phthalates, quaternary ammonium compounds, and air pollutants) and their potential to influence three key outcomes: (1) susceptibility to respiratory infection, including SARS-CoV-2 (2) severity of the resultant disease progression, and (3) impact on vaccine efficacy. The result of this project will be an online, interactive database which will show what evidence is currently available between involuntary exposures to select environmental chemicals and immune health effects, data gaps that require further research, and data rich areas that may support further analysis. Search and study eligibility: We will search PubMed for epidemiological or toxicological literature on select toxicants from each of the chemical classes and each of the three outcomes listed above. Study appraisal and synthesis of methods: For each study, two independent reviewers will conduct title and abstract screening as well as full text review for data extraction of study characteristics. Study quality will not be evaluated in this evidence mapping. The main findings from the systematic evidence map will be visualized using a publicly available and interactive database hosted on Tableau Public.

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

Abstract Background Systematic reviews are increasingly prevalent in environmental health due to their ability to synthesize evidence while reducing bias. Different systematic review methods have been developed by the US National Toxicology Program’s Office of Health Assessment and Translation (OHAT), the US Environmental Protection Agency’s (EPA) Integrated Risk Information System (IRIS), and by the US EPA under the Toxic Substances Control Act (TSCA), including the approach to assess risk of bias (ROB), one of the most vital steps which is used to evaluate internal validity of the studies. Our objective was to compare the performance of three tools (OHAT, IRIS, TSCA) in assessing ROB. Methods We selected a systematic review on polybrominated diphenyl ethers and intelligence quotient and/or attention deficit hyperactivity disorder because it had been endorsed by the National Academy of Sciences. Two reviewers followed verbatim instructions from the tools and independently applied each tool to assess ROB in 15 studies previously identified. We documented the time to apply each tool and the impact the ROB ratings for each tool had on the final rating of the quality of the overall body of evidence. Results The time to complete the ROB assessments varied widely (mean = 20, 32, and 40 min per study for the OHAT, IRIS, and TSCA tools, respectively). All studies were rated overall “low” or “uninformative” using IRIS, due to “deficient” or “critically deficient” ratings in one or two domains. Similarly, all studies were rated “unacceptable” using the TSCA tool because of one “unacceptable” rating in a metric related to statistical power. Approximately half of the studies had “low” or “probably low ROB” ratings across all domains with the OHAT and Navigation Guide tools. Conclusions Tools that use overall ROB or study quality ratings, such as IRIS and TSCA, may reduce the available evidence to assess the harms of environmental exposures by erroneously excluding studies, which leads to inaccurate conclusions about the quality of the body of evidence. We recommend using ROB tools that circumvents these issues, such as OHAT and Navigation Guide. Systematic review registration This review has not been registered as it is not a systematic review.

Abstract Background Perfluoroalkyl substances (PFAS) and polybrominated diphenyl ethers (PBDEs) are used in consumer products for their water repellent and flame retardant properties, respectively. However, there is widespread prenatal exposure and concern about their potential harm to the developing fetus. Here, we utilized data from a demographically diverse cohort of women in San Francisco, CA to examine associations between prenatal exposure to PFAS and PBDEs with gestational age and birth weight for gestational age z-scores. Methods Women included in this analysis were enrolled in the Chemicals in our Bodies (CIOB) cohort study (N = 506). PFAS and PBDEs were measured in serum obtained during the second trimester of pregnancy. Linear regression models were used to calculate crude and adjusted β coefficients for the association between PFAS and PBDE concentrations in tertiles and gestational age and birth weight z-scores. Individual PFAS and PBDE concentrations, as well as their sums, were examined in separate models. Results The highest compared to lowest tertile of BDE-47 was associated with shorter gestational age (β = − 0.49, 95% confidence interval [CI] = − 0.95, − 0.02). Additionally, exposure to BDE-47 and BDE-99 in the middle tertile was also associated with a reduction in birth weight z-scores (β = − 0.26, 95% CI = -0.48, − 0.04; β = − 0.25, 95% CI = -0.47, − 0.04, respectively) compared to those in the lowest tertile of exposure. No consistent associations were observed between increasing PFAS concentrations and gestational age or birth weight z-scores. Discussion Among a diverse group of pregnant women in the San Francisco Bay Area, we found non-linear associations between prenatal exposure to PBDEs during the second trimester of pregnancy and birth weight z-scores. However, most PFAS congeners were not associated with adverse birth outcomes. PFAS and PBDE concentrations were lower in our cohort relative to other studies. Future research should assess the effects of emerging and persistent PFAS and PBDEs on birth outcomes, as some congeners are being phased out and replaced by chemically similar structures.

Abstract 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.

Abstract Background Previous studies have shown a correlation between fluoride concentrations in urine and community water fluoride concentrations. However, there are no studies of the relationship between community water fluoridation, urine, serum, and amniotic fluid fluoride concentrations in pregnant women in the US. The aim of this study was to determine the relationship between maternal urine fluoride (MUF), maternal urine fluoride adjusted for specific gravity (MUFSG), maternal serum fluoride (MSF), amniotic fluid fluoride (AFF) concentrations during pregnancy, and community water fluoridation in Northern California. Methods Archived samples of urine, serum and amniotic fluid collected from second trimester pregnant women in Northern California from 47 different communities in Northern California and one from Montana (n = 48), were analyzed for fluoride using an ion specific electrode following acid microdiffusion. Women’s addresses were matched to publicly reported water fluoride concentrations. We examined whether fluoride concentrations in biospecimens differed by fluoridation status of the community water, and determined the association between water fluoride concentrations and biospecimen fluoride concentrations using linear regression models adjusted for maternal age, smoking, Body Mass Index (BMI), race/ethnicity, and gestational age at sample collection. Results Fluoride concentrations in the community water supplies ranged from 0.02 to 1.00 mg/L. MUF, MSF , and AFF concentrations were significantly higher in pregnant women living in communities adhering to the U.S. recommended water fluoride concentration (0.7 mg/L), as compared with communities with less than 0.7 mg/L fluoride in drinking water. When adjusted for maternal age, smoking status, BMI, race/ethnicity, and gestational age at sample collection, a 0.1 mg/L increase in community water fluoride concentration was positively associated with higher concentrations of MUF (B = 0.052, 95% CI:0.019,0.085), MUFSG (B = 0.028, 95% CI: -0.006, 0.062), MSF (B = 0.001, 95% CI: 0.000, 0.003) and AFF (B = 0.001, 95% CI: 0.000, 0.002). Conclusions We found universal exposure to fluoride in pregnant women and to the fetus via the amniotic fluid. Fluoride concentrations in urine, serum, and amniotic fluid from women were positively correlated to public records of community water fluoridation. Community water fluoridation remains a major source of fluoride exposure for pregnant women living in Northern California.

Background: The World Health Organization (WHO) and the International Labour Organization (ILO) have produced the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury (WHO/ILO Joint Estimates). For these, systematic reviews of studies estimating the prevalence of exposure to selected occupational risk factors have been conducted to provide input data for estimations of the number of exposed workers. A critical part of systematic review methodology is to assess the quality of evidence across studies. In this article, we present the approach applied in these WHO/ILO systematic reviews for performing such assessments on studies of prevalence of exposure. It is called the Quality of Evidence in Studies estimating Prevalence of Exposure to Occupational risk factors (QoE-SPEO) approach. We describe QoE-SPEO’s development to date, demonstrate its feasibility reporting results from pilot testing and case studies, note its strengths and limitations, and suggest how QoE-SPEO should be tested and developed further. Methods: Following a comprehensive literature review, and using expert opinion, selected existing quality of evidence assessment approaches used in environmental and occupational health were reviewed and analysed for their relevance to prevalence studies. Relevant steps and components from the existing approaches were adopted or adapted for QoE-SPEO. New steps and components were developed. We elicited feedback from other systematic review methodologists and exposure scientists and reached consensus on the QoE-SPEO approach. Ten individual experts pilot-tested QoE-SPEO. To assess inter-rater agreement, we counted ratings of expected (actual and non-spurious) heterogeneity and quality of evidence and calculated a raw measure of agreement (Pi) between individual raters and rater teams for the downgrade domains. Pi ranged between 0.00 (no two pilot testers selected the same rating) and 1.00 (all pilot testers selected the same rating). Case studies were conducted of experiences of QoE-SPEO’s use in two WHO/ILO systematic reviews. Results: We found no existing quality of evidence assessment approach for occupational exposure prevalence studies. We identified three relevant, existing approaches for environmental and occupational health studies of the effect of exposures. Assessments using QoE-SPEO comprise three steps: (1) judge the level of expected heterogeneity (defined as non-spurious variability that can be expected in exposure prevalence, within or between individual persons, because exposure may change over space and/or time), (2) assess downgrade domains, and (3) reach a final rating on the quality of evidence. Assessments are conducted using the same five downgrade domains as the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach: (a) risk of bias, (b) indirectness, (c) inconsistency, (d) imprecision, and (e) publication bias. For downgrade domains (c) and (d), the assessment varies depending on the level of expected heterogeneity. There are no upgrade domains. The QoE-SPEO’s ratings are “very low”, “low”, “moderate”, and “high”. To arrive at a final decision on the overall quality of evidence, the assessor starts at “high” quality of evidence and for each domain downgrades by one or two levels for serious concerns or very serious concerns, respectively. In pilot tests, there was reasonable agreement in ratings for expected heterogeneity; 70% of raters selected the same rating. Inter-rater agreement ranged considerably between downgrade domains, both for individual rater pairs (range Pi: 0.36–1.00) and rater teams (0.20–1.00). Sparse data prevented rigorous assessment of inter-rater agreement in quality of evidence ratings. Conclusions: We present QoE-SPEO as an approach for assessing quality of evidence in prevalence studies of exposure to occupational risk factors. It has been developed to its current version (as presented here), has undergone pilot testing, and was applied in the systematic reviews for the WHO/ILO Joint Estimates. While the approach requires further testing and development, it makes steps towards filling an identified gap, and progress made so far can be used to inform future work in this area.

Background: World Health Organization (WHO) and International Labour Organization (ILO) systematic reviews reported sufficient evidence for higher risks of ischemic heart disease and stroke amongst people working long hours (≥55 hours/week), compared with people working standard hours (35–40 hours/week). This article presents WHO/ILO Joint Estimates of global, regional, and national exposure to long working hours, for 194 countries, and the attributable burdens of ischemic heart disease and stroke, for 183 countries, by sex and age, for 2000, 2010, and 2016. Methods and Findings: We calculated population-attributable fractions from estimates of the population exposed to long working hours and relative risks of exposure on the diseases from the systematic reviews. The exposed population was modelled using data from 2324 cross-sectional surveys and 1742 quarterly survey datasets. Attributable disease burdens were estimated by applying the population-attributable fractions to WHO’s Global Health Estimates of total disease burdens. Results: In 2016, 488 million people (95% uncertainty range: 472–503 million), or 8.9% (8.6–9.1) of the global population, were exposed to working long hours (≥55 hours/week). An estimated 745,194 deaths (705,786–784,601) and 23.3 million disability-adjusted life years (22.2–24.4) from ischemic heart disease and stroke combined were attributable to this exposure. The population-attributable fractions for deaths were 3.7% (3.4–4.0) for ischemic heart disease and 6.9% for stroke (6.4–7.5); for disability-adjusted life years they were 5.3% (4.9–5.6) for ischemic heart disease and 9.3% (8.7–9.9) for stroke. Conclusions: WHO and ILO estimate exposure to long working hours (≥55 hours/week) is common and causes large attributable burdens of ischemic heart disease and stroke. Protecting and promoting occupational and workers’ safety and health requires interventions to reduce hazardous long working hours.

Background: Synthesizing environmental health science is crucial to taking action to protect public health. Procedures for evidence evaluation and integration are transitioning from “expert-based narrative” to “systematic” review methods. However, little is known about the methodology being utilized for either type of review. Objectives: To appraise the methodological strengths and weaknesses of a sample of “expert-based narrative” and “systematic” reviews in environmental health. Methods: We conducted a comprehensive search of multiple databases and identified relevant reviews using pre-specified eligibility criteria. We applied a modified version of the Literature Review Appraisal Toolkit (LRAT) to three environmental health topics that assessed the utility, validity and transparency of reviews. Results: We identified 29 reviews published between 2003 and 2019, of which 13 (45%) were self-identified as systematic reviews. Across every LRAT domain, systematic reviews received a higher percentage of “satisfactory” ratings compared to non-systematic reviews. In eight of these domains, there was a statistically significant difference observed between the two types of reviews and “satisfactory” ratings. Non-systematic reviews performed poorly with the majority receiving an “unsatisfactory” or “unclear” rating in 11 of the 12 domains. Systematic reviews performed poorly in six of the 12 domains; 10 (77%) did not state the reviews objectives or develop a protocol; eight (62%) did not state the roles and contribution of the authors, or evaluate the internal validity of the included evidence consistently using a valid method; and only seven (54%) stated a pre-defined definition of the evidence bar on which their conclusions were based, or had an author disclosure of interest statement. Discussion: Systematic reviews produced more useful, valid, and transparent conclusions compared to non-systematic reviews, but poorly conducted systematic reviews were prevalent. Ongoing development and implementation of empirically based systematic review methods are required in environmental health to ensure transparent and timely decision making to protect the public’s health.

Background: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing Joint Estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates), with contributions from a large network of experts. Evidence from mechanistic data suggests that exposure to long working hours may cause ischaemic heart disease (IHD). In this paper, we present a systematic review and meta-analysis of parameters for estimating the number of deaths and disability-adjusted life years from IHD that are attributable to exposure to long working hours, for the development of the WHO/ILO Joint Estimates. Objectives: We aimed to systematically review and meta-analyse estimates of the effect of exposure to long working hours (three categories: 41–48, 49–54 and ≥55 h/week), compared with exposure to standard working hours (35–40 h/week), on IHD (three outcomes: prevalence, incidence and mortality). Data sources: We developed and published a protocol, applying the Navigation Guide as an organizing systematic review framework where feasible. We searched electronic databases for potentially relevant records from published and unpublished studies, including MEDLINE, Scopus, Web of Science, CISDOC, PsycINFO, and WHO ICTRP. We also searched grey literature databases, Internet search engines and organizational websites; hand-searched reference lists of previous systematic reviews; and consulted additional experts. Study eligibility and criteria: We included working-age (≥15 years) workers in the formal and informal economy in any WHO and/or ILO Member State but excluded children (aged

Background: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing joint estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates). For this, systematic reviews of studies estimating the prevalence of exposure to selected occupational risk factors will be conducted to provide input data for estimations of the number of exposed workers. A critical part of systematic review methods is to assess risk of bias (RoB) of individual studies. In this article, we present and describe the development of such a tool, called the Risk of Bias in Studies estimating Prevalence of Exposure to Occupational risk factors (RoB-SPEO) tool; report results from RoB-SPEO's pilot testing; note RoB-SPEO's limitations; and suggest how the tool might be tested and developed further. Methods: Selected existing RoB tools used in environmental and occupational health systematic reviews were reviewed and analysed. From existing tools, we identified domains for the new tool and, if necessary, added new domains. For each domain, we then identified and integrated components from the existing tools (i.e. instructions, domains, guiding questions, considerations, ratings and rating criteria), and, if necessary, we developed new components. Finally, we elicited feedback from other systematic review methodologists and exposure scientists and agreed upon RoB-SPEO. Nine experts pilot tested RoB-SPEO, and we calculated a raw measure of inter-rater agreement (Pi) for each of its domain, rating Pi 0.80 as almost perfect agreement. Results: Our review found no standard tool for assessing RoB in prevalence studies of exposure to occupational risk factors. We identified six existing tools for environmental and occupational health systematic reviews and found that their components for assessing RoB differ considerably. With the new RoB-SPEO tool, assessors judge RoB for each of eight domains: (1) bias in selection of participants into the study; (2) bias due to a lack of blinding of study personnel; (3) bias due to exposure misclassification; (4) bias due to incomplete exposure data; (5) bias due to conflict of interest; (6) bias due to selective reporting of exposures; (7) bias due to difference in numerator and denominator; and (8) other bias. The RoB-SPEO's ratings are low, probably low, probably high, high or no information. Pilot testing of the RoB-SPEO tool found substantial inter-rater agreement for six domains (range of Pi for these domains: 0.51–0.80), but poor agreement for two domains (i.e. Pi of 0.31 and 0.33 for biases due to incomplete exposure data and in selection of participants into the study, respectively). Limitations of RoB-SPEO include that it has not yet been fully performance-tested. Conclusions: We developed the RoB-SPEO tool for assessing RoB in prevalence studies of exposure to occupational risk factors. The tool will be applied and its performance tested in the ongoing systematic reviews for the WHO/ILO Joint Estimates.

Abstract Background Systematic reviews, which assess the risk of bias in included studies, are increasingly used to develop environmental hazard assessments and public health guidelines. These research areas typically rely on evidence from human observational studies of exposures, yet there are currently no universally accepted standards for assessing risk of bias in such studies. The risk of bias in non-randomised studies of exposures (ROBINS-E) tool has been developed by building upon tools for risk of bias assessment of randomised trials, diagnostic test accuracy studies and observational studies of interventions. This paper reports our experience with the application of the ROBINS-E tool. Methods We applied ROBINS-E to 74 exposure studies (60 cohort studies, 14 case-control studies) in 3 areas: environmental risk, dietary exposure and drug harm. All investigators provided written feedback, and we documented verbal discussion of the tool. We inductively and iteratively classified the feedback into 7 themes based on commonalities and differences until all the feedback was accounted for in the themes. We present a description of each theme. Results We identified practical concerns with the premise that ROBINS-E is a structured comparison of the observational study being rated to the ‘ideal’ randomised controlled trial. ROBINS-E assesses 7 domains of bias, but relevant questions related to some critical sources of bias, such as exposure and funding source, are not assessed. ROBINS-E fails to discriminate between studies with a single risk of bias or multiple risks of bias. ROBINS-E is severely limited at determining whether confounders will bias study outcomes. The construct of co-exposures was difficult to distinguish from confounders. Applying ROBINS-E was time-consuming and confusing. Conclusions Our experience suggests that the ROBINS-E tool does not meet the need for an international standard for evaluating human observational studies for questions of harm relevant to public and environmental health. We propose that a simpler tool, based on empirical evidence of bias, would provide accurate measures of risk of bias and is more likely to meet the needs of the environmental and public health community.

Background: Preterm birth (PTB),22 PTB: preterm birth defined as birth at gestational age

Abstract Background Environmental pollution exposure during pregnancy has been identified as a risk factor for preterm birth. Most studies have evaluated exposures individually and in limited study populations. Methods We examined the associations between several environmental exposures, both individually and cumulatively, and risk of preterm birth in Fresno County, California. We also evaluated early (

Background: There are reports of developmental and reproductive health effects associated with the widely used biocide triclosan. Objective: Apply the Navigation Guide systematic review methodology to answer the question: Does exposure to triclosan have adverse effects on human development or reproduction? Methods: We applied the first 3 steps of the Navigation Guide methodology: 1) Specify a study question, 2) Select the evidence, and 3) Rate quality and strength of the evidence. We developed a protocol, conducted a comprehensive search of the literature, and identified relevant studies using pre-specified criteria. We assessed the number and type of all relevant studies. We evaluated each included study for risk of bias and rated the quality and strength of the evidence for the selected outcomes. We conducted a meta-analysis on a subset of suitable data. Results: We found 4282 potentially relevant records, and 81 records met our inclusion criteria. Of the more than 100 endpoints identified by our search, we focused our evaluation on hormone concentration outcomes, which had the largest human and non-human mammalian data set. Three human studies and 8 studies conducted in rats reported thyroxine levels as outcomes. The rat data were amenable to meta-analysis. Because only one of the human thyroxine studies quantified exposure, we did not conduct a meta-analysis of the human data. Through meta-analysis of the data for rats, we estimated for prenatal exposure a 0.09% (95% CI: −0.20, 0.02) reduction in thyroxine concentration per mg triclosan/kg-bw in fetal and young rats compared to control. For postnatal exposure we estimated a 0.31% (95% CI: −0.38, −0.23) reduction in thyroxine per mg triclosan/kg-bw, also compared to control. Overall, we found low to moderate risk of bias across the human studies and moderate to high risk of bias across the non-human studies, and assigned a “moderate/low” quality rating to the body of evidence for human thyroid hormone alterations and a “moderate” quality rating to the body of evidence for non-human thyroid hormone alterations. Conclusion: Based on this application of the Navigation Guide systematic review methodology, we concluded that there was “sufficient” non-human evidence and “inadequate” human evidence of an association between triclosan exposure and thyroxine concentrations, and consequently, triclosan is “possibly toxic” to reproductive and developmental health. Thyroid hormone disruption is an upstream indicator of developmental toxicity. Additional endpoints may be identified as being of equal or greater concern as other data are developed or evaluated. Keywords: Soap, Personal care, Antibacterial, Thyroid, Policy, Risk assessment

Preterm birth (PTB) is the leading cause of newborn deaths around the world. Spontaneous preterm birth (sPTB) accounts for two-thirds of all PTBs; however, there remains an unmet need of detecting and preventing sPTB. Although the dysregulation of the immune system has been implicated in various studies, small sizes and irreproducibility of results have limited identification of its role. Here, we present a cross-study meta-analysis to evaluate genome-wide differential gene expression signals in sPTB. A comprehensive search of the NIH genomic database for studies related to sPTB with maternal whole blood samples resulted in data from three separate studies consisting of 339 samples. After aggregating and normalizing these transcriptomic datasets and performing a meta-analysis, we identified 210 genes that were differentially expressed in sPTB relative to term birth. These genes were enriched in immune-related pathways, showing upregulation of innate immunity and downregulation of adaptive immunity in women who delivered preterm. An additional analysis found several of these differentially expressed at mid-gestation, suggesting their potential to be clinically relevant biomarkers. Furthermore, a complementary analysis identified 473 genes differentially expressed in preterm cord blood samples. However, these genes demonstrated downregulation of the innate immune system, a stark contrast to findings using maternal blood samples. These immune-related findings were further confirmed by cell deconvolution as well as upstream transcription and cytokine regulation analyses. Overall, this study identified a strong immune signature related to sPTB as well as several potential biomarkers that could be translated to clinical use.