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

薄荷醇、薄荷和烟草味电子烟产品的肺部毒理学评价和化学相互作用

• 批准号: 10347694
• 负责人: Thivanka Mudalige Muthumalage
• 金额: $ 14.09万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347694
• 关键词: 3-Dimensional; Acute; Acute Lung Injury; Address; Adverse effects; Aerosols; Air; Asthma; Authorization documentation; Biological; Biological Markers; Categories; Cells; Chemicals; Chemistry; Chronic; Chronic Obstructive Airway Disease; DNA Damage; Data; Development; Disease; Disease model; Disease susceptibility; Dose; Elastases; Electrical Resistance; Electronic Nicotine Delivery Systems; Electronic cigarette; Evaluation; Exposure to; Flavoring; Free Radicals; Functional disorder; Generations; Genus Mentha; Goals; Health; Ice; Immune; Immune response; In Vitro; Inbred BALB C Mice; Inflammation Mediators; Inflammatory Response; Investigation; JUUL; Liquid substance; Lung; Lung diseases; Lymphoid; Mainstreaming; Mass Fragmentography; Measures; Menthol; Methods; Molecular; Mucins; Mucosal Immune Responses; Mucous body substance; Mus; Myelogenous; Normal tissue morphology; Onset of illness; Outcome Study; Oxidants; Pathologic Processes; Pharmaceutical Preparations; Population; Predisposition; Process; Pulmonary Emphysema; Pyroglyphidae; Regimen; Regulation; Respiratory System; Spin Trapping; Stains; Standardization; Structure of parenchyma of lung; TNF gene; Testing; Tissues; Tobacco; Tobacco smoke; Toxic effect; Toxicology; aerosolized; asthmatic; base; biomarker signature; chemokine; combustible cigarette; comparative; cytokine; cytotoxicity; e-cigarette aerosols; electronic liquid; experimental study; exposure to cigarette smoke; in vivo; in vivo Model; insight; lipid mediator; lipidomics; metabolomics; potential biomarker; predictive marker; proteomic signature; respiratory; response; screening; specific biomarkers; tobacco flavor; vape pens; vaping; vapor; 3-Dimensional; Acute; Acute Lung Injury; Address; Adverse effects; Aerosols; Air; Asthma; Authorization documentation; Biological; Biological Markers; Categories; Cells; Chemicals; Chemistry; Chronic; Chronic Obstructive Airway Disease; DNA Damage; Data; Development; Disease; Disease model; Disease susceptibility; Dose; Elastases; Electrical Resistance; Electronic Nicotine Delivery Systems; Electronic cigarette; Evaluation; Exposure to; Flavoring; Free Radicals; Functional disorder; Generations; Genus Mentha; Goals; Health; Ice; Immune; Immune response; In Vitro; Inbred BALB C Mice; Inflammation Mediators; Inflammatory Response; Investigation; JUUL; Liquid substance; Lung; Lung diseases; Lymphoid; Mainstreaming; Mass Fragmentography; Measures; Menthol; Methods; Molecular; Mucins; Mucosal Immune Responses; Mucous body substance; Mus; Myelogenous; Normal tissue morphology; Onset of illness; Outcome Study; Oxidants; Pathologic Processes; Pharmaceutical Preparations; Population; Predisposition; Process; Pulmonary Emphysema; Pyroglyphidae; Regimen; Regulation; Respiratory System; Spin Trapping; Stains; Standardization; Structure of parenchyma of lung; TNF gene; Testing; Tissues; Tobacco; Tobacco smoke; Toxic effect; Toxicology; aerosolized; asthmatic; base; biomarker signature; chemokine; combustible cigarette; comparative; cytokine; cytotoxicity; e-cigarette aerosols; electronic liquid; experimental study; exposure to cigarette smoke; in vivo; in vivo Model; insight; lipid mediator; lipidomics; metabolomics; potential biomarker; predictive marker; proteomic signature; respiratory; response; screening; specific biomarkers; tobacco flavor; vape pens; vaping; vapor

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.

摘要电子香烟口味，烟草，薄荷醇和冷却口味已广泛流行。 申请人提出的提案要研究“化学”，“毒性”和精神病和烟草的“毒性”和“健康影响” 调味的电子尼古丁输送系统（末端）产品。该提议解决了毒理学 这些口味及其在正常和预先存在的呼吸系统上的含义及其宪法在呼吸系统上 通过表征化学物质，使用体外和体内模型来确定毒性，以及 识别潜在的疾病生物标志物。薄荷醇/冷却和烟草调味的末端 将比较类别，即电子液体，vape棒和豆荚。中心假设是薄荷醇/薄荷 和烟草口味包含有害的调味化学物质引起的不良细胞和分子变化 肺组织和预先存在的条件加剧了风味暴露后的毒理学反应。 目标是确定精神病/冷却和烟草口味及其肺毒性的成分 确定潜在的疾病生物标志物。目标1：确定心态，类似心态（冷却）的化学反应和 烟草口味，包括在雾化时形成的调味化学品和二级产品。受欢迎的 烟草和精神病/薄荷/冷却口味的末端将被雾化，其化学物质将是 特征。 AIM 2：确定体外和体内毒性和精神醇的健康影响 （冷却）和烟草调味的末端3D组织和小鼠（C57BL/6J和BALB/C）在正常下 和预先存在的呼吸条件。薄荷/薄荷和烟草的急性暴露到epiairway3d （正常和解散）将进行对小鼠的慢性暴露。使用空气式接口（ALI） 来自正常，COPD和哮喘供体的气溶胶Epiairway 3D组织，口味的体外毒性将是 决定。通过香烟烟雾（CS）暴露（或药物）在小鼠中诱导的COPD和哮喘状况 随后长期暴露于精神病/造币和烟草口味，体内呼吸毒理学作用 将确定正常状态和疾病状态。拟议的体外和体内模型将为我们提供相关的 由于烟草和心理/冷却蒸气而引起的疾病签名生物标志物。目标3：确定体外和 Epiairway中薄荷醇，类似薄荷醇的（冷却）和烟草调味化学物质的体内毒性和健康作用 在正常和预先存在的呼吸条件下，3D组织和小鼠（C57BL/6J和BALB/C）。确定 精神病/冷却和烟草末端中存在的调味化学物质将用于急性和慢性体外 和体内模型。将进行剂量依赖性实验以确定诱导的毒性。 使用COPD和哮喘诱导的小鼠，将确定调味化学物质的毒理学作用。这会 允许候选人在这些调味末端识别关键化学物质，负责在 肺细胞和小鼠。此外，这项研究将确定这些确定的化学物质在呼吸下的作用 疾病状况和疾病生物标志物加剧。