Mechanisms of toxicity and biomarkers of flavoring and flavor enhancing chemicals in emerging tobacco and non-tobacco products.

Tobacco products containing flavorings, such as electronic nicotine delivery devices (ENDS) or e-cigarettes, cigars/cigarillos, waterpipes, and heat-not-burn devices (iQOS) are continuously evolving. In addition to increasing the exposure of teenagers and adults to nicotine containing flavoring products and flavoring enhancers, chances of nicotine addiction through chronic use and abuse also increase. These flavorings are believed to be safe for ingestion, but little information is available about their effects on the lungs. In this review, we have discussed the in vitro and in vivo data on toxicity of flavoring chemicals in lung cells. We have further discussed the common flavoring agents, such as diacetyl and menthol, currently available detection methods, and the toxicological mechanisms associated with oxidative stress, inflammation, mucociliary clearance, and DNA damage in cells, mice, and humans. Finally, we present potential biomarkers that could be utilized for future risk assessment. This review provides crucial parameters important for evaluation of risk associated with flavoring agents and flavoring enhancers used in tobacco products and ENDS. Future studies can be designed to address the potential toxicity of inhaled flavorings and their biomarkers in users as well as in chronic exposure studies.