Lion Shahab, PhD; Maciej L. Goniewicz, PhD; Benjamin C. Blount, PhD; Jamie Brown, PhD; Ann McNeill, PhD; K. Udeni Alwis, PhD; June Feng, PhD; Lanqing Wang, PhD; Robert West, PhD
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health and the U.S. Food and Drug Administration.
Acknowledgment: The authors thank Kate Sheals and Victoria Nelson for their help with data collection and the Centers for Disease Control and Prevention reviewers for providing a thorough review of the manuscript.
Financial Support: This work was supported by Cancer Research UK (grant C27061/A16929, with additional funding from grants C1417/A14135 and C36048/A11654). Dr. Brown's post is funded by a fellowship from the Society for the Study of Addiction, and Cancer Research UK also provides support (grants C1417/A7972 and C44576/A19501). Drs. McNeill and West are part of the UK Centre for Tobacco and Alcohol Studies, which is a UK Clinical Research Collaboration Public Health Research Centre of Excellence. Funding from the Medical Research Council, British Heart Foundation, Cancer Research UK, Economic and Social Research Council, and the National Institute for Health Research under the auspices of the UK Clinical Research Collaboration is gratefully acknowledged (grant MR/K023195/1). Dr. Goniewicz was supported by the National Institute on Drug Abuse and the National Cancer Institute of the National Institutes of Health (awards R01DA037446 and P30 CA016056, respectively) and by an award from Roswell Park Alliance Foundation.
Disclosures: Dr. Shahab reports grants from Cancer Research UK during the conduct of the study and grants from Pfizer (unrestricted research funding to study smoking cessation) and personal fees from Atlantis Health Care outside of the submitted work. Dr. Goniewicz reports grants from Pfizer (2011 GRAND [Global Research Awards for Nicotine Dependence] recipient) and personal fees from Johnson & Johnson (as a member of the advisory board) outside the submitted work. Dr. Brown reports grants (unrestricted research funding to study smoking cessation) from Pfizer outside the submitted work. Dr. West reports grants, personal fees, and nonfinancial support (that is, research grants, consultancy, travel, and hospitality) from Pfizer, Johnson & Johnson, and GlaxoSmithKline outside the submitted work; in addition, Dr. West's salary is funded by Cancer Research UK and he is an advisor to the UK National Centre for Smoking Cessation and Training. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-1107.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: Not available. Statistical code and data set: Available from Dr. Shahab (e-mail, email@example.com).
Requests for Single Reprints: Lion Shahab, PhD, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Street, London WC1E 7HB, United Kingdom; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Shahab and West: Department of Epidemiology and Public Health, University College London, 1-19 Torrington Street, London WC1E 7HB, United Kingdom.
Dr. Goniewicz: Department of Health Behavior, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263.
Drs. Blount, Alwis, Feng, and Wang: Tobacco and Volatiles Branch, Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, 4770 Buford Highway, Atlanta, GA 30341.
Dr. Brown: Department of Clinical, Educational and Health Psychology, University College London, 1-19 Torrington Street, London WC1E 7HB, United Kingdom.
Dr. McNeill: Addictions Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 4 Windsor Walk, London SE5 8AF, United Kingdom.
Author Contributions: Conception and design: L. Shahab, M.L. Goniewicz, J. Brown, A. McNeill, R. West.
Analysis and interpretation of the data: L. Shahab, M.L. Goniewicz, B.C. Blount, J. Brown, J. Feng, L. Wang, R. West.
Drafting of the article: L. Shahab, B.C. Blount, A. McNeill, K.U. Alwis, R. West.
Critical revision of the article for important intellectual content: L. Shahab, M.L. Goniewicz, B.C. Blount, J. Brown, A. McNeill, R. West.
Final approval of the article: L. Shahab, M.L. Goniewicz, B.C. Blount, J. Brown, A. McNeill, R. West.
Statistical expertise: L. Shahab.
Obtaining of funding: L. Shahab, B.C. Blount, J. Brown.
Administrative, technical, or logistic support: L. Shahab, M.L. Goniewicz.
Collection and assembly of data: L. Shahab, M.L. Goniewicz, B.C. Blount, J. Feng.
Given the rapid increase in the popularity of e-cigarettes and the paucity of associated longitudinal health-related data, the need to assess the potential risks of long-term use is essential.
To compare exposure to nicotine, tobacco-related carcinogens, and toxins among smokers of combustible cigarettes only, former smokers with long-term e-cigarette use only, former smokers with long-term nicotine replacement therapy (NRT) use only, long-term dual users of both combustible cigarettes and e-cigarettes, and long-term users of both combustible cigarettes and NRT.
The following 5 groups were purposively recruited: combustible cigarette–only users, former smokers with long-term (≥6 months) e-cigarette–only or NRT-only use, and long-term dual combustible cigarette–e-cigarette or combustible cigarette–NRT users (n = 36 to 37 per group; total n = 181).
Sociodemographic and smoking characteristics were assessed. Participants provided urine and saliva samples and were analyzed for biomarkers of nicotine, tobacco-specific N-nitrosamines (TSNAs), and volatile organic compounds (VOCs).
After confounders were controlled for, no clear between-group differences in salivary or urinary biomarkers of nicotine intake were found. The e-cigarette–only and NRT-only users had significantly lower metabolite levels for TSNAs (including the carcinogenic metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol [NNAL]) and VOCs (including metabolites of the toxins acrolein; acrylamide; acrylonitrile; 1,3-butadiene; and ethylene oxide) than combustible cigarette–only, dual combustible cigarette–e-cigarette, or dual combustible cigarette–NRT users. The e-cigarette–only users had significantly lower NNAL levels than all other groups. Combustible cigarette–only, dual combustible cigarette–NRT, and dual combustible cigarette–e-cigarette users had largely similar levels of TSNA and VOC metabolites.
Cross-sectional design with self-selected sample.
Former smokers with long-term e-cigarette–only or NRT-only use may obtain roughly similar levels of nicotine compared with smokers of combustible cigarettes only, but results varied. Long-term NRT-only and e-cigarette–only use, but not dual use of NRTs or e-cigarettes with combustible cigarettes, is associated with substantially reduced levels of measured carcinogens and toxins relative to smoking only combustible cigarettes.
Cancer Research UK.
Appendix Table 1. Urinary and Saliva Biomarker Levels, by Group*
Table 1. Major Toxicants and Carcinogens Related to Tobacco Use
Table 2. Sociodemographic, Smoking, Physical Health, and Subjective Well-Being Characteristics of Study Participants
Urinary and salivary nicotine metabolite levels, by group.
Boxplots show the median with interquartile range (25th percentile, 75th percentile). Error bars show Tukey's whiskers, and crosses indicate arithmetic means (geometric means are provided in Appendix Table 1). Circles indicate outliers. Cigarette = combustible cigarette; EC = e-cigarette; NRT = nicotine replacement therapy.
* Measured in urine. Data are raw values divided by the ratio of observed urinary metabolites to covariate-adjusted creatinine levels. Values below the limit of detection were imputed by the limit of detection divided by square root of 2.
† Measured in saliva. There were no significant between-group differences.
Table 3. Adjusted Biomarker Levels by Group as a Proportion of Cigarette-Only Smoker Levels*
Urinary metabolite levels for selected toxins and carcinogens, by group.
Data are raw values divided by ratio of observed urinary metabolites to covariate-adjusted creatinine levels. The levels below the limit of detection were imputed by the limit of detection divided by square root of 2. Boxplots show the median with interquartile range (25th percentile, 75th percentile). Error bars show Tukey's whiskers, and cross indicate arithmetic means (geometric means are provided in Appendix Table 1). Circles indicate outliers. Significant pairwise comparisons are presented in Appendix Table 1. Cigarette = combustible cigarette; EC = e-cigarette; NRT = nicotine replacement therapy. A. Tobacco-specific N-nitrosamine. NNAL = 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. B. Acrolein. 3HPMA = N-acetyl-S-(3-hydroxypropyl)-L-cysteine. C. Acrylamide. AAMA = N-acetyl-S-(2-carbamoylethyl)-L-cysteine. D. Acrylonitrile. CYMA = N-acetyl-S-(2-cyanoethyl)-L-cysteine. E. 1,3-butadiene. MHBMA3 = N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine. F. Ethylene oxide. HEMA = N-acetyl-S-(2-hydroxyethyl)-L-cysteine.
Appendix Table 2. Proportion of Samples Below Limit of Detection, by Group and Across All Samples*
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Henri-Jean Aubin, Pascal Guénel, Marie-Christine Boutron-Ruault, Mireille Matrat, Amandine Luquiens, Patrick Dupont
CESP, Fac. de médecine - Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris-Saclay, AP-HP, Hôpitaux Universitaires Paris-Sud, 94800, Villejuif, France.
March 2, 2017
Conflict of Interest:
Henri-Jean Aubin was member of advisory boards for Pfizer, D&A Pharma, Ethypharm, and Lundbeck, and has received sponsorship to attend scientific meetings, speaker honoraria and consultancy fees from Bioprojet, D&A Pharma, Ethypharm, Lundbeck, Merck-Serono, Novartis, and Pfizer. He is also member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials (ACTIVE) Group, which is supported by Abbvie, Alkermes, Ethypharm, Lilly, Lundbeck, and Pfizer.
Inferring that carcinogens exposure intensity reduction reduces harm may be misleading
In their recent article, Shahab et al(1) reported from a small-size cross-sectional study that long-term nicotine replacement therapy (NRT) and e-cigarette use are associated with reduced levels of carcinogens and toxins relative to cigarette smoking. They conclude that the lower levels of carcinogens and toxins confirm the “known low risk for complications from long-term NRT use” and support the assertion that e-cigarettes may be less harmful than smoking. While the inference that carcinogen exposure intensity reduction may reduce cancer risk may seem obvious at first, we would like to make the point that, for the best we know today, duration is more strongly associated with cancer risk than intensity of exposure. Notably, regarding the lung cancer risk in smokers, it has long been demonstrated that the excess incident rate is proportional to the fourth power of smoking duration multiplied by the number of cigarettes per day(2). Therefore, findings of a reduced carcinogen exposure should not rule out the possibility of a significant increased risk of cancer in case of long-term exposure. Hence the report of the Surgeon General on the health consequences of smoking stated in 2004 that smokers should “quit as soon as possible”(3).Moreover, we do not share the view that NRT safety profile is well-established(1), as the study on which this statement has been based only showed that, in about 2000 long-term nicotine replacement therapy users, there was no association of lung cancer events with the mean number of nicotine gums used(4). However, when restricting the analysis to the sustained cigarette quitters, the association between mean number of nicotine gums used and lung cancer events became statistically significant. We made the point elsewhere that the safety of long term nicotine use, especially regarding the cardiovascular and oncologic risks, remains questionable (5).We do recognize that long-term e-cigarette or NRT use is likely to reduce harm compared to continuing smoking cigarette, and we certainly hope that the harm reduction avenue will eventually fulfill its promises. But we would like to warn against misleading intuitive inference of a simple relationship between carcinogen exposure intensity and cancer risk reduction, regardless of exposure duration. Indeed, this could mislead former smokers into long-term e-smoking instead of altogether quitting.1. Shahab L, Goniewicz ML, Blount BC, Brown J, McNeill A, Alwis KU, et al. Nicotine, Carcinogen, and Toxin Exposure in Long-Term E-Cigarette and Nicotine Replacement Therapy Users: A Cross-sectional Study. Ann Intern Med. 2017;7(10):M16-1107.2. Peto J. That the effects of smoking should be measured in pack-years: misconceptions 4. Br J Cancer. 2012;107(3):406-7.3. U.S.-Department-of-Health-and-Human-Services. The Health Consequences of Smoking: A Report of the Surgeon General. U.S. Department of Health and Human Services. The Health Consequences of Smoking: A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. ed. Atlanta, GA: U.S: Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2004.4. Murray RP, Connett JE, Zapawa LM. Does nicotine replacement therapy cause cancer? Evidence from the Lung Health Study. Nicotine Tob Res. 2009;11(9):1076-82.5. Dupont P, Benyamina A, Aubin HJ. [Safety of long-term nicotine use: An ongoing debate]. Revue des Maladies Respiratoires. 2016;27(16):30085-7.
Lion Shahab, PhD1*, Maciej L. Goniewicz, PhD2, Benjamin C. Blount, PhD3, Jamie Brown, PhD4, Robert West, PhD1
University College London,Roswell Park Cancer Institute, CDC
June 1, 2017
Conflict of Interest:
Conflict of Interest: LS has received an honorarium for a talk, an unrestricted research grant and travel expenses to attend meetings and workshops from Pfizer, a pharmaceutical company that makes smoking cessation products, and has acted as paid reviewer for grant awarding bodies and as a paid consultant for health care companies. MLG reports research grants from and served as an advisory board member to pharmaceutical companies that manufacture smoking cessation medications. JB has received unrestricted research funding from Pfizer to study smoking cessation. RW has received travel funds and hospitality from, and undertaken research and consultancy for, pharmaceutical companies that manufacture or research products aimed at helping smokers to stop. BCB has no conflicts of interest to declare.
Aubin and colleagues argue that in our article we have produced misleading claims regarding estimated risk reduction from switching from conventional cigarettes to e-cigarettes because duration of exposure is more important than degree of exposure in raising cancer risk. We acknowledge that assessing whether e-cigarette use actually reduces harm among conventional cigarette smokers is challenging and that the adverse health effects of tobacco are related to duration of use, not just exposure. However, both are essential causal factors and to the extent that risk is broadly proportionate to either, a reduction in degree or duration of exposure will yield a proportionate reduction in risk. This is borne out by the evidence. Epidemiological studies directly support a link between the degree of exposure to nitrosamines, and other tobacco-specific toxicants assessed in our study, with subsequent cancer risk in conventional cigarette smokers (1) as well as lifelong never smokers (2). Based on this evidence, it’s likely that significantly reduced exposure in e-cigarette compared with cigarette users results in reduced cancer risk.Aubin et al further argue that nicotine can have adverse effects. While it is important to acknowledge that nicotine is not risk-free, particularly for vulnerable populations, including pregnant women and adolescents, post-marketing surveillance of licensed nicotine products and the epidemiological evidence from adult users of snus (a form of smokeless tobacco that is low in carcinogens but high in nicotine) in Sweden indicate that such effects are small relative to other constituents of tobacco smoke (3).Crucially, in the context of harm reduction it is important to quantify and compare risks. E-cigarette use can be expected to carry some risk, so adult conventional cigarette smokers who switch completely to e-cigarettes instead of quitting smoking without the aid of such a device will be worse off than they would have been. However, smokers who switch to e-cigarette use who would otherwise have carried on smoking will benefit from a reduction in risk. Thus, a key determinant of whether e-cigarette use produces a public health gain is whether it causes more people to stop smoking than would otherwise have been the case, while not leading to initiation of either product among never users, particularly youth (4). The only population level estimate undertaken thus far has been in England, and it used time series analysis to estimate an additional 20,000 ex-smokers per year linked temporally with the increase in prevalence of e-cigarette use (5).1. Yuan JM, Gao YT, Murphy SE, Carmella SG, Wang R, Zhong Y, et al. Urinary levels of cigarette smoke constituent metabolites are prospectively associated with lung cancer development in smokers. Cancer Res. 2011;71(21):6749-57.2. Yuan JM, Butler LM, Gao YT, Murphy SE, Carmella SG, Wang R, et al. Urinary metabolites of a polycyclic aromatic hydrocarbon and volatile organic compounds in relation to lung cancer development in lifelong never smokers in the Shanghai Cohort Study. Carcinogenesis. 2014;35(2):339-45.3. Shields PG. Long-term nicotine replacement therapy: cancer risk in context. Cancer Prev Res (Phila). 2011;4(11):1719-23.4. Cherng ST, Tam J, Christine PJ, Meza R. Modeling the Effects of E-cigarettes on Smoking Behavior: Implications for Future Adult Smoking Prevalence. Epidemiology. 2016;27(6):819-26.5. Beard E, West R, Michie S, Brown J. Association between electronic cigarette use and changes in quit attempts, success of quit attempts, use of smoking cessation pharmacotherapy, and use of stop smoking services in England: time series analysis of population trends. BMJ. 2016;354:i4645.
Shahab L, Goniewicz ML, Blount BC, Brown J, McNeill A, Alwis KU, et al. Nicotine, Carcinogen, and Toxin Exposure in Long-Term E-Cigarette and Nicotine Replacement Therapy Users: A Cross-sectional Study. Ann Intern Med. 2017;166:390–400. doi: 10.7326/M16-1107
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Published: Ann Intern Med. 2017;166(6):390-400.
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