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

Abstract

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 meta-analysis of in vitro assessment studies: biological impact of a candidate modified-risk tobacco product aerosol compared with cigarette smoke on human organotypic cultures of the aerodigestive tract

“…This cluster contains genes that represent the main branches of the oxidative stress response, namely: the glutathione system (GCLC, GCLM, MGST1, GSR), the thioredoxin system (thioredoxin reductase 1, TXNRD1), the peroxiredoxin system (PRDX1, SRXN1), quinone NAD(P)H dehydrogenase 1 (NQO1), and metabolic adjustments for NAPDH production (glucose-6-phosphate dehydrogenase (G6PD)). A similar impact on the oxidative stress response pathways was observed previously in rat lung tissue exposed to 3R4F CS 56 and in human lung tissue under oxidative stress conditions. 57 – 59 The altered gene expression in this cluster further showed that THS2.2 aerosol induced a transient oxidative stress response that was limited to the 4 h after exposure time point across all three cultures (an exception was observed for NQO1 in the nasal culture).…”

New ideas, old problems? Heated tobacco products – a systematic review

“…The tobacco industry has performed multiple studies regarding health consequences of HTP use. The results of in vitro and in vivo studies indicate that HTP aerosols have lower toxicity and no new hazards compared to conventional cigarette smoke [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. The results of humanbased studies also suggest that switching from conventional cigarettes to IQOS or glo leads to reductions in exposure to smoke toxicants in a manner comparable to quitting tobacco use [74][75][76][77][78].…”

“…Following the manufacturer recommendations, especially proper cleaning of the device after each 20 tobacco sticks seems to be crucial to provide proper thermal regulation and reduce emissions of harmful substances. Most of the research regarding the chemical composition of generated aerosol was carried out on brand new, never used devices [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. Independent researchers showed that the use of 1 IQOS tobacco stick left a significant amount of debris, fluid, and fragments of cast-leaf in the device holder [8].…”

Impact of sample preparation upon intracellular metabolite measurements in 3D cell culture systems

“…For toxicological assessment, changes in metabolic profiles and their relationship to various biochemical pathways are investigated. Untargeted approaches have been used for this purpose, for instance, to explore the global impact of environmental chemical contaminants on earthworms (Griffith et al 2018 ) or on human cells (Hartung et al 2017 ), or to assess the impact of tobacco exposure on in vitro systems (Iskandar et al 2017 ; Kogel et al 2016 ; Zanetti et al 2017 ). For in vitro toxicology studies, two-dimensional (2D) cell cultures have been the most commonly investigated systems for decades.…”