PROJECT SUMMARY The overall goal of this project is to assess the impact of exposure to Superfund-relevant volatile organic compounds (VOCs) on cardiometabolic disease, the underlying conditions that contributes to diabetes, cardiovascular and liver diseases. VOCs such as trichloroethylene, benzene, acrolein, formaldehyde, xylene and butadiene are major chemicals of concern at most Superfund sites and extensive previous work suggests the exposure to VOC could have a variety of adverse health effects. Nevertheless, whether exposure to VOCs at levels relevant to neighborhood adjacent to Superfund sites could adversely affect cardiometabolic health remains unknown. Our extensive studies with animal exposed to different VOCs suggest that chronic exposure to low dose VOCs could increase blood pressure, inflict vascular injury, accelerate atherosclerosis, and induce liver disease. Nevertheless, the cardiometabolic risk of VOCs has not been evaluated and longitudinal data to interrogate exposure-response relationships are missing. Hence, to assess CMD risk imposed by VOCs, we will test the hypothesis that exposure to VOCs exacerbates/induces vascular and hepatic dysfunction leading to a cascade of events that increase CMD risk. To assess the impact of VOC exposures, we will examine 1200 residents of Jefferson County, including those who live in areas adjacent to Superfund sites such as Lee’s Lane and Distiller Farm, as well as high VOC emission, such as the Rubbertown neighborhood. In each participant, we will assess CMD risk by measuring arterial stiffness, marker of hepatocyte death, as well as suite of biomarkers indicative of risk for diabetes, cardiovascular and liver diseases. To determine population-level VOC exposure and its relationship with CMD-related hospital admissions and mortality, we will establish a network of VOC monitors to measure VOC levels throughout Jefferson County and monitor domestic wastewater for urinary VOC metabolites. We will monitor wastewater every other month for 3 years, and assess the extent to which population-level exposure estimates reflect ambient air VOC levels and individual-level exposure (Aim 1), and how these estimates relate to population-level and individual-level CMD risk. To obtain longitudinal data, we will examine CMD progression and determine the association between individual-level and community-level VOC exposures with vascular and hepatic function and other indices of cardiometabolic risk. This will help us in assessing how VOC exposure and/or residential proximity to Superfund sites affects the risk of CMD and this excessive risk differs from that imposed by background VOC exposures in urban neighborhood. We expect that completion of this project will lead to the development of quantitative risk models and rigorous estimates of the additional CMD risk attributable to residential VOC exposures.