Abuse of evidence and argument: a response to Stanton Glantz' criticisms of an expert letter to WHO on tobacco harm reduction


By Dr Farsalinos

Few days ago, a critique to the letter sent to WHO Director General Margaret Chan was released in an online blog. The comment is based on the fact that in the letter we cited the original idea for tobacco harm reduction expressed by Michael Russell in 1991. The author of the critique, Prof Stanton Glantz, presented in brief Russell’s proposal, and then he mentions:

While this was probably a reasonable summary of the evidence in 1991, 23 years ago, it does not reflect several important things that we now know about the mechanisms by which smoking causes disease and the adverse effects of nicotine

Then, he presents several arguments in an effort to show that there is plenty of evidence to support that e-cigarettes cause harm.


Herein, I will present some of the arguments in the critique and will show that in most cases the claims are completely “evidence-abused, based on cherry-picking of completely irrelevant studies in order to deliver a false message about potential harm associated with e-cigarette use.



Critique argument #1

There is a highly nonlinear dose-response for the effects of smoke exposure on cardiovascular disease risk, with large effects at low levels of exposure.” (reference: Institute of Medicine.  Secondhand Smoke Exposure and Cardiovascular Effects: Making Sense of the Evidence.  2009.  Also see Barnoya J, Glantz S. Cardiovascular effects of secondhand smoke: nearly as large as smoking. Circulation 2005 May 24;111(20):2684-98.)


Remarkably, in order to present the cardiovascular risk of smoking, he cited a study about second-hand smoking exposure!! I would have thought that he ignores evidence showing that the cardiovascular risk of smoking is pretty linearly associated with cigarette consumption, but I am sure he is aware of the study I mention: the INTERHEART study showed that “A clear dose-response relation existed between number of cigarettes smoked per day and risk of AMI.” (Teo et al. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study. Lancet 2006;368:647-658). The odds of developing myocardial infarction increased by 1.056 for every additional cigarette smoked per day. In any case, there is a question on how this argument is related to the letter sent to the WHO or to e-cigarettes and tobacco harm reduction in general.



Critique argument #2

The ultrafine particles that cigarettes (and e-cigarettes) deliver have substantial adverse effects on the cardiovascular system.(reference: Institute of Medicine.  Secondhand Smoke Exposure and Cardiovascular Effects: Making Sense of the Evidence.  2009.  Also see Barnoya J, Glantz S. Cardiovascular effects of secondhand smoke: nearly as large as smoking. Circulation 2005 May 24;111(20):2684-98 and Grana RL, Benowitz N, Glantz SA.  E-cigarettes: a scientific review.  Circulation 2014 May 13;129(19):1972-86. doi: 10.1161/CIRCULATIONAHA.114.007667.)


The same studies were again cited in the second argument, with the addition of the latest review on e-cigarettes. However, this is a direct mis-presentation of evidence, since there is not even a single study indicating that particles emitted from e-cigarettes represent a risk factor for cardiovascular disease. The review cited (co-authored by the writer of the critique) is again a mis-presentation of science, making an arbitrary conclusion that the evidence linking environmental pollution or cigarette smoke particles with cardiovascular disease can be applied to e-cigarettes. He is missing the fact that it is not the size but the composition that matters (Farsalinos & Polosa. Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review. Ther Adv Drug Safety 2014;5:67-86). For example, the smallest-size microparticles are emitted when you boil water (Ogulei et al. Analysis of indoor particle size distributions in an occupied townhouse using positive matrix factorization. Indoor Air 2006;16:204-215). Common sense, not any citation, is needed to understand that water vapor particles do not contribute to cardiovascular disease. Thus, the discussion about the size of the particles is irrelevant and scientifically flawed. Of course, the composition of the particles emitted from e-cigarettes is completely different from environmental pollution or cigarette smoke, but this is something completely ignored by the author of the critique. The studies cited by him are completely irrelevant and provide no information about e-cigarettes; mentioning e-cigarettes in parentheses is an obvious attempt to misinform by implying that such evidence exists. In fact, if we want e-cigarettes to be as effective substitutes to smoking as possible, we need to improve nicotine delivery to and absorption from the lungs. Right now, e-cigarettes are not comparable to tobacco cigarettes in this aspect (Farsalinos et al. Nicotine absorption from electronic cigarette use: comparison between first and new-generation devices. Sci Rep 2014;4:4133), and one way to improve this is by finding the ideal size of particles that will deliver nicotine more effectively.



Critique argument #3

Nicotine may not be a primary carcinogen, but has carcinogenic effects and likely promotes cancers once established through angiogenic (promoting growth of blood vessels in tumors) effects. (reference: Grando SA.  Connections of nicotine to cancer.  Nature Reviews Cancer 2014:  14:  419–429.  doi:10.1038/nrc3725  Published online 15 May 2014.  See also Zhu BQ, Heeschen C, Sievers RE, Karliner JS, Parmley WW, Glantz SA, Cooke JP.   Second hand smoke stimulates tumor angiogenesis and growth. Cancer Cell 2003 Sep;4(3):191-6.)


This argument (as well as the attached references) is based on nothing more than laboratory studies, mostly in cultured cells and few in animals. For example, Grando et al. delivered nicotine to rats at levels similar to the daily intake of snus users. They found several types of cancer to be developed, but the nicotine levels were so high for the animals that half of them died due to nicotine overdose (“In an initial proofofconcept study, we injected A/J mice subcutaneously with the dose of nicotine lethal to 50% of animals tested (LD50), 3 mg per kg, five times per week for 24 months, yielding an average dose of 2.1 mg per kg per day. This dose is approximately equal to the dose of nicotine consumed by a regular Scandinavian snus user” (emphasis added - Grando SA.  Connections of nicotine to cancer.  Nature Reviews Cancer 2014:14:419–429). Obviously, such studies are completely irrelevant to the real clinical practice. There are no clinical studies which have found elevated cancer incidence from nicotine intake. Even if such a study may be published in the future, the risk is expected to be much lower compared to smoking. Let’s not forget that nicotine is officially not a carcinogen (IARC). That is why authorities like the MHRA encourage the long-term use of nicotine in order to quit smoking or reduce cigarette consumption.  Evidence from snus use also suggests that there is no carcinogenic potential of nicotine intake in the form smokeless tobacco, with the exception of a slightly elevated risk of pancreatic cancer - still much lower compared to smoking (Lee PN. Epidemiological evidence relating snus to health--an updated review based on recent publications. Harm Reduct J 2013;10:36; see also: Farsalinos & Polosa. Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review. Ther Adv Drug Safety 2014;5:67-86).



Critique argument #4

A dose of nicotine via nasal spray has the same immediate adverse effect on arterial function as smoking a cigarette.” (reference: Neunteufl T, Heher S, Kostner K, Mitulovic G, Lehr S, Khoschsorur G, Schmid RW, Maurer G, Stefenelli T. Contribution of Nicotine to Acute Endothelial Dysfunction in Long-Term Smokers.  J Am Coll Cardiol 2002;39:251-256.)


The study cited in the critique evaluated the acute effects of nicotine administration on endothelial function. Indeed, they found an immediate decrease in endothelial function; however, the effects of smoking were much more intense compared to nicotine delivery alone. Moreover, this study did not determine the effects of long-term nicotine intake as smoking substitute. There are significant discrepancies between the acute and chronic effects of an intervention on endothelial function. A characteristic example is exercise. Although studies have shown that long-term exercise training is beneficial (Pahkala K et al. Association of physical activity with vascular endothelial function and intima-media thickness. Circulation 2011;124:1956-1963; Pahkala K et al. Vascular endothelial function and leisure-time physical activity in adolescents. Circulation 2008;118:2353-2359), other studies have found that acute exercise has adverse effects (Silvestro A et al. Vitamin C prevents endothelial dysfunction induced by acute exercise in patients with intermittent claudication. Atherosclerosis 2002;165:277-283; Harvey PJ et al. Hemodynamic after-effects of acute dynamic exercise in sedentary normotensive postmenopausal women. J Hypertens 2005;23:285-292). The reason for using exercise as an example is because exercise has immediate hemodynamic changes (elevation in blood pressure and heart rate), similar to nicotine intake, which may affect endothelial function measurements. In any case, it is important to know if endothelial dysfunction associated with chronic smoking is reversed (or at least is not further progressing) when smokers switch to e-cigarettes (or other cleaner forms of nicotine). Unlike what the author of the critique implies, there is no evidence to support his arguments that there will be any harm from this approach. On the contrary, since it is rather obvious that chronic smoking impairs endothelial function by a variety of mechanisms and exposure to toxins besides nicotine (Charakida M et al. Assessment of atherosclerosis: the role of flow-mediated dilatation.  Eur Heart J 2010;31:2854-2861), switching to e-cigarettes is expected to be beneficial.



Further comments

Instead of discussing about other comments mentioned in that critique (such as e-cigarette marketing to and adoption by youngsters, which is simply a theoretical and fear-mongering claim rather than evidence-based statements), I find it more important to expose the basic strategy followed in the critique, which is to mis-present science, to make arbitrary conclusions about e-cigarettes based on irrelevant citations, and to characteristically avoid mentioning that the impact on health should be assessed in relation to smoking continuation. I leave it to the readers to decide whether such comments are based on ignorance or represent an effort to deliberately misinform and produce confusion, both to regulators and to smokers. The main results (and maybe intentions?) of such a strategy are:

 1.      To discourage switching from tobacco cigarettes to e-cigarettes.

2.        2.      To implement restrictions that will give a huge competitive advantage to tobacco cigarettes.



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