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.
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.
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2).
Ulrike
U
Kogel
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2).
Bjoern
B
Titz
Biology consultant, Max-Baermann-Str. 21, 51429 Bergisch Gladbach, Germany.
Walter K
WK
Schlage
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2).
Catherine
C
Nury
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2).
Florian
F
Martin
Philip Morris International Research Laboratories, 50 Science Park Road, Singapore, Singapore(2).
Alberto
A
Oviedo
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2).
Stefan
S
Lebrun
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2).
Ashraf
A
Elamin
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2).
Emmanuel
E
Guedj
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2).
Keyur
K
Trivedi
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2).
Nikolai V
NV
Ivanov
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2).
Patrick
P
Vanscheeuwijck
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2).
Manuel C
MC
Peitsch
Philip Morris International Research and Development, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland(2). Electronic address: julia.hoeng@pmi.com.
Julia
J
Hoeng
D000336:Aerosols; D000818:Animals; D003257:Consumer Product Safety; D004305:Dose-Response Relationship, Drug; D066300:Electronic Nicotine Delivery Systems / Q000009:adverse effects*; D004867:Equipment Design; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005819:Genetic Markers; D040261:Harm Reduction; D006358:Hot Temperature; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008610:Menthol / Q000032:analysis / Q000633:toxicity*; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D040901:Proteomics; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D012906:Smoke / Q000009:adverse effects* / Q000032:analysis; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics; D049490:Systems Biology; D013997:Time Factors; D019460:Tobacco Industry; D062789:Tobacco Products / Q000032:analysis / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*; D043922:Toxicogenetics; D059467:Transcriptome / Q000187:drug effects
D000336:Aerosols; D005819:Genetic Markers; D012906:Smoke; D008610:Menthol
Lipidomics; Modified risk tobacco product; Proteomics; Subchronic inhalation toxicity; Systems toxicology; Transcriptomics