A comparative toxicological evaluation of emerging nicotine analogs 6-methyl nicotine and nicotinamide: a scoping review

Thermal degradation of flavored e-liquids in e-cigarettes (e-cigs) produces oxidants, volatile organic compounds, and heavy metals. Inhalation toxicology studies have revealed exposure to these toxicants may be toxic to humans. These studies informed the FDA’s regulation of nicotine-containing E-cigs under the Tobacco Regulation Act (TRA) (2020) and the banning of all flavors in E-cig bars apart from tobacco and menthol. Furthermore, tobacco companies aiming to sell nicotine products on the US market ought to submit a premarket tobacco product application (PMTA) and obtain approval from the FDA before marketing. Nonetheless, because the PMTA process is lengthy/complicated, vape/tobacco companies utilized a loophole in the TRA (2020) and have introduced nicotine analogs in E-cig bars, such as 6-methyl nicotine (6-MN) and nicotinamide, which are not derived from nicotine or tobacco. These companies claim these analogs to be ‘safer’ alternatives to nicotine while providing similar satisfaction as nicotine. However, the safety profiles of these analogs are entirely unknown. Therefore, in this review, we have extrapolated the current literature on 6-MN and nicotinamide, and speculated their potential mode of toxicity through alterations in intracellular ROS and activation of nicotinic acetylcholine receptors, transient receptor potential ankyrin-1, and NF-κB. These biomolecules are pivotal in the onset and regulation of pulmonary diseases such as COPD, asthma, and lung tumorigenesis/remodeling. Thus, primary research is urgently warranted to inform regulatory agencies of these emerging nicotine analogs' potential adverse health effects. This article provides insightful information on emerging vape products' potential toxicity for environmental toxicology research and regulation.