Background: Prenatal exposures to endocrine-disrupting chemicals (EDCs) during critical developmental windows have been implicated in the etiologies of a wide array of adverse perinatal and pediatric outcomes. Epidemiological studies have concentrated on the health effects of individual chemicals, despite the understanding that EDCs act together via common mechanisms, that pregnant women are exposed to multiple EDCs simultaneously, and that substantial toxicological evidence of adverse developmental effects has been documented. There is a move toward multipollutant models in environmental epidemiology; however, there is no current consensus on appropriate statistical methods. Objectives: We aimed to review the statistical methods used in these studies, to identify additional applicable methods, and to determine the strengths and weaknesses of each method for addressing the salient statistical and epidemiological challenges. Methods: We searched Embase, MEDLINE, and Web of Science for epidemiological studies of endocrine-sensitive outcomes in the children of mothers exposed to EDC mixtures during pregnancy and identified alternative statistical methods from the wider literature. Discussion: We identified 74 studies and analyzed the methods used to estimate mixture health effects, identify important mixture components, account for nonmonotonicity in exposure–response relationships, assess interactions, and identify windows of exposure susceptibility. We identified both frequentist and Bayesian methods that are robust to multicollinearity, performing shrinkage, variable selection, dimension reduction, statistical learning, or smoothing, including methods that were not used by the studies included in our review. Conclusions: Compelling motivation exists for analyzing EDCs as mixtures, yet many studies make simplifying assumptions about EDC additivity, relative potency, and linearity, or overlook the potential for bias due to asymmetries in chemical persistence. We discuss the potential impacts of these choices and suggest alternative methods to improve analyses of prenatal exposure to EDC mixtures. https://doi.org/10.1289/EHP2207

Objective: We sought to assess the effect of long-term exposure to ambient air pollution on the prevalence of self-reported health outcomes in Australian women. Design: Cross-sectional study. Setting and participants: The geocoded residential addresses of 26 991 women across 3 age cohorts in the Australian Longitudinal Study on Women's Health between 2006 and 2011 were linked to nitrogen dioxide (NO ₂ ) exposure estimates from a land-use regression model. Annual average NO ₂ concentrations and residential proximity to roads were used as proxies of exposure to ambient air pollution. Outcome measures: Self-reported disease presence for diabetes mellitus, heart disease, hypertension, stroke, asthma, chronic obstructive pulmonary disease and self-reported symptoms of allergies, breathing difficulties, chest pain and palpitations. Methods: Disease prevalence was modelled by population-averaged Poisson regression models estimated by generalised estimating equations. Associations between symptoms and ambient air pollution were modelled by multilevel mixed logistic regression. Spatial clustering was accounted for at the postcode level. Results: No associations were observed between any of the outcome and exposure variables considered at the 1% significance level after adjusting for known risk factors and confounders. Conclusions: Long-term exposure to ambient air pollution was not associated with self-reported disease prevalence in Australian women. The observed results may have been due to exposure and outcome misclassification, lack of power to detect weak associations or an actual absence of associations with self-reported outcomes at the relatively low annual average air pollution exposure levels across Australia.

Per- and polyfluoroalkyl substances (PFAS) have been associated with higher cholesterol and liver function markers in some studies, but the evidence for specific cardiometabolic conditions has been inconclusive. We quantified the associations of single and combined PFAS with cardiometabolic markers and conditions in a cross-sectional study of three Australian communities with PFAS-contaminated water from the historical use of aqueous film-forming foam in firefighting activities, and three comparison communities. Participants gave blood samples for measurement of nine PFAS, four lipids, six liver function markers, and completed a survey on sociodemographic characteristics and eight cardiometabolic conditions. We estimated differences in mean biomarker concentrations per doubling in single PFAS concentrations (linear regression) and per interquartile range increase in the PFAS mixture (Bayesian kernel machine regression). We estimated prevalence ratios of biomarker concentrations outside reference limits and self-reported cardiometabolic conditions (Poisson regression). We recruited 881 adults in exposed communities and 801 in comparison communities. We observed higher mean total cholesterol with higher single and mixture PFAS concentrations in blood serum (e.g., 0.18 mmol/L, 95% credible interval -0.06 to 0.42, higher total cholesterol concentrations with an interquartile range increase in all PFAS concentrations in Williamtown, New South Wales), with varying certainty across communities and PFAS. There was less consistency in direction of associations for liver function markers. Serum perfluorooctanoic acid (PFOA) concentrations were positively associated with the prevalence of self-reported hypercholesterolemia in one of three communities, but PFAS concentrations were not associated with self-reported type II diabetes, liver disease, or cardiovascular disease. Our study is one of few that has simultaneously quantified the associations of blood PFAS concentrations with multiple biomarkers and cardiometabolic conditions in multiple communities. Our findings for total cholesterol were consistent with previous studies; however, substantial uncertainty in our estimates and the cross-sectional design limit causal inference.

Environmental chemical contamination is a recognised risk factor for psychological distress, but has been seldom studied in the context of per- and polyfluoroalkyl substances (PFAS) contamination. We examined psychological distress in a cross-sectional study of three Australian communities exposed to PFAS from the historical use of aqueous film-forming foam in firefighting activities, and three comparison communities without environmental contamination. Participation was voluntary following recruitment from a PFAS blood-testing program (exposed) or random selection (comparison). Participants provided blood samples and completed a survey on their exposure history, sociodemographic characteristics, and four measures of psychological distress (Kessler-6, Distress Questionnaire-5, Patient Health Questionnaire-15, and Generalised Anxiety Disorder-7). We estimated prevalence ratios (PR) of clinically-significant psychological distress scores, and differences in mean scores: (1) between exposed and comparison communities; (2) per doubling in PFAS serum concentrations in exposed communities; (3) for factors that affect the perceived risk of living in a community exposed to PFAS; and (4) in relation to self-reported health concerns. We recruited 881 adults in exposed communities and 801 in comparison communities. We observed higher levels of self-reported psychological distress in exposed communities than in comparison communities (e.g., Katherine compared to Alice Springs, Northern Territory: clinically-significant anxiety scores, adjusted PR = 2.82, 95 % CI 1.16-6.89). We found little evidence to suggest that psychological distress was associated with PFAS serum concentrations (e.g., Katherine, PFOS and anxiety, adjusted PR = 0.85, 95 % CI 0.65-1.10). Psychological distress was higher among exposed participants who were occupationally exposed to firefighting foam, used bore water on their properties, or were concerned about their health. Psychological distress was substantially more prevalent in exposed communities than in comparison communities. Our findings suggest that the perception of risks to health, rather than PFAS exposure, contribute to psychological distress in communities with PFAS contamination.