PROJECT SUMMARY/ABSTRACT In the United States (US), diabetes mellitus affects an estimated 34.2 million people, representing 10.5% of the population, with 90-95% of diabetes cases characterized as type 2 diabetes mellitus (T2DM). Diabetes prevalence has increased over time, with disparities by race/ethnicity. A review endorsed by the American Diabetes Association recently identified exposure from toxic metals/metalloids, such as arsenic (As), as a risk factor for T2DM. Less is known regarding the role of uranium (U). Drinking water represents a major source of inorganic As and U exposure in the US, for both users of unregulated private wells and of regulated public water. A current gap in knowledge is the contribution of drinking water to total As and U exposure, as determined in urine, in general US populations, and whether drinking water As and U exposures are associated with T2DM risk nationwide. Our objective is to examine the association of drinking water As and U exposures with a) urinary metal/metalloid concentrations, and b) T2DM incidence and prevalence. Evaluating drinking water metals/metalloids and T2DM can directly inform drinking water regulations that currently do not consider T2DM as a health endpoint. Nationwide, analyses in diverse epidemiological populations are needed to assess T2DM susceptibility across race/ethnicity and socioeconomic status groups, critical to understanding and reducing health disparities. It is also important to assess whether the current public water Maximum Contaminant Levels (MCLs) for As and U are adequately health protective. The association between water As and U with their corresponding concentrations in urine in US populations has historically been difficult to examine due to a lack of water composition data that could be linked to epidemiologic cohorts. Recently, however, robust estimates of public water As and U and private well As data have been developed nationwide. We will study three diverse epidemiologic cohorts in the US: the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective study of cardiovascular disease among diverse urban communities (incidence and prevalence); the Strong Heart Family Study (SHS), a prospective study of cardiovascular disease among American Indian communities (incidence and prevalence); and the National Health and Nutrition Examination Survey (NHANES), a series of cross-sectional surveys representative of the general US population (prevalence). We will evaluate the association of water As and U with T2DM risk by sex, race/ethnicity, age, SES, and by levels of the other metal. We hypothesize that the contribution of drinking water to urinary metal/metalloid concentrations will decrease following the implementation of the As and U MCL change. This study will highlight subpopulations at increased susceptibility of water As and U-associated T2DM, will identify regions and communities where future interventions to reduce drinking water As exposures are needed, and ...