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的化学性质的持续变化， 被汽化的液体具有复杂的监管以及促进所有年龄段的使用流行。我们的化学- CAL /毒理学研究集中在电子液体上。在过去一年中发生的重大变化 五年的电子液体化学包括使用许多新兴成分（EI）。其中包括：（a）非 预防性冷却剂（例如，最初开发用于剃须的威尔金森剑“WS”化学品 霜剂）; B）酸，以质子化游离碱尼古丁，从而允许高尼古丁产品在吸入时不刺激， 动作（例如，JUULTM）; c）合成尼古丁而不是烟草尼古丁（如受制造商希望 逃避美国的“烟草产品”监管），以及4）甜味和果味香料化学品（作为隐形成分 在不受管制的“烟草”味产品中）。各种各样的变化正在迅速而持续地发生。那里 是一个迫切需要的工作，跟踪这些变化，并确定其毒理学影响。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WS类中四种令人担忧的EI化学品）以及 >20 μ g/mL; B）S和R烟碱形式加上三种其它烟草生物碱（例如，去甲烟碱， 强致癌物NNN的前体）作为使用天然/合成尼古丁的指标;以及c）酸添加剂 提维斯这些数据将在UCR /PSU电子烟数据收集中进行组织。在目标2中，我们将 研究两种纯EI的效力和生物学效应（例如，WS化合物和酸）以及 令人担忧的风味混合物（例如，EI与香料化学品、溶剂和尼古丁的组合）。第一次毒检 将在不加热的情况下进行冰学研究。气溶胶将在云室中使用流体产生 含有生理盐水加上所关注的单个成分化学品或化学混合物。展会- 将使用“3D EpiAirway”组织在空气/液体界面（ALI）处确保。毒性作用将使用 蛋白质组组织分析并使用相关作用模式测定法（例如，炎症和氧化- 积极的压力反应）。将对每种受试化学品进行暴露裕度（莫伊）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，但在气溶胶生产过程中使用相关的EC热量水平进行加热。商用电子烟液 产品也将进行测试。所有暴露将在ALI使用Cultex系统和3D EpiAirway进行 组织.总的来说，这项研究将揭示新成分化学品在高度可变/ 改变电子商务市场。结果将揭示这些化学物质的EC水平是否在3D培养物中有毒。 人体呼吸道组织以及这些组织对接触的反应。风险评估分析将确定 最大的公共健康问题的化学成分。关于R尼古丁的工作将为该领域提供信息- 研究这种非烟草形式的尼古丁在欧盟产品中的普遍性和可能的毒理学影响。