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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES ACADEMY OF MEDICINE

FACULTY OF MEDICINE DEPARTMENT OF PULMONOLOGY

KĘSTUTIS KRASAUSKAS

ACUTE EFFECTS OF BURNED AND HEATED TOBACCO SMOKE ON THE RESPIRATORY SYSTEM IN HEALTHY NON-SMOKERS

Final Master Thesis Biomedical sciences, Medicine Supervisor: Prof. K. Malakauskas Kaunas 2019

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CONTENTS

SUMMARY ... 2 SANTRAUKA ... 4 ACKNOWLEDGMENTS... 5 CONFLICT OF INTEREST ... 6

ETHICS COMMITEE APPROVAL ... 7

ABBREVIATIONS LIST ... 8

TERMS ... 9

INTRODUCTION ... 10

1. AIMS AND OBJECTIVES ... 11

2. LITERATURE REVIEW ... 12

3. RESEARCH METHODOLOGY... 18

4. RESULTS ... 23

5. DISCUSSION OF THE RESULTS ... 26

CONCLUSIONS ... 30

RECOMMENDATIONS ... 31

LITERATURE ... 32

ADDITIONAL DOCUMENTS ... 34 SANTRAUKA ...Error! Bookmark not defined.

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SUMMARY

Author: Kęstutis Krasauskas

Title: Acute effects of burned and heated tobacco smoke on the respiratory system in healthy non-smokers.

Aim: To evaluate the acute effects of conventional burned tobacco cigarettes and heated tobacco system smoke on the respiratory system in healthy non-smokers.

Objectives:

1. To measure the acute changes in exhaled carbon monoxide levels (eCO) caused by smoking heated tobacco and burned tobacco.

2. To measure the acute changes in lung function caused by smoking heated tobacco and burned tobacco.

3. To measure the acute changes in exhaled breath condensate pH (EBC) caused by smoking heated tobacco and burned tobacco.

Methods: During the first visit baseline measurements were taken in this order: exhaled CO levels, spirometry and EBC pH. Each volunteer then had to perform a coin flip to determine which method of smoking would be used first, heated tobacco stick or traditional burn tobacco cigarette. This was followed by volunteers proceeding to have a smoking session with the randomly chosen option. During the smoking session, participants were asked to take 10 deep inhales/puffs at regular intervals of 15-20 seconds. Thirty minutes after the smoking session volunteers return to the laboratory and repeat the same measurements they did for baseline. Three days of no tobacco use separated the testing between heated tobacco and burn tobacco. During the second visit participants repeated baseline measurements: eCO, spirometry and EBC pH. This was then followed by a smoking session with the remaining method of tobacco smoking. Once again, 30 minutes after the smoking session volunteers returned to the laboratory and repeated the same measurements they did for baseline.

Participants: Research subjects were volunteers from Lithuanian University of Health Sciences, who fit the inclusion criteria: healthy, non-smokers, adults. 11 students (6 males, 5 females, mean age 23.8±1.8 years old) have taken part and completed the study.

Results: Heated tobacco system smoking did not cause a statistically significant increase in eCO levels, which remained at baseline (0 PPM) in 10 out of 11 participants. However, smoking conventional cigarette did cause a statistically significant increase in eCO levels of 3.74±0.47 PPM (p<0.05). Both heated tobacco and conventional cigarettes led to a statistically significant elevation in EBC pH, from 6.72±(0.13) to 6.9±(0.12) and from 6.77±(0.11) to 6.95±(0.11) respectively (p<0.05). Furthermore, no difference was found between the two groups, as in each case a mean EBC pH

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3 increase of 0.18 was achieved. Finally, pulmonary function remained stable and did not change with either of the two smoking methods.

Conclusions: No differences were found between heated tobacco and conventional cigarettes when their acute effects on pulmonary function and EBC pH were evaluated. However, smoking conventional cigarettes resulted in significantly increased eCO levels, which display a potentially more detrimental effect to smokers’ pulmonary health.

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4

SANTRAUKA

Darbo autorius: Kęstutis Krasauskas

Darbo pavadinimas: Ūmūs deginamo ir kaitinamo tabako efektai sveikų ir nerūkančių žmonių kvėpavimo sistemose.

Tikslas: Įvertinti ūmų deginamo tabako cigarečių ir kaitinamo tabako istemos efektą sveikų ir nerūkančių žmonių kvėpavimo sistemose.

Uždaviniai: 1. Įvertinti ūmų kaitinamo ir deginamo tabako poveikį iškvėpto anglies monoksido kiekiui. 2. Įvertinti ūmų kaitinamo ir deginamo tabako poveikį plaučių funkcijai. 3. Įvertinti ūmų kaitinamo ir deginamo tabako poveikį iškvėpto kondensato pH.

Metodai: Pirmo apsilankymo metu buvo atliekami pradiniai matavimai prieš rūkymą: iškvėpto CO kiekis, plaučių funkcijos parametrai ir iškvėpto oro kondensato pH. Tuomet atsitiktine tvarka (monetos metimu) buvo išrinkta, kuris rūkymo būdas bus pirmas – tabako cigaretė ar kaitinamo tabako sistema. Rūkymo metu dalyviai atliko 10 gilių įkvėpimų kas 15-20 sekundžių. Trisdešimt minučių po rūkymo matavimai buvo pakartoti ir palyginti su pradiniais rezultatais. Po trijų dienų, per kurias dalyviai turėjo nevartoti jokių tabako gaminių, atliekami tie patys pakartotiniai matavimai su kitu, nei pirmąją dieną, tabako rūkymo būdu.

Tyrimo dalyviai: Tyrimo dalyviais buvo pasirinkti savanoriai LSMU studentai, kurie atitiko numatytus kriterijus – jie turėjo būti sveiki, nerūkantys bei pilnamečiai. 11 studentų (6 vyrai, 5 moterys, vid.amž. 23.8±1.8) dalyvavo ir praėjo visus tyrimo etapus.

Tyrimo rezultatai: Kaitinimo tabako sistemos rūkymas nesukėlė statistiškai reikšmingo skirtumo iškvėpto anglies monoksido kiekyje, kuris išliko ties pradine reikšme (0 PPM) 10 iš 11 savanorių. Tuo tarpu, klasikinės deginamo tabako cigaretės sukėlė statistiškai reikšmingą skirtumą, 3.74±0.47 PPM (p<0.05). Vertinant iškvėpto kondensato pH buvo nustatytas statistiškai reikšmingas skirtumas su abiejais rūkymo būdais, deginamo tabako cigaretės pakilo nuo 6.77±(0.11) iki 6.95±(0.11) ir su kaitinamo tabako sistema pakilo nuo 6.72±(0.13) iki 6.9±(0.12) (p<0.05). Skirtumo tarp abiejų rūkymo metodų nebuvo rasta, nes abiejais atvejais vidutiniškai pH pakilo 0.18. Plaučių funkcija išliko pastovi ir nebuvo rastas statistiškai reikšmingas skirtumas su nei vienu rūkymo būdu.

Išvados: Skirtumo tarp deginamo tabako cigarečių ir kaitinamo tabako nebuvo rasta, kai buvo tiriami jų ūmūs poveikiai iškvėpto oro kondensato pH ir plaučių funkcijai. Tačiau, deginamo tabako cigarečių rūkymas ženkliai padidina anglies monoksido lygį iškvepiamame ore, kas potencialiai gali turėti žalingesnį poveikį rūkančiojo kvėpavimo sistemai.

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ACKNOWLEDGMENTS

The research was planned and carried out during the study year of 2018-2019 in the Lithuanian University of Health Sciences, Kaunas Clinics, Pulmonology department. I would like to thank all the people who were involved in this process.

First, to my thesis supervisor, Prof. Kęstutis Malakauskas, who suggested this topic and encouraged me to go through with it, advised and guided me during the process.

Second, to the head of the Pulmonology department, Prof. Skaidrius Miliauskas, for allowing me to proceed with the research and for giving me access to the resources of the Pulmonology department. Third, I am also very grateful to all the volunteers who took time to not only participate, but to complete the required testing period.

Special thanks go to the laboratory staff and technicians of the Pulmonology department, for assisting me during the testing phase.

Finally, I would like to thank all my friends who helped me during various stages of this thesis.

This could not have been possible without the help, guidance and support that I received from everyone.

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CONFLICT OF INTEREST

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ETHICS COMMITEE APPROVAL

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ABBREVIATIONS LIST

3R4F – standard cigarette reference, used in academic research. ALT – alanine transaminase

BAL – broncho-alveolar lavage BAT – British American Tobacco CC – conventional cigarette CO – carbon monoxide CO2 – carbon dioxide

EBC – exhaled breath condensate ECO – exhaled carbon monoxide FDA – Food and drug administration FEV – forced expiratory volume FVC – forced vital capacity HTP – heated tobacco product KC – Kaunas Clinics

LUHS – Lithuanian University of Health Sciences MEF –maximal expiratory flow

MRTP – modified risk tobacco product PFT – pulmonary function test

PMI – Phillip Morris International PPM – parts per million

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TERMS

Broncho-alveolar lavage–is a medical procedure during which a bronchoscope is passed through the nose or mouth into the lungs. A small amount of fluid is introduced and then collected for analysis. This procedure is typically performed to diagnose lung diseases such as infections and cancer.

Exhaled breath condensate – is collected from a person breathing into an apparatus, which cools and condenses it into a fluid. Expired air contains various volatile molecules. This sample gives information about the makeup of respiratory fluid and it allows for pH measurements to be performed. IQOS – PMIs electronic tobacco heating system.

Spirometry – is a standard pulmonary function test, which is based on airflow into and out of the lungs. This test is most often used to diagnose conditions such as COPD, asthma and various restrictive lung diseases. Main parameters:

FVC– forced vital capacity is the greatest total amount of air a person can forcefully breathe out after breathing in to fully fill the lungs, as deeply as possible. Lower value could be down to restrictive or obstructive lung diseases.

FEV1–forced expired volume is the amount of air forced out of lungs in 1 second. Lower values can be indicative of obstructive disease and the severity/grade of it.

FEV1/VC – this is a calculated ratio of two parameters: FEV1 and VC. Healthy lungs will have a high value for these two measurements ratio, lower values suggest something is blocking the airway. In healthy adults should be around 70-85%, gradually decreasing with age. Obstructive and restrictive diseases cause changes in FEV1 and FVC.

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INTRODUCTION

There has been much controversy associated with Phillip Morris International (PMI) claims over heated tobacco products (HTP) such as IQOS; it is advertised as a smoke-free device, which allows exploitation of indoors smoking bans. Furthermore, PMIs own research does not fully support their claims that IQOS is a safer alternative to conventional cigarettes (CC) and will encourage users to quit smoking [1].

Another important issue is the lack of independent research on the harmful substances released in IQOS smoke, as majority of the available sources are provided by PMI. In 2016, PMI submitted documents to have the Food and Drug Administration (FDA) categorise IQOS as a modified risk tobacco product (MRTP) [2]. HTP are often criticised for their appearance being similar to e-cigarettes that are popular among teens [3], and for using packaging that resembles high-end smart phones, strategy aimed at appealing to children and young adults [4].

As of November 2017, there were 31 studies of HTP available for peer review, but 20 of these had strong connections with the tobacco industry [5].While independent studies concentrated on spreading awareness about the use and second hand emissions, industry affiliated research focused on aspects where HTP appeared superior to CC. This is particularly troublesome as tobacco industry has a stake and a long history of manipulating scientific research related to tobaccos effect on health [5-10].

For instance, British American Tobacco and PMI released material to support the argument that additives did not add to cigarette toxicity. Meanwhile the independent analysis of PMI’s own documents showed that in fact it did, and that many toxic substances increased when additives such as menthol were added [9].

Therefore, it is vital for independent research, which has no ties to the tobacco industry to cover the topic of HTP, especially with the recent success of IQOS.

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1.

AIMS AND OBJECTIVES

Aims:

To evaluate the acute effects of burned and heated tobacco smoke on the respiratory system in healthy non-smokers.

Objectives:

1. To measure the acute changes in exhaled carbon monoxide levels (eCO) caused by smoking heated tobacco and burned tobacco.

2. To measure the acute changes in lung function caused by smoking heated tobacco and burned tobacco.

3. To measure the acute changes in exhaled breath condensate pH (EBC) caused by smoking heated tobacco and burned tobacco.

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2.

LITERATURE REVIEW

2.1 BACKGROUND AND HISTORY OF HTP

Conventional cigarettes have been the most popular form of tobacco smoking for centuries, currently it is estimated that there are around 1 billion smokers globally [11]. Changes over the last few decades, such as increased taxation, public smoking bans, restriction of advertisement and strict government regulation, are attempts to reduce the total number of smokers and by extension, the number of deaths, which amount to more than 7 million deaths globally every year [12]. These restrictions have forced the tobacco industry to look for alternatives, which came in the form of Modified Risk Tobacco Products. At the forefront of MRTP are heated tobacco products, IQOS being the newest and the most successful addition.

The first commercial heat not burn product was a smokeless cigarette introduced in 1988, the R.J Reynolds ‘Premier’. However, smokers described it as difficult to use and many disliked the taste. Additionally, the process of smoking it still required partial combustion at the time. After spending $325 million, it was pulled from the market in 1989, however the concept remained, and similar products would keep re-emerging, but seeing little success. This concept was later re-launched as ‘Eclipse’ in the mid 1990s. PMI made another attempt in 1998; they released an electronic cigarette-heating device known as ‘Accord’. This time it was advertised as ‘low smoke’ and claimed reduced health risks. Attempts were made to get product endorsement by medical publishers without requiring long-term studies of health risks. However, like its predecessors ‘Accord’ saw little success, and majority of its users continued smoking regular cigarettes. In 2007 PMI released ‘Heatbar’, lower second hand smoke emission was its main benefit, but shortly after the release, it was discontinued like many others before it [13].

IQOS is PMIs newest attempt, when it was introduced in 2014 it was only available in two locations: Nagoya, Japan and Milan, Italy. Since then it has shown substantial growth and success, currently claiming to have almost 7 million users. In 2016, less than 2 years after its initial release, IQOS was available in more than 20 countries. As of 2019, IQOS can be purchased in 43 different countries, in Europe, Asia, Africa and Central America. Additionally, heat-stick sales are predicted to more than double to as many as 100 billion units by 2021 [14]. HTP market is a major factor why PMI predicts a future where conventional cigarettes are obsolete.

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2.2 IQOS STRUCTURE AND THE PROCESS OF SMOKING

IQOS uses an electric heating element that heats instead of burning the tobacco. The smoking system consists of a portable charger with an encased holder and uses heat-sticks as a source of tobacco; these are disposable tobacco cartridges, which have been dipped in propylene glycol (Pictures 1,3)[15].

First, the holder is removed, then a single tobacco cartridge is inserted, and the device is turned on. After a few moments, it heats up to 350°C [16]. Heating tobacco instead of burning it results in less smell, odour and smoke. Due to this reason, IQOS is often advertised as a smoke free device. Smoke is generated by thermogenic degradation and pyrolysis, which is identical to the way traditional tobacco cigarettes are smoked (Picture 2)[15]. This leads to the release of nicotine, chemical compounds and particulates.

Picture 1: IQOS device with a pack of tobacco cartridges

(https://www.tobaccoasia.com/features/a-smoke-free-future-in-the-making/)

Picture 2: Customer tries IQOS in store in Tokyo

(https://www.reuters.com/article/us-japan-tobacco-idUSKCN0WV0GQ)

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Picture 3: IQOS structure

(https://www.reuters.com/investigates/special-report/tobacco-iqos-science/)

2.3 PREVALENCE AND PATTERNS

Due to IQOS being a relatively recent product, it is difficult to estimate the precise number of users. However, growing market share and production shows increased prevalence of use.

As Japan is a ‘hotbed’ for HTP market, with millions of users and new products being released every year, it can be used to study the demographic characteristics of the smoker population. Between 2015 and 2016, around 1 million Japanese users, switched from CC to IQOS. Japan currently has over 3 million active IQOS users. While the prevalence of smoking in the general population was 17.8%,

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15 the prevalence of IQOS was 1.2 and the use of e-cigarettes was 0.5%. Majority of the tobacco users had initiated tobacco use with cigarettes, a very small percentage had initiated with IQOS 0.3% [17].

In a sample of 8000 people, mean age of general population was 53.6 (± 17.9), while mean age of IQOS users was 38.5 (± 9.8). Per age group in general population sample, 50+ and 40-49 were the two largest groups with 55.9% and 18.3% respectively. Meanwhile, in IQOS user sample, 30-39 and 40-49 were the largest groups with 36.8% and 28.4%. By gender, the general population sample was split into 48% male and 52% female, while IQOS population sample was 82% males and 18% females. Overall this means that similarly to CC, there are a lot more male users in proportion to female, additionally IQOS targets a younger audience, people between the ages of 30 to 49 in particular [17]. Although different regions will have different cultures and customs, a similar demographic pattern should follow, with slight variation. Additionally, IQOS user sample displayed that 63.6% were exclusive to IQOS, 20.3% used CC and IQOS, while the remaining 16.1% used a variety of devices [17].

PMI also increased its investments of heat-stick production, from $1.2 billion in 2016 to $1.5 billion in 2017. This allowed the company to produce 50 billion heat-stick units in a year, illustrating growing consumer base [18].

Furthermore, according to government data of South Korea, Indonesia and Italy, since the launch of IQOS, their tobacco imports grew significantly. For example, in 2017 South Korea experienced the highest tobacco imports in 15 years. It imported over $200 million worth of tobacco products, equating to 61% increase from 2016, with $124.1 million [19].

PMI website claims that around 6.6 million people have switched from CC to IQOS. Majority of these are in East Asia, Japan and South Korea in particular. This region has experienced the most significant growth, and at a much faster rate.

2.4 SOCIETY AND HTP

Results from exploratory studies of IQOS usage patterns found that, it appeals to some customers more based on what culture they are a part of. Cultures with strong virtues of cleanliness, exclusivity and high technological development were more receptive to the marketing of IQOS, which was one of the main factors for its massive success in Japan and Korea [20]. Other groups of people who are unfamiliar with the new taste, high price, its inconvenient utility and strict maintenance might be deterred from making the transition to HTP. Desire to keep up with the innovations is strongest with teenagers and young adults, explaining HTP product popularity with students and young professionals. To further add to this effect, it is packaged in way to resemble smart phones. Perception of IQOS in

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16 society is strongly influenced by marketing. It is often advertised as a healthier, cleaner and a modern alternative to conventional cigarettes, portraying CC as out-dated and old-fashioned.

2.5 HEALTH EFFECTS

PMI preclinical studies submitted to FDA displayed possible liver toxicity. Laboratory rats were exposed to aerosol from IQOS at different durations, 5 and 90 days. After 90 days of exposure, increased liver weight and raised ALT was found in female rats. These measurements are indicative of hepatocellular hypertrophy and injury. Furthermore, hepatocellular vacuolisation, which is a sign of acute liver injury, was significantly increased in IQOS exposed female rats, similar effects were not observed in animals exposed to CC aerosols. Additionally, human clinical data collected by PMI showed plasma bilirubin increase in IQOS subjects after 5 days of exposure. [21].

Animals exposed to IQOS were found to have systemic neutrophilia, which was almost 75% higher than in rats exposed to 3R4F smoke. Neutrophil count remained elevated for up to 6 weeks during the recovery period [22].

Lastly, IQOS exposed animals had more significant thymus atrophy than 3R4F group, based on organ weight and histology. This is important, as thymus atrophy is associated with decreased memory T cell numbers and immune system function [22].

Another self-report study looked at symptoms due to inhaling second hand smoke, produced by HTP, used by other people. In people who had experienced second hand HTP smoke (n=119), 37% of them mentioned at least one symptom. These included feeling ill, eye discomfort and sore throat, listed from most to least reported. 49% of non-smokers reported feeling at least one symptom, while 41% former smokers and only 26% current smokers experienced these symptoms [23].

PMI’s preclinical and clinical data indicates possible hepatotoxicity, especially in an acute setting. Although IQOS exposes users to lower levels of some toxins than conventional cigarettes, unexpected organ toxicity may now be a factor. This might be particularly dangerous when in combination with other hepatotoxic substances such as alcohol, medication, herbal supplements and recreational drugs. Accumulative effect of these substances would increase the likelihood of acute liver injury.

2.6 ACUTE PULMONARY EFFECTS OF IQOS SMOKING

Data related to pulmonary system listed below was extracted from PMI’s MRTP application. To compare IQOS and CC, PMI performed a 90-day inhalations study on 10-week-old rats. Animals were nose-exposed to flow-pass inhalation of aerosols for 6 hours per day. Aerosols were diluted with filtered air to match target nicotine concentrations, which were 15-50 µg per litre.

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17 Preclinical studies revealed that while IQOS releases lower levels of toxins than a 3R4F cigarette smoke, but IQOS emissions contained higher levels of volatile organic compounds, these included acrolein, acetaldehyde and formaldehyde. IQOS-exposed rats were also found to have elevated numbers of inflammatory cells in broncho-alveolar lavage (BAL), but this still remained significantly below the cellularity of 3R4F-exposed rats. Respiratory histopathology also found epithelial hyperplasia and metaplasia in IQOS exposed rats, once again this was at lower values than 3R4F exposed group [22].

Human clinical study results were also extracted from PMI’s MRTP application. Two studies were performed in Japan and USA. Both studies used healthy adults who smoked at least 10 CC per day for the last 3 years. These were divided into groups of menthol CC, no smoking, and menthol IQOS heat-sticks. Participants were examined at day 5 and day 90; dual use was discouraged during the study. All participants kept a diary of their tobacco use during the study. At day 90 measurements of WBC, CRP and PFT were taken. Results were then compared between CC, IQOS and no smoking groups. It was reported that FEV1 without bronchodilator was the same in all 3 groups at day 90 [22].

Therefore, a conclusion can be made that IQOS causes a significant inflammatory injury to the pulmonary system, however at a lesser degree than 3R4F. However, most research fails to examine the effects of IQOS and CC dual use, which might lead to exaggerated effects on health. Additionally, 90-day study did not record any change on spirometry, for a change to be achieved a long-term study lasting years should be performed.

2.7 HTP COMPARED TO CC

Japan-based study with 148 participants, had measurements of PF, CRP and WBC taken at baseline (day 0) and day 90. Study groups included non-smokers, menthol CC and menthol IQOS. At day 0 baseline measurements showed no differences. At day 90, slightly decreased plasma WBC in IQOS and CC groups was found. Significant CRP changes were not detected for either group from baseline to 90 days (median: 0mg/L). FEV1 without bronchodilator administration also showed no difference at day 90, between all 3 groups.

US-based study with 88 participants underwent similar testing by recording age, sex, PFT, WBC and CRP. Study groups included non-smokers, menthol CC and menthol IQOS. No significant changes were recorded between baseline values at day 0 and day 90. More extensive PFT were performed than in the Japan-based study, bronchodilator administration was included. At day 90, PMI did not report any significant changes in PFT between CC and IQOS groups.

Another study, which included 12 healthy smokers who reported smoking 10 or more CC per day for at least 5 years, was performed. First baseline exhaled CO values were recorded, followed by 10 puffs of CC or HTP devices (iGLO, IQOS). Exhaled CO levels were then measured at 5, 10, 15, 30

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18 and 45 minutes after smoking. In contrast to CC (11-17 PPM), HTP did not cause an increase in eCO levels in any of the study participants [24].

Finally, one of the most recent articles related to the topic of IQOS health effects, was published on the 10th of February 2019 by the European Respiratory Society. It demonstrated that IQOS exposure is as damaging as CC and e-cigarettes to human lung cells. Chronic exposure of environmental triggers such as, allergens and smoke lead to airway remodelling. This is based on key processes such as extracellular matrix reorganisation, airway cell proliferation and mitochondrial damage. Additionally, if these processes continue for prolonged period of time, results can be severe with diseases such as asthma or COPD. Data obtained during the study, suggests that e-cigs, CC and IQOS exposure leads to abnormal mitochondrial function, airway inflammation and remodelling. All three smoking types have also been found to increase respiratory infection occurrence by increasing microbial adherence to the airways. Therefore, similarly to CC and e-cigs, IQOS has the capability to cause oxidative stress, airway inflammation, infection and remodelling. Overall, IQOS does not appear to be the safer option, like it is advertised to be [25].

3.

RESEARCH METHODOLOGY

The research was carried out in the Department of Pulmonology, at LUHS, Kaunas, from February to March 2019.Research population consisted of 39LUHS students who volunteered before passing the inclusion criteria. The inclusion criteria were:

1. Young adults, age from 18 to 30 years old 2. Non-smokers

3. Healthy, no acute or chronic conditions which could affect the pulmonary system

4. Able to undergo the required procedures during the different stages of testing until it is completed

Non-smokers were defined as people who did not smoke tobacco or any other substances regularly, and people who have quit smoking for at least 5 years. Participants were asked to avoid any social smoking during the testing period. Active smokers were excluded as it was decided that their respiratory systems would be less sensitive to acute changes, additionally pH and CO values are different in chronic smokers due to continuous exposure.

Therefore, from an initial total of 39 volunteers comprising of Lithuanian and International students, 20 were excluded due to being active smokers, 6 were unable to attend all of the required testing and 2 had active pulmonary diseases (bronchitis, common cold).

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19 In the end 11 students, who met the criteria, managed to participate and complete all of the required testing. Volunteers were informed about the procedures and signed forms of consent before engaging in research.

During the first visit baseline measurements were taken in this order: exhaled CO levels, spirometry and EBC pH. Each volunteer then had to perform a coin flip to determine which method of smoking would be used first, heated tobacco stick or traditional burn tobacco cigarette. This was followed by volunteers proceeding to have a smoking session with the randomly chosen option. During the smoking session, participants were asked to take 10 deep inhales/puffs at regular intervals of 15-20 seconds. Thirty minutes after the smoking session volunteers return to the laboratory and repeat the same measurements they did for baseline. Three days of no tobacco use separated the testing between heated tobacco and burn tobacco. During the second visit participants repeated baseline measurements: eCO, spirometry and EBC pH. This was then followed by a smoking session with the remaining method of tobacco smoking. Once again, 30 minutes after the smoking session volunteers returned to the laboratory and repeated the same measurements they did for baseline.

Volunteer returns to perform testing with the other method of smoking. First baseline, then post smoking session measurments.

3 days of no tobacco use to separate the testing between both methods of smoking Repeat the same measurements 30 minutes after the smoking session Volunteer proceeds to a smoking session with the randomly chosen method

A smoking method is chosen at random by a coin flip (IQOS or CC) Baseline measurements of exhaled CO, PFT, and EBC pH are performd

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20 IQOS is made to mimic the experience of smoking a conventional cigarette. According to PMI the average number of inhalations with IQOS is 14. IQOS heat-sticks have the same filter and tobacco, only differ in flavour. The same package was used for everyone; only a single heat-stick per person was required to be smoked. Before testing the holder was cleaned of any left-over residue and fully charged. For conventional burn tobacco cigarettes, Marlboro Gold was the chosen brand. Marlboro Gold and IQOS heat-sticks are both produced by Marlboro, under PMI. All cigarettes came from the same package, and only 1 cigarette per person was required to be smoked.

Neither of the packages states the amount of nicotine. However, a study found that a conventional tobacco cigarette provides around 2 mg of nicotine, while the aerosol from a heat-stick amounts to around 1.4 mg.

Tests for obtaining data:

Before arriving participants were informed to not consume alcohol, avoid strenuous exercise, wear comfortable clothing and to not eat a large meal prior to testing.

Spirometry

Used to assess lung function, based on measurements of volume and speed of air that is inhaled and exhaled. Parameters such as FVC, FVC%, FEV1, FEV1%, Maximum Expiratory Flow at 50% of Vital Flow Capacity (MEF 50% VFC) and MEF 50% VFC% were evaluated.

Laboratory technicians were asked to calibrate the spirometry apparatus prior to use. Procedure for one person took a few minutes. First the procedure was explained to the volunteers. They were then asked to take a seat, a clip was placed to keep the nostrils closed during the test, this ensures all of the exhaled air is expelled through the mouth and recorded by the spirometer. Participants were then asked to wrap their lips tightly on the spirometer mouthpiece in order to avoid air leakage. First, 2-3 normal breaths at rest are recorded; this is followed by fully exhaling, and taking a deep breath completely filling your lungs, after this air should be exhaled forcefully in 1 second, to fully empty the lungs once again. After recording results from one participant, the mouthpiece was changed, and another participant would follow the same procedure.

Exhaled breath condensate pH analysis

First, the use of the apparatus and the procedure were explained. Participants were asked to take a seat and to breathe regularly for 10-15 minutes, until enough condensate was accumulated. Mouthpiece part of the apparatus had to be tightly sealed with lips, to prevent air from escaping. The breath exhalate is then condensed via an inbuilt cooling system at -15C to -20C. The collected sample reflects the fluid that lines the respiratory system. Condensate consists of aerosolised particles, water

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21 vapour and water-soluble volatile gases. After the procedure was completed, the collected condensate is transferred to another laboratory where the pH could be measured. After recording results from one participant, the mouthpiece would be changed and another, participant would follow the same procedure

Exhaled breath condensate reflects the changes in the respiratory fluid lining the airways. Additionally, measuring EBC pH can be used as a practical, non-invasive indicator of inflammation. Long term cigarette smoking is known to cause pulmonary inflammation. However, the acute effects of smoking are much less understood. Previously published studies which focused on the effect of CC smoke on EBC pH have achieved varying results. It was also found that EBC pH can be influenced by many factors such as, the collection system used, methodology, degree of airway inflammation and other. We chose this as one of our measurements, as we were unable to find any other studies which investigated the acute effect of HTP smoke on EBC pH.

Exhaled breath CO

Measured in exhaled air by a carbon monoxide meter, Bedfont Micro Smokerlyzer Micro III. First, the use of the apparatus and the procedure were explained. The meter is then switched on, calibrated and set ready to record values. After pressing ‘GO’, participants must take a breath and hold it for 15 seconds, after the countdown they must blow into to the apparatus to fully empty their lungs, recorded values are displayed on the screen. After recording results from one participant, the mouthpiece would be changed, and another would follow the same procedure.

Carbon monoxide is a low molecular weight gas, which has no colour, taste or odour. It is produced during the incomplete burning of carbon base fuel. CO can be found everywhere at varying levels which are directly linked to the amount of combustion present. It is toxic to most animals because it binds to haemoglobin, and causes diminished oxygen carrying capacity. CO binds to haemoglobin almost 200 times faster than oxygen, which is why even a slight elevation can cause clinical symptoms. Exhaled CO is also used as a biomarker that is most commonly measured to evaluate the level of smoking. Although, the diagnostic value of eCO is not fully understood yet, it has been strongly linked to the processes of inflammation in diseases like asthma, COPD and lung cancer. People who smoke a pack per day (20 cigarettes) can have levels of eCO measured at

anywhere from 15 to 35 PPM. This is important because, physical symptoms such as increased heart rate and reduced physical performance can be detected from as little as 5 PPM. Additionally, the insufficient amount of oxygen must be compensated by putting extra stress on the heart, possibly contributing to heart disease in the long term.

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22 However, Heated Tobacco Products such as IQOS, function at a much lower temperature than traditional tobacco cigarettes. This means that the tobacco is heated instead of burned. Heating tobacco does not lead to the incomplete combustion of carbon products and therefore, CO emissions are greatly reduced to negligible levels. Measurement of eCO is practical and non-invasive test which suits us in our study to evaluate the acute effects of smoking HTP.

Statistical data analysis

Statistical analysis was performed with Statistical Package for Social Sciences (SPSS) program. Significance level was determined at 0.05%, therefore confidence level was 95. Calculations of means, standard deviation and t-test were performed. T-test was used to determine the significance in change between means. Standard deviation was used to express how much values differed from the mean, it was displayed in brackets next to mean values.

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23

4. RESULTS

Table 1. Displays the change from baseline to post smoking values with both methods: cigarettes and IQOS.

Characteristics of the research population

From the total of 11 people who fit the criteria and managed to complete all of the required testing, the split between males and females was almost equal, with 6 males and 5 females. The youngest volunteer was 21 years old, while the oldest was 27. Mean age was 23.8 years, with a standard deviation of ±1.78. Majority of the participants were Caucasian with 6, Hispanic with 2, Arab with 2 and Asian with 1. The lowest recorded BMI was 18.1, while the highest was 26.8. Mean BMI was 22.63, with a standard deviation of ±2.84.

Exhaled carbon monoxide

Graph 1 - Mean exhaled carbon monoxide levels after inhalation from heated tobacco and conventional cigarettes. Baseline Mean (SD) Cigarette Mean (SD) p value Cigarette Baseline Mean (SD) IQOS Mean (SD) p value IQOS CO 0 3.73 (0.47) < 0.05 0 0.09 (0.3) NS pH 6.72 (0.13) 6.9 (0.12) < 0.05 6.77 (0.11) 6.95 (0.11) < 0.05 FEV1 (L) 4.35 (0.85) 4.35 (0.75) NS 4.37 (0.85) 4.30 (0.8) NS FVC (L) 4.89 (1.11) 4.87 (1.02) NS 4.86 (1.13) 4.81 (1.07) NS MEF50% of FVC (L/sec) 5.92 (1.13) 5.83 (1.15) NS 5.89 (1.16) 5.72 (1.24) NS 3.7 0.1 0 0.5 1 1.5 2 2.5 3 3.5 4

Baseline 30 minutes after a

smoking session Ex h al e d C O P P M Conventional cigarettes IQOS

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24 Baseline exhaled CO was recorded at 0 PPM in all of the participants. After a smoking session with IQOS, no significant increase in eCO levels were recorded 0.09±0.3 PPM. Instead it remained at a baseline value of 0 PPM in 10 out of 11 participants and only increased to 1 PPM in the remaining participant. While after a smoking session with CC, there was a statistically significant increase in eCO levels to 3.73±0.47 PPM (Graph 1).

Exhaled breath condensate pH

Graph 2 – A. Acute change in exhaled breath condensate pH after inhalation from conventional cigarettes. B. Acute change in exhaled breath condensate pH after inhalation from heated tobacco product (IQOS).

Statistically significant increase of EBC pH was achieved by both means of smoking. In terms of CC, the baseline pH of 6.72±0.13 increased to a post smoking pH of 6.9±0.12. While, IQOS achieved very similar results where, the baseline pH of 6.77±0.11 increased to a post smoking pH of 6.95±0.11. When baseline pH is taken into consideration, mean increase of 0.18 was recorded with both methods of smoking. The lowest recorded EBC pH value was 6.55 and the highest was 7.12.

When EBC pH was measured after a smoking session with conventional cigarettes, 10 out of 11 participants followed the trend of increased post smoking pH, however in 1 participant a decrease of 0.19 was recorded (Graph 2A). While measuring EBC pH after a smoking session with IQOS it was found that all participants followed the trend of increased post smoking pH (Graph 2B).

5.70 5.90 6.10 6.30 6.50 6.70 6.90 7.10

Baseline 30 min. after a smoking

session EB C p H

B

6.5 6.6 6.7 6.8 6.9 7 7.1

Baseline 30 min. after a smoking

session EB C p H

A

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25

Lung function test – Spirometry

No significant changes occurred between the mean of baseline and the post smoking session values, with either IQOS or CC. Spirometry parameters which were included: FEV1, FEV1%, FVC, FVC%, MEV50%VFC, MEV50%VFC%.

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26

5.

DISCUSSION OF THE RESULTS

It is difficult to discuss the results obtained during this study, mainly because of how recent of a product IQOS is. In contrast, scientific material on conventional cigarettes has been available for over half of a century. Meanwhile, heated tobacco products have a limited amount of independent research and no long-term studies.

However, this study managed to achieve results and come to similar conclusions to those from previously published articles. This is one of the first independent studies, which looked at the acute effect of HTP and compared it to the effect of CC.

We found no significant eCO elevation in our subjects after a smoking session with IQOS. Other published research on the topic of electronic smoking devices has reported similar findings, these included data from the manufacturer and independent research [26-28]. 2018 study that looked at eCO levels after inhaling smoke from new generation devices also found that, HTP did not cause an elevation in eCO; meanwhile CC did result in a significant increase (Picture 4)[24]. Despite of achieving the same conclusion, eCO was measured at higher levels in other studies. This was attributed to factors such as higher ambient CO levels; research subjects were active smokers and larger volumes of smoke were administered prior to testing. Records from tobacco industry provide further confirmation, where it is stated that a single CC has around 30 mg of CO emission, while a single IQOS heat-stick was measured of having a negligible 0.436 mg [29,30].

Picture 4 : Exhaled CO levels after inhalation from new generation heated tobacco products and own brand cigarettes.

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27 Chemical analysis of HTP and CC aerosols confirms reduction in CO. Various volatile organic compound and polycyclic aromatic hydrocarbons were also found to be from 80 to 99% less present in HTP, when compared to CC [31,32]. However, when a tobacco stick is ignited and smoked the way a traditional tobacco cigarette would be, a sharp increase in CO and CO2 is recorded. Hence, the process of heating tobacco instead of burning it can be directly linked to reduced CO and CO2 emissions.

When it comes to EBC, we found that both methods of smoking, IQOS and CC led to a significant increase in pH. Interestingly, this increase was of the same magnitude with both methods. However, no studies on the topic of HTP and their effect on EBC pH have been published so far. Therefore, only the effect of CC smoke on EBC pH can be discussed.

Previously published articles report no significant changes in EBC pH among healthy smokers [33,34]. While, more recent studies have found an acute increase in EBC pH, which lasted for several hours after smoking CC (Picture 5)[35]. Meanwhile, the opposite was seen in people with conditions such as allergic rhinitis [36], asthma [33,37] and COPD, as it was found that smoking caused EBC pH to be significantly reduced. This suggests that some people might have a different respiratory system response to smoking, based on the degree of airway inflammation and further irritation caused by smoke. It is also thought that EBC pH results are partially influenced by what type of collecting device is used [38].

Picture 5: EBC pH in asymptomatic smokers after smoking a single cigarette

(https://www.karger.com/Article/FullText/245325)

Picture 6: Exhaled breath condensate pH, post gas standardization, in healthy subjects and patients with disease.

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28 When we compared our results to results obtained from other EBC pH normative studies (8.0 pH) [39], it was evident that our mean pH values (6.72, 6.77, 6.9, 6.95 pH) were significantly more acidic (Picture 6). This is due to variations in methodology in the field of EBC. The process of gas standardisation (de-aeration) with argon allows for CO2 to be removed before the analysis of EBC pH is performed. Gas standardisation was not used during our study. Scholars argue whether CO2 should be included or removed from the sample. Gas standardisation leads to a mean increase in pH of 0.94 (Picture 7) [40,41]. Because of divided opinions and methodologies, comparison between EBC studies is made difficult. In conclusion, it evident that EBC pH is influenced by many factors including: airway inflammation, allergies, smoking, collecting device type and methodology.

Picture 7: Exhaled breath condensate pH, post gas standardisation, in healthy subjects and patients with disease. (https://erj.ersjournals.com/content/28/1/252)

As expected, no change occurred to PFT immediately after smoking. In order to achieve changes in pulmonary function, which would be caused by smoking, a long-term study lasting many years should take place. IQOS was only released in 2014 and prior to it, HTP had very low numbers of users, there are no long-term studies available yet. Despite of recording no change in spirometry, it should still be noted that smokers often experience clinical symptoms, while retaining normal spirometry values [42].

However, there is currently an on-going, observational cohort study in Kazakhstan, which will be completed in 2023. It will look at the long-term effects of smoking IQOS and compare them to

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29 those of CC smokers. Areas of focus will be respiratory symptoms, exacerbations, exercise intolerance and changes in lung function [43].

Important factors

To summarise, when analysing our findings, some features need to be given thought:

First, the scale of the study, results from small research populations need to be looked at carefully. At the same time our results had a small deviation around the mean and almost every subject displayed a very similar pattern of change from baseline to post-smoking values. Out of 22 cases, smoking caused EBC pH to rise in 21 of these. Furthermore, values of exhaled CO after smoking CC differed by only 1 PPM between the subjects.

Second, there are other HTP devices available such as iGLO. We only used IQOS as it has the largest number of users, tobacco stick sales and are expected to continue growing. Although several similar devices fall under the umbrella term of HTP, we cannot extend our study to these. Our study was product and laboratory specific, therefore other similar devices should be evaluated individually.

Third, our focus was the acute effect of smoking; assumptions should not be made on the possible long-term effects of HTP until completed longitudinal studies are published.

Importance of this study

As innovation is always ahead of research and regulation, it is important for independent sources of information to be available on the topic. This study looks at already available material published online, additionally; our own investigation is carried out to compare IQOS and CC.

This was the first study to look at EBC pH changes caused by IQOS smoke, and to compare it to the results of CC.

Additionally, our results were confirmed by other published studies, proving that HTP do not cause an elevation in exhaled post-smoking CO levels.

Another important factor is that the results of our measurements have been achieved after as little as 10 puffs/inhalations, showing that chronic smoking is not required for physiological changes to take place. One of the most interesting findings was that, post-smoking elevation in EBC pH was of the same magnitude with both IQOS and CC.

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CONCLUSIONS

1. Heated tobacco did not cause an elevation in post-smoking eCO levels, while conventional cigarettes did so to a significant degree. This displays that conventional cigarettes can have a potentially more detrimental effect to the smokers’ pulmonary health; through the medium of higher CO emissions.

2. In case of the acute effect on lung function, no differences were found between heated tobacco and conventional cigarettes. Lung function remained stable and did not undergo any significant changes with either of the smoking methods.

3. Both heated tobacco and conventional cigarettes caused a significant increase in post-smoking EBC pH. When baseline values were taken into consideration it was found that both methods of smoking achieved an increase of the same magnitude.

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RECOMMENDATIONS

New products will keep being introduced by the tobacco industry, and it is in everyone’s best interest to stay vigilant to the possible harmful effects that come from using these products. No matter what method of tobacco heating is used, resultant smoke is toxic and addictive. Tobacco smoke has thousands of chemicals, many of which are known cancer-causing substances. Aerosols released from tobacco smoke cause negative health effects such as inflammation, increased risk of infection,

worsening allergic conditions, decreased physical performance etc. Furthermore, social smoking and second hand smoke exposure should be avoided just as much as picking up smoking yourself.

Teenagers, students and young professionals should be especially careful, as they are the main targets of tobacco marketing campaigns.

We found that HTP had negligible CO emissions, together with having as much as 99% lower levels of various volatile organic compounds and polycyclic aromatic hydrocarbons. From this aspect HTP appear to have a less detrimental effect on health than CC. It could be argued that these factors alone are enough to label HTP as a healthier alternative to CC, but unexpected organ toxicity may be a factor instead [21].Another important factor in our study was that IQOS and CC, both caused a

significant elevation in post-smoking EBC pH. Effects of this are not well understood, but changes in airway fluid pH are strongly linked to respiratory diseases and airway inflammation. Furthermore, analysis of PMIs own material does not support the claim that IQOS encourages users to quit smoking [5].There was also no evidence for improvement in respiratory function or airway inflammation in users who switched from CC to IQOS [22]. Additionally, recently published articles by the European Respiratory Society demonstrated that IQOS exposure is as damaging as CC or e-cigarettes to human lung cells.

Choosing the most suiting product as an alternative to traditional tobacco cigarettes can play a key role in reducing or quitting smoking all together. Hence, a risk-benefit ratio should be estimated before making the transition to HTP.

To conclude, HTP are among the possible alternatives to CC. However, it should not be looked at lightly, as it is still a tobacco product with many detrimental health effects.

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LITERATURE

1. Fernandez E. Heated tobacco product claims by tobacco industry scrutinized by UCSF researchers. EurekAlert, 2018.

2. Philip Morris MRTP Applications. Fda.gov. 2019.

3. Stein R. FDA Panel Gives Qualified Support To Claims For 'Safer' Smoking Device, 2018. 4. McKelvey K, Popova L, et al. Heated tobacco products likely appeal to adolescents and young

adults Tobacco Control, 2018.

5. Simonavicius E, McNeill A, et al. Heat-not-burn tobacco products: a systematic literature review. PubMed, 2018.

6. Neilsen K. A tobacco industry study of airline cabin air quality: dropping inconvenient findings, PubMed, 2004.

7. Barnes R, Hammond S, et al. The Tobacco Industry’s Role in the 16 Cities Study of Second hand Tobacco Smoke: Do the Data Support the Stated Conclusions? Environmental Health Perspectives, 2007.

8. Richard L. Barnes, Stanton A. Glantz. Endotoxins in Tobacco Smoke: Shifting Tobacco

Industry Positions, Nicotine & Tobacco Research, Volume 9, Issue 10, 2007, Pages 995–1004. 9. Wertz MS, Kyriss T, et al. The toxic effects of cigarette additives, PLOS medicine, 2011. 10. Velicer C, Aguinaga-Bialous S, et al. Tobacco companies' efforts to undermine ingredient

disclosure: the Massachusetts benchmark study. Tob Control. 2016. 11. World Health Organization, News, Fact sheets, Detail - Tobacco, 2018.

12. Centers for Disease Control and Prevention, Data and Statistics, Fast Facts and Fact Sheets, 2018.

13. Electric smoking system, History. wikipedia.org. 2019.

14. Mulier T. Marlboro Maker Confident in Smokeless After iQos Slowdown, 2018.

15. Auer R, Concha-Lozano N, et al. Heat-Not-Burn Tobacco Cigarettes: Smoke by Any Other Name. JAMA Internal Medicine. 17 (7): 1050–1052, 2017.

16. Our Tobacco Heating system - IQOS. PMI, 2018.

17. A van der Plas. Prevalence and Patterns of Tobacco Use in Japan after the Commercialization of a Heat-Not-Burn Alternative (IQOS) to Cigarettes. PMI, 2017.

18. Wan W. Big Tobacco’s new cigarette is sleek, smokeless — but is it any better for you? The Washington Post, 2017.

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33 20. Hair EC, Bennett M, et al. Examining perceptions about IQOS heated tobacco product:

consumer studies in Japan and Switzerland Tobacco Control 2018;27:s70-s73, 2018. 21. Glantz SA. Heated tobacco products: the example of IQOS. Tob Control, 2018.

22. Moazed F, Chun L, et al. Assessment of industry data on pulmonary and immunosuppressive effects of IQOS. Tobacco Control, 2018.

23. Tabuchi T, Gallus S, et al. Heat-not-burntobaccoproduct use in Japan: its prevalence, predictors and perceivedsymptomsfromexposure to secondhand heat-not-burntobacco

aerosol. TobControl 2018.

24. Pasquale Caponnetto, Marilena Maglia. Carbon monoxide levels after inhalation from new generation heated tobacco products, 2018.

25. Sukhwinder Singh Sohal, Mathew Suji Eapen, et al. IQOS exposure impairs human airway cell homeostasis: direct comparison with traditional cigarette and e-cigarette. ERJ Open Research, 2019.

26. Vansickel A, Cobb C, Weaver M, Eissenberg T. A Clinical Laboratory Model for Evaluating the Acute Effects of Electronic "Cigarettes": Nicotine Delivery Profile and Cardiovascular and Subjective Effects. 2019.

27. Farsalinos K, Polosa R. Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review. Therapeutic Advances in Drug Safety. 2014;5(2):67-86.38

28. Campagna D, Cibella F, Caponnetto P, et al. Changes in breathomics from a 1-year randomized smoking cessation trial of electronic cigarettes. European Journal of Clinical Investigation. 2016;46(8):698-706.

29. G.Jaccard,D.Tafin Djoko, et al. Comparative assessment of HPHC yields in the Tobacco Heating System THS2.2 and commercial cigarettes. Regulatory Toxicology and Pharmacology, Volume 90, 2017, Pages 1-8.

30. Mark Forster, Stacy Fiebelkorn, et al. Assessment of novel tobacco heating product THP1.0. Part 3: Comprehensive chemical characterisation of harmful and potentially harmful aerosol emissions. Regulatory Toxicology and Pharmacology Volume 93, 2018, Pages 14-33. 31. Auer R, Concha-Lozano N, Jacot-Sadowski I, Cornuz J, Berthet A.

Heat-Not-BurnTobaccoCigarettes: Smoke by AnyOtherName. JAMA Intern Med. 2017;177(7):1050– 1052. doi:10.1001/jamainternmed.2017.1419

32. Mallock N, Böss L, Burk R, Danziger M, Welsch T, Hahn H, et al. Levelsofselectedanalytes in theemissionsof “heat not burn” tobaccoproductsthat are relevant to assesshumanhealthrisks. Arch Toxicol. 2018;92:2145–9.

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ADDITIONAL DOCUMENTS

Attachment 1 - Mean carbon monoxide concentrations in groups of smokers.

(https://pmj.bmj.com/content/78/918/233)

Attachment 2 - Baseline CO breath levels measured on non-smokers, smokers with normal lung function and smokers with

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35

Attachment 3 - Concentrations of 8 Volatile Organic Compounds, 16 Polycyclic Aromatic

Hydrocarbons, 3 Inorganic Compounds, and Nicotine in Mainstream Aerosol and Temperature of the HNB IQOS Cigarette and Conventional Cigarettes.

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