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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access  Full Text Article                                                                                                                     Review Article 

The Content of Harmful and Potentially Harmful Constituents in Heated Tobacco Product: Systematic Review

Shoim Hidayat, Putri Ayuni Alayyannur* 

Department of Occupational Safety and Health, Faculty of Public Health, Airlangga University, Indonesia

Indonesia is a home to 65 million smokers and one of the countries with the highest number of smokers in the world. A recent study of 2018 Basic Health Research by the Ministry of Health showed that the prevalence of smoking in Indonesia showed no sign of decline despite highly aggressive tobacco control policies in Indonesia. The astronomically high number of smokers in Indonesia calls for a new approach in dealing with the issue. 

Smoking has long been associated scientifically with increased morbidity and premature mortality. most of health hazards due to smoking comes from exposure to cigarette smoke (smoke aerosol), formed from the burning process of tobacco in conventional cigarettes ¹. This propels the implementation of the concept of tobacco harm reduction by striving for products for those still craving for tobacco can still consume, but at a lower risk.

In terms of toxicology, health risks arising from toxic substances is largely determined by the exposure dose, that is, the amount of real toxic substances entering the body. Meanwhile, the exposure dose is largely determined by the level and duration of exposure. Thus, if the exposure level is lower, the exposure dose will also be lower, and in turn, the potential toxicity also decreases. Vice versa, the higher the exposure level, the higher the potential toxicity will be. Along with the concept of harm reduction, increased awareness of smoking-related health risks and technological developments, an innovation was born in the form of heated tobacco products as a lower risk alternative to conventional cigarettes. Heated tobacco product (HTP) is one instance of alternative tobacco products that do not undergo a burning or combustion process, but only a heating process. 

When a cigarette burns, in many publications, about 6,000 - 8,000 kinds of chemical compounds in cigarette smoke are mentioned ^2,3. The chemical compounds in cigarette smoke are very complex and dynamic. Dynamic in this case means that the physicochemical properties of the compound contained can change rapidly and instantly, for example, the vapor generated from the combustion process immediately turns into particles, or vice versa. Also, the size of the existing particles can vary in size ⁴. This is inversely proportional to HTP. Research by HTP producers and several independent institutions found that by eliminating the combustion process, there was a decrease in the levels of chemical compounds that can potentially cause health problems (Harmful an Potentially Harmful Constituents/HPHC) in HTP by up to 90% compared to the HPHCs produced by the 3R4F reference cigarette ⁵.

To date, there have been many foreign studies that have tried to analyze heated tobacco products. Previous studies are summarized briefly, including a brief discussion of the challenges with adapting standard analytical methods used to tobacco smoke. This literature review will discuss from the toxicological aspects whether there is a difference in the HPHC content between conventional cigarettes and HTP.

The type of data used was secondary data in the form of quantitative data, qualitative data or a combination thereof. Textbooks underlying the theory in this study was also used. Study search and selection were performed using Medline, Scopus, PubMed and Database Web of Science, limited to studies conducted until July 2020 with a search period up to September 2020. The search included terms related to HnB in general (‘Heat not burn’, ‘Tobacco Heating System’, ‘Electronic Nicotine Delivery System’, ‘Novel Tobacco Product’) and brand names (‘IQOS’, ‘Ploom’, ‘Heets’, ‘glo’, ‘PNV’), and were limited to studies published from 2010, thereby excluding obsolete or outdated papers on HnB devices. Prior to further discussion of papers to be used as reference, at the preliminary stage the researchers carried out a process of screening titles and abstracts from the study then independently filtered the papers completely in accordance with the objectives of this study. 

The method used for this literature review was tradition review, that is a method of literature review on a topic selected based on the knowledge and experience possessed by the researcher. Systematic Literature Review is a literature review method that is used using predetermined stages. It identified, assessed, and interpreted the whole findings of a study topic, to answer predetermined research questions. The selection of papers was also not carried out subjectively by researchers, but using predetermined protocols and filters. 

The use of publications in this study referred to inclusion and exclusion criteria. The inclusion criteria included literatures and publication journals focusing on the discussion of the use of heated tobacco technology and publications that have been peer-reviewed. Textbooks on basic theories of toxicology and disease risk assessment were also utilized. The publications that were directly related to studies on HPHCs in heated tobacco products were limited to those published after 2010. However, publications prior to 2010 were still used for supporting references. The exclusion criteria included publications that have not been peer-reviewed, did not focus on heated tobacco products, were not published in Englilsh and could no longer be downloaded or documented. Sources used in this study included publications containing subjects on HPHC emission both in HTPs or conventional cigarettes.

The process of searching and filtering databases from journals or scientific publications on either heated tobacco products (HTP) or e-cigarettes were performed from July 2020 to September 2020. There were 248 publications from the initial searching which would be then narrowed to 22 scientific publications and become a reference in this study (Figure 1).

Figure 1: Schematic of the Process of Searching and Screening HTP-related Journals/Publications

3.1. HPHC Content in HTPs

The main driver of the conception of heated tobacco products is the need for an alternative for people who desire nicotine at lower risks. Health risks to smokers are caused more by exposure to HPHCs arising from the combustion process, not due to nicotine exposure. There was not enough evidence showing that nicotine is carcinogenic ³. Several heated tobacco products, both ready-to-market or just prototypes, can be seen in table 1.

Table 1: Heated Tobacco Products That Are Ready to Market or Just Prototypes

Source: Simonavicius E. et al., 2018 ⁶

The studies included in this literature review were reviewed with impartial view toward sources of funding. However, manufacturers who financed and report their own product findings were inherently bound by conflicts of interest. Table 2 is a summary of both independent or sponsor manufacturer studies. 

Table 2: Summary of Independent and Sponsor Manufacturer Studies

CO, CO₂ and NO_x gases are markers of combustion. By eliminating the combustion process, the levels of CO, CO₂ and NO_x in HTP decreased significantly compared to conventional cigarette smoke ^12,13.

Table 3: Mean Levels ± SD (Standard Deviation) of Combustion Marker Gases in Conventional Cigarettes Compared to HTPs

Source: Eaton, 2018 ¹²

The data in table 3 shows that in the use of heated tobacco products, no combustion occurs, only heating. It is shown by the low levels of combustion markers namely CO, CO₂ and NO_x in HTPs. Low exposure to CO was also demonstrated by Caponneto et al. (2018) where the level of CO exhalation—as a biomarker of CO exposure in HTP users—was significantly lower compared to conventional cigarette consumers ²⁵. 

Mitoya et al. (2016), in their study showed a difference in HPHC levels of office space, residential air exposed to HTPs and conventional cigarettes ²⁶. In general, spaces exposed to HTP aerosols showed lover levels of HPHC compared to those exposed to cigarette smoke, except for a few compounds such as nicotine and acetaldehyde, which were similar to conventional cigarettes. In addition, it was shown that H₂O₂—one of free radical compounds in the ROS (reactive oxygen species) group—is 5 times lower in HTP aerosols than conventional cigarettes ²⁷. These studies corroborated existing studies concluding that the level of chemical compounds of mainstream smoke of conventional cigarettes largely is 90% higher than heated tobacco products ^{13, 5, 10, 28, 29}. Table 5 shows a decrease in the concentration of most of HPHCs in HTPs compared to conventional cigarettes ¹³.

Table 4: Content of HPHC Compounds in HTP Aerosols and Conventional Cigarettes and Their Decrease

Source: Foster et al., 2018 ¹³

As shown in table 4, all parameters in HTP have lower levels than conventional cigarettes, albeit with varying degrees. A small decrease is observed in TPM, water and tar (NFDPM). Meanwhile, other parameters are 70-99% lower for HTP.

A number of studies examining 9 TobReg priority constituents in conventional cigarettes and HTP showed that HPHC levels of HTP were largely lower than conventional cigarettes ^{13, 30, 12}. The decreases are shown in table 5.

Table 5: Content of 9 HPHCs Recommended in Mainstream Aerosols per Stick

Source: Foster et al., 2018 ¹³

As shown in Table 5, all 9 HPHC compounds recommended for reduction (TobReg priority constituents) were shown to have 90% lower levels in HTP. The study by Poynton et al., 2017 on the 9 HPHC compounds and other toxic compounds also showed similar results, as presented in Table 6 ¹⁴.

Table 6: Levels of Several Compounds in HTP Aerosols Compared to Conventional Cigarettes (3R4F)

Source: Poynton et al., 2017 ¹⁴

The results showed that all 9 HPHCs (nine TobReg priority constituent) were shown to be lower in HTP compared to conventional cigarettes.

ACKNOWLEDGEMENTS 

Researchers would like to declare our gratefulness to the KABAR team, all the authors of the article that we cite.

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