We know a lot about how e-cigarettes cause disease

The evidence on the health effects of e-cigarettes was the subject of two recently published reviews that focus on cardiovascular, pulmonary and immunologic effects of e-cigarettes. These reviews complement earlier reviews on the pulmonary effects of e-cigarettes, e-cigarettes and smoking cessation, and the gateway effect for smoking among youth and young adults.

Taken together these reviews provide an extensive summary of what we know about e-cigarettes that goes way beyond simplistic thinking that e-cigarettes are simply a way to get “nicotine without the tar.” There is so much information in these new reviews that summarizing them is all but impossible. Hopefully these highlights will lead people to study them.

The first of these new reviews, “Cardiorespiratory and Immunologic Effects of Electronic Cigarettes” by Rachel Keith and Aruni Bhatnagar explains why just avoiding the combustion products in conventional cigarettes does not mean that e-cigarettes are safer than cigarettes that most e-cigarette advocates ignore:

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.

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 [11–14], 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, paragraph breaks added for readability]

The section headings in the paper demonstrate its scope, which is a synthesis of evidence from 106 other papers:

• E-cigarettes and respiratory injury
  • Genotoxicity of e-cigarettes
  • Effects of e-cigarettes on lung structure and function
  • Respiratory effects of e-cigarettes in humans
• Cardiovascular effects of e-cigarettes
  • Human studies
  • Cardiotoxicity of e-cigarettes in experimental models
• E-cigarettes and the immune response
  • Human studies
  • Immunogenic responses of e-cigarette aerosols in vitro
  • Immune changes in animal models

The available evidence also suggests that inhaled nicotine itself has adverse health effects despite the fact that NRT is safe to use. As Keith and Bhatnagar sum up at the end of their review:

E-cigarettes were developed with the expectation that the delivery of nicotine without combustion-derived chemicals would prevent or minimize most of the adverse effects of smoking. This expectation was based on the belief that nicotine per se has little contribution to the pathology of smoking. However, extensive evidence suggests that this view may not be correct. Work discussed above clearly shows that the hemodynamic effects of e-cigarette use may be due to nicotine alone [63••]. It has also been reported that nicotine by itself could promote DNA damage [28], induce lung injury [37, 39], amplify immune responses [85], and disrupt endothelial barriers [13]. Nonetheless, this toxicity profile of nicotine, thrown in sharp relief by recent findings, is in stark contrast with decades of experience showing a good safety profile of nicotine replacement therapies. Reasons for disparate toxicity profiles of nicotine in different scenarios remain unclear; however, it seems likely that long-term effects of nicotine alone are not well known, or that toxicity of nicotine may depend on the route and speed of administration.

They also highlight the fact that the biological insult of e-cigarettes is, in some important ways, different from cigarettes,

In many studies, the effects observed with e-cigarettes are of the same magnitude as those seen with combustible cigarettes; however, in most cases, pathologic changes due to e-cigarettes are milder than those with combustible cigarettes [32, 69•, 79]. Indeed, switching from combustible cigarettes to e-cigarettes has been reported to improve endothelial function and vascular stiffness [105]. However, it is unclear whether this acute improvement in vascular function persists with chronic use of e-cigarettes. Hence, neither short-term improvements nor the relatively milder changes in some parameters with e-cigarettes versus combustible cigarettes imply unalloyed harm reduction. As reported by several investigators [43•, 100••, 104], the nature and the type of tissue injury inflicted by e-cigarettes are distinct from that caused by combustible cigarettes. For instance, even though in animal models, e-cigarettes, unlike combustible cigarettes, do not cause emphysematous changes, they stimulate the accumulation of lipid-laden macrophages, which could lead to dysregulation of the pulmonary surfactant and thereby compromise air-exchange and alter innate immunity [100••], pathological changes distinct from those seen with combustible cigarettes. Likewise, e-cigarettes alter the expression of many more genes than combustible cigarettes and the pattern of these changes differ between the two products [43•]. Therefore, comparing e-cigarettes with combustible cigarettes using the same readouts and endpoints may be misleading as the two exposures differ markedly in the nature of the injury they induce and the types of tissues they affect.

They sum up the biological evidence:

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.

They also note emerging evidence that e-cigarettes increase cancer risk: “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 second new review paper, “E-cigarettes and cardiopulmonary health,” is based on a 2015 workshop held at the National Heart Lung and Blood Institute of funded investigators to identify areas for future research. It is based on 170 studies.

The topics covered include:

• Device characteristics
• User profiles and patterns of use
• Dosimetry
• Health effects of e-liquid constituents
• Nicotine
  • Pharmacology
  • Nicotine and cardiovascular disease
  • Nicotine and pulmonary disease
  • Nicotine exposure during sensitive windows of development
• Flavor constituents
• PG and VG
• Thermal decomposition products
• Cardiovascular health effects of e-cigarette aerosols
  • Effects on vascular function and ECs
  • Effects on platelets
  • Effects on hemodynamics and sympathomimetic activity
  • Effects on heart tissue
• Pulmonary health effects of e-cigarettes
  • Biochemical effects on the conducting airways
  • Lessons learned from animal studies
• THC and vaping
• Update on the recent e-cigarette, or vaping, EVALI epidemic
• Recent epidemiological studies
• Smoking cessation trials
• Second- and third-hand e-cigarette exposure risk
• E-cigarette public health risk assessment
• Research gaps

While the focus of the paper is on identifying future research needs, it also summarizes what we know.

It identifies several adverse cardiovascular, pulmonary and developmental effects of nicotine exposure and highlights the the differences between inhaled nicotine and NRT: “Limitations of nicotine medication studies [to understanding the effects of nicotine in e-cigarettes] include the fact that the subjects are all former smokers, nicotine medication use is generally of short duration (weeks or months), and the delivery of nicotine by gum or patch is sustained and does not simulate the spike in nicotine levels seen after smoking combustible cigarettes or e-cigarettes. In contrast, regular e-cigarette exposure likely takes place over years to decades, with vascular nicotine eliciting chronic hemodynamic changes.“

The paper highlights adverse biological effects of several flavors, including diacetyl (butter flavor), cinnamaledehye, and vanillin well beyond effects on taste of e-cigarettes and how they can react with PG and VG to create toxic acetyls. They sum up that the effects of flavors go well beyond simply making e-cigarettes more attractive to youth:

Sweet and bitter taste receptors are G-protein-coupled receptors expressed in airway epithelia where they regulate innate immunity. The sweet (T1R) and bitter (T2R) taste receptors are expressed in the nasal passages/upper airways, while only bitter/T2R taste receptors are expressed in the lower airways.⁶³ This raises the possibility that inhalation of flavor compounds may stimulate airway taste receptors and affect immune function. Their activation may disrupt innate airway defense by suppressing the release of antimicrobial peptides that are capable of killing a variety of respiratory pathogens. In the lower airways, T2R activation leads to an increase in ciliary beating and may have other physiological functions via its effects on cytoplasmic Ca²⁺, a universal second messenger. There is some evidence that toxicity is cell type-dependent, suggesting that mechanistic investigations must be cell-specific.^57,64 In summary, the adverse impact of flavor compounds in e-cigarettes include the potential for (1) increased appeal of these products, particularly to the youth market, (2) influence on patterns of use and smoking topography, (3) changes in cell signaling, and (4) increased cellular toxicity (Figure 1 [reproduced above]).

They highlight the similarities and differences between the toxins in e-cigarettes and cigarettes and the implications for cardiovascular disease:

There is a common perception e-cigarettes may be safer than combustible cigarettes, since they deliver much lower levels of oxidants, volatile organic chemicals, and other noxious chemicals associated with tobacco cigarette smoke and cardiovascular risk.²⁵ However, both combustible tobacco products and e-cigarettes deliver oxidants, toxic metals, and potentially toxic carbonyls, which have been associated with cardiovascular disease.^84,85 Moreover, e-cigarette-derived particles are spread among a wider size range than those generated by standard cigarettes. Known toxicants in e-cigarettes (eg, acrolein, aldehydes, PG, and metals) may also contribute to cardiovascular damage in a different manner than toxicant-induced cardiovascular damage from combustible cigarettes

As with the Keith and Bhatnagar paper, there is much more detail in this paper on a wide range of biological effects of e-cigarettes. Anyone seriously interested in the discussion of health effects of e-cigarettes needs to study both these papers.

These papers complement and update another excellent review of the pulmonary effects of e-cigarettes, “What are the respiratory effects of e-cigarettes?” which reviews 193 papers.

None of these papers, however, has a detailed discussion of the epidemiological studies on human health effects of e-cigarettes. Fortunately, there is an excellent recent review and meta-analysis of e-cigarettes and lung disease: “E-cigarette Use and Respiratory Disorder: An Integrative Review of Converging Evidence from Epidemiological and Laboratory Studies” based on 132 papers that I discussed in an earlier blog post.

Neither has a detailed discussion of e-cigarettes and cessation, which we cover in our review ““E-Cigarette Use and Adult Cigarette Smoking Cessation: A Meta-Analysis,” based on 100 papers which is summarized in an earlier blog post.

Finally, neither discusses the gateway effect (youth starting nicotine use with e-cigarettes then starting to smoke cigarettes) in any detail, which are reviewed in “Is e-cigarette use in non-smoking young adults associated with later smoking? A systematic review and meta-analysis” based on 38 papers. I discussed this paper in an earlier blog post, as well as subsequent papers further strengthening the conclusion that the gateway effect is real and substantial.

So, here is my suggested reading list of reviews for people who want to get up to speed on (most of) the latest research on e-cigarettes:

• 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.
• Tarran R, Barr RG, Benowitz NL, Bhatnagar A, Chu HW, Dalton P, Doerschuk CM, Drummond MB, Gold DR, Goniewicz ML, Gross ER, Hansel NN, Hopke PK, Kloner RA, Mikheev VB, Neczypor EW, Pinkerton KE, Postow L, Rahman I, Samet JM, Salathe M, Stoney CM, Tsao PS, Widome R, Xia T, Xiao D, Wold LE. E-Cigarettes and Cardiopulmonary Health. Function (Oxf). 2021 Feb 8;2(2):zqab004. doi: 10.1093/function/zqab004. PMID: 33748758; PMCID: PMC7948134.
• Gotts JE, Jordt SE, McConnell R, Tarran R. What are the respiratory effects of e-cigarettes? BMJ. 2019 Sep 30;366:l5275. doi: 10.1136/bmj.l5275. Erratum in: BMJ. 2019 Oct 15;367:l5980. PMID: 31570493; PMCID: PMC7850161.
• Wills TA, Soneji SS, Choi K, Jaspers I, Tam EK. E-cigarette use and respiratory disorders: an integrative review of converging evidence from epidemiological and laboratory studies. Eur Respir J. 2021 Jan 21;57(1):1901815. doi: 10.1183/13993003.01815-2019. PMID: 33154031; PMCID: PMC7817920.
• Wang RJ, Bhadriraju S, Glantz SA. E-Cigarette Use and Adult Cigarette Smoking Cessation: A Meta-Analysis. Am J Public Health. 2021 Feb;111(2):230-246. doi: 10.2105/AJPH.2020.305999. Epub 2020 Dec 22. PMID: 33351653; PMCID: PMC7811087.
• Khouja JN, Suddell SF, Peters SE, Taylor AE, Munafò MR. Is e-cigarette use in non-smoking young adults associated with later smoking? A systematic review and meta-analysis. Tob Control. 2020 Mar 10;30(1):8–15. doi: 10.1136/tobaccocontrol-2019-055433. Epub ahead of print. PMID: 32156694; PMCID: PMC7803902.

While there is always more to learn, I don’t see how anyone can read this material and think that e-cigarettes are “appropriate for the protection of public health.”