Pulmonary toxicological evaluation and chemical interactions of menthol, mint, and tobacco flavored e-cigarette products

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SUMMARY Electronic cigarette flavors, tobacco, menthol, and cooling flavors have become widely popular. The applicant proposes to investigate “Chemistry”, “Toxicity”, and “Health effects” of menthol/mint and tobacco flavored electronic nicotine delivery systems (ENDS) products. This proposal addresses the toxicological implications of these flavors and their constituents on the respiratory system under normal and pre-existing conditions by characterizing chemicals, determining the toxicity using in vitro and in vivo models, and identifying potential biomarkers of disease. Menthol/cooling and tobacco flavored ENDS from all available categories will be compared, i.e., e-liquids, vape bars, and pods. The central hypothesis is that menthol/mint and tobacco flavors contain harmful flavoring chemicals inducing adverse cellular and molecular changes in the lung tissue and pre-existing conditions exacerbate the toxicological response upon flavor exposures. The Goal is to identify constituents of menthol/cooling and tobacco flavors and their pulmonary toxicity and to determine potential biomarkers of disease. Aim 1: Identify the chemistry of menthol, menthol-like (cooling), and tobacco flavors, including flavoring chemicals and secondary products formed upon aerosolization. Popular ENDS of tobacco and menthol/mint/cooling flavors will be aerosolized and their chemicals will be characterized. Aim 2: Determine in vitro and in vivo toxicity and health effects of menthol, menthol-like (cooling), and tobacco flavored ENDS in EpiAirway 3D tissues and mice (C57BL/6J and BALB/C) under normal and pre-existing respiratory conditions. Acute exposure of menthol/mint and tobacco ENDS to EpiAirway3D (normal and diseased) and chronic exposure to mice will be conducted. Using an air-liquid-interface (ALI) aerosol EpiAirway 3D tissues from normal, COPD, and asthmatic donors, in vitro toxicity of flavors will be determined. By inducing COPD and asthma conditions in mice by cigarette smoke (CS) exposure (or drug) and subsequent chronic exposure to menthol/mint and tobacco flavors, in vivo respiratory toxicological effects in normal and disease states will be determined. Proposed in vitro and in vivo models will provide us relevant signature biomarkers of disease due to tobacco and menthol/cooling vapors. Aim 3: Determine in vitro and in vivo toxicity and health effects of menthol, menthol-like (cooling), and tobacco flavoring chemicals in EpiAirway 3D tissues and mice (C57BL/6J and BALB/C) under normal and pre-existing respiratory conditions. Identified flavoring chemicals present in menthol/cooling and tobacco ENDS will be used for acute and chronic in vitro and in vivo models, respectively. Dose-dependent experiments will be conducted to determine induced toxicity. Using COPD and asthma induced mice, toxicological effects of flavoring chemicals will be determined. This will allow the candidate to identify key chemicals in these flavored ENDS responsible for causing adverse effects in lung cells and mice. Further, this study will determine the effects of these identified chemicals under respiratory disease conditions and biomarkers of disease exacerbation.