Skutki zdrowotne palenia w odniesieniu do alternatywnych wyrobów tytoniowych

Introduction

The first mention about tobacco smoking dates back to 5000 BC. Beginning with using tobacco during rituals or religious events, its cultivation and consumption increased significantly with the colonization of today’s America by Europeans in the 16th century. The popularity of tobacco products grew at a rapid pace, which contributed to the development of the tobacco industry in the 18th century [1]. Currently, around 21% of the global population (35% of men and 6% of women) smoke some tobacco products. However, it is forecasted that the percentage of smokers worldwide in 2030 will decrease to 17%. In relation to World Health Organization (WHO) statistics, smoking contributes to 10% of deaths worldwide. Currently about 7 million of people die because of smoking each year, and this number may exceed 8 million in 2030 [2].
Increased popularity of tobacco products is followed by a great number of scientific reports indicating their harmfulness. Tobacco cigarette (TC) smoke contains a mixture of around 5000 chemical substances [3]. The main components of their aerosol are: nicotine, tar, carbon monoxide (CO), polyaromatic hydrocarbons (PAHs), tobacco-specific nitrosamines (TSNAs), volatile organic compounds (VOCs), free radicals and heavy metals [4–6]. Many of these substances are classified as harmful or potentially harmful constituents (HPHCs) for humans [7]. The U.S. Food and Drug Administration published a list of 93 HPHCs present in tobacco products and cigarette smoke [8]. Furthermore, many of these chemicals are classified according to the International Agency for Research on Cancer (IARC) as carcinogenic for humans (group 1, i.e. nickel, benzene or 4-aminobiphenyl), probably cancerogenic for humans (group 2A, i.e. benzo[a]pyrene, 1,3-butadiene, formaldehyde or N-nitrosodimethylamine) or possibly carcinogenic for humans (2B, i.e. acetaldehyde, hydrazine, lead or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)) [9–11]. Exposure to such a huge number of toxic substances contributes to the development of tobacco-related diseases, such as cancer, cardiovascular disease, respiratory diseases such as chronic obstuctive pulmonary disease (COPD) and impairment of reproductive function and fetus development [12].
Quitting smoking or at least reducing the number of cigarettes smoked per day seem to be the best options for smoking addicts [13]. However, in order to limit smokers’ exposure to hazardous substances accumulated in tobacco smoke, the tobacco industry has also introduced some novel products, such as electronic cigarettes and heat-not-burn products, to the market [14, 15]. These cigarettes are characterized by limited components and also significantly reduced numbers of some toxic constituents emitted with their aerosol. Therefore they may be less harmful than conventional tobacco cigarettes and they may potentially be used by smokers who do not want to quit smoking tobacco products completely. However, the safety of these products is still under debate. On the one hand, toxicological studies indicate the presence of dangerous substances in their vapors. However, their values are lower when compared to conventional cigarettes. Furthermore, presence of the aforementioned substances in these novel cigarettes’ smoke may affect smokers’ health in a negative way. Nevertheless, long-term exposure effects are still unknown, especially for never-smokers [16–21].
The following work attempts to summarize current knowledge about health consequences of two most popular novel cigarettes: e-cigarettes and heat-not-burn products. Due to the rapidly growing market of alternative smoking devices, it is necessary to clearly determine benefits and any potential risks of using such products instead of conventional tobacco cigarettes, especially for non-smokers who want to try these products. Therefore, this review compares only the currently known health consequences of smoking tobacco, electronic and HnB cigarettes, based on findings from studies with humans.

Health consequences of smoking conventional tobacco cigarettes

Tobacco constituents and substances derived from their pyrolysis, as well as some additional ingredients of tobacco cigarettes, have an adverse effect on the smokers’ body. By inhaling these hazardous substances, various biological processes are activated in smokers’ bodies [22]. The spectrum of health consequences of tobacco smoking depends on many factors, such as: type of tobacco products, number of years of smoking, number of cigarettes smoked per day, age of smoking initiation, the likelihood of cessation and nicotine dependence [23].
The first adverse health effects of smoking may be observed immediately or shortly after using cigarettes. Huge amounts of toxic substances absorbed by smokers with tobacco aerosol increase the amount of free radicals and reduce activity of antioxidants, which leads to an oxidative-antioxidative imbalance and induction of oxidative stress. As a consequence, it activates the inflammation and impairs the immune response [24, 25]. Furthermore, the accumulation of oxidants also affects peroxidation of lipids, proteins and nucleic acids. Moreover, respiratory impairment, such as irradiation, cough, increased mucus production, dyspnea or wheezing may be observed [26]. Finally, smoking tobacco may lead to nicotine addiction [27].
Intensive smoking of tobacco products directly or indirectly contributes to the appearance of further negative health outcomes. Impairment of the immune response may cause increased probability of infectious diseases [28]. Furthermore, smoking tobacco influences asthma-relevant factors, such as airways irradiation, and persistent inflammation, increased production of mucus, dyspnea and wheezing have an impact on asthma exacerbation [29]. In addition, smoking is a significant risk factor of atherosclerosis, the occurrence of which increases likelihood of serious cardiovascular diseases for smokers in the future. Tobacco smokers are characterized by elevated levels of triglycerides and low-density lipoprotein (LDL) particles with a decreased level of high-density lipoprotein (HDL). Furthermore, increased activity of fibrinogen and plasminogen activator inhibitor 1 during smoking has been observed [30]. Moreover, tobacco smoking has an adverse impact on glucose homeostasis, which is associated with decline in glucose uptake due to insulin resistance, which may predispose to diabetes mellitus type 2 [31].
Long-term smoking is the main factor for increasing the possibility of developing chronic obstructive pulmonary disease (COPD) due to chronic inflammation and subsequent remodeling of peripheral airways and emphysematous lung parenchymal destruction [32]. Furthermore, smoking is a major risk factor of cardiovascular disease because of atherosclerosis and possible acute thrombosis activation by tobacco aerosol toxic constituents [33]. These hazardous substances may contribute to activation of biochemical pathways that subsequently affect age-related macular degeneration [34] or rheumatoid arthritis development [35]. In addition, tobacco smoke increases the probability of developing almost 19 different types of cancer, such as: respiratory system (lung, larynx and oral cavity), genitourinary system (kidney, bladder and uterine cervix), gastrointestinal system (esophagus, pancreas, stomach, colorectal and liver cancer) and acute myeloid leukemia [36]. Finally, cigarette smoke has an adverse health impact on fetus development and for infants (impairment of organ development, malformations or death). Moreover, smoking also negatively affects maternal health and may cause a decline in the likelihood of becoming pregnant or may become a source of some problems during pregnancy [37]. The main health consequences of tobacco cigarette smoking are summarized in Figure 1.

Currently known health consequences of e-cigarettes

E-cigarettes are battery-operated devices with cartridges that generate puffs by heating an element of an atomizer [38]. It was believed that e-cigarettes containing only specific substances (nicotine, flavorings, propylene glycol or vegetable glycerin [15]) may have some positive health effects by reducing the smokers’ exposure to dangerous elements present in aerosol from tobacco cigarettes. However, toxicological studies show presence of dangerous substances in their vapors: heavy metals, free radicals (7 × 1011 particles/puff vs. 1014–1016 particles/puff for TC) [17, 39] or hazardous ingredients emitted during overheating of propylene glycol or glycerin (e.g. acrolein, formaldehyde). Despite the fact that their values are lower and mostly within limits when compared to conventional cigarettes, the presence of these chemicals in e-cigarette aerosol may have a negative health effect for people who have never smoked [16, 40]. In addition, acute exposure of healthy smokers to e-cigarette aerosol activates oxidative stress (with increased levels of sNox2 and 8-isoprostaglandin F2a) and reduces the amount of antioxidants (non-significant decline in vitamin E) and impairs endothelial function (non-significant decline in flow-mediated dilation) [41].
In a large-scale Internet survey of e-cigarette usage, nearly 60% of respondents noticed occasional undesirable side effects, such as sore and dry mouth and throat, coughing or problems with gums. Consumers who previously smoked conventional tobacco products also noted mitigating reactions of co-existing respiratory diseases (including asthma and COPD). However, a small group of these respondents highlighted worsening in the state of their illnesses [20, 42]. Furthermore, during the investigation of specific symptoms in volunteers (n = 41) who wanted to smoke e-cigarettes for the first time, the authors summarized that about 60% of the respondents felt bad after using ECs: they started coughing or had irritated eyes, chest pains, and also an upset stomach [43]. The case report of a 20-year-old male sailor showed shortness of breath, cough and facial flushing after using e-cigarettes. This suggests the development of eosinophilic pneumonitis after exposure to e-cigarette vapor [44]. A case study of a 33-year-old man with germ line tumor showed that after 3 months from switching to e-cigarettes, computed tomography showed presence of new pulmonary changes specific for respiratory bronchiolitis-intestinal lung disease [45]. Prolonged exposure to e-cigarettes also caused enlargement of distal airspace [46].
Investigation of the effects of propylene glycol and glycerine for lung function in healthy volunteers (n = 20) and asthmatic patients (n = 10) indicated incidences of cough, mucosal secretion and chest pains for both groups (healthy vs. asthmatic). However, the authors did not report any significant reduction in lung functions (FeNO or CRP) in asthmatic patients [47]. Studies on healthy smokers showed that 5-minute vaping increases lung flow resistance and decreases fractional exhaled nitric oxide (FeNO) concentration. An increase of peripheral flow resistance is connected with narrowing of smooth muscles in airways and can lead to the appearance of specific symptoms [48]. Similar studies detected that e-cigarette smoke (after 5-minute vaping) is responsible for reduction of forced expiratory volume in 1 s (FEV1) and forced expiratory flow at 25% (FEF25) [49], and a decrease in FeNO (for healthy e-cigarette smokers and e-cigarette smokers with mild asthma) [50]. Investigation of the effect of tobacco- and cherry-flavored e-cigarettes compared to tobacco cigarettes for basic respiratory parameters in 105 participants indicated that e-cigarette usage reduced exhaled CO, but for dual users this level was significantly higher. Moreover, for users of both tobacco- and cherry-flavored e-cigarettes, the authors observed an increased forced vital capacity (FVC) and increased FEV1 for cherry-flavored EC smokers and dual users [51]. Other studies involving smokers and non-smokers showed that active and passive smoking of e-cigarettes also causes small changes in airways, when compared with TCs [52]. A huge observational study on about 4 500 current and former smokers at risk/with COPD symptoms revealed that for about 350 of the participants possible negative symptoms connected with e-cigarette usage, such as increased chronic bronchitis prevalence (connected with elevated probability of COPD development) and a decrease in some basic lung functions, were observed [53].
Short-term vaping may increase heart rate (up to 17.2 beats per minute) and diastolic blood pressure and reduce oxygen saturation. However, the results differ between types of e-cigarette device, used e-liquids and nicotine doses [54–56]. Moreover, current findings are inconclusive, as some studies only showed effects of vaping on elevated oxygen saturation, without any changes of heart rate or blood pressure [57]. In addition, as the data suggest, acute smoking of e-cigarettes increases the level of oxidized low-density lipoprotein (LDL) (compared to never-smokers) [58], and may also affect epithelial dysfunction [41]. Finally, e-cigarette liquids contain high concentrations of nicotine, which may lead to developing addiction. There is some evidence of nicotine poisoning (by ingestion or through the skin) among e-cigarette smokers [59]. The literature provides several case reports of burns caused by e-cigarettes. Most often they were caused by overheating and battery explosion in the devices [60–62].

Current known health consequences of heat-not-burn products

Heat-not-burn products, such as the IQOS system, are electric devices which comprise an electronic heating mechanism and a plug impregnated with glycerine. Using a metal flange allows the tobacco to be heated at lower temperature (up to 350°C) without combustion. This solution allows the smokers’ exposure to toxic components of tobacco smoke to be reduced [63]. However, as current findings suggest, even this lower temperature of aerosol production is enough to melt the polymer-film filter and release potentially hazardous substances such as formaldehyde cyanohydrin, 1,2-diacetin or ε-caprolactone [19]. In addition, HnB cigarettes may contain similar nicotine content as conventional tobacco cigarettes [64]. Another study highlighted the presence of some carbonyl compounds and nitrosamines in their aerosol [65]. Despite the fact that heat-not-burn products reduce exposure to harmful or potentially harmful constituents when compared to tobacco cigarettes (up to 70–95%), presence of the aforementioned substances in their aerosol may be dangerous for never-smokers in particular [66].
IQOS heat-not-burn products were introduced to the market in 2014 (Japan and Italy), and therefore there is only a limited number of trials researching the health consequences of using this novel type of cigarettes. In addition, the available data focus mostly on determination of chemical composition or some basic mechanisms, such as oxidative stress or inflammation, potentially activated by the aerosol of these products (in vivo and in vitro studies). There are only a few clinical trials which compare basic health parameters of smokers of conventional cigarette smokers and those who switched to HnB products.
Additionally, most of the assessments are carried out by the manufacturer of IQOS. There is also lack of data about the long-term effects of these products on health outcomes. For this reason, it is difficult to clearly determine the health consequences associated with using HnB cigarettes.
Six-month trials by Philip Morris International showed significant improvements in high-density lipoprotein cholesterol (HDL-C), haemoglobin with irreversibly bound carbon monoxide (COHb), white blood cells (WBC), total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and FEV1 biomarkers for smokers who switched from tobacco cigarettes to IQOS [67]. Pre-clinical studies by the IQOS manufacturer indicated less chemotaxis and reduced integroty of human coronary arterial endothelial cells (HCAEC) monolayer [68].
In addition, exposure to IQOS aerosol leads to reduced adhesion of monocytic cells to HCAECs and a decline in molecular changes for both of those cell types, which may suggest reduced risk of atherosclerosis and cardiovascular disease when compared to tobacco cigarettes [69]. However, there is no independent clinical trial on the effect of HnB products on atherosclerosis/cardiovascular diseases in humans.
Current literature findings suggest that HnB cigarette aerosol may enhance oxidative stress and the inflammatory response due to increased amounts of free radicals and other toxic compounds [65]. Single use of an IQOS cigarette causes activation of oxidative stress (increased level of Nox2, H2O2, 8-iso-PGF2a), reduction of antioxidants (reduction of HBA) and increased levels of platelet activation markers (sCD40L, sP-selectin) in healthy smokers. In addition, acute exposure to IQOS smoke increases systolic blood pressure and endothelial dysfunction [70]. Furthermore, other clinical data show that acute exposure to IQOS aerosol increases levels of bilirubin and ALT for IQOS smokers (compared to tobacco cigarettes and non-smokers), which may suggest hepatotoxicity of these products [71]. Finally, there are two case reports of 20- and 16-year-old men in whom smoking HnB cigarettes caused acute eosinophilic pneumonia (AEP) [72, 73]. Table 1 summarizes the currently known consequences of smoking conventional tobacco cigarettes (TCs), e-cigarettes (ECs) and heat-not-burn cigarettes (HnB).

Conclusions

Collected literature data indicate that short-term exposure to smoke from conventional cigarettes, e-cigarettes and HnB products affects the occurrence of respiratory symptoms, i.e. dry mouth, cough, and increased mucus secretion. In addition, oxidative stress is activated in healthy smokers in each of the cases, which can contribute to inflammation, remodeling, and chronic respiratory symptoms. In addition, TCs, ECs and HnB may contain comparable concentrations of nicotine, the use of which may have an influence on the occurrence of addiction, which has been noted in each case.
In the case of novel smoking devices – e-cigarettes and HnB products – compared to standard cigarettes, they reduce smokers’ exposure to HPHCs from cigarette smoke, which may reduce the risk of smoking-related diseases. However, these products are not free of toxic substances, which can negatively affect non-smokers’ health. In addition, we do not have enough clear evidence to comprehensively determine the health consequences of smoking e-cigarettes and HnB products. Current findings are based on assessing short-term effects of smoking those products on basic health parameters, mainly compared to TCs or after switching to these novel alternative smoking products. The existing studies were carried out mainly on small groups of smokers, using various products and research methodologies, which makes it difficult to precisely compare their results. In addition, there is no analysis of the long-term use of such products on the health of their consumers.
In the future, long-term studies regarding the effects of smoking e-cigarettes and HnB products on the health of smokers, pregnant women and the development of the fetus and the newborn should be carried out. Additionally, scientific research should focus on determining the relationship between smoke exposure of these products and the development of cardiovascular, respiratory or cancer diseases. In particular, we should investigate the determination of the subsequent impact of individual smoke components on the activation of individual signaling pathways and structural changes that contribute to the development of specific diseases. Also, in the conducted research it would be necessary to harmonize the methodology used and the compared tobacco products.

Conflict of interest

The authors declare no conflict of interest.

References

1. Maritz GS, Mutemwa M. Tobacco smoking: patterns, health consequencesfor adults, and the long-term health of the offspring. Glob J Health Sci 2012; 4: 62-75.
2. World Health Organization. WHO report on the global tobacco epidemic, 2017: monitoring tobacco use and prevention policies. Geneva: World Health Organization 2017.
3. Pfeifer GP, Denissenko MF, Olivier M, et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 2002; 21: 7435-7451.
4. Harris JE. Cigarette smoke components and disease: cigarette smoke is more than a triad of tar, nicotine, and carbon monoxide. Smok Tob Control Monogr 1996; 7: 59-75.
5. International Agency for Research on Cancer, editor. IARC monographs on the evaluation of carcinogenic risks to humans, volume 83, Tobacco smoke and involuntary smoking: this publication represents the views and expert opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, which met in Lyon, 11-18 June 2002. Lyon: IARC; 2004; 1452.
6. IARC Monographs. Tobacco Smoking. In: Personal Habits and Indoor Combustions. International Agency for Research on Cancer 2012.
7. Talhout R, Schulz T, Florek E, et al. Hazardous compounds in tobacco smoke. Int J Environ Res Public Health 2011; 8: 613-628.
8. Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke; Established List [Internet]. Federal Register. 2012 [cited 2019 Aug 21]. Available from: https://www.federalregister.gov/documents/2012/04/03/2012-7727/harmful-and-potentially-harmful-constituents-in-tobacco-products-and-tobacco-smoke-established-list
9. Smith CJ, Perfetti TA, Rumple MA, et al. “IARC group 2A Carcinogens” reported in cigarette mainstream smoke. Food Chem Toxicol 2000; 38: 371-383.
10. Smith CJ, Livingston SD, Doolittle DJ. An international literature survey of “IARC group I carcinogens” reported in mainstream cigarette smoke. Food Chem Toxicol 1997; 35: 1107-1130.
11. Smith CJ, Perfetti TA, Rumple MA, et al. “IARC Group 2B carcinogens” reported in cigarette mainstream smoke. Food Chem Toxicol 2001; 39: 183-205.
12. CDCTobaccoFree. Health Effects of Cigarette Smoking [Internet]. Centers for Disease Control and Prevention. 2019 [cited 2019 Aug 21]. Available from: https://www.cdc.gov/tobacco/data_statistics/fact_sheets/health_effects/effects_cig_smoking/index.htm
13. Jha P, Peto R. Global effects of smoking, of quitting, and of taxing tobacco. N Engl J Med 2014; 370: 60-68.
14. McKelvey K, Popova L, Kim M, et al. Heated tobacco products likely appeal to adolescents and young adults. Tob Control 2018; 27 (Suppl 1): s41-s47.
15. Geiss O, Bianchi I, Barahona F, Barrero-Moreno J. Characterisation of mainstream and passive vapours emitted by selected electronic cigarettes. Int J Hyg Environ Health 2015; 218: 169-180.
16. Hajek P, Etter JF, Benowitz N, et al. Electronic cigarettes: review of use, content, safety, effects on smokers and potential for harm and benefit: electronic cigarettes: a review. Addiction 2014; 109: 1801-1810.
17. Sussan TE, Gajghate S, Thimmulappa RK, et al. Exposure to electronic cigarettes impairs pulmonary anti-bacterial and anti-viral defenses in a mouse model. PLoS One 2015; 10: e0116861.
18. Popova L, Lempert LK, Glantz SA. Light and mild redux: heated tobacco products’ reduced exposure claims are likely to be misunderstood as reduced risk claims. Tob Control 2018; 27 (Suppl 1): s87-s95.
19. Davis B, Williams M, Talbot P. iQOS: evidence of pyrolysis and release of a toxicant from plastic. Tob Control 2019; 28: 34-41.
20. Farsalinos K, Romagna G, Tsiapras D, et al. Characteristics, perceived side effects and benefits of electronic cigarette use: a worldwide survey of more than 19,000 consumers. Int J Environ Res Public Health 2014; 11: 4356-4373.
21. Farsalinos KE, Yannovits N, Sarri T, et al. Nicotine delivery to the aerosol of a heat-not-burn tobacco product: comparison with a tobacco cigarette and e-cigarettes. Nicotine Tob Res 2018; 20: 1004-1009.
22. Bergen AW, Caporaso N. Cigarette smoking. J Natl Cancer Inst 1999; 91: 1365-1375.
23. Hu MC, Davies M, Kandel DB. Epidemiology and correlates of daily smoking and nicotine dependence among young adults in the United States. Am J Public Health 2006; 96: 299-308.
24. Lee J, Taneja V, Vassallo R. Cigarette smoking and inflammation: cellular and molecular mechanisms. J Dent Res 2012; 91: 142-149.
25. Jorsaraei A, Gholam S, Mahjoub S, et al. DNA, protein and lipid peroxidation as oxidative stress biomarkers in seminal plasma of smoker and nonsmoker infertile men. Casp J Appl Sci Res 2015; 4: 16-23.
26. Willemse BWM, Postma DS, Timens W, ten Hacken NHT. The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation. Eur Respir J 2004; 23: 464-476.
27. Benowitz NL. Nicotine addiction. N Engl J Med 2010; 362: 2295-2303.
28. Arcavi L, Benowitz NL. Cigarette smoking and infection. Arch Intern Med 2004; 164: 2206-2216.
29. Tamimi A, Serdarevic D, Hanania NA. The effects of cigarette smoke on airway inflammation in asthma and COPD: therapeutic implications. Respir Med 2012; 106: 319-328.
30. Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease. J Am Coll Cardiol 2004; 43: 1731-1737.
31. Xu H, Wang Q, Sun Q, et al. In type 2 diabetes induced by cigarette smoking, activation of p38 MAPK is involved in pancreatic beta-cell apoptosis. Environ Sci Pollut Res 2018; 25: 9817-9827.
32. Laniado-Laborín R. Smoking and chronic obstructive pulmonary disease (COPD). Parallel epidemics of the 21st century. Int J Environ Res Public Health 2009; 6: 209-224.
33. Messner B, Bernhard D. Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol 2014; 34: 509-515.
34. Velilla S, García-Medina JJ, García-Layana A, et al. Smoking and age-related macular degeneration: review and update. J Ophthalmol 2013; 2013: 895147.
35. Chang K, Yang S, Kim S, et al. Smoking and rheumatoid arthritis. Int J Mol Sci 2014; 15: 22279-22295.
36. DeVita VT, Lawrence TS, Rosenberg SA. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. Lippincott Williams & Wilkins 2008; 1748.
37. Jaakkola JJ, Gissler M. Maternal smoking in pregnancy, fetal development, and childhood asthma. Am J Public Health 2004; 94: 136-140.
38. Alawsi F, Nour R, Prabhu S. Are e-cigarettes a gateway to smoking or a pathway to quitting? BDJ 2015; 219: 111-115.
39. John G, Kohse K, Orasche J, et al. The composition of cigarette smoke determines inflammatory cell recruitment to the lung in COPD mouse models. Clin Sci 2014; 126: 207-221.
40. Grana R, Benowitz N, Glantz SA. E-cigarettes: a scientific review. Circulation 2014; 129: 1972-1986.
41. Carnevale R, Sciarretta S, Violi F, et al. Acute impact of tobacco vs electronic cigarette smoking on oxidative stress and vascular function. Chest 2016; 150: 606-612.
42. Caponnetto P, Campagna D, Papale G, et al. The emerging phenomenon of electronic cigarettes. Expert Rev Respir Med 2012; 6: 63-74.
43. Chen M, Hall M, Parada H, et al. Symptoms during adolescents’ first use of cigarettes and e-cigarettes: a pilot study. Int J Environ Res Public Health 2017; 14: 1260.
44. Thota D, Latham E. Case report of electronic cigarettes possibly associated with eosinophilic pneumonitis in a previously healthy active-duty sailor. J Emerg Med 2014; 47: 15-17.
45. Flower M, Nandakumar L, Singh M, et al. Respiratory bronchiolitis-associated interstitial lung disease secondary to electronic nicotine delivery system use confirmed with open lung biopsy: RB-ILD secondary to ENDS use. Respirol Case Rep 2017; 5: e00230.
46. Garcia-Arcos I, Geraghty P, Baumlin N, et al. Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner. Thorax 2016; 71: 1119-1129.
47. Clapp PW, Jaspers I. Electronic cigarettes: their constituents and potential links to asthma. Curr Allergy Asthma Rep 2017; 17: 79.
48. Vardavas CI, Anagnostopoulos N, Kougias M, et al. Short-term pulmonary effects of using an electronic cigarette: impact on respiratory flow resistance, impedance, and exhaled nitric oxide. Chest J 2012; 141: 1400-1406.
49. Ferrari M, Zanasi A, Nardi E, et al. Short-term effects of a nicotine-free e-cigarette compared to a traditional cigarette in smokers and non-smokers. BMC Pulm Med 2015; 15: 120.
50. Lappas AS, Tzortzi AS, Konstantinidi EM, et al. Short-term respiratory effects of e-cigarettes in healthy individuals and smokers with asthma: E-cigarette effects in healthy and asthmatics. Respirology 2018; 23: 291-297.
51. D’Ruiz CD, O’Connell G, Graff DW, Yan XS. Measurement of cardiovascular and pulmonary function endpoints and other physiological effects following partial or complete substitution of cigarettes with electronic cigarettes in adult smokers. Regul Toxicol Pharmacol 2017; 87: 36-53.
52. Flouris AD, Chorti MS, Poulianiti KP, et al. Acute impact of active and passive electronic cigarette smoking on serum cotinine and lung function. Inhal Toxicol 2013; 25: 91-101.
53. COPDGene and SPIROMICS Investigators; Bowler RP, Hansel NN, Jacobson S, et al. Electronic cigarette use in US adults at risk for or with COPD: analysis from two observational cohorts. J Gen Intern Med 2017; 32: 1315-1322.
54. Cooke WH, Pokhrel A, Dowling C, et al. Acute inhalation of vaporized nicotine increases arterial pressure in young non-smokers: a pilot study. Clin Auton Res 2015; 25: 267-270.
55. Farsalinos K, Cibella F, Caponnetto P, et al. Effect of continuous smoking reduction and abstinence on blood pressure and heart rate in smokers switching to electronic cigarettes. Intern Emerg Med 2016; 11: 85-94.
56. Spindle TR, Hiler MM, Breland AB, et al. The influence of a mouthpiece-based topography measurement device on electronic cigarette user’s plasma nicotine concentration, heart rate, and subjective effects under directed and ad libitum use conditions. Nicotine Tob Res 2017; 19: 469-476.
57. McAuley TR, Hopke PK, Zhao J, Babaian S. Comparison of the effects of e-cigarette vapor and cigarette smoke on indoor air quality. Inhal Toxicol 2012; 24: 850-857.
58. Moheimani RS, Bhetraratana M, Yin F, et al. Increased cardiac sympathetic activity and oxidative stress in habitual electronic cigarette users: implications for cardiovascular risk. JAMA Cardiol 2017; 2: 278-284.
59. Bartschat S, Mercer-Chalmers-Bender K, Beike J, et al. Not only smoking is deadly: fatal ingestion of e-juice – a case report. Int J Legal Med 2015; 129: 481-486.
60. Walsh K, Sheikh Z, Johal K, Khwaja N. Rare case of accidental fire and burns caused by e-cigarette batteries. BMJ Case Rep 2016; 2016: bcr2015212868.
61. Vaught B, Spellman J, Shah A, et al. Facial trauma caused by electronic cigarette explosion. Ear Nose Throat J 2017; 96: 139-142.
62. Bauman ZM, Roman J, Singer M, Vercruysse GA. Canary in the coal mine – initial reports of thermal injury secondary to electronic cigarettes. Burns 2017; 43: e38-e42.
63. Kim M. Philip Morris International introduces new heat-not-burn product, IQOS, in South Korea. Tob Control 2018; 27: e76-e78.
64. Bekki K, Inaba Y, Uchiyama S, Kunugita N. Comparison of chemicals in mainstream smoke in heat-not-burn tobacco and combustion cigarettes. J UOEH 2017; 39: 201-207.
65. Kaur G, Muthumalage T, Rahman I. Mechanisms of toxicity and biomarkers of flavoring and flavor enhancing chemicals in emerging tobacco and non-tobacco products. Toxicol Lett 2018; 288: 143-155.
66. Farsalinos KE, Yannovits N, Sarri T, et al. Carbonyl emissions from a novel heated tobacco product (IQOS): comparison with an e-cigarette and a tobacco cigarette: carbonyl emissions in heated tobacco product. Addiction 2018; 113: 2099-2106.
67. Lüdicke F, Ansari SM, Lama N, et al. Effects of switching to a heat-not-burn tobacco product on biologically-relevant biomarkers to assess a candidate modified risk tobacco product: a randomized trial. Cancer Epidemiol Biomarkers Prev 2019; doi: 10.1158/1055-9965.EPI-18-0915.
68. van der Toorn M, Frentzel S, De Leon H, et al. Aerosol from a candidate modified risk tobacco product has reduced effects on chemotaxis and transendothelial migration compared to combustion of conventional cigarettes. Food Chem Toxicol 2015; 86: 81-87.
69. Poussin C, Laurent A, Peitsch MC, et al. Systems toxicology-based assessment of the candidate modified risk tobacco product THS2.2 for the adhesion of monocytic cells to human coronary arterial endothelial cells. Toxicology 2016; 339: 73-86.
70. Biondi-Zoccai G, Sciarretta S, Bullen C, et al. Acute effects of heat‐not‐burn, electronic vaping, and traditional tobacco combustion cigarettes: the Sapienza University of Rome – Vascular Assessment of Proatherosclerotic Effects of Smoking (SUR – VAPES) 2 Randomized Trial. J Am Heart Assoc 2019; 8: e010455.
71. Chun L, Moazed F, Matthay M, et al. Possible hepatotoxicity of IQOS. Tob Control 2018; 27 (Suppl 1): s39-s40.
72. Kamada T, Yamashita Y, Tomioka H. Acute eosinophilic pneumonia following heat-not-burn cigarette smoking: AEP caused by heat-not-burn cigarette. Respirol Case Rep 2016; 4: e00190.
73. Aokage T, Tsukahara K, Fukuda Y, et al. Heat-not-burn cigarettes induce fulminant acute eosinophilic pneumonia requiring extracorporeal membrane oxygenation. Respir Med Case Rep 2019; 26: 87-90.