44. A systematic review and meta-analysis of the toxicity of heated tobacco products compared to conventional cigarettes
Main Article Content
Abstract
The toxicity of heated tobacco products (HTPs) has recently garnered intense focus. This systematic review and meta-analysis aimed to synthesize the findings of randomized controlled trials (RCTs) evaluating the toxicity of HTPs compared to conventional cigarettes (CCs) using biomarkers of exposure (BoEs) endpoints. Ten original articles were selected from 187 eligible articles across three electronic databases: PubMed, Sciencedirect, and ProQuest (2010-2023), following PRISMA 2020 guidelines. The results revealed significantly lower levels of 14 important BoEs (1-OH, 2-AN, 3-HMPMA, 3-HPMA, 4-ABP, CEMA, CoHb, HEMA, MHBMA, NNAL, NNN, S-PMA, TNeq, and O-Tol) in HTP users compared to CC users, with the highest reduction observed in TNeq (68.6%) and the lowest in CEMA (13.4%). The toxicity of HTPs, as assessed through BoEs, is substantially reduced compared to CCs. Nonetheless, further independent and comprehensive studies are needed to evaluate the safety of HTPs more thoroughly.
Article Details
Keywords
Heated tobacco products (HTPs), conventional cigarettes (CCs), toxicity, biomarkers of exposure, meta-analysis
References
1. WHO. WHO report on the global tobacco epidemic, 2023. 2023. Protect people from tobacco smoke. WHO, Geneva. https://www.who.int/publications/i/item/9789240077164
2. Warren GW, Alberg AJ, Kraft AS, et al. The 2014 Surgeon General’s report: “The health consequences of smoking-50 years of progress”: a paradigm shift in cancer care. Cancer. Jul 1 2014;120(13):1914-6. doi:10.1002/cncr.28695.
3. Jankowski M, Brozek GM, Lawson J, et al. New ideas, old problems? Heated tobacco products - a systematic review. Int J Occup Med Environ Health. Oct 16 2019;32(5):595-634. doi:10.13075/ijomeh.1896.01433.
4. Taylor M, Thorne D, Carr T, et al. Assessment of novel tobacco heating product THP1.0. Part 6: A comparative in vitro study using contemporary screening approaches. Regul Toxicol Pharmacol. Mar 2018;93:62-70. doi:10.1016/j.yrtph.2017.08.016.
5. Vukas J, Mallock-Ohnesorg N, Rüther T, et al. Two Different Heated Tobacco Products vs. Cigarettes: Comparison of Nicotine Delivery and Subjective Effects in Experienced Users. Toxics. Jun 11 2023;11(6). doi:10.3390/toxics11060525.
6. Mallock N, Pieper E, Hutzler C, et al. Heated Tobacco Products: A Review of Current Knowledge and Initial Assessments. Front Public Health. 2019;7:287. doi:10.3389/fpubh.2019.00287.
7. Jaccard G, Tafin Djoko D, Moennikes O, et al. Comparative assessment of HPHC yields in the Tobacco Heating System THS2.2 and commercial cigarettes. Regul Toxicol Pharmacol. Nov 2017;90:1-8. doi:10.1016/j.yrtph.2017.08.006.
8. Lempert LK, Bialous S, Glantz S. FDA’s reduced exposure marketing order for IQOS: why it is not a reliable global model. Tob Control. Aug 2022;31(e1):e83-e87. doi:10.1136/tobaccocontrol-2020-056316.
9. Sun T, Anandan A, Lim CCW, et al. Global prevalence of heated tobacco product use, 2015-22: A systematic review and meta-analysis. Addiction. Aug 2023;118(8):1430-1444. doi:10.1111/add.16199.
10. Joan Dymphna P Reaño, Marie Barrientos-Regala, Reginald P Arimado, et al. A Systematic Review and Meta-Analysis on Human Biomarkers of Exposure from Heated Tobacco Products Compared to Conventional Cigarettes among Adult Smokers. Jour Clin Med Res. 2022;3(2):1-17.
11. Drovandi A, Salem S, Barker D, et al. Human Biomarker Exposure From Cigarettes Versus Novel Heat-Not-Burn Devices: A Systematic Review and Meta-Analysis. Nicotine Tob Res. Jun 12 2020;22(7):1077-1085. doi:10.1093/ntr/ntz200.
12. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. J Clin Epidemiol. Jun 2021;134:178-189. doi:10.1016/j.jclinepi.2021.03.001.
13. Cochrane Methods Network. Risk of Bias 2 (RoB 2) tool. Available at https://methods.cochrane.org/risk-bias-2. Cochrane. Accessed 24/02/2024, 2024. https://methods.cochrane.org/risk-bias-2
14. Shepperd CJ, Newland N, Eldridge A, et al. A single-blinded, single-centre, controlled study in healthy adult smokers to identify the effects of a reduced toxicant prototype cigarette on biomarkers of exposure and of biological effect versus commercial cigarettes. BMC Public Health. 2013;13:690. doi:https://doi.org/10.1186/1471-2458-13-690.
15. Haziza C, de La Bourdonnaye G, Donelli A, et al. Reduction in Exposure to Selected Harmful and Potentially Harmful Constituents Approaching Those Observed Upon Smoking Abstinence in Smokers Switching to the Menthol Tobacco Heating System 2.2 for 3 Months (Part 1). Nicotine Tob Res. Apr 17 2020;22(4):539-548. doi:10.1093/ntr/ntz013.
16. Gale N, McEwan M, Hardie G, et al. Changes in biomarkers of exposure and biomarkers of potential harm after 360 days in smokers who either continue to smoke, switch to a tobacco heating product or quit smoking. Internal and Emergency Medicine. 2022;17(7):2017-2030. doi:https://doi.org/10.1007/s11739-022-03062-1.
17. Martin Leroy C, Jarus-Dziedzic K, Ancerewicz J, et al. Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 7: A one-month, randomized, ambulatory, controlled clinical study in Poland. Regul Toxicol Pharmacol. Nov 1 2012;64(2 Suppl):S74-84. doi:10.1016/j.yrtph.2012.08.006.
18. Lüdicke F, Picavet P, Baker G, et al. Effects of Switching to the Tobacco Heating System 2.2 Menthol, Smoking Abstinence, or Continued Cigarette Smoking on Biomarkers of Exposure: A Randomized, Controlled, Open-Label, Multicenter Study in Sequential Confinement and Ambulatory Settings (Part 1). Nicotine Tob Res. Jan 5 2018;20(2):161-172. doi:10.1093/ntr/ntw287.
19. Miura N, Yuki D, Minami N, et al. A study to investigate changes in the levels of biomarkers of exposure to selected cigarette smoke constituents in Japanese adult male smokers who switched to a non-combustion inhaler type of tobacco product. Regul Toxicol Pharmacol. Apr 2015;71(3):498-506. doi:10.1016/j.yrtph.2015.02.007.
20. Sakaguchi C, Kakehi A, Minami N, et al. Exposure evaluation of adult male Japanese smokers switched to a heated cigarette in a controlled clinical setting. Regul Toxicol Pharmacol. Aug 2014;69(3):338-47. doi:10.1016/j.yrtph.2014.04.016.
21. Tran CT, Bosilkovska M, de La Bourdonnaye G, et al. Reduced levels of biomarkers of exposure in smokers switching to the Carbon-Heated Tobacco Product 1.0: a controlled, randomized, open-label 5-day exposure trial. Sci Rep. Nov 5 2020;10(1):19227. doi:10.1038/s41598-020-76222-y.
22. Tricker AR, Jang IJ, Martin Leroy C, et al. Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 4: Eight-day randomized clinical trial in Korea. Regul Toxicol Pharmacol. Nov 1 2012;64(2 Suppl):S45-53. doi:10.1016/j.yrtph.2012.08.013.
23. Yuki D, Takeshige Y, Nakaya K, et al. Assessment of the exposure to harmful and potentially harmful constituents in healthy Japanese smokers using a novel tobacco vapor product compared with conventional cigarettes and smoking abstinence. Regul Toxicol Pharmacol. Jul 2018;96:127-134. doi:10.1016/j.yrtph.2018.05.001.
24. Yuki D, Kikuchi A, Suzuki T, et al. Assessment of the exposure to selected smoke constituents in adult smokers using in-market heated tobacco products: a randomized, controlled study. Sci Rep. Oct 28 2022;12(1):18167. doi:10.1038/s41598-022-22997-1.
25. Chang CM, Edwards SH, Arab A, et al. Biomarkers of Tobacco Exposure: Summary of an FDA-Sponsored Public Workshop. Cancer Epidemiol Biomarkers Prev. Mar 2017;26(3):291-302. doi:10.1158/1055-9965.EPI-16-0675.
26. Nemukula M, Mogale MA, Mkhondo HB, et al. Association of Carboxyhemoglobin Levels with Peripheral Arterial Disease in Chronic Smokers Managed at Dr George Mukhari Academic Hospital. Int J Environ Res Public Health. Aug 2 2020;17(15)doi:10.3390/ijerph17155581.
27. Bellamri M, Yao L, Bonala R, et al. Bioactivation of the tobacco carcinogens 4-aminobiphenyl (4-ABP) and 2-amino-9H-pyrido[2,3-b]indole (AalphaC) in human bladder RT4 cells. Arch Toxicol. Jul 2019;93(7):1893-1902. doi:10.1007/s00204-019-02486-7.
28. Lochan R, Reeves HL, Daly AK, et al. The role of tobacco-derived carcinogens in pancreas cancer. ISRN Oncol. 2011;2011:249235. doi:10.5402/2011/249235.
29. Simonavicius E, McNeill A, Shahab L, et al. Heat-not-burn tobacco products: a systematic literature review. Tob Control. Sep 2019;28(5):582-594. doi:10.1136/tobaccocontrol-2018-054419.
30. Hartmann-Boyce J, Butler AR, Theodoulou A, et al. Biomarkers of potential harm in people switching from smoking tobacco to exclusive e-cigarette use, dual use or abstinence: secondary analysis of Cochrane systematic review of trials of e-cigarettes for smoking cessation. Addiction. Mar 2023;118(3):539-545. doi:10.1111/add.16063.
31. Hendlin YH, Vora M, Elias J, et al. Financial Conflicts of Interest and Stance on Tobacco Harm Reduction: A Systematic Review. Am J Public Health. Jul 2019;109(7):e1-e8. doi:10.2105/AJPH.2019.305106.
2. Warren GW, Alberg AJ, Kraft AS, et al. The 2014 Surgeon General’s report: “The health consequences of smoking-50 years of progress”: a paradigm shift in cancer care. Cancer. Jul 1 2014;120(13):1914-6. doi:10.1002/cncr.28695.
3. Jankowski M, Brozek GM, Lawson J, et al. New ideas, old problems? Heated tobacco products - a systematic review. Int J Occup Med Environ Health. Oct 16 2019;32(5):595-634. doi:10.13075/ijomeh.1896.01433.
4. Taylor M, Thorne D, Carr T, et al. Assessment of novel tobacco heating product THP1.0. Part 6: A comparative in vitro study using contemporary screening approaches. Regul Toxicol Pharmacol. Mar 2018;93:62-70. doi:10.1016/j.yrtph.2017.08.016.
5. Vukas J, Mallock-Ohnesorg N, Rüther T, et al. Two Different Heated Tobacco Products vs. Cigarettes: Comparison of Nicotine Delivery and Subjective Effects in Experienced Users. Toxics. Jun 11 2023;11(6). doi:10.3390/toxics11060525.
6. Mallock N, Pieper E, Hutzler C, et al. Heated Tobacco Products: A Review of Current Knowledge and Initial Assessments. Front Public Health. 2019;7:287. doi:10.3389/fpubh.2019.00287.
7. Jaccard G, Tafin Djoko D, Moennikes O, et al. Comparative assessment of HPHC yields in the Tobacco Heating System THS2.2 and commercial cigarettes. Regul Toxicol Pharmacol. Nov 2017;90:1-8. doi:10.1016/j.yrtph.2017.08.006.
8. Lempert LK, Bialous S, Glantz S. FDA’s reduced exposure marketing order for IQOS: why it is not a reliable global model. Tob Control. Aug 2022;31(e1):e83-e87. doi:10.1136/tobaccocontrol-2020-056316.
9. Sun T, Anandan A, Lim CCW, et al. Global prevalence of heated tobacco product use, 2015-22: A systematic review and meta-analysis. Addiction. Aug 2023;118(8):1430-1444. doi:10.1111/add.16199.
10. Joan Dymphna P Reaño, Marie Barrientos-Regala, Reginald P Arimado, et al. A Systematic Review and Meta-Analysis on Human Biomarkers of Exposure from Heated Tobacco Products Compared to Conventional Cigarettes among Adult Smokers. Jour Clin Med Res. 2022;3(2):1-17.
11. Drovandi A, Salem S, Barker D, et al. Human Biomarker Exposure From Cigarettes Versus Novel Heat-Not-Burn Devices: A Systematic Review and Meta-Analysis. Nicotine Tob Res. Jun 12 2020;22(7):1077-1085. doi:10.1093/ntr/ntz200.
12. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. J Clin Epidemiol. Jun 2021;134:178-189. doi:10.1016/j.jclinepi.2021.03.001.
13. Cochrane Methods Network. Risk of Bias 2 (RoB 2) tool. Available at https://methods.cochrane.org/risk-bias-2. Cochrane. Accessed 24/02/2024, 2024. https://methods.cochrane.org/risk-bias-2
14. Shepperd CJ, Newland N, Eldridge A, et al. A single-blinded, single-centre, controlled study in healthy adult smokers to identify the effects of a reduced toxicant prototype cigarette on biomarkers of exposure and of biological effect versus commercial cigarettes. BMC Public Health. 2013;13:690. doi:https://doi.org/10.1186/1471-2458-13-690.
15. Haziza C, de La Bourdonnaye G, Donelli A, et al. Reduction in Exposure to Selected Harmful and Potentially Harmful Constituents Approaching Those Observed Upon Smoking Abstinence in Smokers Switching to the Menthol Tobacco Heating System 2.2 for 3 Months (Part 1). Nicotine Tob Res. Apr 17 2020;22(4):539-548. doi:10.1093/ntr/ntz013.
16. Gale N, McEwan M, Hardie G, et al. Changes in biomarkers of exposure and biomarkers of potential harm after 360 days in smokers who either continue to smoke, switch to a tobacco heating product or quit smoking. Internal and Emergency Medicine. 2022;17(7):2017-2030. doi:https://doi.org/10.1007/s11739-022-03062-1.
17. Martin Leroy C, Jarus-Dziedzic K, Ancerewicz J, et al. Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 7: A one-month, randomized, ambulatory, controlled clinical study in Poland. Regul Toxicol Pharmacol. Nov 1 2012;64(2 Suppl):S74-84. doi:10.1016/j.yrtph.2012.08.006.
18. Lüdicke F, Picavet P, Baker G, et al. Effects of Switching to the Tobacco Heating System 2.2 Menthol, Smoking Abstinence, or Continued Cigarette Smoking on Biomarkers of Exposure: A Randomized, Controlled, Open-Label, Multicenter Study in Sequential Confinement and Ambulatory Settings (Part 1). Nicotine Tob Res. Jan 5 2018;20(2):161-172. doi:10.1093/ntr/ntw287.
19. Miura N, Yuki D, Minami N, et al. A study to investigate changes in the levels of biomarkers of exposure to selected cigarette smoke constituents in Japanese adult male smokers who switched to a non-combustion inhaler type of tobacco product. Regul Toxicol Pharmacol. Apr 2015;71(3):498-506. doi:10.1016/j.yrtph.2015.02.007.
20. Sakaguchi C, Kakehi A, Minami N, et al. Exposure evaluation of adult male Japanese smokers switched to a heated cigarette in a controlled clinical setting. Regul Toxicol Pharmacol. Aug 2014;69(3):338-47. doi:10.1016/j.yrtph.2014.04.016.
21. Tran CT, Bosilkovska M, de La Bourdonnaye G, et al. Reduced levels of biomarkers of exposure in smokers switching to the Carbon-Heated Tobacco Product 1.0: a controlled, randomized, open-label 5-day exposure trial. Sci Rep. Nov 5 2020;10(1):19227. doi:10.1038/s41598-020-76222-y.
22. Tricker AR, Jang IJ, Martin Leroy C, et al. Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 4: Eight-day randomized clinical trial in Korea. Regul Toxicol Pharmacol. Nov 1 2012;64(2 Suppl):S45-53. doi:10.1016/j.yrtph.2012.08.013.
23. Yuki D, Takeshige Y, Nakaya K, et al. Assessment of the exposure to harmful and potentially harmful constituents in healthy Japanese smokers using a novel tobacco vapor product compared with conventional cigarettes and smoking abstinence. Regul Toxicol Pharmacol. Jul 2018;96:127-134. doi:10.1016/j.yrtph.2018.05.001.
24. Yuki D, Kikuchi A, Suzuki T, et al. Assessment of the exposure to selected smoke constituents in adult smokers using in-market heated tobacco products: a randomized, controlled study. Sci Rep. Oct 28 2022;12(1):18167. doi:10.1038/s41598-022-22997-1.
25. Chang CM, Edwards SH, Arab A, et al. Biomarkers of Tobacco Exposure: Summary of an FDA-Sponsored Public Workshop. Cancer Epidemiol Biomarkers Prev. Mar 2017;26(3):291-302. doi:10.1158/1055-9965.EPI-16-0675.
26. Nemukula M, Mogale MA, Mkhondo HB, et al. Association of Carboxyhemoglobin Levels with Peripheral Arterial Disease in Chronic Smokers Managed at Dr George Mukhari Academic Hospital. Int J Environ Res Public Health. Aug 2 2020;17(15)doi:10.3390/ijerph17155581.
27. Bellamri M, Yao L, Bonala R, et al. Bioactivation of the tobacco carcinogens 4-aminobiphenyl (4-ABP) and 2-amino-9H-pyrido[2,3-b]indole (AalphaC) in human bladder RT4 cells. Arch Toxicol. Jul 2019;93(7):1893-1902. doi:10.1007/s00204-019-02486-7.
28. Lochan R, Reeves HL, Daly AK, et al. The role of tobacco-derived carcinogens in pancreas cancer. ISRN Oncol. 2011;2011:249235. doi:10.5402/2011/249235.
29. Simonavicius E, McNeill A, Shahab L, et al. Heat-not-burn tobacco products: a systematic literature review. Tob Control. Sep 2019;28(5):582-594. doi:10.1136/tobaccocontrol-2018-054419.
30. Hartmann-Boyce J, Butler AR, Theodoulou A, et al. Biomarkers of potential harm in people switching from smoking tobacco to exclusive e-cigarette use, dual use or abstinence: secondary analysis of Cochrane systematic review of trials of e-cigarettes for smoking cessation. Addiction. Mar 2023;118(3):539-545. doi:10.1111/add.16063.
31. Hendlin YH, Vora M, Elias J, et al. Financial Conflicts of Interest and Stance on Tobacco Harm Reduction: A Systematic Review. Am J Public Health. Jul 2019;109(7):e1-e8. doi:10.2105/AJPH.2019.305106.