Project Summary / Abstract: Overall The overall objective of the Penn State TCORS is to provide a science base for FDA to take regulatory actions to reduce the harm from tobacco products. Our center will accomplish this through a collaboration of experienced and new tobacco regulatory scientists focusing on state-of-the-art basic and translational research on the toxicity and addiction of diverse tobacco products. This includes developing new research methods that have the potential to be used in the tobacco regulatory field beyond the scope of the Penn State TCORS research program. While toxicity is a very broad scientific field, our focus will be on the characterization of oxidants in tobacco smoke and in aerosols, and their biological effects in persons who use tobacco products. We will examine several tobacco products including e-cigarettes (EC), little cigars and nicotine pouches. Overall, these studies are a logical extension of our previous work on oxidants produced by combustible and non-combustible tobacco products and the impact of product design characteristics on their production. In addition, they stem from our previous research on the feasibility of a reduced nicotine standard for cigarettes to minimally-addicting or nonaddicting levels. These studies indicated that some smokers will continue to use lowered nicotine products and that additional strategies are needed to reduce tobacco harm including providing safe alternative sources of nicotine to addicted smokers and determining which tobacco product characteristics are associated with greater harm. Thus, the overall integrative theme of our center is to better understand how product design characteristics of diverse and alternative tobacco products affect their toxicity and addictiveness. Our proposed Center will address several CTP scientific domains including Toxicity, Addiction and Product Composition and Design using a highly interdisciplinary and integrative approach. In Project 1, we will conduct translational studies in both laboratory animal models and EC users to address the hypothesis that inhaled EC oxidants and their potential for harm are influenced by product design features and the biological effects of these oxidants can be measured through biomarkers of both exposure and harm. In Project 2, we will investigate the potential toxicity related to oxidant production in little cigar smokers and design features that may affect human exposure using epidemiologic data and clinical and laboratory studies. In Project 3, we will focus on the nicotine pouch as an alternative tobacco product by conducting a randomized controlled clinical trial to test that hypothesis that biomarkers of harm, including those related to oxidative stress, are significantly reduced in smokers who are provided high nicotine pouches. The PSTCORS will also continue its strong support of career development in tobacco regulatory science through an integrated and multidisciplinary series of educational programs and research support through the Career Development Core. Finally, in support of all Center activities will be a mature and experienced system of cores: Administrative Core, Biostatistics and Data Management Core and Biomarker and Analytical Chemistry Core.

Project Narrative: Overall The overall objective of the Penn State TCORS is to provide a science base for reducing the harm from tobacco products. We are pursuing the Food and Drug Administration’s Comprehensive Plan for Tobacco and Nicotine Regulation by determining the toxicity of aerosols, smoke, and oral exposures of tobacco products that may be used as substitutions for cigarettes. This includes identifying the specific characteristics of non- cigarette products that can be regulated to reduce harm.