Emerging nicotine analogs and device design characteristics on toxicity assessment

The National Cancer Institute awarded the University of Rochester $583,304 on August 13, 2026, under the Cancer Cause and Prevention Research program (CFDA 93.393) to investigate toxicological assessment of emerging nicotine analogs in electronic nicotine delivery systems (ENDS).

The research addresses a substantial knowledge gap regarding the safety profile of novel nicotine analogs, including 6-methyl nicotine and nicotinamide, which manufacturers have introduced to circumvent premarket tobacco product application requirements. No inhalation exposure studies have evaluated these analogs against conventional ENDS products. The award funds investigation into how device wattage, coil materials, coil resistance (sub-ohm to high-ohm), and different nicotine types affect delivery of harmful and potentially harmful constituents. The study hypothesizes that emerging nicotine analog-containing products generate more harmful chemicals than tobacco-derived or synthetic nicotine, inducing toxicity through reactive oxygen species and aldehyde-induced protein carbonylation, with downstream effects on epithelial permeability and inflammation.

The research is performed at the University of Rochester, Rochester, New York. The project period extends through July 31, 2031. The award is structured as a Project Grant, the standard assistance type for investigator-initiated research under NCI's Cancer Cause and Prevention Research portfolio.

Abstract

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.