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Tobacco Heating System: a Scientific Review of the Scientific

Literature on Aerosol Composition
MARIA GONTA*, https://orcid.org/0000-0003-3476-0967,
VIORICA GLADCHI, https://orcid.org/0000-0002-5847-4466,
ELENA BUNDUCHI, https://orcid.org/0000-0002-6036-9091
Moldova State University, Faculty of Chemistry and Chemical Technology, Department of Industrial and Ecological
Chemistry, 60 A. Mateevici Str., Chisinau MD-2009, Republic of Moldova

Abstract: Regulation of the concentration of toxic substances derived from tobacco products is carried
out to reduce the incidence of deaths and diseases caused by the use of tobacco cigarettes, as well as to
decrease attractiveness, addiction, and toxicity. In this context, modified risk tobacco products (MRTPs)
have been developed to provide alternative products that have the potential to reduce the risk and harm
to the population when compared to smoking conventional cigarettes. One example of an MRTP is the
Tobacco Heating System (THS2.2), which, unlike conventional cigarettes, heats the tobacco instead of
burning it, producing a significantly reduced amount of harmful and potentially harmful constituents
(HPHCs). To review the data on the content of HPHCs in the aerosols and smoke of conventional
cigarettes and those of the THS2.2 type, a critical review of scientific publications in this field was
conducted from January 2015 to May 2022. The selection of scientific publications from open sources
was carried out from the Scopus, Web of Science, Google Scholar, PubMed, MedLine databases, and
others. A similar analysis was carried out on the information already available on the websites of Philip
Morris International (PMI), Elsevier, Springer, and other relevant web resources that include
information on the use of the THS2.2. After conducting a comprehensive analysis of results from both
independent and industry-sponsored studies, it was noted that HPHCs are not completely eliminated
from the aerosol produced by heated tobacco products (HTPs). However, the levels of these HPHCs
from the PMI List of 58 Constituents (PMI-58 list) are consistently lower and significantly reduced when
compared to the mainstream smoke emitted by conventional cigarettes. This suggests that while HTPs
present reduced emissions of toxicants in comparison, they are not completely free from risks.

Keywords: tobacco heating system, conventional cigarettes, harmful and potentially harmful
constituents

1. Introduction
According to their manufacturers, heated tobacco products (HTPs) are a class of tobacco products
created as alternative options to conventional cigarettes, as they are claimed to reduce the consumer's
risk of illness by inhaling fewer and smaller amounts of harmful substances.
There are extensive published reviews of heated tobacco products [1-8] that summarise studies on
the health risks and composition of these products in comparison to conventional cigarettes.
The goal of this review was to evaluate the scientific evidence currently available regarding the
qualitative composition of the Tobacco Heating System, commercialised under the IQOS brand (THS2.2
aerosol, Philip Morris International (PMI) product), and cigarette smoke. Moreover, the study examined
the levels of harmful and potentially harmful constituents (HPHCs) from the PMI-58 list emitted by
THS2.2 devices, as measured by expert groups within the company, to ensure they are not higher than
the levels established by independent expert groups (independent laboratories).
Heated tobacco products require independent research to assess their safety for public health. The
main task of this systematic review of the current literature (2015-2022) was to conduct a comprehensive
investigation of the literature in this field, examining the quality and concentrations of HPHCs in
systematic evaluations reported by both independent reviewers and those from the tobacco industry. It
*email: mvgonta@yahoo.com

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was equally important to identify and compare the methodology applied in the qualitative and
quantitative determination of these compounds, and its compliance with standards for determining
HPHC concentrations. Also of particular interest to the research was the study of the concentration levels
of 56 other constituents, which are not included in the PMI-58 list or the FDA list for HPHCs in the
emissions ofHTPs.

2. Materials and methods

In order to review the data on the content of HPHCs emitted as a result of smoking conventional
cigarettes and those from the THS 2.2, a critical review of scientific publications in this field was
conducted.
The study involved a systematic review of scientific articles, following procedures for generalisation
and critical analysis. As a result, systematic methods were used to compare and generalise the findings
of research on THS2.2. A detailed description of the systematic review methodology was presented in
the PRISMA 2020 protocol (PRISMA – The Preferred Reporting Items for Systematic Reviews and
Meta-Analyses) [9, 10], which outlines the stages of conducting the study and was applied for the case
study.
To broaden the identification of research in the targeted field, the selection of scientific publications
from open sources was carried out from the databases Scopus, Web of Science, Google Scholar,
PubMed, MedLine, Embase, PsycINFO, ProQuest, CORE, Index Copernicus, SJR, and others.
The search was conducted using the following keywords: "Philip Morris International Inc. (PMI)",
"PMI List of 58 Constituents (PMI-58)", "Harmful and Potentially Harmful Constituents (HPHCs)", "I-
Quit-Ordinary-Smoking (IQOS)", "Tobacco Heating System (THS, THS 2.2)", "Heated Tobacco
Product (HTP)", "New Tobacco Products", "Aerosol", "No Combustion and No Smoke", "THS2.2",
"Conventional Combustion Cigarettes from the University of Kentucky (3R4F)", "Heat-not-Burn
(HNB)", "Volatile Organic Chemicals (VOCs)", "Nicotine", "Tobacco Harm Reduction", "Modified
Risk Tobacco Product (MRTP)", "Toxicology", "Health Canada Intense (HCI)", "Carcinogen (CA)",
"Cardiovascular Toxicant (CT)", "Electrically Heated Cigarette Smoking System", "The United States
Food and Drug Administration (FDA, US FDA)".
In the selection process, the titles and summaries of papers relevant to the research theme were
initially used. In cases where the material was pertinent, full scientific publications were obtained and
reviewed. Special attention was given to the bibliographic references cited in these papers, which served
as an additional source of information. Additionally, information already available on the websites of
PMI, Elsevier, Springer, and other relevant web resources providing information on the use of THS 2.2
was analysed.
After the information was analysed, only those scientific publications presented in English, available
in relevant international databases, with a DOI (Digital Object Identifier), and published between 1st
January 2015 and 31st May 2022, were selected. Duplicate papers, conference presentations, brief
summaries without analysis of primary data, collections of papers from scientific events, and papers
presenting findings on the composition of air in spaces where THS devices were used were excluded.
Similarly, papers analysing toxicological effects and the dynamics of toxicological parameters over time
(which did not align with the purpose of the study), as well as those in which HPHC concentrations in
the aerosol were not specified or were not compared with HPHC content in the smoke of conventional
cigarettes, were excluded. Studies focusing on health impacts, human organs affected by smoking or
using THS systems, pharmacokinetic studies, and other medical-related studies were also excluded. The
review did not include papers related to methodological issues (such as comparisons of analysis methods,
precision when using different methods, or analysis of combined methods) or those where imperfect
research methods were applied, and the experimental procedures or the number of repetitions were not
clearly described.
The search for bibliographic sources, analysis, and selection of scientific papers was carried out
independently by three researchers. After analysing the results, in cases of ambiguity or unclear

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expression, the final decision regarding the inclusion or exclusion of scientific papers was made
collectively, following discussions and presenting arguments from all perspectives. The information
obtained during the search and selection of scientific papers for further meta-analysis is shown in Figure
1.
During the search for bibliographic sources, 435 papers were identified. After the initial screening
of titles and abstracts, 217 of these papers were removed due to duplicate entries, records flagged as
ineligible by automation tools, or because the materials were preprints that had not undergone final
journal review. Another 25 papers were subsequently excluded during the second analysis because they
were conference abstracts, promotional materials, or studies not in English. Of the 193 eligible papers,
178 studies were excluded for various reasons: they were toxicological or pharmacokinetic studies,
studies focused on the methodology of the experiment, studies using flawed research methods or other
methodologies, or articles that were outside the scope of the review.

Records identified from database searches

(n = 435): Records removed before screening
Scopus (n=101); Web of Science (n=89); (n = 217)
PubMed (n=76); Google Scholar (n=83); Duplicate records removed (n = 177)
Identification

MedLine (n=34); PsycINFO (n=17); Records marked as ineligible by automation tools

Embase (n=10); ProQuest (n=12); (n = 21)
SJR (n=7); CORE (n=4); Removed because materials are preprints and have not
Index Copernicus (n=2). passed final journal review (n = 5)
Removed for other reasons (n = 14)

Records excluded
(n = 25)
Screening

- 10 conference abstracts
Records screened - 7 promotional materials
(n = 218) - 8 studies not in English

Reports excluded
Eligibility

Full-text articles assessed (n = 178)

for eligibility Reason 1: Toxicological Studies (n = 86)
(n = 193) Reason 2: Imperfect Research Methods or other
methodologies (n = 12)
Reason 3: Articles being out of scope of the review (n=80)
Included

Studies included
in the meta-analysis
(n = 15)

Figure 1. PRISMA Flow Diagram

After analysing the contents of the remaining papers for the review, 15 scientific papers remained,
which analyse the content of HPHCs in cigarette smoke and THS devices. Of these, 10 papers represent
the results of independent studies, while 5 papers were published by members of research teams within
PMI's scientific laboratories. The research initiated by PMI was carried out by scientists in Switzerland
(5 papers). Independent studies were conducted in professional scientific laboratories in Japan (3
papers), China (2 papers), Germany, Finland, the USA, France, and Switzerland (each with one
publication).

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3. Results and discussions

3.1. Analysis of publications in the field
During the investigated period, 10 articles containing pertinent, independent experimental data were
published regarding the HPHC content of THS products, which represent the heat-not-burn tobacco
product introduced to global markets. These data are compared with the values of harmful and potentially
harmful substances found in conventional 3R4F cigarettes (Table 1).

Table 1. Data on the content of HPHCs presented by independent sources,

compared with the PMI-58 list
Source [11] [12] [2] [13] [14] [15] [16] [17] [18] [19]
Total measured
58 35 14 26 9 31 30 42 20 16
components
Detected
components from 58 26 12 12 7 12 28 8 3 6
the PMI-58 list
% of the PMI-58 list 100 45 21 21 12 21 48 14 5 10

The results presented in scientific articles were published in specialised journals: Tobacco Control
(6.953 IF), Nicotine & Tobacco Research (5.825 IF), Archives of Toxicology (5.153 IF), JAMA Internal
Medicine (44.424 IF), Journal of UOEH (0.90 IS), Chemical Research in Toxicology (3.973 IF),
Toxicology Letters (4.271 IF), Journal of Hazardous Materials (14.224 IF), Environmental Science and
Pollution Research (5.19 IF), and Environmental Health and Preventive Medicine.
All publications used THS2.2 products, branded as IQOS and produced by Philip Morris
International Inc., and the reference cigarette 3R4F, purchased from the University of Kentucky (USA).
Both products were tested using the Health Canada Intense puff regime. Chemical analysis of the aerosol
emitted by the THS2.2 and the reference cigarette smoke (3R4F) was carried out using methods such as
comprehensive gas chromatography-mass spectrometry, high-performance liquid chromatography
coupled to a fluorescence detector, gas chromatography coupled with a flame ionisation detector, liquid
chromatography tandem mass spectrometry, FTIR spectroscopy, and others. The concentrations of the
detected substances are expressed in mg/stick, µg/stick, or ng/stick.
The systematic review of the data presented in these papers is complicated due to several factors,
among which the following stand out:
- An uneven distribution of the determined components. The total number of components
determined and the number of components included in the PMI-58 list vary significantly depending on
the goals of each research project (Table 1). The most comprehensive compilation of information is
found in the source by [11]. This source reports concentrations of 100% and 95% HPHCs in the aerosols
produced by THS2.2 and conventional cigarette smoke (3R4F), both of which are included in the PMI-
58 list. The study by Gideon St. Helen provides a review of PMI-generated data submitted to the FDA
for the MRTP application. Although this scientific study is associated with the PMI group, it has
historically been treated as independent in public sources. As a result, we have categorised it under
independent sources. Other studies analyse a much smaller number of substances from this list, making
it difficult to compare and analyse the data.
- The number of replicates for the analyses varies from one article to another, and even from one
parameter to another within the same article [2, 13].
- The issue regarding the determination of "Tar" is also significant. In three independent studies,
researchers determined the Tar for THS products in comparison to cigarettes. To understand why this
comparison lacks scientific validity and is misleading, it is important to clarify the meaning and origin
of Tar. Tar is simply the total weight of solid and liquid residue in cigarette smoke after the weight of
nicotine and water has been subtracted [20]. Tar does not provide any indication of the composition of
the smoke, particularly the amount of HPHCs. As a consequence, the World Health Organization (WHO)
has removed Tar from its list of analytes to be measured in smoke, and their new list comprises 39

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HPHCs, which is the only meaningful way to compare products from a health impact perspective. The
International Organization for Standardization (ISO) has proposed a method to measure Nicotine-Free
Dry Particulate Matter, which involves determining the total particulate matter and subsequently
measuring nicotine and nicotine-free dry particulate matter. This is equivalent to the difference between
total particulate matter and the sum of water and nicotine content. In THS products, the aerosol typically
contains around 80% water. To ensure accurate measurement and comparisons, the WHO
TobLabNetwork and ISO are developing specific methods for determining water content in high-water
aerosols. They are also working on developing and validating methods to measure the contents and
emissions of nicotine and other substances in tobacco products, including nicotine, carbon monoxide,
and aldehydes in HTP emissions.
As a result, these factors degrade the quality of statistical processing and reduce the accuracy of
result comparisons.
Another peculiarity is that several parameters determined in various independent scientific
publications are not included in the PMI-58 list. For example, in source [18], only 5% of the detected
components are found in the PMI-58 list, in source [14] the proportion of these substances is 12%, in
source [19] it is 10%, and in source [17] only 14% of the detected substances are included in the PMI-
58 list (Table 1).
The analysis of results presented in six scientific papers published by scientists from PMI shows that
all of the research was conducted by scientists at PMI's Centre for Research & Development (R&D)
located in Switzerland. The data were obtained as part of research comparing the levels of hazardous
and potentially harmful constituents (HPHCs) found in PMI's THS aerosol with those found in smoke
from a reference cigarette, based on analyses by Labstat International ULC, an independent contract
research organisation [26]; chemical composition, genotoxicity, cytotoxicity, and physical properties of
the THS aerosol [22]; comparative assessment of HPHC yields in the THS2.2 and commercial cigarettes
[23]; an experimental investigation into the operation of an electrically heated tobacco system (HTS)
[24]; and comprehensive chemical characterisation of the aerosol generated by a heated tobacco product
through untargeted screening [25] (Table 4). The publications were published in prestigious specialised
journals: Analytical and Bioanalytical Chemistry (3.286 IF, Springer Publishing), Regulatory
Toxicology and Pharmacology (3.271 IF), Thermochimica Acta (3.378 IF, Elsevier Publishing), and
Frontiers in Pharmacology (5.988 IF, indexed in the Web of Science database). The analysis of data on
the content of HPHCs presented by PMI scientists is provided in Table 2.

Table 2. Data on the content of HPHCs presented by PMI

Source [21] [22] [23] [24] [25]
Detected components from the PMI-
58 58 46 34 10
58 list
% of the PMI-58 list 100 100 79 59 17

3.2. Tobacco-specific nitrosamines: a review of the studied literature

Cigarette smoke contains 4,800 different chemical compounds, of which 69 substances were
identified as carcinogenic in 2000. In addition to benzo(a)pyrene, the list of carcinogens in smoke
includes nine other polycyclic aromatic hydrocarbons, four aromatic amines, nitrosamines, aldehydes,
and other organic and inorganic substances [27]. The carcinogenic potential of these substances has been
evaluated according to the classification of carcinogenic substances established by the International
Agency for Research on Cancer (IARC) [28]. According to this classification, cigarette smoke contains
69 animal carcinogens, 48 of which are "possibly carcinogenic to humans", 8 are "probably carcinogenic
to humans", and 11 have been scientifically proven to be harmful and carcinogenic to humans.
Polycyclic aromatic hydrocarbons and tobacco-specific N-nitrosamines (TSNAs) are two major
groups of carcinogens present in tobacco and cigarette smoke that can cause lung cancer in both smokers
and non-smokers exposed to cigarette smoke [29]. Nicotine is an alkaloid found in tobacco, along with

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other related compounds such as nornicotine, anatabine, anabasine, cotinine, and myosmine, which are
also highly addictive for humans [30]. Nicotine is a secondary amine, while nornicotine, anabasine, and
anatabine are tertiary amines. These amines interact with nitrosating substances to produce TSNAs.
Nitrosation of these amines under mild conditions leads to the formation of N'-nitrosonornicotine
(NNN), N'-nitrosoanabasine (NAB), and N'-nitrosoanatabine (NAT). NAB and NAT consist of
anabasine and anatabine.
N'-nitrosonornicotine (NNN), 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N'-nitro-
soanatabine (NAT), and NAB are four of seven tobacco-specific N-nitrosoamines (TSNAs). The
nitrosation of nicotine produces NNN and NNK, which are particularly significant due to their extremely
high carcinogenic activity [30]. NNK causes lung cancer in rodents regardless of the method of
administration. Similarly, NNK induces malignant tumours in the liver, pancreas, and nasal mucosa.
NNN causes malignant tumours in the oesophagus, nasal cavity, and lungs in rats, and in the respiratory
tract in mice. NAB is almost non-carcinogenic [28, 30].
The WHO has imposed restrictions to regulate the concentration of toxic substances in tobacco
products, aiming to reduce deaths and diseases resulting from tobacco cigarette use, as well as to reduce
their attractiveness, addictiveness, and toxicity. An effort is being made to establish effective legislation
for the complete avoidance of passive smoking in indoor spaces due to its negative effects on public
health. In this context, Philip Morris International (PMI) has developed a Heated Tobacco Product (HTP)
that the company claims is not intended to emit smoke or secondhand smoke [14].
PMI’s HTP is a new tobacco product that Philip Morris International first launched in 2014 in Japan
and Italy and is now available in approximately 82 different countries [27]. However, there is limited
scientific evidence regarding the toxicity and risks of HTPs.
The composition of the aerosols released from HTPs, in which the tobacco is heated to a maximum
of 350°C, has been scientifically studied. It has been discovered that heating releases volatile
components into the aerosols, particularly nitrosamines, along with other pollutants. NJ Leigh and
colleagues [31] have hypothesised that HTPs may be a significant source of tobacco-specific nitro-
samines (TSNAs).
The authors [30] used an analytical method that is sensitive and selective enough to detect all
tobacco-specific nitrosamines for the analysis of TSNAs from the aerosols generated during the burning
of conventional cigarettes and HTPs. The first method developed was the use of a thermal energy
analyser (TEA) detector, which is a nitroso-method offering satisfactory sensitivity for the detection of
TSNAs. However, nitroso-compounds such as NAB and NNK are more complex, and the TEA detector
could not detect them. Thus, liquid chromatography/mass spectrometry and high-performance liquid
chromatography/tandem mass spectrometry have been identified as more sensitive and selective
methods for TSNA detection.
In the fillers of HTPs and 3R4F traditionally burned cigarettes, all four types of TSNA were identified
[14], and it was discovered that the detected contents are in about the same ratio in each type of cigarette.
When compared to typical cigarette smoke, the TSNA amounts found in the aerosols produced by the
HTP system were substantially lower. For example, NNN in the aerosols produced by the HTP
constituted 19.2 ± 2.1 ng/stick, and in 3R4F cigarettes, it was 311.1 ± 24.3 ng/stick (Table 3),
representing a 93.6% reduction for HTP.
The transfer rates of TSNAs for HTPs and 3R4F were estimated by determining the amount of TSNA
in tobacco and aerosols. The authors found that the transfer rates for NNN, NAT, and NNK in HTPs
were higher than those in conventional 3R4F cigarette burning (20.35% and 16.4%, respectively).

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Table 3. Comparative concentrations of TSNAs in IQOS HTP and 3R4F reference cigarettes, as
reflected in various bibliographic references (ng/stick)
TSNA THS2.2 3R4F Reduction Biblio-
mean±CI mean±CI rate (%) graphic
reference
N-nitrosoanabasine <3.15 33.7 ± 8.5 92.5
N′-nitrosoanatabine 20.5 ± 0.5 318 ± 74 94.6 [22]
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone 6.7 ± 0.6 266 ± 15 97.5
N′-nitrosonornicotine 17.2 ± 1.25 309 ± 41 94.7
N′-nitrosonornicotine 19.2 ± 2.1 311.1± 24.3 93.6
N′-nitrosoanatabine 34.0 ± 3.1 246.4± 16.9 85.9
[14]
N-nitrosoanabasine 4.5 ± 0.5 30.4 ± 2.0 94.6
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone 12.3 ± 1.5 250.4± 13.7 94.8
N′-nitrosonornicotine 10.2 ± 0.486 283 ± 27.8 96.4
N′-nitrosoanatabine 14 ± 1.13 270 ± 22.9 94.8
[23]
N-nitrosoanabasine 1.92 ± 0.182 30.2 ± 2.61 93.6
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone 6.75 ± 0.493 264 ± 26.4 97.4
N′-nitrosonornicotine 10.50 ± 0.46 276.00 96.20
N′-nitrosoanatabine 18.10 ± 0.67 251.00 92.79
[12]
N-nitrosoanabasine 5.60 ± 0.31 24.00 76.67
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone 7.30 ± 0.34 243.00 97.00
N′-nitrosonornicotine 10.1 271 96
N′-nitrosoanatabine 14.7 254 94
[11]
N-nitrosoanabasine 2.35 29 92
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone 12.19 ± 1.79 263.33±3.71 94.8
N′-nitrosonornicotine 17.2 ± 1.25 309 ± 41 94.7
[3]
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone 6.7 ± 0.6 266 ± 15 97.5

With the exception of two methods, HPHC analyses [23] for THS2.2 and 3R4F cigarettes were based
on official Health Canada methods [32]. These methods included tobacco-specific nitrosamine analysis,
which was performed using a mass spectrometry method in tandem with liquid chromatography,
according to Labstat International's TMS-135 internal method. The results obtained by G. Jaccard et al.
[23] (Philip Morris International) from the analysis of TSNAs in aerosols obtained from THS2.2
cigarettes showed lower levels compared to those presented in [14]. The most toxic TSNAs (NNN and
NNK) in the aerosols for THS2.2 showed concentrations of 19.2 ± 2.1 ng/stick for NNN and 12.3 ± 1.5
ng/stick for NNK, which are almost twice as low as the levels presented in [14], where NNN was 10.2
± 0.486 ng/stick and NNK was 6.75 ± 0.493 ng/stick. The authors assert that, when considering
commercially available cigarette products from different markets worldwide, the average reduction in
aerosol yields for THS2.2 compared to 3R4F reference cigarettes is similarly observed.
It is noted in [12] that only a few independent researchers have published scientific papers on the
comparative study of HPHCs for different types of heated tobacco products. As a result of the study, the
authors [12] reported emissions of HPHCs from THS2.2 that were similar to those observed in other
studies when heating under the HCI regime (Table 3), with reduction effects in the HCI regime being
comparable to those in other studies. The study concludes that HTP products contain some harmful
components similar to regular 3R4F cigarettes and that "advertising slogans like 'heat-not-burn' are not
a substitute for scientific research." The removal of N-nitrosamines (NNN, NNK, NAT > 90%, NAB >
70%) occurs mainly through volatilisation and transfer from the tobacco filler to the main emissions,
although some NAB may be produced from the thermosynthesis of a tobacco precursor.
It should be noted that a reduction in harmful component emissions does not necessarily translate
into a decrease in the risks or effects associated with smoking. Independent studies should be conducted,
particularly regarding long-term health effects. According to [11], only 40 (43%) of the 93 harmful
(HPHC) or potentially harmful constituents on the FDA's list of HPHCs are included in the PMI-58 list
for HTP main aerosols. HTP emissions had lower concentrations of every compound on the PMI list of
58 constituents compared to typical 3R4F reference cigarette smoke. In contrast, concentrations of 56
other constituents, which were not on the PMI-58 list or the FDA's list for HPHCs, were higher in IQOS
emissions. Twenty-two of these were higher by more than 200%, and seven were higher by more than

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1000% compared to the reference cigarette smoke 3R4F. It remains unclear how these compounds affect
the body or how harmful they may be. Health concerns could be minimised by eliminating or reducing
exposure to these HPHCs.
It is significant to note that 50 of the 53 unidentified HPHCs in HTP emissions (non-PMI-58
substances) are carcinogenic, including 2,6-dimethylaniline, benz[j]aceanthrylene, ethylbenzene, and
furan. The toxicity of many non-PMI-58 compounds is poorly understood. According to the authors,
some of these chemicals are either produced during the thermal decomposition or are flavour ingredients
in HTPs. Therefore, it is believed that while emissions from HTPs may reduce exposure to some
toxicants, they may also increase exposure to others of unknown toxicity.

3.2. Other HPHCs in tobacco product emissions

Radioactive elements
It goes without saying that the presence of radioactive substances in tobacco products and their smoke
is a significant reason to stop smoking in general or to avoid using a specific product whose emissions
are known to contain radioactive substances. The US Food and Drug Administration has included the
element polonium-210 (210Po) in the list of regulated compounds for tobacco products because there is
evidence of its carcinogenic effects.
The radionuclides polonium-210 (210Po) and lead-210 (210Pb), which are present in and on the
surface of tobacco leaves, occur naturally. Much of the 210Po and 210Pb activity in tobacco arises from
the uptake of radon-222 (222Rn) aerosols by leaf trichomes, while a smaller amount comes from root
transfer. In early 1964, Radford and Hunt hypothesised that the presence of 210Po in tobacco smoke and
its preferential localisation in the bronchial epithelium would be a cause of lung cancer [33].
The PMI-developed HTP electronic system heats tobacco to 350°C; however, it remains uncertain
whether 210Po and 210Pb volatilise in the HTP aerosol under these thermal conditions. Regarding the
quantification of 210Po content, a recent study [34] examined various tobacco products, including
conventional cigarette brands, the 1R6F reference cigarette, bronze-labelled tobacco sticks, Heet® (the
IQOS Heet® bronze label), and some free tobacco samples. The researchers found that the amounts of
210Po in tobacco sticks (23.7 ± 2.1 mBq.g⁻¹ of tobacco), conventional cigarettes (25.2 ± 2.6 mBq.g⁻¹ of
tobacco), and reference cigarettes (22.3 ± 0.4 mBq.g⁻¹ of tobacco) were nearly identical. These results
suggest that all the tested products contain tobacco from a common origin. According to the findings on
the transfer of radionuclides into the main smoke, Heets® had a 210Po level in the main aerosol that
was 1.8 ± 0.3% lower than that of conventional cigarettes (13.6 ± 4.2%). The authors explain the
reduction of 210Po and 210Pb in the main aerosol of HTP compared to conventional cigarettes by the
fact that only a marginal fraction of the stick tobacco is heated; with HTP, only 15% of the Heets®
tobacco is heated to 330°C.

Free Radicals
There is evidence that exposure to free radicals can lead to oxidative stress and that they play an
important role in the development of tobacco-related diseases such as coronary and vascular diseases,
chronic obstructive pulmonary disease, and cancer [35]. At the same time, free radicals, which present
potential health risks, are not included in the FDA's list. Given the properties of free radicals, it is crucial
that their generation be considered when assessing the toxicological profile of tobacco products.
The authors of a study [36] compared the type and quantity of free radicals in the mainstream aerosol
of 3R4F research cigarettes, two types of electronic cigarettes, and a heat-not-burn tobacco product,
using electron paramagnetic resonance (EPR) spectroscopy. The study revealed that the radicals found
in the smoke of conventional cigarettes were oxygen-centred, most probably alkoxy radicals, whereas a
signal for carbon-centred radicals near the detection limit was observed in the aerosol from the HTP.
Radical levels were found to be of the same order as background concentrations in air, with spectra for
air and HTP aerosol being very similar. The levels of organic radicals were (25.9 ± 0.6) nmol/stick and
(0.394 ± 0.055) nmol/stick.

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The authors [37] conducted a study aimed at measuring and characterising the production of free
radicals from the aerosol of several products in the HNB category, including IQOS. The study was based
on literature data showing that cigarette smoke contains high concentrations (>10¹⁶ molecules per puff)
of highly reactive free radicals, both in the gas phase and as longer-lived radicals in the particle phase
(tar). Characterisation and determination of their nature-either electrophilic or nucleophilic-are
important because the chemical characteristics of these radicals can predict the potential targets of
molecules in the human body.
The authors' data from electron paramagnetic resonance spectroscopy demonstrate that radicals are
present in the aerosol of HNB products. They also discovered that user behaviours (such as puff duration
and quantity) and device features (such as voltage and coil resistance) impact radical levels. Thus, the
research cigarette (1R6F) produced significantly more gas-phase radicals per session, with an average
of 567.6 ± 78.3 pmol radicals per puff, 45 times more than PMI HTP (12.6 ± 1.1 pmol radicals per puff).
Of their total, the largest part was composed of non-polar radicals. Particle-phase radicals were detected
only in the reference cigarette 1R6F (744 ± 7.5 pmol per puff).
Although it has been demonstrated that HNB-type products, such as PMI HTP, significantly lower
users' exposure to highly reactive free radicals, the authors point out that these exposure levels are still
significantly higher than those from other environmental sources.

Volatile Organic Compounds (VOCs)

Many health conditions are associated with a contaminated environment, making environmental
dangers a significant factor in determining human health. The generation of tropospheric ozone, a
photochemical oxidant that, at high concentrations, can affect materials, flora, and human health, is
facilitated by VOC emissions. International and national environmental protection bodies regulate
outdoor VOCs (non-methane volatile organic compounds and nitrogen oxides, NOx). These regulations
primarily aim to limit the emissions of VOCs resulting from the use of organic solvents in certain
industrial activities. The US Food and Drug Administration's List of HPHCs for Human Health in
Tobacco Products and Tobacco Smoke includes many of the substances on the VOC list regulated by
environmental authorities. Therefore, VOCs can act both directly and indirectly on human health.
Volatile organic compounds are a class of organic substances with relatively high vapour pressures
at room temperature due to their relatively low boiling points (up to 300°C). The thermal conditions for
the emission of molecules from this group of volatile substances are met, as the operating temperature
of PMI HTP can reach 350°C. Data from numerous independent studies, as well as those acquired by
the manufacturer (PMI), demonstrate the high qualitative presence of compounds from the VOC list in
the aerosol composition (Table 4). At the same time, according to the same data set, it can be deduced
that the production of volatiles from PMI HTP is also quantitatively 1-2 orders lower than that found in
conventional cigarettes.

Table 4. Maximum and minimum concentrations, health impacts, and the presence of volatile
compound classes in the constituents of IQOS aerosol and conventional cigarette smoke emissions,
as presented in the reviewed bibliographic references
Maximum and minimum Health impact acc The presence in
Pollutant concentrations FDA VOCs
IQOS 3R4F
1,3-Butadiene, µg 0.21-0.342 38.5-116.7 CA, RT, RDT +
1-Aminonaphthalene, ng NQ-0.077 22.4-19.01 CA
2-Aminonaphthalene, ng NQ-0.046 5.69-17.5 CA
3-Aminobiphenyl, ng NQ-0.032 1.81-4.5
4-Aminobiphenyl, ng NQ-˂0.05 2.24-3.26 CA
Acetaldehyde, µg 35.5-461.0 567-2540 CA, RT, AD +
Acetamide, µg 1.7-4.3 12.9-38.7 CA
Acetone, µg 3.37-35.5 95.5-736 RT +
Acrolein, µg 0.77-11.8 56.7-193 RT, CT +
Acrylamide, µg 1.39-1.73 4.46-4.8 CA +

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Acrylonitrile, µg NQ-0.258 21.2-32.73 CA, RT +

Ammonia, µg 2.5-14.2 11.1-39.3 RT
Arsenic, ng 0.36-1.2 7.71-67 CA, CT, RDT
Benz[a]anthracene, ng 0.53-2.65 5.43-33 CA, CT +
Benzene, µg 0.07-4.41 45.7-106 CA, CT, RDT +
Benzo[a]pyrene, ng NQ-1.19 4.58-20 CA +
Butyraldehyde, µg 0.09-26.1 14.8-114
Cadmium, ng ˂0.075 - ˂0.35 89.2-161 CA, RT, RDT
Carbon monoxide, mg 0.21-0.727 33.4-49.1 RDT
Catechol, µg 7.0-16.4 84.1-95.9 CA +
Chromium, ng ND-11 LOQ-11.9 CA, RT, RDT
Crotonaldehyde, µg 0.7-7.5 10.1-68.8 CA
Dibenz[a,h]anthracene, ng 0.01-0.124 0.38-1.7 CA
Ethylene oxide, µg 0.04-0.20 16-29.4 CA, RT, RDT +
Formaldehyde, µg 1.79-25.2 56.5-130.3 CA, RT +
Hydrogen cyanide, µg NQ-4.81 70.9-826 RT, CT
Hydroquinone, µg 0.99-8.1 83-94
Isoprene, µg 0.14-5.24 863-1160 CA +
Lead, ng ˂0.5 - ˂3.35 27.8-31.2 CT, CT, RTD
m-Cresol, µg ˂0.019-0.042 3.2-12.1 CA, RT +
Mercury, ng 0.81-2.04 3.68-4.8 CA, RDT
Methyl-ethyl-ketone, µg 0.63-10 183-241 RT +
Nickel, ng ND-15.9 LOQ-15.9 CA, RT
Nicotine, mg 0.43-2.27 1.7-2.7 RDT, AD
Nitric oxide, µg 5.5-19.9 89.4-529
Nitrobenzene, 0.01-0.188 0.01-8.62 CA, RT, RDT +
Nitrogen oxides, µg 14.2-17.3 52-565
N-nitrosoanabasine, ng 1.92-5.6 24-33.7
N-nitrosoanatabine, ng 7.2-36.7 246.4-318
NNK, ng 3.4-12.3 85.5-266 CA
NNN, ng 6.2-29 92.1-311.1 CA
o-Cresol, µg 0.03-0.78 4.15-4.86 CA, RT +
o-Toluidine, ng 0.45-1.82 85.5-137 CA +
p-Cresol, µg 0.03-0.073 7.25-12.1 CA, RT +
Phenol, µg NQ-1.51 7.04-15.6 RT, CT +
Propionaldehyde, µg 7.8-16.8 29.6-147 +
Propylene oxide, ng 0.148-142 1.32-1103 CA, RT +
Pyrene, ng 1.84-8.2 17.52-89 +
Pyridine, µg 0.58-13.7 29.7-68.4 +
Quinoline, µg 0.10-0.14 0.36-43
Resorcinol, µg ˂ 0.016-0.055 1.72-2.14
Selenium, ng ˂ 0.40-1.57 1.62-4.42 RT
Styrene, µg 0.23-1.05 13.9-33.3 CA +
Toluene, µg 0.36-2.59 73.6-208 RT, RDT +
Vinyl chloride, ng 0.657-3.54 93.4-116.6 CA +
Carcinogen (CA); Respiratory Toxicant (RT); Cardiovascular Toxicant (CT); Reproductive or Developmental Toxicants (RDT); Addictive
(AD); Volatile Organic Compounds (VOCs)

4. Conclusions
The bibliographic investigation of the literature reveals that heated tobacco products (HTPs) are
qualitatively less harmful substitutes compared to traditional 3R4F cigarettes. It has been observed that
heated tobacco products (HTPs) generate lower concentrations of harmful and potentially harmful
constituents (HPHCs) compared to traditional 3R4F cigarettes, with the exception of propylene glycol,
glycerol, and acetol. The reduction in yields for certain substances studied in the research starts at over
50% and can reach more than 90%.
The nicotine levels provided in the HTP aerosol were found to be 70–80% compared to those of
conventional combustion. However, it should be noted that the reduction in emissions of harmful
components cannot be interpreted as equivalent to a proportional reduction in risks/harms for smokers.
Further independent studies should be undertaken, particularly regarding the long-term health effects.

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There is a discrepancy between independent and industry investigations regarding the number of
compounds tested (priority-regulated toxicants). For both the HCI and ISO smoking regimes, emission
monitoring of HTP products is carried out.
To better understand the distinction between industrial and independent laboratories, it is suggested
to conduct a meta-analysis combining results from both groups, with testing for heterogeneity. Cochran's
Q test can be used to assess heterogeneity among the eligible studies, quantified by the I-squared statistic.
A probability value of less than 0.1 (p < 0.1) indicates statistically significant heterogeneity.
Subsequently, the influence of moderator variables on heterogeneity can be determined using two-way
analysis of variance (ANOVA).
The analysis of the literature data revealed that all concentration levels of substances from the PMI-
58 list of 58 constituents were lower in the aerosols of HTPs compared to the mainstream smoke of the
3R4F reference cigarettes. However, the levels of 56 other constituents, which are not included in the
PMI-58 list or the FDA list for HPHC, were higher in HTP emissions: 22 were more than 200% higher,
and seven were more than 1000% higher than in the smoke of the 3R4F reference cigarettes. The impact
of these substances on the body and their toxicity is unknown. It is important to note that of the 53
unidentified compounds in HTP emissions (non-PMI-58 substances), 50 are carcinogenic. In the
reviewed investigations, it is assumed that some of these substances are components of flavour additives
in HTPs or products of their thermal degradation. Therefore, it is considered that HTP emissions reduce
exposure to some toxicants but increase exposure to other substances, the toxicity of which is unknown.
The authors of the reviewed articles mention that although it has been demonstrated that HNB-type
products, including HTPs, significantly reduce users’ exposure to highly reactive free radicals, the
exposure levels remain much higher than those obtained from other sources concerning ambient air
pollution.

Acknowledgments: Philip Morris Sales and Marketing SRL is the sole source of funding and sponsor
of this research publication.

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Manuscript received: 16.07.2024

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