Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
Arch Toxicol. 2019 Nov;93(11):3229-3247. doi: 10.1007/s00204-019-02565-9. Epub 2019 Sep 7.
We previously proposed a systems toxicology framework for in vitro assessment of e-liquids. The framework starts with the first layer aimed at screening the potential toxicity of e-liquids, followed by the second layer aimed at investigating the toxicity-related mechanism of e-liquids, and finally, the third layer aimed at evaluating the toxicity-related mechanism of the corresponding aerosols. In this work, we applied this framework to assess the impact of the e-liquid MESH Classic Tobacco and its aerosol compared with that of cigarette smoke (CS) from the 3R4F reference cigarette. In the first layer, we evaluated the cytotoxicity profile of the MESH Classic Tobacco e-liquid (containing humectants, nicotine, and flavors) and its Base e-liquid (containing humectant and nicotine only) in comparison with total particulate matter (TPM) of 3R4F CS using primary bronchial epithelial cell cultures. In the second layer, the same culture model was used to explore changes in specific markers using high-content screening assays to identify potential toxicity-related mechanisms induced by the MESH Classic Tobacco and Base e-liquids beyond cell viability in comparison with the 3R4F CS TPM-induced effects. Finally, in the third layer, we compared the impact of exposure to the MESH Classic Tobacco or Base aerosols with 3R4F CS using human organotypic air-liquid interface buccal and small airway epithelial cultures. The results showed that the cytotoxicity of the MESH Classic Tobacco liquid was similar to the Base liquid but lower than 3R4F CS TPM at comparable nicotine concentrations. Relative to 3R4F CS exposure, MESH Classic Tobacco aerosol exposure did not cause tissue damage and elicited lower changes in the mRNA, microRNA, and protein markers. In the context of tobacco harm reduction strategy, the framework is suitable to assess the potential-reduced impact of electronic cigarette aerosol relative to CS.
我们之前提出了一个用于体外评估电子烟液的系统毒理学框架。该框架从第一层开始，旨在筛选电子烟液的潜在毒性，然后进入第二层，旨在研究电子烟液的毒性相关机制，最后进入第三层，旨在评估相应气溶胶的毒性相关机制。在这项工作中，我们应用该框架评估了电子烟液 MESH Classic Tobacco 及其气溶胶与 3R4F 参考香烟 CS 的影响。在第一层，我们使用原代支气管上皮细胞培养物，评估了 MESH Classic Tobacco 电子烟液（含有保湿剂、尼古丁和香料）及其 Base 电子烟液（仅含有保湿剂和尼古丁）与 3R4F CS 的总颗粒物（TPM）的细胞毒性谱。在第二层，使用相同的培养模型，使用高内涵筛选测定法探索特定标志物的变化，以鉴定 MESH Classic Tobacco 和 Base 电子烟液除细胞活力之外，诱导的潜在毒性相关机制与 3R4F CS TPM 诱导的效应相比。最后，在第三层，我们使用人器官型气液界面颊和小气道上皮培养物，比较暴露于 MESH Classic Tobacco 或 Base 气溶胶与 3R4F CS 的影响。结果表明，MESH Classic Tobacco 液体的细胞毒性与 Base 液体相似，但在可比尼古丁浓度下低于 3R4F CS TPM。与 3R4F CS 暴露相比，MESH Classic Tobacco 气溶胶暴露不会引起组织损伤，并引起 mRNA、microRNA 和蛋白质标志物的变化较小。在减少烟草危害的策略背景下，该框架适用于评估电子烟气溶胶相对于 CS 的潜在降低影响。
