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

 描述(由申请人提供)：我们对癌症发生的分子机制及其关系的理解使我们能够创建一套预测工具，可以应用于一系列现有的和新的烟草产品，以告知癌症风险。这些工具在短期分析中是准确的，适用于癌症的人类祖细胞，并概括了原发癌症中可能需要数十年才能发展起来的变化。这类分析的量化结果对于制定监管政策和传达相对风险应该非常有用。我们利用具有代谢能力的永生化人支气管上皮细胞建立了一种体外癌前病变模型，现在将扩展到三种口腔上皮细胞系，以测试电子暴露的急性和慢性影响。 香烟(E-cig)含有尼古丁和常见香料化学物质的气雾剂。电子烟行业正处于一个重要的发展时期，发布了100多种输送设备，为用户提供了调整气雾剂产生电压的机会，并通过&gt；7764种独特的“风味化学品”菜单定制他们的尼古丁解决方案。这些风味化学物质大多是糖果性质的，食品级的，当用作食品成分时通常被认为是安全的。然而，香料在加热或燃烧后吸入时的毒理学效应以及它们如何影响尼古丁释放出的成分(如NNK、甲醛)的沉积特征尚不清楚。例如，双乙酰和乙酰丙酰在吸入时与呼吸系统疾病有关，在159种测试调味品中发现了74%，并且很容易在产生的气雾剂中检测到超过消费者安全的水平。将研究在低电压和高电压下产生的标准尼古丁溶液和不添加标准尼古丁溶液的12种主要风味化学品，以全面评估这些复杂混合物产生的气雾剂对口腔上皮细胞的毒理学影响。将描述不同尼古丁风味化学混合物产生的气溶胶的毒理成分，电压增加对气溶胶成分的影响，以及这些变量如何影响口腔-气管内的沉积情况。通过将这些口腔上皮细胞系急性和长期暴露在不同的E-CIG气雾剂中，获得敏感的读数，以告知与这些E-CIG产品的细胞毒性、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风险模型的开发，该模型将E-CIG气雾剂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。

 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.