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不断变化 电子烟液体的监管复杂，并且促进了所有年龄段的使用流行。我们的化学- 校准/毒理学研究主要集中在电子液体上。过去一段时间发生的主要变化 在电子烟液化学领域的五年时间包括使用许多新兴成分 (EI)。其中包括：a) 非 糖果凉味剂（例如，最初开发用于剃须的威尔金森剑“WS”化学品 面霜）； b) 酸质子化游离碱尼古丁，以产生吸入时不刺激的高尼古丁产品 化（例如，JUULTM）； c) 合成尼古丁而不是烟草尼古丁（受制造商希望的启发 作为“烟草产品”逃避美国监管），以及 4) 甜味和果味化学品（作为隐形成分） 在不受管制的“烟草”口味产品中）。成分的变化正在快速且持续地发生。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， 将在广泛的市场调查中对 600 种商业产品进行分析，以确定：a) 我们的目标分析物列表（183 种化合物，包括 WS 类中的四种令人担忧的 EI 化学品）以及任何 EI >20μg/mL； b) S 和 R 尼古丁形式以及其他三种烟草生物碱（例如，降尼古丁，它是一种 强致癌物NNN的前体）作为使用天然/合成尼古丁的指标； c) 酸添加物 提夫。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 EI（例如 WS 化合物和酸）以及 令人担忧的香料混合物（例如，EI 与香料化学品、溶剂和尼古丁的组合）。这第一个毒物—— 生态学工作将在没有加热的情况下进行。将使用流体在云室中产生气溶胶 含有生理盐水加上单一化学成分或相关化学混合物。世博会- 确定将使用“3D EpiAirway”组织在空气/液体界面（ALI）处。毒性作用将通过以下方式确定： 蛋白质组组织分析并使用相关的作用模式测定（例如炎症和氧化）进行确认 积极的应激反应）。将对每种经过测试的化学物质进行暴露裕度 (MOE) 分析，以标记 健康影响，包括癌症风险。对于目标 3，我们将进行第二次毒理学工作，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。商用电子烟油 产品也将接受测试。所有曝光将在 ALI 上使用 Cultex 系统和 3D EpiAirway 完成 组织。总体而言，该研究将揭示新成分化学品在高度可变/ 不断变化的 EC 市场。结果将揭示这些化学物质的 EC 水平在 3D 培养物中是否有毒。 人类呼吸组织以及这些组织如何对暴露做出反应。风险评估分析将确定 最受公共卫生关注的化学成分。 R 尼古丁的研究将为该领域提供信息—— 调查 EC 产品中这种非烟草形式的尼古丁的流行程度和可能的毒理学影响。