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They initiate olfactory, gustatory, and chemesthetic sensations; influence human brain cognition and emotion; and guide a wide variety of behaviors essential for survival, including protective reactions, such as avoidance of contaminated foods and potential toxicants. Electronic nicotine delivery systems (ENDS) aerosolize e-liquids for inhaled consumption that typically contain flavorants, propylene glycol, vegetable glycerin, and nicotine. E-liquid aerosols also contain toxicants, such as formaldehyde, acetaldehyde, acrolein, and heavy metals. Chemosensory evaluation of ENDS aerosol plays an essential role in the assessment of whether a product will attract new users of all ages, as well as determining their likely use patterns, perceptions of product harm, satisfaction, and product selection. Nicotine and individual flavorant constituents stimulate multiple sensory receptor systems in complex patterns, initiating distinctive sensory perceptions depending on the chemical properties and quantity in the aerosol. There are limited data on chemosensory evaluation of ENDS aerosols and their influence on ENDS use and protective biologic mechanisms. This two-part manuscript provides an overview of (i) the physiology of the olfactory, gustatory, and chemesthetic chemosensory systems, their detection mechanisms, and their role in protective defenses; and (ii) the in vitro, in vivo, and in silico computer-based methodology available to evaluate ENDS irritants and toxicants, their impact on chemosensory pathways, the current state of the science related to e-liquid and ENDS aerosols, and challenges for future studies and scientific innovation.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf090","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T05:55:11Z","timestamp":1753422911000},"page":"261-271","source":"Crossref","is-referenced-by-count":0,"title":["Chemosensory tobacco product toxicology part 1: sensory 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