A lower impact of an acute exposure to electronic cigarette aerosols than to cigarette smoke in human organotypic buccal and small airway cultures was demonstrated using systems toxicology assessment

March 5, 2019

Filippo Zanetti1, Athanasios Kondylis1, Florian Martin1, Patrice Leroy1, Shoaib Majeed1, Sandro Steiner1, Yang Xiang1, Laura Ortega Torres1, Keyur Trivedi1, Emmanuel Guedj1, Celine Merg1, Stefan Frentzel1, Nikolai V. Ivanov1, Utkarsh Doshi2, Kyeonghee Monica Lee2, Willie J. McKinneyJr2, Manuel C. Peitsch1, Julia Hoeng1

1 Philip Morris International R&D, Philip Morris Products S.A.NeuchâtelSwitzerland
2 Altria Client Services LLCRichmondUSA

Human organotypic buccal and small airway cultures were exposed in two independent exposure systems (Vitrocell® 24/48), one for 3R4F reference cigarette smoke and the other for e-cigarette aerosol exposures to summarize the exposure-induced impacts into four main cellular processes: the cell fate, cell proliferation, cell stress, and inflammatory process.


In the context of tobacco harm-reduction strategy, the potential reduced impact of electronic cigarette (EC) exposure should be evaluated relative to the impact of cigarette smoke exposure. We conducted a series of in vitro studies to compare the biological impact of an acute exposure to aerosols of “test mix” (flavors, nicotine, and humectants), “base” (nicotine and humectants), and “carrier” (humectants) formulations using MarkTen® EC devices with the impact of exposure to smoke of 3R4F reference cigarettes, at a matching puff number, using human organotypic air–liquid interface buccal and small airway cultures. We measured the concentrations of nicotine and carbonyls deposited in the exposure chamber after each exposure experiment. The deposited carbonyl concentrations were used as representative measures to assess the reduced exposure to potentially toxic volatile substances. We followed a systems toxicology approach whereby functional biological endpoints, such as histopathology and ciliary beating frequency, were complemented by multiplex and omics assays to measure secreted inflammatory proteins and whole-genome transcriptomes, respectively. Among the endpoints analyzed, the only parameters that showed a significant response to EC exposure were secretion of proteins and whole-genome transcriptomes. Based on the multiplex and omics analyzes, the cellular responses to EC aerosol exposure were tissue type-specific; however, those alterations were much smaller than those following cigarette smoke exposure, even when the EC aerosol exposure under the testing conditions resulted in a deposited nicotine concentration approximately 200 times that in saliva of EC users.

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