Project 1: Manipulating E-cigarette Nicotine to Promote Public Health

PROJECT SUMMARY – PROJECT 1 Historically, the tobacco industry manipulated nicotine in cigarettes to promote smoking. They are now following the same playbook for e-cigarettes (ECs), manipulating the nicotine dimensions of concentration and form, and more recently have begun manipulating isomer composition through the use of synthetic nicotine. These

manipulations have led to ECs with increased palatability and nicotine delivery, maximizing their appeal and addictiveness, particularly to young people. While ECs may be a less harmful alternative for smokers who completely switch, EC uptake, use, and addiction among young people is alarming.The overall integrative theme

of The Ohio State University Tobacco Center for Regulatory Science is: “Flipping the Script”: Using the Industry's Nicotine Playbook to Maximize Public Health. J ust as the tobacco industry manipulates nicotine to create ECs that appeal to young people, we posit that the FDA, through nicotine regulation, can make products

unappealing to young people while still providing smokers with a less harmful alternative with sufficient appeal and satisfaction. To test this hypothesis, Project 1 (P1) will examine the unique and combined effects of nicotine form, concentration, and isomer on EC product appeal, abuse liability, use patterns, and toxicity (Study 1), and

determine if an EC product standard requiring a minimum level of free-base (FB) nicotine (nicotine form) would reduce the appeal of ECs for young adults but not older adult smokers (Study 2). In Study 1, using a double- young adult (21-24-years) exclusive EC users with no/minimal history of smoking and

older adult cigarette smokers will vape 8 lab-prepared, tobacco-flavored liquids varied by nicotine dimensions. Outcomes will include subjective effects, nicotine pharmacokinetics, and puffing topography. blind crossover design, (•25-years) To assess the toxicological effects of varying EC nicotine dimensions, topography data will be used in puff-playback

toxicology studies with in vitro air-liquid interface exposures for cancer, cardiovascular and respiratory disease surrogate markers. Nicotine isomers may have different metabolic routes and rates, so we will also examine nicotine metabolism rate. In Study 2, young adult exclusive EC users with minimal/no history of smoking and

older adult smokers will complete a single-visit, double-blind, randomized crossover trial to vape e-liquids at 2 nicotine concentrations and 2 isomer ratios, with varying FB nicotine fractions to assess outcomes of appeal. P1 is significant and innovative because it will be the first to systematically examine the impact of nicotine

dimensions (including isomer composition) on EC abuse liability, compare pharmacological, toxicological, and metabolic profiles of nicotine isomers in humans, and determine whether regulations limiting FB nicotine fraction in EC liquids are appropriate for the protection of public health. Integrated with P3-4, results will also inform

marketing and product regulations that reduce appeal and dissuade EC use in youth and non-users but not adult tobacco users. P1 will address the FDA scientific domains of Product Composition and Design, Addiction, Toxicity, Health Effects, and Behavior.