Comparison of tobacco heating products and conventional cigarette: a systematic review


Authors

Name Affiliation
Dorota Marszałek
HealthQuest
Maciej Niewada
HealthQuest
Aneta Mela
HealthQuest; Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
Katarzyna Budka
HealthQuest
Paweł Sobczak
HealthQuest
Witold Wrona
HealthQuest
contributed: 2019-06-22
final review: 2019-09-21
published: 2019-09-24
Abstract

Heat-not-burn products, which are supposed to reduce the harmful effects of exposure to cigarette smoke components (harm reduction approach), are under development. Comprehensive evaluation of the newest available on the market tobacco heating products (THPs) in comparison with conventional cigarettes (CC) within pre-clinical and clinical studies. A systematic review of the literature was performed in MEDLINE, EMBASE, The Cochrane Library, Center for Reviews and Dissemination databases. Primary clinical studies from the highest level of credibility (randomized controlled clinical trials), evaluating the use of THP compared to the use of a CC by smokers were searched. Additionally in order to study impact of passive smoking on health, pre-clinical studies and studies evaluating indoor air quality were included. In the review 9 randomized clinical trials, 37 pre-clinical studies and 6 studies evaluating the impact of heat-not-burn products on indoor air quality were included. Studies demonstrated that switching from CC to THP is associated with reduction of harmful and potentially harmful constituents’ exposure and probable less harm in clinical risk markers in comparison with the continuation of smoking conventional cigarettes while maintaining comparable nicotine delivery. Results suggest no negative impact on indoor air quality when using THP in an indoor environment. THPs compared to CC smoking (within the analyzed risk factors) shows a tendency to limit negative health influence. The assessment of heat-not-burn product impact on the risk of smoking-related diseases requires further research and long-term observations.



Keywords: tobacco heating product, heat-not-burn, Tobacco Heating System 2.2, THS 2.2, IQOS, Tobacco Heating Product 1.0, THP 1.0, Glo, Ploom TECH, iFUSE, PAX, modified risk tobacco product, systematic review

Background

Smoking has been recognized by the World Health Organization (WHO) as a health problem caused by tobacco addiction (ICD-10: F17 - Mental and behavioural disorders due to use of tobacco) [[1],[2]]. Addiction to smoking is caused by nicotine and behavioural addictions. Nicotine addiction is associated with the need to maintain specific concentrations of nicotine in the blood serum, while behavioural addiction depends on psychological, environmental, cultural and social factors [[3]]. There are around 1.1 billion smokers in the world [[4]]. The tobacco epidemic is one of the world's greatest threats to public health. According to data from the WHO, over 6 million deaths per year is a direct result of smoking, while approx. 890,000 deaths occur due to tobacco smoke exposure on non-smokers [4]. According to estimates of the WHO in 2025, the prevalence of cigarette smoking will reach 18.9% in the world population [[5]]. Unfortunately less than 5-10% of smokers who tried to quit are smoking free for 6 months or longer [[6],[7]].

Smoking causes many serious diseases, including cardiovascular diseases, lung cancer and chronic obstructive pulmonary disease [[8],[9],[10]]. It is widely recognized that the adverse effects of smoking are not primarily caused by nicotine, but by toxic substances released during the combustion of tobacco [[11]]. Cigarette smoke is a very complex mixture in which over 6,000 chemicals have been identified. Among them, about 100 compounds are thought to contribute to smoking-related diseases[[12]]. Epidemiological studies showed that inhalation of tobacco smoke by non-smokers (so-called passive smoking) is associated with a serious health risk [[13]].

Harm reduction approach

The main strategies to reduce health-related harm associated with smoking are prevention of starting smoking and promotion of smoking cessation. In the treatment of smoking addiction, methods are used to strengthen motivation and to speed up the decision to give up the addiction, support the patient in the actions taken and reduce the symptoms of withdrawal [[14]].

Heat-not-burn systems and e-cigarette

Heat-not-burn products and e-cigarettes, which are supposed to reduce the harmful effects of exposure to cigarette smoke components (harm reduction approach), are under development as alternatives to cigarettes for smokers who are not able or not willing to quit smoking. A recent review indicated that limited evidence suggests that e-cigarettes may be effective in reducing cigarette use among adult smokers willing to quit [[15]].

Heat-not-burn products are tobacco products that produce an aerosol containing nicotine and other chemicals that are inhaled by the user. Tobacco heating products imitate the action of traditional cigarettes and  are not e-cigarettes, because THPs heat tobacco to release nicotine, while in the e-cigarette a liquid, which may contain nicotine is heated [[16]]. The main components of liquids heated in the e-cigarette are nicotine (in nicotine-containing products), propylene glycol (± glycerol) and flavours.

THPs heat tobacco up to 240-350°C (dependent on the device), which is much lower than the combustion temperature, to aerosolize nicotine from specially designed cigarettes, or a heated sealed chamber, to aerosolize nicotine directly from tobacco leaf. Hybrid THPs fuses tobacco heating and vaping technology. Examples of THPs include IQOS (Tobacco Heating System 2.2, THS 2.2; Philip Morris International), Ploom TECH (Japan Tobacco International), Glo (Tobacco Heating Product 1.0, THP 1.0; British American Tobacco), iFUSE (British American Tobacco) and PAX (PAX Labs) [16, [17]].

We aimed to compare the newest available on the market THPs with conventional cigarettes in terms of clinical harm.

Methods

In order to compare THPs with a conventional cigarette, a systematic review of the literature was carried out in database systems: MEDLINE, EMBASE, The Cochrane Library and Center for Reviews and Dissemination. Keywords included i.e.: "tobacco", "tobacco products", "heated", "heating", "modified risk" and "heat-not-burn." The review was carried out with a cut-off date of August 2, 2018.

Primary clinical studies with the highest level of reliability (randomized controlled clinical trials), published in full-text or as conference abstracts, evaluating switching from conventional cigarettes to newest available on the market THPs in comparison with continued smoking conventional cigarettes, were searched. Additionally in order to study mainstream aerosol, toxicology and impact of passive smoking on health, pre-clinical studies and studies evaluating indoor air quality were included.

Randomized trials assessing in particular clinically relevant endpoints, exposure to harmful and potentially harmful constituents (HPHCs) as defined by WHO [[18]] and Food and Drug Administration (FDA) [[19]] guidelines, clinical risk markers and safety were searched.

Within pre-clinical evaluation studies assessing aerosol chemistry, toxicology and in vitro studies, in which newest available on the market THPs were compared to conventional cigarettes, were included. Exclusion criteria were: older devices (for which the next upgraded version is available), prototypes, devices not commercially available. The detailed scope and search strategy are shown in the appendixes A and B.

Results

The review and selection of studies were carried out independently by two reviewers. The first stage of selection was based on abstracts, and then on full texts of the publications. Stages of review and selection of studies are presented in the PRISMA  diagram [[20]] (see appendix C).

The review included:

·         37 pre-clinical studies (32 studies for THS 2.2, 10 studies for THP 1.0, 1 studies for Ploom TECH, 3 studies for iFUSE);

·         9 randomized clinical trials (8 trials for THS 2.2, 2 trials for THP 1.0, 1 trial for Ploom TECH);

·         6 studies evaluating indoor air quality (5 studies for THS 2.2, 1 studies for THP 1.0).

Pre-clinical studies

Assessment of pre-clinical studies is presented in appendix H. Conclusions and discussion are presented in appendix I.

Clinical trials

The review included 9 randomized clinical trials evaluating the use of THPs compared to smoking CCs. Characteristics of the included randomized clinical trials is presented in appendix F. Detailed numerical results of the studies included in the analysis are presented in appendixes J and K.

The analysis of the included studies indicates a high risk of bias in one domain (blinding of participants and personnel). Additionally, for the studies Brossard 2017a, Brossard 2017b (Brossard 2017 [[21]]), Yuki 2017 [[22]] and Gee 2017 [[23]], the “other factors” domain also indicates a high risk of bias (crossover study), but these studies were aimed at assessing pharmacokinetics or puffing topography, so the selection of study type is justified. The analysis of other domains did not show a high risk of bias (see Appendix D).

Exposure to harmful and potentially harmful constituents (HPHC), nicotine concentration and pharmacokinetics

The exposure to HPHC was assessed in five trials [[24],[25],[26],[27],[28]]. The list of evaluated harmful or potentially harmful constituents assessed in the included trials (abbreviations explained in the appendix G) covers a wide range of chemical classes and organ toxicity classes as defined by the FDA (carcinogen, cardiovascular toxicant, respiratory toxicant, reproductive and developmental toxicant, addiction potential) [24,25,[29]].

Five studies showed that switching from CC to THP in smokers was associated with a reduction in exposure to all 18 analyzed HPHC as compared to the continuation of smoking CCs both after 5 and 90 days (Table 1) regardless of cigarettes type (menthol and non-menthol) [24,25,26,27,28]. The concentrations of exposure markers in the THP groups were comparable to those observed in the smoking cessation group. Comparable concentrations of total nicotine equivalents, nicotine and cotinine were observed in the analysed groups in most of included studies (Table 2). Only in the Gale 2018 study, the total concentration of nicotine equivalents after 5 days was statistically significantly lower in the THP groups than in the continuation of smoking group, both for comparisons with non-menthol (THS 2.2 vs CC, THP 1.0 vs CC) and menthol cigarettes (THP 1.0 vs CC) [26].

Three studies (Brossard 2017a and Brossard 2017b [21], Yuki 2017 [22]) compared pharmacokinetics of nicotine between THPs and CCs. In both Brossard 2017 [21] studies the plasma concentration profile of nicotine was comparable for THP and CC, suggesting similar absorption of nicotine. However, Yuki 2017 [22] study showed that THP evaluated in this study delivered lower maximum observed plasma nicotine concentration and total exposure to nicotine compared to a conventional cigarette (45,7% and 68,3%, respectively). These results can be explained by differences in nicotine intake, as participants used the assessed THP (Ploom TECH) for the first time, and puff duration and number were fixed by study researchers.

In three studies [24, 25, 23] puffing topography were evaluated (results not included in this publication).


Table 1. Markers of exposure to harmful or potentially harmful constituents - THP vs conventional cigarette.

HPHC

Day

THP vs CC

Ludicke 2018

Haziza 2016d

Haziza 2016a

Haziza 2016b

Gale 2018

NNAL

5






90



NA

NA

NA

NNN

5






90



NA

NA

NA

COHb

5





NA

90



NA

NA

NA

eCO

5

NA

NA

NA

NA


90

NA

NA

NA

NA

NA

MHBMA

5






90



NA

NA

NA

3-HPMA

5






90



NA

NA

NA

S-PMA

5






90



NA

NA

NA

1-OHP

5






90



NA

NA

NA

4-ABP

5






90



NA

NA

NA

1-NA

5





NA

90



NA

NA

NA

2-NA

5






90



NA

NA

NA

o-toluidine

5






90



NA

NA

NA

CEMA

5






90



NA

NA

NA

HEMA

5






90



NA

NA

NA

3-HMPMA

5






90



NA

NA

NA

3-OH-B[a]P

5





NA

90



NA

NA

NA

AAMA

5

NA

NA

NA

NA


90

NA

NA

NA

NA

NA

GAMA

5

NA

NA

NA

NA


90

NA

NA

NA

NA

NA

NA – not available

    Reduction of concentration; result in favour of THP (no information on statistical significance)

    Reduction of concentration; statistically significant result in favour of THP

NNAL - 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; NNN - N-nitrosonornicotine); COHb – carboxyhemoglobin; eCO - exhaled carbon monoxide; MHBMA - monohydroxybutenyl mercapturic acid; 3-HPMA - 3-hydroxypropylmercapturic acid; S-PMA - S-phenylmercapturic acid; 1-OHP - 1-hydroxypyrene; 4-ABP - 4-aminobiphenyl; 1-NA - 1-aminonaphthalene; 2-NA - 2-aminonaphthalene; CEMA - 2-cyanoethylmercapturic acid; HEMA - 2-hydroxyethylmercapturic acid; 3-HMPMA - 3-hydroxy-1-methylpropylmercapturic acid; 3-OH-B[a]P - 3-hydroxy-benzo(a)pyrene; AAMA - N-acetyl-S-(2-carbamoylethyl)cysteine); GAMA - N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine.

S-BMA - S-benzylmercapturic acid;.

 

Table 2. Concentrations of nicotine, cotinine and nicotine equivalent - THP vs conventional cigarette.

 

Day

THP vs CC

Ludicke 2018

Haziza 2016d

Haziza 2016a

Haziza 2016b

Gale 2018

Nicotine equivalent

5


NA




90


NA

NA

NA

NA

Nicotine

5

NA

NA



NA

90

NA

NA

NA

NA

NA

Cotinine

5

NA

NA



NA

90

NA

NA

NA

NA

NA

NA – not available

     Reduction of concentration; statistically significant result in favour of THP

 Result statistically insignificant

 

Clinical risk markers

The results in terms of clinical risk markers are presented in Table 6. In the Ludicke 2018 study [27] statistically significant changes were observed in favor of THP vs CC for endothelial dysfunction, oxidative stress, inflammation markers and lipid metabolism. Clinical risk markers were also evaluated in the Haziza 2016d study but not fully reported [28].

Studies primarily focused on exposure to HPHCs were not powered to estimate clinical risk markers differences.


Table 3. Clinical risk markers at 90 days - THP vs conventional cigarette.

Outcome

THP vs CC

Ludicke 2018

Endothelial dysfunction

sICAM-1


Oxidative stress

8-epi-PGF2α


Platelet activity

11-DTX-B2


Cardiovascular risk/function

Fibrinogen


Homocysteine


hs-CRP


Systolic blood pressure


Diastolic blood pressure


Metabolic syndrome

Blood glucose


HbA1c


Body weight


Waist circumference


Inflammation

WBC


Lipid metabolism

LDL cholesterol


HDL cholesterol


Triglycerides


Total cholesterol


Lung function

FEV1


     Decrease; statistically significant result in favour of THP

     Increase; statistically significant result in favour of THP

 Result statistically insignificant

 

Indoor air quality

No randomized studies evaluating indoor air quality were found. Summary of findings on indoor air quality assessment is presented in appendix L.

Discussion

Nine randomized clinical trials were included in the analysis. Randomized trials have shown that the use of THPs is associated with a reduction in exposure to 18 out of 93 constituents, most of which were identified as HPHCs by FDA [[30], [31]], compared to continuing CC smoking.

Our results are consistent with most recent independent review, evaluating THPs secondhand emissions and its use by humans [[32]]. The review also included studies on older versions of devices (for which the next version is available) as well as non-randomized studies and case reports. However, the review does not cover all pre-clinical studies, but only those that evaluated mainstream emissions. Findings showed the use of THPs is associated with exposure to toxic substances, but at substantially lower levels than CCs.

According to the German Federal Institute for Risk Assessment, levels of major carcinogens are markedly reduced (by about 80-99%) in the analyzed THP products’ emissions in comparison to conventional cigarettes. Substantial reductions of toxicant levels might be regarded as a discrete benefit compared to the use of conventional cigarettes, even if potential consequences for human health still need to be explored [[33]]. Similarly, according to Public Health England (PHE) and Rijksinstituut voor Volksgezondheid en Milieu (RIVM) opinions, THPs may be considerably less harmful than tobacco cigarettes [[34], [35]]. Korean Ministry of Food and Drug Safety (KFDA) suggest that THPs also contain carcinogens, however their levels are significantly (by more than 90%) reduced [[36]. According to the Toxicology Committee of the British Health Ministry, the risk associated with the use of THPs cannot be quantified due to shortcomings in the available information and the uncertain relationship between the concentration of harmful constituents and potential negative health outcomes. Moreover, concentrations of particular aerosol compounds differ from those observed in CC smoke, so it is not possible to extrapolate from epidemiological data on smoking risks, in particular after considering the complexity of interactions that occur between chemical compounds in producing adverse health effects. However, according to Committee the use of THPs is probably less harmful than the use of CCs, but the best way to limit the harmful health effect is smoking cessation [[37], [38]].

The lack of blinding in included randomized studies results from the differences in the appearance of the tested products (THPs and CC) and the lack of technical possibility of using an identical device. However, Ludicke 2018 and Gale 2018 study [26,27] indicated that the laboratories were blinded to the randomization scheme. Main limitation is lack of studies focused on clinical outcomes, such as the occurrence of smoking-related diseases and death due to smoking-related diseases. However, the assessment of the occurrence of cardiovascular diseases, lung cancer and chronic obstructive pulmonary disease (COPD) would require a significant extension of the follow up in clinical trials, as smoking-related symptoms and deaths usually occur after a long asymptomatic period [[39]. Therefore it is important to evaluate surrogate endpoints suitable for risk assessment in short-term trials to determine the risk reduction profile and the potential long-term effect [[40]]. Clinical risk markers assessed in the studies were selected from multiple clinical risk components across several biological processes and mechanisms associated with smoking-related diseases, including inflammation markers, oxidative stress, platelet activation, lipid metabolism and lung function. The selection was based on epidemiological evidence on relationship between the clinical risk endpoint and at least one known smoking-related health outcome, clinical evidence linking smoking to the clinical risk endpoint (consistent with the epidemiological evidence) and clinical evidence linking smoking cessation to the reversibility of the endpoint [40]. The interpretation of results in the context of reducing smoking-related disease risk by switching to THP can only be made indirectly and its confirmation in direct studies requires long-term observations and evaluation of clinically relevant endpoints.

Results of pre-clinical studies evaluating aerosol chemistry and physics indicate about 90% reduction of combustion markers and harmful or potentially harmful constituents in THPs aerosol compared to CCs smoke. Both in vitro and in vivo standard toxicology studies as well as data from systems toxicology assessment indicate that THPs are less toxic than CCs (see appendixes H and I).

Results of included studies suggest that there is no negative impact on indoor air quality when using THP in an indoor environment, which can affect the risks associated with passive smoking (see appendix L).

All randomized trials and majority of pre-clinical studies as well as studies evaluating indoor air quality were sponsored by the THPs manufacturers. Independent evidence are needed to validate current findings, although cited review found largely similar results for independent and industry-funded studies [32].

Conclusions

It has been shown that switching to THPs from smoking CCs is associated with reduced exposure to some HPHCs and likely improvement of clinical risk markers related to oxidative stress, endothelial dysfunction, lipid metabolism, inflammation and lung function as compared to continuing smoking of CCs while maintaining similar concentrations of nicotine. The impact on smoking related diseases needs to be explored in long term follow up clinical trials, but THPs certainly should not be perceived as alternative approach to smoking cessation.

The identified studies revealed no negative impact of heat-not-burn product on indoor air quality, which might reduce the risks associated with passive smoking of CC.

Summary

THPs are intended for use by people addicted to nicotine who refused or failed smoking cessation, and can be an opportunity to reduce the negative effects of exposure to HPHCs contained in traditional cigarette smoke.

THPs compared to smoking CCs (within the analyzed risk factors) can offer reduction of HPHCs exposure. Its impact on smoking-related diseases risk requires further long-term studies.

Funding

This research was funded by Philip Morris Polska S.A. The study protocol was written by the investigator, who also conducted the study. Philip Morris Polska S.A. had no involvement in the study conduct, data analysis and writing of the manuscript.


[1] Gajewski P (red.). Interna Szczeklika. Medycyna Praktyczna, Cracow 2016.

[2] World Health Organisation (WHO): International classification of diseases [cited 13.05.2019]. Available from: https://icd.who.int/browse10/2010/en#/F17

[3] Samochowiec J, Rogoziński D, Hajduk A i wsp. Diagnostyka, mechanizm uzależnienia i metody leczenia uzależnienia od nikotyny. Alkoholizm i Narkomania, Tom 14, Nr 3, s. 323-40.

[4] World Health Organisation (WHO): WHO fact sheet. May 2017 [cited 13.05.2019]. Available from: http://www.who.int/mediacentre/factsheets/fs339/en/

[5] World Health Organisation (WHO): WHO Global Report on trends in tobacco smoking 2000-2025 [cited 13.05.2019]. Available from: http://www.who.int/tobacco/publications/surveillance/reportontrendstobaccosmoking/en/index4.html

[6] Reid RD, Pritchard G, Walker K, Aitken D, Mullen KA, Pipe A. Managing smoking cessation. CMAJ. 2016 Dec 6;188(17-18):E484-E492. Epub 2016 Oct 3.

[7] Messer K, Trinidad DR, Al-Delaimy WK, Pierce JP. Smoking cessation rates in the United States: a comparison of young adult and older smokers. Am J Public Health. 2008 Feb;98(2):317-22.

[8] Institute of Medicine. Scientific Standards for Studies on Modified Risk Tobacco Products. National Academy of Sciences, 2012.

[9] Giovino GA. The tobacco epidemic in the United States. Am J Prev Med. 2007 Dec;33(6 Suppl):S318-26.

[10] Secretan B, Straif K, Baan R et al. WHO International Agency for Research on Cancer Monograph Working Group. A review of human carcinogens--Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol. 2009 Nov;10(11):1033-4.

[11] Food and Drug Administration: Protecting American Families: Comprehensive Approach to Nicotine and Tobacco [cited 13.05.2019]. Available from: https://www.fda.gov/newsevents/speeches/ucm569024.htm

[12] PMI Science: PMI-58 List of Harmful and Potentially Harmful Constituents [cited 13.05.2019]. Available from: https://www.pmiscience.com/science/platform-development/the-pmi-58-list-of-harmful-and potentially-harmful-constituents

[13] World Health Organization: Stan zagrożenia epidemią palenia tytoniu w Polsce, 2009 [cited 13.05.2019]. Available from: http://www2.mz.gov.pl/wwwfiles/ma_struktura/docs/raport_epidemia_16082010.pdf

[14] Górecka D, Bała M. Leczenie uzależnienia od tytoniu [cited 13.05.2019]. Available from: https://www.mp.pl/poz/psychiatria/uzaleznienia/89907,leczenie-uzaleznienia-od-tytoniu

[15] Livingston CJ, Freeman RJ, Costales VC, Westhoff JL, Caplan LS, Sherin KM, Niebuhr DW. Electronic Nicotine Delivery Systems or E-cigarettes: American College of Preventive Medicine's Practice Statement. Am J Prev Med. 2019 Jan;56(1):167-178.

[16] World Health Organization:  Heated tobacco products (HTPs) information sheet [cited 13.05.2019]. Available from: http://www.who.int/tobacco/publications/prod_regulation/heated-tobacco-products/en/

[17] PMI: IQOS [cited 13.05.2019]. Available from: https://www.pmi.com/markets/poland/pl/science-and-innovation/breakthrough-products-for-smokers

[18] WHO Technical Report Series. The Scientific Basis of Tobacco Product Regulation 2008 [cited 13.05.2019]. Available from: http://apps.who.int/iris/bitstream/handle/10665/43997/TRS951_eng.pdf?sequence=1&isAllowed=y

[19] Food and Drug Administration: Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke Under Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act. DRAFT GUIDANCE [cited 13.05.2019]. Available from: https://www.fda.gov/downloads/AnimalVeterinary/NewsEvents/CVMUpdates/UCM297828.pdf

[20] Moher D, Liberati A, Tetzlaff J et al. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Medicine 2009; 6(7): e1000097.

[21] Brossard P, Weitkunat R, Poux V. et al. Nicotine pharmacokinetic profiles of the Tobacco Heating System 2.2, cigarettes and nicotine gum in Japanese smokers. Regul Toxicol Pharmacol. 2017 Oct;89:193-199.

[22] Yuki D, Sakaguchi C, Kikuchi A, Futamura Y. Pharmacokinetics of nicotine following the controlled use of a prototype novel tobacco vapor product. Regulatory Toxicology and Pharmacology 87 (2017) 30e35.

[23] Gee J, Prasad K, Slayford S, Gray A, Nother K, Cunningham A, Mavropoulou E, Proctor C. Assessment of tobacco heating product THP1.0. Part 8: Study to determine puffing topography, mouth level exposure and consumption among Japanese users. Regul Toxicol Pharmacol. 2018 Mar;93:84-91.

[24] Haziza C, de La Bourdonnaye G, Skiada D. et al. Evaluation of the Tobacco Heating System 2.2. Part 8: 5-Day randomized reduced exposure clinical study in Poland. Regul Toxicol Pharmacol. 2016 Nov 30;81 Suppl 2:S139-S150.

[25] Haziza C, de La Bourdonnaye G, Merlet S. et al. Assessment of the reduction in levels of exposure to harmful and potentially harmful constituents in Japanese subjects using a novel tobacco heating system compared with conventional cigarettes and smoking abstinence: A randomized controlled study in confinement. Regul Toxicol Pharmacol. 2016 Nov;81:489-499.

[26] Gale N, McEwan M, Eldridge A.C et al. Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to Tobacco Heating Products: A Randomized, Controlled Study in Healthy Japanese Subjects. Nicotine & Tobacco Research, 2018, 1–8.

[27] Lüdicke F, Picavet P, Baker G. et al. Effects of Switching to the Tobacco Heating System 2.2 Menthol, Smoking Abstinence, or Continued Cigarette Smoking on Biomarkers of Exposure: A Randomized, Controlled, Open-Label, Multicenter Study in Sequential Confinement and Ambulatory Settings (Part 1). Nicotine Tob Res. 2018 Jan 5;20(2):161-172.

[28] Haziza C, de La Bourdonnaye G, Picavet P et al.. Reduced Exposure to Harmful and Potentially Harmful Constituents After 90 Days of Use of Tobacco Heating System 2.2 Menthol in the U.S.: A Comparison with Continued Cigarete Use or Smoking Abstinence. SRNT – 22nd Annual Meeting, Chicago, USA, 2-5 March 2016. Poster.

[29] Theophilus E.H, Coggins C.R.E, Chen P, Schmidt E, Borgerding M.F. Magnitudes of biomarker reductions in response to controlled reductions in cigarettes smoked per day: A one-week clinical confinement study. Regul Toxicol Pharmacol, 2015, 71(2): 225-234.

[30] Food and Drug Administration: Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke: Established List [cited 13.05.2019]. Available from: https://www.fda.gov/TobaccoProducts/Labeling/RulesRegulationsGuidance/ucm297786.htm

[31] Food and Drug Administration: Reporting Harmful and Potentially Harmful Constituents [cited 13.05.2019]. Available from: https://www.fda.gov/TobaccoProducts/GuidanceComplianceRegulatoryInformation/ucm297752.htm

[32] Simonavicius E, McNeill A, Shahab L, Brose LS. Heat-not-burn tobacco products: a systematic literature review. Tob Control. 2018 Sep 4. pii: tobaccocontrol-2018-054419. doi: 10.1136/tobaccocontrol-2018-054419.

[33] German Federal Institute for Risk Assessment’s (BfR) Independent Scientific Assessment of IQOS. 7 May 2018.

[34] McNeill A, Brose LS, Calder R, Bauld L & Robson D (2018). Evidence review of e-cigarettes and heated tobacco products 2018. A report commissioned by Public Health England. London: Public Health England [cited 13.05.2019]. Available from:  https://www.gov.uk/government/publications/e-cigarettes-and-heated-tobacco-products-evidence-review/evidence-review-of-e-cigarettes-and-heated-tobacco-products-2018-executive-summary#heated-tobacco-products

[35] RIVM. Addictive nicotine and harmful substances also present in heated tobacco [cited 13.05.2019]. Available from: https://www.rivm.nl/en/news/addictive-nicotine-and-harmful-substances-also-present-in-heated-tobacco

[36] PMI assessment of the KFDA statement [cited 13.05.2019]. Available from:  https://www.pmiscience.com/discover/news/pmi-assessment-of-the-kfda-statement

[37] Committee on Toxicity: Statement on the toxicological evaluation of novel heat-not-burn tobacco products, 2017 [cited 13.05.2019]. Available from: https://cot.food.gov.uk/sites/default/files/heat_not_burn_tobacco_statement.pdf

[38] Committee on Toxicity: Toxicological evaluation of novel heat-not-burntobacco products –non-technical summary, 2017 [cited 13.05.2019]. Available from: https://cot.food.gov.uk/sites/default/files/heat_not_burn_tobacco_summary.pdf

[39] Narodowy Fundusz Zdrowia: Program profilaktyki chorób odtytoniowych – palenie jest uleczalne [cited 13.05.2019]. Available from: http://www.nfz.gov.pl/download/gfx/nfz/pl/defaultaktualnosci/293/1669/1/54_2005_zal.pdf

[40] Lüdicke F, Picavet P, Baker G et al. Effects of Switching to the Menthol Tobacco Heating System 2.2, Smoking Abstinence, or Continued Cigarette Smoking on Clinically Relevant Risk Markers: A Randomized, Controlled, Open-Label, Multicenter Study in Sequential Confinement and Ambulatory Settings (Part 2). Nicotine Tob Res. 2018 Jan 5;20(2):173-182.


SUPPLEMENT/APPENDIX


Appendix A. Scope

Scope

Table 1. Inclusion and exclusion criteria.

Inclusion criteria

Exclusion criteria

1.  Primary clinical studies:

·     randomized controlled clinical trials,

·     published in full-text or as the conference abstracts,

·     evaluating switching from conventional cigarettes to newest available on the market tobacco heating products (THPs) by smokers in comparison with continuation of smoking conventional cigarettes,

·     studies assessing in particular clinically relevant endpoints, exposure to harmful and potentially harmful constituents, considered in the World Health Organization (WHO) and Food and Drug Administration (FDA) guidelines regarding their reporting, clinical risk markers and safety,

2.  Pre-clinical studies:

·     studies assessing aerosol chemistry, toxicology and in vitro studies, in which newest available on the market THPs were compared to conventional cigarettes,

3.  Indoor air quality:

·     studies assessing indoor air quality, in which newest available on the market THPs were compared to conventional cigarettes.

·    older versions of devices (for which the next version is available),

·    prototypes,

·    devices not commercially available.

 


Appendix B. Search strategy

Table 2. Search strategy for studies on the effectiveness and safety of Tobacco Heating System in the MEDLINE (PubMed) database system - 08/02/2018.

Query

Key word

Results

1

tobacco

117 015

2

"Tobacco Products"[Mesh]

5 994

3

#1 OR #2

117 015

4

heated

20 463

5

heating

51 758

6

„modified risk

255

7

heat-not-burn OR „heat not burn

55

8

3T

6 764

9

glo

1 310

10

iFuse

20

11

THP

12 129

12

Tobacco Heating Product

85

13

IQOS

21

14

THS

1 588

15

Tobacco Heating System

81

16

iSmoke

0

17

Lil

290

18

Pax

2 624

19

Ploom

11

20

ZeroStyle

0

21

V2 AND Pro

101

22

#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21

91 845

23

#3 AND #22

732

 

Table 3. Search strategy for studies on the effectiveness and safety of Tobacco Heating System in the Embase (Elsevier) database system - 08/02/2018.

Query

Key word

Results

1

'tobacco'/exp OR tobacco

142 419

2

'tobacco products'

4 145

3

#1 OR #2

142 419

4

heated

23 025

5

heating

61 692

6

‘modified risk

383

7

‘heat-not-burn’ OR ‘heat not burn

66

8

3T

17 100

9

glo

5 329

10

iFuse

42

11

THP

16 889

12

Tobacco Heating Product

125

13

IQOS

16

14

THS

2 324

15

Tobacco Heating System

135

16

iSmoke

0

17

Lil

862

18

Pax

3 903

19

Ploom

13

20

ZeroStyle

0

21

V2 AND Pro

319

22

#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21

124 928

23

#3 AND #22

1 054

 

Table 4. Search strategy for studies on the effectiveness and safety of Tobacco Heating System in the Cochrane Library database system - 08/02/2018.

Query

Key word

Results

1

MeSH descriptor: [tobacco] explode all trees

147

2

tobacco

13 261

3

#1 OR #2

13 261

4

heated

961

5

heating

1 103

6

‘modified risk

9 408

7

‘heat-not-burn’ OR ‘heat not burn

6 322

8

3T

613

9

glo

71

10

iFuse

14

11

THP

199

12

Tobacco Heating Product

32

13

IQOS

4

14

THS

119

15

Tobacco Heating System

47

16

iSmoke

0

17

Lil

12

18

Pax

45

19

Ploom

0

20

ZeroStyle

0

21

V2 AND Pro

36

22

#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21

17 768

23

#3 AND #2

421

24

#23 in Cochrane Reviews

259

25

#23 in Other Reviews

3

26

#23 in Clinical Trials

150

27

#23 in Economic Evaluations

7

28

#23 in Cochrane Groups

2

 

Table 5. Search strategy for studies on the effectiveness and safety of Tobacco Heating System in the Centre for Reviews and Dissemination database system - 08/02/2018.

Query

Key word

Results

1

MeSH DESCRIPTOR Tobacco Products EXPLODE ALL TREES

13

2

tobacco

468

3

#1 OR #2

468

4

heated

39

5

heating

42

6

modified risk

2

7

heat-not-burn OR heat not burn

174

8

3T

3

9

glo

1

10

iFuse

4

11

THP

1

12

Tobacco Heating Product

0

13

IQOS

0

14

THS

2

15

Tobacco Heating System

0

16

iSmoke

0

17

Lil

1

18

Pax

1

19

Ploom

0

20

ZeroStyle

0

21

V2 AND Pro

0

22

#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21

248

23

#3 AND #22

4

 

 


 

Appendix C. PRISMA diagram

Figure 1. Scheme of subsequent stages of search and selection of studies for tobacco heating products (PRISMA diagram [[1]]).

Identified publications:

MEDLINE (PubMed): 732

EMBASE (Elsevier): 1,054

the Cochrane Library: 421

Centre for Reviews and Dissemination: 4

 


MEDLINE, EMBASE, the Cochrane Libraryelimination of repetition and selection based on abstracts and titles in the EndNote program: 1,759

Centre for Reviews and Dissemination: 4

 

 


 

Excluded publications on the basis of a review of abstracts and titles: 1,701

Review of full texts and abstracts: 98

 

 

 

 

 

Identified publications based on references of found reports: 0

Excluded publications on the basis of a review of full texts of the publication – 36 articles:

- another intervention: 29 articles

- another trial methods: 6 articles

- another comparator: 1 article

 

 

 

 

 


 

 

 

 

Additionally included publications: 3 conference presentations + 4 conference posters

 

 

 

 

 


Included studies (59 articles, 10 conference data):

·      9 randomized clinical trials (10 articles, 2 conference posters, 1 conference abstract)

·      37 pre-clinical studies (42 articles)

·      6 indoor air quality studies (7 articles, 3 conference presentations, 4 conference posters)

 

 

 

 





 

 


Appendix D. Assessment of the risk of bias

Table 6. Assessment of the risk of bias in included studies using the Cochrane Risk of Bias Tool [[2]].

Study

Random sequence generation

Allocation concealment

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data addressed

Selective reporting

Other factors

Ludicke 2018

low

unclear

high

low*

low

low

low

Haziza 2016d***

low

unclear

high

unclear

low

low

low

Haziza 2016a

low

unclear

high

unclear

low

low

low

Haziza 2016b

low

unclear

high

unclear

low

low

low

Gale
2018

low

unclear

high

low*

low

low

low

Brossard 2017#

low

unclear

high

unclear

low

low

high**

Brossard 2017#

low

unclear

high

unclear

low

low

high**

Yuki 2017#

low

unclear

high

unclear

low

low

high**

Gee 2017##

low

unclear

high

unclear

low

low

high**

* laboratories were blinded to randomization scheme; ** crossover study; *** unpublished study, characteristics and results available in the form of a conference poster; # study aimed at assessing pharmacokinetics; ## study aimed at assessing puffing topography.

 


Appendix E. List of included and excluded studies

Table 7. List of publications included in the analysis.

Nr

Symbol

Publication

Pre-clinical studies – aerosol chemistry and physics

1

Bekki 2017

Bekki K, Inaba Y, Uchiyama S, Kunugita N. Comparison of Chemicals in Mainstream Smoke in Heat-not-burn Tobacco and Combustion Cigarettes. J UOEH. 2017;39(3):201-207. doi: 10.7888/juoeh.39.201.

2

Crooks 2018

Crooks I, Neilson L, Scott K, Reynolds L, Oke T, Forster M, Meredith C, McAdam K, Proctor C. Evaluation of flavourings potentially used in a heated tobacco product: Chemical analysis, in vitro mutagenicity, genotoxicity, cytotoxicity and in vitro tumour promoting activity. Food Chem Toxicol. 2018 Aug;118:940-52.

3

Eaton 2018

Eaton D, Jakaj B, Forster M, Nicol J, Mavropoulou E, Scott K, Liu C, McAdam K, Murphy J, Proctor CJ. Assessment of tobacco heating product THP1.0. Part 2: Product design, operation and thermophysical characterisation. Regul Toxicol Pharmacol. 2018 Mar;93:4-13.

4

Farsalinos 2017

Farsalinos KE, Yannovits N, Sarri T, Voudris V, Poulas K. Nicotine Delivery to the Aerosol of a Heat-Not-Burn Tobacco Product: Comparison With a Tobacco Cigarette and E-Cigarettes. Nicotine Tob Res. 2017.

5

Farsalinos 2018

Farsalinos KE, Yannovits N, Sarri T, Voudris V, Poulas K, Leischow SJ. Carbonyl emissions from a novel heated tobacco product (IQOS): comparison with an e-cigarette and a tobacco cigarette. Addiction. 2018 Nov;113(11):2099-106.

6

Forster 2018

Forster M, Fiebelkorn S, Yurteri C, Mariner D, Liu C, Wright C, McAdam K, Murphy J, Proctor C. Assessment of novel tobacco heating product THP1.0. Part 3: Comprehensive chemical characterisation of harmful and potentially harmful aerosol emissions. Regul Toxicol Pharmacol. 2018 Mar;93:14-33.

7

Jaccard 2017

Jaccard G, Tafin Djoko D, Moennikes O, Jeannet C, Kondylis A, Belushkin M. Comparative assessment of HPHC yields in the Tobacco Heating System THS2.2 and commercial cigarettes. Regul Toxicol Pharmacol. 2017 Nov;90:1-8.

8

Jaccard 2018

Jaccard G, Kondylis A, Gunduz I, Pijnenburg J, Belushkin M. Investigation and comparison of the transfer of TSNA from tobacco to cigarette mainstream smoke and to the aerosol of a heated tobacco product, THS2.2. Regul Toxicol Pharmacol. 2018 Aug;97:103-9.

9

Li 2018

Li X, Luo Y, Jiang X, Zhang H, Zhu F, Hu S, Hou H, Hu Q, Pang Y. Chemical Analysis and Simulated Pyrolysis of Tobacco Heating System 2.2 Compared to Conventional Cigarettes. Nicotine Tob Res. 2018 Jan 8.

10

Poynton 2017

Poynton S, Sutton J, Goodall S, Margham J, Forster M, Scott K, Liu C, McAdam K, Murphy J, Proctor C. A novel hybrid tobacco product that delivers a tobacco flavour note with vapour aerosol (Part 1): Product operation and preliminary aerosol chemistry assessment. Food Chem Toxicol. 2017 Aug;106(Pt A):522-32.

11

Pratte 2017_1

Pratte P, Cosandey S, Goujon Ginglinger C. Innovative methodology based on thermo-denuder principle for the detection of combustion related solid particles or high boiling point droplets: Applications to cigarette and the Tobacco Heating System THS 2.2. Journal of Aerosol Science.

12

Pratte 2017_2

Pratte P, Cosandey S, Goujon Ginglinger C. Investigation of solid particles in the mainstream aerosol of the Tobacco Heating System THS2.2 and mainstream smoke of a 3R4F reference cigarette. Hum Exp Toxicol. 2017 Nov;36(11):1115-20.

13

Savareear 2017

Savareear B, Lizak R, Brokl M, Wright C, Liu C, Focant JF. Headspace solid-phase microextraction coupled to comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry for the analysis of aerosol from tobacco heating product. J Chromatogr A. 2017 Oct 20;1520:135-42.

14

Schaller 2016_1

Schaller JP, Keller D, Poget L, Pratte P, Kaelin E, McHugh D, Cudazzo G, Smart D, Tricker AR, Gautier L, Yerly M, Reis Pires R, Le Bouhellec S, Ghosh D, Hofer I, Garcia E, Vanscheeuwijck P, Maeder S. Evaluation of the Tobacco Heating System 2.2. Part 2: Chemical composition, genotoxicity, cytotoxicity, and physical properties of the aerosol. Regul Toxicol Pharmacol. 2016 Nov 30;81 Suppl 2:S27-47..

15

Schaller 2016_2

Schaller JP, Pijnenburg JPM, Ajithkumar A, Tricker AR .Evaluation of the Tobacco Heating System 2.2. Part 3: Influence of the tobacco blend on the formation of harmful and potentially harmful constituents of the Tobacco Heating System 2.2 aerosol. Regul Toxicol Pharmacol. 2016 Nov 30;81 Suppl 2:S48-58.

16

Uchiyama 2018

Uchiyama S, Noguchi M, Takagi N, Hayashida H, Inaba Y, Ogura H, Kunugita N. Simple Determination of Gaseous and Particulate Compounds Generated from Heated Tobacco Products. Chem Res Toxicol. 2018 Jul 16;31(7):585-93.

Pre-clinical studies – standard toxicology assessment

1

Schaller 2016

Schaller J.P, Keller D, Poget L, et al. Evaluation of the Tobacco Heating System 2.2. Part 2: Chemical composition, genotoxicity, cytotoxicity, and physical properties of the aerosol; Regulatory Toxicology and Pharmacology; 81; 2016; S27 - S47.

2

Breheny 2017

Breheny D, Adamson J, Azzopardi D. A novel hybrid tobacco product that delivers a tobacco flavour note with vapour aerosol (Part 2): In vitro biological assessment and comparison with different tobacco-heating products; Food and Chemical Toxicology; 106; 2017; 533 – 546.

3

Jaunky 2018

Jaunky T, Adamson J, Santopietro S. Assessment of tobacco heating product THP1.0. Part 5: In vitro dosimetric and cytotoxic assessment; Regulatory Toxicology and Pharmacology; 93; 2018; 52 – 61.

4

Thorne 2018

Thorne D, Breheny D, Proctor C, Gaca M. Assessment of novel tobacco heating product THP1.0. Part 7: Comparative in vitro toxicological evaluation; Regulatory Toxicology and Pharmacology; 93; 2018; 71 – 83.

5

Crooks 2018

Crooks I, Neilson L, Scott K, et al. Evaluation of flavourings potentially used in a heated tobacco product: Chemical analysis, in vitro mutagenicity, genotoxicity, cytotoxicity and in vitro tumour promoting activity, Food Chem Toxicol. 2018; 118: 940 - 952.

6

Wong 2016

Wong E.T, Kogel U, Veljkovic E, et al. Evaluation of the Tobacco Heating System 2.2. Part 4: 90-day OECD 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects compared with cigarette smoke; Regulatory Toxicology and Pharmacology; 81; 2016; S59 - S81.

Sewer A, Kogel U, Talikka M, et al. Evaluation of the Tobacco Heating System 2.2 (THS2.2). Part 5:

microRNA expression from a 90-day rat inhalation study indicates that exposure to THS2.2 aerosol causes reduced effects on lung tissue compared with cigarette smoke; Regulatory Toxicology and Pharmacology; 81; 2016; S82 - S92.

7

Oviedo 2016

Oviedo A, Lebrun S, Kogel U, et al. 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; Regulatory Toxicology and Pharmacology; 81; 2016; S93 - S122.

Kogel U, Titz B, Schlage W.K, et al. 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; Regulatory Toxicology and Pharmacology; 81; 2016; S123 - S138.

Pre-clinical studies – systems toxicology assessment

1

Gonzalez-Suarez 2016

Gonzalez-Suarez I, Martin F, Marescotti D, Guedj E, Acali S, Johne S, Dulize R, Baumer K, Peric D, Goedertier D, Frentzel S, Ivanov NV, Mathis C, Hoeng J, Peitsch MC. In Vitro Systems Toxicology Assessment of a Candidate Modified Risk Tobacco Product Shows Reduced Toxicity Compared to That of a Conventional Cigarette. Chem Res Toxicol. 2016 Jan 19;29(1):3-18.

2

Haswell 2018

Haswell LE, Corke S, Verrastro I, Baxter A, Banerjee A, Adamson J, Jaunky T, Proctor C, Gaça M, Minet E. In vitro RNA-seq-based toxicogenomics assessment shows reduced biological effect of tobacco heating products when compared to cigarette smoke. Sci Rep. 2018 Feb 5;8(1):1145.

3

Iskandar 2017a

Iskandar AR, Mathis C, Martin F, Leroy P, Sewer A, Majeed S, Kuehn D, Trivedi K, Grandolfo D, Cabanski M, Guedj E, Merg C, Frentzel S, Ivanov NV, Peitsch MC, Hoeng J. 3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product. ALTEX. 2017;34(1):23-48

4

Iskandar 2017b

Iskandar AR, Mathis C, Schlage WK, Frentzel S, Leroy P, Xiang Y, Sewer A, Majeed S, Ortega-Torres L, Johne S, Guedj E, Trivedi K, Kratzer G, Merg C, Elamin A, Martin F, Ivanov NV, Peitsch MC, Hoeng J. A systems toxicology approach for comparative assessment: Biological impact of an aerosol from a candidate modified-risk tobacco product and cigarette smoke on human organotypic bronchial epithelial cultures. Toxicol In Vitro. 2017 Mar;39:29-51.

5

Iskandar 2017c

Iskandar AR, Titz B, Sewer A, Leroy P, Schneider T, Zanetti F, Mathis C, Elamin A, Frentzel S, Schlage WK, Martin F, Ivanov NV, Peitsch MC, Hoeng J. 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. Toxicol Res (Camb). 2017 May 29;6(5):631-653.

6

Iskandar 2017d

Iskandar AR, Martinez Y, Martin F, Schlage WK, Leroy P, Sewer A, Torres LO, Majeed S, Merg C, Trivedi K, Guedj E, Frentzel S, Mathis C, Ivanov NV, Peitsch MC, Hoeng J. Comparative effects of a candidate modified-risk tobacco product Aerosol and cigarette smoke on human organotypic small airway cultures: a systems toxicology approach. Toxicol Res (Camb). 2017 Sep 28;6(6):930-946.

7

Jaunky 2018

Jaunky T, Adamson J, Santopietro S, Terry A, Thorne D, Breheny D, Proctor C, Gaça M. Assessment of tobacco heating product THP1.0. Part 5: In vitro dosimetric and cytotoxic assessment. Regul Toxicol Pharmacol. 2018 Mar;93:52-61.

8

Lo Sasso 2016

Lo Sasso G, Titz B, Nury C, Boué S, Phillips B, Belcastro V, Schneider T, Dijon S, Baumer K, Peric D, Dulize R, Elamin A, Guedj E, Buettner A, Leroy P, Kleinhans S, Vuillaume G, Veljkovic E, Ivanov NV, Martin F, Vanscheeuwijck P, Peitsch MC, Hoeng J. Effects of cigarette smoke, cessation and switching to a candidate modified risk tobacco product on the liver in Apoe -/- mice--a systems toxicology analysis. Inhal Toxicol. 2016 Apr;28(5):226-40.

9

Malinska 2018

Malinska D, Szymański J, Patalas-Krawczyk P, Michalska B, Wojtala A, Prill M, Partyka M, Drabik K, Walczak J, Sewer A, Johne S, Luettich K, Peitsch MC, Hoeng J, Duszyński J, Szczepanowska J, van der Toorn M, Wieckowski MR. 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. Food Chem Toxicol. 2018 May;115:1-12.

10

Philips 2016

Phillips B, Veljkovic E, Boué S, Schlage WK, Vuillaume G, Martin F, Titz B, Leroy P, Buettner A, Elamin A, Oviedo A, Cabanski M, De León H, Guedj E, Schneider T, Talikka M, Ivanov NV, Vanscheeuwijck P, Peitsch MC, Hoeng J. An 8-Month Systems Toxicology Inhalation/Cessation Study in Apoe-/- Mice to Investigate Cardiovascular and Respiratory Exposure Effects of a Candidate Modified Risk Tobacco Product, THS 2.2, Compared With Conventional Cigarettes. Toxicol Sci. 2016 Feb;149(2):411-32.

Titz B, Boué S, Phillips B, Talikka M, Vihervaara T, Schneider T, Nury C, Elamin A, Guedj E, Peck MJ, Schlage WK, Cabanski M, Leroy P, Vuillaume G, Martin F, Ivanov NV, Veljkovic E, Ekroos K, Laaksonen R, Vanscheeuwijck P, Peitsch MC, Hoeng J. Effects of Cigarette Smoke, Cessation, and Switching to Two Heat-Not-Burn Tobacco Products on Lung Lipid Metabolism in C57BL/6 and Apoe-/- Mice-An Integrative Systems Toxicology Analysis. Toxicol Sci. 2016 Feb;149(2):441-57.

11

Poussin 2016

Poussin C, Laurent A, Peitsch MC, Hoeng J, De Leon H. Systems toxicology-based assessment of the candidate modified risk tobacco product THS2.2 for the adhesion of monocytic cells to human coronary arterial endothelial cells. Toxicology. 2016 Jan 2;339:73-86.

12

Taylor 2018

Taylor M, Thorne D, Carr T, Breheny D, Walker P, Proctor C, Gaça M. Assessment of novel tobacco heating product THP1.0. Part 6: A comparative in vitro study using contemporary screening approaches. Regul Toxicol Pharmacol. 2018 Mar;93:62-70.

13

van der Toorn 2015

van der Toorn M, Frentzel S, De Leon H, Goedertier D, Peitsch MC, Hoeng J. Aerosol from a candidate modified risk tobacco product has reduced effects on chemotaxis and transendothelial migration compared to combustion of conventional cigarettes. Food Chem Toxicol. 2015 Dec;86:81-7.

14

van der Toorn 2018

van der Toorn M, Sewer A, Marescotti D, Johne S, Baumer K, Bornand D, Dulize R, Merg C, Corciulo M, Scotti E, Pak C, Leroy P, Guedj E, Ivanov N, Martin F, Peitsch M, Hoeng J, Luettich. The biological effects of long-term exposure of human bronchial epithelial cells to total particulate matter from a candidate modified-risk tobacco product. Toxicol In Vitro. 2018 Aug;50:95-108.

15

Zanetti 2016

Zanetti F, Sewer A, Mathis C, Iskandar AR, Kostadinova R, Schlage WK, Leroy P, Majeed S, Guedj E, Trivedi K, Martin F, Elamin A, Merg C, Ivanov NV, Frentzel S, Peitsch MC, Hoeng J. Systems Toxicology Assessment of the Biological Impact of a Candidate Modified Risk Tobacco Product on Human Organotypic Oral Epithelial Cultures. Chem Res Toxicol. 2016 Aug 15;29(8):1252-69.

16

Zanetti 2017

Zanetti F, Titz B, Sewer A, Lo Sasso G, Scotti E, Schlage WK, Mathis C, Leroy P, Majeed S, Torres LO, Keppler BR, Elamin A, Trivedi K, Guedj E, Martin F, Frentzel S, Ivanov NV, Peitsch MC, Hoeng J. Comparative systems toxicology analysis of cigarette smoke and aerosol from a candidate modified risk tobacco product in organotypic human gingival epithelial cultures: A 3-day repeated exposure study. Food Chem Toxicol. 2017 Mar;101:15-35.

Randomized controlled trials

1

Ludicke 2018

(NCT01970995)

Lüdicke F, Picavet P, Baker G, Haziza C, Poux V, Lama N, Weitkunat R. Effects of Switching to the Tobacco Heating System 2.2 Menthol, Smoking Abstinence, or Continued Cigarette Smoking on Biomarkers of Exposure: A Randomized, Controlled, Open-Label, Multicenter Study in Sequential Confinement and Ambulatory Settings (Part 1). Nicotine Tob Res. 2018 Jan 5;20(2):161-172.

Lüdicke F, Picavet P, Baker G, Haziza C, Poux V, Lama N, Weitkunat R. Effects of Switching to the Menthol Tobacco Heating System 2.2, Smoking Abstinence, or Continued Cigarette Smoking on Clinically Relevant Risk Markers: A Randomized, Controlled, Open-Label, Multicenter Study in Sequential Confinement and Ambulatory Settings (Part 2). Nicotine Tob Res. 2018 Jan 5;20(2):173-182.

Haziza C, Lama N, Donelli A, Picavet P, Baker G, Ancerewicz J, Benzimra M, Franzon M, Endo M, Ludicke F. Reduced Exposure to Harmful and Potentially Harmful Constituents After 90 Days of Use of Tobacco Heating System 2.2 Menthol in Japan: A Comparison with Continued Cigarete Use or Smoking Abstinence. SRNT – 22nd Annual Meeting, Chicago, USA, 2-5 March 2016. Plakat.

Picavet P, Haziza C, Lama N, Donelli A, Baker G, Ancerewicz J, Benzimra M, Franzon M, Masahiro Endo MD, Ludicke F. Reduced exposure to harmful and potentially harmful constituents after 90 days of use of tobacco heating system 2.2 in Japan: A comparison with continued combustible cigarette use or smoking abstinence. Toxicology Letters. Volume 259, Supplement, 10 October 2016, Page S141.

2

Haziza 2016d

(NCT01989156)

Haziza C, de La Bourdonnaye G, Picavet P, Baker G, Skiada D, Merlet S, Franzon M, Farmer F, Lewis W, Ludicke F. Reduced Exposure to Harmful and Potentially Harmful Constituents After 90 Days of Use of Tobacco Heating System 2.2 Menthol in the U.S.: A Comparison with Continued Cigarete Use or Smoking Abstinence. SRNT – 22nd Annual Meeting, Chicago, USA, 2-5 March 2016. Plakat.

3

Haziza 2016a

(NCT01959932)

Haziza C, de La Bourdonnaye G, Skiada D, Ancerewicz J, Baker G, Picavet P, Lüdicke F. Evaluation of the Tobacco Heating System 2.2. Part 8: 5-Day randomized reduced exposure clinical study in Poland. Regul Toxicol Pharmacol. 2016 Nov 30;81 Suppl 2:S139-S150.

Haziza C, de La Bourdonnaye G, Skiada D, Ancerewicz J, Baker G, Picavet P, Lüdicke F. Biomarker of exposure level data set in smokers switching from conventional cigarettes to Tobacco Heating System 2.2, continuing smoking or abstaining from smoking for 5 days. Data Brief. 2016 Nov 18;10:283-293.

Martin F, Talikka M, Ivanov NV, Haziza C, Hoeng J, Peitsch MC. Evaluation of the tobacco heating system 2.2. Part 9: Application of systems pharmacology to identify exposure response markers in peripheral blood of smokers switching to THS2.2. Regul Toxicol Pharmacol. 2016 Nov 30;81 Suppl 2:S151-S157.

4

Haziza 2016b

(NCT01970982)

Haziza C, de La Bourdonnaye G, Merlet S, Benzimra M, Ancerewicz J, Donelli A, Baker G, Picavet P, Lüdicke F. Assessment of the reduction in levels of exposure to harmful and potentially harmful constituents in Japanese subjects using a novel tobacco heating system compared with conventional cigarettes and smoking abstinence: A randomized controlled study in confinement. Regul Toxicol Pharmacol. 2016 Nov;81:489-499.

5

Gale 2018

Gale N, McEwan M, Eldridge A.C et al. Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to Tobacco Heating Products: A Randomized, Controlled Study in Healthy Japanese Subjects. Nicotine & Tobacco Research, 2018, 1–8.

6, 7

Brossard 2017

(NCT01959607,

NCT01967706)

Brossard P, Weitkunat R, Poux V, Lama N, Haziza C, Picavet P, Baker G, Lüdicke F. Nicotine pharmacokinetic profiles of the Tobacco Heating System 2.2, cigarettes and nicotine gum in Japanese smokers. Regul Toxicol Pharmacol. 2017 Oct;89:193-199.

8

Yuki 2017

Yuki D, Sakaguchi C, Kikuchi A, Futamura Y. Pharmacokinetics of nicotine following the controlled use of a prototype novel tobacco vapor product. Regulatory Toxicology and Pharmacology 87 (2017) 30e35.

9

Gee 2017

Gee J, Prasad K, Slayford S, Gray A, Nother K, Cunningham A, Mavropoulou E, Proctor C. Assessment of tobacco heating product THP1.0. Part 8: Study to determine puffing topography, mouth level exposure and consumption among Japanese users. Regul Toxicol Pharmacol. 2018 Mar;93:84-91.

Indoor air quality studies

1

Mitova 2016

 

Mitova MI, Campelos PB, Goujon-Ginglinger CG, Maeder S, Mottier N, Rouget EG, Tharin M, Tricker AR. Comparison of the impact of the Tobacco Heating System 2.2 and a cigarette on indoor air quality. Regul Toxicol Pharmacol. 2016 Oct;80:91-101.

Mottier N, Tharin M, Cluse C, Crudo JR, Lueso MG, Goujon-Ginglinger CG, Jaquier A, Mitova MI, Rouget EG, Schaller M, Solioz J. Validation of selected analytical methods using accuracy profiles to assess the impact of a Tobacco Heating System on indoor air quality. Talanta. 2016 Sep 1;158:165-78.

Mitova M, Campelos P, Goujon-Ginglinger C, Maeder S, Mottier N, Rouget E, Tharin M, Smith M, Tricker A. Indoor Air Chemistry Assessment of environmental aerosol generated by Tobacco Heating System 2.2. ACT 36th Annual Meeting. Red Rock Resort. Summerlin, Nevada, November 8-11, 2015. Plakat konferencyjny. https://www.pmiscience.com/resources/docs/default-source/library-documents/mitova.pdf?sfvrsn=1b17f606_0

Goujon-Ginglinger C, Campelos P, Maeder S, Mitova M, Mottier N, Rouget E, Tharin M, Tricker A, Smith M. Indoor Air Chemistry Comparative study between conventional cigarette and heat-not-burn technology. Plakat konferencyjny. https://www.pmiscience.com/resources/docs/default-source/library-documents/coujon_poster.pdf?sfvrsn=517f606_2

Goujon-Ginglinger C. Air Quality assessment during indor use of the Tobacco Heating System 2.2. Japan Society for Environment Chemistry. June, 7-9. Shizuoka (Japan). Prezentacja konferencyjna. https://www.pmiscience.com/resources/docs/default-source/Presentations_Latest/jsfec-2017_ggoujon_air-quality-assessment-during-indoor-use-of-ths-2-2.pdf?sfvrsn=722dca06_0

Goujon-Ginglinger C, Mitova M, Maeder S, Smith M. Air quality assessment during indor use of the Tobacco Heating System THS 2.2. EUROTOX 2017, Bratislava. September 10-13, 2017. Plakat konferencyjny. https://www.pmiscience.com/resources/docs/default-source/Posters_Latest/eurotox-2017-goujonginglinger-air-quality-assessment-during-indoor-use-of-ths-2-2.pdf?sfvrsn=f8d3cd06_0

Goujon-Ginglinger C, Mitova M, Maeder S. Indoor Air Quality Assessment of the Tobacco Heating System THS 2.2, Electronic Cigarettes and Cigarette using a dedicated Exposure Room Atmos’Fair, 7th Edition. October, 12 2016. Prezentacja konferencyjna. https://www.pmiscience.com/resources/docs/default-source/library-documents/goujon_atmos_fair_2016_indoor_air_quality_assessment.pdf?sfvrsn=62aef706_2

Mitova M, Goujon-Ginglinger C, Rotach M, Maeder S. Air Quality assessment during indor use of the Tobacco Heating System 2.2. CORESTA 2017, October, 8-12 2017. Kitzbuhel (Austria). Prezentacja konferencyjna. https://www.pmiscience.com/resources/docs/default-source/Presentations_Latest/coresta-2017-mitova-air-quality-assessment-during-indoor-use.pdf?sfvrsn=30bccc06_0

Tharin M, Bielik N, Rouget E, Rotach M, Glabasnia A. Assessment of the total volatile organic compounds in indoor air during use of the Tobacco Heating System THS 2.2. Smoke Science and Product Technology (SSPT 2017), Kitzbühel, Austria. 08. –12. October 2017. Plakat konferencyjny. https://www.pmiscience.com/resources/docs/default-source/Posters_Latest/coresta-2017-glabasnia-assessment-of-the-total-volatile-organic-compoundsf4b4a5852f88696a9e88ff040043f5e9.pdf?sfvrsn=243ccc06_0

2

Pratte 2017

Pratte P, Cosandey S, Goujon Ginglinger C. Investigation of solid particles in the mainstream aerosol of the Tobacco Heating System THS2.2 and mainstream smoke of a 3R4F reference cigarette. Human and Experimental Toxicology 2017, Vol. 36(11) 1115–1120.

3

Protano 2016

Protano C, Manigrasso M, Avino P, Sernia S, Vitali M. Second-hand smoke exposure generated by new electronic devices (IQOS® and e-cigs) and traditional cigarettes: submicron particle behaviour in human respiratory system, Ann Ig 2016; 28: 109-112.

4

Protano 2017

Protano C, Manigrasso M, Avino P, Vitali M. Second-hand smoke generated by combustion and electronic smoking devices used in real scenarios: Ultrafine particle pollution and age-related dose assessment. Environment International 107 (2017) 190–195.

5

Ruprecht 2017

Ruprecht A.A, De Marco C, Saffari A, et al. Environmental pollution and emission factors of electronic cigarettes, heat-not-burn tobacco products, and conventional cigarettes. Aerosol Science and Technology 2017, 51:6, 674-684.

6

Forster 2018

Forster M, McAughey J, Prasad K, Mavropoulou E, Proctor C. Assessment of tobacco heating product THP1.0. Part 4: Characterisation of indoor air quality and odour. Regulatory Toxicology and Pharmacology 93 (2018) 34e51.

 

Table 8. List of publications excluded from the analysis.

Nr

Publication

Reason for exclusion

Pre-clinical studies

1

Lindson-Hawley N, Hartmann-Boyce J, Fanshawe TR, Begh R, Farley A, Lancaster T. Interventions to reduce harm from continued tobacco use. Cochrane Database Syst Rev. 2016 Oct 13;10:CD005231.

Another intervention

2

Adamson J, Jaunky T, Thorne D, Gaça MD. Characterisation of the borgwaldt LM4E system for in vitro exposures to undiluted aerosols from next generation tobacco and nicotine products (NGPs). Food Chem Toxicol. 2018 Mar;113:337-344.

Another comparator

3

Ansari, S., K. Baumer, et al. (2016). Comprehensive Systems Biology Analysis of a 7-Month Cigarette Smoke Inhalation Study in C57bl/6 Mice. Sci Data 3: 150077.

Another intervention

4

Bombick, B. R., J. T. Avalos, et al. (1998). Comparative Studies of the Mutagenicity of Environmental Tobacco Smoke from Cigarettes That Burn or Primarily Heat Tobacco.  Environmental and Molecular Mutagenesis 31(2): 169-175.

Another intervention

5

Bombick, B. R., H. Murli, et al. (1998). Chemical and Biological Studies of a New Cigarette That Primarily Heats Tobacco. Part 2. In Vitro Toxicology of Mainstream Smoke Condensate. Food and Chemical Toxicology 36(3): 183-190.

Another intervention

6

Bombick D.W., Ayres P.H., Putnam K., Bombick B.R., Doolittle D.J. Chemical and biological studies of a new cigarette that primarily heats tobacco. Part 3. In vitro toxicity of whole smoke. Food and Chemical Toxicology 1998 36:3 (191-197)

Another intervention

7

Bombick, D. W., K. Putnam, et al. (1998). Comparative Cytotoxicity Studies of Smoke Condensates from Different Types of Cigarettes and Tobaccos. Toxicology in Vitro 12(3): 241-249.

Another intervention

8

Camacho, O. M., J. Sommarstrom, et al. (2016). Reference Change Values in Concentrations of Urinary and Salivary Biomarkers of Exposure and Mouth Level Exposure in Individuals Participating in an Ambulatory Smoking Study. Pract Lab Med 5: 47-56.

Another intervention

9

Coggins, C. R., P. H. Ayres, et al. (1989). Ninety-Day Inhalation Study in Rats, Comparing Smoke from Cigarettes That Heat Tobacco with Those That Burn Tobacco. Fundam Appl Toxicol 13(3): 460-483.

Another intervention

10

Davis B, Williams M, Talbot P. iQOS: evidence of pyrolysis and release of a toxicant from plastic. Tob Control. 2018 Mar 13. pii: tobaccocontrol-2017-054104. doi: 10.1136/tobaccocontrol-2017-054104. [Epub ahead of print]

Another trial methods

11

Doolittle, D. J., C. K. Lee, et al. (1990). Genetic Toxicology Studies Comparing the Activity of Sidestream Smoke from Cigarettes Which Burn or Only Heat Tobacco. Mutation Research 240(2): 59-72.

Another intervention

12

Elamin, A., B. Titz, et al. (2016). Quantitative Proteomics Analysis Using 2d-Page to Investigate the Effects of Cigarette Smoke and Aerosol of a Prototypic Modified Risk Tobacco Product on the Lung Proteome in C57bl/6 Mice.  Journal of Proteomics 145: 237-245.

Another intervention

13

Fields W, Fowler K, Hargreaves V, Reeve L, Bombick B. Development, qualification, validation and application of the neutral red uptake assay in Chinese Hamster Ovary (CHO) cells using a VITROCELL® VC10® smoke exposure system; Toxicology in Vitro; 40; 2017; 144–152.

Another intervention