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

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 电子烟香精、烟草香精、薄荷醇香精、清凉香精已广泛流行。 申请人提议调查薄荷醇/薄荷和烟草的“化学”、“毒性”和“健康影响” 调味电子尼古丁输送系统 (ENDS) 产品。该提案涉及毒理学 这些味道及其成分在正常和预先存在的情况下对呼吸系统的影响 通过表征化学品、使用体外和体内模型确定毒性来确定条件，以及 识别疾病的潜在生物标志物。所有可用的薄荷醇/清凉和烟草味 ENDS 将比较不同类别，即电子烟油、电子烟棒和烟弹。中心假设是薄荷醇/薄荷 烟草香料含有有害的调味化学物质，会导致细胞和分子发生不利的变化 肺组织和预先存在的条件会加剧风味暴露后的毒理学反应。这 目标是确定薄荷醇/清凉味和烟草香料的成分及其肺部毒性，并 确定疾病的潜在生物标志物。目标 1：确定薄荷醇、类薄荷醇（清凉味）和薄荷醇的化学性质 烟草香料，包括调味化学品和气雾化后形成的次级产品。受欢迎的 烟草和薄荷醇/薄荷/清凉香料的烟头将被雾化，其化学物质将被雾化。 特点。目标 2：确定薄荷醇、薄荷醇样物质的体外和体内毒性和健康影响 （冷却）和正常情况下 EpiAirway 3D 组织和小鼠（C57BL/6J 和 BALB/C）中的烟草味 ENDS 和已有的呼吸系统疾病。急性暴露于薄荷醇/薄荷和烟草 ENDS 至 EpiAirway3D 将对小鼠（正常和患病）和长期暴露进行实验。使用气液界面 (ALI) 来自正常、慢性阻塞性肺病和哮喘供体的气溶胶 EpiAirway 3D 组织，香料的体外毒性将 决定。通过接触香烟烟雾（CS）（或药物）诱发小鼠慢性阻塞性肺病和哮喘病 随后长期接触薄荷醇/薄荷和烟草香料，体内呼吸道毒理学影响 将确定正常和疾病状态。拟议的体外和体内模型将为我们提供相关的 烟草和薄荷醇/清凉蒸气引起的疾病的标志性生物标志物。目标 3：确定体外和体内 EpiAirway 中薄荷醇、薄荷醇类（清凉）和烟草调味化学品的体内毒性和健康影响 正常和预先存在的呼吸条件下的 3D 组织和小鼠（C57BL/6J 和 BALB/C）。已鉴定 薄荷醇/清凉和烟草中存在的调味化学品将用于急性和慢性体外治疗 和体内模型。将进行剂量依赖性实验以确定诱导的毒性。 使用慢性阻塞性肺病和哮喘诱发的小鼠，将确定调味化学品的毒理学作用。这将 允许考生识别这些调味电子烟中的关键化学物质，这些化学物质会造成不良影响 肺细胞和小鼠。此外，这项研究将确定这些已确定的化学物质对呼吸道的影响 疾病状况和疾病恶化的生物标志物。