In Vitro Systems Toxicology Assessment of a Candidate Modified Risk Tobacco Product Shows Reduced Toxicity Compared to a Conventional Cigarette


Published By  I Gonzalez-Suarez, F Martin, D Marescotti, E Guedj, S Acali, S Johne, R Dulize, K Baumer, D Peric, D Goedertier, S Frentzel, NV Ivanov, C Mathis, J Hoeng, M Peitsch

Published in Chemical Research in Toxicology¬†    

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 the 3R4F reference cigarette in normal primary human bronchial epithelial cells. Chemical characterization of THS 2.2 aerosol showed reduced levels of harmful constituents compared to 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 a 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 endpoints. 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 endpoints, but the responses occurred at doses between three and fifteen times higher than those of 3R4F. The level of biological network perturbation was also significantly reduced following THS 2.2 aerosol exposure compared to 3R4F cigarette smoke. Taken together, the data suggest that THS 2.2 aerosol is less toxic than a combustible cigarette smoke and thus, may have the potential to reduce the risk for smoke-related diseases.