Evaluation of the Tobacco Heating System 2.2. Part 7: Systems toxicological assessment of a mentholated version revealed reduced cellular and molecular exposure effects compared with mentholated and non-mentholated cigarette smoke

• Published in: Regulatory toxicology and pharmacology 2016-11, Vol.81, p.S123-S138
• Main Authors: Kogel, Ulrike, Titz, Bjoern, Schlage, Walter K., Nury, Catherine, Martin, Florian, Oviedo, Alberto, Lebrun, Stefan, Elamin, Ashraf, Guedj, Emmanuel, Trivedi, Keyur, Ivanov, Nikolai V., Vanscheeuwijck, Patrick, Peitsch, Manuel C., Hoeng, Julia
• Format: Article
• Language: English
• Subjects: Aerosols; Animals; Consumer Product Safety; Dose-Response Relationship, Drug; Electronic Nicotine Delivery Systems - adverse effects; Equipment Design; Female; Gene Expression Profiling; Gene Expression Regulation - drug effects; Genetic Markers; Harm Reduction; Hot Temperature; Humans; Inhalation Exposure - adverse effects; Lipidomics; Lung - drug effects; Lung - metabolism; Lung - pathology; Male; Menthol - analysis; Menthol - toxicity; Modified risk tobacco product; Nasal Mucosa - drug effects; Nasal Mucosa - metabolism; Nasal Mucosa - pathology; Pneumonia - chemically induced; Pneumonia - genetics; Pneumonia - pathology; Pneumonia - prevention & control; Proteomics; Rats, Sprague-Dawley; Risk Assessment; Smoke - adverse effects; Smoke - analysis; Smoking - adverse effects; Smoking - genetics; Subchronic inhalation toxicity; Systems Biology; Systems toxicology; Time Factors; Tobacco Industry; Tobacco Products - analysis; Tobacco Products - toxicity; Toxicity Tests - methods; Toxicogenetics; Transcriptome - drug effects; Transcriptomics
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2016.11.001

Modified risk tobacco products (MRTPs) are being developed with the aim of reducing smoking-related health risks. The Tobacco Heating System 2.2 (THS2.2) is a candidate MRTP that uses the heat-not-burn principle. Here, systems toxicology approaches were engaged to assess the respiratory effects of mentholated THS2.2 (THS2.2M) in a 90-day rat inhalation study (OECD test guideline 413). The standard endpoints were complemented by transcriptomics and quantitative proteomics analyses of respiratory nasal epithelium and lung tissue and by lipidomics analysis of lung tissue. The adaptive response of the respiratory nasal epithelium to conventional cigarette smoke (CS) included squamous cell metaplasia and an inflammatory response, with high correspondence between the molecular and histopathological results. In contrast to CS exposure, the adaptive tissue and molecular changes to THS2.2M aerosol exposure were much weaker and were limited mostly to the highest THS2.2M concentration in female rats. In the lung, CS exposure induced an inflammatory response, triggered cellular stress responses, and affected sphingolipid metabolism. These responses were not observed or were much lower after THS2.2M aerosol exposure. Overall, this system toxicology analysis complements and reconfirms the results from classical toxicological endpoints and further suggests potentially reduced health risks of THS2.2M. •Systems toxicology assessment of candidate modified risk tobacco product (THS2.2M).•Systems toxicology analyses were used to compare THS2.2M with a reference cigarette.•Assessment of exposure effects using proteomics, transcriptomics, and lipidomics.•Exposure showed lower effects of THS2.2M aerosol on rat nose and lung tissue.•Molecular insights on inflammation or cell stress complemented apical endpoints.