Relative risks of childhood developmental vulnerabilities in three Australian communities with exposure to per- and polyfluoroalkyl substances: data linkage study.

Background: Aqueous film forming foams (AFFF) containing per- and polyfluoroalkyl substances (PFAS) caused local environmental contamination in three Australian residential areas: Katherine in the Northern Territory (NT), Oakey in Queensland (Qld) and Williamtown in New South Wales (NSW). We examined whether children who lived in these areas had higher risks of developmental vulnerabilities than children who lived in comparison areas without known contamination. Methods: All children identified in the Medicare Enrolment File-a consumer directory for Australia's universal healthcare insurance scheme-who ever lived in exposure areas, and a sample of children who ever lived in selected comparison areas, were linked to the Australian Early Development Census (AEDC). The AEDC data were available from four cycles: 2009, 2012, 2015 and 2018. For each exposure area, we estimated relative risks (RRs) of developmental vulnerability on each of five AEDC domains and a summary measure, adjusting for sociodemographic characteristics and other potential confounders. Findings: We included 2,429 children from the NT, 2,592 from Qld and 510 from NSW. We observed lower risk of developmental vulnerability in the Communication skills and general knowledge domain in Katherine (RR = 0.74, 95% confidence interval (CI) 0.57 to 0.97), and higher risks of developmental vulnerability in the same domain (RR = 1.49, 95% CI 1.18 to 1.87) and in the Physical health and wellbeing domain in Oakey (RR = 1.31, 95% CI 1.06 to 1.61). Risks of developmental vulnerabilities on other domains were not different from those in the relevant comparison areas or were uncertain due to small numbers of events. Conclusion: There was inadequate evidence for increased risks of developmental vulnerabilities in children who ever lived in three PFAS-affected areas in Australia.

Relative Risks of Adverse Perinatal Outcomes in Three Australian Communities Exposed to Per- and Polyfluoroalkyl Substances: Data Linkage Study.

INTRODUCTION: Firefighting foams containing per- and polyfluoroalkyl substances (PFAS) have caused environmental contamination in several Australian residential areas, including Katherine in the Northern Territory (NT), Oakey in Queensland (Qld), and Williamtown in New South Wales (NSW). We examined whether the risks of adverse perinatal outcomes were higher in mothers living in these exposure areas than in selected comparison areas without known contamination. METHODS: We linked residential addresses in exposure areas to addresses collected in the jurisdictional Perinatal Data Collections of the NT (1986-2017), Qld (2007-2018), and NSW (1994-2018) to select all pregnancies from mothers who gave birth while living in these areas. We also identified one comparison group for each exposure area by selecting pregnancies where the maternal address was in selected comparison areas. We examined 12 binary perinatal outcomes and three growth measurements. For each exposure area, we estimated relative risks (RRs) of adverse outcomes and differences in means of growth measures, adjusting for sociodemographic characteristics and other potential confounders. RESULTS: We included 16,970 pregnancies from the NT, 4654 from Qld, and 7475 from NSW. We observed elevated risks of stillbirth in Oakey (RR = 2.59, 95% confidence interval (CI) 1.25 to 5.39) and of postpartum haemorrhage (RR = 1.94, 95% CI 1.13 to 3.33) and pregnancy-induced hypertension (RR = 1.88, 95% CI 1.30 to 2.73) in Williamtown. The risks of other perinatal outcomes were not materially different from those in the relevant comparison areas or were uncertain due to small numbers of events. CONCLUSIONS: There was limited evidence for increased risks of adverse perinatal outcomes in mothers living in areas with PFAS contamination from firefighting foams. We found higher risks of some outcomes in individual areas, but these were not consistent across all areas under study and could have been due to chance, bias, or confounding.

Psychological distress in three Australian communities living with environmental per- and polyfluoroalkyl substances contamination.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Liver and cardiometabolic markers and conditions in a cross-sectional study of three Australian communities living with environmental per- and polyfluoroalkyl substances contamination.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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). RESULTS: 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. DISCUSSION: 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.

Prenatal exposure to mixtures of persistent environmental chemicals and fetal growth outcomes in Western Australia.

BACKGROUND: Environmental chemicals have been implicated in the etiology of impaired fetal growth. However, few studies have assessed the effects of chemical mixtures or considered the possibility of non-monotonic exposure-response relationships for chemicals that act through the endocrine system. METHODS: We assessed exposure to polybrominated diphenyl ethers, organochlorine pesticides, metals, and perfluorinated alkyl substances in blood and urine samples collected approximately two weeks prior to delivery in 166 non-smoking pregnant women, and subsequent birth weight, length, and head circumference of neonates who were part of the Australian Maternal Exposures to Toxic Substances (AMETS) study. We used Bayesian structured additive regression models with spike-slab priors to estimate mixture effects, identify important exposures, and model non-linearity in exposure-response relationships. RESULTS: Mixtures of polybrominated diphenyl ethers, organochlorine pesticides, metals, and perfluorinated alkyl substances were not associated with fetal growth outcomes. Estimated change in fetal growth outcomes for an increase in exposure from the 25th to 75th percentile suggested no meaningful associations; the strongest evidence was for a small inverse association between birth weight and cesium exposure measured in whole blood (-124 g, 90% credible interval: -240 to -3 g). We identified several chemicals that may be associated with fetal growth non-linearly; however, 90% credible intervals contained small values consistent with no meaningful association. CONCLUSIONS: Using a Bayesian penalized regression method, we assessed the shapes of exposure-response relationships, controlled for confounding by co-exposure, and estimated the single and combined effects of a large mixture of correlated environmental chemicals on fetal growth. Our findings, based on a small sample of mother-neonate pairs, suggest that mixtures of persistent chemicals are not associated with birth weight, length, and head circumference. The potential for non-monotonic relationships between environmental chemicals and fetal growth outcomes warrants further study.

Performance of variable and function selection methods for estimating the nonlinear health effects of correlated chemical mixtures: A simulation study.

Statistical methods for identifying harmful chemicals in a correlated mixture often assume linearity in exposure-response relationships. Nonmonotonic relationships are increasingly recognized (eg, for endocrine-disrupting chemicals); however, the impact of nonmonotonicity on exposure selection has not been evaluated. In a simulation study, we assessed the performance of Bayesian kernel machine regression (BKMR), Bayesian additive regression trees (BART), Bayesian structured additive regression with spike-slab priors (BSTARSS), generalized additive models with double penalty (GAMDP) and thin plate shrinkage smoothers (GAMTS), multivariate adaptive regression splines (MARS), and lasso penalized regression. We simulated realistic exposure data based on pregnancy exposure to 17 phthalates and phenols in the US National Health and Nutrition Examination Survey using a multivariate copula. We simulated data sets of size N = 250 and compared methods across 32 scenarios, varying by model size and sparsity, signal-to-noise ratio, correlation structure, and exposure-response relationship shapes. We compared methods in terms of their sensitivity, specificity, and estimation accuracy. In most scenarios, BKMR, BSTARSS, GAMDP, and GAMTS achieved moderate to high sensitivity (0.52-0.98) and specificity (0.21-0.99). BART and MARS achieved high specificity (≥0.90), but low sensitivity in low signal-to-noise ratio scenarios (0.20-0.51). Lasso was highly sensitive (0.71-0.99), except for quadratic relationships (≤0.27). Penalized regression methods that assume linearity, such as lasso, may not be suitable for studies of environmental chemicals hypothesized to have nonmonotonic relationships with outcomes. Instead, BKMR, BSTARSS, GAMDP, and GAMTS are attractive methods for flexibly estimating the shapes of exposure-response relationships and selecting among correlated exposures.

Statistical Methodology in Studies of Prenatal Exposure to Mixtures of Endocrine-Disrupting Chemicals: A Review of Existing Approaches and New Alternatives.

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 exposure­response 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.

Long-term ambient air pollution exposure and self-reported morbidity in the Australian Longitudinal Study on Women's Health: a cross-sectional study.

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 (NO2) exposure estimates from a land-use regression model. Annual average NO2 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.