Table 1.

Studies included in the review.

Authors, Year of Publication	Material	Country	Funder	Main Objective
Van der Toorn, 2018	in vitro epithelial cells	Switzerland	dependent	functional and molecular changes in human bronchial epithelial BEAS-2B cells following a 12-week exposure to total particulate matter (TPM) from the aerosol of a candidate modified-risk tobacco product (cMRTP) in comparison with those following exposure to TPM from the 3R4F reference cigarette.
Sohal, 2019	in vitro human bronchial epithelial cells, human airway smooth muscle (ASM) cells	Australia	independent	exposure to IQOS has the same damaging effect on human airway epithelial and smooth muscle cells as traditional tobacco cigarette and eCigs in vitro.
Miyashita, 2018	human in vivo human airway epithelial cells	UK	independent	e-cigarette vapour increases pneumococcal adhesion to airway cells.
Malinska, 2018	in vitro human bronchial epithelial cells	Poland	dependent	assessment of mitochondrial function following short- and long-term exposure of human bronchial epithelial cells to total particulate matter from a candidate modified-risk tobacco product and reference cigarettes.
Leigh, 2018	in vitro human bronchial epithelial cells	US	independent	the potential toxic effects of inhaling emissions from an HTP in comparison with electronic and combustible tobacco cigarettes.
Walczak, 2020	in vitro human bronchial epithelial cells	Poland	dependent	morphology and dynamics of the mitochondrial network in human bronchial epithelial cells exposed to total particulate matter (TPM) generated from 3R4F reference cigarette smoke and from aerosol from a new candidate modified risk tobacco product, the Tobacco Heating System (THS 2.2).
Adriaens, 2018	human	Belgium	independent	to investigate the effect of using an IQOS™ on eCO, acute cigarette craving, withdrawal symptoms and subjective positive and negative experiences after overnight smoking abstinence, compared to using an e-cigarette or a regular tobacco cigarette; and to investigate which product (e-cigarette or IQOS™) would be preferred.
Kamada, 2016	human case report	Japan	independent	report the first case of AEP caused by smoking HC
Aokage, 2019	human case report	Japan	independent	report a successfully treated case of fatal AEP, presumably induced by HNBC use.
Tabuchi, 2018	human	Japan	independent	to assess interest in HnB tobacco products (including IQOS, Ploom and Glo), its prevalence in 2015, 2016 and 2017, to examine the symptoms from exposure to secondhand HNB tobacco aerosol in Japan.
Lee, 2019	human	Korea	independent	assessment of association of the HnB’s use with perceived stress, physical activity and internet use.
Lopez, 2016	human	US	independent	to expand existing clinical laboratory methods to examine, in cigarette smokers, the acute effects of a “heat, not burn” “loose-leaf tobacco vaporizer” (LLTV).
Poussin, 2016	in vitro human endothelial cells	Switzerland	dependent	to compare the biological impact of aqueous extracts from a candidate MRTP, Tobacco Heating System (THS) 2.2 (electrically-heated tobacco technology), and the 3R4F reference cigarette on monocytic cell-HCAEC adhesion combining functional measurements from an in vitro adhesion assay with transcriptomics and inflammatory protein marker data to investigate changes at the molecular level.
Van der Toorn, 2015	in vitro monocytic cell line and human coronary arterial endothelial cells	Switzerland	dependent	the effect from a new candidate modified risk tobacco product, the tobacco heating system (THS) 2.2, on the migratory behavior of monocytes in comparison with combustible 3R4F reference cigarettes.
Lüdicke, 2018	human	Japan	dependent	risk markers of smoking-related diseases.
Haziza, 2020a	human	US	dependent	the exposure reduction to selected HPHCs in smokers switching to menthol Tobacco Heating System (mTHS) 2.2 compared with smokers continuing smoking menthol cigarettes (mCCs) and smoking abstinence (SA).
Haziza, 2020b	human	US	dependent	offering an alternative to cigarettes for smokers while substantially reducing the exposure to harmful and potentially harmful constituents found in cigarette smoke.
Haziza, 2016a	human	Japan	dependent	demonstrate exposure reduction to a selected set of HPHCs when switching from CCs to THS 2.2, as compared to continued CC use and smoking abstinence (SA) for five days.
Lüdicke, 2016	human	Poland	dependent	to investigate the effects of exposure to selected harmful and potentially harmful constituents (HPHCs) of cigarette smoke in adult smokers who switched to a carbon-heated tobacco product (CHTP), compared with adult smokers who continued to smoke CCs and those who abstained from smoking for five days.
Lüdicke, 2017	human	Switzerland	dependent	examined whether the levels of selected biomarkers of exposure were reduced in smokers who switched from CCs to THS 2.1, as compared to smokers that continued to smoke CCs.
Lüdicke, 2018	human	Japan	dependent	examined the impact of switching to mTHS on biomarkers of exposure to HPHCs relative to menthol CCs (mCCs) and smoking abstinence (SA).
Ogden, 2015	human	US	dependent	evaluation of biomarkers of biological effect (e.g., inflammation, lipids, hypercoaguable state).
Biondi-Zoccai, 2019	human	Italy	independent	to appraise the acute effects of single use of HNBC, EVC and TC in healthy smokers.
Gale, 2021	human	UK	dependent	investigating whether biomarkers of exposure (BoE) to smoke toxicants are reduced when smokers switch from smoking cigarettes to using the glo THP.
Haziza, 2016b	human	Poland	dependent	to demonstrate a reduction in exposure to HPHCs.