Developing a National-Scale Exposure Index for Combined Environmental Hazards and Social Stressors and Applications to the Environmental Influences on Child Health Outcomes (ECHO) Cohort.

Tools for assessing multiple exposures across several domains (e.g., physical, chemical, and social) are of growing importance in social and environmental epidemiology because of their value in uncovering disparities and their impact on health outcomes. Here we describe work done within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study to build a combined exposure index. Our index considered both environmental hazards and social stressors simultaneously with national coverage for a 10-year period. Our goal was to build this index and demonstrate its utility for assessing differences in exposure for pregnancies enrolled in the ECHO-wide Cohort Study. Our unitless combined exposure index, which collapses census-tract level data into a single relative measure of exposure ranging from 0-1 (where higher values indicate higher exposure to hazards), includes indicators for major air pollutants and air toxics, features of the built environment, traffic exposures, and social determinants of health (e.g., lower educational attainment) drawn from existing data sources. We observed temporal and geographic variations in index values, with exposures being highest among participants living in the West and Northeast regions. Pregnant people who identified as Black or Hispanic (of any race) were at higher risk of living in a "high" exposure census tract (defined as an index value above 0.5) relative to those who identified as White or non-Hispanic. Index values were also higher for pregnant people with lower educational attainment. Several recommendations follow from our work, including that environmental and social stressor datasets with higher spatial and temporal resolutions are needed to ensure index-based tools fully capture the total environmental context.

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.

Addressing systemic problems with exposure assessments to protect the public's health.

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.

Disparities in chemical exposures among pregnant women and neonates by socioeconomic and demographic characteristics: A nontargeted approach.

BACKGROUND: Exposure to environmental chemicals during pregnancy adversely affects maternal and infant health, and identifying socio-demographic differences in exposures can inform contributions to health inequities. METHODS: We recruited 294 demographically diverse pregnant participants in San Francisco from the Mission Bay/Moffit Long (MB/ML) hospitals, which serve a primarily higher income population, and Zuckerberg San Francisco General Hospital (ZSFGH), which serves a lower income population. We collected maternal and cord sera, which we screened for 2420 unique formulas and their isomers using high-resolution mass spectrometry using LC-QTOF/MS. We assessed differences in chemical abundances across socioeconomic and demographic groups using linear regression adjusting for false discovery rate. RESULTS: Our participants were racially diverse (31% Latinx, 16% Asian/Pacific Islander, 5% Black, 5% other or multi-race, and 43% white). A substantial portion experienced financial strain (28%) and food insecurity (20%) during pregnancy. We observed significant abundance differences in maternal (9 chemicals) and cord sera (39 chemicals) between participants who delivered at the MB/ML hospitals versus ZSFGH. Of the 39 chemical features differentially detected in cord blood, 18 were present in pesticides, one per- or poly-fluoroalkyl substance (PFAS), 21 in plasticizers, 24 in cosmetics, and 17 in pharmaceuticals; 4 chemical features had unknown sources. A chemical feature annotated as 2,4-dichlorophenol had higher abundances among Latinx compared to white participants, those delivering at ZSFGH compared to MB/ML, those with food insecurity, and those with financial strain. Post-hoc QTOF analyses indicated the chemical feature was either 2,4-dichlorophenol or 2,5-dichlorophenol, both of which have potential endocrine-disrupting effects. CONCLUSIONS: Chemical exposures differed between delivery hospitals, likely due to underlying social conditions faced by populations served. Differential exposures to 2,4-dichlorophenol or 2,5-dichlorophenol may contribute to disparities in adverse outcomes.

Toxic Substances Control Act (TSCA) Implementation: How the Amended Law Has Failed to Protect Vulnerable Populations from Toxic Chemicals in the United States.

Exposures to industrial chemicals are widespread and can increase the risk of adverse health effects such as cancer, developmental disorders, respiratory effects, diabetes, and reproductive problems. The amended Toxic Substances Control Act (amended TSCA) requires the U.S. Environmental Protection Agency (EPA) to evaluate risks of chemicals in commerce, account for risk to potentially exposed and susceptible populations, and mitigate risks for chemicals determined to pose an unreasonable risk to human health and the environment. This analysis compares EPA's first 10 chemical risk evaluations under amended TSCA to best scientific practices for conducting risk assessments. We find EPA's risk evaluations underestimated human health risks of chemical exposures by excluding conditions of use and exposure pathways; not considering aggregate exposure and cumulative risk; not identifying all potentially exposed or susceptible subpopulations, and not quantifying differences in risk for susceptible groups; not addressing data gaps; and using flawed systematic review approaches to identify and evaluate the relevant evidence. We present specific recommendations for improving the implementation of amended TSCA using the best available science to ensure equitable, socially just safeguards to public health. Failing to remedy these shortcomings will result in continued systematic underestimation of risk for all chemicals evaluated under amended TSCA.

Associations between social, biologic, and behavioral factors and biomarkers of oxidative stress during pregnancy: Findings from four ECHO cohorts.

BACKGROUND: Lower socioeconomic status (SES) and elevated psychosocial stress are known contributors to adverse pregnancy outcomes; however, biological mechanisms linking these factors to adverse pregnancy outcomes are not well-characterized. Oxidative stress may be an important, yet understudied mechanistic pathway. We used a pooled study design to examine biological, behavioral, and social factors as predictors of prenatal oxidative stress biomarkers. METHODS: Leveraging four pregnancy cohorts from the Environmental influences on Child Health Outcomes (ECHO) Program spanning multiple geographic regions across the United States (U.S.) (N = 2082), we measured biomarkers of oxidative stress in urine samples at up to three time points during pregnancy, including 8-isoprostane-prostaglandin F2α (8-isoPGF2α), its major metabolite, 2,3-dinor-5,6-dihydro-15-F2t-isoprostane, and prostaglandin F2α (PGF2α). Maternal age, pre-pregnancy body mass index, marital/partnered status, parity, and smoking status were included as biological and behavioral factors while race/ethnicity, maternal education, and stressful life events were considered social factors. We examined associations between each individual biological, behavioral, and social factor with oxidative stress biomarkers using multivariable-adjusted linear mixed models. RESULTS: Numerous biological, behavioral, and social factors were associated with elevated levels of 8-isoPGF2α, its major metabolite, and PGF2α. Pregnant people who were current smokers relative to non-smokers or had less than a high school education relative to a college degree had 11.04% (95% confidence interval [CI] = -1.97%, 25.77%) and 9.13% (95% CI = -1.02%, 20.32%) higher levels of 8-isoPGF2α, respectively. CONCLUSIONS: Oxidative stress biomarkers are elevated among pregnant people with higher socioeconomic disadvantage and may represent one pathway linking biological, behavioral, and social factors to adverse pregnancy and child health outcomes, which should be explored in future work.

Assessing the quality of evidence in studies estimating prevalence of exposure to occupational risk factors: The QoE-SPEO approach applied in the systematic reviews from the WHO/ILO Joint Estimates of the Work-related burden of disease and Injury.

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.

Global, regional, and national burdens of ischemic heart disease and stroke attributable to exposure to long working hours for 194 countries, 2000-2016: A systematic analysis from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury.

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.

Drinking water contaminants in California and hypertensive disorders in pregnancy.

Environmental pollutants have been associated with hypertensive disorders in pregnancy including gestational hypertension, preeclampsia, and eclampsia, though few have focused on drinking water contamination. Water pollution can be an important source of exposures that may contribute to adverse pregnancy outcomes. METHODS: We linked water quality data on 13 contaminants and two violations from the California Communities Environmental Health Screening Tool to birth records from vital statistics and hospital discharge records (2007-2012) to examine the relationship between drinking water contamination and hypertensive disorders in pregnancy. We examined contaminants in single- and multipollutant models. Additionally, we examined if the relationship between water contamination and hypertensive disorders in pregnancy differed by neighborhood poverty, individual socioeconomic status, and race/ethnicity. RESULTS: Arsenic, nitrate, trihalomethane, hexavalent chromium, and uranium were detected in a majority of water systems. Increased risk of hypertensive disorders in pregnancy was modestly associated with exposure to cadmium, lead, trihalomethane, and hexavalent chromium in drinking water after adjusting for covariates in single pollutant models with odds ratios ranging from 1.01 to 1.08. In multipollutant models, cadmium was consistent, lead and trihalomethane were stronger, and additional contaminants were associated with hypertensive disorders in pregnancy including trichloroethylene, 1,2-Dibromo-3-chloropropane, nitrate, and tetrachloroethylene. Other contaminants either showed null results or modest inverse associations. The relationship between water contaminants and hypertensive disorders in pregnancy did not differ by neighborhood poverty. CONCLUSIONS: We found increased risk of hypertensive disorders in pregnancy associated with exposure to several contaminants in drinking water in California. Results for cadmium, lead, trihalomethane, and hexavalent chromium were robust in multipollutant models.

Exposure to formaldehyde and asthma outcomes: A systematic review, meta-analysis, and economic assessment.

BACKGROUND: Every major federal regulation in the United States requires an economic analysis estimating its benefits and costs. Benefit-cost analyses related to regulations on formaldehyde exposure have not included asthma in part due to lack of clarity in the strength of the evidence. OBJECTIVES: 1) To conduct a systematic review of evidence regarding human exposure to formaldehyde and diagnosis, signs, symptoms, exacerbations, or other measures of asthma in humans; and 2) quantify the annual economic benefit for decreases in formaldehyde exposure. METHODS: We developed and registered a protocol in PROSPERO (Record ID #38766, CRD 42016038766). We conducted a comprehensive search of articles published up to April 1, 2020. We evaluated potential risk of bias for included studies, identified a subset of studies to combine in a meta-analysis, and rated the overall quality and strength of the evidence. We quantified economics benefit to children from a decrease in formaldehyde exposure using assumptions consistent with EPA's proposed formaldehyde rule. RESULTS: We screened 4,821 total references and identified 150 human studies that met inclusion criteria; of these, we focused on 90 studies reporting asthma status of all participants with quantified measures of formaldehyde directly relevant to our study question. Ten studies were combinable in a meta-analysis for childhood asthma diagnosis and five combinable for exacerbation of childhood asthma (wheezing and shortness of breath). Studies had low to probably-low risk of bias across most domains. A 10-µg/m3 increase in formaldehyde exposure was associated with increased childhood asthma diagnosis (OR = 1.20, 95% CI: [1.02, 1.41]). We also found a positive association with exacerbation of childhood asthma (OR = 1.08, 95% CI: [0.92, 1.28]). The overall quality and strength of the evidence was rated as "moderate" quality and "sufficient" for asthma diagnosis and asthma symptom exacerbation in both children and adults. We estimated that EPA's proposed rule on pressed wood products would result in 2,805 fewer asthma cases and total economic benefit of $210 million annually. CONCLUSION: We concluded there was "sufficient evidence of toxicity" for associations between exposure to formaldehyde and asthma diagnosis and asthma symptoms in both children and adults. Our research documented that when exposures are ubiquitous, excluding health outcomes from benefit-cost analysis can underestimate the true benefits to health from environmental regulations.

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.

The effect of exposure to long working hours on ischaemic heart disease: A systematic review and meta-analysis from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury.

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 < 15 years) and unpaid domestic workers. We included randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies which contained an estimate of the effect of exposure to long working hours (41-48, 49-54 and ≥55 h/week), compared with exposure to standard working hours (35-40 h/week), on IHD (prevalence, incidence or mortality). STUDY APPRAISAL AND SYNTHESIS METHODS: At least two review authors independently screened titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. Missing data were requested from principal study authors. We combined relative risks using random-effect meta-analysis. Two or more review authors assessed the risk of bias, quality of evidence and strength of evidence, using Navigation Guide and GRADE tools and approaches adapted to this project. RESULTS: Thirty-seven studies (26 prospective cohort studies and 11 case-control studies) met the inclusion criteria, comprising a total of 768,751 participants (310,954 females) in 13 countries in three WHO regions (Americas, Europe and Western Pacific). The exposure was measured using self-reports in all studies, and the outcome was assessed with administrative health records (30 studies) or self-reported physician diagnosis (7 studies). The outcome was defined as incident non-fatal IHD event in 19 studies (8 cohort studies, 11 case-control studies), incident fatal IHD event in two studies (both cohort studies), and incident non-fatal or fatal ("mixed") event in 16 studies (all cohort studies). Because we judged cohort studies to have a relatively lower risk of bias, we prioritized evidence from these studies and treated evidence from case-control studies as supporting evidence. For the bodies of evidence for both outcomes with any eligible studies (i.e. IHD incidence and mortality), we did not have serious concerns for risk of bias (at least for the cohort studies). No eligible study was found on the effect of long working hours on IHD prevalence. Compared with working 35-40 h/week, we are uncertain about the effect on acquiring (or incidence of) IHD of working 41-48 h/week (relative risk (RR) 0.98, 95% confidence interval (CI) 0.91 to 1.07, 20 studies, 312,209 participants, I2 0%, low quality of evidence) and 49-54 h/week (RR 1.05, 95% CI 0.94 to 1.17, 18 studies, 308,405 participants, I2 0%, low quality of evidence). Compared with working 35-40 h/week, working ≥55 h/week may have led to a moderately, clinically meaningful increase in the risk of acquiring IHD, when followed up between one year and 20 years (RR 1.13, 95% CI 1.02 to 1.26, 22 studies, 339,680 participants, I2 5%, moderate quality of evidence). Compared with working 35-40 h/week, we are very uncertain about the effect on dying (mortality) from IHD of working 41-48 h/week (RR 0.99, 95% CI 0.88 to 1.12, 13 studies, 288,278 participants, I2 8%, low quality of evidence) and 49-54 h/week (RR 1.01, 95% CI 0.82 to 1.25, 11 studies, 284,474 participants, I2 13%, low quality of evidence). Compared with working 35-40 h/week, working ≥55 h/week may have led to a moderate, clinically meaningful increase in the risk of dying from IHD when followed up between eight and 30 years (RR 1.17, 95% CI 1.05 to 1.31, 16 studies, 726,803 participants, I2 0%, moderate quality of evidence). Subgroup analyses found no evidence for differences by WHO region and sex, but RRs were higher among persons with lower SES. Sensitivity analyses found no differences by outcome definition (exclusively non-fatal or fatal versus "mixed"), outcome measurement (health records versus self-reports) and risk of bias ("high"/"probably high" ratings in any domain versus "low"/"probably low" in all domains). CONCLUSIONS: We judged the existing bodies of evidence for human evidence as "inadequate evidence for harmfulness" for the exposure categories 41-48 and 49-54 h/week for IHD prevalence, incidence and mortality, and for the exposure category ≥55 h/week for IHD prevalence. Evidence on exposure to working ≥55 h/week was judged as "sufficient evidence of harmfulness" for IHD incidence and mortality. Producing estimates for the burden of IHD attributable to exposure to working ≥55 h/week appears evidence-based, and the pooled effect estimates presented in this systematic review could be used as input data for the WHO/ILO Joint Estimates.

Examining Joint Effects of Air Pollution Exposure and Social Determinants of Health in Defining "At-Risk" Populations Under the Clean Air Act: Susceptibility of Pregnant Women to Hypertensive Disorders of Pregnancy.

Pregnant women are uniquely susceptible to adverse effects of air pollution exposure due to vulnerabilities and health consequences during pregnancy (e.g., hypertensive disorders of pregnancy [HDP]) compared to the general population. Because the Clean Air Act (CAA) creates a duty to protect at-risk groups, the regulatory assessment of at-risk populations has both policy and scientific foundations. Previously, pregnant women have not been specially protected in establishing the margin of safety for the ozone and particulate matter (PM) standards. Due to physiological changes, pregnant women can be at greater risk of adverse effects of air pollution and should be considered an at-risk population. Women with preexisting conditions, women experiencing poverty, and groups that suffer systematic discrimination may be particularly susceptible to cardiac effects of air pollutants during pregnancy. We rigorously reviewed 11 studies of over 1.3 million pregnant women in the United States to characterize the relationship between ozone or PM exposure and HDP. Findings were generally mixed, with a few studies reporting a joint association between ozone or PM and social determinants or pre-existing chronic health conditions related to HDP. Adequate evidence associates exposure to PM with an adverse effect of HDP among pregnant women not evident among non-gravid populations.

Environmental pollution and social factors as contributors to preterm birth in Fresno County.

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 (< 34 weeks) and spontaneous preterm birth. We used the Communities Environmental Health Screening Tool and linked hospital discharge records by census tract from 2009 to 2012. The environmental factors included air pollution, drinking water contaminants, pesticides, hazardous waste, traffic exposure and others. Social factors, including area-level socioeconomic status (SES) and race/ethnicity were also evaluated as potential modifiers of the relationship between pollution and preterm birth. RESULTS: In our study of 53,843 births, risk of preterm birth was associated with higher exposure to cumulative pollution scores and drinking water contaminants. Risk of preterm birth was twice as likely for those exposed to high versus low levels of pollution. An exposure-response relationship was observed across the quintiles of the pollution burden score. The associations were stronger among early preterm births in areas of low SES. CONCLUSIONS: In Fresno County, we found multiple pollution exposures associated with increased risk for preterm birth, with higher associations among the most disadvantaged. This supports other evidence finding environmental exposures are important risk factors for preterm birth, and furthermore the burden is higher in areas of low SES. This data supports efforts to reduce the environmental burden on pregnant women.

Cumulative Risk and Impact Modeling on Environmental Chemical and Social Stressors.

PURPOSE OF REVIEW: The goal of this review is to identify cumulative modeling methods used to evaluate combined effects of exposures to environmental chemicals and social stressors. The specific review question is: What are the existing quantitative methods used to examine the cumulative impacts of exposures to environmental chemical and social stressors on health? RECENT FINDINGS: There has been an increase in literature that evaluates combined effects of exposures to environmental chemicals and social stressors on health using regression models; very few studies applied other data mining and machine learning techniques to this problem. The majority of studies we identified used regression models to evaluate combined effects of multiple environmental and social stressors. With proper study design and appropriate modeling assumptions, additional data mining methods may be useful to examine combined effects of environmental and social stressors.

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.

Environmental influences on reproductive health: the importance of chemical exposures.

Chemical exposures during pregnancy can have a profound and life-long impact on human health. Because of the omnipresence of chemicals in our daily life, there is continuous contact with chemicals in food, water, air, and consumer products. Consequently, human biomonitoring studies show that pregnant women around the globe are exposed to a variety of chemicals. In this review we provide a summary of current data on maternal and fetal exposure, as well as health consequences from these exposures. We review several chemical classes, including polychlorinated biphenyls, perfluoroalkyl substances, polybrominated diphenyl ethers, phenols, phthalates, pesticides, and metals. Additionally, we discuss environmental disparities and vulnerable populations, and future research directions. We conclude by providing some recommendations for prevention of chemical exposure and its adverse reproductive health consequences.