Project Summary/Abstract 1,4-Dioxane (1,4-DX) is a synthetic chemical historically used as a stabilizer of chlorinated solvents and currently used in a range of consumer and personal care products. Over one-fifth of the US public drinking water supply contains detectable levels of 1,4-DX, and approximately 7% of drinking water samples tested exceed the federal cancer risk level of 0.35 μg/L. Widespread contamination of drinking water has been observed in groundwater in Nassau and Suffolk Counties of Long Island, New York, where 75% of population have water sources with 1,4-DX concentrations exceeding 0.35 μg/L. Furthermore, standard municipal treatment systems are ineffective at removing 1,4-DX, enabling its persistence in drinking water supplies. The US Environmental Protection Agency (EPA) has designated 1,4-DX as a “high priority” chemical and classified it as a probable human carcinogen based on evidence from experimental animal studies, primarily based on effects on the liver. Despite the high prevalence in the environment and potential human health risks, there is a paucity of human exposure and health data. We will apply novel approaches to evaluate exposure to 1,4-DX and co-occurring contaminants (such as the volatile organic compounds 1,1-dichloroethane (DCA), trichloroethylene (TCE), and 1,1,1-trichloroethane (TCA)) in two communities: Long Island, New York (our primary study area) and Cape Fear River Watershed, North Carolina (secondary study area). We will use our newly developed, highly sensitive mass spectrometry-based assay for assessment of exposure to 1,4-DX in water and blood samples. In addition, we will evaluate associations between exposure to 1,4-DX and co- contaminants and levels of endogenous metabolites and lipids in blood using both untargeted and targeted metabolomics. The use of biomonitoring and metabolomics provide powerful tools to assess early exposures and biological changes in the years preceding clinical manifestation of disease. We propose a cross-sectional study on Long Island (an area with many Superfund sites potentially contributing to contamination of drinking water with 1,4-DX) to i) assess human exposure to 1,4-DX and evaluate the relationship between environmental and biological exposure indicators, ii) evaluate temporal variability of exposure to 1,4-DX and metabolite levels by comparing data from two different US regions with different water sources (ground water in NY and surface water in NC), and iii) evaluate the relationship between 1,4-DX exposure and metabolites of biological responses particularly for liver toxicity and carcinogenesis. This project will greatly enhance our understanding of the extent of exposure to 1,4-DX (and its co-occurring contaminants) in drinking water and the potential for human health effects. The results will provide scientific evidence for policy makers to set guidelines for concentration standards for 1,4-DX and provide researchers in the Superfund Research Program w...