title: Evaluation of the Tobacco Heating System 2.2. Part 4: 90-day OECD 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects compared with cigarette smoke.
abstract: The objective of the study was to characterize the toxicity from sub-chronic inhalation of test atmospheres from the candidate modified risk tobacco product (MRTP), Tobacco Heating System version 2.2 (THS2.2), and to compare it with that of the 3R4F reference cigarette. A 90-day nose-only inhalation study on Sprague-Dawley rats was performed, combining classical and systems toxicology approaches. Reduction in respiratory minute volume, degree of lung inflammation, and histopathological findings in the respiratory tract organs were significantly less pronounced in THS2.2-exposed groups compared with 3R4F-exposed groups. Transcriptomics data obtained from nasal epithelium and lung parenchyma showed concentration-dependent differential gene expression following 3R4F exposure that was less pronounced in the THS2.2-exposed groups. Molecular network analysis showed that inflammatory processes were the most affected by 3R4F, while the extent of THS2.2 impact was much lower. Most other toxicological endpoints evaluated did not show exposure-related effects. Where findings were observed, the effects were similar in 3R4F- and THS2.2-exposed animals. In summary, toxicological changes observed in the respiratory tract organs of THS2.2 aerosol-exposed rats were much less pronounced than in 3R4F-exposed rats while other toxicological endpoints either showed no exposure-related effects or were comparable to what was observed in the 3R4F-exposed rats.
authors: Philip Morris International Research Laboratories Pte Ltd, 50 Science Park Road, The Kendall #02-07 Science Park II, 117406, Singapore(1).
authors: Ee Tsin
authors: ET
authors: Wong
authors: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland(1).
authors: Ulrike
authors: U
authors: Kogel
authors: Philip Morris International Research Laboratories Pte Ltd, 50 Science Park Road, The Kendall #02-07 Science Park II, 117406, Singapore(1).
authors: Emilija
authors: E
authors: Veljkovic
authors: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland(1).
authors: Florian
authors: F
authors: Martin
authors: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland(1).
authors: Yang
authors: Y
authors: Xiang
authors: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland(1).
authors: Stephanie
authors: S
authors: Boue
authors: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland(1).
authors: Gregory
authors: G
authors: Vuillaume
authors: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland(1).
authors: Patrice
authors: P
authors: Leroy
authors: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland(1).
authors: Emmanuel
authors: E
authors: Guedj
authors: Former employee of Philip Morris International R&D, Philip Morris Products S.A., Switzerland.
authors: Gregory
authors: G
authors: Rodrigo
authors: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland(1).
authors: Nikolai V
authors: NV
authors: Ivanov
authors: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland(1).
authors: Julia
authors: J
authors: Hoeng
authors: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland(1).
authors: Manuel C
authors: MC
authors: Peitsch
authors: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland(1). Electronic address: Patrick.Vanscheeuwijck@pmi.com.
authors: Patrick
authors: P
authors: Vanscheeuwijck
mesh_terms: D000336:Aerosols; D000818:Animals; D019295:Computational Biology; D003257:Consumer Product Safety; D066300:Electronic Nicotine Delivery Systems / Q000009:adverse effects*; D004867:Equipment Design; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics; D040261:Harm Reduction; D006358:Hot Temperature; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects; D008297:Male; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D017207:Rats, Sprague-Dawley; D012137:Respiratory System / Q000187:drug effects / Q000503:physiopathology; D018570:Risk Assessment; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics; D049490:Systems Biology; D013997:Time Factors; D019460:Tobacco Industry; D062789:Tobacco Products / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000336:Aerosols; D012906:Smoke
keywords: Heat-not-burn; Inhalation systems toxicology; Inhalation toxicology study; Modified risk tobacco product; Pulmonary inflammation