The biological evidence of e-cig dangers keeps piling up

Rachel Keith and Aruni Bhatnagar just published “Cardiorespiratory and Immunologic Effects of Electronic Cigarettes,” which is a nice overview of the growing biological evidence base that e-cigarettes have a lot of adverse health effects, many similar to cigarettes.

This material is particularly important because the people who continue to promote e-cigarettes for “harm reduction” continue to simply ignore it.

As Keith and Bhatnagar state in the Introduction to their paper:

Because e-cigarettes do not burn tobacco, and because they generate lower levels of combustion products than conventional cigarettes [7], some believe that e-cigarettes are a safer alternative to combustible cigarettes, and that they could aid smoking cessation among those who will not, or cannot quit smoking [8]. The full inventory of the chemicals generated by combustible cigarettes exceeds several thousand. Some of these chemicals are highly poisonous and toxic, and many incite or promote cancinogenesis, cardiovascular injury, and pulmonary damage [9]. Hence, it seems reasonable to expect that nicotine, without reactive chemicals, must be less toxic than nicotine delivered with a mixture of combustion-generated toxins. This expectation derives the oft-repeated mantra that “people smoke for nicotine, but they die from tar” [10]. And from it, it follows that if all the tar (as well as other combustion products) were removed, inhaling nicotine will be much safer. Unfortunately, for many reasons, the situation is more complicated than expected. [emphasis added]

They go on to explain:

First, avoiding combustion does not remove all noxious chemicals. Although e-cigarettes do not form high levels of strongly carcinogenic benzopyrenes and tobacco-specific nitrosamines, heating mixtures of nicotine and propylene glycol and vegetable glycerin (PG:VG) in e-cigarettes generates reactive carbonyls such as formaldehyde, acetaldehyde, and acrolein [1114], which have been variably linked to carcinogenesis [15] , cardiovascular injury [16, 17], and increased risk of cardiovascular disease [18]. The generation of carbonyls from e-cigarettes varies with use patterns, e-liquid ingredients, and operating conditions [19], and even though the extent of carbonyl generation by e-cigarettes is generally lower than by combustible cigarettes, daily carbonyl exposure from e-cigarettes could still exceed exposure limits [20]. Second, e-cigarette aerosols sporadically contain metals (Fe, Ni, Cu, Cr, Zn, Pb), generated by the heating coil [21], which could add to the toxicity of the aerosol. Third, like combustible cigarettes, e-cigarettes produce aerosols that contain fine and ultrafine particles [22], which can trigger cardiovascular events and promote the progression of pulmonary and cardiovascular disease [23]. Finally, a direct comparison of the relative toxicity of e-cigarettes and combustible cigarettes may not be entirely meaningful. Toxicity due to a chemical, drug, or exposure depends upon its dose. Therefore, even though per puff, e-cigarettes may generate lower levels of toxins; their toxicity may approach that of combustible cigarettes if the use of e-cigarettes (exposure/dose) is higher than that of combustible cigarettes. For instance, if e-cigarettes are half as harmful as combustible cigarettes, but are used twice as much, there would be little harm reduction by using e-cigarettes over combustible cigarettes. Therefore, for both e-cigarettes and combustible cigarettes, harm could be reduced only by reducing exposure. Here too, the relationship is not straightforward. The dose response relationship between smoking and ischemic heart disease, for instance, is non-linear. It shows that smoking just 3 cigarettes a day imparts 80% of the harm attributable to smoking 20–40 cigarettes per day [24•]. In other words, 85–92% reduction in exposure results in only 20% harm reduction. Therefore, reducing toxin exposure by using e-cigarettes may not result in proportional harm reduction. Indeed, as discussed below, recent evidence suggests that even though e-cigarettes generate lower levels of toxins than combustible cigarettes, their use may be associated with significant cardiorespiratory injury as well as immune dysregulation. [emphasis added]

They sum up their findings at the end of the paper:

In summary, the weight-of-evidence discussed above warrants the view that the use of e-cigarettes has multiple adverse health effects. Acute use of e-cigarettes leads to an increase in heart rate and blood pressure [40], as well as obstruction of conducting airways [39], and arterial stiffness [61]. Flow-mediated dilation is diminished [69•], transcutaneous oxygen tension is decreased [106], and a characteristic immune response [40, 41, 81] is activated. Chronic use of e-cigarettes has been found to be associated with a shift in cardiac autonomic balance towards sympathetic predominance [64] and dysregulation of immune-related genes [82]. In animal models, long-term exposure to e-cigarette aerosols lead to DNA damage and inhibition of DNA repair and the development of adenocarcinoma and bladder urothelial hyperplasia [28]. Lipid-laden macrophages accumulate in the lung, accompanied by extensive changes in lipid metabolism and transport [100••]. Taken together, these observations raise the possibility that habitual use of e-cigarettes could cause tissue injury, which could compromise lung function and increase the risk of developing heart disease and stroke. The use of e-cigarettes could also compromise the ability to remove microbial pathogens and thereby increase susceptibility to viral, fungal, and bacterial infection. Data from experimental models also support the notion that the use of e-cigarettes could increase the risk of developing several types of cancer. Nevertheless, it remains to be seen whether long-term use of e-cigarettes is indeed associated with such adverse events in humans.

The paper limits itself to a review of the biology and does not study any of the available epidemiological studies, but many show that e-cigs have been in use long enough to detect adverse effects on lung and cardiovascular disease and that dual use (which is common) is more dangerous than smoking alone. As more time passes — which will allow assessment of “long-term” health effects — it is likely that these associations will just get stronger.

The question for people, public health advocates, and regulators and policymakers is whether to continue promoting these products for decades while the “long-term” evidence accumulates.

We already have enough evidence to recognize that such an approach amounts to wishful thinking.

Here is the abstract from the paper:

Purpose of Review

Although e-cigarettes have become popular, especially among youth, the health effects associated with e-cigarette use remain unclear. This review discusses current evidence relating to the cardiovascular, pulmonary, and immunological effects of e-cigarettes.

Recent Findings

The use of e-cigarettes by healthy adults has been shown to increase blood pressure, heart rate, and arterial stiffness, as well as resistance to air flow in lungs. Inhalation of e-cigarette aerosol has been shown to elicit immune responses and increase the production of immunomodulatory cytokines in young tobacco-naïve individuals. In animal models, long-term exposure to e-cigarettes leads to marked changes in lung architecture, dysregulation of immune genes, and low-grade inflammation. Exposure to e-cigarette aerosols in mice has been shown to induce DNA damage, inhibit DNA repair, and promote carcinogenesis. Chronic exposure to e-cigarettes has also been reported to result in the accumulation of lipid-laden macrophages in the lung and dysregulation of lipid metabolism and transport in mice. Although, the genotoxic and inflammatory effects of e-cigarettes are milder than those of combustible cigarettes, some of the cardiorespiratory effects of the two insults are comparable. The toxicity of e-cigarettes has been variably linked to nicotine, as well as other e-cigarette constituents, operating conditions, and use patterns.


The use of e-cigarettes in humans is associated with significant adverse cardiorespiratory and immunological changes. Data from animal models and in vitro studies support the notion that long-term use of e-cigarettes may pose significant health risks.

The full citation is Keith R, Bhatnagar A. Cardiorespiratory and Immunologic Effects of Electronic Cigarettes. Curr Addict Rep. 2021 Mar 5:1-11. doi: 10.1007/s40429-021-00359-7. Epub ahead of print. PMID: 33717828; PMCID: PMC7935224. It is available for free here.

Published by Stanton Glantz

Stanton Glantz is a retired Professor of Medicine who served on the University of California San Francisco faculty for 45 years. He conducts research on tobacco and cannabis control and cardiovascular disease/

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