Electronic Cigarettes: Emerging Ingredients, Acids, Toxicants, and Indicators of Non-Tobacco Nicotine

电子烟：新兴成分、酸、有毒物质和非烟草尼古丁指标

• 批准号: 10884691
• 负责人: Prudence Talbot
• 金额: $ 66.93万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10884691
• 关键词: 3-Dimensional; Abbreviations; Acids; Acute; Adverse effects; Aerosols; Age; Air; Alkaloids; Benzoic Acids; Biological; Biological Assay; Carcinogens; Cells; Chemicals; Chemistry; Chromatography; Chronic; Collaborations; Commerce; Consensus; Coupled; Cream; Data; Data Collection; Development; Device Designs; Electronic cigarette; Environment; Evolution; Exposure to; Family Smoking Prevention and Tobacco Control Act; Flavoring; Formulation; Foundations; Gases; Genus Mentha; Glycerol; Health; Heating; Human; Human body; Individual; Inflammatory; Ingredients and Chemicals; Inhalation; Instagram; International; Ions; Laws; Liquid substance; Malignant Neoplasms; Manufacturer; Marketing; Methods; Molecular; Monitor; Nicotine; Oxidative Stress; Oxidoreductase; Parents; Physiological; Poison; Prevalence; Process; Production; Propylene Glycols; Proteomics; Public Health; Reaction; Regulation; Research; Rewards; Risk Assessment; Running; Saline; Science; Sodium Chloride; Solvents; Surveys; System; Teenagers; Testing; Tetrazolium; Tissues; Tobacco; Toxic effect; Toxicology; Volatile Oils; Work; aerosolized; base; biological adaptation to stress; cancer risk; design; e-cigarette aerosols; electronic cigarette user; electronic liquid; interest; liquid chromatography mass spectrometry; liquid formulation; nornicotine; pulegone; respiratory; social media; three dimensional cell culture; tobacco flavor; tobacco products; toxicant; vaping; young adult

Continuing change in both electronic cigarette (EC) aerosolization device design and the chemistry of the e- liquids that are vaped has complicated regulation as well as promoted use prevalence at all ages. Our chemi- cal / toxicological studies have focused on the e-liquids. The major changes that have occurred during the last five years in e-liquid chemistry include the use of many emerging ingredients (EIs). These include: a) non- confectionary cooling agents (e.g., the Wilkinson Sword “WS” chemicals originally developed for use in shaving creams); b) acids to protonate free-base nicotine to allow high nicotine products that are not harsh upon inhala- tion (e.g., JUULTM); c) synthetic nicotine rather than tobacco nicotine (as inspired by manufacturer hopes of evading U.S. regulation as “tobacco products”), and 4) sweet and fruity flavor chemicals (as stealth ingredients in non-regulated “tobacco”-flavored products). Ingredient changes are occurring quickly and constantly. There is an urgent need for work that tracks these changes and determines their toxicological implications. In Aim 1, 600 commercial products will be analyzed in a broad market survey to determine: a) the flavor chemicals on our target analyte list (183 compounds, including four worrisome EI chemicals in the WS class) plus any EIs at >20 g/mL; b) both the S and R nicotine forms plus three other tobacco alkaloids (e.g., nornicotine, which is a precursor for the potent carcinogen NNN) as indicators of use of natural / synthetic nicotine; and c) acid addi- tives. The data will be organized within the UCR /PSU Electronic Cigarette Data Collection. In Aim 2, we will investigate the potency and biological effects of both pure EIs (e.g., the WS compounds and acids) as well as worrisome flavor mixtures (e.g., EIs in combination with flavor chemicals, solvents, and nicotine). This first tox- icology effort will be carried out without heating. Aerosols will be generated in a cloud chamber using fluids containing physiological saline plus an individual ingredient chemical or a chemical mixture of concern. Expo- sures will be at the air/liquid interface (ALI) using “3D EpiAirway” tissue. Toxic effects will be identified using proteomic tissue analyses and confirmed using relevant mode-of action assays (e.g., inflammatory and oxida- tive stress responses). Margin of exposure (MOE) analyses will be carried out for each chemical tested to flag health effects including cancer risk. For Aim 3, we will carry out the second toxicology effort, repeating the work of Aim 2 but with heating using relevant EC heat levels during aerosol production. Commercial e-liquid products will also be tested. All exposures will be done at the ALI using a Cultex system and 3D EpiAirway tissue. Overall, the study will reveal the toxicity implications of new ingredient chemicals in the highly variable / changing EC marketplace. The results will reveal if the EC levels of these chemicals are toxic in 3D cultures of human respiratory tissues and how these tissues respond to exposure. Risk assessment analyses will identify the ingredient chemicals of greatest public health concern. The work on R nicotine will inform the field regard- ing the prevalence and possible toxicological implications of this non-tobacco form of nicotine in EC products.

电子烟(EC)雾化装置设计和电子烟化学成分的持续变化 被蒸发的液体有复杂的监管，并促进了所有年龄段的使用普及率。我们的化学- CAL/毒理学研究的重点是电子液体。过去一年中发生的主要变化 五年的电子液体化学包括许多新兴成分的使用(EIS)。这些措施包括：a)非 糖果冷却剂(例如，最初开发用于剃须的Wilkinson Sword“WS”化学品 奶油)；b)酸以质子化游离基尼古丁，以允许高尼古丁产品，对吸入不刺激性- (C)合成尼古丁，而不是烟草尼古丁(受制造商希望的 逃避美国监管的“烟草产品”)，以及4)甜味和水果味的化学物质(隐形成分 在不受管制的“烟草”调味产品中)。成分的变化正在迅速而持续地发生。那里 迫切需要跟踪这些变化并确定其毒理学影响的工作。在目标1中， 600种商业产品将在广泛的市场调查中进行分析，以确定：a) 我们的目标分析物列表(183种化合物，包括四种令人担忧的WS类EI化学物质)加上任何EIS &gt；20g/mL；b)S和R尼古丁均与其他三种烟草生物碱形成(如去甲尼古丁，它是一种 强致癌物质NNN的前体)作为使用天然/合成尼古丁的指示物；以及c)酸添加- 当然。这些数据将在UCR/PSU电子烟数据收集中进行组织。在目标2中，我们将 研究纯EIS(如WS化合物和酸)的效力和生物学效应 令人担忧的风味混合物(例如，EIS与风味化学品、溶剂和尼古丁相结合)。这是第一次毒检- 生物研究工作将在没有供暖的情况下进行。气溶胶将在云室中使用流体产生 含有生理盐水，外加一种单独的化学成分或化学混合物。世博会- Sure将使用“3D EpiAirway”纸巾在空气/液体界面(ALI)。毒性影响将使用以下方法确定 蛋白质组组织分析，并使用相关的作用模式分析(例如，炎症和氧化- 主动应激反应)。将对每一种被测试的化学品进行暴露边际(MOE)分析 对健康的影响，包括癌症风险。对于目标3，我们将进行第二次毒理学努力，重复 目标2的工作，但在气雾剂生产过程中使用相关的EC热量水平进行加热。商用电子液体 产品也将接受测试。所有曝光都将在ALI使用cultex系统和3D EpiAirway进行 组织。总体而言，这项研究将揭示新成分化学品在高度可变的/ 改变电子商务市场。结果将揭示这些化学物质的EC水平在3D培养中是否有毒 人类呼吸道组织以及这些组织对暴露的反应。风险评估分析将确定 最受公众健康关注的配料化学品。关于R尼古丁的工作将向现场提供关于- 调查这种非烟草形式的尼古丁在EC产品中的流行率和可能的毒理学影响。