Deposition Profile and Toxicology of E-Cigarettes in the Oral Epithelium

电子烟在口腔上皮细胞中的沉积概况和毒理学

• 批准号: 9117092
• 负责人: Steven A Belinsky
• 金额: $ 54.5万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117092
• 关键词: Acids; Acute; Aerosols; Affect; Agar; Alcohols; Alkanes; Biological; Biological Assay; Biological Models; Breathing; Burn injury; Cataloging; Catalogs; Cell Line; Cells; Chemicals; Chronic; Cigarette; Comet Assay; Complex; Complex Mixtures; DNA Adducts; DNA Damage; Deoxyguanosine; Deposition; Development; Devices; Diacetyl; Dose; Electronic cigarette; Epigenetic Process; Epithelial Cells; Evolution; Exposure to; Flavoring; Food; Formaldehyde; Gases; Gene Chips; Gene Expression; Generations; Genes; Glycerol; Growth; Heating; Homeostasis; Human; In Vitro; Industry; Link; Long-Term Effects; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Metals; Methods; Methylation; MicroRNAs; Minor; Modeling; Molecular; Mutation; Nature; Nicotine; Nude Mice; Oral; Oral cavity; Particle Size; Physiological; Poison; Policies; Population; Premalignant; Property; Propylene Glycols; Protocols documentation; Reactive Oxygen Species; Relative Risks; Research; Respiratory System; Respiratory tract structure; Risk; Risk Assessment; Safety; Statistical Models; Stem cells; System; Techniques; Testing; The Cancer Genome Atlas; Tobacco; Tobacco-Associated Carcinogen; Toxic effect; Toxicant exposure; Toxicology; Trachea; Trees; Xenograft procedure; cancer risk; cell motility; cytotoxic; cytotoxicity; gene induction; genotoxicity; in vitro Model; insight; malignant mouth neoplasm; meetings; micronucleus; oral cavity epithelium; particle; predictive tools; public health relevance; response; tobacco carcinogenesis; tool; tumorigenic; voltage

 DESCRIPTION (provided by applicant): Our understanding of the molecular mechanisms and their relationship to the development of cancer has enabled the creation of a set of predictive tools that can be applied across a range of existing and new tobacco products to inform risk for cancer. These tools are accurate in short-term assays, applicable to human progenitor cells for cancer, and recapitulate changes seen in primary cancer that can take decades to develop. Quantitative results from such assays should be highly useful for establishing regulatory policies and communicating relative risk. We have developed an in vitro pre-malignancy model using metabolically competent immortalized human bronchial epithelial cells that will now be extended to three oral epithelial cell lines to test the acute and chronic effects of exposure to electronic cigarette (E-cig) aerosols containing nicotine and common classes of flavor chemicals. The E-cig industry is in a major period of evolution with the release of more than one hundred delivery devices that afford the user the opportunity to adjust the voltage for aerosol generation and to customize their nicotine solution with a menu of >7764 unique "flavor chemicals". Most of these flavor chemicals are confectionary in nature, food grade, and generally recognized as safe when used as food constituents. However, the toxicological effects of flavors when inhaled after heating or burning and how they may influence the deposition profile of the components released from nicotine (e.g., NNK, formaldehyde) are unknown. For example, diacetyl and acetyl propionyl are associated with respiratory disease when inhaled, found in 74% of 159 tested flavorings, and readily detected in the generated aerosols at levels that exceed consumer safety. The 12 major classes of flavor chemicals with and without the addition of a standard nicotine solution generated at a low and high voltage will be studied to provide a comprehensive assessment of the toxicological effects of the aerosols generated from these complex mixtures on the oral epithelial cell. The aerosols generated from the different nicotine-flavor chemical mixtures with respect to toxicological components, the effect of increased voltage on aerosol composition, and how these variables impact the deposition profile within the oral-tracheal tract will be characterized. A sensitive readout will be obtained by acute and chronic in vitro exposure of these oral epithelial cell lines to the different E-cig aerosols to inform many aspects related o the cytotoxic, genotoxic, and carcinogenic potential of these E-cig products. The compilation of these findings will support development of a risk model that links chemical constituents within the E-cig aerosol to the detrimental biological effects observed in the in vitro studies.

 描述（由适用提供）：我们对分子机制及其与癌症发展的关系的理解使创建了一系列预测工具，这些工具可以应用于一系列现有和新的烟草产品，以告知癌症风险。这些工具在短期测定中是准确的，适用于人类祖细胞的癌症，并概括了在原发性癌症中看到的变化，这可能需要数十年的发展。此类测定法的定量结果对于建立监管政策和交流相对风险应该非常有用。我们已经使用代谢有效的永生化人支气管上皮细胞开发了一种体外恶性模型，该模型现在将扩展到三个口腔上皮细胞系，以测试暴露于电子的急性和慢性效应 香烟（E-cig）气溶胶，含有尼古丁和常见的风味化学物质。 E-Cig行业正处于一个重大的发展时期，其中发布了一百多个送货设备，这些设备使用户有机会调整气溶胶生成电压，并使用> 7764> 7764独特的“风味化学品”的菜单自定义其尼古丁解决方案。这些风味化学物质中的大多数本质上是糖果，食品等级，当用作食物构成时通常被认为是安全的。然而，在加热或燃烧后遗传的口味的毒理学作用以及它们如何影响从尼古丁释放的成分（例如NNK，甲醛）的沉积曲线是未知的。例如，二乙酰基和乙酰基丙酰遗传后与呼吸道疾病有关，在159种测试调味料中的74％中发现，并且在产生的气溶胶中很容易检测到超过消费者安全的水平。 12个主要类别的风味化学品，有或不添加在低压和高压下产生的标准尼古丁溶液，以提供对这些复杂混合物在口腔上皮细胞上产生的气溶胶的毒理学作用的全面评估。相对于毒理学成分，由不同的尼古丁味的化学混合物产生的气溶胶，电压增加对气溶胶组成的影响以及这些变量如何影响口腔 - 流动区内的沉积曲线。这些口腔上皮细胞系在不同的E-cig气溶胶中急性和慢性体外暴露将获得敏感的读数，以告知与这些E-CIG产物的细胞毒性，遗传毒性和致癌潜力相关的许多方面。这些发现的汇编将支持开发一种风险模型，该风险模型将E-CIG气溶胶中的化学构成与体外研究中观察到的有害生物学效应联系起来。