Evaluation of Biomarkers of Exposure in Smokers Switching to a Carbon-Heated Tobacco Product: A Controlled, Randomized, Open-Label 5-Day Exposure Study

Frank Lüdicke, Christelle Haziza, Rolf Weitkunat, John Magnette, Frank Lüdicke, Christelle Haziza, Rolf Weitkunat, John Magnette

Abstract

Introduction: Tobacco harm reduction aims to provide reduced risk alternatives to adult smokers who would otherwise continue smoking combustible cigarettes (CCs). This randomized, open-label, three-arm, parallel-group, single-center, short-term confinement study aimed to investigate the effects of exposure to selected harmful and potentially harmful constituents (HPHCs) of cigarette smoke in adult smokers who switched to a carbon-heated tobacco product (CHTP) compared with adult smokers who continued to smoke CCs and those who abstained from smoking for 5 days.

Methods: Biomarkers of exposure to HPHCs, including nicotine and urinary excretion of mutagenic material, were measured in 24-hour urine and blood samples in 112 male and female Caucasian smokers switching from CCs to the CHTP ad libitum use. Puffing topography was assessed during product use.

Results: Switching to the CHTP or smoking abstinence (SA) resulted in marked decreases from baseline to Day 5 in all biomarkers of exposure measured, including carboxyhemoglobin (43% and 55% decrease in the CHTP and SA groups, respectively). The urinary excretion of mutagenic material was also markedly decreased on Day 5 compared with baseline (89% and 87% decrease in the CHTP and SA groups, respectively). No changes in biomarkers of exposure to HPHCs or urinary mutagenic material were observed between baseline and Day 5 in the CC group.

Conclusions: Our results provide clear evidence supporting a reduction in the level of exposure to HPHCs of tobacco smoke in smokers who switch to CHTP under controlled conditions, similar to that observed in SA.

Implications: The reductions observed in biomarkers of exposure to HPHCs of tobacco smoke in this short-term study could potentially also reduce the incidence of cancer, cardiovascular and respiratory diseases in those smokers who switch to a heated tobacco product.

© The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.

Figures

Figure 1.
Figure 1.
Subject disposition. CC: combustible cigarettes; SA: smoking abstinence; CHTP: carbon-heated tobacco product; N: number of subjects.
Figure 2.
Figure 2.
Relative (%) change (mean and 95% CI) from baseline to end of exposure (Day 5/6) per study group. CC: combustible cigarette; SA: smoking abstinence; CHTP: carbon-heated tobacco product MD2-E7; CI: confidence interval; MHBMA: mono-hydroxybutenyl mercapturic acid; HPMA: hydroxypropylmercapturic acid; OHP: hydroxypyrene and its glucuronide and sulfate conjugates; ABP: aminobiphenyl; S-PMA: S-phenylmercapturic acid; NNAL: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol.

References

    1. IOM (Institute of Medicine). Clearing the Smoke - Assessing the Science Base for Tobacco Harm Reduction. Washington, DC: The National Academies Press; 2001. Accessed November 26, 2015.
    1. Slade J. Nicotine delivery device. In: Orleans CT, Slade J, eds. Nicotine Addiction: Principles and Management. New York, NY: Oxford University Press; 1993:3–23.
    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(5):525–534. doi:10.1080/14622200701239548.
    1. Felter JL, Lee RL, Solanky A, et al.; Philip Morris USA. Electrically heated cigarette smoking system with internal manifolding for puff detection. US6810883 B2. November 8, 2002.
    1. Buchhalter AR, Eissenberg T. Preliminary evaluation of a novel smoking system: effects on subjective and physiological measures and on smoking behavior. Nicotine Tob Res. 2000;2(1):39–43. doi:10.1080/14622200050011286.
    1. Holzman D. Safe cigarette alternatives? Industry critics say ‘not yet’. J Natl Cancer Inst. 1999;91(6):502–504. doi:10.1093/jnci/91.6.502.
    1. Caraballo RS, Pederson LL, Gupta N. New tobacco products: do smokers like them? Tob Control. 2006;15(1):39–44. doi:10.1136/tc.2005.012856.
    1. FDA (Food and Drug Administration). Guidance for Industry - Modified Risk Tobacco Product Applications - Draft Guidance 2012. Accessed November 26, 2015.
    1. Kogel U, Schlage WK, Martin F, et al. A 28-day rat inhalation study with an integrated molecular toxicology endpoint demonstrates reduced exposure effects for a prototypic modified risk tobacco product compared with conventional cigarettes. Food Chem Toxicol. 2014;68:204–217. doi:10.1016/j.fct.2014.02.034.
    1. Talikka M, Sierro N, Ivanov NV, et al. Genomic impact of cigarette smoke, with application to three smoking-related diseases. Crit Rev Toxicol. 2012;42(10):877–889. doi:10.3109/10408444.2012.725244.
    1. Phillips B, Veljkovic E, Peck MJ, et al. A 7-month cigarette smoke inhalation study in C57BL/6 mice demonstrates reduced lung inflammation and emphysema following smoking cessation or aerosol exposure from a prototypic modified risk tobacco product. Food Chem Toxicol. 2015;80:328–345. doi:10.1016/j.fct.2015.03.009.
    1. van der Toorn M, Frentzel S, Goedertier D, Peitsch M, Hoeng J, De Leon H. A prototypic modified risk tobacco product exhibits reduced effects on chemotaxis and transendothelial migration of monocytes compared with a reference cigarette. Food Chem Toxicol. 2015;80:277–286. doi:10.1016/j.fct.2015.03.026.
    1. Benowitz NL, Jacob P, III, Bernert JT, et al. Carcinogen exposure during short-term switching from regular to “light” cigarettes. Cancer Epidemiol Biomarkers Prev. 2005;14(6):1376–1383. doi:10.1158/1055-9965.EPI-04-0667.
    1. Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict. 1991;86(9):1119–1127. Accessed November 26, 2015.
    1. Einisto P, Nohmi T, Watanabe M, Ishidate M., Jr Sensitivity of Salmonella typhimurium YG1024 to urine mutagenicity caused by cigarette smoking. Mutat Res. 1990;245(2):87–92. Accessed November 26, 2015.
    1. Scherer G, Urban M, Engl J, Hagedorn HW, Riedel K. Influence of smoking charcoal filter tipped cigarettes on various biomarkers of exposure. Inhal Toxicol. 2006;18(10):821–829. doi:10.1080/08958370600747945.
    1. Sarkar M, Kapur S, Frost-Pineda K, et al. Evaluation of biomarkers of exposure to selected cigarette smoke constituents in adult smokers switched to carbon-filtered cigarettes in short-term and long-term clinical studies. Nicotine Tob Res. 2008;10(12):1761–1772. doi:10.1080/14622200802443718.
    1. Carmella SG, Chen M, Han S, et al. Effects of smoking cessation on eight urinary tobacco carcinogen and toxicant biomarkers. Chem Res Toxicol. 2009;22(4):734–741. Erratum in Chem Res Toxicol. 2012 Mar 19;25(3):763. doi:10.1021/tx800479s.
    1. IARC (International Agency for Research on Cancer). Monographs on the Evaluation of Carcinogenic Risks to Humans: Chemical Agents and Related Occupations. Vol 100F Geneva, Switzerland: WHO Press; 2012. Accessed November 26, 2015.
    1. Boogaard PJ, van Sittert NJ. Suitability of S-phenyl mercapturic acid and trans-trans-muconic acid as biomarkers for exposure to low concentrations of benzene. Environ Health Perspect. 1996;104(suppl 6):1151–1157. Accessed November 26, 2015.
    1. Riedel K, Scherer G, Engl J, Hagedorn HW, Tricker AR. Determination of three carcinogenic aromatic amines in urine of smokers and nonsmokers. J Anal Toxicol. 2006;30(3):187–195. doi:10.1093/jat/30.3.187.
    1. Jongeneelen FJ, Anzion RB, Scheepers PT, et al. 1-Hydroxypyrene in urine as a biological indicator of exposure to polycyclic aromatic hydrocarbons in several work environments. Ann Occup Hyg. 1988;32(1):35–43. doi:10.1093/annhyg/32.1.35.
    1. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry. Toxicological Profile for Carbon Monoxide 2012. Accessed November 23, 2014.
    1. Hecht SS, Carmella SG, Chen M, et al. Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation. Cancer Res. 1999;59(3):590–596. Accessed November 26, 2015.
    1. Hecht SS. Metabolic activation and detoxification of tobacco-specific nitrosamines-a model for cancer prevention strategies. Drug Metab Rev. 1994;26(1–2):373–390. doi:10.3109/03602539409029803.
    1. Mure K, Hayatsu H, Takeuchi T, Takeshita T, Morimoto K. Heavy cigarette smokers show higher mutagenicity in urine. Mutat Res. 1997;373(1):107–111. doi:10.1016/S0027-5107(96)00195-9.
    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(2):225–234. doi:10.1016/j.yrtph.2014.12.023.
    1. Tricker AR, Jang IJ, Martin Leroy C, Lindner D, Dempsey R. Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 4: eight-day randomized clinical trial in Korea. Regul Toxicol Pharmacol. 2012;64(suppl 2):S45–53. doi:10.1016/j.yrtph.2012.08.
    1. Marian C, O’Connor RJ, Djordjevic MV, Rees VW, Hatsukami DK, Shields PG. Reconciling human smoking behavior and machine smoking patterns: implications for understanding smoking behavior and the impact on laboratory studies. Cancer Epidemiol Biomarkers Prev. 2009;18(12):3305–3320. doi:10.1158/1055-9965.EPI-09-1014.
    1. Rees VW, Wayne GF, Connolly GN. Puffing style and human exposure minimally altered by switching to a carbon-filtered cigarette. Cancer Epidemiol Biomarkers Prev. 2008;17(11):2995–3003. doi:10.1158/1055-9965.EPI-07-2533.
    1. Benowitz NL, Hall SM, Stewart S, Wilson M, Dempsey D, Jacob P., III Nicotine and carcinogen exposure with smoking of progressively reduced nicotine content cigarette. Cancer Epidemiol Biomarkers Prev. 2007;16(11):2479–2485. doi:10.1158/1055-9965.EPI-07-0393.
    1. Hatsukami DK, Kotlyar M, Hertsgaard LA, et al. Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and cessation. Addiction. 2010;105(2):343–355. doi:10.1158/1055-9965.EPI-07-0393.
    1. Fiore M, Baker T. Reduced nicotine cigarettes - A promising regulatory pathway. N Engl J Med. 2015;373(14):1289–1291. doi:10.1056/NEJMp1509510.
    1. Hu Q, Hou H. Tobacco Smoke Exposure Biomarkers. Boca Raton, FL: CRC Press, Taylor & Francis Group; 2015.

Source: PubMed

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