title: In Vitro Systems Toxicology Assessment of a Candidate Modified Risk Tobacco Product Shows Reduced Toxicity Compared to That of a Conventional Cigarette.
abstract: Cigarette smoke increases the risk for respiratory and other diseases. Although smoking prevalence has declined over the years, millions of adults choose to continue to smoke. Modified risk tobacco products (MRTPs) are potentially valuable tools for adult smokers that are unwilling to quit their habit. Here, we investigated the biological impact of a candidate MRTP, the tobacco-heating system (THS) 2.2, compared to that of the 3R4F reference cigarette in normal primary human bronchial epithelial cells. Chemical characterization of the THS 2.2 aerosol showed reduced levels of harmful constituents compared to those of a combustible cigarette. Multiparametric indicators of cellular toxicity were measured via real-time cellular analysis and high-content screening. The study was complemented by a whole transcriptome analysis, followed by computational approaches to identify and quantify perturbed molecular pathways. Exposure of cells to 3R4F cigarette smoke resulted in a dose-dependent response in most toxicity end points. Moreover, we found a significant level of perturbation in multiple biological pathways, particularly in those related to cellular stress. By contrast, exposure to THS 2.2 resulted in an overall lower biological impact. At 3R4F doses, no toxic effects were observed. A toxic response was observed for THS 2.2 in some functional end points, but the responses occurred at doses between 3 and 15 times higher than those of 3R4F. The level of biological network perturbation was also significantly reduced following THS 2.2 aerosol exposure compared to that of 3R4F cigarette smoke. Taken together, the data suggest that THS 2.2 aerosol is less toxic than combustible cigarette smoke and thus may have the potential to reduce the risk for smoke-related diseases.
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gonzalez-Suarez
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Diego
authors.initials: D
authors.lastname: Marescotti
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guedj
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Acali
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Johne
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Remi
authors.initials: R
authors.lastname: Dulize
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Karine
authors.initials: K
authors.lastname: Baumer
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Peric
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Goedertier
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frentzel
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Ivanov
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Mathis
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
mesh_terms: D000336:Aerosols / Q000737:chemistry; D001980:Bronchi / Q000166:cytology / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D012307:Risk Factors; D012906:Smoke / Q000009:adverse effects*; D062789:Tobacco Products / Q000633:toxicity*
chemical_list: D000336:Aerosols; D012906:Smoke