Quantitative risk assessment (QRA) can provide a useful and efficient approach to address questions that might arise regarding human health risk and potential influence of tobacco products on public health. In evaluation of substantial equivalence (SE) applications, differences in harmful and potentially harmful constituents (HPHCs) may necessitate the determination of whether a new product raises different questions of public health; thus results from QRA are a valuable metric. This study is to evaluate impacts of several important exposure parameters, such as consumption rate, body weight, and lifespan, on estimated long-term health risks of combustible cigarettes and smokeless tobacco products in the context of SE evaluations. Different values of consumption rates, body weight, and lifespan are obtained from the most recent Centers for Disease Control and Prevention reports, National Health Interview Survey, the 1999-2016 National Health and Nutrition Examination Survey, US Environmental Protection Agency (USEPA) and US Food and Drug Administration recommended values, and the literature. Potential health risks are evaluated following a standard QRA process, utilizing toxicity values from regulatory sources and standard default values for other exposure factors. Results of the study indicate that tobacco consumption rates exert the most influence on estimated long-term health risks from exposure to HPHCs in tobacco products. Recent updates on body weight and lifespan values recommended by the USEPA have minimal impacts on predicted long-term health risks of tobacco users compared to previously recommended values. Regardless of the exposure parameters values, given the comparative assessment of risk between the new and corresponding predicate products in the context of an SE evaluation, the same input values would be applied for both products. Thus, the resulting difference between the estimated risk for each product would not be affected.