Intended for healthcare professionals


Evidence about electronic cigarettes: a foundation built on rock or sand?

BMJ 2015; 351 doi: (Published 15 September 2015) Cite this as: BMJ 2015;351:h4863

Evidence about nicotine toxicity and the dry puff phenomenon

Grimsrud wrote an alarming comment about the negative effects of nicotine on cancer disease. He cites a review by Sanner and Grimsrud about the nicotine effects on cancer [1]. It is characteristic that all evidence in that review was derived from cell and animal laboratory studies. On the contrary, their discussion about human effects was only related to smoking or oral tobacco use and not to nicotine. Another recent review on nicotine carcinogenicity by Grando [2] cited an impressive number of studies, all of which were again laboratory studies. It is characteristic that in many (if not most) cases the amount of nicotine used in the experiments is by far larger than applicable to human smokers. Characteristically, Grando cited one of his own studies in which he tried to reproduce the daily dose of nicotine consumed by Scandinavian snus users in A/J mice through subcutaneous injections [3]. Impressively, the nicotine dose was lethal for 50% of the animals (LD50), clearly showing that the experiment was irrelevant to human effects. Another study linked nicotine with breast cancer, but exposed cells to 5mM of nicotine which is about 20,000 times higher than plasma nicotine levels in humans [4].

In that context, it is surprising and worrying that scientists pay so much attention to laboratory studies but ignore human epidemiological data. The Lung Health Study followed-up long term nicotine users for 7.5 years and found no elevated incidence of cancer [5]. The evidence of snus is extensive and convincing. Snus use is associated with minimal cancer risk, for which nicotine probably plays no role [6-8]. For these reasons, major health organizations have recommended the long-term use of pharmaceutical nicotine products as substitutes to smoking. Smoking pregnant women are also included in those who could use nicotine replacement therapy for smoking cessation [9,10]. It would be at least ironic to discourage pregnant women who cannot quit smoking “cold-turkey” from using nicotine replacement therapy, allowing them to be exposed to the thousands of toxins present in cigarette smoke. Thus, the whole issue about the risks of nicotine is of minimal concern and, thus, irrelevant and misleading when discussed in the context of continuous smoking. As for never smokers, the scientific community has unanimously made it clear that nicotine use is not recommended for this population.

Bareham quotes some statements from Goniewicz, which represent legitimate but theoretical concerns. Many scientists (including myself) have repeatedly supported that monitoring of use by non-intended population (never smoking adults and youth) is important and that measures to avoid use by this population but promote use by smokers are needed. But this is different from supporting that use by non-intended population is really happening at any level besides experimentation. It is becoming common for studies to discuss about nicotine addiction from e-cigarettes and subsequent gateway to smoking, but it is shocking to see that in reality neither regular nor nicotine use was assessed in those studies. [11,12]. One of them [12] was even accompanied by an editorial titled: “Electronic cigarettes are another route to nicotine addiction in youth” [13], while there was absolutely no evidence that the study subjects used nicotine-containing e-cigarettes or became addicted to e-cigarette use, since none of the these were assessed in the study. This represents a classic example of distortion of science, which is reaching unprecedented levels in the case of e-cigarettes. Until recently, this was observed only in press releases and the newsmedia, but now it seems to be happening to scientific publications.

Finally, Bareham presents the argument that flavoured e-liquid may mask the dry puff harsh taste observed when liquid is overheated. This argument is invalid for a simple reason: the dry puff phenomenon was originally observed and detected by e-cigarette users, not by scientists. Every experienced e-cigarette users known this phenomenon, and it was much later (in 2013) that the phenomenon was presented and explained in scientific literature [14,15]. It is well-known that the vast majority of e-cigarette users use flavoured e-liquids, thus the phenomenon is observed with flavoured e-cigarettes. Obviously, more studies are needed to further characterize this phenomenon; however, it is more reasonable to generate conclusions based on currently available evidence rather than focus only on concerns that remain unsupported by evidence.

1. Sanner T, Grimsrud TK. Nicotine: carcinogenicity and effects on response to cancer treatment – a review. Front Oncol (Cancer epidemiology and prevention) 2015;5:196.
2. Grando SA. Connections of nicotine to cancer. Nature Rev Cancer 2014. doi:10.1038/nrc3725.
3. Galitovskiy V, Chernyavsky AI, Edwards RA, Grando SA. Muscle sarcomas and alopecia in A/J mice chronically treated with nicotine. Life Sci. 2012;91:1109–1112.
4. Bavarva JH1, Tae H, Settlage RE, Garner HR. Characterizing the Genetic Basis for Nicotine Induced Cancer Development: A Transcriptome Sequencing Study. PLoS One. 2013 Jun 18;8(6):e67252.
5. Murray RP, Connett JE, Zapawa LM. Does nicotine replacement therapy cause cancer? Evidence from the Lung Health Study. Nicotine Tob Res. 2009;11(9):1076-1082.
6. Lee PN, Hamling JS. Systematic review of the relation between smokeless tobacco and cancer in Europe and North America. BMC Med 2009;7:36.
7. Lee PN. Summary of the epidemiological evidence relating snus to health. Regul Toxicol Pharmacol 2011;59:197–214.
8. Fagerstrom K. Nicotine: pharmacology, toxicity and therapeutic use. J Smoking Cess 2014;9:52-59.
9. Eastham R, Gosakan R. Smoking and smoking cessation in pregnancy. The Obstetrician & Gynaecologist 2010;12:103–109.
10. Royal College of Physicians (RCP) A report of the Tobacco Advisory Group of The Royal College of Physicians. London, RCP; 2000. Nicotine Addiction in Britain.
11. Leventhal AM, Strong DR, Kirkpatrick MG, Unger JB, Sussman S, Riggs NR, Stone MD, Khoddam R, Samet JM, Audrain-McGovern J. Association of Electronic Cigarette Use With Initiation of Combustible Tobacco Product Smoking in Early Adolescence. JAMA. 2015 Aug 18;314(7):700-707.
12. Primack BA, Soneji S, Stoolmiller M, Fine MJ, Sargent JD. Progression to Traditional Cigarette Smoking After Electronic Cigarette Use Among US Adolescents and Young Adults. JAMA Ped 2015
13. Klein JD. Electronic cigarettes are another route to nicotine addiction in youth. JAMA Ped 2015;
14. Romagna G, Allifranchini E, Bocchietto E, Todeschi S, Esposito M, Farsalinos K. Cytotoxicity evaluation of electronic cigarette vapour extract on cultured mammalian fibroblasts (ClearStream-LIFE): comparison with tobacco cigarette smoke extract. Inhal Toxicol 2013;25:354-361.
15. Farsalinos KE, Romagna G, Tsiapras D, Kyrzopoulos S, Voudris V. Evaluation of electronic cigarette use (vaping) topography and estimation of liquid consumption: implications for research protocol standards definition and for public health authorities' regulation. Int J Environ Res Public Health 2013;10:2500-2514.

Competing interests: A small minority of my studies on e-cigarettes were performed using unrestricted funds provided to the institution Onassis Cardiac Surgery Center) by e-cigarette companies.

19 September 2015
Konstantinos Farsalinos
Onassis Cardiac Surgery Center
Sygrou 356, Kallithea 17674, Greece