DESCRIPTION (provided by applicant): Cardiovascular Toxicity of Tobacco Products The Family Smoking Prevention and Tobacco Control Act grants the FDA the authority to regulate tobacco products to protect public health. However, to set standards for tobacco products, it is important to know which components of conventional, new and emerging tobacco products induce cardiovascular injury so as to provide toxicity thresholds for harmful and potentially harmful constituents (HPHC) in tobacco products. However, to identify HPHC toxicity, it is important to determine how this toxicity could be identified and associated with disease risk and what assays best compare the toxic properties of different tobacco products. Although for toxicological profiling a high-throughput in vitro method is preferable, CVD is a complex disease that develops from the dysfunction of several organ systems. Therefore, the cardiovascular toxicity of tobacco products cannot be estimated in simple in vitro systems. Hence, we will use an animal model and determine the relative toxicity of major HPHCs in cigarette smoke and electronic cigarette aerosol, determine the toxicity profile of individual HPHCs, specifically aldehydes, and assess how the toxicity of an individual HPHC is modified by other HPHCs and nicotine. To validate this toxicity profile in humans, we will examine the relationship between exposure to different HPHCs and cardiovascular toxicity in a well-characterized cohort. Successful completion of this project will lead to quantitative and rigorous evaluation of the cardiovascular toxicity of the major HPHCs in tobacco products and to the validation of an association between exposure to individual HPHCs and cardiovascular toxicity in humans. These findings will provide new information regarding the contribution of individual aldehydes in HPHC mixtures to the cardiovascular toxicity of tobacco smoke and, as such, will be useful in developing informed threshold limits and the policies needed to regulate HPHC levels in cigarettes, electronic cigarettes, smokeless tobacco as well as in other emerging tobacco-derived products.