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

Cam Tuan Tran, Marija Bosilkovska, Guillaume de La Bourdonnaye, Nicolas Blanc, Christelle Haziza, Cam Tuan Tran, Marija Bosilkovska, Guillaume de La Bourdonnaye, Nicolas Blanc, Christelle Haziza

Abstract

In addition to smoking cessation, for those who would otherwise continue to smoke, replacing cigarettes with less harmful alternatives can reduce the harms of smoking. Heating instead of burning tobacco reduces, or eliminates, the formation of harmful and potentially harmful constituents (HPHC) that are found in cigarette smoke. The Carbon-Heated Tobacco Product (CHTP), a heat-not-burn tobacco product, mimics the cigarette smoking ritual. This randomized, open-label, two-arm, parallel-group, short-term confinement study tested the hypothesis that the geometric means of the BoExp levels for subjects switching to CHTP 1.0 for 5 days are lower relative to those continuing to smoke cigarettes. Biomarkers of exposure (BoExp), including nicotine, urinary excretion of mutagenic constituents (Ames test), and cytochrome P450 (CYP) 1A2 activity, were measured in blood and/or 24-h urine samples during ad libitum product use. Nicotine exposure remained at similar levels in individuals using CHTP as in those continuing to smoke cigarettes. Switching to CHTP resulted in marked decreases in all other urinary BoExp (56-97%), carboxyhemoglobin (59%), urinary mutagenic constituents, and CYP1A2 activity compared with continued cigarette smoking. Our results provide evidence of decreased exposure to 15 selected HPHCs in smokers switching from cigarettes to exclusive CHTP use.Trial registration ClinicalTrials.gov: NCT02503254; Date of first registration: 20/07/2015 https://www.clinicaltrials.gov/ct2/show/NCT02503254 .Study protocol Study protocol published at: https://www.clinicaltrials.gov/ProvidedDocs/54/NCT02503254/Prot_000.pdf .

Conflict of interest statement

All authors are (or were) employees of Philip Morris Products S.A. or worked for Philip Morris Products S.A. under contractual agreements.

Figures

Figure 1
Figure 1
Subject disposition. CC cigarette, CHTP Carbon-Heated Tobacco Product.
Figure 2
Figure 2
Biomarkers of exposure level reductions (%) on Day 5, CHTP relative to cigarettes. Values are geometric least square mean ratios and 95% confidence intervals. Acronyms of biomarkers of exposure are provided in Supplementary Table 1. CHTP 1.0 Carbon-Heated Tobacco Product 1.0.

References

    1. Benowitz NL. Emerging nicotine delivery products. Implications for public health. Ann. Am. Thorac. Soc. 2014;11:231–235. doi: 10.1513/AnnalsATS.201312-433PS.
    1. Abrams DB, et al. Harm minimization and tobacco control: Reframing societal views of nicotine use to rapidly save lives. Annu. Rev. Public Health. 2018;39:193–213. doi: 10.1146/annurev-publhealth-040617-013849.
    1. Haziza C, et al. Evaluation of the tobacco heating system 2.2. Part 8: 5-day randomized reduced exposure clinical study in Poland. Regul. Toxicol. Pharmacol. RTP. 2016;81:S139–150. doi: 10.1016/j.yrtph.2016.11.003.
    1. Ludicke F, 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. 2017;20:161–172. doi: 10.1093/ntr/ntw287.
    1. Haziza C, et al. Assessment of the reduction in levels of exposure to harmful and potentially harmful constituents in japanese subjects using a novel tobacco heating system compared with conventional cigarettes and smoking abstinence: a randomized controlled study in confinement. Regul. Toxicol. Pharmacol. 2016;81:489–499. doi: 10.1016/j.yrtph.2016.09.014.
    1. Gale N, et al. Changes in biomarkers of exposure on switching from a conventional cigarette to tobacco heating products: a randomized, controlled study in healthy Japanese subjects. Nicotine Tob. Res. 2018;21:1220–1227. doi: 10.1093/ntr/nty104.
    1. IOM (Institute of Medicine). Clearing the smoke—assessing the science base for tobacco harm reduction (Washington, DC: The National Academies Press, accessed on 06 March 2017); (2001).
    1. Creamer MR, et al. Tobacco product use and cessation indicators among adults—United States, 2018. Morb. Mortal. Wkly Rep. 2019;68:1013. doi: 10.15585/mmwr.mm6845a2.
    1. Orleans CT, Slade J. Nicotine Addiction: Principles and Management. Oxford: Oxford University Press; 1993. pp. 3–23.
    1. Pederson LL, Nelson DE. Literature review and summary of perceptions, attitudes, beliefs, and marketing of potentially reduced exposure products: communication implications. Nicotine Tob. Res. 2007;9:525–534. doi: 10.1080/14622200701239548.
    1. Felter, J. L. et al. (Google Patents, 2004).
    1. Caputi TL. Industry watch: heat-not-burn tobacco products are about to reach their boiling point. Tob. Control. 2017;26:609–610. doi: 10.1136/tobaccocontrol-2016-053264.
    1. FDA (Food and Drug Administration). Guidance for industry—modified risk tobacco product applications—draft guidance (2012).
    1. Phillips BW, et al. A 90-day oecd tg 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects of the aerosol from the carbon heated tobacco product version 1.2 (chtp1.2) compared with cigarette smoke. I. Inhalation exposure, clinical pathology and histopathology. Food Chem. Toxicol. 2018;116:388–413. doi: 10.1016/j.fct.2018.04.015.
    1. Ludicke F, Haziza C, Weitkunat R, Magnette J. Evaluation of biomarkers of exposure in smokers switching to a carbon-heated tobacco product: a controlled, randomized, open-label 5-day exposure study. Nicotine Tob. Res. 2016;18:1606–1613. doi: 10.1093/ntr/ntw022.
    1. Fagerstrom K, Russ C, Yu CR, Yunis C, Foulds J. The fagerstrom test for nicotine dependence as a predictor of smoking abstinence: a pooled analysis of varenicline clinical trial data. Nicotine Tob. Res. 2012;14:1467–1473. doi: 10.1093/ntr/nts018.
    1. Haziza C, et al. Biomarker of exposure level data set in smokers switching from conventional cigarettes to tobacco heating system 2.2, continuing smoking or abstaining from smoking for 5 days. Data Brief. 2017;10:283–293. doi: 10.1016/j.dib.2016.11.047.
    1. WHO Study Group et al. WHO study group on tobacco product regulation—report on the scientific basis of tobacco product regulations: Fifth report of a WHO study group. (2015).
    1. FDA (Food and Drug Administration). Guidance for industry—reporting harmful and potentially harmful constituents in tobacco products and tobacco smoke under section 904(a)(3) of the federal food, drug, and cosmetic act—draft guidance (2012).
    1. Goniewicz ML, et al. Elimination kinetics of the tobacco-specific biomarker and lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Cancer Epidemiol. Biomark. Prev. 2009;18:3421–3425. doi: 10.1158/1055-9965.epi-09-0874.
    1. Faber MS, Fuhr U. Time response of cytochrome p450 1a2 activity on cessation of heavy smoking. Clin. Pharmacol. Ther. 2004;76:178–184. doi: 10.1016/j.clpt.2004.04.003.
    1. Tricker AR. Biomarkers derived from nicotine and its metabolites: a review. Beiträge zur Tabakforschung/Contrib. Tob. Res. 2014;22:147–175.
    1. Lindner D, Smith S, Leroy CM, Tricker AR. Comparison of exposure to selected cigarette smoke constituents in adult smokers and nonsmokers in a European, multicenter, observational study. Cancer Epidemiol. Biomark. Prev. 2011;20:1524–1536. doi: 10.1158/1055-9965.epi-10-1186.
    1. Theophilus EH, Coggins CRE, Chen P, Schmidt ER, Borgerding MF. Magnitudes of biomarker reductions in response to controlled reductions in cigarettes smoked per day: a one-week clinical confinement study. Regul. Toxicol. Pharmacol. 2015;71:225–234. doi: 10.1016/j.yrtph.2014.12.023.
    1. Scherer G, Urban M, Engl J, Hagedorn HW, Riedel K. Influence of smoking charcoal filter tipped cigarettes on various biomarkers of exposure. Inhalation Toxicol. 2006;18:821–829. doi: 10.1080/08958370600747945.
    1. WHO (World Health Organization). WHO guidelines for indoor air quality: selected pollutants (2010).
    1. Mahoney JJ, Vreman HJ, Stevenson DK, Van Kessel AL. Measurement of carboxyhemoglobin and total hemoglobin by five specialized spectrophotometers (co-oximeters) in comparison with reference methods. Clin. Chem. 1993;39:1693–1700. doi: 10.1093/clinchem/39.8.1693.
    1. Carmella SG, et al. Correction to effects of smoking cessation on eight urinary tobacco carcinogen and toxicant biomarkers. Chem. Res. Toxicol. 2012;25:763. doi: 10.1021/tx300048h.
    1. Park SL, et al. Mercapturic acids derived from the toxicants acrolein and crotonaldehyde in the urine of cigarette smokers from five ethnic groups with differing risks for lung cancer. PLoS ONE. 2015;10:e0124841. doi: 10.1371/journal.pone.0124841.
    1. Torikai K, Yoshida S, Takahashi H. Effects of temperature, atmosphere and PH on the generation of smoke compounds during tobacco pyrolysis. Food Chem. Toxicol. 2004;42:1409–1417. doi: 10.1016/j.fct.2004.04.002.
    1. Schettgen T, Ochsmann E, Alt A, Kraus T. A biomarker approach to estimate the daily intake of benzene in non-smoking and smoking individuals in Germany. J. Expo. Sci. Environ. Epidemiol. 2010;20:427–433. doi: 10.1038/jes.2009.32.
    1. Carmella, S. G. et al. Effects of smoking cessation on eight urinary tobacco carcinogen and toxicant biomarkers Chem. Res. Toxicol.22, 734–741. Erratum in Chem Res Toxicol. 2012;2025(2013):2763, (2009).
    1. Feng S, et al. Evaluation of urinary 1-hydroxypyrene, s-phenylmercapturic acid, trans, trans-muconic acid, 3-methyladenine, 3-ethyladenine, 8-hydroxy-2'-deoxyguanosine and thioethers as biomarkers of exposure to cigarette smoke. Biomarkers. 2006;11:28–52. doi: 10.1080/13547500500399730.
    1. Toxicology Data Network. 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (casrn: 64091-91-4). (accessed 20 August 2014); (2010).
    1. Fischer S, Spiegelhalder B, Eisenbarth J, Preussmann R. Investigations on the origin of tobacco-specific nitrosamines in mainstream smoke of cigarettes. Carcinogenesis. 1990;11:723–730. doi: 10.1093/carcin/11.5.723.
    1. Moldoveanu SC, Borgerding M. Formation of tobacco specific nitrosamines in mainstream cigarette smoke; part 1, FTC smoking. Contrib. Tob. Res. 2008;23:19–31.
    1. Hecht SS, et al. Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation. Can. Res. 1999;59:590–596.
    1. Mure K, Hayatsu H, Takeuchi T, Takeshita T, Morimoto K. Heavy cigarette smokers show higher mutagenicity in urine. Mutat. Res. 1997;373:107–111. doi: 10.1016/S0027-5107(96)00195-9.
    1. Hammond D, Fong GT, Cummings KM, Hyland A. Smoking topography, brand switching, and nicotine delivery: results from an in vivo study. Cancer Epidemiol. Biomark. Preven. 2005;14:1370–1375. doi: 10.1158/1055-9965.epi-04-0498.
    1. Hajek P, et al. Nicotine intake from electronic cigarettes on initial use and after 4 weeks of regular use. Nicotine Tob. Res. 2014;17:175–179. doi: 10.1093/ntr/ntu153.
    1. Reilly SM, et al. Effects of topography-related puff parameters on carbonyl delivery in mainstream cigarette smoke. Chem. Res. Toxicol. 2017;30:1463–1469. doi: 10.1021/acs.chemrestox.7b00104.
    1. Baker R. Temperature variation within a cigarette combustion coal during the smoking cycle. High Temp. Sci. 1975;7:236.
    1. Miyake T, Shibamoto T. Quantitative analysis by gas chromatography of volatile carbonyl compounds in cigarette smoke. J. Chromatogr. A. 1995;693:376–381. doi: 10.1016/0021-9673(94)01179-I.
    1. U.S. Department of Health and Human Services. The health consequences of smoking—50 years of progress: a report of the surgeon general (2014).
    1. Sitkauskiene B, Stravinskaite K, Sakalauskas R, Dicpinigaitis PV. Changes in cough reflex sensitivity after cessation and resumption of cigarette smoking. Pulm. Pharmacol. Ther. 2007;20:240–243. doi: 10.1016/j.pupt.2006.08.005.
    1. Dicpinigaitis PV, et al. Effect of smoking cessation on cough reflex sensitivity. Eur. Respir. J. 2006;28:786–790. doi: 10.1183/09031936.06.00007806.
    1. Etter JF. Short-term change in self-reported copd symptoms after smoking cessation in an internet sample. Eur. Respir. J. 2010;35:1249–1255. doi: 10.1183/09031936.00090509.
    1. Gratziou C. Respiratory, cardiovascular and other physiological consequences of smoking cessation. Curr. Med. Res. Opin. 2009;25:535–545. doi: 10.1185/03007990802707642.
    1. Hughes JR. Effects of abstinence from tobacco: valid symptoms and time course. Nicotine Tob. Res. 2007;9:315–327. doi: 10.1080/14622200701188919.
    1. Sitkauskiene B, Dicpinigaitis PV. Effect of smoking on cough reflex sensitivity in humans. Lung. 2010;188:S29–32. doi: 10.1007/s00408-009-9188-9.
    1. Motooka Y, et al. Adverse events of smoking cessation treatments (nicotine replacement therapy and non-nicotine prescription medication) and electronic cigarettes in the food and drug administration adverse event reporting system, 2004–2016. SAGE Open Med. 2018;6:1–11. doi: 10.1177/2050312118777953.

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