|
 
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| REVIEW ARTICLE |
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| Year : 2019 | Volume
: 4
| Issue : 1 | Page : 1-5 |
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Potential health risks of long-term e-cigarette use
Eric A Klomparens1, Yuchuan Ding2
1 Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
2 Department of Neurosurgery, Wayne State University School of Medicine; John D. Dingell VA Medical Center, Detroit, MI, USA
| Date of Submission | 11-Feb-2019 |
| Date of Acceptance | 11-Feb-2019 |
| Date of Web Publication | 9-Apr-2019 |
Correspondence Address:
Dr. Yuchuan Ding
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ed.ed_10_19
E-cigarettes are becoming increasingly popular in recent years, especially among adolescents. Many healthcare professionals are unsure of what health consequences can be expected after long-term use of e-cigarettes. This review focuses on the currently published data of long-term e-cigarette vapor exposure in cells, animals, and humans. Most research suggests that e-cigarettes are not harmless. Increased oxidative stress from free radicals and systemic inflammation occur after weeks or months of exposure. E-cigarette vapor contains multiple known human carcinogens which are found in the serum of users, and DNA damage is seen in exposed animals. Pulmonary changes seen after months of exposure in mice are reminiscent of chronic obstructive pulmonary disease (COPD), and human users report increased respiratory symptoms. Cardiovascular disease risk is also likely, with e-cigarette use leading to multiple pathophysiological changes and possibly associated with an increased risk of myocardial infarction. Limitations of the current research are discussed, including the retrospective nature of most human data to date. A call for large, longitudinal prospective studies is deemed necessary to better understand the causal role of long-term e-cigarette use in chronic disease formation.
Keywords: Chronic, disease, long-term, pathophysiological changes, tobacco cigarettes
How to cite this article:
Klomparens EA, Ding Y. Potential health risks of long-term e-cigarette use. Environ Dis 2019;4:1-5 |
| Introduction | |  |
E-cigarettes have been increasing in popularity across the world over the last decade. Use of e-cigarettes among adolescents is especially increasing in the past few years.[1] While some people switch to e-cigarettes as a harm reduction technique instead of smoking tobacco cigarettes, many e-cigarette users also smoke cigarettes concurrently.[2] Much of the controversy over e-cigarettes is that they appeal to a younger audience and are causing adolescents who have never smoked tobacco cigarettes to become addicted to nicotine. Recent studies suggest that many adolescents are likely to use e-cigarettes for long periods of time or go on to use tobacco cigarettes as well.[1]
Many healthcare professionals are unsure of the health effects that can be expected from long-term use of e-cigarettes, which makes it difficult to make recommendations to the public regarding their use.[3] Because e-cigarettes have only become popular in the past few years, there are no decades-long epidemiologic data available to assess whether e-cigarette use causes cancer, COPD, and heart disease like tobacco cigarettes do. However, there are many published studies assessing the pathophysiological effects that occur after weeks or months of exposure to e-cigarette vapor. As such, this review focuses on the current data that informs what health consequences can be expected or predicted when a person uses e-cigarettes for long periods.
| Health Risks | | |
Oxidative stress
Free radicals and oxidative stress play a key role in many chronic disease pathologies associated with tobacco use, including DNA damage leading to cancer, genesis of atherosclerosis, pulmonary toxicity, and activation of inflammatory responses.[4] E-cigarette vapor has a high concentration of free radicals, but this concentration is orders of magnitude less than that found in cigarette smoke.[4],[5] The specific concentration of free radicals generated is dependent on multiple factors, including the amount of power used to heat the e-liquid solution, the solvents used in the e-liquid, and the flavoring chemicals used.[4] The free radicals in e-cigarette vapor have been shown within both in vitro and in mouse models to cause lipid peroxidation, which provides evidence that the free radicals in vapor lead to biologically relevant damage.[4] Oxidative stress and lipid oxidation are associated with important pathophysiological changes in the body, including generation of atherosclerosis and increased risk of cardiac disease.[2] As such, long-term e-cigarette use may expose the body to large amounts of oxidative stress, which may lead to cardiovascular disease after many years.
| Inflammation and Cytotoxicity | | |
Acute e-cigarette vapor exposure leads to the activation of proinflammatory pathways. Exposure of human neutrophils to e-cigarette vapor for 6-h led to neutrophil shape change, increased release of MMP-9 and CXCL8, and increased expression of CD11b and CD66b.[6] These changes in neutrophils are similar to the changes that occur due to cigarette smoke exposure. Similarly, multiple inflammatory markers increased significantly after periodontal fibroblasts and gingival epithelial cells were exposed to e-cigarette vapor for 15 min, including COX-2, S100A8, and RAGE.[7] Protein carbonylation also increased after e-cigarette vapor exposure, which is thought to mediate DNA damage.[7] Another study of human gingival cells revealed that e-cigarette vapor exposure causes cell damage and death, including increased apoptosis and necrosis mediated partially by increased caspase-3 pathway activity.[8]
The conclusions of these short-term studies are recapitulated by a study in which mice were exposed to e-cigarette vapor daily for 3 and 6 months. Following exposure, circulating inflammatory markers were significantly increased, including interleukin-8, leukemia inhibitory factor-1, epidermal growth factor, and angiopoietin-1.[9] Vapor exposure also caused fibrosis of multiple organs, including the heart, kidneys, and liver. In a mouse strain made to be susceptible to COPD and oxidative stress, signs of organ dysfunction were present, including a 20% reduction in renal filtration rate, increased blood pressures, and decreased heart rate.[9] This study demonstrates that long-term daily exposure to e-cigarette vapor causes chronic, systemic inflammatory responses in multiple organ systems and may reduce organ functionality in more susceptible animals. Because chronic inflammation is thought to be an important contributor to many of tobacco smoking's detrimental effects, it is likely that e-cigarette use could increase the risk of similar diseases.[9]
| Carcinogen Burden and Cancer | | |
E-cigarette vapor contains multiple known carcinogens.[10],[11] Some e-cigarette vapors have been shown to contain benzene, a known carcinogen, while others do not.[10] Increased power levels of the e-cigarette device produce increased levels of benzene. The highest measured concentration of benzene in e-cigarette vapor is forty times lower than that of a standard tobacco cigarette, but this concentration is still considered non-negligible.[10] Other known carcinogens present in e-cigarette vapor include formaldehyde and acetaldehyde; the reported concentrations of these carbonyl compounds in e-cigarette vapor, however, vary widely between studies, and are also dependent on power settings and the specific e-cigarette device and e-liquid used.[11] The mutagenicity of e-cigarette vapor was assessed by a study in human epithelial cell lines which revealed that exposure to nicotine-free e-cigarette vapor for 1 week leads to an approximately 1.5-fold increase in double-stranded DNA breaks as well as increased apoptosis and necrosis of cells, as compared to controls.[12] Nicotine-containing e-cigarette vapors caused a further 50% increase in DNA breaks.[12] Similar evidence is found in animal studies, with rats exposed to e-cigarette vapor for 4 weeks demonstrating increased strand breaks in the DNA of circulating leukocytes as well as increased mutagenic metabolites in the rats' urine.[13]
Regarding data in humans, a study of smokers evaluated the concentrations of multiple toxicants in serum while smoking tobacco cigarettes and again after 2 weeks of switching to using e-cigarettes.[14] Serum concentrations of nicotine remained unchanged but 12 other toxicant concentrations were significantly decreased, including those of four known human carcinogens: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), ethylene oxide, 1,3-butadiene, and benzene.[14] The concentrations of these toxicants after 2 weeks of e-cigarette use ranged from 20% to 50% of the baseline levels; however, half of the participants reported still smoking tobacco cigarettes during the study period, and hence, these numbers may underrepresent the difference between e-cigarette and tobacco cigarette use.[14] A similar study of forty smokers who switched to using e-cigarettes found reductions of toxicants after 4 weeks of e-cigarette use.[15] Participants who used only e-cigarettes and not tobacco cigarettes over the 4-week period had 80% less carbon monoxide and 79% less of the main metabolite of acrolein.[15] Acrolein is thought to cause toxicity by multiple mechanisms, including production of carcinogens, immune activation, neuronal damage, and atherosclerotic plaque development.[15]
Another study in humans was done in which ex-smokers who switched exclusively to e-cigarettes for 6 months were compared to dual-users (concurrent e-cigarette and tobacco cigarette users).[16] The exclusive e-cigarette users had significantly reduced urine concentrations of multiple known carcinogens and other toxins. Metabolites of NNK, a major carcinogen in cigarette smoke, decreased by 97% compared to the dual-users. Concentrations of the major metabolites of multiple volatile organic compounds (VOCs) ranged from 3% to 42% in exclusive e-cigarette users as compared to dual-users.[16] VOCs include known carcinogens as well as toxicants known to play a role in pulmonary pathophysiology.[16] These studies clearly demonstrate that e-cigarette use leads to reduced exposure to multiple toxins and carcinogens as compared to tobacco smoking, but e-cigarette use still causes some exposure to many of the toxins known to be in cigarette smoke and therefore cannot be considered completely safe. Because of the dose-dependent nature of the toxicity of the carcinogens and other toxicants present in e-cigarette vapor and the many other factors which contribute to damage caused by such toxicants, making predictions regarding long-term deleterious effects due to such exposure is very difficult.
| Lung Disease | | |
A major focus of e-cigarette research to date has been on the effects on the lungs, as this is the point of absorption into the body. A study in mice exposed to e-cigarette vapor with and without nicotine for 4 months revealed that nicotine-containing vapor exposure led multiple pathophysiologic changes in the lungs that are characteristic of COPD, including airway hyper-reactivity, distal airspace enlargement, and increased inflammatory protein production. Mice exposed to nicotine-free vapor did not show such changes.[17] However, a similar study in which mice were exposed to nicotine-containing vapor for 8 months did not find significantly increased airspace enlargement.[18] Another study in mice revealed that 3 weeks of exposure to nicotine-containing vapor caused a blunting of mucociliary clearance (MCC).[19] As the MCC response is an important mechanism to reduce the lungs' exposure to infectious agents, toxins, and other damaging compounds, a reduction in MCC likely increases cellular damage in the respiratory system due to the toxins in e-cigarette vapor as well as increases the risk of infection.[19] This is evidenced by a separate study which found that 2 weeks of e-cigarette vapor exposure in mice leads to decreased bacterial and viral clearance from the lungs, suggesting that e-cigarette use may lead to increased risk of recurrent pulmonary infections.[5]
A few survey-based cross-sectional studies in humans have been completed to date regarding respiratory function in e-cigarette users. One study of over 1300 participants who were either at risk for or had COPD analyzed the association of e-cigarette use to COPD complications. The participants who report that they had ever used e-cigarettes were 8% more likely to have chronic bronchitis, after accounting for other factors including age, race, and current tobacco smoking status.[20] Ever using e-cigarettes was also associated with increased COPD exacerbations after adjusting for other factors.[20] A similar study of adults found that e-cigarette use was positively associated both with a diagnosis of COPD and a diagnosis of asthma, after adjusting for the current and past tobacco cigarette use.[21] Regarding adolescents, a large cohort of high school students (11th or 12th grade) was asked about past and present e-cigarette use, tobacco cigarette use, bronchitis symptoms, and wheezing.[22] In the participants who had never smoked tobacco cigarettes, current and past e-cigarette use were both associated with increased bronchitis symptoms (odds ratio: OR 1.70 for past users, OR: 1.52 for current users), and current e-cigarette use in never-tobacco smokers was associated with increased risk of wheeze (OR: 1.86).[22] A similar study of secondary school students in Hong Kong found that current e-cigarette use was associated with a significantly increased risk of chronic cough or phlegm in those who did not currently smoke tobacco cigarettes.[23] These human studies suggest that e-cigarette use could increase respiratory symptomatology and potentially increase the risk of chronic pulmonary diseases such as asthma or chronic bronchitis.[22],[23] However, these studies need to be supplemented by more rigorous, prospective trials before causality can be determined.
| Cardiovascular Disease | | |
E-cigarettes likely increase the risk of cardiovascular disease to some degree. Eight months of daily e-cigarette vapor in mice caused significantly increased aortic stiffness, decreased reactivity to vasodilators, and insignificantly decreased ejection fraction.[18] This suggests that many years of e-cigarette use may lead to increased blood pressure and decreased systolic heart functionality.[18] In humans, exclusive e-cigarette users of at least 1-year duration had alterations in their heart rate variability similar to that seen in tobacco smokers, reflecting the increased sympathetic tone and decreased vagal tone; such alterations are known to be associated with an increased risk of suffering a myocardial infarction (MI) or sudden cardiac death.[24] The e-cigarette users also had increased levels of low-density lipoprotein (LDL) oxidizability compared to nonusers, reflecting the oxidative stress that e-cigarettes cause and leading to increased susceptibility to atherosclerosis generation.[24] However, another study did not find a significant difference in LDL oxidizability between e-cigarette users and nonuser controls.[25] Finally, and perhaps most importantly, a cross-sectional study based on data from the National Health Interview Surveys conducted in 2014 and 2016 concluded that current every-day e-cigarette use is associated with an increased risk of having had an MI at some point in life (OR = 1.79) even after adjusting for the past and current tobacco cigarette use.[2] Some contention regarding the validity of these results has been brought up by other researchers, specifically regarding the fact that 95% of the current e-cigarette users in the study are past or current smokers, and that the survey did not specify whether the participants started using e-cigarettes before or after they had the MI.[26] While it is difficult to interpret this association without information regarding the timing of e-cigarette use and the MI, it certainly raises alarms that e-cigarette use could potentially be implicated in increasing the risk of major cardiovascular events and disease.
| Comparing E-Cigarettes and Traditional Tobacco Cigarettes | | |
While many review papers have been devoted to the topic of comparing e-cigarettes and tobacco cigarettes, it is important to briefly mention key points of this discussion. Most researchers seem to think that e-cigarettes are most likely less harmful than tobacco cigarettes in all regards. This view is evidenced by nearly all research done, with findings of lesser amounts of most known tobacco-related toxicants and carcinogens in the serum of ex-smokers who switched to e-cigarettes,[10],[14],[15],[16] lower concentrations of free radicals per puff in e-cigarette vapor as compared to cigarette smoke,[4],[5] and less cardiovascular dysfunction in mice exposed to e-cigarette vapor compared to those exposed to cigarette smoke.[18] However, given the relative paucity of data concerning e-cigarettes as compared to that available for tobacco cigarettes, there is still a strong undertone of uncertainty as to how greatly these differences in biomarkers and animal data will translate to outcomes regarding disease and death.
Limitations of the current research
One of the major difficulties with research on e-cigarettes is that there are a great number of both e-cigarette devices and e-liquids. The chemical makeup of each of these is unique and thus lead to the different toxic chemical composition of the vapor produced.[11] Furthermore, many current e-cigarette devices have user-controlled power or temperature settings, as well as individualized puff duration and frequency of use.[27] All these variables together lead to countless combinations, and nonhuman studies have used varying protocols concerning their exposure of cells or animals to e-cigarette vapor. These differences are important and make inter-study comparisons very difficult, and such differences are likely a reason for many of the contradictory results between some studies. Similarly, concentrations of toxins in e-cigarette vapor have varied widely between studies, and the emission of such toxins has found to be dependent on temperature, power, puff duration, and type of device.[11],[28] Ensuring that animal and cell line e-cigarette vapor exposure corresponds to real-world e-cigarette usage is very difficult,[29] and so interpreting the data from nonhuman research is imperfect.
Regarding human studies, much of the long-term data currently available are dependent on participant-reported usage of e-cigarettes, abstinence from tobacco cigarettes, and symptomatology. As such, this data are prone to multiple errors. Furthermore, problematic is the fact that most e-cigarette users who have participated in these studies are ex-tobacco smokers and thus are at increased risk for these diseases of interest before e-cigarette use.[26] Many of the current studies are cross-sectional or retrospective, disallowing from causative inference. Nearly, all studies have been done with the goal of comparing e-cigarettes to tobacco cigarettes; as such, many studies have made conclusions and recommendations based on comparisons to a known major health detriment instead of based on the data regarding e-cigarettes alone. Given the new trends of e-cigarette use among young people who have never used tobacco cigarettes, it is important to assess e-cigarette toxicity as a standalone entity. Finally, while some data are available regarding long-term use of e-cigarettes, the longest study to date still only discusses the use of 1-year duration. Diseases such as cancers, COPD, and atherosclerotic cardiovascular disease take many years to develop fully, and so it is still too soon to say with certainty if e-cigarettes cause any of these deadly diseases.
| Conclusion and Perspective | | |
E-cigarette use is not risk-free. It is likely that long-term, daily use of e-cigarettes increases the risk of pulmonary and cardiovascular disease as well as carcinogenesis. The pathophysiological underpinnings of such diseases are present in cells, animals, and people exposed to e-cigarette vapor for weeks or longer. Some cross-sectional data suggests e-cigarette use is associated with increased risk of MI and symptoms of respiratory disease. The extent to which long-term e-cigarette use increases such risk is difficult to determine, given the currently available data. There is a clear need for more sophisticated research on this topic, including large, prospective, longitudinal cohort studies to be able to quantify the risk that long-term e-cigarette use incurs for each disease. Given the trends of increasing e-cigarette use among adolescents and adults, understanding the long-term consequences of e-cigarette use is critically important. Future e-cigarette research needs to provide information regarding specific health outcomes related to e-cigarette use, including quantifying the increased risk accrued for acquiring asthma, COPD, various cancers, and cardiovascular disease. Research also needs to be expanded to include participants who have never smoked tobacco cigarettes to ensure a lack of confounding effect on results. The history of tobacco research and advertising is a sad and gory one, and so we must learn from our past mistakes and be certain of the authenticity and precision of the data surrounding e-cigarette use. Only with true and complete data can we give helpful and honest recommendations regarding their long-term use.
Financial support and sponsorship
This work was supported in part by a Merit Review Award (I01RX-001964-01) from the US Department of Veterans Affairs Rehabilitation R&D Service.
Conflicts of interest
There are no conflicts of interest.
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