PROJECT SUMMARY/ABSTRACT The overarching objective of this proposal is to evaluate changes in levels of arsenic and uranium in public and private drinking water over several decades across the state of California, and to elucidate the relationship between long-term exposure to these contaminants and the risk of cardiovascular diseases (stroke, acute myocardial infarction) and chronic kidney disease in a large prospective cohort. Inorganic arsenic (As) naturally occurs in soil and groundwater globally. While arsenic in drinking water (wAs) is regulated in US community water supplies, the maximum contaminant level was recently reduced and enforced beginning in the early 2000s. Rural populations, however, rely on private wells which are not regulated for contaminants and may contain higher levels of wAs found in groundwater. Exposure to As has been linked to systemic inflammation and endothelial dysfunction, as well as kidney damage. A limited but growing body of evidence suggests that low-to-moderate levels of wAs present in the US increases the risk of cardiovascular disease (CVD) outcomes, including stroke and myocardial infarction. Few epidemiologic studies have evaluated the association between wAs and chronic kidney disease (CKD), a prevalent disease found at higher rates of unknown cause in some rural regions of California. Another drinking water contaminant, uranium (wU), which naturally occurs in groundwater, shares similar toxicologic properties to wAs and is particularly nephrotoxic. Given wU may co- occur with wAs, exposure to elevated levels of both contaminants may exacerbate the risk of CVD and CKD. In collaboration with the California Office of Environmental Health Hazard Assessment, a geospatial dataset of annual wAs and wU levels (1990-2020) has been developed using measurements from community water supplies and private wells, and spatially allocated to water system boundaries and private groundwater grids (1x1 mile grids), respectively. Our study proposes to first evaluate spatiotemporal trends and the co- occurrence of wAs and wU in community water supplies and private wells across California. We will leverage the geospatial dataset to estimate long-term residential drinking water levels of wAs and wU for participants in the California Teachers Study cohort (enrolled in 1995-96). We will conduct two epidemiologic studies evaluating the association between exposure to wAs and the prospective risks of CVD (including stroke and acute myocardial infarction) and CKD (stage 3 CKD to end stage renal disease) incidence/mortality. We will assess whether risk is greater for participants with the highest exposure levels of both wAs and wU. In summary, our study will describe trends in wAs and wU over time for both public and private water sources, identify regions in California with elevated exposure, as well as contribute to limited knowledge about exposure to low-to-moderate wAs levels and joint exposure to wU and the risks of CVD and CKD in the US.

PROJECT NARRATIVE This proposal uses drinking water quality data for community water supplies (CWS) and regions that rely on private groundwater (1-mile grids) in California to describe spatiotemporal trends in annual levels of arsenic (wAs) and uranium (wU) between 1990-2020, as it relates to monitoring (subject vs. not subject to regulation) and changes to the US EPA maximum contaminant levels (occurring in the early 2000s). We then propose to investigate the association between long-term wAs exposure, and possible effect modification by co-exposure to wU, and two prevalent and etiologically relevant chronic diseases—cardiovascular disease and chronic kidney disease—in the California Teachers Study, a large prospective cohort of women living in California who have been followed for health outcomes for over 20 years. Our proposal seeks to provide critical information for future policy decisions by first describing the effectiveness of regulatory action in reducing levels of wAs and wU and identifying populations that remain exposed to high levels (e.g., private well users), and second addressing key gaps in knowledge about low-to-moderate wAs exposure, the unknown effects of wU co- exposure and the risk of cardiovascular and chronic kidney diseases.