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Systems toxicological assessment of a mentholated heat-not-burn modified risk tobacco product in a 90-day OECD 413 rat inhalation study demonstrates reduced exposure effects and provides mechanistic insights

ABSTRACT: Toward the reduction of smoking-related health risks potential reduced risk products (pRRPs) are being developed. The Tobacco Heating System (THS) 2.2 is a recently developed pRRP, which relies on the heat-not-burn principle. We present results from the systems-toxicology arm of a 90-day Organization for Economic Co-operation and Development test guideline 413 inhalation study for the assessment of a mentholated version of THS2.2 (THS2.2M). Sprague-Dawley rats were nose-only exposed, 6?h/day, 5 days/week to filtered air, three concentrations of THS2.2M aerosol (15μg/l, 23μg/l, 50μg/l nicotine), cigarette smoke (CS) from the reference cigarette 3R4F (23μg/l nicotine), or CS from reference cigarettes with two different menthol concentrations (23μg/l nicotine; 1.2 and 2.4 mg menthol/cigarette). Reversibility of the exposure effects was assessed in a subset of the groups following 42 days of filtered air exposure. Standard toxicology endpoints were complemented by transcriptomics and quantitative proteomics analyses of nasal epithelium and lung tissue and by lipidomics analysis of lung tissue. The adaptive response of the nasal epithelium to CS exposure 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 reduced and mostly limited to the highest THS2.2M concentration in female rats. In the lung, CS exposure induced an inflammatory response, triggered cellular stress responses (e.g., oxidative stress and xenobiotic metabolism), and affected sphingolipid metabolism. These responses were not observed or much lower upon THS2.2M aerosol exposure. All in all, this system toxicology analysis complements and reconfirms the classical toxicological endpoints and further suggests a potentially reduced risk of THS2.2M.

INSTRUMENT(S): Affymetrix GeneChip Scanner 3000 7G

ORGANISM(S): Rattus norvegicus  

SUBMITTER: Kogel Ulrike   Vincenzo Belcastro   Alberto Oviedo  

PROVIDER: E-MTAB-4493 | ArrayExpress | 2016-10-03


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