Grant Number:	1R01CA309279-01A1 Interpret this number
Primary Investigator:	Rahman, Irfan
Organization:	University Of Rochester
Project Title:	Emerging Nicotine Analogs and Device Design Characteristics on Toxicity Assessment
Fiscal Year:	2026

SUMMARY Recently, Electronic nicotine delivery systems (ENDS) manufacturers have introduced nicotine analogs, such as 6-methyl nicotine (6-MN/metatine) and nicotinamide (nixamide/nixodine/nixotin-free base and -salt) in ENDS products to circumvent the premarket tobacco product application (PMTA), which is a stringent regulatory process. There is a substantial gap in knowledge of the toxicological assessment of these emerging nicotine analogs in disposable bars and liquids. This is because no inhalation exposure studies have been conducted on them for safety vs regular ENDS. Furthermore, the toxicological impacts of different wattages of the devices aerosolizing these ENDS analogs, their differentially engineered coils (different coil materials), and different coil resistances (from sub ohm to high ohms) in ENDS on the toxicity of these nicotine analogs are lacking. Our preliminary data suggest that the toxicity of aerosols in ENDS are dependent not only on coil engineering, but also on coil resistance. Thus, the toxicity studies of novel emerging nicotine analogs ENDS and the effect of different wattage devices and their interaction with different types of coils and coil resistances are urgently needed. We hypothesize that the emerging nicotine analog-containing ENDS vaping bars and e-liquids, compared to tobacco-derived or synthetic nicotine, generate more harmful chemicals, and exposure to these induces toxicity with lung cellular changes via the reactive oxygen species (ROS)/aldehyde-induced protein carbonylation, epithelial permeability, and inflammation. We propose to investigate the impact of ENDS device safety controls, varying coil resistance and coil design, nicotine analogs, and different types of nicotine on delivering harmful and potentially harmful constituents (HPHCs). Three specific aims are proposed to test the hypothesis: Aim 1: To determine the physicochemical nature of emerging nicotine analogs/products (6-methyl nicotine and nicotinamide) and synthetic (TFN) and tobacco-derived nicotine (TDN) based on device coil resistance (0.6, 0.9 and 1.4 Ω ohms), and device characteristics (varying wattages) regulation on aerosol particle size, ROS, and aldehyde release. Aim 2: To determine the toxicity of emerging nicotine analog products 6-MN/metatine, nicotinamide, and TFN/TDN based on coil resistance and other device characteristics on cellular model systems (primary lung epithelial cells and 3D lung cellular models) on epithelial permeability and inflammation utilizing air-liquid interface and in mouse lungs. Aim 3: To determine the specific chemical adducts, such as 6-methyl nicotine-carbonyl adducts, nicotinamide-hydroxy alkylation adducts/constituents derived from aerosolization of emerging nicotine/nicotine-like analog products based on coil resistance impacting on cellular toxicity. Overall, these findings will contribute to evidence-based regulatory science for public health interventions related to novel emerging nicotine analog ENDS use. We propose the use of vertebrate animals (mouse model) for aerosol exposure to ENDS products as in vitro cell culture models cannot be substituted for understanding the pathophysiology of living system.





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