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（由申请人提供）：我们对分子机制及其与癌症发展的关系的理解使得能够创建一套预测工具，这些工具可以应用于一系列现有和新型烟草产品，以告知癌症风险。这些工具在短期检测中是准确的，适用于人类癌症祖细胞，并概括了原发性癌症中可能需要数十年才能形成的变化。此类测定的定量结果对于制定监管政策和传达相对风险非常有用。我们使用具有代谢能力的永生化人支气管上皮细胞开发了一种体外癌前模型，该模型现在将扩展到三种口腔上皮细胞系，以测试暴露于电子的急性和慢性影响 含有尼古丁和常见类别香料化学物质的香烟（电子烟）气雾剂。电子烟行业正处于一个重要的发展时期，发布了一百多种输送设备，这些设备使用户有机会调整气雾生成的电压，并通过超过 7764 种独特的“风味化学品”菜单定制尼古丁解决方案。大多数这些香料化学品本质上是糖果，食品级，并且在用作食品成分时通常被认为是安全的。然而，加热或燃烧后吸入香料的毒理学效应以及它们如何影响尼古丁释放的成分（例如 NNK、甲醛）的沉积曲线尚不清楚。例如，二乙酰和乙酰丙酰吸入后与呼吸道疾病有关，在 159 种测试调味品中，有 74% 都含有二乙酰和乙酰丙酰，并且在产生的气溶胶中很容易检测到，其含量超出了消费者的安全水平。将研究添加或不添加在低电压和高电压下产生的标准尼古丁溶液的 12 类主要风味化学品，以全面评估这些复杂混合物产生的气溶胶对口腔上皮细胞的毒理学影响。将对不同尼古丁味化学混合物产生的气溶胶的毒理学成分、电压升高对气溶胶成分的影响以及这些变量如何影响口腔气管道内的沉积曲线进行表征。通过将这些口腔上皮细胞系在体外急性和慢性暴露于不同的电子烟气溶胶，可以获得灵敏的读数，以了解与这些电子烟产品的细胞毒性、基因毒性和致癌潜力相关的许多方面。这些发现的汇编将支持风险模型的开发，该模型将电子烟气溶胶中的化学成分与体外研究中观察到的有害生物效应联系起来。