Evaluation of the Tobacco Heating System 2.2. Part 6: 90-day OECD 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects of a mentholated version compared with mentholated and non-mentholated cigarette smoke.
The toxicity of a mentholated version of the Tobacco Heating System (THS2.2M), a candidate modified risk tobacco product (MRTP), was characterized in a 90-day OECD inhalation study. Differential gene and protein expression analysis of nasal epithelium and lung tissue was also performed to record exposure effects at the molecular level. Rats were exposed to filtered air (sham), to THS2.2M (at 15, 23 and 50 μg nicotine/l), to two mentholated reference cigarettes (MRC) (at 23 μg nicotine/l), or to the 3R4F reference cigarette (at 23 μg nicotine/l). MRCs were designed to meet 3R4F specifications. Test atmosphere analyses demonstrated that aldehydes were reduced by 75%-90% and carbon monoxide by 98% in THS2.2M aerosol compared with MRC smoke; aerosol uptake was confirmed by carboxyhemoglobin and menthol concentrations in blood, and by the quantities of urinary nicotine metabolites. Systemic toxicity and alterations in the respiratory tract were significantly lower in THS2.2M-exposed rats compared with MRC and 3R4F. Pulmonary inflammation and the magnitude of the changes in gene and protein expression were also dramatically lower after THS2.2M exposure compared with MRCs and 3R4F. No menthol-related effects were observed after MRC mainstream smoke-exposure compared with 3R4F.
Philip Morris International Research Laboratories Pte Ltd, 50 Science Park Road #02-07, The Kendall, Science Park II, Singapore 117406, Singapore(2).
Alberto
A
Oviedo
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2).
Stefan
S
Lebrun
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2).
Ulrike
U
Kogel
Philip Morris International Research Laboratories Pte Ltd, 50 Science Park Road #02-07, The Kendall, Science Park II, Singapore 117406, Singapore(2).
Jenny
J
Ho
Philip Morris International Research Laboratories Pte Ltd, 50 Science Park Road #02-07, The Kendall, Science Park II, Singapore 117406, Singapore(2).
Wei Teck
WT
Tan
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2).
Bjoern
B
Titz
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2).
Patrice
P
Leroy
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2).
Gregory
G
Vuillaume
Former employee of Philip Morris International R&D, Switzerland.
Monali
M
Bera
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2).
Florian
F
Martin
Former employee of Philip Morris International R&D, Switzerland.
Gregory
G
Rodrigo
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2).
Marco
M
Esposito
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2).
Ruth
R
Dempsey
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2).
Nikolai V
NV
Ivanov
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2).
Julia
J
Hoeng
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2).
Manuel C
MC
Peitsch
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland(2). Electronic address: Patrick.vanscheeuwijck@pmi.com.
Patrick
P
Vanscheeuwijck
D000336:Aerosols; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D019295:Computational Biology; 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; D023281:Genomics; D040261:Harm Reduction; D006358:Hot Temperature; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008610:Menthol / Q000032:analysis / Q000633:toxicity*; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D012906:Smoke / Q000009:adverse effects* / Q000032:analysis; D012907:Smoking / Q000009:adverse effects* / Q000097:blood / Q000235:genetics / Q000652:urine; 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; D015415:Biomarkers; D005819:Genetic Markers; D012906:Smoke; D008610:Menthol
Heat-not-burn; Inhalation; Menthol; Potential reduced risk product; Pulmonary inflammation; Toxicity